When Mary’s* grandmother had her leg amputated at the knee, doctors prescribed gabapentin for her phantom leg pain.
“I remember thinking that was super weird,” Mary said, because she herself had a prescription for gabapentin too. Mary is 28, and has been taking the drug—a generic medication also sold as Neurontin—for nearly a decade. Her doctor gave it to her to balance out the effects of her ADHD medication, Concerta. “Why was something I was taking to take the edge off an ADHD drug also being given to an amputee?” she wondered.
Indeed, the Food and Drug Administration hasn't actually approved gabapentin for either of those uses—gabapentin is approved for treating seizures and nerve pain that can happen after shingles. Yet its reach extends much, much further. A person might receive it for migraines, fibromyalgia, hot flashes, depression, bipolar disorder, restless leg syndrome, anxiety, and a wide variety of other nerve and chronic pain issues. It's even given to cats and dogs with chronic pain.
“It's the ‘let's just throw something at the wall and hope that it magically sticks’ drug," said Jordan Covvey, an assistant professor of pharmacy administration at Duquesne University School of Pharmacy. "There’s a lot of damage that could be happening with that sort of strategy."
Treating conditions like chronic pain, depression, or anxiety is hard. The medications doctors have to offer can come with side effects, the potential for misuse, and sometimes they just plain don't work. Gabapentin has been considered relatively safe, and its broad effects on the brain mean, theoretically, that it could help a wide variety of disorders. It's said to have a calming effect and touted as non-addictive. As a result, it is often the drug of choice when Plans A, B, or C don't work out. And some people say it works for them.
But recent studies and data are now questioning gabapentin's role as a benign catch-all. They're finding that, when used along with other drugs, gabapentin does have the potential to be misused, and is linked to an increased risk of death when combined with opioids—a connection that's particularly alarming since it's so often prescribed for pain. A handful of lawsuits allege that its use is associated with suicide, a worrying correlation for a medication given to people with pre-existing mental health disorders.
All these emerging risks are compounded by many experts saying that the evidence for gabapentin's non-FDA-approved uses, like Mary’s and her grandmother’s, isn't convincing after all. When it's given to people with depression or pain or anxiety, even if it's not hurting them outright, it might not be helping.
For a drug that may not be providing any benefit, are the risks worth it?
Pharma execs in the 90s lied to the public to get more people to take gabapentin
Despite the fact that there’s new scrutiny on gabapentin, the number of people taking it continues to rise. In the United States, its use more than tripled between 2002 and 2015. Gabapentin was the 10th most commonly prescribed medication in 2017, when there were almost 70 million prescriptions—more than for amoxicillin, one of the most frequently prescribed antibiotics.
The vast majority of gabapentin prescriptions are for off-label uses, or uses not approved by the FDA—an estimated 95 percent, according to a study of nationwide data. One survey found that gabapentin has the highest proportion of off-label prescriptions out of 160 commonly used drugs.
These incredibly large numbers just don’t make sense, said Chris Goodman, an assistant professor of clinical internal medicine at the University of South Carolina School of Medicine, who has published two papers examining gabapentin use in the U.S. There are no well-designed, placebo-controlled clinical trials for several of its off-label applications, said Joe Ross, a primary care physician at Yale University and a researcher on pharmaceutical policy. Some off-label uses may have one or two studies, but the results are either modest or inconsistent—overall, only about 20 percent of gabapentin's off-label uses have data supporting them, Ross said.
Gabapentin, and a similar drug called pregabalin, are referred to as gabapentinoids. Gabapentinoids are shaped similarly to a neurotransmitter called GABA that can block neurons and reduce the activity of the central nervous system. Because interacting with GABA receptors in the brain can lead to many different effects, the idea was that gabapentinoids could possibly affect many other conditions."The problem is that the research doesn’t strongly support the use of gabapentin in pretty much any of these instances,” Covvey said.
Goodman thinks there is reason to be wary of doctors writing so many off-label gabapentin prescriptions: When it was first patented, the company that produced it spent millions of dollars on a deceptive marketing campaign specifically to promote gabapentin's off-label potential. He thinks it's worth asking if the legacy of that marketing campaign is in some way responsible for the sheer amount of off-label use that still takes place today.
The company that made Neurontin, Parke-Davis, was a subsidiary of Warner-Lambert, which eventually got bought by Pfizer. Per 800 pages of documents that have been made public through lawsuits, it’s clear how gabapentin was pushed on doctors: Parke-Davis rated doctors by the dollar value of the prescriptions they could potentially write. They zeroed in on doctors who were influential and affiliated with major medical centers, who they thought could encourage their colleagues to use gabapentin too. The company wrote in their internal documents from the mid 1990s that this strategy would be “one of the most effective ways to communicate our message.” (The documents are in the Drug Industry Document Archive at the University of California San Francisco Library.)
