Rheumatology Advance Access originally published online on April 29, 2008
Rheumatology 2008 47(8):1117-1123; doi:10.1093/rheumatology/ken110
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Is there any evidence to support the use of anti-depressants in painful rheumatological conditions? Systematic review of pharmacological and clinical studies
1Internal Medicine Department and Pain Clinic, Hotel Dieu Hospital, Paris Descartes University, Paris, 2Rheumatology Department, Hautepierre Hospital, Strasbourg, 3Rheumatology Department, Henri Mondor Hospital, Creteil and 4Pain Clinic, St Antoine Hospital, Paris, France.
Correspondence to: S. Perrot, Service de Médecine Interne et Thérapeutique, Consultation de la Douleur, Hotel Dieu, 1 Place du Parvis Notre Dame, 7500 Paris, France. E-mail: serge.perrot{at}htd.aphp.fr; sergperrot{at}aol.com
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Abstract |
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Top
Abstract
IntroductionThe aim of this study was to review the evidence supporting the use of anti-depressants in painful rheumatological conditions. A systematic review of papers published between 1966 and 2007, in five European languages, on anti-depressants in rheumatological conditions was performed. Papers were scored using Jadad method and analgesic ES was calculated. We selected 78 clinical studies and 12 meta-analyses, from 140 papers. The strongest evidence of an analgesic effect of anti-depressants has been obtained for fibromyalgia. A weak analgesic effect is observed for chronic low back pain, with an efficacy level close to that of analgesics. In RA and AS, there is no analgesic effect of anti-depressants, but these drugs may help to manage fatigue and sleep disorders. There is no clear evidence of an analgesic effect inOA, but studies have poor methodological quality. Analgesic effects of anti-depressants are independent of their anti-depressant effects. Tricyclic anti-depressants (TCAs), even at low doses, have analgesic effects equivalent to those of serotonin and noradrenalin reuptake inhibitors (SNRIs), but are less well tolerated. Selective serotonin reuptake inhibitors (SSRIs) have modest analgesic effects, but higher doses are required to achieve analgesia. Anti-depressant drugs, particularly TCAs and SNRIs, have analgesic effects in chronic rheumatic painful states in which analgesics and NSAIDs are not very efficient, such as fibromyalgia and chronic low back pain. In inflammatory rheumatic diseases, anti-depressants may be useful for managing fatigue and sleep disorders. Further studies are required to compare anti-depressants with other analgesics in the management of chronic painful rheumatological conditions.
KEY WORDS: Pain, Musculoskeletal, Anti-depressants, Fibromyalgia, Low back pain, Rheumatoid arthritis, Osteoarthritis, Ankylosing spondylitis
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Introduction |
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Pain is the main symptom of most rheumatological conditions. In some cases, standard analgesics (acetaminophen, NSAIDs and opioids) are ineffective and other drugs, such as anti-depressants, are required. Anti-depressants are increasingly prescribed for conditions such as fibromyalgia, RA, SpAs, low back pain and OA. However, the results obtained with anti-depressants are highly variable [1–4] and the use of anti-depressants for analgesia remains controversial. We review here the evidence supporting the use of anti-depressants in painful rheumatological conditions, with a view to helping rheumatologists to understand the background of anti-depressant use in their daily practice [5–8].
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Publication search and review |
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This work was carried out by a working group of 10 experts for the CEDR (Cercle d’Etude de la Douleur en Rhumatologie), a specific interest group of the French Society of Rheumatology focusing on rheumatic pain. Eight of the experts involved were rheumatologists. One of these rheumatologists was also a trained pharmacologist, and another was a methodology expert. The other experts were a psychiatrist and a pharmacologist. We aimed: (i) to review published papers concerning the use of anti-depressants for treating pain in rheumatic conditions and; (ii) to assess the available evidence concerning the appropriateness and relevance of anti-depressant use. We searched the Medline (National Library of Medicine), EMBASE, Pascal and Cochrane databases for publications in five European languages (French, English, Spanish, Italian and German). The search terms used were: anti-depressant, pain, joint diseases, rheumatoid arthritis, osteoarthritis, low back pain, fibromyalgia, fibrositis, rheumatic diseases, spondylarthropathy, ankylosing spondylarthritis, and sympathetic dystrophy. We searched for articles published from 1966 to June 2007. The references contained in the papers identified and in clinical practice guidelines and systematic reviews published in the same period completed the search. Two participants independently evaluated each paper, using Jadad's method, awarding a score from 0 to 5 [9], and each paper was classified and graded in terms of its evidence category, as described by Shekelle et al. [10]. Studies were included or rejected based on their final rating. With only a few exceptions, corresponding to cases in which no better equivalent paper could be retrieved, a rating of less than two resulted in rejection of the paper. With this selection method, we identified 140 relevant papers. We selected 78 clinical studies and 12 meta-analyses and literature reviews for analysis.
