Raphael J. Leo, MD, MA

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

 

 

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

 

 

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

 

 

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

 

 

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

 

 

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

 

 

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

 

 

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

 

 

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

 

 

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

 

 

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

 

 

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

 

 

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

CASE Bleeding, bewildered

Mr. K, age 23, a South Asian male, is discovered in the bathroom bleeding profusely. Mr. K’s parents inform emergency medical services (EMS) personnel that Mr. K is “not in his right mind” and speculate that he is depressed. EMS personnel find Mr. K sitting in a pool of blood in the bathtub, holding a cloth over his pubic area and complaining of significant pain. They estimate that Mr. K has lost approximately 1 L of blood. Cursory evaluation reveals that his penis is severed; no other injuries or lacerations are notable. Mr. K states, “I did not want it anymore.” A kitchen knife that he used to self-amputate is found nearby. He is awake, alert, and able to follow simple directives.

In the emergency room, Mr. K is in mild-to-moderate distress. He has no history of medical illness, but his parents report that he previously required psychiatric treatment. Mr. K is not able to elaborate. He reluctantly discloses an intermittent history of Cannabis use. Physical examination reveals tachycardia (heart rate: 115 to 120 beats per minute), and despite blood loss, systolic hypertension (blood pressure: 142/70 to 167/70 mm Hg). His pulse oximetry is 97% to 99%; he is afebrile. Laboratory tests are notable for anemia (hemoglobin, 7.2 g/dL [reference range, 14.0 to 17.5 g/dL]; hematocrit, 21.2% [reference range, 41% to 50%]) and serum toxicology screen is positive for benzodiazepines, which had been administered en route to allay his distress.

Mr. K continues to hold pressure on his pubic area. When pressure is released, active arterial spurting of bright red blood is notable. Genital examination reveals a cleanly amputated phallus. Emergent surgical intervention is required to stop the hemorrhage and reattach the penis. Initially, Mr. K is opposed to reattachment, but after a brief discussion with his parents, he consents to surgery. Urology and plastic surgery consultations are elicited to perform the microvascular portion of the procedure.

[polldaddy:9881368]

The authors’ observations

Self-injurious behaviors occur in approximately 1% to 4% of adults in the United States, with chronic and severe self-injury occurring among approximately 1% of the U.S. population.^1,2 Intentional GSM is a relatively rare catastrophic event that is often, but not solely, associated with severe mental illness. Because many cases go unreported, the prevalence of GSM is difficult to estimate.^3,4 Although GSM has been described in both men and women, the literature has predominantly focused on GSM among men.⁵ Genital self-injury has been described in several (ie, ethnic/racial and religious) contexts and has been legally sanctioned.^6-8

Psychiatric disorders associated with, and precipitating factors underlying, GSM have long remained elusive.⁸ GSM has been described in case reports and small case series in both psychiatric and urologic literature. These reports provide incomplete descriptions of the diagnostic conditions and psychosocial factors underlying male GSM.

A recent systematic review of 173 cases of men who engaged in GSM published in the past 115 years (since the first case of GSM was published in the psychiatric literature⁹) revealed that having some form of psychopathology elevates the probability of GSM^10,11; rarely the individual did not have a psychiatric condition.^11-17 Nearly one-half of the men had psychosis; most had a schizophrenia spectrum disorder diagnosis. Other psychiatric conditions associated with GSM include personality disorders, substance use disorder, and gender dysphoria. GSM is rarely associated with anxiety or mood disorders.

GSM is a heterogeneous form of self-injury that ranges from superficial genital lacerations, amputation, or castration to combinations of these injuries. Compared with individuals with other psychiatric disorders, a significantly greater proportion of individuals with schizophrenia spectrum disorders engage in self-amputation (auto-penectomy). By contrast, persons with gender dysphoria tend to engage in self-castration at significantly higher rates than those with other psychiatric conditions.¹¹ Despite these trends, clinicians should not infer a specific psychiatric diagnosis based on the severity or type of self-inflicted injury.

 

 

HISTORY Command hallucinations

Postoperatively, Mr. K is managed in the trauma intensive care unit. During psychiatric consultation, Mr. K demonstrates a blunted affect. His speech is low in volume but clear and coherent. His thoughts are generally linear for specific lines of inquiry (eg, about perceived level of pain) but otherwise are impoverished. Mr. K often digresses into repetitively mumbled prayers. He appears distracted, as if responding to internal stimuli. Although he acknowledges the GSM, he does not discuss the factors underlying his decision to proceed with auto-penectomy. Over successive evaluations, he reluctantly discloses that he had been experiencing disparaging auditory hallucinations that told him that his penis “was too small” and commanded him to “cut it off.”

Psychiatric history reveals that Mr. K required psychiatric hospitalization 7 months earlier due to new-onset auditory hallucinations, paranoia, and thought disorganization, in the context of daily Cannabis use. At the time, the differential diagnosis included new-onset schizophrenia and substance-induced psychosis. His symptoms improved quickly with risperidone, 2 mg/d, and he was discharged in a stable condition with referrals for outpatient care. Mr. K admits he had stopped taking risperidone several weeks before the GSM because he was convinced that he had been cured. At that time, Mr. K had told his parents he was no longer required to take medication or engage in outpatient psychiatric treatment, and they did not question this. Mr. K struggled to sustain part-time employment (in a family business), having taken a leave of absence from graduate school after his first hospitalization. He continued to use Cannabis regularly but denies being intoxicated at the time of the GSM. Throughout his surgical hospitalization, Mr. K’s thoughts remain disorganized. He denies that the GSM was a suicide attempt or having current suicidal thoughts, intent, or plans. He also denies having religious preoccupations, over-valued religious beliefs, or delusions.

