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Rheumatology Advance Access published online on August 12, 2008
Rheumatology, doi:10.1093/rheumatology/ken317
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Review

Amitriptyline in the treatment of fibromyalgia: a systematic review of its efficacy

B. Nishishinya1,2,3, G. Urrútia1,4, B. Walitt5, A. Rodriguez6, X. Bonfill1,4, C. Alegre6 and G. Darko5

1Iberoamerican Cochrane Center, Public Health and Clinical Epidemiology Service, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, 2Universitat Autònoma de Barcelona, Barcelona, 3Kovacs Foundation, Palma de Mallorca, 4CIBER Epidemiología y Salud Pública (CIBERESP), Spain, 5Washington Hospital Center, WA, USA and 6Hospital de la Vall d’Hebron, Barcelona, Spain.

Correspondence to: G. Urrútia, Centro Cochrane Iberoamericano, Hospital de la Santa Creu i Sant Pau, C/Sant Antoni Maria Claret 171, 08041 Barcelona, Spain. E-mail: gurrutia{at}santpau.es


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
The objective of this study was to assess the efficacy and safety of amitriptyline as a treatment of FM. A comprehensive computerized search in Medline (Pubmed), EMBASE and The Cochrane Library was performed. Randomized controlled trials (RCTs) comparing amitriptyline vs placebo in adult patients suffering from FM were identified, the methodological quality was assessed and the results of the main outcomes were evaluated. Ten RCTs were identified. Large clinical variability and statistical heterogeneity precluded quantitative meta-analysis. Overall, the study quality was moderate to high. Amitriptyline 25 mg/day (six RCTs) demonstrated a therapeutic response compared with placebo in the domains of pain, sleep, fatigue and overall patient and investigator impression. This benefit was generally seen at 6–8 weeks of treatment but no effect was noted at 12 weeks. Amitriptyline 50 mg/day (four RCTs) did not demonstrate a therapeutic effect compared with placebo. Neither dose of amitriptyline had an effect on tender points count. No clear statements on adverse events with amitriptyline can be made due to inconsistencies in data among the studies. A definitive clinical recommendation regarding the efficacy of amitriptyline for FM symptoms cannot be made. There is some evidence to support the short-term efficacy of amitriptyline 25 mg/day in FM. There is no evidence to support the efficacy of amitriptyline at higher doses or for periods >8 weeks. More stringent RCTs with longer follow-up periods are required to determine the long-term efficacy and safety of the amitriptyline and define its role in the multidisciplinary management of FM.

KEY WORDS: Fibromyalgia, Amitriptyline, Randomized controlled trials, Systematic review, Tricyclic anti-depressants


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
FM is a common chronic pain condition that affects >2% of the adult population in the developed world [1–4]. FM is a chronic condition of pain, stiffness and tenderness of the muscles, tendons and joints in the absence of clinically apparent pathology. These painful symptoms often co-exist with restless and unrefreshing sleep, fatigue, headaches, anxiety, depression, exercise intolerance and neurocognitive and neuroendocrine dysfunction [5]. FM has substantial impact on quality of life (QoL) [6] and adversely affects both social and work functioning [7].

While FM is one of the most common musculoskeletal pain syndromes, its pathogenesis is not known. Recent evidence implicates the central nervous system as key in maintaining pain and other somatic symptoms of FM [8–11]. Current treatment approaches to FM pain attempt to influence these central mechanisms. This had led to a range of medical treatments being used, including anti-depressants, opioids, NSAIDs, sedatives, muscle relaxants and anti-epileptics.

Several studies that reported tricyclic anti-depressants (TCAs) are effective compared with placebo in the treatment of FM [12–15] established amitriptyline and other TCAs as the cornerstone of drug therapy in FM for 20 yrs. Amitriptyline is currently recommended by experts [16] in the context of a multidisciplinary strategy that includes both pharmacological and non-pharmacologic therapies in the management of FM. It is believed that the effectiveness of TCAs is related to modulation of the monoamine neurotransmitters serotonin and norepinephrine [17–19]. However, the role of these neurotransmitters in FM pathogenesis is still unknown.

