Applied Evidence

Despite encouraging data that antibiotic prescribing is on the decline, patients are still prescribed antibiotics frequently, making these agents the 12th most frequently used drug class.¹ At the same time, prescribers are caring for patients with increasingly complex drug regimens that provide fertile ground for drug interactions with these antibiotics. And, of course, lifestyle factors such as alcohol consumption are a consideration when any prescription is written.

As pharmacists, we find that certain questions about antibiotic prescribing and interactions come up with frequency. These questions often pertain to the use of warfarin, oral contraceptives, drugs that prolong the QT interval, and alcohol. But conflicting reports about issues such as monitoring international normalized ratio (INR) in patients taking warfarin and antibiotics, and whether (or which) antibiotics decrease the efficacy of oral contraceptives (OCs) can make decision-making challenging.

This review provides evidence-based answers to questions you may have. It also details some reliable sources of information you can consult (TABLE 1^2-7) when discussing treatment options with other members of the health care team.

1. Which antibiotics are preferable when a patient is taking warfarin, and are preemptive warfarin dose reductions advisable?

The simple answer is that agents with a lower likelihood of affecting the INR, such as penicillin G, clindamycin, and 1st- and 4th-generation cephalosporins, are a good place to start, and whether to preemptively reduce the warfarin dose hinges on the antibiotic being prescribed.

The more detailed answer. The fundamental mechanisms of interaction between warfarin and antibiotics are two-fold:⁸

• Antimicrobial agents disrupt gastrointestinal flora that synthesize vitamin K.
• Antimicrobials inhibit cytochrome p450 (CYP450) enzymes (primarily CYP2C9 and 3A4), which are responsible for the metabolism of warfarin.

The antibiotics most likely to interfere with warfarin are TMP/SMX, ciprofloxacin, levofloxacin, metronidazole, fluconazole, azithromycin, and clarithromycin (TABLE 2).^9,10 Low-risk agents include clindamycin, cephalexin, and penicillin G. When prescribing an antibiotic for a patient taking warfarin, it is important not only to be aware of the agents that should be avoided, but also the agents that do not require more frequent monitoring of INR.

Preemptive warfarin dose reductions? Some physicians make preemptive warfarin dose reductions in an attempt to avoid supratherapeutic INRs in patients being prescribed antibiotics. But the evidence suggests that this step should be considered only in the presence of the antibiotics TMP/SMX and metronidazole.^9,11

A 2008 study investigated the anticoagulation effects of a 10% to 20% preemptive warfarin dose reduction vs no dosing change in patients taking TMP/SMX or levofloxacin. The investigators found that the preemptive warfarin dose reduction (intervention) significantly decreased the number of supratherapeutic INR values above 4 when compared to controls (2 of 8 vs 8 of 9).¹²

In the dose-reduction group, no patients receiving TMP/SMX developed a subtherapeutic INR, whereas 40% (4 of 10 patients) who received levofloxacin developed a subtherapeutic INR.¹² The authors of the study concluded that a prophylactic warfarin dose reduction of 10% to 20% is effective in maintaining therapeutic anticoagulation in patients receiving TMP/SMX. They added that while no change in warfarin dosing is necessary with levofloxacin, short-term INR follow-up is a prudent approach to prevent subtherapeutic INRs. Others recommend INR monitoring when antibiotic therapy is started and stopped and whenever the dose is changed.⁹

A 2010 retrospective, single-center, cohort study looked at patients who were taking metronidazole and warfarin. Researchers compared those who received a preemptive dose reduction of warfarin (mean reduction was 34.6% ± 13.4%) to those who did not and found a statistically significant mean difference in INR of 1.28 (P=.01).¹³

Almost half (46%) of the patients who did not receive a warfarin dose reduction had an INR >4, whereas none of the patients in the warfarin dose reduction group did (P=.05). Although this secondary outcome was not statistically significant (most likely due to the small sample population [N=20]), the implication is clinically significant. Two patients who reduced their dose had a subtherapeutic INR compared to none of the patients in the control group, which was also not a statistically significant difference.

The authors concluded that a 30% to 35% reduction in mean daily warfarin dose is effective in maintaining therapeutic anticoagulation in patients started on metronidazole.

Significant bleeding events. A retrospective cohort study of slightly more than 22,000 veterans who were prescribed warfarin for ≥30 uninterrupted days and given antibiotics with either a high or low risk for interaction with warfarin were studied for significant bleeding events for one month.¹⁰ Ninety-three significant bleeding events occurred in the high-risk group and 36 occurred in the low-risk group over the course of the study. The agent associated with the greatest increased risk of bleeding was TMP/SMX (hazard ratio [HR]=2.09; 95% CI, 1.45-3.02). Of note, metronidazole was not included in this study endpoint.

When TMP/SMX or metronidazole can’t be avoided, consider reducing the patient’s warfarin dose by 10% to 35% and rechecking the INR 5 days after starting the antibiotic.

The study’s secondary endpoint of INR >4 found that 10% of patients taking metronidazole and 8% of patients taking TMP/SMX in addition to warfarin had INRs >4. Almost 10% (9.7%) of patients prescribed fluconazole had a peak INR value >6. Patients taking low-risk antibiotics (clindamycin or cephalexin) had no increased risk of bleeding. Monitoring INR within 3 to 14 days of starting patients on antibiotics was found to decrease the risk of serious bleeding events (HR=0.61; 95% CI, 0.42-0.88). More frequent INR monitoring by itself (without preemptive warfarin dose reductions) is appropriate for other antibiotics, including macrolides, tetracyclines, and some cephalosporins (2nd and 3rd generation).⁹

THE BOTTOM LINE When prescribing antibiotics for patients taking warfarin, try to choose agents with a lower likelihood of affecting INR such as penicillin G, clindamycin, and 1st- and 4th-generation cephalosporins. With these agents, there is no need for more frequent INR testing or preemptive reductions in warfarin dose. In patients for whom the use of TMP/SMX or metronidazole can’t be avoided, consider reducing the patient’s warfarin dose by 10% to 35% and rechecking the INR 5 days after starting the antibiotic.^9,11,12 When prescribing agents such as fluoroquinolones, macrolides, and tetracyclines, do not reduce the patient’s warfarin dose preemptively and recheck INR 5 days after starting therapy.

2. Do antibiotics decrease the efficacy of oral contraceptives?

It’s unlikely, but antibiotics may reduce the efficacy of OCs.

There have been few, but well documented, reports of women using OCs who became pregnant after taking antimicrobials.¹⁴ It is recognized that rifampin, an inducer of enzymes that metabolize estrogens, decreases the efficacy of OCs.¹⁵ Ketoconazole’s interaction seems less well documented, but combining the agent with low-estrogen (low-dose) OCs warrants caution.¹⁶ What is not well understood is whether more common or broad-spectrum antibiotics also increase the risk of OC failure.

Three mechanisms have been proposed:¹⁶

• Antimicrobials affect hepatic enzyme induction, which increases metabolism of hormones.
• Broad-spectrum antibiotics reduce gut bacteria, which alters enterohepatic circulation and reduces plasma hormone concentrations.
• Antibiotics increase gastrointestinal motility, which decreases absorption (and reabsorption) of OCs.

A 2007 study found that when physicians and pharmacists were surveyed and asked if broad-spectrum antibiotics have a clinically significant interaction with OCs, 83% of physicians and 89% of pharmacists answered “Yes;”¹⁷ however, a large epidemiologic study performed in the United States showed no association between antibiotic use and OC failure.¹⁸

After this report, investigators in the Netherlands completed a similar cross-over analysis and found that there was a relationship between the use of antibiotics and breakthrough pregnancy in a population-based prescription database, but that the results didn’t hold for broad-spectrum antibiotics or in a sensitivity analysis.¹⁹ Pharmacokinetic studies are also conflicting, as some have shown an effect on serum hormone levels, while others have not.^15,20-22

High- vs low-risk agents. Ciprofloxacin did not affect hormone levels in 2 studies.^20,21 Rifampin and voriconazole may enhance systemic exposure to OCs.^15,22 And erythromycin and azithromycin may interact with OCs, but the clinical significance of this interaction is still unknown.¹⁶

Short-courses of TMP/SMX are generally thought to be safe;¹⁶ a small study looked at cotrimoxazole 1 g twice daily in 9 women taking long-term OC steroids and found that short courses of the drug were unlikely to cause any adverse effects on contraceptive control.²³ Tetracyclines and penicillins were the antibiotics most frequently involved in case reports of pregnancy from the United Kingdom (TABLE 3²).¹⁶

When prescribing fluoroquinolones, macrolides, and tetracyclines, do not reduce the patient's warfarin dose preemptively.

It is hypothesized that some women may have a higher risk of OC failure than others due to how they metabolize ethinyl estradiol.²⁴ Another hypothesis is that some women have gut flora that is more susceptible to the antibiotic being used. And still another possibility is that lower doses of hormones are being used in OCs than were studied for this interaction.¹⁵ Anything that decreases the concentration of these lower-dose OCs is concerning, especially in patients with a higher body mass index (BMI). The few pharmacokinetic studies that have been conducted show that it takes longer for OCs to reach a steady state in obese women and that they have a lower area under the curve (AUC) and maximum estrogen concentration than women with a normal BMI.²⁵

THE BOTTOM LINE Because the degree of variability between patients is unknown and obesity rates are increasing, concern that low-dose OCs may lose efficacy when combined with antibiotics is warranted. While the absolute risk of breakthrough pregnancy seems small, the most conservative approach is to advise patients to use a back-up method of contraception during times of antibiotic use.

3. Which drugs prolong QT intervals?

Macrolides and fluoroquinolones are 2 classes of antibiotics associated with prolonged QT intervals, but other drugs and risk factors are important to consider, as well.

Physicians often receive phone calls from pharmacists warning about drug-drug interactions when they prescribe macrolides or fluoroquinolones for patients already taking medications known to prolong QT intervals or inhibit cytochrome P450 enzymes. Long QT syndrome increases the risk of TdP, a life-threatening arrhythmia. While TdP is rare, its severity warrants a discussion of risk factors and the likelihood of occurrence.

Anything that decreases the concentration of lower-dose OCs is concerning, especially in patients with a higher body mass index.

Two QT interval prolonging medications used together in healthy individuals does not warrant a change in therapy. TdP is most likely to occur when 2 or more QT interval prolonging medications are used in a patient who is already at high risk for arrhythmia because of risk factors such as prolonged QT interval at baseline, family history of prolonged QT intervals, female gender, age >60 years, electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia), underlying comorbid diseases (eg, chronic heart failure, left ventricular hypertrophy, atrial fibrillation), hypertension, bradycardia, and genetic (ion channel) polymorphisms.^26,27

Antiarrhythmics and antipsychotics are most commonly associated with drug-induced prolonged QT interval, with most case reports and research being linked to antiarrhythmics (TABLE 4²).²⁸ But macrolide and fluoroquinolone antibiotics also have been associated with TdP, although to a lesser extent. In a retrospective analysis of case reports of TdP involving macrolides, erythromycin was present (with or without other medications thought to prolong QT) in 53% of the cases and clarithromycin was involved in 36% of the reports.²⁹

An analysis of 2 studies by the US Food and Drug Administration estimated an occurrence rate of serious cardiac arrhythmias of 46 to 85 per 100,000 users with cardiovascular disease, compared to 5 to 44 per 100,000 users without cardiovascular disease.³⁰ And this may underestimate the actual incidence because spontaneous reporting of adverse effects declines the longer a drug is on the market. Ciprofloxacin is associated with less risk than levofloxacin and gatifloxacin (the latter of which is no longer available in the United States).²⁶

Using 2 drugs that may increase the QT interval is likely safe in the absence of certain risk factors.

A recent population-based study using data on over 10.6 million people from the Taiwan National Health Insurance Database examined the risk of cardiovascular death among patients using new-generation macrolides, fluoroquinolones, and β-lactam/β-lactamase inhibitors.³¹ The absolute risk of cardiovascular death per 1000 individuals was 0.06 for clarithromycin, 0.12 for ciprofloxacin, 0.13 for amoxicillin-clavulanate, 0.36 for azithromycin, 0.39 for levofloxacin, and 0.46 for moxifloxacin. The mean interval between first antibiotic use and the adverse cardiac event was <4 days. Not surprisingly, the highest risk was seen in patients with underlying cardiovascular disease.

Patients don't need to avoid alcohol while taking metronidazole.

Another population-based study, this time conducted in Hong Kong, evaluated the cardiovascular safety of clarithromycin compared to that of amoxicillin. Clarithromycin was found to increase the incidence of myocardial infarction, arrhythmia, and cardiac mortality in the short term, with the risk returning to baseline after treatment concluded.³² A binational cohort study of Danish and Swedish adults confirmed that fluoroquinolones (especially ciprofloxacin) do not increase the risk of a serious arrhythmia compared to penicillins.³³

THE BOTTOM LINE For patients taking other QT interval prolonging medications or who are at a higher risk for TdP, consider using clarithromycin over erythromycin or azithromycin for a macrolide antibiotic or ciprofloxacin over levofloxacin or moxifloxacin if a fluoroquinolone is warranted. Using 2 drugs that may increase the QT interval is likely safe in the absence of certain risk factors.

4. Should patients avoid alcohol while taking metronidazole?

Probably not.

Warning patients against drinking alcohol while taking metronidazole has been a common practice for years. The mechanism for this theorized interaction was thought to be similar to the interaction between disulfiram and ethanol.³⁴ Disulfiram inhibits hepatic aldehyde dehydrogenase (ALDH) when combined with alcohol, which leads to increased levels of acetaldehyde in the blood and symptoms of flushing, palpitations, nausea, vomiting, headache, and visual disturbances.³⁵ However, multiple studies using rats have found that metronidazole does not inhibit ALDH or increase acetaldehyde concentrations like disulfiram does.³⁴

A 2000 review article discussed 6 cases involving serious metronidazole-ethanol interactions. Ethanol alone was found to explain the reaction in 2 of the cases, and the remaining 4 could be linked to the use of other drugs or disease states.³⁵ A 2002 Finnish study found no statistically significant differences in objective or subjective signs of a disulfiram-like interaction.³⁴ When considering the symptoms associated with the interaction, it is important to remember that many of the symptoms can result from metronidazole therapy alone, regardless of whether other medications or alcohol are used.³⁵

THE BOTTOM LINE Researchers have failed to identify a clinically significant interaction between metronidazole and alcohol. Avoiding alcohol while taking metronidazole does not appear to be necessary.

CORRESPONDENCE
Mary Onysko, PharmD, BCPS, University of Wyoming, School of Pharmacy Health Sciences Center, Room 292, 1000 E. University Avenue, Laramie, WY 82071; [email protected].

Despite encouraging data that antibiotic prescribing is on the decline, patients are still prescribed antibiotics frequently, making these agents the 12th most frequently used drug class.¹ At the same time, prescribers are caring for patients with increasingly complex drug regimens that provide fertile ground for drug interactions with these antibiotics. And, of course, lifestyle factors such as alcohol consumption are a consideration when any prescription is written.

As pharmacists, we find that certain questions about antibiotic prescribing and interactions come up with frequency. These questions often pertain to the use of warfarin, oral contraceptives, drugs that prolong the QT interval, and alcohol. But conflicting reports about issues such as monitoring international normalized ratio (INR) in patients taking warfarin and antibiotics, and whether (or which) antibiotics decrease the efficacy of oral contraceptives (OCs) can make decision-making challenging.

This review provides evidence-based answers to questions you may have. It also details some reliable sources of information you can consult (TABLE 1^2-7) when discussing treatment options with other members of the health care team.

1. Which antibiotics are preferable when a patient is taking warfarin, and are preemptive warfarin dose reductions advisable?

The simple answer is that agents with a lower likelihood of affecting the INR, such as penicillin G, clindamycin, and 1st- and 4th-generation cephalosporins, are a good place to start, and whether to preemptively reduce the warfarin dose hinges on the antibiotic being prescribed.

The more detailed answer. The fundamental mechanisms of interaction between warfarin and antibiotics are two-fold:⁸

• Antimicrobial agents disrupt gastrointestinal flora that synthesize vitamin K.
• Antimicrobials inhibit cytochrome p450 (CYP450) enzymes (primarily CYP2C9 and 3A4), which are responsible for the metabolism of warfarin.

The antibiotics most likely to interfere with warfarin are TMP/SMX, ciprofloxacin, levofloxacin, metronidazole, fluconazole, azithromycin, and clarithromycin (TABLE 2).^9,10 Low-risk agents include clindamycin, cephalexin, and penicillin G. When prescribing an antibiotic for a patient taking warfarin, it is important not only to be aware of the agents that should be avoided, but also the agents that do not require more frequent monitoring of INR.

Preemptive warfarin dose reductions? Some physicians make preemptive warfarin dose reductions in an attempt to avoid supratherapeutic INRs in patients being prescribed antibiotics. But the evidence suggests that this step should be considered only in the presence of the antibiotics TMP/SMX and metronidazole.^9,11

A 2008 study investigated the anticoagulation effects of a 10% to 20% preemptive warfarin dose reduction vs no dosing change in patients taking TMP/SMX or levofloxacin. The investigators found that the preemptive warfarin dose reduction (intervention) significantly decreased the number of supratherapeutic INR values above 4 when compared to controls (2 of 8 vs 8 of 9).¹²

In the dose-reduction group, no patients receiving TMP/SMX developed a subtherapeutic INR, whereas 40% (4 of 10 patients) who received levofloxacin developed a subtherapeutic INR.¹² The authors of the study concluded that a prophylactic warfarin dose reduction of 10% to 20% is effective in maintaining therapeutic anticoagulation in patients receiving TMP/SMX. They added that while no change in warfarin dosing is necessary with levofloxacin, short-term INR follow-up is a prudent approach to prevent subtherapeutic INRs. Others recommend INR monitoring when antibiotic therapy is started and stopped and whenever the dose is changed.⁹

A 2010 retrospective, single-center, cohort study looked at patients who were taking metronidazole and warfarin. Researchers compared those who received a preemptive dose reduction of warfarin (mean reduction was 34.6% ± 13.4%) to those who did not and found a statistically significant mean difference in INR of 1.28 (P=.01).¹³

Almost half (46%) of the patients who did not receive a warfarin dose reduction had an INR >4, whereas none of the patients in the warfarin dose reduction group did (P=.05). Although this secondary outcome was not statistically significant (most likely due to the small sample population [N=20]), the implication is clinically significant. Two patients who reduced their dose had a subtherapeutic INR compared to none of the patients in the control group, which was also not a statistically significant difference.

The authors concluded that a 30% to 35% reduction in mean daily warfarin dose is effective in maintaining therapeutic anticoagulation in patients started on metronidazole.

Significant bleeding events. A retrospective cohort study of slightly more than 22,000 veterans who were prescribed warfarin for ≥30 uninterrupted days and given antibiotics with either a high or low risk for interaction with warfarin were studied for significant bleeding events for one month.¹⁰ Ninety-three significant bleeding events occurred in the high-risk group and 36 occurred in the low-risk group over the course of the study. The agent associated with the greatest increased risk of bleeding was TMP/SMX (hazard ratio [HR]=2.09; 95% CI, 1.45-3.02). Of note, metronidazole was not included in this study endpoint.

When TMP/SMX or metronidazole can’t be avoided, consider reducing the patient’s warfarin dose by 10% to 35% and rechecking the INR 5 days after starting the antibiotic.

The study’s secondary endpoint of INR >4 found that 10% of patients taking metronidazole and 8% of patients taking TMP/SMX in addition to warfarin had INRs >4. Almost 10% (9.7%) of patients prescribed fluconazole had a peak INR value >6. Patients taking low-risk antibiotics (clindamycin or cephalexin) had no increased risk of bleeding. Monitoring INR within 3 to 14 days of starting patients on antibiotics was found to decrease the risk of serious bleeding events (HR=0.61; 95% CI, 0.42-0.88). More frequent INR monitoring by itself (without preemptive warfarin dose reductions) is appropriate for other antibiotics, including macrolides, tetracyclines, and some cephalosporins (2nd and 3rd generation).⁹

THE BOTTOM LINE When prescribing antibiotics for patients taking warfarin, try to choose agents with a lower likelihood of affecting INR such as penicillin G, clindamycin, and 1st- and 4th-generation cephalosporins. With these agents, there is no need for more frequent INR testing or preemptive reductions in warfarin dose. In patients for whom the use of TMP/SMX or metronidazole can’t be avoided, consider reducing the patient’s warfarin dose by 10% to 35% and rechecking the INR 5 days after starting the antibiotic.^9,11,12 When prescribing agents such as fluoroquinolones, macrolides, and tetracyclines, do not reduce the patient’s warfarin dose preemptively and recheck INR 5 days after starting therapy.

2. Do antibiotics decrease the efficacy of oral contraceptives?

It’s unlikely, but antibiotics may reduce the efficacy of OCs.

There have been few, but well documented, reports of women using OCs who became pregnant after taking antimicrobials.¹⁴ It is recognized that rifampin, an inducer of enzymes that metabolize estrogens, decreases the efficacy of OCs.¹⁵ Ketoconazole’s interaction seems less well documented, but combining the agent with low-estrogen (low-dose) OCs warrants caution.¹⁶ What is not well understood is whether more common or broad-spectrum antibiotics also increase the risk of OC failure.

Three mechanisms have been proposed:¹⁶

• Antimicrobials affect hepatic enzyme induction, which increases metabolism of hormones.
• Broad-spectrum antibiotics reduce gut bacteria, which alters enterohepatic circulation and reduces plasma hormone concentrations.
• Antibiotics increase gastrointestinal motility, which decreases absorption (and reabsorption) of OCs.

A 2007 study found that when physicians and pharmacists were surveyed and asked if broad-spectrum antibiotics have a clinically significant interaction with OCs, 83% of physicians and 89% of pharmacists answered “Yes;”¹⁷ however, a large epidemiologic study performed in the United States showed no association between antibiotic use and OC failure.¹⁸

After this report, investigators in the Netherlands completed a similar cross-over analysis and found that there was a relationship between the use of antibiotics and breakthrough pregnancy in a population-based prescription database, but that the results didn’t hold for broad-spectrum antibiotics or in a sensitivity analysis.¹⁹ Pharmacokinetic studies are also conflicting, as some have shown an effect on serum hormone levels, while others have not.^15,20-22

High- vs low-risk agents. Ciprofloxacin did not affect hormone levels in 2 studies.^20,21 Rifampin and voriconazole may enhance systemic exposure to OCs.^15,22 And erythromycin and azithromycin may interact with OCs, but the clinical significance of this interaction is still unknown.¹⁶

Short-courses of TMP/SMX are generally thought to be safe;¹⁶ a small study looked at cotrimoxazole 1 g twice daily in 9 women taking long-term OC steroids and found that short courses of the drug were unlikely to cause any adverse effects on contraceptive control.²³ Tetracyclines and penicillins were the antibiotics most frequently involved in case reports of pregnancy from the United Kingdom (TABLE 3²).¹⁶

When prescribing fluoroquinolones, macrolides, and tetracyclines, do not reduce the patient's warfarin dose preemptively.

It is hypothesized that some women may have a higher risk of OC failure than others due to how they metabolize ethinyl estradiol.²⁴ Another hypothesis is that some women have gut flora that is more susceptible to the antibiotic being used. And still another possibility is that lower doses of hormones are being used in OCs than were studied for this interaction.¹⁵ Anything that decreases the concentration of these lower-dose OCs is concerning, especially in patients with a higher body mass index (BMI). The few pharmacokinetic studies that have been conducted show that it takes longer for OCs to reach a steady state in obese women and that they have a lower area under the curve (AUC) and maximum estrogen concentration than women with a normal BMI.²⁵

THE BOTTOM LINE Because the degree of variability between patients is unknown and obesity rates are increasing, concern that low-dose OCs may lose efficacy when combined with antibiotics is warranted. While the absolute risk of breakthrough pregnancy seems small, the most conservative approach is to advise patients to use a back-up method of contraception during times of antibiotic use.

3. Which drugs prolong QT intervals?

Macrolides and fluoroquinolones are 2 classes of antibiotics associated with prolonged QT intervals, but other drugs and risk factors are important to consider, as well.

Physicians often receive phone calls from pharmacists warning about drug-drug interactions when they prescribe macrolides or fluoroquinolones for patients already taking medications known to prolong QT intervals or inhibit cytochrome P450 enzymes. Long QT syndrome increases the risk of TdP, a life-threatening arrhythmia. While TdP is rare, its severity warrants a discussion of risk factors and the likelihood of occurrence.

Anything that decreases the concentration of lower-dose OCs is concerning, especially in patients with a higher body mass index.

Two QT interval prolonging medications used together in healthy individuals does not warrant a change in therapy. TdP is most likely to occur when 2 or more QT interval prolonging medications are used in a patient who is already at high risk for arrhythmia because of risk factors such as prolonged QT interval at baseline, family history of prolonged QT intervals, female gender, age >60 years, electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia), underlying comorbid diseases (eg, chronic heart failure, left ventricular hypertrophy, atrial fibrillation), hypertension, bradycardia, and genetic (ion channel) polymorphisms.^26,27

Antiarrhythmics and antipsychotics are most commonly associated with drug-induced prolonged QT interval, with most case reports and research being linked to antiarrhythmics (TABLE 4²).²⁸ But macrolide and fluoroquinolone antibiotics also have been associated with TdP, although to a lesser extent. In a retrospective analysis of case reports of TdP involving macrolides, erythromycin was present (with or without other medications thought to prolong QT) in 53% of the cases and clarithromycin was involved in 36% of the reports.²⁹

An analysis of 2 studies by the US Food and Drug Administration estimated an occurrence rate of serious cardiac arrhythmias of 46 to 85 per 100,000 users with cardiovascular disease, compared to 5 to 44 per 100,000 users without cardiovascular disease.³⁰ And this may underestimate the actual incidence because spontaneous reporting of adverse effects declines the longer a drug is on the market. Ciprofloxacin is associated with less risk than levofloxacin and gatifloxacin (the latter of which is no longer available in the United States).²⁶

Using 2 drugs that may increase the QT interval is likely safe in the absence of certain risk factors.

A recent population-based study using data on over 10.6 million people from the Taiwan National Health Insurance Database examined the risk of cardiovascular death among patients using new-generation macrolides, fluoroquinolones, and β-lactam/β-lactamase inhibitors.³¹ The absolute risk of cardiovascular death per 1000 individuals was 0.06 for clarithromycin, 0.12 for ciprofloxacin, 0.13 for amoxicillin-clavulanate, 0.36 for azithromycin, 0.39 for levofloxacin, and 0.46 for moxifloxacin. The mean interval between first antibiotic use and the adverse cardiac event was <4 days. Not surprisingly, the highest risk was seen in patients with underlying cardiovascular disease.

Patients don't need to avoid alcohol while taking metronidazole.

Another population-based study, this time conducted in Hong Kong, evaluated the cardiovascular safety of clarithromycin compared to that of amoxicillin. Clarithromycin was found to increase the incidence of myocardial infarction, arrhythmia, and cardiac mortality in the short term, with the risk returning to baseline after treatment concluded.³² A binational cohort study of Danish and Swedish adults confirmed that fluoroquinolones (especially ciprofloxacin) do not increase the risk of a serious arrhythmia compared to penicillins.³³

THE BOTTOM LINE For patients taking other QT interval prolonging medications or who are at a higher risk for TdP, consider using clarithromycin over erythromycin or azithromycin for a macrolide antibiotic or ciprofloxacin over levofloxacin or moxifloxacin if a fluoroquinolone is warranted. Using 2 drugs that may increase the QT interval is likely safe in the absence of certain risk factors.

4. Should patients avoid alcohol while taking metronidazole?

Probably not.

Warning patients against drinking alcohol while taking metronidazole has been a common practice for years. The mechanism for this theorized interaction was thought to be similar to the interaction between disulfiram and ethanol.³⁴ Disulfiram inhibits hepatic aldehyde dehydrogenase (ALDH) when combined with alcohol, which leads to increased levels of acetaldehyde in the blood and symptoms of flushing, palpitations, nausea, vomiting, headache, and visual disturbances.³⁵ However, multiple studies using rats have found that metronidazole does not inhibit ALDH or increase acetaldehyde concentrations like disulfiram does.³⁴

A 2000 review article discussed 6 cases involving serious metronidazole-ethanol interactions. Ethanol alone was found to explain the reaction in 2 of the cases, and the remaining 4 could be linked to the use of other drugs or disease states.³⁵ A 2002 Finnish study found no statistically significant differences in objective or subjective signs of a disulfiram-like interaction.³⁴ When considering the symptoms associated with the interaction, it is important to remember that many of the symptoms can result from metronidazole therapy alone, regardless of whether other medications or alcohol are used.³⁵

THE BOTTOM LINE Researchers have failed to identify a clinically significant interaction between metronidazole and alcohol. Avoiding alcohol while taking metronidazole does not appear to be necessary.

CORRESPONDENCE
Mary Onysko, PharmD, BCPS, University of Wyoming, School of Pharmacy Health Sciences Center, Room 292, 1000 E. University Avenue, Laramie, WY 82071; [email protected].

Despite encouraging data that antibiotic prescribing is on the decline, patients are still prescribed antibiotics frequently, making these agents the 12th most frequently used drug class.¹ At the same time, prescribers are caring for patients with increasingly complex drug regimens that provide fertile ground for drug interactions with these antibiotics. And, of course, lifestyle factors such as alcohol consumption are a consideration when any prescription is written.

As pharmacists, we find that certain questions about antibiotic prescribing and interactions come up with frequency. These questions often pertain to the use of warfarin, oral contraceptives, drugs that prolong the QT interval, and alcohol. But conflicting reports about issues such as monitoring international normalized ratio (INR) in patients taking warfarin and antibiotics, and whether (or which) antibiotics decrease the efficacy of oral contraceptives (OCs) can make decision-making challenging.

This review provides evidence-based answers to questions you may have. It also details some reliable sources of information you can consult (TABLE 1^2-7) when discussing treatment options with other members of the health care team.

1. Which antibiotics are preferable when a patient is taking warfarin, and are preemptive warfarin dose reductions advisable?

The simple answer is that agents with a lower likelihood of affecting the INR, such as penicillin G, clindamycin, and 1st- and 4th-generation cephalosporins, are a good place to start, and whether to preemptively reduce the warfarin dose hinges on the antibiotic being prescribed.

The more detailed answer. The fundamental mechanisms of interaction between warfarin and antibiotics are two-fold:⁸

• Antimicrobial agents disrupt gastrointestinal flora that synthesize vitamin K.
• Antimicrobials inhibit cytochrome p450 (CYP450) enzymes (primarily CYP2C9 and 3A4), which are responsible for the metabolism of warfarin.

The antibiotics most likely to interfere with warfarin are TMP/SMX, ciprofloxacin, levofloxacin, metronidazole, fluconazole, azithromycin, and clarithromycin (TABLE 2).^9,10 Low-risk agents include clindamycin, cephalexin, and penicillin G. When prescribing an antibiotic for a patient taking warfarin, it is important not only to be aware of the agents that should be avoided, but also the agents that do not require more frequent monitoring of INR.

Preemptive warfarin dose reductions? Some physicians make preemptive warfarin dose reductions in an attempt to avoid supratherapeutic INRs in patients being prescribed antibiotics. But the evidence suggests that this step should be considered only in the presence of the antibiotics TMP/SMX and metronidazole.^9,11

A 2008 study investigated the anticoagulation effects of a 10% to 20% preemptive warfarin dose reduction vs no dosing change in patients taking TMP/SMX or levofloxacin. The investigators found that the preemptive warfarin dose reduction (intervention) significantly decreased the number of supratherapeutic INR values above 4 when compared to controls (2 of 8 vs 8 of 9).¹²

In the dose-reduction group, no patients receiving TMP/SMX developed a subtherapeutic INR, whereas 40% (4 of 10 patients) who received levofloxacin developed a subtherapeutic INR.¹² The authors of the study concluded that a prophylactic warfarin dose reduction of 10% to 20% is effective in maintaining therapeutic anticoagulation in patients receiving TMP/SMX. They added that while no change in warfarin dosing is necessary with levofloxacin, short-term INR follow-up is a prudent approach to prevent subtherapeutic INRs. Others recommend INR monitoring when antibiotic therapy is started and stopped and whenever the dose is changed.⁹

A 2010 retrospective, single-center, cohort study looked at patients who were taking metronidazole and warfarin. Researchers compared those who received a preemptive dose reduction of warfarin (mean reduction was 34.6% ± 13.4%) to those who did not and found a statistically significant mean difference in INR of 1.28 (P=.01).¹³

Almost half (46%) of the patients who did not receive a warfarin dose reduction had an INR >4, whereas none of the patients in the warfarin dose reduction group did (P=.05). Although this secondary outcome was not statistically significant (most likely due to the small sample population [N=20]), the implication is clinically significant. Two patients who reduced their dose had a subtherapeutic INR compared to none of the patients in the control group, which was also not a statistically significant difference.

The authors concluded that a 30% to 35% reduction in mean daily warfarin dose is effective in maintaining therapeutic anticoagulation in patients started on metronidazole.

Significant bleeding events. A retrospective cohort study of slightly more than 22,000 veterans who were prescribed warfarin for ≥30 uninterrupted days and given antibiotics with either a high or low risk for interaction with warfarin were studied for significant bleeding events for one month.¹⁰ Ninety-three significant bleeding events occurred in the high-risk group and 36 occurred in the low-risk group over the course of the study. The agent associated with the greatest increased risk of bleeding was TMP/SMX (hazard ratio [HR]=2.09; 95% CI, 1.45-3.02). Of note, metronidazole was not included in this study endpoint.

When TMP/SMX or metronidazole can’t be avoided, consider reducing the patient’s warfarin dose by 10% to 35% and rechecking the INR 5 days after starting the antibiotic.

The study’s secondary endpoint of INR >4 found that 10% of patients taking metronidazole and 8% of patients taking TMP/SMX in addition to warfarin had INRs >4. Almost 10% (9.7%) of patients prescribed fluconazole had a peak INR value >6. Patients taking low-risk antibiotics (clindamycin or cephalexin) had no increased risk of bleeding. Monitoring INR within 3 to 14 days of starting patients on antibiotics was found to decrease the risk of serious bleeding events (HR=0.61; 95% CI, 0.42-0.88). More frequent INR monitoring by itself (without preemptive warfarin dose reductions) is appropriate for other antibiotics, including macrolides, tetracyclines, and some cephalosporins (2nd and 3rd generation).⁹

THE BOTTOM LINE When prescribing antibiotics for patients taking warfarin, try to choose agents with a lower likelihood of affecting INR such as penicillin G, clindamycin, and 1st- and 4th-generation cephalosporins. With these agents, there is no need for more frequent INR testing or preemptive reductions in warfarin dose. In patients for whom the use of TMP/SMX or metronidazole can’t be avoided, consider reducing the patient’s warfarin dose by 10% to 35% and rechecking the INR 5 days after starting the antibiotic.^9,11,12 When prescribing agents such as fluoroquinolones, macrolides, and tetracyclines, do not reduce the patient’s warfarin dose preemptively and recheck INR 5 days after starting therapy.

