Doi:10.1016/j.ejpain.2005.03.004

European Journal of Pain 10 (2006) 185–192 Guidelines for the use of antidepressants in painful rheumatic conditions Serge Perrot *, Emmanuel Maheu, Rose-Marie Javier, Alain Eschalier, Anne Coutaux, Manuela LeBars, Philippe Bertin, Bernard Bannwarth, Richard Tre ves Cercle dÕe´tude de la douleur en rhumatologie, CEDR, Limoges, France Received 31 August 2004; accepted 11 March 2005 Available online 18 April 2005 Objectives: Antidepressants are widely used to treat painful chronic rheumatic conditions but, contrary to neuropathic conditions, little is known about their true analgesic properties and value in these situations. Our group, which focuses on pain in rheumatology,aimed to develop recommendations for the use of antidepressants in rheumatology, based on evidence-based review of publisheddata and expert opinion.
Method: We identified relevant drugs and conditions and searched Medline, Embase and Pascal (1966–2003) for relevant publica- tions in a number of European languages. We scored each study for quality, and used an expert consensus approach to formulaterecommendations.
Results: We identified 77 studies and 12 meta-analyses and literature review on the use of antidepressant to treat painful rheuma- tological conditions. Forty-nine of these clinical studies were considered valid and were used to develop the recommendations. Whenevidence was lacking we based recommendations on our clinical experience.
Conclusions: These recommendations for the treatment of painful rheumatological conditions with antidepressants were devel- oped using evidence-based and expert consensus approaches and are the first of their kind in this field. Our review of the literaturehighlights the need for further, well-designed clinical studies of the use of antidepressants to treat painful rheumatologicalconditions.
Ó 2005 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. Allrights reserved.
Keywords: Pain; Musculoskeletal; Antidepressants; Treatment; Recommendations effectively. However, in some cases, additional treat-ments, such as antidepressants and anticonvulsants, Pain is the main symptom of many rheumatic condi- diseases. In many cases, analgesics, non steroidal anti- of antidepressants inflammatory drugs (NSAIDs) or opioids control pain is increasingfor many conditions, including fibromyalgia, rheuma-toid arthritis, spondylarthropathies, low back pain and * Corresponding author. Address: centre de la Douleur, hoˆpital osteoarthritis. Although antidepressants have often been Cochin-Tarnier, 89 Rue dÕAssas, 75006 Paris, France. Tel.: +33 1 58 41 shown to reduce pain, the results obtained are variable 15 01; fax: +33 1 58 41 15 00.
E-mail address: (S. Perrot).
1090-3801/$32 Ó 2005 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rightsreserved.
doi:10.1016/j.ejpain.2005.03.004 S. Perrot et al. / European Journal of Pain 10 (2006) 185–192 2.3. Guideline development questions remain unanswered All potentially relevant papers were retrieved and For example: Does the analgesic effect depend their findings were analyzed by all members. The list on the antidepressant effect? What is the optimal dose? of clinical questions used to define the scope of the liter- When is such treatment appropriate? How long should ature search was also used to structure the recommenda- treatment be continued? tions together with another set of guidelines (on the use Guidelines are therefore required concerning the use of opioids for the treatment of chronic pain) which had of these drugs. This document reviews the available evi- been developed by a similar expert group, including one dence and then proposes a framework for the develop- of the CEDR panel members (). Sepa- ment of guidelines, without providing detailed advice rate sections were drafted by various participants using about doses or formulations. It is designed to be a start- the evidence from the literature review wherever ing point for discussion and to be sufficiently flexible to gain practical acceptance in different countries. It aims The draft recommendations were circulated among to help prescribers (in primary care or specialist settings) the authors for further review and critical evaluation.
to use antidepressants appropriately for the manage- A Delphi approach was then employed to reach con- ment of pain in rheumatic conditions.
sensus and all the recommendations were collated andsent back to the experts, who were asked to rank the10 most important proposals. A final draft of the rec-ommendations was generated, taking into account the comments and criticisms of the nine panel members.
