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European Journal of Pain 10 (2006) 185–192 www.EuropeanJournalPain.com 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 Ban
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  Guidelines for the use of antidepressants in painfulrheumatic conditions Serge Perrot  * , Emmanuel Maheu, Rose-Marie Javier, Alain Eschalier, Anne Coutaux,Manuela LeBars, Philippe Bertin, Bernard Bannwarth, Richard Tre`ves Cercle d   e´ tude de la douleur en rhumatologie, CEDR, Limoges, France Received 31 August 2004; accepted 11 March 2005Available online 18 April 2005 Abstract 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.   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 1. Introduction Pain is the main symptom of many rheumatic condi-tions, inflammatory conditions and degenerativediseases. In many cases, analgesics, non steroidal anti-inflammatory drugs (NSAIDs) or opioids control paineffectively. However, in some cases, additional treat-ments, such as antidepressants and anticonvulsants,are required (Curatolo and Bogduk, 2001; Sawynoket al., 2001; Watson and Peter, 1994). The prescriptionof antidepressants (Blier and Abbott, 2001; Brysonand Wilde, 1996; Eschalier et al., 1998) is increasingfor many conditions, including fibromyalgia, rheuma-toid arthritis, spondylarthropathies, low back pain andosteoarthritis. Although antidepressants have often beenshown to reduce pain, the results obtained are variable(Barkin and Fawcett, 2000; Lynch, 2001; Onghena and 1090-3801/$32   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 * Corresponding author. Address: centre de la Douleur, hoˆpitalCochin-Tarnier, 89 Rue d  Assas, 75006 Paris, France. Tel.: +33 1 58 4115 01; fax: +33 1 58 41 15 00. E-mail address:  serge.perrot@cch.ap-hop-paris.fr (S. Perrot).www.EuropeanJournalPain.comEuropean Journal of Pain 10 (2006) 185–192  Van Houdenhove, 1992; Zitman et al., 1992) and manyquestions remain unanswered (Egbunike and Chaffe,1990; Phillip and Fickinger, 1993; Sindrup et al.,1992). For example: Does the analgesic effect dependon the antidepressant effect? What is the optimal dose?When is such treatment appropriate? How long shouldtreatment be continued?Guidelines are therefore required concerning the useof these drugs. This document reviews the available evi-dence and then proposes a framework for the develop-ment of guidelines, without providing detailed adviceabout doses or formulations. It is designed to be a start-ing point for discussion and to be sufficiently flexible togain practical acceptance in different countries. It aimsto help prescribers (in primary care or specialist settings)to use antidepressants appropriately for the manage-ment of pain in rheumatic conditions. 2. Methods  2.1. The expert panel  This study was carried out by a working group of nine experts for the CEDR (Cercle d  Etude de la Doul-eur en Rhumatologie) a specific interest group of theFrench Society of Rheumatology that focuses on rheu-matic pain. Seven of the experts involved in this studywere rheumatologists, one of whom was also a pharma-cologist. The other members were a psychiatrist and aneurologist/pharmacologist.  2.2. Search strategy Relevant treatments and conditions were identifiedby the panel. We then searched the Medline, Embaseand Pascal databases for publications in several Euro-pean languages. Search terms used were: antidepressant,pain, rheumatoid arthritis, osteoarthritis, low back pain,fibromyalgia, fibrositis, rheumatic diseases, spond-ylarthropathy, ankylosing spondylarthritis, and sympa-thetic dystrophy. The search period covered 1966 toAugust 2002. Studies were scored using the EULARguidelines, from 0 to 28 (Pendleton et al., 2000), basedon a checklist. This checklist consists of 27 items distrib-uted between five sub-scales and was developed on thebasis of epidemiological principles, reviews of studydesigns, and existing checklists for the assessment of randomised controlled trials. This methodologicalchecklist provides a quality assessment of the reporting,external and internal validity and statistical power of each study. All studies are scored 0–1 for 26 questionsand 0–2 for one question, giving a maximum score of 28. Power calculations are scored as 1 if present and 0if absent.  