Abstract

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.

Introduction

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

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

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.

Fig. 1.

Identification of eligible RCTs.

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.

Table 1.

Description of the included studies

References N Dose (mg/day) Study design Duration (weeks) Outcomes Co-interventions 
Carette et al. [2770 50 RCT, parallel Morning stiffness (min), Pain (VAS 0–10), total myalgic score (TMS Likert 1–5), sleep quality (Likert 1–3), patient assessment (Likert 1–5), physician assessment (Likert 1–5) Acetaminophen 
Carette et al. [28126 50 RCT, parallel 24 Pain (VAS 0–10, McGill Pain Questionnaire 0–78), Fatigue (VAS 0–10), sleep (VAS 0–10), Feeling on awakening (VAS 0–10), morning stiffness (VAS 0–10), global assessment of fibromyalgia (VAS 0–10), sickness impact profile (SIP), HAQ (0–3), Arthritis Impact Measurement Scales (AIMS), physician global assessment (VAS 0–10), total myalgic score (TMS Likert 1–5) Acetaminophen 
Fors et al. [3055 50 RCT, parallel Pain (VAS 0–10), State-Trait Anxiety Inventory-Trait (STAI-T 20–80), Beck Depression Inventory (BDI 0–21), Automatic Negative Thoughts Questionnaire (ATQ-30) Scores In addition, patients were also randomly assigned to three psychological interventions: (i) pleasant guided imagery (PI) audiotape; (ii) attention imagery (AI); and (iii) a control group with a blank audiotape. 
Scudds et al. [3136 50 RCT, cross-over The total myalgic score (TMS Likert 1–5), pain threshold, pain tolerance, pain (McGill Pain Questionnaire, MGPQ 0–78), patient assessment of global treatment (Likert 1–5) Acetaminophen 
Carette et al. [2922 25 RCT, cross-over EEG changes, pain (VAS 0–10), fatigue (VAS 0–10), sleep (VAS 0–10), global severity (VAS 0–10), point tenderness, total myalgic score (TMS Likert 1–5) Acetaminophen 
Ginsberg et al. [3246 25 RCT, parallel Proportion of responders in each treatment group. A responder must have at least three of the following four criteria: (i) at least 50% improvement in patient global assessment, (ii) at least 50% improvement of physician global assessment, (iii) at least 50% improvement in pain and (iv) at least 25% reduction in tender point score Pain (VAS 0–10), patient assessment of global treatment (VAS 0–10), wake up tired (Likert 1–5), asleep disturbance (VAS 0–10), fatigue (VAS 0–10), physician global assessment (VAS 0–10), morning stiffness (min) Paracetamol 
Goldenberg et al. [3362 25 RCT, parallel Pain (VAS 0–10), morning stiffness (VAS 0–10), fatigue (VAS 0–10), sleep (VAS 0–10), physician global evaluation (VAS 0–10), tender point score (Likert 0–2) Acetaminophen 
Goldenberg et al. [3431 25 RCT, cross-over Pain (VAS 0–10), morning stiffness (VAS 0–10), fatigue (VAS 0–10), sleep (VAS 0–10), feeling refreshed upon awakening (VAS 0–10), global well-being (VAS 0–10), fibromyalgia impact questionnaire (FIQ 0–100), Beck Depression Inventory (BDI 0–21), physician global evaluation (VAS 0–10), tender point score (Likert 0–2) Acetaminophen 
Hannonen et al. [3587 25–37.5 RCT, parallel 12 Proportion of responders as assessed by physicians, global health (VAS 0–10), pain (VAS 0–10), sleep quality and quantity (VAS 0–10), fatigue (VAS 0–10), sheehan's disability scales (VAS 0–10), Nottingham Health Profile (NHP), tender points (0–18), physician's clinical impression of the severity (CIS Likert 3, 0, −3), physician's clinical global impression of tolerability (CGI Likert 1–4) Paracetamol 