The Delphi method is an exercise in group communi- 2.1. The expert panel cation among a panel of geographically dispersed ex-perts. It enables experts to deal systematically with a This study was carried out by a working group of complex problem or task. The essence of the tech- nine experts for the CEDR (Cercle dÕEtude de la Doul- nique is fairly straightforward. It comprises a series eur en Rhumatologie) a specific interest group of the of questionnaires sent by post or e-mail to a pre- French Society of Rheumatology that focuses on rheu- selected group of experts. These questionnaires are de- matic pain. Seven of the experts involved in this study signed to elicit and to develop individual responses to were rheumatologists, one of whom was also a pharma- the problems posed and to enable the experts to refine cologist. The other members were a psychiatrist and a their views as the groupÕs work progresses in accor- dance with the assigned task. The Delphi methodmakes it possible to overcome the disadvantages of 2.2. Search strategy conventional committee action. The group interactionin Delphi is anonymous, in that the originator of Relevant treatments and conditions were identified comments, forecasts, and the like is not identified.
by the panel. We then searched the Medline, Embase These elements are presented to the group in such a and Pascal databases for publications in several Euro- way as to suppress any identification. Here are the pean languages. Search terms used were: antidepressant, ten steps for the Delphi method: pain, rheumatoid arthritis, osteoarthritis, low back pain,fibromyalgia, fibrositis, rheumatic diseases, spond- 1. Formation of a team to undertake and to monitor ylarthropathy, ankylosing spondylarthritis, and sympa- a Delphi on a given subject.
thetic dystrophy. The search period covered 1966 to 2. Selection of one or more panels to participate in August 2002. Studies were scored using the EULAR the exercise. Panel members are usually experts guidelines, from 0 to 28 (based in the area to be investigated.
on a checklist. This checklist consists of 27 items distrib- uted between five sub-scales and was developed on the basis of epidemiological principles, reviews of study 4. Testing the questionnaire for proper wording (e.g., designs, and existing checklists for the assessment of 5. Transmission of the first questionnaires to the checklist provides a quality assessment of the reporting, external and internal validity and statistical power of 6. Analysis of the first-round responses.
each study. All studies are scored 0–1 for 26 questions 7. Preparation of the second-round questionnaires and 0–2 for one question, giving a maximum score of (and possible testing).
28. Power calculations are scored as 1 if present and 0 8. Transmission of the second-round questionnaires to the panelists.
S. Perrot et al. / European Journal of Pain 10 (2006) 185–192 9. Analysis of the second-round responses (steps 7–9 pram were found to have a positive effect on neuro- are reiterated as long as many times as required to pathic pain. Venlafaxine was recently shown to reduce achieve stable results).
neuropathic pain following chemotherapy for breast 10. Preparation of a report by the analysis team to cancer (and may also improve present the conclusions of the exercise.
fibromyalgic patients (). But, exceptin neuropathic conditions and in fibromyalgia, there is The recommendations were then tested according the no convincing study that really aimed to compare TCAs AGREE method () by two with SSRIs or other new antidepressants in specific independent reviewers and the strength of the evidence chronic pain states and specifically rheumatological.
supporting each recommendation was indicated, from For most of the authors antidepressant analgesic effects A to D (). The purpose of the Ap- are independent of their effects on mood ( praisal of Guidelines Research & Evaluation (AGREE)Instrument is to provide a framework for assessing the 3.2. Evaluation of the dose–response effect in chronic pain quality of clinical practice guidelines. The AGREEInstrument is designed to assess guidelines developed There is no clear evidence for a dose-dependent re- by local, regional, national or international groups.