2. Do antibiotics decrease the efficacy of oral contraceptives?

It’s unlikely, but antibiotics may reduce the efficacy of OCs.

There have been few, but well documented, reports of women using OCs who became pregnant after taking antimicrobials.¹⁴ It is recognized that rifampin, an inducer of enzymes that metabolize estrogens, decreases the efficacy of OCs.¹⁵ Ketoconazole’s interaction seems less well documented, but combining the agent with low-estrogen (low-dose) OCs warrants caution.¹⁶ What is not well understood is whether more common or broad-spectrum antibiotics also increase the risk of OC failure.

Three mechanisms have been proposed:¹⁶

• Antimicrobials affect hepatic enzyme induction, which increases metabolism of hormones.
• Broad-spectrum antibiotics reduce gut bacteria, which alters enterohepatic circulation and reduces plasma hormone concentrations.
• Antibiotics increase gastrointestinal motility, which decreases absorption (and reabsorption) of OCs.

A 2007 study found that when physicians and pharmacists were surveyed and asked if broad-spectrum antibiotics have a clinically significant interaction with OCs, 83% of physicians and 89% of pharmacists answered “Yes;”¹⁷ however, a large epidemiologic study performed in the United States showed no association between antibiotic use and OC failure.¹⁸

After this report, investigators in the Netherlands completed a similar cross-over analysis and found that there was a relationship between the use of antibiotics and breakthrough pregnancy in a population-based prescription database, but that the results didn’t hold for broad-spectrum antibiotics or in a sensitivity analysis.¹⁹ Pharmacokinetic studies are also conflicting, as some have shown an effect on serum hormone levels, while others have not.^15,20-22

High- vs low-risk agents. Ciprofloxacin did not affect hormone levels in 2 studies.^20,21 Rifampin and voriconazole may enhance systemic exposure to OCs.^15,22 And erythromycin and azithromycin may interact with OCs, but the clinical significance of this interaction is still unknown.¹⁶

Short-courses of TMP/SMX are generally thought to be safe;¹⁶ a small study looked at cotrimoxazole 1 g twice daily in 9 women taking long-term OC steroids and found that short courses of the drug were unlikely to cause any adverse effects on contraceptive control.²³ Tetracyclines and penicillins were the antibiotics most frequently involved in case reports of pregnancy from the United Kingdom (TABLE 3²).¹⁶

When prescribing fluoroquinolones, macrolides, and tetracyclines, do not reduce the patient's warfarin dose preemptively.

It is hypothesized that some women may have a higher risk of OC failure than others due to how they metabolize ethinyl estradiol.²⁴ Another hypothesis is that some women have gut flora that is more susceptible to the antibiotic being used. And still another possibility is that lower doses of hormones are being used in OCs than were studied for this interaction.¹⁵ Anything that decreases the concentration of these lower-dose OCs is concerning, especially in patients with a higher body mass index (BMI). The few pharmacokinetic studies that have been conducted show that it takes longer for OCs to reach a steady state in obese women and that they have a lower area under the curve (AUC) and maximum estrogen concentration than women with a normal BMI.²⁵

THE BOTTOM LINE Because the degree of variability between patients is unknown and obesity rates are increasing, concern that low-dose OCs may lose efficacy when combined with antibiotics is warranted. While the absolute risk of breakthrough pregnancy seems small, the most conservative approach is to advise patients to use a back-up method of contraception during times of antibiotic use.

3. Which drugs prolong QT intervals?

Macrolides and fluoroquinolones are 2 classes of antibiotics associated with prolonged QT intervals, but other drugs and risk factors are important to consider, as well.

Physicians often receive phone calls from pharmacists warning about drug-drug interactions when they prescribe macrolides or fluoroquinolones for patients already taking medications known to prolong QT intervals or inhibit cytochrome P450 enzymes. Long QT syndrome increases the risk of TdP, a life-threatening arrhythmia. While TdP is rare, its severity warrants a discussion of risk factors and the likelihood of occurrence.

Anything that decreases the concentration of lower-dose OCs is concerning, especially in patients with a higher body mass index.

Two QT interval prolonging medications used together in healthy individuals does not warrant a change in therapy. TdP is most likely to occur when 2 or more QT interval prolonging medications are used in a patient who is already at high risk for arrhythmia because of risk factors such as prolonged QT interval at baseline, family history of prolonged QT intervals, female gender, age >60 years, electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia), underlying comorbid diseases (eg, chronic heart failure, left ventricular hypertrophy, atrial fibrillation), hypertension, bradycardia, and genetic (ion channel) polymorphisms.^26,27

Antiarrhythmics and antipsychotics are most commonly associated with drug-induced prolonged QT interval, with most case reports and research being linked to antiarrhythmics (TABLE 4²).²⁸ But macrolide and fluoroquinolone antibiotics also have been associated with TdP, although to a lesser extent. In a retrospective analysis of case reports of TdP involving macrolides, erythromycin was present (with or without other medications thought to prolong QT) in 53% of the cases and clarithromycin was involved in 36% of the reports.²⁹

An analysis of 2 studies by the US Food and Drug Administration estimated an occurrence rate of serious cardiac arrhythmias of 46 to 85 per 100,000 users with cardiovascular disease, compared to 5 to 44 per 100,000 users without cardiovascular disease.³⁰ And this may underestimate the actual incidence because spontaneous reporting of adverse effects declines the longer a drug is on the market. Ciprofloxacin is associated with less risk than levofloxacin and gatifloxacin (the latter of which is no longer available in the United States).²⁶

Using 2 drugs that may increase the QT interval is likely safe in the absence of certain risk factors.

A recent population-based study using data on over 10.6 million people from the Taiwan National Health Insurance Database examined the risk of cardiovascular death among patients using new-generation macrolides, fluoroquinolones, and β-lactam/β-lactamase inhibitors.³¹ The absolute risk of cardiovascular death per 1000 individuals was 0.06 for clarithromycin, 0.12 for ciprofloxacin, 0.13 for amoxicillin-clavulanate, 0.36 for azithromycin, 0.39 for levofloxacin, and 0.46 for moxifloxacin. The mean interval between first antibiotic use and the adverse cardiac event was <4 days. Not surprisingly, the highest risk was seen in patients with underlying cardiovascular disease.

Patients don't need to avoid alcohol while taking metronidazole.

Another population-based study, this time conducted in Hong Kong, evaluated the cardiovascular safety of clarithromycin compared to that of amoxicillin. Clarithromycin was found to increase the incidence of myocardial infarction, arrhythmia, and cardiac mortality in the short term, with the risk returning to baseline after treatment concluded.³² A binational cohort study of Danish and Swedish adults confirmed that fluoroquinolones (especially ciprofloxacin) do not increase the risk of a serious arrhythmia compared to penicillins.³³

THE BOTTOM LINE For patients taking other QT interval prolonging medications or who are at a higher risk for TdP, consider using clarithromycin over erythromycin or azithromycin for a macrolide antibiotic or ciprofloxacin over levofloxacin or moxifloxacin if a fluoroquinolone is warranted. Using 2 drugs that may increase the QT interval is likely safe in the absence of certain risk factors.

4. Should patients avoid alcohol while taking metronidazole?

Probably not.

Warning patients against drinking alcohol while taking metronidazole has been a common practice for years. The mechanism for this theorized interaction was thought to be similar to the interaction between disulfiram and ethanol.³⁴ Disulfiram inhibits hepatic aldehyde dehydrogenase (ALDH) when combined with alcohol, which leads to increased levels of acetaldehyde in the blood and symptoms of flushing, palpitations, nausea, vomiting, headache, and visual disturbances.³⁵ However, multiple studies using rats have found that metronidazole does not inhibit ALDH or increase acetaldehyde concentrations like disulfiram does.³⁴

A 2000 review article discussed 6 cases involving serious metronidazole-ethanol interactions. Ethanol alone was found to explain the reaction in 2 of the cases, and the remaining 4 could be linked to the use of other drugs or disease states.³⁵ A 2002 Finnish study found no statistically significant differences in objective or subjective signs of a disulfiram-like interaction.³⁴ When considering the symptoms associated with the interaction, it is important to remember that many of the symptoms can result from metronidazole therapy alone, regardless of whether other medications or alcohol are used.³⁵

THE BOTTOM LINE Researchers have failed to identify a clinically significant interaction between metronidazole and alcohol. Avoiding alcohol while taking metronidazole does not appear to be necessary.

CORRESPONDENCE
Mary Onysko, PharmD, BCPS, University of Wyoming, School of Pharmacy Health Sciences Center, Room 292, 1000 E. University Avenue, Laramie, WY 82071; [email protected].

Neuropathic hand complaints—for which patients typically seek medical attention when the pain or paresthesia starts to interfere with their daily routine—are common and diverse. The ability to assess and accurately diagnose upper extremity compression neuropathies is critical for physicians in primary care.

Assessment starts, of course, with a thorough history of the present illness and past medical history, which helps define a broad differential diagnosis and identify comorbidities. Physical examination, including judicious use of provocative testing, allows you to objectively identify the pathologic deficit, evaluate function and coordination of multiple organ systems, and detect nerve dysfunction. The results determine whether additional tools, such as electrodiagnostic testing, are needed.

We’ve created this guide, detailed in the text, tables, and figures that follow, to help you hone your ability to accurately diagnose patients who present with compression neuropathies of the hand.

The medical history: Knowing what to ask

To clearly define a patient’s symptoms and disability, start with a thorough history of the presenting complaint.

Inquire about symptom onset and chronicity. Did the pain or paresthesia begin after an injury? Are the symptoms associated with repetitive use of the extremity? Do they occur at night?

Pinpoint the location or distribution of pain or paresthesia. It is paramount to identify the affected nerve.^1,2 Ask patients to complete a hand or upper extremity profile documenting location and/or type of numbness, tingling, or decreased sensation. A diagram of the peripheral nerves responsible for sensory innervation of the hand (FIGURE 1) is an effective way to screen individuals at high risk of carpal tunnel syndrome (CTS) or ulnar tunnel syndrome (UTS).^1,2

A patient report such as, “My whole hand is numb,” calls for a follow-up question to determine whether the little finger is affected,³ which would indicate that the ulnar nerve, rather than just the median nerve, is involved. And if a patient reports feeling as if he or she is wearing gloves or mittens, it is essential to consider the possibility of a systemic neuropathy rather than a single peripheral neuropathy.³

Gather basic patient information. Inquire about hand dominance, occupation, and baseline function, any or all of which may be critical in the assessment and initiation of treatment.^4,5

Review systemic conditions and medications

A broad range of comorbidities, such as cervical radiculopathy, diabetes, hypothyroidism, and vitamin deficiencies (TABLE 1),^6,7 may be responsible for neuropathic hand complaints, and a thorough review of systemic complaints and past medical history is critical. Include a medication history and a review of prior procedures, such as post-traumatic surgeries of the hand or upper extremity or nerve decompression surgeries, which may provide additional insight into disease etiology.

Symptoms guide physical exam, provocative testing

A physical examination, including provocative testing, follows based on reported symptoms, medical history, and suspected source of nerve compression.

Carpal tunnel syndrome

CTS is the most common peripheral neuropathy.⁸ Patients often report nocturnal pain or paresthesia in the distal median nerve distribution, comprising the palmar surface of the thumb, index, middle, and radial half of the ring finger.

Researchers have identified 6 standardized clinical criteria for the diagnosis of CTS. Two criteria—numbness mostly in median nerve territory and nocturnal numbness—can be ascertained during the history of present illness.The other 4, detailed below, will be found during the physical exam.⁹

Thenar weakness or atrophy.⁹ Begin your evaluation by inspecting the thenar musculature for atrophic changes. Motor exam of intrinsic musculature innervated by the recurrent motor branch of the median nerve includes assessment of thumb abduction strength (assessed by applying resistance to the metacarpophalangeal joint [MCPJ] base towards the palm in the position of maximal abduction) and opposition strength (assessed by applying force to the MCPJ from the ulnar aspect).¹⁰

Positive Phalen’s test.⁹ Provocative testing for CTS includes Phalen’s test (sensitivity 43%-86%, specificity 48%-67%),¹¹ which is an attempt to reproduce the numbness or tingling in the median nerve territory within 60 seconds of full wrist flexion. Ask the patient to hold his or her forearms vertically with elbows resting on the table (allowing gravity to flex the wrists),¹² and to tell you if numbness or tingling occurs.

Consider the possibility of a systemic neuropathy in patients who report that they feel as though they are wearing gloves.

Positive Tinel’s sign.⁹ Tinel’s sign (sensitivity 45%-75%, specificity 48%-67%)¹¹ is performed by lightly tapping the median nerve from the proximal to distal end over the carpal tunnel. The test is positive if paresthesia results. Provocative testing may also include Durkan’s test, also known as the carpal compression test. Durkan’s test (sensitivity 49%-89%, specificity 54%-96%)¹¹ involves placing your thumb directly over the carpal tunnel and holding light compression for 60 seconds, or until paresthesia is reported.

Positive 2-point discrimination test.⁹ To assess CTS disease severity, use 2-point discrimination to evaluate the patient’s sensation qualitatively and quantitatively. Two-point discrimination can only be tested, however, if light touch sensation is intact. It is typically performed by lightly applying 2 caliper points at fixed distances sufficient to blanch the skin, but some clinicians have used other tools, such as a modified paperclip.¹³ The smallest distance at which the patient can detect 2 distinct stimuli is then recorded.

Researchers have reported an average of 3 to 5 mm for 2-point discrimination at the fingertipand a normal 2-point discrimination of 6 to 9 mm in the volar surface of the hand (TABLE 2).^14,15

The scratch collapse test (sensitivity 64%, specificity 99%) is a supplemental exam that uses a different outcome measure to diagnose CTS.¹⁶ It involves lightly scratching the skin over the compressed carpal tunnel while the patient performs sustained resisted bilateral shoulder external rotation in an adducted position. A momentary loss of muscle resistance to external rotation indicates a positive test.

Pronator syndrome

Pronator syndrome (PS) is a proximal median neuropathy that may present in isolation or in combination with CTS as a double crush syndrome. Clinical symptoms include features of CTS and sensory paresthesias in the palm and distal forearm in the distribution of the palmar cutaneous branch of the median nerve. PS is commonly associated with volar proximal forearm pain exacerbated by repetitive activities involving pronation and supination.

PS is not easy to assess. Palpatory examination of a large supracondylar process at the distal humerus proximal to the medial epicondyle on its anteromedial aspect can be difficult, especially if the patient is overweight. And motor weakness is not a prominent feature. What’s more, power assessment of the pronator teres, flexor carpi radialis, and flexor digitorum superficialis may exacerbate symptoms.

Because the symptoms of PS and CTS may be the same, PS provocation maneuvers should be performed on patients with CTS symptoms and paresthesia involving the palm. Start by testing for Tinel’s sign over the pronator teres muscle, although this has been found to be positive in less than 50% of PS cases.¹⁷ Palpate the antecubital fossa and the proximal aspect of the pronator teres muscle to assess for discomfort or tenderness.

Pronator compression test. The pronator compression test has been found to be the most sensitive way to assess PS.^18,19 This test involves direct compression of the proximal and radial edge of the pronator teres muscle belly along the proximal volar forearm with the thumb.²⁰ It is performed bilaterally on supinated upper extremities, with the clinician applying pressure on each forearm simultaneously (FIGURE 2). If the symptoms in the hand are reproduced in ≤30 seconds, the test is positive. In a study of 10 patients with surgically confirmed PS, the pronator compression test was positive in every case.^20,21

Resistance testing. You can also evaluate the pronator teres compression site by testing the patient’s ability to resist pronation with his or her elbow extended and the forearm in neutral position. To test for compression from the bicipital aponeurosis, ask the patient to flex the elbow to approximately 120° to 130° and apply active supinated resistance.²² Likewise, resistance of the long finger proximal interphalangeal joint (IPJ) to flexion—a maneuver performed with elbow fully extended—assesses compression from the fibrous arcade of the flexor digitorum superficialis (FDS).²¹ A positive resistance test will reproduce the reported symptoms.

Ulnar tunnel syndrome

Symptoms of UTS, which is much less common than CTS, include pain in the wrist and hand that is associated with paresthesia or numbness in the small finger and ulnar half of the ring finger. Patients may report difficulty with motor tasks involving grip and pinch strength or fatigue with prolonged action of the intrinsic muscles. Many also report an exacerbation of symptoms associated with increased wrist flexion or at night.

Evaluation of UTS requires a full assessment of the upper extremity, starting with observation of hand posture and muscle bulk to identify signs of chronic nerve compression. The contralateral extremity serves as a control to the neuropathic hand. Classically, chronic ulnar nerve compression leads to intrinsic muscle atrophy, evidenced by loss of topographical soft tissue bulk in the first dorsal web space, the palmar transverse metacarpal arch, and the hypothenar area.²³ Ulnar motor nerve dysfunction is limited to the intrinsic muscles of the hand. The inverted pyramid sign, signified by atrophy of the transverse head of the adductor pollicis, is another visual aberrancy,²⁴ as is clawing of the ring finger and small finger. The clawing, which involves hyperextension of the MCPJ and flexion of the proximal and distal IPJ, is commonly known as Duchenne’s sign. FIGURE 3 demonstrates hypothenar atrophy and the loss of muscle bulk in the first dorsal web space.

When you suspect UTS, palpate the wrist and hand in an attempt to locate a mass or area of tenderness. Not all patients with a volar ganglion cyst responsible for UTS present with a palpable mass, but tenderness along the radial aspect of the pisiform or an undefined fullness in this area may be noted.²⁵ Any patient with a palpable mass should be tested for Tinel’s sign over the mass and undergo a thorough vascular assessment. Fracture of the hook of the hamate is indicated by tenderness in the region approximated by the intersection of Kaplan’s line and the proximal extension line from the ring finger.

Perform 2-point discrimination testing at the palmar distal aspect of the small finger and ulnar half of the ring finger. This tests the superficial sensory division of the ulnar nerve that travels within Guyon’s canal. Testing the dorsal ulnar cutaneous nerve involves the skin of the dorso-ulnar hand and dorsum of the long finger proximal to the IPJ. If this area is spared and the palmar distal ulnar digits are affected, compression within Guyon’s canal is likely. If both areas are affected, suspect a more proximal compression site at the cubital tunnel, as the dorsal ulnar cutaneous nerve branches proximal to Guyon’s canal.²⁶

Ulnar motor nerve dysfunction in UTS is limited to the intrinsic muscles of the hand. Assessment of intrinsic muscle function is described in TABLE 3.^27-32 It is important to become familiar with the tests and maneuvers described, but also to be aware that a comprehensive evaluation of ulnar nerve motor function requires a combination of tests.

Cubital tunnel syndrome

Cubital tunnel syndrome—the second most common peripheral neuropathy⁸—involves the proximal site of ulnar nerve compression in the upper extremity. Patients typically report symptoms similar to those of UTS, with sensory paresthesia in the ulnar digits and intrinsic weakness. To learn more about the symptoms, ask if the onset of pain or paresthesia is related to a particular elbow position, such as increased elbow flexion.

Notably, pain is usually not the initial complaint, unless the disease is advanced. This may be the reason atrophic intrinsic changes are 4 times more likely to be seen in patients with cubital tunnel syndrome than in those with CTS.³³ You’re more likely to hear about vague motor problems, including hand clumsiness and difficulty with fine coordination of the fingers.³⁴ Thus, it is important to evaluate patients for concurrent UTS and/or CTS, as well as for differentiation.

Focus on the elbow. Whenever you suspect cubital tunnel syndrome, pay special attention to the elbow. Examine the carrying angle of the elbow in relation to the contralateral extremity. Deformity may provide clues to a history of trauma. Assess the ulnar nerve during active flexion and extension to identify a subluxatable nerve at the cubital tunnel. Examine the ulno-humeral joint for crepitus, and palpate the joint line for large osteophytes and/or ganglion cysts.

Motor examination of the ulnar nerve primarily focuses on the intrinsic muscles detailed in TABLE 3,^27-32 although the flexor carpi ulnaris (FCU) and flexor digitorum profundus (FDP) to the ring finger and small finger are also innervated by the ulnar nerve. The FCU mediates the power grip, and can be tested by resisted wrist flexion and ulnar deviation. Ring finger and small finger FDP strength should be examined by resistance testing at the distal IPJ.

Provocative testing of cubital tunnel syndrome includes Tinel’s sign (performed over the cubital tunnel), the elbow flexion test (performed with elbow in maximum flexion and wrist at neutral position and held for 60 seconds), and the pressure provocation test (performed by applying pressure to the ulnar nerve just proximal to the cubital tunnel with your index and long fingers for 60 seconds while the patient’s elbow is at 20° flexion with the forearm supinated). For each test, eliciting distal paresthesia in ulnar nerve territory is a positive result. The sensitivity of these tests ranges from 70% (Tinel’s sign) to 98% (combined elbow flexion and pressure); specificity ranges from 95% to 99%.³⁵

The scratch collapse test for cubital tunnel syndrome evaluation is similar to the version used to assess for CTS; the only difference is the location of the site that is scratched, in this case the cubital tunnel. The reported sensitivity and specificity are 69% and 99%, respectively.¹¹

Wartenberg’s syndrome

When you suspect ulnar tunnel syndrome, palpate the wrist and hand in an attempt to locate a mass or area of tenderness.

When a patient reports paresthesia or pain along the radial aspect of the forearm that radiates into the dorsal thumb and index and middle fingers, consider Wartenberg’s syndrome—compression of the superficial radial nerve. The condition, also known as “cheiralgia paresthetica,” may exist anywhere along the course of the nerve in the forearm,³⁶ but the compression typically occurs 9 cm proximal to the radial styloid.

Assess the skin over the forearm and hand for evidence of prior trauma, surgical scars, or external compression sources, such as a watch.^37-39 Then use palpation to identify superficial or deep masses along the nerve.⁴⁰ Perform Tinel’s sign by lightly tapping along the nerve course from proximal to distal in the forearm. The test is positive if paresthesias are provoked distally.^41,42

Motor function of the extremity is unaffected in Wartenberg’s syndrome, unless a prior traumatic injury occurred or a comorbidity exists. Comorbidities to consider include de Quervain’s tenosynovitis, cervical radiculopathy, injury to the lateral antebrachial cutaneous nerve, and CTS.

Gross sensory testing usually is negative, but 2-point discrimination may show diminished responses. Testing distribution includes the dorsal radial wrist and hand, dorsal thumb skin proximal to the IPJ, and the dorsal surface of the index, middle, and radial half of the ring finger proximal to the IPJ.

Proceed with caution. Provocative testing with a pronated forearm and a flexed and ulnar-deviated wrist may exacerbate symptoms,^12,42 and Finkelstein’s maneuver (isolated ulnar deviation at the wrist to elicit pain over the first dorsal wrist compartment) and Phalen’s test may elicit false-positive results. Upper motor neuron exams (ie, deep tendon reflexes) and Hoffman’s sign (reflexive flexion of the terminal phalanges of the thumb and index finger induced by flicking or tapping the distal phalanx of the long finger) should be symmetric to the contralateral extremity.

In patients with more than one compression injury, Spurling’s sign (neck extension and lateral rotation towards the affected extremity) may induce paresthesia when combined with axial compression, while the shoulder abduction test (shoulder 90° abduction, with external rotation) may diminish reported paresthesia. In those for whom Wartenberg’s syndrome is their only compression injury, however, these provocative maneuvers will be negative.

Anterior interosseous nerve syndrome

A rare clinical entity that affects the anterior interosseous innervated muscles in the forearm, anterior interosseous nerve syndrome (AINS)’s etiology is unclear. But it is likely related to a spontaneous neuritis rather than a compressive etiology.⁴³ Paresis or paralysis of the flexor pollicis longus (FPL) and the flexor digitorum profundus (FDP) of the index and long finger is its hallmark, but patients may report vague forearm pain associated with weakness or absence of function.

Examination begins with a visual assessment and palpation of the forearm and hand for atrophy or a space-occupying lesion. Notably, sensory function of the hand should remain at baseline despite the motor dysfunction, as the anterior interosseous is purely a motor nerve.

Motor testing should focus on the median and anterior interosseous innervated muscles.

The FPL is tested by isolated thumb IPJ flexion and the Kiloh and Nevin sign—the inability to make an “OK” sign with the thumb and index finger.⁴⁴ Assess pinch grasp with a maximally flexed thumb IPJ and distal IPJ of the index finger. Anterior interosseous nerve dysfunction results in a flattened pinch without IPJ or distal IPJ flexion, which increases the contact of the thumb and index finger pulp.⁴⁵ In a series of 14 patients, researchers reported complete paralysis of FPL and FDP index finger in 5 patients, isolated paralysis of FPL in 7 patients, and isolated paralysis of FDP index and long fingers in 2 patients. None had isolated paralysis of the FDP long finger.⁴⁶FIGURE 4 shows complete (A) and incomplete (B) paralysis.

Pain is usually not the initial complaint with cubital tunnel syndrome. You're more likely to hear about hand clumsiness and difficulty with fine coordination of the fingers.

Evaluation of AINS also includes assessment of FPL and FDP tendon integrity with passive tenodesis. The appearance of the hand at rest should reflect the natural digital cascade. In a completely relaxed or anesthetized hand, the forearm is placed in wrist supination and extension, allowing gravity to extend the wrist and placing the thumb MCPJ at 30° flexion, the index finger MCPJ at 40°, and the small finger MCPJ at 70°. The thumb IPJ should approximate the radial fingertip pulp of the index finger. The forearm is then pronated and flexed at the wrist, straightening the thumb MCPJ and producing a mild flexion cascade at the proximal and distal IPJ of the index, long, ring, and small fingers within 20° of full extension. This dynamic exercise is used to confirm that the patient has an intact tenodesis effect, thus excluding tendon lacerations or ruptures from the differential diagnosis. In one study, in 9 of 33 cases of partial or complete isolated index finger FPL or FDP, paralysis was initially diagnosed as tendon rupture.⁴⁷

When to consider electrodiagnostic testing

Electrodiagnostic testing—a combination of electromyography and nerve conduction studies to assess the status of a peripheral nerve⁴⁸—provides objective data that can help diagnose a challenging presentation, rule out a competing diagnosis, or clarify an atypical clinical picture or vague subjective history. This type of testing is also used to localize the entrapment site, identify a patient with polyneuropathy or brachial plexopathy, and assess the severity of nerve injury or presence of a double crush syndrome.^49,50 Any patient with signs and symptoms of a compression neuropathy and supportive findings on physical exam should be referred for electrodiagnostic testing and/or to a surgeon specializing in treating these conditions.

CORRESPONDENCE
Kyle J. MacGillis, MD, University of Illinois at Chicago, Department of Orthopaedic Surgery, 835 South Wolcott Avenue, M/C 844, Chicago, IL 60612; [email protected].

Neuropathic hand complaints—for which patients typically seek medical attention when the pain or paresthesia starts to interfere with their daily routine—are common and diverse. The ability to assess and accurately diagnose upper extremity compression neuropathies is critical for physicians in primary care.

Assessment starts, of course, with a thorough history of the present illness and past medical history, which helps define a broad differential diagnosis and identify comorbidities. Physical examination, including judicious use of provocative testing, allows you to objectively identify the pathologic deficit, evaluate function and coordination of multiple organ systems, and detect nerve dysfunction. The results determine whether additional tools, such as electrodiagnostic testing, are needed.

We’ve created this guide, detailed in the text, tables, and figures that follow, to help you hone your ability to accurately diagnose patients who present with compression neuropathies of the hand.

The medical history: Knowing what to ask

To clearly define a patient’s symptoms and disability, start with a thorough history of the presenting complaint.

Inquire about symptom onset and chronicity. Did the pain or paresthesia begin after an injury? Are the symptoms associated with repetitive use of the extremity? Do they occur at night?

Pinpoint the location or distribution of pain or paresthesia. It is paramount to identify the affected nerve.^1,2 Ask patients to complete a hand or upper extremity profile documenting location and/or type of numbness, tingling, or decreased sensation. A diagram of the peripheral nerves responsible for sensory innervation of the hand (FIGURE 1) is an effective way to screen individuals at high risk of carpal tunnel syndrome (CTS) or ulnar tunnel syndrome (UTS).^1,2

A patient report such as, “My whole hand is numb,” calls for a follow-up question to determine whether the little finger is affected,³ which would indicate that the ulnar nerve, rather than just the median nerve, is involved. And if a patient reports feeling as if he or she is wearing gloves or mittens, it is essential to consider the possibility of a systemic neuropathy rather than a single peripheral neuropathy.³

Gather basic patient information. Inquire about hand dominance, occupation, and baseline function, any or all of which may be critical in the assessment and initiation of treatment.^4,5

Review systemic conditions and medications

A broad range of comorbidities, such as cervical radiculopathy, diabetes, hypothyroidism, and vitamin deficiencies (TABLE 1),^6,7 may be responsible for neuropathic hand complaints, and a thorough review of systemic complaints and past medical history is critical. Include a medication history and a review of prior procedures, such as post-traumatic surgeries of the hand or upper extremity or nerve decompression surgeries, which may provide additional insight into disease etiology.

Symptoms guide physical exam, provocative testing

A physical examination, including provocative testing, follows based on reported symptoms, medical history, and suspected source of nerve compression.

Carpal tunnel syndrome

CTS is the most common peripheral neuropathy.⁸ Patients often report nocturnal pain or paresthesia in the distal median nerve distribution, comprising the palmar surface of the thumb, index, middle, and radial half of the ring finger.

Researchers have identified 6 standardized clinical criteria for the diagnosis of CTS. Two criteria—numbness mostly in median nerve territory and nocturnal numbness—can be ascertained during the history of present illness.The other 4, detailed below, will be found during the physical exam.⁹

Thenar weakness or atrophy.⁹ Begin your evaluation by inspecting the thenar musculature for atrophic changes. Motor exam of intrinsic musculature innervated by the recurrent motor branch of the median nerve includes assessment of thumb abduction strength (assessed by applying resistance to the metacarpophalangeal joint [MCPJ] base towards the palm in the position of maximal abduction) and opposition strength (assessed by applying force to the MCPJ from the ulnar aspect).¹⁰

Positive Phalen’s test.⁹ Provocative testing for CTS includes Phalen’s test (sensitivity 43%-86%, specificity 48%-67%),¹¹ which is an attempt to reproduce the numbness or tingling in the median nerve territory within 60 seconds of full wrist flexion. Ask the patient to hold his or her forearms vertically with elbows resting on the table (allowing gravity to flex the wrists),¹² and to tell you if numbness or tingling occurs.

Consider the possibility of a systemic neuropathy in patients who report that they feel as though they are wearing gloves.

Positive Tinel’s sign.⁹ Tinel’s sign (sensitivity 45%-75%, specificity 48%-67%)¹¹ is performed by lightly tapping the median nerve from the proximal to distal end over the carpal tunnel. The test is positive if paresthesia results. Provocative testing may also include Durkan’s test, also known as the carpal compression test. Durkan’s test (sensitivity 49%-89%, specificity 54%-96%)¹¹ involves placing your thumb directly over the carpal tunnel and holding light compression for 60 seconds, or until paresthesia is reported.

Positive 2-point discrimination test.⁹ To assess CTS disease severity, use 2-point discrimination to evaluate the patient’s sensation qualitatively and quantitatively. Two-point discrimination can only be tested, however, if light touch sensation is intact. It is typically performed by lightly applying 2 caliper points at fixed distances sufficient to blanch the skin, but some clinicians have used other tools, such as a modified paperclip.¹³ The smallest distance at which the patient can detect 2 distinct stimuli is then recorded.

Researchers have reported an average of 3 to 5 mm for 2-point discrimination at the fingertipand a normal 2-point discrimination of 6 to 9 mm in the volar surface of the hand (TABLE 2).^14,15

The scratch collapse test (sensitivity 64%, specificity 99%) is a supplemental exam that uses a different outcome measure to diagnose CTS.¹⁶ It involves lightly scratching the skin over the compressed carpal tunnel while the patient performs sustained resisted bilateral shoulder external rotation in an adducted position. A momentary loss of muscle resistance to external rotation indicates a positive test.

Pronator syndrome

Pronator syndrome (PS) is a proximal median neuropathy that may present in isolation or in combination with CTS as a double crush syndrome. Clinical symptoms include features of CTS and sensory paresthesias in the palm and distal forearm in the distribution of the palmar cutaneous branch of the median nerve. PS is commonly associated with volar proximal forearm pain exacerbated by repetitive activities involving pronation and supination.

PS is not easy to assess. Palpatory examination of a large supracondylar process at the distal humerus proximal to the medial epicondyle on its anteromedial aspect can be difficult, especially if the patient is overweight. And motor weakness is not a prominent feature. What’s more, power assessment of the pronator teres, flexor carpi radialis, and flexor digitorum superficialis may exacerbate symptoms.

Because the symptoms of PS and CTS may be the same, PS provocation maneuvers should be performed on patients with CTS symptoms and paresthesia involving the palm. Start by testing for Tinel’s sign over the pronator teres muscle, although this has been found to be positive in less than 50% of PS cases.¹⁷ Palpate the antecubital fossa and the proximal aspect of the pronator teres muscle to assess for discomfort or tenderness.

Pronator compression test. The pronator compression test has been found to be the most sensitive way to assess PS.^18,19 This test involves direct compression of the proximal and radial edge of the pronator teres muscle belly along the proximal volar forearm with the thumb.²⁰ It is performed bilaterally on supinated upper extremities, with the clinician applying pressure on each forearm simultaneously (FIGURE 2). If the symptoms in the hand are reproduced in ≤30 seconds, the test is positive. In a study of 10 patients with surgically confirmed PS, the pronator compression test was positive in every case.^20,21

Resistance testing. You can also evaluate the pronator teres compression site by testing the patient’s ability to resist pronation with his or her elbow extended and the forearm in neutral position. To test for compression from the bicipital aponeurosis, ask the patient to flex the elbow to approximately 120° to 130° and apply active supinated resistance.²² Likewise, resistance of the long finger proximal interphalangeal joint (IPJ) to flexion—a maneuver performed with elbow fully extended—assesses compression from the fibrous arcade of the flexor digitorum superficialis (FDS).²¹ A positive resistance test will reproduce the reported symptoms.

