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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,
Manuela LeBars, Philippe Bertin, Bernard Bannwarth, Richard Tre`ves
Cercle detude de la douleur en rhumatologie, CEDR, Limoges, France

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 publica-
tions 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 rheuma-
tological 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 devel-
oped 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 eectively. However, in some cases, additional treat-


ments, such as antidepressants and anticonvulsants,
Pain is the main symptom of many rheumatic condi- are required (Curatolo and Bogduk, 2001; Sawynok
tions, inammatory conditions and degenerative et al., 2001; Watson and Peter, 1994). The prescription
diseases. In many cases, analgesics, non steroidal anti- of antidepressants (Blier and Abbott, 2001; Bryson
inammatory drugs (NSAIDs) or opioids control pain and Wilde, 1996; Eschalier et al., 1998) is increasing
for many conditions, including bromyalgia, rheuma-
*
toid arthritis, spondylarthropathies, low back pain and
Corresponding author. Address: centre de la Douleur, hopital
Cochin-Tarnier, 89 Rue dAssas, 75006 Paris, France. Tel.: +33 1 58 41
osteoarthritis. Although antidepressants have often been
15 01; fax: +33 1 58 41 15 00. shown to reduce pain, the results obtained are variable
E-mail address: serge.perrot@cch.ap-hop-paris.fr (S. Perrot). (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
186 S. Perrot et al. / European Journal of Pain 10 (2006) 185192

Van Houdenhove, 1992; Zitman et al., 1992) and many 2.3. Guideline development
questions remain unanswered (Egbunike and Chae,
1990; Phillip and Fickinger, 1993; Sindrup et al., All potentially relevant papers were retrieved and
1992). For example: Does the analgesic eect depend their ndings were analyzed by all members. The list
on the antidepressant eect? What is the optimal dose? of clinical questions used to dene 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 (Kalso et al., 2003). 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 suciently exible to possible.
gain practical acceptance in dierent 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 and
sent back to the experts, who were asked to rank the
10 most important proposals. A nal draft of the rec-
ommendations was generated, taking into account the
2. Methods
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 dEtude de la Doul-
nique is fairly straightforward. It comprises a series
eur en Rhumatologie) a specic 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 rene
cologist. The other members were a psychiatrist and a
their views as the groups work progresses in accor-
neurologist/pharmacologist.
dance with the assigned task. The Delphi method
makes it possible to overcome the disadvantages of
2.2. Search strategy conventional committee action. The group interaction
in Delphi is anonymous, in that the originator of
Relevant treatments and conditions were identied comments, forecasts, and the like is not identied.
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 identication. Here are the
pean languages. Search terms used were: antidepressant, ten steps for the Delphi method:
pain, rheumatoid arthritis, osteoarthritis, low back pain,
bromyalgia, brositis, 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 (Pendleton et al., 2000), based in the area to be investigated.
on a checklist. This checklist consists of 27 items distrib- 3. Development of the rst-round Delphi
uted between ve sub-scales and was developed on the questionnaire.
basis of epidemiological principles, reviews of study 4. Testing the questionnaire for proper wording (e.g.,
designs, and existing checklists for the assessment of ambiguities, vagueness).
randomised controlled trials. This methodological 5. Transmission of the rst questionnaires to the
checklist provides a quality assessment of the reporting, panelists.
external and internal validity and statistical power of 6. Analysis of the rst-round responses.
each study. All studies are scored 01 for 26 questions 7. Preparation of the second-round questionnaires
and 02 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
if absent. to the panelists.
S. Perrot et al. / European Journal of Pain 10 (2006) 185192 187

