European Journal of Pain 10 (2006) 185192 www.EuropeanJournalPain.

com

Guidelines for the use of antidepressants in painful rheumatic conditions

Serge Perrot *, Emmanuel Maheu, Rose-Marie Javier, Alain Eschalier, Anne Coutaux, ` ves Manuela LeBars, Philippe Bertin, Bernard Bannwarth, Richard Tre
tude de la douleur en rhumatologie, CEDR, Limoges, France Cercle de Received 31 August 2004; accepted 11 March 2005 Available 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 published data and expert opinion. Method: We identied relevant drugs and conditions and searched Medline, Embase and Pascal (19662003) for relevant publications in a number of European languages. We scored each study for quality, and used an expert consensus approach to formulate recommendations. Results: We identied 77 studies and 12 meta-analyses and literature review on the use of antidepressant to treat painful rheumatological conditions. Forty-nine of these clinical studies were considered valid and were used to develop the recommendations. When evidence was lacking we based recommendations on our clinical experience. Conclusions: These recommendations for the treatment of painful rheumatological conditions with antidepressants were developed using evidence-based and expert consensus approaches and are the rst of their kind in this eld. Our review of the literature highlights the need for further, well-designed clinical studies of the use of antidepressants to treat painful rheumatological conditions. 2005 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved.
Keywords: Pain; Musculoskeletal; Antidepressants; Treatment; Recommendations

1. Introduction Pain is the main symptom of many rheumatic conditions, inammatory conditions and degenerative diseases. In many cases, analgesics, non steroidal antiinammatory drugs (NSAIDs) or opioids control pain
pital Corresponding author. Address: centre de la Douleur, ho Cochin-Tarnier, 89 Rue dAssas, 75006 Paris, France. Tel.: +33 1 58 41 15 01; fax: +33 1 58 41 15 00. E-mail address: serge.perrot@cch.ap-hop-paris.fr (S. Perrot).
*

eectively. However, in some cases, additional treatments, such as antidepressants and anticonvulsants, are required (Curatolo and Bogduk, 2001; Sawynok et al., 2001; Watson and Peter, 1994). The prescription of antidepressants (Blier and Abbott, 2001; Bryson and Wilde, 1996; Eschalier et al., 1998) is increasing for many conditions, including bromyalgia, rheumatoid arthritis, spondylarthropathies, low back pain and osteoarthritis. Although antidepressants have often been shown 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 rights reserved. doi:10.1016/j.ejpain.2005.03.004

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Van Houdenhove, 1992; Zitman et al., 1992) and many questions remain unanswered (Egbunike and Chae, 1990; Phillip and Fickinger, 1993; Sindrup et al., 1992). For example: Does the analgesic eect depend on the antidepressant eect? What is the optimal dose? When is such treatment appropriate? How long should treatment be continued? Guidelines are therefore required concerning the use of these drugs. This document reviews the available evidence and then proposes a framework for the development of guidelines, without providing detailed advice about doses or formulations. It is designed to be a starting point for discussion and to be suciently exible to gain practical acceptance in dierent countries. It aims to help prescribers (in primary care or specialist settings) to use antidepressants appropriately for the management of pain in rheumatic conditions.

2.3. Guideline development All potentially relevant papers were retrieved and their ndings were analyzed by all members. The list of clinical questions used to dene the scope of the literature search was also used to structure the recommendations together with another set of guidelines (on the use of opioids for the treatment of chronic pain) which had been developed by a similar expert group, including one of the CEDR panel members (Kalso et al., 2003). Separate sections were drafted by various participants using the evidence from the literature review wherever possible. The draft recommendations were circulated among the authors for further review and critical evaluation. A Delphi approach was then employed to reach consensus and all the recommendations were collated and sent back to the experts, who were asked to rank the 10 most important proposals. A nal draft of the recommendations was generated, taking into account the comments and criticisms of the nine panel members. The Delphi method is an exercise in group communication among a panel of geographically dispersed experts. It enables experts to deal systematically with a complex problem or task. The essence of the technique is fairly straightforward. It comprises a series of questionnaires sent by post or e-mail to a preselected group of experts. These questionnaires are designed to elicit and to develop individual responses to the problems posed and to enable the experts to rene their views as the groups work progresses in accordance with the assigned task. The Delphi method makes it possible to overcome the disadvantages of conventional committee action. The group interaction in Delphi is anonymous, in that the originator of comments, forecasts, and the like is not identied. These elements are presented to the group in such a way as to suppress any identication. Here are the ten steps for the Delphi method: 1. Formation of a team to undertake and to monitor a Delphi on a given subject. 2. Selection of one or more panels to participate in the exercise. Panel members are usually experts in the area to be investigated. 3. Development of the rst-round Delphi questionnaire. 4. Testing the questionnaire for proper wording (e.g., ambiguities, vagueness). 5. Transmission of the rst questionnaires to the panelists. 6. Analysis of the rst-round responses. 7. Preparation of the second-round questionnaires (and possible testing). 8. Transmission of the second-round questionnaires to the panelists.