Heymann et al. [3680 25 RCT, parallel Verbal evaluation scale for global improvement (VSGI Likert 1–5) Fibromyalgia impact questionnaire (FIQ 0–100) Tender points (0–18) Acetaminophen 
References N Dose (mg/day) Study design Duration (weeks) Outcomes Co-interventions 
Carette et al. [2770 50 RCT, parallel Morning stiffness (min), Pain (VAS 0–10), total myalgic score (TMS Likert 1–5), sleep quality (Likert 1–3), patient assessment (Likert 1–5), physician assessment (Likert 1–5) Acetaminophen 
Carette et al. [28126 50 RCT, parallel 24 Pain (VAS 0–10, McGill Pain Questionnaire 0–78), Fatigue (VAS 0–10), sleep (VAS 0–10), Feeling on awakening (VAS 0–10), morning stiffness (VAS 0–10), global assessment of fibromyalgia (VAS 0–10), sickness impact profile (SIP), HAQ (0–3), Arthritis Impact Measurement Scales (AIMS), physician global assessment (VAS 0–10), total myalgic score (TMS Likert 1–5) Acetaminophen 
Fors et al. [3055 50 RCT, parallel Pain (VAS 0–10), State-Trait Anxiety Inventory-Trait (STAI-T 20–80), Beck Depression Inventory (BDI 0–21), Automatic Negative Thoughts Questionnaire (ATQ-30) Scores In addition, patients were also randomly assigned to three psychological interventions: (i) pleasant guided imagery (PI) audiotape; (ii) attention imagery (AI); and (iii) a control group with a blank audiotape. 
Scudds et al. [3136 50 RCT, cross-over The total myalgic score (TMS Likert 1–5), pain threshold, pain tolerance, pain (McGill Pain Questionnaire, MGPQ 0–78), patient assessment of global treatment (Likert 1–5) Acetaminophen 
Carette et al. [2922 25 RCT, cross-over EEG changes, pain (VAS 0–10), fatigue (VAS 0–10), sleep (VAS 0–10), global severity (VAS 0–10), point tenderness, total myalgic score (TMS Likert 1–5) Acetaminophen 
Ginsberg et al. [3246 25 RCT, parallel Proportion of responders in each treatment group. A responder must have at least three of the following four criteria: (i) at least 50% improvement in patient global assessment, (ii) at least 50% improvement of physician global assessment, (iii) at least 50% improvement in pain and (iv) at least 25% reduction in tender point score Pain (VAS 0–10), patient assessment of global treatment (VAS 0–10), wake up tired (Likert 1–5), asleep disturbance (VAS 0–10), fatigue (VAS 0–10), physician global assessment (VAS 0–10), morning stiffness (min) Paracetamol 
Goldenberg et al. [3362 25 RCT, parallel Pain (VAS 0–10), morning stiffness (VAS 0–10), fatigue (VAS 0–10), sleep (VAS 0–10), physician global evaluation (VAS 0–10), tender point score (Likert 0–2) Acetaminophen 
Goldenberg et al. [3431 25 RCT, cross-over Pain (VAS 0–10), morning stiffness (VAS 0–10), fatigue (VAS 0–10), sleep (VAS 0–10), feeling refreshed upon awakening (VAS 0–10), global well-being (VAS 0–10), fibromyalgia impact questionnaire (FIQ 0–100), Beck Depression Inventory (BDI 0–21), physician global evaluation (VAS 0–10), tender point score (Likert 0–2) Acetaminophen 
Hannonen et al. [3587 25–37.5 RCT, parallel 12 Proportion of responders as assessed by physicians, global health (VAS 0–10), pain (VAS 0–10), sleep quality and quantity (VAS 0–10), fatigue (VAS 0–10), sheehan's disability scales (VAS 0–10), Nottingham Health Profile (NHP), tender points (0–18), physician's clinical impression of the severity (CIS Likert 3, 0, −3), physician's clinical global impression of tolerability (CGI Likert 1–4) Paracetamol 
Heymann et al. [3680 25 RCT, parallel Verbal evaluation scale for global improvement (VSGI Likert 1–5) Fibromyalgia impact questionnaire (FIQ 0–100) Tender points (0–18) Acetaminophen 

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.

Table 2.

Assessment of methodological quality of studies

References N JADAD score Losses to follow-up n/N (%) Method of randomization Concealment Method of blinding ITT analysis Funding source 
Carette et al. [2670 11/70 (15.7) Unclear Unclear Adequate No Arthritis Society 
Carette et al. [28126 30/124 (22.2) Adequate Adequate Adequate Yes Canadian Arthritis Society and Merk Frosst Canada 
Carette et al. [29]a 22 2/22 (9) Adequate Unclear Adequate No Canadian Arthritis Society and Merk Frosst Canada 
Fors et al. [3055 3/55 (5.5) Adequate Adequate Adequate Unclear Norwegian University of Science and Technology 
Ginsberg et al. [3246 5/46 (10.9) Unclear Unclear Adequate Yes Not specified 
Goldenberg et al. [3362 2/62 (3.2) Unclear Unclear Unclear No Arthritis Foundation, Multipurpose 
Goldenberg et al. [34]a 31 2/31 (6.5) Adequate Adequate Adequate No Lot Page Found, Newton-Wellesley Hospital. Newton, Massachusetts 
Hannonen et al. [3587 25/87 (28.8) Adequate Adequate Adequate Yes Roche Oy, Finland 
Heymann et al. [3680 10/80 (12.5) Adequate Adequate Adequate No Not specified 
Scudds et al. [31]a 36 3/36 (8.3) Unclear Unclear Adequate No The Arthritis Society Studentship 
References N JADAD score Losses to follow-up n/N (%) Method of randomization Concealment Method of blinding ITT analysis Funding source 
Carette et al. [2670 11/70 (15.7) Unclear Unclear Adequate No Arthritis Society 
Carette et al. [28126 30/124 (22.2) Adequate Adequate Adequate Yes Canadian Arthritis Society and Merk Frosst Canada 
Carette et al. [29]a 22 2/22 (9) Adequate Unclear Adequate No Canadian Arthritis Society and Merk Frosst Canada 
Fors et al. [3055 3/55 (5.5) Adequate Adequate Adequate Unclear Norwegian University of Science and Technology 
Ginsberg et al. [3246 5/46 (10.9) Unclear Unclear Adequate Yes Not specified 
Goldenberg et al. [3362 2/62 (3.2) Unclear Unclear Unclear No Arthritis Foundation, Multipurpose 
Goldenberg et al. [34]a 31 2/31 (6.5) Adequate Adequate Adequate No Lot Page Found, Newton-Wellesley Hospital. Newton, Massachusetts 
Hannonen et al. [3587 25/87 (28.8) Adequate Adequate Adequate Yes Roche Oy, Finland 
Heymann et al. [3680 10/80 (12.5) Adequate Adequate Adequate No Not specified 
Scudds et al. [31]a 36 3/36 (8.3) Unclear Unclear Adequate No The Arthritis Society Studentship 

aCross-over study.

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).

Table 3.

Results: amitriptyline 50 mg

References Study type Patient's global assessment Pain (VAS) Tender points (0–18 ACR) Physician's global assessment (VAS) Sleep disturbance (VAS) Fatigue (VAS) 
Carette et al. [27Parallel (9 weeks) ND between groups ND between group Intragroup dif: AMI yes, Pcb no ND between groups Intragroup dif: AMI no, Pcb no ND between groups Better AMI (P = 0.02) (Improvement: 70% AMI versus 40% Pcb) Not measured 
Carette et al. [28Parallel (24 weeks) ND between groups ND between groups Intragroup dif: AMI yes, Pcb yes ND between groups ND between groups ND between groups ND between groups 
Fors et al. [30Parallel (4 weeks) Not measured ND between groups Not measured Not measured Not measured Not measured 
Scudds et al. [31Cross-over (4 weeks) ND between groups Intragroup dif: AMI yes, Pcb no Not measured Not measured Not measured Not measured Not measured 
References Study type Patient's global assessment Pain (VAS) Tender points (0–18 ACR) Physician's global assessment (VAS) Sleep disturbance (VAS) Fatigue (VAS) 
Carette et al. [27Parallel (9 weeks) ND between groups ND between group Intragroup dif: AMI yes, Pcb no ND between groups Intragroup dif: AMI no, Pcb no ND between groups Better AMI (P = 0.02) (Improvement: 70% AMI versus 40% Pcb) Not measured 
Carette et al. [28Parallel (24 weeks) ND between groups ND between groups Intragroup dif: AMI yes, Pcb yes ND between groups ND between groups ND between groups ND between groups 
Fors et al. [30Parallel (4 weeks) Not measured ND between groups Not measured Not measured Not measured Not measured 
Scudds et al. [31Cross-over (4 weeks) ND between groups Intragroup dif: AMI yes, Pcb no Not measured Not measured Not measured Not measured Not measured 

ND: No Difference; AMI: Amitriptyline; Pcb: Placebo Intragroup differences: not specified when not reported. Information in bold indicates positive results where the difference observed between amitriptyline and placebo is statistically significant.