9. Analysis of the second-round responses (steps 79 pram were found to have a positive eect 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 (Tasmuth et al., 2002), and may also improve
present the conclusions of the exercise. bromyalgic patients (Sayar et al., 2003). But, except
in neuropathic conditions and in bromyalgia, there is
The recommendations were then tested according the no convincing study that really aimed to compare TCAs
AGREE method (AGREE Collaboration, 1999) by two with SSRIs or other new antidepressants in specic
independent reviewers and the strength of the evidence chronic pain states and specically rheumatological.
supporting each recommendation was indicated, from For most of the authors antidepressant analgesic eects
A to D (Shekelle et al., 1999). The purpose of the Ap- are independent of their eects on mood (Magni, 1991).
praisal of Guidelines Research & Evaluation (AGREE)
Instrument is to provide a framework for assessing the 3.2. Evaluation of the doseresponse eect in chronic pain
quality of clinical practice guidelines. The AGREE
Instrument 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 (McQuay et al., 1993). However, we identied no
to guidelines in any disease area. The AGREE Instru- studies that dealt specically with rheumatic pain. Con-
ment assesses both the quality of the reporting, and icting data have been obtained concerning the possible
the quality of some aspects of recommendations. It pro- relationship between concentration and analgesic eect,
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 patients outcomes. types of neuropathic pain reported a relationship be-
tween serum drug concentration and analgesic eect
(Furlanut et al., 1993; Sindrup et al., 1991). For the
3. Results newer antidepressants, also in neuropathic pain, some
studies suggested that plasma concentration and eect
We identied 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 uoxetine and citalopram for neuropathic pain)
review. The results are summarised below. (see references in Ansari (2000)).

3.1. Global review of analgesic eects of antidepressants 3.3. Onset of action in chronic pain

3.1.1. Analgesic eect 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 (Onghena and Van Houdenh- observed within one week of starting treatment, whereas
ove, 1992) found that antidepressants had an analgesic the antidepressant response usually occurs after the rst
eect, conrmed by Lynch in a meta-analysis of 59 stud- two weeks (see references in Onghena and Van Hou-
ies (Lynch, 2001). In neuropathic pain, the results are denhove (1992)).
convincing and have demonstrated dierential analgesic
eects regarding the group of the drug: McQuay et al. 3.4. Evaluation of dierent routes and patterns of
(1996) and Sindrup and Jensen (1999) found that TCAs administration
were more eective than serotonin-specic reuptake
inhibitors (SSRIs) in relieving neuropathic pain. In The advantages of the various routes of administra-
global assessment of eects of antidepressants in chronic tion are unclear in humans. Due to a marked rst-pass
pain states, most of the authors have concluded that the eect, oral bioavailability ranges from 20 to 80% (see
tricyclic group of antidepressants is analgesic and that references in Furlanut et al. (1993)) and genetic poly-
data regarding selective serotonin reuptake inhibitors morphism may also play a role in the pronounced phar-
are conicting (Lynch, 2001). 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 (Smith, 1998) found little reason to rst-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 (Ansari, 2000), only paroxetine and citalo- to have no other real advantage, despite reports that this
188 S. Perrot et al. / European Journal of Pain 10 (2006) 185192

