As doctors have tried to steer their chronic pain patients away from highly addictive opioids, many have turned to two antiseizure drugs, but a new review finds they are only "modestly effective" at treating pain.
Gabapentin and pregabalin are being prescribed to manage all types of pain, but clinical trial data shows that the drugs have limited effectiveness, said lead researcher Craig Williams, a professor of pharmacy with Oregon State University in Corvallis, Ore.
In fact, patients on a placebo tended to report one-third to one-half the pain reduction benefit of patients who took either gabapentin or pregabalin.
“When you dig into those trials, it's not very impressive,” Williams said. “I think if I pulled in a dozen of my clinical colleagues and said, 'Let's sit down, look at this data together,' at the end they would not be very impressed with the pain benefits these drugs offer.”
Data show that the number needed to treat for gabapentin is 1 out of 7 people, said Dr. Houman Danesh, director of integrative pain management with the Icahn School of Medicine at Mount Sinai, in New York City.
“That means if you treat seven patients, one of them will respond for pain control,” Danesh said. “I think a lot of physicians when they start gabapentin don't realize that.”
Approximately 1 in 5 adults with chronic pain are taking a gabapentinoid, the class of medication to which these two drugs belong, the researchers said in background notes.
Gabapentin prescriptions increased to 64 million a year in 2016, up from 39 million in 2012, the researchers said. During that same period, spending on pregabalin more than doubled, from $2 billion to nearly $4.5 billion a year. The widespread use of both medications is largely due to the opioid epidemic, which has caused doctors to cast around for any non-narcotic treatments they can find, Williams explained.
“In general, you stop a seizure by dampening transmission by neurons, and pain wherever it's occurring is transmitted to the brain via neurons,” Williams said. “So, it's not a crazy concept to say if I can kind of dampen down neurotransmission, I can maybe modulate or reduce pain sensation.”
There's also a possibility that these drugs help by calming the patient down about their pain, Danesh said, noting that pregabalin is approved to treat anxiety in Europe.
But the clinical trials that led to both drugs being approved for pain management by the U.S. Food and Drug Administration were not designed to look at long-term use, and resulted in their approval for only a few select applications, the researchers added.
To this day, gabapentin is only FDA-approved to treat a single type of pain, nerve pain caused by a herpes flare-up, Williams noted.
Safer than opioids, but less effective
Pregabalin's usefulness is somewhat broader, having been approved to treat nerve pain from a herpes flare-up, diabetic peripheral neuropathy, fibromyalgia and nerve pain associated with a spinal cord injury, he said.
“They should be used primarily for nerve pain — burning, sharp, static, tingling kind of pain,” Danesh said. “If you're using it for low back pain, it's probably not the best use of the medication."
For this review, Williams and his colleagues evaluated clinical trial data submitted for FDA approval of the two drugs, as well as trials that compared the drugs against each other.
Studies show both drugs work about as well as the other in treating pain, and that's not very well at all, Williams said.
“On an 11-point pain scale, you could say, on average, gabapentinoids reduced pain by two points and placebo by about one point,” Williams said. “Pain of eight going to seven or five going to three, that's not insignificant, certainly for that individual patient, but that's not terribly effective. It's not a magnitude of benefit like taking pain of eight down to two.”
Further, prescription numbers indicate the drugs are being doled out to treat all sorts of pain beyond the nerve pain that formed the basis of their approval.
“I'd say in practice, it's common for patients to receive these for all kinds of chronic pains — for low back pain, for persistent dental pain, for just musculoskeletal shoulder and elbow pain, and kind of whatever might ail them that day,” Williams said. “These are seen pretty widely as an alternative to opioids for chronic pain from a lot of different sources.”
The new study was published Dec. 18 in the journal Drugs.
Part of the reason gabapentinoids have been so widely adopted is that they don't carry the same sort of drug interaction risks as other pain relievers, said Dr. Jianren Mao, chief of pain medicine at Massachusetts General Hospital in Boston.
“Particularly for elderly populations, they often take a very long list of medications,” Mao said. “Having a medication with a reasonable, low kind of drug interaction profile, I think it's helpful.”
That's not to say these drugs don't have side effects, though.
Dizziness, drowsiness and daytime sleepiness are the most prominent side effects — “essentially all that comes with warnings put on labels to not operate heavy machinery,” Williams said.
Side effects like hair loss seen in patients
There are also other less well-known side effects, the experts added. “Most people don't realize that gabapentin can cause hair loss,” Danesh said. “I know it's a completely vain thing, but if you're prescribed a medication you should be totally aware of such side effects.”
There's also the risk that gabapentinoids could be co-used with illicit drugs to augment a person's high, Williams said. This could increase the risk of overdose, because the drugs affect the central nervous system (CNS).
An FDA warning put out in 2019 “was specifically for respiratory suppression and slowed breathing when these gabapentinoids are used with other medications that suppress the CNS, like muscle relaxants and like opioids,” Williams said.
Pain experts said one reason why gabapentinoids are used so widely off-label is that there simply aren't enough good options for pain relief.
“The hard thing that we run into in pain management is that a lot of the medications that we use are modestly effective. There's no one medication that we can say is the perfect medication for any patient,” said Dr. Desimir Mijatovic, a pain physician with the Cleveland Clinic's Center for Spine Health. “So, I do think that the people who prescribe these medications are very well aware of their limitations.”
Williams agreed that some patients still might benefit from gabapentinoids, but that doctors need to monitor them closely to make sure the good outweighs the ill.
“The article should serve as kind of a, I think a, bit of a caution sign to limit the durations, like we do with opioids, and come back to that patient and ask them in a few weeks, 'Is this helping?'” Williams said. “And if not, don't continue it long-term because data is not long-term and the side effects are substantial, and I think often underappreciated by prescribers in practice.”
Doctors should also look at other means of pain relief, particularly if it's not nerve-related pain, Williams added.
These include over-the-counter pain relievers, stretching, physical therapy, counseling and meditation.
“I wish I had a great new medicine to present along with this and say, 'Hey, use this instead,'” Williams said. “Unfortunately, that medicine just may not exist. Searching for a pharmacologic answer to chronic pain is probably just a rabbit hole we've been going down for the past couple of decades.”
The Mayo Clinic has more about medication decisions for chronic pain.
SOURCES: Craig Williams, PharmD, professor, pharmacy, Oregon State University, Corvallis, Ore.; Houman Danesh, MD, director, integrative pain management, Icahn School of Medicine at Mount Sinai, New York City; Jianren Mao, MD, PhD, chief, pain medicine, Massachusetts General Hospital, Boston; Desimir Mijatovic, MD, pain physician, Cleveland Clinic's Center for Spine Health; Drugs, Dec. 18, 2022