Table 4.

Results: amitriptyline 25 mg.

References Study type Patient's global assessment (VAS) Pain (VAS) Tender points (0–18 ACR) Physician's global assessment (VAS) Sleep disturbance (VAS) Fatigue (VAS) 
Carette Cross-over (8 weeks) Better AMI (P < 0.05) Better AMI (P < 0.05) ND between groups Better AMI (P < 0.05) Better AMI (P < 0.05) Better AMI (P < 0.05) 
et al. [29 AMI: 5.47 ± 3.03 AMI: 5.07 ± 3.22 Intragroup dif: AMI: 4.81 ± 2.81 AMI: 3.93 ± 3.14 AMI: 5.62 ± 3.07 
  Pcb: 7.11 ± 2.14 Pcb: 7.13 ± 2.41 AMI no, Pcb no Pcb: 6.36 ± 1.59 Pcb: 6.51 ± 2.69 Pcb: 7.64 ± 1.8 
  (▵ AMI: −1.80) (▵ AMI: −2.05)  (▵ AMI: −1.59) (Δ AMI: −3.56) (Δ AMI: −2.22) 
Ginsberg Parallel (8 weeks) Better AMI (P < 0.001) Better AMI (P < 0.001) Better AMI (P < 0.001) Better AMI (P < 0.001) Better AMI (P = 0.003) Better AMI (P < 0.001) 
et al. [32 AMI: 3.90 ± 2.3 AMI: 3.8 ± 2.4 AMI: 10.2 ± 4.8 AMI: 3.5 ± 2.1 AMI: 2.6 ± 3.1 AMI: 3.8 ± 2.5 
  Pcb: 6.80 ± 1.8 Pcb: 7.0 ± 1.3 Pcb: 13.9 ± 3.1 Pcb: 5.9 ± 1.7 Pcb: 5.1 ± 3.0 Pcb: 5.9 ± 2.2 
  (Δ AMI: −3.8) (Δ AMI: −3.5) (Δ AMI: −4.6) (Δ AMI: −3.5) (Δ AMI: −2.6) (Δ AMI: −3.5) 
Goldenberg Parallel (6 weeks) Better AMI (P < 0.001) ND between groups ND between groups Better AMI (P < 0.001) Better AMI (P < 0.001) Better AMI (P < 0.001) 
et al. [33Compares four arms: AMI vs AMI+naproxen vs naproxen vs placebo No raw data (graphs) (Δ AMI: −3.0) Intragroup dif: AMI yes, Pcb no Intragroup dif: AMI yes, Pcb no No raw data (graphs) (Δ AMI: aprox –4.0) No raw data (graphs) (Δ AMI: −3.9) No raw data (graphs) (Δ AMI: −3.2) 
Goldenberg Cross-over (6 weeks) Better AMI (P = 0.02) Better AMI (P = 0.02) ND between groups Better AMI (P = 0.04) Better AMI (P < 0.001) ND between groups 
et al. [34 AMI: 61.60 ± 29.5 AMI: 64.4 ± 28.3  AMI: 64.2 ± 25.2 AMI: 57.0 ± 34.8  
  Pcb: 76.80 ± 24.8 Pcb: 81.5 ± 16.5  Pcb: 74.7 ± 19.9 Pcb: 74.6 ± 2 3.9  
  (Δ AMI: −5.0) (Δ AMI: −4.0)  (Δ AMI: −0.9) (Δ AMI: −11)  
Hannonen Parallel (12 weeks) ND between groups ND between groups ND between groups ND between groups ND between groups ND between groups 
et al. [35 Intragroup dif: Intragroup dif: Intragroup dif: Intragroup dif: Intragroup dif: Intragroup dif: 
  AMI yes, Pcb no AMI yes, Pcb no AMI yes, Pcb no AMI yes, Pcb no AMI yes, Pcb no AMI yes, Pcb no 
Heymann Parallel (8 weeks) Better AMI (P = 0.009) Not measured ND between groups Not measured Not measured Not measured 
et al. [36 (Improvement: 87%  Intragroup dif:    
  AMI vs 55% Pcb)  AMI yes, Pcb yes    
References Study type Patient's global assessment (VAS) Pain (VAS) Tender points (0–18 ACR) Physician's global assessment (VAS) Sleep disturbance (VAS) Fatigue (VAS) 
Carette Cross-over (8 weeks) Better AMI (P < 0.05) Better AMI (P < 0.05) ND between groups Better AMI (P < 0.05) Better AMI (P < 0.05) Better AMI (P < 0.05) 