2. Methods 2.1. The expert panel This study was carried out by a working group of nine experts for the CEDR (Cercle dEtude de la Douleur en Rhumatologie) a specic interest group of the French Society of Rheumatology that focuses on rheumatic pain. Seven of the experts involved in this study were rheumatologists, one of whom was also a pharmacologist. The other members were a psychiatrist and a neurologist/pharmacologist. 2.2. Search strategy Relevant treatments and conditions were identied by the panel. We then searched the Medline, Embase and Pascal databases for publications in several European languages. Search terms used were: antidepressant, pain, rheumatoid arthritis, osteoarthritis, low back pain, bromyalgia, brositis, rheumatic diseases, spondylarthropathy, ankylosing spondylarthritis, and sympathetic dystrophy. The search period covered 1966 to August 2002. Studies were scored using the EULAR guidelines, from 0 to 28 (Pendleton et al., 2000), based on a checklist. This checklist consists of 27 items distributed between ve sub-scales and was developed on the basis of epidemiological principles, reviews of study designs, and existing checklists for the assessment of randomised controlled trials. This methodological checklist provides a quality assessment of the reporting, external and internal validity and statistical power of each study. All studies are scored 01 for 26 questions and 02 for one question, giving a maximum score of 28. Power calculations are scored as 1 if present and 0 if absent.

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9. Analysis of the second-round responses (steps 79 are reiterated as long as many times as required to achieve stable results). 10. Preparation of a report by the analysis team to present the conclusions of the exercise. The recommendations were then tested according the AGREE method (AGREE Collaboration, 1999) by two independent reviewers and the strength of the evidence supporting each recommendation was indicated, from A to D (Shekelle et al., 1999). The purpose of the Appraisal of Guidelines Research & Evaluation (AGREE) Instrument is to provide a framework for assessing the quality of clinical practice guidelines. The AGREE Instrument is designed to assess guidelines developed by local, regional, national or international groups. The AGREE Instrument is generic and can be applied to guidelines in any disease area. The AGREE Instrument assesses both the quality of the reporting, and the quality of some aspects of recommendations. It provides an assessment of the predicted validity of a guideline, the likelihood that it will achieve its intended outcome. It does not assess the impact of a guideline on patients outcomes.

pram were found to have a positive eect on neuropathic pain. Venlafaxine was recently shown to reduce neuropathic pain following chemotherapy for breast cancer (Tasmuth et al., 2002), and may also improve bromyalgic patients (Sayar et al., 2003). But, except in neuropathic conditions and in bromyalgia, there is no convincing study that really aimed to compare TCAs with SSRIs or other new antidepressants in specic chronic pain states and specically rheumatological. For most of the authors antidepressant analgesic eects are independent of their eects on mood (Magni, 1991). 3.2. Evaluation of the doseresponse eect in chronic pain There is no clear evidence for a dose-dependent response to antidepressant treatment in terms of pain relief (McQuay et al., 1993). However, we identied no studies that dealt specically with rheumatic pain. Conicting data have been obtained concerning the possible relationship between concentration and analgesic eect, 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 neuropathic pain reported a relationship between serum drug concentration and analgesic eect (Furlanut et al., 1993; Sindrup et al., 1991). For the newer antidepressants, also in neuropathic pain, some studies suggested that plasma concentration and eect are correlated (e.g. for sertraline and paroxetine for neuropathic pain) and others reported no such correlation (e.g. for uoxetine 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 antidepressant response. An analgesic response is usually observed within one week of starting treatment, whereas the antidepressant response usually occurs after the rst two weeks (see references in Onghena and Van Houdenhove (1992)). 3.4. Evaluation of dierent routes and patterns of administration The advantages of the various routes of administration are unclear in humans. Due to a marked rst-pass eect, oral bioavailability ranges from 20 to 80% (see references in Furlanut et al. (1993)) and genetic polymorphism may also play a role in the pronounced pharmacokinetic variability observed with these drugs. Parenteral administration overcomes the problem of rst-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

