Drug Therapy

The narrative review by Modesto-Lowe et al¹ in this issue on the potential therapeutic use of cannabis for peripheral neuropathy is only the latest in a vogue string of examinations on how medical marijuana may be used to manage complex conditions. While the authors should be lauded for acknowledging that the role of cannabis in treating peripheral neuropathy is far from settled (“the unknown” in their title), the high stakes involved warrant even more stringent scrutiny than they suggest.

See related article

We are in the midst of an epidemic of chronic opioid use with massive repercussions, and it did not start overnight. Mounting calls for liberalizing narcotic use across a broad range of pain conditions accumulated gradually during the patient-advocacy era of the 1990s, with supporting “evidence” coming mostly from small uncontrolled studies, anecdotal reports, and industry pressure.² Although cannabis and opioids are not interchangeable, we should be cautious about concluding that cannabis is effective and that it should be used to treat chronic pain.

CHRONIC PAIN IS COMPLICATED

Peripheral neuropathy, by definition, is a chronic pain condition. Unlike acute pain, chronic pain is characterized by biologic, psychologic, and social complexities that require nuance to manage and study.

Such nuance is lacking in most recent reviews of the medical use of cannabis. The conditions in question are often studied as if they were transient and acute, eg, employing short-term studies and rudimentary measures such as numeric pain-rating scales or other snapshots of pain intensity. Results of these shortsighted assessments are impossible to extrapolate to long-term outcomes.

Whether cannabis therapy for chronic pain conditions is sustainable remains to be seen. Outcomes in chronic pain should not be defined simply by pain reduction, but by other dimensions such as changes in pain-related disability and quality of life, development of pharmacologic tolerance or dependence, adverse effects, and other “collateral damage.” We are far from understanding these issues, which require highly controlled and regulated longitudinal studies.

A recent Cochrane review³ of the efficacy of cannabis-based medicines for chronic neuropathic pain found that harms might outweigh the benefits. The quality of evidence was rated as very low to moderate; the reviewers cited small sample sizes and exclusion of important subgroups of patients (eg, those with substance abuse or other psychiatric comorbidities). Such exclusions are the crux of a major problem with cannabis research: studies are not naturalistic. The gritty reality of chronic pain management is paramount, and failing to consider the high-risk biopsychosocial factors typical of patients with chronic pain is naïve and, frankly, dangerous.

The true danger of cannabis lies in what we already know with certainty. As the authors discuss, cannabis undisputedly results in dose-dependent cognitive and motivational problems. If we are preaching physical therapy and home exercise to counter deconditioning, socialization to reverse depression, cognitive-behavioral therapy to increase coping, returning to work to prevent prolonged disability, and other active measures to prevent pain from becoming chronic, then why would we suggest treatments known to blunt motivation, energy, concentration, and overall mood? As a general central nervous system suppressant,⁴ cannabis works broadly against our best efforts to rehabilitate patients and restore their overall function.

ALL CANNABIS IS NOT THE SAME

The authors use the general term cannabis in their title, yet rightly unpack the differences between medical marijuana, tetrahydrocannabinol (THC), and cannabidiol (CBD). However, in the minds of untrained and pain-stricken patients seeking rapid relief and practical solutions, such distinctions are likely irrelevant.

The danger in the barrage of publications examining cannabis vs medical marijuana vs THC vs CBD is that they all communicate an unintentional yet problematic message: that marijuana of some sort for pain is acceptable to try. And in the face of financial pressures, changing legal landscapes, insurance coverage volatility, and access issues, are patients really going to always secure prescriptions for well-regulated CBD (lacking psychoactive THC) from thoughtful and well-informed physicians, or will they turn to convenient street suppliers?

Simplified perceptions of safety and efficacy across all cannabis products do not help. More troublesome would be to extrapolate safety to other forms of marijuana known to be dangerous, such as synthetic cannabinoids, which in some instances have been associated with catastrophic outcomes.⁵ The slippery slope is real: if the message becomes that some (or most) marijuana is benign or even therapeutic, what is to curb a widespread and unregulated epidemic?

YOUTH AT RISK

Some groups are more vulnerable than others to the potential negative effects of cannabis. In a study at a medical cannabis dispensary in San Francisco,⁶ adolescents and young adults used more marijuana than older users did and had higher rates of “use when bored” and eventual pharmacologic dependence. Sustained use of marijuana by young people places them at risk of serious psychiatric disorders, with numerous studies demonstrating the unfolding of schizophrenia, depression, bipolar disorder, and more.⁷

As the authors point out, cannabis may be contraindicated in those already burdened with mental health problems. If we recall that comorbid psychiatric disorders are the norm rather than the exception in chronic pain conditions,⁸ can we recommend cannabis therapy for most patients with chronic pain with confidence that it will not cause unintended problems? Evidence already shows that even well-established medical marijuana services attract (and perhaps unintentionally debilitate) a certain high-risk demographic: young, socioeconomically disadvantaged men with other comorbid psychiatric and substance use disorders, who ultimately rank poorly in functional health measures compared with the general population.⁹

NOT REEFER MADNESS, BUT REEFER CAUTION

I am not advocating the fear-mongering misinformation campaigns of the past. We should not exaggerate and warn about “reefer madness” or equate marijuana with untruths about random violence or complete bedlam. Nonetheless, concerns for widespread amotivation, worsening psychiatric states, chronic disability, and chemical dependence are very real.

Needed are tightly regulated, well-controlled, and long-term prospective studies involving isolated CBD formulations lacking THC. Over time, perhaps only formulations approved by the US Food and Drug Administration will be embraced. In the meantime, more comprehensive approaches should be recommended, such as team-based interdisciplinary rehabilitation programs that have shown efficacy in handling chronic pain complexities.^10,11

If such steps are unlikely, physicians should nonetheless stand united in sending a message of cautious optimism regarding medical marijuana, educating their patients not only about recently advertised potential yet inconclusive benefits, but also about the well-known and actual certitudes of its harms for use in chronic pain management. There is plenty of bad and worse information to share with patients, and there is a slippery slope of epidemic proportions to be wary about.

The narrative review by Modesto-Lowe et al¹ in this issue on the potential therapeutic use of cannabis for peripheral neuropathy is only the latest in a vogue string of examinations on how medical marijuana may be used to manage complex conditions. While the authors should be lauded for acknowledging that the role of cannabis in treating peripheral neuropathy is far from settled (“the unknown” in their title), the high stakes involved warrant even more stringent scrutiny than they suggest.

See related article

We are in the midst of an epidemic of chronic opioid use with massive repercussions, and it did not start overnight. Mounting calls for liberalizing narcotic use across a broad range of pain conditions accumulated gradually during the patient-advocacy era of the 1990s, with supporting “evidence” coming mostly from small uncontrolled studies, anecdotal reports, and industry pressure.² Although cannabis and opioids are not interchangeable, we should be cautious about concluding that cannabis is effective and that it should be used to treat chronic pain.

CHRONIC PAIN IS COMPLICATED

Peripheral neuropathy, by definition, is a chronic pain condition. Unlike acute pain, chronic pain is characterized by biologic, psychologic, and social complexities that require nuance to manage and study.

Such nuance is lacking in most recent reviews of the medical use of cannabis. The conditions in question are often studied as if they were transient and acute, eg, employing short-term studies and rudimentary measures such as numeric pain-rating scales or other snapshots of pain intensity. Results of these shortsighted assessments are impossible to extrapolate to long-term outcomes.

Whether cannabis therapy for chronic pain conditions is sustainable remains to be seen. Outcomes in chronic pain should not be defined simply by pain reduction, but by other dimensions such as changes in pain-related disability and quality of life, development of pharmacologic tolerance or dependence, adverse effects, and other “collateral damage.” We are far from understanding these issues, which require highly controlled and regulated longitudinal studies.

A recent Cochrane review³ of the efficacy of cannabis-based medicines for chronic neuropathic pain found that harms might outweigh the benefits. The quality of evidence was rated as very low to moderate; the reviewers cited small sample sizes and exclusion of important subgroups of patients (eg, those with substance abuse or other psychiatric comorbidities). Such exclusions are the crux of a major problem with cannabis research: studies are not naturalistic. The gritty reality of chronic pain management is paramount, and failing to consider the high-risk biopsychosocial factors typical of patients with chronic pain is naïve and, frankly, dangerous.

The true danger of cannabis lies in what we already know with certainty. As the authors discuss, cannabis undisputedly results in dose-dependent cognitive and motivational problems. If we are preaching physical therapy and home exercise to counter deconditioning, socialization to reverse depression, cognitive-behavioral therapy to increase coping, returning to work to prevent prolonged disability, and other active measures to prevent pain from becoming chronic, then why would we suggest treatments known to blunt motivation, energy, concentration, and overall mood? As a general central nervous system suppressant,⁴ cannabis works broadly against our best efforts to rehabilitate patients and restore their overall function.

ALL CANNABIS IS NOT THE SAME

The authors use the general term cannabis in their title, yet rightly unpack the differences between medical marijuana, tetrahydrocannabinol (THC), and cannabidiol (CBD). However, in the minds of untrained and pain-stricken patients seeking rapid relief and practical solutions, such distinctions are likely irrelevant.

The danger in the barrage of publications examining cannabis vs medical marijuana vs THC vs CBD is that they all communicate an unintentional yet problematic message: that marijuana of some sort for pain is acceptable to try. And in the face of financial pressures, changing legal landscapes, insurance coverage volatility, and access issues, are patients really going to always secure prescriptions for well-regulated CBD (lacking psychoactive THC) from thoughtful and well-informed physicians, or will they turn to convenient street suppliers?

Simplified perceptions of safety and efficacy across all cannabis products do not help. More troublesome would be to extrapolate safety to other forms of marijuana known to be dangerous, such as synthetic cannabinoids, which in some instances have been associated with catastrophic outcomes.⁵ The slippery slope is real: if the message becomes that some (or most) marijuana is benign or even therapeutic, what is to curb a widespread and unregulated epidemic?

YOUTH AT RISK

Some groups are more vulnerable than others to the potential negative effects of cannabis. In a study at a medical cannabis dispensary in San Francisco,⁶ adolescents and young adults used more marijuana than older users did and had higher rates of “use when bored” and eventual pharmacologic dependence. Sustained use of marijuana by young people places them at risk of serious psychiatric disorders, with numerous studies demonstrating the unfolding of schizophrenia, depression, bipolar disorder, and more.⁷

As the authors point out, cannabis may be contraindicated in those already burdened with mental health problems. If we recall that comorbid psychiatric disorders are the norm rather than the exception in chronic pain conditions,⁸ can we recommend cannabis therapy for most patients with chronic pain with confidence that it will not cause unintended problems? Evidence already shows that even well-established medical marijuana services attract (and perhaps unintentionally debilitate) a certain high-risk demographic: young, socioeconomically disadvantaged men with other comorbid psychiatric and substance use disorders, who ultimately rank poorly in functional health measures compared with the general population.⁹

NOT REEFER MADNESS, BUT REEFER CAUTION

I am not advocating the fear-mongering misinformation campaigns of the past. We should not exaggerate and warn about “reefer madness” or equate marijuana with untruths about random violence or complete bedlam. Nonetheless, concerns for widespread amotivation, worsening psychiatric states, chronic disability, and chemical dependence are very real.

Needed are tightly regulated, well-controlled, and long-term prospective studies involving isolated CBD formulations lacking THC. Over time, perhaps only formulations approved by the US Food and Drug Administration will be embraced. In the meantime, more comprehensive approaches should be recommended, such as team-based interdisciplinary rehabilitation programs that have shown efficacy in handling chronic pain complexities.^10,11

If such steps are unlikely, physicians should nonetheless stand united in sending a message of cautious optimism regarding medical marijuana, educating their patients not only about recently advertised potential yet inconclusive benefits, but also about the well-known and actual certitudes of its harms for use in chronic pain management. There is plenty of bad and worse information to share with patients, and there is a slippery slope of epidemic proportions to be wary about.

The narrative review by Modesto-Lowe et al¹ in this issue on the potential therapeutic use of cannabis for peripheral neuropathy is only the latest in a vogue string of examinations on how medical marijuana may be used to manage complex conditions. While the authors should be lauded for acknowledging that the role of cannabis in treating peripheral neuropathy is far from settled (“the unknown” in their title), the high stakes involved warrant even more stringent scrutiny than they suggest.

See related article

We are in the midst of an epidemic of chronic opioid use with massive repercussions, and it did not start overnight. Mounting calls for liberalizing narcotic use across a broad range of pain conditions accumulated gradually during the patient-advocacy era of the 1990s, with supporting “evidence” coming mostly from small uncontrolled studies, anecdotal reports, and industry pressure.² Although cannabis and opioids are not interchangeable, we should be cautious about concluding that cannabis is effective and that it should be used to treat chronic pain.

CHRONIC PAIN IS COMPLICATED

Peripheral neuropathy, by definition, is a chronic pain condition. Unlike acute pain, chronic pain is characterized by biologic, psychologic, and social complexities that require nuance to manage and study.

Such nuance is lacking in most recent reviews of the medical use of cannabis. The conditions in question are often studied as if they were transient and acute, eg, employing short-term studies and rudimentary measures such as numeric pain-rating scales or other snapshots of pain intensity. Results of these shortsighted assessments are impossible to extrapolate to long-term outcomes.

Whether cannabis therapy for chronic pain conditions is sustainable remains to be seen. Outcomes in chronic pain should not be defined simply by pain reduction, but by other dimensions such as changes in pain-related disability and quality of life, development of pharmacologic tolerance or dependence, adverse effects, and other “collateral damage.” We are far from understanding these issues, which require highly controlled and regulated longitudinal studies.

A recent Cochrane review³ of the efficacy of cannabis-based medicines for chronic neuropathic pain found that harms might outweigh the benefits. The quality of evidence was rated as very low to moderate; the reviewers cited small sample sizes and exclusion of important subgroups of patients (eg, those with substance abuse or other psychiatric comorbidities). Such exclusions are the crux of a major problem with cannabis research: studies are not naturalistic. The gritty reality of chronic pain management is paramount, and failing to consider the high-risk biopsychosocial factors typical of patients with chronic pain is naïve and, frankly, dangerous.

The true danger of cannabis lies in what we already know with certainty. As the authors discuss, cannabis undisputedly results in dose-dependent cognitive and motivational problems. If we are preaching physical therapy and home exercise to counter deconditioning, socialization to reverse depression, cognitive-behavioral therapy to increase coping, returning to work to prevent prolonged disability, and other active measures to prevent pain from becoming chronic, then why would we suggest treatments known to blunt motivation, energy, concentration, and overall mood? As a general central nervous system suppressant,⁴ cannabis works broadly against our best efforts to rehabilitate patients and restore their overall function.

ALL CANNABIS IS NOT THE SAME

The authors use the general term cannabis in their title, yet rightly unpack the differences between medical marijuana, tetrahydrocannabinol (THC), and cannabidiol (CBD). However, in the minds of untrained and pain-stricken patients seeking rapid relief and practical solutions, such distinctions are likely irrelevant.

The danger in the barrage of publications examining cannabis vs medical marijuana vs THC vs CBD is that they all communicate an unintentional yet problematic message: that marijuana of some sort for pain is acceptable to try. And in the face of financial pressures, changing legal landscapes, insurance coverage volatility, and access issues, are patients really going to always secure prescriptions for well-regulated CBD (lacking psychoactive THC) from thoughtful and well-informed physicians, or will they turn to convenient street suppliers?

Simplified perceptions of safety and efficacy across all cannabis products do not help. More troublesome would be to extrapolate safety to other forms of marijuana known to be dangerous, such as synthetic cannabinoids, which in some instances have been associated with catastrophic outcomes.⁵ The slippery slope is real: if the message becomes that some (or most) marijuana is benign or even therapeutic, what is to curb a widespread and unregulated epidemic?

YOUTH AT RISK

Some groups are more vulnerable than others to the potential negative effects of cannabis. In a study at a medical cannabis dispensary in San Francisco,⁶ adolescents and young adults used more marijuana than older users did and had higher rates of “use when bored” and eventual pharmacologic dependence. Sustained use of marijuana by young people places them at risk of serious psychiatric disorders, with numerous studies demonstrating the unfolding of schizophrenia, depression, bipolar disorder, and more.⁷

As the authors point out, cannabis may be contraindicated in those already burdened with mental health problems. If we recall that comorbid psychiatric disorders are the norm rather than the exception in chronic pain conditions,⁸ can we recommend cannabis therapy for most patients with chronic pain with confidence that it will not cause unintended problems? Evidence already shows that even well-established medical marijuana services attract (and perhaps unintentionally debilitate) a certain high-risk demographic: young, socioeconomically disadvantaged men with other comorbid psychiatric and substance use disorders, who ultimately rank poorly in functional health measures compared with the general population.⁹

NOT REEFER MADNESS, BUT REEFER CAUTION

I am not advocating the fear-mongering misinformation campaigns of the past. We should not exaggerate and warn about “reefer madness” or equate marijuana with untruths about random violence or complete bedlam. Nonetheless, concerns for widespread amotivation, worsening psychiatric states, chronic disability, and chemical dependence are very real.

Needed are tightly regulated, well-controlled, and long-term prospective studies involving isolated CBD formulations lacking THC. Over time, perhaps only formulations approved by the US Food and Drug Administration will be embraced. In the meantime, more comprehensive approaches should be recommended, such as team-based interdisciplinary rehabilitation programs that have shown efficacy in handling chronic pain complexities.^10,11

If such steps are unlikely, physicians should nonetheless stand united in sending a message of cautious optimism regarding medical marijuana, educating their patients not only about recently advertised potential yet inconclusive benefits, but also about the well-known and actual certitudes of its harms for use in chronic pain management. There is plenty of bad and worse information to share with patients, and there is a slippery slope of epidemic proportions to be wary about.

In the article by Chaitoff et al (Men’s health 2018: BPH, prostate cancer, erectile dysfunction, supplements. Cleve Clin J Med 2018; 85(11):871–880, doi:10.3949/ccjm.85a.18011), the prostate-specific antigen level of a 60-year-old man was given as 5.1 mg/dL. The unit of measure should have been 5.1 ng/mL. This has been corrected online.

In the article by Chaitoff et al (Men’s health 2018: BPH, prostate cancer, erectile dysfunction, supplements. Cleve Clin J Med 2018; 85(11):871–880, doi:10.3949/ccjm.85a.18011), the prostate-specific antigen level of a 60-year-old man was given as 5.1 mg/dL. The unit of measure should have been 5.1 ng/mL. This has been corrected online.

In the article by Chaitoff et al (Men’s health 2018: BPH, prostate cancer, erectile dysfunction, supplements. Cleve Clin J Med 2018; 85(11):871–880, doi:10.3949/ccjm.85a.18011), the prostate-specific antigen level of a 60-year-old man was given as 5.1 mg/dL. The unit of measure should have been 5.1 ng/mL. This has been corrected online.

ABSTRACT

Purpose Our study examined the efficacy of a primary-care intervention in reducing opioid use among patients who have chronic non-cancer pain (CNCP). We also recorded the intervention’s effect on patients’ decisions to leave (or stay) with the primary-care practice.

Methods A family physician (FP) identified 41 patients in his practice who had CNCP of at least 6 month’s duration and were using opioids. The intervention with each patient involved an initial discussion of ethical principles, evidence-based practice, and current published guidelines. Following the discussion, patients self-selected to participate with their FP in a continuing tapering program or to accept referral to a pain center for management of their opioid medications. Tapering ranged from a 10% reduction per week to a more rapid 25% to 50% reduction every few days. Twenty-seven patients continued tapering with their FP, and 6 months later were retrospectively placed in the Taper Group. Fourteen patients chose not to pursue the tapering option and were referred to a single-modality medical pain clinic (MPC). All patients had the option of staying with the FP for other medical care.

Results At baseline and again at 6 months post-initial intervention, the MPC Group was taking significantly higher daily doses of morphine equivalents than the Taper Group. The Taper Group at 6 months was taking significantly lower average daily narcotic doses in morphine equivalents than at baseline. No significant baseline-to-6 month differences were found in the MPC Group. Contrary to many physicians’ fear of losing patients following candid discussions about opioid use, 40 of the 41 patients continued with the FP for other health needs.

Conclusions FPs can frankly discuss opioid use with their patients based on ethical principles and evidence-based recommendations and employ a tapering protocol consistent with current opioid treatment guidelines without jeopardizing the patient-physician relationship.

[polldaddy:10180698]

Opioid prescriptions for chronic noncancer pain (CNCP) have increased significantly over the past 25 years in the United States.¹ Despite methodologic concerns surrounding research on opioid harms, prescription opioid misuse among CNCP patients is estimated to be 21% to 29% and prescription addiction 8% to 12%.² Tragically, with the overall increase in opioid use for CNCP, substance-related hospital admissions and deaths due to opioid overdose have also risen.³

Increased opioid use began in 1985 when the World Health Organization expanded its ethical mandate for pain relief in dying patients to include relief from all cancer pain.³ Opioid use then accelerated following Portenoy and Foley’s 1986 article⁴ and the 1997 consensus statement by the American Academy of Pain Medicine (AAPM) and the American Pain Society (APS),⁵ with both organizations arguing that opioids have a role in the treatment of CNCP. Increased use of opioids for CNCP continued throughout the 1990s and 2000s, as many states passed legislation removing sanctions on prescribing long-term and high-dose opioid therapy, and pharmaceutical companies aggressively marketed sustained-release opioids.³

A balanced approach to opioids. While acknowledging the serious public health problems of drug abuse, addiction, and diversion of opioids from licit to illicit uses, clinical research and regulation leaders have called for a balanced approach that recognizes the legitimate medical need for opioids for CNCP. In 2009 the APS, in partnership with the AAPM, published evidence-based guidelines on chronic opioid therapy (COT) for adults with CNCP.⁶ In developing these guidelines, a multidisciplinary panel of experts conducted systematic reviews of available evidence and made recommendations on formulating COT for individuals, initiating and titrating therapy, regularly monitoring patients, and managing opioid-related adverse effects. Additional recommendations addressed the use of therapies focusing on psychosocial factors. The APS-AAPM guidelines received the highest rating in a systematic review critically appraising 13 guidelines that address the use of opioids for CNCP.⁷

Continue to: When opioid use is prolonged...

When opioid use is prolonged. Most primary care physicians are aware of the risks of prolonged opioid use, and many have successfully tapered or discontinued opioid medications for patients in acute or pre-chronic stages of pain.⁸ However, many physicians face the challenge of patients who have used COT for a longer time. The APS-AAPM guidelines may help primary care physicians at any stage of treating CNCP patients.

METHODS

Purpose and design. This retrospective study, which reviewed pretest-posttest findings between and within study groups, received an exempt status from Creighton University’s institutional review board. We designed the study to determine the efficacy of an intervention protocol to reduce opioid use by patients with CNCP who had been in a family physician (FP)'s panel for quite some time. Furthermore, because a common fear among primary care providers is that raising concerns with patients about their opioid use may cause those patients to leave their panel,⁹ our study also recorded how many patients stayed with their FP after initiation of the opioid management protocol.

Subjects. This study tracked 41 patients with CNCP in 1 FP’s panel. Inclusion criteria for participation was: 1) presence of CNCP for at least 6 months, 2) current use of opioid medication for CNCP, 3) age of at least 16 years, and 4) ability to read and write English. Two exclusion criteria were the presence of a surgically correctable condition or an organic brain syndrome or psychosis.

Clinical intervention. The FP identified eligible patients in his practice that were taking opioids for CNCP and initiated a discussion with each of them emphasizing his desire to follow the ethical principles of beneficence, nonmaleficence, respect for autonomy, and justice.¹⁰ The FP also presented his reasons for wanting the patient to stop using opioid medication. They included his beliefs that:

1) COT was not safe for the patient based on a growing body of published evidence of harm and death from COT³;
2) long-term use of opioids could lead to misuse, abuse, or addiction²;
3) prolonged opioid use paradoxically increases pain sensitivity that does not resolve with discontinuation of opioid maintenance^11,12 (although pain tolerance does improve after opioid cessation); and
4) the patient’s current pain medications were not in line with published guidelines for use of opioids for CNCP.⁶

Initially, 45 patients were eligible for the study, but 4 declined participation before the intervention discussion and were immediately referred to a single-modality medical pain clinic (MPC). These patients were not included in subsequent analyses. Of the remaining 41 patients, all had a discussion with the MD about ethical principles, practice guidelines, and the importance of opioid tapering. After the discussion, patients decided whether to continue with the plan to taper their opioid therapy or to not taper their therapy and so receive a referral to an MPC.

Continue to: The 27 patients who chose to work with...

The 27 patients who chose to work with their FP started an individually tailored opioid-tapering program and were retrospectively placed in the Taper Group 6 months later. Tapering ranged from a slow 10% reduction in dosage per week to a more rapid 25% to 50% reduction every few days. Although evidence to guide specific recommendations on the rate of reduction is lacking, a slower rate may reduce unpleasant symptoms of opioid withdrawal.⁶ Following the patient-FP discussion, the 14 patients who chose not to pursue the tapering option were referred to an MPC for pain management, but could opt to remain with the FP for all other medical care. At 6 months post-discussion, we retrospectively assigned these 14 patients to the MPC Group.

Measures. We obtained demographic and medical information, including age, gender, race, marital status, and medication level in morphine equivalents, from the electronic health record. Medication level in morphine equivalents was recorded at the beginning of the intervention and again 6 months later. All analyses were conducted using SPSS Version 24 (IBM Corp, Armonk, NY) with P<.05 used to indicate statistical significance.

RESULTS

Between-group differences. The Taper and MPC groups did not differ significantly on demographic variables, with mean ages, respectively, at 57 and 51 years, sex 56% and 50% female, race 74% and 79% white, and marital status 48% and 50% married.

Patients who tapered opioid usage under FP guidance significantly reduced daily morphine equivalents over 6 months.

We found significant differences between the Taper and MPC groups on total daily dose in morphine equivalents at baseline and at 6 months following initial intervention. The Levene’s test for equality of variances was statistically significant, indicating unequal variances between the groups. In our SPSS analyses, we therefore used the option “equal variances not assumed.” TABLE 1 lists resultant means, standard deviations, individual sample t-test scores, and confidence intervals. The MPC Group was taking significantly higher daily doses of morphine equivalents than the Taper Group both at baseline and at 6 months following initial intervention.

Within-group differences. Paired sample t tests indicated significant differences between baseline and 6-month average daily narcotic doses in morphine equivalents for the Taper Group. No significant difference was found between baseline and 6-month daily morphine equivalents for the MPC group. These results indicated that patients who continued opioid tapering with the FP significantly reduced their daily morphine equivalents over the 6 months of the study. Patients in the MPC Group reduced morphine equivalents over the 6 months, but the reduction was not statistically significant. Paired sample t test results are presented in TABLE 2.

Continue to: Patient retention

Patient retention. All but one of the 41 patients in the Tapering and MPC groups continued with the FP for the remainder of their health care needs. Contrary to some physicians’ fears, the patients in this study maintained continuity with their FP.

DISCUSSION

Results of this study indicate that an intervention consisting of a physician-patient discussion of ethical principles and evidence-based practice, followed by individualized opioid tapering per published guidelines, led to a significant reduction in opioid use in patients with CNCP. The Taper Group, which completed the intervention, exhibited significant morphine reductions between baseline and 6-month follow-up. This did not hold true for the MPC Group.

The MPC Group, despite participating in the discussion with the FP, chose not to complete the tapering program and was referred to a single-modality MPC where opioids were managed rather than tapered. While the MPC group reduced daily opioid dose levels, the reduction was not statistically significant. A possible reason for no difference within the MPC Group may be that they had greater dependence on opioids, as their baseline average daily dose was much higher than that in the Taper Group (173 mg vs 31 mg, respectively). Although we did not assess anxiety directly, we speculate that the MPC Group was more anxious about opioid reduction than the Taper Group, and that this anxiety potentially led 4 patients to opt out of the initial FP discussion and 14 patients to self-select out of the tapering program following the discussion.

Of the 14 patients who opted not to participate with their FP in opioid tapering, 13 remained with him for all other care.

The FP intervention was successful for the Taper Group. For MPC patients, an enhanced intervention including behavior health strategies¹³ might have reduced anxiety and increased motivation¹⁴ to continue tapering. Based on moderate-quality evidence, APS-AAPM guidelines strongly recommend that CNCP be viewed as a complex biopsychosocial condition. Therefore, clinicians who prescribe opioids should routinely integrate psychotherapeutic interventions, functional restoration, interdisciplinary therapy, and other adjunctive nonopioid therapies.⁶

Opioid tapering within multidisciplinary rehabilitation programs is possible without significant worsening of pain, mood, and function.¹⁵ Recently, an outpatient opioid-tapering support intervention showed promise for efficacy in reducing prescription opioid doses without resultant increases in pain intensity or pain interference.¹⁶

Continue to: The tapering protocol in our study...

The tapering protocol in our study and the inclusion of behavioral health co-interventions are also recommended by the 2016 guidelines published by the Center for Disease Control and Prevention.¹⁷ More information on the similarities and differences among the various guidelines is available online.^18,19

Caveats with our study. Patients’ entry into the Taper or MPC groups occurred through self-selection rather than random assignment. Thus, caution is recommended in interpreting findings of the FP intervention. And, we did not measure patients’ levels of pain, so differences between groups may have been possible. In addition, the number of patients per group was relatively small, which may have accounted for the lack of significance in the MPC Group findings. Conversely, significant reductions in opioid use in the small tapering sample suggests a relatively robust intervention, despite a lack of random assignment to treatment conditions.

These findings suggest that FPs can have a frank conversation about opioid use with their patients based on ethical principles and evidence-based practice, and employ a tapering protocol consistent with current opioid treatment guidelines. Furthermore, this approach appears not to jeopardize the patient-physician relationship.

CORRESPONDENCE
Thomas P. Guck, PhD, Creighton University School of Medicine, 2412 Cuming Street, Omaha, NE 68131; [email protected].

ABSTRACT

Purpose Our study examined the efficacy of a primary-care intervention in reducing opioid use among patients who have chronic non-cancer pain (CNCP). We also recorded the intervention’s effect on patients’ decisions to leave (or stay) with the primary-care practice.

Methods A family physician (FP) identified 41 patients in his practice who had CNCP of at least 6 month’s duration and were using opioids. The intervention with each patient involved an initial discussion of ethical principles, evidence-based practice, and current published guidelines. Following the discussion, patients self-selected to participate with their FP in a continuing tapering program or to accept referral to a pain center for management of their opioid medications. Tapering ranged from a 10% reduction per week to a more rapid 25% to 50% reduction every few days. Twenty-seven patients continued tapering with their FP, and 6 months later were retrospectively placed in the Taper Group. Fourteen patients chose not to pursue the tapering option and were referred to a single-modality medical pain clinic (MPC). All patients had the option of staying with the FP for other medical care.

Results At baseline and again at 6 months post-initial intervention, the MPC Group was taking significantly higher daily doses of morphine equivalents than the Taper Group. The Taper Group at 6 months was taking significantly lower average daily narcotic doses in morphine equivalents than at baseline. No significant baseline-to-6 month differences were found in the MPC Group. Contrary to many physicians’ fear of losing patients following candid discussions about opioid use, 40 of the 41 patients continued with the FP for other health needs.

Conclusions FPs can frankly discuss opioid use with their patients based on ethical principles and evidence-based recommendations and employ a tapering protocol consistent with current opioid treatment guidelines without jeopardizing the patient-physician relationship.

[polldaddy:10180698]

Opioid prescriptions for chronic noncancer pain (CNCP) have increased significantly over the past 25 years in the United States.¹ Despite methodologic concerns surrounding research on opioid harms, prescription opioid misuse among CNCP patients is estimated to be 21% to 29% and prescription addiction 8% to 12%.² Tragically, with the overall increase in opioid use for CNCP, substance-related hospital admissions and deaths due to opioid overdose have also risen.³

Increased opioid use began in 1985 when the World Health Organization expanded its ethical mandate for pain relief in dying patients to include relief from all cancer pain.³ Opioid use then accelerated following Portenoy and Foley’s 1986 article⁴ and the 1997 consensus statement by the American Academy of Pain Medicine (AAPM) and the American Pain Society (APS),⁵ with both organizations arguing that opioids have a role in the treatment of CNCP. Increased use of opioids for CNCP continued throughout the 1990s and 2000s, as many states passed legislation removing sanctions on prescribing long-term and high-dose opioid therapy, and pharmaceutical companies aggressively marketed sustained-release opioids.³

A balanced approach to opioids. While acknowledging the serious public health problems of drug abuse, addiction, and diversion of opioids from licit to illicit uses, clinical research and regulation leaders have called for a balanced approach that recognizes the legitimate medical need for opioids for CNCP. In 2009 the APS, in partnership with the AAPM, published evidence-based guidelines on chronic opioid therapy (COT) for adults with CNCP.⁶ In developing these guidelines, a multidisciplinary panel of experts conducted systematic reviews of available evidence and made recommendations on formulating COT for individuals, initiating and titrating therapy, regularly monitoring patients, and managing opioid-related adverse effects. Additional recommendations addressed the use of therapies focusing on psychosocial factors. The APS-AAPM guidelines received the highest rating in a systematic review critically appraising 13 guidelines that address the use of opioids for CNCP.⁷

Continue to: When opioid use is prolonged...

When opioid use is prolonged. Most primary care physicians are aware of the risks of prolonged opioid use, and many have successfully tapered or discontinued opioid medications for patients in acute or pre-chronic stages of pain.⁸ However, many physicians face the challenge of patients who have used COT for a longer time. The APS-AAPM guidelines may help primary care physicians at any stage of treating CNCP patients.

METHODS

Purpose and design. This retrospective study, which reviewed pretest-posttest findings between and within study groups, received an exempt status from Creighton University’s institutional review board. We designed the study to determine the efficacy of an intervention protocol to reduce opioid use by patients with CNCP who had been in a family physician (FP)'s panel for quite some time. Furthermore, because a common fear among primary care providers is that raising concerns with patients about their opioid use may cause those patients to leave their panel,⁹ our study also recorded how many patients stayed with their FP after initiation of the opioid management protocol.

Subjects. This study tracked 41 patients with CNCP in 1 FP’s panel. Inclusion criteria for participation was: 1) presence of CNCP for at least 6 months, 2) current use of opioid medication for CNCP, 3) age of at least 16 years, and 4) ability to read and write English. Two exclusion criteria were the presence of a surgically correctable condition or an organic brain syndrome or psychosis.

Clinical intervention. The FP identified eligible patients in his practice that were taking opioids for CNCP and initiated a discussion with each of them emphasizing his desire to follow the ethical principles of beneficence, nonmaleficence, respect for autonomy, and justice.¹⁰ The FP also presented his reasons for wanting the patient to stop using opioid medication. They included his beliefs that:

1) COT was not safe for the patient based on a growing body of published evidence of harm and death from COT³;
2) long-term use of opioids could lead to misuse, abuse, or addiction²;
3) prolonged opioid use paradoxically increases pain sensitivity that does not resolve with discontinuation of opioid maintenance^11,12 (although pain tolerance does improve after opioid cessation); and
4) the patient’s current pain medications were not in line with published guidelines for use of opioids for CNCP.⁶

Initially, 45 patients were eligible for the study, but 4 declined participation before the intervention discussion and were immediately referred to a single-modality medical pain clinic (MPC). These patients were not included in subsequent analyses. Of the remaining 41 patients, all had a discussion with the MD about ethical principles, practice guidelines, and the importance of opioid tapering. After the discussion, patients decided whether to continue with the plan to taper their opioid therapy or to not taper their therapy and so receive a referral to an MPC.

Continue to: The 27 patients who chose to work with...

The 27 patients who chose to work with their FP started an individually tailored opioid-tapering program and were retrospectively placed in the Taper Group 6 months later. Tapering ranged from a slow 10% reduction in dosage per week to a more rapid 25% to 50% reduction every few days. Although evidence to guide specific recommendations on the rate of reduction is lacking, a slower rate may reduce unpleasant symptoms of opioid withdrawal.⁶ Following the patient-FP discussion, the 14 patients who chose not to pursue the tapering option were referred to an MPC for pain management, but could opt to remain with the FP for all other medical care. At 6 months post-discussion, we retrospectively assigned these 14 patients to the MPC Group.

Measures. We obtained demographic and medical information, including age, gender, race, marital status, and medication level in morphine equivalents, from the electronic health record. Medication level in morphine equivalents was recorded at the beginning of the intervention and again 6 months later. All analyses were conducted using SPSS Version 24 (IBM Corp, Armonk, NY) with P<.05 used to indicate statistical significance.

RESULTS

Between-group differences. The Taper and MPC groups did not differ significantly on demographic variables, with mean ages, respectively, at 57 and 51 years, sex 56% and 50% female, race 74% and 79% white, and marital status 48% and 50% married.

Patients who tapered opioid usage under FP guidance significantly reduced daily morphine equivalents over 6 months.

We found significant differences between the Taper and MPC groups on total daily dose in morphine equivalents at baseline and at 6 months following initial intervention. The Levene’s test for equality of variances was statistically significant, indicating unequal variances between the groups. In our SPSS analyses, we therefore used the option “equal variances not assumed.” TABLE 1 lists resultant means, standard deviations, individual sample t-test scores, and confidence intervals. The MPC Group was taking significantly higher daily doses of morphine equivalents than the Taper Group both at baseline and at 6 months following initial intervention.

Within-group differences. Paired sample t tests indicated significant differences between baseline and 6-month average daily narcotic doses in morphine equivalents for the Taper Group. No significant difference was found between baseline and 6-month daily morphine equivalents for the MPC group. These results indicated that patients who continued opioid tapering with the FP significantly reduced their daily morphine equivalents over the 6 months of the study. Patients in the MPC Group reduced morphine equivalents over the 6 months, but the reduction was not statistically significant. Paired sample t test results are presented in TABLE 2.

Continue to: Patient retention

Patient retention. All but one of the 41 patients in the Tapering and MPC groups continued with the FP for the remainder of their health care needs. Contrary to some physicians’ fears, the patients in this study maintained continuity with their FP.

DISCUSSION

Results of this study indicate that an intervention consisting of a physician-patient discussion of ethical principles and evidence-based practice, followed by individualized opioid tapering per published guidelines, led to a significant reduction in opioid use in patients with CNCP. The Taper Group, which completed the intervention, exhibited significant morphine reductions between baseline and 6-month follow-up. This did not hold true for the MPC Group.

