Evidence-Based Reviews

Antidepressants for chronic pain

Current Psychiatry. 2019 February;18(2):8-16,21-22

Author(s):

Certain agents may mitigate pain associated with neuropathy, fibromyalgia, headache, and IBS.

References

1. Paoli F, Darcourt G, Cossa P. Preliminary note on the action of imipramine in painful states [in French]. Rev Neurol (Paris). 1960;102:503-504.
2. Fields HL, Heinricher MM, Mason P. Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci. 1991;14:219-245.
3. Hunt SP, Mantyh PW. The molecular dynamics of pain control. Nat Rev Neurosci. 2001;2(2):83-91.
4. Lamont LA, Tranquilli WJ, Grimm KA. Physiology of pain. Vet Clin North Am Small Anim Pract. 2000;30(4):703-728, v.
5. Fields HL, Basbaum AI, Heinricher MM. Central nervous system mechanisms of pain modulation. In: McMahon S, Koltzenburg M, eds. Wall and Melzack’s Textbook of Pain. 5th ed. Burlington, MA: Elsevier Health Sciences; 2005:125-142.
6. Marks DM, Shah MJ, Patkar AA, et al. Serotonin-norepinephrine reuptake inhibitors for pain control: premise and promise. Curr Neuropharmacol. 2009;7(4):331-336.
7. Baba H, Shimoji K, Yoshimura M. Norepinephrine facilitates inhibitory transmission in substantia gelatinosa of adult rat spinal cord (part 1): effects on axon terminals of GABAergic and glycinergic neurons. Anesthesiology. 2000;92(2):473-484.
8. Carter GT, Sullivan MD. Antidepressants in pain management. Curr Opin Investig Drugs. 2002;3(3):454-458.
9. Kawasaki Y, Kumamoto E, Furue H, et al. Alpha 2 adrenoceptor-mediated presynaptic inhibition of primary afferent glutamatergic transmission in rat substantia gelatinosa neurons. Anesthesiology. 2003;98(3):682-689.
10. McCleane G. Antidepressants as analgesics. CNS Drugs. 2008;22(2):139-156.
11. Ansari A. The efficacy of newer antidepressants in the treatment of chronic pain: a review of current literature. Harv Rev Psychiatry. 2000;7(5):257-277.
12. Egbunike IG, Chaffee BJ. Antidepressants in the management of chronic pain syndromes. Pharmacotherapy. 1990;10(4):262-270.
13. Fishbain DA. Evidence-based data on pain relief with antidepressants. Ann Med. 2000;32(5):305-316.
14. Fishbain DA, Detke MJ, Wernicke J, et al. The relationship between antidepressant and analgesic responses: findings from six placebo-controlled trials assessing the efficacy of duloxetine in patients with major depressive disorder. Curr Med Res Opin. 2008;24(11):3105-3115.
15. Harada E, Tokuoka H, Fujikoshi S, et al. Is duloxetine’s effect on painful physical symptoms in depression an indirect result of improvement of depressive symptoms? Pooled analyses of three randomized controlled trials. Pain. 2016;157(3):577-584.
16. Kehoe WA. Antidepressants for chronic pain: selection and dosing considerations. Am J Pain Med. 1993;3(4):161-165.
17. Damush TM, Kroenke K, Bair MJ, et al. Pain self-management training increases self-efficacy, self-management behaviours and pain and depression outcomes. Eur J Pain. 2016;20(2):1070-1078.
18. DeVeaugh-Geiss AM, West SL, Miller WC, et al. The adverse effects of comorbid pain on depression outcomes in primary care patients: results from the ARTIST trial. Pain Medicine. 2010;11(5):732-741.
19. Egloff N, Cámara RJ, von Känel R, et al. Hypersensitivity and hyperalgesia in somatoform pain disorders. Gen Hosp Psychiatry. 2014;36(3):284-290.
20. Goesling J, Clauw DW, Hassett AL. Pain and depression: an integrative review of neurobiological and psychological factors. Curr Psych Reports. 2013;15(12):421.
21. Kroenke K, Wu J, Bair MJ, et al. Reciprocal relationship between pain and depression: a 12-Month longitudinal analysis in primary care. J Pain. 2011;12(9):964-973.