Mr. K identifies as heterosexual, and denies experiencing distress related to sexual orientation or gender identity or guilt related to sexual impulses or actions. He also denies having a history of trauma or victimization and does not report any symptoms of posttraumatic stress disorder or body dysmorphic disorder.

The authors’ observations

There are numerous psychological factors underlying and engendered by GSM.^18-22 Delusions, hallucinations, a need for atonement, suicidal ideation, and subjective guilt have been reported among individuals engaging in GSM who have psychosis (Table 1).¹¹ Severe forms of GSM, such as castration, occur among individuals who manifest more symptoms and greater severity of psychopathology.

Little is known about how many individuals who engage in GSM eventually complete suicide. Although suicidal ideation and intent have been infrequently associated with GSM, suicide has been most notably reported among patients with schizophrenia spectrum disorders and psychotic mood disorders.^11,18,23-26 For these individuals, suicidal ideation co-occurred with delusions, hallucinations, and pathological guilt preoccupations. Significant self-inflicted injury can be harbinger of distress that could lead to suicide if not optimally treated. Other psychosocial stressors, such as disruptions in interpersonal functioning arising from changes in or loss of social support or perceived rejection, may contribute to a patient’s level of distress, complicating underlying psychiatric disturbances and increasing vulnerability toward GSM.^11,27

Substance use also increases vulnerability toward GSM.^11,18,24,28 As is the case with patients who engage in various non-GSM self-injurious behaviors,^29,30 substance use or intoxication likely contribute to disinhibition or a dissociative state, which enables individuals to engage in self-injury.³⁰

A lack of access to treatment is a rare precipitant for GSM, except among individuals with gender dysphoria. Studies have found that many patients with gender dysphoria who performed self-castration did so in a premeditated manner with low suicidal intent, and the behavior often was related to a lack of or refusal for gender confirmation surgery.^31-34

In the hospital setting, surgical/urological interventions need to be directed at the potentially life-threatening sequelae of self-injury. Although complications vary, depending on the type of injury incurred, urgent measures are needed to manage blood loss because hemorrhage can be fatal.^23,35,36 Other consequences that can arise include urinary fistulae, urethral strictures, mummification of the glans penis, and development of sensory abnormalities after repair of the injured tissues or reattachment.⁸ More superficial injuries may require only hemostasis and simple suturing, whereas extensive injuries, such as complete amputation, can be addressed through microvascular techniques.

The psychiatrist’s role. The psychiatrist should act as an advocate for the GSM patient to create an environment conducive to healing. A patient who is experiencing hallucinations or delusions may feel overwhelmed by medical and familial attention. Pharmacologic treatment for prevailing mental illness, such as psychosis, should be initiated in the inpatient setting. An estimated 20% to 25% of those who self-inflict genital injury may repeatedly mutilate their genitals.^19,28 Patients unduly influenced by command hallucinations, delusional thought processes, mood disturbances, or suicidal ideation may attempt to complete the injury, or reinjure themselves after surgical/urological intervention, which may require safety measures, such as 1:1 observation, restraints, or physical barriers, to prevent reinjury.³⁷

Self-injury elicits strong, emotional responses from health care professionals, including fascination, apprehension, and hopelessness. Psychiatrists who care for such patients should monitor members of the patient’s treatment team for psychological reactions. In addition, the patient’s behavior while hospitalized may stir feelings of retaliation, anger, fear, and frustration.^11,24,37 Collaborative relationships with medical and surgical specialties can help staff manage emotional reactions and avoid the inadvertent expression of those feelings in their interactions with the patient; these reactions might otherwise undermine treatment.^24,34 Family education can help mitigate any guilt family members may harbor for not preventing the injury.³⁷

Although efforts to understand the intended goal(s) and precipitants of the self-injury are likely to be worthwhile, the overwhelming distress associated with GSM and its emergent treatment may preclude intensive exploration. Assessing precipitants of self-injury should be approached using a nonjudgmental, dispassionate, matter-of-fact manner that conveys concern for the patient³⁸ and reassures the patient that the clinician has heard and, ideally, understands the patient’s distress.³⁹ Forced exploration during the prevailing stress of treatment may overwhelm the patient, prove to be overly distressing, and compel the patient to act out in self-injurious ways. Therefore, exploration of the underpinnings of GSM may need to be postponed until surgical treatment is completed, the patient’s symptoms have been managed with psychopharmacologic intervention, and the patient has been transitioned to the safety and close monitoring of an acute psychiatric inpatient setting.

 

 

TREATMENT Restarting medication

While on the surgical unit, Mr. K is restarted on risperidone, 2 mg/d. He appears to tolerate the medication without adverse effects. However, because Mr. K continues to experience auditory hallucinations, and the treatment team remains concerned that he might again experience commands to harm himself, he is transferred to an acute psychiatric inpatient setting.

Urology follow-up reveals necrosis/mummification of the replanted penis and an open scrotal wound. After discussing options with the patient and family, the urologist transfers Mr. K back to the surgical unit for wound closure and removal of the replanted penis. A urethrostomy is performed to allow for bladder emptying.