Ulnar tunnel syndrome

Symptoms of UTS, which is much less common than CTS, include pain in the wrist and hand that is associated with paresthesia or numbness in the small finger and ulnar half of the ring finger. Patients may report difficulty with motor tasks involving grip and pinch strength or fatigue with prolonged action of the intrinsic muscles. Many also report an exacerbation of symptoms associated with increased wrist flexion or at night.

Evaluation of UTS requires a full assessment of the upper extremity, starting with observation of hand posture and muscle bulk to identify signs of chronic nerve compression. The contralateral extremity serves as a control to the neuropathic hand. Classically, chronic ulnar nerve compression leads to intrinsic muscle atrophy, evidenced by loss of topographical soft tissue bulk in the first dorsal web space, the palmar transverse metacarpal arch, and the hypothenar area.²³ Ulnar motor nerve dysfunction is limited to the intrinsic muscles of the hand. The inverted pyramid sign, signified by atrophy of the transverse head of the adductor pollicis, is another visual aberrancy,²⁴ as is clawing of the ring finger and small finger. The clawing, which involves hyperextension of the MCPJ and flexion of the proximal and distal IPJ, is commonly known as Duchenne’s sign. FIGURE 3 demonstrates hypothenar atrophy and the loss of muscle bulk in the first dorsal web space.

When you suspect UTS, palpate the wrist and hand in an attempt to locate a mass or area of tenderness. Not all patients with a volar ganglion cyst responsible for UTS present with a palpable mass, but tenderness along the radial aspect of the pisiform or an undefined fullness in this area may be noted.²⁵ Any patient with a palpable mass should be tested for Tinel’s sign over the mass and undergo a thorough vascular assessment. Fracture of the hook of the hamate is indicated by tenderness in the region approximated by the intersection of Kaplan’s line and the proximal extension line from the ring finger.

Perform 2-point discrimination testing at the palmar distal aspect of the small finger and ulnar half of the ring finger. This tests the superficial sensory division of the ulnar nerve that travels within Guyon’s canal. Testing the dorsal ulnar cutaneous nerve involves the skin of the dorso-ulnar hand and dorsum of the long finger proximal to the IPJ. If this area is spared and the palmar distal ulnar digits are affected, compression within Guyon’s canal is likely. If both areas are affected, suspect a more proximal compression site at the cubital tunnel, as the dorsal ulnar cutaneous nerve branches proximal to Guyon’s canal.²⁶

Ulnar motor nerve dysfunction in UTS is limited to the intrinsic muscles of the hand. Assessment of intrinsic muscle function is described in TABLE 3.^27-32 It is important to become familiar with the tests and maneuvers described, but also to be aware that a comprehensive evaluation of ulnar nerve motor function requires a combination of tests.

Cubital tunnel syndrome

Cubital tunnel syndrome—the second most common peripheral neuropathy⁸—involves the proximal site of ulnar nerve compression in the upper extremity. Patients typically report symptoms similar to those of UTS, with sensory paresthesia in the ulnar digits and intrinsic weakness. To learn more about the symptoms, ask if the onset of pain or paresthesia is related to a particular elbow position, such as increased elbow flexion.

Notably, pain is usually not the initial complaint, unless the disease is advanced. This may be the reason atrophic intrinsic changes are 4 times more likely to be seen in patients with cubital tunnel syndrome than in those with CTS.³³ You’re more likely to hear about vague motor problems, including hand clumsiness and difficulty with fine coordination of the fingers.³⁴ Thus, it is important to evaluate patients for concurrent UTS and/or CTS, as well as for differentiation.

Focus on the elbow. Whenever you suspect cubital tunnel syndrome, pay special attention to the elbow. Examine the carrying angle of the elbow in relation to the contralateral extremity. Deformity may provide clues to a history of trauma. Assess the ulnar nerve during active flexion and extension to identify a subluxatable nerve at the cubital tunnel. Examine the ulno-humeral joint for crepitus, and palpate the joint line for large osteophytes and/or ganglion cysts.

Motor examination of the ulnar nerve primarily focuses on the intrinsic muscles detailed in TABLE 3,^27-32 although the flexor carpi ulnaris (FCU) and flexor digitorum profundus (FDP) to the ring finger and small finger are also innervated by the ulnar nerve. The FCU mediates the power grip, and can be tested by resisted wrist flexion and ulnar deviation. Ring finger and small finger FDP strength should be examined by resistance testing at the distal IPJ.

Provocative testing of cubital tunnel syndrome includes Tinel’s sign (performed over the cubital tunnel), the elbow flexion test (performed with elbow in maximum flexion and wrist at neutral position and held for 60 seconds), and the pressure provocation test (performed by applying pressure to the ulnar nerve just proximal to the cubital tunnel with your index and long fingers for 60 seconds while the patient’s elbow is at 20° flexion with the forearm supinated). For each test, eliciting distal paresthesia in ulnar nerve territory is a positive result. The sensitivity of these tests ranges from 70% (Tinel’s sign) to 98% (combined elbow flexion and pressure); specificity ranges from 95% to 99%.³⁵

The scratch collapse test for cubital tunnel syndrome evaluation is similar to the version used to assess for CTS; the only difference is the location of the site that is scratched, in this case the cubital tunnel. The reported sensitivity and specificity are 69% and 99%, respectively.¹¹

Wartenberg’s syndrome

When you suspect ulnar tunnel syndrome, palpate the wrist and hand in an attempt to locate a mass or area of tenderness.

When a patient reports paresthesia or pain along the radial aspect of the forearm that radiates into the dorsal thumb and index and middle fingers, consider Wartenberg’s syndrome—compression of the superficial radial nerve. The condition, also known as “cheiralgia paresthetica,” may exist anywhere along the course of the nerve in the forearm,³⁶ but the compression typically occurs 9 cm proximal to the radial styloid.

Assess the skin over the forearm and hand for evidence of prior trauma, surgical scars, or external compression sources, such as a watch.^37-39 Then use palpation to identify superficial or deep masses along the nerve.⁴⁰ Perform Tinel’s sign by lightly tapping along the nerve course from proximal to distal in the forearm. The test is positive if paresthesias are provoked distally.^41,42

Motor function of the extremity is unaffected in Wartenberg’s syndrome, unless a prior traumatic injury occurred or a comorbidity exists. Comorbidities to consider include de Quervain’s tenosynovitis, cervical radiculopathy, injury to the lateral antebrachial cutaneous nerve, and CTS.

Gross sensory testing usually is negative, but 2-point discrimination may show diminished responses. Testing distribution includes the dorsal radial wrist and hand, dorsal thumb skin proximal to the IPJ, and the dorsal surface of the index, middle, and radial half of the ring finger proximal to the IPJ.

Proceed with caution. Provocative testing with a pronated forearm and a flexed and ulnar-deviated wrist may exacerbate symptoms,^12,42 and Finkelstein’s maneuver (isolated ulnar deviation at the wrist to elicit pain over the first dorsal wrist compartment) and Phalen’s test may elicit false-positive results. Upper motor neuron exams (ie, deep tendon reflexes) and Hoffman’s sign (reflexive flexion of the terminal phalanges of the thumb and index finger induced by flicking or tapping the distal phalanx of the long finger) should be symmetric to the contralateral extremity.

In patients with more than one compression injury, Spurling’s sign (neck extension and lateral rotation towards the affected extremity) may induce paresthesia when combined with axial compression, while the shoulder abduction test (shoulder 90° abduction, with external rotation) may diminish reported paresthesia. In those for whom Wartenberg’s syndrome is their only compression injury, however, these provocative maneuvers will be negative.

Anterior interosseous nerve syndrome

A rare clinical entity that affects the anterior interosseous innervated muscles in the forearm, anterior interosseous nerve syndrome (AINS)’s etiology is unclear. But it is likely related to a spontaneous neuritis rather than a compressive etiology.⁴³ Paresis or paralysis of the flexor pollicis longus (FPL) and the flexor digitorum profundus (FDP) of the index and long finger is its hallmark, but patients may report vague forearm pain associated with weakness or absence of function.

Examination begins with a visual assessment and palpation of the forearm and hand for atrophy or a space-occupying lesion. Notably, sensory function of the hand should remain at baseline despite the motor dysfunction, as the anterior interosseous is purely a motor nerve.

Motor testing should focus on the median and anterior interosseous innervated muscles.

The FPL is tested by isolated thumb IPJ flexion and the Kiloh and Nevin sign—the inability to make an “OK” sign with the thumb and index finger.⁴⁴ Assess pinch grasp with a maximally flexed thumb IPJ and distal IPJ of the index finger. Anterior interosseous nerve dysfunction results in a flattened pinch without IPJ or distal IPJ flexion, which increases the contact of the thumb and index finger pulp.⁴⁵ In a series of 14 patients, researchers reported complete paralysis of FPL and FDP index finger in 5 patients, isolated paralysis of FPL in 7 patients, and isolated paralysis of FDP index and long fingers in 2 patients. None had isolated paralysis of the FDP long finger.⁴⁶FIGURE 4 shows complete (A) and incomplete (B) paralysis.

Pain is usually not the initial complaint with cubital tunnel syndrome. You're more likely to hear about hand clumsiness and difficulty with fine coordination of the fingers.

Evaluation of AINS also includes assessment of FPL and FDP tendon integrity with passive tenodesis. The appearance of the hand at rest should reflect the natural digital cascade. In a completely relaxed or anesthetized hand, the forearm is placed in wrist supination and extension, allowing gravity to extend the wrist and placing the thumb MCPJ at 30° flexion, the index finger MCPJ at 40°, and the small finger MCPJ at 70°. The thumb IPJ should approximate the radial fingertip pulp of the index finger. The forearm is then pronated and flexed at the wrist, straightening the thumb MCPJ and producing a mild flexion cascade at the proximal and distal IPJ of the index, long, ring, and small fingers within 20° of full extension. This dynamic exercise is used to confirm that the patient has an intact tenodesis effect, thus excluding tendon lacerations or ruptures from the differential diagnosis. In one study, in 9 of 33 cases of partial or complete isolated index finger FPL or FDP, paralysis was initially diagnosed as tendon rupture.⁴⁷

When to consider electrodiagnostic testing

Electrodiagnostic testing—a combination of electromyography and nerve conduction studies to assess the status of a peripheral nerve⁴⁸—provides objective data that can help diagnose a challenging presentation, rule out a competing diagnosis, or clarify an atypical clinical picture or vague subjective history. This type of testing is also used to localize the entrapment site, identify a patient with polyneuropathy or brachial plexopathy, and assess the severity of nerve injury or presence of a double crush syndrome.^49,50 Any patient with signs and symptoms of a compression neuropathy and supportive findings on physical exam should be referred for electrodiagnostic testing and/or to a surgeon specializing in treating these conditions.

CORRESPONDENCE
Kyle J. MacGillis, MD, University of Illinois at Chicago, Department of Orthopaedic Surgery, 835 South Wolcott Avenue, M/C 844, Chicago, IL 60612; [email protected].

Neuropathic hand complaints—for which patients typically seek medical attention when the pain or paresthesia starts to interfere with their daily routine—are common and diverse. The ability to assess and accurately diagnose upper extremity compression neuropathies is critical for physicians in primary care.

Assessment starts, of course, with a thorough history of the present illness and past medical history, which helps define a broad differential diagnosis and identify comorbidities. Physical examination, including judicious use of provocative testing, allows you to objectively identify the pathologic deficit, evaluate function and coordination of multiple organ systems, and detect nerve dysfunction. The results determine whether additional tools, such as electrodiagnostic testing, are needed.

We’ve created this guide, detailed in the text, tables, and figures that follow, to help you hone your ability to accurately diagnose patients who present with compression neuropathies of the hand.

The medical history: Knowing what to ask

To clearly define a patient’s symptoms and disability, start with a thorough history of the presenting complaint.

Inquire about symptom onset and chronicity. Did the pain or paresthesia begin after an injury? Are the symptoms associated with repetitive use of the extremity? Do they occur at night?

Pinpoint the location or distribution of pain or paresthesia. It is paramount to identify the affected nerve.^1,2 Ask patients to complete a hand or upper extremity profile documenting location and/or type of numbness, tingling, or decreased sensation. A diagram of the peripheral nerves responsible for sensory innervation of the hand (FIGURE 1) is an effective way to screen individuals at high risk of carpal tunnel syndrome (CTS) or ulnar tunnel syndrome (UTS).^1,2

A patient report such as, “My whole hand is numb,” calls for a follow-up question to determine whether the little finger is affected,³ which would indicate that the ulnar nerve, rather than just the median nerve, is involved. And if a patient reports feeling as if he or she is wearing gloves or mittens, it is essential to consider the possibility of a systemic neuropathy rather than a single peripheral neuropathy.³

Gather basic patient information. Inquire about hand dominance, occupation, and baseline function, any or all of which may be critical in the assessment and initiation of treatment.^4,5

Review systemic conditions and medications

A broad range of comorbidities, such as cervical radiculopathy, diabetes, hypothyroidism, and vitamin deficiencies (TABLE 1),^6,7 may be responsible for neuropathic hand complaints, and a thorough review of systemic complaints and past medical history is critical. Include a medication history and a review of prior procedures, such as post-traumatic surgeries of the hand or upper extremity or nerve decompression surgeries, which may provide additional insight into disease etiology.

Symptoms guide physical exam, provocative testing

A physical examination, including provocative testing, follows based on reported symptoms, medical history, and suspected source of nerve compression.

Carpal tunnel syndrome

CTS is the most common peripheral neuropathy.⁸ Patients often report nocturnal pain or paresthesia in the distal median nerve distribution, comprising the palmar surface of the thumb, index, middle, and radial half of the ring finger.

Researchers have identified 6 standardized clinical criteria for the diagnosis of CTS. Two criteria—numbness mostly in median nerve territory and nocturnal numbness—can be ascertained during the history of present illness.The other 4, detailed below, will be found during the physical exam.⁹

Thenar weakness or atrophy.⁹ Begin your evaluation by inspecting the thenar musculature for atrophic changes. Motor exam of intrinsic musculature innervated by the recurrent motor branch of the median nerve includes assessment of thumb abduction strength (assessed by applying resistance to the metacarpophalangeal joint [MCPJ] base towards the palm in the position of maximal abduction) and opposition strength (assessed by applying force to the MCPJ from the ulnar aspect).¹⁰

Positive Phalen’s test.⁹ Provocative testing for CTS includes Phalen’s test (sensitivity 43%-86%, specificity 48%-67%),¹¹ which is an attempt to reproduce the numbness or tingling in the median nerve territory within 60 seconds of full wrist flexion. Ask the patient to hold his or her forearms vertically with elbows resting on the table (allowing gravity to flex the wrists),¹² and to tell you if numbness or tingling occurs.

Consider the possibility of a systemic neuropathy in patients who report that they feel as though they are wearing gloves.

Positive Tinel’s sign.⁹ Tinel’s sign (sensitivity 45%-75%, specificity 48%-67%)¹¹ is performed by lightly tapping the median nerve from the proximal to distal end over the carpal tunnel. The test is positive if paresthesia results. Provocative testing may also include Durkan’s test, also known as the carpal compression test. Durkan’s test (sensitivity 49%-89%, specificity 54%-96%)¹¹ involves placing your thumb directly over the carpal tunnel and holding light compression for 60 seconds, or until paresthesia is reported.

Positive 2-point discrimination test.⁹ To assess CTS disease severity, use 2-point discrimination to evaluate the patient’s sensation qualitatively and quantitatively. Two-point discrimination can only be tested, however, if light touch sensation is intact. It is typically performed by lightly applying 2 caliper points at fixed distances sufficient to blanch the skin, but some clinicians have used other tools, such as a modified paperclip.¹³ The smallest distance at which the patient can detect 2 distinct stimuli is then recorded.

Researchers have reported an average of 3 to 5 mm for 2-point discrimination at the fingertipand a normal 2-point discrimination of 6 to 9 mm in the volar surface of the hand (TABLE 2).^14,15

The scratch collapse test (sensitivity 64%, specificity 99%) is a supplemental exam that uses a different outcome measure to diagnose CTS.¹⁶ It involves lightly scratching the skin over the compressed carpal tunnel while the patient performs sustained resisted bilateral shoulder external rotation in an adducted position. A momentary loss of muscle resistance to external rotation indicates a positive test.

Pronator syndrome

Pronator syndrome (PS) is a proximal median neuropathy that may present in isolation or in combination with CTS as a double crush syndrome. Clinical symptoms include features of CTS and sensory paresthesias in the palm and distal forearm in the distribution of the palmar cutaneous branch of the median nerve. PS is commonly associated with volar proximal forearm pain exacerbated by repetitive activities involving pronation and supination.

PS is not easy to assess. Palpatory examination of a large supracondylar process at the distal humerus proximal to the medial epicondyle on its anteromedial aspect can be difficult, especially if the patient is overweight. And motor weakness is not a prominent feature. What’s more, power assessment of the pronator teres, flexor carpi radialis, and flexor digitorum superficialis may exacerbate symptoms.

Because the symptoms of PS and CTS may be the same, PS provocation maneuvers should be performed on patients with CTS symptoms and paresthesia involving the palm. Start by testing for Tinel’s sign over the pronator teres muscle, although this has been found to be positive in less than 50% of PS cases.¹⁷ Palpate the antecubital fossa and the proximal aspect of the pronator teres muscle to assess for discomfort or tenderness.

Pronator compression test. The pronator compression test has been found to be the most sensitive way to assess PS.^18,19 This test involves direct compression of the proximal and radial edge of the pronator teres muscle belly along the proximal volar forearm with the thumb.²⁰ It is performed bilaterally on supinated upper extremities, with the clinician applying pressure on each forearm simultaneously (FIGURE 2). If the symptoms in the hand are reproduced in ≤30 seconds, the test is positive. In a study of 10 patients with surgically confirmed PS, the pronator compression test was positive in every case.^20,21

Resistance testing. You can also evaluate the pronator teres compression site by testing the patient’s ability to resist pronation with his or her elbow extended and the forearm in neutral position. To test for compression from the bicipital aponeurosis, ask the patient to flex the elbow to approximately 120° to 130° and apply active supinated resistance.²² Likewise, resistance of the long finger proximal interphalangeal joint (IPJ) to flexion—a maneuver performed with elbow fully extended—assesses compression from the fibrous arcade of the flexor digitorum superficialis (FDS).²¹ A positive resistance test will reproduce the reported symptoms.

Ulnar tunnel syndrome

Symptoms of UTS, which is much less common than CTS, include pain in the wrist and hand that is associated with paresthesia or numbness in the small finger and ulnar half of the ring finger. Patients may report difficulty with motor tasks involving grip and pinch strength or fatigue with prolonged action of the intrinsic muscles. Many also report an exacerbation of symptoms associated with increased wrist flexion or at night.

Evaluation of UTS requires a full assessment of the upper extremity, starting with observation of hand posture and muscle bulk to identify signs of chronic nerve compression. The contralateral extremity serves as a control to the neuropathic hand. Classically, chronic ulnar nerve compression leads to intrinsic muscle atrophy, evidenced by loss of topographical soft tissue bulk in the first dorsal web space, the palmar transverse metacarpal arch, and the hypothenar area.²³ Ulnar motor nerve dysfunction is limited to the intrinsic muscles of the hand. The inverted pyramid sign, signified by atrophy of the transverse head of the adductor pollicis, is another visual aberrancy,²⁴ as is clawing of the ring finger and small finger. The clawing, which involves hyperextension of the MCPJ and flexion of the proximal and distal IPJ, is commonly known as Duchenne’s sign. FIGURE 3 demonstrates hypothenar atrophy and the loss of muscle bulk in the first dorsal web space.

When you suspect UTS, palpate the wrist and hand in an attempt to locate a mass or area of tenderness. Not all patients with a volar ganglion cyst responsible for UTS present with a palpable mass, but tenderness along the radial aspect of the pisiform or an undefined fullness in this area may be noted.²⁵ Any patient with a palpable mass should be tested for Tinel’s sign over the mass and undergo a thorough vascular assessment. Fracture of the hook of the hamate is indicated by tenderness in the region approximated by the intersection of Kaplan’s line and the proximal extension line from the ring finger.

Perform 2-point discrimination testing at the palmar distal aspect of the small finger and ulnar half of the ring finger. This tests the superficial sensory division of the ulnar nerve that travels within Guyon’s canal. Testing the dorsal ulnar cutaneous nerve involves the skin of the dorso-ulnar hand and dorsum of the long finger proximal to the IPJ. If this area is spared and the palmar distal ulnar digits are affected, compression within Guyon’s canal is likely. If both areas are affected, suspect a more proximal compression site at the cubital tunnel, as the dorsal ulnar cutaneous nerve branches proximal to Guyon’s canal.²⁶

Ulnar motor nerve dysfunction in UTS is limited to the intrinsic muscles of the hand. Assessment of intrinsic muscle function is described in TABLE 3.^27-32 It is important to become familiar with the tests and maneuvers described, but also to be aware that a comprehensive evaluation of ulnar nerve motor function requires a combination of tests.

Cubital tunnel syndrome

Cubital tunnel syndrome—the second most common peripheral neuropathy⁸—involves the proximal site of ulnar nerve compression in the upper extremity. Patients typically report symptoms similar to those of UTS, with sensory paresthesia in the ulnar digits and intrinsic weakness. To learn more about the symptoms, ask if the onset of pain or paresthesia is related to a particular elbow position, such as increased elbow flexion.

Notably, pain is usually not the initial complaint, unless the disease is advanced. This may be the reason atrophic intrinsic changes are 4 times more likely to be seen in patients with cubital tunnel syndrome than in those with CTS.³³ You’re more likely to hear about vague motor problems, including hand clumsiness and difficulty with fine coordination of the fingers.³⁴ Thus, it is important to evaluate patients for concurrent UTS and/or CTS, as well as for differentiation.

Focus on the elbow. Whenever you suspect cubital tunnel syndrome, pay special attention to the elbow. Examine the carrying angle of the elbow in relation to the contralateral extremity. Deformity may provide clues to a history of trauma. Assess the ulnar nerve during active flexion and extension to identify a subluxatable nerve at the cubital tunnel. Examine the ulno-humeral joint for crepitus, and palpate the joint line for large osteophytes and/or ganglion cysts.

Motor examination of the ulnar nerve primarily focuses on the intrinsic muscles detailed in TABLE 3,^27-32 although the flexor carpi ulnaris (FCU) and flexor digitorum profundus (FDP) to the ring finger and small finger are also innervated by the ulnar nerve. The FCU mediates the power grip, and can be tested by resisted wrist flexion and ulnar deviation. Ring finger and small finger FDP strength should be examined by resistance testing at the distal IPJ.

Provocative testing of cubital tunnel syndrome includes Tinel’s sign (performed over the cubital tunnel), the elbow flexion test (performed with elbow in maximum flexion and wrist at neutral position and held for 60 seconds), and the pressure provocation test (performed by applying pressure to the ulnar nerve just proximal to the cubital tunnel with your index and long fingers for 60 seconds while the patient’s elbow is at 20° flexion with the forearm supinated). For each test, eliciting distal paresthesia in ulnar nerve territory is a positive result. The sensitivity of these tests ranges from 70% (Tinel’s sign) to 98% (combined elbow flexion and pressure); specificity ranges from 95% to 99%.³⁵

The scratch collapse test for cubital tunnel syndrome evaluation is similar to the version used to assess for CTS; the only difference is the location of the site that is scratched, in this case the cubital tunnel. The reported sensitivity and specificity are 69% and 99%, respectively.¹¹

Wartenberg’s syndrome

When you suspect ulnar tunnel syndrome, palpate the wrist and hand in an attempt to locate a mass or area of tenderness.

When a patient reports paresthesia or pain along the radial aspect of the forearm that radiates into the dorsal thumb and index and middle fingers, consider Wartenberg’s syndrome—compression of the superficial radial nerve. The condition, also known as “cheiralgia paresthetica,” may exist anywhere along the course of the nerve in the forearm,³⁶ but the compression typically occurs 9 cm proximal to the radial styloid.

Assess the skin over the forearm and hand for evidence of prior trauma, surgical scars, or external compression sources, such as a watch.^37-39 Then use palpation to identify superficial or deep masses along the nerve.⁴⁰ Perform Tinel’s sign by lightly tapping along the nerve course from proximal to distal in the forearm. The test is positive if paresthesias are provoked distally.^41,42

Motor function of the extremity is unaffected in Wartenberg’s syndrome, unless a prior traumatic injury occurred or a comorbidity exists. Comorbidities to consider include de Quervain’s tenosynovitis, cervical radiculopathy, injury to the lateral antebrachial cutaneous nerve, and CTS.

Gross sensory testing usually is negative, but 2-point discrimination may show diminished responses. Testing distribution includes the dorsal radial wrist and hand, dorsal thumb skin proximal to the IPJ, and the dorsal surface of the index, middle, and radial half of the ring finger proximal to the IPJ.

Proceed with caution. Provocative testing with a pronated forearm and a flexed and ulnar-deviated wrist may exacerbate symptoms,^12,42 and Finkelstein’s maneuver (isolated ulnar deviation at the wrist to elicit pain over the first dorsal wrist compartment) and Phalen’s test may elicit false-positive results. Upper motor neuron exams (ie, deep tendon reflexes) and Hoffman’s sign (reflexive flexion of the terminal phalanges of the thumb and index finger induced by flicking or tapping the distal phalanx of the long finger) should be symmetric to the contralateral extremity.

In patients with more than one compression injury, Spurling’s sign (neck extension and lateral rotation towards the affected extremity) may induce paresthesia when combined with axial compression, while the shoulder abduction test (shoulder 90° abduction, with external rotation) may diminish reported paresthesia. In those for whom Wartenberg’s syndrome is their only compression injury, however, these provocative maneuvers will be negative.

Anterior interosseous nerve syndrome

A rare clinical entity that affects the anterior interosseous innervated muscles in the forearm, anterior interosseous nerve syndrome (AINS)’s etiology is unclear. But it is likely related to a spontaneous neuritis rather than a compressive etiology.⁴³ Paresis or paralysis of the flexor pollicis longus (FPL) and the flexor digitorum profundus (FDP) of the index and long finger is its hallmark, but patients may report vague forearm pain associated with weakness or absence of function.

Examination begins with a visual assessment and palpation of the forearm and hand for atrophy or a space-occupying lesion. Notably, sensory function of the hand should remain at baseline despite the motor dysfunction, as the anterior interosseous is purely a motor nerve.

Motor testing should focus on the median and anterior interosseous innervated muscles.

The FPL is tested by isolated thumb IPJ flexion and the Kiloh and Nevin sign—the inability to make an “OK” sign with the thumb and index finger.⁴⁴ Assess pinch grasp with a maximally flexed thumb IPJ and distal IPJ of the index finger. Anterior interosseous nerve dysfunction results in a flattened pinch without IPJ or distal IPJ flexion, which increases the contact of the thumb and index finger pulp.⁴⁵ In a series of 14 patients, researchers reported complete paralysis of FPL and FDP index finger in 5 patients, isolated paralysis of FPL in 7 patients, and isolated paralysis of FDP index and long fingers in 2 patients. None had isolated paralysis of the FDP long finger.⁴⁶FIGURE 4 shows complete (A) and incomplete (B) paralysis.

Pain is usually not the initial complaint with cubital tunnel syndrome. You're more likely to hear about hand clumsiness and difficulty with fine coordination of the fingers.

Evaluation of AINS also includes assessment of FPL and FDP tendon integrity with passive tenodesis. The appearance of the hand at rest should reflect the natural digital cascade. In a completely relaxed or anesthetized hand, the forearm is placed in wrist supination and extension, allowing gravity to extend the wrist and placing the thumb MCPJ at 30° flexion, the index finger MCPJ at 40°, and the small finger MCPJ at 70°. The thumb IPJ should approximate the radial fingertip pulp of the index finger. The forearm is then pronated and flexed at the wrist, straightening the thumb MCPJ and producing a mild flexion cascade at the proximal and distal IPJ of the index, long, ring, and small fingers within 20° of full extension. This dynamic exercise is used to confirm that the patient has an intact tenodesis effect, thus excluding tendon lacerations or ruptures from the differential diagnosis. In one study, in 9 of 33 cases of partial or complete isolated index finger FPL or FDP, paralysis was initially diagnosed as tendon rupture.⁴⁷

When to consider electrodiagnostic testing

Electrodiagnostic testing—a combination of electromyography and nerve conduction studies to assess the status of a peripheral nerve⁴⁸—provides objective data that can help diagnose a challenging presentation, rule out a competing diagnosis, or clarify an atypical clinical picture or vague subjective history. This type of testing is also used to localize the entrapment site, identify a patient with polyneuropathy or brachial plexopathy, and assess the severity of nerve injury or presence of a double crush syndrome.^49,50 Any patient with signs and symptoms of a compression neuropathy and supportive findings on physical exam should be referred for electrodiagnostic testing and/or to a surgeon specializing in treating these conditions.

CORRESPONDENCE
Kyle J. MacGillis, MD, University of Illinois at Chicago, Department of Orthopaedic Surgery, 835 South Wolcott Avenue, M/C 844, Chicago, IL 60612; [email protected].

Electronic cigarettes (e-cigarettes) have become increasingly popular over the last decade. Although they are perceived by many to be safer than traditional cigarettes, many of the devices still contain nicotine, and inhaling their vapors exposes users to toxic substances, including lead, cadmium, and nickel—heavy metals that are associated with significant health problems.¹ (For more on how e-cigarettes work, see “Cigarettes vs e-cigarettes: How does the experience (and cost) compare?”)

In addition, many people use e-cigarettes as a means to stop smoking, but few who do so achieve abstinence.^2,3 They frequently end up utilizing both, increasing their health risks by exposing themselves to the dangers of 2 products instead of one.¹

Further complicating the issue is that the manufacture and distribution of e-cigarettes has not been well regulated. Without regulation, there is no way to know with certainty how much nicotine the devices contain and what else is in them.

Things, however, are changing. The Food and Drug Administration (FDA) recently announced that e-cigarettes and other tobacco products like cigars and hookahs will now be regulated in the same way the government regulates tobacco cigarettes and smokeless tobacco.⁴ The rule will not take effect immediately because companies requested time to comply, but once it is enacted, packaging will be required to list what the products contain, among other changes.

Keeping up on the latest information on e-cigarettes is now—and will continue to be—important as family physicians are increasingly asked about them. What follows is a review of what we know about their potential risks.

© 2016 iStock

A nicotine system developed by a pharmacist

E-cigarettes, or electronic nicotine delivery systems, were patented in 2003 by a Chinese pharmacist.⁵ Since their introduction to North America and Europe in 2007, the devices have become known by over 400 different brand names.⁶ Consumption among adults doubled by 2012, and by 2014, about 4% of US adults used e-cigarettes every day or some days.⁷ Many of them are dual users of tobacco and electronic cigarettes. In fact, Jenkins and colleagues reports in this issue of JFP (see "E-cigarettes: Who's using them and why?") that over half of cigarette smokers (52%) in their study use e-cigarettes, usually to either lower their cigarette consumption or aid in smoking cessation. (Throughout this article, we will use “cigarettes” and “smoking” to refer to the use of traditional tobacco cigarettes.)

In addition to concern over an increase in use among the general population, there is significant concern about the increase in e-cigarette use among US middle and high school students.^1,8,9 In 2015, e-cigarettes were the most commonly used smoking product among middle and high school students, with 620,000 middle school students and nearly 2.4 million high school students using the battery-powered devices in the past 30 days.¹⁰

Many factors have contributed to the growing popularity of e-cigarettes.

• Perceived safety. With tobacco’s dangers so thoroughly documented, many advertising campaigns tout e-cigarettes as less dangerous than conventional cigarettes in terms of their ability to cause cardiac and lung diseases and low birth weights. This is largely because e-cigarettes do not produce the combustion products of tar, ash, or carbon monoxide. In addition, many consumers are mistakenly less fearful about the nicotine added to many e-cigarettes.
• Expectation that it helps smokers quit. Many smokers view e-cigarettes as an aid to smoking cessation.⁶ In fact, testimonials of efficacy in tobacco cessation abound in promotional materials and on the Web, and e-cigarettes are recommended by some physicians as a means to quit or lessen smoking of tobacco cigarettes.¹¹
• Wide availability and opportunities for use. The use of electronic nicotine delivery devices is sometimes permitted in places where smoking of conventional cigarettes is banned, although rules vary widely in different parts of the country. In addition, e-cigarettes are readily available for purchase on the Internet without age verification.
• Extensive advertising. There are increasing concerns that advertising campaigns unduly target adolescents, young adults, and women.^12-155 In addition to advertising, the media and social influences play significant roles in young people’s experimentation with “vaping,” the term for inhaling electronic cigarette aerosols.^14,15
• Regulation, legislation remain controversial. Currently, e-cigarettes are not required to be tested before marketing,¹⁶ but that may change with the FDA’s new regulations. The British National Public Health body, Public Health England, has documented public health benefits of e-cigarettes when used as a way to quit smoking, and provides evidence that the devices are less dangerous than traditional cigarettes.¹⁷ But this issue and public policy are the subject of ongoing debate. In 2015, the United Kingdom made it illegal to sell e-cigarettes or e-liquids to people younger than 18 years of age and urged child-proof packaging.

What’s “in” an e-cigarette—and are the ingredients toxic?

Because e-cigarettes are relatively new to the global marketplace, little research exists regarding the long-term effects and safety of their use, especially among habitual users.

Vapor/refills. E-liquids may contain a variety of substances because they have been largely unregulated, but they generally include some combination of nicotine, propylene glycol, glycerin, and flavorings. In fact, up to 7000 flavors are available,⁶ including such kid-friendly flavors as chocolate, cherry crush, and bubble gum.

Since many individuals continue to use traditional and electronic cigarettes, they end up in double jeopardy of toxicity through exposure to the dangers of both.

When the refills do contain nicotine, users generally derive less of the substance from the electronic devices than they do from a conventional cigarette. Researchers found that individual puffs from an e-cigarette contained 0 to 35 µg nicotine per puff.^1,18 Assuming an amount at the high end of the spectrum (30 µg nicotine), it would take about 30 puffs of an e-cigarette to derive the same amount of nicotine (1 mg) typically delivered by a conventional cigarette.

The chemical make-up of the vapor and the biologic effects on animal models have been investigated using 42 different liquid refills.^19,20 All contained potentially harmful compounds, but the levels were within exposure limits authorized by the FDA. These potentially dangerous chemicals include the known toxins formaldehyde, acrolein, and hydrocarbons.²⁰

An inflammatory response to the inhalation of the vapors was demonstrated in mouse lungs; exposure to e-cigarette aerosols reduced lung glutathione—an important enzyme in maintaining oxidation-reduction balance—to a degree similar to that of cigarette smoke exposure.²⁰ Less of the enzyme facilitates increased pulmonary inflammation.