The MPC Group, despite participating in the discussion with the FP, chose not to complete the tapering program and was referred to a single-modality MPC where opioids were managed rather than tapered. While the MPC group reduced daily opioid dose levels, the reduction was not statistically significant. A possible reason for no difference within the MPC Group may be that they had greater dependence on opioids, as their baseline average daily dose was much higher than that in the Taper Group (173 mg vs 31 mg, respectively). Although we did not assess anxiety directly, we speculate that the MPC Group was more anxious about opioid reduction than the Taper Group, and that this anxiety potentially led 4 patients to opt out of the initial FP discussion and 14 patients to self-select out of the tapering program following the discussion.

Of the 14 patients who opted not to participate with their FP in opioid tapering, 13 remained with him for all other care.

The FP intervention was successful for the Taper Group. For MPC patients, an enhanced intervention including behavior health strategies¹³ might have reduced anxiety and increased motivation¹⁴ to continue tapering. Based on moderate-quality evidence, APS-AAPM guidelines strongly recommend that CNCP be viewed as a complex biopsychosocial condition. Therefore, clinicians who prescribe opioids should routinely integrate psychotherapeutic interventions, functional restoration, interdisciplinary therapy, and other adjunctive nonopioid therapies.⁶

Opioid tapering within multidisciplinary rehabilitation programs is possible without significant worsening of pain, mood, and function.¹⁵ Recently, an outpatient opioid-tapering support intervention showed promise for efficacy in reducing prescription opioid doses without resultant increases in pain intensity or pain interference.¹⁶

Continue to: The tapering protocol in our study...

The tapering protocol in our study and the inclusion of behavioral health co-interventions are also recommended by the 2016 guidelines published by the Center for Disease Control and Prevention.¹⁷ More information on the similarities and differences among the various guidelines is available online.^18,19

Caveats with our study. Patients’ entry into the Taper or MPC groups occurred through self-selection rather than random assignment. Thus, caution is recommended in interpreting findings of the FP intervention. And, we did not measure patients’ levels of pain, so differences between groups may have been possible. In addition, the number of patients per group was relatively small, which may have accounted for the lack of significance in the MPC Group findings. Conversely, significant reductions in opioid use in the small tapering sample suggests a relatively robust intervention, despite a lack of random assignment to treatment conditions.

These findings suggest that FPs can have a frank conversation about opioid use with their patients based on ethical principles and evidence-based practice, and employ a tapering protocol consistent with current opioid treatment guidelines. Furthermore, this approach appears not to jeopardize the patient-physician relationship.

CORRESPONDENCE
Thomas P. Guck, PhD, Creighton University School of Medicine, 2412 Cuming Street, Omaha, NE 68131; [email protected].

ABSTRACT

Purpose Our study examined the efficacy of a primary-care intervention in reducing opioid use among patients who have chronic non-cancer pain (CNCP). We also recorded the intervention’s effect on patients’ decisions to leave (or stay) with the primary-care practice.

Methods A family physician (FP) identified 41 patients in his practice who had CNCP of at least 6 month’s duration and were using opioids. The intervention with each patient involved an initial discussion of ethical principles, evidence-based practice, and current published guidelines. Following the discussion, patients self-selected to participate with their FP in a continuing tapering program or to accept referral to a pain center for management of their opioid medications. Tapering ranged from a 10% reduction per week to a more rapid 25% to 50% reduction every few days. Twenty-seven patients continued tapering with their FP, and 6 months later were retrospectively placed in the Taper Group. Fourteen patients chose not to pursue the tapering option and were referred to a single-modality medical pain clinic (MPC). All patients had the option of staying with the FP for other medical care.

Results At baseline and again at 6 months post-initial intervention, the MPC Group was taking significantly higher daily doses of morphine equivalents than the Taper Group. The Taper Group at 6 months was taking significantly lower average daily narcotic doses in morphine equivalents than at baseline. No significant baseline-to-6 month differences were found in the MPC Group. Contrary to many physicians’ fear of losing patients following candid discussions about opioid use, 40 of the 41 patients continued with the FP for other health needs.

Conclusions FPs can frankly discuss opioid use with their patients based on ethical principles and evidence-based recommendations and employ a tapering protocol consistent with current opioid treatment guidelines without jeopardizing the patient-physician relationship.

[polldaddy:10180698]

Opioid prescriptions for chronic noncancer pain (CNCP) have increased significantly over the past 25 years in the United States.¹ Despite methodologic concerns surrounding research on opioid harms, prescription opioid misuse among CNCP patients is estimated to be 21% to 29% and prescription addiction 8% to 12%.² Tragically, with the overall increase in opioid use for CNCP, substance-related hospital admissions and deaths due to opioid overdose have also risen.³

Increased opioid use began in 1985 when the World Health Organization expanded its ethical mandate for pain relief in dying patients to include relief from all cancer pain.³ Opioid use then accelerated following Portenoy and Foley’s 1986 article⁴ and the 1997 consensus statement by the American Academy of Pain Medicine (AAPM) and the American Pain Society (APS),⁵ with both organizations arguing that opioids have a role in the treatment of CNCP. Increased use of opioids for CNCP continued throughout the 1990s and 2000s, as many states passed legislation removing sanctions on prescribing long-term and high-dose opioid therapy, and pharmaceutical companies aggressively marketed sustained-release opioids.³

A balanced approach to opioids. While acknowledging the serious public health problems of drug abuse, addiction, and diversion of opioids from licit to illicit uses, clinical research and regulation leaders have called for a balanced approach that recognizes the legitimate medical need for opioids for CNCP. In 2009 the APS, in partnership with the AAPM, published evidence-based guidelines on chronic opioid therapy (COT) for adults with CNCP.⁶ In developing these guidelines, a multidisciplinary panel of experts conducted systematic reviews of available evidence and made recommendations on formulating COT for individuals, initiating and titrating therapy, regularly monitoring patients, and managing opioid-related adverse effects. Additional recommendations addressed the use of therapies focusing on psychosocial factors. The APS-AAPM guidelines received the highest rating in a systematic review critically appraising 13 guidelines that address the use of opioids for CNCP.⁷

Continue to: When opioid use is prolonged...

When opioid use is prolonged. Most primary care physicians are aware of the risks of prolonged opioid use, and many have successfully tapered or discontinued opioid medications for patients in acute or pre-chronic stages of pain.⁸ However, many physicians face the challenge of patients who have used COT for a longer time. The APS-AAPM guidelines may help primary care physicians at any stage of treating CNCP patients.

METHODS

Purpose and design. This retrospective study, which reviewed pretest-posttest findings between and within study groups, received an exempt status from Creighton University’s institutional review board. We designed the study to determine the efficacy of an intervention protocol to reduce opioid use by patients with CNCP who had been in a family physician (FP)'s panel for quite some time. Furthermore, because a common fear among primary care providers is that raising concerns with patients about their opioid use may cause those patients to leave their panel,⁹ our study also recorded how many patients stayed with their FP after initiation of the opioid management protocol.

Subjects. This study tracked 41 patients with CNCP in 1 FP’s panel. Inclusion criteria for participation was: 1) presence of CNCP for at least 6 months, 2) current use of opioid medication for CNCP, 3) age of at least 16 years, and 4) ability to read and write English. Two exclusion criteria were the presence of a surgically correctable condition or an organic brain syndrome or psychosis.

Clinical intervention. The FP identified eligible patients in his practice that were taking opioids for CNCP and initiated a discussion with each of them emphasizing his desire to follow the ethical principles of beneficence, nonmaleficence, respect for autonomy, and justice.¹⁰ The FP also presented his reasons for wanting the patient to stop using opioid medication. They included his beliefs that:

1) COT was not safe for the patient based on a growing body of published evidence of harm and death from COT³;
2) long-term use of opioids could lead to misuse, abuse, or addiction²;
3) prolonged opioid use paradoxically increases pain sensitivity that does not resolve with discontinuation of opioid maintenance^11,12 (although pain tolerance does improve after opioid cessation); and
4) the patient’s current pain medications were not in line with published guidelines for use of opioids for CNCP.⁶

Initially, 45 patients were eligible for the study, but 4 declined participation before the intervention discussion and were immediately referred to a single-modality medical pain clinic (MPC). These patients were not included in subsequent analyses. Of the remaining 41 patients, all had a discussion with the MD about ethical principles, practice guidelines, and the importance of opioid tapering. After the discussion, patients decided whether to continue with the plan to taper their opioid therapy or to not taper their therapy and so receive a referral to an MPC.

Continue to: The 27 patients who chose to work with...

The 27 patients who chose to work with their FP started an individually tailored opioid-tapering program and were retrospectively placed in the Taper Group 6 months later. Tapering ranged from a slow 10% reduction in dosage per week to a more rapid 25% to 50% reduction every few days. Although evidence to guide specific recommendations on the rate of reduction is lacking, a slower rate may reduce unpleasant symptoms of opioid withdrawal.⁶ Following the patient-FP discussion, the 14 patients who chose not to pursue the tapering option were referred to an MPC for pain management, but could opt to remain with the FP for all other medical care. At 6 months post-discussion, we retrospectively assigned these 14 patients to the MPC Group.

Measures. We obtained demographic and medical information, including age, gender, race, marital status, and medication level in morphine equivalents, from the electronic health record. Medication level in morphine equivalents was recorded at the beginning of the intervention and again 6 months later. All analyses were conducted using SPSS Version 24 (IBM Corp, Armonk, NY) with P<.05 used to indicate statistical significance.

RESULTS

Between-group differences. The Taper and MPC groups did not differ significantly on demographic variables, with mean ages, respectively, at 57 and 51 years, sex 56% and 50% female, race 74% and 79% white, and marital status 48% and 50% married.

Patients who tapered opioid usage under FP guidance significantly reduced daily morphine equivalents over 6 months.

We found significant differences between the Taper and MPC groups on total daily dose in morphine equivalents at baseline and at 6 months following initial intervention. The Levene’s test for equality of variances was statistically significant, indicating unequal variances between the groups. In our SPSS analyses, we therefore used the option “equal variances not assumed.” TABLE 1 lists resultant means, standard deviations, individual sample t-test scores, and confidence intervals. The MPC Group was taking significantly higher daily doses of morphine equivalents than the Taper Group both at baseline and at 6 months following initial intervention.

Within-group differences. Paired sample t tests indicated significant differences between baseline and 6-month average daily narcotic doses in morphine equivalents for the Taper Group. No significant difference was found between baseline and 6-month daily morphine equivalents for the MPC group. These results indicated that patients who continued opioid tapering with the FP significantly reduced their daily morphine equivalents over the 6 months of the study. Patients in the MPC Group reduced morphine equivalents over the 6 months, but the reduction was not statistically significant. Paired sample t test results are presented in TABLE 2.

Continue to: Patient retention

Patient retention. All but one of the 41 patients in the Tapering and MPC groups continued with the FP for the remainder of their health care needs. Contrary to some physicians’ fears, the patients in this study maintained continuity with their FP.

DISCUSSION

Results of this study indicate that an intervention consisting of a physician-patient discussion of ethical principles and evidence-based practice, followed by individualized opioid tapering per published guidelines, led to a significant reduction in opioid use in patients with CNCP. The Taper Group, which completed the intervention, exhibited significant morphine reductions between baseline and 6-month follow-up. This did not hold true for the MPC Group.

The MPC Group, despite participating in the discussion with the FP, chose not to complete the tapering program and was referred to a single-modality MPC where opioids were managed rather than tapered. While the MPC group reduced daily opioid dose levels, the reduction was not statistically significant. A possible reason for no difference within the MPC Group may be that they had greater dependence on opioids, as their baseline average daily dose was much higher than that in the Taper Group (173 mg vs 31 mg, respectively). Although we did not assess anxiety directly, we speculate that the MPC Group was more anxious about opioid reduction than the Taper Group, and that this anxiety potentially led 4 patients to opt out of the initial FP discussion and 14 patients to self-select out of the tapering program following the discussion.

Of the 14 patients who opted not to participate with their FP in opioid tapering, 13 remained with him for all other care.

The FP intervention was successful for the Taper Group. For MPC patients, an enhanced intervention including behavior health strategies¹³ might have reduced anxiety and increased motivation¹⁴ to continue tapering. Based on moderate-quality evidence, APS-AAPM guidelines strongly recommend that CNCP be viewed as a complex biopsychosocial condition. Therefore, clinicians who prescribe opioids should routinely integrate psychotherapeutic interventions, functional restoration, interdisciplinary therapy, and other adjunctive nonopioid therapies.⁶

Opioid tapering within multidisciplinary rehabilitation programs is possible without significant worsening of pain, mood, and function.¹⁵ Recently, an outpatient opioid-tapering support intervention showed promise for efficacy in reducing prescription opioid doses without resultant increases in pain intensity or pain interference.¹⁶

Continue to: The tapering protocol in our study...

The tapering protocol in our study and the inclusion of behavioral health co-interventions are also recommended by the 2016 guidelines published by the Center for Disease Control and Prevention.¹⁷ More information on the similarities and differences among the various guidelines is available online.^18,19

Caveats with our study. Patients’ entry into the Taper or MPC groups occurred through self-selection rather than random assignment. Thus, caution is recommended in interpreting findings of the FP intervention. And, we did not measure patients’ levels of pain, so differences between groups may have been possible. In addition, the number of patients per group was relatively small, which may have accounted for the lack of significance in the MPC Group findings. Conversely, significant reductions in opioid use in the small tapering sample suggests a relatively robust intervention, despite a lack of random assignment to treatment conditions.

These findings suggest that FPs can have a frank conversation about opioid use with their patients based on ethical principles and evidence-based practice, and employ a tapering protocol consistent with current opioid treatment guidelines. Furthermore, this approach appears not to jeopardize the patient-physician relationship.

CORRESPONDENCE
Thomas P. Guck, PhD, Creighton University School of Medicine, 2412 Cuming Street, Omaha, NE 68131; [email protected].

From the Fargo Veterans Affairs Health Care System, Fargo, ND (Dr. Dietz, Dr. Hammer, Dr. Zegarra, and Dr. Lo), and the Queen Elizabeth Hospital, Hong Kong, China (Dr. Cho).

Abstract

• Objective: To review the management of patients with Mycoplasma genitalium and Neisseria gonorrhoeae infections.
• Methods: Review of the literature.
• Results: Mycoplasma genitalium and Neisseria gonorrhoeae are organisms that cause urethritis, cervicitis, and pelvic inflammatory disease. There is increasing antibiotic resistance to both organisms, which poses significant challenges to clinicians. Additionally, diagnostic tests for M. genitalium are not widely available, and commonly used tests for both organisms do not provide antibiotic sensitivity information. The increasing resistance of both M. genitalium and N. gonorrhoeae to currently used antimicrobial agents is alarming and warrants cautious monitoring.
• Conclusion: As the yield of new or effective antibiotic therapies has decreased over the past few years, increasing antibiotic resistance will lead to difficult treatment scenarios for sexually transmitted infections caused by these 2 organisms.

Keywords: Mycoplasma genitalium, Neisseria gonorrhoeae, antibiotic resistance, sexually transmitted infections, STIs.

The World Health Organization (WHO) estimates that more than 1 million cases of sexually transmitted Infections (STIs) are acquired every day worldwide,¹ and that the majority of STIs have few or no symptoms, making diagnosis difficult. Two organisms of interest are Mycoplasma genitalium and Neisseria gonorrhoeae. In contrast to Chlamydia trachomatis, which is rarely resistant to treatment regimens, M. genitalium and N. gonorrhoeae are becoming increasingly resistant to antibiotic treatment and pose an impending threat. These bacteria can cause urethritis, cervicitis, and pelvic inflammatory disease (PID). Whereas antibiotic resistance to M. genitalium is emerging, resistance to N. gonorrhea has been a continual problem for decades. Drug resistance, especially for N. gonorrhoeae, is listed as a major threat to efforts to reduce the impact of STIs worldwide.² In 2013, the U.S. Centers for Disease Control and Prevention (CDC) classified N. gonorrhoeae drug resistance as an urgent threat.³ As the yield of new or effective antibiotic therapies has decreased over the past few years, increasing antibiotic resistance will lead to challenging treatment scenarios for STIs caused by these 2 organisms.

Epidemiology and Pathogenesis

M. genitalium

M. genitalium is an emerging pathogen that is an etiologic agent of upper and lower genital tract STIs, such as urethritis, cervicitis, and PID.^4-13 In addition, it is thought to be involved in tubal infertility and acquisition of other sexually transmitted pathogens, including HIV.^7,8,13 The prevalence of M. genitalium in the general U.S. population in 2016 was reported to be approximately 17.2% for males and 16.1% for females.¹⁴ Infections are more common in patients aged 30 years and younger than in older populations.¹⁵ Also, patients self-identifying as black were found to have a higher prevalence of M. genitalium.¹⁴ This organism was first reported as being isolated from the urethras of 2 men with non-gonococcal urethritis (NGU) in London in 1980.^15,16 It is a significant cause of acute and chronic NGU in males, and is estimated to account for 6% to 50% of cases of NGU.^17,18M. genitalium in females has been associated with cervicitis^4,9 and PID.^8,10 A meta-analysis by Lis et al showed that M. genitalium infection was associated with an increased risk for preterm birth and spontaneous abortion.¹¹ In addition, M. genitalium infections occur frequently in HIV-positive patients.^19,20 M. genitalium increases susceptibility for passage of HIV across the epithelium by reducing epithelial barrier integrity.¹⁹

Beta lactams are ineffective against M. genitalium because mycoplasmas lack a cell wall and thus cell wall penicillin-binding proteins.²¹M. genitalium’s abilty to invade host epithelial cells is another mechanism that can protect the bacteria from antibiotic exposure.²⁰ One of the first reports of antibiotic sensitivity testing for M. genitalium, published in 1997, noted that the organism was not susceptible to nalidixic acid, cephalosporins, penicillins, and rifampicin.²² In general, mycoplasmas are normally susceptible to antibiotics that inhibit protein synthesis,²³ and initial good sensitivity to doxycycline and erythromycin was noted but this has since decreased. New antibiotics are on the horizon, but they have not been extensively tested in vivo.²³

N. gonorrhoeae

Gonorrhea is the second most common STI of bacterial origin following C. trachomatis,^24-26 which is rarely resistant to conventional regimens. In 2008, the World Health Organization (WHO) estimated that 106 million cases of N. gonorrhoeae infection were acquired annually and that 36.4 million adults were infected with N. gonorrhoeae.²⁷ In the United States, the CDC estimates that gonorrhea cases are under-reported. An estimated 800,000 or more new cases are reported per year.²⁸

The most common clinical presentations are urethritis in men and cervicitis in women.²⁹ While urethritis is most likely to be symptomatic, only 50% of women with acute gonorrhea are symptomatic.²⁹ In addition to lower urogenital tract infection, N. gonorrhoeae can also cause PID, ectopic pregnancy, infertility in women, and epididymitis in men.^29,30 Rare complications can develop from the spread of N. gonorrhoeae to other parts of the body including the joints, eyes, cardiovascular system, and skin.²⁹

N. gonorrhoeae can attach to the columnar epithelium and causes host innate immune-driven inflammation with neutrophil influx.²⁹ It can avoid the immune response by varying its outer membrane protein expression. The organism is also able to acquire DNA from other Neisseria species³⁰ and genera, which results in reduced susceptibility to therapies.

The Gonococcal Isolate Surveillance Project (GISP), established in 1986, is a collaborative project involving the CDC and STI clinics in 26 cities in the United States along with 5 regional laboratories.³¹ The GISP monitors susceptibilities in N. gonorrhoeae isolates obtained from roughly 6000 symptomatic men each year.³¹ Data collected from the GISP allows clinicians to treat infections with the correct antibiotic. Just as they observed patterns of fluoroquinolone-resistant N. gonorrhoeae, there has been a geographic progression of decreasing susceptibility to cephalosporins in recent years.³¹

The ease with which N. gonorrhoeae can develop resistance is particularly alarming. Sulfonamide use began in the 1930s, but resistance developed within approximately 10 years.^30,32N. gonorrhoeae has acquired resistance to each therapeutic agent used for treatment over the course of its lifetime. One hypothesis is that use of single-dose therapy to rapidly treat the infection has led to treatment failure and allows for selective pressure where organisms with decreased antibiotic susceptibility are more likely to survive.³⁰ However, there is limited evidence to support monotherapy versus combination therapy in treating N. gonorrhoeae.^33,34 It is no exaggeration to say gonorrhea is now at risk of becoming an untreatable disease because of the rapid emergence of multidrug resistant N. gonorrhoeae strains worldwide.³⁵

Diagnosis

Whether the urethritis, cervicitis, or PID is caused by N. gonorrhoeae, M. genitalium, or other non-gonococcal microorganisms (eg, C. trachomatis), no symptoms are specific to any of the microorganisms. Therefore, clinicians rely on laboratory tests to diagnose STIs caused by N. gonorrhoeae or M. genitalium.

M. genitalium

Gram Stain. Because M. genitalium lacks a cell wall, it cannot be identified by routine Gram stain.

Culture. Culturing of this fastidious bacterium might offer the advantage of assessing antibiotic susceptibility;³⁶ however, the procedure is labor intensive and time consuming, and only a few labs in the world have the capability to perform this culture.¹² Thus, this testing method is primarily undertaken for research purposes.

Serological Testing. Because of serologic cross-reactions between Mycoplasma pneumoniae and M. genitalium, there are no standardized serological tests for M. genitalium.³⁷

Nucleic Acid Amplification Tests. M. genitalium diagnosis currently is made based exclusively on nucleic acid amplification testing (NAAT) methodology (polymerase chain reaction [PCR] or transcription-mediated amplification [TMA]), which is the only clinically useful method to detect M. genitalium. TMA for M. genitalium is commercially available in an analyte-specific reagent (ASR) format, but this has not been approved by the Food and Drug Administration (FDA).³⁸ A study analyzing urogenital specimens from female patients via this TMA product found a 98.7% true-positive result when confirmed with repeat testing or alternative-target TMA, and only a 0.5% false-negative rate.³⁸ There is evidence that this TMA product can be used to identify M. genitalium in urine, stool, and pharyngeal samples.³⁹ These assays are currently available in some reference labs and large medical centers but are not widely available. Table 1 summarizes the diagnostic methods for M. genitalium.

N. gonorrhoeae

Gonococcal infection can involve the urogenital tract, but can also be extra-urogenital. The method of diagnoses of urogenital infections has expanded from Gram stain of urethral or cervical discharge and the use of selective media culture (usually Thayer-Martin media)⁴⁰ to molecular methods such as NAATs, which have a higher sensitivity than cultures.^41,42

Gram Stain. A Gram stain that shows polymorphonuclear leukocytes with intracellular gram-negative diplococci can be considered diagnostic for N. gonorrhoeae urethritis infection in symptomatic men when samples are obtained from the urethra.⁴³ A retrospective study of 1148 women with gonorrhea revealed that of 1049 cases of cervical gonorrhea, only 6.4% were positive by smear alone; and of 841 cases of urethral gonorrhea, only 5.1% were positive by smear alone; therefore, other diagnostic methods are generally preferred in women.⁴⁴ Because Gram stain of vaginal specimens is positive in only 50% to 60% of females, its use in women and in suspected extragenital gonococcal infections is not recommended.^43-45 When Gram stain was performed in asymptomatic men, the sensitivity was around 80%.³⁹ Thus, in asymptomatic men with a high pre-test probability of having the infection, the use of other additional testing would increase the rate of detection.⁴³

Culture. Urethral swab specimens from males with symptomatic urethritis and cervical swab samples from females with endocervical infection must be inoculated onto both a selective medium (eg, modified Thayer-Martin medium or Martin Lewis medium) and a nonselective medium (eg, chocolate agar). A selective medium is used because it can suppress the growth of contaminating organisms, and a nonselective medium is used because some strains of N. gonorrhoeae are inhibited by the vancomycin present in the selective medium.⁴⁰ Specimens collected from sterile sites, such as blood, synovial fluid, and cerebrospinal fluid, should be streaked on nonselective medium such as chocolate agar. The material used for collection is critical; the preferred swabs should have plastic or wire shafts and rayon, Dacron, or calcium alginate tips. Materials such as wooden shafts or cotton tips can be toxic to N. gonorrhoeae.⁴⁰ The specimen should be inoculated immediately onto the appropriate medium and transported rapidly to the laboratory, where it should be incubated at 35º to 37ºC with 5% CO₂ and examined at 24 and 48 hours post collection.⁴⁰ If the specimens cannot be inoculated immediately onto the appropriate medium, the specimen swab should be delivered to the lab in a special transport system that can keep the N. gonorrhoeae viable for up to 48 hours at room temperature.⁴⁶

The following specimen collection techniques are recommended by the CDC:⁴⁰

• In males, the cotton swab should be inserted about 2 to 3 cm into the urethral meatus and rotated 360° degrees 2 or 3 times.
• In females, collection of cervical specimens requires inserting the tip of the swab 1 to 2 centimeters into the cervical os and rotating 360° 2 or 3 times.
• Samples obtained outside of the urogenital tract: rectal specimens may be obtained by inserting the swab 3 to 4 cm into the rectal vault. Pharyngeal specimens are to be obtained from the posterior pharynx with a swab.

Culture tests allow the clinician to assess antimicrobial susceptibility and are relatively low cost when compared with nucleic acid detection tests. The sensitivity of culture ranges from 72% to 95% for symptomatic patients, but drops to 65% to 85% for asymptomatic patients.^45-47 This low sensitivity is a major disadvantage of culture tests when compared to NAATs. Other disadvantages are the need for the specimens to be transported under conditions adequate to maintain the viability of organisms and the fact that 24 to 72 hours is required to report presumptive culture results.⁴² Antimicrobial sensitivity testing generally is not recommended; however, it is advisable to perform antimicrobial sensitivity in cases of treatment failure or disseminated gonococcal infection.¹²

Nucleic Acid Amplification Tests. NAATs use techniques that allow the amplification and detection of N. gonorrhoeae DNA or RNA sequences through various methods, which include assays such as PCR (eg, Amplicor; Roche, Nutley, NJ), TMA (eg, APTIMA; Gen-Probe, San Diego, CA), and strand-displacement amplification (SDA; Probe-Tec; Becton Dickinson, Franklin Lake, NJ). While PCR and SDA methods amplify bacterial DNA, TMA amplifies bacterial rRNA.⁴¹

The FDA has cleared NAATs to test endocervical, vaginal, and urethral (men) swab specimens and urine for both men and women. There are several NAATs available to test rectal, oropharyngeal, and conjunctival specimens; however, none of them are FDA-cleared. Some local and commercial laboratories have validated the reliability of these extra-urogenital NAATs.^12,48 Compared to cultures, NAATs have the advantages of being more sensitive and requiring less strict collection and transport conditions. However, they are costlier than cultures, do not provide any antimicrobial susceptibility information, and have varying specificity.^49,50

Rapid Tests. NAAT results are usually available in approximately 1 to 2 days, so there has been significant interest in creating technologies that would allow for a more rapid turnaround time. The GeneXpert CT/NG is a newly developed real-time PCR-based assay that can simultaneously detect C. trachomatis and N. gonorrhoeae. The advantage of this technique is the 90-minute turnaround time and its ability to process more than 90 samples at a time. The specificity of this test for N. gonorrhoeae is similar to that of other NAATs (> 99.3%), suggesting that cross-reactivity is not a significant problem.⁵¹ Table 2 summarizes the test methods used for diagnosing N. gonorrhoeae.

Treatment

M. genitalium

M. genitalium, Mycoplasma hominis, and the ureaplasmas (U. urealyticum and U. parvum) are generally transmitted sexually, and the natural habitat of this Mycoplasmataceae family of bacteria is the genitourinary tract. All the mycoplasmas can cause NGU, cervicitis, and PID. Presently, multiple-drug resistant M. hominis and ureaplasmas remain uncommon, but the prevalence of M. genitalium resistant to multiple antibiotics has increased significantly in recent years.^23,52

In the 1990s, M. genitalium was highly sensitive to the tetracyclines in vitro,⁵³ and doxycycline was the drug of choice for treating NGU. However, it later became apparent that doxycycline was largely ineffective in treating urethritis caused by M. genitalium.^54,55

Subsequently, azithromycin, a macrolide, became popular in treating urethritis in males and cervicitis in females because it was highly active against C. trachomatis⁵⁴ and M. genitalium⁵⁶ and it can be given orally as a single 1-g dose, thus increasing patients’ compliance. However, azithromycin-resistant M. genitalium has rapidly emerged and rates of treatment failure with azithromycin as high as 40% have been reported in recent studies.^57,58 The resistance was found to be mediated by mutations in the 23S rRNA gene upon exposure of M. genitalium to azithromycin.^15,57-59 Multiple studies conducted in various countries (including the United States, Netherlands, England, and France) all found high rates of 23S rRNA gene mutations.^15,57-59M. genitalium samples were analyzed using reverse transcription-PCR and Sanger sequencing of the 23S tRNA to assess rates of macrolide resistance markers. The study found that 50.8% of female participants and 42% of male participants harbored mutations indicating macrolide resistance.¹⁵

An in vitro study conducted in France showed that the respiratory fluoroquinolone moxifloxacin was highly active against mycoplasmas, including M. genitalium.⁶⁰ This study and others led to the use of moxifloxacin in treating infections caused by azithromycin-resistant M. genitalium. Moxifloxacin initially was successful in treating previous treatment failure cases.⁶¹ Unfortunately, the success has been short-lived, as researchers from Japan and Australia have reported moxifloxacin treament failures.^62-64 These treatment failures were related to mutations in the parC and gyrA genes.⁶²

Because M. genitalium exhibits significantly increased resistance to the tetracyclines, macrolides, and fluoroquinolones, leading to treatment failures associated with the resistance, the recently published CDC sexually transmitted diseases guidelines (2015) do not specifically recommend or endorse one class of antibiotics over another to treat M. genitalium infections; this contrasts with their approach for other infections in which they make specific recommendations for treatment.¹² The lack of clear recommendations from the CDC makes standardized treatment for this pathogen difficult. The CDC guidelines do identify M. genitalium as an emerging issue, and mention that a single 1-g dose of azithromycin should likely be recommended over doxycycline due to the low cure rate of 31% seen with doxycycline. Moxifloxacin is mentioned as a possible alternative, but it is noted that the medication has not been evaluated in clinical trials and several studies have shown failures.¹²

Although the existing antibiotics to treat M. genitalium infections are far from desirable, treatment approaches have been recommended:⁶⁵

• Azithromycin or doxycycline should be considered for empiric treatment without documented M. genitalium infection.
• Azithromycin is suggested as the first choice in documented M. genitalium infections.
• In patients with urethritis, azithromycin is recommended over doxycycline based on multiple studies. A single 1-g dose of azithromycin is preferred to an extended regimen due to increased compliance despite the extended regimen being slightly superior in effectiveness. The single-dose regimen is associated with selection of macrolide-resistant strains.⁶⁵
• Women with cervicitis and PID with documented M. genitalium infection should receive an azithromycin-containing regimen.

Although the existing antibiotics on the market could not keep up with the rapid mutations of M. genitalium, a few recent studies have provided a glimmer of hope to tackle this wily microorganism. Two recent studies from Japan demonstrated that sitafloxacin, a novel fluoroquinolone, administered 100 mg twice a day to patients with M. genitalium was superior to other older fluoroquinolones.^66,67 This fluoroquinolone could turn out to be a promising first-line antibiotic for treatment of STIs caused by M. genitalium. Bissessor and colleagues conducted a prospective cohort study of M. genitalium-infected male and female patients attending a STI clinic in Melbourne, Australia, and found that oral pristinamycin is highly effective in treating the M. genitalium strains that are resistant to azithromycin and moxifloxacin.⁶⁸ Jensen et al reported on the novel fluoroketolide solithromycin, which demonstrated superior in vitro activity against M. genitalium compared with doxycycline, fluoroquinolones, and other macrolides.⁶⁹ Solithromycin could potentially become a new antibiotic to treat infection caused by multi-drug resistant M. genitalium.

N. gonorrhoeae

Because of increasing resistance of N. gonorrhoeae to fluoroquinolones in the United States, the CDC recommended against their routine use for all cases of gonorrhea in August 2007.⁷⁰ In some countries, penicillin-, tetracycline-, and ciprofloxacin-resistance rates could be as high as 100%, and these antibacterial agents are no longer treatment options for gonorrhea. The WHO released new N. gonorrhoeae treatment guidelines in 2016 due to high-level of resistance to previously recommended fluoroquinolones and decreased susceptibility to the third-generation cephalosporins, which were a first-line recommendation in the 2003 guidelines.⁴⁵ The CDC’s currently recommended regimens for the treatment of uncomplicated and disseminated gonorrheal infections are summarized in Table 3 and Table 4.¹² Recommendations from the WHO guidelines are very similar to the CDC recommendations.⁴⁵

In light of the increasing resistance of N. gonorrhoeae to cephalosporins, 1 g of oral azithromycin should be added to ceftriaxone 250 mg intramuscularly in treating all cases of gonorrhea. The rationale for adding azithromycin to ceftriaxone is that azithromycin is active against N. gonorrhoeae at a different molecular target at a high dose, and it can also cover other co-pathogens.⁷¹ Unfortunately, susceptibility to cephalosporins has been decreasing rapidly.⁷² The greatest concern is the potential worldwide spread of the strain isolated in Kyoto, Japan, in 2009 from a patient with pharyngeal gonorrhea that was highly resistant to ceftriaxone (minimum inhibitory concentration of 2.0 to 4.0 µg/mL).⁷³ At this time, N. gonorrhoeae isolates that are highly resistant to ceftriaxone are still rare globally.

Although cefixime is listed as an alternative treatment if ceftriaxone is not available, the 2015 CDC gonorrhea treatment guidelines note that N. gonorrhoeae is becoming more resistant to this oral third-generation cephalosporin; this increasing resistance is due in part to the genetic exchange between N. gonorrhoeae and other oral commensals actively taking place in the oral cavity, creating more resistant species. Another possible reason for cefixime resistance is that the concentration of cefixime used in treating gonococcal pharyngeal infection is subtherapeutic.⁷⁴ A recent randomized multicenter trial in the United States compared 2 non-cephalosporin regimens: a single 240-mg dose of intramuscular gentamicin plus a single 2-g dose of oral azithromycin, and a single 320-mg dose of oral gemifloxacin plus a single 2-g dose of oral azithromycin. These combinations achieved 100% and 99.5% microbiological cure rates, respectively, in 401 patients with urogenital gonorrhea.⁷⁵ Thus, these combination regimens can be considered as alternatives when the N. gonorrhoeae is resistant to cephalosporins or the patient is intolerant or allergic to cephalosporins.

Because N. gonorrhoeae has evolved into a “superbug,” becoming resistant to all currently available antimicrobial agents, it is important to focus on developing new agents with unique mechanisms of action to treat N. gonorrhoeae–related infections. Zoliflodacin (ETX0914), a novel topoisomerase II inhibitor, has the potential to become an effective agent to treat multi-drug resistant N. gonorrhoeae. A recent phase 2 trial demonstrated that a single oral 2000-mg dose of zoliflodacin microbiologically cleared 98% of gonorrhea patients, and some of the trial participants were infected with ciprofloxacin- or azithromycin-resistant strains.⁷⁶ An additional phase 2 clinical trial compared oral zoliflodacin and intramuscular ceftriaxone. For uncomplicated urogential infections, 96% of patients in the zoliflodacin group achieved microbiologic cure versus 100% in the ceftriaxone group; however, zoliflodacin was less efficacious for pharyngeal infections.⁷⁷ Gepotidacin (GSK2140944) is another new antimicrobial agent in the pipeline that looks promising. It is a novel first-in-class triazaacenaphthylene that inhibits bacterial DNA replication. A recent phase 2 clinical trial demonstrated that 1.5-g and 3-g single oral doses eradicated urogenital N. gonorrhoeae with microbiological success rates of 97% and 95%, respectively.⁷⁸

Test of Cure

Because of the decreasing susceptibility of M. genitalium and N. gonorrhoeae to recommended treatment regimens, the European Guidelines consider test of cure essential in STIs caused by these 2 organisms to ensure eradication of infection and identify emerging resistance.⁷⁹ However, test of cure is not routinely recommended by the CDC for these organisms in asymptomatic patients.¹²

Sexual Risk-Reduction Counseling

Besides aggressive treatment with appropriate antimicrobial agents, it is also essential that patients and their partners receive counseling to reduce the risk of STI. A recently published systematic review demonstrated that high-intensity counseling could decrease STI incidents in adolescents and adults.⁸⁰

Conclusion

It is clear that these 2 sexually transmitted ”superbugs” are increasingly resistant to antibiotics and pose an increasing threat. Future epidemiological research and drug development studies need to be devoted to these 2 organisms, as well as to the potential development of a vaccine. This is especially important considering that antimicrobials may no longer be recommended when the prevalence of resistance to a particular antimicrobial reaches 5%, as is the case with WHO and other agencies that set the standard of ≥ 95% effectiveness for an antimicrobial to be considered as a recommended treatment.³² With current resistance rates for penicillin, ciprofloxacin, and tetracycline at close to 100% for N. gonorrhoeae in some countries,^30,79 it is important to remain cognizant about current and future treatment options.

Because screening methods for M. genitalium are not available in most countries and there is not an FDA-approved screening method in the United States, M. genitalium poses a significant challenge for clinicians treating urethritis, cervicitis, and PID. Thus, the development of an effective screening method and established screening guidelines for M. genitalium is urgently needed. Better surveillance, prudent use of available antibiotics, and development of novel compounds are necessary to eliminate the impending threat caused by M. genitalium and N. gonorrhoeae.

This article is the result of work supported with resources and the use of facilities at the Fargo VA Health Care System. The contents of this manuscript do not represent the views of the Department of Veterans Affairs or the United States Government.

Corresponding author: Tze Shien Lo, MD, Veterans Affairs Medical Center, 2101 Elm Street N, Fargo, ND 58102.

Financial disclosures: None.

From the Fargo Veterans Affairs Health Care System, Fargo, ND (Dr. Dietz, Dr. Hammer, Dr. Zegarra, and Dr. Lo), and the Queen Elizabeth Hospital, Hong Kong, China (Dr. Cho).

Abstract

• Objective: To review the management of patients with Mycoplasma genitalium and Neisseria gonorrhoeae infections.
• Methods: Review of the literature.
• Results: Mycoplasma genitalium and Neisseria gonorrhoeae are organisms that cause urethritis, cervicitis, and pelvic inflammatory disease. There is increasing antibiotic resistance to both organisms, which poses significant challenges to clinicians. Additionally, diagnostic tests for M. genitalium are not widely available, and commonly used tests for both organisms do not provide antibiotic sensitivity information. The increasing resistance of both M. genitalium and N. gonorrhoeae to currently used antimicrobial agents is alarming and warrants cautious monitoring.
• Conclusion: As the yield of new or effective antibiotic therapies has decreased over the past few years, increasing antibiotic resistance will lead to difficult treatment scenarios for sexually transmitted infections caused by these 2 organisms.