[polldaddy:9881371]

The authors’ observations

Because most published case reports of GSM among men have focused on acute treatment, there is a dearth of literature available on the long-term course of GSM to inform treatment strategies. Because recovery is a non-static process and a patient’s reactions to his injury will likely evolve over time, a multifaceted approach invoking psychiatric and psychotherapeutic interventions is necessary to help patients after initial injury and surgical management^37,40-43 (Table 2^11,20,27,41).

OUTCOME Return to school, work

Mr. K is discharged with close follow-up at a specialized clinic for new-onset psychosis. Post-discharge treatment consists of education about the course of schizophrenia and the need for medication adherence to prevent relapse. Mr. K also is educated on the relationship between Cannabis use and psychosis, and he abstains from illicit substance use. Family involvement is encouraged to help with medication compliance and monitoring for symptom reemergence.

Therapy focuses on exploring the antecedents of the auto-penectomy, Mr. K’s body image issue concerns, and his feelings related to eventual prosthesis implantation. He insists that he cannot recall any precipitating factors for his self-injury other than the command hallucinations. He does not report sexual guilt, although he had been sexually active with his girlfriend in the months prior to his GSM, which goes against his family’s religious beliefs. He reports significant regret and shame for the self-mutilation, and blames himself for not informing family members about his hallucinations. Therapy involves addressing his attribution of blame using cognitive techniques and focuses on measures that can be taken to prevent further self-harm. Efforts are directed at exploring whether cultural and religious traditions impacted the therapeutic alliance, medication adherence, self-esteem and body image, sexuality, and future goals. Over the course of 1 year, he resumes his graduate studies and part-time work, and explores prosthetic placement for cosmetic purposes.

 

The authors’ observations

Research suggests that major self-mutilation among patients with psychotic illness is likely to occur during the first episode or early in the course of illness and/or with suboptimal treatment.^44,45 Mr. K was enlisted in an intensive outpatient treatment program involving biweekly psychotherapy sessions and psychiatric follow-up. Initial sessions focused on education regarding the importance of medication adherence and exploration of signs and symptoms that might suggest reemergence of a psycho­tic decompensation. The psychiatrist monitored Mr. K closely to ensure he was able to tolerate his medications to mitigate the possibility that adverse effects would undermine adherence. Mr. K’s reactions to having a psychiatric illness also were explored because of concerns that such self-appraisals might trigger shame, embarrassment, denial, and other responses that might undermine treatment adherence. His family members were apprised of treatment goals and enlisted to foster adherence with medication and follow-up appointments.

Mr. K’s Cannabis use was addressed because ongoing use likely had a negative impact on his schizophrenia (ie, a greater propensity toward relapse and rehospitalization and a poorer ther­apeutic response to antipsychotic medication).^46,47 He was strongly encouraged to avoid Cannabis and other illicit substances.

Psychiatrists can help in examining the meaning behind the injury while helping the patient to adapt to the sequelae and cultivate skills to meet functional demands.⁴¹ Once Mr. K’s psychotic symptoms were in remission, treatment began to address the antecedents of the GSM, as well as the resultant physical consequences. It was reasonable to explore how Mr. K now viewed his actions, as well as the consequences that his actions produced in terms of his physical appearance, sexual functioning, capacity for sexual intimacy, and reproductive potential. It was also important to recognize how such highly intimate and deeply personal self-schema are framed and organized against his cultural and religious background.^27,33

Body image concerns and expectations for future urologic intervention also should be explored. Although Mr. K was not averse to such exploration, he did not spontaneously address such topics in great depth. The discussion was unforced and effectively left open as an issue that could be explored in future sessions.

 

CASE Bleeding, bewildered

Mr. K, age 23, a South Asian male, is discovered in the bathroom bleeding profusely. Mr. K’s parents inform emergency medical services (EMS) personnel that Mr. K is “not in his right mind” and speculate that he is depressed. EMS personnel find Mr. K sitting in a pool of blood in the bathtub, holding a cloth over his pubic area and complaining of significant pain. They estimate that Mr. K has lost approximately 1 L of blood. Cursory evaluation reveals that his penis is severed; no other injuries or lacerations are notable. Mr. K states, “I did not want it anymore.” A kitchen knife that he used to self-amputate is found nearby. He is awake, alert, and able to follow simple directives.

In the emergency room, Mr. K is in mild-to-moderate distress. He has no history of medical illness, but his parents report that he previously required psychiatric treatment. Mr. K is not able to elaborate. He reluctantly discloses an intermittent history of Cannabis use. Physical examination reveals tachycardia (heart rate: 115 to 120 beats per minute), and despite blood loss, systolic hypertension (blood pressure: 142/70 to 167/70 mm Hg). His pulse oximetry is 97% to 99%; he is afebrile. Laboratory tests are notable for anemia (hemoglobin, 7.2 g/dL [reference range, 14.0 to 17.5 g/dL]; hematocrit, 21.2% [reference range, 41% to 50%]) and serum toxicology screen is positive for benzodiazepines, which had been administered en route to allay his distress.