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Analysis of the identified papers |
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Evaluation criteria were grouped into seven categories: study design, number of patients, average dose of anti-depressants administered, study duration, outcome measurement and our calculation of analgesic effect size (ES). ‘Pain’ was considered the main outcome variable in these studies. Analgesic ES was determined by calculating the standardized difference between two means (anti-depressant analgesic effect vs placebo analgesic effect). ES is the difference between these two means divided by the pooled estimateS.D. We use here the mean change between baseline and the end of the study for quantitative pain data, if such data were available. In cases in which the change between baseline and the end of the study was not described in the original paper, ES was calculated based on the value obtained at the end of the trial, despite the limitations associated with the use of this information. Pain assessed by visual analogue scale (VAS) was retained as the main parameter if available. If VAS pain was not available, the pain dimension of fibromyalgia impact questionnaire (FIQ) or pain assessment of the McGill pain questionnaire was used. If no sufficient data on pain parameters were available for the calculation of ES, we report the conclusions of the authors. ES is reported in the tables with 95% CI. Most of the studies included a small number of patients, so a correction procedure, using Hedge's g, was applied to calculate ES. We considered the ES to be large if it exceeded 1.0, moderate if it was between 0.5 and 0.9 and small if it was between 0.30 and 0.50.
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Classification of anti-depressants |
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Anti-depressants are usually classified according to their mechanism of action (e.g. effect on monoamines) and their chemical structure (e.g. tricyclic) (Table 1) [11]. Most animal studies involving acute nociceptive tests or persistent pain models (neuropathic or nociceptive) have concluded that anti-depressants have an antinociceptive effect or an antihyperalgesic effect. The effects of anti-depressants appear to depend on their activity on monoamines.
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Mechanisms of action underlying the analgesic effects of anti-depressants |
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Anti-depressants are generally considered to have a central effect, reflecting their ability to cross the blood–brain barrier [11]. This has been demonstrated in animal and human studies and may involve both spinal and supraspinal mechanisms [12, 13]. Animal studies have confirmed the involvement of monoaminergic pathways and have demonstrated that intact serotonin and noradrenalin systems and bulbospinal pathways are required for tricyclic anti-depressants (TCAs) (the most frequently studied anti-depressants) to exert their anti-nociceptive effects [11, 14].
However, other mechanisms have also been suggested for TCAs. These mechanisms include a possible effect on opioid receptors, as suggested by several pre-clinical and clinical studies in which naloxone was shown to inhibit the analgesic effect of TCAs [15]. They may also exert an effect by interacting with excitatory amino acids, as they may act as antagonists of N-methyl-D-aspartate (NMDA). It has also been suggested that TCAs may act by blockading sodium channels or inhibiting neuronal adenosine uptake, as adenosine can generate both spinal and supraspinal analgesia.
Some studies have considered a possible peripheral site of action for anti-depressants that could be relevant in rheumatic disorders (reviewed in [12]). A local articular anti-inflammatory effect has been suggested [16]: anti-depressants may inhibit the local joint synthesis of nitric oxide (NO) and prostaglandine E2 (PGE2) in arthritis. Several studies based on models of inflammatory, neuropathic or visceral pain have confirmed that some TCAs and fluoxetine may have a peripheral anti-nociceptive effect [17]. The mechanisms put forward to account for such a peripheral effect differ from those for centrally mediated action. The inhibition of monoamine reuptake, which induces a pain-facilitating effect in the periphery, cannot be involved. None of the other known pharmacological actions of anti-depressants, particularly those of TCAs (antagonism of 
-1 adrenergic action; antagonism of H1 histaminergic and muscarinic receptors; opioidergic activation; NMDA receptor antagonism; adenosine reuptake; ion channel blockade) are likely to account completely for the peripheral effects of these drugs. Further studies, with specific tools, are required to determine more precisely the action of these drugs in the periphery [13].