3. Results We identied 137 relevant papers and, of these, selected 99 for detailed analysis: 77 were randomised controlled studies and 12 were meta-analyses or literature review. The results are summarised below. 3.1. Global review of analgesic eects of antidepressants 3.1.1. Analgesic eect of antidepressants Analysis of 39 studies in various chronic naon-malignant painful conditions (Onghena and Van Houdenhove, 1992) found that antidepressants had an analgesic eect, conrmed by Lynch in a meta-analysis of 59 studies (Lynch, 2001). In neuropathic pain, the results are convincing and have demonstrated dierential analgesic eects regarding the group of the drug: McQuay et al. (1996) and Sindrup and Jensen (1999) found that TCAs were more eective than serotonin-specic reuptake inhibitors (SSRIs) in relieving neuropathic pain. In global assessment of eects of antidepressants in chronic pain states, most of the authors have concluded that the tricyclic group of antidepressants is analgesic and that data regarding selective serotonin reuptake inhibitors are conicting (Lynch, 2001). A review of the use of antidepressants in pain management, including rheumatic conditions (Smith, 1998) found little reason to replace TCAs by SSRIs in pain management. In a other review comparing some of the newer antidepressants with TCAs (Ansari, 2000), only paroxetine and citalo-

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route may accelerate the onset of the therapeutic eect (Pollock et al., 1986). 3.5. Antidepressants side eects Imipraminic drugs, and TCAs in particular, cause side eect in 30100% of patients treated for painful conditions (Eschalier et al., 1998; McQuay et al., 1993). Side eects are more frequent in bromyalgia, occurring in 7095% of cases (Carette et al., 1986; Carette et al., 1994). Side eects parallel TCAs analgesic eects and, in most cases, depend on dose (McQuay et al., 1996). Rapid wash-out may lead to severe symptoms, such as nausea, vomiting, and trembling (Sindrup et al., 1992). Before starting TCA treatments, the physician should check for orthostatic hypotension and perform an ECG. No recommendations have yet been published with a view to preventing the side eects of TCAs. The eects of combined treatment with tramadol should also be monitored (Reus and Rawitscher, 2000), due to frequent co-utilization in rheumatological conditions. SSRIs have been demonstrated to be well tolerated and safe. The only reported side eects are abdominal symptoms at the start of the treatment, and serotoninergic syndrome. Side eects are reported in up to 80% of patients treated for painful conditions (Bird and Broggini, 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 lower rate of treatment drop-outs with SSRIs than with TCAs (Bird and Broggini, 2000; Sindrup et al., 1992; Usha Rani et al., 1996) in pain studies. In bromyalgia, SSRIs are well tolerated, about as well as placebo (Cantini et 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 specic rheumatological conditions 3.6.1. Fibromyalgia syndrome We identied 47 studies on the use of antidepressants in bromyalgia, including 25 controlled trials, most of which involved tricyclic agents; and there were three meta-analyses on this topic (Arnold et al., 2000; OMalley et al., 2000; White and Harth, 1996). The median quality scores for these papers was 14.5 (range: 824). Despite their widespread use, tricyclic drugs have only a moderate eect and only a minority of patients display sustained, marked improvement (Bennett et al., 1988; Bibolotti et al., 1986; Cantini et al., 1994; Caruso et al., 1987; Fossaluzza and De Vita, 1992; Goldenberg et al., 1986, 1996; Hamaty et al., 1989; Hannonen et al., 1998; Heymann et al., 2001; Jaeschke et al., 1991; Quimby et al., 1989; Reynolds et al., 1991; Scudds et al.,

