Fibromyalgia is a chronic widespread pain condition affecting millions of people worldwide.
Current pharmacotherapies are often ineffective and poorly tolerated. Combining different
agents could provide superior pain relief and possibly also fewer side effects. To
assess the efficacy, safety, and tolerability of combination pharmacotherapy compared
to monotherapy or placebo, or both, for the treatment of fibromyalgia pain in adults.
We searched CENTRAL, MEDLINE, and Embase to September 2017. We also searched reference
lists of other reviews and trials registries. Double‐blind, randomised controlled
trials comparing combinations of two or more drugs to placebo or other comparators,
or both, for the treatment of fibromyalgia pain. From all studies, we extracted data
on: participant‐reported pain relief of 30% or 50% or greater; patient global impression
of clinical change (PGIC) much or very much improved or very much improved; any other
pain‐related outcome of improvement; withdrawals (lack of efficacy, adverse events),
participants experiencing any adverse event, serious adverse events, and specific
adverse events (e.g. somnolence and dizziness). The primary comparison was between
combination and one or all single‐agent comparators. We also assessed the evidence
using GRADE and created a 'Summary of findings' table. We identified 16 studies with
1474 participants. Three studies combined a non‐steroidal anti‐inflammatory drug (NSAID)
with a benzodiazepine (306 participants); two combined amitriptyline with fluoxetine
(89 participants); two combined amitriptyline with a different agent (92 participants);
two combined melatonin with an antidepressant (164 participants); one combined carisoprodol,
paracetamol (acetaminophen), and caffeine (58 participants); one combined tramadol
and paracetamol (acetaminophen) (315 participants); one combined malic acid and magnesium
(24 participants); one combined a monoamine oxidase inhibitor with 5‐hydroxytryptophan
(200 participants); and one combined pregabalin with duloxetine (41 participants).
Six studies compared the combination of multiple agents with each component alone
and with inactive placebo; three studies compared combination pharmacotherapy with
each individual component but did not include an inactive placebo group; two studies
compared the combination of two agents with only one of the agents alone; and three
studies compared the combination of two or more agents only with inactive placebo.
Heterogeneity among studies in terms of class of agents evaluated, specific combinations
used, outcomes reported, and doses given prevented any meta‐analysis. None of the
combinations of drugs found provided sufficient data for analysis compared with placebo
or other comparators for our preferred outcomes. We therefore provide a narrative
description of results. There was no or inadequate evidence in any comparison for
primary and secondary outcomes. Two studies only reported any primary outcomes of
interest (patient‐reported pain relief of 30%, or 50%, or greater). For each 'Risk
of bias' item, only half or fewer of studies had unequivocal low risk of bias. Small
size and selective reporting were common as high risk of bias. Our GRADE assessment
was therefore very low for primary outcomes of pain relief of 30% or 50% or greater,
PGIC much or very much improved or very much improved, any pain‐related outcome, participants
experiencing any adverse event, any serious adverse event, or withdrawing because
of an adverse event. Three studies found some evidence that combination pharmacotherapy
reduced pain compared to monotherapy; these trials tested three different combinations:
melatonin and amitriptyline, fluoxetine and amitriptyline, and pregabalin and duloxetine.
Adverse events experienced by participants were not serious, and where they were reported
(in 12 out of 16 studies), all participants experienced them, regardless of treatment.
Common adverse events were nausea, dizziness, somnolence, and headache. There are
few, large, high‐quality trials comparing combination pharmacotherapy with monotherapy
for fibromyalgia, consequently limiting evidence to support or refute the use of combination
pharmacotherapy for fibromyalgia. Combinations of drugs versus single drugs to treat
fibromyalgia pain in adults Bottom line There is no good evidence to prove or disprove
that combining drugs is better than using single drugs for fibromyalgia. Background
People with fibromyalgia experience constant, widespread pain, sleep problems, and
fatigue. Common drugs such as paracetamol (acetaminophen) and ibuprofen are not usually
effective. Medicines used to treat epilepsy or depression can sometimes be effective
for fibromyalgia and other forms of long‐lasting pain where there may be nerve damage.
Many individuals with fibromyalgia take many different drugs to deal with pain. We
did this review to find the evidence about using combinations of drugs compared to
single drugs. Study characteristics In September 2017 we searched for clinical trials
where combinations of medicines were used for fibromyalgia pain in adults. We found
16 studies evaluating combinations of drugs versus one drug for fibromyalgia pain.
Key results These studies looked at combinations of all sorts of different drugs,
but did not provide enough data to draw any conclusions. Many of the studies did not
directly compare a combination of drugs with each single drug. They sometimes compared
a combination of medicines with only one of the medicines in the combination, or with
only placebo. This limited our ability to make any conclusions. Most studies did not
report any of the outcomes important to people with fibromyalgia. Some studies showed
that a combination of drugs is better at reducing pain than one drug alone, but other
studies showed that one drug alone is better than a combination of drugs. Other studies
did not find any difference between combinations of drugs and single drugs. Side effects
were not severe, and generally were not different between combination therapy and
monotherapy. Quality of the evidence We rated the quality of the evidence from studies
using four levels: very low, low, moderate, or high. Very low‐quality evidence means
that we are very uncertain about the results. High‐quality evidence means that we
are very confident in the results. Overall, the quality of evidence for important
outcomes was very low. None of the combinations of drugs provided enough information
for our preferred outcomes. We think that new studies will be very likely to change
any conclusions drawn from these studies.