This systematic review aims to synthesize the evidence from randomized controlled trials (RCTs) into a comprehensive statement about the known effectiveness of amitriptyline as a symptomatic treatment for FM.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Selection criteria
We selected studies for inclusion if they met the following criteria: RCTs that assessed the efficacy of amitriptyline in patients having a clinical diagnosis of FM or fibrositis by any recognized criteria [5, 20–23]. Trials needed to be double-blinded and compare any dose of amitriptyline with placebo. Trials comparing active treatments without a placebo control arm were excluded.

Literature search
We performed an exhaustive computerized literature searches in the following databases EMBASE (via OVID; 1991–2007), The Cochrane Library; 2007, Issue 2 and MEDLINE (via PubMed; 1966–2007). The search combined the terms ‘fibromyalgia’ and ‘fibrositis’ with a validated filter for RCTs [24]. This search strategy was part of a broader previous global search of all pharmacological and non-pharmacological treatments of FM, which is why amitriptyline and TCA were not included as discrete search terms.

Two independent reviewers screened the search results, selecting the studies that fulfilled the inclusion criteria. We examined databases of ongoing trials and checked the reference lists of relevant studies to identify any additional trial. All trials captured by our search that utilized amitriptyline were selected for this review. There was no language restriction. The only non-English paper identified was disqualified by eligibility criteria.

Data abstraction and quality assessment
Two independent reviewers abstracted the relevant data from the included trials, and a third one solved possible disagreements. Data was extracted regarding patients’ and intervention characteristics, methodological quality and results for each group of participants.

Methodological quality was assessed by two independent reviewers by using the Schulz's scale [25] and the Jadad's score [26]. These applications were used to assess the risk of bias in the results of the study by considering the particulars of random sequence generation, concealment of randomization assignments, baseline homogeneity of patient groups and intention to treat analysis. The quality of each study was classified as ‘high’ or ‘low’, depending on the Jadad's score (‘low’ = 0–2 and ‘high’ = 3–5). Discrepancies were settled through discussions with a third reviewer. A consensus was reached about the effectiveness and safety of the intervention for each study.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
Description of the studies
Fifteen studies with amitriptyline were identified, 10 of which met the inclusion criteria [27–36] (n = 615 patients). Three were cross-over trials [29, 31, 34] while seven had a parallel design [27, 28, 30, 32, 33, 35, 36]. Five trials were excluded [37–41]. There was agreement between reviewers about the selection of included/excluded studies. Figure 1 shows the trial flow.


Figure 1
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  		FIG. 1. Identification of eligible RCTs.

 
Among the 10 included RCTs that compared amitriptyline vs placebo, four studies administered the dose of 50 mg/day [27, 28, 30, 31] and six the dose of 25 mg/day [29, 32–36]. Seven of the studies used the ACR [5] as the diagnostic criteria while the three studies that predated these consensus criteria used either the Smythe criteria [20] or the Yunus criteria [21]. Eight of the studies were 8-week long, one study was 12-week long and one study was 24-week long. Sample sizes ranged from 22 to 126 patients, with a mean of 61 patients per study. Sample size calculation method was adequately reported in eight studies. The most common outcomes measures in the studies included patient global assessment measured by Visual Analogic Scale (VAS) (9/10), pain measured by VAS (8/10), tender point counts (8/10) and physician global assessment measured by VAS (7/10). Other outcomes, including QoL, functional status and depression, were not routinely measured. The few studies that did make such measurements tended to use different scales, further complicating comparisons. Most studies used acetaminophen or paracetamol for pain control as a co-intervention. The effect of these treatments on symptoms was not felt to interfere with comparisons between amitriptyline and placebo. Six studies were sponsored by medical associations or foundations, two by a pharmaceutical company and two studies did not state any funding source.

Baseline demographic characteristics and risks factors were well balanced in the studies. Most patients were females (82–100%) of ages that ranged from 36.7 to 53.4 yrs. Between-study differences were noted in FM duration (2.5–15.6 yrs) and baseline pain VAS (4.2–7.3).

All studies reported dropout rates that ranged from 3% to 28.8%, with no differences between the amitriptyline and placebo groups. Two studies [27, 34] showed a dropout rate >20% (22.2 and 28.8%, respectively). The adverse event frequencies were well described in 7/10 studies.

Table 1 describes the main characteristics of the included studies.


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  		TABLE 1. Description of the included studies

 
All included trials were judged to be of high methodological quality according to the Jadad's scale (Table 2). Despite this, there were substantial methodological differences among the trials. Three of the studies utilized a cross-over design while the other seven were comparison trials with a parallel design. Only six studies reported the details of the randomization method and five studies reported the process of allocation concealment. All studies were reported to be double-blind but one study did not provide information about the blinding method used. Three studies applied an intention-to-treat analysis while one study did not provide information concerning the population analysis applied.