Parke-Davis executives spent hundreds of thousands of dollars targeting medical residents to—as explained in one document—“influence physicians from the bottom up” and "to solidify Parke-Davis' role in the resident's mind as he/she evolves into a practicing physician.”
The company invested in “education” as a strategy, as when they organized teleconferences that connected paid doctor “moderators” with other doctors. These events were described publicly as purely educational, but one internal memo from 1995 said that “the key goal of the teleconferences was to increase new Neurontin prescriptions by convincing non-prescribers to begin prescribing and current prescribers to increase their new prescription behavior.”
Lecture series were organized with high-profile names in neurology in which the goals were to improve “public relations within the neurology community, etc., as well as [to impact] the volume of Neurontin new prescriptions.”
Parke-Davis hired medical education companies to write review papers, original articles, and letters to the editor in medical journals about gabapentin for “$13,375 to $18,000 per article,” plus a $1,000 honorarium for the author. The majority of these articles had “favorable” conclusions about gabapentin, and in most instances the payments were not disclosed.
Some of the company-funded research was intended to get FDA approval for treating more conditions, but Parke-Davis said internally that the goal of other studies was to "disseminate the information as widely as possible through the world's medical literature generating excitement in the market and stimulating off-label prescribing despite the lack of FDA approval.”
One such research initiative, called Study of Neurontin: Titration to Effectiveness and Profile of Safety, or STEPS, was an open-label study without a control group where doctors gave epilepsy patients gabapentin and increased their dose until they were either seizure-free, or they reached the maximum dosage. More than 700 doctors participated, and enrolled an average of three patients each, and were given $300 per patient.
The documents reveal that the goal of the study wasn’t to examine the effectiveness of gabapentin at different doses, as the study authors claimed, but to “teach physicians to titrate [finding the most effective dose with the least side effects] Neurontin to clinical effect” and “to give neurologists the opportunity to titrate to higher doses when needed.”
In the New England Journal of Medicine (NEJM) in 2009, researchers took a closer look at the gabapentin studies that were funded by Parke-Davis. One author, epidemiologist Kay Dickersin, said she found a number of reporting biases that affect the results of the research. One placebo-controlled study was delayed because it found that there was no effect on the primary outcome, which was neuropathic pain. Documents showed that the company held the study because “[Parke–Davis employees] should take care not to publish anything that damages neurontin's marketing success.” Trials with findings that were not statistically significant were either not published in full, or were published only after their primary outcomes were changed, which skewed the results to be significant. Other studies were manipulated to minimize or hide negative findings about the drug.
In April 1996, a biologist named David Franklin began working at Parke-Davis. Franklin knew that according to FDA rules, he was not allowed to promote off-label uses of drugs, and yet, the NEJM recounted that an executive allegedly told him:
“I want you out there every day selling Neurontin. ... We all know Neurontin's not growing for adjunctive therapy [when it gets combined with another medication], besides that's not where the money is. Pain management, now that's money...That's where we need to be, holding their hand and whispering in their ear, Neurontin for pain, Neurontin [alone], Neurontin for bipolar, Neurontin for everything. I don't want to see a single patient coming off Neurontin before they've been up to at least 4800 mg/day. I don't want to hear that safety crap either, have you tried Neurontin, every one of you should take one just to see there is nothing, it's a great drug.”
Franklin quit three months later and became a whistleblower, filing a lawsuit that ended with Parke-Davis' parent company pleading guilty in 2004 to resolve criminal charges and civil liabilities and paying $420 million in fines. Despite the lawsuits and guilty pleas, more than ten years later, Michael Steinman, a professor of medicine at UCSF, said it’s hard to know if gabapentin would be so widely used today if it weren’t for all the money poured into the off-label marketing campaigns.
“It certainly didn’t hurt,” he said. “I think the legacy of that has been that off-label prescription of gabapentin has persisted. Gabapetin has found a kind of niche to treat all sorts of things that doctors don’t know what to do with.”
Gabapentin has the potential for misuse and overdose
We know today that gabapentin is not proven to work for as many conditions as Parke-Davis wanted people to believe. But when doctors prescribe their patients gabapentin, it can be without knowing exactly what the approved uses are. Instead they are “largely guided by informal discussion with colleagues or professional meetings, as opposed to prescribers’ evaluation of its merits for a given indication,” according to a 2018 study on gabapentin off-label use.
Seth Landefeld, the chair of the Department of Medicine at the University of Alabama at Birmingham, echoed that doctors will reach for gabapentin in situations where someone is difficult to treat. This tendency has been exacerbated by the opioid crisis—as doctors are searching for alternatives to opioids, gabapentinoid use is increasing, according to a review published by Goodman. The evidence for its use in nerve pain after shingles and diabetic neuropathy created a narrative that gabapentin could be helpful with pain, Goodman said. “From these trials, a house of cards has been built.”