route may accelerate the onset of the therapeutic eect 1989; Simms et al., 1991). A major placebo eect was
(Pollock et al., 1986). identied in bromyalgia studies, and antidepressants
have not been shown to have a lasting eect.
3.5. Antidepressants side eects Amitriptyline is the most widely used drug for which
an eect on pain, fatigue, sleep and general conditions
Imipraminic drugs, and TCAs in particular, cause side has been demonstrated (Carette et al., 1986; Goldenberg
eect in 30100% of patients treated for painful condi- et al., 1986, 1996). Amitriptyline and cyclobenzaprine
tions (Eschalier et al., 1998; McQuay et al., 1993). Side have a greater eect on sleep disorders and fatigue than
eects are more frequent in bromyalgia, occurring in on pain (Carette et al., 1994). Most of the studies re-
7095% of cases (Carette et al., 1986; Carette et al., ported the use of tricyclic drugs at doses lower than
1994). Side eects parallel TCAs analgesic eects and, those used to treat depression, probably due to the side
in most cases, depend on dose (McQuay et al., 1996). Ra- eects of these drugs.
pid wash-out may lead to severe symptoms, such as nau- Recent studies have assessed the eects of newer anti-
sea, vomiting, and trembling (Sindrup et al., 1992). depressants, such as citalopram (Andenberg et al., 2000;
Before starting TCA treatments, the physician should Norregard et al., 1995) and uoxetine (Arnold et al.,
check for orthostatic hypotension and perform an 2002; Cortet et al., 1992; Geller, 1989; Wolfe et al.,
ECG. No recommendations have yet been published 1994) or others (Dwight et al., 1998; Olin et al., 1998;
with a view to preventing the side eects of TCAs. The Sayar et al., 2003), in patients with bromyalgia. In
eects of combined treatment with tramadol should also these cases, the doses used were higher than or similar
be monitored (Reus and Rawitscher, 2000), due to fre- to those used in depression (Simms et al., 1991). 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 eects 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 eects are reported in up to 80% of doses, their ecacy is limited (Arnold et al., 2002).
patients treated for painful conditions (Bird and Brog- Overall, TCAs appear to be the most eective antide-
gini, 2000; Norregard et al., 1995; Wolfe et al., 1994) pressants for the management of pain and other symp-
but are clinically relevant in a lower proportion (0 toms in bromyalgia, even if a large placebo eect was
41%) (Jung et al., 1997). This may account for the lower observed in many of these studies (Heymann et al.,
rate of treatment drop-outs with SSRIs than with TCAs 2001; Lawson, 2002). A symptomatic eect on bromy-
(Bird and Broggini, 2000; Sindrup et al., 1992; Usha algia is observed even at low doses (Ataoglu et al., 1997).
Rani et al., 1996) in pain studies. In bromyalgia, SSRIs SSRIs are better tolerated but less eective, making it
are well tolerated, about as well as placebo (Cantini necessary to increase the dose to obtain signicant pain
et al., 1994; Norregard et al., 1995; Wolfe et al., 1994), relief.
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 specic precisely examined the analgesic and functional eects
rheumatological conditions of antidepressants in low back pain (Salerno et al.,
2002; Staiger et al., 2003; Turner and Denny, 1993;
3.6.1. Fibromyalgia syndrome van Tulder et al., 1997). The median quality score of
We identied 47 studies on the use of antidepressants clinical papers was 11 (range: 615). Analysis of these
in bromyalgia, including 25 controlled trials, most of studies suggested that antidepressants were slightly more
which involved tricyclic agents; and there were three eective than placebo for the relief of low back pain.
meta-analyses on this topic (Arnold et al., 2000; OMal- Antidepressant treatment also tended to improve func-
ley et al., 2000; White and Harth, 1996). The median tion and everyday activities, although this trend was
quality scores for these papers was 14.5 (range: 824). not statistically signicant (Jenkins et al., 1976; Tre`ves
Despite their widespread use, tricyclic drugs have et al., 1991). One study indicated that imipramine was
only a moderate eect and only a minority of patients more eective than placebo, but only in terms of the
display sustained, marked improvement (Bennett et al., numbers of days had to lie down and number of
1988; Bibolotti et al., 1986; Cantini et al., 1994; Caruso days with at least some restriction of normal activity
et al., 1987; Fossaluzza and De Vita, 1992; Goldenberg (Alco et al., 1982). Another study (Pheasant et al.,
et al., 1986, 1996; Hamaty et al., 1989; Hannonen et al., 1983) showed that amitryptyline was better than pla-
1998; Heymann et al., 2001; Jaeschke et al., 1991; Qui- cebo, comparing the use of rescue analgesics in both
mby et al., 1989; Reynolds et al., 1991; Scudds et al., treatment groups. Nortriptyline and maprotiline were
S. Perrot et al. / European Journal of Pain 10 (2006) 185192 189