In addition, human lung cells release pro-inflammatory cytokines when exposed to e-cigarette aerosols.²⁰ Other health risks include:

Harm to indoor air quality/secondhand exposure. Even though e-cigarettes do not emit smoke, bystanders are exposed to the aerosol or vapor exhaled by the user, and researchers have found varying levels of such substances as formaldehyde, acetaldehyde, isoprene, acetic acid, acetone, propanol, propylene glycol, and nicotine in the air. However, it is unclear at this time whether the ultra-fine particles in the e-cigarette vapor have health effects commensurate with the emissions of conventional cigarettes.^1,21,22

Cartridge refill ingestion by children. Accidental nicotine poisonings, particularly among children drawn to the colors, flavors, and scents of the e-liquids, have been problematic. In 2014, for example, over 3500 exposures occurred and more than half of those were in children younger than 6 years of age. (Exposure is defined as contact with the substance in some way including ingestion, inhalation, absorption by the skin/eyes, etc; not all exposures are poisonings or overdoses).²³ Although incidence has tapered off somewhat, the American Association of Poison Control Centers reports that there were 623 exposures across all age groups between January 1, 2016 and April 30, 2016.²³

Many people use e-cigarettes as a means to stop smoking, but few who do so achieve abstinence.

Environmental impact of discarded e-cigarettes. Discarded e-cigarettes filling our landfills is a new and emerging public health concern. Their batteries, as do all batteries, pollute the land and water and have the potential to leach lead into the environment.²⁴ Similarly, incompletely used liquid cartridges and refills may contain nicotine and heavy metals, which add to these risks.²⁴

Explosions. Fires and explosions have been documented with e-cigarette use, mostly due to malfunctioning lithium-ion batteries.²⁵ Thermal injuries to the face and hands can be significant.

Heavy metals. The presence of lead, cadmium, and nickel in inhaled e-cigarette vapor is another area of significant concern, particularly for younger people who might have long-term exposure.¹ All 3 heavy metals are known to be toxic to humans, and safe levels of inhalation have not been established.

Inhalation and/or ingestion of lead, in particular, can cause severe neurologic damage, especially to the developing brains of children.²⁶ Lead also results in hematologic dysfunction. Because of the risks associated with inhalation of this heavy metal, the substance was removed from gasoline years ago.

Inhaled cadmium induces kidney, liver, bone, and respiratory tract pathology²⁷ and can cause organ failure, hypertension, anemias, fractures, osteoporosis, and/or osteomalacia.²⁸ And inhaling nickel produces an inflammatory pulmonary reaction.²⁹

Pregnancy/lactation. Since no clear evidence exists on the safety of e-cigarette use during pregnancy, women should avoid exposure to these vapors during the entire perinatal period. Similarly, the effects of e-cigarettes on infants who are breastfeeding are not established. Pregnant and breastfeeding women should not replace cigarettes with e-cigarettes.^30,31 For pregnant women who smoke, the US Preventive Services Task Force (USPSTF) advises using only behavioral methods to stop cigarette use.³² And until more information becomes available, exposing infants and young children to e-cigarette vapor during breastfeeding is not recommended.

On the flip side, without tobacco, tar, ash, or carbon monoxide, e-cigarettes may have some advantages when compared with the use of traditional cigarettes, but that has not been substantiated.

Don’t substitute one form of nicotine for another

The presence of lead, cadmium, and nickel in inhaled e-cigarette vapor is an area of significant concern.

The USPSTF has not determined the benefit-to-harm ratio of using e-cigarettes as a smoking cessation aid, but recommends prescribing behavioral techniques and/or pharmacologic alternatives instead.³² Because the devices have been promoted as an aid to smoking cessation, intention to quit using tobacco products is a reason often stated for utilizing e-cigarettes.^2,33,34 Indeed, use of e-cigarettes is much more likely among those who already utilize tobacco products.^35-37

At least one study reports that e-cigarettes have efficacy similar to nicotine patches in achieving smoking abstinence among smokers who want to quit.³⁸ Former smokers who used e-cigarettes to quit smoking reported fewer withdrawal symptoms than those who used nicotine skin patches.³⁹ In addition, former smokers were more likely to endorse e-cigarettes than nicotine patches as a tobacco cigarette cessation aid. Significant reduction in tobacco smoke exposure has been demonstrated in dual users of tobacco and electronic cigarettes;^40,41 however, both of these nicotine delivery systems sustain nicotine addiction.

Despite many ongoing studies to determine if e-cigarettes are useful as a smoking cessation aid, the results vary widely and are inconclusive at this time.⁴²

E-cigarettes do not increase long-term tobacco abstinence

Contrary to popular belief, research shows that e-cigarette use among smokers is not associated with long-term tobacco abstinence.¹ E-cigarette users, however, may make more attempts to quit smoking compared with smokers not using them.⁴³ In addition, even though there is some evidence that e-cigarettes help smokers reduce the number of cigarettes smoked per day, simply reducing the daily number of cigarettes does not equate with safety.⁴⁴ Smoking just one to 4 cigarettes per day poses 3 times the risk of myocardial infarction and lung cancer compared with not smoking.⁴⁴ And since many individuals continue to use traditional and electronic cigarettes, they end up in double jeopardy of toxicity through exposure to the dangers of both.

A gateway to other substances of abuse?

Pregnant and breastfeeding women should not replace tobacco cigarettes with e-cigarettes.

There is also fear that nicotine exposure via e-cigarettes, especially in young people, serves as a “gateway” to tobacco consumption and other substance abuses, and increases the risk for nicotine addiction.³⁴ Such nicotine-induced effects are a result of changes in brain chemistry, and have been documented in humans and animals.³⁴

These concerns about negative health consequences, combined with the fact that e-cigarettes are undocumented as a smoking cessation aid, add urgency to the need for legislative and regulatory actions that hopefully can curb all nicotine exposures, particularly for our nation’s youth. In the meantime, it is important for physicians to advise patients—and the public—about the risks of e-cigarettes and the importance of quitting all forms of nicotine inhalation because nicotine—regardless of how it is delivered—is still an addictive drug.

CORRESPONDENCE
Steven Lippmann, MD, University of Louisville School of Medicine, 401 E. Chestnut Street, Suite 610, Louisville, KY 40202; [email protected].

Electronic cigarettes (e-cigarettes) have become increasingly popular over the last decade. Although they are perceived by many to be safer than traditional cigarettes, many of the devices still contain nicotine, and inhaling their vapors exposes users to toxic substances, including lead, cadmium, and nickel—heavy metals that are associated with significant health problems.¹ (For more on how e-cigarettes work, see “Cigarettes vs e-cigarettes: How does the experience (and cost) compare?”)

In addition, many people use e-cigarettes as a means to stop smoking, but few who do so achieve abstinence.^2,3 They frequently end up utilizing both, increasing their health risks by exposing themselves to the dangers of 2 products instead of one.¹

Further complicating the issue is that the manufacture and distribution of e-cigarettes has not been well regulated. Without regulation, there is no way to know with certainty how much nicotine the devices contain and what else is in them.

Things, however, are changing. The Food and Drug Administration (FDA) recently announced that e-cigarettes and other tobacco products like cigars and hookahs will now be regulated in the same way the government regulates tobacco cigarettes and smokeless tobacco.⁴ The rule will not take effect immediately because companies requested time to comply, but once it is enacted, packaging will be required to list what the products contain, among other changes.

Keeping up on the latest information on e-cigarettes is now—and will continue to be—important as family physicians are increasingly asked about them. What follows is a review of what we know about their potential risks.

© 2016 iStock

A nicotine system developed by a pharmacist

E-cigarettes, or electronic nicotine delivery systems, were patented in 2003 by a Chinese pharmacist.⁵ Since their introduction to North America and Europe in 2007, the devices have become known by over 400 different brand names.⁶ Consumption among adults doubled by 2012, and by 2014, about 4% of US adults used e-cigarettes every day or some days.⁷ Many of them are dual users of tobacco and electronic cigarettes. In fact, Jenkins and colleagues reports in this issue of JFP (see "E-cigarettes: Who's using them and why?") that over half of cigarette smokers (52%) in their study use e-cigarettes, usually to either lower their cigarette consumption or aid in smoking cessation. (Throughout this article, we will use “cigarettes” and “smoking” to refer to the use of traditional tobacco cigarettes.)

In addition to concern over an increase in use among the general population, there is significant concern about the increase in e-cigarette use among US middle and high school students.^1,8,9 In 2015, e-cigarettes were the most commonly used smoking product among middle and high school students, with 620,000 middle school students and nearly 2.4 million high school students using the battery-powered devices in the past 30 days.¹⁰

Many factors have contributed to the growing popularity of e-cigarettes.

• Perceived safety. With tobacco’s dangers so thoroughly documented, many advertising campaigns tout e-cigarettes as less dangerous than conventional cigarettes in terms of their ability to cause cardiac and lung diseases and low birth weights. This is largely because e-cigarettes do not produce the combustion products of tar, ash, or carbon monoxide. In addition, many consumers are mistakenly less fearful about the nicotine added to many e-cigarettes.
• Expectation that it helps smokers quit. Many smokers view e-cigarettes as an aid to smoking cessation.⁶ In fact, testimonials of efficacy in tobacco cessation abound in promotional materials and on the Web, and e-cigarettes are recommended by some physicians as a means to quit or lessen smoking of tobacco cigarettes.¹¹
• Wide availability and opportunities for use. The use of electronic nicotine delivery devices is sometimes permitted in places where smoking of conventional cigarettes is banned, although rules vary widely in different parts of the country. In addition, e-cigarettes are readily available for purchase on the Internet without age verification.
• Extensive advertising. There are increasing concerns that advertising campaigns unduly target adolescents, young adults, and women.^12-155 In addition to advertising, the media and social influences play significant roles in young people’s experimentation with “vaping,” the term for inhaling electronic cigarette aerosols.^14,15
• Regulation, legislation remain controversial. Currently, e-cigarettes are not required to be tested before marketing,¹⁶ but that may change with the FDA’s new regulations. The British National Public Health body, Public Health England, has documented public health benefits of e-cigarettes when used as a way to quit smoking, and provides evidence that the devices are less dangerous than traditional cigarettes.¹⁷ But this issue and public policy are the subject of ongoing debate. In 2015, the United Kingdom made it illegal to sell e-cigarettes or e-liquids to people younger than 18 years of age and urged child-proof packaging.

What’s “in” an e-cigarette—and are the ingredients toxic?

Because e-cigarettes are relatively new to the global marketplace, little research exists regarding the long-term effects and safety of their use, especially among habitual users.

Vapor/refills. E-liquids may contain a variety of substances because they have been largely unregulated, but they generally include some combination of nicotine, propylene glycol, glycerin, and flavorings. In fact, up to 7000 flavors are available,⁶ including such kid-friendly flavors as chocolate, cherry crush, and bubble gum.

Since many individuals continue to use traditional and electronic cigarettes, they end up in double jeopardy of toxicity through exposure to the dangers of both.

When the refills do contain nicotine, users generally derive less of the substance from the electronic devices than they do from a conventional cigarette. Researchers found that individual puffs from an e-cigarette contained 0 to 35 µg nicotine per puff.^1,18 Assuming an amount at the high end of the spectrum (30 µg nicotine), it would take about 30 puffs of an e-cigarette to derive the same amount of nicotine (1 mg) typically delivered by a conventional cigarette.

The chemical make-up of the vapor and the biologic effects on animal models have been investigated using 42 different liquid refills.^19,20 All contained potentially harmful compounds, but the levels were within exposure limits authorized by the FDA. These potentially dangerous chemicals include the known toxins formaldehyde, acrolein, and hydrocarbons.²⁰

An inflammatory response to the inhalation of the vapors was demonstrated in mouse lungs; exposure to e-cigarette aerosols reduced lung glutathione—an important enzyme in maintaining oxidation-reduction balance—to a degree similar to that of cigarette smoke exposure.²⁰ Less of the enzyme facilitates increased pulmonary inflammation.

In addition, human lung cells release pro-inflammatory cytokines when exposed to e-cigarette aerosols.²⁰ Other health risks include:

Harm to indoor air quality/secondhand exposure. Even though e-cigarettes do not emit smoke, bystanders are exposed to the aerosol or vapor exhaled by the user, and researchers have found varying levels of such substances as formaldehyde, acetaldehyde, isoprene, acetic acid, acetone, propanol, propylene glycol, and nicotine in the air. However, it is unclear at this time whether the ultra-fine particles in the e-cigarette vapor have health effects commensurate with the emissions of conventional cigarettes.^1,21,22

Cartridge refill ingestion by children. Accidental nicotine poisonings, particularly among children drawn to the colors, flavors, and scents of the e-liquids, have been problematic. In 2014, for example, over 3500 exposures occurred and more than half of those were in children younger than 6 years of age. (Exposure is defined as contact with the substance in some way including ingestion, inhalation, absorption by the skin/eyes, etc; not all exposures are poisonings or overdoses).²³ Although incidence has tapered off somewhat, the American Association of Poison Control Centers reports that there were 623 exposures across all age groups between January 1, 2016 and April 30, 2016.²³

Many people use e-cigarettes as a means to stop smoking, but few who do so achieve abstinence.

Environmental impact of discarded e-cigarettes. Discarded e-cigarettes filling our landfills is a new and emerging public health concern. Their batteries, as do all batteries, pollute the land and water and have the potential to leach lead into the environment.²⁴ Similarly, incompletely used liquid cartridges and refills may contain nicotine and heavy metals, which add to these risks.²⁴

Explosions. Fires and explosions have been documented with e-cigarette use, mostly due to malfunctioning lithium-ion batteries.²⁵ Thermal injuries to the face and hands can be significant.

Heavy metals. The presence of lead, cadmium, and nickel in inhaled e-cigarette vapor is another area of significant concern, particularly for younger people who might have long-term exposure.¹ All 3 heavy metals are known to be toxic to humans, and safe levels of inhalation have not been established.

Inhalation and/or ingestion of lead, in particular, can cause severe neurologic damage, especially to the developing brains of children.²⁶ Lead also results in hematologic dysfunction. Because of the risks associated with inhalation of this heavy metal, the substance was removed from gasoline years ago.

Inhaled cadmium induces kidney, liver, bone, and respiratory tract pathology²⁷ and can cause organ failure, hypertension, anemias, fractures, osteoporosis, and/or osteomalacia.²⁸ And inhaling nickel produces an inflammatory pulmonary reaction.²⁹

Pregnancy/lactation. Since no clear evidence exists on the safety of e-cigarette use during pregnancy, women should avoid exposure to these vapors during the entire perinatal period. Similarly, the effects of e-cigarettes on infants who are breastfeeding are not established. Pregnant and breastfeeding women should not replace cigarettes with e-cigarettes.^30,31 For pregnant women who smoke, the US Preventive Services Task Force (USPSTF) advises using only behavioral methods to stop cigarette use.³² And until more information becomes available, exposing infants and young children to e-cigarette vapor during breastfeeding is not recommended.

On the flip side, without tobacco, tar, ash, or carbon monoxide, e-cigarettes may have some advantages when compared with the use of traditional cigarettes, but that has not been substantiated.

Don’t substitute one form of nicotine for another

The presence of lead, cadmium, and nickel in inhaled e-cigarette vapor is an area of significant concern.

The USPSTF has not determined the benefit-to-harm ratio of using e-cigarettes as a smoking cessation aid, but recommends prescribing behavioral techniques and/or pharmacologic alternatives instead.³² Because the devices have been promoted as an aid to smoking cessation, intention to quit using tobacco products is a reason often stated for utilizing e-cigarettes.^2,33,34 Indeed, use of e-cigarettes is much more likely among those who already utilize tobacco products.^35-37

At least one study reports that e-cigarettes have efficacy similar to nicotine patches in achieving smoking abstinence among smokers who want to quit.³⁸ Former smokers who used e-cigarettes to quit smoking reported fewer withdrawal symptoms than those who used nicotine skin patches.³⁹ In addition, former smokers were more likely to endorse e-cigarettes than nicotine patches as a tobacco cigarette cessation aid. Significant reduction in tobacco smoke exposure has been demonstrated in dual users of tobacco and electronic cigarettes;^40,41 however, both of these nicotine delivery systems sustain nicotine addiction.

Despite many ongoing studies to determine if e-cigarettes are useful as a smoking cessation aid, the results vary widely and are inconclusive at this time.⁴²

E-cigarettes do not increase long-term tobacco abstinence

Contrary to popular belief, research shows that e-cigarette use among smokers is not associated with long-term tobacco abstinence.¹ E-cigarette users, however, may make more attempts to quit smoking compared with smokers not using them.⁴³ In addition, even though there is some evidence that e-cigarettes help smokers reduce the number of cigarettes smoked per day, simply reducing the daily number of cigarettes does not equate with safety.⁴⁴ Smoking just one to 4 cigarettes per day poses 3 times the risk of myocardial infarction and lung cancer compared with not smoking.⁴⁴ And since many individuals continue to use traditional and electronic cigarettes, they end up in double jeopardy of toxicity through exposure to the dangers of both.

A gateway to other substances of abuse?

Pregnant and breastfeeding women should not replace tobacco cigarettes with e-cigarettes.

There is also fear that nicotine exposure via e-cigarettes, especially in young people, serves as a “gateway” to tobacco consumption and other substance abuses, and increases the risk for nicotine addiction.³⁴ Such nicotine-induced effects are a result of changes in brain chemistry, and have been documented in humans and animals.³⁴

These concerns about negative health consequences, combined with the fact that e-cigarettes are undocumented as a smoking cessation aid, add urgency to the need for legislative and regulatory actions that hopefully can curb all nicotine exposures, particularly for our nation’s youth. In the meantime, it is important for physicians to advise patients—and the public—about the risks of e-cigarettes and the importance of quitting all forms of nicotine inhalation because nicotine—regardless of how it is delivered—is still an addictive drug.

CORRESPONDENCE
Steven Lippmann, MD, University of Louisville School of Medicine, 401 E. Chestnut Street, Suite 610, Louisville, KY 40202; [email protected].

Electronic cigarettes (e-cigarettes) have become increasingly popular over the last decade. Although they are perceived by many to be safer than traditional cigarettes, many of the devices still contain nicotine, and inhaling their vapors exposes users to toxic substances, including lead, cadmium, and nickel—heavy metals that are associated with significant health problems.¹ (For more on how e-cigarettes work, see “Cigarettes vs e-cigarettes: How does the experience (and cost) compare?”)

In addition, many people use e-cigarettes as a means to stop smoking, but few who do so achieve abstinence.^2,3 They frequently end up utilizing both, increasing their health risks by exposing themselves to the dangers of 2 products instead of one.¹

Further complicating the issue is that the manufacture and distribution of e-cigarettes has not been well regulated. Without regulation, there is no way to know with certainty how much nicotine the devices contain and what else is in them.

Things, however, are changing. The Food and Drug Administration (FDA) recently announced that e-cigarettes and other tobacco products like cigars and hookahs will now be regulated in the same way the government regulates tobacco cigarettes and smokeless tobacco.⁴ The rule will not take effect immediately because companies requested time to comply, but once it is enacted, packaging will be required to list what the products contain, among other changes.

Keeping up on the latest information on e-cigarettes is now—and will continue to be—important as family physicians are increasingly asked about them. What follows is a review of what we know about their potential risks.

© 2016 iStock

A nicotine system developed by a pharmacist

E-cigarettes, or electronic nicotine delivery systems, were patented in 2003 by a Chinese pharmacist.⁵ Since their introduction to North America and Europe in 2007, the devices have become known by over 400 different brand names.⁶ Consumption among adults doubled by 2012, and by 2014, about 4% of US adults used e-cigarettes every day or some days.⁷ Many of them are dual users of tobacco and electronic cigarettes. In fact, Jenkins and colleagues reports in this issue of JFP (see "E-cigarettes: Who's using them and why?") that over half of cigarette smokers (52%) in their study use e-cigarettes, usually to either lower their cigarette consumption or aid in smoking cessation. (Throughout this article, we will use “cigarettes” and “smoking” to refer to the use of traditional tobacco cigarettes.)

In addition to concern over an increase in use among the general population, there is significant concern about the increase in e-cigarette use among US middle and high school students.^1,8,9 In 2015, e-cigarettes were the most commonly used smoking product among middle and high school students, with 620,000 middle school students and nearly 2.4 million high school students using the battery-powered devices in the past 30 days.¹⁰

Many factors have contributed to the growing popularity of e-cigarettes.

• Perceived safety. With tobacco’s dangers so thoroughly documented, many advertising campaigns tout e-cigarettes as less dangerous than conventional cigarettes in terms of their ability to cause cardiac and lung diseases and low birth weights. This is largely because e-cigarettes do not produce the combustion products of tar, ash, or carbon monoxide. In addition, many consumers are mistakenly less fearful about the nicotine added to many e-cigarettes.
• Expectation that it helps smokers quit. Many smokers view e-cigarettes as an aid to smoking cessation.⁶ In fact, testimonials of efficacy in tobacco cessation abound in promotional materials and on the Web, and e-cigarettes are recommended by some physicians as a means to quit or lessen smoking of tobacco cigarettes.¹¹
• Wide availability and opportunities for use. The use of electronic nicotine delivery devices is sometimes permitted in places where smoking of conventional cigarettes is banned, although rules vary widely in different parts of the country. In addition, e-cigarettes are readily available for purchase on the Internet without age verification.
• Extensive advertising. There are increasing concerns that advertising campaigns unduly target adolescents, young adults, and women.^12-155 In addition to advertising, the media and social influences play significant roles in young people’s experimentation with “vaping,” the term for inhaling electronic cigarette aerosols.^14,15
• Regulation, legislation remain controversial. Currently, e-cigarettes are not required to be tested before marketing,¹⁶ but that may change with the FDA’s new regulations. The British National Public Health body, Public Health England, has documented public health benefits of e-cigarettes when used as a way to quit smoking, and provides evidence that the devices are less dangerous than traditional cigarettes.¹⁷ But this issue and public policy are the subject of ongoing debate. In 2015, the United Kingdom made it illegal to sell e-cigarettes or e-liquids to people younger than 18 years of age and urged child-proof packaging.

What’s “in” an e-cigarette—and are the ingredients toxic?

Because e-cigarettes are relatively new to the global marketplace, little research exists regarding the long-term effects and safety of their use, especially among habitual users.

Vapor/refills. E-liquids may contain a variety of substances because they have been largely unregulated, but they generally include some combination of nicotine, propylene glycol, glycerin, and flavorings. In fact, up to 7000 flavors are available,⁶ including such kid-friendly flavors as chocolate, cherry crush, and bubble gum.

Since many individuals continue to use traditional and electronic cigarettes, they end up in double jeopardy of toxicity through exposure to the dangers of both.

When the refills do contain nicotine, users generally derive less of the substance from the electronic devices than they do from a conventional cigarette. Researchers found that individual puffs from an e-cigarette contained 0 to 35 µg nicotine per puff.^1,18 Assuming an amount at the high end of the spectrum (30 µg nicotine), it would take about 30 puffs of an e-cigarette to derive the same amount of nicotine (1 mg) typically delivered by a conventional cigarette.

The chemical make-up of the vapor and the biologic effects on animal models have been investigated using 42 different liquid refills.^19,20 All contained potentially harmful compounds, but the levels were within exposure limits authorized by the FDA. These potentially dangerous chemicals include the known toxins formaldehyde, acrolein, and hydrocarbons.²⁰

An inflammatory response to the inhalation of the vapors was demonstrated in mouse lungs; exposure to e-cigarette aerosols reduced lung glutathione—an important enzyme in maintaining oxidation-reduction balance—to a degree similar to that of cigarette smoke exposure.²⁰ Less of the enzyme facilitates increased pulmonary inflammation.

In addition, human lung cells release pro-inflammatory cytokines when exposed to e-cigarette aerosols.²⁰ Other health risks include:

Harm to indoor air quality/secondhand exposure. Even though e-cigarettes do not emit smoke, bystanders are exposed to the aerosol or vapor exhaled by the user, and researchers have found varying levels of such substances as formaldehyde, acetaldehyde, isoprene, acetic acid, acetone, propanol, propylene glycol, and nicotine in the air. However, it is unclear at this time whether the ultra-fine particles in the e-cigarette vapor have health effects commensurate with the emissions of conventional cigarettes.^1,21,22

Cartridge refill ingestion by children. Accidental nicotine poisonings, particularly among children drawn to the colors, flavors, and scents of the e-liquids, have been problematic. In 2014, for example, over 3500 exposures occurred and more than half of those were in children younger than 6 years of age. (Exposure is defined as contact with the substance in some way including ingestion, inhalation, absorption by the skin/eyes, etc; not all exposures are poisonings or overdoses).²³ Although incidence has tapered off somewhat, the American Association of Poison Control Centers reports that there were 623 exposures across all age groups between January 1, 2016 and April 30, 2016.²³

Many people use e-cigarettes as a means to stop smoking, but few who do so achieve abstinence.

Environmental impact of discarded e-cigarettes. Discarded e-cigarettes filling our landfills is a new and emerging public health concern. Their batteries, as do all batteries, pollute the land and water and have the potential to leach lead into the environment.²⁴ Similarly, incompletely used liquid cartridges and refills may contain nicotine and heavy metals, which add to these risks.²⁴

Explosions. Fires and explosions have been documented with e-cigarette use, mostly due to malfunctioning lithium-ion batteries.²⁵ Thermal injuries to the face and hands can be significant.

Heavy metals. The presence of lead, cadmium, and nickel in inhaled e-cigarette vapor is another area of significant concern, particularly for younger people who might have long-term exposure.¹ All 3 heavy metals are known to be toxic to humans, and safe levels of inhalation have not been established.

Inhalation and/or ingestion of lead, in particular, can cause severe neurologic damage, especially to the developing brains of children.²⁶ Lead also results in hematologic dysfunction. Because of the risks associated with inhalation of this heavy metal, the substance was removed from gasoline years ago.

Inhaled cadmium induces kidney, liver, bone, and respiratory tract pathology²⁷ and can cause organ failure, hypertension, anemias, fractures, osteoporosis, and/or osteomalacia.²⁸ And inhaling nickel produces an inflammatory pulmonary reaction.²⁹

Pregnancy/lactation. Since no clear evidence exists on the safety of e-cigarette use during pregnancy, women should avoid exposure to these vapors during the entire perinatal period. Similarly, the effects of e-cigarettes on infants who are breastfeeding are not established. Pregnant and breastfeeding women should not replace cigarettes with e-cigarettes.^30,31 For pregnant women who smoke, the US Preventive Services Task Force (USPSTF) advises using only behavioral methods to stop cigarette use.³² And until more information becomes available, exposing infants and young children to e-cigarette vapor during breastfeeding is not recommended.

On the flip side, without tobacco, tar, ash, or carbon monoxide, e-cigarettes may have some advantages when compared with the use of traditional cigarettes, but that has not been substantiated.

Don’t substitute one form of nicotine for another

The presence of lead, cadmium, and nickel in inhaled e-cigarette vapor is an area of significant concern.

The USPSTF has not determined the benefit-to-harm ratio of using e-cigarettes as a smoking cessation aid, but recommends prescribing behavioral techniques and/or pharmacologic alternatives instead.³² Because the devices have been promoted as an aid to smoking cessation, intention to quit using tobacco products is a reason often stated for utilizing e-cigarettes.^2,33,34 Indeed, use of e-cigarettes is much more likely among those who already utilize tobacco products.^35-37

At least one study reports that e-cigarettes have efficacy similar to nicotine patches in achieving smoking abstinence among smokers who want to quit.³⁸ Former smokers who used e-cigarettes to quit smoking reported fewer withdrawal symptoms than those who used nicotine skin patches.³⁹ In addition, former smokers were more likely to endorse e-cigarettes than nicotine patches as a tobacco cigarette cessation aid. Significant reduction in tobacco smoke exposure has been demonstrated in dual users of tobacco and electronic cigarettes;^40,41 however, both of these nicotine delivery systems sustain nicotine addiction.

Despite many ongoing studies to determine if e-cigarettes are useful as a smoking cessation aid, the results vary widely and are inconclusive at this time.⁴²

E-cigarettes do not increase long-term tobacco abstinence

Contrary to popular belief, research shows that e-cigarette use among smokers is not associated with long-term tobacco abstinence.¹ E-cigarette users, however, may make more attempts to quit smoking compared with smokers not using them.⁴³ In addition, even though there is some evidence that e-cigarettes help smokers reduce the number of cigarettes smoked per day, simply reducing the daily number of cigarettes does not equate with safety.⁴⁴ Smoking just one to 4 cigarettes per day poses 3 times the risk of myocardial infarction and lung cancer compared with not smoking.⁴⁴ And since many individuals continue to use traditional and electronic cigarettes, they end up in double jeopardy of toxicity through exposure to the dangers of both.

A gateway to other substances of abuse?

Pregnant and breastfeeding women should not replace tobacco cigarettes with e-cigarettes.

There is also fear that nicotine exposure via e-cigarettes, especially in young people, serves as a “gateway” to tobacco consumption and other substance abuses, and increases the risk for nicotine addiction.³⁴ Such nicotine-induced effects are a result of changes in brain chemistry, and have been documented in humans and animals.³⁴

These concerns about negative health consequences, combined with the fact that e-cigarettes are undocumented as a smoking cessation aid, add urgency to the need for legislative and regulatory actions that hopefully can curb all nicotine exposures, particularly for our nation’s youth. In the meantime, it is important for physicians to advise patients—and the public—about the risks of e-cigarettes and the importance of quitting all forms of nicotine inhalation because nicotine—regardless of how it is delivered—is still an addictive drug.

CORRESPONDENCE
Steven Lippmann, MD, University of Louisville School of Medicine, 401 E. Chestnut Street, Suite 610, Louisville, KY 40202; [email protected].

CASE › Alice L, a 39-year-old woman with an unremarkable medical history asks to see her primary care provider right away, concerned she might have contracted Lyme disease. She had been hiking the overgrown trails on her family-owned ranch in Florida, and the next day she noticed a black tick stuck to her forearm. Using tweezers, she pulled the whole tick off intact, put it in a plastic cup, and immediately sought medical attention. How should her family physician (FP) advise her?

Lyme disease is the most common tick-borne illness in the United States, with more than 25,000 cases confirmed in this country in 2014.¹ It is concentrated mostly in the northeast and upper Midwest, and less frequently occurs in the Pacific coastal regions of Oregon and northern California. Cases have also increasingly been reported in the southwest region of the Appalachian Mountains and the mountainous regions of southern Virginia.²

In 2014, the only states reporting no incidence of Lyme disease were Colorado, Hawaii, Louisiana, New Mexico, and Oklahoma.¹ Lyme disease is also endemic in several regions in Northern Europe, Eastern Asia, and Northern Africa.^1,3-7 According to the Centers for Disease Control and Prevention (CDC), boys ages 5 to 9 years are most affected.¹

Disease transmission: Duration of tick attachment is important

The spirochete that causes Lyme disease, Borrelia burgdorferi, is transmitted to humans by the Ixodes tick. The Ixodes scapularis (deer tick) is common in the eastern and northern midwestern states and I pacificus is common in the western United States.

The life cycle. These small, dark-colored ticks have a 2-year life cycle that is comprised of 4 developmental stages: egg, larva, nymph, and adult. Eggs are laid in spring and hatch into larvae during late summer. The larvae feed on small animals (eg, mice, chipmunks, birds) and can acquire B burgdorferi infection at this stage. The larvae then molt into nymphs (<2 mm, and difficult to see), which feed again the following spring to early summer and may transmit the infection to a new host. Nymphs become adult ticks in mid-October to early-November, when the females feed again, mainly on large animals.

Humans usually become infected from May through August, when both they and the nymph ticks are most active outdoors. The ticks are able to attach themselves to their host without being noticed because they secrete small amounts of saliva with anesthetic properties while feeding. Many ticks also secrete a cement-like substance that keeps them firmly attached.

Adult ticks can also transmit the disease and are larger and more easily recognized. Transmission of the spirochete requires that the tick be attached to the new host for 36 to 48 hours,¹ allowing the spirochete to travel from the mid-gut of the tick to the salivary glands and into the host.

Two of the most important factors to consider when assessing the risk of transmission is how long the tick was attached and whether it was engorged. Only about a quarter of individuals with Lyme disease recall having had a tick bite.^1,3-6,8

Clinical presentation: Early and late findings

Symptoms of early Lyme disease usually start one to 2 weeks after a tick bite, but may start up to 30 days later. The most common presentation is a painless skin rash—erythema migrans (EM). It starts as a single red papule at the site of the bite (multiple lesions appear in 10% to 20% of cases⁹) and may progress to a painless erythematous lesion with red borders and a partial central clearing—the classic EM rash (FIGURE). Less commonly, the center of the lesion can appear vesicular or necrotic.

Although a rash occurs in 80% of Lyme disease cases, only 20% to 35% of the rashes develop into a classic bull's-eye lesion.³ Tick bites—and thus rashes—typically occur near or at the axilla, inguinal region, popliteal fossa, or at the belt line.

Individuals who don’t exhibit a rash may be asymptomatic or have nonspecific symptoms or flu-like symptoms of fatigue, fever, chills, myalgia, and headache.⁴ If Lyme disease continues untreated, the patient may experience extra-cutaneous complications, most often involving the joints and the nervous and cardiovascular systems.^3-7

Ixodes ticks are also vectors for human granulocytic anaplasmosis (HGA) and babesiosis, which can cause a variety of symptoms. Keep these diseases in mind when a patient presents with severe or atypical features of Lyme disease.⁵ The benefit of antibiotics after a tick bite to reduce the incidence of HGA or babesiosis is unclear.¹⁰

Late manifestations of Lyme disease can occur within one to 2 months of infection or even months to years after tick exposure, often resulting in substantial morbidity.^3-7,11 Musculoskeletal symptoms are the most common manifestations of late, disseminated disease, usually presenting as transient asymmetrical oligoarticular arthralgias or myalgia. Arthritis also occurs in 60% of untreated patients with late disease.^4,5 Large joint effusions are typical, with synovial fluid studies showing high quantities of polymorphonuclear leukocytes (25,000/mm³).⁵ Joint symptoms that persist after antibiotic treatment are called antibiotic-refractory Lyme arthritis.^4-7

Neurologic involvement affects 10% to 15% of untreated patients.^3,4 It can present as lymphocytic meningitis (most common), cranial neuropathies, motor or sensory radiculoneuropathy, mononeuritis multiplex, cerebellar ataxia, or myelitis. Late neurologic Lyme disease may also present as a subacute mild encephalopathy affecting memory and concentration. When cranial neuropathies are involved, it is usually as unilateral facial nerve palsy (but may be bilateral). Always consider Lyme disease in endemic areas when patients have severe Bell's palsy.