Keywords: Mycoplasma genitalium, Neisseria gonorrhoeae, antibiotic resistance, sexually transmitted infections, STIs.

The World Health Organization (WHO) estimates that more than 1 million cases of sexually transmitted Infections (STIs) are acquired every day worldwide,¹ and that the majority of STIs have few or no symptoms, making diagnosis difficult. Two organisms of interest are Mycoplasma genitalium and Neisseria gonorrhoeae. In contrast to Chlamydia trachomatis, which is rarely resistant to treatment regimens, M. genitalium and N. gonorrhoeae are becoming increasingly resistant to antibiotic treatment and pose an impending threat. These bacteria can cause urethritis, cervicitis, and pelvic inflammatory disease (PID). Whereas antibiotic resistance to M. genitalium is emerging, resistance to N. gonorrhea has been a continual problem for decades. Drug resistance, especially for N. gonorrhoeae, is listed as a major threat to efforts to reduce the impact of STIs worldwide.² In 2013, the U.S. Centers for Disease Control and Prevention (CDC) classified N. gonorrhoeae drug resistance as an urgent threat.³ As the yield of new or effective antibiotic therapies has decreased over the past few years, increasing antibiotic resistance will lead to challenging treatment scenarios for STIs caused by these 2 organisms.

Epidemiology and Pathogenesis

M. genitalium

M. genitalium is an emerging pathogen that is an etiologic agent of upper and lower genital tract STIs, such as urethritis, cervicitis, and PID.^4-13 In addition, it is thought to be involved in tubal infertility and acquisition of other sexually transmitted pathogens, including HIV.^7,8,13 The prevalence of M. genitalium in the general U.S. population in 2016 was reported to be approximately 17.2% for males and 16.1% for females.¹⁴ Infections are more common in patients aged 30 years and younger than in older populations.¹⁵ Also, patients self-identifying as black were found to have a higher prevalence of M. genitalium.¹⁴ This organism was first reported as being isolated from the urethras of 2 men with non-gonococcal urethritis (NGU) in London in 1980.^15,16 It is a significant cause of acute and chronic NGU in males, and is estimated to account for 6% to 50% of cases of NGU.^17,18M. genitalium in females has been associated with cervicitis^4,9 and PID.^8,10 A meta-analysis by Lis et al showed that M. genitalium infection was associated with an increased risk for preterm birth and spontaneous abortion.¹¹ In addition, M. genitalium infections occur frequently in HIV-positive patients.^19,20 M. genitalium increases susceptibility for passage of HIV across the epithelium by reducing epithelial barrier integrity.¹⁹

Beta lactams are ineffective against M. genitalium because mycoplasmas lack a cell wall and thus cell wall penicillin-binding proteins.²¹M. genitalium’s abilty to invade host epithelial cells is another mechanism that can protect the bacteria from antibiotic exposure.²⁰ One of the first reports of antibiotic sensitivity testing for M. genitalium, published in 1997, noted that the organism was not susceptible to nalidixic acid, cephalosporins, penicillins, and rifampicin.²² In general, mycoplasmas are normally susceptible to antibiotics that inhibit protein synthesis,²³ and initial good sensitivity to doxycycline and erythromycin was noted but this has since decreased. New antibiotics are on the horizon, but they have not been extensively tested in vivo.²³

N. gonorrhoeae

Gonorrhea is the second most common STI of bacterial origin following C. trachomatis,^24-26 which is rarely resistant to conventional regimens. In 2008, the World Health Organization (WHO) estimated that 106 million cases of N. gonorrhoeae infection were acquired annually and that 36.4 million adults were infected with N. gonorrhoeae.²⁷ In the United States, the CDC estimates that gonorrhea cases are under-reported. An estimated 800,000 or more new cases are reported per year.²⁸

The most common clinical presentations are urethritis in men and cervicitis in women.²⁹ While urethritis is most likely to be symptomatic, only 50% of women with acute gonorrhea are symptomatic.²⁹ In addition to lower urogenital tract infection, N. gonorrhoeae can also cause PID, ectopic pregnancy, infertility in women, and epididymitis in men.^29,30 Rare complications can develop from the spread of N. gonorrhoeae to other parts of the body including the joints, eyes, cardiovascular system, and skin.²⁹

N. gonorrhoeae can attach to the columnar epithelium and causes host innate immune-driven inflammation with neutrophil influx.²⁹ It can avoid the immune response by varying its outer membrane protein expression. The organism is also able to acquire DNA from other Neisseria species³⁰ and genera, which results in reduced susceptibility to therapies.

The Gonococcal Isolate Surveillance Project (GISP), established in 1986, is a collaborative project involving the CDC and STI clinics in 26 cities in the United States along with 5 regional laboratories.³¹ The GISP monitors susceptibilities in N. gonorrhoeae isolates obtained from roughly 6000 symptomatic men each year.³¹ Data collected from the GISP allows clinicians to treat infections with the correct antibiotic. Just as they observed patterns of fluoroquinolone-resistant N. gonorrhoeae, there has been a geographic progression of decreasing susceptibility to cephalosporins in recent years.³¹

The ease with which N. gonorrhoeae can develop resistance is particularly alarming. Sulfonamide use began in the 1930s, but resistance developed within approximately 10 years.^30,32N. gonorrhoeae has acquired resistance to each therapeutic agent used for treatment over the course of its lifetime. One hypothesis is that use of single-dose therapy to rapidly treat the infection has led to treatment failure and allows for selective pressure where organisms with decreased antibiotic susceptibility are more likely to survive.³⁰ However, there is limited evidence to support monotherapy versus combination therapy in treating N. gonorrhoeae.^33,34 It is no exaggeration to say gonorrhea is now at risk of becoming an untreatable disease because of the rapid emergence of multidrug resistant N. gonorrhoeae strains worldwide.³⁵

Diagnosis

Whether the urethritis, cervicitis, or PID is caused by N. gonorrhoeae, M. genitalium, or other non-gonococcal microorganisms (eg, C. trachomatis), no symptoms are specific to any of the microorganisms. Therefore, clinicians rely on laboratory tests to diagnose STIs caused by N. gonorrhoeae or M. genitalium.

M. genitalium

Gram Stain. Because M. genitalium lacks a cell wall, it cannot be identified by routine Gram stain.

Culture. Culturing of this fastidious bacterium might offer the advantage of assessing antibiotic susceptibility;³⁶ however, the procedure is labor intensive and time consuming, and only a few labs in the world have the capability to perform this culture.¹² Thus, this testing method is primarily undertaken for research purposes.

Serological Testing. Because of serologic cross-reactions between Mycoplasma pneumoniae and M. genitalium, there are no standardized serological tests for M. genitalium.³⁷

Nucleic Acid Amplification Tests. M. genitalium diagnosis currently is made based exclusively on nucleic acid amplification testing (NAAT) methodology (polymerase chain reaction [PCR] or transcription-mediated amplification [TMA]), which is the only clinically useful method to detect M. genitalium. TMA for M. genitalium is commercially available in an analyte-specific reagent (ASR) format, but this has not been approved by the Food and Drug Administration (FDA).³⁸ A study analyzing urogenital specimens from female patients via this TMA product found a 98.7% true-positive result when confirmed with repeat testing or alternative-target TMA, and only a 0.5% false-negative rate.³⁸ There is evidence that this TMA product can be used to identify M. genitalium in urine, stool, and pharyngeal samples.³⁹ These assays are currently available in some reference labs and large medical centers but are not widely available. Table 1 summarizes the diagnostic methods for M. genitalium.

N. gonorrhoeae

Gonococcal infection can involve the urogenital tract, but can also be extra-urogenital. The method of diagnoses of urogenital infections has expanded from Gram stain of urethral or cervical discharge and the use of selective media culture (usually Thayer-Martin media)⁴⁰ to molecular methods such as NAATs, which have a higher sensitivity than cultures.^41,42

Gram Stain. A Gram stain that shows polymorphonuclear leukocytes with intracellular gram-negative diplococci can be considered diagnostic for N. gonorrhoeae urethritis infection in symptomatic men when samples are obtained from the urethra.⁴³ A retrospective study of 1148 women with gonorrhea revealed that of 1049 cases of cervical gonorrhea, only 6.4% were positive by smear alone; and of 841 cases of urethral gonorrhea, only 5.1% were positive by smear alone; therefore, other diagnostic methods are generally preferred in women.⁴⁴ Because Gram stain of vaginal specimens is positive in only 50% to 60% of females, its use in women and in suspected extragenital gonococcal infections is not recommended.^43-45 When Gram stain was performed in asymptomatic men, the sensitivity was around 80%.³⁹ Thus, in asymptomatic men with a high pre-test probability of having the infection, the use of other additional testing would increase the rate of detection.⁴³

Culture. Urethral swab specimens from males with symptomatic urethritis and cervical swab samples from females with endocervical infection must be inoculated onto both a selective medium (eg, modified Thayer-Martin medium or Martin Lewis medium) and a nonselective medium (eg, chocolate agar). A selective medium is used because it can suppress the growth of contaminating organisms, and a nonselective medium is used because some strains of N. gonorrhoeae are inhibited by the vancomycin present in the selective medium.⁴⁰ Specimens collected from sterile sites, such as blood, synovial fluid, and cerebrospinal fluid, should be streaked on nonselective medium such as chocolate agar. The material used for collection is critical; the preferred swabs should have plastic or wire shafts and rayon, Dacron, or calcium alginate tips. Materials such as wooden shafts or cotton tips can be toxic to N. gonorrhoeae.⁴⁰ The specimen should be inoculated immediately onto the appropriate medium and transported rapidly to the laboratory, where it should be incubated at 35º to 37ºC with 5% CO₂ and examined at 24 and 48 hours post collection.⁴⁰ If the specimens cannot be inoculated immediately onto the appropriate medium, the specimen swab should be delivered to the lab in a special transport system that can keep the N. gonorrhoeae viable for up to 48 hours at room temperature.⁴⁶

The following specimen collection techniques are recommended by the CDC:⁴⁰

• In males, the cotton swab should be inserted about 2 to 3 cm into the urethral meatus and rotated 360° degrees 2 or 3 times.
• In females, collection of cervical specimens requires inserting the tip of the swab 1 to 2 centimeters into the cervical os and rotating 360° 2 or 3 times.
• Samples obtained outside of the urogenital tract: rectal specimens may be obtained by inserting the swab 3 to 4 cm into the rectal vault. Pharyngeal specimens are to be obtained from the posterior pharynx with a swab.

Culture tests allow the clinician to assess antimicrobial susceptibility and are relatively low cost when compared with nucleic acid detection tests. The sensitivity of culture ranges from 72% to 95% for symptomatic patients, but drops to 65% to 85% for asymptomatic patients.^45-47 This low sensitivity is a major disadvantage of culture tests when compared to NAATs. Other disadvantages are the need for the specimens to be transported under conditions adequate to maintain the viability of organisms and the fact that 24 to 72 hours is required to report presumptive culture results.⁴² Antimicrobial sensitivity testing generally is not recommended; however, it is advisable to perform antimicrobial sensitivity in cases of treatment failure or disseminated gonococcal infection.¹²

Nucleic Acid Amplification Tests. NAATs use techniques that allow the amplification and detection of N. gonorrhoeae DNA or RNA sequences through various methods, which include assays such as PCR (eg, Amplicor; Roche, Nutley, NJ), TMA (eg, APTIMA; Gen-Probe, San Diego, CA), and strand-displacement amplification (SDA; Probe-Tec; Becton Dickinson, Franklin Lake, NJ). While PCR and SDA methods amplify bacterial DNA, TMA amplifies bacterial rRNA.⁴¹

The FDA has cleared NAATs to test endocervical, vaginal, and urethral (men) swab specimens and urine for both men and women. There are several NAATs available to test rectal, oropharyngeal, and conjunctival specimens; however, none of them are FDA-cleared. Some local and commercial laboratories have validated the reliability of these extra-urogenital NAATs.^12,48 Compared to cultures, NAATs have the advantages of being more sensitive and requiring less strict collection and transport conditions. However, they are costlier than cultures, do not provide any antimicrobial susceptibility information, and have varying specificity.^49,50

Rapid Tests. NAAT results are usually available in approximately 1 to 2 days, so there has been significant interest in creating technologies that would allow for a more rapid turnaround time. The GeneXpert CT/NG is a newly developed real-time PCR-based assay that can simultaneously detect C. trachomatis and N. gonorrhoeae. The advantage of this technique is the 90-minute turnaround time and its ability to process more than 90 samples at a time. The specificity of this test for N. gonorrhoeae is similar to that of other NAATs (> 99.3%), suggesting that cross-reactivity is not a significant problem.⁵¹ Table 2 summarizes the test methods used for diagnosing N. gonorrhoeae.

Treatment

M. genitalium

M. genitalium, Mycoplasma hominis, and the ureaplasmas (U. urealyticum and U. parvum) are generally transmitted sexually, and the natural habitat of this Mycoplasmataceae family of bacteria is the genitourinary tract. All the mycoplasmas can cause NGU, cervicitis, and PID. Presently, multiple-drug resistant M. hominis and ureaplasmas remain uncommon, but the prevalence of M. genitalium resistant to multiple antibiotics has increased significantly in recent years.^23,52

In the 1990s, M. genitalium was highly sensitive to the tetracyclines in vitro,⁵³ and doxycycline was the drug of choice for treating NGU. However, it later became apparent that doxycycline was largely ineffective in treating urethritis caused by M. genitalium.^54,55

Subsequently, azithromycin, a macrolide, became popular in treating urethritis in males and cervicitis in females because it was highly active against C. trachomatis⁵⁴ and M. genitalium⁵⁶ and it can be given orally as a single 1-g dose, thus increasing patients’ compliance. However, azithromycin-resistant M. genitalium has rapidly emerged and rates of treatment failure with azithromycin as high as 40% have been reported in recent studies.^57,58 The resistance was found to be mediated by mutations in the 23S rRNA gene upon exposure of M. genitalium to azithromycin.^15,57-59 Multiple studies conducted in various countries (including the United States, Netherlands, England, and France) all found high rates of 23S rRNA gene mutations.^15,57-59M. genitalium samples were analyzed using reverse transcription-PCR and Sanger sequencing of the 23S tRNA to assess rates of macrolide resistance markers. The study found that 50.8% of female participants and 42% of male participants harbored mutations indicating macrolide resistance.¹⁵

An in vitro study conducted in France showed that the respiratory fluoroquinolone moxifloxacin was highly active against mycoplasmas, including M. genitalium.⁶⁰ This study and others led to the use of moxifloxacin in treating infections caused by azithromycin-resistant M. genitalium. Moxifloxacin initially was successful in treating previous treatment failure cases.⁶¹ Unfortunately, the success has been short-lived, as researchers from Japan and Australia have reported moxifloxacin treament failures.^62-64 These treatment failures were related to mutations in the parC and gyrA genes.⁶²

Because M. genitalium exhibits significantly increased resistance to the tetracyclines, macrolides, and fluoroquinolones, leading to treatment failures associated with the resistance, the recently published CDC sexually transmitted diseases guidelines (2015) do not specifically recommend or endorse one class of antibiotics over another to treat M. genitalium infections; this contrasts with their approach for other infections in which they make specific recommendations for treatment.¹² The lack of clear recommendations from the CDC makes standardized treatment for this pathogen difficult. The CDC guidelines do identify M. genitalium as an emerging issue, and mention that a single 1-g dose of azithromycin should likely be recommended over doxycycline due to the low cure rate of 31% seen with doxycycline. Moxifloxacin is mentioned as a possible alternative, but it is noted that the medication has not been evaluated in clinical trials and several studies have shown failures.¹²

Although the existing antibiotics to treat M. genitalium infections are far from desirable, treatment approaches have been recommended:⁶⁵

• Azithromycin or doxycycline should be considered for empiric treatment without documented M. genitalium infection.
• Azithromycin is suggested as the first choice in documented M. genitalium infections.
• In patients with urethritis, azithromycin is recommended over doxycycline based on multiple studies. A single 1-g dose of azithromycin is preferred to an extended regimen due to increased compliance despite the extended regimen being slightly superior in effectiveness. The single-dose regimen is associated with selection of macrolide-resistant strains.⁶⁵
• Women with cervicitis and PID with documented M. genitalium infection should receive an azithromycin-containing regimen.

Although the existing antibiotics on the market could not keep up with the rapid mutations of M. genitalium, a few recent studies have provided a glimmer of hope to tackle this wily microorganism. Two recent studies from Japan demonstrated that sitafloxacin, a novel fluoroquinolone, administered 100 mg twice a day to patients with M. genitalium was superior to other older fluoroquinolones.^66,67 This fluoroquinolone could turn out to be a promising first-line antibiotic for treatment of STIs caused by M. genitalium. Bissessor and colleagues conducted a prospective cohort study of M. genitalium-infected male and female patients attending a STI clinic in Melbourne, Australia, and found that oral pristinamycin is highly effective in treating the M. genitalium strains that are resistant to azithromycin and moxifloxacin.⁶⁸ Jensen et al reported on the novel fluoroketolide solithromycin, which demonstrated superior in vitro activity against M. genitalium compared with doxycycline, fluoroquinolones, and other macrolides.⁶⁹ Solithromycin could potentially become a new antibiotic to treat infection caused by multi-drug resistant M. genitalium.

N. gonorrhoeae

Because of increasing resistance of N. gonorrhoeae to fluoroquinolones in the United States, the CDC recommended against their routine use for all cases of gonorrhea in August 2007.⁷⁰ In some countries, penicillin-, tetracycline-, and ciprofloxacin-resistance rates could be as high as 100%, and these antibacterial agents are no longer treatment options for gonorrhea. The WHO released new N. gonorrhoeae treatment guidelines in 2016 due to high-level of resistance to previously recommended fluoroquinolones and decreased susceptibility to the third-generation cephalosporins, which were a first-line recommendation in the 2003 guidelines.⁴⁵ The CDC’s currently recommended regimens for the treatment of uncomplicated and disseminated gonorrheal infections are summarized in Table 3 and Table 4.¹² Recommendations from the WHO guidelines are very similar to the CDC recommendations.⁴⁵

In light of the increasing resistance of N. gonorrhoeae to cephalosporins, 1 g of oral azithromycin should be added to ceftriaxone 250 mg intramuscularly in treating all cases of gonorrhea. The rationale for adding azithromycin to ceftriaxone is that azithromycin is active against N. gonorrhoeae at a different molecular target at a high dose, and it can also cover other co-pathogens.⁷¹ Unfortunately, susceptibility to cephalosporins has been decreasing rapidly.⁷² The greatest concern is the potential worldwide spread of the strain isolated in Kyoto, Japan, in 2009 from a patient with pharyngeal gonorrhea that was highly resistant to ceftriaxone (minimum inhibitory concentration of 2.0 to 4.0 µg/mL).⁷³ At this time, N. gonorrhoeae isolates that are highly resistant to ceftriaxone are still rare globally.

Although cefixime is listed as an alternative treatment if ceftriaxone is not available, the 2015 CDC gonorrhea treatment guidelines note that N. gonorrhoeae is becoming more resistant to this oral third-generation cephalosporin; this increasing resistance is due in part to the genetic exchange between N. gonorrhoeae and other oral commensals actively taking place in the oral cavity, creating more resistant species. Another possible reason for cefixime resistance is that the concentration of cefixime used in treating gonococcal pharyngeal infection is subtherapeutic.⁷⁴ A recent randomized multicenter trial in the United States compared 2 non-cephalosporin regimens: a single 240-mg dose of intramuscular gentamicin plus a single 2-g dose of oral azithromycin, and a single 320-mg dose of oral gemifloxacin plus a single 2-g dose of oral azithromycin. These combinations achieved 100% and 99.5% microbiological cure rates, respectively, in 401 patients with urogenital gonorrhea.⁷⁵ Thus, these combination regimens can be considered as alternatives when the N. gonorrhoeae is resistant to cephalosporins or the patient is intolerant or allergic to cephalosporins.

Because N. gonorrhoeae has evolved into a “superbug,” becoming resistant to all currently available antimicrobial agents, it is important to focus on developing new agents with unique mechanisms of action to treat N. gonorrhoeae–related infections. Zoliflodacin (ETX0914), a novel topoisomerase II inhibitor, has the potential to become an effective agent to treat multi-drug resistant N. gonorrhoeae. A recent phase 2 trial demonstrated that a single oral 2000-mg dose of zoliflodacin microbiologically cleared 98% of gonorrhea patients, and some of the trial participants were infected with ciprofloxacin- or azithromycin-resistant strains.⁷⁶ An additional phase 2 clinical trial compared oral zoliflodacin and intramuscular ceftriaxone. For uncomplicated urogential infections, 96% of patients in the zoliflodacin group achieved microbiologic cure versus 100% in the ceftriaxone group; however, zoliflodacin was less efficacious for pharyngeal infections.⁷⁷ Gepotidacin (GSK2140944) is another new antimicrobial agent in the pipeline that looks promising. It is a novel first-in-class triazaacenaphthylene that inhibits bacterial DNA replication. A recent phase 2 clinical trial demonstrated that 1.5-g and 3-g single oral doses eradicated urogenital N. gonorrhoeae with microbiological success rates of 97% and 95%, respectively.⁷⁸

Test of Cure

Because of the decreasing susceptibility of M. genitalium and N. gonorrhoeae to recommended treatment regimens, the European Guidelines consider test of cure essential in STIs caused by these 2 organisms to ensure eradication of infection and identify emerging resistance.⁷⁹ However, test of cure is not routinely recommended by the CDC for these organisms in asymptomatic patients.¹²

Sexual Risk-Reduction Counseling

Besides aggressive treatment with appropriate antimicrobial agents, it is also essential that patients and their partners receive counseling to reduce the risk of STI. A recently published systematic review demonstrated that high-intensity counseling could decrease STI incidents in adolescents and adults.⁸⁰

Conclusion

It is clear that these 2 sexually transmitted ”superbugs” are increasingly resistant to antibiotics and pose an increasing threat. Future epidemiological research and drug development studies need to be devoted to these 2 organisms, as well as to the potential development of a vaccine. This is especially important considering that antimicrobials may no longer be recommended when the prevalence of resistance to a particular antimicrobial reaches 5%, as is the case with WHO and other agencies that set the standard of ≥ 95% effectiveness for an antimicrobial to be considered as a recommended treatment.³² With current resistance rates for penicillin, ciprofloxacin, and tetracycline at close to 100% for N. gonorrhoeae in some countries,^30,79 it is important to remain cognizant about current and future treatment options.

Because screening methods for M. genitalium are not available in most countries and there is not an FDA-approved screening method in the United States, M. genitalium poses a significant challenge for clinicians treating urethritis, cervicitis, and PID. Thus, the development of an effective screening method and established screening guidelines for M. genitalium is urgently needed. Better surveillance, prudent use of available antibiotics, and development of novel compounds are necessary to eliminate the impending threat caused by M. genitalium and N. gonorrhoeae.

This article is the result of work supported with resources and the use of facilities at the Fargo VA Health Care System. The contents of this manuscript do not represent the views of the Department of Veterans Affairs or the United States Government.

Corresponding author: Tze Shien Lo, MD, Veterans Affairs Medical Center, 2101 Elm Street N, Fargo, ND 58102.

Financial disclosures: None.

From the Fargo Veterans Affairs Health Care System, Fargo, ND (Dr. Dietz, Dr. Hammer, Dr. Zegarra, and Dr. Lo), and the Queen Elizabeth Hospital, Hong Kong, China (Dr. Cho).

Abstract

• Objective: To review the management of patients with Mycoplasma genitalium and Neisseria gonorrhoeae infections.
• Methods: Review of the literature.
• Results: Mycoplasma genitalium and Neisseria gonorrhoeae are organisms that cause urethritis, cervicitis, and pelvic inflammatory disease. There is increasing antibiotic resistance to both organisms, which poses significant challenges to clinicians. Additionally, diagnostic tests for M. genitalium are not widely available, and commonly used tests for both organisms do not provide antibiotic sensitivity information. The increasing resistance of both M. genitalium and N. gonorrhoeae to currently used antimicrobial agents is alarming and warrants cautious monitoring.
• Conclusion: As the yield of new or effective antibiotic therapies has decreased over the past few years, increasing antibiotic resistance will lead to difficult treatment scenarios for sexually transmitted infections caused by these 2 organisms.

Keywords: Mycoplasma genitalium, Neisseria gonorrhoeae, antibiotic resistance, sexually transmitted infections, STIs.

The World Health Organization (WHO) estimates that more than 1 million cases of sexually transmitted Infections (STIs) are acquired every day worldwide,¹ and that the majority of STIs have few or no symptoms, making diagnosis difficult. Two organisms of interest are Mycoplasma genitalium and Neisseria gonorrhoeae. In contrast to Chlamydia trachomatis, which is rarely resistant to treatment regimens, M. genitalium and N. gonorrhoeae are becoming increasingly resistant to antibiotic treatment and pose an impending threat. These bacteria can cause urethritis, cervicitis, and pelvic inflammatory disease (PID). Whereas antibiotic resistance to M. genitalium is emerging, resistance to N. gonorrhea has been a continual problem for decades. Drug resistance, especially for N. gonorrhoeae, is listed as a major threat to efforts to reduce the impact of STIs worldwide.² In 2013, the U.S. Centers for Disease Control and Prevention (CDC) classified N. gonorrhoeae drug resistance as an urgent threat.³ As the yield of new or effective antibiotic therapies has decreased over the past few years, increasing antibiotic resistance will lead to challenging treatment scenarios for STIs caused by these 2 organisms.

Epidemiology and Pathogenesis

M. genitalium

M. genitalium is an emerging pathogen that is an etiologic agent of upper and lower genital tract STIs, such as urethritis, cervicitis, and PID.^4-13 In addition, it is thought to be involved in tubal infertility and acquisition of other sexually transmitted pathogens, including HIV.^7,8,13 The prevalence of M. genitalium in the general U.S. population in 2016 was reported to be approximately 17.2% for males and 16.1% for females.¹⁴ Infections are more common in patients aged 30 years and younger than in older populations.¹⁵ Also, patients self-identifying as black were found to have a higher prevalence of M. genitalium.¹⁴ This organism was first reported as being isolated from the urethras of 2 men with non-gonococcal urethritis (NGU) in London in 1980.^15,16 It is a significant cause of acute and chronic NGU in males, and is estimated to account for 6% to 50% of cases of NGU.^17,18M. genitalium in females has been associated with cervicitis^4,9 and PID.^8,10 A meta-analysis by Lis et al showed that M. genitalium infection was associated with an increased risk for preterm birth and spontaneous abortion.¹¹ In addition, M. genitalium infections occur frequently in HIV-positive patients.^19,20 M. genitalium increases susceptibility for passage of HIV across the epithelium by reducing epithelial barrier integrity.¹⁹

Beta lactams are ineffective against M. genitalium because mycoplasmas lack a cell wall and thus cell wall penicillin-binding proteins.²¹M. genitalium’s abilty to invade host epithelial cells is another mechanism that can protect the bacteria from antibiotic exposure.²⁰ One of the first reports of antibiotic sensitivity testing for M. genitalium, published in 1997, noted that the organism was not susceptible to nalidixic acid, cephalosporins, penicillins, and rifampicin.²² In general, mycoplasmas are normally susceptible to antibiotics that inhibit protein synthesis,²³ and initial good sensitivity to doxycycline and erythromycin was noted but this has since decreased. New antibiotics are on the horizon, but they have not been extensively tested in vivo.²³

N. gonorrhoeae

Gonorrhea is the second most common STI of bacterial origin following C. trachomatis,^24-26 which is rarely resistant to conventional regimens. In 2008, the World Health Organization (WHO) estimated that 106 million cases of N. gonorrhoeae infection were acquired annually and that 36.4 million adults were infected with N. gonorrhoeae.²⁷ In the United States, the CDC estimates that gonorrhea cases are under-reported. An estimated 800,000 or more new cases are reported per year.²⁸

The most common clinical presentations are urethritis in men and cervicitis in women.²⁹ While urethritis is most likely to be symptomatic, only 50% of women with acute gonorrhea are symptomatic.²⁹ In addition to lower urogenital tract infection, N. gonorrhoeae can also cause PID, ectopic pregnancy, infertility in women, and epididymitis in men.^29,30 Rare complications can develop from the spread of N. gonorrhoeae to other parts of the body including the joints, eyes, cardiovascular system, and skin.²⁹

N. gonorrhoeae can attach to the columnar epithelium and causes host innate immune-driven inflammation with neutrophil influx.²⁹ It can avoid the immune response by varying its outer membrane protein expression. The organism is also able to acquire DNA from other Neisseria species³⁰ and genera, which results in reduced susceptibility to therapies.

The Gonococcal Isolate Surveillance Project (GISP), established in 1986, is a collaborative project involving the CDC and STI clinics in 26 cities in the United States along with 5 regional laboratories.³¹ The GISP monitors susceptibilities in N. gonorrhoeae isolates obtained from roughly 6000 symptomatic men each year.³¹ Data collected from the GISP allows clinicians to treat infections with the correct antibiotic. Just as they observed patterns of fluoroquinolone-resistant N. gonorrhoeae, there has been a geographic progression of decreasing susceptibility to cephalosporins in recent years.³¹

The ease with which N. gonorrhoeae can develop resistance is particularly alarming. Sulfonamide use began in the 1930s, but resistance developed within approximately 10 years.^30,32N. gonorrhoeae has acquired resistance to each therapeutic agent used for treatment over the course of its lifetime. One hypothesis is that use of single-dose therapy to rapidly treat the infection has led to treatment failure and allows for selective pressure where organisms with decreased antibiotic susceptibility are more likely to survive.³⁰ However, there is limited evidence to support monotherapy versus combination therapy in treating N. gonorrhoeae.^33,34 It is no exaggeration to say gonorrhea is now at risk of becoming an untreatable disease because of the rapid emergence of multidrug resistant N. gonorrhoeae strains worldwide.³⁵

Diagnosis

Whether the urethritis, cervicitis, or PID is caused by N. gonorrhoeae, M. genitalium, or other non-gonococcal microorganisms (eg, C. trachomatis), no symptoms are specific to any of the microorganisms. Therefore, clinicians rely on laboratory tests to diagnose STIs caused by N. gonorrhoeae or M. genitalium.

M. genitalium

Gram Stain. Because M. genitalium lacks a cell wall, it cannot be identified by routine Gram stain.

Culture. Culturing of this fastidious bacterium might offer the advantage of assessing antibiotic susceptibility;³⁶ however, the procedure is labor intensive and time consuming, and only a few labs in the world have the capability to perform this culture.¹² Thus, this testing method is primarily undertaken for research purposes.

Serological Testing. Because of serologic cross-reactions between Mycoplasma pneumoniae and M. genitalium, there are no standardized serological tests for M. genitalium.³⁷

Nucleic Acid Amplification Tests. M. genitalium diagnosis currently is made based exclusively on nucleic acid amplification testing (NAAT) methodology (polymerase chain reaction [PCR] or transcription-mediated amplification [TMA]), which is the only clinically useful method to detect M. genitalium. TMA for M. genitalium is commercially available in an analyte-specific reagent (ASR) format, but this has not been approved by the Food and Drug Administration (FDA).³⁸ A study analyzing urogenital specimens from female patients via this TMA product found a 98.7% true-positive result when confirmed with repeat testing or alternative-target TMA, and only a 0.5% false-negative rate.³⁸ There is evidence that this TMA product can be used to identify M. genitalium in urine, stool, and pharyngeal samples.³⁹ These assays are currently available in some reference labs and large medical centers but are not widely available. Table 1 summarizes the diagnostic methods for M. genitalium.

N. gonorrhoeae

Gonococcal infection can involve the urogenital tract, but can also be extra-urogenital. The method of diagnoses of urogenital infections has expanded from Gram stain of urethral or cervical discharge and the use of selective media culture (usually Thayer-Martin media)⁴⁰ to molecular methods such as NAATs, which have a higher sensitivity than cultures.^41,42

Gram Stain. A Gram stain that shows polymorphonuclear leukocytes with intracellular gram-negative diplococci can be considered diagnostic for N. gonorrhoeae urethritis infection in symptomatic men when samples are obtained from the urethra.⁴³ A retrospective study of 1148 women with gonorrhea revealed that of 1049 cases of cervical gonorrhea, only 6.4% were positive by smear alone; and of 841 cases of urethral gonorrhea, only 5.1% were positive by smear alone; therefore, other diagnostic methods are generally preferred in women.⁴⁴ Because Gram stain of vaginal specimens is positive in only 50% to 60% of females, its use in women and in suspected extragenital gonococcal infections is not recommended.^43-45 When Gram stain was performed in asymptomatic men, the sensitivity was around 80%.³⁹ Thus, in asymptomatic men with a high pre-test probability of having the infection, the use of other additional testing would increase the rate of detection.⁴³

Culture. Urethral swab specimens from males with symptomatic urethritis and cervical swab samples from females with endocervical infection must be inoculated onto both a selective medium (eg, modified Thayer-Martin medium or Martin Lewis medium) and a nonselective medium (eg, chocolate agar). A selective medium is used because it can suppress the growth of contaminating organisms, and a nonselective medium is used because some strains of N. gonorrhoeae are inhibited by the vancomycin present in the selective medium.⁴⁰ Specimens collected from sterile sites, such as blood, synovial fluid, and cerebrospinal fluid, should be streaked on nonselective medium such as chocolate agar. The material used for collection is critical; the preferred swabs should have plastic or wire shafts and rayon, Dacron, or calcium alginate tips. Materials such as wooden shafts or cotton tips can be toxic to N. gonorrhoeae.⁴⁰ The specimen should be inoculated immediately onto the appropriate medium and transported rapidly to the laboratory, where it should be incubated at 35º to 37ºC with 5% CO₂ and examined at 24 and 48 hours post collection.⁴⁰ If the specimens cannot be inoculated immediately onto the appropriate medium, the specimen swab should be delivered to the lab in a special transport system that can keep the N. gonorrhoeae viable for up to 48 hours at room temperature.⁴⁶

The following specimen collection techniques are recommended by the CDC:⁴⁰

• In males, the cotton swab should be inserted about 2 to 3 cm into the urethral meatus and rotated 360° degrees 2 or 3 times.
• In females, collection of cervical specimens requires inserting the tip of the swab 1 to 2 centimeters into the cervical os and rotating 360° 2 or 3 times.
• Samples obtained outside of the urogenital tract: rectal specimens may be obtained by inserting the swab 3 to 4 cm into the rectal vault. Pharyngeal specimens are to be obtained from the posterior pharynx with a swab.

Culture tests allow the clinician to assess antimicrobial susceptibility and are relatively low cost when compared with nucleic acid detection tests. The sensitivity of culture ranges from 72% to 95% for symptomatic patients, but drops to 65% to 85% for asymptomatic patients.^45-47 This low sensitivity is a major disadvantage of culture tests when compared to NAATs. Other disadvantages are the need for the specimens to be transported under conditions adequate to maintain the viability of organisms and the fact that 24 to 72 hours is required to report presumptive culture results.⁴² Antimicrobial sensitivity testing generally is not recommended; however, it is advisable to perform antimicrobial sensitivity in cases of treatment failure or disseminated gonococcal infection.¹²

Nucleic Acid Amplification Tests. NAATs use techniques that allow the amplification and detection of N. gonorrhoeae DNA or RNA sequences through various methods, which include assays such as PCR (eg, Amplicor; Roche, Nutley, NJ), TMA (eg, APTIMA; Gen-Probe, San Diego, CA), and strand-displacement amplification (SDA; Probe-Tec; Becton Dickinson, Franklin Lake, NJ). While PCR and SDA methods amplify bacterial DNA, TMA amplifies bacterial rRNA.⁴¹

The FDA has cleared NAATs to test endocervical, vaginal, and urethral (men) swab specimens and urine for both men and women. There are several NAATs available to test rectal, oropharyngeal, and conjunctival specimens; however, none of them are FDA-cleared. Some local and commercial laboratories have validated the reliability of these extra-urogenital NAATs.^12,48 Compared to cultures, NAATs have the advantages of being more sensitive and requiring less strict collection and transport conditions. However, they are costlier than cultures, do not provide any antimicrobial susceptibility information, and have varying specificity.^49,50

Rapid Tests. NAAT results are usually available in approximately 1 to 2 days, so there has been significant interest in creating technologies that would allow for a more rapid turnaround time. The GeneXpert CT/NG is a newly developed real-time PCR-based assay that can simultaneously detect C. trachomatis and N. gonorrhoeae. The advantage of this technique is the 90-minute turnaround time and its ability to process more than 90 samples at a time. The specificity of this test for N. gonorrhoeae is similar to that of other NAATs (> 99.3%), suggesting that cross-reactivity is not a significant problem.⁵¹ Table 2 summarizes the test methods used for diagnosing N. gonorrhoeae.