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Clinical pharmacology of anti-depressants for the treatment of painful conditions |
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Evaluation of the dose–response effect in chronic pain
There is no clear evidence for a dose-dependent response to anti-depressant treatment in terms of pain relief, and we did not identify any pharmacological studies dealing specifically with rheumatic pain. Conflicting data have been obtained concerning the possible relationship between concentration and analgesic effect, but current therapeutic plasma concentration ranges seem to give an acceptable response for TCAs. Several studies in which TCAs were administered for various types of pain reported a relationship between serum drug concentration and analgesic effect [18]. A curvilinear concentration–response relationship has been reported for some TCAs (see references in [19]). Low doses of TCAs are frequently used for pain management [20], probably due to the distressing side-effects potentially associated with the use of higher doses, which might interfere with pain reduction or compliance (see references in [1, 21, 22]). Conflicting data have been obtained for the newer anti-depressants, with some studies suggesting that plasma concentration and effect are correlated (e.g. for paroxetine in neuropathic pain) and others reporting no such correlation (e.g. for fluoxetine and citalopram for neuropathic pain) (see references in [23]).
Onset of action in chronic pain
The analgesic response seems to begin before the anti-depressant response. An analgesic response is usually observed within 1 week of starting treatment, whereas the anti-depressant response usually occurs after 2 weeks (see references in [1, 24]). However, some studies have demonstrated a considerable time lag before effective pain management (e.g. [25]) due to the length of the titration period.
Evaluation of different routes and patterns of administration
The advantages of the various routes of administration are unclear in humans. Due to a marked first-pass effect, oral bioavailability ranges from 20% to 80% (see references in [19]). Genetic polymorphism may also play a role in the pronounced pharmacokinetic variability observed with these drugs [26]. Parenteral administration overcomes the problem of first-pass metabolism and results in high plasma concentrations. However, apart from a possible indication in patients unable to swallow, the parenteral route seems to have no other real advantage, despite reports that this route may accelerate the onset of the therapeutic effect [27].
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Evidence for the clinical efficacy of anti-depressants in various painful conditions |
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Several meta-analyses and reviews of studies dealing with various chronic non-malignant painful conditions [1, 28–35] have demonstrated an analgesic effect of anti-depressants. Onghena and Van Houdenhove [1] found, in their meta-analysis, a mean ES of 0.64 for patients with chronic pain treated with anti-depressants. Tricyclic drugs appeared to be more efficient than heterocyclic drugs (ES = 0.69 ± 0.1 vs 0.36 + 0.17). In contrast, serotonergic drugs were not found to be significantly more effective than noradrenergic drugs (ES = 0.32 ± 0.21 vs 0.4 ± 0.16). Drugs inhibiting both monoamines less selectively (mixed action) were significantly more effective than drugs inhibiting a single monoamine selectively (ES = 0.73 ± 0.12). These authors also dealt with rheumatic pain separately, and showed that the analgesic ES for rheumatic pain was smaller (0.37 ± 0.19) than that for neuropathic pain. A critical review of the use of anti-depressants in the management of pain, including that experienced by patients with rheumatic conditions [2], found that there was little reason to replace TCAs by SSRIs in pain management. Too few comparative trials have been carried out for definitive conclusions to be drawn, but there is a clear trend against the use of SSRIs [29, 30, 36] for pain management. Mixed-action anti-depressants (SNRIs), such as venlafaxine [37, 38], milnacipran and duloxetine [39], have considerable potential for pain management, because they have both serotonergic and adrenergic effects and are better tolerated than TCAs (lower levels of undesirable blocking of cholinergic, adrenergic and histaminergic receptors).
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Evidence for analgesic effects of anti-depressants in specific rheumatological conditions |
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Anti-depressants for treating fibromyalgia syndrome
We identified 52 studies on the use of anti-depressants in fibromyalgia (Table 2), including 28 controlled trials, most of which involved TCAs, and five meta-analyses and reviews [40–44]. A major placebo effect was identified in early studies of the effects of TCAs on pain in fibromyalgia, and no long-lasting effect of anti-depressants has been demonstrated for this condition [41–43]. This effect is similar to that reported for most of the drugs tested for fibromyalgia treatment [41], and may reflect a particular aspect of this syndrome.
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TCAs
Despite their widespread use, TCAs have only a moderate analgesic effect and only a minority of patients display sustained, marked improvement [45–60]. When possible to calculate, we found an analgesic ES of TCAs in fibromyalgia of 0.23 (95% CI: –0.35, 0.81) [55] to 1.34 (95% CI: –0.70, 1.98) [58], with a mean analgesic ES of around 0.50, similar to the results obtained in previous studies of the effects of TCAs in chronic pain conditions [1]. Amitriptyline is the most widely used drug for which an effect on pain, fatigue, sleep and general condition has been demonstrated [45, 46, 55, 58]. Amitriptyline and cyclobenzaprine begin to act after one week, and have a greater effect on sleep disorders and fatigue than on pain [53, 55, 60], even at low doses [55, 58]. Most studies reported the use of TCAs at lower doses than that used to treat depression, as TCA has been reported to have an effect on fibromyalgia at low doses, independently of mood disorders [49]. The adverse effects of TCAs are also a limiting factor for increasing doses in fibromyalgia syndrome.
SSRIs
Several studies have assessed the effects of SSRIs, which may be better tolerated than TCAs [61–68]. Citalopram [61, 62] has a small analgesic ES, from 0.18 (–0.43, 0.78) to 0.45 (–0.23, 1.12). Fluoxetine [63–66] has a stronger analgesic ES than citalopram and paroxetine. This ES is dose-related, ranging from 0.45 (–0.38, 1.29) for a dose of 20 mg [57] to 1.08 (0.41, 1.74) at higher doses [66], greater than those used to treat patients with depression. Paroxetine [67, 68], even at high doses (up to 62.5 mg/day), has only a weak significant effect on pain and function in fibromyalgia, with an ES of 0.19 (–0.7, 0.56). Attempts have been made to combine TCAs and SSRIs [56, 57], and this combination has been reported to have a greater analgesic ES. Such combinations seem to be synergic, possibly due to greater drug bioavailability. In conclusion, SSRIs are better tolerated but less effective than TCAs for the treatment of fibromyalgia. It is therefore necessary to increase the dose to obtain significant pain relief and improvement.
SNRIs
Recent studies on fibromyalgia have focused on newer anti-depressants, the SNRIs: venlafaxine [38, 69], duloxetine [70, 71] and milnacipran [72]. Studies on these drugs, with the exception of those dealing with venlafaxine, were generally of good methodological quality, with studies carried out over long periods (at least 3 months). Duloxetine [60–120 mg daily, analgesic ES of 0.53 (0.27, 0.79)] and milnacipran [100–200 mg daily, analgesic ES of 0.54 (0.09, 1.03)] have been found to be similarly effective against pain in fibromyalgia. These treatments were significantly more effective than placebo, not only against pain, but also for function (assessed by the FIQ), clinical global impression of change (assessed both by the patient and the physician), sleep and fatigue. These effects are independent of depressive symptoms. The analgesic effect is therefore not related to any anti-depressive effect of these treatments.
The effects on fibromyalgia of several other anti-depressants, including moclobemide—a monoamine oxidase inhibitor [59]—and ritanserin [73], have been studied. Moclobemide had no significant effect, and the methodological quality of the study on ritanserin was too low for any conclusions to be drawn about possible significant effects.