Mr. K continues to hold pressure on his pubic area. When pressure is released, active arterial spurting of bright red blood is notable. Genital examination reveals a cleanly amputated phallus. Emergent surgical intervention is required to stop the hemorrhage and reattach the penis. Initially, Mr. K is opposed to reattachment, but after a brief discussion with his parents, he consents to surgery. Urology and plastic surgery consultations are elicited to perform the microvascular portion of the procedure.

[polldaddy:9881368]

The authors’ observations

Self-injurious behaviors occur in approximately 1% to 4% of adults in the United States, with chronic and severe self-injury occurring among approximately 1% of the U.S. population.^1,2 Intentional GSM is a relatively rare catastrophic event that is often, but not solely, associated with severe mental illness. Because many cases go unreported, the prevalence of GSM is difficult to estimate.^3,4 Although GSM has been described in both men and women, the literature has predominantly focused on GSM among men.⁵ Genital self-injury has been described in several (ie, ethnic/racial and religious) contexts and has been legally sanctioned.^6-8

Psychiatric disorders associated with, and precipitating factors underlying, GSM have long remained elusive.⁸ GSM has been described in case reports and small case series in both psychiatric and urologic literature. These reports provide incomplete descriptions of the diagnostic conditions and psychosocial factors underlying male GSM.

A recent systematic review of 173 cases of men who engaged in GSM published in the past 115 years (since the first case of GSM was published in the psychiatric literature⁹) revealed that having some form of psychopathology elevates the probability of GSM^10,11; rarely the individual did not have a psychiatric condition.^11-17 Nearly one-half of the men had psychosis; most had a schizophrenia spectrum disorder diagnosis. Other psychiatric conditions associated with GSM include personality disorders, substance use disorder, and gender dysphoria. GSM is rarely associated with anxiety or mood disorders.

GSM is a heterogeneous form of self-injury that ranges from superficial genital lacerations, amputation, or castration to combinations of these injuries. Compared with individuals with other psychiatric disorders, a significantly greater proportion of individuals with schizophrenia spectrum disorders engage in self-amputation (auto-penectomy). By contrast, persons with gender dysphoria tend to engage in self-castration at significantly higher rates than those with other psychiatric conditions.¹¹ Despite these trends, clinicians should not infer a specific psychiatric diagnosis based on the severity or type of self-inflicted injury.

 

 

HISTORY Command hallucinations

Postoperatively, Mr. K is managed in the trauma intensive care unit. During psychiatric consultation, Mr. K demonstrates a blunted affect. His speech is low in volume but clear and coherent. His thoughts are generally linear for specific lines of inquiry (eg, about perceived level of pain) but otherwise are impoverished. Mr. K often digresses into repetitively mumbled prayers. He appears distracted, as if responding to internal stimuli. Although he acknowledges the GSM, he does not discuss the factors underlying his decision to proceed with auto-penectomy. Over successive evaluations, he reluctantly discloses that he had been experiencing disparaging auditory hallucinations that told him that his penis “was too small” and commanded him to “cut it off.”

Psychiatric history reveals that Mr. K required psychiatric hospitalization 7 months earlier due to new-onset auditory hallucinations, paranoia, and thought disorganization, in the context of daily Cannabis use. At the time, the differential diagnosis included new-onset schizophrenia and substance-induced psychosis. His symptoms improved quickly with risperidone, 2 mg/d, and he was discharged in a stable condition with referrals for outpatient care. Mr. K admits he had stopped taking risperidone several weeks before the GSM because he was convinced that he had been cured. At that time, Mr. K had told his parents he was no longer required to take medication or engage in outpatient psychiatric treatment, and they did not question this. Mr. K struggled to sustain part-time employment (in a family business), having taken a leave of absence from graduate school after his first hospitalization. He continued to use Cannabis regularly but denies being intoxicated at the time of the GSM. Throughout his surgical hospitalization, Mr. K’s thoughts remain disorganized. He denies that the GSM was a suicide attempt or having current suicidal thoughts, intent, or plans. He also denies having religious preoccupations, over-valued religious beliefs, or delusions.

Mr. K identifies as heterosexual, and denies experiencing distress related to sexual orientation or gender identity or guilt related to sexual impulses or actions. He also denies having a history of trauma or victimization and does not report any symptoms of posttraumatic stress disorder or body dysmorphic disorder.

The authors’ observations

There are numerous psychological factors underlying and engendered by GSM.^18-22 Delusions, hallucinations, a need for atonement, suicidal ideation, and subjective guilt have been reported among individuals engaging in GSM who have psychosis (Table 1).¹¹ Severe forms of GSM, such as castration, occur among individuals who manifest more symptoms and greater severity of psychopathology.

Little is known about how many individuals who engage in GSM eventually complete suicide. Although suicidal ideation and intent have been infrequently associated with GSM, suicide has been most notably reported among patients with schizophrenia spectrum disorders and psychotic mood disorders.^11,18,23-26 For these individuals, suicidal ideation co-occurred with delusions, hallucinations, and pathological guilt preoccupations. Significant self-inflicted injury can be harbinger of distress that could lead to suicide if not optimally treated. Other psychosocial stressors, such as disruptions in interpersonal functioning arising from changes in or loss of social support or perceived rejection, may contribute to a patient’s level of distress, complicating underlying psychiatric disturbances and increasing vulnerability toward GSM.^11,27

Substance use also increases vulnerability toward GSM.^11,18,24,28 As is the case with patients who engage in various non-GSM self-injurious behaviors,^29,30 substance use or intoxication likely contribute to disinhibition or a dissociative state, which enables individuals to engage in self-injury.³⁰

A lack of access to treatment is a rare precipitant for GSM, except among individuals with gender dysphoria. Studies have found that many patients with gender dysphoria who performed self-castration did so in a premeditated manner with low suicidal intent, and the behavior often was related to a lack of or refusal for gender confirmation surgery.^31-34

In the hospital setting, surgical/urological interventions need to be directed at the potentially life-threatening sequelae of self-injury. Although complications vary, depending on the type of injury incurred, urgent measures are needed to manage blood loss because hemorrhage can be fatal.^23,35,36 Other consequences that can arise include urinary fistulae, urethral strictures, mummification of the glans penis, and development of sensory abnormalities after repair of the injured tissues or reattachment.⁸ More superficial injuries may require only hemostasis and simple suturing, whereas extensive injuries, such as complete amputation, can be addressed through microvascular techniques.

The psychiatrist’s role. The psychiatrist should act as an advocate for the GSM patient to create an environment conducive to healing. A patient who is experiencing hallucinations or delusions may feel overwhelmed by medical and familial attention. Pharmacologic treatment for prevailing mental illness, such as psychosis, should be initiated in the inpatient setting. An estimated 20% to 25% of those who self-inflict genital injury may repeatedly mutilate their genitals.^19,28 Patients unduly influenced by command hallucinations, delusional thought processes, mood disturbances, or suicidal ideation may attempt to complete the injury, or reinjure themselves after surgical/urological intervention, which may require safety measures, such as 1:1 observation, restraints, or physical barriers, to prevent reinjury.³⁷

Self-injury elicits strong, emotional responses from health care professionals, including fascination, apprehension, and hopelessness. Psychiatrists who care for such patients should monitor members of the patient’s treatment team for psychological reactions. In addition, the patient’s behavior while hospitalized may stir feelings of retaliation, anger, fear, and frustration.^11,24,37 Collaborative relationships with medical and surgical specialties can help staff manage emotional reactions and avoid the inadvertent expression of those feelings in their interactions with the patient; these reactions might otherwise undermine treatment.^24,34 Family education can help mitigate any guilt family members may harbor for not preventing the injury.³⁷

Although efforts to understand the intended goal(s) and precipitants of the self-injury are likely to be worthwhile, the overwhelming distress associated with GSM and its emergent treatment may preclude intensive exploration. Assessing precipitants of self-injury should be approached using a nonjudgmental, dispassionate, matter-of-fact manner that conveys concern for the patient³⁸ and reassures the patient that the clinician has heard and, ideally, understands the patient’s distress.³⁹ Forced exploration during the prevailing stress of treatment may overwhelm the patient, prove to be overly distressing, and compel the patient to act out in self-injurious ways. Therefore, exploration of the underpinnings of GSM may need to be postponed until surgical treatment is completed, the patient’s symptoms have been managed with psychopharmacologic intervention, and the patient has been transitioned to the safety and close monitoring of an acute psychiatric inpatient setting.

 

 

TREATMENT Restarting medication

While on the surgical unit, Mr. K is restarted on risperidone, 2 mg/d. He appears to tolerate the medication without adverse effects. However, because Mr. K continues to experience auditory hallucinations, and the treatment team remains concerned that he might again experience commands to harm himself, he is transferred to an acute psychiatric inpatient setting.

Urology follow-up reveals necrosis/mummification of the replanted penis and an open scrotal wound. After discussing options with the patient and family, the urologist transfers Mr. K back to the surgical unit for wound closure and removal of the replanted penis. A urethrostomy is performed to allow for bladder emptying.

[polldaddy:9881371]

The authors’ observations

Because most published case reports of GSM among men have focused on acute treatment, there is a dearth of literature available on the long-term course of GSM to inform treatment strategies. Because recovery is a non-static process and a patient’s reactions to his injury will likely evolve over time, a multifaceted approach invoking psychiatric and psychotherapeutic interventions is necessary to help patients after initial injury and surgical management^37,40-43 (Table 2^11,20,27,41).

OUTCOME Return to school, work

Mr. K is discharged with close follow-up at a specialized clinic for new-onset psychosis. Post-discharge treatment consists of education about the course of schizophrenia and the need for medication adherence to prevent relapse. Mr. K also is educated on the relationship between Cannabis use and psychosis, and he abstains from illicit substance use. Family involvement is encouraged to help with medication compliance and monitoring for symptom reemergence.

Therapy focuses on exploring the antecedents of the auto-penectomy, Mr. K’s body image issue concerns, and his feelings related to eventual prosthesis implantation. He insists that he cannot recall any precipitating factors for his self-injury other than the command hallucinations. He does not report sexual guilt, although he had been sexually active with his girlfriend in the months prior to his GSM, which goes against his family’s religious beliefs. He reports significant regret and shame for the self-mutilation, and blames himself for not informing family members about his hallucinations. Therapy involves addressing his attribution of blame using cognitive techniques and focuses on measures that can be taken to prevent further self-harm. Efforts are directed at exploring whether cultural and religious traditions impacted the therapeutic alliance, medication adherence, self-esteem and body image, sexuality, and future goals. Over the course of 1 year, he resumes his graduate studies and part-time work, and explores prosthetic placement for cosmetic purposes.