Treatment

M. genitalium

M. genitalium, Mycoplasma hominis, and the ureaplasmas (U. urealyticum and U. parvum) are generally transmitted sexually, and the natural habitat of this Mycoplasmataceae family of bacteria is the genitourinary tract. All the mycoplasmas can cause NGU, cervicitis, and PID. Presently, multiple-drug resistant M. hominis and ureaplasmas remain uncommon, but the prevalence of M. genitalium resistant to multiple antibiotics has increased significantly in recent years.^23,52

In the 1990s, M. genitalium was highly sensitive to the tetracyclines in vitro,⁵³ and doxycycline was the drug of choice for treating NGU. However, it later became apparent that doxycycline was largely ineffective in treating urethritis caused by M. genitalium.^54,55

Subsequently, azithromycin, a macrolide, became popular in treating urethritis in males and cervicitis in females because it was highly active against C. trachomatis⁵⁴ and M. genitalium⁵⁶ and it can be given orally as a single 1-g dose, thus increasing patients’ compliance. However, azithromycin-resistant M. genitalium has rapidly emerged and rates of treatment failure with azithromycin as high as 40% have been reported in recent studies.^57,58 The resistance was found to be mediated by mutations in the 23S rRNA gene upon exposure of M. genitalium to azithromycin.^15,57-59 Multiple studies conducted in various countries (including the United States, Netherlands, England, and France) all found high rates of 23S rRNA gene mutations.^15,57-59M. genitalium samples were analyzed using reverse transcription-PCR and Sanger sequencing of the 23S tRNA to assess rates of macrolide resistance markers. The study found that 50.8% of female participants and 42% of male participants harbored mutations indicating macrolide resistance.¹⁵

An in vitro study conducted in France showed that the respiratory fluoroquinolone moxifloxacin was highly active against mycoplasmas, including M. genitalium.⁶⁰ This study and others led to the use of moxifloxacin in treating infections caused by azithromycin-resistant M. genitalium. Moxifloxacin initially was successful in treating previous treatment failure cases.⁶¹ Unfortunately, the success has been short-lived, as researchers from Japan and Australia have reported moxifloxacin treament failures.^62-64 These treatment failures were related to mutations in the parC and gyrA genes.⁶²

Because M. genitalium exhibits significantly increased resistance to the tetracyclines, macrolides, and fluoroquinolones, leading to treatment failures associated with the resistance, the recently published CDC sexually transmitted diseases guidelines (2015) do not specifically recommend or endorse one class of antibiotics over another to treat M. genitalium infections; this contrasts with their approach for other infections in which they make specific recommendations for treatment.¹² The lack of clear recommendations from the CDC makes standardized treatment for this pathogen difficult. The CDC guidelines do identify M. genitalium as an emerging issue, and mention that a single 1-g dose of azithromycin should likely be recommended over doxycycline due to the low cure rate of 31% seen with doxycycline. Moxifloxacin is mentioned as a possible alternative, but it is noted that the medication has not been evaluated in clinical trials and several studies have shown failures.¹²

Although the existing antibiotics to treat M. genitalium infections are far from desirable, treatment approaches have been recommended:⁶⁵

• Azithromycin or doxycycline should be considered for empiric treatment without documented M. genitalium infection.
• Azithromycin is suggested as the first choice in documented M. genitalium infections.
• In patients with urethritis, azithromycin is recommended over doxycycline based on multiple studies. A single 1-g dose of azithromycin is preferred to an extended regimen due to increased compliance despite the extended regimen being slightly superior in effectiveness. The single-dose regimen is associated with selection of macrolide-resistant strains.⁶⁵
• Women with cervicitis and PID with documented M. genitalium infection should receive an azithromycin-containing regimen.

Although the existing antibiotics on the market could not keep up with the rapid mutations of M. genitalium, a few recent studies have provided a glimmer of hope to tackle this wily microorganism. Two recent studies from Japan demonstrated that sitafloxacin, a novel fluoroquinolone, administered 100 mg twice a day to patients with M. genitalium was superior to other older fluoroquinolones.^66,67 This fluoroquinolone could turn out to be a promising first-line antibiotic for treatment of STIs caused by M. genitalium. Bissessor and colleagues conducted a prospective cohort study of M. genitalium-infected male and female patients attending a STI clinic in Melbourne, Australia, and found that oral pristinamycin is highly effective in treating the M. genitalium strains that are resistant to azithromycin and moxifloxacin.⁶⁸ Jensen et al reported on the novel fluoroketolide solithromycin, which demonstrated superior in vitro activity against M. genitalium compared with doxycycline, fluoroquinolones, and other macrolides.⁶⁹ Solithromycin could potentially become a new antibiotic to treat infection caused by multi-drug resistant M. genitalium.

N. gonorrhoeae

Because of increasing resistance of N. gonorrhoeae to fluoroquinolones in the United States, the CDC recommended against their routine use for all cases of gonorrhea in August 2007.⁷⁰ In some countries, penicillin-, tetracycline-, and ciprofloxacin-resistance rates could be as high as 100%, and these antibacterial agents are no longer treatment options for gonorrhea. The WHO released new N. gonorrhoeae treatment guidelines in 2016 due to high-level of resistance to previously recommended fluoroquinolones and decreased susceptibility to the third-generation cephalosporins, which were a first-line recommendation in the 2003 guidelines.⁴⁵ The CDC’s currently recommended regimens for the treatment of uncomplicated and disseminated gonorrheal infections are summarized in Table 3 and Table 4.¹² Recommendations from the WHO guidelines are very similar to the CDC recommendations.⁴⁵

In light of the increasing resistance of N. gonorrhoeae to cephalosporins, 1 g of oral azithromycin should be added to ceftriaxone 250 mg intramuscularly in treating all cases of gonorrhea. The rationale for adding azithromycin to ceftriaxone is that azithromycin is active against N. gonorrhoeae at a different molecular target at a high dose, and it can also cover other co-pathogens.⁷¹ Unfortunately, susceptibility to cephalosporins has been decreasing rapidly.⁷² The greatest concern is the potential worldwide spread of the strain isolated in Kyoto, Japan, in 2009 from a patient with pharyngeal gonorrhea that was highly resistant to ceftriaxone (minimum inhibitory concentration of 2.0 to 4.0 µg/mL).⁷³ At this time, N. gonorrhoeae isolates that are highly resistant to ceftriaxone are still rare globally.

Although cefixime is listed as an alternative treatment if ceftriaxone is not available, the 2015 CDC gonorrhea treatment guidelines note that N. gonorrhoeae is becoming more resistant to this oral third-generation cephalosporin; this increasing resistance is due in part to the genetic exchange between N. gonorrhoeae and other oral commensals actively taking place in the oral cavity, creating more resistant species. Another possible reason for cefixime resistance is that the concentration of cefixime used in treating gonococcal pharyngeal infection is subtherapeutic.⁷⁴ A recent randomized multicenter trial in the United States compared 2 non-cephalosporin regimens: a single 240-mg dose of intramuscular gentamicin plus a single 2-g dose of oral azithromycin, and a single 320-mg dose of oral gemifloxacin plus a single 2-g dose of oral azithromycin. These combinations achieved 100% and 99.5% microbiological cure rates, respectively, in 401 patients with urogenital gonorrhea.⁷⁵ Thus, these combination regimens can be considered as alternatives when the N. gonorrhoeae is resistant to cephalosporins or the patient is intolerant or allergic to cephalosporins.

Because N. gonorrhoeae has evolved into a “superbug,” becoming resistant to all currently available antimicrobial agents, it is important to focus on developing new agents with unique mechanisms of action to treat N. gonorrhoeae–related infections. Zoliflodacin (ETX0914), a novel topoisomerase II inhibitor, has the potential to become an effective agent to treat multi-drug resistant N. gonorrhoeae. A recent phase 2 trial demonstrated that a single oral 2000-mg dose of zoliflodacin microbiologically cleared 98% of gonorrhea patients, and some of the trial participants were infected with ciprofloxacin- or azithromycin-resistant strains.⁷⁶ An additional phase 2 clinical trial compared oral zoliflodacin and intramuscular ceftriaxone. For uncomplicated urogential infections, 96% of patients in the zoliflodacin group achieved microbiologic cure versus 100% in the ceftriaxone group; however, zoliflodacin was less efficacious for pharyngeal infections.⁷⁷ Gepotidacin (GSK2140944) is another new antimicrobial agent in the pipeline that looks promising. It is a novel first-in-class triazaacenaphthylene that inhibits bacterial DNA replication. A recent phase 2 clinical trial demonstrated that 1.5-g and 3-g single oral doses eradicated urogenital N. gonorrhoeae with microbiological success rates of 97% and 95%, respectively.⁷⁸

Test of Cure

Because of the decreasing susceptibility of M. genitalium and N. gonorrhoeae to recommended treatment regimens, the European Guidelines consider test of cure essential in STIs caused by these 2 organisms to ensure eradication of infection and identify emerging resistance.⁷⁹ However, test of cure is not routinely recommended by the CDC for these organisms in asymptomatic patients.¹²

Sexual Risk-Reduction Counseling

Besides aggressive treatment with appropriate antimicrobial agents, it is also essential that patients and their partners receive counseling to reduce the risk of STI. A recently published systematic review demonstrated that high-intensity counseling could decrease STI incidents in adolescents and adults.⁸⁰

Conclusion

It is clear that these 2 sexually transmitted ”superbugs” are increasingly resistant to antibiotics and pose an increasing threat. Future epidemiological research and drug development studies need to be devoted to these 2 organisms, as well as to the potential development of a vaccine. This is especially important considering that antimicrobials may no longer be recommended when the prevalence of resistance to a particular antimicrobial reaches 5%, as is the case with WHO and other agencies that set the standard of ≥ 95% effectiveness for an antimicrobial to be considered as a recommended treatment.³² With current resistance rates for penicillin, ciprofloxacin, and tetracycline at close to 100% for N. gonorrhoeae in some countries,^30,79 it is important to remain cognizant about current and future treatment options.

Because screening methods for M. genitalium are not available in most countries and there is not an FDA-approved screening method in the United States, M. genitalium poses a significant challenge for clinicians treating urethritis, cervicitis, and PID. Thus, the development of an effective screening method and established screening guidelines for M. genitalium is urgently needed. Better surveillance, prudent use of available antibiotics, and development of novel compounds are necessary to eliminate the impending threat caused by M. genitalium and N. gonorrhoeae.

This article is the result of work supported with resources and the use of facilities at the Fargo VA Health Care System. The contents of this manuscript do not represent the views of the Department of Veterans Affairs or the United States Government.

Corresponding author: Tze Shien Lo, MD, Veterans Affairs Medical Center, 2101 Elm Street N, Fargo, ND 58102.

Financial disclosures: None.

This centennial year update focuses primarily on immunization, but also reviews epidemiology, transmission, and treatment.

EPIDEMIOLOGY

2017–2018 was a bad season

The 2017–2018 influenza epidemic was memorable, dominated by influenza A(H3N2) viruses with morbidity and mortality rates approaching pandemic numbers. It lasted 19 weeks, killed more people than any other epidemic since 2010, particularly children, and was associated with 30,453 hospitalizations—almost twice the previous season high in some parts of the United States.²

Regrettably, 171 unvaccinated children died during 2017–2018, accounting for almost 80% of deaths.² The mean age of the children who died was 7.1 years; 51% had at least 1 underlying medical condition placing them at risk for influenza-related complications, and 57% died after hospitalization.²

Recent estimates of the incidence of symptomatic influenza among all ages ranged from 3% to 11%, which is slightly lower than historical estimates. The rates were higher for children under age 18 than for adults.³ Interestingly, influenza A(H3N2) accounted for 50% of cases of non-mumps viral parotitis during the 2014–2015 influenza season in the United States.⁴

Influenza C exists but is rare

Influenza A and B account for almost all influenza-related outpatient visits and hospitalizations. Surveillance data from May 2013 through December 2016 showed that influenza C accounts for 0.5% of influenza-related outpatient visits and hospitalizations, particularly affecting children ages 6 to 24 months. Medical comorbidities and copathogens were seen in all patients requiring intensive care and in most hospitalizations.⁵ Diagnostic tests for influenza C are not widely available.

Dogs and cats: Factories for new flu strains?

While pigs and birds are the major reservoirs of influenza viral genetic diversity from which infection is transmitted to humans, dogs and cats have recently emerged as possible sources of novel reassortant influenza A.⁶ With their frequent close contact with humans, our pets may prove to pose a significant threat.

Obesity a risk factor for influenza

Obesity emerged as a risk factor for severe influenza in the 2009 pandemic. Recent data also showed that obesity increases the duration of influenza A virus shedding, thus increasing duration of contagiousness.⁷

Influenza a cardiovascular risk factor

Previous data showed that influenza was a risk factor for cardiovascular events. Two recent epi­demiologic studies from the United Kingdom showed that laboratory-confirmed influenza was associated with higher rates of myocardial infarction and stroke for up to 4 weeks.^8,9

Which strain is the biggest threat?

Predicting which emerging influenza serotype may cause the next pandemic is difficult, but influenza A(H7N9), which had not infected humans until 2013 but has since infected about 1,600 people in China and killed 37% of them, appears to have the greatest potential.¹⁰

National influenza surveillance programs and influenza-related social media applications have been developed and may get a boost from technology. A smartphone equipped with a temperature sensor can instantly detect one’s temperature with great precision. A 2018 study suggested that a smartphone-driven thermometry application correlated well with national influenza-like illness activity and improved its forecast in real time and up to 3 weeks in advance.¹¹

TRANSMISSION

Humidity may not block transmission

Animal studies have suggested that humidity in the air interferes with transmission of airborne influenza virus, partially from biologic inactivation. But when a recent study used humidity-controlled chambers to investigate the stability of the 2009 influenza A(H1N1) virus in suspended aerosols and stationary droplets, the virus remained infectious in aerosols across a wide range of relative humidities, challenging the common belief that humidity destabilizes respiratory viruses in aerosols.¹²

One sick passenger may not infect the whole plane

Transmission of respiratory viruses on airplane flights has long been considered a potential avenue for spreading influenza. However, a recent study that monitored movements of individuals on 10 transcontinental US flights and simulated inflight transmission based on these data showed a low probability of direct transmission, except for passengers seated in close proximity to an infectious passenger.¹³

WHAT’S IN THE NEW FLU SHOT?

The 2018–2019 quadrivalent vaccine for the Northern Hemisphere¹⁴ contains the following strains:

• A/Michigan/45/2015 A(H1N1)pdm09-like virus
• A/Singapore/INFIMH-16-0019/2016 (H3N2)-like virus
• B/Colorado/06/2017-like virus (Victoria lineage)
• B/Phuket/3073/2013-like virus (Yamagata lineage).

The A(H3N2) (Singapore) and B/Victoria lineage components are new this year. The A(H3N2) strain was the main cause of the 2018 influenza epidemic in the Southern Hemisphere.

The quadrivalent live-attenuated vaccine, which was not recommended during the 2016–2017 and 2017–2018 influenza seasons, has made a comeback and is recommended for the 2018–2019 season in people for whom it is appropriate based on age and comorbidities.¹⁵ Although it was effective against influenza B and A(H3N2) viruses, it was less effective against the influenza A(H1N1)pdm09-like viruses during the 2013–2014 and 2015–2016 seasons.

A/Slovenia/2903/2015, the new A(H1N1)pdm09-like virus included in the 2018–2019 quadrivalent live-attenuated vaccine, is significantly more immunogenic than its predecessor, A/Bolivia/559/2013, but its clinical effectiveness remains to be seen.

How effective is it?

Influenza vaccine effectiveness in the 2017–2018 influenza season was 36% overall, 67% against A(H1N1), 42% against influenza B, and 25% against A(H3N2).¹⁶ It is estimated that influenza vaccine prevents 300 to 4,000 deaths annually in the United States alone.¹⁷

A 2018 Cochrane review¹⁷ concluded that vaccination reduced the incidence of influenza by about half, with 2.3% of the population contracting the flu without vaccination compared with 0.9% with vaccination (risk ratio 0.41, 95% confidence interval 0.36–0.47). The same review found that 71 healthy adults need to be vaccinated to prevent 1 from experiencing influenza, and 29 to prevent 1 influenza-like illness.

Several recent studies showed that influenza vaccine effectiveness varied based on age and influenza serotype, with higher effectiveness in people ages 5 to 17 and ages 18 to 64 than in those age 65 and older.^18–20 A mathematical model of influenza transmission and vaccination in the United States determined that even relatively low-efficacy influenza vaccines can be very useful if optimally distributed across age groups.²¹

Vaccination rates are low, and ‘antivaxxers’ are on the rise

Although the influenza vaccine is recommended in the United States for all people age 6 months and older regardless of the state of their health, vaccination rates remain low. In 2016, only 37% of employed adults were vaccinated. The highest rate was for government employees (45%), followed by private employees (36%), followed by the self-employed (30%).²²

A national goal is to immunize 80% of all Americans and 90% of at-risk populations (which include children and the elderly).²³ The number of US hospitals that require their employees to be vaccinated increased from 37.1% in 2013 to 61.4% in 2017.²⁴ Regrettably, as of March 2018, 14 lawsuits addressing religious objections to hospital influenza vaccination mandates have been filed.²⁵

Despite hundreds of studies demonstrating the efficacy, safety, and cost savings of influenza vaccination, the antivaccine movement has been growing in the United States and worldwide.²⁶ All US states except West Virginia, Mississippi, and California allow nonmedical exemptions from vaccination based on religious or personal belief.²⁷ Several US metropolitan areas represent “hot spots” for these exemptions.²⁸ This may render such areas vulnerable to vaccine-preventable diseases, including influenza.

Herd immunity: We’re all in this together

Some argue that the potential adverse effects and the cost of vaccination outweigh the benefits, but the protective benefits of herd immunity are significant for those with comorbidities or compromised immunity.

Educating the public about herd immunity and local influenza vaccination uptake increases people’s willingness to be vaccinated.²⁹ A key educational point is that at least 70% of a community needs to be vaccinated to prevent community outbreaks; this protects everyone, including those who do not mount a protective antibody response to influenza vaccination and those who are not vaccinated.

DOES ANNUAL VACCINATION BLUNT ITS EFFECTIVENESS?

Some studies from the 1970s and 1980s raised concern over a possible negative effect of annual influenza vaccination on vaccine effectiveness. The “antigenic distance hypothesis” holds that vaccine effectiveness is influenced by antigenic similarity between the previous season’s vaccine serotypes and the epidemic serotypes, as well as the antigenic similarity between the serotypes of the current and previous seasons.

A meta-analysis of studies from 2010 through 2015 showed significant inconsistencies in repeat vaccination effects within and between seasons and serotypes. It also showed that vaccine effectiveness may be influenced by more than 1 previous season, particularly for influenza A(H3N2), in which repeated vaccination can blunt the hemagglutinin antibody response.³⁰

A study from Japan showed that people who needed medical attention for influenza in the previous season were at lower risk of a similar event in the current season.³¹ Prior-season influenza vaccination reduced current-season vaccine effectiveness only in those who did not have medically attended influenza in the prior season. This suggests that infection is more immunogenic than vaccination, but only against the serotype causing the infection and not the other serotypes included in the vaccine.

An Australian study showed that annual influenza vaccination did not decrease vaccine effectiveness against influenza-associated hospitalization. Rather, effectiveness increased by about 15% in those vaccinated in both current and previous seasons compared with those vaccinated in either season alone.³²

European investigators showed that repeated seasonal influenza vaccination in the elderly prevented the need for hospitalization due to influenza A(H3N2) and B, but not A(H1N1)pdm09.³³

High-dose vaccine for older adults

The high-dose influenza vaccine has been licensed since 2009 for use in the United States for people ages 65 and older.

Recent studies confirmed that high-dose vaccine is more effective than standard-dose vaccine in veterans³⁴ and US Medicare beneficiaries.³⁵

The high-dose vaccine is rapidly becoming the primary vaccine given to people ages 65 and older in retail pharmacies, where vaccination begins earlier in the season than in providers’ offices.³⁶ Some studies have shown that the standard-dose vaccine wanes in effectiveness toward the end of the influenza season (particularly if the season is long) if it is given very early. It remains to be seen whether the same applies to the high-dose influenza vaccine.

Some advocate twice-annual influenza vaccination, particularly for older adults living in tropical and subtropical areas, where influenza seasons are more prolonged. However, a recently published study observed reductions in influenza-specific hemagglutination inhibition and cell-mediated immunity after twice-annual vaccination.³⁷

Vaccination is beneficial during pregnancy

Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants.

One recently published study showed that 18% of infants who developed influenza required hospitalization.³⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively.

Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.³⁹

Some studies have shown that influenza virus infection can increase susceptibility to certain bacterial infections. A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.⁴⁰

Factors that make vaccination less effective

Several factors including age-related frailty and iatrogenic and disease-related immunosuppression can affect vaccine effectiveness.

Frailty. A recent study showed that vaccine effectiveness was 77.6% in nonfrail older adults but only 58.7% in frail older adults.⁴¹

Immunosuppression. Temporary discontinuation of methotrexate for 2 weeks after influenza vaccination in patients with rheumatoid arthritis improves vaccine immunogenicity without precipitating disease flare.⁴² Solid-organ and hematopoietic stem cell transplant recipients who received influenza vaccine were less likely to develop pneumonia and require intensive care unit admission.⁴³

The high-dose influenza vaccine is more immunogenic than the standard-dose vaccine in solid-organ transplant recipients.⁴⁴

Statins are widely prescribed and have recently been associated with reduced influenza vaccine effectiveness against medically attended acute respiratory illness, but their benefits in preventing cardiovascular events outweigh this risk.⁴⁵

FUTURE VACCINE CONSIDERATIONS

Moving away from eggs

During the annual egg-based production process, which takes several months, the influenza vaccine acquires antigenic changes that allow replication in eggs, particularly in the hemagglutinin protein, which mediates receptor binding. This process of egg adaptation may cause antigenic changes that decrease vaccine effectiveness against circulating viruses.

The cell-based baculovirus influenza vaccine grown in dog kidney cells has higher antigenic content and is not subject to the limitations of egg-based vaccine, although it still requires annual updates. A recombinant influenza vaccine reduces the probability of influenza-like illness by 30% compared with the egg-based influenza vaccine, but also still requires annual updates.⁴⁶ The market share of these non-egg-based vaccines is small, and thus their effectiveness has yet to be demonstrated.

The US Department of Defense administered the cell-based influenza vaccine to about one-third of Armed Forces personnel, their families, and retirees in the 2017–2018 influenza seasons, and data on its effectiveness are expected in the near future.⁴⁷

A universal vaccine would be ideal

The quest continues for a universal influenza vaccine, one that remains protective for several years and does not require annual updates.⁴⁸ Such a vaccine would protect against seasonal epidemic influenza drift variants and pandemic strains. More people could likely be persuaded to be vaccinated once rather than every year.

David Schumick, medical illustrator; adapted from reference 49; illustration of the influenza hemagglutinin created in part with data from reference 50.

An ideal universal vaccine would be suitable for all age groups, at least 75% effective against symptomatic influenza virus infection, protective against all influenza A viruses (influenza A, not B, causes pandemics and seasonal epidemics), and durable through multiple influenza seasons.⁵¹

Research and production of such a vaccine are expected to require funding of about $1 billion over the next 5 years.

Boosting effectiveness

Estimates of influenza vaccine effectiveness range from 40% to 60% in years when the vaccine viruses closely match the circulating viruses, and variably lower when they do not match. The efficacy of most other vaccines given to prevent other infections is much higher.

New technologies to improve influenza vaccine effectiveness are needed, particularly for influenza A(H3N2) viruses, which are rapidly evolving and are highly susceptible to egg-adaptive mutations in the manufacturing process.

In one study, a nanoparticle vaccine formulated with a saponin-based adjuvant induced hemagglutination inhibition responses that were even greater than those induced by the high-dose vaccine.⁵²

Immunoglobulin A (IgA) may be a more effective vaccine target than traditional influenza vaccines that target IgG, since different parts of IgA may engage the influenza virus simultaneously.⁵³

Vaccines can be developed more quickly than in the past. The timeline from viral sequencing to human studies with deoxyribonucleic acid plasmid vaccines decreased from 20 months in 2003 for the severe acquired respiratory syndrome coronavirus to 11 months in 2006 for influenza A/Indonesia/2006 (H5), to 4 months in 2009 for influenza A/California/2009 (H1), to 3.5 months in 2016 for Zika virus.⁵⁴ This is because it is possible today to sequence a virus and insert the genetic material into a vaccine platform without ever having to grow the virus.

Numerous studies have found anti-influenza medications to be effective. Nevertheless, in an analysis of the 2011–2016 influenza seasons, only 15% of high-risk patients were prescribed anti-influenza medications within 2 days of symptom onset, including 37% in those with laboratory-confirmed influenza.⁵⁵ Fever was associated with an increased rate of antiviral treatment, but 25% of high-risk outpatients were afebrile. Empiric treatment of 4 high-risk outpatients with acute respiratory illness was needed to treat 1 patient with influenza.⁵⁵

Treatment with a neuraminidase inhibitor within 2 days of illness has recently been shown to improve survival and shorten duration of viral shedding in patients with avian influenza A(H7N9) infection.⁵⁶ Antiviral treatment within 2 days of illness is associated with improved outcomes in transplant recipients⁵⁷ and with a lower risk of otitis media in children.⁵⁸

Appropriate anti-influenza treatment is as important as avoiding unnecessary antibiotics. Regrettably, as many as one-third of patients with laboratory-confirmed influenza are prescribed antibiotics.⁵⁹

The US Food and Drug Administration warns against fraudulent unapproved over-the-counter influenza products.⁶⁰

Baloxavir marboxil

Baloxavir marboxil is a new anti-influenza medication approved in Japan in February 2018 and anticipated to be available in the United States sometime in 2019.

This prodrug is hydrolyzed in vivo to the active metabolite, which selectively inhibits cap-dependent endonuclease enzyme, a key enzyme in initiation of messenger ribonucleic acid synthesis required for influenza viral replication.⁶¹

In a double-blind phase 3 trial, the median time to alleviation of influenza symptoms is 26.5 hours shorter with baloxavir marboxil than with placebo. One tablet was as effective as 5 days of the neuraminidase inhibitor oseltamivir and was associated with greater reduction in viral load 1 day after initiation, and similar side effects.⁶² Of concern is the emergence of nucleic acid substitutions conferring resistance to baloxavir; this occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 and 3 trials, respectively.

CLOSING THE GAPS

Several gaps in the management of influenza persist since the 1918 pandemic.¹ These include gaps in epidemiology, prevention, diagnosis, treatment, and prognosis.

• Global networks wider than current ones are needed to address this global disease and to prioritize coordination efforts.
• Establishing and strengthening clinical capacity is needed in limited resource settings. New technologies are needed to expedite vaccine development and to achieve progress toward a universal vaccine.
• Current diagnostic tests do not distinguish between seasonal and novel influenza A viruses of zoonotic origin, which are expected to cause the next pandemic.
• Current antivirals have been shown to shorten duration of illness in outpatients with uncomplicated influenza, but the benefit in hospitalized patients has been less well established.
• In 2007, resistance of seasonal influenza A(H1N1) to oseltamivir became widespread. In 2009, pandemic influenza A(H1N1), which is highly susceptible to oseltamivir, replaced the seasonal virus and remains the predominantly circulating A(H1N1) strain.
• A small-molecule fragment, N-cyclohexyaltaurine, binds to the conserved hemagglutinin receptor-binding site in a manner that mimics the binding mode of the natural receptor sialic acid. This can serve as a template to guide the development of novel broad-spectrum small-molecule anti-influenza drugs.⁶³
• Biomarkers that can accurately predict development of severe disease in patients with influenza are needed.

This centennial year update focuses primarily on immunization, but also reviews epidemiology, transmission, and treatment.

EPIDEMIOLOGY

2017–2018 was a bad season

The 2017–2018 influenza epidemic was memorable, dominated by influenza A(H3N2) viruses with morbidity and mortality rates approaching pandemic numbers. It lasted 19 weeks, killed more people than any other epidemic since 2010, particularly children, and was associated with 30,453 hospitalizations—almost twice the previous season high in some parts of the United States.²

Regrettably, 171 unvaccinated children died during 2017–2018, accounting for almost 80% of deaths.² The mean age of the children who died was 7.1 years; 51% had at least 1 underlying medical condition placing them at risk for influenza-related complications, and 57% died after hospitalization.²

Recent estimates of the incidence of symptomatic influenza among all ages ranged from 3% to 11%, which is slightly lower than historical estimates. The rates were higher for children under age 18 than for adults.³ Interestingly, influenza A(H3N2) accounted for 50% of cases of non-mumps viral parotitis during the 2014–2015 influenza season in the United States.⁴

Influenza C exists but is rare

Influenza A and B account for almost all influenza-related outpatient visits and hospitalizations. Surveillance data from May 2013 through December 2016 showed that influenza C accounts for 0.5% of influenza-related outpatient visits and hospitalizations, particularly affecting children ages 6 to 24 months. Medical comorbidities and copathogens were seen in all patients requiring intensive care and in most hospitalizations.⁵ Diagnostic tests for influenza C are not widely available.

Dogs and cats: Factories for new flu strains?

While pigs and birds are the major reservoirs of influenza viral genetic diversity from which infection is transmitted to humans, dogs and cats have recently emerged as possible sources of novel reassortant influenza A.⁶ With their frequent close contact with humans, our pets may prove to pose a significant threat.

Obesity a risk factor for influenza

Obesity emerged as a risk factor for severe influenza in the 2009 pandemic. Recent data also showed that obesity increases the duration of influenza A virus shedding, thus increasing duration of contagiousness.⁷

Influenza a cardiovascular risk factor

Previous data showed that influenza was a risk factor for cardiovascular events. Two recent epi­demiologic studies from the United Kingdom showed that laboratory-confirmed influenza was associated with higher rates of myocardial infarction and stroke for up to 4 weeks.^8,9

Which strain is the biggest threat?

Predicting which emerging influenza serotype may cause the next pandemic is difficult, but influenza A(H7N9), which had not infected humans until 2013 but has since infected about 1,600 people in China and killed 37% of them, appears to have the greatest potential.¹⁰

National influenza surveillance programs and influenza-related social media applications have been developed and may get a boost from technology. A smartphone equipped with a temperature sensor can instantly detect one’s temperature with great precision. A 2018 study suggested that a smartphone-driven thermometry application correlated well with national influenza-like illness activity and improved its forecast in real time and up to 3 weeks in advance.¹¹

TRANSMISSION

Humidity may not block transmission

Animal studies have suggested that humidity in the air interferes with transmission of airborne influenza virus, partially from biologic inactivation. But when a recent study used humidity-controlled chambers to investigate the stability of the 2009 influenza A(H1N1) virus in suspended aerosols and stationary droplets, the virus remained infectious in aerosols across a wide range of relative humidities, challenging the common belief that humidity destabilizes respiratory viruses in aerosols.¹²

One sick passenger may not infect the whole plane

Transmission of respiratory viruses on airplane flights has long been considered a potential avenue for spreading influenza. However, a recent study that monitored movements of individuals on 10 transcontinental US flights and simulated inflight transmission based on these data showed a low probability of direct transmission, except for passengers seated in close proximity to an infectious passenger.¹³

WHAT’S IN THE NEW FLU SHOT?

The 2018–2019 quadrivalent vaccine for the Northern Hemisphere¹⁴ contains the following strains:

• A/Michigan/45/2015 A(H1N1)pdm09-like virus
• A/Singapore/INFIMH-16-0019/2016 (H3N2)-like virus
• B/Colorado/06/2017-like virus (Victoria lineage)
• B/Phuket/3073/2013-like virus (Yamagata lineage).

The A(H3N2) (Singapore) and B/Victoria lineage components are new this year. The A(H3N2) strain was the main cause of the 2018 influenza epidemic in the Southern Hemisphere.

The quadrivalent live-attenuated vaccine, which was not recommended during the 2016–2017 and 2017–2018 influenza seasons, has made a comeback and is recommended for the 2018–2019 season in people for whom it is appropriate based on age and comorbidities.¹⁵ Although it was effective against influenza B and A(H3N2) viruses, it was less effective against the influenza A(H1N1)pdm09-like viruses during the 2013–2014 and 2015–2016 seasons.

A/Slovenia/2903/2015, the new A(H1N1)pdm09-like virus included in the 2018–2019 quadrivalent live-attenuated vaccine, is significantly more immunogenic than its predecessor, A/Bolivia/559/2013, but its clinical effectiveness remains to be seen.

How effective is it?

Influenza vaccine effectiveness in the 2017–2018 influenza season was 36% overall, 67% against A(H1N1), 42% against influenza B, and 25% against A(H3N2).¹⁶ It is estimated that influenza vaccine prevents 300 to 4,000 deaths annually in the United States alone.¹⁷

A 2018 Cochrane review¹⁷ concluded that vaccination reduced the incidence of influenza by about half, with 2.3% of the population contracting the flu without vaccination compared with 0.9% with vaccination (risk ratio 0.41, 95% confidence interval 0.36–0.47). The same review found that 71 healthy adults need to be vaccinated to prevent 1 from experiencing influenza, and 29 to prevent 1 influenza-like illness.

Several recent studies showed that influenza vaccine effectiveness varied based on age and influenza serotype, with higher effectiveness in people ages 5 to 17 and ages 18 to 64 than in those age 65 and older.^18–20 A mathematical model of influenza transmission and vaccination in the United States determined that even relatively low-efficacy influenza vaccines can be very useful if optimally distributed across age groups.²¹

Vaccination rates are low, and ‘antivaxxers’ are on the rise

Although the influenza vaccine is recommended in the United States for all people age 6 months and older regardless of the state of their health, vaccination rates remain low. In 2016, only 37% of employed adults were vaccinated. The highest rate was for government employees (45%), followed by private employees (36%), followed by the self-employed (30%).²²

A national goal is to immunize 80% of all Americans and 90% of at-risk populations (which include children and the elderly).²³ The number of US hospitals that require their employees to be vaccinated increased from 37.1% in 2013 to 61.4% in 2017.²⁴ Regrettably, as of March 2018, 14 lawsuits addressing religious objections to hospital influenza vaccination mandates have been filed.²⁵

Despite hundreds of studies demonstrating the efficacy, safety, and cost savings of influenza vaccination, the antivaccine movement has been growing in the United States and worldwide.²⁶ All US states except West Virginia, Mississippi, and California allow nonmedical exemptions from vaccination based on religious or personal belief.²⁷ Several US metropolitan areas represent “hot spots” for these exemptions.²⁸ This may render such areas vulnerable to vaccine-preventable diseases, including influenza.

Herd immunity: We’re all in this together

Some argue that the potential adverse effects and the cost of vaccination outweigh the benefits, but the protective benefits of herd immunity are significant for those with comorbidities or compromised immunity.

Educating the public about herd immunity and local influenza vaccination uptake increases people’s willingness to be vaccinated.²⁹ A key educational point is that at least 70% of a community needs to be vaccinated to prevent community outbreaks; this protects everyone, including those who do not mount a protective antibody response to influenza vaccination and those who are not vaccinated.

DOES ANNUAL VACCINATION BLUNT ITS EFFECTIVENESS?

Some studies from the 1970s and 1980s raised concern over a possible negative effect of annual influenza vaccination on vaccine effectiveness. The “antigenic distance hypothesis” holds that vaccine effectiveness is influenced by antigenic similarity between the previous season’s vaccine serotypes and the epidemic serotypes, as well as the antigenic similarity between the serotypes of the current and previous seasons.

A meta-analysis of studies from 2010 through 2015 showed significant inconsistencies in repeat vaccination effects within and between seasons and serotypes. It also showed that vaccine effectiveness may be influenced by more than 1 previous season, particularly for influenza A(H3N2), in which repeated vaccination can blunt the hemagglutinin antibody response.³⁰

A study from Japan showed that people who needed medical attention for influenza in the previous season were at lower risk of a similar event in the current season.³¹ Prior-season influenza vaccination reduced current-season vaccine effectiveness only in those who did not have medically attended influenza in the prior season. This suggests that infection is more immunogenic than vaccination, but only against the serotype causing the infection and not the other serotypes included in the vaccine.

An Australian study showed that annual influenza vaccination did not decrease vaccine effectiveness against influenza-associated hospitalization. Rather, effectiveness increased by about 15% in those vaccinated in both current and previous seasons compared with those vaccinated in either season alone.³²

European investigators showed that repeated seasonal influenza vaccination in the elderly prevented the need for hospitalization due to influenza A(H3N2) and B, but not A(H1N1)pdm09.³³

High-dose vaccine for older adults

The high-dose influenza vaccine has been licensed since 2009 for use in the United States for people ages 65 and older.

Recent studies confirmed that high-dose vaccine is more effective than standard-dose vaccine in veterans³⁴ and US Medicare beneficiaries.³⁵

The high-dose vaccine is rapidly becoming the primary vaccine given to people ages 65 and older in retail pharmacies, where vaccination begins earlier in the season than in providers’ offices.³⁶ Some studies have shown that the standard-dose vaccine wanes in effectiveness toward the end of the influenza season (particularly if the season is long) if it is given very early. It remains to be seen whether the same applies to the high-dose influenza vaccine.

Some advocate twice-annual influenza vaccination, particularly for older adults living in tropical and subtropical areas, where influenza seasons are more prolonged. However, a recently published study observed reductions in influenza-specific hemagglutination inhibition and cell-mediated immunity after twice-annual vaccination.³⁷

Vaccination is beneficial during pregnancy

Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants.

One recently published study showed that 18% of infants who developed influenza required hospitalization.³⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively.

Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.³⁹

Some studies have shown that influenza virus infection can increase susceptibility to certain bacterial infections. A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.⁴⁰

Factors that make vaccination less effective

Several factors including age-related frailty and iatrogenic and disease-related immunosuppression can affect vaccine effectiveness.

Frailty. A recent study showed that vaccine effectiveness was 77.6% in nonfrail older adults but only 58.7% in frail older adults.⁴¹

Immunosuppression. Temporary discontinuation of methotrexate for 2 weeks after influenza vaccination in patients with rheumatoid arthritis improves vaccine immunogenicity without precipitating disease flare.⁴² Solid-organ and hematopoietic stem cell transplant recipients who received influenza vaccine were less likely to develop pneumonia and require intensive care unit admission.⁴³

The high-dose influenza vaccine is more immunogenic than the standard-dose vaccine in solid-organ transplant recipients.⁴⁴

Statins are widely prescribed and have recently been associated with reduced influenza vaccine effectiveness against medically attended acute respiratory illness, but their benefits in preventing cardiovascular events outweigh this risk.⁴⁵

FUTURE VACCINE CONSIDERATIONS

Moving away from eggs

During the annual egg-based production process, which takes several months, the influenza vaccine acquires antigenic changes that allow replication in eggs, particularly in the hemagglutinin protein, which mediates receptor binding. This process of egg adaptation may cause antigenic changes that decrease vaccine effectiveness against circulating viruses.

The cell-based baculovirus influenza vaccine grown in dog kidney cells has higher antigenic content and is not subject to the limitations of egg-based vaccine, although it still requires annual updates. A recombinant influenza vaccine reduces the probability of influenza-like illness by 30% compared with the egg-based influenza vaccine, but also still requires annual updates.⁴⁶ The market share of these non-egg-based vaccines is small, and thus their effectiveness has yet to be demonstrated.

The US Department of Defense administered the cell-based influenza vaccine to about one-third of Armed Forces personnel, their families, and retirees in the 2017–2018 influenza seasons, and data on its effectiveness are expected in the near future.⁴⁷

A universal vaccine would be ideal

The quest continues for a universal influenza vaccine, one that remains protective for several years and does not require annual updates.⁴⁸ Such a vaccine would protect against seasonal epidemic influenza drift variants and pandemic strains. More people could likely be persuaded to be vaccinated once rather than every year.

David Schumick, medical illustrator; adapted from reference 49; illustration of the influenza hemagglutinin created in part with data from reference 50.

An ideal universal vaccine would be suitable for all age groups, at least 75% effective against symptomatic influenza virus infection, protective against all influenza A viruses (influenza A, not B, causes pandemics and seasonal epidemics), and durable through multiple influenza seasons.⁵¹

Research and production of such a vaccine are expected to require funding of about $1 billion over the next 5 years.

Boosting effectiveness

Estimates of influenza vaccine effectiveness range from 40% to 60% in years when the vaccine viruses closely match the circulating viruses, and variably lower when they do not match. The efficacy of most other vaccines given to prevent other infections is much higher.