signicantly more eective than placebo, but nonethe- published guidelines on the treatment of chronic pain
less had only moderate analgesic eects (Atkinson (Kalso et al., 2003) we propose the following guidelines
et al., 1998; Atkinson et al., 1999; Dickens et al., concerning the use of antidepressants in painful rheu-
2000). 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 (Shekelle et al., 1999).
of a patients depression status. Selective serotonin reup-
take inhibitors (SSRIs) do not appear to be benecial. 1. Due to their analgesic and antidepressant proper-
The eect of antidepressants on health-related quality ties, antidepressants can improve the symptoms
of life, mood and functional status is unclear (Staiger and quality of life of patients suering from pain-
et al., 2003; Ward, 1986). ful chronic degenerative and inammatory osteo-
articular and spinal diseases. Their use should be
3.6.3. Osteoarthritis and inammatory rheumatic diseases included in a global management programme
We identied 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 bromyalgia. They
were placebo-controlled and one compared amitrypti- should not be rst choice analgesic treatment in
line with paroxetine. Only eight of these 15 trials were low back pain, osteoarthritis and inammatory
considered to meet the minimum standards in terms rheumatic painful diseases. A
of methodological quality to demonstrate ecacy (Ash 3. To increase compliance, patients prescribed anti-
et al., 1999; Bird and Broggini, 2000; Frank et al., 1988; depressants for analgesic use should be informed
Ganvir et al., 1980; Grace et al., 1985; Koh et al., of the type of drug, its side eects, the aim of the
1997; Macfarlane et al., 1986; Parker et al., 2003).These treatment and the expected delay until the analge-
studies scored from 13 to 22 on a scale with a maximum sic eects begin. D
of 28 (median quality score: 16.4). In almost all these tri- 4. Antidepressants may be prescribed as analgesics in
als, ecacy in the control of pain and symptoms was non-depressed patients. The rst-choice treatment
independent of the antidepressant eect (with the excep- should be a TCA, initiated at a low dose, which
tion of Parker et al. (2003) and Sarzi Puttini et al. is then increased to the maximal tolerated dose
(1988)), which included depressed patients). Thus, ami- or to the minimal eective dose. A
tryptyline, trimipramine, dothiepine and paroxetine 5. Newer antidepressants with mixed action or spe-
may have analgesic eects in patients with RA, and ami- cic serotonin reuptake inhibitors should be tried
tryptiline may be eective in reducing symptoms in AS. only if TCAs prove to be ineective, poorly toler-
Analgesic eects 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)
(1030 mg daily) may be sucient to provide an analge- can be tried after failure of the initial antidepres-
sic eect (Fowler et al., 1977; Hood et al., 2001; Mac- sant treatment, regardless of whether this failure
Neill and Dick, 1976; McQuay et al., 1992). is related to a lack of ecacy or unbearable side
None of the studies specically dealt with OA; it is eects. C
therefore dicult to determine whether antidepressants 6. The side eects of antidepressants used as analge-
are benecial 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 signicant analgesic eect with TCAs and initiation and throughout the treatment period. A
SSRIs (Gringras, 1976; McDonald Scott, 1969; Thorpe 7. If TCAs are prescribed to elderly patients, the phy-
and Marchant-Williams, 1974; Usha Rani et al., 1996). sician should monitor blood pressure, cognition
In the study perfomed by Lin et al. (2003) in a large and intestinal transit. B
and diverse population of older adults with arthritis 8. The assessment of treatment ecacy should not be
(mostly osteoarthritis) and comorbid depression, bene- limited to pain evaluation. It should include func-
ts 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
of life. 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 be
maintained for at least 4 weeks before being
Based on the ndings of the 75 studies analyzed, the stopped due to lack of ecacy. Total duration
clinical experience of the expert panel, and previously should be determined with respect to the initial
190 S. Perrot et al. / European Journal of Pain 10 (2006) 185192

objectives, accepted by both the patients and the of antidepressants. Some clinicians have reported suc-
physician, and after careful risk-benet evaluation. cessful treatment with SSRIs following the failure of tri-
D 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 inu-
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 eects. Another eld 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 ecacy of antidepressants or to reduce their adverse
category 1 evidence; C = based on category 3 evidence eects. Following the development of clinical guidelines
or extrapolated recommendation from category 1 or 2 (AGREE Collaboration, 1999), 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 (Shekelle et al., relevant, according to most recent clinical ndings,
1999). and mostly to both the patients and physicians
experience.

4. Conclusions
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