A Cochrane review, a type of highly respected analysis that combines results from multiple studies, found that while gabapentin does seem to provide pain relief for its on-label uses, the support for others was limited. Reviews on other off-label applications, like for migraine, fibromyalgia, mental illness, and substance dependence have “found modest to no effect on relevant clinical outcomes,” according to a 2018 paper in Substance Abuse: Research and Treatment.
While gabapentin certainly has fewer side effects and risks than opioids, Covvey said, there is growing evidence that people—and especially those with opioid-use disorder—are misusing gabapentinoids. That makes pain patients a problematic group to be taking gabapentin—there have been reports of recreational gabapentin use, or intentional misuse, with one study reporting that these cases are increasing at “an alarming rate.” One study found that, from 2008 to 2012, there was a 3,000 percent increase in people saying they used gabapentin “to get high."
It wasn’t until 2017 that researchers conducted a national assessment of gabapentin misuse, and found that gabapentin use showed similar patterns to other medications that are misused. In small studies that included surveys from patients, they found that gabapentin was being used alongside opioids to increase their high. These consequences can be deadly: Using gabapentin at the same time as opioids is associated with four times the risk of “respiratory depression,” which is the main cause of death for overdoses.
According to a 2019 report of drug misuse in the U.S. by Quest Diagnostics, use of non-prescribed gabapentin rose 40 percent in just one year, from 2017 to 2018, which puts its misuse higher than that of opioids and benzodiazepines. "This makes gabapentin the most commonly misused prescription drug in 11 states and in the top three drug groups in an additional 10 states," the report said. The same report acknowledged there wasn't a lot of risk for misuse or addiction when gabapentin was taken alone. But when it's taken in combination with other medications, like muscle relaxants, opioids, or even anxiety medications, it can lead to a person feeling high, and the risks increase.
Still, gabapentin is not classified as a controlled substance—which have different regulations for refills—at the federal level. Since 2016, several states have implemented or are creating laws to add more checks to the gabapentin-prescribing process. Ohio, Kentucky, and West Virginia have made it a controlled substance at the state level because of an increase in gabapentin-linked deaths. In January of this year, Michigan classified gabapentin as a Schedule 5 substance, which is the same scheduling as certain cough medicines that contain codeine. Virginia followed suit in July of this year, and Alabama will do the same starting in November 2019.
Goodman said that, while the opioid crisis didn't help, he thinks the rise in prescriptions would have happened anyway. “The industry influence was too heavy, clinicians were already increasing their use of these drugs prior to the opioid crisis being publicized,” he said. “The most frustrating aspect of this increase in gabapentinoids is that we actually know a great deal about the manipulation of trial reporting, regulators, clinicians, and others—yet here we are."
As a drug for mental health, the evidence for gabapentin is sparse
Even-less examined than gabapentin for other types of pain are the prescriptions for mental health disorders. Mary’s doctor did tell her that gabapentin was an epilepsy medication being used off-label, but also said with confidence that it was helpful as a mood stabilizer. Nicole, a 30-year-old living in Los Angeles who didn't want to use her last name, was prescribed gabapentin in high school for major depressive disorder—her doctor said that gabapentin was effective for evening out mood swings.
But the few studies that exist haven't been able to back those claims. In 2000, there were two randomized, placebo-controlled trials that showed that gabapentin did not work better than placebo for bipolar, and one study found that gabapentin was worse than placebos when treating bipolar mania. Another review on gabapentin looked at studies on gabapentin's effects on psychiatric diseases—it showed some positive results in treating social phobia, but that it was not effective for panic disorder, OCD, or bipolar disorder.
Rebecca*, 31, was given gabapentin for generalized anxiety after trying Celexa and Effexor, two commonly used medications. She said she went home, looked gabapentin up, saw all of its off-label uses and thought to herself: "It can’t possibly do all of this."
Rebecca took the medication, but isn't sure it did much. "I was already on other medications for psychiatric reasons, and I had cycled through so many different pills and dosages that it all blended together," she said. "In retrospect I'm not sure any of it made a difference at all." When she went off of gabapentin a couple of months ago, she didn't notice any symptoms, good or bad.
There have been recent claims that taking gabapentin could be linked to an increased risk of suicide in populations prone to mental health issues, though studies on this have been mixed and more investigation is needed. According to Bloomberg, there are more than 1,000 lawsuits accusing now-owner Pfizer of promoting gabapentin for off-label mental health use and alleging that they don't mention the risk for increased suicidality. In 2010, Pfizer settled a wrongful death lawsuit which alleged that gabapentin led to a minister's death by suicide. It was the second suicide-related settlement related to the drug; the first was for $400,000 for a death in Massachusetts.