New technologies to improve influenza vaccine effectiveness are needed, particularly for influenza A(H3N2) viruses, which are rapidly evolving and are highly susceptible to egg-adaptive mutations in the manufacturing process.

In one study, a nanoparticle vaccine formulated with a saponin-based adjuvant induced hemagglutination inhibition responses that were even greater than those induced by the high-dose vaccine.⁵²

Immunoglobulin A (IgA) may be a more effective vaccine target than traditional influenza vaccines that target IgG, since different parts of IgA may engage the influenza virus simultaneously.⁵³

Vaccines can be developed more quickly than in the past. The timeline from viral sequencing to human studies with deoxyribonucleic acid plasmid vaccines decreased from 20 months in 2003 for the severe acquired respiratory syndrome coronavirus to 11 months in 2006 for influenza A/Indonesia/2006 (H5), to 4 months in 2009 for influenza A/California/2009 (H1), to 3.5 months in 2016 for Zika virus.⁵⁴ This is because it is possible today to sequence a virus and insert the genetic material into a vaccine platform without ever having to grow the virus.

Numerous studies have found anti-influenza medications to be effective. Nevertheless, in an analysis of the 2011–2016 influenza seasons, only 15% of high-risk patients were prescribed anti-influenza medications within 2 days of symptom onset, including 37% in those with laboratory-confirmed influenza.⁵⁵ Fever was associated with an increased rate of antiviral treatment, but 25% of high-risk outpatients were afebrile. Empiric treatment of 4 high-risk outpatients with acute respiratory illness was needed to treat 1 patient with influenza.⁵⁵

Treatment with a neuraminidase inhibitor within 2 days of illness has recently been shown to improve survival and shorten duration of viral shedding in patients with avian influenza A(H7N9) infection.⁵⁶ Antiviral treatment within 2 days of illness is associated with improved outcomes in transplant recipients⁵⁷ and with a lower risk of otitis media in children.⁵⁸

Appropriate anti-influenza treatment is as important as avoiding unnecessary antibiotics. Regrettably, as many as one-third of patients with laboratory-confirmed influenza are prescribed antibiotics.⁵⁹

The US Food and Drug Administration warns against fraudulent unapproved over-the-counter influenza products.⁶⁰

Baloxavir marboxil

Baloxavir marboxil is a new anti-influenza medication approved in Japan in February 2018 and anticipated to be available in the United States sometime in 2019.

This prodrug is hydrolyzed in vivo to the active metabolite, which selectively inhibits cap-dependent endonuclease enzyme, a key enzyme in initiation of messenger ribonucleic acid synthesis required for influenza viral replication.⁶¹

In a double-blind phase 3 trial, the median time to alleviation of influenza symptoms is 26.5 hours shorter with baloxavir marboxil than with placebo. One tablet was as effective as 5 days of the neuraminidase inhibitor oseltamivir and was associated with greater reduction in viral load 1 day after initiation, and similar side effects.⁶² Of concern is the emergence of nucleic acid substitutions conferring resistance to baloxavir; this occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 and 3 trials, respectively.

CLOSING THE GAPS

Several gaps in the management of influenza persist since the 1918 pandemic.¹ These include gaps in epidemiology, prevention, diagnosis, treatment, and prognosis.

• Global networks wider than current ones are needed to address this global disease and to prioritize coordination efforts.
• Establishing and strengthening clinical capacity is needed in limited resource settings. New technologies are needed to expedite vaccine development and to achieve progress toward a universal vaccine.
• Current diagnostic tests do not distinguish between seasonal and novel influenza A viruses of zoonotic origin, which are expected to cause the next pandemic.
• Current antivirals have been shown to shorten duration of illness in outpatients with uncomplicated influenza, but the benefit in hospitalized patients has been less well established.
• In 2007, resistance of seasonal influenza A(H1N1) to oseltamivir became widespread. In 2009, pandemic influenza A(H1N1), which is highly susceptible to oseltamivir, replaced the seasonal virus and remains the predominantly circulating A(H1N1) strain.
• A small-molecule fragment, N-cyclohexyaltaurine, binds to the conserved hemagglutinin receptor-binding site in a manner that mimics the binding mode of the natural receptor sialic acid. This can serve as a template to guide the development of novel broad-spectrum small-molecule anti-influenza drugs.⁶³
• Biomarkers that can accurately predict development of severe disease in patients with influenza are needed.

This centennial year update focuses primarily on immunization, but also reviews epidemiology, transmission, and treatment.

EPIDEMIOLOGY

2017–2018 was a bad season

The 2017–2018 influenza epidemic was memorable, dominated by influenza A(H3N2) viruses with morbidity and mortality rates approaching pandemic numbers. It lasted 19 weeks, killed more people than any other epidemic since 2010, particularly children, and was associated with 30,453 hospitalizations—almost twice the previous season high in some parts of the United States.²

Regrettably, 171 unvaccinated children died during 2017–2018, accounting for almost 80% of deaths.² The mean age of the children who died was 7.1 years; 51% had at least 1 underlying medical condition placing them at risk for influenza-related complications, and 57% died after hospitalization.²

Recent estimates of the incidence of symptomatic influenza among all ages ranged from 3% to 11%, which is slightly lower than historical estimates. The rates were higher for children under age 18 than for adults.³ Interestingly, influenza A(H3N2) accounted for 50% of cases of non-mumps viral parotitis during the 2014–2015 influenza season in the United States.⁴

Influenza C exists but is rare

Influenza A and B account for almost all influenza-related outpatient visits and hospitalizations. Surveillance data from May 2013 through December 2016 showed that influenza C accounts for 0.5% of influenza-related outpatient visits and hospitalizations, particularly affecting children ages 6 to 24 months. Medical comorbidities and copathogens were seen in all patients requiring intensive care and in most hospitalizations.⁵ Diagnostic tests for influenza C are not widely available.

Dogs and cats: Factories for new flu strains?

While pigs and birds are the major reservoirs of influenza viral genetic diversity from which infection is transmitted to humans, dogs and cats have recently emerged as possible sources of novel reassortant influenza A.⁶ With their frequent close contact with humans, our pets may prove to pose a significant threat.

Obesity a risk factor for influenza

Obesity emerged as a risk factor for severe influenza in the 2009 pandemic. Recent data also showed that obesity increases the duration of influenza A virus shedding, thus increasing duration of contagiousness.⁷

Influenza a cardiovascular risk factor

Previous data showed that influenza was a risk factor for cardiovascular events. Two recent epi­demiologic studies from the United Kingdom showed that laboratory-confirmed influenza was associated with higher rates of myocardial infarction and stroke for up to 4 weeks.^8,9

Which strain is the biggest threat?

Predicting which emerging influenza serotype may cause the next pandemic is difficult, but influenza A(H7N9), which had not infected humans until 2013 but has since infected about 1,600 people in China and killed 37% of them, appears to have the greatest potential.¹⁰

National influenza surveillance programs and influenza-related social media applications have been developed and may get a boost from technology. A smartphone equipped with a temperature sensor can instantly detect one’s temperature with great precision. A 2018 study suggested that a smartphone-driven thermometry application correlated well with national influenza-like illness activity and improved its forecast in real time and up to 3 weeks in advance.¹¹

TRANSMISSION

Humidity may not block transmission

Animal studies have suggested that humidity in the air interferes with transmission of airborne influenza virus, partially from biologic inactivation. But when a recent study used humidity-controlled chambers to investigate the stability of the 2009 influenza A(H1N1) virus in suspended aerosols and stationary droplets, the virus remained infectious in aerosols across a wide range of relative humidities, challenging the common belief that humidity destabilizes respiratory viruses in aerosols.¹²

One sick passenger may not infect the whole plane

Transmission of respiratory viruses on airplane flights has long been considered a potential avenue for spreading influenza. However, a recent study that monitored movements of individuals on 10 transcontinental US flights and simulated inflight transmission based on these data showed a low probability of direct transmission, except for passengers seated in close proximity to an infectious passenger.¹³

WHAT’S IN THE NEW FLU SHOT?

The 2018–2019 quadrivalent vaccine for the Northern Hemisphere¹⁴ contains the following strains:

• A/Michigan/45/2015 A(H1N1)pdm09-like virus
• A/Singapore/INFIMH-16-0019/2016 (H3N2)-like virus
• B/Colorado/06/2017-like virus (Victoria lineage)
• B/Phuket/3073/2013-like virus (Yamagata lineage).

The A(H3N2) (Singapore) and B/Victoria lineage components are new this year. The A(H3N2) strain was the main cause of the 2018 influenza epidemic in the Southern Hemisphere.

The quadrivalent live-attenuated vaccine, which was not recommended during the 2016–2017 and 2017–2018 influenza seasons, has made a comeback and is recommended for the 2018–2019 season in people for whom it is appropriate based on age and comorbidities.¹⁵ Although it was effective against influenza B and A(H3N2) viruses, it was less effective against the influenza A(H1N1)pdm09-like viruses during the 2013–2014 and 2015–2016 seasons.

A/Slovenia/2903/2015, the new A(H1N1)pdm09-like virus included in the 2018–2019 quadrivalent live-attenuated vaccine, is significantly more immunogenic than its predecessor, A/Bolivia/559/2013, but its clinical effectiveness remains to be seen.

How effective is it?

Influenza vaccine effectiveness in the 2017–2018 influenza season was 36% overall, 67% against A(H1N1), 42% against influenza B, and 25% against A(H3N2).¹⁶ It is estimated that influenza vaccine prevents 300 to 4,000 deaths annually in the United States alone.¹⁷

A 2018 Cochrane review¹⁷ concluded that vaccination reduced the incidence of influenza by about half, with 2.3% of the population contracting the flu without vaccination compared with 0.9% with vaccination (risk ratio 0.41, 95% confidence interval 0.36–0.47). The same review found that 71 healthy adults need to be vaccinated to prevent 1 from experiencing influenza, and 29 to prevent 1 influenza-like illness.

Several recent studies showed that influenza vaccine effectiveness varied based on age and influenza serotype, with higher effectiveness in people ages 5 to 17 and ages 18 to 64 than in those age 65 and older.^18–20 A mathematical model of influenza transmission and vaccination in the United States determined that even relatively low-efficacy influenza vaccines can be very useful if optimally distributed across age groups.²¹

Vaccination rates are low, and ‘antivaxxers’ are on the rise

Although the influenza vaccine is recommended in the United States for all people age 6 months and older regardless of the state of their health, vaccination rates remain low. In 2016, only 37% of employed adults were vaccinated. The highest rate was for government employees (45%), followed by private employees (36%), followed by the self-employed (30%).²²

A national goal is to immunize 80% of all Americans and 90% of at-risk populations (which include children and the elderly).²³ The number of US hospitals that require their employees to be vaccinated increased from 37.1% in 2013 to 61.4% in 2017.²⁴ Regrettably, as of March 2018, 14 lawsuits addressing religious objections to hospital influenza vaccination mandates have been filed.²⁵

Despite hundreds of studies demonstrating the efficacy, safety, and cost savings of influenza vaccination, the antivaccine movement has been growing in the United States and worldwide.²⁶ All US states except West Virginia, Mississippi, and California allow nonmedical exemptions from vaccination based on religious or personal belief.²⁷ Several US metropolitan areas represent “hot spots” for these exemptions.²⁸ This may render such areas vulnerable to vaccine-preventable diseases, including influenza.

Herd immunity: We’re all in this together

Some argue that the potential adverse effects and the cost of vaccination outweigh the benefits, but the protective benefits of herd immunity are significant for those with comorbidities or compromised immunity.

Educating the public about herd immunity and local influenza vaccination uptake increases people’s willingness to be vaccinated.²⁹ A key educational point is that at least 70% of a community needs to be vaccinated to prevent community outbreaks; this protects everyone, including those who do not mount a protective antibody response to influenza vaccination and those who are not vaccinated.

DOES ANNUAL VACCINATION BLUNT ITS EFFECTIVENESS?

Some studies from the 1970s and 1980s raised concern over a possible negative effect of annual influenza vaccination on vaccine effectiveness. The “antigenic distance hypothesis” holds that vaccine effectiveness is influenced by antigenic similarity between the previous season’s vaccine serotypes and the epidemic serotypes, as well as the antigenic similarity between the serotypes of the current and previous seasons.

A meta-analysis of studies from 2010 through 2015 showed significant inconsistencies in repeat vaccination effects within and between seasons and serotypes. It also showed that vaccine effectiveness may be influenced by more than 1 previous season, particularly for influenza A(H3N2), in which repeated vaccination can blunt the hemagglutinin antibody response.³⁰

A study from Japan showed that people who needed medical attention for influenza in the previous season were at lower risk of a similar event in the current season.³¹ Prior-season influenza vaccination reduced current-season vaccine effectiveness only in those who did not have medically attended influenza in the prior season. This suggests that infection is more immunogenic than vaccination, but only against the serotype causing the infection and not the other serotypes included in the vaccine.

An Australian study showed that annual influenza vaccination did not decrease vaccine effectiveness against influenza-associated hospitalization. Rather, effectiveness increased by about 15% in those vaccinated in both current and previous seasons compared with those vaccinated in either season alone.³²

European investigators showed that repeated seasonal influenza vaccination in the elderly prevented the need for hospitalization due to influenza A(H3N2) and B, but not A(H1N1)pdm09.³³

High-dose vaccine for older adults

The high-dose influenza vaccine has been licensed since 2009 for use in the United States for people ages 65 and older.

Recent studies confirmed that high-dose vaccine is more effective than standard-dose vaccine in veterans³⁴ and US Medicare beneficiaries.³⁵

The high-dose vaccine is rapidly becoming the primary vaccine given to people ages 65 and older in retail pharmacies, where vaccination begins earlier in the season than in providers’ offices.³⁶ Some studies have shown that the standard-dose vaccine wanes in effectiveness toward the end of the influenza season (particularly if the season is long) if it is given very early. It remains to be seen whether the same applies to the high-dose influenza vaccine.

Some advocate twice-annual influenza vaccination, particularly for older adults living in tropical and subtropical areas, where influenza seasons are more prolonged. However, a recently published study observed reductions in influenza-specific hemagglutination inhibition and cell-mediated immunity after twice-annual vaccination.³⁷

Vaccination is beneficial during pregnancy

Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants.

One recently published study showed that 18% of infants who developed influenza required hospitalization.³⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively.

Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.³⁹

Some studies have shown that influenza virus infection can increase susceptibility to certain bacterial infections. A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.⁴⁰

Factors that make vaccination less effective

Several factors including age-related frailty and iatrogenic and disease-related immunosuppression can affect vaccine effectiveness.

Frailty. A recent study showed that vaccine effectiveness was 77.6% in nonfrail older adults but only 58.7% in frail older adults.⁴¹

Immunosuppression. Temporary discontinuation of methotrexate for 2 weeks after influenza vaccination in patients with rheumatoid arthritis improves vaccine immunogenicity without precipitating disease flare.⁴² Solid-organ and hematopoietic stem cell transplant recipients who received influenza vaccine were less likely to develop pneumonia and require intensive care unit admission.⁴³

The high-dose influenza vaccine is more immunogenic than the standard-dose vaccine in solid-organ transplant recipients.⁴⁴

Statins are widely prescribed and have recently been associated with reduced influenza vaccine effectiveness against medically attended acute respiratory illness, but their benefits in preventing cardiovascular events outweigh this risk.⁴⁵

FUTURE VACCINE CONSIDERATIONS

Moving away from eggs

During the annual egg-based production process, which takes several months, the influenza vaccine acquires antigenic changes that allow replication in eggs, particularly in the hemagglutinin protein, which mediates receptor binding. This process of egg adaptation may cause antigenic changes that decrease vaccine effectiveness against circulating viruses.

The cell-based baculovirus influenza vaccine grown in dog kidney cells has higher antigenic content and is not subject to the limitations of egg-based vaccine, although it still requires annual updates. A recombinant influenza vaccine reduces the probability of influenza-like illness by 30% compared with the egg-based influenza vaccine, but also still requires annual updates.⁴⁶ The market share of these non-egg-based vaccines is small, and thus their effectiveness has yet to be demonstrated.

The US Department of Defense administered the cell-based influenza vaccine to about one-third of Armed Forces personnel, their families, and retirees in the 2017–2018 influenza seasons, and data on its effectiveness are expected in the near future.⁴⁷

A universal vaccine would be ideal

The quest continues for a universal influenza vaccine, one that remains protective for several years and does not require annual updates.⁴⁸ Such a vaccine would protect against seasonal epidemic influenza drift variants and pandemic strains. More people could likely be persuaded to be vaccinated once rather than every year.

David Schumick, medical illustrator; adapted from reference 49; illustration of the influenza hemagglutinin created in part with data from reference 50.

An ideal universal vaccine would be suitable for all age groups, at least 75% effective against symptomatic influenza virus infection, protective against all influenza A viruses (influenza A, not B, causes pandemics and seasonal epidemics), and durable through multiple influenza seasons.⁵¹

Research and production of such a vaccine are expected to require funding of about $1 billion over the next 5 years.

Boosting effectiveness

Estimates of influenza vaccine effectiveness range from 40% to 60% in years when the vaccine viruses closely match the circulating viruses, and variably lower when they do not match. The efficacy of most other vaccines given to prevent other infections is much higher.

New technologies to improve influenza vaccine effectiveness are needed, particularly for influenza A(H3N2) viruses, which are rapidly evolving and are highly susceptible to egg-adaptive mutations in the manufacturing process.

In one study, a nanoparticle vaccine formulated with a saponin-based adjuvant induced hemagglutination inhibition responses that were even greater than those induced by the high-dose vaccine.⁵²

Immunoglobulin A (IgA) may be a more effective vaccine target than traditional influenza vaccines that target IgG, since different parts of IgA may engage the influenza virus simultaneously.⁵³

Vaccines can be developed more quickly than in the past. The timeline from viral sequencing to human studies with deoxyribonucleic acid plasmid vaccines decreased from 20 months in 2003 for the severe acquired respiratory syndrome coronavirus to 11 months in 2006 for influenza A/Indonesia/2006 (H5), to 4 months in 2009 for influenza A/California/2009 (H1), to 3.5 months in 2016 for Zika virus.⁵⁴ This is because it is possible today to sequence a virus and insert the genetic material into a vaccine platform without ever having to grow the virus.

Numerous studies have found anti-influenza medications to be effective. Nevertheless, in an analysis of the 2011–2016 influenza seasons, only 15% of high-risk patients were prescribed anti-influenza medications within 2 days of symptom onset, including 37% in those with laboratory-confirmed influenza.⁵⁵ Fever was associated with an increased rate of antiviral treatment, but 25% of high-risk outpatients were afebrile. Empiric treatment of 4 high-risk outpatients with acute respiratory illness was needed to treat 1 patient with influenza.⁵⁵

Treatment with a neuraminidase inhibitor within 2 days of illness has recently been shown to improve survival and shorten duration of viral shedding in patients with avian influenza A(H7N9) infection.⁵⁶ Antiviral treatment within 2 days of illness is associated with improved outcomes in transplant recipients⁵⁷ and with a lower risk of otitis media in children.⁵⁸

Appropriate anti-influenza treatment is as important as avoiding unnecessary antibiotics. Regrettably, as many as one-third of patients with laboratory-confirmed influenza are prescribed antibiotics.⁵⁹

The US Food and Drug Administration warns against fraudulent unapproved over-the-counter influenza products.⁶⁰

Baloxavir marboxil

Baloxavir marboxil is a new anti-influenza medication approved in Japan in February 2018 and anticipated to be available in the United States sometime in 2019.

This prodrug is hydrolyzed in vivo to the active metabolite, which selectively inhibits cap-dependent endonuclease enzyme, a key enzyme in initiation of messenger ribonucleic acid synthesis required for influenza viral replication.⁶¹

In a double-blind phase 3 trial, the median time to alleviation of influenza symptoms is 26.5 hours shorter with baloxavir marboxil than with placebo. One tablet was as effective as 5 days of the neuraminidase inhibitor oseltamivir and was associated with greater reduction in viral load 1 day after initiation, and similar side effects.⁶² Of concern is the emergence of nucleic acid substitutions conferring resistance to baloxavir; this occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 and 3 trials, respectively.

CLOSING THE GAPS

Several gaps in the management of influenza persist since the 1918 pandemic.¹ These include gaps in epidemiology, prevention, diagnosis, treatment, and prognosis.

• Global networks wider than current ones are needed to address this global disease and to prioritize coordination efforts.
• Establishing and strengthening clinical capacity is needed in limited resource settings. New technologies are needed to expedite vaccine development and to achieve progress toward a universal vaccine.
• Current diagnostic tests do not distinguish between seasonal and novel influenza A viruses of zoonotic origin, which are expected to cause the next pandemic.
• Current antivirals have been shown to shorten duration of illness in outpatients with uncomplicated influenza, but the benefit in hospitalized patients has been less well established.
• In 2007, resistance of seasonal influenza A(H1N1) to oseltamivir became widespread. In 2009, pandemic influenza A(H1N1), which is highly susceptible to oseltamivir, replaced the seasonal virus and remains the predominantly circulating A(H1N1) strain.
• A small-molecule fragment, N-cyclohexyaltaurine, binds to the conserved hemagglutinin receptor-binding site in a manner that mimics the binding mode of the natural receptor sialic acid. This can serve as a template to guide the development of novel broad-spectrum small-molecule anti-influenza drugs.⁶³
• Biomarkers that can accurately predict development of severe disease in patients with influenza are needed.

Primary care physicians are tasked with a wide variety of issues affecting men. This article reviews the latest research in 4 areas of men’s health commonly addressed in primary care:

• Medical management of benign prostatic hyperplasia (BPH)
• Prostate cancer screening and treatment
• Medical management of erectile dysfunction
• Use of supplements.

See related commentary

MEDICAL MANAGEMENT OF BPH

An 84-year-old man with a history of hypertension, type 2 diabetes, hyperlipidemia, BPH, mild cognitive impairment, and osteoarthritis presents for a 6-month follow-up, accompanied by his son.

Two years ago he was started on a 5-alpha reductase inhibitor and an alpha-blocker for worsening BPH symptoms. His BPH symptoms are currently under control, with an American Urological Association (AUA) symptom index score of 7 of a possible 35 (higher scores being worse).

However, both the patient and son are concerned about the number of medications he is on and wonder if some could be eliminated.

Assessment tools

BPH is a common cause of lower urinary tract symptoms in older men. Evidence-based tools to help the clinician and patient decide on when to consider treatment for symptoms are:

• The AUA symptom index¹
• The International Prostate Symptom Score (IPSS).²

An AUA symptom index score or IPSS score of 8 through 19 of a possible 35 is consistent with moderate symptoms, while a score of 20 or higher indicates severe symptoms.

Combination therapy or monotherapy?

Monotherapy with an alpha-blocker or a 5-alpha reductase inhibitor is often the first-line treatment for BPH-related lower urinary tract symptoms.³ However, combination therapy with both an alpha-blocker and a 5-alpha reductase inhibitor is another evidence-based option.

The Medical Therapy of Prostatic Symptoms study,⁴ a randomized controlled trial, reported that long-term combination therapy reduced the risk of BPH clinical progression better than monotherapy. The same trial also found that either combination therapy or finasteride alone (a 5-alpha reductase inhibitor) reduced the risk of acute urinary retention and the future need for invasive therapy.

Monotherapy after a period of combination therapy?

There is also evidence to support switching from combination to monotherapy after an initial treatment period.

Matsukawa et al⁵ examined the effects of withdrawing the alpha-blocker from BPH combination therapy in a study in 140 patients. For 12 months, all patients received the alpha-blocker silodosin and the 5-alpha reductase inhibitor dutasteride. At 12 months, the remaining 132 patients (8 patients had been lost to follow-up) were randomized to continue combination therapy or to take dutasteride alone for another 12 months. They were evaluated at 0, 12, and 24 months by questionnaires (the IPSS and Overactive Bladder Symptom Score) and urodynamic testing (uroflowmetry, cystometrography, and pressure-flow studies).

There were no significant differen­ces in subjective symptoms and bladder outlet obstruction between patients who continued combination therapy and those who switched to dutasteride monotherapy. In the monotherapy group, those whose symptoms worsened weighed more (68.8 kg vs 62.6 kg, P =.002) and had a higher body mass index (BMI) (26.2 kg/m² vs 22.8 kg/m², P < .001) than those whose symptoms stayed the same or got better.

These findings of successful alpha-blocker withdrawal were consistent with those of other studies.

The Symptom Management After Reducing Therapy study⁶ showed that 80% of men with an IPSS score less than 20 who changed to dutasteride monotherapy did not have a noticeable worsening of their symptoms.

Baldwin et al⁷ noted similar success after withdrawing the alpha-blocker doxazosin in patients on finasteride.

Review all medications

The National Health and Nutrition Examination Survey noted that the estimated prevalence of polypharmacy increased from 8% in 1999 to 15% in 2011.⁸ Many commonly used medications, such as decongestants, antihistamines, and anticholinergic agents, can worsen BPH symptoms,⁹ so it is reasonable to consistently review the patient’s medications to weigh the risks and benefits and determine which ones align with the patient’s personal care goals.

BPH: Take-home points

• Combination therapy with an alpha-blocker and a 5-alpha reductase inhibitor is an effective regimen for BPH.
• Polypharmacy is a significant problem in the elderly.
• Withdrawing the alpha-blocker component from BPH combination therapy can be considered after 1 year of combination therapy in patients whose symptoms have been well controlled.

A 60-year-old patient calls you after receiving his laboratory testing report from his insurance physical. His prostate-specific antigen (PSA) level is 5.1 ng/mL, and he has several questions:

• Should he have agreed to the screening?
• How effective is the screening?
• What are the next steps?

Is PSA screening useful?

Over the last few years, there has been great debate as to the utility of screening for prostate cancer.

The US Centers for Disease Control and Prevention¹⁰ reported that in 2014, an estimated 172,258 men in the United States were diagnosed with prostate cancer, but only 28,343 men died of it. These statistics support the notion that screening programs may be detecting what might otherwise be a silent disease.

The US Preventive Services Task Force (USPSTF)¹¹ recommends against blanket PSA screening, in view of the low probability that it reduces the risk of death from prostate cancer. For men ages 55 through 69, current guidelines give a grade C recommendation to PSA screening, meaning there is moderate agreement that the benefit is likely small, and screening should be selectively offered based on professional judgment and patient preference. In men ages 70 and older who are not at high risk, the guideline gives screening a grade D recommendation, meaning there is moderate evidence that there is no benefit from the practice. This is a change from the 2012 USPSTF guidelines,¹² which gave a grade D recommendation to PSA screening for all ages.

The American Urological Association¹³ recommends against PSA screening in men under age 40 or ages 70 and older. It does not recommend routine screening in those ages 40 to 54 at average risk, but it says the decision should be individualized in this age group in those at higher risk (eg, with a positive family history, African American). At ages 55 through 69, it recommends shared decision-making, taking into account cancer risk and life expectancy. In those who opt for screening, an interval of 2 years or more may be preferred over annual screening to reduce the risk of overdiagnosis.

The USPSTF recommendations rely heavily on data from 2 trials: the European Randomized Study of Screening for Prostate Cancer (ERSPC)¹⁴ and the Prostate, Lung, Colorectal, and Ovarian Screening (PLCO) trial.¹⁵

The ERSPC¹⁴ demonstrated that screening for prostate cancer reduced deaths from prostate cancer by 20%, with an absolute risk difference of 0.71 deaths per 1,000 men; 1,410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent 1 death from prostate cancer. Screening also decreased the risk of developing metastatic disease by 30%.¹⁶ On the negative side, screening increased the risk of overdiagnosis and other harms such as bleeding, sepsis, and incontinence.

The PLCO trial,¹⁵ in contrast, found no difference in death rates between men randomly assigned to annual screening and those assigned to usual care. Differences between the trial results were thought to be due to different practice settings as well as study implementation and compliance.

Tsodikov et al¹⁷ reanalyzed data from the ERSPC and the PLCO trial using 3 different mathematical models to estimate the effects of screening in both trials compared with no screening. The analysis found no evidence that the effects of screening vs not screening differed between the 2 trials, ultimately concluding that PSA screening reduced prostate cancer deaths by 25% to 32%, which the authors inferred was primarily a result of earlier detection of cancer.

The Cluster Randomized Trial of PSA Testing for Prostate Cancer,¹⁸ published in March 2018, explored the effect of single PSA screening vs no screening on prostate cancer mortality rates in 419,582 men ages 50 through 69. Although screening detected more cases of low-risk prostate cancer, there was no significant difference in prostate cancer mortality rates after a median follow-up of 10 years. However, 10% to 15% of the control group was estimated to have also been screened, and these results do not directly speak to the efficacy of serial PSA screening.

Extended follow-up of this trial is planned to report on long-term survival benefits and whether screening lowers the risk of metastasis.

Imaging-guided prostate biopsy

Once a patient is found to have an elevated PSA level, standard practice has been to perform transrectal ultrasonography to obtain 12 core biopsy samples. The results indicate whether the prostate contains cancer, how aggressive the cancer is (Gleason score), and whether there is extracapsular extension.

In the past, magnetic resonance imaging (MRI) of the prostate before biopsy was thought to be too costly, and many insurance plans do not currently cover it.

Pahwa et al,¹⁹ however, in a cost-effectiveness study using a decision-analysis model, found that using MRI to detect lesions and then guide biopsy by triaging patients into proper treatment pathways added health benefits in a cost-effective manner in 94.05% of simulations. These benefits were found across all age groups.

This study demonstrated that doctors could use MRI to better evaluate patients for potentially harmful lesions. If a focus of cancer is found, it can be biopsied; if no cancer is seen on MRI, the patient can avoid biopsy completely. Additionally, though MRI tended to miss low-risk cancers, these cancers are thought to disproportionately lead to higher healthcare costs through unnecessary treatment. Therefore, a negative MRI study was believed to be an excellent sign that the patient does not have aggressive prostate cancer. This approach led to a net gain of 0.251 additional quality-adjusted life years compared with the standard biopsy strategy.

The Prostate MRI Imaging Study²⁰ also found MRI to be effective in the prostate cancer workup. In this trial, 576 men who had never undergone biopsy underwent multiparametric MRI, transrectal ultrasonography-guided biopsy, and the reference standard, ie, transperineal template prostate mapping biopsy. Of those who underwent biopsy, 71% received a diagnosis of prostate cancer, and 40% had clinically significant disease. In patients with clinically significant disease, MRI was more sensitive than ultrasonography-guided biopsy (93% vs 48%, P < .0001) but less specific (41% vs 96%, P < .0001).

Based on these findings, if biopsy were performed only in those who had suspicious lesions on MRI, 27% of men with elevated PSA could avoid biopsy and its potential complications such as bleeding and sepsis, which occurred in 5.9% of the biopsy group.

The Prostate Evaluation for Clinically Important Disease: Sampling Using Image Guidance or Not? trial²¹ more recently studied MRI with or without targeted biopsy vs standard transrectal ultrasonography-guided biopsy in 500 men who had not undergone biopsy before, and reported similar results. MRI with or without biopsy led to fewer biopsies and less overdetection of clinically insignificant prostate cancers compared with the standard approach. Furthermore, those in the MRI-targeted biopsy group were 13% less likely to receive a diagnosis of clinically insignificant cancer than those who received the standard biopsy (adjusted difference −13 percentage points, 95% confidence interval [CI] −19 to −7, P < .001).

Together, these data provide another argument for adding multiparametric MRI to the workup of men with an elevated PSA level.

Surveillance vs treatment for prostate cancer

Once prostate cancer is diagnosed, surveillance is becoming an increasingly common management strategy.

The Prostate Cancer Intervention Versus Observation Trial (PIVOT),²² one of the largest and longest trials involving cancer patients, offered further evidence that active surveillance and less intervention for men with prostate cancer is a better approach in many cases. This trial compared prostatectomy and observation alone in a randomized fashion. Inclusion for the study required men to be medically fit for radical prostatectomy, along with having histologically confirmed localized prostate cancer (stage T1-T2NxM0 in the tumor-node-metastasis classification system) of any grade diagnosed within the last 12 months.

During 19.5 years of follow-up, 223 (61.3%) of the 364 men randomly assigned to radical prostatectomy died, compared with 245 (66.8%) of 367 men in the observation group; the difference was not statistically different (P = .06). Only 9.4% of the deaths were due to prostate cancer, 7.4% in the surgery group and 11.4% in the observation group (P = .06).

Surgery was associated with a lower all-cause mortality rate than observation in the subgroup of patients with intermediate-risk prostate cancer (defined as PSA 10–20 ng/mL and a Gleason score of 7). Surgery was also associated with less disease progression.²²

This finding is in line with previous data from the Scandinavian Prostate Cancer Group Study Number 4,²³ as well as the much larger Prostate Testing for Cancer and Treatment (ProtecT) trial,²⁴ both of which reported that metastasis was 1.5 and 2.6 times as common, respectively, in participants in the active surveillance groups. However, in the PIVOT trial, those in the surgery group were significantly more likely than those in the observation group to have erectile dysfunction and urinary incontinence at 10 years.

Therefore, in men with localized disease and in those with low-risk PSA levels, both the PIVOT and ProtecT trials suggest that death from prostate cancer is uncommon and that observation may be more appropriate.

Prostate cancer: Take-home points

• A new look at 2 large trials of PSA screening strengthened evidence that testing in the right patient population can reduce deaths from prostate cancer, but a third recently published trial that found no benefit from 1-time screening may reopen debate on the topic.
• MRI offers a better method than ultrasonography-guided biopsy to triage patients thought to be at high risk of prostate cancer and tends to limit costly overtreatment of disease that likely would not cause death.
• Surgery for prostate cancer may not prolong life but could reduce disease progression, at the risk of more adverse effects.
• Shared decision-making should be practiced when deciding whether to use active surveillance or active treatment of diagnosed prostate cancer.

A 62-year-old man with hypertension, hyperlipidemia, peripheral artery disease, and type 2 diabetes presents for a 6-month follow-up. His medications include aspirin, metformin, lisinopril, and atorvastatin, all of which he takes without problems. Over the past several months, he has noticed that his erections are not adequate for sexual intercourse. He recently heard that a generic version of sildenafil has just become available, and he wonders if it might benefit him.

Erectile dysfunction is common, associated with chronic diseases

Erectile dysfunction, ie, persistent inability to obtain and maintain an erection sufficient to permit satisfactory sexual intercourse,^25,26 is estimated to affect nearly 20% of men over the age of 20 and 75% of men over the age of 75.²⁷

In age-adjusted models, erectile dysfunction has been shown²⁸ to be associated with:

• History of cardiovascular disease (odds ratio [OR] 1.63, 95% CI 1.02–2.63)
• Diabetes (OR 3.90, 95% CI 2.16–7.04)
• Treated hypertension vs no hypertension (OR 2.22, 95% CI 1.30–3.80)
• Current smoking vs never smoking (OR 1.63, 95% CI 1.01–2.62)
• BMI greater than 30 kg/m² vs less than 25 kg/m² (OR 1.80, 95% CI 1.03–3.14).

Because of the strong association between cardiovascular disease and erectile dysfunction, the presence of one often suggests the need to screen for the other.²⁹ While tools such as the International Index of Erectile Function (IIEF-5) have been developed to evaluate erectile dysfunction, it is most often diagnosed on the basis of clinical impression, while validated assessment methods are reserved for clinical trials.²⁸

Multiple causes of erectile dysfunction

Erectile dysfunction arises from inadequate penile tissue response to a sexual signal. The response can be disrupted at several points. For example, damage to vascular smooth muscle cells (eg, from age or obesity) and endothelial cells (from smoking or diabetes) and narrowing of the vascular lumen (from atherosclerosis or hypertension) have all been shown to impair engorgement of the corpus cavernosum.³⁰ In addition, denervation from prostate surgery or spinal trauma and psychogenic causes should be recognized in discussions with patients.

Drugs for erectile dysfunction

Pharmacologic management of erectile dysfunction includes oral, sublingual, intracavernosal, and intraurethral therapies.³¹ Treatment in primary care settings usually includes addressing underlying chronic diseases³² and prescribing phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil, and avanafil). These drugs work by increasing local concentrations of cyclic guanosine monophosphate in the corpus cavernosum to induce vasodilation.³³

While these 4 drugs are still patent-protected, a manufacturer has been allowed to introduce a generic version of sildenafil into US markets, and a generic version of tadalafil is expected to be available soon.

Sildenafil, tadalafil, and vardenafil have been studied and found to have some degree of effectiveness in erectile dysfunction caused by damage to the penile vasculature, denervation, and spinal cord injury.³⁴ All drugs of this class have adverse effects including headache, facial flushing, and nasal congestion, but the drugs are generally well tolerated.³⁵

Sildenafil and tadalafil improve IIEF-5 scores by a similar margin, raising scores on the erectile domain subsection from approximately 14 of a possible 30 to approximately 24 of 30 in a trial of both drugs.³⁶ However, multiple crossover studies comparing the 2 drugs have shown that nearly 75% of patients prefer tadalafil to sildenafil,^36,37 perhaps because of tadalafil’s longer duration of action.³⁴

There is little evidence to suggest that vardenafil is more effective or more often preferred by patients than tadalafil or sidenafil.^34,38 And though data on the newest drug on the market, avanafil, are limited, a meta-analysis concluded that it may be less effective than tadalafil and without significant differences in terms of safety.³⁹

Other treatments

Lifestyle modifications, especially smoking cessation and exercise, have been shown to reduce the risk of erectile dysfunction with varying effect sizes across studies.^40–42 Moreover, factors such as obesity, alcohol use, and smoking may cause irreversible harm, and thus a healthy lifestyle should be encouraged.⁴¹

While there is only weak evidence for the use of psychological interventions alone for treating most types of erectile dysfunction, one meta-analysis found that the combination of psychological intervention and a phosphodiesterase-5 inhibitor improved sexual satisfaction more than drug therapy alone.⁴³

Erectile dysfunction: Take-home points

• Erectile dysfunction is common, affecting nearly 20% of men over the age of 20 and over 75% of men over the age of 75.
• Erectile dysfunction is often associated with chronic disease and may suggest the need to screen for cardiovascular disease.
• Treating underlying chronic diseases may help, and phosphodiesterase-5 inhibitors are effective; tadalafil may be most often preferred.

A 68-year-old man with a history of hypertension, BPH, and erectile dysfunction presents for a 6-month follow-up. His medication use includes lisinopril, which he takes without problems. He denies any new physical symptoms. His physical examination is unremarkable. He says he has heard about supplements that might help with his sexual performance and hopes to discuss recommendations during the visit.