In conclusion, for fibromyalgia, a condition in which classical analgesics are not very effective, anti-depressants seem to be relevant and effective analgesics [74]. This may be because pain and other symptoms in fibromyalgia are related largely to central sensitization, rather than to peripheral articular and muscular mechanisms. These drugs are effective against fibromyalgia pain, regardless of the patient's depression status. The use of TCAs at low doses or of SNRIs at the same doses used in patients with depression could be recommended. This would not only relieve pain, but would also help to alleviate fatigue, sleep disorders and functional impairment. The advantages of anti-depressants over other central-acting drugs, such as anti-convulsants and D3 agonists, for the treatment of fibromyalgia remain unclear.
Anti-depressants in low back pain
Eleven [75–85] randomized controlled trials on the use of anti-depressants to treat low back pain have been published (Table 3), and seven reviews have specifically examined the analgesic and functional effects of anti-depressants in low back pain [86–92]. TCAs are the anti-depressants most frequently tested in low back pain, with only two studies dealing with an SSRI, paroxetine [83, 84], one with a noradrenalin reuptake inhibitor (NRI), bupropion [85], and none with SNRIs. The methodological quality of most of these studies was low, well below that for studies of fibromyalgia. Three of the 11 studies demonstrated a clear analgesic effect. Nortriptyline [81], at a dose of 50–150 mg/day, has an analgesic ES of 0.45 (0.00, 0.90), amitryptiline 150 mg [80] has an analgesic ES of 0.63 (–0.01, 1.27), like maprotiline [82], with an ES of 0.64 (0.06, 1.20). Anti-depressants also tend to improve function and everyday activities, although this trend was not found to be statistically significant [75, 79]. One study indicated that imipramine was more effective than placebo, but only in terms of the ‘numbers of days the patient had to lie down’ and ‘number of days with at least some restriction of normal activity’ [76]. Another study [77] showed that amitriptyline was better than placebo, comparing the use of rescue analgesics in the two treatment groups.
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In conclusion, in chronic low back pain, anti-depressants appear to provide moderate relief of symptoms, regardless of the patient's depression status. The analgesic effect is moderate, but of a similar magnitude to that of classical analgesics and NSAIDs [92] for chronic low back pain. SSRIs seem to be less effective than TCAs [78, 82], and SNRIs have yet to be tested. The effects of anti-depressants on health-related quality of life, mood and functional status in patients with low back pain are unclear [86, 91]. In chronic low back pain, anti-depressants could be recommended when classical analgesics and NSAIDs have failed, or if long-term treatment with NSAIDs is poorly tolerated, as a second-line treatment. However, this recommendation would require further validation by appropriate studies.
OA and inflammatory rheumatic diseases
We identified 15 randomized controlled trials on OA, RA and AS [93–108] (Table 4). Fourteen of these studies were placebo-controlled and one compared amitriptyline with paroxetine. Only eight of these 15 trials were considered to meet minimum standards for methodological quality to demonstrate efficacy [93–101] and ES was calculated in only five studies, due to a lack of available data. A significant analgesic ES was found in three studies, with trimipramine [96], amitriptyline [108] and dothiepin [99].
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In most of these trials, patients with different joint diseases were pooled (OA, RA and AS). Some studies included patients with depressive disorders associated with joint diseases [97, 98]. However, in the study performed by Lin et al. [102], in a large and diverse population of older adults with arthritis (mostly OA) and comorbid depression, the benefits of improvements in depression care extended beyond the reduction of depressive symptoms, with decreases in pain and improvements in functional status and quality of life also observed.
In conclusion, TCAs [amitriptyline (10–30 mg daily)] have only weak analgesic effects in patients with RA, with or without depressive symptoms [103, 104]. In AS, amitriptyline may effectively alleviate several symptoms (pain, fatigue and sleep disorders); this analgesic and symptom-relieving effect has not been confirmed with other anti-depressants [105]. Indeed, in these inflammatory conditions, other analgesics, such as NSAIDs, are highly efficient. There is no great need for alternative analgesics and we would not recommend the use of anti-depressants for pain management. However, further studies on effects on fatigue and sleep disorders should be carried out as these are important symptoms of these conditions.
No specific studies have been performed on OA, with some OA cases being pooled with RA and AS. It is therefore difficult to determine whether anti-depressants have any beneficial effects on pain related to OA [94, 106–108], and there are currently no validated data supporting the use of anti-depressants in patients with OA.