Patients may present with altered mental status, neck stiffness, pain, and headaches.^4-7 The classic triad (known as Bannwarth syndrome) consists of lymphocytic meningitis, cranial neuritis, and radiculoneuritis. However, these conditions do not always occur together.^3,4

Cardiovascular complications occur in 4% to 8% of untreated patients,^4,5 usually one to 2 months following infection. Varying degrees of atrioventricular (AV) block can be seen, but third-degree block is most common. A less frequent complication is Lyme carditis, seen in 4% to 10% of patients.¹² The pathophysiology of Lyme carditis is not well understood.¹¹ It may present as chest pain, dyspnea on exertion, fatigue, palpitations, or syncope, often involving an AV block. Less frequent complications include myopericarditis, bundle branch block, and heart failure.

Post-treatment Lyme disease syndrome refers to the nonspecific symptoms of fatigue, sleep disorders, headaches, memory and concentration difficulties, myalgia, and arthralgias that may persist after successful antibiotic treatment. (We’ll discuss the specifics of treatment in a bit.) Post-treatment Lyme disease syndrome occurs in about 5% of patients properly treated for Lyme disease.¹³ The pathogenesis remains unknown, but some experts believe that lingering symptoms result from residual damage to tissues and the immune system. Education, rehabilitation, anti-inflammatory agents, antidepressants, a healthy diet, and plenty of rest have been recommended as treatment modalities.^1,13

Chronic Lyme disease is also important to keep in mind. Although there is no standard definition for it, chronic Lyme disease refers broadly to chronic symptoms in patients who may or may not have Lyme disease—eg, an individual who may have been treated for presumed B burgdorferi infection without solid clinical or serologic confirmation.^3-5 Chronic Lyme disease can often share somatic symptoms with other conditions such as fibromyalgia, chronic fatigue syndrome, and irritable bowel syndrome. Treatment often relies on a solid, trusting patient-doctor relationship, cognitive behavioral therapy, and regular counseling. Antibiotics are usually not necessary.

Dx: Serologic testing is preferred if clinical findings are insufficient

Erythema migrans and a history of tick exposure are sufficient to diagnose Lyme disease, without serologic confirmation.

Lyme disease can be diagnosed clinically in patients who have an EM rash and a history of tick exposure. This is the only clinical presentation sufficient to make the diagnosis of Lyme disease without the need of confirmatory serologic testing.^3,6 In the case of a tick bite but no rash, defer serologic testing unless associated symptoms arise (described earlier), at which time the accuracy of test results would be more trustworthy.¹⁰ Testing of ticks for infection with B burgdorferi is not recommended due to a lack of laboratory standardization.¹⁰

Two methods of laboratory testing are available to diagnose Lyme disease: direct, using cultures to detect B burgdorferi-specific proteins; and indirect, involving assays for antibodies.

Serologic testing. The CDC and Infectious Diseases Society of America recommend serology as the preferred initial diagnostic test. Tests for antibodies have good sensitivity and specificity in patients who have had untreated infection for a month or longer. However, these tests should not be used to screen individuals who have a low probability of infection, due to the tests’ poor positive predictive value.

The serologic tests used are the enzyme-linked immunosorbent assay (ELISA) and indirect fluorescent-antibody (IFA) assay. These assays use a whole-cell sonicate of B burgdorferi and yield a significant number of false-positive results due to cross-reactive antigens such as flagellar and heat-shock proteins if other spirochetal infections are present. To increase testing specificity, both the CDC and European guidelines strongly recommend a 2-tier approach using an ELISA or IFA assay initially, followed by the more specific Western blot to confirm the diagnosis when the assay samples are positive or equivocal.¹

The Western blot is interpreted using standardized criteria requiring at least 2 of 3 bands for a positive IgM diagnosis and 5 of 10 bands for a positive IgG diagnosis. Antibodies against Borrelia species are slow to develop. IgM generally is undetectable for the first one to 2 weeks after infection, and IgG often does not emerge for 4 to 6 weeks.

With patients who are seronegative at presentation, but for whom there is strong suspicion of Borrelia infection, it is advisable to obtain evidence of seroconversion, preferably within 8 to 14 days after presentation. Early antibiotic treatment may prevent the development of seropositivity.^1,3-7,14

Past or newly acquired infection? IgM and IgG produced in response to B burgdorferi may persist for years following antimicrobial therapy, which makes it impossible to distinguish between past and newly acquired infections based on seropositivity alone. These persistently elevated levels are not an indication of ineffective treatment or chronic infection. Therefore, it is not recommended to repeat serologic testing for documentation of treatment effectiveness or cure.

Since no serologic test has sufficient specificity to be used alone, efforts are being made to develop testing that detects antibodies against the 26-mer peptide from the sixth invariant region (C6) of the VlsE lipoprotein (C6VlsE). In 2007, the US Food and Drug Administration (FDA) approved a C6 ELISA for first-tier testing; unfortunately, it still has the problem of cross-reactivity with other spirochetal and viral pathogens. The C6 ELISA may one day be approved as a single-tier test.^4-7,14

Culture. The isolation of Borrelia species by culture is not routinely performed because it is expensive and requires special media and laboratory expertise, as well as a prolonged period of observation (6 to 12 weeks). Furthermore, this technique lacks sensitivity with samples taken from anywhere other than the rash site of patients with EM, in whom there is little need for laboratory diagnosis. Culture of cerebrospinal fluid has a positive yield of less than 10%,⁵ and it is extremely rare to isolate the spirochete from joint fluid. Therefore, negative results do not exclude a diagnosis of disease.^4,5,14

The CDC recommends against cultures, immunofluorescence staining, and cell sorting of cell wall-deficient or cystic forms of B burgdorferi.¹

Polymerase-chain reaction (PCR). This test is used to amplify genomic DNA of B burgdorferi and is most useful in patients with Lyme arthritis because of a high rate of DNA detection in synovial fluid samples (60% to 85%).⁵ In skin biopsies from EM lesions, PCR sensitivity can range from 25% to 90%.⁵ The PCR test is also used in cases of diagnostic uncertainty, but is generally performed only for research purposes. Negative findings do not exclude diagnosis of the disease.^5,6,14

Urine antigen test. This test has a high false-positive rate and is generally not recommended.^1,5

Treatment: Begin antibiotics ASAP

Treat Lyme disease with antibiotics as soon as the diagnosis is made. Early treatment hastens relief from symptoms and halts progression of later stages of the disease. The preferred antibiotics for early localized disease are doxycycline 100 mg orally twice daily; amoxicillin 500 mg orally 3 times a day; or cefuroxime axetil 500 mg orally twice a day (TABLE 1).¹⁰ Cefuroxime axetil is also appropriate if EM can’t be clearly distinguished from bacterial cellulitis. Reserve intravenous (IV) regimens for patients with more serious presentations (eg, neurologic symptoms and symptomatic cardiac disease) and for those with refractory Lyme arthritis (TABLE 2).¹⁰

Macrolides are not recommended as first-line therapy for early Lyme disease because they are less effective.¹⁰ However, macrolides may be used with patients unable to take the preferred antibiotics. Because there have been intermittent shortages of doxycycline, minocycline—another second-generation tetracycline with a similar chemical structure and antibacterial action—has been proposed as an alternative treatment.¹⁵

Ceftriaxone IV is preferred especially for patients presenting with an AV block or myopericarditis associated with early Lyme disease. The recommended course of treatment is usually 14 days. A temporary pacemaker may be required for patients with advanced blocks. Oral antibiotics may be started as soon as the AV block is resolved, or for outpatient therapy.

For adults who have early Lyme disease with acute neurologic manifestations such as meningitis or radiculopathy, IV antibiotics for 14 days are recommended. Cefotaxime has efficacy similar to ceftriaxone but requires multiple doses a day, making the latter the preferred treatment. Penicillin G 18 to 24 million units per day, divided into doses given every 4 hours, is also a satisfactory alternative.^10,16 The American Academy of Neurology states that no definitive data exist to establish superiority, or lack thereof, of either oral or parenteral treatment.¹⁷

Lyme arthritis can be treated with oral doxycycline, amoxicillin, or cefuroxime axetil for 28 days. For patients with persistent or recurrent joint swelling who have been treated with a course of oral antibiotics, administer an additional 4 weeks of oral antibiotics or 2 to 4 weeks of IV ceftriaxone.¹⁰ A second 4-week course of oral antibiotics is also suggested for patients whose symptoms have greatly improved but not fully resolved.^3,4,7,10

For post-Lyme syndromes, antibiotics have not proved useful and are not recommended for patients with chronic (>6 months) subjective symptoms.^10,16 A recent study in Europe failed to show that antibiotic treatment for 12 weeks reduced symptoms or improved quality of life in patients with persistent symptoms associated with Lyme disease.¹⁸

Prognosis: It varies with specific complications

Arthritis occurs in 60% of untreated patients with late disease.

EM resolves within a few days or weeks (up to 8 weeks) after initiation of treatment. Generally, between 70% and 85% of patients with Lyme neuroborreliosis make a complete recovery, usually 6 to 12 months after initiation of therapy; and up to 90% of patients with facial palsy recover.⁶ Residual neurologic complications (facial nerve dysfunction, radiculopathies, vision or hearing loss, ataxia) have been documented in 5% to 28% of patients one year after therapy. Lyme arthritis resolves spontaneously, but it can take years and may require anti-inflammatory treatment.^5,6

Prevention: Simple measures pay off

Advise patients to avoid ticks by avoiding brushy areas, especially at times when ticks are active. Wearing appropriate outdoor clothing (light-colored garments, long-sleeved shirts, and pants tucked into socks or boot tops) are key preventive steps. The possibility of transmission of B burgdorferi from an infected tick increases with time of attachment. Therefore, individuals spending time outdoors should apply insect repellent (N,N-diethyl-3-methylbenzamide (DEET) or permethrin), check for ticks daily, and remove them promptly if found. Applying pesticides and managing the landscape on one’s property also helps control tick populations.

Antimicrobial prophylaxis with a single 200-mg dose of oral doxycycline is appropriate for a patient who has no contraindications if there is known tick exposure and the patient lives in an area with at least a 20% incidence of Lyme disease, or for any patient who has a tick still attached (and it has been there for 36 hours).^6,10 Prophylaxis can be started within 72 hours of tick removal.

Monitor all patients closely for up to 30 days for signs and symptoms of tick-borne diseases.

A Lyme-disease vaccine in humans was approved by the FDA in 1998, but was removed from the market in 2002 because of poor sales and theoretical concerns about triggering autoimmune arthritis.^{1,4-6,8,10,19}

CASE › Ms. L’s FP opts to forgo doxycycline prophylaxis because she discovered the tick on her arm within 24 hours of the hiking expedition and removed it completely intact. In addition, the FP factored into her decision the fact that Lyme disease is not prevalent in Florida. The FP advised Ms. L about the signs and symptoms to watch for and made sure that a follow-up telephone appointment was scheduled for the next 4 to 6 weeks. Ms. L was also given ample educational pamphlets on the prevention of tick bites and Lyme disease.

CORRESPONDENCE
Sayed K. Ali, MD, FACP, Orlando Veterans Affairs Medical Center, 13800 Veterans Way, Orlando, FL, 32827; [email protected].

CASE › Alice L, a 39-year-old woman with an unremarkable medical history asks to see her primary care provider right away, concerned she might have contracted Lyme disease. She had been hiking the overgrown trails on her family-owned ranch in Florida, and the next day she noticed a black tick stuck to her forearm. Using tweezers, she pulled the whole tick off intact, put it in a plastic cup, and immediately sought medical attention. How should her family physician (FP) advise her?

Lyme disease is the most common tick-borne illness in the United States, with more than 25,000 cases confirmed in this country in 2014.¹ It is concentrated mostly in the northeast and upper Midwest, and less frequently occurs in the Pacific coastal regions of Oregon and northern California. Cases have also increasingly been reported in the southwest region of the Appalachian Mountains and the mountainous regions of southern Virginia.²

In 2014, the only states reporting no incidence of Lyme disease were Colorado, Hawaii, Louisiana, New Mexico, and Oklahoma.¹ Lyme disease is also endemic in several regions in Northern Europe, Eastern Asia, and Northern Africa.^1,3-7 According to the Centers for Disease Control and Prevention (CDC), boys ages 5 to 9 years are most affected.¹

Disease transmission: Duration of tick attachment is important

The spirochete that causes Lyme disease, Borrelia burgdorferi, is transmitted to humans by the Ixodes tick. The Ixodes scapularis (deer tick) is common in the eastern and northern midwestern states and I pacificus is common in the western United States.

The life cycle. These small, dark-colored ticks have a 2-year life cycle that is comprised of 4 developmental stages: egg, larva, nymph, and adult. Eggs are laid in spring and hatch into larvae during late summer. The larvae feed on small animals (eg, mice, chipmunks, birds) and can acquire B burgdorferi infection at this stage. The larvae then molt into nymphs (<2 mm, and difficult to see), which feed again the following spring to early summer and may transmit the infection to a new host. Nymphs become adult ticks in mid-October to early-November, when the females feed again, mainly on large animals.

Humans usually become infected from May through August, when both they and the nymph ticks are most active outdoors. The ticks are able to attach themselves to their host without being noticed because they secrete small amounts of saliva with anesthetic properties while feeding. Many ticks also secrete a cement-like substance that keeps them firmly attached.

Adult ticks can also transmit the disease and are larger and more easily recognized. Transmission of the spirochete requires that the tick be attached to the new host for 36 to 48 hours,¹ allowing the spirochete to travel from the mid-gut of the tick to the salivary glands and into the host.

Two of the most important factors to consider when assessing the risk of transmission is how long the tick was attached and whether it was engorged. Only about a quarter of individuals with Lyme disease recall having had a tick bite.^1,3-6,8

Clinical presentation: Early and late findings

Symptoms of early Lyme disease usually start one to 2 weeks after a tick bite, but may start up to 30 days later. The most common presentation is a painless skin rash—erythema migrans (EM). It starts as a single red papule at the site of the bite (multiple lesions appear in 10% to 20% of cases⁹) and may progress to a painless erythematous lesion with red borders and a partial central clearing—the classic EM rash (FIGURE). Less commonly, the center of the lesion can appear vesicular or necrotic.

Although a rash occurs in 80% of Lyme disease cases, only 20% to 35% of the rashes develop into a classic bull's-eye lesion.³ Tick bites—and thus rashes—typically occur near or at the axilla, inguinal region, popliteal fossa, or at the belt line.

Individuals who don’t exhibit a rash may be asymptomatic or have nonspecific symptoms or flu-like symptoms of fatigue, fever, chills, myalgia, and headache.⁴ If Lyme disease continues untreated, the patient may experience extra-cutaneous complications, most often involving the joints and the nervous and cardiovascular systems.^3-7

Ixodes ticks are also vectors for human granulocytic anaplasmosis (HGA) and babesiosis, which can cause a variety of symptoms. Keep these diseases in mind when a patient presents with severe or atypical features of Lyme disease.⁵ The benefit of antibiotics after a tick bite to reduce the incidence of HGA or babesiosis is unclear.¹⁰

Late manifestations of Lyme disease can occur within one to 2 months of infection or even months to years after tick exposure, often resulting in substantial morbidity.^3-7,11 Musculoskeletal symptoms are the most common manifestations of late, disseminated disease, usually presenting as transient asymmetrical oligoarticular arthralgias or myalgia. Arthritis also occurs in 60% of untreated patients with late disease.^4,5 Large joint effusions are typical, with synovial fluid studies showing high quantities of polymorphonuclear leukocytes (25,000/mm³).⁵ Joint symptoms that persist after antibiotic treatment are called antibiotic-refractory Lyme arthritis.^4-7

Neurologic involvement affects 10% to 15% of untreated patients.^3,4 It can present as lymphocytic meningitis (most common), cranial neuropathies, motor or sensory radiculoneuropathy, mononeuritis multiplex, cerebellar ataxia, or myelitis. Late neurologic Lyme disease may also present as a subacute mild encephalopathy affecting memory and concentration. When cranial neuropathies are involved, it is usually as unilateral facial nerve palsy (but may be bilateral). Always consider Lyme disease in endemic areas when patients have severe Bell's palsy.

Patients may present with altered mental status, neck stiffness, pain, and headaches.^4-7 The classic triad (known as Bannwarth syndrome) consists of lymphocytic meningitis, cranial neuritis, and radiculoneuritis. However, these conditions do not always occur together.^3,4

Cardiovascular complications occur in 4% to 8% of untreated patients,^4,5 usually one to 2 months following infection. Varying degrees of atrioventricular (AV) block can be seen, but third-degree block is most common. A less frequent complication is Lyme carditis, seen in 4% to 10% of patients.¹² The pathophysiology of Lyme carditis is not well understood.¹¹ It may present as chest pain, dyspnea on exertion, fatigue, palpitations, or syncope, often involving an AV block. Less frequent complications include myopericarditis, bundle branch block, and heart failure.

Post-treatment Lyme disease syndrome refers to the nonspecific symptoms of fatigue, sleep disorders, headaches, memory and concentration difficulties, myalgia, and arthralgias that may persist after successful antibiotic treatment. (We’ll discuss the specifics of treatment in a bit.) Post-treatment Lyme disease syndrome occurs in about 5% of patients properly treated for Lyme disease.¹³ The pathogenesis remains unknown, but some experts believe that lingering symptoms result from residual damage to tissues and the immune system. Education, rehabilitation, anti-inflammatory agents, antidepressants, a healthy diet, and plenty of rest have been recommended as treatment modalities.^1,13

Chronic Lyme disease is also important to keep in mind. Although there is no standard definition for it, chronic Lyme disease refers broadly to chronic symptoms in patients who may or may not have Lyme disease—eg, an individual who may have been treated for presumed B burgdorferi infection without solid clinical or serologic confirmation.^3-5 Chronic Lyme disease can often share somatic symptoms with other conditions such as fibromyalgia, chronic fatigue syndrome, and irritable bowel syndrome. Treatment often relies on a solid, trusting patient-doctor relationship, cognitive behavioral therapy, and regular counseling. Antibiotics are usually not necessary.

Dx: Serologic testing is preferred if clinical findings are insufficient

Erythema migrans and a history of tick exposure are sufficient to diagnose Lyme disease, without serologic confirmation.

Lyme disease can be diagnosed clinically in patients who have an EM rash and a history of tick exposure. This is the only clinical presentation sufficient to make the diagnosis of Lyme disease without the need of confirmatory serologic testing.^3,6 In the case of a tick bite but no rash, defer serologic testing unless associated symptoms arise (described earlier), at which time the accuracy of test results would be more trustworthy.¹⁰ Testing of ticks for infection with B burgdorferi is not recommended due to a lack of laboratory standardization.¹⁰

Two methods of laboratory testing are available to diagnose Lyme disease: direct, using cultures to detect B burgdorferi-specific proteins; and indirect, involving assays for antibodies.

Serologic testing. The CDC and Infectious Diseases Society of America recommend serology as the preferred initial diagnostic test. Tests for antibodies have good sensitivity and specificity in patients who have had untreated infection for a month or longer. However, these tests should not be used to screen individuals who have a low probability of infection, due to the tests’ poor positive predictive value.

The serologic tests used are the enzyme-linked immunosorbent assay (ELISA) and indirect fluorescent-antibody (IFA) assay. These assays use a whole-cell sonicate of B burgdorferi and yield a significant number of false-positive results due to cross-reactive antigens such as flagellar and heat-shock proteins if other spirochetal infections are present. To increase testing specificity, both the CDC and European guidelines strongly recommend a 2-tier approach using an ELISA or IFA assay initially, followed by the more specific Western blot to confirm the diagnosis when the assay samples are positive or equivocal.¹

The Western blot is interpreted using standardized criteria requiring at least 2 of 3 bands for a positive IgM diagnosis and 5 of 10 bands for a positive IgG diagnosis. Antibodies against Borrelia species are slow to develop. IgM generally is undetectable for the first one to 2 weeks after infection, and IgG often does not emerge for 4 to 6 weeks.

With patients who are seronegative at presentation, but for whom there is strong suspicion of Borrelia infection, it is advisable to obtain evidence of seroconversion, preferably within 8 to 14 days after presentation. Early antibiotic treatment may prevent the development of seropositivity.^1,3-7,14

Past or newly acquired infection? IgM and IgG produced in response to B burgdorferi may persist for years following antimicrobial therapy, which makes it impossible to distinguish between past and newly acquired infections based on seropositivity alone. These persistently elevated levels are not an indication of ineffective treatment or chronic infection. Therefore, it is not recommended to repeat serologic testing for documentation of treatment effectiveness or cure.

Since no serologic test has sufficient specificity to be used alone, efforts are being made to develop testing that detects antibodies against the 26-mer peptide from the sixth invariant region (C6) of the VlsE lipoprotein (C6VlsE). In 2007, the US Food and Drug Administration (FDA) approved a C6 ELISA for first-tier testing; unfortunately, it still has the problem of cross-reactivity with other spirochetal and viral pathogens. The C6 ELISA may one day be approved as a single-tier test.^4-7,14

Culture. The isolation of Borrelia species by culture is not routinely performed because it is expensive and requires special media and laboratory expertise, as well as a prolonged period of observation (6 to 12 weeks). Furthermore, this technique lacks sensitivity with samples taken from anywhere other than the rash site of patients with EM, in whom there is little need for laboratory diagnosis. Culture of cerebrospinal fluid has a positive yield of less than 10%,⁵ and it is extremely rare to isolate the spirochete from joint fluid. Therefore, negative results do not exclude a diagnosis of disease.^4,5,14

The CDC recommends against cultures, immunofluorescence staining, and cell sorting of cell wall-deficient or cystic forms of B burgdorferi.¹

Polymerase-chain reaction (PCR). This test is used to amplify genomic DNA of B burgdorferi and is most useful in patients with Lyme arthritis because of a high rate of DNA detection in synovial fluid samples (60% to 85%).⁵ In skin biopsies from EM lesions, PCR sensitivity can range from 25% to 90%.⁵ The PCR test is also used in cases of diagnostic uncertainty, but is generally performed only for research purposes. Negative findings do not exclude diagnosis of the disease.^5,6,14

Urine antigen test. This test has a high false-positive rate and is generally not recommended.^1,5

Treatment: Begin antibiotics ASAP

Treat Lyme disease with antibiotics as soon as the diagnosis is made. Early treatment hastens relief from symptoms and halts progression of later stages of the disease. The preferred antibiotics for early localized disease are doxycycline 100 mg orally twice daily; amoxicillin 500 mg orally 3 times a day; or cefuroxime axetil 500 mg orally twice a day (TABLE 1).¹⁰ Cefuroxime axetil is also appropriate if EM can’t be clearly distinguished from bacterial cellulitis. Reserve intravenous (IV) regimens for patients with more serious presentations (eg, neurologic symptoms and symptomatic cardiac disease) and for those with refractory Lyme arthritis (TABLE 2).¹⁰

Macrolides are not recommended as first-line therapy for early Lyme disease because they are less effective.¹⁰ However, macrolides may be used with patients unable to take the preferred antibiotics. Because there have been intermittent shortages of doxycycline, minocycline—another second-generation tetracycline with a similar chemical structure and antibacterial action—has been proposed as an alternative treatment.¹⁵

Ceftriaxone IV is preferred especially for patients presenting with an AV block or myopericarditis associated with early Lyme disease. The recommended course of treatment is usually 14 days. A temporary pacemaker may be required for patients with advanced blocks. Oral antibiotics may be started as soon as the AV block is resolved, or for outpatient therapy.

For adults who have early Lyme disease with acute neurologic manifestations such as meningitis or radiculopathy, IV antibiotics for 14 days are recommended. Cefotaxime has efficacy similar to ceftriaxone but requires multiple doses a day, making the latter the preferred treatment. Penicillin G 18 to 24 million units per day, divided into doses given every 4 hours, is also a satisfactory alternative.^10,16 The American Academy of Neurology states that no definitive data exist to establish superiority, or lack thereof, of either oral or parenteral treatment.¹⁷

Lyme arthritis can be treated with oral doxycycline, amoxicillin, or cefuroxime axetil for 28 days. For patients with persistent or recurrent joint swelling who have been treated with a course of oral antibiotics, administer an additional 4 weeks of oral antibiotics or 2 to 4 weeks of IV ceftriaxone.¹⁰ A second 4-week course of oral antibiotics is also suggested for patients whose symptoms have greatly improved but not fully resolved.^3,4,7,10

For post-Lyme syndromes, antibiotics have not proved useful and are not recommended for patients with chronic (>6 months) subjective symptoms.^10,16 A recent study in Europe failed to show that antibiotic treatment for 12 weeks reduced symptoms or improved quality of life in patients with persistent symptoms associated with Lyme disease.¹⁸

Prognosis: It varies with specific complications

Arthritis occurs in 60% of untreated patients with late disease.

EM resolves within a few days or weeks (up to 8 weeks) after initiation of treatment. Generally, between 70% and 85% of patients with Lyme neuroborreliosis make a complete recovery, usually 6 to 12 months after initiation of therapy; and up to 90% of patients with facial palsy recover.⁶ Residual neurologic complications (facial nerve dysfunction, radiculopathies, vision or hearing loss, ataxia) have been documented in 5% to 28% of patients one year after therapy. Lyme arthritis resolves spontaneously, but it can take years and may require anti-inflammatory treatment.^5,6

Prevention: Simple measures pay off

Advise patients to avoid ticks by avoiding brushy areas, especially at times when ticks are active. Wearing appropriate outdoor clothing (light-colored garments, long-sleeved shirts, and pants tucked into socks or boot tops) are key preventive steps. The possibility of transmission of B burgdorferi from an infected tick increases with time of attachment. Therefore, individuals spending time outdoors should apply insect repellent (N,N-diethyl-3-methylbenzamide (DEET) or permethrin), check for ticks daily, and remove them promptly if found. Applying pesticides and managing the landscape on one’s property also helps control tick populations.

Antimicrobial prophylaxis with a single 200-mg dose of oral doxycycline is appropriate for a patient who has no contraindications if there is known tick exposure and the patient lives in an area with at least a 20% incidence of Lyme disease, or for any patient who has a tick still attached (and it has been there for 36 hours).^6,10 Prophylaxis can be started within 72 hours of tick removal.

Monitor all patients closely for up to 30 days for signs and symptoms of tick-borne diseases.

A Lyme-disease vaccine in humans was approved by the FDA in 1998, but was removed from the market in 2002 because of poor sales and theoretical concerns about triggering autoimmune arthritis.^{1,4-6,8,10,19}

CASE › Ms. L’s FP opts to forgo doxycycline prophylaxis because she discovered the tick on her arm within 24 hours of the hiking expedition and removed it completely intact. In addition, the FP factored into her decision the fact that Lyme disease is not prevalent in Florida. The FP advised Ms. L about the signs and symptoms to watch for and made sure that a follow-up telephone appointment was scheduled for the next 4 to 6 weeks. Ms. L was also given ample educational pamphlets on the prevention of tick bites and Lyme disease.

CORRESPONDENCE
Sayed K. Ali, MD, FACP, Orlando Veterans Affairs Medical Center, 13800 Veterans Way, Orlando, FL, 32827; [email protected].

CASE › Alice L, a 39-year-old woman with an unremarkable medical history asks to see her primary care provider right away, concerned she might have contracted Lyme disease. She had been hiking the overgrown trails on her family-owned ranch in Florida, and the next day she noticed a black tick stuck to her forearm. Using tweezers, she pulled the whole tick off intact, put it in a plastic cup, and immediately sought medical attention. How should her family physician (FP) advise her?

Lyme disease is the most common tick-borne illness in the United States, with more than 25,000 cases confirmed in this country in 2014.¹ It is concentrated mostly in the northeast and upper Midwest, and less frequently occurs in the Pacific coastal regions of Oregon and northern California. Cases have also increasingly been reported in the southwest region of the Appalachian Mountains and the mountainous regions of southern Virginia.²

In 2014, the only states reporting no incidence of Lyme disease were Colorado, Hawaii, Louisiana, New Mexico, and Oklahoma.¹ Lyme disease is also endemic in several regions in Northern Europe, Eastern Asia, and Northern Africa.^1,3-7 According to the Centers for Disease Control and Prevention (CDC), boys ages 5 to 9 years are most affected.¹

Disease transmission: Duration of tick attachment is important

The spirochete that causes Lyme disease, Borrelia burgdorferi, is transmitted to humans by the Ixodes tick. The Ixodes scapularis (deer tick) is common in the eastern and northern midwestern states and I pacificus is common in the western United States.

The life cycle. These small, dark-colored ticks have a 2-year life cycle that is comprised of 4 developmental stages: egg, larva, nymph, and adult. Eggs are laid in spring and hatch into larvae during late summer. The larvae feed on small animals (eg, mice, chipmunks, birds) and can acquire B burgdorferi infection at this stage. The larvae then molt into nymphs (<2 mm, and difficult to see), which feed again the following spring to early summer and may transmit the infection to a new host. Nymphs become adult ticks in mid-October to early-November, when the females feed again, mainly on large animals.

Humans usually become infected from May through August, when both they and the nymph ticks are most active outdoors. The ticks are able to attach themselves to their host without being noticed because they secrete small amounts of saliva with anesthetic properties while feeding. Many ticks also secrete a cement-like substance that keeps them firmly attached.

Adult ticks can also transmit the disease and are larger and more easily recognized. Transmission of the spirochete requires that the tick be attached to the new host for 36 to 48 hours,¹ allowing the spirochete to travel from the mid-gut of the tick to the salivary glands and into the host.

Two of the most important factors to consider when assessing the risk of transmission is how long the tick was attached and whether it was engorged. Only about a quarter of individuals with Lyme disease recall having had a tick bite.^1,3-6,8

Clinical presentation: Early and late findings

Symptoms of early Lyme disease usually start one to 2 weeks after a tick bite, but may start up to 30 days later. The most common presentation is a painless skin rash—erythema migrans (EM). It starts as a single red papule at the site of the bite (multiple lesions appear in 10% to 20% of cases⁹) and may progress to a painless erythematous lesion with red borders and a partial central clearing—the classic EM rash (FIGURE). Less commonly, the center of the lesion can appear vesicular or necrotic.

Although a rash occurs in 80% of Lyme disease cases, only 20% to 35% of the rashes develop into a classic bull's-eye lesion.³ Tick bites—and thus rashes—typically occur near or at the axilla, inguinal region, popliteal fossa, or at the belt line.

Individuals who don’t exhibit a rash may be asymptomatic or have nonspecific symptoms or flu-like symptoms of fatigue, fever, chills, myalgia, and headache.⁴ If Lyme disease continues untreated, the patient may experience extra-cutaneous complications, most often involving the joints and the nervous and cardiovascular systems.^3-7

Ixodes ticks are also vectors for human granulocytic anaplasmosis (HGA) and babesiosis, which can cause a variety of symptoms. Keep these diseases in mind when a patient presents with severe or atypical features of Lyme disease.⁵ The benefit of antibiotics after a tick bite to reduce the incidence of HGA or babesiosis is unclear.¹⁰

Late manifestations of Lyme disease can occur within one to 2 months of infection or even months to years after tick exposure, often resulting in substantial morbidity.^3-7,11 Musculoskeletal symptoms are the most common manifestations of late, disseminated disease, usually presenting as transient asymmetrical oligoarticular arthralgias or myalgia. Arthritis also occurs in 60% of untreated patients with late disease.^4,5 Large joint effusions are typical, with synovial fluid studies showing high quantities of polymorphonuclear leukocytes (25,000/mm³).⁵ Joint symptoms that persist after antibiotic treatment are called antibiotic-refractory Lyme arthritis.^4-7

Neurologic involvement affects 10% to 15% of untreated patients.^3,4 It can present as lymphocytic meningitis (most common), cranial neuropathies, motor or sensory radiculoneuropathy, mononeuritis multiplex, cerebellar ataxia, or myelitis. Late neurologic Lyme disease may also present as a subacute mild encephalopathy affecting memory and concentration. When cranial neuropathies are involved, it is usually as unilateral facial nerve palsy (but may be bilateral). Always consider Lyme disease in endemic areas when patients have severe Bell's palsy.

Patients may present with altered mental status, neck stiffness, pain, and headaches.^4-7 The classic triad (known as Bannwarth syndrome) consists of lymphocytic meningitis, cranial neuritis, and radiculoneuritis. However, these conditions do not always occur together.^3,4

Cardiovascular complications occur in 4% to 8% of untreated patients,^4,5 usually one to 2 months following infection. Varying degrees of atrioventricular (AV) block can be seen, but third-degree block is most common. A less frequent complication is Lyme carditis, seen in 4% to 10% of patients.¹² The pathophysiology of Lyme carditis is not well understood.¹¹ It may present as chest pain, dyspnea on exertion, fatigue, palpitations, or syncope, often involving an AV block. Less frequent complications include myopericarditis, bundle branch block, and heart failure.

Post-treatment Lyme disease syndrome refers to the nonspecific symptoms of fatigue, sleep disorders, headaches, memory and concentration difficulties, myalgia, and arthralgias that may persist after successful antibiotic treatment. (We’ll discuss the specifics of treatment in a bit.) Post-treatment Lyme disease syndrome occurs in about 5% of patients properly treated for Lyme disease.¹³ The pathogenesis remains unknown, but some experts believe that lingering symptoms result from residual damage to tissues and the immune system. Education, rehabilitation, anti-inflammatory agents, antidepressants, a healthy diet, and plenty of rest have been recommended as treatment modalities.^1,13

Chronic Lyme disease is also important to keep in mind. Although there is no standard definition for it, chronic Lyme disease refers broadly to chronic symptoms in patients who may or may not have Lyme disease—eg, an individual who may have been treated for presumed B burgdorferi infection without solid clinical or serologic confirmation.^3-5 Chronic Lyme disease can often share somatic symptoms with other conditions such as fibromyalgia, chronic fatigue syndrome, and irritable bowel syndrome. Treatment often relies on a solid, trusting patient-doctor relationship, cognitive behavioral therapy, and regular counseling. Antibiotics are usually not necessary.

Dx: Serologic testing is preferred if clinical findings are insufficient

Erythema migrans and a history of tick exposure are sufficient to diagnose Lyme disease, without serologic confirmation.

Lyme disease can be diagnosed clinically in patients who have an EM rash and a history of tick exposure. This is the only clinical presentation sufficient to make the diagnosis of Lyme disease without the need of confirmatory serologic testing.^3,6 In the case of a tick bite but no rash, defer serologic testing unless associated symptoms arise (described earlier), at which time the accuracy of test results would be more trustworthy.¹⁰ Testing of ticks for infection with B burgdorferi is not recommended due to a lack of laboratory standardization.¹⁰

Two methods of laboratory testing are available to diagnose Lyme disease: direct, using cultures to detect B burgdorferi-specific proteins; and indirect, involving assays for antibodies.