A burgeoning, unregulated industry

Since the passage of the Dietary Supplement and Health Education Act in 1994, a law that decreased oversight of the supplement industry, spending on supplements has skyrocketed to over $41.1 billion each year.⁴⁴ Advertisements for these products typically claim that they improve general mental and physical health, sexual and romantic performance, leanness, and muscularity.⁴⁵ A national survey of men ages 57 and older reported that the most popular products were aimed at nutrition (such as multivitamins), cardiovascular health (such as omega-3 fatty acids), and chronic conditions (such as saw palmetto for BPH).⁴⁶

Little evidence of efficacy

There is little evidence to support the use of most supplements to improve men’s health. For example, a study in 82,405 men found no association between mortality rates and multivitamin use (hazard ratio [HR] 1.07, 95% CI 0.96–1.19).⁴⁷ Even for specific uses, such as cognitive performance, randomized trials exploring the effects of multivitamins in men have been largely negative.⁴⁸

The positive trials that have been reported are often of low quality and are funded by supplement manufacturers. For example, one of the few trials that reported a positive association between multivitamin supplementation and cognition in men was underpowered (N = 51) and found improvement in only 1 of 19 cognitive domains.⁴⁹ Despite the poor design and results to the contrary, this industry-funded study nevertheless concluded that multivitamins may play a role in improving elements of memory.

Evidence of possible harm from antioxidants

While not always specific to men, many meta-analyses have explored the effects of antioxidant supplements on cardiovascular and mortality risk. Most of them concluded that antioxidant supplements have no benefit and that some may actually be harmful.

For example, multiple meta-analyses of vitamin E supplementation found no cardiovascular benefit but possible increases in all-cause mortality rates in those taking high doses (risk ratio 1.04, 95% CI 1.01–1.07).^50,51

Another meta-analysis of 180,938 partici­pants in high-quality studies found an increased risk of all-cause mortality associated with independent intake of several antioxidant vitamins, including beta-carotene (risk ratio 1.07, 95% CI 1.02–1.11) and vitamin A (risk ratio 1.16, 95% CI 1.10–1.24), while intake of vitamin C and selenium had no impact on mortality.⁵²

Similarly, although nearly 10% of US adults report taking omega-3 fatty acid supplements, a review of 24 randomized controlled trials and meta-analyses published between 2005 and 2012 concluded that only 2 supported the use of these supplements for any health benefit.⁵³

Can supplements improve sexual function, prostate health?

To improve sexual function. A 2015 narrative review of the ingredients in General Nutrition Center’s top 30 best-selling products targeted at improving men’s sexual performance (including improving libido and erectile dysfunction) found only poor evidence for any efficacy.⁵⁴ The few studies that did support the use of select supplements, including B vitamins in people with diabetes, L-arginine, and yohimbine, were deemed to be of poor quality or showed a smaller effect size compared with standard medical therapy.

To prevent prostate cancer. Studies of supplement use to improve prostate health have had mixed results. For example, multiple large case-control studies have suggested that taking vitamin D^55,56 or vitamin C⁵⁷ is not associated with prostate cancer risk, while increased vitamin A^58,59 and E^60,61 intake is associated with inconsistent increases in prostate cancer risk.

In the Selenium and Vitamin E Cancer Prevention Trial,⁶² a randomized controlled trial in 35,533 men, those assigned to receive vitamin E supplementation were 17% more likely to get prostate cancer than were those assigned to placebo (HR 1.17, 99% CI 1.004–1.36, P = .008).

However, there are plausible biologic links between nutraceuticals and prostate cancer. For example, studies have linked genetic polymorphisms in vitamin D receptors⁶³ as well as intake of natural androgen receptor modulators, such as the most active polyphenol in green tea,⁶⁴ to prostate cancer risk and aggressiveness in certain populations. This led a recent review to conclude that there is some biologic plausibility, but at present little epidemiologic evidence, to support any dietary supplement’s ability to broadly affect prostate cancer risk.⁶⁵

Interest continues in exploring the targeted use of nutraceuticals as adjuvant therapy in specific populations at risk of prostate cancer.^66,67

To treat BPH. There is a similar dearth of clinical or population-based evidence that supplements can broadly affect BPH symptoms. For example, in a 2012 Cochrane review of Serenoa repens (saw palmetto) utilizing only high-quality evidence, there was no evidence that supplement use significantly reduced lower urinary tract symptoms, nocturia, or peak urine flow in BPH patients, and this was true even when the supplement was taken at triple-strength doses.⁶⁸

For other diseases. There is also limited evidence that supplements can affect other chronic diseases. For example, a meta-analysis of 3,803 patients found that glucosamine, chondroitin, and their combination had no impact on joint pain or joint space narrowing in patients with osteoarthritis of the knee or hip.⁶⁹

Even when there is some evidence to suggest benefit from supplementation, study heterogeneity and varying evidence quality limit confidence in the conclusions. For example, meta-analyses suggest garlic may improve blood pressure control in those with hypertension⁷⁰ and improve lipid and blood glucose control in type 2 diabetes.⁷¹ However, most of the trials included in those systematic reviews were underpowered, with samples as low as 10 patients, and many suffered from improper design, such as inadequate blinding of researchers. In addition, these meta-analyses often do not report adverse events, suggesting that higher quality studies would be needed to adequately measure event rates. As such, there is need for caution and a case-by-case review before recommending even a seemingly benign supplement like garlic to patients.

In total, there is only limited evidence to support the efficacy of supplements across many diseases and concerns common to men in primary care. This includes improving general health, cardiovascular health, sexual functioning, or other chronic diseases. While a supplement’s placebo effect may at times provide some benefit, supplements are much less strictly regulated since the passing of the 1994 act, and even vitamin supplementation has been shown to be associated with negative health outcomes. As such, a patient’s use of supplements requires careful consideration and shared decision-making.

Supplements: Take-home points

• Supplements are only loosely regulated by the federal government.
• There is some biologic but limited epidemiologic evidence for the use of multivitamins to improve cognition or mortality rates; for the use of antioxidant vitamins or omega-3 fatty acids to improve cardiovascular health; for the use of any of the top-selling sexual enhancement supplements to improve libido or erectile function; and for the use of vitamins or other supplements for improving BPH or reducing prostate cancer risk. Using supplements may in some cases be harmful.
• Given the heterogeneity of studies of supplements to manage chronic diseases and a lack of reporting of adverse events, careful consideration is needed when recommending supplements to patients.

Primary care physicians are tasked with a wide variety of issues affecting men. This article reviews the latest research in 4 areas of men’s health commonly addressed in primary care:

• Medical management of benign prostatic hyperplasia (BPH)
• Prostate cancer screening and treatment
• Medical management of erectile dysfunction
• Use of supplements.

See related commentary

MEDICAL MANAGEMENT OF BPH

An 84-year-old man with a history of hypertension, type 2 diabetes, hyperlipidemia, BPH, mild cognitive impairment, and osteoarthritis presents for a 6-month follow-up, accompanied by his son.

Two years ago he was started on a 5-alpha reductase inhibitor and an alpha-blocker for worsening BPH symptoms. His BPH symptoms are currently under control, with an American Urological Association (AUA) symptom index score of 7 of a possible 35 (higher scores being worse).

However, both the patient and son are concerned about the number of medications he is on and wonder if some could be eliminated.

Assessment tools

BPH is a common cause of lower urinary tract symptoms in older men. Evidence-based tools to help the clinician and patient decide on when to consider treatment for symptoms are:

• The AUA symptom index¹
• The International Prostate Symptom Score (IPSS).²

An AUA symptom index score or IPSS score of 8 through 19 of a possible 35 is consistent with moderate symptoms, while a score of 20 or higher indicates severe symptoms.

Combination therapy or monotherapy?

Monotherapy with an alpha-blocker or a 5-alpha reductase inhibitor is often the first-line treatment for BPH-related lower urinary tract symptoms.³ However, combination therapy with both an alpha-blocker and a 5-alpha reductase inhibitor is another evidence-based option.

The Medical Therapy of Prostatic Symptoms study,⁴ a randomized controlled trial, reported that long-term combination therapy reduced the risk of BPH clinical progression better than monotherapy. The same trial also found that either combination therapy or finasteride alone (a 5-alpha reductase inhibitor) reduced the risk of acute urinary retention and the future need for invasive therapy.

Monotherapy after a period of combination therapy?

There is also evidence to support switching from combination to monotherapy after an initial treatment period.

Matsukawa et al⁵ examined the effects of withdrawing the alpha-blocker from BPH combination therapy in a study in 140 patients. For 12 months, all patients received the alpha-blocker silodosin and the 5-alpha reductase inhibitor dutasteride. At 12 months, the remaining 132 patients (8 patients had been lost to follow-up) were randomized to continue combination therapy or to take dutasteride alone for another 12 months. They were evaluated at 0, 12, and 24 months by questionnaires (the IPSS and Overactive Bladder Symptom Score) and urodynamic testing (uroflowmetry, cystometrography, and pressure-flow studies).

There were no significant differen­ces in subjective symptoms and bladder outlet obstruction between patients who continued combination therapy and those who switched to dutasteride monotherapy. In the monotherapy group, those whose symptoms worsened weighed more (68.8 kg vs 62.6 kg, P =.002) and had a higher body mass index (BMI) (26.2 kg/m² vs 22.8 kg/m², P < .001) than those whose symptoms stayed the same or got better.

These findings of successful alpha-blocker withdrawal were consistent with those of other studies.

The Symptom Management After Reducing Therapy study⁶ showed that 80% of men with an IPSS score less than 20 who changed to dutasteride monotherapy did not have a noticeable worsening of their symptoms.

Baldwin et al⁷ noted similar success after withdrawing the alpha-blocker doxazosin in patients on finasteride.

Review all medications

The National Health and Nutrition Examination Survey noted that the estimated prevalence of polypharmacy increased from 8% in 1999 to 15% in 2011.⁸ Many commonly used medications, such as decongestants, antihistamines, and anticholinergic agents, can worsen BPH symptoms,⁹ so it is reasonable to consistently review the patient’s medications to weigh the risks and benefits and determine which ones align with the patient’s personal care goals.

BPH: Take-home points

• Combination therapy with an alpha-blocker and a 5-alpha reductase inhibitor is an effective regimen for BPH.
• Polypharmacy is a significant problem in the elderly.
• Withdrawing the alpha-blocker component from BPH combination therapy can be considered after 1 year of combination therapy in patients whose symptoms have been well controlled.

A 60-year-old patient calls you after receiving his laboratory testing report from his insurance physical. His prostate-specific antigen (PSA) level is 5.1 ng/mL, and he has several questions:

• Should he have agreed to the screening?
• How effective is the screening?
• What are the next steps?

Is PSA screening useful?

Over the last few years, there has been great debate as to the utility of screening for prostate cancer.

The US Centers for Disease Control and Prevention¹⁰ reported that in 2014, an estimated 172,258 men in the United States were diagnosed with prostate cancer, but only 28,343 men died of it. These statistics support the notion that screening programs may be detecting what might otherwise be a silent disease.

The US Preventive Services Task Force (USPSTF)¹¹ recommends against blanket PSA screening, in view of the low probability that it reduces the risk of death from prostate cancer. For men ages 55 through 69, current guidelines give a grade C recommendation to PSA screening, meaning there is moderate agreement that the benefit is likely small, and screening should be selectively offered based on professional judgment and patient preference. In men ages 70 and older who are not at high risk, the guideline gives screening a grade D recommendation, meaning there is moderate evidence that there is no benefit from the practice. This is a change from the 2012 USPSTF guidelines,¹² which gave a grade D recommendation to PSA screening for all ages.

The American Urological Association¹³ recommends against PSA screening in men under age 40 or ages 70 and older. It does not recommend routine screening in those ages 40 to 54 at average risk, but it says the decision should be individualized in this age group in those at higher risk (eg, with a positive family history, African American). At ages 55 through 69, it recommends shared decision-making, taking into account cancer risk and life expectancy. In those who opt for screening, an interval of 2 years or more may be preferred over annual screening to reduce the risk of overdiagnosis.

The USPSTF recommendations rely heavily on data from 2 trials: the European Randomized Study of Screening for Prostate Cancer (ERSPC)¹⁴ and the Prostate, Lung, Colorectal, and Ovarian Screening (PLCO) trial.¹⁵

The ERSPC¹⁴ demonstrated that screening for prostate cancer reduced deaths from prostate cancer by 20%, with an absolute risk difference of 0.71 deaths per 1,000 men; 1,410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent 1 death from prostate cancer. Screening also decreased the risk of developing metastatic disease by 30%.¹⁶ On the negative side, screening increased the risk of overdiagnosis and other harms such as bleeding, sepsis, and incontinence.

The PLCO trial,¹⁵ in contrast, found no difference in death rates between men randomly assigned to annual screening and those assigned to usual care. Differences between the trial results were thought to be due to different practice settings as well as study implementation and compliance.

Tsodikov et al¹⁷ reanalyzed data from the ERSPC and the PLCO trial using 3 different mathematical models to estimate the effects of screening in both trials compared with no screening. The analysis found no evidence that the effects of screening vs not screening differed between the 2 trials, ultimately concluding that PSA screening reduced prostate cancer deaths by 25% to 32%, which the authors inferred was primarily a result of earlier detection of cancer.

The Cluster Randomized Trial of PSA Testing for Prostate Cancer,¹⁸ published in March 2018, explored the effect of single PSA screening vs no screening on prostate cancer mortality rates in 419,582 men ages 50 through 69. Although screening detected more cases of low-risk prostate cancer, there was no significant difference in prostate cancer mortality rates after a median follow-up of 10 years. However, 10% to 15% of the control group was estimated to have also been screened, and these results do not directly speak to the efficacy of serial PSA screening.

Extended follow-up of this trial is planned to report on long-term survival benefits and whether screening lowers the risk of metastasis.

Imaging-guided prostate biopsy

Once a patient is found to have an elevated PSA level, standard practice has been to perform transrectal ultrasonography to obtain 12 core biopsy samples. The results indicate whether the prostate contains cancer, how aggressive the cancer is (Gleason score), and whether there is extracapsular extension.

In the past, magnetic resonance imaging (MRI) of the prostate before biopsy was thought to be too costly, and many insurance plans do not currently cover it.

Pahwa et al,¹⁹ however, in a cost-effectiveness study using a decision-analysis model, found that using MRI to detect lesions and then guide biopsy by triaging patients into proper treatment pathways added health benefits in a cost-effective manner in 94.05% of simulations. These benefits were found across all age groups.

This study demonstrated that doctors could use MRI to better evaluate patients for potentially harmful lesions. If a focus of cancer is found, it can be biopsied; if no cancer is seen on MRI, the patient can avoid biopsy completely. Additionally, though MRI tended to miss low-risk cancers, these cancers are thought to disproportionately lead to higher healthcare costs through unnecessary treatment. Therefore, a negative MRI study was believed to be an excellent sign that the patient does not have aggressive prostate cancer. This approach led to a net gain of 0.251 additional quality-adjusted life years compared with the standard biopsy strategy.

The Prostate MRI Imaging Study²⁰ also found MRI to be effective in the prostate cancer workup. In this trial, 576 men who had never undergone biopsy underwent multiparametric MRI, transrectal ultrasonography-guided biopsy, and the reference standard, ie, transperineal template prostate mapping biopsy. Of those who underwent biopsy, 71% received a diagnosis of prostate cancer, and 40% had clinically significant disease. In patients with clinically significant disease, MRI was more sensitive than ultrasonography-guided biopsy (93% vs 48%, P < .0001) but less specific (41% vs 96%, P < .0001).

Based on these findings, if biopsy were performed only in those who had suspicious lesions on MRI, 27% of men with elevated PSA could avoid biopsy and its potential complications such as bleeding and sepsis, which occurred in 5.9% of the biopsy group.

The Prostate Evaluation for Clinically Important Disease: Sampling Using Image Guidance or Not? trial²¹ more recently studied MRI with or without targeted biopsy vs standard transrectal ultrasonography-guided biopsy in 500 men who had not undergone biopsy before, and reported similar results. MRI with or without biopsy led to fewer biopsies and less overdetection of clinically insignificant prostate cancers compared with the standard approach. Furthermore, those in the MRI-targeted biopsy group were 13% less likely to receive a diagnosis of clinically insignificant cancer than those who received the standard biopsy (adjusted difference −13 percentage points, 95% confidence interval [CI] −19 to −7, P < .001).

Together, these data provide another argument for adding multiparametric MRI to the workup of men with an elevated PSA level.

Surveillance vs treatment for prostate cancer

Once prostate cancer is diagnosed, surveillance is becoming an increasingly common management strategy.

The Prostate Cancer Intervention Versus Observation Trial (PIVOT),²² one of the largest and longest trials involving cancer patients, offered further evidence that active surveillance and less intervention for men with prostate cancer is a better approach in many cases. This trial compared prostatectomy and observation alone in a randomized fashion. Inclusion for the study required men to be medically fit for radical prostatectomy, along with having histologically confirmed localized prostate cancer (stage T1-T2NxM0 in the tumor-node-metastasis classification system) of any grade diagnosed within the last 12 months.

During 19.5 years of follow-up, 223 (61.3%) of the 364 men randomly assigned to radical prostatectomy died, compared with 245 (66.8%) of 367 men in the observation group; the difference was not statistically different (P = .06). Only 9.4% of the deaths were due to prostate cancer, 7.4% in the surgery group and 11.4% in the observation group (P = .06).

Surgery was associated with a lower all-cause mortality rate than observation in the subgroup of patients with intermediate-risk prostate cancer (defined as PSA 10–20 ng/mL and a Gleason score of 7). Surgery was also associated with less disease progression.²²

This finding is in line with previous data from the Scandinavian Prostate Cancer Group Study Number 4,²³ as well as the much larger Prostate Testing for Cancer and Treatment (ProtecT) trial,²⁴ both of which reported that metastasis was 1.5 and 2.6 times as common, respectively, in participants in the active surveillance groups. However, in the PIVOT trial, those in the surgery group were significantly more likely than those in the observation group to have erectile dysfunction and urinary incontinence at 10 years.

Therefore, in men with localized disease and in those with low-risk PSA levels, both the PIVOT and ProtecT trials suggest that death from prostate cancer is uncommon and that observation may be more appropriate.

Prostate cancer: Take-home points

• A new look at 2 large trials of PSA screening strengthened evidence that testing in the right patient population can reduce deaths from prostate cancer, but a third recently published trial that found no benefit from 1-time screening may reopen debate on the topic.
• MRI offers a better method than ultrasonography-guided biopsy to triage patients thought to be at high risk of prostate cancer and tends to limit costly overtreatment of disease that likely would not cause death.
• Surgery for prostate cancer may not prolong life but could reduce disease progression, at the risk of more adverse effects.
• Shared decision-making should be practiced when deciding whether to use active surveillance or active treatment of diagnosed prostate cancer.

A 62-year-old man with hypertension, hyperlipidemia, peripheral artery disease, and type 2 diabetes presents for a 6-month follow-up. His medications include aspirin, metformin, lisinopril, and atorvastatin, all of which he takes without problems. Over the past several months, he has noticed that his erections are not adequate for sexual intercourse. He recently heard that a generic version of sildenafil has just become available, and he wonders if it might benefit him.

Erectile dysfunction is common, associated with chronic diseases

Erectile dysfunction, ie, persistent inability to obtain and maintain an erection sufficient to permit satisfactory sexual intercourse,^25,26 is estimated to affect nearly 20% of men over the age of 20 and 75% of men over the age of 75.²⁷

In age-adjusted models, erectile dysfunction has been shown²⁸ to be associated with:

• History of cardiovascular disease (odds ratio [OR] 1.63, 95% CI 1.02–2.63)
• Diabetes (OR 3.90, 95% CI 2.16–7.04)
• Treated hypertension vs no hypertension (OR 2.22, 95% CI 1.30–3.80)
• Current smoking vs never smoking (OR 1.63, 95% CI 1.01–2.62)
• BMI greater than 30 kg/m² vs less than 25 kg/m² (OR 1.80, 95% CI 1.03–3.14).

Because of the strong association between cardiovascular disease and erectile dysfunction, the presence of one often suggests the need to screen for the other.²⁹ While tools such as the International Index of Erectile Function (IIEF-5) have been developed to evaluate erectile dysfunction, it is most often diagnosed on the basis of clinical impression, while validated assessment methods are reserved for clinical trials.²⁸

Multiple causes of erectile dysfunction

Erectile dysfunction arises from inadequate penile tissue response to a sexual signal. The response can be disrupted at several points. For example, damage to vascular smooth muscle cells (eg, from age or obesity) and endothelial cells (from smoking or diabetes) and narrowing of the vascular lumen (from atherosclerosis or hypertension) have all been shown to impair engorgement of the corpus cavernosum.³⁰ In addition, denervation from prostate surgery or spinal trauma and psychogenic causes should be recognized in discussions with patients.

Drugs for erectile dysfunction

Pharmacologic management of erectile dysfunction includes oral, sublingual, intracavernosal, and intraurethral therapies.³¹ Treatment in primary care settings usually includes addressing underlying chronic diseases³² and prescribing phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil, and avanafil). These drugs work by increasing local concentrations of cyclic guanosine monophosphate in the corpus cavernosum to induce vasodilation.³³

While these 4 drugs are still patent-protected, a manufacturer has been allowed to introduce a generic version of sildenafil into US markets, and a generic version of tadalafil is expected to be available soon.

Sildenafil, tadalafil, and vardenafil have been studied and found to have some degree of effectiveness in erectile dysfunction caused by damage to the penile vasculature, denervation, and spinal cord injury.³⁴ All drugs of this class have adverse effects including headache, facial flushing, and nasal congestion, but the drugs are generally well tolerated.³⁵

Sildenafil and tadalafil improve IIEF-5 scores by a similar margin, raising scores on the erectile domain subsection from approximately 14 of a possible 30 to approximately 24 of 30 in a trial of both drugs.³⁶ However, multiple crossover studies comparing the 2 drugs have shown that nearly 75% of patients prefer tadalafil to sildenafil,^36,37 perhaps because of tadalafil’s longer duration of action.³⁴

There is little evidence to suggest that vardenafil is more effective or more often preferred by patients than tadalafil or sidenafil.^34,38 And though data on the newest drug on the market, avanafil, are limited, a meta-analysis concluded that it may be less effective than tadalafil and without significant differences in terms of safety.³⁹

Other treatments

Lifestyle modifications, especially smoking cessation and exercise, have been shown to reduce the risk of erectile dysfunction with varying effect sizes across studies.^40–42 Moreover, factors such as obesity, alcohol use, and smoking may cause irreversible harm, and thus a healthy lifestyle should be encouraged.⁴¹

While there is only weak evidence for the use of psychological interventions alone for treating most types of erectile dysfunction, one meta-analysis found that the combination of psychological intervention and a phosphodiesterase-5 inhibitor improved sexual satisfaction more than drug therapy alone.⁴³

Erectile dysfunction: Take-home points

• Erectile dysfunction is common, affecting nearly 20% of men over the age of 20 and over 75% of men over the age of 75.
• Erectile dysfunction is often associated with chronic disease and may suggest the need to screen for cardiovascular disease.
• Treating underlying chronic diseases may help, and phosphodiesterase-5 inhibitors are effective; tadalafil may be most often preferred.

A 68-year-old man with a history of hypertension, BPH, and erectile dysfunction presents for a 6-month follow-up. His medication use includes lisinopril, which he takes without problems. He denies any new physical symptoms. His physical examination is unremarkable. He says he has heard about supplements that might help with his sexual performance and hopes to discuss recommendations during the visit.

A burgeoning, unregulated industry

Since the passage of the Dietary Supplement and Health Education Act in 1994, a law that decreased oversight of the supplement industry, spending on supplements has skyrocketed to over $41.1 billion each year.⁴⁴ Advertisements for these products typically claim that they improve general mental and physical health, sexual and romantic performance, leanness, and muscularity.⁴⁵ A national survey of men ages 57 and older reported that the most popular products were aimed at nutrition (such as multivitamins), cardiovascular health (such as omega-3 fatty acids), and chronic conditions (such as saw palmetto for BPH).⁴⁶

Little evidence of efficacy

There is little evidence to support the use of most supplements to improve men’s health. For example, a study in 82,405 men found no association between mortality rates and multivitamin use (hazard ratio [HR] 1.07, 95% CI 0.96–1.19).⁴⁷ Even for specific uses, such as cognitive performance, randomized trials exploring the effects of multivitamins in men have been largely negative.⁴⁸

The positive trials that have been reported are often of low quality and are funded by supplement manufacturers. For example, one of the few trials that reported a positive association between multivitamin supplementation and cognition in men was underpowered (N = 51) and found improvement in only 1 of 19 cognitive domains.⁴⁹ Despite the poor design and results to the contrary, this industry-funded study nevertheless concluded that multivitamins may play a role in improving elements of memory.

Evidence of possible harm from antioxidants

While not always specific to men, many meta-analyses have explored the effects of antioxidant supplements on cardiovascular and mortality risk. Most of them concluded that antioxidant supplements have no benefit and that some may actually be harmful.

For example, multiple meta-analyses of vitamin E supplementation found no cardiovascular benefit but possible increases in all-cause mortality rates in those taking high doses (risk ratio 1.04, 95% CI 1.01–1.07).^50,51

Another meta-analysis of 180,938 partici­pants in high-quality studies found an increased risk of all-cause mortality associated with independent intake of several antioxidant vitamins, including beta-carotene (risk ratio 1.07, 95% CI 1.02–1.11) and vitamin A (risk ratio 1.16, 95% CI 1.10–1.24), while intake of vitamin C and selenium had no impact on mortality.⁵²

Similarly, although nearly 10% of US adults report taking omega-3 fatty acid supplements, a review of 24 randomized controlled trials and meta-analyses published between 2005 and 2012 concluded that only 2 supported the use of these supplements for any health benefit.⁵³

Can supplements improve sexual function, prostate health?

To improve sexual function. A 2015 narrative review of the ingredients in General Nutrition Center’s top 30 best-selling products targeted at improving men’s sexual performance (including improving libido and erectile dysfunction) found only poor evidence for any efficacy.⁵⁴ The few studies that did support the use of select supplements, including B vitamins in people with diabetes, L-arginine, and yohimbine, were deemed to be of poor quality or showed a smaller effect size compared with standard medical therapy.

To prevent prostate cancer. Studies of supplement use to improve prostate health have had mixed results. For example, multiple large case-control studies have suggested that taking vitamin D^55,56 or vitamin C⁵⁷ is not associated with prostate cancer risk, while increased vitamin A^58,59 and E^60,61 intake is associated with inconsistent increases in prostate cancer risk.

In the Selenium and Vitamin E Cancer Prevention Trial,⁶² a randomized controlled trial in 35,533 men, those assigned to receive vitamin E supplementation were 17% more likely to get prostate cancer than were those assigned to placebo (HR 1.17, 99% CI 1.004–1.36, P = .008).

However, there are plausible biologic links between nutraceuticals and prostate cancer. For example, studies have linked genetic polymorphisms in vitamin D receptors⁶³ as well as intake of natural androgen receptor modulators, such as the most active polyphenol in green tea,⁶⁴ to prostate cancer risk and aggressiveness in certain populations. This led a recent review to conclude that there is some biologic plausibility, but at present little epidemiologic evidence, to support any dietary supplement’s ability to broadly affect prostate cancer risk.⁶⁵

Interest continues in exploring the targeted use of nutraceuticals as adjuvant therapy in specific populations at risk of prostate cancer.^66,67

To treat BPH. There is a similar dearth of clinical or population-based evidence that supplements can broadly affect BPH symptoms. For example, in a 2012 Cochrane review of Serenoa repens (saw palmetto) utilizing only high-quality evidence, there was no evidence that supplement use significantly reduced lower urinary tract symptoms, nocturia, or peak urine flow in BPH patients, and this was true even when the supplement was taken at triple-strength doses.⁶⁸

For other diseases. There is also limited evidence that supplements can affect other chronic diseases. For example, a meta-analysis of 3,803 patients found that glucosamine, chondroitin, and their combination had no impact on joint pain or joint space narrowing in patients with osteoarthritis of the knee or hip.⁶⁹

Even when there is some evidence to suggest benefit from supplementation, study heterogeneity and varying evidence quality limit confidence in the conclusions. For example, meta-analyses suggest garlic may improve blood pressure control in those with hypertension⁷⁰ and improve lipid and blood glucose control in type 2 diabetes.⁷¹ However, most of the trials included in those systematic reviews were underpowered, with samples as low as 10 patients, and many suffered from improper design, such as inadequate blinding of researchers. In addition, these meta-analyses often do not report adverse events, suggesting that higher quality studies would be needed to adequately measure event rates. As such, there is need for caution and a case-by-case review before recommending even a seemingly benign supplement like garlic to patients.

In total, there is only limited evidence to support the efficacy of supplements across many diseases and concerns common to men in primary care. This includes improving general health, cardiovascular health, sexual functioning, or other chronic diseases. While a supplement’s placebo effect may at times provide some benefit, supplements are much less strictly regulated since the passing of the 1994 act, and even vitamin supplementation has been shown to be associated with negative health outcomes. As such, a patient’s use of supplements requires careful consideration and shared decision-making.

Supplements: Take-home points

• Supplements are only loosely regulated by the federal government.
• There is some biologic but limited epidemiologic evidence for the use of multivitamins to improve cognition or mortality rates; for the use of antioxidant vitamins or omega-3 fatty acids to improve cardiovascular health; for the use of any of the top-selling sexual enhancement supplements to improve libido or erectile function; and for the use of vitamins or other supplements for improving BPH or reducing prostate cancer risk. Using supplements may in some cases be harmful.
• Given the heterogeneity of studies of supplements to manage chronic diseases and a lack of reporting of adverse events, careful consideration is needed when recommending supplements to patients.

Primary care physicians are tasked with a wide variety of issues affecting men. This article reviews the latest research in 4 areas of men’s health commonly addressed in primary care:

• Medical management of benign prostatic hyperplasia (BPH)
• Prostate cancer screening and treatment
• Medical management of erectile dysfunction
• Use of supplements.

See related commentary

MEDICAL MANAGEMENT OF BPH

An 84-year-old man with a history of hypertension, type 2 diabetes, hyperlipidemia, BPH, mild cognitive impairment, and osteoarthritis presents for a 6-month follow-up, accompanied by his son.

Two years ago he was started on a 5-alpha reductase inhibitor and an alpha-blocker for worsening BPH symptoms. His BPH symptoms are currently under control, with an American Urological Association (AUA) symptom index score of 7 of a possible 35 (higher scores being worse).

However, both the patient and son are concerned about the number of medications he is on and wonder if some could be eliminated.

Assessment tools

BPH is a common cause of lower urinary tract symptoms in older men. Evidence-based tools to help the clinician and patient decide on when to consider treatment for symptoms are:

• The AUA symptom index¹
• The International Prostate Symptom Score (IPSS).²

An AUA symptom index score or IPSS score of 8 through 19 of a possible 35 is consistent with moderate symptoms, while a score of 20 or higher indicates severe symptoms.

Combination therapy or monotherapy?

Monotherapy with an alpha-blocker or a 5-alpha reductase inhibitor is often the first-line treatment for BPH-related lower urinary tract symptoms.³ However, combination therapy with both an alpha-blocker and a 5-alpha reductase inhibitor is another evidence-based option.

The Medical Therapy of Prostatic Symptoms study,⁴ a randomized controlled trial, reported that long-term combination therapy reduced the risk of BPH clinical progression better than monotherapy. The same trial also found that either combination therapy or finasteride alone (a 5-alpha reductase inhibitor) reduced the risk of acute urinary retention and the future need for invasive therapy.

Monotherapy after a period of combination therapy?

There is also evidence to support switching from combination to monotherapy after an initial treatment period.

Matsukawa et al⁵ examined the effects of withdrawing the alpha-blocker from BPH combination therapy in a study in 140 patients. For 12 months, all patients received the alpha-blocker silodosin and the 5-alpha reductase inhibitor dutasteride. At 12 months, the remaining 132 patients (8 patients had been lost to follow-up) were randomized to continue combination therapy or to take dutasteride alone for another 12 months. They were evaluated at 0, 12, and 24 months by questionnaires (the IPSS and Overactive Bladder Symptom Score) and urodynamic testing (uroflowmetry, cystometrography, and pressure-flow studies).

There were no significant differen­ces in subjective symptoms and bladder outlet obstruction between patients who continued combination therapy and those who switched to dutasteride monotherapy. In the monotherapy group, those whose symptoms worsened weighed more (68.8 kg vs 62.6 kg, P =.002) and had a higher body mass index (BMI) (26.2 kg/m² vs 22.8 kg/m², P < .001) than those whose symptoms stayed the same or got better.

These findings of successful alpha-blocker withdrawal were consistent with those of other studies.

The Symptom Management After Reducing Therapy study⁶ showed that 80% of men with an IPSS score less than 20 who changed to dutasteride monotherapy did not have a noticeable worsening of their symptoms.

Baldwin et al⁷ noted similar success after withdrawing the alpha-blocker doxazosin in patients on finasteride.

Review all medications

The National Health and Nutrition Examination Survey noted that the estimated prevalence of polypharmacy increased from 8% in 1999 to 15% in 2011.⁸ Many commonly used medications, such as decongestants, antihistamines, and anticholinergic agents, can worsen BPH symptoms,⁹ so it is reasonable to consistently review the patient’s medications to weigh the risks and benefits and determine which ones align with the patient’s personal care goals.

BPH: Take-home points

• Combination therapy with an alpha-blocker and a 5-alpha reductase inhibitor is an effective regimen for BPH.
• Polypharmacy is a significant problem in the elderly.
• Withdrawing the alpha-blocker component from BPH combination therapy can be considered after 1 year of combination therapy in patients whose symptoms have been well controlled.

A 60-year-old patient calls you after receiving his laboratory testing report from his insurance physical. His prostate-specific antigen (PSA) level is 5.1 ng/mL, and he has several questions:

• Should he have agreed to the screening?
• How effective is the screening?
• What are the next steps?

Is PSA screening useful?

Over the last few years, there has been great debate as to the utility of screening for prostate cancer.

The US Centers for Disease Control and Prevention¹⁰ reported that in 2014, an estimated 172,258 men in the United States were diagnosed with prostate cancer, but only 28,343 men died of it. These statistics support the notion that screening programs may be detecting what might otherwise be a silent disease.

The US Preventive Services Task Force (USPSTF)¹¹ recommends against blanket PSA screening, in view of the low probability that it reduces the risk of death from prostate cancer. For men ages 55 through 69, current guidelines give a grade C recommendation to PSA screening, meaning there is moderate agreement that the benefit is likely small, and screening should be selectively offered based on professional judgment and patient preference. In men ages 70 and older who are not at high risk, the guideline gives screening a grade D recommendation, meaning there is moderate evidence that there is no benefit from the practice. This is a change from the 2012 USPSTF guidelines,¹² which gave a grade D recommendation to PSA screening for all ages.

The American Urological Association¹³ recommends against PSA screening in men under age 40 or ages 70 and older. It does not recommend routine screening in those ages 40 to 54 at average risk, but it says the decision should be individualized in this age group in those at higher risk (eg, with a positive family history, African American). At ages 55 through 69, it recommends shared decision-making, taking into account cancer risk and life expectancy. In those who opt for screening, an interval of 2 years or more may be preferred over annual screening to reduce the risk of overdiagnosis.

The USPSTF recommendations rely heavily on data from 2 trials: the European Randomized Study of Screening for Prostate Cancer (ERSPC)¹⁴ and the Prostate, Lung, Colorectal, and Ovarian Screening (PLCO) trial.¹⁵

The ERSPC¹⁴ demonstrated that screening for prostate cancer reduced deaths from prostate cancer by 20%, with an absolute risk difference of 0.71 deaths per 1,000 men; 1,410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent 1 death from prostate cancer. Screening also decreased the risk of developing metastatic disease by 30%.¹⁶ On the negative side, screening increased the risk of overdiagnosis and other harms such as bleeding, sepsis, and incontinence.

The PLCO trial,¹⁵ in contrast, found no difference in death rates between men randomly assigned to annual screening and those assigned to usual care. Differences between the trial results were thought to be due to different practice settings as well as study implementation and compliance.

Tsodikov et al¹⁷ reanalyzed data from the ERSPC and the PLCO trial using 3 different mathematical models to estimate the effects of screening in both trials compared with no screening. The analysis found no evidence that the effects of screening vs not screening differed between the 2 trials, ultimately concluding that PSA screening reduced prostate cancer deaths by 25% to 32%, which the authors inferred was primarily a result of earlier detection of cancer.

The Cluster Randomized Trial of PSA Testing for Prostate Cancer,¹⁸ published in March 2018, explored the effect of single PSA screening vs no screening on prostate cancer mortality rates in 419,582 men ages 50 through 69. Although screening detected more cases of low-risk prostate cancer, there was no significant difference in prostate cancer mortality rates after a median follow-up of 10 years. However, 10% to 15% of the control group was estimated to have also been screened, and these results do not directly speak to the efficacy of serial PSA screening.

Extended follow-up of this trial is planned to report on long-term survival benefits and whether screening lowers the risk of metastasis.

Imaging-guided prostate biopsy

Once a patient is found to have an elevated PSA level, standard practice has been to perform transrectal ultrasonography to obtain 12 core biopsy samples. The results indicate whether the prostate contains cancer, how aggressive the cancer is (Gleason score), and whether there is extracapsular extension.

In the past, magnetic resonance imaging (MRI) of the prostate before biopsy was thought to be too costly, and many insurance plans do not currently cover it.

Pahwa et al,¹⁹ however, in a cost-effectiveness study using a decision-analysis model, found that using MRI to detect lesions and then guide biopsy by triaging patients into proper treatment pathways added health benefits in a cost-effective manner in 94.05% of simulations. These benefits were found across all age groups.

This study demonstrated that doctors could use MRI to better evaluate patients for potentially harmful lesions. If a focus of cancer is found, it can be biopsied; if no cancer is seen on MRI, the patient can avoid biopsy completely. Additionally, though MRI tended to miss low-risk cancers, these cancers are thought to disproportionately lead to higher healthcare costs through unnecessary treatment. Therefore, a negative MRI study was believed to be an excellent sign that the patient does not have aggressive prostate cancer. This approach led to a net gain of 0.251 additional quality-adjusted life years compared with the standard biopsy strategy.

The Prostate MRI Imaging Study²⁰ also found MRI to be effective in the prostate cancer workup. In this trial, 576 men who had never undergone biopsy underwent multiparametric MRI, transrectal ultrasonography-guided biopsy, and the reference standard, ie, transperineal template prostate mapping biopsy. Of those who underwent biopsy, 71% received a diagnosis of prostate cancer, and 40% had clinically significant disease. In patients with clinically significant disease, MRI was more sensitive than ultrasonography-guided biopsy (93% vs 48%, P < .0001) but less specific (41% vs 96%, P < .0001).