Side-effects of anti-depressants in rheumatic disorders
The side-effects of anti-depressants are related to their pharmacological properties [109, 110]. TCAs may cause side-effects in 30–100% of patients treated for painful conditions [11, 30]. These side-effects parallel the analgesic effects and are, in most cases, dose-dependent [104, 111]. The blockade of muscarinic cholinergic receptors may lead to dysuria, constipation, mouth dryness, drowsiness, eye accommodation disorders, tachycardia, memory disorders and confusion. The blockade of 1-noradrenergic receptors may induce orthostatic hypotension, tachycardia and dizziness. The blockade of histaminic H1 receptors may result in sedation, somnolence and weight gain. Trembling, tachycardia and impotence have also been attributed to noradrenalin reuptake inhibition. Serotonin reuptake inhibition may cause nausea, somnolence, drowsiness and fatigue, and may induce a serotonergic syndrome. New anti-depressants, such as venlafaxine, minalcipran and duloxetine may also induce specific side-effects (e.g. hypertension for venlafaxine) but have no anti-cholinergic effects and do not block - and histaminic-H1 receptors. Side-effects are more frequent in fibromyalgia, occurring in 70–95% of cases [44, 46]. Rapid wash-out of TCAs may lead to severe symptoms, such as nausea, vomiting and trembling [112]. Before starting TCA treatment, the physician should check for orthostatic hypotension and perform an ECG. The effects of combined treatment with tramadol should also be monitored [113]. SSRIs have been shown to be generally better tolerated than TCAs [100, 108] in pain studies. Some studies of SSRIs in patients with fibromyalgia have shown these drugs to be as well tolerated as placebo [56, 61, 65]. Furthermore, no tests are required before starting SSRIs treatment.
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Conclusions |
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Anti-depressants have been shown to have analgesic effects in several rheumatological conditions and could be tested in patients with chronic pain related to rheumatic disorders [21, 89, 114]. Fibromyalgia is the most suitable rheumatological condition for treatment with anti-depressants as analgesics, even in the absence of characterized depressive symptoms, and TCAs and SNRIs should be preferred. In chronic low back pain, TCAs should be tried when classical analgesics and NSAIDs have failed, or to avoid the side-effects of long-term NSAID treatments. In these conditions, TCAs may slightly improve pain and function. In RA and AS, TCAs should be not be used as analgesics, but could be tested as possible treatments for improving global management and specifically for the treatment of symptoms other than pain, such as fatigue and sleep disorders. There is currently no evidence to support the use of anti-depressants in OA. In all cases, TCAs appear to be more effective, but less well tolerated, than SSRIs. The newer anti-depressants, SNRIs (venlafaxine, milnacipran, duloxetine) and SNERIs [selective norepinephrine (noradrenalin) reuptake inhibitors; reboxetine] appear to be promising treatments for fibromyalgia and their use for other chronic pain indications, such as low back pain and OA, is being developed. Efforts should be made to identify the most appropriate anti-depressant for use in each painful chronic rheumatological condition and to validate the specific role of anti-depressants in pain management aside from analgesics and NSAIDs in rheumatology.
The authors would like to thank Julie Sappa for her useful help with English.
Disclosure statement: The authors have declared no conflicts of interest.
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  J. B. Fontenele, L. K. A. M. Leal, and F. H. C. Felix Comment on: Is there any evidence to support the use of anti-depressants in painful rheumatological conditions? Systematic review of pharmacological and clinical studies & Amitriptyline in the treatment of fibromyalgia: a systematic review of its efficacy Rheumatology, March 1, 2009; 48(3): 322 - 323. [Full Text] [PDF]
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S. Perrot, R.-M. Javier, M. Marty, C. Le Jeunne, F. Laroche, and the Cercle d'Etude de la Douleur en Rhumatologie ( Comment on: Is there any evidence to support the use of anti-depressants in painful rheumatological conditions? Systematic review of pharmacological and clinical studies: reply Rheumatology, March 1, 2009; 48(3): 323 - 323. [Full Text] [PDF]
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