Original Investigation | Neurology

Comparison of Amitriptyline and US Food and Drug Administration–Approved

Treatments for Fibromyalgia
A Systematic Review and Network Meta-analysis
Hussein M. Farag, PharmD, MSc, PhD; Ismaeel Yunusa, PharmD, PhD; Hardik Goswami, BPharm, MSc, PhD; Ihtisham Sultan, PharmD;
Joanne A. Doucette, MSc, MSLIS; Tewodros Eguale, MD, PhD

Abstract Key Points

Question What pharmacological
IMPORTANCE Amitriptyline is an established medication used off-label for the treatment of
treatments for adults with fibromyalgia
fibromyalgia, but pregabalin, duloxetine, and milnacipran are the only pharmacological agents
are associated with the highest efficacy
approved by the US Food and Drug Administration (FDA) to treat fibromyalgia.
and acceptability?

OBJECTIVE To investigate the comparative effectiveness and acceptability associated with Findings In this systematic review and
pharmacological treatment options for fibromyalgia. network meta-analysis of 36
randomized clinical trials (11 930
DATA SOURCES Searches of PubMed/MEDLINE, Cochrane Library, Embase, and Clinicaltrials.gov patients with fibromyalgia), duloxetine
were conducted on November 20, 2018, and updated on July 29, 2020. (120 mg) was associated with higher
efficacy in treating pain and depression,
STUDY SELECTION Randomized clinical trials (RCTs) comparing amitriptyline or any FDA-approved while amitriptyline was associated with
doses of investigated drugs. higher efficacy and acceptability in
improving sleep, fatigue, and health-
DATA EXTRACTION AND SYNTHESIS This study follows the Preferred Reporting Items for related quality of life outcomes.
Systematic Reviews and Meta-analyses reporting guideline. Four independent reviewers extracted
Meaning These findings suggest that
data using a standardized data extraction sheet and assessed quality of RCTs. A random-effects
with the heterogeneity of fibromyalgia
bayesian network meta-analysis (NMA) was conducted. Data were analyzed from August 2020 to
symptoms, pharmacological treatments
January 2021.
should be tailored to individual
symptoms, including pain, sleep
MAIN OUTCOMES AND MEASURES Comparative effectiveness and acceptability (defined as
problems, depressed mood, fatigue, and
discontinuation of treatment owing to adverse drug reactions) associated with amitriptyline
health-related quality of life.
(off-label), pregabalin, duloxetine, and milnacipran (on-label) in reducing fibromyalgia symptoms.
The following doses were compared: 60-mg and 120-mg duloxetine; 150-mg, 300-mg, 450-mg, and
600-mg pregabalin; 100-mg and 200-mg milnacipran; and amitriptyline. Effect sizes are reported + Supplemental content
as standardized mean differences (SMDs) for continuous outcomes and odds ratios (ORs) for Author affiliations and article information are
dichotomous outcomes with 95% credible intervals (95% CrIs). Findings were considered listed at the end of this article.

statistically significant when the 95% CrI did not include the null value (0 for SMD and 1 for OR).
Relative treatment ranking using the surface under the cumulative ranking curve (SUCRA) was also
evaluated.

RESULTS A total of 36 studies (11 930 patients) were included. The mean (SD) age of patients was
48.4 (10.4) years, and 11 261 patients (94.4%) were women. Compared with placebo, amitriptyline
was associated with reduced sleep disturbances (SMD, −0.97; 95% CrI, −1.10 to −0.83), fatigue (SMD,
−0.64; 95% CrI, −0.75 to −0.53), and improved quality of life (SMD, −0.80; 95% CrI, −0.94 to −0.65).
Duloxetine 120 mg was associated with the highest improvement in pain (SMD, −0.33; 95% CrI,
−0.36 to −0.30) and depression (SMD, −0.25; 95% CrI, −0.32 to −0.17) vs placebo. All treatments

(continued)

Open Access. This is an open access article distributed under the terms of the CC-BY License.

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Abstract (continued)

were associated with inferior acceptability (higher dropout rate) than placebo, except amitriptyline
(OR, 0.78; 95% CrI, 0.31 to 1.66). According to the SUCRA-based relative ranking of treatments,
duloxetine 120 mg was associated with higher efficacy for treating pain and depression, while
amitriptyline was associated with higher efficacy for improving sleep, fatigue, and overall quality
of life.

CONCLUSIONS AND RELEVANCE These findings suggest that clinicians should consider how
treatments could be tailored to individual symptoms, weighing the benefits and acceptability, when
prescribing medications to patients with fibromyalgia.

