Depression Management during the Presence of Pain: An Overview

Abstract

Background: Depression and anxiety are frequently associated with increased risk of medical problems. Severity of these problems varies from persistent pain to severe cardiovascular illness. The pathophysiology of chronic pain and depression overlap in the noradrenergic and seratonergic pathways. Antidepressants, especially dual acting which affect both pathways, are a frequent and effective choice of treatment for chronic pain. Although the coexistence of depression and pain, the treatment differs in terms of depression pain comorbidity and painful symptoms in depression. The aim of this study is to discover and integrate the data about pain.

Methods: We have searched the literature from databases with the keywords “pain”, “depression” and “painful symptoms”. The search was limited to human studies of adults published in English. Because of the large number of studies a second search was required. The extracted data that have on consensus are taken.10 clinical trial, 3 reviews and 2 metaanalysis that all reviewers agreed have scoped.

Results: We found evidences of strong relationship between pain perception and depression.

Conclusion: The painful symptoms of depression and pain syndromes associated with depression must clearly be identified. Duloxetine has studied extensively and found to be effective in depression. Further studies with different drugs are required.

Keywords: Depression; Painful symptoms; Pain

Introduction

Pain is an unpleasant feeling often caused by noxious stimuli and represents most common reason for patients to seek for medical counsel [1]. The prevalence of chronic pain differs. In United States the prevalence of moderate to severe chronic pain in adults is 35.5 % [2] while it is 19% in Europe [3]. Depending on the definition, the worldwide prevalence is estimated to be between 11%-55% [4]. Acute pain can warn for life-threatening problems while chronic persistent pain may not. Unlike acute pain, chronic pain is associated with functional and structural changes in peripheral and central nervous system and may be a co-existing plague with different problems. Regardless from the comorbid problem, untreated or undertreated chronic pain has significant physical, psychological, social and financial consequences [5]. One of the frequent co-morbidity of chronic pain is depression. This coexistence is not astonishing according to the involvement of some common regions of brain and pathways. Some of the descending neural tracts that project to spinal cord constitute an endogenous analgesic pathway and these tracts originate from periaqueductal grey matter. Involvement of these regions in depression results with chronic pain. Three categories of chronic pain are recognized: neuropathic pain (result of a damage or dysfunction either in peripheral nerves or central nervous system), inflammatory pain and non-inflammatory non-neuropathic pain (also called functional pain). It may be difficult to identify the painful symptoms of depression and pain syndromes associated with depression. Since the treatment approaches are different, sagacious clinical decision is important for the choice of the treatment.

The aim of this study is to review and integrate the data both about the painful symptoms of depression and pain syndromes associated with depression.

Methods

We searched the literature from several databases with the keywords “depression, pain” we obtained over 4000 clinical trial. If the keywords are “depression, painful symptoms” it is lesser but over 3000. The search was limited to human studies of adults published in English. The results of this search showed that large numbers of studies have done for the same purpose thus a second search was undertaken to identify the relationship between pain and depression. All extracted data were independently reviewed by authors and only studies that have a consensus included. For this purpose 10 clinical trial, 3 review and 2 metaanalysis were reviewed.

Results

Depression and pain

Many depression-linked physical problems (gastrointestinal like dyspepsia and loss of appetite, and fatigue, insomnia and pain) may mask emotional problems (anxiety, guilt etc.) and be refractory to treatment. Although most interactions between depression and its physical symptoms are well known, some are still unclear. There is growing evidence that depression and depressive symptoms influence physical pathology [6].

As Bair et al. note in their review, the prevalence of pain symptoms in patients with depression range from 15% to 100% (mean 65%) [7]. The prevalence also varies according to setting: among patients in pain clinics 52%, in psychiatric clinics 38%, in orthopedic clinics 56%, in dental clinics 85%, in gynecology clinics 13%, in primary care clinics 27%. The authors also report that a major symptom of depression in primary care clinics is pain. Over 50% of these patients have somatic complaints of which at least 60% were pain related. They also found that increase of pain complaints associates with increased severity of depression. Furthermore, severity of the pain associates with poor depression outcomes. Howland et al. reported that overall pain and pain while awake predict insufficient response to antidepressants [8]. Ehnvall et al. studied 186 treatment resistant depressed patients: increase of pain during depression is associated with increased rejection sensitivity [9]. The combination of pain and depression is also associated with older age, female gender and lower education level. Rethelyi et al. found in their epidemiological survey of 12,640 Hungarian adults, among patients with pain-related disability (33%), the prevalence of depression symptoms was 30% and positively correlated with age and lower education [10]. Nicholl et al. studied the comorbidity of mood disorders and chronic pain in a British population with 149, 611 participants: multisite chronic pain was more prevalent in patients with bipolar disorder and major depressive disorder [11]