sponse to antidepressant treatment in terms of pain re- The AGREE Instrument is generic and can be applied lief However, we identified no to guidelines in any disease area. The AGREE Instru- studies that dealt specifically with rheumatic pain. Con- ment assesses both the quality of the reporting, and flicting data have been obtained concerning the possible the quality of some aspects of recommendations. It pro- relationship between concentration and analgesic effect, vides an assessment of the predicted validity of a guide- but current therapeutic plasma concentration ranges line, the likelihood that it will achieve its intended seem to give an acceptable response for TCAs. Several outcome. It does not assess the impact of a guideline studies in which TCAs were administered for various on patientsÕ outcomes.
types of neuropathic pain reported a relationship be-tween serum drug concentration and analgesic effect(For the newer antidepressants, also in neuropathic pain, somestudies suggested that plasma concentration and effect We identified 137 relevant papers and, of these, se- are correlated (e.g. for sertraline and paroxetine for neu- lected 99 for detailed analysis: 77 were randomised con- ropathic pain) and others reported no such correlation trolled studies and 12 were meta-analyses or literature (e.g. for fluoxetine and citalopram for neuropathic pain) review. The results are summarised below.
(see references in ).
3.1. Global review of analgesic effects of antidepressants 3.3. Onset of action in chronic pain 3.1.1. Analgesic effect of antidepressants The analgesic response seems to start before the anti- Analysis of 39 studies in various chronic naon-malig- depressant response. An analgesic response is usually nant painful conditions ( observed within one week of starting treatment, whereas found that antidepressants had an analgesic the antidepressant response usually occurs after the first effect, confirmed by Lynch in a meta-analysis of 59 stud- two weeks (see references in ies (In neuropathic pain, the results are convincing and have demonstrated differential analgesiceffects regarding the group of the drug: 3.4. Evaluation of different routes and patterns of and found that TCAs were more effective than serotonin-specific reuptakeinhibitors (SSRIs) in relieving neuropathic pain. In The advantages of the various routes of administra- global assessment of effects of antidepressants in chronic tion are unclear in humans. Due to a marked first-pass pain states, most of the authors have concluded that the effect, oral bioavailability ranges from 20 to 80% (see tricyclic group of antidepressants is analgesic and that references in and genetic poly- data regarding selective serotonin reuptake inhibitors morphism may also play a role in the pronounced phar- are conflicting (). A review of the use of macokinetic variability observed with these drugs.
antidepressants in pain management, including rheu- Parenteral administration overcomes the problem of matic conditions (found little reason to first-pass metabolism, and results in high plasma con- replace TCAs by SSRIs in pain management. In a other centrations. However, apart from a possible indication review comparing some of the newer antidepressants in patients unable to swallow, the parenteral route seems with TCAs (only paroxetine and citalo- to have no other real advantage, despite reports that this S. Perrot et al. / European Journal of Pain 10 (2006) 185–192 route may accelerate the onset of the therapeutic effect ). A major placebo effect was identified in fibromyalgia studies, and antidepressantshave not been shown to have a lasting effect.
3.5. Antidepressants side effects Amitriptyline is the most widely used drug for which an effect on pain, fatigue, sleep and general conditions Imipraminic drugs, and TCAs in particular, cause side has been demonstrated ( effect in 30–100% of patients treated for painful condi- Amitriptyline and cyclobenzaprine have a greater effect on sleep disorders and fatigue than effects are more frequent in fibromyalgia, occurring in on pain (). Most of the studies re- 70–95% of cases ported the use of tricyclic drugs at doses lower than Side effects parallel TCAs analgesic effects and, those used to treat depression, probably due to the side in most cases, depend on dose (Ra- effects of these drugs.
pid wash-out may lead to severe symptoms, such as nau- Recent studies have assessed the effects of newer anti- sea, vomiting, and trembling ( depressants, such as citalopram ( Before starting TCA treatments, the physician should ) and fluoxetine ( check for orthostatic hypotension and perform an ECG. No recommendations have yet been published with a view to preventing the side effects of TCAs. The ), in patients with fibromyalgia. In effects of combined treatment with tramadol should also these cases, the doses used were higher than or similar be monitored due to fre- to those used in depression ). Few quent co-utilization in rheumatological conditions.