Based on these findings, if biopsy were performed only in those who had suspicious lesions on MRI, 27% of men with elevated PSA could avoid biopsy and its potential complications such as bleeding and sepsis, which occurred in 5.9% of the biopsy group.

The Prostate Evaluation for Clinically Important Disease: Sampling Using Image Guidance or Not? trial²¹ more recently studied MRI with or without targeted biopsy vs standard transrectal ultrasonography-guided biopsy in 500 men who had not undergone biopsy before, and reported similar results. MRI with or without biopsy led to fewer biopsies and less overdetection of clinically insignificant prostate cancers compared with the standard approach. Furthermore, those in the MRI-targeted biopsy group were 13% less likely to receive a diagnosis of clinically insignificant cancer than those who received the standard biopsy (adjusted difference −13 percentage points, 95% confidence interval [CI] −19 to −7, P < .001).

Together, these data provide another argument for adding multiparametric MRI to the workup of men with an elevated PSA level.

Surveillance vs treatment for prostate cancer

Once prostate cancer is diagnosed, surveillance is becoming an increasingly common management strategy.

The Prostate Cancer Intervention Versus Observation Trial (PIVOT),²² one of the largest and longest trials involving cancer patients, offered further evidence that active surveillance and less intervention for men with prostate cancer is a better approach in many cases. This trial compared prostatectomy and observation alone in a randomized fashion. Inclusion for the study required men to be medically fit for radical prostatectomy, along with having histologically confirmed localized prostate cancer (stage T1-T2NxM0 in the tumor-node-metastasis classification system) of any grade diagnosed within the last 12 months.

During 19.5 years of follow-up, 223 (61.3%) of the 364 men randomly assigned to radical prostatectomy died, compared with 245 (66.8%) of 367 men in the observation group; the difference was not statistically different (P = .06). Only 9.4% of the deaths were due to prostate cancer, 7.4% in the surgery group and 11.4% in the observation group (P = .06).

Surgery was associated with a lower all-cause mortality rate than observation in the subgroup of patients with intermediate-risk prostate cancer (defined as PSA 10–20 ng/mL and a Gleason score of 7). Surgery was also associated with less disease progression.²²

This finding is in line with previous data from the Scandinavian Prostate Cancer Group Study Number 4,²³ as well as the much larger Prostate Testing for Cancer and Treatment (ProtecT) trial,²⁴ both of which reported that metastasis was 1.5 and 2.6 times as common, respectively, in participants in the active surveillance groups. However, in the PIVOT trial, those in the surgery group were significantly more likely than those in the observation group to have erectile dysfunction and urinary incontinence at 10 years.

Therefore, in men with localized disease and in those with low-risk PSA levels, both the PIVOT and ProtecT trials suggest that death from prostate cancer is uncommon and that observation may be more appropriate.

Prostate cancer: Take-home points

• A new look at 2 large trials of PSA screening strengthened evidence that testing in the right patient population can reduce deaths from prostate cancer, but a third recently published trial that found no benefit from 1-time screening may reopen debate on the topic.
• MRI offers a better method than ultrasonography-guided biopsy to triage patients thought to be at high risk of prostate cancer and tends to limit costly overtreatment of disease that likely would not cause death.
• Surgery for prostate cancer may not prolong life but could reduce disease progression, at the risk of more adverse effects.
• Shared decision-making should be practiced when deciding whether to use active surveillance or active treatment of diagnosed prostate cancer.

A 62-year-old man with hypertension, hyperlipidemia, peripheral artery disease, and type 2 diabetes presents for a 6-month follow-up. His medications include aspirin, metformin, lisinopril, and atorvastatin, all of which he takes without problems. Over the past several months, he has noticed that his erections are not adequate for sexual intercourse. He recently heard that a generic version of sildenafil has just become available, and he wonders if it might benefit him.

Erectile dysfunction is common, associated with chronic diseases

Erectile dysfunction, ie, persistent inability to obtain and maintain an erection sufficient to permit satisfactory sexual intercourse,^25,26 is estimated to affect nearly 20% of men over the age of 20 and 75% of men over the age of 75.²⁷

In age-adjusted models, erectile dysfunction has been shown²⁸ to be associated with:

• History of cardiovascular disease (odds ratio [OR] 1.63, 95% CI 1.02–2.63)
• Diabetes (OR 3.90, 95% CI 2.16–7.04)
• Treated hypertension vs no hypertension (OR 2.22, 95% CI 1.30–3.80)
• Current smoking vs never smoking (OR 1.63, 95% CI 1.01–2.62)
• BMI greater than 30 kg/m² vs less than 25 kg/m² (OR 1.80, 95% CI 1.03–3.14).

Because of the strong association between cardiovascular disease and erectile dysfunction, the presence of one often suggests the need to screen for the other.²⁹ While tools such as the International Index of Erectile Function (IIEF-5) have been developed to evaluate erectile dysfunction, it is most often diagnosed on the basis of clinical impression, while validated assessment methods are reserved for clinical trials.²⁸

Multiple causes of erectile dysfunction

Erectile dysfunction arises from inadequate penile tissue response to a sexual signal. The response can be disrupted at several points. For example, damage to vascular smooth muscle cells (eg, from age or obesity) and endothelial cells (from smoking or diabetes) and narrowing of the vascular lumen (from atherosclerosis or hypertension) have all been shown to impair engorgement of the corpus cavernosum.³⁰ In addition, denervation from prostate surgery or spinal trauma and psychogenic causes should be recognized in discussions with patients.

Drugs for erectile dysfunction

Pharmacologic management of erectile dysfunction includes oral, sublingual, intracavernosal, and intraurethral therapies.³¹ Treatment in primary care settings usually includes addressing underlying chronic diseases³² and prescribing phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil, and avanafil). These drugs work by increasing local concentrations of cyclic guanosine monophosphate in the corpus cavernosum to induce vasodilation.³³

While these 4 drugs are still patent-protected, a manufacturer has been allowed to introduce a generic version of sildenafil into US markets, and a generic version of tadalafil is expected to be available soon.

Sildenafil, tadalafil, and vardenafil have been studied and found to have some degree of effectiveness in erectile dysfunction caused by damage to the penile vasculature, denervation, and spinal cord injury.³⁴ All drugs of this class have adverse effects including headache, facial flushing, and nasal congestion, but the drugs are generally well tolerated.³⁵

Sildenafil and tadalafil improve IIEF-5 scores by a similar margin, raising scores on the erectile domain subsection from approximately 14 of a possible 30 to approximately 24 of 30 in a trial of both drugs.³⁶ However, multiple crossover studies comparing the 2 drugs have shown that nearly 75% of patients prefer tadalafil to sildenafil,^36,37 perhaps because of tadalafil’s longer duration of action.³⁴

There is little evidence to suggest that vardenafil is more effective or more often preferred by patients than tadalafil or sidenafil.^34,38 And though data on the newest drug on the market, avanafil, are limited, a meta-analysis concluded that it may be less effective than tadalafil and without significant differences in terms of safety.³⁹

Other treatments

Lifestyle modifications, especially smoking cessation and exercise, have been shown to reduce the risk of erectile dysfunction with varying effect sizes across studies.^40–42 Moreover, factors such as obesity, alcohol use, and smoking may cause irreversible harm, and thus a healthy lifestyle should be encouraged.⁴¹

While there is only weak evidence for the use of psychological interventions alone for treating most types of erectile dysfunction, one meta-analysis found that the combination of psychological intervention and a phosphodiesterase-5 inhibitor improved sexual satisfaction more than drug therapy alone.⁴³

Erectile dysfunction: Take-home points

• Erectile dysfunction is common, affecting nearly 20% of men over the age of 20 and over 75% of men over the age of 75.
• Erectile dysfunction is often associated with chronic disease and may suggest the need to screen for cardiovascular disease.
• Treating underlying chronic diseases may help, and phosphodiesterase-5 inhibitors are effective; tadalafil may be most often preferred.

A 68-year-old man with a history of hypertension, BPH, and erectile dysfunction presents for a 6-month follow-up. His medication use includes lisinopril, which he takes without problems. He denies any new physical symptoms. His physical examination is unremarkable. He says he has heard about supplements that might help with his sexual performance and hopes to discuss recommendations during the visit.

A burgeoning, unregulated industry

Since the passage of the Dietary Supplement and Health Education Act in 1994, a law that decreased oversight of the supplement industry, spending on supplements has skyrocketed to over $41.1 billion each year.⁴⁴ Advertisements for these products typically claim that they improve general mental and physical health, sexual and romantic performance, leanness, and muscularity.⁴⁵ A national survey of men ages 57 and older reported that the most popular products were aimed at nutrition (such as multivitamins), cardiovascular health (such as omega-3 fatty acids), and chronic conditions (such as saw palmetto for BPH).⁴⁶

Little evidence of efficacy

There is little evidence to support the use of most supplements to improve men’s health. For example, a study in 82,405 men found no association between mortality rates and multivitamin use (hazard ratio [HR] 1.07, 95% CI 0.96–1.19).⁴⁷ Even for specific uses, such as cognitive performance, randomized trials exploring the effects of multivitamins in men have been largely negative.⁴⁸

The positive trials that have been reported are often of low quality and are funded by supplement manufacturers. For example, one of the few trials that reported a positive association between multivitamin supplementation and cognition in men was underpowered (N = 51) and found improvement in only 1 of 19 cognitive domains.⁴⁹ Despite the poor design and results to the contrary, this industry-funded study nevertheless concluded that multivitamins may play a role in improving elements of memory.

Evidence of possible harm from antioxidants

While not always specific to men, many meta-analyses have explored the effects of antioxidant supplements on cardiovascular and mortality risk. Most of them concluded that antioxidant supplements have no benefit and that some may actually be harmful.

For example, multiple meta-analyses of vitamin E supplementation found no cardiovascular benefit but possible increases in all-cause mortality rates in those taking high doses (risk ratio 1.04, 95% CI 1.01–1.07).^50,51

Another meta-analysis of 180,938 partici­pants in high-quality studies found an increased risk of all-cause mortality associated with independent intake of several antioxidant vitamins, including beta-carotene (risk ratio 1.07, 95% CI 1.02–1.11) and vitamin A (risk ratio 1.16, 95% CI 1.10–1.24), while intake of vitamin C and selenium had no impact on mortality.⁵²

Similarly, although nearly 10% of US adults report taking omega-3 fatty acid supplements, a review of 24 randomized controlled trials and meta-analyses published between 2005 and 2012 concluded that only 2 supported the use of these supplements for any health benefit.⁵³

Can supplements improve sexual function, prostate health?

To improve sexual function. A 2015 narrative review of the ingredients in General Nutrition Center’s top 30 best-selling products targeted at improving men’s sexual performance (including improving libido and erectile dysfunction) found only poor evidence for any efficacy.⁵⁴ The few studies that did support the use of select supplements, including B vitamins in people with diabetes, L-arginine, and yohimbine, were deemed to be of poor quality or showed a smaller effect size compared with standard medical therapy.

To prevent prostate cancer. Studies of supplement use to improve prostate health have had mixed results. For example, multiple large case-control studies have suggested that taking vitamin D^55,56 or vitamin C⁵⁷ is not associated with prostate cancer risk, while increased vitamin A^58,59 and E^60,61 intake is associated with inconsistent increases in prostate cancer risk.

In the Selenium and Vitamin E Cancer Prevention Trial,⁶² a randomized controlled trial in 35,533 men, those assigned to receive vitamin E supplementation were 17% more likely to get prostate cancer than were those assigned to placebo (HR 1.17, 99% CI 1.004–1.36, P = .008).

However, there are plausible biologic links between nutraceuticals and prostate cancer. For example, studies have linked genetic polymorphisms in vitamin D receptors⁶³ as well as intake of natural androgen receptor modulators, such as the most active polyphenol in green tea,⁶⁴ to prostate cancer risk and aggressiveness in certain populations. This led a recent review to conclude that there is some biologic plausibility, but at present little epidemiologic evidence, to support any dietary supplement’s ability to broadly affect prostate cancer risk.⁶⁵

Interest continues in exploring the targeted use of nutraceuticals as adjuvant therapy in specific populations at risk of prostate cancer.^66,67

To treat BPH. There is a similar dearth of clinical or population-based evidence that supplements can broadly affect BPH symptoms. For example, in a 2012 Cochrane review of Serenoa repens (saw palmetto) utilizing only high-quality evidence, there was no evidence that supplement use significantly reduced lower urinary tract symptoms, nocturia, or peak urine flow in BPH patients, and this was true even when the supplement was taken at triple-strength doses.⁶⁸

For other diseases. There is also limited evidence that supplements can affect other chronic diseases. For example, a meta-analysis of 3,803 patients found that glucosamine, chondroitin, and their combination had no impact on joint pain or joint space narrowing in patients with osteoarthritis of the knee or hip.⁶⁹

Even when there is some evidence to suggest benefit from supplementation, study heterogeneity and varying evidence quality limit confidence in the conclusions. For example, meta-analyses suggest garlic may improve blood pressure control in those with hypertension⁷⁰ and improve lipid and blood glucose control in type 2 diabetes.⁷¹ However, most of the trials included in those systematic reviews were underpowered, with samples as low as 10 patients, and many suffered from improper design, such as inadequate blinding of researchers. In addition, these meta-analyses often do not report adverse events, suggesting that higher quality studies would be needed to adequately measure event rates. As such, there is need for caution and a case-by-case review before recommending even a seemingly benign supplement like garlic to patients.

In total, there is only limited evidence to support the efficacy of supplements across many diseases and concerns common to men in primary care. This includes improving general health, cardiovascular health, sexual functioning, or other chronic diseases. While a supplement’s placebo effect may at times provide some benefit, supplements are much less strictly regulated since the passing of the 1994 act, and even vitamin supplementation has been shown to be associated with negative health outcomes. As such, a patient’s use of supplements requires careful consideration and shared decision-making.

Supplements: Take-home points

• Supplements are only loosely regulated by the federal government.
• There is some biologic but limited epidemiologic evidence for the use of multivitamins to improve cognition or mortality rates; for the use of antioxidant vitamins or omega-3 fatty acids to improve cardiovascular health; for the use of any of the top-selling sexual enhancement supplements to improve libido or erectile function; and for the use of vitamins or other supplements for improving BPH or reducing prostate cancer risk. Using supplements may in some cases be harmful.
• Given the heterogeneity of studies of supplements to manage chronic diseases and a lack of reporting of adverse events, careful consideration is needed when recommending supplements to patients.

Bisphosphonate therapy minimizes bone loss and reduces fracture risk by up to 50% in patients with osteoporosis,¹ but it is also associated with increased risks of osteonecrosis of the jaw and atypical femoral fracture. Although atypical femoral fractures are rare, they can have a devastating effect. Patient concern about this complication has contributed to a decrease in bisphosphonate use by about half in the last decade or so,^2,3 and we fear this could result in an increase in hip fracture rates.

In this article, we examine the evidence on bisphosphonate-associated atypical femoral fractures, including risks, pathogenesis, treatment, and prevention.

ATYPICAL FRACTURES INVOLVE THE FEMORAL SHAFT, NOT THE HEAD

An atypical femoral fracture is a transverse fracture of the femoral shaft (diaphysis), defined by both clinical criteria and radiographic appearance.

To be defined as atypical, a femoral fracture must meet 4 of the following 5 criteria⁴:

• Occurs with minimal or no trauma
• Has a predominantly transverse fracture line, originating at the lateral cortex and sometimes becoming oblique as it progresses medially across the femur
• Extends through both cortices and may be associated with a medial spike (complete fractures); or involves only the lateral cortex (incomplete fractures)
• Is noncomminuted or minimally comminuted
• Shows localized periosteal or endosteal thickening (termed “beaking” or “flaring”) of the lateral cortex at the fracture site.

Several minor features are also important but are not required, eg:

• Cortical thickening of the femoral shaft
• Unilateral or bilateral prodromal pain preceding the fracture
• Bilateral incomplete or complete femoral diaphysis fractures
• Delayed fracture healing.

Atypical femoral fracture can occur anywhere along the shaft, from just distal to the lesser trochanter to just proximal to the supracondylar flare. However, most occur in 2 areas, with 1 cluster centered at about 41 mm from the lesser trochanter (more common in relatively younger patients) and the other at 187 mm.⁵

ABSOLUTE RISK IS LOW BUT INCREASES WITH LONGER USE

Atypical femoral fractures are rare. Schilcher et al⁶ reviewed radiographs of 1,234 women who had a subtrochanteric or shaft fracture and found 59 (4.6%) of fractures were atypical. In a systematic review of 14 studies,⁷ the incidence ranged from 3.0 to 9.8 cases per 100,000 patient-years.

Furthermore, not all atypical femoral fractures are in bisphosphonate users: 7.4% were in nonusers in 1 series⁸ and 22% in another.⁹

Nevertheless, most studies show that bis­phosphonate use increases the incidence of atypical femoral fracture, and the incidence increases with duration of use, especially after 3 years.⁷

An international task force of the American Society for Bone and Mineral Research listed the absolute risk as between 3.2 and 50 cases per 100,000 patient-years, with longer use (> 5 years) increasing the risk to about 100 per 100,000 patient-years.⁴ After stopping bis­phosphonate therapy, the risk diminished by 70% per year.⁹

In another study, for 0.1 to 1.9 years of therapy, the age-adjusted atypical fracture rates were 1.78 per 100,000 per year (95% confidence interval [CI] 1.5–2.0), increasing to 113.1 per 100,000 per year (95% CI 69.3–156.8) with exposure from 8 to 9.9 years.¹⁰

A case-control study found that more than 5 years of bisphosphonate use increased the fracture risk by an odds ratio of 2.74 (95% CI 1.25–6.02).¹¹

The incidence of typical femoral fracture was higher in those who adhered better to their oral bisphosphonate regimen in some studies,¹² but the opposite was true in others.¹³

The benefits of bisphosphonate therapy in reducing fracture risk, however, outweigh the risk of atypical fracture.⁴

We do not know whether the rate of atypical femoral fracture is increasing. A review of Kaiser Permanente Northwest records found that the rates of atypical femoral shaft fracture had remained stable from 1996 to 2009. However, 61.9% of patients who met the strict radiographic criteria had taken oral bisphosphonates.¹⁴ These data suggest that bisphosphonate use has not increased the overall population-based risk for subtrochanteric and femoral shaft fractures, but that bisphosphonates and other risk factors may have increased the likelihood that such fractures will exhibit atypical radiographic features.

A population-based study in Denmark¹³ found that alendronate use longer than 10 years was associated with an adjusted 30% lower risk of hip fracture and no increase in the risk of subtrochanteric and femoral shaft fracture. In addition, the risk of subtrochanteric and femoral shaft fracture was lower with high adherence to alendronate treatment (based on medication possession ratio > 80%) compared with low adherence (ratio < 50%) (odds ratio 0.88, 95% CI 0.77–0.99). The risk was not increased in current vs past users.

The Danish study¹³ used the coding of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) to identify subtrochanteric and femoral shaft fractures without radiologic review for atypical radiographic features. The lack of specific ICD-10 coding for subtrochanteric and femoral shaft fractures with atypical radiographic features has limited our knowledge of their incidence.

After an atypical femoral fracture, patients have a significant risk of fracture on the contralateral side. In a case-control study, 28% of patients with atypical femoral fracture suffered a contralateral fracture, compared with 0.9% of patients presenting with a typical fracture pattern (odds ratio 42.6, 95% CI 12.8–142.4).¹⁵

Contralateral fracture occurs from 1 month to 4 years after the index atypical femoral fracture.¹⁶

There are reports of bisphosphonate-related low-impact fractures in other sites such as the tibia¹⁷ and forearm.¹⁸ However, they may be too rare to warrant screening.

Mortality rates

A Swedish database study found that patients with atypical femoral fractures, whether bisphosphonate users or nonusers, do not have higher mortality rates than patients with ordinary subtrochanteric or femoral shaft fractures.¹⁹ Furthermore, the mortality rates for those with atypical femoral fracture were similar to rates in the general population. In contrast, patients with an ordinary femoral fracture had a higher mortality risk than the general population.¹⁹

Other studies suggest that atypical femoral fracture may be associated with a less favorable prognosis in older patients,²⁰ but this could be due to differences in demographics, treatment adherence, or postfracture care.²¹

In addition, functional outcomes as measured by independent mobility at discharge and at 3 months were comparable between patients with atypical fracture and those with typical fracture.²²

IMAGING STUDIES

If a long-term bisphosphonate user presents with hip, thigh, or groin pain, imaging studies are recommended.

Plain radiography

Radiography is usually the first step and should include a frontal view of the pelvis (Figure 1) and 2 views of the full length of each femur. If radiography is not conclusive, bone scan or magnetic resonance imaging (MRI) should be considered.

A linear cortex transverse fracture pattern and focal lateral cortical thickening are the most sensitive and specific radiographic features.^23,24 Because of the risk of fracture on the contralateral side, radiographic study of that side is recommended as well.

Computed tomography

Computed tomography (CT) is not sensitive for early stress fractures and, given the radiation burden, is not recommended in the workup of atypical fracture.

Bone scanning

Bone scanning using technetium 99m-labeled methylene diphosphonate with a gamma camera shows active bone turnover. Stress fractures and atypical femoral fractures are most easily identified in the third (delayed) phase of the bone scan. Although bone scanning is highly sensitive, the specificity is limited by lack of spatial resolution. Atypical femoral fracture appears as increased activity in the subtrochanteric region with a predilection for the lateral cortex.

Dual-energy x-ray absorptiometry

Conventional dual-energy x-ray absorptiometry (DXA) extends only to 1 to 2 cm below the lesser trochanter and can therefore miss atypical fractures, which usually occur farther down. The overall detection rate for DXA was 61% in a sample of 33 patients.²⁵

Newer scanners can look at the entire femoral shaft.²⁶ In addition, newer software can quantify focal thickening (beaking) of the lateral cortex and screen patients who have no symptoms. The results of serial measurements can be graphed so that the practitioner can view trends to help assess or rule out potential asymptomatic atypical femoral fracture.

A localized reaction (periosteal thickening of the lateral cortex or beaking) often precedes atypical femoral fracture. A 2017 study reported that patients with high localized reaction (mean height 3.3 mm) that was of the pointed type and was accompanied by prodromal pain had an increased risk of complete or incomplete atypical femoral fracture at that site.²⁷ This finding is used by the newer DXA software. The predictive value of beaking on extended femoral DXA may be as high as 83%.²⁶

Magnetic resonance imaging

The MRI characteristics of atypical femoral fracture are similar to those of other stress fractures except that there is a lateral-to-medial pattern rather than a medial pattern. The earliest findings include periosteal reaction about the lateral cortex with a normal marrow signal.

MRI may be of particular benefit in patients with known atypical femoral fracture to screen the contralateral leg. It should image the entire length of both femurs. Contrast enhancement is not needed.

Regardless of whether initial findings were discovered on conventional radiographs or DXA, MRI confirmation is needed. Radio­nuclide bone scanning is currently not recommended because it lacks specificity. Combination imaging is recommended, with either radiography plus MRI or DXA plus MRI.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of atypical femoral fracture includes stress fracture, pathologic fracture, hypophosphatasia, and osteogenesis imperfecta.²⁸ Hypophosphatemic osteomalacia can cause Looser zones, which can be confused with atypical femoral fractures but usually occur on the medial side.⁴ Stress fracture of the femur can occur below the lesser trochanter but usually begins in the medial, not the lateral, cortex.

Pathologic fractures from underlying osseous lesions can mimic the cortical beaking of bisphosphonate-related fracture, but they usually show the associated underlying lucent lesion and poorly defined margins. A sinus tract along the region of a chronic osteomyelitis may also appear similar.

Hypophosphatasia is an inborn error of metabolism caused by a loss-of-function mutation in the gene encoding alkaline phosphatase, resulting in pyrophosphate accumulation and causing osteomalacia from impaired mineralization. This can result in femoral pseudofracture that is often bilateral and occurs in the subtrochanteric region.²⁹

Patients with atypical femoral fracture are generally a heterogeneous group, but there are risk factors to note other than bisphosphonate exposure.

Asian women had a risk 8 times higher than white women in 1 study.³⁰

Bone geometry. Mahjoub et al⁸ reported that compared with controls, patients with atypical femoral fracture had greater offset of the femoral shaft from the center of rotation of the femoral head, a more acute angle between the femoral neck and shaft, and greater proximal cortical thickness.

Medications. In addition to bisphosphonates, other drugs associated with atypical femoral fracture include RANK-ligand inhibitors such as denosumab (another drug for osteoporosis),³¹ glucocorticoids,^32,33 and proton pump inhibitors.^32,33

Genetics. Three sisters with atypical femoral fracture were found to have 37 rare mutations in 34 genes, including one in the GGPS1 gene, which codes for geranylgeranyl pyrophosphate synthase—an enzyme that bisphosphonates inhibit.³⁴

Medical conditions other than osteoporosis include collagen diseases, chronic pulmonary disease, asthma, rheumatoid arthritis, and diabetes.³⁵

Clinical recommendations

Current recommendations are to reevaluate bisphosphonate use in patients with osteoporosis after 5 or more years of therapy.³⁶

Given that patients with osteoporosis are at increased risk of typical fracture, those at higher risk should be considered for continued bisphosphonate therapy. Factors for high risk include the following:

• History of fracture on therapy
• Hip T score –2.5 or lower
• Older age (≥ 70)
• Other strong risk factors for fracture such as smoking, alcohol use, corticosteroid use, rheumatoid arthritis, and family history
• World Health Organization FRAX fracture risk score above the country-specific threshold.

Those at lower risk should be considered for a 2- to 3-year bisphosphonate holiday with periodic reevaluation of bone density and, possibly, bone markers.³⁶

WHAT IS THE UNDERLYING PATHOPHYSIOLOGY?

The mechanism by which bisphosphonates increase the risk of atypical femoral fracture is not clear. These drugs work by suppressing bone turnover; however, in theory, prolonged use could suppress it too much and increase bone fragility.

One hypothesis is that bisphosphonates impair the toughening of cortical bone, an important barrier to clinical fracture. This is supported by a study that found bisphosphonate users with atypical femoral fracture had deficits in intrinsic and extrinsic bone toughness, perhaps due to treatment-related increases in matrix mineralization.³⁷ Although this study and others showed an increase in matrix mineralization and reduced mineralization heterogeneity with bisphosphonate use,^38,39 it is unclear whether such changes contributed to reduced toughness or to atypical femoral fracture.

Changes in the skeletal geometry of the lower limb such as femoral neck-shaft angle and femoral curvature alter the stresses and strains experienced by the femoral diaphysis with loading. Because the incidence of incomplete atypical femoral fracture is much greater than that of complete fracture, most incomplete atypical femoral fractures heal before the fracture progresses.

Ultimately, all fractures, including atypical femoral fractures, occur when mechanical stress and strain exceed bone strength.

Antiresorptive drugs such as bisphosphonates, estrogen, calcitonin, and RANK ligand inhibitors prevent hip fracture by increasing the strength of the proximal femur—perhaps at the expense of the strength (or toughness) of the subtrochanteric shaft. It is also possible that treatment-related increases in hip strength (and reduced hip fracture rates) promote or sustain the transfer of stress and strain to femoral regions that experience lesser or no increases in strength from treatment, which likely includes the shaft.^40,41

CT studies in Japanese women with osteoporosis have shown that 2 years of zoledronate therapy had greater effects in the hip than in the femoral shaft, with significant increases in cortical thickness and volumetric bone mineral density at the femoral neck and intertrochanteric region compared with baseline.⁴² But zoledronate did not increase femoral shaft cortical thickness and caused only a minor increase in femoral shaft volumetric bone mineral density. Fracture patterns may have depended on damage and effects of bone turnover on mass and structure.

This hypothetical scenario portrays a possible “hip survival bias” mechanism for atypical femoral fracture, with the association with antiresorptive drugs arising from greater stress and strain in cortical regions where these fractures occur rather than from treatment-related reductions in cortical bone strength or toughness.

PRODROMAL PAIN IS COMMON

From 32% to 76% of patients who have incomplete or developing atypical femoral fracture present with a prodrome of groin or hip pain.^4,43 Prodromal pain occurs any time from 2 weeks to several years before the fracture, presenting as pain in the anterior or lateral thigh or in the groin.

Prodromal pain in a patient on antiresorptive therapy should be a signal for the clinician to obtain a radiograph of the hip and to look for contralateral symptoms and fractures. The most common mechanism of injury appears to be a ground-level fall or even a nontraumatic activity such as walking or stepping off a curb.

MEDICAL MANAGEMENT

In bisphosphonate users with radiographic evidence of atypical femoral fracture, the bis­phosphonate should be discontinued and the patient assessed for calcium and vitamin D deficiency, with supplements prescribed if needed.⁴

For patients with incomplete fracture and persistent pain after 3 months of medical management, prophylactic surgical nail fixation is recommended to prevent complete fracture.

Teriparatide, which has been associated with enhanced bone fracture healing, is a possible treatment to promote healing of atypical femoral fracture, either alone or as an adjunct to surgical fixation. A systematic review published in 2015 supported the use of teriparatide for enhancing fracture healing in atypical femoral fracture.⁴⁴ In addition, a 10-patient series⁴⁵ showed that incomplete fractures without radiolucent lines responded to teriparatide alone, whereas those with radiolucent lines needed intramedullary nailing.

These results suggest that teriparatide works best when the fracture site is stable, either inherently or with surgical fixation.

ORTHOPEDIC CARE

Orthopedic care for atypical femoral fracture differs depending on whether the patient experiences pain and whether the fracture is incomplete or complete. Figure 2 shows a treatment algorithm for atypical femoral fracture.

These are difficult fractures to manage, complicated by delayed healing in the elderly, complex displacement patterns, altered bone geometry, and risk of fracture in the opposite limb, all of which raise questions about recommending protected weight-bearing exercise.

Furthermore, atypical femoral fracture is often associated with increased anterolateral bowing of the femur, making it difficult to insert an intramedullary nail: the radius of curvature of the bone is shorter than that of a standard femoral nail. This mismatch can lead to intraoperative complications such as iatrogenic fracture during prophylactic nailing, malunion from excess straightening of the femur (which can itself lead to leg length discrepancy), and gapping of the fracture site, particularly on the medial side.

Intramedullary nailing is the first-line treatment for complete atypical femoral fracture, although the risk of delayed healing and revision surgery may be somewhat higher than with typical femoral fracture.⁴⁶ Prophylactic intramedullary nailing should be considered for a patient with intractable pain.²

A radiograph of the opposite leg should be obtained routinely, looking for an asymptomatic fracture. Bisphosphonates should be discontinued and calcium and vitamin D continued. Teriparatide therapy can be considered as an alternative treatment.

Conservative management for incomplete fracture without pain

Incomplete atypical femoral fracture unaccompanied by pain can be followed conservatively.⁴⁷ In addition to stopping antiresorptive therapy, patients need to avoid high-impact and repetitive-impact activities such as jumping or running. If pain occurs, patients should begin protected weight-bearing exercise.

Treatment is uncertain for incomplete fracture with pain

For patients with incomplete atypical femoral fracture and pain, treatment is controversial. Regimens that include 2 to 3 months of protected weight-bearing exercise, a full metabolic bone workup, calcium and vitamin D supplementation, and anabolic bone agents have produced some success. Some authors have reported poor results from conservative care, with few patients achieving pain relief or signs of complete healing.^48,49 Additionally, if an incomplete fracture is found in the opposite femur, protected weight-bearing of both legs may not be possible.

Patients with incomplete fracture should be monitored regularly with radiography and physical examination. If there is progression of the fracture, escalation of pain, or failure to heal within 2 to 3 months, then surgical treatment is necessary.

Prophylactic placement of an intramedullary nail to prevent completion of the fracture and allow a return to full weight-bearing is generally advised.⁵⁰ A long locking plate can be used if bone deformities make it difficult to place an intramedullary nail; however, nails are preferred because they allow formation of endochondral callus, which can be helpful in these difficult-to-heal fractures.

Results from retrospective reviews have shown that surgically treated patients with bis­phosphonate-associated incomplete atypical femoral fracture were more likely than those treated nonsurgically to be pain-free (81% vs 64%) and have radiographic healing (100% vs 18% at final follow-up).⁴⁶ Results have also been positive for those with complete atypical femoral fracture. At 6 months, 64% of surgically treated patients were pain-free and 98% were radiographically healed.⁵¹

The unusual geometry of the femur in patients with atypical femoral fracture and the presence of intramedullary cortical callus makes the placement of an intramedullary femoral rod more complex than in typical femoral fracture.⁸

Intramedullary nailing of atypical femoral fracture is a challenge for even the most experienced surgeon, and vigilance is imperative to avoid iatrogenic fracture and malunion.

MANY QUESTIONS REMAIN

We need more studies on the pathophysiology of bisphosphonate-associated atypical femoral fracture, the value of periodic screening with DXA, and which factors predict high risk (eg, Asian ethnicity, use of certain medications, femoral geometry). In addition, we need more data on the success of conservative management of incomplete fracture, including use of teriparatide.

Bisphosphonate therapy minimizes bone loss and reduces fracture risk by up to 50% in patients with osteoporosis,¹ but it is also associated with increased risks of osteonecrosis of the jaw and atypical femoral fracture. Although atypical femoral fractures are rare, they can have a devastating effect. Patient concern about this complication has contributed to a decrease in bisphosphonate use by about half in the last decade or so,^2,3 and we fear this could result in an increase in hip fracture rates.

In this article, we examine the evidence on bisphosphonate-associated atypical femoral fractures, including risks, pathogenesis, treatment, and prevention.

ATYPICAL FRACTURES INVOLVE THE FEMORAL SHAFT, NOT THE HEAD

An atypical femoral fracture is a transverse fracture of the femoral shaft (diaphysis), defined by both clinical criteria and radiographic appearance.

To be defined as atypical, a femoral fracture must meet 4 of the following 5 criteria⁴:

• Occurs with minimal or no trauma
• Has a predominantly transverse fracture line, originating at the lateral cortex and sometimes becoming oblique as it progresses medially across the femur
• Extends through both cortices and may be associated with a medial spike (complete fractures); or involves only the lateral cortex (incomplete fractures)
• Is noncomminuted or minimally comminuted
• Shows localized periosteal or endosteal thickening (termed “beaking” or “flaring”) of the lateral cortex at the fracture site.

Several minor features are also important but are not required, eg:

• Cortical thickening of the femoral shaft
• Unilateral or bilateral prodromal pain preceding the fracture
• Bilateral incomplete or complete femoral diaphysis fractures
• Delayed fracture healing.

Atypical femoral fracture can occur anywhere along the shaft, from just distal to the lesser trochanter to just proximal to the supracondylar flare. However, most occur in 2 areas, with 1 cluster centered at about 41 mm from the lesser trochanter (more common in relatively younger patients) and the other at 187 mm.⁵

ABSOLUTE RISK IS LOW BUT INCREASES WITH LONGER USE

Atypical femoral fractures are rare. Schilcher et al⁶ reviewed radiographs of 1,234 women who had a subtrochanteric or shaft fracture and found 59 (4.6%) of fractures were atypical. In a systematic review of 14 studies,⁷ the incidence ranged from 3.0 to 9.8 cases per 100,000 patient-years.

Furthermore, not all atypical femoral fractures are in bisphosphonate users: 7.4% were in nonusers in 1 series⁸ and 22% in another.⁹

Nevertheless, most studies show that bis­phosphonate use increases the incidence of atypical femoral fracture, and the incidence increases with duration of use, especially after 3 years.⁷

An international task force of the American Society for Bone and Mineral Research listed the absolute risk as between 3.2 and 50 cases per 100,000 patient-years, with longer use (> 5 years) increasing the risk to about 100 per 100,000 patient-years.⁴ After stopping bis­phosphonate therapy, the risk diminished by 70% per year.⁹

In another study, for 0.1 to 1.9 years of therapy, the age-adjusted atypical fracture rates were 1.78 per 100,000 per year (95% confidence interval [CI] 1.5–2.0), increasing to 113.1 per 100,000 per year (95% CI 69.3–156.8) with exposure from 8 to 9.9 years.¹⁰

A case-control study found that more than 5 years of bisphosphonate use increased the fracture risk by an odds ratio of 2.74 (95% CI 1.25–6.02).¹¹

The incidence of typical femoral fracture was higher in those who adhered better to their oral bisphosphonate regimen in some studies,¹² but the opposite was true in others.¹³

The benefits of bisphosphonate therapy in reducing fracture risk, however, outweigh the risk of atypical fracture.⁴

We do not know whether the rate of atypical femoral fracture is increasing. A review of Kaiser Permanente Northwest records found that the rates of atypical femoral shaft fracture had remained stable from 1996 to 2009. However, 61.9% of patients who met the strict radiographic criteria had taken oral bisphosphonates.¹⁴ These data suggest that bisphosphonate use has not increased the overall population-based risk for subtrochanteric and femoral shaft fractures, but that bisphosphonates and other risk factors may have increased the likelihood that such fractures will exhibit atypical radiographic features.

A population-based study in Denmark¹³ found that alendronate use longer than 10 years was associated with an adjusted 30% lower risk of hip fracture and no increase in the risk of subtrochanteric and femoral shaft fracture. In addition, the risk of subtrochanteric and femoral shaft fracture was lower with high adherence to alendronate treatment (based on medication possession ratio > 80%) compared with low adherence (ratio < 50%) (odds ratio 0.88, 95% CI 0.77–0.99). The risk was not increased in current vs past users.

The Danish study¹³ used the coding of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) to identify subtrochanteric and femoral shaft fractures without radiologic review for atypical radiographic features. The lack of specific ICD-10 coding for subtrochanteric and femoral shaft fractures with atypical radiographic features has limited our knowledge of their incidence.

After an atypical femoral fracture, patients have a significant risk of fracture on the contralateral side. In a case-control study, 28% of patients with atypical femoral fracture suffered a contralateral fracture, compared with 0.9% of patients presenting with a typical fracture pattern (odds ratio 42.6, 95% CI 12.8–142.4).¹⁵

Contralateral fracture occurs from 1 month to 4 years after the index atypical femoral fracture.¹⁶

There are reports of bisphosphonate-related low-impact fractures in other sites such as the tibia¹⁷ and forearm.¹⁸ However, they may be too rare to warrant screening.