1989; Simms et al., 1991). A major placebo eect was identied in bromyalgia studies, and antidepressants have not been shown to have a lasting eect. Amitriptyline is the most widely used drug for which an eect on pain, fatigue, sleep and general conditions has been demonstrated (Carette et al., 1986; Goldenberg et al., 1986, 1996). Amitriptyline and cyclobenzaprine have a greater eect on sleep disorders and fatigue than on pain (Carette et al., 1994). Most of the studies reported the use of tricyclic drugs at doses lower than those used to treat depression, probably due to the side eects of these drugs. Recent studies have assessed the eects of newer antidepressants, such as citalopram (Andenberg et al., 2000; Norregard et al., 1995) and uoxetine (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 bromyalgia. In these cases, the doses used were higher than or similar to those used in depression (Simms et al., 1991). Few studies have been carried out on the newer antidepressants and the available studies had low quality scores in many cases. However it seems that although these drugs are better tolerated than tricyclic drugs at high doses, their ecacy is limited (Arnold et al., 2002). Overall, TCAs appear to be the most eective antidepressants for the management of pain and other symptoms in bromyalgia, even if a large placebo eect was observed in many of these studies (Heymann et al., 2001; Lawson, 2002). A symptomatic eect on bromyalgia is observed even at low doses (Ataoglu et al., 1997). SSRIs are better tolerated but less eective, making it necessary to increase the dose to obtain signicant pain relief. 3.6.2. Low back pain Seven randomised, controlled trials of good quality have been published on this topic. Four reviews have precisely examined the analgesic and functional eects of 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: 615). Analysis of these studies suggested that antidepressants were slightly more eective than placebo for the relief of low back pain. Antidepressant treatment also tended to improve function and everyday activities, although this trend was ` ves not statistically signicant (Jenkins et al., 1976; Tre et al., 1991). One study indicated that imipramine was more eective 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 (Alco et al., 1982). Another study (Pheasant et al., 1983) showed that amitryptyline was better than placebo, comparing the use of rescue analgesics in both treatment groups. Nortriptyline and maprotiline were

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signicantly more eective than placebo, but nonetheless had only moderate analgesic eects (Atkinson et al., 1998; Atkinson et al., 1999; Dickens et al., 2000). In conclusion, tricyclic and tetracyclic antidepressants appear to produce moderate symptom reductions for patients with chronic low back pain, independently of a patients depression status. Selective serotonin reuptake inhibitors (SSRIs) do not appear to be benecial. The eect of antidepressants on health-related quality of life, mood and functional status is unclear (Staiger et al., 2003; Ward, 1986). 3.6.3. Osteoarthritis and inammatory rheumatic diseases We identied 15 randomised controlled trials on osteoarthritis (OA), rheumatoid arthritis (RA), and ankylosing spondylitis (AS). Fourteen of these studies were placebo-controlled and one compared amitryptiline with paroxetine. Only eight of these 15 trials were considered to meet the minimum standards in terms of methodological quality to demonstrate ecacy (Ash et al., 1999; Bird and Broggini, 2000; Frank et al., 1988; Ganvir et al., 1980; Grace et al., 1985; Koh et al., 1997; Macfarlane et al., 1986; Parker et al., 2003).These studies scored from 13 to 22 on a scale with a maximum of 28 (median quality score: 16.4). In almost all these trials, ecacy in the control of pain and symptoms was independent of the antidepressant eect (with the exception of Parker et al. (2003) and Sarzi Puttini et al. (1988)), which included depressed patients). Thus, amitryptyline, trimipramine, dothiepine and paroxetine may have analgesic eects in patients with RA, and amitryptiline may be eective in reducing symptoms in AS. Analgesic eects of antidepressant were usually detected after one week of treatment. Low doses of amitryptiline (1030 mg daily) may be sucient to provide an analgesic eect (Fowler et al., 1977; Hood et al., 2001; MacNeill and Dick, 1976; McQuay et al., 1992). None of the studies specically dealt with OA; it is therefore dicult to determine whether antidepressants are benecial for this condition. Some studies grouped together patients with OA, RA and AS, and reported a small, but signicant analgesic eect with TCAs and SSRIs (Gringras, 1976; McDonald Scott, 1969; Thorpe and Marchant-Williams, 1974; Usha Rani et al., 1996). In the study perfomed by Lin et al. (2003) in a large and diverse population of older adults with arthritis (mostly osteoarthritis) and comorbid depression, benets of improved depression care extended beyond reduced depressive symptoms and included decreased pain as well as improved functional status and quality of life. 3.7. General guidelines for the use of antidepressants Based on the ndings of the 75 studies analyzed, the clinical experience of the expert panel, and previously