22. Leo RJ. Chronic pain and comorbid depression. Curr Treat Options Neurol. 2005;7(5):403-412.
23. Bair MJ, Robinson RL, Eckert GJ, et al. Impact of pain on depression treatment response in primary care. Psychosom Med. 2004;66(1):17-22.
24. Karp JF, Scott J, Houck P, et al. Pain predicts longer time to remission during treatment of recurrent depression. J Clin Psychiatry. 2005;66(5):591-597.
25. Kroenke K, Shen J, Oxman TE, et al. Impact of pain on the outcomes of depression treatment: results from the RESPECT trial. Pain. 2008;134(1-2):209-215.
26. Mavandadi S, Ten Have TR, Katz IR, et al. Effect of depression treatment on depressive symptoms in older adulthood: the moderating role of pain. J Am Geriatr Soc. 2007;55(2):202-211.
27. Thielke SM, Fan MY, Sullivan M, et al. Pain limits the effectiveness of collaborative care for depression. Am J Geriatr Psychiatry. 2007;15(8):699-707.
28. Arnow BA, Hunkeler EM, Blasey CM, et al. Comorbid depression, chronic pain, and disability in primary care. Psychosom Med. 2006;68(2):262-268.
29. Demyttenaere K, Bonnewyn A, Bruffaerts R, et al. Comorbid painful physical symptoms and depression: Prevalence, work loss, and help seeking. J Affect Disord. 2006;92(2-3):185-193.
30. Nakao M, Barsky AJ. Clinical application of somatosensory amplification in psychosomatic medicine. Biopsychosoc Med. 2007;1:17.
31. Perez DL, Barsky AJ, Vago DR, et al. A neural circuit framework for somatosensory amplification in somatoform disorders. J Neuropsychiatry Clin Neurosci. 2015;27(1):e40-e50.
32. Fishbain DA, Cutler RB, Rosomoff HL, et al. Do antidepressants have an analgesic effect in psychogenic pain and somatoform pain disorder? A meta-analysis. Psychosom Med. 1998;60(4):503-509.
33. Kleinstäuber M, Witthöft M, Steffanowski A, et al. Pharmacological interventions for somatoform disorders in adults. Cochrane Database Syst Rev. 2014;(11):CD010628.
34. Collins SL, Moore RA, McQuay HJ, et al. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage. 2000;20(6):449-458.
35. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain: a Cochrane review. J Neurol Neurosurg Psychiatry. 2010;81(12):1372-1373.
36. Arnold LM, Keck PE, Welge JA. Antidepressant treatment of fibromyalgia. A meta-analysis and review. Psychosomatics. 2000;41(2):104-113.
37. O’Malley PG, Balden E, Tomkins G, et al. Treatment of fibromyalgia with antidepressants: a meta-analysis. J Gen Intern Med. 2000;15(9):659-666.
38. Tomkins GE, Jackson JL, O’Malley PG, et al. Treatment of chronic headache with antidepressants: a meta-analysis. Am J Med. 2001;111(1):54-63.
39. Jackson JL, O’Malley PG, Tomkins G, et al. Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis. Am J Med. 2000;108(1):65-72.
40. Lesbros-Pantoflickova D, Michetti P, Fried M et al. Meta-analysis: the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 2004;20(11-12):1253-1269.
41. Centre for Clinical Practice at NICE (UK). Neuropathic pain: the pharmacological management of neuropathic pain in adults in non-specialist settings. London, UK: National Institute for Health and Care Excellence, (UK); 2013.
42. O’Connor AB, Dworkin RH. Treatment of neuropathic pain: an overview of recent guidelines. Am J Med. 2009;122(suppl 10):S22-S32.
43. Moulin D, Boulanger A, Clark AJ, et al; Canadian Pain Society. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res Manag. 2014;19(6):328-35.
44. Mu A, Weinberg E, Moulin DE, et al. Pharmacologic management of chronic neuropathic pain: Review of the Canadian Pain Society consensus statement. Can Fam Physician. 2017;63(11):844-852.
45. Finnerup NB, Otto M, McQuay HJ, et al. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain. 2005;118(3):289-305.