Serologic testing. The CDC and Infectious Diseases Society of America recommend serology as the preferred initial diagnostic test. Tests for antibodies have good sensitivity and specificity in patients who have had untreated infection for a month or longer. However, these tests should not be used to screen individuals who have a low probability of infection, due to the tests’ poor positive predictive value.

The serologic tests used are the enzyme-linked immunosorbent assay (ELISA) and indirect fluorescent-antibody (IFA) assay. These assays use a whole-cell sonicate of B burgdorferi and yield a significant number of false-positive results due to cross-reactive antigens such as flagellar and heat-shock proteins if other spirochetal infections are present. To increase testing specificity, both the CDC and European guidelines strongly recommend a 2-tier approach using an ELISA or IFA assay initially, followed by the more specific Western blot to confirm the diagnosis when the assay samples are positive or equivocal.¹

The Western blot is interpreted using standardized criteria requiring at least 2 of 3 bands for a positive IgM diagnosis and 5 of 10 bands for a positive IgG diagnosis. Antibodies against Borrelia species are slow to develop. IgM generally is undetectable for the first one to 2 weeks after infection, and IgG often does not emerge for 4 to 6 weeks.

With patients who are seronegative at presentation, but for whom there is strong suspicion of Borrelia infection, it is advisable to obtain evidence of seroconversion, preferably within 8 to 14 days after presentation. Early antibiotic treatment may prevent the development of seropositivity.^1,3-7,14

Past or newly acquired infection? IgM and IgG produced in response to B burgdorferi may persist for years following antimicrobial therapy, which makes it impossible to distinguish between past and newly acquired infections based on seropositivity alone. These persistently elevated levels are not an indication of ineffective treatment or chronic infection. Therefore, it is not recommended to repeat serologic testing for documentation of treatment effectiveness or cure.

Since no serologic test has sufficient specificity to be used alone, efforts are being made to develop testing that detects antibodies against the 26-mer peptide from the sixth invariant region (C6) of the VlsE lipoprotein (C6VlsE). In 2007, the US Food and Drug Administration (FDA) approved a C6 ELISA for first-tier testing; unfortunately, it still has the problem of cross-reactivity with other spirochetal and viral pathogens. The C6 ELISA may one day be approved as a single-tier test.^4-7,14

Culture. The isolation of Borrelia species by culture is not routinely performed because it is expensive and requires special media and laboratory expertise, as well as a prolonged period of observation (6 to 12 weeks). Furthermore, this technique lacks sensitivity with samples taken from anywhere other than the rash site of patients with EM, in whom there is little need for laboratory diagnosis. Culture of cerebrospinal fluid has a positive yield of less than 10%,⁵ and it is extremely rare to isolate the spirochete from joint fluid. Therefore, negative results do not exclude a diagnosis of disease.^4,5,14

The CDC recommends against cultures, immunofluorescence staining, and cell sorting of cell wall-deficient or cystic forms of B burgdorferi.¹

Polymerase-chain reaction (PCR). This test is used to amplify genomic DNA of B burgdorferi and is most useful in patients with Lyme arthritis because of a high rate of DNA detection in synovial fluid samples (60% to 85%).⁵ In skin biopsies from EM lesions, PCR sensitivity can range from 25% to 90%.⁵ The PCR test is also used in cases of diagnostic uncertainty, but is generally performed only for research purposes. Negative findings do not exclude diagnosis of the disease.^5,6,14

Urine antigen test. This test has a high false-positive rate and is generally not recommended.^1,5

Treatment: Begin antibiotics ASAP

Treat Lyme disease with antibiotics as soon as the diagnosis is made. Early treatment hastens relief from symptoms and halts progression of later stages of the disease. The preferred antibiotics for early localized disease are doxycycline 100 mg orally twice daily; amoxicillin 500 mg orally 3 times a day; or cefuroxime axetil 500 mg orally twice a day (TABLE 1).¹⁰ Cefuroxime axetil is also appropriate if EM can’t be clearly distinguished from bacterial cellulitis. Reserve intravenous (IV) regimens for patients with more serious presentations (eg, neurologic symptoms and symptomatic cardiac disease) and for those with refractory Lyme arthritis (TABLE 2).¹⁰

Macrolides are not recommended as first-line therapy for early Lyme disease because they are less effective.¹⁰ However, macrolides may be used with patients unable to take the preferred antibiotics. Because there have been intermittent shortages of doxycycline, minocycline—another second-generation tetracycline with a similar chemical structure and antibacterial action—has been proposed as an alternative treatment.¹⁵

Ceftriaxone IV is preferred especially for patients presenting with an AV block or myopericarditis associated with early Lyme disease. The recommended course of treatment is usually 14 days. A temporary pacemaker may be required for patients with advanced blocks. Oral antibiotics may be started as soon as the AV block is resolved, or for outpatient therapy.

For adults who have early Lyme disease with acute neurologic manifestations such as meningitis or radiculopathy, IV antibiotics for 14 days are recommended. Cefotaxime has efficacy similar to ceftriaxone but requires multiple doses a day, making the latter the preferred treatment. Penicillin G 18 to 24 million units per day, divided into doses given every 4 hours, is also a satisfactory alternative.^10,16 The American Academy of Neurology states that no definitive data exist to establish superiority, or lack thereof, of either oral or parenteral treatment.¹⁷

Lyme arthritis can be treated with oral doxycycline, amoxicillin, or cefuroxime axetil for 28 days. For patients with persistent or recurrent joint swelling who have been treated with a course of oral antibiotics, administer an additional 4 weeks of oral antibiotics or 2 to 4 weeks of IV ceftriaxone.¹⁰ A second 4-week course of oral antibiotics is also suggested for patients whose symptoms have greatly improved but not fully resolved.^3,4,7,10

For post-Lyme syndromes, antibiotics have not proved useful and are not recommended for patients with chronic (>6 months) subjective symptoms.^10,16 A recent study in Europe failed to show that antibiotic treatment for 12 weeks reduced symptoms or improved quality of life in patients with persistent symptoms associated with Lyme disease.¹⁸

Prognosis: It varies with specific complications

Arthritis occurs in 60% of untreated patients with late disease.

EM resolves within a few days or weeks (up to 8 weeks) after initiation of treatment. Generally, between 70% and 85% of patients with Lyme neuroborreliosis make a complete recovery, usually 6 to 12 months after initiation of therapy; and up to 90% of patients with facial palsy recover.⁶ Residual neurologic complications (facial nerve dysfunction, radiculopathies, vision or hearing loss, ataxia) have been documented in 5% to 28% of patients one year after therapy. Lyme arthritis resolves spontaneously, but it can take years and may require anti-inflammatory treatment.^5,6

Prevention: Simple measures pay off

Advise patients to avoid ticks by avoiding brushy areas, especially at times when ticks are active. Wearing appropriate outdoor clothing (light-colored garments, long-sleeved shirts, and pants tucked into socks or boot tops) are key preventive steps. The possibility of transmission of B burgdorferi from an infected tick increases with time of attachment. Therefore, individuals spending time outdoors should apply insect repellent (N,N-diethyl-3-methylbenzamide (DEET) or permethrin), check for ticks daily, and remove them promptly if found. Applying pesticides and managing the landscape on one’s property also helps control tick populations.

Antimicrobial prophylaxis with a single 200-mg dose of oral doxycycline is appropriate for a patient who has no contraindications if there is known tick exposure and the patient lives in an area with at least a 20% incidence of Lyme disease, or for any patient who has a tick still attached (and it has been there for 36 hours).^6,10 Prophylaxis can be started within 72 hours of tick removal.

Monitor all patients closely for up to 30 days for signs and symptoms of tick-borne diseases.

A Lyme-disease vaccine in humans was approved by the FDA in 1998, but was removed from the market in 2002 because of poor sales and theoretical concerns about triggering autoimmune arthritis.^{1,4-6,8,10,19}

CASE › Ms. L’s FP opts to forgo doxycycline prophylaxis because she discovered the tick on her arm within 24 hours of the hiking expedition and removed it completely intact. In addition, the FP factored into her decision the fact that Lyme disease is not prevalent in Florida. The FP advised Ms. L about the signs and symptoms to watch for and made sure that a follow-up telephone appointment was scheduled for the next 4 to 6 weeks. Ms. L was also given ample educational pamphlets on the prevention of tick bites and Lyme disease.

CORRESPONDENCE
Sayed K. Ali, MD, FACP, Orlando Veterans Affairs Medical Center, 13800 Veterans Way, Orlando, FL, 32827; [email protected].

Prevention of diabetes, as well as early detection and treatment of both prediabetes and diabetes, is critical to the health of our country. Because evidence-based guidelines are key to our ability to effectively address the nation’s diabetes epidemic, the American Diabetes Association (ADA) updates its “Standards of Medical Care in Diabetes” annually to incorporate new evidence or clarifications.

The 2016 standards,¹ available at professional.diabetes.org/jfp, are a valuable resource. Among the latest revisions: an expansion in screening recommendations, a change in the age at which aspirin therapy for women should be considered, and a change in A1C goals for pregnant women with diabetes.

As members of the ADA’s primary care advisory group, we use a question and answer format in the summary that follows to highlight recent revisions and review other recommendations that are of particular relevance to physicians in primary care. It is important to note, however, that ADA recommendations are not intended to preclude clinical judgment and should be applied in the context of excellent medical care.

Diagnosis and screening

Have the 2016 ADA standards changed the way diabetes is diagnosed?

No. The criteria for a diagnosis of diabetes did not change. Diabetes and prediabetes are still screened for and diagnosed with any of the following: a fasting plasma glucose (FPG); a 2-hour 75-g oral glucose tolerance test (OGTT); a random plasma glucose >200 mg/dL with symptoms of hyperglycemia; or A1C criteria (TABLE 1).^1,2 The wording was changed, however, to make it clear that no one test is preferred over another for diagnosis.

Yes. In addition to screening asymptomatic adults of any age who are overweight or obese and have one or more additional risk factors for diabetes, the 2016 standards recommend screening all adults 45 years and older, regardless of weight.

Is an A1C <7% the recommended treatment goal for everyone with diabetes?

No. An A1C <7% is considered reasonable for most, but not all, nonpregnant adults. In the last few years, the ADA has focused more on individualized targets.

Tighter control (<6.5%)—which is associated with lower rates of eye disease, kidney disease, and nerve damage—may be appropriate for patients who have no significant hypoglycemia, no cardiovascular disease (CVD), a shorter duration of diabetes, or a longer expected lifespan.

Conversely, a higher target (<8%) may be appropriate for patients who are older, have longstanding diabetes, advanced macrovascular or microvascular disease, established complications, or a limited life expectancy.^3,4

The latest ADA revisions include an expansion in screening recommendations and changes in the age at which aspirin therapy for women should be considered and in A1C goals for pregnant women with diabetes.

Pregnancy. The 2016 standards have a new target for pregnant women with diabetes: The ADA previously recommended an A1C <6% for this patient population, but now recommends a target A1C between 6% and 6.5%. This may be tightened or relaxed, however, depending on individual risk of hypoglycemia.

In focusing on individualized targets and hypoglycemia avoidance, the ADA notes that attention must be paid to fasting, pre-meal, and post-meal blood glucose levels to achieve treatment goals. The 2016 standards emphasize the importance of patient-centered diabetes care, aligned with a coordinated, team-based chronic care model.

Diabetes self-management education and support is indicated for those who are newly diagnosed, and should be provided periodically based on glucose control and progression of the disease. All patients should receive education on hypoglycemia risk and treatment.

Prediabetes and prevention

What is prediabetes and what can I do to prevent patients with prediabetes from developing diabetes?

Patients with impaired glucose tolerance, impaired fasting glucose, or an A1C between 5.7% and 6.4% are considered to have prediabetes and are at risk for developing type 2 diabetes.

Family physicians should refer patients with prediabetes to intensive diet, physical activity, and behavioral counseling programs like those based on the Diabetes Prevention Program study (www.niddk.nih.gov/about-niddk/research-areas/diabetes/diabetes-prevention-program-dpp/Pages/default.aspx). Goals should include a minimum 7% weight loss and moderate-intensity physical activity, such as brisk walking, for at least 150 minutes per week.

For patients with diabetes, a sustained weight loss of 5% may improve glycemic control and reduce the need for medication.

Lifestyle modification programs have been shown to be very effective in preventing diabetes, with about a 58% reduction in the risk of developing type 2 diabetes after 3 years.⁵ The 2016 standards added a recommendation that physicians encourage the use of new technology, such as text messaging or smart phone apps, to support such efforts.

Should I consider initiating oral antiglycemics in patients with prediabetes?

Yes. Pharmacologic agents, including metformin, acarbose, and pioglitazone, have been shown to decrease progression from prediabetes to type 2 diabetes. Thus, antiglycemics should be considered for certain patients. Metformin is especially appropriate for women with a history of gestational diabetes, patients who are younger than 60 years, and those who have a body mass index (BMI) ≥35 kg/m².⁶

How often should I screen patients with prediabetes?

Patients with prediabetes should be screened annually. Such individuals should also be screened and treated for modifiable cardiovascular risk factors. There is strong evidence that the treatment of obesity can be beneficial for those at any stage of the diabetes spectrum.

© 2016 Joe Gorman

Obesity management

What do the 2016 ADA standards recommend for obese patients with diabetes?

With more than two-thirds of Americans either overweight or obese, the ADA added a new section on obesity management and calls on health care providers to:

• weigh patients and calculate and document their BMI at every visit, and
• counsel those who are overweight or obese on the benefits of even modest weight loss.

The ADA recommends a sustained weight loss of 5%, which can improve glycemic control and reduce the need for diabetes medications,^7-9 although weight loss of ≥7% is optimal. Physicians are also called on to assess each patient’s readiness to engage in therapeutic lifestyle change to maintain a modest weight loss.

Treatment for obesity can include therapeutic lifestyle change (reduction in calories, increase in physical activity) and behavioral therapy. For refractory patients, pharmacologic therapy and bariatric surgery may be considered.

Interventions should be high-intensity (≥16 sessions in 6 months) and focus on diet, physical activity, and behavioral strategies to achieve a 500 to 750 calorie deficit per day.¹⁰ Long-term (≥1 year) comprehensive weight maintenance programs should be prescribed for those who achieve short-term weight loss.^11,12 Such programs should provide at least monthly contact and encourage ongoing monitoring of body weight (weekly or more frequently), continued consumption of a reduced-calorie diet, and participation in high levels of physical activity (200 to 300 minutes per week).

Glycemic treatment

What are some of the key factors that distinguish the different type 2 diabetes medications from one another?

An increasing understanding of diabetes pathophysiology has led to a wider array of medications, making treatment more complex than ever. It is important for physicians to have a strong working knowledge of the various classes of antidiabetic agents and the subtleties between drugs in the same class to best individualize treatment.

Here are the highlights of each class of medication listed in the ADA/European Association for the Study of Diabetes algorithm for the management of type 2 diabetes,¹³ which is available at http://care.diabetesjournals.org/content/38/1/140/F2.large.jpg):

Metformin is the preferred initial medication for all patients who can tolerate it and have no contraindications. The drug is cost-effective, weight neutral, and has had positive cardiovascular and mortality outcomes in long-term studies. Adverse gastrointestinal (GI) effects, including nausea, diarrhea, and dyspepsia, are common but can be reduced with a slow titration of the drug. Metformin should be used with caution in those with renal disease. The dose should be reduced if the estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m² and the drug discontinued if eGFR <30 mL/min/1.73 m².

Sulfonylureas/meglitinides stimulate insulin secretion in a glucose-independent manner. They are cost-effective and have high efficacy early in the disease and with initial use, but the effect wanes as the disease progresses. This class of drugs is associated with weight gain and hypoglycemia. Second-generation sulfonylureas (glipizide, glimepiride) are recommended; meglitinides are more expensive than sulfonylureas.

Patients who fail to achieve or maintain their A1C goal after one year may need to begin insulin therapy.

Thiazolidinediones work to improve insulin sensitivity in the periphery and have a low risk of hypoglycemia. They have been associated with fluid retention, weight gain, and worsening of pre-existing congestive heart failure, but previous cardiovascular concerns (with rosiglitazone)¹⁴ and bladder cancer risks (with pioglitazone)^15-17 have been refuted. Thiazolidinediones are contraindicated in those with Class III and IV congestive heart failure, however, and patients taking them require careful monitoring for weight gain, fluid retention, and exacerbation of heart failure.

Dipeptidyl peptidase-4 inhibitors (DPP4Is) work to reduce the breakdown of endogenous incretin hormones. These oral agents increase insulin secretion in a glucose-dependent manner; more insulin is secreted when glucose is higher and less when glucose is closer to normal. This means that there is a much lower risk of hypoglycemia when a DPP4I is used as monotherapy.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs), which are injectable, also work via incretin hormones and stimulate insulin in a glucose-dependent manner. They are associated with weight loss and low rates of hypoglycemia. Adverse GI effects are common with this class of drugs, but can be reduced by titrating the medication and avoiding overeating. GLP-1RAs can be taken twice daily to once weekly, depending on the specific agent.

Sodium glucose transporter 2 inhibitors (SGLT2Is) are oral agents and the newest class of antidiabetes drugs. The drugs help block the reabsorption of glucose, thereby lowering glucose levels, blood pressure, and weight in many patients. The most common adverse effects are urinary tract and genital yeast infections. SGLT2Is should not be given to patients with advanced renal disease (chronic kidney disease Stages 3B-5) because they will not be effectively absorbed.

The US Food and Drug Administration (FDA) recently issued a warning about the risk of ketoacidosis with these agents,¹⁸ and patients should be advised to stop taking them and to seek immediate medical attention if they develop symptoms of ketoacidosis, such as excessive thirst, frequent urination, nausea and vomiting, abdominal pain, weakness or fatigue, shortness of breath, fruity-scented breath, or confusion.

Insulin is eventually needed by most patients with type 2 diabetes who live long enough to see the disease progress. The most common adverse effects are weight gain and hypoglycemia. There are many types of insulin, but only one that is delivered via inhalation—human insulin inhaled powder. Inhaled insulin, however, has the potential for adverse pulmonary effects, including cough and reduction of peak expiratory flow. Therefore, pulmonary function testing is recommended prior to its use.

Treatment goal attainment should be evaluated every 3 months, and treatment titrated at 3-month intervals if goals are not achieved. The ADA/European Association for the Study of Diabetes’ algorithm indicates that patients are likely to need insulin a year after diagnosis if their A1C goal has not been achieved or maintained.¹³

The following medications are not included in the algorithm but are included in the 2016 standards, and may be helpful for certain patients:

Alpha-glucosidase inhibitors delay the absorption of glucose from the proximal to distal GI tract, thereby reducing postprandial hyperglycemia. Flatulence and leakage of stool—the most common adverse effects—have limited their use in the United States.

Patients ≥40 years will need moderate- to high-intensity statin therapy to lower their atherosclerotic cardiovascular disease risk.

Bile acid sequestrants (colesevelam) treat both hyperlipidemia and diabetes. The medications work by reducing glucose absorption from the GI tract. They reduce postprandial hyperglycemia, with a low risk of hypoglycemia. Colesevelam’s use is limited, however, because of the number of pills needed (6 daily).

Bromocriptine affects satiety levels via the central nervous system, and is available in a specific formulation for the treatment of diabetes. “First-dose” hypotension, however, is an adverse effect of considerable concern.¹

Pramlintide, an injectable amylin mimetic given to patients on prandial insulin, can reduce postprandial glucose levels. The most common adverse effects are upper GI symptoms and hypoglycemia. Due to the adverse effects and the need for an injection with each meal, pramlintide is used infrequently.

Cardiovascular risk reduction

Has the ADA revised its recommendations for cardiovascular disease risk management?

Yes. There have been several changes. The first is in terminology, with atherosclerotic cardiovascular disease (ASCVD) replacing CVD alone. While new recommendations for statin therapy for adults older than 40 years (TABLE 2)¹ were also added, the emphasis remains on therapeutic lifestyle change as an effective treatment for hypertension. These modifications should include at least 150 minutes of moderate physical activity per week and, for most patients, a reduction in total calories, saturated fat, and sodium.

It is important to remind patients that to maximize the benefits in terms of treating hyperglycemia, hypertension, and dyslipidemia, such changes must be maintained over the long term.

Aspirin therapy. The ADA also revised its recommendation regarding aspirin therapy. Based on new evidence in the treatment of women with ASCVD risk, the standards now call for considering aspirin therapy (75-162 mg/d) in both women and men ≥50 years as a primary prevention strategy for those with type 1 or type 2 diabetes with a 10-year ASCVD risk of >10%. (The previous standards recommended this only for women older than 60 years.)

Antiplatelet therapy is now recommended for patients younger than 50 years with multiple risk factors, and as secondary prevention in those with a history of ASCVD.^19-21

Hypertension. The ADA’s recommendations for treating hypertension in patients with diabetes have not changed; the goal remains <140/<90 mm Hg. Lower targets may be appropriate for younger patients, those with albuminuria, and individuals with additional CVD risk factors; however, systolic pressure <130 mm Hg has not been shown to reduce CVD outcomes, and diastolic pressure <70 mm Hg has been associated with higher mortality.²²

Optimal medication and lifestyle therapy are important to achieve goals, with avoidance of undue treatment burden. Angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), but not both, should be included as part of treatment. Other agents, such as a thiazide diuretic, may be needed to achieve individual goals. Serum creatinine/eGFR and serum potassium levels should be monitored with the use of diuretics.

Lipids. The 2016 standards include notable changes in lipid management. The ADA sees a role for ezetimibe for select patients, based on studies such as the IMPROVE IT trial²³ that included participants with diabetes. The ADA also added a table highlighting statin recommendations and delineating high and moderate-intensity statins (TABLE 3).¹ Those younger than 40 years with no other risk factors may not need a statin, but patients ages 40 or older will need moderate- to high-intensity statin therapy to effectively lower ASCVD risk.^24-28

These recommendations reflect a comprehensive plan to reduce ASCVD in this at-risk population, which should also include lifestyle modification, including smoking prevention and quit strategies, as needed.

Microvascular complications

DIABETIC KIDNEY DISEASE

How should I diagnose nephropathy?

The ADA changed the terminology, referring to “diabetic kidney disease” (DKD) rather than nephropathy to highlight the fact that the focus is on kidney disease directly linked to diabetes.

Other recommendations include an annual assessment of urinary albumin (eg, spot urine albumin-to-creatinine ratio and eGFR) for patients who have had type 1 diabetes for ≥5 years and all patients who have type 2 diabetes. Two out of 3 abnormal specimens collected within a 3- to 6-month period indicate the presence of albuminuria.

What can be done to prevent or slow the progression of DKD?

Optimal BP and glycemic control are key,^29-35 along with diet and medication. For patients with DKD, dietary protein intake should be 0.8 g/kg body weight per day. ACE inhibitors and ARBs have been shown to slow the decline in eGFR in patients with elevated urinary albumin excretion (≥30 mg/day).

The ADA sees a role for ezetimibe for select patients, based on studiessuch as the IMPROVE IT trial that included participants with diabetes.

However, neither an ACE inhibitor nor an ARB is recommended for the primary prevention of DKD in patients who have normal BP, normal urine albumin-to-creatinine ratio (<30 mg/g), and normal eGFR. In addition, combined use of an ACE inhibitor and an ARB should be avoided, as it provides no additional benefit and increases the risk of adverse effects.²⁹

RETINOPATHY

How should I manage retinopathy in patients with diabetes?

As with the management of DKD, it is important to optimize glycemic and BP control to reduce the risk, or slow the progression, of retinopathy. Intensive diabetes management, with the goal of achieving near-normal glycemic levels, has been shown in large prospective randomized studies to prevent or delay the onset and progression of diabetic retinopathy.^33,36 The presence of retinopathy is not a contraindication to aspirin therapy for ASCVD prevention, as aspirin does not increase the risk of retinal hemorrhage.

When should patients with diabetes be screened for retinopathy?

Patients with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years of the onset of diabetes. Those with type 2 diabetes should have such an exam shortly after diagnosis. The exam should be repeated annually; if there is no evidence of retinopathy, however, 2-year intervals may be considered.

PERIPHERAL NEUROPATHY

When and how should I screen patients with diabetes for neuropathy?

All patients should be screened for diabetic peripheral neuropathy (DPN) starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes, and continued at least annually thereafter. Assessment should include a detailed history and 10-g monofilament testing, as well as at least one of the following tests: pinprick, temperature, and vibration sensation.

It is important, too, to screen patients with more advanced diabetes for signs and symptoms of autonomic neuropathy. Signs and symptoms may include resting tachycardia, exercise intolerance, orthostatic hypotension, gastroparesis, constipation, impaired neurovascular function, and autonomic failure in response to hypoglycemia. In men, diabetic autonomic neuropathy may cause erectile dysfunction and/or retrograde ejaculation.

How should I manage patients who have DPN?

Tight glycemic control is the only measure that has been shown to prevent or delay the development of DPN or cardiac autonomic neuropathy in patients with type 1 diabetes,^37,38 and to slow the progression of neuropathy in some patients with type 2 diabetes.³⁹

The FDA has approved pregabalin, duloxetine, and tapentadol for the treatment of pain associated with DPN. Tricyclic antidepressants, gabapentin, venlafaxine, carbamazepine, tramadol, and topical capsaicin, although not approved for the treatment of painful DPN, may also be effective in treating neuropathic pain.

For those with autonomic neuropathy, dietary changes and prokinetic agents such as erythromycin may alleviate gastroparesis. Due to extrapyramidal adverse effects, metoclopramide is reserved for the most severe and unresponsive cases. Recurrent urinary tract infections, pyelonephritis, incontinence, or palpable bladder should prompt an evaluation for bladder dysfunction. Controlling lipids and BP, quitting smoking, and making other lifestyle changes can reduce both the development and the progression of autonomic neuropathy.

The presence of retinopathy is not a contraindication to aspirin therapy for atherosclerotic cardiovascular disease prevention, as aspirin does not increase the risk of retinal hemorrhage.

FOOT CARE/PERIPHERAL ARTERIAL DISEASE

What does the ADA recommend regarding foot care for patients with diabetes?

The ADA’s standards recommend an annual comprehensive foot examination to identify risk factors predictive of ulcers and potential amputations. The exam should start with inspection and assessment of foot pulses and should seek to identify loss of peripheral sensation. The examination should include inspection of the skin, assessment of foot deformities, neurologic assessment including 10-g monofilament testing and pinprick or vibration testing or assessment of ankle reflexes, and vascular assessment, including pulses in the legs and feet.⁴⁰

It is also important to screen patients for peripheral arterial disease (PAD), with a comprehensive medical history and physical exam of pulses. Ankle-brachial index testing (ABI) should be performed in patients with signs or symptoms of PAD, including claudication or skin and hair changes in the lower extremities. ABI may be considered for all patients with diabetes starting at age 50 and in those younger than 50 years who have risk factors.⁴¹

Which patients with diabetes are at higher risk for foot complications?

The following are risk factors for foot complications: previous amputation, prior foot ulcer, peripheral neuropathy, foot deformity, peripheral vascular disease, visual impairment, peripheral neuropathy (especially if on dialysis), poor glycemic control, and smoking. Patients with high-risk foot conditions should be educated about their risk and appropriate management.

A well-fitted walking shoe that cushions the feet and redistributes pressure is one option to help patients. Patients with bony deformities may need extra wide or deep shoes and patients with more advanced disease may need custom-fitted shoes.

When should patients be referred to a foot specialist?

Refer patients to a foot care specialist for ongoing preventive care and lifelong surveillance if they smoke or have a history of lower-extremity complications, a loss of protective sensation, structural abnormalities, or PAD.

Prevention of diabetes, as well as early detection and treatment of both prediabetes and diabetes, is critical to the health of our country. Because evidence-based guidelines are key to our ability to effectively address the nation’s diabetes epidemic, the American Diabetes Association (ADA) updates its “Standards of Medical Care in Diabetes” annually to incorporate new evidence or clarifications.

The 2016 standards,¹ available at professional.diabetes.org/jfp, are a valuable resource. Among the latest revisions: an expansion in screening recommendations, a change in the age at which aspirin therapy for women should be considered, and a change in A1C goals for pregnant women with diabetes.

As members of the ADA’s primary care advisory group, we use a question and answer format in the summary that follows to highlight recent revisions and review other recommendations that are of particular relevance to physicians in primary care. It is important to note, however, that ADA recommendations are not intended to preclude clinical judgment and should be applied in the context of excellent medical care.

Diagnosis and screening

Have the 2016 ADA standards changed the way diabetes is diagnosed?

No. The criteria for a diagnosis of diabetes did not change. Diabetes and prediabetes are still screened for and diagnosed with any of the following: a fasting plasma glucose (FPG); a 2-hour 75-g oral glucose tolerance test (OGTT); a random plasma glucose >200 mg/dL with symptoms of hyperglycemia; or A1C criteria (TABLE 1).^1,2 The wording was changed, however, to make it clear that no one test is preferred over another for diagnosis.

Yes. In addition to screening asymptomatic adults of any age who are overweight or obese and have one or more additional risk factors for diabetes, the 2016 standards recommend screening all adults 45 years and older, regardless of weight.

Is an A1C <7% the recommended treatment goal for everyone with diabetes?

No. An A1C <7% is considered reasonable for most, but not all, nonpregnant adults. In the last few years, the ADA has focused more on individualized targets.

Tighter control (<6.5%)—which is associated with lower rates of eye disease, kidney disease, and nerve damage—may be appropriate for patients who have no significant hypoglycemia, no cardiovascular disease (CVD), a shorter duration of diabetes, or a longer expected lifespan.

Conversely, a higher target (<8%) may be appropriate for patients who are older, have longstanding diabetes, advanced macrovascular or microvascular disease, established complications, or a limited life expectancy.^3,4

The latest ADA revisions include an expansion in screening recommendations and changes in the age at which aspirin therapy for women should be considered and in A1C goals for pregnant women with diabetes.

Pregnancy. The 2016 standards have a new target for pregnant women with diabetes: The ADA previously recommended an A1C <6% for this patient population, but now recommends a target A1C between 6% and 6.5%. This may be tightened or relaxed, however, depending on individual risk of hypoglycemia.

In focusing on individualized targets and hypoglycemia avoidance, the ADA notes that attention must be paid to fasting, pre-meal, and post-meal blood glucose levels to achieve treatment goals. The 2016 standards emphasize the importance of patient-centered diabetes care, aligned with a coordinated, team-based chronic care model.

Diabetes self-management education and support is indicated for those who are newly diagnosed, and should be provided periodically based on glucose control and progression of the disease. All patients should receive education on hypoglycemia risk and treatment.

Prediabetes and prevention

What is prediabetes and what can I do to prevent patients with prediabetes from developing diabetes?

Patients with impaired glucose tolerance, impaired fasting glucose, or an A1C between 5.7% and 6.4% are considered to have prediabetes and are at risk for developing type 2 diabetes.

Family physicians should refer patients with prediabetes to intensive diet, physical activity, and behavioral counseling programs like those based on the Diabetes Prevention Program study (www.niddk.nih.gov/about-niddk/research-areas/diabetes/diabetes-prevention-program-dpp/Pages/default.aspx). Goals should include a minimum 7% weight loss and moderate-intensity physical activity, such as brisk walking, for at least 150 minutes per week.

For patients with diabetes, a sustained weight loss of 5% may improve glycemic control and reduce the need for medication.

Lifestyle modification programs have been shown to be very effective in preventing diabetes, with about a 58% reduction in the risk of developing type 2 diabetes after 3 years.⁵ The 2016 standards added a recommendation that physicians encourage the use of new technology, such as text messaging or smart phone apps, to support such efforts.

Should I consider initiating oral antiglycemics in patients with prediabetes?

Yes. Pharmacologic agents, including metformin, acarbose, and pioglitazone, have been shown to decrease progression from prediabetes to type 2 diabetes. Thus, antiglycemics should be considered for certain patients. Metformin is especially appropriate for women with a history of gestational diabetes, patients who are younger than 60 years, and those who have a body mass index (BMI) ≥35 kg/m².⁶

How often should I screen patients with prediabetes?

Patients with prediabetes should be screened annually. Such individuals should also be screened and treated for modifiable cardiovascular risk factors. There is strong evidence that the treatment of obesity can be beneficial for those at any stage of the diabetes spectrum.

© 2016 Joe Gorman

Obesity management

What do the 2016 ADA standards recommend for obese patients with diabetes?

With more than two-thirds of Americans either overweight or obese, the ADA added a new section on obesity management and calls on health care providers to:

• weigh patients and calculate and document their BMI at every visit, and
• counsel those who are overweight or obese on the benefits of even modest weight loss.

The ADA recommends a sustained weight loss of 5%, which can improve glycemic control and reduce the need for diabetes medications,^7-9 although weight loss of ≥7% is optimal. Physicians are also called on to assess each patient’s readiness to engage in therapeutic lifestyle change to maintain a modest weight loss.

Treatment for obesity can include therapeutic lifestyle change (reduction in calories, increase in physical activity) and behavioral therapy. For refractory patients, pharmacologic therapy and bariatric surgery may be considered.

Interventions should be high-intensity (≥16 sessions in 6 months) and focus on diet, physical activity, and behavioral strategies to achieve a 500 to 750 calorie deficit per day.¹⁰ Long-term (≥1 year) comprehensive weight maintenance programs should be prescribed for those who achieve short-term weight loss.^11,12 Such programs should provide at least monthly contact and encourage ongoing monitoring of body weight (weekly or more frequently), continued consumption of a reduced-calorie diet, and participation in high levels of physical activity (200 to 300 minutes per week).

Glycemic treatment

What are some of the key factors that distinguish the different type 2 diabetes medications from one another?

An increasing understanding of diabetes pathophysiology has led to a wider array of medications, making treatment more complex than ever. It is important for physicians to have a strong working knowledge of the various classes of antidiabetic agents and the subtleties between drugs in the same class to best individualize treatment.

Here are the highlights of each class of medication listed in the ADA/European Association for the Study of Diabetes algorithm for the management of type 2 diabetes,¹³ which is available at http://care.diabetesjournals.org/content/38/1/140/F2.large.jpg):

Metformin is the preferred initial medication for all patients who can tolerate it and have no contraindications. The drug is cost-effective, weight neutral, and has had positive cardiovascular and mortality outcomes in long-term studies. Adverse gastrointestinal (GI) effects, including nausea, diarrhea, and dyspepsia, are common but can be reduced with a slow titration of the drug. Metformin should be used with caution in those with renal disease. The dose should be reduced if the estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m² and the drug discontinued if eGFR <30 mL/min/1.73 m².

Sulfonylureas/meglitinides stimulate insulin secretion in a glucose-independent manner. They are cost-effective and have high efficacy early in the disease and with initial use, but the effect wanes as the disease progresses. This class of drugs is associated with weight gain and hypoglycemia. Second-generation sulfonylureas (glipizide, glimepiride) are recommended; meglitinides are more expensive than sulfonylureas.

