Only a minority of patients with moderate to severe fibromyalgia get pain relief from the antiepileptic pregabalin, but the quality of that pain relief is strong, an updated review of the related literature concludes.
“Pregabalin works extraordinarily well in 1 person in 10 who has fibromyalgia and it doesn’t work for the other 9 patients, and that’s probably the same for almost any drug that you might want to use in fibromyalgia,” said study author R. Andrew Moore, PhD, DSc, a senior pain researcher at the University of Oxford, United Kingdom.
“The good news is that when it works, it works not just on the pain, but for sleep, for depression, for quality of life, and for the ability to work. People’s lives can be transformed by getting rid of the pain.”
Like some other drugs, pregabalin is “worth a try,” and if it doesn’t work within about 6 weeks, “it’s never going to work,” said Dr Moore.
The new review was published online September 29 in theCochrane Database of Systematic Reviews.
The review is an update of one originally published in 2009 that examined the effects of pregabalin in all types of pain. This more recent review included only studies of patients with fibromyalgia.
Fibromyalgia is characterized by persistent, widespread pain and tenderness, sleep problems, and fatigue. The condition is “not uncommon” and “affects mostly women in their 50s when they’re perhaps most productive, whether it’s in the home or the workplace, and it can be quite devastating,” said Dr Moore.
Common pain-relieving medications, such as acetaminophen (paracetamol) and ibuprofen, are not usually effective, but drugs used to treat epilepsy or depression can be helpful in relieving pain.
Pregabalin (Lyrica, Pfizer, as well as other generic brands) is an antiepileptic agent also licensed to treat fibromyalgia in the United States and some other parts of the world, although not the United Kingdom.
New Studies
Researchers searched scientific databases for studies of the effects of pregabalin in adults with fibromyalgia who had moderate to severe pain.
The review included eight studies, among them three new published papers. Two of these new studies were of classic design in which patients were randomly assigned at the start of the study to pregabalin or placebo. One used a more sensitive design called enriched enrollment randomized withdrawal, in which participants who had a good pain response and could tolerate the medicine were first identified and then randomly assigned to continued treatment with pregabalin or placebo.
The studies were all randomized and double-blind and included mainly women in their 50s, but they often excluded people with depression. They lasted a minimum of 8 weeks, but one lasted 6 months.
The primary outcome used was changes to the Global Impressions of Change scale. The initial average pain score of study participants was 7 of 10. Their average duration of symptoms was 4 years.
Studies had a low risk of bias, except that the last observation carried forward imputation method used in analyses of the primary outcomes could overestimate treatment effect, according to the authors.Continue Reading
In five high-quality studies that included 1874 participants, the researchers found a notable benefit from pregabalin.
In these studies, the agent increased the number of participants experiencing a reduction of least 50% in pain intensity (substantial benefit) after 12 or 13 weeks of stable treatment (relative risk [RR], 1.8; 95% confidence interval [CI], 1.4 – 2.1).
Substantial benefit with pregabalin at doses of 300 to 600 mg daily was experienced by about 14% of participants with placebo but about 9% more with pregabalin 300 to 600 mg.
“That’s a marvelous response,” commented Dr Moore.
There was also evidence of a more moderate benefit in some patients. Pregabalin increased the number of participants experiencing at least 30% pain intensity reduction after 12 or 13 weeks of stable treatment (RR, 1.5; 95% CI, 1.3 – 1.7).
Moderate benefit was experienced by about 28% of participants with placebo but about 11% more with pregabalin 300 and 600 mg (39%).
Dr Moore noted that while pain relief was predominantly seen at doses of 300 to 600 mg daily, there was not a “strict, straight dose-response relationship.”
Adverse Events
The majority (70% to 90%) of participants in all treatment groups experienced adverse events (AEs). Dizziness, somnolence, weight gain, and peripheral edema were more common with pregabalin than with placebo.
Serious AEs did not differ between active treatment and placebo groups.
Withdrawals due to AEs were about 10% higher with pregabalin than with placebo, but withdrawals due to lack of efficacy were about 6% lower with the active drug.
The authors concluded that pregabalin 300 to 600 mg produces a major reduction in pain intensity with tolerable adverse events for a small proportion of patients (about 10% more than placebo).
This degree of pain relief is typically accompanied by improvements in other areas, including sleep, work productivity, and quality of life, said Dr Moore.
The study results are similar to those seen with other effective medicines in fibromyalgia, such as milnacipran and duloxetine, Dr Moore noted. He added that nonsteroidal anti-inflammatory drugs and antidepressants also work in a small number of patients with chronic pain.
As with other drugs, dosing for pregabalin in the clinic should “start low and go up slow” because if patients are given a high dose right away, “they will stop taking it very quickly” because of intolerable side effects, said Dr Moore.
Switching Rules
Because relatively few patients achieve a worthwhile response with pregabalin, the authors recommend establishing “switching rules” so that when a patient doesn’t respond, they can be switched to an alternative medication.
“If you’re going to get a benefit, you get it early and it tends to remain, and if you don’t get a benefit by week 6, you’re not going to get it,” said Dr Moore.
It’s impossible to know which pain patients will respond to this drug. “Every analysis that has tried to look at patient demographics in any sort of chronic pain has failed,” said Dr Moore.
That’s because myriad factors contribute to drug response, including “multiple” neurologic pathways and neurotransmitters involved in pain, genetics of drug metabolism, and the “utter complexity of pain itself,” said Dr Moore.
Commenting on the study, Daniel Clauw, MD, professor of anesthesiology, medicine (rheumatology) and psychiatry, and director of the Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, said he agrees with the findings.
However, he stressed that “this is about as good as it gets” in treating chronic pain with medications.
“There is really no class of drug in any chronic pain state that does better than this — they all work in only about a third or so of patients. For example, opioids would look even worse than this in any type of chronic pain condition.”
Dr Moore has received grant support from RB relating to individual patient level analyses of trial data on ibuprofen in acute pain and the effects of food on drug absorption of analgesics (2013) and from Grünenthal relating to individual patient level analyses of trial data regarding tapentadol in osteoarthritis and back pain (2015). He has received honoraria for attending boards with Menarini concerning methods of analgesic trial design (2014), with Novartis (2014) about the design of network meta-analyses, and RB on understanding pharmacokinetics of drug uptake (2015). Dr Clauw does consulting for Pfizer and other drug companies.