46. Hempenstall K, Nurmikko TJ, Johnson RW, et al. Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLoS Med. 2005;2(7):e164.
47. Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain. 1999;83(3):389-400.
48. Wu CL, Raja SN. An update on the treatment of postherpetic neuralgia. J Pain. 2008;9(suppl 1):S19-S30.
49. Kroenke K, Krebs EE, Bair MJ. Pharmacotherapy of chronic pain: a synthesis of recommendations from systematic reviews. Gen Hosp Psychiatry. 2009;31(3):206-219.
50. Hearn L, Moore RA, Derry S, et al. Desipramine for neuropathic pain in adults. Cochrane Database Syst Rev. 2014;(9):CD011003.
51. Hearn L, Derry S, Phillips T, et al. Imipramine for neuropathic pain in adults. Cochrane Database Syst Rev. 2014;(5):CD010769.
52. Derry S, Wiffen PJ, Aldington D, et al. Nortriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;1:CD011209.
53. Moore R, Derry S, Aldington D, et al. Amitriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;(7):CD008242.
54. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014;(1):CD007115.
55. Gallagher HC, Gallagher RM, Butler M, et al. Venlafaxine for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;(8):CD011091.
56. Alviar MJ, Hale T, Dungca M. Pharmacologic interventions for treating phantom limb pain. Cochrane Database Syst Rev. 2016;10:CD006380.
57. Dinat N, Marinda E, Moch S, et al. Randomized, Double-Blind, Crossover Trial of Amitriptyline for Analgesia in Painful HIV-Associated Sensory Neuropathy. PLoS One. 2015;10(5):e0126297. doi: 10.1371/journal.pone.0126297.eCollection 2015.
58. Mehta S, McIntyre A, Janzen S, et al; Spinal Cord Injury Rehabilitation Evidence Team. Systematic review of pharmacologic treatments of pain after spinal cord injury: an update. Arch Phys Med Rehabil. 2016;97(8):1381-1391.e1.
59. Moore RA, Derry S, Aldington D, et al. Amitriptyline for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2012;(12):CD008242..
60. Walitt B, Urrútia G, Nishishinya MB, et al. Selective serotonin reuptake inhibitors for fibromyalgia syndrome. Cochrane Database Syst Rev. 2015;(6):CD011735.
61. Welsch P, Üçeyler N, Klose P, et al. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia. Cochrane Database Syst Rev. 2018;(2):CD010292.
62. VanderWeide LA, Smith SM, Trinkley KE. A systematic review of the efficacy of venlafaxine for the treatment of fibromyalgia. J Clin Pharm Ther. 2015;40(1):1-6.
63. Welsch P, Bernardy K, Derry S, et al. Mirtazapine for fibromyalgia in adults. Cochrane Database Syst Rev. 2018;(8):CD012708.
64. Lance JW, Curran DA. Treatment of chronic tension headache. Lancet. 1964;283(7345):1236-1239.
65. Jackson JL, William S, Laura S, et al. Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ. 2010;341:c5222. doi: https://doi.org/10.1136/bmj.c5222
66. Xu XM, Liu Y, Dong MX, et al. Tricyclic antidepressants for preventing migraine in adults. Medicine. 2017;96(22):e6989. doi: 10.1097/MD.0000000000006989.
67. Banzi R, Cusi C, Randazzo C, et al. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of migraine in adults. Cochrane Database Syst Rev. 2015;(4):CD002919.
68. Banzi R, Cusi C, Randazzo C, et al. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of tension-type headache in adults. Cochrane Database Syst Rev. 2015;(5):CD011681.
69. Quartero AO, Meineche-Schmidt V, Muris J, et al. Bulking agents, antispasmodic and antidepressant medication for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev. 2005;(2):CD003460.
70. Ford AC, Talley NJ, Schoenfeld PS, et al. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut. 2009;58(3):367-378.