As knowledge of bio-processes influencing depression increases, the link between emotional and physical symptoms and pain may become clearer [12,13]. Hypothalamic-Pituitary-Adrenal (HPA) axis, noradrenergic and seratonergic pathways are well-established overlapping mechanisms of pain and depression [14]. Monoamines regulate both mood and pain symptoms. The ascending pathway of pain (from periphery to Central Nervous System-CNS-) modulates by excitatory glutamate and inhibitory GABA. Descending transmission (from CNS to periphery) is associated with nor adrenaline and serotonin which are the targets of dual-acting antidepressants (mitrazapine, tricyclics and Serotonin or adrenaline Reuptake Inhibitors-SNRI-).

Management of pain in depression

Antidepressants: The hypothesized mechanism of antidepressants in the treatment of pain depends on common neurotransmitters involved in depression, especially seratonin and noradrenaline. The use of antidepressants dates back to the 1960s, since when they have been used for neuropathic pain, chronic back pain and fibromyalgia.

Mirtazapine is a well-known antidepressant agent with a combined receptor affinity that acts with 5 HT1A agonism and 5 HT2 and 5 HT3 antagonism. Freynhagen et al. used mirtazapine in an observational study of 594 patients with chronic pain and comorbid depression: mirtazapine significantly reduced the symptoms [15]. However due to the common adverse effect of antidepressants acting through the 5-HT1 receptor (mirtazapine, mianserin, nefazodone etc.) mirtazapine may cause arthralgia [16]. Yeephu et al. compared 15 mg/day and 30 mg/day doses with placebo in 40 patients with fibromyalgia and found no difference between groups [17].

Dual-acting antidepressants (venlafaxine, duloxetine, milnacipran) modulate selective reuptake of serotonin and noradrenaline and are known to be SNRIs. The analgesic effect of SNRI seems to be due to the shared neurotransmitter pathways of pain with depression. Moreover, relief of pain with the administration of venlafaxine and mirtazapine may be partly due to their affinity to opioid receptors [18].

SNRIs are extensively studied in chronic pain without depression, especially in fibromyalgia, but isolated studies in depression with pain are limited. Huang et al. studied 102 depressed patients with painful physical symptoms treated with 75-225 mg/day venlafaxine for 8 weeks and found that venlafaxine is effective and safe to treat depression plus painful physical symptoms [19]. Berge et al. studied 0-450 mg/day venlafaxine in Swiss patients and found it beneficial [20].Reports about milnacipran is limited regarding chronic pain without depression. A broadly studied SNRI in depression with pain is duloxetin. Li et al. evaluated duloxetin for depression and anxiety in 55 patients with ankylosing spondylitis and reported significant improvement both in spinal pain, BASDAI scores and depressive symptoms [21]. In two 8-week trials with a total of 641 patients Ruskin et al. and [22] and Brecht et al. [23] concluded that duloxetine is superior to placebo.

Despite these few studies of antidepressants, debates continue on the roots of pain in depression and which cases can be accepted as in remission. Some authors suggest that appropriate control of pain in patients with depression may lead to remission in depressive symptoms. For this point of view only duloxetine has been reported. Further studies are required with other treatments. Robinson et al. studied 523 patients with major depression plus pain and remission in depression symptoms was due to the direct effect of treatment, 41% due to pain reduction, and 43% due to functional improvement. Path analysis also indicated 51% of improvement in functioning was due to pain improvement and 43% to mood improvement [24]. Fava et al. [25], Arnold et al. [26] and Beesdo et al. [27] had similar findings.

Other medications: Many clinical trials offered different options from simple analgesics to anticonvulsants and opioids for chronic pain. However, studies of chronic pain and depression are of limited value. Further studies in this population need more analysis of interactions between antidepressants, anticonvulsants and opioid analgesics and addiction. Some studies point to cover prescription of analgesics and frequent administration of opioids [28] and opioid addiction [29] in depressive patients.

Opioids like tramadol have antidepressant as well as analgesic effects. Reeves [30] and Nyhuis [31] et al. revealed that opiates can be used for treatment- resistant depression.

Data about the analgesic effectiveness of anticonvulsants except for gabapentin and pregabalin vary. Pregabalin and duloxetine are approved by the FDA for fibromyalgia. The efficacy and safety of these drugs are well established [32]. Regardless of the evidence, other anticonvulsants, especially gabapentin and carbamazepine are still prescribed both for fibromyalgia and for pain in depressive patients [33,34].

Non-drug treatments of pain in depression: Psychotherapy alone or together with medication has improved physical symptoms and pain in depression. The psychotherapy techniques vary [35,36]. The most frequently-used techniques are cognitive-behavior therapy, operant behavior therapy and psycho dynamically oriented psychotherapy.

Supportive and adjunctive therapies include hypnosis, biofeedback, acupuncture and relaxation trainings.

Conclusion

Major depression increases the risk of several medical problems and there is a link between painful symptoms, anxiety and depression [37]. Probably the most frequent comorbidity is pain and depression. Clinically, severe pain at onset of symptoms predicts poor response to the depression treatment. Alterations of seratonergic and noradrenergic pathways in the central nervous system are the common pathological roots of depression and chronic pain. Severe pain at onset of the symptoms predicts poor response to the depression treatment. Seratonin has a unique role in pain pathways. It plays an algogenic role in peripheral tissues although it acts as an endogenous analgesic role in central nervous system. Unfortunately, this paradigm supports the use of antidepressants which inhibit monoamine and serotonin reuptake for the treatment of painful physical symptoms in depression and anxiety. Dual-acting antidepressants (venlafaxine, duloxetine, milnacipran) have more specific actions on the overlapping pathology of depression and pain. They interact with seratonergic and noradrenergic receptors with different affinity. Moreover, the subtypes of the receptors they interfere may differ leading various analgesic effects. Although some authors do not confirm the difference of their analgesic effects [38], review of the literature suggests that the efficacy of antidepressants (especially SNRIs) may differ and their action may be disease specific. These drugs, especially duloxetin, are broadly studied in the literature. Large clinical trials are about the chronic pain syndromes without depression and the lack of data about the treatment of pain in depression and anxiety continues. Further studies are required concerning the treatment of isolated chronic pain symptoms in depressed patients.

References

1. American Pain Foundation. Based on National Pain Survey, conducted for Ortho-McNeil Pharmaceutical.
2. Harstall C, Ospina M. How prevalent is chronic pain. Pain: Clinical updates. 2003; 11.
3. Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain. 2006; 10: 287-333.
4. Toblin RL, Mack KA, Perveen G, Paulozzi LJ. A population-based survey of chronic pain and its treatment with prescription drugs. Pain. 2011; 152: 1249-1255.
5. Galer BS, Dworkin RH. A clinical guide to neuropathic pain. McGraw- Hill Philadelphia. 2000.
6. Steptoe A, Editor. Depression and physical illness. Cambridge University Press, Cambridge UK. 2007; 421.
7. Bair MJ, Robinson RL, Katon W, Kroenke K. Depression and pain comorbidity: a literature review. Arch Intern Med. 2003; 163: 2433-2445.
8. Howland RH, Wilson MG, Kornstein SG, Clayton AH, Trivedi MH, Wohlreich MM, et al. Factors predicting reduced antidepressant response: experience with the SNRI duloxetine in patients with major depression. Ann Clin Psychiatry. 2008; 20: 209-218.
9. Ehnvall A, Mitchell PB, Hadzi-Pavlovic D, Malhi GS, Parker G. Pain during depression and relationship to rejection sensitivity. Acta Psychiatr Scand. 2009; 119: 375-382.
10. Réthelyi JM, Berghammer R, Kopp MS. Comorbidity of pain-associated disability and depressive symptoms in connection with sociodemographic variables: results from a cross-sectional epidemiological survey in Hungary. Pain. 2001; 93: 115-121.
11. Nicholl BI, Mackay D, Cullen B, Martin DJ, Ul-Haq Z, Mair FS, et al. Chronic multisite pain in major depression and bipolar disorder: cross-sectional study of 149,611 participants in UK Biobank. BMC Psychiatry. 2014; 14: 350.
12. Nemeroff CB. Recent advances in the neurobiology of depression. Psychopharmacol Bull. 2002; 36 Suppl 2: 6-23.
13. Nemeroff CB, Vale WW. The neurobiology of depression: inroads to treatment and new drug discovery. J Clin Psychiatry. 2005; 66 Suppl 7: 5-13.
14. Wise TN, Fishbain DA, Holder-Perkins V. Painful physical symptoms in depression: a clinical challenge. Pain Med. 2007; 8 Suppl 2: S75-82.
15. Freynhagen R, Muth-Selbach U, Lipfert P, Stevens MF, Zacharowski K, Tolle TR, et al. The effect of mirtazapine in patients with chronic pain and concomitant depression. Curr Med Res Opin. 2006; 22: 257-264.
16. Passier A, van Puijenbroek E. Mirtazapine-induced arthralgia. Br J Clin Pharmacol. 2005; 60: 570-572.
17. Yeephu S, Suthisisang C, Suttiruksa S, Prateepavanich P, Limampai P, Russell IJ. Efficacy and safety of mirtazapine in fibromyalgia syndrome patients: a randomized placebo-controlled pilot study. Ann Pharmacother. 2013; 47: 921-932.
18. Schreiber S, Bleich A, Pick CG. Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects--a possible opioid involvement in severe depression? J Mol Neurosci. 2002; 18: 143-149.
19. Huang X, Li C, Luo YL, Wang B, Ji JL. Efficacy of venlafaxine extended-release monotherapy for first-episode depression with painful physical symptoms. Neuroreport. 2013; 24: 364-369.
20. Begre S, Traber M, Gerber M, von Kanel R. Change in pain severity with open label venlafaxine use in patients with a depressive symptomatology: an observational study in primary care. Eur Psychiatry. 2008; 23: 178-186.
21. Li Y, Zhang SL, Zhu J, DU XN, Huang ZF, Huang F. [Impact of duloxetine on depression and anxiety in patients with ankylosing spondylitis: a case-control study]. Zhonghua Yi Xue Za Zhi. 2013; 93: 966-969.
22. Raskin J, Wiltse CG, Siegal A, Sheikh J, Xu J, Dinkel JJ, et al. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled trial. Am J Psychiatry. 2007; 164: 900-909.
23. Brecht S, Courtecuisse C, Debieuvre C, Croenlein J, Desaiah D, Raskin J, et al. Efficacy and safety of duloxetine 60 mg once daily in the treatment of pain in patients with major depressive disorder and at least moderate pain of unknown etiology: a randomized controlled trial. J Clin Psychiatry. 2007; 68: 1707-1716.
24. Robinson MJ, Sheehan D, Gaynor PJ, Marangell LB, Tanaka Y, Lipsius S, et al. Relationship between major depressive disorder and associated painful physical symptoms: analysis of data from two pooled placebo-controlled, randomized studies of duloxetine. Int Clin Psychopharmacol. 2013; 28: 330-338.
25. Fava M, Mallinckrodt CH, Detke MJ, Watkin JG, Wohlreich MM. The effect of duloxetine on painful physical symptoms in depressed patients: do improvements in these symptoms result in higher remission rates? J Clin Psychiatry. 2004; 65: 521-530.
26. Arnold LM, Lu Y, Crofford LJ, Wohlreich M, Detke MJ, Iyengar S, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum. 2004; 50: 2974-2984.
27. Beesdo K, Hartford J, Russell J, Spann M, Ball S, Wittchen HU. The short- and long-term effect of duloxetine on painful physical symptoms in patients with generalized anxiety disorder: results from three clinical trials. J Anxiety Disord. 2009; 23: 1064-1071.
28. Doan BD, Wadden NP. Relationships between depressive symptoms and descriptions of chronic pain. Pain. 1989; 36: 75-84.
29. Nunes EV, Sullivan MA, Levin FR. Treatment of depression in patients with opiate dependence. Biol Psychiatry. 2004; 56: 793-802.
30. Reeves RR, Cox SK. Similar effects of tramadol and venlafaxine in major depressive disorder. South Med J. 2008; 101: 193-195.
31. Nyhuis PW, Gastpar M, Scherbaum N. Opiate treatment in depression refractory to antidepressants and electroconvulsive therapy. J Clin Psychopharmacol. 2008; 28: 593-595.
32. Hauser W, Walitt B, Fitzcharles MA, Sommer C. Review of pharmacological therapies in fibromyalgia syndrome. Arthritis Res Ther. 2014; 16: 201.
33. Argoff CE. The coexistence of neuropathic pain, sleep, and psychiatric disorders: a novel treatment approach. Clin J Pain. 2007; 23: 15-22.
34. Owen RT. Pregabalin: its efficacy, safety and tolerability profile in fibromyalgia syndrome. Drugs Today (Barc). 2007; 43: 857-863.
35. Leo RJ, Pristach CA, Streltzer J. Incorporating pain management training into the psychiatry residency curriculum. Acad Psychiatry. 2003; 27: 1-11.
36. Molton IR, Graham C, Stoelb BL, Jensen MP. Current psychological approaches to the management of chronic pain. Curr Opin Anaesthesiol. 2007; 20: 485-489.
37. Katon W, Lin EH, Kroenke K. The association of depression and anxiety with medical symptom burden in patients with chronic medical illness. Gen Hosp Psychiatry. 2007; 29: 147-155.
38. Krebs EE, Gaynes BN, Gartlehner G, Hansen RA, Thieda P, Morgan LC, et al. Treating the physical symptoms of depression with second-generation antidepressants: a systematic review and metaanalysis. Psychosomatics. 2008; 49: 191-198.