Patients who fail to achieve or maintain their A1C goal after one year may need to begin insulin therapy.

Thiazolidinediones work to improve insulin sensitivity in the periphery and have a low risk of hypoglycemia. They have been associated with fluid retention, weight gain, and worsening of pre-existing congestive heart failure, but previous cardiovascular concerns (with rosiglitazone)¹⁴ and bladder cancer risks (with pioglitazone)^15-17 have been refuted. Thiazolidinediones are contraindicated in those with Class III and IV congestive heart failure, however, and patients taking them require careful monitoring for weight gain, fluid retention, and exacerbation of heart failure.

Dipeptidyl peptidase-4 inhibitors (DPP4Is) work to reduce the breakdown of endogenous incretin hormones. These oral agents increase insulin secretion in a glucose-dependent manner; more insulin is secreted when glucose is higher and less when glucose is closer to normal. This means that there is a much lower risk of hypoglycemia when a DPP4I is used as monotherapy.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs), which are injectable, also work via incretin hormones and stimulate insulin in a glucose-dependent manner. They are associated with weight loss and low rates of hypoglycemia. Adverse GI effects are common with this class of drugs, but can be reduced by titrating the medication and avoiding overeating. GLP-1RAs can be taken twice daily to once weekly, depending on the specific agent.

Sodium glucose transporter 2 inhibitors (SGLT2Is) are oral agents and the newest class of antidiabetes drugs. The drugs help block the reabsorption of glucose, thereby lowering glucose levels, blood pressure, and weight in many patients. The most common adverse effects are urinary tract and genital yeast infections. SGLT2Is should not be given to patients with advanced renal disease (chronic kidney disease Stages 3B-5) because they will not be effectively absorbed.

The US Food and Drug Administration (FDA) recently issued a warning about the risk of ketoacidosis with these agents,¹⁸ and patients should be advised to stop taking them and to seek immediate medical attention if they develop symptoms of ketoacidosis, such as excessive thirst, frequent urination, nausea and vomiting, abdominal pain, weakness or fatigue, shortness of breath, fruity-scented breath, or confusion.

Insulin is eventually needed by most patients with type 2 diabetes who live long enough to see the disease progress. The most common adverse effects are weight gain and hypoglycemia. There are many types of insulin, but only one that is delivered via inhalation—human insulin inhaled powder. Inhaled insulin, however, has the potential for adverse pulmonary effects, including cough and reduction of peak expiratory flow. Therefore, pulmonary function testing is recommended prior to its use.

Treatment goal attainment should be evaluated every 3 months, and treatment titrated at 3-month intervals if goals are not achieved. The ADA/European Association for the Study of Diabetes’ algorithm indicates that patients are likely to need insulin a year after diagnosis if their A1C goal has not been achieved or maintained.¹³

The following medications are not included in the algorithm but are included in the 2016 standards, and may be helpful for certain patients:

Alpha-glucosidase inhibitors delay the absorption of glucose from the proximal to distal GI tract, thereby reducing postprandial hyperglycemia. Flatulence and leakage of stool—the most common adverse effects—have limited their use in the United States.

Patients ≥40 years will need moderate- to high-intensity statin therapy to lower their atherosclerotic cardiovascular disease risk.

Bile acid sequestrants (colesevelam) treat both hyperlipidemia and diabetes. The medications work by reducing glucose absorption from the GI tract. They reduce postprandial hyperglycemia, with a low risk of hypoglycemia. Colesevelam’s use is limited, however, because of the number of pills needed (6 daily).

Bromocriptine affects satiety levels via the central nervous system, and is available in a specific formulation for the treatment of diabetes. “First-dose” hypotension, however, is an adverse effect of considerable concern.¹

Pramlintide, an injectable amylin mimetic given to patients on prandial insulin, can reduce postprandial glucose levels. The most common adverse effects are upper GI symptoms and hypoglycemia. Due to the adverse effects and the need for an injection with each meal, pramlintide is used infrequently.

Cardiovascular risk reduction

Has the ADA revised its recommendations for cardiovascular disease risk management?

Yes. There have been several changes. The first is in terminology, with atherosclerotic cardiovascular disease (ASCVD) replacing CVD alone. While new recommendations for statin therapy for adults older than 40 years (TABLE 2)¹ were also added, the emphasis remains on therapeutic lifestyle change as an effective treatment for hypertension. These modifications should include at least 150 minutes of moderate physical activity per week and, for most patients, a reduction in total calories, saturated fat, and sodium.

It is important to remind patients that to maximize the benefits in terms of treating hyperglycemia, hypertension, and dyslipidemia, such changes must be maintained over the long term.

Aspirin therapy. The ADA also revised its recommendation regarding aspirin therapy. Based on new evidence in the treatment of women with ASCVD risk, the standards now call for considering aspirin therapy (75-162 mg/d) in both women and men ≥50 years as a primary prevention strategy for those with type 1 or type 2 diabetes with a 10-year ASCVD risk of >10%. (The previous standards recommended this only for women older than 60 years.)

Antiplatelet therapy is now recommended for patients younger than 50 years with multiple risk factors, and as secondary prevention in those with a history of ASCVD.^19-21

Hypertension. The ADA’s recommendations for treating hypertension in patients with diabetes have not changed; the goal remains <140/<90 mm Hg. Lower targets may be appropriate for younger patients, those with albuminuria, and individuals with additional CVD risk factors; however, systolic pressure <130 mm Hg has not been shown to reduce CVD outcomes, and diastolic pressure <70 mm Hg has been associated with higher mortality.²²

Optimal medication and lifestyle therapy are important to achieve goals, with avoidance of undue treatment burden. Angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), but not both, should be included as part of treatment. Other agents, such as a thiazide diuretic, may be needed to achieve individual goals. Serum creatinine/eGFR and serum potassium levels should be monitored with the use of diuretics.

Lipids. The 2016 standards include notable changes in lipid management. The ADA sees a role for ezetimibe for select patients, based on studies such as the IMPROVE IT trial²³ that included participants with diabetes. The ADA also added a table highlighting statin recommendations and delineating high and moderate-intensity statins (TABLE 3).¹ Those younger than 40 years with no other risk factors may not need a statin, but patients ages 40 or older will need moderate- to high-intensity statin therapy to effectively lower ASCVD risk.^24-28

These recommendations reflect a comprehensive plan to reduce ASCVD in this at-risk population, which should also include lifestyle modification, including smoking prevention and quit strategies, as needed.

Microvascular complications

DIABETIC KIDNEY DISEASE

How should I diagnose nephropathy?

The ADA changed the terminology, referring to “diabetic kidney disease” (DKD) rather than nephropathy to highlight the fact that the focus is on kidney disease directly linked to diabetes.

Other recommendations include an annual assessment of urinary albumin (eg, spot urine albumin-to-creatinine ratio and eGFR) for patients who have had type 1 diabetes for ≥5 years and all patients who have type 2 diabetes. Two out of 3 abnormal specimens collected within a 3- to 6-month period indicate the presence of albuminuria.

What can be done to prevent or slow the progression of DKD?

Optimal BP and glycemic control are key,^29-35 along with diet and medication. For patients with DKD, dietary protein intake should be 0.8 g/kg body weight per day. ACE inhibitors and ARBs have been shown to slow the decline in eGFR in patients with elevated urinary albumin excretion (≥30 mg/day).

The ADA sees a role for ezetimibe for select patients, based on studiessuch as the IMPROVE IT trial that included participants with diabetes.

However, neither an ACE inhibitor nor an ARB is recommended for the primary prevention of DKD in patients who have normal BP, normal urine albumin-to-creatinine ratio (<30 mg/g), and normal eGFR. In addition, combined use of an ACE inhibitor and an ARB should be avoided, as it provides no additional benefit and increases the risk of adverse effects.²⁹

RETINOPATHY

How should I manage retinopathy in patients with diabetes?

As with the management of DKD, it is important to optimize glycemic and BP control to reduce the risk, or slow the progression, of retinopathy. Intensive diabetes management, with the goal of achieving near-normal glycemic levels, has been shown in large prospective randomized studies to prevent or delay the onset and progression of diabetic retinopathy.^33,36 The presence of retinopathy is not a contraindication to aspirin therapy for ASCVD prevention, as aspirin does not increase the risk of retinal hemorrhage.

When should patients with diabetes be screened for retinopathy?

Patients with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years of the onset of diabetes. Those with type 2 diabetes should have such an exam shortly after diagnosis. The exam should be repeated annually; if there is no evidence of retinopathy, however, 2-year intervals may be considered.

PERIPHERAL NEUROPATHY

When and how should I screen patients with diabetes for neuropathy?

All patients should be screened for diabetic peripheral neuropathy (DPN) starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes, and continued at least annually thereafter. Assessment should include a detailed history and 10-g monofilament testing, as well as at least one of the following tests: pinprick, temperature, and vibration sensation.

It is important, too, to screen patients with more advanced diabetes for signs and symptoms of autonomic neuropathy. Signs and symptoms may include resting tachycardia, exercise intolerance, orthostatic hypotension, gastroparesis, constipation, impaired neurovascular function, and autonomic failure in response to hypoglycemia. In men, diabetic autonomic neuropathy may cause erectile dysfunction and/or retrograde ejaculation.

How should I manage patients who have DPN?

Tight glycemic control is the only measure that has been shown to prevent or delay the development of DPN or cardiac autonomic neuropathy in patients with type 1 diabetes,^37,38 and to slow the progression of neuropathy in some patients with type 2 diabetes.³⁹

The FDA has approved pregabalin, duloxetine, and tapentadol for the treatment of pain associated with DPN. Tricyclic antidepressants, gabapentin, venlafaxine, carbamazepine, tramadol, and topical capsaicin, although not approved for the treatment of painful DPN, may also be effective in treating neuropathic pain.

For those with autonomic neuropathy, dietary changes and prokinetic agents such as erythromycin may alleviate gastroparesis. Due to extrapyramidal adverse effects, metoclopramide is reserved for the most severe and unresponsive cases. Recurrent urinary tract infections, pyelonephritis, incontinence, or palpable bladder should prompt an evaluation for bladder dysfunction. Controlling lipids and BP, quitting smoking, and making other lifestyle changes can reduce both the development and the progression of autonomic neuropathy.

The presence of retinopathy is not a contraindication to aspirin therapy for atherosclerotic cardiovascular disease prevention, as aspirin does not increase the risk of retinal hemorrhage.

FOOT CARE/PERIPHERAL ARTERIAL DISEASE

What does the ADA recommend regarding foot care for patients with diabetes?

The ADA’s standards recommend an annual comprehensive foot examination to identify risk factors predictive of ulcers and potential amputations. The exam should start with inspection and assessment of foot pulses and should seek to identify loss of peripheral sensation. The examination should include inspection of the skin, assessment of foot deformities, neurologic assessment including 10-g monofilament testing and pinprick or vibration testing or assessment of ankle reflexes, and vascular assessment, including pulses in the legs and feet.⁴⁰

It is also important to screen patients for peripheral arterial disease (PAD), with a comprehensive medical history and physical exam of pulses. Ankle-brachial index testing (ABI) should be performed in patients with signs or symptoms of PAD, including claudication or skin and hair changes in the lower extremities. ABI may be considered for all patients with diabetes starting at age 50 and in those younger than 50 years who have risk factors.⁴¹

Which patients with diabetes are at higher risk for foot complications?

The following are risk factors for foot complications: previous amputation, prior foot ulcer, peripheral neuropathy, foot deformity, peripheral vascular disease, visual impairment, peripheral neuropathy (especially if on dialysis), poor glycemic control, and smoking. Patients with high-risk foot conditions should be educated about their risk and appropriate management.

A well-fitted walking shoe that cushions the feet and redistributes pressure is one option to help patients. Patients with bony deformities may need extra wide or deep shoes and patients with more advanced disease may need custom-fitted shoes.

When should patients be referred to a foot specialist?

Refer patients to a foot care specialist for ongoing preventive care and lifelong surveillance if they smoke or have a history of lower-extremity complications, a loss of protective sensation, structural abnormalities, or PAD.

Prevention of diabetes, as well as early detection and treatment of both prediabetes and diabetes, is critical to the health of our country. Because evidence-based guidelines are key to our ability to effectively address the nation’s diabetes epidemic, the American Diabetes Association (ADA) updates its “Standards of Medical Care in Diabetes” annually to incorporate new evidence or clarifications.

The 2016 standards,¹ available at professional.diabetes.org/jfp, are a valuable resource. Among the latest revisions: an expansion in screening recommendations, a change in the age at which aspirin therapy for women should be considered, and a change in A1C goals for pregnant women with diabetes.

As members of the ADA’s primary care advisory group, we use a question and answer format in the summary that follows to highlight recent revisions and review other recommendations that are of particular relevance to physicians in primary care. It is important to note, however, that ADA recommendations are not intended to preclude clinical judgment and should be applied in the context of excellent medical care.

Diagnosis and screening

Have the 2016 ADA standards changed the way diabetes is diagnosed?

No. The criteria for a diagnosis of diabetes did not change. Diabetes and prediabetes are still screened for and diagnosed with any of the following: a fasting plasma glucose (FPG); a 2-hour 75-g oral glucose tolerance test (OGTT); a random plasma glucose >200 mg/dL with symptoms of hyperglycemia; or A1C criteria (TABLE 1).^1,2 The wording was changed, however, to make it clear that no one test is preferred over another for diagnosis.

Yes. In addition to screening asymptomatic adults of any age who are overweight or obese and have one or more additional risk factors for diabetes, the 2016 standards recommend screening all adults 45 years and older, regardless of weight.

Is an A1C <7% the recommended treatment goal for everyone with diabetes?

No. An A1C <7% is considered reasonable for most, but not all, nonpregnant adults. In the last few years, the ADA has focused more on individualized targets.

Tighter control (<6.5%)—which is associated with lower rates of eye disease, kidney disease, and nerve damage—may be appropriate for patients who have no significant hypoglycemia, no cardiovascular disease (CVD), a shorter duration of diabetes, or a longer expected lifespan.

Conversely, a higher target (<8%) may be appropriate for patients who are older, have longstanding diabetes, advanced macrovascular or microvascular disease, established complications, or a limited life expectancy.^3,4

The latest ADA revisions include an expansion in screening recommendations and changes in the age at which aspirin therapy for women should be considered and in A1C goals for pregnant women with diabetes.

Pregnancy. The 2016 standards have a new target for pregnant women with diabetes: The ADA previously recommended an A1C <6% for this patient population, but now recommends a target A1C between 6% and 6.5%. This may be tightened or relaxed, however, depending on individual risk of hypoglycemia.

In focusing on individualized targets and hypoglycemia avoidance, the ADA notes that attention must be paid to fasting, pre-meal, and post-meal blood glucose levels to achieve treatment goals. The 2016 standards emphasize the importance of patient-centered diabetes care, aligned with a coordinated, team-based chronic care model.

Diabetes self-management education and support is indicated for those who are newly diagnosed, and should be provided periodically based on glucose control and progression of the disease. All patients should receive education on hypoglycemia risk and treatment.

Prediabetes and prevention

What is prediabetes and what can I do to prevent patients with prediabetes from developing diabetes?

Patients with impaired glucose tolerance, impaired fasting glucose, or an A1C between 5.7% and 6.4% are considered to have prediabetes and are at risk for developing type 2 diabetes.

Family physicians should refer patients with prediabetes to intensive diet, physical activity, and behavioral counseling programs like those based on the Diabetes Prevention Program study (www.niddk.nih.gov/about-niddk/research-areas/diabetes/diabetes-prevention-program-dpp/Pages/default.aspx). Goals should include a minimum 7% weight loss and moderate-intensity physical activity, such as brisk walking, for at least 150 minutes per week.

For patients with diabetes, a sustained weight loss of 5% may improve glycemic control and reduce the need for medication.

Lifestyle modification programs have been shown to be very effective in preventing diabetes, with about a 58% reduction in the risk of developing type 2 diabetes after 3 years.⁵ The 2016 standards added a recommendation that physicians encourage the use of new technology, such as text messaging or smart phone apps, to support such efforts.

Should I consider initiating oral antiglycemics in patients with prediabetes?

Yes. Pharmacologic agents, including metformin, acarbose, and pioglitazone, have been shown to decrease progression from prediabetes to type 2 diabetes. Thus, antiglycemics should be considered for certain patients. Metformin is especially appropriate for women with a history of gestational diabetes, patients who are younger than 60 years, and those who have a body mass index (BMI) ≥35 kg/m².⁶

How often should I screen patients with prediabetes?

Patients with prediabetes should be screened annually. Such individuals should also be screened and treated for modifiable cardiovascular risk factors. There is strong evidence that the treatment of obesity can be beneficial for those at any stage of the diabetes spectrum.

© 2016 Joe Gorman

Obesity management

What do the 2016 ADA standards recommend for obese patients with diabetes?

With more than two-thirds of Americans either overweight or obese, the ADA added a new section on obesity management and calls on health care providers to:

• weigh patients and calculate and document their BMI at every visit, and
• counsel those who are overweight or obese on the benefits of even modest weight loss.

The ADA recommends a sustained weight loss of 5%, which can improve glycemic control and reduce the need for diabetes medications,^7-9 although weight loss of ≥7% is optimal. Physicians are also called on to assess each patient’s readiness to engage in therapeutic lifestyle change to maintain a modest weight loss.

Treatment for obesity can include therapeutic lifestyle change (reduction in calories, increase in physical activity) and behavioral therapy. For refractory patients, pharmacologic therapy and bariatric surgery may be considered.

Interventions should be high-intensity (≥16 sessions in 6 months) and focus on diet, physical activity, and behavioral strategies to achieve a 500 to 750 calorie deficit per day.¹⁰ Long-term (≥1 year) comprehensive weight maintenance programs should be prescribed for those who achieve short-term weight loss.^11,12 Such programs should provide at least monthly contact and encourage ongoing monitoring of body weight (weekly or more frequently), continued consumption of a reduced-calorie diet, and participation in high levels of physical activity (200 to 300 minutes per week).

Glycemic treatment

What are some of the key factors that distinguish the different type 2 diabetes medications from one another?

An increasing understanding of diabetes pathophysiology has led to a wider array of medications, making treatment more complex than ever. It is important for physicians to have a strong working knowledge of the various classes of antidiabetic agents and the subtleties between drugs in the same class to best individualize treatment.

Here are the highlights of each class of medication listed in the ADA/European Association for the Study of Diabetes algorithm for the management of type 2 diabetes,¹³ which is available at http://care.diabetesjournals.org/content/38/1/140/F2.large.jpg):

Metformin is the preferred initial medication for all patients who can tolerate it and have no contraindications. The drug is cost-effective, weight neutral, and has had positive cardiovascular and mortality outcomes in long-term studies. Adverse gastrointestinal (GI) effects, including nausea, diarrhea, and dyspepsia, are common but can be reduced with a slow titration of the drug. Metformin should be used with caution in those with renal disease. The dose should be reduced if the estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m² and the drug discontinued if eGFR <30 mL/min/1.73 m².

Sulfonylureas/meglitinides stimulate insulin secretion in a glucose-independent manner. They are cost-effective and have high efficacy early in the disease and with initial use, but the effect wanes as the disease progresses. This class of drugs is associated with weight gain and hypoglycemia. Second-generation sulfonylureas (glipizide, glimepiride) are recommended; meglitinides are more expensive than sulfonylureas.

Patients who fail to achieve or maintain their A1C goal after one year may need to begin insulin therapy.

Thiazolidinediones work to improve insulin sensitivity in the periphery and have a low risk of hypoglycemia. They have been associated with fluid retention, weight gain, and worsening of pre-existing congestive heart failure, but previous cardiovascular concerns (with rosiglitazone)¹⁴ and bladder cancer risks (with pioglitazone)^15-17 have been refuted. Thiazolidinediones are contraindicated in those with Class III and IV congestive heart failure, however, and patients taking them require careful monitoring for weight gain, fluid retention, and exacerbation of heart failure.

Dipeptidyl peptidase-4 inhibitors (DPP4Is) work to reduce the breakdown of endogenous incretin hormones. These oral agents increase insulin secretion in a glucose-dependent manner; more insulin is secreted when glucose is higher and less when glucose is closer to normal. This means that there is a much lower risk of hypoglycemia when a DPP4I is used as monotherapy.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs), which are injectable, also work via incretin hormones and stimulate insulin in a glucose-dependent manner. They are associated with weight loss and low rates of hypoglycemia. Adverse GI effects are common with this class of drugs, but can be reduced by titrating the medication and avoiding overeating. GLP-1RAs can be taken twice daily to once weekly, depending on the specific agent.

Sodium glucose transporter 2 inhibitors (SGLT2Is) are oral agents and the newest class of antidiabetes drugs. The drugs help block the reabsorption of glucose, thereby lowering glucose levels, blood pressure, and weight in many patients. The most common adverse effects are urinary tract and genital yeast infections. SGLT2Is should not be given to patients with advanced renal disease (chronic kidney disease Stages 3B-5) because they will not be effectively absorbed.

The US Food and Drug Administration (FDA) recently issued a warning about the risk of ketoacidosis with these agents,¹⁸ and patients should be advised to stop taking them and to seek immediate medical attention if they develop symptoms of ketoacidosis, such as excessive thirst, frequent urination, nausea and vomiting, abdominal pain, weakness or fatigue, shortness of breath, fruity-scented breath, or confusion.

Insulin is eventually needed by most patients with type 2 diabetes who live long enough to see the disease progress. The most common adverse effects are weight gain and hypoglycemia. There are many types of insulin, but only one that is delivered via inhalation—human insulin inhaled powder. Inhaled insulin, however, has the potential for adverse pulmonary effects, including cough and reduction of peak expiratory flow. Therefore, pulmonary function testing is recommended prior to its use.

Treatment goal attainment should be evaluated every 3 months, and treatment titrated at 3-month intervals if goals are not achieved. The ADA/European Association for the Study of Diabetes’ algorithm indicates that patients are likely to need insulin a year after diagnosis if their A1C goal has not been achieved or maintained.¹³

The following medications are not included in the algorithm but are included in the 2016 standards, and may be helpful for certain patients:

Alpha-glucosidase inhibitors delay the absorption of glucose from the proximal to distal GI tract, thereby reducing postprandial hyperglycemia. Flatulence and leakage of stool—the most common adverse effects—have limited their use in the United States.

Patients ≥40 years will need moderate- to high-intensity statin therapy to lower their atherosclerotic cardiovascular disease risk.

Bile acid sequestrants (colesevelam) treat both hyperlipidemia and diabetes. The medications work by reducing glucose absorption from the GI tract. They reduce postprandial hyperglycemia, with a low risk of hypoglycemia. Colesevelam’s use is limited, however, because of the number of pills needed (6 daily).

Bromocriptine affects satiety levels via the central nervous system, and is available in a specific formulation for the treatment of diabetes. “First-dose” hypotension, however, is an adverse effect of considerable concern.¹

Pramlintide, an injectable amylin mimetic given to patients on prandial insulin, can reduce postprandial glucose levels. The most common adverse effects are upper GI symptoms and hypoglycemia. Due to the adverse effects and the need for an injection with each meal, pramlintide is used infrequently.

Cardiovascular risk reduction

Has the ADA revised its recommendations for cardiovascular disease risk management?

Yes. There have been several changes. The first is in terminology, with atherosclerotic cardiovascular disease (ASCVD) replacing CVD alone. While new recommendations for statin therapy for adults older than 40 years (TABLE 2)¹ were also added, the emphasis remains on therapeutic lifestyle change as an effective treatment for hypertension. These modifications should include at least 150 minutes of moderate physical activity per week and, for most patients, a reduction in total calories, saturated fat, and sodium.

It is important to remind patients that to maximize the benefits in terms of treating hyperglycemia, hypertension, and dyslipidemia, such changes must be maintained over the long term.

Aspirin therapy. The ADA also revised its recommendation regarding aspirin therapy. Based on new evidence in the treatment of women with ASCVD risk, the standards now call for considering aspirin therapy (75-162 mg/d) in both women and men ≥50 years as a primary prevention strategy for those with type 1 or type 2 diabetes with a 10-year ASCVD risk of >10%. (The previous standards recommended this only for women older than 60 years.)

Antiplatelet therapy is now recommended for patients younger than 50 years with multiple risk factors, and as secondary prevention in those with a history of ASCVD.^19-21

Hypertension. The ADA’s recommendations for treating hypertension in patients with diabetes have not changed; the goal remains <140/<90 mm Hg. Lower targets may be appropriate for younger patients, those with albuminuria, and individuals with additional CVD risk factors; however, systolic pressure <130 mm Hg has not been shown to reduce CVD outcomes, and diastolic pressure <70 mm Hg has been associated with higher mortality.²²

Optimal medication and lifestyle therapy are important to achieve goals, with avoidance of undue treatment burden. Angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), but not both, should be included as part of treatment. Other agents, such as a thiazide diuretic, may be needed to achieve individual goals. Serum creatinine/eGFR and serum potassium levels should be monitored with the use of diuretics.

Lipids. The 2016 standards include notable changes in lipid management. The ADA sees a role for ezetimibe for select patients, based on studies such as the IMPROVE IT trial²³ that included participants with diabetes. The ADA also added a table highlighting statin recommendations and delineating high and moderate-intensity statins (TABLE 3).¹ Those younger than 40 years with no other risk factors may not need a statin, but patients ages 40 or older will need moderate- to high-intensity statin therapy to effectively lower ASCVD risk.^24-28

These recommendations reflect a comprehensive plan to reduce ASCVD in this at-risk population, which should also include lifestyle modification, including smoking prevention and quit strategies, as needed.

Microvascular complications

DIABETIC KIDNEY DISEASE

How should I diagnose nephropathy?

The ADA changed the terminology, referring to “diabetic kidney disease” (DKD) rather than nephropathy to highlight the fact that the focus is on kidney disease directly linked to diabetes.

Other recommendations include an annual assessment of urinary albumin (eg, spot urine albumin-to-creatinine ratio and eGFR) for patients who have had type 1 diabetes for ≥5 years and all patients who have type 2 diabetes. Two out of 3 abnormal specimens collected within a 3- to 6-month period indicate the presence of albuminuria.

What can be done to prevent or slow the progression of DKD?

Optimal BP and glycemic control are key,^29-35 along with diet and medication. For patients with DKD, dietary protein intake should be 0.8 g/kg body weight per day. ACE inhibitors and ARBs have been shown to slow the decline in eGFR in patients with elevated urinary albumin excretion (≥30 mg/day).

The ADA sees a role for ezetimibe for select patients, based on studiessuch as the IMPROVE IT trial that included participants with diabetes.

However, neither an ACE inhibitor nor an ARB is recommended for the primary prevention of DKD in patients who have normal BP, normal urine albumin-to-creatinine ratio (<30 mg/g), and normal eGFR. In addition, combined use of an ACE inhibitor and an ARB should be avoided, as it provides no additional benefit and increases the risk of adverse effects.²⁹

RETINOPATHY

How should I manage retinopathy in patients with diabetes?

As with the management of DKD, it is important to optimize glycemic and BP control to reduce the risk, or slow the progression, of retinopathy. Intensive diabetes management, with the goal of achieving near-normal glycemic levels, has been shown in large prospective randomized studies to prevent or delay the onset and progression of diabetic retinopathy.^33,36 The presence of retinopathy is not a contraindication to aspirin therapy for ASCVD prevention, as aspirin does not increase the risk of retinal hemorrhage.

When should patients with diabetes be screened for retinopathy?

Patients with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years of the onset of diabetes. Those with type 2 diabetes should have such an exam shortly after diagnosis. The exam should be repeated annually; if there is no evidence of retinopathy, however, 2-year intervals may be considered.

PERIPHERAL NEUROPATHY

When and how should I screen patients with diabetes for neuropathy?

All patients should be screened for diabetic peripheral neuropathy (DPN) starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes, and continued at least annually thereafter. Assessment should include a detailed history and 10-g monofilament testing, as well as at least one of the following tests: pinprick, temperature, and vibration sensation.

It is important, too, to screen patients with more advanced diabetes for signs and symptoms of autonomic neuropathy. Signs and symptoms may include resting tachycardia, exercise intolerance, orthostatic hypotension, gastroparesis, constipation, impaired neurovascular function, and autonomic failure in response to hypoglycemia. In men, diabetic autonomic neuropathy may cause erectile dysfunction and/or retrograde ejaculation.

How should I manage patients who have DPN?

Tight glycemic control is the only measure that has been shown to prevent or delay the development of DPN or cardiac autonomic neuropathy in patients with type 1 diabetes,^37,38 and to slow the progression of neuropathy in some patients with type 2 diabetes.³⁹

The FDA has approved pregabalin, duloxetine, and tapentadol for the treatment of pain associated with DPN. Tricyclic antidepressants, gabapentin, venlafaxine, carbamazepine, tramadol, and topical capsaicin, although not approved for the treatment of painful DPN, may also be effective in treating neuropathic pain.

For those with autonomic neuropathy, dietary changes and prokinetic agents such as erythromycin may alleviate gastroparesis. Due to extrapyramidal adverse effects, metoclopramide is reserved for the most severe and unresponsive cases. Recurrent urinary tract infections, pyelonephritis, incontinence, or palpable bladder should prompt an evaluation for bladder dysfunction. Controlling lipids and BP, quitting smoking, and making other lifestyle changes can reduce both the development and the progression of autonomic neuropathy.

The presence of retinopathy is not a contraindication to aspirin therapy for atherosclerotic cardiovascular disease prevention, as aspirin does not increase the risk of retinal hemorrhage.

FOOT CARE/PERIPHERAL ARTERIAL DISEASE

What does the ADA recommend regarding foot care for patients with diabetes?

The ADA’s standards recommend an annual comprehensive foot examination to identify risk factors predictive of ulcers and potential amputations. The exam should start with inspection and assessment of foot pulses and should seek to identify loss of peripheral sensation. The examination should include inspection of the skin, assessment of foot deformities, neurologic assessment including 10-g monofilament testing and pinprick or vibration testing or assessment of ankle reflexes, and vascular assessment, including pulses in the legs and feet.⁴⁰

It is also important to screen patients for peripheral arterial disease (PAD), with a comprehensive medical history and physical exam of pulses. Ankle-brachial index testing (ABI) should be performed in patients with signs or symptoms of PAD, including claudication or skin and hair changes in the lower extremities. ABI may be considered for all patients with diabetes starting at age 50 and in those younger than 50 years who have risk factors.⁴¹

Which patients with diabetes are at higher risk for foot complications?

The following are risk factors for foot complications: previous amputation, prior foot ulcer, peripheral neuropathy, foot deformity, peripheral vascular disease, visual impairment, peripheral neuropathy (especially if on dialysis), poor glycemic control, and smoking. Patients with high-risk foot conditions should be educated about their risk and appropriate management.

A well-fitted walking shoe that cushions the feet and redistributes pressure is one option to help patients. Patients with bony deformities may need extra wide or deep shoes and patients with more advanced disease may need custom-fitted shoes.

When should patients be referred to a foot specialist?

Refer patients to a foot care specialist for ongoing preventive care and lifelong surveillance if they smoke or have a history of lower-extremity complications, a loss of protective sensation, structural abnormalities, or PAD.

CASE 1 › Ms. T is an otherwise healthy 76 year old with a history of severe osteoarthritis (OA) in her right knee. She has participated in multiple rounds of physical therapy (PT) over the last 3 years. During the past year, she received 2 intra-articular corticosteroid injections, each of which provided only 3 to 4 weeks of pain relief, and one hyaluronic acid (HA) injection, which provided no benefit whatsoever.

Today, she describes her right knee pain as an 8 out of 10 and is frustrated by her lack of symptom relief. She was planning to have a total knee replacement and is a good surgical candidate, but recently found an article regarding platelet-rich plasma (PRP) injections for knee OA. She wants your opinion as to whether she should try this approach or proceed with surgery.

CASE 2 › Mr. H is a 44-year-old, right-handed dentist who has been suffering from right lateral epicondylitis for the past year. Although he has undergone PT and has been performing exercises at home since his symptoms began, he has not noticed a significant improvement. In the last 5 months, he has been out of work a total of 8 weeks due to the pain. He received one corticosteroid injection last month, which provided no improvement in symptoms. He is not interested in surgery, as he does not want to be out of work for a prolonged period of time.

He reports that one of his friends recently received a PRP injection for lateral epicondylitis and now feels great. He is aware that PRP injections are not covered by his health insurance and says he is willing to pay out of pocket if the treatment works. He wants to know if you recommend this course of action for his elbow pain.

How would you counsel each of these patients about the use of PRP injections for pain relief from their respective orthopedic conditions?

Musculoskeletal symptoms account for 10% to 28% of patients’ complaints to primary care physicians annually.¹ Treatment of both chronic tendinopathies and knee OA—2 of the most common causes of these complaints—typically follows a stepwise approach, beginning with anti-inflammatory and pain medications in addition to PT. Patients who fail to respond to these interventions are often treated with corticosteroid injections, and, in the case of knee OA, viscosupplementation (ie, HA injections) and braces. If these therapies fail, patients are often forced to choose between an invasive surgical procedure or continued pain and limited function.

Platelet-rich plasma is thought to tip the body’s response in favor of regeneration over destruction.

A number of physicians specializing in musculoskeletal medicine have turned to prolotherapy—specifically, dextrose prolotherapy (see “Prolotherapy: Can it help your patient?” J Fam Pract. 2015;64:763-768) and platelet-rich plasma (PRP) therapy—as an alternative treatment for chronic musculoskeletal conditions.

PRP has been used to enhance surgical healing and to treat muscle strains and chondropathies. It drew a great deal of attention in the media when it was used by such high-profile professional athletes as Tiger Woods and Kobe Bryant.

Although PRP therapy is not commonly reimbursed by health insurance companies because of a lack of large, definitive studies supporting its effectiveness, patients are paying anywhere from a few hundred to a few thousand dollars out of pocket for it. They’re doing so in the hope that it will treat their chronic musculoskeletal disorders or at least delay surgical procedures.

But what can these patients reasonably expect from this therapy?

The following review of the evidence for PRP in the treatment of knee OA and tendinopathies (including elbow epicondylitis, patellar tendinitis, and Achilles tendinitis) will help you counsel patients on its appropriate use.

What is PRP?

PRP is defined as a sample of autologous blood with concentrations of platelets above baseline values.² It is made through a one- or 2-stage centrifugation process in which the liquid and solid components of whole blood are separated, and then the liquid components are further separated into portions that are platelet-rich and platelet-poor.