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  		TABLE 2. Assessment of methodological quality of studies

 
Due to clinical and statistical heterogeneity and data-reporting issues of the included studies, our planned meta-analytic approach had to be abandoned. One major factor was the fundamental inability to combine the three cross-over trials with the other seven parallel design trials. This occurred because none of the cross-over trials provided separate baseline data previous to the cross-over therapy. In addition, many of the parallel design trials reported either incomplete results or provided results only in graphical form (3/7). In most cases, there was not enough raw data to justify a meta-analysis. Our attempts to contact the authors to obtain this missing data were not fruitful. Finally, in the few cases where meta-analysis was thought to be possible (up to three RCT), a high statistical heterogeneity (I2 > 50–60%) was identified. We surmise that this occurred due to clinical heterogeneity of basal pain levels and differences in FM duration. Therefore, the forest plots of these results were not informative. Thus, we have only provided individual study results in tabular form (Tables 3 and 4).


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  		TABLE 3. Results: amitriptyline 50 mg

 

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  		TABLE 4. Results: amitriptyline 25 mg.

 
Clinical results
Overall, pain significantly improved in the group treated with amitriptyline compared with placebo in 3/8 studies. Improvements in fatigue (3/6), sleep disturbance (5/7), patient global assessment (5/9) and physician global assessment (4/7) were also noted. Tender point counts improved in only 1/8 studies.

Amitriptyline 25 mg was consistently reported to be more effective compared with placebo than amitriptyline 50 mg. Amitriptyline 25 mg showed a significant improvement in pain (3/5) [29, 32, 34], sleep disturbance (4/5) [29, 32–34], fatigue (3/5) [29, 32, 33] and physician (4/5) [29, 32–34] and patient (5/6) [29, 32–34, 36] global assessment. Morning stiffness improved in one of two studies [32]. Other less frequent outcomes are presented in Tables 3 and 4. Furthermore, in the trials where no differences between amitriptyline 25 mg and placebo were observed, a statistically significant improvement was observed between baseline and final measurements within the amitriptyline arm but not in the placebo arm. There were no reports of either the lack of significant improvement or significant worsening of symptoms with amitriptyline 25 mg.

Interestingly, the clinical effects seen with amitriptyline 25 mg were not seen with amitriptyline 50 mg. Amitriptyline 50 mg only demonstrated significant improvement in sleep disturbance compared with placebo in one of the two studies [27]. No significant differences were observed in any other outcomes assessed in the four trials using this dose. The data regarding differences between baseline and final measurements within each treatment arm is both heterogeneous and scant, making meaningful comment on intragroup differences difficult.

Some of the standard measurements currently used in FM trials were not well represented in the included studies. The Fibromyalgia Impact Questionnaire (FIQ) was assessed in only two studies with contradictory results [34, 36]. Other standard outcome measures of functional ability, QoL and psychological status were also poorly represented. Only four studies assessed these alternative outcomes and they did so in a heterogeneous manner.

Only six studies rigorously reported adverse events. In those studies, the mean adverse event rate was 51.84% (2.8–95%) with any dose of amitriptyline and 36.63% (2.8–80%) in the placebo group. Three studies had a large percentage of adverse effects even in the placebo group (62–80%), while two had very few events or none in that group. Moreover, the adverse events rate was greater in the placebo group compared with the amitriptyline group in two studies, further casting doubts on the reliability of data collection and reporting. However, all adverse effects reported were either mild to moderate; no severe or life threatening events such as cardiac arrhythmias were reported. The most frequently reported adverse events were somnolence, dry mouth, gastrointestinal symptoms and weight gain. There were no differences in the percentage of patients that withdrew from the studies due to treatment side-effects between any dose of amitriptyline and placebo groups.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
This systematic review was designed to determine the efficacy and safety of amitriptyline as a treatment of FM symptoms. Symptomatic improvement was seen in the amitriptyline 25 mg studies for most outcome variables. No such benefits were seen with amitriptyline 50 mg. However, problems with the quality of included studies and limitations of the analysis make definitive statements premature.