2.3. Guideline development All potentially relevant papers were retrieved andtheir findings were analyzed by all members. The listof clinical questions used to define the scope of the liter-ature search was also used to structure the recommenda-tions together with another set of guidelines (on the useof opioids for the treatment of chronic pain) which hadbeen developed by a similar expert group, including oneof the CEDR panel members (Kalso et al., 2003). Sepa-rate sections were drafted by various participants usingthe evidence from the literature review whereverpossible.The draft recommendations were circulated amongthe authors for further review and critical evaluation.A Delphi approach was then employed to reach con-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 thecomments and criticisms of the nine panel members.The Delphi method is an exercise in group communi-cation among a panel of geographically dispersed ex-perts. It enables experts to deal systematically with acomplex problem or task. The essence of the tech-nique is fairly straightforward. It comprises a seriesof questionnaires sent by post or e-mail to a pre-selected group of experts. These questionnaires are de-signed to elicit and to develop individual responses tothe problems posed and to enable the experts to refinetheir views as the group  s work progresses in accor-dance with the assigned task. The Delphi methodmakes it possible to overcome the disadvantages of conventional committee action. The group interactionin Delphi is anonymous, in that the originator of comments, forecasts, and the like is not identified.These elements are presented to the group in such away as to suppress any identification. Here are theten steps for the Delphi method:1. Formation of a team to undertake and to monitora Delphi on a given subject.2. Selection of one or more panels to participate inthe exercise. Panel members are usually expertsin the area to be investigated.3. Development of the first-round Delphiquestionnaire.4. Testing the questionnaire for proper wording (e.g.,ambiguities, vagueness).5. Transmission of the first questionnaires to thepanelists.6. Analysis of the first-round responses.7. Preparation of the second-round questionnaires(and possible testing).8. Transmission of the second-round questionnairesto the panelists. 186  S. Perrot et al. / European Journal of Pain 10 (2006) 185–192  9. Analysis of the second-round responses (steps 7–9are reiterated as long as many times as required toachieve stable results).10. Preparation of a report by the analysis team topresent the conclusions of the exercise.The recommendations were then tested according theAGREE method (AGREE Collaboration, 1999) by twoindependent reviewers and the strength of the evidencesupporting each recommendation was indicated, fromA to D (Shekelle et al., 1999). The purpose of the Ap-praisal of Guidelines Research & Evaluation (AGREE)Instrument is to provide a framework for assessing thequality of clinical practice guidelines. The AGREEInstrument is designed to assess guidelines developedby local, regional, national or international groups.The AGREE Instrument is generic and can be appliedto guidelines in any disease area. The AGREE Instru-ment assesses both the quality of the reporting, andthe quality of some aspects of recommendations. It pro-vides an assessment of the predicted validity of a guide-line, the likelihood that it will achieve its intendedoutcome. It does not assess the impact of a guidelineon patients   outcomes. 3. Results We identified 137 relevant papers and, of these, se-lected 99 for detailed analysis: 77 were randomised con-trolled studies and 12 were meta-analyses or literaturereview. The results are summarised below. 3.1. Global review of analgesic effects of antidepressants3.1.1. Analgesic effect of antidepressants Analysis of 39 studies in various chronic naon-malig-nant painful conditions (Onghena and Van Houdenh-ove, 1992) found that antidepressants had an analgesiceffect, confirmed by Lynch in a meta-analysis of 59 stud-ies (Lynch, 2001). In neuropathic pain, the results areconvincing and have demonstrated differential analgesiceffects regarding the group of the drug: McQuay et al.