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Introduction
Fibromyalgia is a common illness characterized by widespread chronic pain, physical exhaustion,
cognitive difficulties, depressed mood, sleep problems, and deteriorated quality of life (QoL).1 In the
general population, the prevalence of fibromyalgia symptoms ranges between 2% and 4%.2 The
symptoms of fibromyalgia reduce health-related QoL, and pharmacological treatments can improve
health outcomes.1,2
Three drugs are approved by the US Food and Drug Administration (FDA): the gabapentinoid
pregabalin (approved in 2007) and serotonin and norepinephrine reuptake inhibitors (SNRIs)
duloxetine (in 2008) and milnacipran (in 2009). Amitriptyline, a tricyclic antidepressant, is
commonly used off-label for pain relief, fatigue, sleep disturbance, depression, and improving QoL
for patients with fibromyalgia.3 Despite the well-established value of using amitriptyline for
fibromyalgia, the off-label policy renders defining the true efficacy and acceptability profile of the
drug ambiguous.4 The lack of head-to-head trials with FDA-approved treatments makes comparing
the available treatments difficult. Notably, the 3 FDA-approved medications account for an estimated
70% of prescribed drugs for fibromyalgia treatment.5 A comparative evaluation of these
FDA-approved medications with the most commonly used off-label treatment (amitriptyline) could
guide clinicians in medical decision-making.
To our knowledge, no published studies have explicitly evaluated the comparative health
outcomes of amitriptyline vs the FDA-approved drugs.3 Traditional pairwise meta-analysis, in which
all included studies compare the same intervention with the same comparator, is not feasible to
conduct because of the lack of direct comparisons between some treatments. Network meta-
analysis (NMA) combines the direct and indirect sources of evidence associated with outcomes of a
drug use, adding extra strength to the evidence.6 As such, it could be used to compare fibromyalgia
treatments, circumventing the problems currently associated with their evaluation using the
traditional pairwise meta-analysis approach. Hence, we performed an NMA of randomized clinical
trials (RCTs) to evaluate the effectiveness and acceptability associated with amitriptyline and
FDA-approved drugs for treating fibromyalgia.

Methods
The reporting of this NMA follows the Preferred Reporting Items for Systematic Reviews and Meta-
analyses (PRISMA) reporting guideline, and the PRISMA extension statement for Reporting of
Systematic Reviews Incorporating Network Meta-analysis of health care interventions
(PRISMA-NMA).7,8 The study is registered with PROSPERO, number CRD42018116204. First, we
conducted a systematic review of the literature before conducting the NMA by pooling comparable
studies that met our study’s eligibility criteria. An NMA was conducted rather than the traditional

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pairwise meta-analysis because it enables comparison of pooled estimates using direct and indirect
sources of evidence.

Literature Review
The MEDLINE/PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched,
from their inception until November 20, 2018, and updated on July 29, 2020. Key search terms
included fibromyalgia, pregabalin, duloxetine, milnacipran, and amitriptyline. The study protocol and
full search strategy are described in eAppendix 1 and eAppendix 2 in the Supplement. Reference lists
of the selected articles were examined to ensure that all relevant articles were identified. Titles and
abstracts were independently screened by 4 investigators (H.M.F., H.G., I.Y., and I.S.), and potentially
relevant articles were selected for full-text screening. Any disagreement was resolved by
consultation with a fifth investigator (T.E.). The study protocol and changes made to the protocol are
provided eAppendix 3 in the Supplement.

Study Selection
Double-blind RCTs comparing the off-label use of amitriptyline and FDA-approved doses of
pregabalin, duloxetine, or milnacipran head-to-head or with placebo in adults (aged ⱖ18 years) with
fibromyalgia were included, according to the post– and pre–American College of Rheumatology
(ACR) criteria for diagnosing fibromyalgia.9-14 Studies were excluded if they were not RCTs, used
other comparators (such as non-FDA approved doses of pregabalin, duloxetine, and milnacipran,
intravenous lidocaine combined with amitriptyline, growth hormone, desvenlafaxine, all opioids,
phenytoin, fluoxetine, paroxetine, cyclobenzaprine, and clonazepam), were published in languages
other than English, involved nonhuman participants, or had fewer than 5 participants in any
treatment group.

Data Extraction and Outcome Measures

Four investigators (H.M.F., H.G., I.Y., and I.S.) independently extracted the data using the a priori
standardized data extraction sheet. Outcomes included were pain, sleep problems, depression,
fatigue, QoL, and acceptability (defined as discontinuations associated with adverse drug reactions).
The hierarchy of tools for patient-reported outcomes assessment is shown in eTable 1 in the
Supplement.
All trials were independently graded for validity by the same 4 investigators using the Jadad
scale, which scores randomization, double-blinding, and patient withdrawals, giving an aggregate
score for each trial (range, 0-5, with 0 indicating the weakest and 5 the strongest).15

Risk of Bias Assessment

Risk of bias was assessed by 2 investigators (I.Y. and H.M.F.) using the Cochrane Risk of Bias Tool.16
Each study was classified as having low, medium, or high risk of bias.