Significant variability in preparation methods exists, resulting in more than 40 different products.² Some methods centrifuge only once, creating plasma that is separated from red and white blood cells, but without a huge shift in the concentration of platelets; some include white blood cells in the final preparation; and most have differing concentrations of platelets and various growth factors in the end product. Researchers have attempted to classify the various preparations by platelet concentration, inclusion or exclusion of white blood cells, and fibrin content, but no validated system yet exists. Thus, consistency in preparations is lacking.^3,4

PRP is rich not only in platelets, but also in a multitude of other growth factors. It is thought to improve healing by enhancing the body’s natural regenerative processes at the tissue level. In OA, for example, a complex balance of destructive and reparative processes is at play; PRP is thought to tip the body’s response in favor of regeneration over destruction. Similarly, chronic tendinopathy involves a process of destruction, reaction, healing, and degeneration; intervening at the correct point in this pathway with a boost to healing may help the body repair an otherwise diseased tendon.³

What does the evidence show?

Overall, basic science and preclinical research support “the promise” of PRP(strength of recommendation [SOR]: A).⁵ However, patient-centered evidence is lacking, and tremendous variability exists between studies, not only in terms of PRP preparation, but also with regard to:

• Protocol—Was ultrasound guidance used? Did the injection include needling of the tendon? What post-injection rehabilitation was followed?
• Patient population—What treatments were tried in the past? How chronic or severe was the problem?
• Study design—What was the comparison group? How were pain and function measured? Most studies have been small in size and have included various treatment modalities in addition to the PRP injection (most often PT).

Knee OA: PRP may provide short-term benefit, especially in younger patients

Researchers have conducted a number of studies evaluating PRP for knee OA.^6-12 Most have compared PRP to HA—another intra-articular injection that is plagued by mixed, limited, and poor-quality evidence. These trials have had varied results and do not consistently support PRP as superior to HA.

The most well-designed study to date demonstrated that PRP was superior to saline and as effective as HA.¹¹ In addition, the researchers found that a series of 3 PRP injections was superior to 3 injections of HA or only one injection of PRP.

One small randomized controlled trial (RCT) compared PRP injections to saline and found that PRP improved pain and function better than placebo at 6 weeks, 3 months, and 6 months; results appeared to deteriorate after that time period.⁶ Also, the findings suggested that PRP delivered the strongest benefit in younger patients who had less advanced OA.

In addition, a recent systematic review found short-term improvements in functional outcomes in patients treated with PRP injections vs those treated with HA injections and those treated with placebo.¹²

Basic science and preclinical research support “the promise” of platelet-rich plasma, but patient-centered evidence is lacking, and tremendous variability exists between studies.

But before experts can make any conclusive recommendations regarding the use of PRP for knee OA, standardized studies with larger numbers of participants and rigorous methodology must be designed. Notably, no evidence exists of significant harm resulting from PRP injection for knee OA. Therefore, given the mixed evidence in terms of efficacy, there may be a potential benefit to treatment with little negative consequence.

In 2013, the American Academy of Orthopaedic Surgeons (AAOS) stated that they were unable to recommend for or against PRP injection for patients with symptomatic OA of the knee because the evidence was inconclusive.¹³ At the same time, the AAOS was unable to recommend for or against corticosteroid injections, manual therapy, or bracing for knee OA, and recommended against HA injections.¹³ Recently, however, the American Medical Society for Sports Medicine (AMSSM) recommended that HA be used in appropriate patients with knee OA.¹⁴

Such disagreement indicates that evidence is lacking for many modalities employed in the management of knee OA, including the injection of corticosteroids, which is a frequent and generally accepted treatment. Compounding matters is that many of the original studies testing the efficacy of PRP injection in knee OA used HA injections as the comparison, and there is no agreement between AAOS and AMSSM as to its usefulness. Thus, the validity of using HA as a control is suspect.

Tendinopathies: PRP may have benefit, but more research is needed

A number of meta-analyses and systematic review articles have combined the results of studies involving PRP treatment for various tendinopathies.^3,15-17 While most found that PRP may have a benefit (although not long-lasting) and may be of use in attempts to avoid surgery or to return to a desired activity, all reported that more rigorous studies with standardized methodologies must be conducted before PRP can be conclusively recommended for any anatomic site.

Elbow epicondylitis (tennis elbow). The majority of tendinopathy studies have examined the effect of PRP on tennis elbow, although given the small study numbers (N=20-100), high risks of bias, and very different comparison groups, the data are extremely limited. Of the 4 randomized studies,^18-21 2 compared different PRP preparations to whole blood,^18,20 one compared PRP to both saline and corticosteroid,¹⁹ and one compared PRP to corticosteroid alone.²¹

The studies comparing PRP to whole blood found similar outcomes at most time points.^18,20 These studies were of extremely poor quality, and other review articles have defined whole blood as a type of PRP, so this comparison was somewhat inappropriate. One recently published meta-analysis, which included 10 studies comparing either PRP or whole blood to corticosteroid, found that PRP improved pain more than a corticosteroid.²²

The one study that included a comparison of PRP to placebo (saline) suffered from a high dropout rate, and the authors were not able to analyze the primary outcome data. At 3 months, the participants remaining in each group (PRP, saline, or corticosteroid) had similar pain and disability scores.¹⁹ Although the steroid group had improved from baseline at one month, there was no difference between the steroid group and placebo group at 3 months. The PRP group did not differ from the placebo group at any time point.

The study comparing PRP to corticosteroid alone found that PRP’s effects on pain and function exceeded those of the steroid. Specifically, the steroid group initially improved and then worsened, ending the study near their baseline pain and function scores.²¹ The PRP group, on the other hand, showed slow improvement throughout, ending the study with less pain and disability than when they started.

There is no evidence of significant harms associated with platelet-rich plasma treatment, but studies have lacked the power to detect rare but serious problems.

Patellar tendinitis (jumper’s knee). The majority of studies examining the effect of PRP on patellar tendinitis are non-randomized, non-comparative studies. Of the 2 small RCTs that were conducted, one compared PRP to extracorporeal shockwave therapy (ESWT),²³ and the other to dry needling.²⁴

In the ESWT study, there was a slight improvement in pain and function in the PRP group relative to the ESWT group at 6 and 12 months. In the other study, although the PRP group showed an improvement in recovery at 12 weeks relative to the dry needling group, there was no difference between such outcomes as pain and activity in the 2 groups at 26 weeks.

Worth noting here is that like the studies done on OA patients, the research involving patellar tendinitis also used comparative interventions (ESWT and dry needling) that lack high-quality evidence for their use. So whether these were appropriate comparisons is debatable.

Achilles tendinitis. Only one RCT (N=54) has evaluated PRP for the treatment of Achilles tendinitis.²⁵ This study, which compared PRP to saline, excluded patients who had previously completed a course of PT, yet both study groups participated in PT during the study. Although the trial found no difference between groups at any time point (both showed improvement), it was underpowered to detect any difference (positive or negative) between groups, given that most participants likely would have improved with PT anyway.²⁶

PRP has few harms or adverse effects

Most individual studies involving PRP have not reported on harms or side effects; the studies that have reported on them have generally found low rates (2%-5%) of only local, short-term adverse effects.¹⁵ One review article did find that increasing the number of PRP injections increased the rate of adverse effects; however, those effects still appeared to be mild and time-limited.¹⁰

One study reported that 33% (17/51) of patients experienced systemic adverse effects including syncope, dizziness, and nausea at the time of their PRP injection.⁶ Overall, there is no evidence of significant harms associated with PRP treatment, but available studies have lacked the power to detect rare but serious problems.

Looking to the future: Additional considerations

In order to properly evaluate this potentially promising method of care, future studies need to include appropriately chosen controls, specifically defined formulations of PRP, standardized protocols for the injection of PRP, standardized post-injection PT regimens, and patient populations that are clearly defined in terms of severity and chronicity of disease. Furthermore, studies must be rigorously designed in terms of randomization, blinding, and analysis. (Many studies done to date did not use an intention-to-treat protocol, for example). Higher-quality studies with larger numbers of participants are the only way to determine whether PRP is worth all the “buzz.”

Platelet-rich plasma is approved only for use in the operative setting to enhance bone graft handling properties. Office-based injections are an off-label use.

We should keep in mind, too, that the evidence for many of the other treatment options for both tendinopathy and knee OA are similarly problematic, and these modalities are even more widely used than PRP. Given the systemic problems associated with nonsteroidal anti-inflammatory drugs, concerns about possible tendon rupture with corticosteroid injections, and the time and compliance issues associated with PT, PRP may be a safer alternative to more traditional treatments.

An off-label use. PRP does not pass through the standard regulatory pathway of the US Food and Drug Administration (FDA). As a blood product, PRP falls under the regulatory purview of the FDA’s Center for Biologics Evaluation and Research, which has approved PRP only for use in the operative setting to enhance bone graft handling properties.²⁷ Therefore, office-based PRP injections are an off-label use of the treatment.

CASE 1 › You explain to Ms. T that PRP injections are not covered by insurance and that there is not a significant amount of evidence to indicate that an injection would appreciably improve her pain. She decides to proceed with a knee replacement and not to pursue a PRP injection.

CASE 2 › Given the time that Mr. H has invested in traditional conservative management strategies, his time away from work, and that he is not concerned with the out-of-pocket cost associated with PRP, you explain to him that there is some limited evidence that PRP might improve his symptoms. He decides that he would rather try a PRP injection than pursue surgery.

CORRESPONDENCE
Jordan White, MD, MPH, Department of Family Medicine, 111 Brewster Street, Pawtucket, RI 02860; [email protected].

CASE 1 › Ms. T is an otherwise healthy 76 year old with a history of severe osteoarthritis (OA) in her right knee. She has participated in multiple rounds of physical therapy (PT) over the last 3 years. During the past year, she received 2 intra-articular corticosteroid injections, each of which provided only 3 to 4 weeks of pain relief, and one hyaluronic acid (HA) injection, which provided no benefit whatsoever.

Today, she describes her right knee pain as an 8 out of 10 and is frustrated by her lack of symptom relief. She was planning to have a total knee replacement and is a good surgical candidate, but recently found an article regarding platelet-rich plasma (PRP) injections for knee OA. She wants your opinion as to whether she should try this approach or proceed with surgery.

CASE 2 › Mr. H is a 44-year-old, right-handed dentist who has been suffering from right lateral epicondylitis for the past year. Although he has undergone PT and has been performing exercises at home since his symptoms began, he has not noticed a significant improvement. In the last 5 months, he has been out of work a total of 8 weeks due to the pain. He received one corticosteroid injection last month, which provided no improvement in symptoms. He is not interested in surgery, as he does not want to be out of work for a prolonged period of time.

He reports that one of his friends recently received a PRP injection for lateral epicondylitis and now feels great. He is aware that PRP injections are not covered by his health insurance and says he is willing to pay out of pocket if the treatment works. He wants to know if you recommend this course of action for his elbow pain.

How would you counsel each of these patients about the use of PRP injections for pain relief from their respective orthopedic conditions?

Musculoskeletal symptoms account for 10% to 28% of patients’ complaints to primary care physicians annually.¹ Treatment of both chronic tendinopathies and knee OA—2 of the most common causes of these complaints—typically follows a stepwise approach, beginning with anti-inflammatory and pain medications in addition to PT. Patients who fail to respond to these interventions are often treated with corticosteroid injections, and, in the case of knee OA, viscosupplementation (ie, HA injections) and braces. If these therapies fail, patients are often forced to choose between an invasive surgical procedure or continued pain and limited function.

Platelet-rich plasma is thought to tip the body’s response in favor of regeneration over destruction.

A number of physicians specializing in musculoskeletal medicine have turned to prolotherapy—specifically, dextrose prolotherapy (see “Prolotherapy: Can it help your patient?” J Fam Pract. 2015;64:763-768) and platelet-rich plasma (PRP) therapy—as an alternative treatment for chronic musculoskeletal conditions.

PRP has been used to enhance surgical healing and to treat muscle strains and chondropathies. It drew a great deal of attention in the media when it was used by such high-profile professional athletes as Tiger Woods and Kobe Bryant.

Although PRP therapy is not commonly reimbursed by health insurance companies because of a lack of large, definitive studies supporting its effectiveness, patients are paying anywhere from a few hundred to a few thousand dollars out of pocket for it. They’re doing so in the hope that it will treat their chronic musculoskeletal disorders or at least delay surgical procedures.

But what can these patients reasonably expect from this therapy?

The following review of the evidence for PRP in the treatment of knee OA and tendinopathies (including elbow epicondylitis, patellar tendinitis, and Achilles tendinitis) will help you counsel patients on its appropriate use.

What is PRP?

PRP is defined as a sample of autologous blood with concentrations of platelets above baseline values.² It is made through a one- or 2-stage centrifugation process in which the liquid and solid components of whole blood are separated, and then the liquid components are further separated into portions that are platelet-rich and platelet-poor.

Significant variability in preparation methods exists, resulting in more than 40 different products.² Some methods centrifuge only once, creating plasma that is separated from red and white blood cells, but without a huge shift in the concentration of platelets; some include white blood cells in the final preparation; and most have differing concentrations of platelets and various growth factors in the end product. Researchers have attempted to classify the various preparations by platelet concentration, inclusion or exclusion of white blood cells, and fibrin content, but no validated system yet exists. Thus, consistency in preparations is lacking.^3,4

PRP is rich not only in platelets, but also in a multitude of other growth factors. It is thought to improve healing by enhancing the body’s natural regenerative processes at the tissue level. In OA, for example, a complex balance of destructive and reparative processes is at play; PRP is thought to tip the body’s response in favor of regeneration over destruction. Similarly, chronic tendinopathy involves a process of destruction, reaction, healing, and degeneration; intervening at the correct point in this pathway with a boost to healing may help the body repair an otherwise diseased tendon.³

What does the evidence show?

Overall, basic science and preclinical research support “the promise” of PRP(strength of recommendation [SOR]: A).⁵ However, patient-centered evidence is lacking, and tremendous variability exists between studies, not only in terms of PRP preparation, but also with regard to:

• Protocol—Was ultrasound guidance used? Did the injection include needling of the tendon? What post-injection rehabilitation was followed?
• Patient population—What treatments were tried in the past? How chronic or severe was the problem?
• Study design—What was the comparison group? How were pain and function measured? Most studies have been small in size and have included various treatment modalities in addition to the PRP injection (most often PT).

Knee OA: PRP may provide short-term benefit, especially in younger patients

Researchers have conducted a number of studies evaluating PRP for knee OA.^6-12 Most have compared PRP to HA—another intra-articular injection that is plagued by mixed, limited, and poor-quality evidence. These trials have had varied results and do not consistently support PRP as superior to HA.

The most well-designed study to date demonstrated that PRP was superior to saline and as effective as HA.¹¹ In addition, the researchers found that a series of 3 PRP injections was superior to 3 injections of HA or only one injection of PRP.

One small randomized controlled trial (RCT) compared PRP injections to saline and found that PRP improved pain and function better than placebo at 6 weeks, 3 months, and 6 months; results appeared to deteriorate after that time period.⁶ Also, the findings suggested that PRP delivered the strongest benefit in younger patients who had less advanced OA.

In addition, a recent systematic review found short-term improvements in functional outcomes in patients treated with PRP injections vs those treated with HA injections and those treated with placebo.¹²

Basic science and preclinical research support “the promise” of platelet-rich plasma, but patient-centered evidence is lacking, and tremendous variability exists between studies.

But before experts can make any conclusive recommendations regarding the use of PRP for knee OA, standardized studies with larger numbers of participants and rigorous methodology must be designed. Notably, no evidence exists of significant harm resulting from PRP injection for knee OA. Therefore, given the mixed evidence in terms of efficacy, there may be a potential benefit to treatment with little negative consequence.

In 2013, the American Academy of Orthopaedic Surgeons (AAOS) stated that they were unable to recommend for or against PRP injection for patients with symptomatic OA of the knee because the evidence was inconclusive.¹³ At the same time, the AAOS was unable to recommend for or against corticosteroid injections, manual therapy, or bracing for knee OA, and recommended against HA injections.¹³ Recently, however, the American Medical Society for Sports Medicine (AMSSM) recommended that HA be used in appropriate patients with knee OA.¹⁴

Such disagreement indicates that evidence is lacking for many modalities employed in the management of knee OA, including the injection of corticosteroids, which is a frequent and generally accepted treatment. Compounding matters is that many of the original studies testing the efficacy of PRP injection in knee OA used HA injections as the comparison, and there is no agreement between AAOS and AMSSM as to its usefulness. Thus, the validity of using HA as a control is suspect.

Tendinopathies: PRP may have benefit, but more research is needed

A number of meta-analyses and systematic review articles have combined the results of studies involving PRP treatment for various tendinopathies.^3,15-17 While most found that PRP may have a benefit (although not long-lasting) and may be of use in attempts to avoid surgery or to return to a desired activity, all reported that more rigorous studies with standardized methodologies must be conducted before PRP can be conclusively recommended for any anatomic site.

Elbow epicondylitis (tennis elbow). The majority of tendinopathy studies have examined the effect of PRP on tennis elbow, although given the small study numbers (N=20-100), high risks of bias, and very different comparison groups, the data are extremely limited. Of the 4 randomized studies,^18-21 2 compared different PRP preparations to whole blood,^18,20 one compared PRP to both saline and corticosteroid,¹⁹ and one compared PRP to corticosteroid alone.²¹

The studies comparing PRP to whole blood found similar outcomes at most time points.^18,20 These studies were of extremely poor quality, and other review articles have defined whole blood as a type of PRP, so this comparison was somewhat inappropriate. One recently published meta-analysis, which included 10 studies comparing either PRP or whole blood to corticosteroid, found that PRP improved pain more than a corticosteroid.²²

The one study that included a comparison of PRP to placebo (saline) suffered from a high dropout rate, and the authors were not able to analyze the primary outcome data. At 3 months, the participants remaining in each group (PRP, saline, or corticosteroid) had similar pain and disability scores.¹⁹ Although the steroid group had improved from baseline at one month, there was no difference between the steroid group and placebo group at 3 months. The PRP group did not differ from the placebo group at any time point.

The study comparing PRP to corticosteroid alone found that PRP’s effects on pain and function exceeded those of the steroid. Specifically, the steroid group initially improved and then worsened, ending the study near their baseline pain and function scores.²¹ The PRP group, on the other hand, showed slow improvement throughout, ending the study with less pain and disability than when they started.

There is no evidence of significant harms associated with platelet-rich plasma treatment, but studies have lacked the power to detect rare but serious problems.

Patellar tendinitis (jumper’s knee). The majority of studies examining the effect of PRP on patellar tendinitis are non-randomized, non-comparative studies. Of the 2 small RCTs that were conducted, one compared PRP to extracorporeal shockwave therapy (ESWT),²³ and the other to dry needling.²⁴

In the ESWT study, there was a slight improvement in pain and function in the PRP group relative to the ESWT group at 6 and 12 months. In the other study, although the PRP group showed an improvement in recovery at 12 weeks relative to the dry needling group, there was no difference between such outcomes as pain and activity in the 2 groups at 26 weeks.

Worth noting here is that like the studies done on OA patients, the research involving patellar tendinitis also used comparative interventions (ESWT and dry needling) that lack high-quality evidence for their use. So whether these were appropriate comparisons is debatable.

Achilles tendinitis. Only one RCT (N=54) has evaluated PRP for the treatment of Achilles tendinitis.²⁵ This study, which compared PRP to saline, excluded patients who had previously completed a course of PT, yet both study groups participated in PT during the study. Although the trial found no difference between groups at any time point (both showed improvement), it was underpowered to detect any difference (positive or negative) between groups, given that most participants likely would have improved with PT anyway.²⁶

PRP has few harms or adverse effects

Most individual studies involving PRP have not reported on harms or side effects; the studies that have reported on them have generally found low rates (2%-5%) of only local, short-term adverse effects.¹⁵ One review article did find that increasing the number of PRP injections increased the rate of adverse effects; however, those effects still appeared to be mild and time-limited.¹⁰

One study reported that 33% (17/51) of patients experienced systemic adverse effects including syncope, dizziness, and nausea at the time of their PRP injection.⁶ Overall, there is no evidence of significant harms associated with PRP treatment, but available studies have lacked the power to detect rare but serious problems.

Looking to the future: Additional considerations

In order to properly evaluate this potentially promising method of care, future studies need to include appropriately chosen controls, specifically defined formulations of PRP, standardized protocols for the injection of PRP, standardized post-injection PT regimens, and patient populations that are clearly defined in terms of severity and chronicity of disease. Furthermore, studies must be rigorously designed in terms of randomization, blinding, and analysis. (Many studies done to date did not use an intention-to-treat protocol, for example). Higher-quality studies with larger numbers of participants are the only way to determine whether PRP is worth all the “buzz.”

Platelet-rich plasma is approved only for use in the operative setting to enhance bone graft handling properties. Office-based injections are an off-label use.

We should keep in mind, too, that the evidence for many of the other treatment options for both tendinopathy and knee OA are similarly problematic, and these modalities are even more widely used than PRP. Given the systemic problems associated with nonsteroidal anti-inflammatory drugs, concerns about possible tendon rupture with corticosteroid injections, and the time and compliance issues associated with PT, PRP may be a safer alternative to more traditional treatments.

An off-label use. PRP does not pass through the standard regulatory pathway of the US Food and Drug Administration (FDA). As a blood product, PRP falls under the regulatory purview of the FDA’s Center for Biologics Evaluation and Research, which has approved PRP only for use in the operative setting to enhance bone graft handling properties.²⁷ Therefore, office-based PRP injections are an off-label use of the treatment.

CASE 1 › You explain to Ms. T that PRP injections are not covered by insurance and that there is not a significant amount of evidence to indicate that an injection would appreciably improve her pain. She decides to proceed with a knee replacement and not to pursue a PRP injection.

CASE 2 › Given the time that Mr. H has invested in traditional conservative management strategies, his time away from work, and that he is not concerned with the out-of-pocket cost associated with PRP, you explain to him that there is some limited evidence that PRP might improve his symptoms. He decides that he would rather try a PRP injection than pursue surgery.

CORRESPONDENCE
Jordan White, MD, MPH, Department of Family Medicine, 111 Brewster Street, Pawtucket, RI 02860; [email protected].

CASE 1 › Ms. T is an otherwise healthy 76 year old with a history of severe osteoarthritis (OA) in her right knee. She has participated in multiple rounds of physical therapy (PT) over the last 3 years. During the past year, she received 2 intra-articular corticosteroid injections, each of which provided only 3 to 4 weeks of pain relief, and one hyaluronic acid (HA) injection, which provided no benefit whatsoever.

Today, she describes her right knee pain as an 8 out of 10 and is frustrated by her lack of symptom relief. She was planning to have a total knee replacement and is a good surgical candidate, but recently found an article regarding platelet-rich plasma (PRP) injections for knee OA. She wants your opinion as to whether she should try this approach or proceed with surgery.

CASE 2 › Mr. H is a 44-year-old, right-handed dentist who has been suffering from right lateral epicondylitis for the past year. Although he has undergone PT and has been performing exercises at home since his symptoms began, he has not noticed a significant improvement. In the last 5 months, he has been out of work a total of 8 weeks due to the pain. He received one corticosteroid injection last month, which provided no improvement in symptoms. He is not interested in surgery, as he does not want to be out of work for a prolonged period of time.

He reports that one of his friends recently received a PRP injection for lateral epicondylitis and now feels great. He is aware that PRP injections are not covered by his health insurance and says he is willing to pay out of pocket if the treatment works. He wants to know if you recommend this course of action for his elbow pain.

How would you counsel each of these patients about the use of PRP injections for pain relief from their respective orthopedic conditions?

Musculoskeletal symptoms account for 10% to 28% of patients’ complaints to primary care physicians annually.¹ Treatment of both chronic tendinopathies and knee OA—2 of the most common causes of these complaints—typically follows a stepwise approach, beginning with anti-inflammatory and pain medications in addition to PT. Patients who fail to respond to these interventions are often treated with corticosteroid injections, and, in the case of knee OA, viscosupplementation (ie, HA injections) and braces. If these therapies fail, patients are often forced to choose between an invasive surgical procedure or continued pain and limited function.

Platelet-rich plasma is thought to tip the body’s response in favor of regeneration over destruction.

A number of physicians specializing in musculoskeletal medicine have turned to prolotherapy—specifically, dextrose prolotherapy (see “Prolotherapy: Can it help your patient?” J Fam Pract. 2015;64:763-768) and platelet-rich plasma (PRP) therapy—as an alternative treatment for chronic musculoskeletal conditions.

PRP has been used to enhance surgical healing and to treat muscle strains and chondropathies. It drew a great deal of attention in the media when it was used by such high-profile professional athletes as Tiger Woods and Kobe Bryant.

Although PRP therapy is not commonly reimbursed by health insurance companies because of a lack of large, definitive studies supporting its effectiveness, patients are paying anywhere from a few hundred to a few thousand dollars out of pocket for it. They’re doing so in the hope that it will treat their chronic musculoskeletal disorders or at least delay surgical procedures.

But what can these patients reasonably expect from this therapy?

The following review of the evidence for PRP in the treatment of knee OA and tendinopathies (including elbow epicondylitis, patellar tendinitis, and Achilles tendinitis) will help you counsel patients on its appropriate use.

What is PRP?

PRP is defined as a sample of autologous blood with concentrations of platelets above baseline values.² It is made through a one- or 2-stage centrifugation process in which the liquid and solid components of whole blood are separated, and then the liquid components are further separated into portions that are platelet-rich and platelet-poor.

Significant variability in preparation methods exists, resulting in more than 40 different products.² Some methods centrifuge only once, creating plasma that is separated from red and white blood cells, but without a huge shift in the concentration of platelets; some include white blood cells in the final preparation; and most have differing concentrations of platelets and various growth factors in the end product. Researchers have attempted to classify the various preparations by platelet concentration, inclusion or exclusion of white blood cells, and fibrin content, but no validated system yet exists. Thus, consistency in preparations is lacking.^3,4

PRP is rich not only in platelets, but also in a multitude of other growth factors. It is thought to improve healing by enhancing the body’s natural regenerative processes at the tissue level. In OA, for example, a complex balance of destructive and reparative processes is at play; PRP is thought to tip the body’s response in favor of regeneration over destruction. Similarly, chronic tendinopathy involves a process of destruction, reaction, healing, and degeneration; intervening at the correct point in this pathway with a boost to healing may help the body repair an otherwise diseased tendon.³

What does the evidence show?

Overall, basic science and preclinical research support “the promise” of PRP(strength of recommendation [SOR]: A).⁵ However, patient-centered evidence is lacking, and tremendous variability exists between studies, not only in terms of PRP preparation, but also with regard to:

• Protocol—Was ultrasound guidance used? Did the injection include needling of the tendon? What post-injection rehabilitation was followed?
• Patient population—What treatments were tried in the past? How chronic or severe was the problem?
• Study design—What was the comparison group? How were pain and function measured? Most studies have been small in size and have included various treatment modalities in addition to the PRP injection (most often PT).

Knee OA: PRP may provide short-term benefit, especially in younger patients

Researchers have conducted a number of studies evaluating PRP for knee OA.^6-12 Most have compared PRP to HA—another intra-articular injection that is plagued by mixed, limited, and poor-quality evidence. These trials have had varied results and do not consistently support PRP as superior to HA.

The most well-designed study to date demonstrated that PRP was superior to saline and as effective as HA.¹¹ In addition, the researchers found that a series of 3 PRP injections was superior to 3 injections of HA or only one injection of PRP.

One small randomized controlled trial (RCT) compared PRP injections to saline and found that PRP improved pain and function better than placebo at 6 weeks, 3 months, and 6 months; results appeared to deteriorate after that time period.⁶ Also, the findings suggested that PRP delivered the strongest benefit in younger patients who had less advanced OA.

In addition, a recent systematic review found short-term improvements in functional outcomes in patients treated with PRP injections vs those treated with HA injections and those treated with placebo.¹²

Basic science and preclinical research support “the promise” of platelet-rich plasma, but patient-centered evidence is lacking, and tremendous variability exists between studies.

But before experts can make any conclusive recommendations regarding the use of PRP for knee OA, standardized studies with larger numbers of participants and rigorous methodology must be designed. Notably, no evidence exists of significant harm resulting from PRP injection for knee OA. Therefore, given the mixed evidence in terms of efficacy, there may be a potential benefit to treatment with little negative consequence.

In 2013, the American Academy of Orthopaedic Surgeons (AAOS) stated that they were unable to recommend for or against PRP injection for patients with symptomatic OA of the knee because the evidence was inconclusive.¹³ At the same time, the AAOS was unable to recommend for or against corticosteroid injections, manual therapy, or bracing for knee OA, and recommended against HA injections.¹³ Recently, however, the American Medical Society for Sports Medicine (AMSSM) recommended that HA be used in appropriate patients with knee OA.¹⁴

Such disagreement indicates that evidence is lacking for many modalities employed in the management of knee OA, including the injection of corticosteroids, which is a frequent and generally accepted treatment. Compounding matters is that many of the original studies testing the efficacy of PRP injection in knee OA used HA injections as the comparison, and there is no agreement between AAOS and AMSSM as to its usefulness. Thus, the validity of using HA as a control is suspect.

Tendinopathies: PRP may have benefit, but more research is needed

A number of meta-analyses and systematic review articles have combined the results of studies involving PRP treatment for various tendinopathies.^3,15-17 While most found that PRP may have a benefit (although not long-lasting) and may be of use in attempts to avoid surgery or to return to a desired activity, all reported that more rigorous studies with standardized methodologies must be conducted before PRP can be conclusively recommended for any anatomic site.

Elbow epicondylitis (tennis elbow). The majority of tendinopathy studies have examined the effect of PRP on tennis elbow, although given the small study numbers (N=20-100), high risks of bias, and very different comparison groups, the data are extremely limited. Of the 4 randomized studies,^18-21 2 compared different PRP preparations to whole blood,^18,20 one compared PRP to both saline and corticosteroid,¹⁹ and one compared PRP to corticosteroid alone.²¹

The studies comparing PRP to whole blood found similar outcomes at most time points.^18,20 These studies were of extremely poor quality, and other review articles have defined whole blood as a type of PRP, so this comparison was somewhat inappropriate. One recently published meta-analysis, which included 10 studies comparing either PRP or whole blood to corticosteroid, found that PRP improved pain more than a corticosteroid.²²

The one study that included a comparison of PRP to placebo (saline) suffered from a high dropout rate, and the authors were not able to analyze the primary outcome data. At 3 months, the participants remaining in each group (PRP, saline, or corticosteroid) had similar pain and disability scores.¹⁹ Although the steroid group had improved from baseline at one month, there was no difference between the steroid group and placebo group at 3 months. The PRP group did not differ from the placebo group at any time point.

The study comparing PRP to corticosteroid alone found that PRP’s effects on pain and function exceeded those of the steroid. Specifically, the steroid group initially improved and then worsened, ending the study near their baseline pain and function scores.²¹ The PRP group, on the other hand, showed slow improvement throughout, ending the study with less pain and disability than when they started.

There is no evidence of significant harms associated with platelet-rich plasma treatment, but studies have lacked the power to detect rare but serious problems.

Patellar tendinitis (jumper’s knee). The majority of studies examining the effect of PRP on patellar tendinitis are non-randomized, non-comparative studies. Of the 2 small RCTs that were conducted, one compared PRP to extracorporeal shockwave therapy (ESWT),²³ and the other to dry needling.²⁴

In the ESWT study, there was a slight improvement in pain and function in the PRP group relative to the ESWT group at 6 and 12 months. In the other study, although the PRP group showed an improvement in recovery at 12 weeks relative to the dry needling group, there was no difference between such outcomes as pain and activity in the 2 groups at 26 weeks.

Worth noting here is that like the studies done on OA patients, the research involving patellar tendinitis also used comparative interventions (ESWT and dry needling) that lack high-quality evidence for their use. So whether these were appropriate comparisons is debatable.

Achilles tendinitis. Only one RCT (N=54) has evaluated PRP for the treatment of Achilles tendinitis.²⁵ This study, which compared PRP to saline, excluded patients who had previously completed a course of PT, yet both study groups participated in PT during the study. Although the trial found no difference between groups at any time point (both showed improvement), it was underpowered to detect any difference (positive or negative) between groups, given that most participants likely would have improved with PT anyway.²⁶

PRP has few harms or adverse effects

Most individual studies involving PRP have not reported on harms or side effects; the studies that have reported on them have generally found low rates (2%-5%) of only local, short-term adverse effects.¹⁵ One review article did find that increasing the number of PRP injections increased the rate of adverse effects; however, those effects still appeared to be mild and time-limited.¹⁰

One study reported that 33% (17/51) of patients experienced systemic adverse effects including syncope, dizziness, and nausea at the time of their PRP injection.⁶ Overall, there is no evidence of significant harms associated with PRP treatment, but available studies have lacked the power to detect rare but serious problems.

Looking to the future: Additional considerations

In order to properly evaluate this potentially promising method of care, future studies need to include appropriately chosen controls, specifically defined formulations of PRP, standardized protocols for the injection of PRP, standardized post-injection PT regimens, and patient populations that are clearly defined in terms of severity and chronicity of disease. Furthermore, studies must be rigorously designed in terms of randomization, blinding, and analysis. (Many studies done to date did not use an intention-to-treat protocol, for example). Higher-quality studies with larger numbers of participants are the only way to determine whether PRP is worth all the “buzz.”

Platelet-rich plasma is approved only for use in the operative setting to enhance bone graft handling properties. Office-based injections are an off-label use.

We should keep in mind, too, that the evidence for many of the other treatment options for both tendinopathy and knee OA are similarly problematic, and these modalities are even more widely used than PRP. Given the systemic problems associated with nonsteroidal anti-inflammatory drugs, concerns about possible tendon rupture with corticosteroid injections, and the time and compliance issues associated with PT, PRP may be a safer alternative to more traditional treatments.

An off-label use. PRP does not pass through the standard regulatory pathway of the US Food and Drug Administration (FDA). As a blood product, PRP falls under the regulatory purview of the FDA’s Center for Biologics Evaluation and Research, which has approved PRP only for use in the operative setting to enhance bone graft handling properties.²⁷ Therefore, office-based PRP injections are an off-label use of the treatment.

CASE 1 › You explain to Ms. T that PRP injections are not covered by insurance and that there is not a significant amount of evidence to indicate that an injection would appreciably improve her pain. She decides to proceed with a knee replacement and not to pursue a PRP injection.

CASE 2 › Given the time that Mr. H has invested in traditional conservative management strategies, his time away from work, and that he is not concerned with the out-of-pocket cost associated with PRP, you explain to him that there is some limited evidence that PRP might improve his symptoms. He decides that he would rather try a PRP injection than pursue surgery.

CORRESPONDENCE
Jordan White, MD, MPH, Department of Family Medicine, 111 Brewster Street, Pawtucket, RI 02860; [email protected].