Mortality rates

A Swedish database study found that patients with atypical femoral fractures, whether bisphosphonate users or nonusers, do not have higher mortality rates than patients with ordinary subtrochanteric or femoral shaft fractures.¹⁹ Furthermore, the mortality rates for those with atypical femoral fracture were similar to rates in the general population. In contrast, patients with an ordinary femoral fracture had a higher mortality risk than the general population.¹⁹

Other studies suggest that atypical femoral fracture may be associated with a less favorable prognosis in older patients,²⁰ but this could be due to differences in demographics, treatment adherence, or postfracture care.²¹

In addition, functional outcomes as measured by independent mobility at discharge and at 3 months were comparable between patients with atypical fracture and those with typical fracture.²²

IMAGING STUDIES

If a long-term bisphosphonate user presents with hip, thigh, or groin pain, imaging studies are recommended.

Plain radiography

Radiography is usually the first step and should include a frontal view of the pelvis (Figure 1) and 2 views of the full length of each femur. If radiography is not conclusive, bone scan or magnetic resonance imaging (MRI) should be considered.

A linear cortex transverse fracture pattern and focal lateral cortical thickening are the most sensitive and specific radiographic features.^23,24 Because of the risk of fracture on the contralateral side, radiographic study of that side is recommended as well.

Computed tomography

Computed tomography (CT) is not sensitive for early stress fractures and, given the radiation burden, is not recommended in the workup of atypical fracture.

Bone scanning

Bone scanning using technetium 99m-labeled methylene diphosphonate with a gamma camera shows active bone turnover. Stress fractures and atypical femoral fractures are most easily identified in the third (delayed) phase of the bone scan. Although bone scanning is highly sensitive, the specificity is limited by lack of spatial resolution. Atypical femoral fracture appears as increased activity in the subtrochanteric region with a predilection for the lateral cortex.

Dual-energy x-ray absorptiometry

Conventional dual-energy x-ray absorptiometry (DXA) extends only to 1 to 2 cm below the lesser trochanter and can therefore miss atypical fractures, which usually occur farther down. The overall detection rate for DXA was 61% in a sample of 33 patients.²⁵

Newer scanners can look at the entire femoral shaft.²⁶ In addition, newer software can quantify focal thickening (beaking) of the lateral cortex and screen patients who have no symptoms. The results of serial measurements can be graphed so that the practitioner can view trends to help assess or rule out potential asymptomatic atypical femoral fracture.

A localized reaction (periosteal thickening of the lateral cortex or beaking) often precedes atypical femoral fracture. A 2017 study reported that patients with high localized reaction (mean height 3.3 mm) that was of the pointed type and was accompanied by prodromal pain had an increased risk of complete or incomplete atypical femoral fracture at that site.²⁷ This finding is used by the newer DXA software. The predictive value of beaking on extended femoral DXA may be as high as 83%.²⁶

Magnetic resonance imaging

The MRI characteristics of atypical femoral fracture are similar to those of other stress fractures except that there is a lateral-to-medial pattern rather than a medial pattern. The earliest findings include periosteal reaction about the lateral cortex with a normal marrow signal.

MRI may be of particular benefit in patients with known atypical femoral fracture to screen the contralateral leg. It should image the entire length of both femurs. Contrast enhancement is not needed.

Regardless of whether initial findings were discovered on conventional radiographs or DXA, MRI confirmation is needed. Radio­nuclide bone scanning is currently not recommended because it lacks specificity. Combination imaging is recommended, with either radiography plus MRI or DXA plus MRI.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of atypical femoral fracture includes stress fracture, pathologic fracture, hypophosphatasia, and osteogenesis imperfecta.²⁸ Hypophosphatemic osteomalacia can cause Looser zones, which can be confused with atypical femoral fractures but usually occur on the medial side.⁴ Stress fracture of the femur can occur below the lesser trochanter but usually begins in the medial, not the lateral, cortex.

Pathologic fractures from underlying osseous lesions can mimic the cortical beaking of bisphosphonate-related fracture, but they usually show the associated underlying lucent lesion and poorly defined margins. A sinus tract along the region of a chronic osteomyelitis may also appear similar.

Hypophosphatasia is an inborn error of metabolism caused by a loss-of-function mutation in the gene encoding alkaline phosphatase, resulting in pyrophosphate accumulation and causing osteomalacia from impaired mineralization. This can result in femoral pseudofracture that is often bilateral and occurs in the subtrochanteric region.²⁹

Patients with atypical femoral fracture are generally a heterogeneous group, but there are risk factors to note other than bisphosphonate exposure.

Asian women had a risk 8 times higher than white women in 1 study.³⁰

Bone geometry. Mahjoub et al⁸ reported that compared with controls, patients with atypical femoral fracture had greater offset of the femoral shaft from the center of rotation of the femoral head, a more acute angle between the femoral neck and shaft, and greater proximal cortical thickness.

Medications. In addition to bisphosphonates, other drugs associated with atypical femoral fracture include RANK-ligand inhibitors such as denosumab (another drug for osteoporosis),³¹ glucocorticoids,^32,33 and proton pump inhibitors.^32,33

Genetics. Three sisters with atypical femoral fracture were found to have 37 rare mutations in 34 genes, including one in the GGPS1 gene, which codes for geranylgeranyl pyrophosphate synthase—an enzyme that bisphosphonates inhibit.³⁴

Medical conditions other than osteoporosis include collagen diseases, chronic pulmonary disease, asthma, rheumatoid arthritis, and diabetes.³⁵

Clinical recommendations

Current recommendations are to reevaluate bisphosphonate use in patients with osteoporosis after 5 or more years of therapy.³⁶

Given that patients with osteoporosis are at increased risk of typical fracture, those at higher risk should be considered for continued bisphosphonate therapy. Factors for high risk include the following:

• History of fracture on therapy
• Hip T score –2.5 or lower
• Older age (≥ 70)
• Other strong risk factors for fracture such as smoking, alcohol use, corticosteroid use, rheumatoid arthritis, and family history
• World Health Organization FRAX fracture risk score above the country-specific threshold.

Those at lower risk should be considered for a 2- to 3-year bisphosphonate holiday with periodic reevaluation of bone density and, possibly, bone markers.³⁶

WHAT IS THE UNDERLYING PATHOPHYSIOLOGY?

The mechanism by which bisphosphonates increase the risk of atypical femoral fracture is not clear. These drugs work by suppressing bone turnover; however, in theory, prolonged use could suppress it too much and increase bone fragility.

One hypothesis is that bisphosphonates impair the toughening of cortical bone, an important barrier to clinical fracture. This is supported by a study that found bisphosphonate users with atypical femoral fracture had deficits in intrinsic and extrinsic bone toughness, perhaps due to treatment-related increases in matrix mineralization.³⁷ Although this study and others showed an increase in matrix mineralization and reduced mineralization heterogeneity with bisphosphonate use,^38,39 it is unclear whether such changes contributed to reduced toughness or to atypical femoral fracture.

Changes in the skeletal geometry of the lower limb such as femoral neck-shaft angle and femoral curvature alter the stresses and strains experienced by the femoral diaphysis with loading. Because the incidence of incomplete atypical femoral fracture is much greater than that of complete fracture, most incomplete atypical femoral fractures heal before the fracture progresses.

Ultimately, all fractures, including atypical femoral fractures, occur when mechanical stress and strain exceed bone strength.

Antiresorptive drugs such as bisphosphonates, estrogen, calcitonin, and RANK ligand inhibitors prevent hip fracture by increasing the strength of the proximal femur—perhaps at the expense of the strength (or toughness) of the subtrochanteric shaft. It is also possible that treatment-related increases in hip strength (and reduced hip fracture rates) promote or sustain the transfer of stress and strain to femoral regions that experience lesser or no increases in strength from treatment, which likely includes the shaft.^40,41

CT studies in Japanese women with osteoporosis have shown that 2 years of zoledronate therapy had greater effects in the hip than in the femoral shaft, with significant increases in cortical thickness and volumetric bone mineral density at the femoral neck and intertrochanteric region compared with baseline.⁴² But zoledronate did not increase femoral shaft cortical thickness and caused only a minor increase in femoral shaft volumetric bone mineral density. Fracture patterns may have depended on damage and effects of bone turnover on mass and structure.

This hypothetical scenario portrays a possible “hip survival bias” mechanism for atypical femoral fracture, with the association with antiresorptive drugs arising from greater stress and strain in cortical regions where these fractures occur rather than from treatment-related reductions in cortical bone strength or toughness.

PRODROMAL PAIN IS COMMON

From 32% to 76% of patients who have incomplete or developing atypical femoral fracture present with a prodrome of groin or hip pain.^4,43 Prodromal pain occurs any time from 2 weeks to several years before the fracture, presenting as pain in the anterior or lateral thigh or in the groin.

Prodromal pain in a patient on antiresorptive therapy should be a signal for the clinician to obtain a radiograph of the hip and to look for contralateral symptoms and fractures. The most common mechanism of injury appears to be a ground-level fall or even a nontraumatic activity such as walking or stepping off a curb.

MEDICAL MANAGEMENT

In bisphosphonate users with radiographic evidence of atypical femoral fracture, the bis­phosphonate should be discontinued and the patient assessed for calcium and vitamin D deficiency, with supplements prescribed if needed.⁴

For patients with incomplete fracture and persistent pain after 3 months of medical management, prophylactic surgical nail fixation is recommended to prevent complete fracture.

Teriparatide, which has been associated with enhanced bone fracture healing, is a possible treatment to promote healing of atypical femoral fracture, either alone or as an adjunct to surgical fixation. A systematic review published in 2015 supported the use of teriparatide for enhancing fracture healing in atypical femoral fracture.⁴⁴ In addition, a 10-patient series⁴⁵ showed that incomplete fractures without radiolucent lines responded to teriparatide alone, whereas those with radiolucent lines needed intramedullary nailing.

These results suggest that teriparatide works best when the fracture site is stable, either inherently or with surgical fixation.

ORTHOPEDIC CARE

Orthopedic care for atypical femoral fracture differs depending on whether the patient experiences pain and whether the fracture is incomplete or complete. Figure 2 shows a treatment algorithm for atypical femoral fracture.

These are difficult fractures to manage, complicated by delayed healing in the elderly, complex displacement patterns, altered bone geometry, and risk of fracture in the opposite limb, all of which raise questions about recommending protected weight-bearing exercise.

Furthermore, atypical femoral fracture is often associated with increased anterolateral bowing of the femur, making it difficult to insert an intramedullary nail: the radius of curvature of the bone is shorter than that of a standard femoral nail. This mismatch can lead to intraoperative complications such as iatrogenic fracture during prophylactic nailing, malunion from excess straightening of the femur (which can itself lead to leg length discrepancy), and gapping of the fracture site, particularly on the medial side.

Intramedullary nailing is the first-line treatment for complete atypical femoral fracture, although the risk of delayed healing and revision surgery may be somewhat higher than with typical femoral fracture.⁴⁶ Prophylactic intramedullary nailing should be considered for a patient with intractable pain.²

A radiograph of the opposite leg should be obtained routinely, looking for an asymptomatic fracture. Bisphosphonates should be discontinued and calcium and vitamin D continued. Teriparatide therapy can be considered as an alternative treatment.

Conservative management for incomplete fracture without pain

Incomplete atypical femoral fracture unaccompanied by pain can be followed conservatively.⁴⁷ In addition to stopping antiresorptive therapy, patients need to avoid high-impact and repetitive-impact activities such as jumping or running. If pain occurs, patients should begin protected weight-bearing exercise.

Treatment is uncertain for incomplete fracture with pain

For patients with incomplete atypical femoral fracture and pain, treatment is controversial. Regimens that include 2 to 3 months of protected weight-bearing exercise, a full metabolic bone workup, calcium and vitamin D supplementation, and anabolic bone agents have produced some success. Some authors have reported poor results from conservative care, with few patients achieving pain relief or signs of complete healing.^48,49 Additionally, if an incomplete fracture is found in the opposite femur, protected weight-bearing of both legs may not be possible.

Patients with incomplete fracture should be monitored regularly with radiography and physical examination. If there is progression of the fracture, escalation of pain, or failure to heal within 2 to 3 months, then surgical treatment is necessary.

Prophylactic placement of an intramedullary nail to prevent completion of the fracture and allow a return to full weight-bearing is generally advised.⁵⁰ A long locking plate can be used if bone deformities make it difficult to place an intramedullary nail; however, nails are preferred because they allow formation of endochondral callus, which can be helpful in these difficult-to-heal fractures.

Results from retrospective reviews have shown that surgically treated patients with bis­phosphonate-associated incomplete atypical femoral fracture were more likely than those treated nonsurgically to be pain-free (81% vs 64%) and have radiographic healing (100% vs 18% at final follow-up).⁴⁶ Results have also been positive for those with complete atypical femoral fracture. At 6 months, 64% of surgically treated patients were pain-free and 98% were radiographically healed.⁵¹

The unusual geometry of the femur in patients with atypical femoral fracture and the presence of intramedullary cortical callus makes the placement of an intramedullary femoral rod more complex than in typical femoral fracture.⁸

Intramedullary nailing of atypical femoral fracture is a challenge for even the most experienced surgeon, and vigilance is imperative to avoid iatrogenic fracture and malunion.

MANY QUESTIONS REMAIN

We need more studies on the pathophysiology of bisphosphonate-associated atypical femoral fracture, the value of periodic screening with DXA, and which factors predict high risk (eg, Asian ethnicity, use of certain medications, femoral geometry). In addition, we need more data on the success of conservative management of incomplete fracture, including use of teriparatide.

Bisphosphonate therapy minimizes bone loss and reduces fracture risk by up to 50% in patients with osteoporosis,¹ but it is also associated with increased risks of osteonecrosis of the jaw and atypical femoral fracture. Although atypical femoral fractures are rare, they can have a devastating effect. Patient concern about this complication has contributed to a decrease in bisphosphonate use by about half in the last decade or so,^2,3 and we fear this could result in an increase in hip fracture rates.

In this article, we examine the evidence on bisphosphonate-associated atypical femoral fractures, including risks, pathogenesis, treatment, and prevention.

ATYPICAL FRACTURES INVOLVE THE FEMORAL SHAFT, NOT THE HEAD

An atypical femoral fracture is a transverse fracture of the femoral shaft (diaphysis), defined by both clinical criteria and radiographic appearance.

To be defined as atypical, a femoral fracture must meet 4 of the following 5 criteria⁴:

• Occurs with minimal or no trauma
• Has a predominantly transverse fracture line, originating at the lateral cortex and sometimes becoming oblique as it progresses medially across the femur
• Extends through both cortices and may be associated with a medial spike (complete fractures); or involves only the lateral cortex (incomplete fractures)
• Is noncomminuted or minimally comminuted
• Shows localized periosteal or endosteal thickening (termed “beaking” or “flaring”) of the lateral cortex at the fracture site.

Several minor features are also important but are not required, eg:

• Cortical thickening of the femoral shaft
• Unilateral or bilateral prodromal pain preceding the fracture
• Bilateral incomplete or complete femoral diaphysis fractures
• Delayed fracture healing.

Atypical femoral fracture can occur anywhere along the shaft, from just distal to the lesser trochanter to just proximal to the supracondylar flare. However, most occur in 2 areas, with 1 cluster centered at about 41 mm from the lesser trochanter (more common in relatively younger patients) and the other at 187 mm.⁵

ABSOLUTE RISK IS LOW BUT INCREASES WITH LONGER USE

Atypical femoral fractures are rare. Schilcher et al⁶ reviewed radiographs of 1,234 women who had a subtrochanteric or shaft fracture and found 59 (4.6%) of fractures were atypical. In a systematic review of 14 studies,⁷ the incidence ranged from 3.0 to 9.8 cases per 100,000 patient-years.

Furthermore, not all atypical femoral fractures are in bisphosphonate users: 7.4% were in nonusers in 1 series⁸ and 22% in another.⁹

Nevertheless, most studies show that bis­phosphonate use increases the incidence of atypical femoral fracture, and the incidence increases with duration of use, especially after 3 years.⁷

An international task force of the American Society for Bone and Mineral Research listed the absolute risk as between 3.2 and 50 cases per 100,000 patient-years, with longer use (> 5 years) increasing the risk to about 100 per 100,000 patient-years.⁴ After stopping bis­phosphonate therapy, the risk diminished by 70% per year.⁹

In another study, for 0.1 to 1.9 years of therapy, the age-adjusted atypical fracture rates were 1.78 per 100,000 per year (95% confidence interval [CI] 1.5–2.0), increasing to 113.1 per 100,000 per year (95% CI 69.3–156.8) with exposure from 8 to 9.9 years.¹⁰

A case-control study found that more than 5 years of bisphosphonate use increased the fracture risk by an odds ratio of 2.74 (95% CI 1.25–6.02).¹¹

The incidence of typical femoral fracture was higher in those who adhered better to their oral bisphosphonate regimen in some studies,¹² but the opposite was true in others.¹³

The benefits of bisphosphonate therapy in reducing fracture risk, however, outweigh the risk of atypical fracture.⁴

We do not know whether the rate of atypical femoral fracture is increasing. A review of Kaiser Permanente Northwest records found that the rates of atypical femoral shaft fracture had remained stable from 1996 to 2009. However, 61.9% of patients who met the strict radiographic criteria had taken oral bisphosphonates.¹⁴ These data suggest that bisphosphonate use has not increased the overall population-based risk for subtrochanteric and femoral shaft fractures, but that bisphosphonates and other risk factors may have increased the likelihood that such fractures will exhibit atypical radiographic features.

A population-based study in Denmark¹³ found that alendronate use longer than 10 years was associated with an adjusted 30% lower risk of hip fracture and no increase in the risk of subtrochanteric and femoral shaft fracture. In addition, the risk of subtrochanteric and femoral shaft fracture was lower with high adherence to alendronate treatment (based on medication possession ratio > 80%) compared with low adherence (ratio < 50%) (odds ratio 0.88, 95% CI 0.77–0.99). The risk was not increased in current vs past users.

The Danish study¹³ used the coding of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) to identify subtrochanteric and femoral shaft fractures without radiologic review for atypical radiographic features. The lack of specific ICD-10 coding for subtrochanteric and femoral shaft fractures with atypical radiographic features has limited our knowledge of their incidence.

After an atypical femoral fracture, patients have a significant risk of fracture on the contralateral side. In a case-control study, 28% of patients with atypical femoral fracture suffered a contralateral fracture, compared with 0.9% of patients presenting with a typical fracture pattern (odds ratio 42.6, 95% CI 12.8–142.4).¹⁵

Contralateral fracture occurs from 1 month to 4 years after the index atypical femoral fracture.¹⁶

There are reports of bisphosphonate-related low-impact fractures in other sites such as the tibia¹⁷ and forearm.¹⁸ However, they may be too rare to warrant screening.

Mortality rates

A Swedish database study found that patients with atypical femoral fractures, whether bisphosphonate users or nonusers, do not have higher mortality rates than patients with ordinary subtrochanteric or femoral shaft fractures.¹⁹ Furthermore, the mortality rates for those with atypical femoral fracture were similar to rates in the general population. In contrast, patients with an ordinary femoral fracture had a higher mortality risk than the general population.¹⁹

Other studies suggest that atypical femoral fracture may be associated with a less favorable prognosis in older patients,²⁰ but this could be due to differences in demographics, treatment adherence, or postfracture care.²¹

In addition, functional outcomes as measured by independent mobility at discharge and at 3 months were comparable between patients with atypical fracture and those with typical fracture.²²

IMAGING STUDIES

If a long-term bisphosphonate user presents with hip, thigh, or groin pain, imaging studies are recommended.

Plain radiography

Radiography is usually the first step and should include a frontal view of the pelvis (Figure 1) and 2 views of the full length of each femur. If radiography is not conclusive, bone scan or magnetic resonance imaging (MRI) should be considered.

A linear cortex transverse fracture pattern and focal lateral cortical thickening are the most sensitive and specific radiographic features.^23,24 Because of the risk of fracture on the contralateral side, radiographic study of that side is recommended as well.

Computed tomography

Computed tomography (CT) is not sensitive for early stress fractures and, given the radiation burden, is not recommended in the workup of atypical fracture.

Bone scanning

Bone scanning using technetium 99m-labeled methylene diphosphonate with a gamma camera shows active bone turnover. Stress fractures and atypical femoral fractures are most easily identified in the third (delayed) phase of the bone scan. Although bone scanning is highly sensitive, the specificity is limited by lack of spatial resolution. Atypical femoral fracture appears as increased activity in the subtrochanteric region with a predilection for the lateral cortex.

Dual-energy x-ray absorptiometry

Conventional dual-energy x-ray absorptiometry (DXA) extends only to 1 to 2 cm below the lesser trochanter and can therefore miss atypical fractures, which usually occur farther down. The overall detection rate for DXA was 61% in a sample of 33 patients.²⁵

Newer scanners can look at the entire femoral shaft.²⁶ In addition, newer software can quantify focal thickening (beaking) of the lateral cortex and screen patients who have no symptoms. The results of serial measurements can be graphed so that the practitioner can view trends to help assess or rule out potential asymptomatic atypical femoral fracture.

A localized reaction (periosteal thickening of the lateral cortex or beaking) often precedes atypical femoral fracture. A 2017 study reported that patients with high localized reaction (mean height 3.3 mm) that was of the pointed type and was accompanied by prodromal pain had an increased risk of complete or incomplete atypical femoral fracture at that site.²⁷ This finding is used by the newer DXA software. The predictive value of beaking on extended femoral DXA may be as high as 83%.²⁶

Magnetic resonance imaging

The MRI characteristics of atypical femoral fracture are similar to those of other stress fractures except that there is a lateral-to-medial pattern rather than a medial pattern. The earliest findings include periosteal reaction about the lateral cortex with a normal marrow signal.

MRI may be of particular benefit in patients with known atypical femoral fracture to screen the contralateral leg. It should image the entire length of both femurs. Contrast enhancement is not needed.

Regardless of whether initial findings were discovered on conventional radiographs or DXA, MRI confirmation is needed. Radio­nuclide bone scanning is currently not recommended because it lacks specificity. Combination imaging is recommended, with either radiography plus MRI or DXA plus MRI.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of atypical femoral fracture includes stress fracture, pathologic fracture, hypophosphatasia, and osteogenesis imperfecta.²⁸ Hypophosphatemic osteomalacia can cause Looser zones, which can be confused with atypical femoral fractures but usually occur on the medial side.⁴ Stress fracture of the femur can occur below the lesser trochanter but usually begins in the medial, not the lateral, cortex.

Pathologic fractures from underlying osseous lesions can mimic the cortical beaking of bisphosphonate-related fracture, but they usually show the associated underlying lucent lesion and poorly defined margins. A sinus tract along the region of a chronic osteomyelitis may also appear similar.

Hypophosphatasia is an inborn error of metabolism caused by a loss-of-function mutation in the gene encoding alkaline phosphatase, resulting in pyrophosphate accumulation and causing osteomalacia from impaired mineralization. This can result in femoral pseudofracture that is often bilateral and occurs in the subtrochanteric region.²⁹

Patients with atypical femoral fracture are generally a heterogeneous group, but there are risk factors to note other than bisphosphonate exposure.

Asian women had a risk 8 times higher than white women in 1 study.³⁰

Bone geometry. Mahjoub et al⁸ reported that compared with controls, patients with atypical femoral fracture had greater offset of the femoral shaft from the center of rotation of the femoral head, a more acute angle between the femoral neck and shaft, and greater proximal cortical thickness.

Medications. In addition to bisphosphonates, other drugs associated with atypical femoral fracture include RANK-ligand inhibitors such as denosumab (another drug for osteoporosis),³¹ glucocorticoids,^32,33 and proton pump inhibitors.^32,33

Genetics. Three sisters with atypical femoral fracture were found to have 37 rare mutations in 34 genes, including one in the GGPS1 gene, which codes for geranylgeranyl pyrophosphate synthase—an enzyme that bisphosphonates inhibit.³⁴

Medical conditions other than osteoporosis include collagen diseases, chronic pulmonary disease, asthma, rheumatoid arthritis, and diabetes.³⁵

Clinical recommendations

Current recommendations are to reevaluate bisphosphonate use in patients with osteoporosis after 5 or more years of therapy.³⁶

Given that patients with osteoporosis are at increased risk of typical fracture, those at higher risk should be considered for continued bisphosphonate therapy. Factors for high risk include the following:

• History of fracture on therapy
• Hip T score –2.5 or lower
• Older age (≥ 70)
• Other strong risk factors for fracture such as smoking, alcohol use, corticosteroid use, rheumatoid arthritis, and family history
• World Health Organization FRAX fracture risk score above the country-specific threshold.

Those at lower risk should be considered for a 2- to 3-year bisphosphonate holiday with periodic reevaluation of bone density and, possibly, bone markers.³⁶

WHAT IS THE UNDERLYING PATHOPHYSIOLOGY?

The mechanism by which bisphosphonates increase the risk of atypical femoral fracture is not clear. These drugs work by suppressing bone turnover; however, in theory, prolonged use could suppress it too much and increase bone fragility.

One hypothesis is that bisphosphonates impair the toughening of cortical bone, an important barrier to clinical fracture. This is supported by a study that found bisphosphonate users with atypical femoral fracture had deficits in intrinsic and extrinsic bone toughness, perhaps due to treatment-related increases in matrix mineralization.³⁷ Although this study and others showed an increase in matrix mineralization and reduced mineralization heterogeneity with bisphosphonate use,^38,39 it is unclear whether such changes contributed to reduced toughness or to atypical femoral fracture.

Changes in the skeletal geometry of the lower limb such as femoral neck-shaft angle and femoral curvature alter the stresses and strains experienced by the femoral diaphysis with loading. Because the incidence of incomplete atypical femoral fracture is much greater than that of complete fracture, most incomplete atypical femoral fractures heal before the fracture progresses.

Ultimately, all fractures, including atypical femoral fractures, occur when mechanical stress and strain exceed bone strength.

Antiresorptive drugs such as bisphosphonates, estrogen, calcitonin, and RANK ligand inhibitors prevent hip fracture by increasing the strength of the proximal femur—perhaps at the expense of the strength (or toughness) of the subtrochanteric shaft. It is also possible that treatment-related increases in hip strength (and reduced hip fracture rates) promote or sustain the transfer of stress and strain to femoral regions that experience lesser or no increases in strength from treatment, which likely includes the shaft.^40,41

CT studies in Japanese women with osteoporosis have shown that 2 years of zoledronate therapy had greater effects in the hip than in the femoral shaft, with significant increases in cortical thickness and volumetric bone mineral density at the femoral neck and intertrochanteric region compared with baseline.⁴² But zoledronate did not increase femoral shaft cortical thickness and caused only a minor increase in femoral shaft volumetric bone mineral density. Fracture patterns may have depended on damage and effects of bone turnover on mass and structure.

This hypothetical scenario portrays a possible “hip survival bias” mechanism for atypical femoral fracture, with the association with antiresorptive drugs arising from greater stress and strain in cortical regions where these fractures occur rather than from treatment-related reductions in cortical bone strength or toughness.

PRODROMAL PAIN IS COMMON

From 32% to 76% of patients who have incomplete or developing atypical femoral fracture present with a prodrome of groin or hip pain.^4,43 Prodromal pain occurs any time from 2 weeks to several years before the fracture, presenting as pain in the anterior or lateral thigh or in the groin.

Prodromal pain in a patient on antiresorptive therapy should be a signal for the clinician to obtain a radiograph of the hip and to look for contralateral symptoms and fractures. The most common mechanism of injury appears to be a ground-level fall or even a nontraumatic activity such as walking or stepping off a curb.

MEDICAL MANAGEMENT

In bisphosphonate users with radiographic evidence of atypical femoral fracture, the bis­phosphonate should be discontinued and the patient assessed for calcium and vitamin D deficiency, with supplements prescribed if needed.⁴

For patients with incomplete fracture and persistent pain after 3 months of medical management, prophylactic surgical nail fixation is recommended to prevent complete fracture.

Teriparatide, which has been associated with enhanced bone fracture healing, is a possible treatment to promote healing of atypical femoral fracture, either alone or as an adjunct to surgical fixation. A systematic review published in 2015 supported the use of teriparatide for enhancing fracture healing in atypical femoral fracture.⁴⁴ In addition, a 10-patient series⁴⁵ showed that incomplete fractures without radiolucent lines responded to teriparatide alone, whereas those with radiolucent lines needed intramedullary nailing.

These results suggest that teriparatide works best when the fracture site is stable, either inherently or with surgical fixation.

ORTHOPEDIC CARE

Orthopedic care for atypical femoral fracture differs depending on whether the patient experiences pain and whether the fracture is incomplete or complete. Figure 2 shows a treatment algorithm for atypical femoral fracture.

These are difficult fractures to manage, complicated by delayed healing in the elderly, complex displacement patterns, altered bone geometry, and risk of fracture in the opposite limb, all of which raise questions about recommending protected weight-bearing exercise.

Furthermore, atypical femoral fracture is often associated with increased anterolateral bowing of the femur, making it difficult to insert an intramedullary nail: the radius of curvature of the bone is shorter than that of a standard femoral nail. This mismatch can lead to intraoperative complications such as iatrogenic fracture during prophylactic nailing, malunion from excess straightening of the femur (which can itself lead to leg length discrepancy), and gapping of the fracture site, particularly on the medial side.

Intramedullary nailing is the first-line treatment for complete atypical femoral fracture, although the risk of delayed healing and revision surgery may be somewhat higher than with typical femoral fracture.⁴⁶ Prophylactic intramedullary nailing should be considered for a patient with intractable pain.²

A radiograph of the opposite leg should be obtained routinely, looking for an asymptomatic fracture. Bisphosphonates should be discontinued and calcium and vitamin D continued. Teriparatide therapy can be considered as an alternative treatment.

Conservative management for incomplete fracture without pain

Incomplete atypical femoral fracture unaccompanied by pain can be followed conservatively.⁴⁷ In addition to stopping antiresorptive therapy, patients need to avoid high-impact and repetitive-impact activities such as jumping or running. If pain occurs, patients should begin protected weight-bearing exercise.

Treatment is uncertain for incomplete fracture with pain

For patients with incomplete atypical femoral fracture and pain, treatment is controversial. Regimens that include 2 to 3 months of protected weight-bearing exercise, a full metabolic bone workup, calcium and vitamin D supplementation, and anabolic bone agents have produced some success. Some authors have reported poor results from conservative care, with few patients achieving pain relief or signs of complete healing.^48,49 Additionally, if an incomplete fracture is found in the opposite femur, protected weight-bearing of both legs may not be possible.

Patients with incomplete fracture should be monitored regularly with radiography and physical examination. If there is progression of the fracture, escalation of pain, or failure to heal within 2 to 3 months, then surgical treatment is necessary.

Prophylactic placement of an intramedullary nail to prevent completion of the fracture and allow a return to full weight-bearing is generally advised.⁵⁰ A long locking plate can be used if bone deformities make it difficult to place an intramedullary nail; however, nails are preferred because they allow formation of endochondral callus, which can be helpful in these difficult-to-heal fractures.

Results from retrospective reviews have shown that surgically treated patients with bis­phosphonate-associated incomplete atypical femoral fracture were more likely than those treated nonsurgically to be pain-free (81% vs 64%) and have radiographic healing (100% vs 18% at final follow-up).⁴⁶ Results have also been positive for those with complete atypical femoral fracture. At 6 months, 64% of surgically treated patients were pain-free and 98% were radiographically healed.⁵¹

The unusual geometry of the femur in patients with atypical femoral fracture and the presence of intramedullary cortical callus makes the placement of an intramedullary femoral rod more complex than in typical femoral fracture.⁸

Intramedullary nailing of atypical femoral fracture is a challenge for even the most experienced surgeon, and vigilance is imperative to avoid iatrogenic fracture and malunion.

MANY QUESTIONS REMAIN

We need more studies on the pathophysiology of bisphosphonate-associated atypical femoral fracture, the value of periodic screening with DXA, and which factors predict high risk (eg, Asian ethnicity, use of certain medications, femoral geometry). In addition, we need more data on the success of conservative management of incomplete fracture, including use of teriparatide.

Several months ago, we invited readers to submit short personalized commentaries on articles that changed the way they approach a specific clinical problem and the way they take care of patients. In this issue of the Journal, addiction specialist Charles Reznikoff, MD, discusses 3 observational studies that focused on how prescribing opioids for acute pain can lead to chronic opioid use and addiction, and how these studies have influenced his practice.

Although observational studies rank lower on the level-of-evidence scale than randomized controlled trials, they can intellectually stimulate and inform us in ways that lead us to modify how we deliver clinical care.

The initial prescribing of pain medications and the management of patients with chronic pain are currently under intense scrutiny, and are the topic of much discussion in the United States. The opioid epidemic has spilled over into all aspects of daily life, far beyond the medical community. But since we physicians are the only legal and regulated source of narcotics and other pain medications, we are under the microscope—and rightly so.

We, our patients, the pharmaceutical industry, legislators, and the law enforcement community struggle to navigate a complex maze, one with moving walls. Not long ago, physicians were told that we were not attentive enough to our patients’ suffering and needed to do better at relieving it. “Pain” became a vital sign and a recorded metric of quality care. Some excellent changes evolved from this focus, such as increased emphasis on postoperative regional and local pain control. But pain measurements continue to be recorded at every outpatient visit, an almost mindless requirement.

Recently, a patient with lupus nephritis whom I was seeing for blood pressure management reported a pain level of 8 on a scale of 10. I confess that I usually don’t even look at these metrics, but for whatever reason I saw her answer. I asked her about it. She had burned her finger while cooking and said, “I had no idea what number to pick. I picked 8. It’s no big deal.”

But the ongoing emphasis on this metric may lead some patients to expect total pain relief, a problematic expectation in those with chronic pain syndromes such as fibromyalgia. As Dr. Reznikoff points out, a large proportion of patients report they have chronic pain, and many (but clearly not all) suffer from recognized or masked chronic anxiety and depression disorders¹ that may well influence how they use pain medications.

Thus, while physicians indeed are on the front lines of offering initial prescriptions for pain medications, we remain betwixt and between in the challenges of responding to the immediate needs of our patients while trying to predict the long-term effects of our prescription on the individual patient and of our prescribing patterns on society in general.

I again welcome your submissions describing how individual publications have affected your personal approach to managing patients and specific diseases. We will publish selected contributions in print and online.

Several months ago, we invited readers to submit short personalized commentaries on articles that changed the way they approach a specific clinical problem and the way they take care of patients. In this issue of the Journal, addiction specialist Charles Reznikoff, MD, discusses 3 observational studies that focused on how prescribing opioids for acute pain can lead to chronic opioid use and addiction, and how these studies have influenced his practice.

Although observational studies rank lower on the level-of-evidence scale than randomized controlled trials, they can intellectually stimulate and inform us in ways that lead us to modify how we deliver clinical care.

The initial prescribing of pain medications and the management of patients with chronic pain are currently under intense scrutiny, and are the topic of much discussion in the United States. The opioid epidemic has spilled over into all aspects of daily life, far beyond the medical community. But since we physicians are the only legal and regulated source of narcotics and other pain medications, we are under the microscope—and rightly so.

We, our patients, the pharmaceutical industry, legislators, and the law enforcement community struggle to navigate a complex maze, one with moving walls. Not long ago, physicians were told that we were not attentive enough to our patients’ suffering and needed to do better at relieving it. “Pain” became a vital sign and a recorded metric of quality care. Some excellent changes evolved from this focus, such as increased emphasis on postoperative regional and local pain control. But pain measurements continue to be recorded at every outpatient visit, an almost mindless requirement.

Recently, a patient with lupus nephritis whom I was seeing for blood pressure management reported a pain level of 8 on a scale of 10. I confess that I usually don’t even look at these metrics, but for whatever reason I saw her answer. I asked her about it. She had burned her finger while cooking and said, “I had no idea what number to pick. I picked 8. It’s no big deal.”

But the ongoing emphasis on this metric may lead some patients to expect total pain relief, a problematic expectation in those with chronic pain syndromes such as fibromyalgia. As Dr. Reznikoff points out, a large proportion of patients report they have chronic pain, and many (but clearly not all) suffer from recognized or masked chronic anxiety and depression disorders¹ that may well influence how they use pain medications.

Thus, while physicians indeed are on the front lines of offering initial prescriptions for pain medications, we remain betwixt and between in the challenges of responding to the immediate needs of our patients while trying to predict the long-term effects of our prescription on the individual patient and of our prescribing patterns on society in general.

I again welcome your submissions describing how individual publications have affected your personal approach to managing patients and specific diseases. We will publish selected contributions in print and online.

Several months ago, we invited readers to submit short personalized commentaries on articles that changed the way they approach a specific clinical problem and the way they take care of patients. In this issue of the Journal, addiction specialist Charles Reznikoff, MD, discusses 3 observational studies that focused on how prescribing opioids for acute pain can lead to chronic opioid use and addiction, and how these studies have influenced his practice.

Although observational studies rank lower on the level-of-evidence scale than randomized controlled trials, they can intellectually stimulate and inform us in ways that lead us to modify how we deliver clinical care.

The initial prescribing of pain medications and the management of patients with chronic pain are currently under intense scrutiny, and are the topic of much discussion in the United States. The opioid epidemic has spilled over into all aspects of daily life, far beyond the medical community. But since we physicians are the only legal and regulated source of narcotics and other pain medications, we are under the microscope—and rightly so.

We, our patients, the pharmaceutical industry, legislators, and the law enforcement community struggle to navigate a complex maze, one with moving walls. Not long ago, physicians were told that we were not attentive enough to our patients’ suffering and needed to do better at relieving it. “Pain” became a vital sign and a recorded metric of quality care. Some excellent changes evolved from this focus, such as increased emphasis on postoperative regional and local pain control. But pain measurements continue to be recorded at every outpatient visit, an almost mindless requirement.

Recently, a patient with lupus nephritis whom I was seeing for blood pressure management reported a pain level of 8 on a scale of 10. I confess that I usually don’t even look at these metrics, but for whatever reason I saw her answer. I asked her about it. She had burned her finger while cooking and said, “I had no idea what number to pick. I picked 8. It’s no big deal.”

But the ongoing emphasis on this metric may lead some patients to expect total pain relief, a problematic expectation in those with chronic pain syndromes such as fibromyalgia. As Dr. Reznikoff points out, a large proportion of patients report they have chronic pain, and many (but clearly not all) suffer from recognized or masked chronic anxiety and depression disorders¹ that may well influence how they use pain medications.

Thus, while physicians indeed are on the front lines of offering initial prescriptions for pain medications, we remain betwixt and between in the challenges of responding to the immediate needs of our patients while trying to predict the long-term effects of our prescription on the individual patient and of our prescribing patterns on society in general.

I again welcome your submissions describing how individual publications have affected your personal approach to managing patients and specific diseases. We will publish selected contributions in print and online.