Neurology

Here are 5 articles from the February issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Short-term lung function better predicts mortality risk in SSc

To take the posttest, go to: https://bit.ly/2RrRuIY
Expires November 26, 2019

2. Healthier lifestyle in midlife women reduces subclinical carotid atherosclerosis

To take the posttest, go to: https://bit.ly/2TvDH5G
Expires November 28, 2019

3. Three commonly used quick cognitive assessments often yield flawed results

To take the posttest, go to: https://bit.ly/2G1qkHn
Expires November 28, 2019

4. Missed HIV screening opportunities found among subsequently infected youth

To take the posttest, go to: https://bit.ly/2HGa8Nm
Expires November 29, 2019

5. Aspirin appears underused to prevent preeclampsia in SLE patients

To take the posttest, go to: https://bit.ly/2G0dU2v
Expires January 2, 2019

Here are 5 articles from the February issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Short-term lung function better predicts mortality risk in SSc

To take the posttest, go to: https://bit.ly/2RrRuIY
Expires November 26, 2019

2. Healthier lifestyle in midlife women reduces subclinical carotid atherosclerosis

To take the posttest, go to: https://bit.ly/2TvDH5G
Expires November 28, 2019

3. Three commonly used quick cognitive assessments often yield flawed results

To take the posttest, go to: https://bit.ly/2G1qkHn
Expires November 28, 2019

4. Missed HIV screening opportunities found among subsequently infected youth

To take the posttest, go to: https://bit.ly/2HGa8Nm
Expires November 29, 2019

5. Aspirin appears underused to prevent preeclampsia in SLE patients

To take the posttest, go to: https://bit.ly/2G0dU2v
Expires January 2, 2019

Here are 5 articles from the February issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Short-term lung function better predicts mortality risk in SSc

To take the posttest, go to: https://bit.ly/2RrRuIY
Expires November 26, 2019

2. Healthier lifestyle in midlife women reduces subclinical carotid atherosclerosis

To take the posttest, go to: https://bit.ly/2TvDH5G
Expires November 28, 2019

3. Three commonly used quick cognitive assessments often yield flawed results

To take the posttest, go to: https://bit.ly/2G1qkHn
Expires November 28, 2019

4. Missed HIV screening opportunities found among subsequently infected youth

To take the posttest, go to: https://bit.ly/2HGa8Nm
Expires November 29, 2019

5. Aspirin appears underused to prevent preeclampsia in SLE patients

To take the posttest, go to: https://bit.ly/2G0dU2v
Expires January 2, 2019

What makes us pull a hand away from a hot stove or flinch at a pinprick? Researchers from the National Center for Complementary and Integrative Health say they have identified activity in the brain that governs these reactions.

Alexander Chesler, PhD, senior author of the study, says we already know a lot about local spinal cord circuits for simple reflexive responses, but “the mechanisms underlying more complex behaviors remain poorly understood.”

Using heat as the source of discomfort in their experiments, the researchers found a predictable sequence of behaviors—likened to the sequence of responding to walking cautiously on a hot beach, then hopping as the heat intensifies, then running to a water source. “This kind of ‘feed-forward’ circuitry is unique because it is an upward spiral,” says Arnab Barik, PhD, one of the study authors. “The more this pathway is activated by harmful activity, the more it reacts, leading to dramatic behavioral responses.”

The experiments showed that the parts of the brainstem involved in this circuit are the parabrachial nucleus (PBNI) and the dorsal reticular formation in the medulla (MdD). Standing on a hot surface activated a group of nerve cells in the PBNI, triggering escape responses through connections to the MdD. Interestingly, the PBNI cells express a gene that codes for substances that also contribute to multiple disease processes.

“Our data provide evidence that the PBNI produces streams of information with distinct functional significance,” says Arnab Barik, PhD, one of the study authors. “The brainstem-spinal cord pathway identified in this study selectively controls pain response and elicits appropriate behaviors based on sensory input.”

Further investigation, the researchers say, can help us understand how pain is encoded in the brain. The study findings may also offer opportunities to understand how the body becomes dysregulated during chronic pain.

What makes us pull a hand away from a hot stove or flinch at a pinprick? Researchers from the National Center for Complementary and Integrative Health say they have identified activity in the brain that governs these reactions.

Alexander Chesler, PhD, senior author of the study, says we already know a lot about local spinal cord circuits for simple reflexive responses, but “the mechanisms underlying more complex behaviors remain poorly understood.”

Using heat as the source of discomfort in their experiments, the researchers found a predictable sequence of behaviors—likened to the sequence of responding to walking cautiously on a hot beach, then hopping as the heat intensifies, then running to a water source. “This kind of ‘feed-forward’ circuitry is unique because it is an upward spiral,” says Arnab Barik, PhD, one of the study authors. “The more this pathway is activated by harmful activity, the more it reacts, leading to dramatic behavioral responses.”

The experiments showed that the parts of the brainstem involved in this circuit are the parabrachial nucleus (PBNI) and the dorsal reticular formation in the medulla (MdD). Standing on a hot surface activated a group of nerve cells in the PBNI, triggering escape responses through connections to the MdD. Interestingly, the PBNI cells express a gene that codes for substances that also contribute to multiple disease processes.

“Our data provide evidence that the PBNI produces streams of information with distinct functional significance,” says Arnab Barik, PhD, one of the study authors. “The brainstem-spinal cord pathway identified in this study selectively controls pain response and elicits appropriate behaviors based on sensory input.”

Further investigation, the researchers say, can help us understand how pain is encoded in the brain. The study findings may also offer opportunities to understand how the body becomes dysregulated during chronic pain.

What makes us pull a hand away from a hot stove or flinch at a pinprick? Researchers from the National Center for Complementary and Integrative Health say they have identified activity in the brain that governs these reactions.

Alexander Chesler, PhD, senior author of the study, says we already know a lot about local spinal cord circuits for simple reflexive responses, but “the mechanisms underlying more complex behaviors remain poorly understood.”

Using heat as the source of discomfort in their experiments, the researchers found a predictable sequence of behaviors—likened to the sequence of responding to walking cautiously on a hot beach, then hopping as the heat intensifies, then running to a water source. “This kind of ‘feed-forward’ circuitry is unique because it is an upward spiral,” says Arnab Barik, PhD, one of the study authors. “The more this pathway is activated by harmful activity, the more it reacts, leading to dramatic behavioral responses.”

The experiments showed that the parts of the brainstem involved in this circuit are the parabrachial nucleus (PBNI) and the dorsal reticular formation in the medulla (MdD). Standing on a hot surface activated a group of nerve cells in the PBNI, triggering escape responses through connections to the MdD. Interestingly, the PBNI cells express a gene that codes for substances that also contribute to multiple disease processes.

“Our data provide evidence that the PBNI produces streams of information with distinct functional significance,” says Arnab Barik, PhD, one of the study authors. “The brainstem-spinal cord pathway identified in this study selectively controls pain response and elicits appropriate behaviors based on sensory input.”

Further investigation, the researchers say, can help us understand how pain is encoded in the brain. The study findings may also offer opportunities to understand how the body becomes dysregulated during chronic pain.

Among adults with below-average fitness, aerobic exercise significantly improves executive function, according to a randomized clinical trial published in Neurology.

Chris Leary

“The effect of aerobic exercise on executive function was more pronounced as age increased, suggesting that it may mitigate age-related declines,” wrote Yaakov Stern, PhD, chief of cognitive neuroscience in the department of neurology at Columbia University, New York, and his research colleagues.

Research indicates that aerobic exercise provides cognitive benefits across the lifespan, but controlled exercise studies have been limited to elderly individuals, the researchers wrote. To examine the effects of aerobic exercise on cognitive function in younger, healthy adults, they conducted a randomized, parallel-group, observer-masked, community-based clinical trial. The investigators enrolled 132 cognitively normal people aged 20-67 years with aerobic capacity below the median. About 70% were women, and participants’ mean age was about 40 years.

“We hypothesized that aerobic exercise would have cognitive benefits, even in this younger age range, but that age might moderate the nature or degree of the benefit,” Dr. Stern and his colleagues wrote.

Participants were nonsmoking, habitual nonexercisers with below-average fitness by American Heart Association standards. The investigators used baseline aerobic capacity testing to establish safe exercise measures and heart rate targets.

The investigators randomly assigned participants to a group that performed aerobic exercise or to a control group that performed stretching and toning four times per week for 6 months. Outcome measures included domains of cognitive function (such as executive function, episodic memory, processing speed, language, and attention), everyday function, aerobic capacity, body mass index, and cortical thickness.

During a 2-week run-in period, participants went to their choice of five YMCA of New York City fitness centers three times per week. They had to attend at least five of these sessions to stay in the study. In both study arms, training sessions consisted of 10-15 minutes of warm-up and cooldown and 30-40 minutes of workout. Coaches contacted participants weekly to monitor their progress, and participants wore heart rate monitors during each session. Exercises in the control group were designed to promote flexibility and improve core strength. In the aerobic exercise group, participants had a choice of exercises such as walking on a treadmill, cycling on a stationary bike, or using an elliptical machine, and they gradually increased their exercise intensity to 75% of maximum heart rate by week 5. A total of 94 participants – 50 in the control group and 44 in the aerobic exercise group – completed the 6-month trial.

Executive function, but not other cognitive measures, improved significantly in the aerobic exercise group. The effect on executive function was greater in older participants. For example, at age 40 years, the executive function measure increased by 0.228 standard deviation units from baseline; at age 60, it increased by 0.596 standard deviation units.

In addition, cortical thickness increased significantly in the aerobic exercise group in the left caudal middle frontal cortex Brodmann area; this effect did not differ by age. Improvement on executive function in the aerobic exercise group was greater among participants without an APOE E4 allele, contrasting with the findings of prior studies.

“Since a difference of 0.5 standard deviations is equivalent to 20 years of age-related difference in performance on these tests, the people who exercised were testing as if they were about 10 years younger at age 40 and about 20 years younger at age 60,” Dr. Stern said in a press release. “Since thinking skills at the start of the study were poorer for participants who were older, our findings suggest that aerobic exercise is more likely to improve age-related declines in thinking skills rather than improve performance in those without a decline.”

Furthermore, aerobic exercise significantly increased aerobic capacity and significantly decreased body mass index, whereas stretching and toning did not.

“Participants in this trial scheduled their exercise sessions on their own and exercised by themselves,” the authors noted. “In addition, they were allowed to choose whatever aerobic exercise modality they preferred, so long as they reached target heart rates, enhancing the flexibility of the intervention.” Limitations of the study include its relatively small sample size and the large number of participants who dropped out of the study between consenting to participate and randomization.

The trial was funded by the National Institutes of Health. Dr. Stern reported receiving a grant from the California Walnut Commission and consulting with Eli Lilly, Axovant Sciences, Takeda, and AbbVie. A coauthor reported grant support from AposTherapy, LIH Medical, and the Everest Foundation.

[email protected]

SOURCE: Stern Y et al. Neurology. 2019 Jan 30. doi: 10.1212/WNL.0000000000007003.
 

Among adults with below-average fitness, aerobic exercise significantly improves executive function, according to a randomized clinical trial published in Neurology.

Chris Leary

“The effect of aerobic exercise on executive function was more pronounced as age increased, suggesting that it may mitigate age-related declines,” wrote Yaakov Stern, PhD, chief of cognitive neuroscience in the department of neurology at Columbia University, New York, and his research colleagues.

Research indicates that aerobic exercise provides cognitive benefits across the lifespan, but controlled exercise studies have been limited to elderly individuals, the researchers wrote. To examine the effects of aerobic exercise on cognitive function in younger, healthy adults, they conducted a randomized, parallel-group, observer-masked, community-based clinical trial. The investigators enrolled 132 cognitively normal people aged 20-67 years with aerobic capacity below the median. About 70% were women, and participants’ mean age was about 40 years.

“We hypothesized that aerobic exercise would have cognitive benefits, even in this younger age range, but that age might moderate the nature or degree of the benefit,” Dr. Stern and his colleagues wrote.

Participants were nonsmoking, habitual nonexercisers with below-average fitness by American Heart Association standards. The investigators used baseline aerobic capacity testing to establish safe exercise measures and heart rate targets.

The investigators randomly assigned participants to a group that performed aerobic exercise or to a control group that performed stretching and toning four times per week for 6 months. Outcome measures included domains of cognitive function (such as executive function, episodic memory, processing speed, language, and attention), everyday function, aerobic capacity, body mass index, and cortical thickness.

During a 2-week run-in period, participants went to their choice of five YMCA of New York City fitness centers three times per week. They had to attend at least five of these sessions to stay in the study. In both study arms, training sessions consisted of 10-15 minutes of warm-up and cooldown and 30-40 minutes of workout. Coaches contacted participants weekly to monitor their progress, and participants wore heart rate monitors during each session. Exercises in the control group were designed to promote flexibility and improve core strength. In the aerobic exercise group, participants had a choice of exercises such as walking on a treadmill, cycling on a stationary bike, or using an elliptical machine, and they gradually increased their exercise intensity to 75% of maximum heart rate by week 5. A total of 94 participants – 50 in the control group and 44 in the aerobic exercise group – completed the 6-month trial.

Executive function, but not other cognitive measures, improved significantly in the aerobic exercise group. The effect on executive function was greater in older participants. For example, at age 40 years, the executive function measure increased by 0.228 standard deviation units from baseline; at age 60, it increased by 0.596 standard deviation units.

In addition, cortical thickness increased significantly in the aerobic exercise group in the left caudal middle frontal cortex Brodmann area; this effect did not differ by age. Improvement on executive function in the aerobic exercise group was greater among participants without an APOE E4 allele, contrasting with the findings of prior studies.

“Since a difference of 0.5 standard deviations is equivalent to 20 years of age-related difference in performance on these tests, the people who exercised were testing as if they were about 10 years younger at age 40 and about 20 years younger at age 60,” Dr. Stern said in a press release. “Since thinking skills at the start of the study were poorer for participants who were older, our findings suggest that aerobic exercise is more likely to improve age-related declines in thinking skills rather than improve performance in those without a decline.”

Furthermore, aerobic exercise significantly increased aerobic capacity and significantly decreased body mass index, whereas stretching and toning did not.

“Participants in this trial scheduled their exercise sessions on their own and exercised by themselves,” the authors noted. “In addition, they were allowed to choose whatever aerobic exercise modality they preferred, so long as they reached target heart rates, enhancing the flexibility of the intervention.” Limitations of the study include its relatively small sample size and the large number of participants who dropped out of the study between consenting to participate and randomization.

The trial was funded by the National Institutes of Health. Dr. Stern reported receiving a grant from the California Walnut Commission and consulting with Eli Lilly, Axovant Sciences, Takeda, and AbbVie. A coauthor reported grant support from AposTherapy, LIH Medical, and the Everest Foundation.

[email protected]

SOURCE: Stern Y et al. Neurology. 2019 Jan 30. doi: 10.1212/WNL.0000000000007003.
 

Among adults with below-average fitness, aerobic exercise significantly improves executive function, according to a randomized clinical trial published in Neurology.

Chris Leary

“The effect of aerobic exercise on executive function was more pronounced as age increased, suggesting that it may mitigate age-related declines,” wrote Yaakov Stern, PhD, chief of cognitive neuroscience in the department of neurology at Columbia University, New York, and his research colleagues.

Research indicates that aerobic exercise provides cognitive benefits across the lifespan, but controlled exercise studies have been limited to elderly individuals, the researchers wrote. To examine the effects of aerobic exercise on cognitive function in younger, healthy adults, they conducted a randomized, parallel-group, observer-masked, community-based clinical trial. The investigators enrolled 132 cognitively normal people aged 20-67 years with aerobic capacity below the median. About 70% were women, and participants’ mean age was about 40 years.

“We hypothesized that aerobic exercise would have cognitive benefits, even in this younger age range, but that age might moderate the nature or degree of the benefit,” Dr. Stern and his colleagues wrote.

Participants were nonsmoking, habitual nonexercisers with below-average fitness by American Heart Association standards. The investigators used baseline aerobic capacity testing to establish safe exercise measures and heart rate targets.

The investigators randomly assigned participants to a group that performed aerobic exercise or to a control group that performed stretching and toning four times per week for 6 months. Outcome measures included domains of cognitive function (such as executive function, episodic memory, processing speed, language, and attention), everyday function, aerobic capacity, body mass index, and cortical thickness.

During a 2-week run-in period, participants went to their choice of five YMCA of New York City fitness centers three times per week. They had to attend at least five of these sessions to stay in the study. In both study arms, training sessions consisted of 10-15 minutes of warm-up and cooldown and 30-40 minutes of workout. Coaches contacted participants weekly to monitor their progress, and participants wore heart rate monitors during each session. Exercises in the control group were designed to promote flexibility and improve core strength. In the aerobic exercise group, participants had a choice of exercises such as walking on a treadmill, cycling on a stationary bike, or using an elliptical machine, and they gradually increased their exercise intensity to 75% of maximum heart rate by week 5. A total of 94 participants – 50 in the control group and 44 in the aerobic exercise group – completed the 6-month trial.

Executive function, but not other cognitive measures, improved significantly in the aerobic exercise group. The effect on executive function was greater in older participants. For example, at age 40 years, the executive function measure increased by 0.228 standard deviation units from baseline; at age 60, it increased by 0.596 standard deviation units.

In addition, cortical thickness increased significantly in the aerobic exercise group in the left caudal middle frontal cortex Brodmann area; this effect did not differ by age. Improvement on executive function in the aerobic exercise group was greater among participants without an APOE E4 allele, contrasting with the findings of prior studies.

“Since a difference of 0.5 standard deviations is equivalent to 20 years of age-related difference in performance on these tests, the people who exercised were testing as if they were about 10 years younger at age 40 and about 20 years younger at age 60,” Dr. Stern said in a press release. “Since thinking skills at the start of the study were poorer for participants who were older, our findings suggest that aerobic exercise is more likely to improve age-related declines in thinking skills rather than improve performance in those without a decline.”

Furthermore, aerobic exercise significantly increased aerobic capacity and significantly decreased body mass index, whereas stretching and toning did not.

“Participants in this trial scheduled their exercise sessions on their own and exercised by themselves,” the authors noted. “In addition, they were allowed to choose whatever aerobic exercise modality they preferred, so long as they reached target heart rates, enhancing the flexibility of the intervention.” Limitations of the study include its relatively small sample size and the large number of participants who dropped out of the study between consenting to participate and randomization.

The trial was funded by the National Institutes of Health. Dr. Stern reported receiving a grant from the California Walnut Commission and consulting with Eli Lilly, Axovant Sciences, Takeda, and AbbVie. A coauthor reported grant support from AposTherapy, LIH Medical, and the Everest Foundation.

[email protected]

SOURCE: Stern Y et al. Neurology. 2019 Jan 30. doi: 10.1212/WNL.0000000000007003.
 

Approximately 55 years ago, tricyclic antidepressants (TCAs) began to be used to treat neuropathic pain.¹ Eventually, clinical trials emerged suggesting the utility of TCAs for other chronic pain conditions, such as fibromyalgia (FM) and migraine prophylaxis. However, despite TCAs’ effectiveness in mitigating painful conditions, their adverse effects limited their use.

Pharmacologic advancements have led to the development of other antidepressant classes, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), and the use of these agents has come to eclipse that of TCAs. In the realm of pain management, such developments have raised the hope of possible alternative co-analgesic agents that could avoid the adverse effects associated with TCAs. Some of these agents have demonstrated efficacy for managing chronic pain states, while others have demonstrated only limited utility.

This article provides a synopsis of systematic reviews and meta-analyses examining the role of antidepressant therapy for managing several chronic pain conditions, including pain associated with neuropathy, FM, headache, and irritable bowel syndrome (IBS). Because the literature base is rapidly evolving, it is necessary to revisit the information gleaned from clinical data with respect to treatment effectiveness, and to clarify how antidepressants might be positioned in the management of chronic pain.

The effectiveness of antidepressants for pain

The pathophysiologic processes that precipitate and maintain chronic pain conditions are complex (Box 1^2-10). The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects and indirect effects (Box 2^{2,3,8,10,11-33}).

Box 1

During the last several decades, anti­depressants have been used to address—and have demonstrated clinical utility for—a variety of chronic pain states. However, antidepressants are not a panacea; some chronic pain conditions are more responsive to antidepressants than are others. The chronic painful states most amenable to antidepressants are those that result primarily from a process of neural sensitization, as opposed to acute somatic or visceral nociception. Hence, several meta-analyses and evidence-based reviews have long suggested the usefulness of antidepressants for mitigating pain associated with neuropathy,^34,35 FM,^36,37 headache,³⁸ and IBS.^39,40

Box 2

Continue to: Neuropathic pain

Several treatment guidelines advocate for the use of antidepressants for neuropathic pain.^41-44 For decades, TCAs have been employed off-label to successfully treat many patients with neuropathic pain states. Early investigations suggested that TCAs were robustly efficacious in managing patients with neuropathy.^45-48 Calculated number-needed-to-treat (NNT) values for TCAs were quite low (ie, reflecting that few patients would need to be treated to yield a positive response in one patient compared with placebo), and were comparable to, if not slightly better than, the NNTs generated for anticonvulsants and α2-δ ligands, such as gabapentin or pregabalin.^45-48

Unfortunately, early studies involving TCAs conducted many years ago do not meet contemporary standards of methodological rigor; they featured relatively small samples of patients assessed for brief post-treatment intervals with variable outcome measures. Thus, the NNT values obtained in meta-analyses based on these studies may overestimate treatment benefits.⁴⁹ Further, NNT values derived from meta-analyses tended to combine all drugs within a particular antidepressant class (eg, amitriptyline, nortriptyline, desipramine, and imipramine among the TCAs) employed at diverse doses. Taken together, these limitations raise questions about the results of those meta-analyses.

Subsequent meta-analyses, which employed strict criteria to eliminate data from studies with potential sources of bias and used a primary outcome of frequencies of patients reporting at least 30% pain reduction compared with a placebo-controlled sample, suggest that the effectiveness of TCAs as a class for treating neuropathic pain is not as compelling as once was thought. Meta-analyses of studies employing specific TCAs revealed that there was little evidence to support the use of desipramine,⁵⁰ imipramine,⁵¹ or nortriptyline⁵² in managing diabetic neuropathy or postherpetic neuralgia. Studies evaluating amitriptyline (dose range 12.5 to 150 mg/d), found low-level evidence of effectiveness; the benefit was expected to be present for a small subset (approximately 25%) of patients with neuropathic pain.⁵³

There is moderate-quality evidence that duloxetine (60 to 120 mg/d) can produce a ≥50% improvement in pain severity ratings among patients with diabetic peripheral neuropathy.⁵⁴ Although head-to-head studies with other antidepressants are limited, it appears that duloxetine and amitriptyline have comparable efficacy, even though the NNTs for amitriptyline were derived from lower-quality studies than those for duloxetine. Duloxetine is the only antidepressant to receive FDA approval for managing diabetic neuropathy. By contrast, studies assessing the utility of venlafaxine in neuropathic pain comprised small samples for brief durations, which limits the ability to draw clear (unbiased) support for its usefulness.⁵⁵

Given the diversity of pathophysiologic processes underlying the disturbances that cause neuropathic pain disorders, it is unsurprising that the effectiveness of amitriptyline and duloxetine were not generalizable to all neuropathic pain states. Although amitriptyline produced pain-mitigating effects in patients with diabetic neuropathy and post-herpetic neuralgia, and duloxetine mitigated pain among patients with diabetic neuropathy, there was no evidence to suggest their effectiveness in phantom limb pain or human immunodeficiency virus-related and spinal cord-related neuropathies.^{35,53,54,56-58}

Continue to: Fibromyalgia

As with the issues encountered in interpreting the effectiveness of antidepressants in neuropathic pain, interpreting results gleaned from clinical trials of antidepressants for treating FM are fraught with similar difficulties. Although amitriptyline has been a first-line treatment for FM for many years, the evidence upon which such recommendations were based consisted of low-level studies that had a significant potential for bias.⁵⁹ Large randomized trials would offer more compelling data regarding the efficacy of amitriptyline, but the prohibitive costs of such studies makes it unlikely they will be conducted. Amitriptyline (25 to 50 mg/d) was effective in mitigating FM-related pain in a small percentage of patients studied, with an estimated NNT of 4.⁵⁹ Adverse effects, often contributing to treatment discontinuation, were encountered more frequently among patients who received amitriptyline compared with placebo.

Selective serotonin reuptake inhibitors failed to demonstrate significant pain relief (estimated NNT of 10), or improvement in fatigue or sleep problems, even though the studies upon which such conclusions were based were low-level studies with a high potential for bias.⁶⁰ Although SSRIs have limited utility for mitigating pain, they are still quite useful for reducing depression among patients with FM.⁶⁰

By contrast, the SNRIs duloxetine and milnacipran provided clinically relevant benefit over placebo in the frequency of patients reporting pain relief of ≥30%, as well as patients’ global impression of change.⁶¹ These agents, however, failed to provide clinically relevant benefit over placebo in improving health-related quality of life, reducing sleep problems, or improving fatigue. Nonetheless, duloxetine and milnacipran are FDA-approved for managing pain in FM. Studies assessing the efficacy of venlafaxine in the treatment of FM to date have been limited by small sample sizes, inconsistent dosing, lack of a placebo control, and lack of blinding, which limits the ability to clearly delineate the role of venlafaxine in managing FM.⁶²

Mirtazapine (15 to 45 mg/d) showed a clinically relevant benefit compared with placebo for participant-reported pain relief of ≥30% and sleep disturbances. There was no benefit in terms of participant-reported improvement of quality of life, fatigue, or negative mood.⁶³ The evidence was considered to be of low quality overall.

Headache

Amitriptyline has been employed off-label to address headache prophylaxis since 1964.⁶⁴ Compared with placebo, it is efficacious in ameliorating migraine frequency and intensity as well as the frequency of tension headache.^65,66 However, SSRIs and SNRIs (venlafaxine) failed to produce significant reductions in migraine frequency or severity or the frequencies of tension headache when compared with placebo.^67,68

Continue to: Irritable bowel syndrome

Early studies addressing antidepressant efficacy in IBS reveal inconsistencies. For example, whereas some suggest that TCAs are effective in mitigating chronic, severe abdominal pain,^39,40 others concluded that TCAs failed to demonstrate a significant analgesic benefit.⁶⁹ A recent meta-analysis that restricted analysis of efficacy to randomized controlled trials (RCTs) with more rigorous methodological adherence found that pain relief in IBS is possible with both TCAs as well as SSRIs. However, adverse effects were more commonly encountered with TCAs than with SSRIs. Some of the inconsistencies in treatment efficacy reported in early studies may be due to variations in responsiveness of subsets of IBS patients. Specifically, the utility of TCAs appears to be best among patients with diarrheal-type (as opposed to constipation-type) IBS, presumably due to TCAs’ anticholinergic effects, whereas SSRIs may provide more of a benefit for patients with predominantly constipation-type IBS.^40,70

Other chronic pain conditions

Antidepressants have been used to assist in the management of several other pain conditions, including oral-facial pain, interstitial cystitis, non-cardiac chest pain, and others. The role of antidepressants for such conditions remains unclear due to limitations in the prevailing empirical work, such as few trials, small sample sizes, variations in outcome measures, and insufficient randomization and blinding.^71-76 The interpretation of results from systematic reviews and meta-analyses is limited because of these shortcomings.⁷⁷ Hence, it has not always been possible to determine whether, and to what extent, patients with such conditions may benefit from antidepressants.

Neuromodulatory effects and efficacy for pain

The interplay of norepinephrine (NE) and serotonin (5-HT) neurotransmitter systems and cellular mechanisms involved in the descending modulation of pain pathways is complex. Experimental animal models of pain modulation suggest that 5-HT can both inhibit as well as promote pain perception by different physiological mechanisms, in contrast to NE, which is predominately inhibitory. While 5-HT in the descending modulating system can inhibit pain transmission ascending to the brain from the periphery, it appears that an intact noradrenergic system is necessary for the inhibitory influences of the serotonergic system to be appreciated.^16,78,79 Deficiencies in one or both of these neurotransmitter systems may contribute to hyperactive pain processing, and thereby precipitate or maintain chronic pain.

Pain mitigation may be achieved best by enhancing both neurotransmitters simultaneously, less so by enhancing NE alone, and least by enhancing 5-HT alone.⁶ The ability to impact pain modulation would, therefore, depend on the degree to which an antidepressant capitalizes on both noradrenergic and serotonergic neurotransmission. Antidepressants commonly employed to manage pain are presented in Table 1^{47,60,68,80-88} according to their primary neurotransmitter effects. Thus, the literature summarized above suggests that antidepressants that influence both NE and 5-HT transmission have greater analgesic effects than antidepressants with more specific effects, such as influencing 5-HT reuptake alone.^80-85 It is unsurprising, therefore, that the SSRIs have not been demonstrated to be as consistently analgesic.^{47,60,68,80,86-88}

Similarly, pharmacodynamic and pharmacokinetic differences within antidepressant classes may influence analgesic effectiveness. Simultaneous effects on NE and 5-HT are achieved at low doses with duloxetine and milnacipran. By contrast, 5-HT effects predominate at low doses for venlafaxine. To achieve pain-mitigating effects, higher doses of venlafaxine generally are required.⁸⁹ Therefore, inconsistencies across studies regarding the analgesic benefits of venlafaxine may be attributable to variability in dosing; patients treated with lower doses may not have experienced sufficient NE effects to garner positive results.

Continue to: The differences in analgesic efficacy...

The differences in analgesic efficacy among specific TCAs may be understood in a similar fashion. Specifically, tertiary TCAs (imipramine and amitriptyline) inhibit both 5-HT and NE reuptake.^6,90 Secondary amines (desipramine and nortriptyline) predominantly impact NE reuptake, possibly accounting for the lesser pain-mitigating benefit achieved with these agents, such as for treating neuro­pathic pain. Further, in vivo imipramine and amitriptyline are rapidly metabolized to secondary amines that are potent and selective NE reuptake inhibitors. In this way, the secondary amines may substantially lose the ability to modulate pain transmission because of the loss of concurrent 5-HT influences.⁹⁰

Clinical pearls

The following practical points can help guide clinicians regarding the usefulness of antidepressants for pain management:

• Antidepressants can alleviate symptoms of depression and pain. The pain-mitigating effects of antidepressants are possible even among chronic pain patients who are not depressed. Antidepressants may confer benefits for chronic pain patients with depression and other comorbid conditions, such as somatic symptom and related disorders.
• Antidepressants are useful for select chronic pain states. Although the noradrenergic and serotonergic antidepressants (SNRIs and, to some extent, amitriptyline) appear to have efficacy for neuropathic pain and FM, the benefits of SSRIs appear to be less robust. On the other hand, SSRIs and TCAs may have potential benefit for patients with IBS. However, the results of meta-analyses are limited in the ability to provide information about which patients will best respond to which specific antidepressant or how well. Future research directed at identifying characteristics that can predict which patients are likely to benefit from one antidepressant vs another would help inform how best to tailor treatment to individual needs.
• The pain-mitigating effects of antidepressants often emerge early in the course of treatment (often before mood-elevating effects are observed). For example, in the case of amitriptyline, pain relief may be possible for some patients at doses generally lower than those required for mood-elevating effects. To date, there is limited information in the literature to determine what constitutes a sufficient duration of treatment, or when treatment should be modified.
• Failure to reduce pain should raise questions about whether the dose should be increased, an alternative agent should be tried, or combinations with other analgesic agents should be considered. Failure to achieve pain-mitigating effects with one antidepressant does not mean failure with others. Hence, failure to achieve desired effects with one agent might warrant an empirical trial with another agent. Presently, too few double-blind RCTs have been conducted to assess the pain-mitigating effects of other antidepressants (eg, bupropion and newer SNRIs such as desvenlafaxine and levomilnacipran). Meta-analysis of the analgesic effectiveness of these agents or comparisons to the efficacy of other antidepressant classes is, therefore, impossible at this time.

Because many chronic pain states are complex, patients will seldom experience clinically relevant benefit from any one intervention.⁵³ The bigger implication for clinical research is to determine whether there is a sequence or combination of medication use that will provide overall better clinical effectiveness.⁵³ Only limited data are available exploring the utility of combining pharmacologic approaches to address pain.⁹¹ For example, preliminary evidence suggests that combinations of complementary strategies, such as duloxetine combined with pregabalin, may result in significantly greater numbers of FM patients achieving ≥30% pain reduction compared with monotherapy with either agent alone or placebo.⁹²

• Antidepressant selection may need to be based on medication-related adverse effect profiles and the potential for drug interactions. These factors are useful to consider in delineating multimodal treatment regimens for chronic pain in light of patients’ comorbidities and co-medication regimen. For example, the adverse effects of TCAs (anticholinergic and alpha-adrenergic influences) limit their utility for treating pain. Some of these effects can be more problematic in select populations, such as older adults or those with orthostatic difficulties, among others. TCAs are contraindicated in patients with closed-angle glaucoma, recent myocardial infarction, cardiac arrhythmias, poorly controlled seizures, or severe benign prostatic hypertrophy. Although the pain-mitigating effects of SNRIs have not been demonstrated to significantly exceed those of TCAs,^68,93,94 SNRIs would offer an advantage of greater tolerability of adverse effects and relative safety in patients with comorbid medical conditions that would otherwise preclude TCA use. The adverse effects and common drug interactions associated with antidepressants are summarized in Table 2⁹⁵.

Conclusion

Chronic, nonmalignant pain conditions afflict many patients and significantly impair their ability to function. Because of heightened concerns related to the appropriateness of, and restricting inordinate access to, long-term opioid analgesics, clinicians need to explore the usefulness of co-analgesic agents, such as antidepressants. Significant comorbidities exist between psychiatric disorders and chronic pain, and psychiatrists are uniquely positioned to diagnose and treat psychiatric comorbidities, as well as pain, among their patients, especially since they understand the kinetics and dynamics of antidepressants.

Bottom Line

Antidepressants can alleviate symptoms of depression and pain. Noradrenergic and serotonergic antidepressants appear to have efficacy for pain associated with neuropathy and fibromyalgia, while selective serotonin reuptake inhibitors and tricyclic antidepressants may have benefit for patients with irritable bowel syndrome. However, evidence regarding which patients will best respond to which specific antidepressant is limited.

Continue to: Related Resources

• Williams AM, Knox ED. When to prescribe antidepressants to treat comorbid depression and pain disorders. Current Psychiatry. 2017;16(1):55-58.
• Maletic V, Demuri B. Chronic pain and depression: treatment of 2 culprits in common. Current Psychiatry. 2016;15(3):41,47-50,52.

Drug Brand Names

Amitriptyline • Elavil, Endep
Bupropion • Wellbutrin, Zyban
Carisoprodol • Rela, Soma
Cyclobenzaprine • Amrix, Flexeril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Fluoxetine • Prozac
Gabapentin • Horizant, Neurontin
Imipramine • Tofranil
Levomilnacipran • Fetzima
Methadone • Dolophine, Methadose
Milnacipran • Savella
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Pregabalin • Lyrica, Lyrica CR
Tapentadol • Nucynta
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Warfarin • Coumadin, Jantoven

Approximately 55 years ago, tricyclic antidepressants (TCAs) began to be used to treat neuropathic pain.¹ Eventually, clinical trials emerged suggesting the utility of TCAs for other chronic pain conditions, such as fibromyalgia (FM) and migraine prophylaxis. However, despite TCAs’ effectiveness in mitigating painful conditions, their adverse effects limited their use.

Pharmacologic advancements have led to the development of other antidepressant classes, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), and the use of these agents has come to eclipse that of TCAs. In the realm of pain management, such developments have raised the hope of possible alternative co-analgesic agents that could avoid the adverse effects associated with TCAs. Some of these agents have demonstrated efficacy for managing chronic pain states, while others have demonstrated only limited utility.

This article provides a synopsis of systematic reviews and meta-analyses examining the role of antidepressant therapy for managing several chronic pain conditions, including pain associated with neuropathy, FM, headache, and irritable bowel syndrome (IBS). Because the literature base is rapidly evolving, it is necessary to revisit the information gleaned from clinical data with respect to treatment effectiveness, and to clarify how antidepressants might be positioned in the management of chronic pain.

The effectiveness of antidepressants for pain

The pathophysiologic processes that precipitate and maintain chronic pain conditions are complex (Box 1^2-10). The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects and indirect effects (Box 2^{2,3,8,10,11-33}).

Box 1

During the last several decades, anti­depressants have been used to address—and have demonstrated clinical utility for—a variety of chronic pain states. However, antidepressants are not a panacea; some chronic pain conditions are more responsive to antidepressants than are others. The chronic painful states most amenable to antidepressants are those that result primarily from a process of neural sensitization, as opposed to acute somatic or visceral nociception. Hence, several meta-analyses and evidence-based reviews have long suggested the usefulness of antidepressants for mitigating pain associated with neuropathy,^34,35 FM,^36,37 headache,³⁸ and IBS.^39,40

Box 2

Continue to: Neuropathic pain

Several treatment guidelines advocate for the use of antidepressants for neuropathic pain.^41-44 For decades, TCAs have been employed off-label to successfully treat many patients with neuropathic pain states. Early investigations suggested that TCAs were robustly efficacious in managing patients with neuropathy.^45-48 Calculated number-needed-to-treat (NNT) values for TCAs were quite low (ie, reflecting that few patients would need to be treated to yield a positive response in one patient compared with placebo), and were comparable to, if not slightly better than, the NNTs generated for anticonvulsants and α2-δ ligands, such as gabapentin or pregabalin.^45-48

Unfortunately, early studies involving TCAs conducted many years ago do not meet contemporary standards of methodological rigor; they featured relatively small samples of patients assessed for brief post-treatment intervals with variable outcome measures. Thus, the NNT values obtained in meta-analyses based on these studies may overestimate treatment benefits.⁴⁹ Further, NNT values derived from meta-analyses tended to combine all drugs within a particular antidepressant class (eg, amitriptyline, nortriptyline, desipramine, and imipramine among the TCAs) employed at diverse doses. Taken together, these limitations raise questions about the results of those meta-analyses.

Subsequent meta-analyses, which employed strict criteria to eliminate data from studies with potential sources of bias and used a primary outcome of frequencies of patients reporting at least 30% pain reduction compared with a placebo-controlled sample, suggest that the effectiveness of TCAs as a class for treating neuropathic pain is not as compelling as once was thought. Meta-analyses of studies employing specific TCAs revealed that there was little evidence to support the use of desipramine,⁵⁰ imipramine,⁵¹ or nortriptyline⁵² in managing diabetic neuropathy or postherpetic neuralgia. Studies evaluating amitriptyline (dose range 12.5 to 150 mg/d), found low-level evidence of effectiveness; the benefit was expected to be present for a small subset (approximately 25%) of patients with neuropathic pain.⁵³

There is moderate-quality evidence that duloxetine (60 to 120 mg/d) can produce a ≥50% improvement in pain severity ratings among patients with diabetic peripheral neuropathy.⁵⁴ Although head-to-head studies with other antidepressants are limited, it appears that duloxetine and amitriptyline have comparable efficacy, even though the NNTs for amitriptyline were derived from lower-quality studies than those for duloxetine. Duloxetine is the only antidepressant to receive FDA approval for managing diabetic neuropathy. By contrast, studies assessing the utility of venlafaxine in neuropathic pain comprised small samples for brief durations, which limits the ability to draw clear (unbiased) support for its usefulness.⁵⁵

Given the diversity of pathophysiologic processes underlying the disturbances that cause neuropathic pain disorders, it is unsurprising that the effectiveness of amitriptyline and duloxetine were not generalizable to all neuropathic pain states. Although amitriptyline produced pain-mitigating effects in patients with diabetic neuropathy and post-herpetic neuralgia, and duloxetine mitigated pain among patients with diabetic neuropathy, there was no evidence to suggest their effectiveness in phantom limb pain or human immunodeficiency virus-related and spinal cord-related neuropathies.^{35,53,54,56-58}

Continue to: Fibromyalgia

As with the issues encountered in interpreting the effectiveness of antidepressants in neuropathic pain, interpreting results gleaned from clinical trials of antidepressants for treating FM are fraught with similar difficulties. Although amitriptyline has been a first-line treatment for FM for many years, the evidence upon which such recommendations were based consisted of low-level studies that had a significant potential for bias.⁵⁹ Large randomized trials would offer more compelling data regarding the efficacy of amitriptyline, but the prohibitive costs of such studies makes it unlikely they will be conducted. Amitriptyline (25 to 50 mg/d) was effective in mitigating FM-related pain in a small percentage of patients studied, with an estimated NNT of 4.⁵⁹ Adverse effects, often contributing to treatment discontinuation, were encountered more frequently among patients who received amitriptyline compared with placebo.

Selective serotonin reuptake inhibitors failed to demonstrate significant pain relief (estimated NNT of 10), or improvement in fatigue or sleep problems, even though the studies upon which such conclusions were based were low-level studies with a high potential for bias.⁶⁰ Although SSRIs have limited utility for mitigating pain, they are still quite useful for reducing depression among patients with FM.⁶⁰

By contrast, the SNRIs duloxetine and milnacipran provided clinically relevant benefit over placebo in the frequency of patients reporting pain relief of ≥30%, as well as patients’ global impression of change.⁶¹ These agents, however, failed to provide clinically relevant benefit over placebo in improving health-related quality of life, reducing sleep problems, or improving fatigue. Nonetheless, duloxetine and milnacipran are FDA-approved for managing pain in FM. Studies assessing the efficacy of venlafaxine in the treatment of FM to date have been limited by small sample sizes, inconsistent dosing, lack of a placebo control, and lack of blinding, which limits the ability to clearly delineate the role of venlafaxine in managing FM.⁶²

Mirtazapine (15 to 45 mg/d) showed a clinically relevant benefit compared with placebo for participant-reported pain relief of ≥30% and sleep disturbances. There was no benefit in terms of participant-reported improvement of quality of life, fatigue, or negative mood.⁶³ The evidence was considered to be of low quality overall.

Headache

Amitriptyline has been employed off-label to address headache prophylaxis since 1964.⁶⁴ Compared with placebo, it is efficacious in ameliorating migraine frequency and intensity as well as the frequency of tension headache.^65,66 However, SSRIs and SNRIs (venlafaxine) failed to produce significant reductions in migraine frequency or severity or the frequencies of tension headache when compared with placebo.^67,68

Continue to: Irritable bowel syndrome

Early studies addressing antidepressant efficacy in IBS reveal inconsistencies. For example, whereas some suggest that TCAs are effective in mitigating chronic, severe abdominal pain,^39,40 others concluded that TCAs failed to demonstrate a significant analgesic benefit.⁶⁹ A recent meta-analysis that restricted analysis of efficacy to randomized controlled trials (RCTs) with more rigorous methodological adherence found that pain relief in IBS is possible with both TCAs as well as SSRIs. However, adverse effects were more commonly encountered with TCAs than with SSRIs. Some of the inconsistencies in treatment efficacy reported in early studies may be due to variations in responsiveness of subsets of IBS patients. Specifically, the utility of TCAs appears to be best among patients with diarrheal-type (as opposed to constipation-type) IBS, presumably due to TCAs’ anticholinergic effects, whereas SSRIs may provide more of a benefit for patients with predominantly constipation-type IBS.^40,70

Other chronic pain conditions

Antidepressants have been used to assist in the management of several other pain conditions, including oral-facial pain, interstitial cystitis, non-cardiac chest pain, and others. The role of antidepressants for such conditions remains unclear due to limitations in the prevailing empirical work, such as few trials, small sample sizes, variations in outcome measures, and insufficient randomization and blinding.^71-76 The interpretation of results from systematic reviews and meta-analyses is limited because of these shortcomings.⁷⁷ Hence, it has not always been possible to determine whether, and to what extent, patients with such conditions may benefit from antidepressants.

Neuromodulatory effects and efficacy for pain

The interplay of norepinephrine (NE) and serotonin (5-HT) neurotransmitter systems and cellular mechanisms involved in the descending modulation of pain pathways is complex. Experimental animal models of pain modulation suggest that 5-HT can both inhibit as well as promote pain perception by different physiological mechanisms, in contrast to NE, which is predominately inhibitory. While 5-HT in the descending modulating system can inhibit pain transmission ascending to the brain from the periphery, it appears that an intact noradrenergic system is necessary for the inhibitory influences of the serotonergic system to be appreciated.^16,78,79 Deficiencies in one or both of these neurotransmitter systems may contribute to hyperactive pain processing, and thereby precipitate or maintain chronic pain.

Pain mitigation may be achieved best by enhancing both neurotransmitters simultaneously, less so by enhancing NE alone, and least by enhancing 5-HT alone.⁶ The ability to impact pain modulation would, therefore, depend on the degree to which an antidepressant capitalizes on both noradrenergic and serotonergic neurotransmission. Antidepressants commonly employed to manage pain are presented in Table 1^{47,60,68,80-88} according to their primary neurotransmitter effects. Thus, the literature summarized above suggests that antidepressants that influence both NE and 5-HT transmission have greater analgesic effects than antidepressants with more specific effects, such as influencing 5-HT reuptake alone.^80-85 It is unsurprising, therefore, that the SSRIs have not been demonstrated to be as consistently analgesic.^{47,60,68,80,86-88}

Similarly, pharmacodynamic and pharmacokinetic differences within antidepressant classes may influence analgesic effectiveness. Simultaneous effects on NE and 5-HT are achieved at low doses with duloxetine and milnacipran. By contrast, 5-HT effects predominate at low doses for venlafaxine. To achieve pain-mitigating effects, higher doses of venlafaxine generally are required.⁸⁹ Therefore, inconsistencies across studies regarding the analgesic benefits of venlafaxine may be attributable to variability in dosing; patients treated with lower doses may not have experienced sufficient NE effects to garner positive results.

Continue to: The differences in analgesic efficacy...

The differences in analgesic efficacy among specific TCAs may be understood in a similar fashion. Specifically, tertiary TCAs (imipramine and amitriptyline) inhibit both 5-HT and NE reuptake.^6,90 Secondary amines (desipramine and nortriptyline) predominantly impact NE reuptake, possibly accounting for the lesser pain-mitigating benefit achieved with these agents, such as for treating neuro­pathic pain. Further, in vivo imipramine and amitriptyline are rapidly metabolized to secondary amines that are potent and selective NE reuptake inhibitors. In this way, the secondary amines may substantially lose the ability to modulate pain transmission because of the loss of concurrent 5-HT influences.⁹⁰

Clinical pearls

The following practical points can help guide clinicians regarding the usefulness of antidepressants for pain management:

• Antidepressants can alleviate symptoms of depression and pain. The pain-mitigating effects of antidepressants are possible even among chronic pain patients who are not depressed. Antidepressants may confer benefits for chronic pain patients with depression and other comorbid conditions, such as somatic symptom and related disorders.
• Antidepressants are useful for select chronic pain states. Although the noradrenergic and serotonergic antidepressants (SNRIs and, to some extent, amitriptyline) appear to have efficacy for neuropathic pain and FM, the benefits of SSRIs appear to be less robust. On the other hand, SSRIs and TCAs may have potential benefit for patients with IBS. However, the results of meta-analyses are limited in the ability to provide information about which patients will best respond to which specific antidepressant or how well. Future research directed at identifying characteristics that can predict which patients are likely to benefit from one antidepressant vs another would help inform how best to tailor treatment to individual needs.
• The pain-mitigating effects of antidepressants often emerge early in the course of treatment (often before mood-elevating effects are observed). For example, in the case of amitriptyline, pain relief may be possible for some patients at doses generally lower than those required for mood-elevating effects. To date, there is limited information in the literature to determine what constitutes a sufficient duration of treatment, or when treatment should be modified.
• Failure to reduce pain should raise questions about whether the dose should be increased, an alternative agent should be tried, or combinations with other analgesic agents should be considered. Failure to achieve pain-mitigating effects with one antidepressant does not mean failure with others. Hence, failure to achieve desired effects with one agent might warrant an empirical trial with another agent. Presently, too few double-blind RCTs have been conducted to assess the pain-mitigating effects of other antidepressants (eg, bupropion and newer SNRIs such as desvenlafaxine and levomilnacipran). Meta-analysis of the analgesic effectiveness of these agents or comparisons to the efficacy of other antidepressant classes is, therefore, impossible at this time.

Because many chronic pain states are complex, patients will seldom experience clinically relevant benefit from any one intervention.⁵³ The bigger implication for clinical research is to determine whether there is a sequence or combination of medication use that will provide overall better clinical effectiveness.⁵³ Only limited data are available exploring the utility of combining pharmacologic approaches to address pain.⁹¹ For example, preliminary evidence suggests that combinations of complementary strategies, such as duloxetine combined with pregabalin, may result in significantly greater numbers of FM patients achieving ≥30% pain reduction compared with monotherapy with either agent alone or placebo.⁹²

• Antidepressant selection may need to be based on medication-related adverse effect profiles and the potential for drug interactions. These factors are useful to consider in delineating multimodal treatment regimens for chronic pain in light of patients’ comorbidities and co-medication regimen. For example, the adverse effects of TCAs (anticholinergic and alpha-adrenergic influences) limit their utility for treating pain. Some of these effects can be more problematic in select populations, such as older adults or those with orthostatic difficulties, among others. TCAs are contraindicated in patients with closed-angle glaucoma, recent myocardial infarction, cardiac arrhythmias, poorly controlled seizures, or severe benign prostatic hypertrophy. Although the pain-mitigating effects of SNRIs have not been demonstrated to significantly exceed those of TCAs,^68,93,94 SNRIs would offer an advantage of greater tolerability of adverse effects and relative safety in patients with comorbid medical conditions that would otherwise preclude TCA use. The adverse effects and common drug interactions associated with antidepressants are summarized in Table 2⁹⁵.

Conclusion

Chronic, nonmalignant pain conditions afflict many patients and significantly impair their ability to function. Because of heightened concerns related to the appropriateness of, and restricting inordinate access to, long-term opioid analgesics, clinicians need to explore the usefulness of co-analgesic agents, such as antidepressants. Significant comorbidities exist between psychiatric disorders and chronic pain, and psychiatrists are uniquely positioned to diagnose and treat psychiatric comorbidities, as well as pain, among their patients, especially since they understand the kinetics and dynamics of antidepressants.

Bottom Line

Antidepressants can alleviate symptoms of depression and pain. Noradrenergic and serotonergic antidepressants appear to have efficacy for pain associated with neuropathy and fibromyalgia, while selective serotonin reuptake inhibitors and tricyclic antidepressants may have benefit for patients with irritable bowel syndrome. However, evidence regarding which patients will best respond to which specific antidepressant is limited.

Continue to: Related Resources

• Williams AM, Knox ED. When to prescribe antidepressants to treat comorbid depression and pain disorders. Current Psychiatry. 2017;16(1):55-58.
• Maletic V, Demuri B. Chronic pain and depression: treatment of 2 culprits in common. Current Psychiatry. 2016;15(3):41,47-50,52.

Drug Brand Names

Amitriptyline • Elavil, Endep
Bupropion • Wellbutrin, Zyban
Carisoprodol • Rela, Soma
Cyclobenzaprine • Amrix, Flexeril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Fluoxetine • Prozac
Gabapentin • Horizant, Neurontin
Imipramine • Tofranil
Levomilnacipran • Fetzima
Methadone • Dolophine, Methadose
Milnacipran • Savella
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Pregabalin • Lyrica, Lyrica CR
Tapentadol • Nucynta
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Warfarin • Coumadin, Jantoven

Approximately 55 years ago, tricyclic antidepressants (TCAs) began to be used to treat neuropathic pain.¹ Eventually, clinical trials emerged suggesting the utility of TCAs for other chronic pain conditions, such as fibromyalgia (FM) and migraine prophylaxis. However, despite TCAs’ effectiveness in mitigating painful conditions, their adverse effects limited their use.

Pharmacologic advancements have led to the development of other antidepressant classes, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), and the use of these agents has come to eclipse that of TCAs. In the realm of pain management, such developments have raised the hope of possible alternative co-analgesic agents that could avoid the adverse effects associated with TCAs. Some of these agents have demonstrated efficacy for managing chronic pain states, while others have demonstrated only limited utility.

This article provides a synopsis of systematic reviews and meta-analyses examining the role of antidepressant therapy for managing several chronic pain conditions, including pain associated with neuropathy, FM, headache, and irritable bowel syndrome (IBS). Because the literature base is rapidly evolving, it is necessary to revisit the information gleaned from clinical data with respect to treatment effectiveness, and to clarify how antidepressants might be positioned in the management of chronic pain.

The effectiveness of antidepressants for pain

The pathophysiologic processes that precipitate and maintain chronic pain conditions are complex (Box 1^2-10). The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects and indirect effects (Box 2^{2,3,8,10,11-33}).

Box 1

During the last several decades, anti­depressants have been used to address—and have demonstrated clinical utility for—a variety of chronic pain states. However, antidepressants are not a panacea; some chronic pain conditions are more responsive to antidepressants than are others. The chronic painful states most amenable to antidepressants are those that result primarily from a process of neural sensitization, as opposed to acute somatic or visceral nociception. Hence, several meta-analyses and evidence-based reviews have long suggested the usefulness of antidepressants for mitigating pain associated with neuropathy,^34,35 FM,^36,37 headache,³⁸ and IBS.^39,40

Box 2

Continue to: Neuropathic pain

Several treatment guidelines advocate for the use of antidepressants for neuropathic pain.^41-44 For decades, TCAs have been employed off-label to successfully treat many patients with neuropathic pain states. Early investigations suggested that TCAs were robustly efficacious in managing patients with neuropathy.^45-48 Calculated number-needed-to-treat (NNT) values for TCAs were quite low (ie, reflecting that few patients would need to be treated to yield a positive response in one patient compared with placebo), and were comparable to, if not slightly better than, the NNTs generated for anticonvulsants and α2-δ ligands, such as gabapentin or pregabalin.^45-48

Unfortunately, early studies involving TCAs conducted many years ago do not meet contemporary standards of methodological rigor; they featured relatively small samples of patients assessed for brief post-treatment intervals with variable outcome measures. Thus, the NNT values obtained in meta-analyses based on these studies may overestimate treatment benefits.⁴⁹ Further, NNT values derived from meta-analyses tended to combine all drugs within a particular antidepressant class (eg, amitriptyline, nortriptyline, desipramine, and imipramine among the TCAs) employed at diverse doses. Taken together, these limitations raise questions about the results of those meta-analyses.

Subsequent meta-analyses, which employed strict criteria to eliminate data from studies with potential sources of bias and used a primary outcome of frequencies of patients reporting at least 30% pain reduction compared with a placebo-controlled sample, suggest that the effectiveness of TCAs as a class for treating neuropathic pain is not as compelling as once was thought. Meta-analyses of studies employing specific TCAs revealed that there was little evidence to support the use of desipramine,⁵⁰ imipramine,⁵¹ or nortriptyline⁵² in managing diabetic neuropathy or postherpetic neuralgia. Studies evaluating amitriptyline (dose range 12.5 to 150 mg/d), found low-level evidence of effectiveness; the benefit was expected to be present for a small subset (approximately 25%) of patients with neuropathic pain.⁵³

There is moderate-quality evidence that duloxetine (60 to 120 mg/d) can produce a ≥50% improvement in pain severity ratings among patients with diabetic peripheral neuropathy.⁵⁴ Although head-to-head studies with other antidepressants are limited, it appears that duloxetine and amitriptyline have comparable efficacy, even though the NNTs for amitriptyline were derived from lower-quality studies than those for duloxetine. Duloxetine is the only antidepressant to receive FDA approval for managing diabetic neuropathy. By contrast, studies assessing the utility of venlafaxine in neuropathic pain comprised small samples for brief durations, which limits the ability to draw clear (unbiased) support for its usefulness.⁵⁵

Given the diversity of pathophysiologic processes underlying the disturbances that cause neuropathic pain disorders, it is unsurprising that the effectiveness of amitriptyline and duloxetine were not generalizable to all neuropathic pain states. Although amitriptyline produced pain-mitigating effects in patients with diabetic neuropathy and post-herpetic neuralgia, and duloxetine mitigated pain among patients with diabetic neuropathy, there was no evidence to suggest their effectiveness in phantom limb pain or human immunodeficiency virus-related and spinal cord-related neuropathies.^{35,53,54,56-58}

Continue to: Fibromyalgia

As with the issues encountered in interpreting the effectiveness of antidepressants in neuropathic pain, interpreting results gleaned from clinical trials of antidepressants for treating FM are fraught with similar difficulties. Although amitriptyline has been a first-line treatment for FM for many years, the evidence upon which such recommendations were based consisted of low-level studies that had a significant potential for bias.⁵⁹ Large randomized trials would offer more compelling data regarding the efficacy of amitriptyline, but the prohibitive costs of such studies makes it unlikely they will be conducted. Amitriptyline (25 to 50 mg/d) was effective in mitigating FM-related pain in a small percentage of patients studied, with an estimated NNT of 4.⁵⁹ Adverse effects, often contributing to treatment discontinuation, were encountered more frequently among patients who received amitriptyline compared with placebo.

Selective serotonin reuptake inhibitors failed to demonstrate significant pain relief (estimated NNT of 10), or improvement in fatigue or sleep problems, even though the studies upon which such conclusions were based were low-level studies with a high potential for bias.⁶⁰ Although SSRIs have limited utility for mitigating pain, they are still quite useful for reducing depression among patients with FM.⁶⁰

By contrast, the SNRIs duloxetine and milnacipran provided clinically relevant benefit over placebo in the frequency of patients reporting pain relief of ≥30%, as well as patients’ global impression of change.⁶¹ These agents, however, failed to provide clinically relevant benefit over placebo in improving health-related quality of life, reducing sleep problems, or improving fatigue. Nonetheless, duloxetine and milnacipran are FDA-approved for managing pain in FM. Studies assessing the efficacy of venlafaxine in the treatment of FM to date have been limited by small sample sizes, inconsistent dosing, lack of a placebo control, and lack of blinding, which limits the ability to clearly delineate the role of venlafaxine in managing FM.⁶²

Mirtazapine (15 to 45 mg/d) showed a clinically relevant benefit compared with placebo for participant-reported pain relief of ≥30% and sleep disturbances. There was no benefit in terms of participant-reported improvement of quality of life, fatigue, or negative mood.⁶³ The evidence was considered to be of low quality overall.

Headache

Amitriptyline has been employed off-label to address headache prophylaxis since 1964.⁶⁴ Compared with placebo, it is efficacious in ameliorating migraine frequency and intensity as well as the frequency of tension headache.^65,66 However, SSRIs and SNRIs (venlafaxine) failed to produce significant reductions in migraine frequency or severity or the frequencies of tension headache when compared with placebo.^67,68

Continue to: Irritable bowel syndrome

Early studies addressing antidepressant efficacy in IBS reveal inconsistencies. For example, whereas some suggest that TCAs are effective in mitigating chronic, severe abdominal pain,^39,40 others concluded that TCAs failed to demonstrate a significant analgesic benefit.⁶⁹ A recent meta-analysis that restricted analysis of efficacy to randomized controlled trials (RCTs) with more rigorous methodological adherence found that pain relief in IBS is possible with both TCAs as well as SSRIs. However, adverse effects were more commonly encountered with TCAs than with SSRIs. Some of the inconsistencies in treatment efficacy reported in early studies may be due to variations in responsiveness of subsets of IBS patients. Specifically, the utility of TCAs appears to be best among patients with diarrheal-type (as opposed to constipation-type) IBS, presumably due to TCAs’ anticholinergic effects, whereas SSRIs may provide more of a benefit for patients with predominantly constipation-type IBS.^40,70

Other chronic pain conditions

Antidepressants have been used to assist in the management of several other pain conditions, including oral-facial pain, interstitial cystitis, non-cardiac chest pain, and others. The role of antidepressants for such conditions remains unclear due to limitations in the prevailing empirical work, such as few trials, small sample sizes, variations in outcome measures, and insufficient randomization and blinding.^71-76 The interpretation of results from systematic reviews and meta-analyses is limited because of these shortcomings.⁷⁷ Hence, it has not always been possible to determine whether, and to what extent, patients with such conditions may benefit from antidepressants.

Neuromodulatory effects and efficacy for pain

The interplay of norepinephrine (NE) and serotonin (5-HT) neurotransmitter systems and cellular mechanisms involved in the descending modulation of pain pathways is complex. Experimental animal models of pain modulation suggest that 5-HT can both inhibit as well as promote pain perception by different physiological mechanisms, in contrast to NE, which is predominately inhibitory. While 5-HT in the descending modulating system can inhibit pain transmission ascending to the brain from the periphery, it appears that an intact noradrenergic system is necessary for the inhibitory influences of the serotonergic system to be appreciated.^16,78,79 Deficiencies in one or both of these neurotransmitter systems may contribute to hyperactive pain processing, and thereby precipitate or maintain chronic pain.

Pain mitigation may be achieved best by enhancing both neurotransmitters simultaneously, less so by enhancing NE alone, and least by enhancing 5-HT alone.⁶ The ability to impact pain modulation would, therefore, depend on the degree to which an antidepressant capitalizes on both noradrenergic and serotonergic neurotransmission. Antidepressants commonly employed to manage pain are presented in Table 1^{47,60,68,80-88} according to their primary neurotransmitter effects. Thus, the literature summarized above suggests that antidepressants that influence both NE and 5-HT transmission have greater analgesic effects than antidepressants with more specific effects, such as influencing 5-HT reuptake alone.^80-85 It is unsurprising, therefore, that the SSRIs have not been demonstrated to be as consistently analgesic.^{47,60,68,80,86-88}

Similarly, pharmacodynamic and pharmacokinetic differences within antidepressant classes may influence analgesic effectiveness. Simultaneous effects on NE and 5-HT are achieved at low doses with duloxetine and milnacipran. By contrast, 5-HT effects predominate at low doses for venlafaxine. To achieve pain-mitigating effects, higher doses of venlafaxine generally are required.⁸⁹ Therefore, inconsistencies across studies regarding the analgesic benefits of venlafaxine may be attributable to variability in dosing; patients treated with lower doses may not have experienced sufficient NE effects to garner positive results.

Continue to: The differences in analgesic efficacy...

The differences in analgesic efficacy among specific TCAs may be understood in a similar fashion. Specifically, tertiary TCAs (imipramine and amitriptyline) inhibit both 5-HT and NE reuptake.^6,90 Secondary amines (desipramine and nortriptyline) predominantly impact NE reuptake, possibly accounting for the lesser pain-mitigating benefit achieved with these agents, such as for treating neuro­pathic pain. Further, in vivo imipramine and amitriptyline are rapidly metabolized to secondary amines that are potent and selective NE reuptake inhibitors. In this way, the secondary amines may substantially lose the ability to modulate pain transmission because of the loss of concurrent 5-HT influences.⁹⁰

Clinical pearls

The following practical points can help guide clinicians regarding the usefulness of antidepressants for pain management:

• Antidepressants can alleviate symptoms of depression and pain. The pain-mitigating effects of antidepressants are possible even among chronic pain patients who are not depressed. Antidepressants may confer benefits for chronic pain patients with depression and other comorbid conditions, such as somatic symptom and related disorders.
• Antidepressants are useful for select chronic pain states. Although the noradrenergic and serotonergic antidepressants (SNRIs and, to some extent, amitriptyline) appear to have efficacy for neuropathic pain and FM, the benefits of SSRIs appear to be less robust. On the other hand, SSRIs and TCAs may have potential benefit for patients with IBS. However, the results of meta-analyses are limited in the ability to provide information about which patients will best respond to which specific antidepressant or how well. Future research directed at identifying characteristics that can predict which patients are likely to benefit from one antidepressant vs another would help inform how best to tailor treatment to individual needs.
• The pain-mitigating effects of antidepressants often emerge early in the course of treatment (often before mood-elevating effects are observed). For example, in the case of amitriptyline, pain relief may be possible for some patients at doses generally lower than those required for mood-elevating effects. To date, there is limited information in the literature to determine what constitutes a sufficient duration of treatment, or when treatment should be modified.
• Failure to reduce pain should raise questions about whether the dose should be increased, an alternative agent should be tried, or combinations with other analgesic agents should be considered. Failure to achieve pain-mitigating effects with one antidepressant does not mean failure with others. Hence, failure to achieve desired effects with one agent might warrant an empirical trial with another agent. Presently, too few double-blind RCTs have been conducted to assess the pain-mitigating effects of other antidepressants (eg, bupropion and newer SNRIs such as desvenlafaxine and levomilnacipran). Meta-analysis of the analgesic effectiveness of these agents or comparisons to the efficacy of other antidepressant classes is, therefore, impossible at this time.

Because many chronic pain states are complex, patients will seldom experience clinically relevant benefit from any one intervention.⁵³ The bigger implication for clinical research is to determine whether there is a sequence or combination of medication use that will provide overall better clinical effectiveness.⁵³ Only limited data are available exploring the utility of combining pharmacologic approaches to address pain.⁹¹ For example, preliminary evidence suggests that combinations of complementary strategies, such as duloxetine combined with pregabalin, may result in significantly greater numbers of FM patients achieving ≥30% pain reduction compared with monotherapy with either agent alone or placebo.⁹²

• Antidepressant selection may need to be based on medication-related adverse effect profiles and the potential for drug interactions. These factors are useful to consider in delineating multimodal treatment regimens for chronic pain in light of patients’ comorbidities and co-medication regimen. For example, the adverse effects of TCAs (anticholinergic and alpha-adrenergic influences) limit their utility for treating pain. Some of these effects can be more problematic in select populations, such as older adults or those with orthostatic difficulties, among others. TCAs are contraindicated in patients with closed-angle glaucoma, recent myocardial infarction, cardiac arrhythmias, poorly controlled seizures, or severe benign prostatic hypertrophy. Although the pain-mitigating effects of SNRIs have not been demonstrated to significantly exceed those of TCAs,^68,93,94 SNRIs would offer an advantage of greater tolerability of adverse effects and relative safety in patients with comorbid medical conditions that would otherwise preclude TCA use. The adverse effects and common drug interactions associated with antidepressants are summarized in Table 2⁹⁵.

Conclusion

Chronic, nonmalignant pain conditions afflict many patients and significantly impair their ability to function. Because of heightened concerns related to the appropriateness of, and restricting inordinate access to, long-term opioid analgesics, clinicians need to explore the usefulness of co-analgesic agents, such as antidepressants. Significant comorbidities exist between psychiatric disorders and chronic pain, and psychiatrists are uniquely positioned to diagnose and treat psychiatric comorbidities, as well as pain, among their patients, especially since they understand the kinetics and dynamics of antidepressants.

Bottom Line

Antidepressants can alleviate symptoms of depression and pain. Noradrenergic and serotonergic antidepressants appear to have efficacy for pain associated with neuropathy and fibromyalgia, while selective serotonin reuptake inhibitors and tricyclic antidepressants may have benefit for patients with irritable bowel syndrome. However, evidence regarding which patients will best respond to which specific antidepressant is limited.

Continue to: Related Resources

• Williams AM, Knox ED. When to prescribe antidepressants to treat comorbid depression and pain disorders. Current Psychiatry. 2017;16(1):55-58.
• Maletic V, Demuri B. Chronic pain and depression: treatment of 2 culprits in common. Current Psychiatry. 2016;15(3):41,47-50,52.

Drug Brand Names

Amitriptyline • Elavil, Endep
Bupropion • Wellbutrin, Zyban
Carisoprodol • Rela, Soma
Cyclobenzaprine • Amrix, Flexeril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Fluoxetine • Prozac
Gabapentin • Horizant, Neurontin
Imipramine • Tofranil
Levomilnacipran • Fetzima
Methadone • Dolophine, Methadose
Milnacipran • Savella
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Pregabalin • Lyrica, Lyrica CR
Tapentadol • Nucynta
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Warfarin • Coumadin, Jantoven

Thymectomy may continue to benefit patients with myasthenia gravis 5 years after the procedure, according to an extension study published in Lancet Neurology. Patients with generalized nonthymomatous myasthenia gravis who underwent thymectomy had better long-term clinical outcomes and required less prednisone, compared with patients who received prednisone alone.

Douglas Levere/University at Buffalo

The study evaluated the clinical status, medication requirements, and adverse events of patients with myasthenia gravis who completed a randomized controlled trial of thymectomy plus prednisone versus prednisone alone and agreed to participate in a rater-blinded 2-year extension.

“Thymectomy within the first few years of the disease course in addition to prednisone therapy confers benefits that persist for 5 years ... in patients with generalized nonthymomatous myasthenia gravis,” said lead study author Gil I. Wolfe, MD, chair of the department of neurology at the University at Buffalo in New York, and his research colleagues. “Results from the extension study provide further support for the use of thymectomy in management of myasthenia gravis and should encourage serious consideration of this treatment option in discussions between clinicians and their patients,” they wrote. “Our results should lead to revision of clinical guidelines in favor of thymectomy and could potentially reverse downward trends in the use of thymectomy in overall management of myasthenia gravis.”

The main 3-year results of the Thymectomy Trial in Nonthymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) were reported in 2016; the international trial found that thymectomy plus prednisone was superior to prednisone alone at 3 years (N Engl J Med. 2016 Aug 11;375[6]:511-22). The extension study aimed to assess the durability of the treatment response.

MGTX enrolled patients aged 18-65 years who had generalized nonthymomatous myasthenia gravis of less than 5 years’ duration and Myasthenia Gravis Foundation of America Clinical Classification Class II-IV disease. Of 111 patients who completed MGTX, 68 entered the extension study, and 50 completed the 60-month assessment (24 patients in the prednisone alone group and 26 patients in the prednisone plus thymectomy group).

At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted average Quantitative Myasthenia Gravis (QMG) scores (5.47 vs. 9.34) and mean alternate-day prednisone doses (24 mg vs. 48 mg), compared with patients who received prednisone alone. Twelve of 35 patients in the thymectomy group and 14 of 33 patients in the prednisone group had at least one adverse event by month 60. No treatment-related deaths occurred in the extension phase.

At 5 years, significantly more patients who underwent thymectomy had minimal manifestation status (i.e., no functional limitations from the disease other than some muscle weakness) – 88% versus 58%. The corresponding figures at 3 years were 67% and 47%.

In addition, 3-year and 5-year data indicate that the need for hospitalization is reduced after surgery, compared with medical therapy alone, Dr. Wolfe said.

Two patients in each treatment arm had an increase of 2 points or more in the QMG score, indicating clinical worsening.

“Our current findings reinforce the benefit of thymectomy seen in [MGTX], dispelling doubts about the procedure’s benefits and how long those benefits last,” said Dr. Wolfe. “We do hope that the new findings help reverse the apparent reluctance to do thymectomy and that the proportion of patients with myasthenia gravis who undergo thymectomy will increase.”

The authors noted that the small sample size of the extension study may limit its generalizability.

The study received funding from the National Institutes of Health. Dr. Wolfe reported grants from the NIH, the Muscular Dystrophy Association, the Myasthenia Gravis Foundation of America, CSL-Behring, and ArgenX, as well as personal fees from Grifols, Shire, and Alexion Pharmaceuticals. Coauthors reported working with and receiving funds from agencies, foundations, and pharmaceutical companies.

[email protected]

SOURCE: Wolfe GI et al. Lancet Neurol. 2019 Jan 25. doi: 10.1016/S1474-4422(18)30392-2.

Thymectomy may continue to benefit patients with myasthenia gravis 5 years after the procedure, according to an extension study published in Lancet Neurology. Patients with generalized nonthymomatous myasthenia gravis who underwent thymectomy had better long-term clinical outcomes and required less prednisone, compared with patients who received prednisone alone.

Douglas Levere/University at Buffalo

The study evaluated the clinical status, medication requirements, and adverse events of patients with myasthenia gravis who completed a randomized controlled trial of thymectomy plus prednisone versus prednisone alone and agreed to participate in a rater-blinded 2-year extension.

“Thymectomy within the first few years of the disease course in addition to prednisone therapy confers benefits that persist for 5 years ... in patients with generalized nonthymomatous myasthenia gravis,” said lead study author Gil I. Wolfe, MD, chair of the department of neurology at the University at Buffalo in New York, and his research colleagues. “Results from the extension study provide further support for the use of thymectomy in management of myasthenia gravis and should encourage serious consideration of this treatment option in discussions between clinicians and their patients,” they wrote. “Our results should lead to revision of clinical guidelines in favor of thymectomy and could potentially reverse downward trends in the use of thymectomy in overall management of myasthenia gravis.”

The main 3-year results of the Thymectomy Trial in Nonthymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) were reported in 2016; the international trial found that thymectomy plus prednisone was superior to prednisone alone at 3 years (N Engl J Med. 2016 Aug 11;375[6]:511-22). The extension study aimed to assess the durability of the treatment response.

MGTX enrolled patients aged 18-65 years who had generalized nonthymomatous myasthenia gravis of less than 5 years’ duration and Myasthenia Gravis Foundation of America Clinical Classification Class II-IV disease. Of 111 patients who completed MGTX, 68 entered the extension study, and 50 completed the 60-month assessment (24 patients in the prednisone alone group and 26 patients in the prednisone plus thymectomy group).

At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted average Quantitative Myasthenia Gravis (QMG) scores (5.47 vs. 9.34) and mean alternate-day prednisone doses (24 mg vs. 48 mg), compared with patients who received prednisone alone. Twelve of 35 patients in the thymectomy group and 14 of 33 patients in the prednisone group had at least one adverse event by month 60. No treatment-related deaths occurred in the extension phase.

At 5 years, significantly more patients who underwent thymectomy had minimal manifestation status (i.e., no functional limitations from the disease other than some muscle weakness) – 88% versus 58%. The corresponding figures at 3 years were 67% and 47%.

In addition, 3-year and 5-year data indicate that the need for hospitalization is reduced after surgery, compared with medical therapy alone, Dr. Wolfe said.

Two patients in each treatment arm had an increase of 2 points or more in the QMG score, indicating clinical worsening.

“Our current findings reinforce the benefit of thymectomy seen in [MGTX], dispelling doubts about the procedure’s benefits and how long those benefits last,” said Dr. Wolfe. “We do hope that the new findings help reverse the apparent reluctance to do thymectomy and that the proportion of patients with myasthenia gravis who undergo thymectomy will increase.”

The authors noted that the small sample size of the extension study may limit its generalizability.

The study received funding from the National Institutes of Health. Dr. Wolfe reported grants from the NIH, the Muscular Dystrophy Association, the Myasthenia Gravis Foundation of America, CSL-Behring, and ArgenX, as well as personal fees from Grifols, Shire, and Alexion Pharmaceuticals. Coauthors reported working with and receiving funds from agencies, foundations, and pharmaceutical companies.

[email protected]

SOURCE: Wolfe GI et al. Lancet Neurol. 2019 Jan 25. doi: 10.1016/S1474-4422(18)30392-2.

Thymectomy may continue to benefit patients with myasthenia gravis 5 years after the procedure, according to an extension study published in Lancet Neurology. Patients with generalized nonthymomatous myasthenia gravis who underwent thymectomy had better long-term clinical outcomes and required less prednisone, compared with patients who received prednisone alone.

Douglas Levere/University at Buffalo

The study evaluated the clinical status, medication requirements, and adverse events of patients with myasthenia gravis who completed a randomized controlled trial of thymectomy plus prednisone versus prednisone alone and agreed to participate in a rater-blinded 2-year extension.

“Thymectomy within the first few years of the disease course in addition to prednisone therapy confers benefits that persist for 5 years ... in patients with generalized nonthymomatous myasthenia gravis,” said lead study author Gil I. Wolfe, MD, chair of the department of neurology at the University at Buffalo in New York, and his research colleagues. “Results from the extension study provide further support for the use of thymectomy in management of myasthenia gravis and should encourage serious consideration of this treatment option in discussions between clinicians and their patients,” they wrote. “Our results should lead to revision of clinical guidelines in favor of thymectomy and could potentially reverse downward trends in the use of thymectomy in overall management of myasthenia gravis.”

The main 3-year results of the Thymectomy Trial in Nonthymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) were reported in 2016; the international trial found that thymectomy plus prednisone was superior to prednisone alone at 3 years (N Engl J Med. 2016 Aug 11;375[6]:511-22). The extension study aimed to assess the durability of the treatment response.

MGTX enrolled patients aged 18-65 years who had generalized nonthymomatous myasthenia gravis of less than 5 years’ duration and Myasthenia Gravis Foundation of America Clinical Classification Class II-IV disease. Of 111 patients who completed MGTX, 68 entered the extension study, and 50 completed the 60-month assessment (24 patients in the prednisone alone group and 26 patients in the prednisone plus thymectomy group).

At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted average Quantitative Myasthenia Gravis (QMG) scores (5.47 vs. 9.34) and mean alternate-day prednisone doses (24 mg vs. 48 mg), compared with patients who received prednisone alone. Twelve of 35 patients in the thymectomy group and 14 of 33 patients in the prednisone group had at least one adverse event by month 60. No treatment-related deaths occurred in the extension phase.

At 5 years, significantly more patients who underwent thymectomy had minimal manifestation status (i.e., no functional limitations from the disease other than some muscle weakness) – 88% versus 58%. The corresponding figures at 3 years were 67% and 47%.

In addition, 3-year and 5-year data indicate that the need for hospitalization is reduced after surgery, compared with medical therapy alone, Dr. Wolfe said.

Two patients in each treatment arm had an increase of 2 points or more in the QMG score, indicating clinical worsening.

“Our current findings reinforce the benefit of thymectomy seen in [MGTX], dispelling doubts about the procedure’s benefits and how long those benefits last,” said Dr. Wolfe. “We do hope that the new findings help reverse the apparent reluctance to do thymectomy and that the proportion of patients with myasthenia gravis who undergo thymectomy will increase.”

The authors noted that the small sample size of the extension study may limit its generalizability.

The study received funding from the National Institutes of Health. Dr. Wolfe reported grants from the NIH, the Muscular Dystrophy Association, the Myasthenia Gravis Foundation of America, CSL-Behring, and ArgenX, as well as personal fees from Grifols, Shire, and Alexion Pharmaceuticals. Coauthors reported working with and receiving funds from agencies, foundations, and pharmaceutical companies.

[email protected]

SOURCE: Wolfe GI et al. Lancet Neurol. 2019 Jan 25. doi: 10.1016/S1474-4422(18)30392-2.

After a disappointing interim analysis, Roche and its collaborator AC Immune are halting two phase 3 trials of the antiamyloid antibody crenezumab.

CREAD 1 and CREAD 2 enrolled patients with prodromal-to-mild sporadic Alzheimer’s disease. The preplanned interim safety and efficacy analysis determined that neither study was likely to meet the primary endpoint of change from baseline on the Clinical Dementia Rating-sum of boxes score.

There were no unexpected safety signals associated with the drug, despite a quadrupling of the phase 3 dose from that used in phase 2. The company in its press release said that it will continue to conduct the Autosomal Dominant Alzheimer’s Disease (ADAD) trial as part of the Alzheimer’s Prevention Initiative (API). ADAD is a large South American trial of crenezumab in Colombian families with familial Alzheimer’s caused by mutations in the presenilin-1 gene (PSEN1).

Roche did not release any data but said the trial results will be discussed at an upcoming scientific meeting.

“While the results with crenezumab are disappointing, they meaningfully contribute to our understanding of Alzheimer’s disease,” Sandra Horning, MD, Roche’s chief medical officer and executive vice president for global development, said in an interview. “We gratefully acknowledge the participants in the CREAD trials and the efforts of everyone involved in this important program.”

The decision was not a surprise to researchers who have followed the antibody’s development. It advanced into phase 3 with lackluster phase 2 cognitive, imaging, and biomarker data. Its selection as the therapeutic agent for the ADAD trial was a key driver in its continued development, securing Roche $100 million in federal funds to help launch ADAD, the first-ever Alzheimer’s primary prevention study.

Despite its failure in sporadic Alzheimer’s, there is still some hope that crenezumab might benefit people with the PSEN1 mutation, said Richard Caselli, MD, professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center.

“The Colombian trial is aimed at dominantly-inherited AD due to a PSEN1 mutation, so it is different enough to imagine it still might make a difference in patients in whom amyloid metabolism is actually defective due to functionally altered amyloid precursor protein or gamma secretase,” he said in an interview. “Possibly some might argue that many of the patients in the crenezumab trial likely had additional pathologies so that even if the AD component responded, the overall clinical picture might not reflect it due to the other components. That would be interesting if proven and could even argue against equating young-onset with late-onset AD, at least for clinical purposes, as is currently envisioned.”

Michael Wolfe, PhD, had a different take on the matter.

“Although amyloid-beta [Abeta] production is not necessarily altered in sporadic AD, there is essentially the same pathology, presentation, and progression with familial and sporadic AD, suggesting a common molecular mechanism,” said Dr. Wolfe, who is the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence. “It’s hard to say Abeta is the pathogenic species in familial but not sporadic AD.

The antibodies that have been failing for 5 years now were designed in the early 2000s, Dr. Kupiec pointed out, when knowledge of the various amyloid species was still immature. Newer candidates can target specific conformations of the protein – monomers and oligomers – before they aggregate into insoluble sheets. “Solanezumab was the first of these, paving the way for this new generation of antibodies,” Dr. Kupiec said.

Because they target soluble Abeta, not amyloid plaques, these domain-specific antibodies are less likely to elicit ARIA (amyloid-related imaging abnormalities), the inflammatory reaction that’s been associated with plaque dissolution in other antibody trials. ARIA has been a dose-limiting step for antiamyloid antibodies – one that conformationally targeted antibodies could avoid, Dr. Kupiec said.

“There may be some limited success with the these, and there may be enough of a treatment effect to secure approval,” he said. “The question is: Can we generate a higher effect size with an antibody that is more selective to the toxic forms of Abeta?”

PMN310 is ProMIS’ attempt to thread this needle. In preclinical studies, the antibody did not bind to amyloid monomers, plaques, or vascular Abeta aggregates. The company expects to take this antibody into phase 1 trials later this year.

“If we have a molecule that doesn’t bind to monomers or to plaques, but only to the toxic oligomer, then that is an something well worth testing in the clinic,” he said.

Dr. Caselli and Dr. Wolfe have no financial disclosures.

[email protected]

After a disappointing interim analysis, Roche and its collaborator AC Immune are halting two phase 3 trials of the antiamyloid antibody crenezumab.

CREAD 1 and CREAD 2 enrolled patients with prodromal-to-mild sporadic Alzheimer’s disease. The preplanned interim safety and efficacy analysis determined that neither study was likely to meet the primary endpoint of change from baseline on the Clinical Dementia Rating-sum of boxes score.

There were no unexpected safety signals associated with the drug, despite a quadrupling of the phase 3 dose from that used in phase 2. The company in its press release said that it will continue to conduct the Autosomal Dominant Alzheimer’s Disease (ADAD) trial as part of the Alzheimer’s Prevention Initiative (API). ADAD is a large South American trial of crenezumab in Colombian families with familial Alzheimer’s caused by mutations in the presenilin-1 gene (PSEN1).

Roche did not release any data but said the trial results will be discussed at an upcoming scientific meeting.

“While the results with crenezumab are disappointing, they meaningfully contribute to our understanding of Alzheimer’s disease,” Sandra Horning, MD, Roche’s chief medical officer and executive vice president for global development, said in an interview. “We gratefully acknowledge the participants in the CREAD trials and the efforts of everyone involved in this important program.”

The decision was not a surprise to researchers who have followed the antibody’s development. It advanced into phase 3 with lackluster phase 2 cognitive, imaging, and biomarker data. Its selection as the therapeutic agent for the ADAD trial was a key driver in its continued development, securing Roche $100 million in federal funds to help launch ADAD, the first-ever Alzheimer’s primary prevention study.

Despite its failure in sporadic Alzheimer’s, there is still some hope that crenezumab might benefit people with the PSEN1 mutation, said Richard Caselli, MD, professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center.

“The Colombian trial is aimed at dominantly-inherited AD due to a PSEN1 mutation, so it is different enough to imagine it still might make a difference in patients in whom amyloid metabolism is actually defective due to functionally altered amyloid precursor protein or gamma secretase,” he said in an interview. “Possibly some might argue that many of the patients in the crenezumab trial likely had additional pathologies so that even if the AD component responded, the overall clinical picture might not reflect it due to the other components. That would be interesting if proven and could even argue against equating young-onset with late-onset AD, at least for clinical purposes, as is currently envisioned.”

Michael Wolfe, PhD, had a different take on the matter.

“Although amyloid-beta [Abeta] production is not necessarily altered in sporadic AD, there is essentially the same pathology, presentation, and progression with familial and sporadic AD, suggesting a common molecular mechanism,” said Dr. Wolfe, who is the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence. “It’s hard to say Abeta is the pathogenic species in familial but not sporadic AD.

The antibodies that have been failing for 5 years now were designed in the early 2000s, Dr. Kupiec pointed out, when knowledge of the various amyloid species was still immature. Newer candidates can target specific conformations of the protein – monomers and oligomers – before they aggregate into insoluble sheets. “Solanezumab was the first of these, paving the way for this new generation of antibodies,” Dr. Kupiec said.

Because they target soluble Abeta, not amyloid plaques, these domain-specific antibodies are less likely to elicit ARIA (amyloid-related imaging abnormalities), the inflammatory reaction that’s been associated with plaque dissolution in other antibody trials. ARIA has been a dose-limiting step for antiamyloid antibodies – one that conformationally targeted antibodies could avoid, Dr. Kupiec said.

“There may be some limited success with the these, and there may be enough of a treatment effect to secure approval,” he said. “The question is: Can we generate a higher effect size with an antibody that is more selective to the toxic forms of Abeta?”

PMN310 is ProMIS’ attempt to thread this needle. In preclinical studies, the antibody did not bind to amyloid monomers, plaques, or vascular Abeta aggregates. The company expects to take this antibody into phase 1 trials later this year.

“If we have a molecule that doesn’t bind to monomers or to plaques, but only to the toxic oligomer, then that is an something well worth testing in the clinic,” he said.

Dr. Caselli and Dr. Wolfe have no financial disclosures.

[email protected]

After a disappointing interim analysis, Roche and its collaborator AC Immune are halting two phase 3 trials of the antiamyloid antibody crenezumab.

CREAD 1 and CREAD 2 enrolled patients with prodromal-to-mild sporadic Alzheimer’s disease. The preplanned interim safety and efficacy analysis determined that neither study was likely to meet the primary endpoint of change from baseline on the Clinical Dementia Rating-sum of boxes score.

There were no unexpected safety signals associated with the drug, despite a quadrupling of the phase 3 dose from that used in phase 2. The company in its press release said that it will continue to conduct the Autosomal Dominant Alzheimer’s Disease (ADAD) trial as part of the Alzheimer’s Prevention Initiative (API). ADAD is a large South American trial of crenezumab in Colombian families with familial Alzheimer’s caused by mutations in the presenilin-1 gene (PSEN1).

Roche did not release any data but said the trial results will be discussed at an upcoming scientific meeting.

“While the results with crenezumab are disappointing, they meaningfully contribute to our understanding of Alzheimer’s disease,” Sandra Horning, MD, Roche’s chief medical officer and executive vice president for global development, said in an interview. “We gratefully acknowledge the participants in the CREAD trials and the efforts of everyone involved in this important program.”

The decision was not a surprise to researchers who have followed the antibody’s development. It advanced into phase 3 with lackluster phase 2 cognitive, imaging, and biomarker data. Its selection as the therapeutic agent for the ADAD trial was a key driver in its continued development, securing Roche $100 million in federal funds to help launch ADAD, the first-ever Alzheimer’s primary prevention study.

Despite its failure in sporadic Alzheimer’s, there is still some hope that crenezumab might benefit people with the PSEN1 mutation, said Richard Caselli, MD, professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center.

“The Colombian trial is aimed at dominantly-inherited AD due to a PSEN1 mutation, so it is different enough to imagine it still might make a difference in patients in whom amyloid metabolism is actually defective due to functionally altered amyloid precursor protein or gamma secretase,” he said in an interview. “Possibly some might argue that many of the patients in the crenezumab trial likely had additional pathologies so that even if the AD component responded, the overall clinical picture might not reflect it due to the other components. That would be interesting if proven and could even argue against equating young-onset with late-onset AD, at least for clinical purposes, as is currently envisioned.”

Michael Wolfe, PhD, had a different take on the matter.

“Although amyloid-beta [Abeta] production is not necessarily altered in sporadic AD, there is essentially the same pathology, presentation, and progression with familial and sporadic AD, suggesting a common molecular mechanism,” said Dr. Wolfe, who is the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence. “It’s hard to say Abeta is the pathogenic species in familial but not sporadic AD.

The antibodies that have been failing for 5 years now were designed in the early 2000s, Dr. Kupiec pointed out, when knowledge of the various amyloid species was still immature. Newer candidates can target specific conformations of the protein – monomers and oligomers – before they aggregate into insoluble sheets. “Solanezumab was the first of these, paving the way for this new generation of antibodies,” Dr. Kupiec said.

Because they target soluble Abeta, not amyloid plaques, these domain-specific antibodies are less likely to elicit ARIA (amyloid-related imaging abnormalities), the inflammatory reaction that’s been associated with plaque dissolution in other antibody trials. ARIA has been a dose-limiting step for antiamyloid antibodies – one that conformationally targeted antibodies could avoid, Dr. Kupiec said.

“There may be some limited success with the these, and there may be enough of a treatment effect to secure approval,” he said. “The question is: Can we generate a higher effect size with an antibody that is more selective to the toxic forms of Abeta?”

PMN310 is ProMIS’ attempt to thread this needle. In preclinical studies, the antibody did not bind to amyloid monomers, plaques, or vascular Abeta aggregates. The company expects to take this antibody into phase 1 trials later this year.

“If we have a molecule that doesn’t bind to monomers or to plaques, but only to the toxic oligomer, then that is an something well worth testing in the clinic,” he said.

Dr. Caselli and Dr. Wolfe have no financial disclosures.

[email protected]

Every year, thousands of us vow to “get in shape” by eating right and exercising. (Whether we keep that resolution is another story.) But while we view physical exercise as a way to lose or maintain weight, reduce stress, or even hone athletic skills, we seldom think about exercising one of the most important muscles in our body: the brain.

“What?” you say. “The brain is not like other muscles.” No, it’s not … and yet, it isn’t as different as we used to think. Historically (maybe histologically?), it was believed that if nerve cells in the adult brain were damaged or had died, they, unlike other cells in the body, were not replaced. Longstanding scientific belief was that while the brain compensated for damage by making new connections to undamaged nerve cells, it could not regenerate because it does not contain stem cells.¹

But since the late 1990s, scientists have been debunking the negative myths about our brains as we age. They are not as static and unable to change as we have been led to fear! In fact, in 1998, American and Swedish scientists demonstrated that adult humans can generate new brain cells.^1,2 Moreover, the brain does replicate neurons in the hippocampus, the area in our brains that is central to learning and memory. Neurons continue to grow and change beyond the first years of development and well into adulthood.

So learning (and teaching) movements to encourage the rebuilding of our neurons is key to keeping our minds sharp. In his work, Ratey found that “our physical movements can directly influence our ability to learn, think, and remember.”³ He also tells us that exercise enhances circulation to the brain, “priming it for improved function, including mental health as well as cognitive ability.”⁴

No, you can’t put your brain on a treadmill to get, and help keep, it “in shape.” But you can do something to maintain mental sharpness and delay decline in mental agility. And these exercises don’t require a health club membership or special equipment. They can be done anytime, anywhere … and no one knows you are doing them!

I’m talking about neurobics, a term coined to describe exercises that keep us mentally fit.⁵ The purpose of these activities is to work our brains in nonroutine or unexpected ways, using all of our senses to experience, or re-experience, a common activity.

Not sure what that means? Here are some examples:

Spend time in a new environment. Go to a different park or a new store. Travel, by the way, seems to slow age-related mental decline.

Continue to: Smell new odors in the morning

Smell new odors in the morning. Have new scents, like a bottle of mint extract, ready to smell first thing in the morning, to “wake up” your brain.

Take a shower with your eyes closed. Other senses become more active when you cannot see, and a shower engages several.

Try brushing your teeth with your nondominant hand. This may be difficult for some of us—and it definitely requires full attention the first time you try it!

Learn to read braille. This is a tough one, but learning to read with your fingers definitely involves one of your senses in a new context. Or, you could try learning American Sign Language, which also uses your fingers to communicate.

Respond to a situation differently. Catch yourself in a normal, unconscious response to a situation, and choose to respond in an alternate (and preferably better) way.

Continue to: Find a new route to work

Find a new route to work. It doesn’t have to be longer, just different. You may even find a faster way to work once you break your routine.

Act confidently. In a situation you are unsure about, choose to act confidently. You’ll notice that your mind gets very active once you adopt the assumption that you will know what to do.

Distinguish coins using only your sense of touch. This brain exercise can be used to kill time while waiting for an appointment. If you really want a challenge, see if you can distinguish paper currency denominations by touch.

Leave the lights off in the house. Get around your home by memory and feel. This certainly fully engages your attention—but be careful, of course!

If you give neurobics a try, let me know what you think! Or if you have other tips for staying mentally “fit,” please share them. I can be reached at [email protected]. And thank you to my friend Gail, who suggested this topic to me!

Every year, thousands of us vow to “get in shape” by eating right and exercising. (Whether we keep that resolution is another story.) But while we view physical exercise as a way to lose or maintain weight, reduce stress, or even hone athletic skills, we seldom think about exercising one of the most important muscles in our body: the brain.

“What?” you say. “The brain is not like other muscles.” No, it’s not … and yet, it isn’t as different as we used to think. Historically (maybe histologically?), it was believed that if nerve cells in the adult brain were damaged or had died, they, unlike other cells in the body, were not replaced. Longstanding scientific belief was that while the brain compensated for damage by making new connections to undamaged nerve cells, it could not regenerate because it does not contain stem cells.¹

But since the late 1990s, scientists have been debunking the negative myths about our brains as we age. They are not as static and unable to change as we have been led to fear! In fact, in 1998, American and Swedish scientists demonstrated that adult humans can generate new brain cells.^1,2 Moreover, the brain does replicate neurons in the hippocampus, the area in our brains that is central to learning and memory. Neurons continue to grow and change beyond the first years of development and well into adulthood.

So learning (and teaching) movements to encourage the rebuilding of our neurons is key to keeping our minds sharp. In his work, Ratey found that “our physical movements can directly influence our ability to learn, think, and remember.”³ He also tells us that exercise enhances circulation to the brain, “priming it for improved function, including mental health as well as cognitive ability.”⁴

No, you can’t put your brain on a treadmill to get, and help keep, it “in shape.” But you can do something to maintain mental sharpness and delay decline in mental agility. And these exercises don’t require a health club membership or special equipment. They can be done anytime, anywhere … and no one knows you are doing them!

I’m talking about neurobics, a term coined to describe exercises that keep us mentally fit.⁵ The purpose of these activities is to work our brains in nonroutine or unexpected ways, using all of our senses to experience, or re-experience, a common activity.

Not sure what that means? Here are some examples:

Spend time in a new environment. Go to a different park or a new store. Travel, by the way, seems to slow age-related mental decline.

Continue to: Smell new odors in the morning

Smell new odors in the morning. Have new scents, like a bottle of mint extract, ready to smell first thing in the morning, to “wake up” your brain.

Take a shower with your eyes closed. Other senses become more active when you cannot see, and a shower engages several.

Try brushing your teeth with your nondominant hand. This may be difficult for some of us—and it definitely requires full attention the first time you try it!

Learn to read braille. This is a tough one, but learning to read with your fingers definitely involves one of your senses in a new context. Or, you could try learning American Sign Language, which also uses your fingers to communicate.

Respond to a situation differently. Catch yourself in a normal, unconscious response to a situation, and choose to respond in an alternate (and preferably better) way.

Continue to: Find a new route to work

Find a new route to work. It doesn’t have to be longer, just different. You may even find a faster way to work once you break your routine.

Act confidently. In a situation you are unsure about, choose to act confidently. You’ll notice that your mind gets very active once you adopt the assumption that you will know what to do.

Distinguish coins using only your sense of touch. This brain exercise can be used to kill time while waiting for an appointment. If you really want a challenge, see if you can distinguish paper currency denominations by touch.

Leave the lights off in the house. Get around your home by memory and feel. This certainly fully engages your attention—but be careful, of course!

If you give neurobics a try, let me know what you think! Or if you have other tips for staying mentally “fit,” please share them. I can be reached at [email protected]. And thank you to my friend Gail, who suggested this topic to me!

Every year, thousands of us vow to “get in shape” by eating right and exercising. (Whether we keep that resolution is another story.) But while we view physical exercise as a way to lose or maintain weight, reduce stress, or even hone athletic skills, we seldom think about exercising one of the most important muscles in our body: the brain.

“What?” you say. “The brain is not like other muscles.” No, it’s not … and yet, it isn’t as different as we used to think. Historically (maybe histologically?), it was believed that if nerve cells in the adult brain were damaged or had died, they, unlike other cells in the body, were not replaced. Longstanding scientific belief was that while the brain compensated for damage by making new connections to undamaged nerve cells, it could not regenerate because it does not contain stem cells.¹

But since the late 1990s, scientists have been debunking the negative myths about our brains as we age. They are not as static and unable to change as we have been led to fear! In fact, in 1998, American and Swedish scientists demonstrated that adult humans can generate new brain cells.^1,2 Moreover, the brain does replicate neurons in the hippocampus, the area in our brains that is central to learning and memory. Neurons continue to grow and change beyond the first years of development and well into adulthood.

So learning (and teaching) movements to encourage the rebuilding of our neurons is key to keeping our minds sharp. In his work, Ratey found that “our physical movements can directly influence our ability to learn, think, and remember.”³ He also tells us that exercise enhances circulation to the brain, “priming it for improved function, including mental health as well as cognitive ability.”⁴

No, you can’t put your brain on a treadmill to get, and help keep, it “in shape.” But you can do something to maintain mental sharpness and delay decline in mental agility. And these exercises don’t require a health club membership or special equipment. They can be done anytime, anywhere … and no one knows you are doing them!

I’m talking about neurobics, a term coined to describe exercises that keep us mentally fit.⁵ The purpose of these activities is to work our brains in nonroutine or unexpected ways, using all of our senses to experience, or re-experience, a common activity.

Not sure what that means? Here are some examples:

Spend time in a new environment. Go to a different park or a new store. Travel, by the way, seems to slow age-related mental decline.

Continue to: Smell new odors in the morning

Smell new odors in the morning. Have new scents, like a bottle of mint extract, ready to smell first thing in the morning, to “wake up” your brain.

Take a shower with your eyes closed. Other senses become more active when you cannot see, and a shower engages several.

Try brushing your teeth with your nondominant hand. This may be difficult for some of us—and it definitely requires full attention the first time you try it!

Learn to read braille. This is a tough one, but learning to read with your fingers definitely involves one of your senses in a new context. Or, you could try learning American Sign Language, which also uses your fingers to communicate.

Respond to a situation differently. Catch yourself in a normal, unconscious response to a situation, and choose to respond in an alternate (and preferably better) way.

Continue to: Find a new route to work

Find a new route to work. It doesn’t have to be longer, just different. You may even find a faster way to work once you break your routine.

Act confidently. In a situation you are unsure about, choose to act confidently. You’ll notice that your mind gets very active once you adopt the assumption that you will know what to do.

Distinguish coins using only your sense of touch. This brain exercise can be used to kill time while waiting for an appointment. If you really want a challenge, see if you can distinguish paper currency denominations by touch.

Leave the lights off in the house. Get around your home by memory and feel. This certainly fully engages your attention—but be careful, of course!

If you give neurobics a try, let me know what you think! Or if you have other tips for staying mentally “fit,” please share them. I can be reached at [email protected]. And thank you to my friend Gail, who suggested this topic to me!

Vice Admiral Jerome M. Adams, MD, MPH, is the 20th Surgeon General of the United States, a post created in 1871.

Dr. Adams holds degrees in biochemistry and psychology from the University of Maryland, Baltimore County; a master’s degree in public health from the University of California, Berkeley; and a medical degree from the Indiana University, Indianapolis. He is a board-certified anesthesiologist and associate clinical professor of anesthesia at Indiana University.

At the 2018 Executive Advisory Board meeting of the Doctors Company, Richard E. Anderson, MD, FACP, chairman and chief executive officer of the Doctors Company, spoke with Dr. Adams about the opioid epidemic’s enormous impact on communities and health services in the United States.

Dr. Anderson: Dr. Adams, you’ve been busy since taking over as Surgeon General of the United States. What are some of the key challenges that you’re facing in this office?

Dr. Adams: You know, there are many challenges facing our country, but it boils down to a lack of wellness. We know that only 10% of health is due to health care, 20% of health is genetics, and the rest is a combination of behavior and environment.

My motto is “better health through better partnerships,” because I firmly believe that if we break out of our silos and reach across the traditional barriers that have been put up by funding, by reimbursement, and by infrastructure, then we can ultimately achieve wellness in our communities.

You asked what I’ve been focused on as Surgeon General. Well, I’m focused on three main areas right now.

No. 1 is the opioid epidemic. It is a scourge across our country. A person dies every 12½ minutes from an opioid overdose and that’s far too many. Especially when we know that many of those deaths can be prevented.

Another area I’m focused on is demonstrating the link between community health and economic prosperity. We want folks to invest in health because we know that not only will it achieve better health for individuals and communities but it will create a more prosperous nation, also.

And finally, I’m raising awareness about the links between our nation’s health and our safety and security – particularly our national security. Unfortunately, 7 out of 10 young people between the ages of 18 and 24 years old in our country are ineligible for military service. That’s because they can’t pass the physical, they can’t meet the educational requirements, or they have a criminal record.

So, our nation’s poor health is not just a matter of diabetes or heart disease 20 or 30 years down the road. We are literally a less-safe country right now because we’re an unhealthy country.
 

Dr. Anderson: Regarding the opioid epidemic, what are some of the programs that are available today that you find effective? What would you like to see us do as a nation to respond to the epidemic?

Dr. Adams: Recently, I was at a hospital in Alaska where they have implemented a neonatal abstinence syndrome protocol and program that is being looked at around the country – and others are attempting to replicate it.

We know that if you keep mom and baby together, baby does better, mom does better, hospital stays are shorter, costs go down, and you’re keeping that family unit intact. This prevents future problems for both the baby and the mother. That’s just one small example.

I’m also very happy to see that the prescribing of opioids is going down 20%-25% across the country. And there are even larger decreases in the military and veteran communities. That’s really a testament to doctors and the medical profession finally waking up. And I say this as a physician myself, as an anesthesiologist, as someone who is involved in acute and chronic pain management.

Four out of five people with substance use disorder say they started with a prescription opioid. Many physicians will say, “Those aren’t my patients,” but unfortunately when we look at the PDMP [prescription drug monitoring program] data across the country we do a poor job of predicting who is and who isn’t going to divert. It may not be your patient, but it could be their son or the babysitter who is diverting those overprescribed opioids.

One thing that I really think we need to lean into as health care practitioners is providing medication-assisted treatment, or MAT. We know that the gold standard for treatment and recovery is medication-assisted treatment of some form. But we also know it’s not nearly available enough and that there are barriers on the federal and state levels.

We need you to continue to talk to your congressional representatives and let them know which barriers you perceive because the data waiver comes directly from Congress.

Still, any ER can prescribe up to 3 days of MAT to someone. I’d much rather have our ER doctors putting patients on MAT and then connecting them to treatment, than sending them back out into the arms of a drug dealer after they put them into acute withdrawal with naloxone.

We also have too many pregnant women who want help but can’t find any treatment because no one out there will take care of pregnant moms. We need folks to step up to the plate and get that data waiver in our ob/gyn and primary care sectors.

Ultimately, we need hospitals and health care leaders to create an environment that makes providers feel comfortable providing that service by giving them the training and the support to be able to do it.

We also need to make sure we’re co-prescribing naloxone for those who are at risk for opioid overdose.
 

Dr. Anderson: Just so we are clear, are you in favor of regular prescribing of naloxone, along with prescriptions for opioids? Is that correct?

Dr. Adams: I issued the first Surgeon General’s advisory from more than 10 years earlier this year to help folks understand that over half of our opioid overdoses occur in a home setting. We all know that an anoxic brain injury occurs in 4-5 minutes. We also know that most ambulances and first responders aren’t going to show up in 4-5 minutes.

If we want to make a dent in this overdose epidemic, we need everyone to consider themselves a first responder. We need to look at it the same as we look at CPR; we need everyone carrying naloxone. That was one of the big pushes from my Surgeon General’s advisory.

How can providers help? Well, they can coprescribe naloxone to folks on high morphine milligram equivalents (MME) who are at risk. If grandma has naloxone at home and her grandson overdoses in the garage, then at least it’s in the same house. Naloxone is not the treatment for the opioid epidemic. But we can’t get someone who is dead into treatment.

I have no illusions that simply making naloxone available is going to turn the tide, but it certainly is an important part of it.
 

Dr. Anderson: From your unique viewpoint, how much progress do you see in relation to the opioid epidemic? Do you think we’re approaching an inflection point, or do you think there’s a long way to go before this starts to turn around?

Dr. Adams: When I talk about the opioid epidemic, I have two angles. No.1, I want to raise awareness about the opioid epidemic – the severity of it, and how everyone can lean into it in their own way. Whether it’s community citizens, providers, law enforcement, the business community, whomever.

But in addition to raising awareness, I want to instill hope.

I was in Huntington, West Virginia, just a few weeks ago at the epicenter of the opioid epidemic. They’ve been able to turn their opioid overdose rates around by providing peer recovery coaches to individuals and making sure naloxone is available throughout the community. You save the life and then you connect them to care.

We know that the folks who are at highest risk for overdose deaths are the ones who just overdosed. They come out of the ER where we’ve watched them for a few hours and then we send them right back out into the arms of the drug dealer to do exactly what we know they will do medically because we’ve thrown them into withdrawal and they try to get their next fix.

If we can partner with law enforcement, then we can turn our opioid overdose rates around.

A story of recovery that I want to share with you is about a guy named Jonathan, who I met when I was in Rhode Island.

Jonathan overdosed, but his roommate had access to naloxone, which he administered. Jonathan was taken to the ER and then connected with a peer recovery coach. He is now in recovery and has actually become a peer recovery coach himself. Saving this one life will now enable us to save many more.

Yet we still prescribe more than 80% of the world’s opioids to less than 5% of the world’s population. So, we still have an overprescribing epidemic, but we’ve surpassed the inflection point there. Prescribing is coming down.

But another part of this epidemic was that we squeezed the balloon in one place and, as prescribing opioids went down, lots of people switched over to heroin. That’s when we really first started to see overdose rates go up.

Well, it’s important for folks to know that, through law enforcement, through partnerships with the public health community, through an increase in syringe service programs, and through other touch points, heroin use is now going down in most places.

Unfortunately, now we’re seeing the third wave of the epidemic, and that’s fentanyl and carfentanil.






 

Vice Admiral Jerome M. Adams, MD, MPH, is the 20th Surgeon General of the United States, a post created in 1871.

Dr. Adams holds degrees in biochemistry and psychology from the University of Maryland, Baltimore County; a master’s degree in public health from the University of California, Berkeley; and a medical degree from the Indiana University, Indianapolis. He is a board-certified anesthesiologist and associate clinical professor of anesthesia at Indiana University.

At the 2018 Executive Advisory Board meeting of the Doctors Company, Richard E. Anderson, MD, FACP, chairman and chief executive officer of the Doctors Company, spoke with Dr. Adams about the opioid epidemic’s enormous impact on communities and health services in the United States.

Dr. Anderson: Dr. Adams, you’ve been busy since taking over as Surgeon General of the United States. What are some of the key challenges that you’re facing in this office?

Dr. Adams: You know, there are many challenges facing our country, but it boils down to a lack of wellness. We know that only 10% of health is due to health care, 20% of health is genetics, and the rest is a combination of behavior and environment.

My motto is “better health through better partnerships,” because I firmly believe that if we break out of our silos and reach across the traditional barriers that have been put up by funding, by reimbursement, and by infrastructure, then we can ultimately achieve wellness in our communities.

You asked what I’ve been focused on as Surgeon General. Well, I’m focused on three main areas right now.

No. 1 is the opioid epidemic. It is a scourge across our country. A person dies every 12½ minutes from an opioid overdose and that’s far too many. Especially when we know that many of those deaths can be prevented.

Another area I’m focused on is demonstrating the link between community health and economic prosperity. We want folks to invest in health because we know that not only will it achieve better health for individuals and communities but it will create a more prosperous nation, also.

And finally, I’m raising awareness about the links between our nation’s health and our safety and security – particularly our national security. Unfortunately, 7 out of 10 young people between the ages of 18 and 24 years old in our country are ineligible for military service. That’s because they can’t pass the physical, they can’t meet the educational requirements, or they have a criminal record.

So, our nation’s poor health is not just a matter of diabetes or heart disease 20 or 30 years down the road. We are literally a less-safe country right now because we’re an unhealthy country.
 

Dr. Anderson: Regarding the opioid epidemic, what are some of the programs that are available today that you find effective? What would you like to see us do as a nation to respond to the epidemic?

Dr. Adams: Recently, I was at a hospital in Alaska where they have implemented a neonatal abstinence syndrome protocol and program that is being looked at around the country – and others are attempting to replicate it.

We know that if you keep mom and baby together, baby does better, mom does better, hospital stays are shorter, costs go down, and you’re keeping that family unit intact. This prevents future problems for both the baby and the mother. That’s just one small example.

I’m also very happy to see that the prescribing of opioids is going down 20%-25% across the country. And there are even larger decreases in the military and veteran communities. That’s really a testament to doctors and the medical profession finally waking up. And I say this as a physician myself, as an anesthesiologist, as someone who is involved in acute and chronic pain management.

Four out of five people with substance use disorder say they started with a prescription opioid. Many physicians will say, “Those aren’t my patients,” but unfortunately when we look at the PDMP [prescription drug monitoring program] data across the country we do a poor job of predicting who is and who isn’t going to divert. It may not be your patient, but it could be their son or the babysitter who is diverting those overprescribed opioids.

One thing that I really think we need to lean into as health care practitioners is providing medication-assisted treatment, or MAT. We know that the gold standard for treatment and recovery is medication-assisted treatment of some form. But we also know it’s not nearly available enough and that there are barriers on the federal and state levels.

We need you to continue to talk to your congressional representatives and let them know which barriers you perceive because the data waiver comes directly from Congress.

Still, any ER can prescribe up to 3 days of MAT to someone. I’d much rather have our ER doctors putting patients on MAT and then connecting them to treatment, than sending them back out into the arms of a drug dealer after they put them into acute withdrawal with naloxone.

We also have too many pregnant women who want help but can’t find any treatment because no one out there will take care of pregnant moms. We need folks to step up to the plate and get that data waiver in our ob/gyn and primary care sectors.

Ultimately, we need hospitals and health care leaders to create an environment that makes providers feel comfortable providing that service by giving them the training and the support to be able to do it.

We also need to make sure we’re co-prescribing naloxone for those who are at risk for opioid overdose.
 

Dr. Anderson: Just so we are clear, are you in favor of regular prescribing of naloxone, along with prescriptions for opioids? Is that correct?

Dr. Adams: I issued the first Surgeon General’s advisory from more than 10 years earlier this year to help folks understand that over half of our opioid overdoses occur in a home setting. We all know that an anoxic brain injury occurs in 4-5 minutes. We also know that most ambulances and first responders aren’t going to show up in 4-5 minutes.

If we want to make a dent in this overdose epidemic, we need everyone to consider themselves a first responder. We need to look at it the same as we look at CPR; we need everyone carrying naloxone. That was one of the big pushes from my Surgeon General’s advisory.

How can providers help? Well, they can coprescribe naloxone to folks on high morphine milligram equivalents (MME) who are at risk. If grandma has naloxone at home and her grandson overdoses in the garage, then at least it’s in the same house. Naloxone is not the treatment for the opioid epidemic. But we can’t get someone who is dead into treatment.

I have no illusions that simply making naloxone available is going to turn the tide, but it certainly is an important part of it.
 

Dr. Anderson: From your unique viewpoint, how much progress do you see in relation to the opioid epidemic? Do you think we’re approaching an inflection point, or do you think there’s a long way to go before this starts to turn around?

Dr. Adams: When I talk about the opioid epidemic, I have two angles. No.1, I want to raise awareness about the opioid epidemic – the severity of it, and how everyone can lean into it in their own way. Whether it’s community citizens, providers, law enforcement, the business community, whomever.

But in addition to raising awareness, I want to instill hope.

I was in Huntington, West Virginia, just a few weeks ago at the epicenter of the opioid epidemic. They’ve been able to turn their opioid overdose rates around by providing peer recovery coaches to individuals and making sure naloxone is available throughout the community. You save the life and then you connect them to care.

We know that the folks who are at highest risk for overdose deaths are the ones who just overdosed. They come out of the ER where we’ve watched them for a few hours and then we send them right back out into the arms of the drug dealer to do exactly what we know they will do medically because we’ve thrown them into withdrawal and they try to get their next fix.

If we can partner with law enforcement, then we can turn our opioid overdose rates around.

A story of recovery that I want to share with you is about a guy named Jonathan, who I met when I was in Rhode Island.

Jonathan overdosed, but his roommate had access to naloxone, which he administered. Jonathan was taken to the ER and then connected with a peer recovery coach. He is now in recovery and has actually become a peer recovery coach himself. Saving this one life will now enable us to save many more.

Yet we still prescribe more than 80% of the world’s opioids to less than 5% of the world’s population. So, we still have an overprescribing epidemic, but we’ve surpassed the inflection point there. Prescribing is coming down.

But another part of this epidemic was that we squeezed the balloon in one place and, as prescribing opioids went down, lots of people switched over to heroin. That’s when we really first started to see overdose rates go up.

Well, it’s important for folks to know that, through law enforcement, through partnerships with the public health community, through an increase in syringe service programs, and through other touch points, heroin use is now going down in most places.

Unfortunately, now we’re seeing the third wave of the epidemic, and that’s fentanyl and carfentanil.






 

Vice Admiral Jerome M. Adams, MD, MPH, is the 20th Surgeon General of the United States, a post created in 1871.

Dr. Adams holds degrees in biochemistry and psychology from the University of Maryland, Baltimore County; a master’s degree in public health from the University of California, Berkeley; and a medical degree from the Indiana University, Indianapolis. He is a board-certified anesthesiologist and associate clinical professor of anesthesia at Indiana University.

At the 2018 Executive Advisory Board meeting of the Doctors Company, Richard E. Anderson, MD, FACP, chairman and chief executive officer of the Doctors Company, spoke with Dr. Adams about the opioid epidemic’s enormous impact on communities and health services in the United States.

Dr. Anderson: Dr. Adams, you’ve been busy since taking over as Surgeon General of the United States. What are some of the key challenges that you’re facing in this office?

Dr. Adams: You know, there are many challenges facing our country, but it boils down to a lack of wellness. We know that only 10% of health is due to health care, 20% of health is genetics, and the rest is a combination of behavior and environment.

My motto is “better health through better partnerships,” because I firmly believe that if we break out of our silos and reach across the traditional barriers that have been put up by funding, by reimbursement, and by infrastructure, then we can ultimately achieve wellness in our communities.

You asked what I’ve been focused on as Surgeon General. Well, I’m focused on three main areas right now.

No. 1 is the opioid epidemic. It is a scourge across our country. A person dies every 12½ minutes from an opioid overdose and that’s far too many. Especially when we know that many of those deaths can be prevented.

Another area I’m focused on is demonstrating the link between community health and economic prosperity. We want folks to invest in health because we know that not only will it achieve better health for individuals and communities but it will create a more prosperous nation, also.

And finally, I’m raising awareness about the links between our nation’s health and our safety and security – particularly our national security. Unfortunately, 7 out of 10 young people between the ages of 18 and 24 years old in our country are ineligible for military service. That’s because they can’t pass the physical, they can’t meet the educational requirements, or they have a criminal record.

So, our nation’s poor health is not just a matter of diabetes or heart disease 20 or 30 years down the road. We are literally a less-safe country right now because we’re an unhealthy country.
 

Dr. Anderson: Regarding the opioid epidemic, what are some of the programs that are available today that you find effective? What would you like to see us do as a nation to respond to the epidemic?

Dr. Adams: Recently, I was at a hospital in Alaska where they have implemented a neonatal abstinence syndrome protocol and program that is being looked at around the country – and others are attempting to replicate it.

We know that if you keep mom and baby together, baby does better, mom does better, hospital stays are shorter, costs go down, and you’re keeping that family unit intact. This prevents future problems for both the baby and the mother. That’s just one small example.

I’m also very happy to see that the prescribing of opioids is going down 20%-25% across the country. And there are even larger decreases in the military and veteran communities. That’s really a testament to doctors and the medical profession finally waking up. And I say this as a physician myself, as an anesthesiologist, as someone who is involved in acute and chronic pain management.

Four out of five people with substance use disorder say they started with a prescription opioid. Many physicians will say, “Those aren’t my patients,” but unfortunately when we look at the PDMP [prescription drug monitoring program] data across the country we do a poor job of predicting who is and who isn’t going to divert. It may not be your patient, but it could be their son or the babysitter who is diverting those overprescribed opioids.

One thing that I really think we need to lean into as health care practitioners is providing medication-assisted treatment, or MAT. We know that the gold standard for treatment and recovery is medication-assisted treatment of some form. But we also know it’s not nearly available enough and that there are barriers on the federal and state levels.

We need you to continue to talk to your congressional representatives and let them know which barriers you perceive because the data waiver comes directly from Congress.

Still, any ER can prescribe up to 3 days of MAT to someone. I’d much rather have our ER doctors putting patients on MAT and then connecting them to treatment, than sending them back out into the arms of a drug dealer after they put them into acute withdrawal with naloxone.

We also have too many pregnant women who want help but can’t find any treatment because no one out there will take care of pregnant moms. We need folks to step up to the plate and get that data waiver in our ob/gyn and primary care sectors.

Ultimately, we need hospitals and health care leaders to create an environment that makes providers feel comfortable providing that service by giving them the training and the support to be able to do it.

We also need to make sure we’re co-prescribing naloxone for those who are at risk for opioid overdose.
 

Dr. Anderson: Just so we are clear, are you in favor of regular prescribing of naloxone, along with prescriptions for opioids? Is that correct?

Dr. Adams: I issued the first Surgeon General’s advisory from more than 10 years earlier this year to help folks understand that over half of our opioid overdoses occur in a home setting. We all know that an anoxic brain injury occurs in 4-5 minutes. We also know that most ambulances and first responders aren’t going to show up in 4-5 minutes.

If we want to make a dent in this overdose epidemic, we need everyone to consider themselves a first responder. We need to look at it the same as we look at CPR; we need everyone carrying naloxone. That was one of the big pushes from my Surgeon General’s advisory.

How can providers help? Well, they can coprescribe naloxone to folks on high morphine milligram equivalents (MME) who are at risk. If grandma has naloxone at home and her grandson overdoses in the garage, then at least it’s in the same house. Naloxone is not the treatment for the opioid epidemic. But we can’t get someone who is dead into treatment.

I have no illusions that simply making naloxone available is going to turn the tide, but it certainly is an important part of it.
 

Dr. Anderson: From your unique viewpoint, how much progress do you see in relation to the opioid epidemic? Do you think we’re approaching an inflection point, or do you think there’s a long way to go before this starts to turn around?

Dr. Adams: When I talk about the opioid epidemic, I have two angles. No.1, I want to raise awareness about the opioid epidemic – the severity of it, and how everyone can lean into it in their own way. Whether it’s community citizens, providers, law enforcement, the business community, whomever.

But in addition to raising awareness, I want to instill hope.

I was in Huntington, West Virginia, just a few weeks ago at the epicenter of the opioid epidemic. They’ve been able to turn their opioid overdose rates around by providing peer recovery coaches to individuals and making sure naloxone is available throughout the community. You save the life and then you connect them to care.

We know that the folks who are at highest risk for overdose deaths are the ones who just overdosed. They come out of the ER where we’ve watched them for a few hours and then we send them right back out into the arms of the drug dealer to do exactly what we know they will do medically because we’ve thrown them into withdrawal and they try to get their next fix.

If we can partner with law enforcement, then we can turn our opioid overdose rates around.

A story of recovery that I want to share with you is about a guy named Jonathan, who I met when I was in Rhode Island.

Jonathan overdosed, but his roommate had access to naloxone, which he administered. Jonathan was taken to the ER and then connected with a peer recovery coach. He is now in recovery and has actually become a peer recovery coach himself. Saving this one life will now enable us to save many more.

Yet we still prescribe more than 80% of the world’s opioids to less than 5% of the world’s population. So, we still have an overprescribing epidemic, but we’ve surpassed the inflection point there. Prescribing is coming down.

But another part of this epidemic was that we squeezed the balloon in one place and, as prescribing opioids went down, lots of people switched over to heroin. That’s when we really first started to see overdose rates go up.

Well, it’s important for folks to know that, through law enforcement, through partnerships with the public health community, through an increase in syringe service programs, and through other touch points, heroin use is now going down in most places.

Unfortunately, now we’re seeing the third wave of the epidemic, and that’s fentanyl and carfentanil.






 

Civilian patients with mild traumatic brain injury (TBI) who are black, have psychiatric history or lower education, or whose injury was caused by assault might be at greater risk of developing posttraumatic stress disorder or major depression, a longitudinal study suggests.

Stockdevil/Thinkstock

“Our findings may have implications for surveillance and treatment of mental disorders after TBI,” wrote Murray B. Stein, MD, MPH, and his associates. The study was published Jan. 30 in JAMA Psychiatry.

The researchers looked at the risk factors for and prevalence of posttraumatic stress disorder (PTSD) and major depressive disorder among 1,155 patients. The patients were enrolled at 11 level 1 trauma centers across the United States after they were evaluated for mild TBI in emergency departments as part of a prospective study called Transforming Research and Clinical Knowledge in Traumatic Brain Injury, or TRACK-TBI. The comparison group was 230 patients with nonhead orthopedic trauma injuries, wrote Dr. Stein, distinguished professor of psychiatry and family medicine and public health at the University of California, San Diego, and his associates.

They found that each additional year of education was associated with a significant 11% reduction in the risk of developing PTSD after mild TBI (P = .005). Also, black patients had a greater than fivefold higher risk of PTSD (P less than.001) than that of individuals who were not black.

Among patients with a history of mental illness and those who had experienced their injury as a result of assault or violence – as opposed to a motor vehicle accident or fall, for example – both had a greater than threefold higher risk of developing PTSD (odds ratio, 3.57 and 3.43 respectively). A prior TBI was nonsignificantly associated with an increased risk of developing PTSD.

Lower education duration, being black, or a history of mental illness also were all significantly associated with an increased risk of developing major depressive disorder after mild TBI.

However, duration of lost consciousness or posttraumatic amnesia, evidence of brain injury on CT, or hospitalization did not predict an increased risk of PTSD or major depression.

“Although MDD and PTSD are prevalent after TBI, little is known about which patients are at risk for developing them,” Dr. Stein and his associates wrote.

Noting that having a prior mental health problem was an “exceptionally strong” risk factor for PTSD and MDD after TBI, the authors said this could represent continuation or exacerbation of the prior mental health issue, or the triggering of a new episode in a person with a past history who had recovered.

“However, in either case this finding underscores the importance of clinicians being aware of the mental health history of their patients with [mild TBI], as this information is central to expectations regarding both short-term and long-term outcome,” they wrote.

Dr. Stein and his associates cited as a limitation their reliance on patient or family report. In addition, they said, the elevated risk for mental disorders among black individuals after mild TBI, which was independent of socioeconomic status or cause of injury, was not understood. “Unmeasured covariates may be part of the explanation; this is a topic needing further study,” they wrote.

The study was supported by the National Institutes of Health, the U.S. Department of Defense, Abbott Laboratories, and One Mind. Four authors declared consultancies, advisory board positions, speaking fees, and shares or stock options with the pharmaceutical and private industry. Two authors declared grants from the study sponsors.

SOURCE: Stein MB et al. JAMA Psychiatry. 2019. Jan 30. doi: 10.1001/jamapsychiatry.2018.4288.

Civilian patients with mild traumatic brain injury (TBI) who are black, have psychiatric history or lower education, or whose injury was caused by assault might be at greater risk of developing posttraumatic stress disorder or major depression, a longitudinal study suggests.

Stockdevil/Thinkstock

“Our findings may have implications for surveillance and treatment of mental disorders after TBI,” wrote Murray B. Stein, MD, MPH, and his associates. The study was published Jan. 30 in JAMA Psychiatry.

The researchers looked at the risk factors for and prevalence of posttraumatic stress disorder (PTSD) and major depressive disorder among 1,155 patients. The patients were enrolled at 11 level 1 trauma centers across the United States after they were evaluated for mild TBI in emergency departments as part of a prospective study called Transforming Research and Clinical Knowledge in Traumatic Brain Injury, or TRACK-TBI. The comparison group was 230 patients with nonhead orthopedic trauma injuries, wrote Dr. Stein, distinguished professor of psychiatry and family medicine and public health at the University of California, San Diego, and his associates.

They found that each additional year of education was associated with a significant 11% reduction in the risk of developing PTSD after mild TBI (P = .005). Also, black patients had a greater than fivefold higher risk of PTSD (P less than.001) than that of individuals who were not black.

Among patients with a history of mental illness and those who had experienced their injury as a result of assault or violence – as opposed to a motor vehicle accident or fall, for example – both had a greater than threefold higher risk of developing PTSD (odds ratio, 3.57 and 3.43 respectively). A prior TBI was nonsignificantly associated with an increased risk of developing PTSD.

Lower education duration, being black, or a history of mental illness also were all significantly associated with an increased risk of developing major depressive disorder after mild TBI.

However, duration of lost consciousness or posttraumatic amnesia, evidence of brain injury on CT, or hospitalization did not predict an increased risk of PTSD or major depression.

“Although MDD and PTSD are prevalent after TBI, little is known about which patients are at risk for developing them,” Dr. Stein and his associates wrote.

Noting that having a prior mental health problem was an “exceptionally strong” risk factor for PTSD and MDD after TBI, the authors said this could represent continuation or exacerbation of the prior mental health issue, or the triggering of a new episode in a person with a past history who had recovered.

“However, in either case this finding underscores the importance of clinicians being aware of the mental health history of their patients with [mild TBI], as this information is central to expectations regarding both short-term and long-term outcome,” they wrote.

Dr. Stein and his associates cited as a limitation their reliance on patient or family report. In addition, they said, the elevated risk for mental disorders among black individuals after mild TBI, which was independent of socioeconomic status or cause of injury, was not understood. “Unmeasured covariates may be part of the explanation; this is a topic needing further study,” they wrote.

The study was supported by the National Institutes of Health, the U.S. Department of Defense, Abbott Laboratories, and One Mind. Four authors declared consultancies, advisory board positions, speaking fees, and shares or stock options with the pharmaceutical and private industry. Two authors declared grants from the study sponsors.

SOURCE: Stein MB et al. JAMA Psychiatry. 2019. Jan 30. doi: 10.1001/jamapsychiatry.2018.4288.

Civilian patients with mild traumatic brain injury (TBI) who are black, have psychiatric history or lower education, or whose injury was caused by assault might be at greater risk of developing posttraumatic stress disorder or major depression, a longitudinal study suggests.

Stockdevil/Thinkstock

“Our findings may have implications for surveillance and treatment of mental disorders after TBI,” wrote Murray B. Stein, MD, MPH, and his associates. The study was published Jan. 30 in JAMA Psychiatry.

The researchers looked at the risk factors for and prevalence of posttraumatic stress disorder (PTSD) and major depressive disorder among 1,155 patients. The patients were enrolled at 11 level 1 trauma centers across the United States after they were evaluated for mild TBI in emergency departments as part of a prospective study called Transforming Research and Clinical Knowledge in Traumatic Brain Injury, or TRACK-TBI. The comparison group was 230 patients with nonhead orthopedic trauma injuries, wrote Dr. Stein, distinguished professor of psychiatry and family medicine and public health at the University of California, San Diego, and his associates.

They found that each additional year of education was associated with a significant 11% reduction in the risk of developing PTSD after mild TBI (P = .005). Also, black patients had a greater than fivefold higher risk of PTSD (P less than.001) than that of individuals who were not black.

Among patients with a history of mental illness and those who had experienced their injury as a result of assault or violence – as opposed to a motor vehicle accident or fall, for example – both had a greater than threefold higher risk of developing PTSD (odds ratio, 3.57 and 3.43 respectively). A prior TBI was nonsignificantly associated with an increased risk of developing PTSD.

Lower education duration, being black, or a history of mental illness also were all significantly associated with an increased risk of developing major depressive disorder after mild TBI.

However, duration of lost consciousness or posttraumatic amnesia, evidence of brain injury on CT, or hospitalization did not predict an increased risk of PTSD or major depression.

“Although MDD and PTSD are prevalent after TBI, little is known about which patients are at risk for developing them,” Dr. Stein and his associates wrote.

Noting that having a prior mental health problem was an “exceptionally strong” risk factor for PTSD and MDD after TBI, the authors said this could represent continuation or exacerbation of the prior mental health issue, or the triggering of a new episode in a person with a past history who had recovered.

“However, in either case this finding underscores the importance of clinicians being aware of the mental health history of their patients with [mild TBI], as this information is central to expectations regarding both short-term and long-term outcome,” they wrote.

Dr. Stein and his associates cited as a limitation their reliance on patient or family report. In addition, they said, the elevated risk for mental disorders among black individuals after mild TBI, which was independent of socioeconomic status or cause of injury, was not understood. “Unmeasured covariates may be part of the explanation; this is a topic needing further study,” they wrote.

The study was supported by the National Institutes of Health, the U.S. Department of Defense, Abbott Laboratories, and One Mind. Four authors declared consultancies, advisory board positions, speaking fees, and shares or stock options with the pharmaceutical and private industry. Two authors declared grants from the study sponsors.

SOURCE: Stein MB et al. JAMA Psychiatry. 2019. Jan 30. doi: 10.1001/jamapsychiatry.2018.4288.

One of the common symptoms described by postconcussion patients is that their heads feel a bit foggy. It may not be simply by chance that “foggy” is the best word to describe the atmosphere surrounding the entire field of concussion diagnosis and management.

KatarzynaBialasiewicz/Thinkstock

Back in the Dark Ages, when the diagnosis of concussion was a simpler binary call, the issue of management seldom created much discussion. If the patient lost consciousness or was amnesic, he (it was less frequently she) could return to activity when his headache was gone and he could remember what he was supposed to do when the quarterback called for a “Red 34, Drive Right Smash” play. That may have even been during the second half of the game in which he was injured.

As it became more widely understood that the diagnosis of concussion didn’t require loss of consciousness and that repeated concussions could have serious sequelae, management became a bit fuzzier. No one had thought much about the recuperative process. Into this vacuum came a wide variety of researchers and providers. Concussion management blossomed into a cottage industry, populated by neurologists, orthopedists, trainers, sports medicine specialists, and physical therapists. Not surprisingly, much of their advice was based on unproven assumptions, including the concept of “brain rest.”

It has taken time, but fortunately, folks with patience and wisdom have questioned these assumptions and begun collecting data. The result of these investigations and others has prompted the American Academy of Pediatrics to publish an updated set of guidelines on concussion management that includes the observation that extended school absence may slow the rehabilitation process (Pediatrics. 2018 Dec. doi: 10.1542/peds.2018-3074).

It is becoming clear that management of concussion can be rather complex and must be individualized to each patient. In my experience, the postconcussion period can unmask behavioral, cognitive, and emotional problems that were preexisting but had received little or no attention. For example, the trauma of the event may trigger anxiety about further injury or exacerbate depression that had been building for years. The student who “couldn’t do algebra” following a head injury may have had a lifelong learning disability that had gone unnoticed. The student athlete with prolonged postconcussion symptoms may indeed have another more serious problem. Hopefully, the new guidelines from the AAP will be a first step toward a more thoughtful and scientifically driven approach to concussion management.

It would be nice if that approach could filter down to the management of the more common but less dramatic pediatric injuries. There is hope. Choosing Wisely – a patient/parent–targeted initiative by the American Board of Internal Medicine Foundation in cooperation with the AAP – points out that, although half of the pediatric head injury patients seen in emergency departments received CT scan, only a third of those studies were indicated. Parents are encouraged to learn more about the risks of CT scans and question the physician when one is recommended.

But, doctors’ habits and old wives’ tales die slowly. I hope that you no longer recommend that parents keep their children awake after a head injury, or wake them every hour to check their pupils. Those counterproductive recommendations make about as much sense as staying out of the swimming pool for an hour after eating a chocolate chip cookie.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

One of the common symptoms described by postconcussion patients is that their heads feel a bit foggy. It may not be simply by chance that “foggy” is the best word to describe the atmosphere surrounding the entire field of concussion diagnosis and management.

KatarzynaBialasiewicz/Thinkstock

Back in the Dark Ages, when the diagnosis of concussion was a simpler binary call, the issue of management seldom created much discussion. If the patient lost consciousness or was amnesic, he (it was less frequently she) could return to activity when his headache was gone and he could remember what he was supposed to do when the quarterback called for a “Red 34, Drive Right Smash” play. That may have even been during the second half of the game in which he was injured.

As it became more widely understood that the diagnosis of concussion didn’t require loss of consciousness and that repeated concussions could have serious sequelae, management became a bit fuzzier. No one had thought much about the recuperative process. Into this vacuum came a wide variety of researchers and providers. Concussion management blossomed into a cottage industry, populated by neurologists, orthopedists, trainers, sports medicine specialists, and physical therapists. Not surprisingly, much of their advice was based on unproven assumptions, including the concept of “brain rest.”

It has taken time, but fortunately, folks with patience and wisdom have questioned these assumptions and begun collecting data. The result of these investigations and others has prompted the American Academy of Pediatrics to publish an updated set of guidelines on concussion management that includes the observation that extended school absence may slow the rehabilitation process (Pediatrics. 2018 Dec. doi: 10.1542/peds.2018-3074).

It is becoming clear that management of concussion can be rather complex and must be individualized to each patient. In my experience, the postconcussion period can unmask behavioral, cognitive, and emotional problems that were preexisting but had received little or no attention. For example, the trauma of the event may trigger anxiety about further injury or exacerbate depression that had been building for years. The student who “couldn’t do algebra” following a head injury may have had a lifelong learning disability that had gone unnoticed. The student athlete with prolonged postconcussion symptoms may indeed have another more serious problem. Hopefully, the new guidelines from the AAP will be a first step toward a more thoughtful and scientifically driven approach to concussion management.

It would be nice if that approach could filter down to the management of the more common but less dramatic pediatric injuries. There is hope. Choosing Wisely – a patient/parent–targeted initiative by the American Board of Internal Medicine Foundation in cooperation with the AAP – points out that, although half of the pediatric head injury patients seen in emergency departments received CT scan, only a third of those studies were indicated. Parents are encouraged to learn more about the risks of CT scans and question the physician when one is recommended.

But, doctors’ habits and old wives’ tales die slowly. I hope that you no longer recommend that parents keep their children awake after a head injury, or wake them every hour to check their pupils. Those counterproductive recommendations make about as much sense as staying out of the swimming pool for an hour after eating a chocolate chip cookie.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

One of the common symptoms described by postconcussion patients is that their heads feel a bit foggy. It may not be simply by chance that “foggy” is the best word to describe the atmosphere surrounding the entire field of concussion diagnosis and management.

KatarzynaBialasiewicz/Thinkstock

Back in the Dark Ages, when the diagnosis of concussion was a simpler binary call, the issue of management seldom created much discussion. If the patient lost consciousness or was amnesic, he (it was less frequently she) could return to activity when his headache was gone and he could remember what he was supposed to do when the quarterback called for a “Red 34, Drive Right Smash” play. That may have even been during the second half of the game in which he was injured.

As it became more widely understood that the diagnosis of concussion didn’t require loss of consciousness and that repeated concussions could have serious sequelae, management became a bit fuzzier. No one had thought much about the recuperative process. Into this vacuum came a wide variety of researchers and providers. Concussion management blossomed into a cottage industry, populated by neurologists, orthopedists, trainers, sports medicine specialists, and physical therapists. Not surprisingly, much of their advice was based on unproven assumptions, including the concept of “brain rest.”

It has taken time, but fortunately, folks with patience and wisdom have questioned these assumptions and begun collecting data. The result of these investigations and others has prompted the American Academy of Pediatrics to publish an updated set of guidelines on concussion management that includes the observation that extended school absence may slow the rehabilitation process (Pediatrics. 2018 Dec. doi: 10.1542/peds.2018-3074).

It is becoming clear that management of concussion can be rather complex and must be individualized to each patient. In my experience, the postconcussion period can unmask behavioral, cognitive, and emotional problems that were preexisting but had received little or no attention. For example, the trauma of the event may trigger anxiety about further injury or exacerbate depression that had been building for years. The student who “couldn’t do algebra” following a head injury may have had a lifelong learning disability that had gone unnoticed. The student athlete with prolonged postconcussion symptoms may indeed have another more serious problem. Hopefully, the new guidelines from the AAP will be a first step toward a more thoughtful and scientifically driven approach to concussion management.

It would be nice if that approach could filter down to the management of the more common but less dramatic pediatric injuries. There is hope. Choosing Wisely – a patient/parent–targeted initiative by the American Board of Internal Medicine Foundation in cooperation with the AAP – points out that, although half of the pediatric head injury patients seen in emergency departments received CT scan, only a third of those studies were indicated. Parents are encouraged to learn more about the risks of CT scans and question the physician when one is recommended.

But, doctors’ habits and old wives’ tales die slowly. I hope that you no longer recommend that parents keep their children awake after a head injury, or wake them every hour to check their pupils. Those counterproductive recommendations make about as much sense as staying out of the swimming pool for an hour after eating a chocolate chip cookie.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].