(1996) and Sindrup and Jensen (1999) found that TCAs were more effective than serotonin-specific reuptakeinhibitors (SSRIs) in relieving neuropathic pain. Inglobal assessment of effects of antidepressants in chronicpain states, most of the authors have concluded that thetricyclic group of antidepressants is analgesic and thatdata regarding selective serotonin reuptake inhibitorsare conflicting (Lynch, 2001). A review of the use of antidepressants in pain management, including rheu-matic conditions (Smith, 1998) found little reason toreplace TCAs by SSRIs in pain management. In a otherreview comparing some of the newer antidepressantswith TCAs (Ansari, 2000), only paroxetine and citalo-pram were found to have a positive effect on neuro-pathic pain. Venlafaxine was recently shown to reduceneuropathic pain following chemotherapy for breastcancer (Tasmuth et al., 2002), and may also improvefibromyalgic patients (Sayar et al., 2003). But, exceptin neuropathic conditions and in fibromyalgia, there isno convincing study that really aimed to compare TCAswith SSRIs or other new antidepressants in specificchronic pain states and specifically rheumatological.For most of the authors antidepressant analgesic effectsare independent of their effects on mood (Magni, 1991). 3.2. Evaluation of the dose–response effect in chronic pain There is no clear evidence for a dose-dependent re-sponse to antidepressant treatment in terms of pain re-lief (McQuay et al., 1993). However, we identified nostudies that dealt specifically with rheumatic pain. Con-flicting data have been obtained concerning the possiblerelationship between concentration and analgesic effect,but current therapeutic plasma concentration rangesseem to give an acceptable response for TCAs. Severalstudies in which TCAs were administered for varioustypes of neuropathic pain reported a relationship be-tween serum drug concentration and analgesic effect(Furlanut et al., 1993; Sindrup et al., 1991). For thenewer antidepressants, also in neuropathic pain, somestudies suggested that plasma concentration and effectare correlated (e.g. for sertraline and paroxetine for neu-ropathic pain) and others reported no such correlation(e.g. for fluoxetine and citalopram for neuropathic pain)(see references in Ansari (2000)). 3.3. Onset of action in chronic pain The analgesic response seems to start before the anti-depressant response. An analgesic response is usuallyobserved within one week of starting treatment, whereasthe antidepressant response usually occurs after the firsttwo weeks (see references in Onghena and Van Hou-denhove (1992)). 3.4. Evaluation of different routes and patterns of administration The advantages of the various routes of administra-tion are unclear in humans. Due to a marked first-passeffect, oral bioavailability ranges from 20 to 80% (seereferences in Furlanut et al. (1993)) and genetic poly-morphism may also play a role in the pronounced phar-macokinetic variability observed with these drugs.Parenteral administration overcomes the problem of first-pass metabolism, and results in high plasma con-centrations. However, apart from a possible indicationin patients unable to swallow, the parenteral route seemsto have no other real advantage, despite reports that this S. Perrot et al. / European Journal of Pain 10 (2006) 185–192  187  route may accelerate the onset of the therapeutic effect(Pollock et al., 1986). 3.5. Antidepressants side effects Imipraminicdrugs,andTCAsinparticular,causesideeffect in 30–100% of patients treated for painful condi-tions (Eschalier et al., 1998; McQuay et al., 1993). Sideeffects are more frequent in fibromyalgia, occurring in70–95% of cases (Carette et al., 1986; Carette et al.,1994). Side effects parallel TCAs analgesic effects and,inmostcases,dependondose(McQuayetal.,1996).Ra-pid wash-out may lead to severe symptoms, such as nau-sea, vomiting, and trembling (Sindrup et al., 1992).Before starting TCA treatments, the physician shouldcheck for orthostatic hypotension and perform anECG. No recommendations have yet been publishedwith a view to preventing the side effects of TCAs. Theeffects of combined treatment with tramadol should alsobe monitored (Reus and Rawitscher, 2000), due to fre-quent co-utilization in rheumatological conditions.SSRIs have been demonstrated to be well toleratedand safe. The only reported side effects are abdominalsymptoms at the start of the treatment, and serotoniner-gic syndrome. Side effects are reported in up to 80% of patients treated for painful conditions (Bird and Brog-gini, 2000; Norregard et al., 1995; Wolfe et al., 1994)but are clinically relevant in a lower proportion (0– 41%) (Jung et al., 1997). This may account for the lowerrate of treatment drop-outs with SSRIs than with TCAs(Bird and Broggini, 2000; Sindrup et al., 1992; UshaRani et al., 1996) in pain studies. In fibromyalgia, SSRIsare well tolerated, about as well as placebo (Cantiniet al., 1994; Norregard et al., 1995; Wolfe et al., 1994),and are therefore more readily prescribed. Furthermore,no tests are required before starting SSRI treatment.Combination with tramadol is also not recommended. 