published guidelines on the treatment of chronic pain (Kalso et al., 2003) we propose the following guidelines concerning the use of antidepressants in painful rheumatic conditions. The strength of the evidence supporting each recommendation is indicated, from A to D (Shekelle et al., 1999). 1. Due to their analgesic and antidepressant properties, antidepressants can improve the symptoms and quality of life of patients suering from painful chronic degenerative and inammatory osteoarticular and spinal diseases. Their use should be included in a global management programme together with non-pharmacological approaches. A 2. Antidepressants, especially tricyclic drugs, are recommended as analgesics for bromyalgia. They should not be rst choice analgesic treatment in low back pain, osteoarthritis and inammatory rheumatic painful diseases. A 3. To increase compliance, patients prescribed antidepressants for analgesic use should be informed of the type of drug, its side eects, the aim of the treatment and the expected delay until the analgesic eects begin. D 4. Antidepressants may be prescribed as analgesics in non-depressed patients. The rst-choice treatment should be a TCA, initiated at a low dose, which is then increased to the maximal tolerated dose or to the minimal eective dose. A 5. Newer antidepressants with mixed action or specic serotonin reuptake inhibitors should be tried only if TCAs prove to be ineective, poorly tolerated or if they are contraindicated. Another antidepressant (from the same class or another class) can be tried after failure of the initial antidepressant treatment, regardless of whether this failure is related to a lack of ecacy or unbearable side eects. C 6. The side eects of antidepressants used as analgesics are similar to those observed in the treatment of depression. They may be treated from treatment initiation and throughout the treatment period. A 7. If TCAs are prescribed to elderly patients, the physician should monitor blood pressure, cognition and intestinal transit. B 8. The assessment of treatment ecacy should not be limited to pain evaluation. It should include functional evaluation, analgesic consumption, sleep (quality and duration) evaluation, and psychosociological assessment, and should be started after one week of treatment. A 9. There is no optimal duration of antidepressant treatment. Antidepressant treatment should be maintained for at least 4 weeks before being stopped due to lack of ecacy. Total duration should be determined with respect to the initial

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objectives, accepted by both the patients and the physician, and after careful risk-benet evaluation. D 10. After 3 to 6 months of remission, the dose may be gradually decreased, with regular pain assessments. Stopping the treatment too abruptly may lead to nausea, vomiting and trembling. B A = based on category 1 evidence; B = based on category 2 evidence or extrapolated recommendation from category 1 evidence; C = based on category 3 evidence or extrapolated recommendation from category 1 or 2 evidence; D: based on category 4 evidence or extrapolated from category 2 or 3 evidence (Shekelle et al., 1999).

of antidepressants. Some clinicians have reported successful treatment with SSRIs following the failure of tricyclics drugs, however no clinical studies have been performed in this area. Further studies are needed to investigate the role of plasma concentration, the inuence of concomitant psychiatric disturbances, and the type of organic lesions on the analgesic response to antidepressant eects. Another eld for future research is the possibility of co-administering drugs to increase the ecacy of antidepressants or to reduce their adverse eects. Following the development of clinical guidelines (AGREE Collaboration, 1999), we have planned to revise these recommendations in a next future, to keep it relevant, according to most recent clinical ndings, and mostly to both the patients and physicians experience.

4. Conclusions References Guidelines should be based on available evidence and this was the goal of this expert group. However, we soon realised that little or no evidence was available for many of the key issues, because of the paucity of appropriate clinical studies and as clinical studies does not reect the real clinical situations, e.g. and long-term utilization in painful chronic situations. The published studies provide little information useful to determine which individuals respond to antidepressants with analgesic eects. More studies have focused on bromyalgia than on other conditions, but although there is a trend towards the use antidepressants in bromyalgia, no clear analgesic eects have been demonstrated in this situation. The results of studies on osteoarthritis, low back pain and rheumatoid arthritis are not very convincing. There has also been no comparative study of patients with different, specic rheumatological conditions. It is also not yet possible to determine which type of pain will respond most strongly to treatment with antidepressants. Furthermore, it is not possible to dene predictive factors for analgesic eects: psychological status does not predict analgesic eect and antidepressants do not exhibit more powerful analgesic eects in depressed patients. These recommendations have been tested by two independent reviewers, according the AGREE method (AGREE Collaboration, 1999), specically dedicated for the assessment of clinical guidelines. Global assessment was good, and specic assessments of each the 6 domains were rated with scores ranging from 53% to 100%, thus allowing the spreading of these recommendations. These recommendations also gave us the opportunity to dene research guidelines. The responsiveness of many chronic pain conditions, especially rheumatological, to antidepressants has not been assessed in controlled settings and we know very little about the long-term (months to years) ecacy and adverse eects
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