Assessment of Clinical Assumptions

Transitivity is the distribution of patient and study characteristics that are potential modifiers of
treatment outcomes and must be sufficiently similar across trials before an indirect comparison. It is
a fundamental assumption underlying NMA.17 The credibility of transitivity in the data was evaluated
by qualitatively assessing the distribution of the potential modifiers across the different direct
comparisons.18

Statistical Analysis
We performed an NMA for each outcome using a bayesian multiple treatment comparison with
random effects. Noninformative (vague) priors (mean = 0; variance = 10000) were used for all
parameters to render them a priori independent, and to ensure the results were primarily driven by
the data.19,20 All eligible trials and subgroups, excluding trials that did not report the effect estimates

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of the interventions, were analyzed. The summary odds ratios (ORs) for the acceptability
(dichotomous) outcome and standardized mean differences (SMDs) for the pain, sleep problems,
depression, fatigue, and QoL (continuous) outcomes were determined.6 Findings were considered
statistically significant when the 95% credible interval (CrI) did not include the null value (0 for SMD
and 1 for OR). For clinical interpretation, Cohen d for effect size was used; an SMD less than 0.40 was
a small difference between the experimental and control groups; 0.40 to 0.70, a moderate
difference; and greater than 0.70, a large difference.21 When no variability measures were reported,
imputation of the maximum SD from another study using the same measurement scale was
performed.22 When studies did not report mean change, these values were calculated as the
arithmetic difference between baseline and follow-up.
In this NMA, group-level data were used; the binomial likelihood was used for dichotomous and
the normal likelihood for continuous outcomes.23 A random-effects model was computed using the
Markov chain Monte Carlo (MCMC) methods with Gibbs sampling based on simulations of 50 000
iterations of 3 chains.24,25 To avoid the burn-in period, the first 10 000 iterations were rejected.26
The restricted maximum likelihood estimation method was used to estimate the heterogeneity,
assuming a common estimate for heterogeneity variance among different comparisons for each
outcome. Consistency was evaluated by examining the agreement between direct and indirect
estimates in all closed loops and by assuming loop-specific heterogeneity using the loop-specific
approach.27 To assess the consistency of the evidence, a node-splitting analysis was also conducted
for each comparison in the treatment network that had both direct and indirect sources of evidence.
In this approach, 1 of the treatment comparisons is split into a parameter for both direct and indirect
evidence to determine if they agree.28
Rank probabilities were summarized using the surface under the cumulative ranking (SUCRA)
curve and with a rankogram plot, considering the location and all the relative treatment effects.29
The SUCRA value would be 0 when a treatment is certain to be the worst and 1 when it is certain to be
the best. A random-effects NMA within a bayesian framework using MCMC was performed using
WinBUGS software, version 1.4.3 (MRC Biostatistics Unit).30 The statistical evaluation of
inconsistency and production of network graphs and summary figures were conducted using
network package in the Stata statistical software, version 15.1 (StataCorp).31 Data were analyzed from
August 2020 to January 2021.
To evaluate whether small studies tended to yield different results, comparison-adjusted funnel
plots were evaluated for each outcome.32 Sensitivity analyses were conducted in which studies with
a sample size of 100 participants or fewer were excluded, to assess the robustness of the findings.33

Results
Characteristics and Risk of Bias of the Included Studies
The literature search retrieved 1415 records; of these, 36 RCTs with 11 930 participants were included
(Figure 1). The median (range) follow-up was 12 weeks (4-52). A total of 30 studies had a parallel
design,34-66 whereas 3 studies had a crossover design.67-69 There were 33 studies that used the ACR
1990 criteria for the classification and diagnosis of fibromyalgia,37-69 2 studies used Yunus
criteria,35,36 and 1 study used the Smyth criteria (eTable 2 in the Supplement).34 The risk of bias
assessment is reported in eTable 3 in the Supplement. Network diagrams for eligible comparisons for
the outcomes are shown in Figure 2; eFigure 1 in the Supplement presents the network plots
weighted by the risk of bias.
We found 10 clinical trials that evaluated amitriptyline,34-42,67 11 trials that evaluated
milnacipran,57-66,69 8 trials that evaluated duloxetine,43-50 and 7 trials that evaluated pregabalin
(eTable 2 in the Supplement).51-56,68

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Evaluation of Clinical Assumptions

The mean (SD) age of participants was 48.4 (10.4) years; 11 261 participants were women (94.4%).
The distribution of age, sex, and fibromyalgia diagnosis was comparable across studies. Hence, the
transitivity assumption was plausible (eTable 2 in the Supplement).