 

The authors’ observations

Research suggests that major self-mutilation among patients with psychotic illness is likely to occur during the first episode or early in the course of illness and/or with suboptimal treatment.^44,45 Mr. K was enlisted in an intensive outpatient treatment program involving biweekly psychotherapy sessions and psychiatric follow-up. Initial sessions focused on education regarding the importance of medication adherence and exploration of signs and symptoms that might suggest reemergence of a psycho­tic decompensation. The psychiatrist monitored Mr. K closely to ensure he was able to tolerate his medications to mitigate the possibility that adverse effects would undermine adherence. Mr. K’s reactions to having a psychiatric illness also were explored because of concerns that such self-appraisals might trigger shame, embarrassment, denial, and other responses that might undermine treatment adherence. His family members were apprised of treatment goals and enlisted to foster adherence with medication and follow-up appointments.

Mr. K’s Cannabis use was addressed because ongoing use likely had a negative impact on his schizophrenia (ie, a greater propensity toward relapse and rehospitalization and a poorer ther­apeutic response to antipsychotic medication).^46,47 He was strongly encouraged to avoid Cannabis and other illicit substances.

Psychiatrists can help in examining the meaning behind the injury while helping the patient to adapt to the sequelae and cultivate skills to meet functional demands.⁴¹ Once Mr. K’s psychotic symptoms were in remission, treatment began to address the antecedents of the GSM, as well as the resultant physical consequences. It was reasonable to explore how Mr. K now viewed his actions, as well as the consequences that his actions produced in terms of his physical appearance, sexual functioning, capacity for sexual intimacy, and reproductive potential. It was also important to recognize how such highly intimate and deeply personal self-schema are framed and organized against his cultural and religious background.^27,33

Body image concerns and expectations for future urologic intervention also should be explored. Although Mr. K was not averse to such exploration, he did not spontaneously address such topics in great depth. The discussion was unforced and effectively left open as an issue that could be explored in future sessions.

 

CASE Bleeding, bewildered

Mr. K, age 23, a South Asian male, is discovered in the bathroom bleeding profusely. Mr. K’s parents inform emergency medical services (EMS) personnel that Mr. K is “not in his right mind” and speculate that he is depressed. EMS personnel find Mr. K sitting in a pool of blood in the bathtub, holding a cloth over his pubic area and complaining of significant pain. They estimate that Mr. K has lost approximately 1 L of blood. Cursory evaluation reveals that his penis is severed; no other injuries or lacerations are notable. Mr. K states, “I did not want it anymore.” A kitchen knife that he used to self-amputate is found nearby. He is awake, alert, and able to follow simple directives.

In the emergency room, Mr. K is in mild-to-moderate distress. He has no history of medical illness, but his parents report that he previously required psychiatric treatment. Mr. K is not able to elaborate. He reluctantly discloses an intermittent history of Cannabis use. Physical examination reveals tachycardia (heart rate: 115 to 120 beats per minute), and despite blood loss, systolic hypertension (blood pressure: 142/70 to 167/70 mm Hg). His pulse oximetry is 97% to 99%; he is afebrile. Laboratory tests are notable for anemia (hemoglobin, 7.2 g/dL [reference range, 14.0 to 17.5 g/dL]; hematocrit, 21.2% [reference range, 41% to 50%]) and serum toxicology screen is positive for benzodiazepines, which had been administered en route to allay his distress.

Mr. K continues to hold pressure on his pubic area. When pressure is released, active arterial spurting of bright red blood is notable. Genital examination reveals a cleanly amputated phallus. Emergent surgical intervention is required to stop the hemorrhage and reattach the penis. Initially, Mr. K is opposed to reattachment, but after a brief discussion with his parents, he consents to surgery. Urology and plastic surgery consultations are elicited to perform the microvascular portion of the procedure.

[polldaddy:9881368]

The authors’ observations

Self-injurious behaviors occur in approximately 1% to 4% of adults in the United States, with chronic and severe self-injury occurring among approximately 1% of the U.S. population.^1,2 Intentional GSM is a relatively rare catastrophic event that is often, but not solely, associated with severe mental illness. Because many cases go unreported, the prevalence of GSM is difficult to estimate.^3,4 Although GSM has been described in both men and women, the literature has predominantly focused on GSM among men.⁵ Genital self-injury has been described in several (ie, ethnic/racial and religious) contexts and has been legally sanctioned.^6-8

Psychiatric disorders associated with, and precipitating factors underlying, GSM have long remained elusive.⁸ GSM has been described in case reports and small case series in both psychiatric and urologic literature. These reports provide incomplete descriptions of the diagnostic conditions and psychosocial factors underlying male GSM.

A recent systematic review of 173 cases of men who engaged in GSM published in the past 115 years (since the first case of GSM was published in the psychiatric literature⁹) revealed that having some form of psychopathology elevates the probability of GSM^10,11; rarely the individual did not have a psychiatric condition.^11-17 Nearly one-half of the men had psychosis; most had a schizophrenia spectrum disorder diagnosis. Other psychiatric conditions associated with GSM include personality disorders, substance use disorder, and gender dysphoria. GSM is rarely associated with anxiety or mood disorders.