studies have been carried out on the newer antidepres- SSRIs have been demonstrated to be well tolerated sants and the available studies had low quality scores and safe. The only reported side effects are abdominal in many cases. However it seems that although these symptoms at the start of the treatment, and serotoniner- drugs are better tolerated than tricyclic drugs at high gic syndrome. Side effects are reported in up to 80% of doses, their efficacy is limited ( patients treated for painful conditions ( Overall, TCAs appear to be the most effective antide- pressants for the management of pain and other symp- but are clinically relevant in a lower proportion (0– toms in fibromyalgia, even if a large placebo effect was 41%) ). This may account for the lower observed in many of these studies ( rate of treatment drop-outs with SSRIs than with TCAs A symptomatic effect on fibromy- algia is observed even at low doses in pain studies. In fibromyalgia, SSRIs SSRIs are better tolerated but less effective, making it are well tolerated, about as well as placebo ( necessary to increase the dose to obtain significant pain and are therefore more readily prescribed. Furthermore,no tests are required before starting SSRI treatment.
3.6.2. Low back pain Combination with tramadol is also not recommended.
Seven randomised, controlled trials of good quality have been published on this topic. Four reviews have 3.6. Use of antidepressants in patients with specific precisely examined the analgesic and functional effects of antidepressants in low back pain 3.6.1. Fibromyalgia syndrome ). The median quality score of We identified 47 studies on the use of antidepressants clinical papers was 11 (range: 6–15). Analysis of these in fibromyalgia, including 25 controlled trials, most of studies suggested that antidepressants were slightly more which involved tricyclic agents; and there were three effective than placebo for the relief of low back pain.
meta-analyses on this topic ( Antidepressant treatment also tended to improve func- tion and everyday activities, although this trend was quality scores for these papers was 14.5 (range: 8–24).
not statistically significant Despite their widespread use, tricyclic drugs have ). One study indicated that imipramine was only a moderate effect and only a minority of patients more effective than placebo, but only in terms of the display sustained, marked improvement ( ‘‘numbers of days had to lie down'' and ‘‘number of days with at least some restriction of normal activity'' showed that amitryptyline was better than pla- cebo, comparing the use of rescue analgesics in both treatment groups. Nortriptyline and maprotiline were S. Perrot et al. / European Journal of Pain 10 (2006) 185–192 significantly more effective than placebo, but nonethe- published guidelines on the treatment of chronic pain less had only moderate analgesic effects ( () we propose the following guidelines concerning the use of antidepressants in painful rheu- ). In conclusion, tricyclic and tetracyclic antidepres- matic conditions. The strength of the evidence support- sants appear to produce moderate symptom reductions ing each recommendation is indicated, from A to D for patients with chronic low back pain, independently of a patientÕs depression status. Selective serotonin reup-take inhibitors (SSRIs) do not appear to be beneficial.