Evaluation of Statistical Inconsistency

The loop-specific approach did not suggest any inconsistency between closed loops, except in the
placebo–milnacipran 100 mg–milnacipran 200 mg loop for acceptability. Furthermore, the node-
splitting approach did not suggest the presence of statistical inconsistency for any outcome (eTable 4
in the Supplement).

Outcomes
Pain
A total of 35 trials assessed pain (11 423 patients).34-39,41-69 Of these, the Visual Analogue Scale (VAS)
was used in 18 trials35,36,38,39,42,51,52,55,57-60,62-67; Brief Pain Inventory, 9 trials44-50,61,69; Numeric
Rating Scale, 7 trials34,37,41,53,54,56,68; and Fibromyalgia Impact Questionnaire (FIQ), 1 trial43 (eTable 1
and eTable 2 in the Supplement).
Compared with placebo, duloxetine 120 mg was associated with the highest pain reduction
(SMD, −0.33; 95% CrI, −0.36 to −0.30), followed by pregabalin 450 mg (SMD, −0.30; 95% CrI, −0.32
to −0.27). Milnacipran 100 mg was associated with the lowest reduction in pain (SMD, −0.17; 95%
CrI, −0.20 to −0.15). According to SUCRA, duloxetine 120 mg (99.1%) and pregabalin 450 mg

Figure 1. Study Selection Flowchart

1230 Records identified through 185 Additional records identified

database searching through other sources
785 Embase 117 Website search
253 Cochrane 68 ClinicalTrials.gov
192 PubMed

1415 Total identified records

802 Duplicates removed

613 Records screened

524 Records excluded on the basis

of title or abstract
376 Irrelevant
57 Review
42 Conference abstract
28 Protocol
13 Nonrandomized controlled trial
8 Animal experiment

89 Full-text articles assessed for eligibility

53 Full-text articles excluded

24 Conference abstract or unable
to obtain full texts
19 Did not report outcome that
met the inclusion criteria
9 Not original research
1 Non-English literature

36 Studies included in quantitative

synthesis (network meta-analysis)

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(86.8%) were associated with the highest probability of effectiveness for fibromyalgia pain (eTable 5
and eFigure 2 in the Supplement).

Sleep
A total of 16 trials35,36,38,39,42,44,50,51,53-57,63,67,69(4452 patients) assessed sleep. Of these,
635,36,38,39,42,67 used VAS, 344,50,56 used Brief Pain Inventory, 351,55,63 used the Medical Outcomes

Figure 2. Network Diagrams

A Pain outcome network diagram B Sleep outcome network diagram

Pregabalin 300 mg Pregabalin 150 mg Pregabalin 300 mg

Pregabalin 150 mg

Pregabalin 450 mg Amitriptyline

Pregabalin 450 mg
Amitriptyline

Placebo
Pregabalin 600 mg

Placebo
Duloxetine 60 mg Pregabalin 600 mg
Milnacipran 200 mg

Duloxetine 120 mg Milnacipran 100 mg Duloxetine 60 mg

Milnacipran 200 mg

Duloxetine 120 mg
Milnacipran 100 mg

C Depression outcome network diagram D Fatigue outcome network diagram

Pregabalin 300 mg Pregabalin 150 mg Pregabalin 300 mg

Pregabalin 150 mg

Pregabalin 450 mg Amitriptyline

Pregabalin 450 mg Amitriptyline

Placebo
Pregabalin 600 mg Pregabalin 600 mg Placebo

Duloxetine 60 mg Milnacipran 200 mg

Duloxetine 60 mg Milnacipran 200 mg

Duloxetine 120 mg Milnacipran 100 mg

Duloxetine 120 mg
Milnacipran 100 mg

E Quality of life outcome network diagram F Acceptability outcome network diagram

Pregabalin 300 mg Pregabalin 300 mg

Pregabalin 150 mg
Pregabalin 150 mg

Pregabalin 450 mg
Amitriptyline Amitriptyline
Pregabalin 450 mg

Placebo
Placebo
Pregabalin 600 mg
Pregabalin 600 mg

Duloxetine 60 mg Milnacipran 200 mg

Duloxetine 60 mg
Milnacipran 200 mg
Duloxetine 120 mg Milnacipran 100 mg
Duloxetine 120 mg Milnacipran 100 mg

Network diagrams showing fibromyalgia treatment comparisons in clinical trials with respect to the number of studies and sample sizes. The width of the line is proportional to the
number of trials directly comparing each pair of treatments, and the size of each node is proportional to the sample size of randomized participants.

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Study Sleep Scale (MOS), 253,54 used Numeric Rating Scale, 157 used the Jenkins Scale, and 169 used
the Sleep Quality Scale.
Although all the treatments, except milnacipran 200 mg, were associated with reduced sleep
problems, amitriptyline was associated with the highest improvement compared with placebo (SMD,
−0.97; 95% CrI, −1.10 to −0.83), followed by pregabalin 600 mg (SMD, −0.60; 95% CrI, −0.67 to
−0.54). Duloxetine 60 mg was associated with the least improvement (SMD, −0.21; 95% CrI, −0.30
to −0.13). According to SUCRA, amitriptyline (98.3%) and pregabalin 600 mg (82%) were associated
with the highest probability of effectiveness on sleep (eTable 6 and eFigure 3 in the Supplement).

Depression
A total of 19 trials37,42-46,48-53,56,59,61-64,68 (8138 patients) evaluated depression in fibromyalgia. Of
these, 837,48-50,59,61-63 used Beck Depression Inventory, 543-46,52 used Hamilton Depression Rating
Scale, 351,53,68 used Hospital Anxiety and Depression Scale, 242,64 used VAS, and 156 used FIQ.
Compared with placebo, duloxetine 120 mg (SMD, −0.25; 95% CrI, −0.32 to −0.17), duloxetine
60 mg (SMD, −0.24; 95% CrI, −0.27 to −0.20), pregabalin 600 mg (SMD, −0.23; 95% CrI, −0.28 to
−0.17), pregabalin 300 mg (SMD, −0.22; 95% CrI, −0.26 to −0.19), pregabalin 450 mg (SMD, −0.14;
95% CrI, −0.18 to −0.09), milnacipran 100 mg (SMD, −0.10; 95% CrI, −0.12 to −0.07), milnacipran
200 mg (SMD, −0.07; 95% CrI, −0.10 to −0.04), and pregabalin 150 mg (SMD, −0.04; 95% CrI, −0.07
to −0.02) were associated with improved depression. Amitriptyline was not significantly different
from placebo. According to SUCRA, duloxetine 120 mg (88.4%), duloxetine 60 mg (85.9%), and
pregabalin 600 mg (80.3%) were associated with the highest probability of effectiveness on
depression (eTable 7 and eFigure 4 in the Supplement).

Fatigue
A total of 21 trials35,38,39,42,43,45,46,48,50,51,53,56,59-64,66,67 (8172 patients) evaluated fatigue. Of these,
945,46,48,59-63,66 used Multidimensional Fatigue Inventory, 635,38,39,42,64,67 used VAS, 343,50,56 used
FIQ, 251,53 used Multidimensional Assessment of Fatigue Global Index, and 169 used Fatigue
Severity Scale.
All treatments were associated with improved fatigue; amitriptyline was associated with the
greatest improvement (SMD, −0.64; 95% CrI, −0.75 to −0.53), followed by pregabalin 150 mg (SMD,
−0.27; 95% CrI, −0.29 to −0.24), and pregabalin 600 mg (SMD, −0.25; 95% CrI, −0.36 to −0.14).
Milnacipran 100 mg (SMD, −0.10; 95% CrI, −0.14 to −0.05) and duloxetine 120 mg (SMD, −0.12; 95%
CrI, −0.16 to −0.08) were associated with the least improvement in fatigue. According to SUCRA,
amitriptyline (100%) and pregabalin 150 mg (83.8%) were associated with the highest probability of
effectiveness on fatigue (eTable 8 and eFigure 5 in the Supplement).

Quality of Life
A total of 25 trials37-40,42-47,49-51,53-56,59-63,66,68,69 (10 219 patients) evaluated QoL. Of these,
1840,42-44,46,47,50,53-56,60-63,66,68,69 used FIQ, 445,49,51,59 used the Short Form 36 Health Survey, 137
used Sickness Impact Profile, 138 used patient global evaluation of fibromyalgia symptoms by VAS,
and 139 used the General Health Questionnaire.
Compared with placebo, amitriptyline (SMD, −0.80; 95% CrI, −0.94 to −0.65), duloxetine 120
mg (SMD, −0.39; 95% CrI, −0.55 to −0.23), duloxetine 60 mg (SMD, −0.22; 95% CrI, −0.35 to −0.09),
pregabalin 450 mg (SMD, −0.18; 95% CrI, −0.29 to −0.06), pregabalin 300 mg (SMD, −0.14; 95%
CrI, −0.23 to −0.06), and pregabalin 150 mg (SMD, −0.12; 95% CrI, −0.23 to −0.02) were associated
with improved QoL. Pregabalin 600 mg, milnacipran 100 mg, and milnacipran 200 mg were not
associated with improved QoL. According to SUCRA, amitriptyline (100%) and duloxetine 120 mg
(88.4%) were associated with the highest probability of effectiveness on QoL (eTable 9 and
eFigure 6 in the Supplement).

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Acceptability
There were 26 trials35,37-40,43-46,49-51,53,55-63,65,66,68,69 (9833 patients) that evaluated
discontinuations associated with adverse drug reactions. Amitriptyline did not differ from placebo
(OR, 0.78; 95% CrI, 0.31-1.66), while all the other treatments were associated with lower
acceptability. According to SUCRA, amitriptyline (93.2%) was associated with the highest probability
of being the most acceptable (eTable 10, eTable 11, and eFigure 7 in the Supplement).

Simultaneous Ranking of the Interventions

Figure 3 presents SUCRA for the following outcome comparisons: pain vs acceptability; pain vs sleep;
pain vs depression; pain vs QoL; depression vs sleep; fatigue vs sleep. The rest of the simultaneous
ranking of interventions are presented in eFigure 8 in the Supplement.

Additional Analyses
Comparison-adjusted funnel plots suggested a publication bias for pain (1 trial each for milnacipran
100 mg and 200 mg with biased estimates favoring the drugs) (eFigure 2F in the Supplement), and
QoL (1 trial for duloxetine 60 mg and 1 for milnacipran 200 mg with biased outcomes against the
drugs) (eFigure 6F in the Supplement). There was no evidence of publication bias for sleep
(eFigure 3F in the Supplement), depression (eFigure 4F in the Supplement), fatigue (eFigure 5F in the
Supplement), or acceptability (eFigure 7D in the Supplement).
The results of the sensitivity analyses are presented in eFigure 9 and eTable 12 in the
Supplement. In the sensitivity analysis, all treatments except amitriptyline and pregabalin 150 mg
were associated with improvements in pain (SMD between −0.17 and −0.48) compared with placebo.
All pregabalin doses were associated with improved sleep (SMD between −0.55 and −0.80). None
of the included treatments were associated with better outcomes than placebo for depression.
Pregabalin 150 mg, pregabalin 600 mg, duloxetine 60 mg, milnacipran 100 mg, and milnacipran 200
mg were associated with improved fatigue (SMD between −0.11 and −0.31). Pregabalin 300 mg,
pregabalin 450 mg, duloxetine 60 mg, and duloxetine 120 mg were associated with improved QoL
(SMD between −0.19 and −0.37).

Discussion
This systematic review and NMA study of 36 double-blind randomized clinical trials, which included
11 930 patients, assessed the comparative effectiveness and acceptability associated with
amitriptyline compared with FDA-approved treatments for reducing the symptoms of fibromyalgia
in adults. The NMA found that off-label use of amitriptyline was associated with large improvement in
sleep and QoL, a moderate improvement in fatigue, a small improvement in pain, and was not
associated with improvement in depression compared with placebo. Duloxetine 120 mg was
associated with improvment in all effectiveness outcomes, with the greatest improvements in pain
and depression.
We also found that pregabalin 600 mg, 450 mg, and 150 mg were associated with a moderate
improvement in sleep symptoms. Although pregabalin 600 mg was associated with improved QoL,
pregabalin generally showed only a small improvements in the other measured symptoms.
Milnacipran 100 mg was associated with small improvements in all outcomes except QoL;
milnacipran 200 mg was associated with small reductions in pain, depression, and fatigue, but did
not improve sleep and QoL outcomes. Pregabalin, duloxetine, and milnacipran were associated with
worse acceptability than placebo, while the acceptability outcomes associated with amitriptyline did
not significantly differ from placebo.
Most of the results from the SUCRA corroborate previous reviews in confirming the therapeutic
outcomes associated with pregabalin, duloxetine, and milnacipran in the treatment of
fibromyalgia.70 However, this NMA’s findings are consistent with a 2011 study by Hauser et al70
regarding the greater effectiveness associated with amitriptyline in reducing sleep disturbances,

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 JAMA Network Open | Neurology Comparison of Amitriptyline and Food and Drug Administration–Approved Treatments for Fibromyalgia

fatigue, and improving QoL compared with duloxetine. In addition, amitriptyline was associated with
greater improvements in sleep, fatigue, and QoL than pregabalin. Our results are similar to a 2015
study by Moore et al3 in the acceptability of amitriptyline compared with placebo. In contrast to a
2018 study by Cipriani et al71 that found amitriptyline to be the antidepressant associated with the
most efficacy among patients with major depressive disorder, this NMA found that amitriptyline was

Figure 3. Cluster Ranking Plot for Relative Effectiveness and Acceptability

A Cluster ranking for pain vs acceptability B Cluster ranking for pain vs sleep
100 Best 100
Amitriptyline Best
SUCRA values for acceptability outcome

Placebo Amitriptyline

SUCRA values for sleep outcome

Pregabalin 600 mg
80
80
Pregabalin 150 mg
Pregabalin 450 mg
60
Pregabalin 300 mg Duloxetine 60 mg
60
Pregabalin 450 mg Milnacipran 200 mg Pregabalin 300 mg
40
Duloxetine 120 mg
Duloxetine 120 mg
Milnacipran 100 mg
Milnacipran 100 mg
40 Duloxetine 60 mg
Pregabalin 600 mg 20
Milnacipran 200 mg Worst
Pregabalin 150 mg Placebo
20 Worst 0

0 20 40 60 80 100 0 20 40 60 80 100
SUCRA values for pain outcome SUCRA values for pain outcome

C Cluster ranking for pain vs depression D Cluster ranking for pain vs quality of life

100 100 Best

Amitriptyline
SUCRA values for quality of life outcome

Duloxetine 120 mg
SUCRA values for depression outcome

Duloxetine 60 mg Duloxetine 120 mg

80 80
Pregabalin 300 mg Pregabalin 600 mg Best
Duloxetine 60 mg
Pregabalin 450 mg
60 60
Pregabalin 450 mg Pregabalin 300 mg

Milnacipran 100 mg Pregabalin 150 mg Pregabalin 600 mg

40 40
Milnacipran 200 mg
Placebo
20 20
Worst Pregabalin 150 mg
Milnacipran 100 mg
Amitriptyline Milnacipran 200 mg
Placebo Worst
0 0

0 20 40 60 80 100 0 20 40 60 80 100
SUCRA values for pain outcome SUCRA values for pain outcome

E Cluster ranking for depression vs sleep F Cluster ranking for fatigue vs sleep
100 100
Amitriptyline Best Amitriptyline
Pregabalin 600 mg Best
SUCRA values for sleep outcome

SUCRA values for sleep outcome

Pregabalin 600 mg
80 80
Pregabalin 150 mg
Pregabalin 150 mg
Pregabalin 450 mg Pregabalin 450 mg
60 60
Duloxetine
Milnacipran 200 mg 120 mg Milnacipran 200 mg
Pregabalin 300 mg Duloxetine 120 mg
40 40
Pregabalin 300 mg
Milnacipran 100 mg Milnacipran 100 mg
20 20 Duloxetine 60 mg
Duloxetine 60 mg
Worst Worst
Placebo Placebo
0 0

0 20 40 60 80 100 0 20 40 60 80 100
SUCRA values for depression outcome SUCRA values for fatigue outcome

SUCRA indicates surface under the cumulative ranking. Each plot shows SUCRA values on a scale of 0% to 100% for 2 outcomes. Drugs with the same color belong to a similar
effectiveness/acceptability profile. The upper right quadrant represents the more favorable interventions on the joint outcomes; lower right quadrant, more favorable on the
horizontal axis outcome but less on the vertical axis outcome; lower left quadrant, less favorable on both outcomes; the upper left quadrant, more favorable on the vertical axis
outcome but less on the horizontal axis outcome.

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 JAMA Network Open | Neurology Comparison of Amitriptyline and Food and Drug Administration–Approved Treatments for Fibromyalgia

not associated with reducing fibromyalgia’s depressive symptoms. This difference may be explained
by the pathophysiological causes of depression and fibromyalgia. In fibromyalgia, depression can be
a direct result of pain, compounded by various comorbidities.72
Our study emphasizes the need for the pharmacological treatments to be selected and tailored
to individual symptoms, acceptability, and adverse effect profiles of the drugs.1 Considering the
dose-dependent adverse effects of all drugs, it is recommended to start at a low dose and increase
slowly, if necessary.70
Unfortunately, pharmacological treatments will provide a modest effect for most patients. For
that reason, nonpharmacological approaches that promote physical activity and coping skills should
be recommended to all patients.1 Cognitive behavioral therapy, aerobic exercise, tai chi,
hydrotherapy, mindfulness-based stress reduction, and multicomponent therapies have been
associated with reducing fibromyalgia symptoms and can be recommended either alone or in
conjunction with pharmacological treatment.73 A 2020 study by Smith et al74 showed variations in
effect sizes from trials of pharmacological treatments to control chronic pain (including fibromyalgia
pain) over time. However, this NMA used random-effects modeling and thus accounted for variations
within and between all included studies.
The strength of this NMA includes a comprehensive search of the literature and retrieval of 36
eligible studies with a total of 11 930 participants. Given that off-label use of drugs without strong
scientific evidence is associated with adverse health outcomes,4 this NMA adds to the literature
regarding the evidence of effectiveness and acceptability of amitriptyline vs FDA-approved drugs.
With a plethora of FDA-approved and off-label treatment options for patients with fibromyalgia, our
NMA provides information that could guide clinicians and patients in making rational, evidence-
based decisions while considering the risk-benefit profiles. Future studies may consider including
other off-label treatment options that are not as common as amitriptyline.