et al. [29 AMI: 5.47 ± 3.03 AMI: 5.07 ± 3.22 Intragroup dif: AMI: 4.81 ± 2.81 AMI: 3.93 ± 3.14 AMI: 5.62 ± 3.07 
  Pcb: 7.11 ± 2.14 Pcb: 7.13 ± 2.41 AMI no, Pcb no Pcb: 6.36 ± 1.59 Pcb: 6.51 ± 2.69 Pcb: 7.64 ± 1.8 
  (▵ AMI: −1.80) (▵ AMI: −2.05)  (▵ AMI: −1.59) (Δ AMI: −3.56) (Δ AMI: −2.22) 
Ginsberg Parallel (8 weeks) Better AMI (P < 0.001) Better AMI (P < 0.001) Better AMI (P < 0.001) Better AMI (P < 0.001) Better AMI (P = 0.003) Better AMI (P < 0.001) 
et al. [32 AMI: 3.90 ± 2.3 AMI: 3.8 ± 2.4 AMI: 10.2 ± 4.8 AMI: 3.5 ± 2.1 AMI: 2.6 ± 3.1 AMI: 3.8 ± 2.5 
  Pcb: 6.80 ± 1.8 Pcb: 7.0 ± 1.3 Pcb: 13.9 ± 3.1 Pcb: 5.9 ± 1.7 Pcb: 5.1 ± 3.0 Pcb: 5.9 ± 2.2 
  (Δ AMI: −3.8) (Δ AMI: −3.5) (Δ AMI: −4.6) (Δ AMI: −3.5) (Δ AMI: −2.6) (Δ AMI: −3.5) 
Goldenberg Parallel (6 weeks) Better AMI (P < 0.001) ND between groups ND between groups Better AMI (P < 0.001) Better AMI (P < 0.001) Better AMI (P < 0.001) 
et al. [33Compares four arms: AMI vs AMI+naproxen vs naproxen vs placebo No raw data (graphs) (Δ AMI: −3.0) Intragroup dif: AMI yes, Pcb no Intragroup dif: AMI yes, Pcb no No raw data (graphs) (Δ AMI: aprox –4.0) No raw data (graphs) (Δ AMI: −3.9) No raw data (graphs) (Δ AMI: −3.2) 
Goldenberg Cross-over (6 weeks) Better AMI (P = 0.02) Better AMI (P = 0.02) ND between groups Better AMI (P = 0.04) Better AMI (P < 0.001) ND between groups 
et al. [34 AMI: 61.60 ± 29.5 AMI: 64.4 ± 28.3  AMI: 64.2 ± 25.2 AMI: 57.0 ± 34.8  
  Pcb: 76.80 ± 24.8 Pcb: 81.5 ± 16.5  Pcb: 74.7 ± 19.9 Pcb: 74.6 ± 2 3.9  
  (Δ AMI: −5.0) (Δ AMI: −4.0)  (Δ AMI: −0.9) (Δ AMI: −11)  
Hannonen Parallel (12 weeks) ND between groups ND between groups ND between groups ND between groups ND between groups ND between groups 
et al. [35 Intragroup dif: Intragroup dif: Intragroup dif: Intragroup dif: Intragroup dif: Intragroup dif: 
  AMI yes, Pcb no AMI yes, Pcb no AMI yes, Pcb no AMI yes, Pcb no AMI yes, Pcb no AMI yes, Pcb no 
Heymann Parallel (8 weeks) Better AMI (P = 0.009) Not measured ND between groups Not measured Not measured Not measured 
et al. [36 (Improvement: 87%  Intragroup dif:    
  AMI vs 55% Pcb)  AMI yes, Pcb yes    

ND: No Difference; AMI: Amitriptyline; Pcb: Placebo; Intragroup differences: not specified if not reported; Mean values (±s.d.) for AMI and Pcb groups are provided at the end of the study; Δ AMI: Change from baseline in the AMI group (in order to assess the relevance of the effect). Information in bold indicates positive results where the difference observed between amitriptyline and placebo is statistically significant.

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

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.

graphic

Acknowledgements

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.

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