71. Coss-Adame E, Erdogan A, Rao SS. Treatment of esophageal (noncardiac) chest pain: an expert review. Clin Gastroenterol Hepatol. 2014;12(8):1224-1245.
72. Kelada E, Jones A. Interstitial cystitis. Arch Gynecol Obstet. 2007;275(4):223-229.
73. Leo RJ, Dewani S. A systematic review of the utility of antidepressant pharmacotherapy in the treatment of vulvodynia pain. J Sex Med. 2013;10(10):2497-2505.
74. McMillan R, Forssell H, Buchanan JA, et al. Interventions for treating burning mouth syndrome. Cochrane Database Syst Rev. 2016;11:CD002779.
75. Patel DN. Inconclusive results of a systematic review of efficacy of antidepressants on orofacial pain disorders. Evid Based Dent. 2013;14(2):55-56.
76. Wang W, Sun YH, Wang YY, et al. Treatment of functional chest pain with antidepressants: a meta-analysis. Pain Physician. 2012;15(2):E131-E142.
77. Lavis JN. How can we support the use of systematic reviews in policymaking? PLoS Med. 2009;6(11):e1000141. doi: 10.1371/journal.pmed.1000141.
78. Sorkin L. Nociceptive transmission within the spinal cord. Mt Sinai J Med. 1991;58(3):208-216.
79. Yokogawa F, Kiuchi Y, Ishikawa Y, et al. An investigation of monoamine receptors involved in antinociceptive effects of antidepressants. Anesth Analg. 2002;95(1):163-168, table of contents.
80. Lynch ME. Antidepressants as analgesics: a review of randomized controlled trials. J Psychiatry Neurosci. 2001;26(1):30-36.
81. Max MB. Treatment of post-herpetic neuralgia: antidepressants. Ann Neurol. 1994;35(suppl):S50-S53.
82. Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992;326(19):1250-1256.
83. McQuay HJ, Tramèr M, Nye BA, et al. A systematic review of antidepressants in neuropathic pain. Pain. 1996;68(2-3):217-227.
84. Mochizucki D. Serotonin and noradrenaline reuptake inhibitors in animal models of pain. Hum Psychopharmacol Clin Exp. 2004;19(suppl 1):15-19.
85. Sussman N. SNRIs versus SSRIs: mechanisms of action in treating depression and painful physical symptoms. Primary Care Companion J Clin Psychiatry. 2003;5(suppl 7):19-26.
86. Bundeff AW, Woodis CB. Selective serotonin reuptake inhibitors for the treatment of irritable bowel syndrome. Ann Pharmacother. 2014;48(6):777-784.
87. Jung AC, Staiger T, Sullivan M. The efficacy of selective serotonin reuptake inhibitors for the management of chronic pain. J Gen Intern Med. 1997;12(6):384-389.
88. Xie C, Tang Y, Wang Y, et al. Efficacy and safety of antidepressants for the treatment of irritable bowel syndrome: a meta-analysis. PLoS One. 2015;10(8):e0127815. doi: 10.1371/journal.pone.0127815. eCollection 2015.
89. Zijlstra TR , Barendregt PJ , van de Laar MA. Venlafaxine in fibromyalgia: results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum. 2002;46(suppl 9):S105.
90. Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology. 2001;25(6):871-880.
91. Thorpe J, Shum B, Moore RA, et al. Combination pharmacotherapy for the treatment of fibromyalgia in adults. Cochrane Database Syst Rev. 2018;(2):CD010585.
92. Gilron I, Chaparro LE, Tu D, et al. Combination of pregabalin with duloxetine for fibromyalgia: a randomized controlled trial. Pain. 2016;157(7):1532-1540.
93. Häuser W, Petzke F, Üçeyler N, et al. Comparative efficacy and acceptability of amitriptyline, duloxetine and milnacipran in fibromyalgia syndrome: a systematic review with meta-analysis. Rheumatology (Oxford). 2011;50(3):532-543.
94. Hossain SM, Hussain SM, Ekram AR. Duloxetine in painful diabetic neuropathy: a systematic review. Clin J Pain. 2016;32(11):1005-1010.
95. Riediger C, Schuster T, Barlinn K, et al. Adverse effects of antidepressants for chronic pain: a systematic review and meta-analysis. Front Neurol. 2017;8:307.