1. Due to their analgesic and antidepressant proper- The effect of antidepressants on health-related quality ties, antidepressants can improve the symptoms of life, mood and functional status is unclear ( and quality of life of patients suffering from pain- ful chronic degenerative and inflammatory osteo-articular and spinal diseases. Their use should be 3.6.3. Osteoarthritis and inflammatory rheumatic diseases included in a global management programme We identified 15 randomised controlled trials on together with non-pharmacological approaches. A osteoarthritis (OA), rheumatoid arthritis (RA), and 2. Antidepressants, especially tricyclic drugs, are rec- ankylosing spondylitis (AS). Fourteen of these studies ommended as analgesics for fibromyalgia. They were placebo-controlled and one compared amitrypti- should not be first choice analgesic treatment in line with paroxetine. Only eight of these 15 trials were low back pain, osteoarthritis and inflammatory considered to meet the minimum standards in terms rheumatic painful diseases. A of methodological quality to demonstrate efficacy ( 3. To increase compliance, patients prescribed anti- depressants for analgesic use should be informed of the type of drug, its side effects, the aim of the treatment and the expected delay until the analge- studies scored from 13 to 22 on a scale with a maximum sic effects begin. D of 28 (median quality score: 16.4). In almost all these tri- 4. Antidepressants may be prescribed as analgesics in als, efficacy in the control of pain and symptoms was non-depressed patients. The first-choice treatment independent of the antidepressant effect (with the excep- should be a TCA, initiated at a low dose, which is then increased to the maximal tolerated dose which included depressed patients). Thus, ami- or to the minimal effective dose. A tryptyline, trimipramine, dothiepine and paroxetine 5. Newer antidepressants with mixed action or spe- may have analgesic effects in patients with RA, and ami- cific serotonin reuptake inhibitors should be tried tryptiline may be effective in reducing symptoms in AS.
only if TCAs prove to be ineffective, poorly toler- Analgesic effects of antidepressant were usually detected ated or if they are contraindicated. Another anti- after one week of treatment. Low doses of amitryptiline depressant (from the same class or another class) (10–30 mg daily) may be sufficient to provide an analge- can be tried after failure of the initial antidepres- sant treatment, regardless of whether this failure is related to a lack of efficacy or unbearable side None of the studies specifically dealt with OA; it is therefore difficult to determine whether antidepressants 6. The side effects of antidepressants used as analge- are beneficial for this condition. Some studies grouped sics are similar to those observed in the treatment together patients with OA, RA and AS, and reported of depression. They may be treated from treatment a small, but significant analgesic effect with TCAs and initiation and throughout the treatment period. A 7. If TCAs are prescribed to elderly patients, the phy- sician should monitor blood pressure, cognition In the study perfomed by in a large and intestinal transit. B and diverse population of older adults with arthritis 8. The assessment of treatment efficacy should not be (mostly osteoarthritis) and comorbid depression, bene- limited to pain evaluation. It should include func- fits of improved depression care extended beyond re- tional evaluation, analgesic consumption, sleep duced depressive symptoms and included decreased (quality and duration) evaluation, and psycho- pain as well as improved functional status and quality sociological assessment, and should be started after one week of treatment. A 9. There is no optimal duration of antidepressant 3.7. General guidelines for the use of antidepressants treatment. Antidepressant treatment should bemaintained for at least 4 weeks before being Based on the findings of the 75 studies analyzed, the stopped due to lack of efficacy. Total duration clinical experience of the expert panel, and previously should be determined with respect to the initial S. Perrot et al. / European Journal of Pain 10 (2006) 185–192 objectives, accepted by both the patients and the of antidepressants. Some clinicians have reported suc- physician, and after careful risk-benefit evaluation.
cessful treatment with SSRIs following the failure of tri- cyclics drugs, however no clinical studies have been 10. After 3 to 6 months of remission, the dose may be performed in this area. Further studies are needed to gradually decreased, with regular pain assess- investigate the role of plasma concentration, the influ- ments. Stopping the treatment too abruptly may ence of concomitant psychiatric disturbances, and the lead to nausea, vomiting and trembling. B type of organic lesions on the analgesic response to anti-depressant effects. Another field for future research is A = based on category 1 evidence; B = based on cat- the possibility of co-administering drugs to increase egory 2 evidence or extrapolated recommendation from the efficacy of antidepressants or to reduce their adverse category 1 evidence; C = based on category 3 evidence effects. Following the development of clinical guidelines or extrapolated recommendation from category 1 or 2 (we have planned to re- evidence; D: based on category 4 evidence or extrapo- vise these recommendations in a next future, to keep it lated from category 2 or 3 evidence ( relevant, according to most recent clinical findings, and mostly to both the patientÕs and physicianÕsexperience.
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