3.6. Use of antidepressants in patients with specificrheumatological conditions3.6.1. Fibromyalgia syndrome We identified 47 studies on the use of antidepressantsin fibromyalgia, including 25 controlled trials, most of which involved tricyclic agents; and there were threemeta-analyses on this topic (Arnold et al., 2000; O  Mal-ley et al., 2000; White and Harth, 1996). The medianquality scores for these papers was 14.5 (range: 8–24).Despite their widespread use, tricyclic drugs haveonly a moderate effect and only a minority of patientsdisplay sustained, marked improvement (Bennett et al.,1988; Bibolotti et al., 1986; Cantini et al., 1994; Carusoet al., 1987; Fossaluzza and De Vita, 1992; Goldenberget al., 1986, 1996; Hamaty et al., 1989; Hannonen et al.,1998; Heymann et al., 2001; Jaeschke et al., 1991; Qui-mby et al., 1989; Reynolds et al., 1991; Scudds et al.,1989; Simms et al., 1991). A major placebo effect wasidentified in fibromyalgia studies, and antidepressantshave not been shown to have a lasting effect.Amitriptyline is the most widely used drug for whichan effect on pain, fatigue, sleep and general conditionshas been demonstrated (Carette et al., 1986; Goldenberget al., 1986, 1996). Amitriptyline and cyclobenzaprinehave a greater effect on sleep disorders and fatigue thanon pain (Carette et al., 1994). Most of the studies re-ported the use of tricyclic drugs at doses lower thanthose used to treat depression, probably due to the sideeffects of these drugs.Recent studies have assessed the effects of newer anti-depressants, such as citalopram (Andenberg et al., 2000;Norregard et al., 1995) and fluoxetine (Arnold et al.,2002; Cortet et al., 1992; Geller, 1989; Wolfe et al.,1994) or others (Dwight et al., 1998; Olin et al., 1998;Sayar et al., 2003), in patients with fibromyalgia. Inthese cases, the doses used were higher than or similarto those used in depression (Simms et al., 1991). Fewstudies have been carried out on the newer antidepres-sants and the available studies had low quality scoresin many cases. However it seems that although thesedrugs are better tolerated than tricyclic drugs at highdoses, their efficacy is limited (Arnold et al., 2002).Overall, TCAs appear to be the most effective antide-pressants for the management of pain and other symp-toms in fibromyalgia, even if a large placebo effect wasobserved in many of these studies (Heymann et al.,2001; Lawson, 2002). A symptomatic effect on fibromy-algia is observed even at low doses (Ataoglu et al., 1997).SSRIs are better tolerated but less effective, making itnecessary to increase the dose to obtain significant painrelief. 3.6.2. Low back pain Seven randomised, controlled trials of good qualityhave been published on this topic. Four reviews haveprecisely examined the analgesic and functional effectsof antidepressants in low back pain (Salerno et al.,2002; Staiger et al., 2003; Turner and Denny, 1993;van Tulder et al., 1997). The median quality score of clinical papers was 11 (range: 6–15). Analysis of thesestudies suggested that antidepressants were slightly moreeffective than placebo for the relief of low back pain.Antidepressant treatment also tended to improve func-tion and everyday activities, although this trend wasnot statistically significant (Jenkins et al., 1976; Tre`veset al., 1991). One study indicated that imipramine wasmore effective than placebo, but only in terms of the‘‘numbers of days had to lie down’’ and ‘‘number of days with at least some restriction of normal activity’’(Alcoff et al., 1982). Another study (Pheasant et al., 1983) showed that amitryptyline was better than pla-cebo, comparing the use of rescue analgesics in bothtreatment groups. Nortriptyline and maprotiline were 188  S. Perrot et al. / European Journal of Pain 10 (2006) 185–192
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