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

The pathophysiology of chronic pain

The pathophysiologic processes precipitating and maintaining chronic pain conditions are complex. Persistent and chronic pain results from changes in sensitivity within both ascending pathways (relaying pain information from the periphery to the spinal cord and brain) and descending pain pathways (functioning to modulate ascending pain information).^2,3 Tissue damage or peripheral nerve injury can lead to a cascade of neuroplastic changes within the CNS, resulting in hyperexcitability within the ascending pain pathways.

The descending pain pathways consist of the midbrain periaqueductal gray area (PGA), the rostroventral medulla (RVM), and the dorsolateral pontomesencephalic tegmentum (DLPT). The axons of the RVM (the outflow of which is serotonergic) and DLPT (the outflow of which is noradrenergic) terminate in the dorsal horn of the spinal cord,⁴ and thereby dampen pain signals arising from the periphery. Diminished output from descending pain pathways can heighten the pain experience. Input from the cortex, hypothalamus, and amygdala (among other structures) converges upon the PGA, RVM and DLPT, and can influence the degree of pain modulation emerging from descending pathways. In this way, thoughts, appraisals, and mood are believed to comprise cognitive and affective modifiers of pain experiences.

Devising effective chronic pain treatment becomes challenging; multimodal treatment approaches often are advocated, including pharmacologic treatment with analgesics in combination with co-analgesic medications such as antidepressants. Although a description of multimodal treatment is beyond the scope of this article, such treatment also would encompass physical therapy, occupational therapy, and psychotherapeutic interventions to augment rehabilitative efforts and the functional capabilities of patients who struggle with persisting pain.

Although the direct pain-mitigating effects of antidepressants are not fully understood, it is believed that augmentation of monoamine neurotransmission from supraspinal nuclei (ie, the RVM and DLPT) modulate pain transmission from the periphery.^5,6 In addition, there is evidence that some effects of tricyclic antidepressants can modulate several other functions that impact peripheral and central sensitization.^7-10

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,³⁸and IBS.^39,40

Box 2

Antidepressants’ direct and indirect pain-mitigating effects and psychiatric comorbidities

The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects (impacting neurotransmission of descending pathways independent of influences on mood) and indirect effects (presumably impacting cortical and limbic output to the periaqueductal gray area, the rostroventral medulla, and the dorsolateral pontomesencephalic tegmentum brought about by improvement in mood and/or cognitive appraisals) (Figure^{2,3,8,10,11,15,20,22,28,29}). Support for the direct analgesic effects has been garnered from initial empirical work that demonstrated pain relief among patients with pain who are not depressed. Additionally, among patients who have depression and experience pain, analgesia reportedly often occurs within 2 weeks, which is before antidepressant effects are appreciated,^11-15 and, at least for some antidepressants, occurs at doses far lower than those required to produce mood-elevating effects.^11,12,16

On the other hand, it is well established that significant comorbidities exist between chronic pain states and psychiatric disorders (eg, depression and somatic symptom and related disorders).^17-21 There may be common physiological substrates underlying chronic pain and depression.^20,22 There are bidirectional influences of limbic (affective) systems and those CNS structures involved in pain processing and integration. The effects of pain and depression are reciprocal; the presence of one makes the management of the other more challenging.^23-27 Mood disturbances can, therefore, impact pain processing by acting as affective and cognitive amplifiers of pain by leading to catastrophizing, pain severity augmentation, poor coping with pain-related stress, etc.^28,29 It is plausible that the mood-elevating effects of antidepressants can improve pain by indirect effects, by modulating limbic activity, which in turn, impacts coping, cognitive appraisals of pain, etc.

Patients with somatoform disorders (using pre-DSM-5 terminology) frequently present with chronic pain, often in multiple sites.¹⁹ Such patients are characterized by hypervigilance for, and a predisposition to focus on, physical sensations and to appraise these sensations as reflecting a pathological state.³⁰ Neuroimaging studies have begun to identify those neural circuits involved in somatoform disorders, many of which act as cognitive and affective amplifiers of visceral-somatic sensory processing. Many of these neural circuits overlap, and interact with, those involved in pain processing.³¹ Antidepressants can mitigate the severity of unexplained physical complaints, including pain, among patients who somatize^32,33; however, due to the heterogeneity of studies upon which this claim is based, the quality of the evidence is reportedly low.³³ There is uncertainty whether, or to what extent, antidepressant benefits among patients who somatize are due to a direct impact on pain modulation, or indirect effects on mood or cognitive appraisals/perceptions.

Despite the uncertainties about the exact mechanisms through which antidepressants exert analgesic effects, antidepressants can be appropriately used to treat patients with selected chronic pain syndromes, regardless of whether or not the patient has a psychiatric comorbidity. For those patients with pain and psychiatric comorbidities, the benefits may be brought about via direct mechanisms, indirect mechanisms, or a combination of both.

Continue to: Neuropathic pain

References

Migraine: Expanding our Tx arsenal

Antidepressants for chronic pain

References

The effectiveness of antidepressants for pain

Pages

Next Article: