Combination pharmacotherapy for the treatment of fibromyalgia

  • Protocol
  • Intervention


  • Ian Gilron,

    Corresponding author
    1. Queen's University, Departments of Anesthesiology & Perioperative Medicine & Biomedical & Molecular Sciences, Kingston, ON, Canada
    • Ian Gilron, Departments of Anesthesiology & Perioperative Medicine & Biomedical & Molecular Sciences, Queen's University, 76 Stuart Street, Victory 2 Pavillion, Kingston, ON, K7L 2V7, Canada.

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  • Bonnie Shum,

    1. Queens University, Anesthesiology & perioperative Medicine, Kingston, ON, Canada
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  • R Andrew Moore,

    1. University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), Oxford, Oxfordshire, UK
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  • Philip J Wiffen

    1. University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), Oxford, Oxfordshire, UK
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This is the protocol for a review and there is no abstract. The objectives are as follows:

The objectives of this review are to evaluate the efficacy (primary), tolerability (secondary) and safety (secondary) of various drug combinations for the treatment of fibromyalgia pain.


Description of the condition

Fibromyalgia is a complex, multisystem disorder characterised by a constellation of symptoms including chronic widespread pain, sleep disturbance, fatigue, irritable bowel syndrome, depressed mood and cognitive dysfunction. These symptoms are reflected in functional disability and impaired quality of life (Wolfe 2009; Arnold 2012). Fibromyalgia is highly prevalent, affecting 3% to 5% of the general population, with a female predominance (Wolfe 1995; Gran 2003). Of note, however, recent studies have shown a much higher prevalence of fibromyalgia in patients diagnosed with migraine (22.2%) (Ifergane 2006) and low back pain (39%) (Hüppe 2004). In addition to being personally devastating to the afflicted individual and his/her family, fibromyalgia also exerts a major adverse socioeconomic impact on society (e.g. see White 1999; Silverman 2009).

Description of the intervention

Over the past 30 years, hundreds of randomised controlled trials have evaluated a wide variety of pharmacological interventions (e.g. NSAIDs, antidepressants, opioids and anticonvulsants) and non-pharmacological interventions (e.g. exercise, acupuncture and cognitive behavioural therapy) for the treatment of various aspects of fibromyalgia (Goldenberg 2004). In addition to exercise and cognitive behavioural therapy, pharmacotherapy remains an important and proven strategy for the management of fibromyalgia and its associated morbidities. Current and new drugs, however, reduce pain by only 25% to 40% on average and meaningful relief occurs in only 40% to 60% of patients, in part due to incomplete drug efficacy and dose-limiting adverse effects (Sultan 2008; Hauser 2009a; Häuser 2009b). Several systematic reviews, using the outcome of at least 50% pain relief in longer-term trials (8 to 14 weeks), indicate that drug-specific response rates are low and numbers needed to treat (NNTs) are high; this is the case with pregabalin (Moore 2009), gabapentin (Moore 2011), milnacipran (Derry 2012), duloxetine (Sultan 2008; Lunn 2009 ) and amitriptyline (Moore 2012a). For many drugs, the evidence is limited and does not show any obvious benefit, for example with lacosamide (Hearn 2012). The importance of the outcome of at least 50% pain relief is that good pain reduction also results in improved sleep, fatigue, depression, symptoms, quality of life and work (Moore 2010a; Straube 2011). It is also what patients want from treatment (O'Brien 2010).

These limitations in clinical practice have led some to hypothesise that a combination of different analgesic drugs acting through different mechanisms may provide superior outcomes compared to monotherapy (Mease 2008). Combination analgesics have been proven to produce additive effects in acute pain (Moore 2012b) and possibly also in neuropathic pain (Chaparro 2012).

How the intervention might work

As monotherapy most drugs for fibromyalgia often have intrinsic limitations in their analgesic efficacy, dose-limiting side effects or both. Combining two or more drugs with different pharmacological mechanisms has the potential to provide additive or possibly even synergistic effects in pain reduction, producing superior outcomes compared to monotherapy, provided that there is less additivity in terms of drug side effects in the combination.

Why it is important to do this review

The appealing rationale for combination pharmacotherapy has led to the practice of polypharmacy in clinical practice. Recent data indicate that at least 34% of patients with fibromyalgia are being prescribed two or more analgesic medications at the same time (Berger 2007). However, given the potential for both pain reduction and drug side effects to be compounded in a drug combination, rigorous combination-specific evidence must exist in order to provide a rationale for the practice of combination pharmacotherapy. The question of whether using two or more drugs together really is better than using any one alone also needs to be answered.


The objectives of this review are to evaluate the efficacy (primary), tolerability (secondary) and safety (secondary) of various drug combinations for the treatment of fibromyalgia pain.


Criteria for considering studies for this review

Types of studies

Double-blind, randomised controlled studies comparing combinations of two or more drugs to placebo and/or at least one other comparator for the treatment of fibromyalgia pain. Studies must include pain assessment as a primary or secondary outcome. Full journal publications or summary clinical trial reports are required, with brief abstracts excluded. Non-randomised studies, case reports and other clinical observations will be excluded.

Types of participants

Adult participants (18 years and older) with a diagnosis of fibromyalgia.

Types of interventions

Combinations of two or more different drugs administered by any route.

Types of outcome measures

Studies needed to report pain assessment as either the primary or secondary outcome.

We anticipate that a variety of outcome measures will be used in the studies. The majority of studies are expected to use standard subjective scales for pain intensity or pain relief, or both, and we will pay particular attention to IMMPACT definitions for moderate and substantial benefit in chronic pain studies (Dworkin 2008). These are defined as at least 30% pain relief over baseline (moderate), at least 50% pain relief over baseline (substantial), much or very much improved on Patient Global Impression of Change (PGIC) (moderate) and very much improved on PGIC (substantial).

Primary outcomes
  1. Patient-reported pain relief of 30% or greater

  2. Patient-reported pain relief of 50% or greater

  3. Patient-reported global impression of clinical change (PGIC) much or very much improved

  4. Patient-reported global impression of clinical change (PGIC) very much improved

Secondary outcomes
  1. Any pain-related outcome indicating some improvement

  2. Withdrawals due to lack of efficacy

  3. Participants experiencing any adverse event

  4. Participants experiencing any serious adverse event

  5. Withdrawals due to adverse events

  6. Specific adverse events, particularly somnolence and dizziness

Search methods for identification of studies

Electronic searches

We will search the following databases for studies:

  • Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library);


  • EMBASE (via Ovid).

We have developed a search strategy for MEDLINE and we will adapt this for the other databases (see Appendix 1). There will be no language restrictions.

Searching other resources

We will also search the reference lists of over 50 published systematic reviews on the subject of fibromyalgia pharmacotherapy for eligible clinical trials.

Data collection and analysis

Selection of studies

We will determine study eligibility by reading each study identified by the search. Two review authors will read all studies independently and reach agreement by discussion. The studies will not be anonymised before assessment.

Data extraction and management

Two review authors will independently extract data using a standard form and check for agreement before entry into RevMan 5 (RevMan 2012) or any other analysis. We will include information about the pain condition and number of participants treated, drugs and dosing regimens, study design (placebo or active control), study duration and follow-up, analgesic outcome measures and results, withdrawals and adverse events (participants experiencing any adverse event or serious adverse event).

Assessment of risk of bias in included studies

We will use the 'Risk of bias' tool available in RevMan 5 to report on sequence generation, allocation concealment, blinding and other risks such as reporting of dropouts, and use the Oxford Quality Score (Jadad 1996) as the basis for inclusion, limiting inclusion to studies that are randomised and double-blind as a minimum.

Measures of treatment effect

The primary comparison of interest will be between study drug(s) and one or both single-agent comparators. We will also make comparisons of each two-drug combination and any other placebo and/or active treatment comparators. We will combine studies if they evaluate the same drug class combination at roughly similar doses and durations of treatment. We will use RevMan 5 to analyse study data for binary outcomes.