Limitations
This NMA has several limitations. First, fewer than 75% of trials included more than 100 patients per
group, which may introduce bias due to small-study effects. Second, while this NMA might be used
as guide for future drug development, the NMA did not include all the available pharmacological
technologies, although the included treatments accounted for more than 70% of the fibromyalgia
prescribed treatments.5 Third, the SUCRA curve was used to estimate a ranking probability of
comparative effectiveness, but it has limitations, and the results should be interpreted with caution.

Conclusions
The findings of this NMA support the therapeutic effectiveness associated with pregabalin,
duloxetine, and milnacipran and suggest that the off-label use of amitriptyline was also associated
with favorable efficacy and acceptability in the treatment of fibromyalgia. These findings suggest
that for optimal health outcomes in patients with fibromyalgia, pharmacological treatments should
be tailored toward individual symptoms. Furthermore, this NMA extends previous research by
evaluating the comparative effectiveness and acceptability of amitriptyline vs FDA-approved drugs
using a bayesian approach. Future studies are needed to include individual patient data in the NMA to
identify specific individual characteristics that may influence the effectiveness and acceptability of
fibromyalgia pharmacological drugs.

ARTICLE INFORMATION
Accepted for Publication: April 2, 2022.
Published: May 19, 2022. doi:10.1001/jamanetworkopen.2022.12939

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 JAMA Network Open | Neurology Comparison of Amitriptyline and Food and Drug Administration–Approved Treatments for Fibromyalgia

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Farag HM
et al. JAMA Network Open.
Corresponding Author: Tewodros Eguale, MD, PhD, Department of Pharmaceutical Economics and Policy,
Massachusetts College of Pharmacy and Health Sciences, 179 Longwood Ave, Boston, MA 02115 (tewodros.eguale
@mcphs.edu).
Author Affiliations: Department of Pharmaceutical Economics and Policy, Massachusetts College of Pharmacy
and Health Sciences, Boston (Farag, Yunusa, Goswami, Sultan, Doucette, Eguale); Department of Clinical
Pharmacy and Outcomes Sciences, College of Pharmacy, University of South Carolina, Colombia (Yunusa);
Biostatistics and Research Decision Sciences and Health Economics and Decision Sciences, Merck & Co, North
Wales, Pennsylvania (Goswami); Health Economics and Outcomes Research Neuroscience, AbbVie, Cambridge,
Massachusetts (Sultan); Department of Medicine, McGill University Health Centre, Montreal, Canada (Eguale).
Author Contributions: Drs Eguale and Farag had full access to all of the data in the study and take responsibility for
the integrity of the data and the accuracy of the data analysis.
Concept and design: Farag, Yunusa, Goswami, Eguale.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Farag, Goswami, Sultan, Eguale.
Critical revision of the manuscript for important intellectual content: Yunusa, Goswami, Doucette, Eguale.
Statistical analysis: Farag, Goswami, Eguale.
Obtained funding: Eguale.
Administrative, technical, or material support: Yunusa, Sultan, Doucette.
Supervision: Eguale.
Conflict of Interest Disclosures: None reported.
Funding/Support: School of Pharmacy-Boston, Massachusetts College of Pharmacy and Health
Sciences (MCPHS).
Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and
decision to submit the manuscript for publication.

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SUPPLEMENT.
eAppendix 1. Study Protocol
eAppendix 2. Search Strategy
eReferences
eAppendix 3. Changes Made to the Protocol
eTable 1. Hierarchy of Tools for Patient-Reported Outcomes Assessment
eTable 2. Study and Patient Characteristics
eTable 3. Risk of Bias Assessment
eTable 4. Assessments of Inconsistencies
eTable 5. Pain Outcome: League Table
eTable 6. Sleep Outcome: League Table
eTable 7. Depression Outcome: League Table
eTable 8. Fatigue Outcome: League Table
eTable 9. Quality of Life Outcome: League Table
eTable 10. Acceptability Outcome: League Table
eFigure 1. Network Plots
eFigure 2. Pain Outcome: Results
eFigure 3. Sleep Outcome: Results
eFigure 4. Depression Outcome: Results
eFigure 5. Fatigue Outcome: Results
eFigure 6. Quality of Life Outcome: Results
eFigure 7. Acceptability Outcome: Results
eTable 11. Acceptability Outcome: Direct Pairwise Comparisons (Estimates as Odds Ratios [ORs] and 95% Credible
Intervals [95% CrI])
eFigure 8. Cluster Ranking Plots for Relative Effectiveness and Acceptability
eFigure 9. Sensitivity Analysis Removing Studies With Small Sample Size for Each Outcome (Presented as Interval
Plots)
eTable 12. Sensitivity Analysis Removing Studies With Small Sample Size for Each Outcome (Presented as League
Tables)

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