The interesting difference in efficacy by dose was not an anticipated finding in this study. We had expected a dose-related effect on FM symptoms with amitriptyline. A normal dose–response curve has been demonstrated in the treatment of depression and neuropathy with amitriptyline; the low doses of amitriptyline used in FM therapy are typically subtherapeutic in the treatment of the aforementioned disorders [42, 43]. This lack of efficacy seen at higher doses of amitriptyline in our systematic review does not appear to be caused by dose-related increases in side-effects or drop-outs. In fact, no important differences were noted in side-effects or drop-outs between the 25 mg and the 50 mg dosing regimen. Prior studies do bolster this observation. More potent monoamine inhibitors, such as monoamine oxidase inhibitors (MAOIs) have failed to provide symptomatic relief in FM [40, 44], while less potent monoamine inhibitors, such as tramadol, have been shown to help [45]. If this dose-related observation is demonstrated in future studies, it may provide a hint into the physiological underpinnings of FM.

These results may, in part, explain one of the notorious clinical problems that bedevil FM treatment. Tachyphylaxis with amitriptyline is a well-known clinical problem, with amitriptyline often losing its clinical efficacy after 3 months [46]. This study suggests that dose escalation practices may contribute to this problem. However, the short duration of the RCTs prevent any definitive comment about this issue or other clinical questions about the long-term efficacy and safety in the treatment of the chronic symptoms of FM. Future trials should focus on determining both the proper dose and the long-term efficacy and safety of amitriptyline in the treatment of FM.

Adverse events were frequently reported with amitriptyline at all doses. The events appear to be generally mild and an infrequent cause of study withdrawal. No severe adverse events, such as arrhythmia, were reported in any of the trials. However, the disparity in adverse event rates among the studies makes interpretation challenging. The wide variability suggests that these estimates of adverse events are a function of study design and data collection and may not well reflect the adverse event rate in general clinical use. Also, the adverse events rate was greater in the placebo group compared with the amitriptyline group in two studies, further casting doubts on the reliability of data collection and reporting. However, few studies using a dose of 25 mg in the treatment of chronic pain have showed that amitriptyline has no substantial adverse effects at this low dose [47].

The limitations of this systematic review need to be considered in interpreting these results. First, most trials did not assess for depression or anxiety disorders. Both depression and anxiety are commonly associated with FM [48], making it a possible confounder in these studies. There were also important issues regarding methodological quality of the RCTs reviewed. While the included studies were rated as high methodological quality according to the Jadad's scale, this measure does not capture many quality issues important in performing a systematic review. Issues related to length of follow-up, sample size, drop-out rates and data reporting are essential to meaningful systematic reviews are not captured by current quality scales. Overall, these RCTs would be rated as fair to poor on the aforementioned issues [49], which would undermine the strength of the apparently favourable results for amitriptyline 25 mg. Finally, while a consistent therapeutic effect with amitriptyline 25 mg was seen in nearly all outcomes, the clinical relevance of this effect remains unclear. Due to problems with heterogeneity and data reporting, we were only able to perform a qualitative analysis based on reported P-values from each individual trial. We would have much preferred to been able to combine the raw data together to perform a quantitative meta-analysis. Such an analysis would have provided a more precise estimate of the effect size of amitriptyline on the different FM symptom domains. These estimates would have provided a better understanding of the clinical relevance of the statistical improvements reported.

Our methodology only considers amitriptyline as a monotherapy, which gives little insight into its efficacy as part of a multi-disciplinary treatment plan that couples combinations of pharmacological therapies with non-pharmacological cognitive and physical therapies that are currently recommended in clinical treatment guidelines. To date, only observational studies have examined the use of amitriptyline as part of a multi-disciplinary programme. These studies tend to report favourable results, but suffer from major biases that preclude their inclusion in this systematic review.

In conclusion, there is some evidence supporting the efficacy of amitriptyline 25 mg for the short-term treatment of FM symptoms, although better studies are needed to specify the magnitude of the effect and its clinical relevance. There is no evidence supporting the use of higher doses of amitriptyline or using it for periods longer than 8 weeks.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
Funding: The authors received a grant by the Agència d'Avaluació de Tecnologia i Recerca Mèdiques (146/24/2004), Catalonia.

Disclosure statement: The authors have declared no conflicts of interest.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 28 February 2008; revised version accepted 7 July 2008.
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Rheumatology, March 1, 2009; 48(3): 323 - 324.
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