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Guest Editorial DOI: 10.5455/bcp.20150825014707

Treatment of Pain with

Bradley Kerr1,3, Curtis Benson2,4, Katherine Mifflin2,4, Sam J.B. Jesudasan5,8, Serdar Dursun6,9, Glen Baker7,10

Klinik Psikofarmakoloji Bulteni - Bulletin of Clinical Psychopharmacology 2015;25(3):209-12

INTRODUCTION antidepressants (SNRIs) for most chronic pain conditions9,14,15,31. Chronic pain can result in impairments in quality Since monoaminergic systems are involved in of life, mood, sleep and cognition1-5. A high degree both depression and chronic pain, it is not of comorbidity often exists between chronic pain surprising that antidepressants have been used and psychiatric disorders, including depression frequently for treating chronic pain. However, it and anxiety, and the co-existence of depression should also be noted that many antidepressants and chronic pain may result in increased have a true effect in that they are difficulties in treating both conditions5-9. In the effective at reducing pain in people without relationship between depression and pain, it depression5,10,13,14. Pain conditions in which appears that one can influence the development antidepressants are used for treatment include of the other, i.e., major depression can be a strong irritable bowel syndrome, central pain syndrome, predictor of subsequently developing pain and arthritis, fibromyalgia, low back pain, migraine, vice versa9. There is still considerable uncertainty , chemo-induced about the reasons for the co-occurrence of pain neuropathies and postherpetic neuralgia and depression, although this is an active area of (shingles-associated pain)5,10,14,16,17. Often these research5,10-12. pain conditions are treated with TCAs, which are Patients experiencing chronic pain are often inhibitors of the reuptake of NA and 5-HT. The treated with antidepressants13-18. Most of the relative lack of responsiveness to SSRIs and antidepressants produce increased functional relative success of TCAs in many chronic pain availability of the biogenic amines noradrenaline patients suggest that noradrenergic pathways may (NA) and/or 5-hydroxytryptamine (5-HT, be more important in chronic pain than in major serotonin)19,20, and there is now considerable depressive disorder. The SNRIs are also reported evidence also implicating GABAergic and to be more effective than SSRIs in the glutamatergic mechanisms in the management of chronic pain17,31,32, further effects of these drugs21-23. Interestingly, these four supporting the importance of NA in pain. neurotransmitter systems also appear to be Interestingly, it has been reported that TCAs with a involved in the development and/or modulation more balanced inhibition of reuptake of NA and of pain24-30, suggesting common mechanisms for 5-HT tend to be more effective in treating the development of depression and chronic pain. neuropathic pain than those that are much more However, while selective serotonin reuptake potent at inhibiting reuptake of NA than that of inhibitor antidepressants (SSRIs) are used 5-HT13. TCAs can also affect other systems directly frequently in treatment of depression, they are not or indirectly (5-HT binding to its receptors; NA’s as effective as antidepressants (TCAs) or interaction with α2-adrenoreceptors; serotonin-noradrenaline receptor density in the brain; binding to NMDA

Klinik Psikofarmakoloji Bulteni - Bulletin of Clinical Psychopharmacology, Volume 25, Issue 3 (September 01, 2015, pp. 209-320) 209 Treatment of pain with antidepressants

and/or AMPA glutamate receptors; blockade of depression43-45. voltage-gated sodium channels; adenosine uptake There has been a great deal of interest in the in the periphery; and indirect dopaminergic NMDA receptor antagonist and its rapid actions)10,13, and some of these additional effects acting antidepressant action when infused46,47, and may be contributing to their analgesic actions. it is interesting that this drug has also been used in However, it should also be remembered that TCAs treatment of therapy-resistant chronic pain48. may be poorly tolerated by the elderly and that Several neuroactive steroids (NASs), which are cardiotoxicity is a potential risk with TCAs13,17,32. rapid acting allosteric modulators at receptors The main focus of research on the involvement such as the GABA-A receptor and the NDMA of biogenic amines in pain and depression has glutamate receptor, have been reported to have been on NA and 5-HT, but there is increasing antidepressant and analgesic properties49-54. These evidence for a role of dopamine in the perception NASs or perhaps analogues of them or drugs that and regulation of pain33-36. Although the TCAs have have specific actions on these NASs should be of very little effect on dopamine reuptake, their increased interest in future studies on the adrenergic effect may produce indirect treatment of pain. dopaminergic effects via desensitization of dopamine D2 receptors33. In addition, the atypical Acknowledgements antidepressant (inhibits reuptake of NA and dopamine) has been reported to be effective Research funds have been provided by CIHR, the in treating neuropathic pain37. MS Society of Canada, the University of Alberta, the According to some authors, monoamine Abraham and Freda Berger Fund and the Donald oxidase inhibitors (MAOIs) should not be used in and Nancy Cranston Fund. The authors are treating pain disorders10,38, but (PLZ), grateful to Karyn Crawford for her expert an MAOI which also elevates brain GABA levels secretarial assistance. and has anxiolytic properties, has been reported to be effective in treating pain associated with depression39,40. This drug produces a marked 1PhD, 2BSc, Department of Anesthesiology and Pain elevation in brain and spinal cord levels of 5-HT Medicine, University of Alberta, Edmonton, Alberta, and NA41,42 and also appears to attenuate pain in Canada the EAE animal model of multiple sclerosis 3PhD, 4BSc, 5BSc, MSc, 6MD, PhD, 7PhD, DSc, (Benson, Mifflin, Baker and Kerr, unpublished), a Neuroscience and Mental Health Institute, University of neurological disorder in which pain is a frequent Alberta, Edmonton, Alberta, Canada symptom. 8BSc, MSc, 9MD, PhD, 10PhD, DSc, Neurochemical The differing analgesic effects of Research Unit, Department of Psychiatry, University of antidepressants based on their ability to inhibit Alberta, Edmonton, Alberta Canada reuptake of NA and 5-HT and the reported success with bupropion in treating neuropathic pain, Correspondence Address: Glen Baker, PhD, DSc, along with the proposed indirect actions of TCAs Neuroscience and Mental Health Institute, University on the dopaminergic system, suggest that of Alberta, Edmonton, Alberta, Canada treatment of chronic pain using triple reuptake Neurochemical Research Unit, Department of inhibitor antidepressants (which inhibit NA, 5-HT Psychiatry, University of Alberta, Edmonton, Alberta and dopamine reuptake) may be an interesting Canada avenue to pursue. Such drugs are currently being Phone: (780) 492-5994 investigated for possible use in pain and Email address: [email protected]

210 Klinik Psikofarmakoloji Bulteni - Bulletin of Clinical Psychopharmacology, Volume 25, Issue 3 (September 01, 2015, pp. 209-320) Kerr B, Benson C, Mifflin K, Jesudasan SJB, Dursun S, Baker G

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