GSM is a heterogeneous form of self-injury that ranges from superficial genital lacerations, amputation, or castration to combinations of these injuries. Compared with individuals with other psychiatric disorders, a significantly greater proportion of individuals with schizophrenia spectrum disorders engage in self-amputation (auto-penectomy). By contrast, persons with gender dysphoria tend to engage in self-castration at significantly higher rates than those with other psychiatric conditions.¹¹ Despite these trends, clinicians should not infer a specific psychiatric diagnosis based on the severity or type of self-inflicted injury.

 

 

HISTORY Command hallucinations

Postoperatively, Mr. K is managed in the trauma intensive care unit. During psychiatric consultation, Mr. K demonstrates a blunted affect. His speech is low in volume but clear and coherent. His thoughts are generally linear for specific lines of inquiry (eg, about perceived level of pain) but otherwise are impoverished. Mr. K often digresses into repetitively mumbled prayers. He appears distracted, as if responding to internal stimuli. Although he acknowledges the GSM, he does not discuss the factors underlying his decision to proceed with auto-penectomy. Over successive evaluations, he reluctantly discloses that he had been experiencing disparaging auditory hallucinations that told him that his penis “was too small” and commanded him to “cut it off.”

Psychiatric history reveals that Mr. K required psychiatric hospitalization 7 months earlier due to new-onset auditory hallucinations, paranoia, and thought disorganization, in the context of daily Cannabis use. At the time, the differential diagnosis included new-onset schizophrenia and substance-induced psychosis. His symptoms improved quickly with risperidone, 2 mg/d, and he was discharged in a stable condition with referrals for outpatient care. Mr. K admits he had stopped taking risperidone several weeks before the GSM because he was convinced that he had been cured. At that time, Mr. K had told his parents he was no longer required to take medication or engage in outpatient psychiatric treatment, and they did not question this. Mr. K struggled to sustain part-time employment (in a family business), having taken a leave of absence from graduate school after his first hospitalization. He continued to use Cannabis regularly but denies being intoxicated at the time of the GSM. Throughout his surgical hospitalization, Mr. K’s thoughts remain disorganized. He denies that the GSM was a suicide attempt or having current suicidal thoughts, intent, or plans. He also denies having religious preoccupations, over-valued religious beliefs, or delusions.

Mr. K identifies as heterosexual, and denies experiencing distress related to sexual orientation or gender identity or guilt related to sexual impulses or actions. He also denies having a history of trauma or victimization and does not report any symptoms of posttraumatic stress disorder or body dysmorphic disorder.

The authors’ observations

There are numerous psychological factors underlying and engendered by GSM.^18-22 Delusions, hallucinations, a need for atonement, suicidal ideation, and subjective guilt have been reported among individuals engaging in GSM who have psychosis (Table 1).¹¹ Severe forms of GSM, such as castration, occur among individuals who manifest more symptoms and greater severity of psychopathology.

Little is known about how many individuals who engage in GSM eventually complete suicide. Although suicidal ideation and intent have been infrequently associated with GSM, suicide has been most notably reported among patients with schizophrenia spectrum disorders and psychotic mood disorders.^11,18,23-26 For these individuals, suicidal ideation co-occurred with delusions, hallucinations, and pathological guilt preoccupations. Significant self-inflicted injury can be harbinger of distress that could lead to suicide if not optimally treated. Other psychosocial stressors, such as disruptions in interpersonal functioning arising from changes in or loss of social support or perceived rejection, may contribute to a patient’s level of distress, complicating underlying psychiatric disturbances and increasing vulnerability toward GSM.^11,27

Substance use also increases vulnerability toward GSM.^11,18,24,28 As is the case with patients who engage in various non-GSM self-injurious behaviors,^29,30 substance use or intoxication likely contribute to disinhibition or a dissociative state, which enables individuals to engage in self-injury.³⁰

A lack of access to treatment is a rare precipitant for GSM, except among individuals with gender dysphoria. Studies have found that many patients with gender dysphoria who performed self-castration did so in a premeditated manner with low suicidal intent, and the behavior often was related to a lack of or refusal for gender confirmation surgery.^31-34

In the hospital setting, surgical/urological interventions need to be directed at the potentially life-threatening sequelae of self-injury. Although complications vary, depending on the type of injury incurred, urgent measures are needed to manage blood loss because hemorrhage can be fatal.^23,35,36 Other consequences that can arise include urinary fistulae, urethral strictures, mummification of the glans penis, and development of sensory abnormalities after repair of the injured tissues or reattachment.⁸ More superficial injuries may require only hemostasis and simple suturing, whereas extensive injuries, such as complete amputation, can be addressed through microvascular techniques.

The psychiatrist’s role. The psychiatrist should act as an advocate for the GSM patient to create an environment conducive to healing. A patient who is experiencing hallucinations or delusions may feel overwhelmed by medical and familial attention. Pharmacologic treatment for prevailing mental illness, such as psychosis, should be initiated in the inpatient setting. An estimated 20% to 25% of those who self-inflict genital injury may repeatedly mutilate their genitals.^19,28 Patients unduly influenced by command hallucinations, delusional thought processes, mood disturbances, or suicidal ideation may attempt to complete the injury, or reinjure themselves after surgical/urological intervention, which may require safety measures, such as 1:1 observation, restraints, or physical barriers, to prevent reinjury.³⁷

Self-injury elicits strong, emotional responses from health care professionals, including fascination, apprehension, and hopelessness. Psychiatrists who care for such patients should monitor members of the patient’s treatment team for psychological reactions. In addition, the patient’s behavior while hospitalized may stir feelings of retaliation, anger, fear, and frustration.^11,24,37 Collaborative relationships with medical and surgical specialties can help staff manage emotional reactions and avoid the inadvertent expression of those feelings in their interactions with the patient; these reactions might otherwise undermine treatment.^24,34 Family education can help mitigate any guilt family members may harbor for not preventing the injury.³⁷

Although efforts to understand the intended goal(s) and precipitants of the self-injury are likely to be worthwhile, the overwhelming distress associated with GSM and its emergent treatment may preclude intensive exploration. Assessing precipitants of self-injury should be approached using a nonjudgmental, dispassionate, matter-of-fact manner that conveys concern for the patient³⁸ and reassures the patient that the clinician has heard and, ideally, understands the patient’s distress.³⁹ Forced exploration during the prevailing stress of treatment may overwhelm the patient, prove to be overly distressing, and compel the patient to act out in self-injurious ways. Therefore, exploration of the underpinnings of GSM may need to be postponed until surgical treatment is completed, the patient’s symptoms have been managed with psychopharmacologic intervention, and the patient has been transitioned to the safety and close monitoring of an acute psychiatric inpatient setting.

 

 

TREATMENT Restarting medication

While on the surgical unit, Mr. K is restarted on risperidone, 2 mg/d. He appears to tolerate the medication without adverse effects. However, because Mr. K continues to experience auditory hallucinations, and the treatment team remains concerned that he might again experience commands to harm himself, he is transferred to an acute psychiatric inpatient setting.

Urology follow-up reveals necrosis/mummification of the replanted penis and an open scrotal wound. After discussing options with the patient and family, the urologist transfers Mr. K back to the surgical unit for wound closure and removal of the replanted penis. A urethrostomy is performed to allow for bladder emptying.

[polldaddy:9881371]

The authors’ observations

Because most published case reports of GSM among men have focused on acute treatment, there is a dearth of literature available on the long-term course of GSM to inform treatment strategies. Because recovery is a non-static process and a patient’s reactions to his injury will likely evolve over time, a multifaceted approach invoking psychiatric and psychotherapeutic interventions is necessary to help patients after initial injury and surgical management^37,40-43 (Table 2^11,20,27,41).

OUTCOME Return to school, work

Mr. K is discharged with close follow-up at a specialized clinic for new-onset psychosis. Post-discharge treatment consists of education about the course of schizophrenia and the need for medication adherence to prevent relapse. Mr. K also is educated on the relationship between Cannabis use and psychosis, and he abstains from illicit substance use. Family involvement is encouraged to help with medication compliance and monitoring for symptom reemergence.

Therapy focuses on exploring the antecedents of the auto-penectomy, Mr. K’s body image issue concerns, and his feelings related to eventual prosthesis implantation. He insists that he cannot recall any precipitating factors for his self-injury other than the command hallucinations. He does not report sexual guilt, although he had been sexually active with his girlfriend in the months prior to his GSM, which goes against his family’s religious beliefs. He reports significant regret and shame for the self-mutilation, and blames himself for not informing family members about his hallucinations. Therapy involves addressing his attribution of blame using cognitive techniques and focuses on measures that can be taken to prevent further self-harm. Efforts are directed at exploring whether cultural and religious traditions impacted the therapeutic alliance, medication adherence, self-esteem and body image, sexuality, and future goals. Over the course of 1 year, he resumes his graduate studies and part-time work, and explores prosthetic placement for cosmetic purposes.

 

The authors’ observations

Research suggests that major self-mutilation among patients with psychotic illness is likely to occur during the first episode or early in the course of illness and/or with suboptimal treatment.^44,45 Mr. K was enlisted in an intensive outpatient treatment program involving biweekly psychotherapy sessions and psychiatric follow-up. Initial sessions focused on education regarding the importance of medication adherence and exploration of signs and symptoms that might suggest reemergence of a psycho­tic decompensation. The psychiatrist monitored Mr. K closely to ensure he was able to tolerate his medications to mitigate the possibility that adverse effects would undermine adherence. Mr. K’s reactions to having a psychiatric illness also were explored because of concerns that such self-appraisals might trigger shame, embarrassment, denial, and other responses that might undermine treatment adherence. His family members were apprised of treatment goals and enlisted to foster adherence with medication and follow-up appointments.

Mr. K’s Cannabis use was addressed because ongoing use likely had a negative impact on his schizophrenia (ie, a greater propensity toward relapse and rehospitalization and a poorer ther­apeutic response to antipsychotic medication).^46,47 He was strongly encouraged to avoid Cannabis and other illicit substances.

Psychiatrists can help in examining the meaning behind the injury while helping the patient to adapt to the sequelae and cultivate skills to meet functional demands.⁴¹ Once Mr. K’s psychotic symptoms were in remission, treatment began to address the antecedents of the GSM, as well as the resultant physical consequences. It was reasonable to explore how Mr. K now viewed his actions, as well as the consequences that his actions produced in terms of his physical appearance, sexual functioning, capacity for sexual intimacy, and reproductive potential. It was also important to recognize how such highly intimate and deeply personal self-schema are framed and organized against his cultural and religious background.^27,33

Body image concerns and expectations for future urologic intervention also should be explored. Although Mr. K was not averse to such exploration, he did not spontaneously address such topics in great depth. The discussion was unforced and effectively left open as an issue that could be explored in future sessions.