We will calculate numbers needed to treat to benefit (NNTB) as the reciprocal of the absolute risk reduction (ARR) (McQuay 1998). For unwanted effects, the NNT becomes the number needed to treat to harm (NNTH) and is calculated in the same manner. We will use dichotomous data to calculate risk ratio (RR) with 95% confidence intervals (CI) using a fixed-effect model unless significant statistical heterogeneity is found. We will not use continuous data in analyses.

Unit of analysis issues

In studies involving more than one active treatment group, we will divide the control treatment group among active treatment arms.

Dealing with missing data

We will use intention-to-treat (ITT) analysis where the ITT population consists of participants who were randomised, took at least one dose of the assigned study medication and provided at least one post-baseline assessment. We will assign missing participants zero improvement.

Assessment of heterogeneity

We will only combine studies evaluating similar conditions for analysis so as to avoid clinical heterogeneity. We will use visual data assessment with L'Abbé plots (L'Abbé 1987) and calculation of the I² statistic to explore statistical heterogeneity when the I² is greater than 50%.

Assessment of reporting biases

The aim of this review is to use dichotomous data of known utility (Moore 2010a). The review will not depend on what authors of the original studies chose to report or not, though we anticipate difficulties with studies failing to report any dichotomous results. Continuous data, which probably poorly reflect efficacy and utility, will be extracted and used if useful for illustrative purposes only. We will undertake assessment of publication bias using a method designed to detect the amount of unpublished data with a null effect required to make any result clinically irrelevant (usually taken to mean a NNT of 10 or higher) (Moore 2008).

Data synthesis

We will use a fixed-effect model for any conducted meta-analyses. However, if it is deemed appropriate to combine heterogeneous studies, we will use a random-effects model.

Subgroup analysis and investigation of heterogeneity

We will group studies according to specific combinations of drug classes (e.g. opioids and anticonvulsants).

Sensitivity analysis

No sensitivity analyses are planned because the evidence base is known to be too small to allow reliable analysis.


This work was funded, in part, by research funding from the Canadian Institutes of Health Research.


Appendix 1. MEDLINE search strategy

1 Fibromyalgia/

2 exp Myofascial Pain Syndromes/

3 (fibromyalgia$ or fibrositi$ or myofascial pain).tw.

4 or/1-3

5 exp Drug Therapy, Combination/

6 (combin$ or cotreat$ or co-treat$ or coadministr$ or co-administr$ or synerg$ or isobol$ or "add on$" or polytherapy).tw.

7 or/5-6

8 4 and 7

The search above will be combined with the following trial design search filter which has been developed for MEDLINE: Cochrane highly sensitive search strategy for identifying randomised trials in MEDLINE: sensitivity- and, precision-maximising version (2008 revision); OVID format.

1. randomized controlled
2. controlled clinical
3. randomized.ab.
4. placebo.ab.
5. clinical trials as
6. randomly.ab.
7. trial.ti.
8. 1 or 2 or 3 or 4 or 5 or 6 or 7
9. not ( and
10. 8 not 9"

What's new

18 August 2014AmendedUpdated author declarations of interest.


Protocol first published: Issue 6, 2013

3 July 2013AmendedMinor amendment to the search strategy.

Contributions of authors

The title was registered by IG. The protocol was written by IG, BS, RAM and PW. BS and IG will assess inclusion of papers and extract data. IG will take on lead authorship for the full review and write up the review. IG, BS, RAM and PW will contribute to the final draft and approve the published version. IG will be responsible for the update.

Declarations of interest

IG and RAM have consulted for various pharmaceutical companies. IG and RAM have received lecture fees from pharmaceutical companies that market analgesics and other healthcare interventions. IG, RAM and PW have received research support from charities, government and industry sources at various times, but no such support was received for this work. BS has no conflicts of interest to declare.

IG: The investigator award is administered by CIHR (Canada’s government research funding agency) with half the funding from Pfizer. The total award is to support IG's research time. This award is now completed (2009-2014). There is no direct relationship between the Cochrane review in question.

Sources of support

Internal sources

  • Queen's University Department of Anesthesiology & Perioperative Medicine, Canada.

    Research time support

External sources

  • Canadian Institutes of Health Research - Industry-Partnered (Pfizer) Investigator Award to IG, Canada.

    Salary support