Meanwhile, the benefits of gabapentin for mental health remain opaque: Some people say it helps them. When Nicole takes it, it does even her out, she said, though she uses it in combination with other medications. “It's hard to tell if gabapentin would really do anything on its own for me, but I do feel comfortable taking it even if what I feel is just a placebo effect,” she said.
Michael, a 41-year-old lawyer in Phoenix, Arizona, was given gabapentin six years ago for anxiety, and takes it because his doctor said it was non-addictive, and he has alcoholism. “Maybe it’s a placebo effect, but I do know that if I start to feel anxiety coming on or if I know that I’ll be in a stressful situation in an hour or so, I can take one or two and feel better," he said.
He doesn’t have many expectations for the drug, but continues to keep it in his regimen anyway. “I’ve run out of my prescription before seeing my doctor and it doesn’t really bother me. I’ve had no physical withdrawals to speak of. If anything it’s more mental if I 'need' a pill and can’t have one.”
It's possible that gabapentin is helpful in certain cases, for certain mental health disorders, or in combination with other drugs—but until more research is done, it won't be clear as to why or when it should be taken for mental health concerns. Given the limited evidence that exists now, experts remain skeptical. “I can't think of a single mental health condition or indication where gabapentin should be used,” Covvey said. “None have any strong indication that gabapentin provides any discernible benefit.”
People who take gabapentin are often in the dark about it
Every drug has risks and benefits. When people take a medication without substantial evidence that it works, the chance they’ll benefit from it is lowered, since they’re now disproportionately exposing themselves to its risks, Ross said. Outside of the potential risks of gabapentin, is it ethical to give a patient a medication that might not do anything, when they could instead take a treatment that might work better?
As long as doctors don't have better alternatives for opioids, or better medications for mental health than current antidepressants or benzodiazepines, gabapentin will continue to fill the gap. “Prescribers are scrambling trying to figure out what alternative therapies are out there to help their patients, and gabapentin is the place that they've turned," Covvey said.
Tatum, a 23-year-old living in Austin, Texas, was prescribed gabapentin two years ago for anxiety. He tried several drugs before that, and while some of them worked, he didn’t like their side effects, so his doctor gave him gabapentin, telling him that it could help anxiety in people who didn't react well to other medications.
Tatum said after taking gabapentin, his anxiety and intrusive thoughts were more manageable. He wasn’t aware of gabapentin’s dicey history, but said he would have taken anything to decrease his anxiety—knowing about it wouldn’t have stopped him.
A nurse practitioner gave gabapentin to Rina, a 19-year-old living in Dallas about a year ago. She didn't explain in depth what it was except to say that it could help with anxiety, and that it was similar to Xanax, but without the risk of getting addicted to it. Rina said she didn’t feel any difference in her anxiety but she did feel tired, and when the prescription ran out she stopped taking it.
This burden of medication trial and error for patients is really high, Covvey said. Trying a dozen different drugs, and dealing with their interactions and side effects, can be exhausting and frustrating. What concerns her is the communication—or lack thereof—that takes place between doctor and patient for gabapentin's off-label uses. Are people being told what the drug is, why they’re trying it, that it’s being used off-label? Are they told about the amount of evidence for what they're trying it for? About its potential for misuse?
“When we go off script without evidence, particularly in instances where we don't discuss that with patients, that really concerns me," Covvey said. "I wonder how often that's happening with gabapentin—if the people being prescribed really understand the actual evidence this is going to work for them."
If doctors are seeing measurable benefits from gabapentin, for mental health or for pain, then Ross thinks it should be studied more systematically. He believes the FDA should require drug manufacturers to do additional safety and efficacy studies once off-label use of a certain medication reaches a certain threshold, say 20 percent of all prescriptions. Otherwise, he said, it ends up being an effort from researchers and patients to ask the tough questions. The FDA did not respond to a request for comment by publication time.
It's on patients to ask even simple questions, like is this doing anything for me? And can I stop it? Mary said that gabapentin isn't harming her, but it can cause minor annoyances. Interactions are one: She's been advised not to take NyQuil or CBD with gabapentin. If she takes it too late at night, waking up can be difficult, or lead to a groggy morning. She also takes Synthroid for an underactive thyroid, her ADHD medication, and birth control, and feels it's a lot of medication to juggle. “It adds up, and I would like to not be on all of those,” she said.
Recently, she’s been trying to wean herself off gabapentin. Her doctor now isn't the same one who prescribed the drug, and it can be tough to figure out who to ask for help with that. “One time in urgent care they asked me about my medications, and I mentioned I was on it and they were like: Huh?" She said. "They thought it was kind of odd.”
*Names have been changed to protect medical privacy.
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