Scott Gottlieb, the Commissioner of the FDA, recently expressed concern about the potential misuse and abuse of gabapentinoids, gabapentin (Neurontin) and pregabalin (Lyrica). Although abuse of gabapentinoids is not widespread yet, use continues to increase, especially for gabapentin. He said the FDA is investigating whether their abuse is growing and what should be done about the problem. “Although limited, the data suggest that gabapentinoid misuse and abuse may be growing, both when taken alone and when taken with opioids, benzodiazepines, or other central nervous system depressants.” Data from GoodRx indicated gabapentin was the sixth-most prescribed drug in the nation in November of 2021, warning of the potential for misuse and overdose deaths.
He said the FDA has looked at social media sites where opioid users share descriptions on methods for misusing or abusing gabapentinoids. “And we’ve tasked our surveillance and epidemiology group inside FDA – who are focused on spotting early patterns of abuse of controlled substances – with investigating the use patterns of the gabapentinoids.” Stay tuned; he said the FDA will have more to say on this soon. Swift attention to this matter is partly a consequence of the lessons of history. “We need to get ahead of these problems.”
In July of 2017, STAT News published an article on gabapentin abuse in the town of Athens, Ohio. The Ohio Board of Pharmacy reported sales of gabapentin prescriptions surpassed oxycodone by 9 million doses in December of 2016. An Athens pharmacist noticed signs of gabapentin misuse five years ago when patients began picking up their prescription refills several days before the prescription ran out. She said: “Gabapentin is so readily available. . . . That, in my opinion, is where a lot of that danger is. It’s available to be abused.” In May of 2017, her pharmacy filled approximately 33 prescriptions of gabapentin per week, dispensing 90 to 120 pills per client.
As providers dole out the drug in mass quantities for conditions such as restless legs syndrome and alcoholism, it is being subverted to a drug of abuse. Gabapentin can enhance the euphoria caused by an opioid and stave off drug withdrawals. In addition, it can bypass the blocking effects of medications used for addiction treatment, enabling patients to get high while in recovery.
This is not simply a new problem or concern. Doctors and researchers have been pointing out the potential for gabapentin abuse for at least six years. In 2012 Smith et al. in “Substance Misuse of Gabapentin” noted gabapentin was prescribed without restriction and escalating doses were recommended. This made it easy to misuse or develop an addiction of the drug. They recommended introducing routine testing for gabapentin in urine screens. “This will inform clinical and political approaches to this possible new and dangerous type of substance misuse, as well as safe management of the distress caused by neuropathic pain.”
A 2014 a Medscape article by Sarah Melton asked, “Has Gabapentin Become a Drug of Abuse?” She summarized a 2004 report describing gabapentin misuse in Florida correctional facilities. A recall at one of the larger facilities revealed that: “only 19 of 96 prescriptions were in the hands of the intended patients.” She then reviewed several reported cases of gabapentin abuse dating back to 2001. There also was a report of “Gabapentin Abuse in Order to Potentiate the Effect of Methadone.”
More recent concerns with the abuse and misuse of gabapentinoids include three separate articles published in 2017. “Abuse and Misuse of Pregabalin and Gabapentin” did a systematic review of fifty-nine studies. The authors’ analysis indicated patients were self-administering higher than recommended doses for the high. “Evidence suggests gabapentinoids possess potential for abuse, particularly in individuals with a history of opioid abuse, and reports of such abuse are increasingly being documented. Prescribers should be aware of high-risk populations and monitor for signs of abuse.”
Shanthanna et al. looked at the “Benefits and Safety of Gabapentinoids in Chronic Low Back Pain.” The authors noted that while there was no clear rationale for using gabapentinoids to treat chronic low back pain (CLBP), they were increasingly used for nonspecific CLBP. They said that despite the widespread use, they found very few RCTs (random control trials) that attempted to assess the benefit of using gabapentin (GB) or pregabalin (PG) in patients with CLBP. “Use of GB and PG, compared to placebo and active analgesic comparators, respectively, were associated with significant increase in adverse effects [with] limited evidence for improvement in pain scores or other outcomes.”
In The New England Journal of Medicine Goodman and Brett said they believed gabapentinoids were being overprescribed in part as a response to the opioid epidemic. They said the FDA approved gabapentinoids for the treatment of postherpetic neuralgia (gabapentin and pregabalin), fibromyalgia (pregabalin) and neuropathic pain associated with diabetes or spinal cord injuries (pregabalin). Yet they have seen clinicians prescribing both for almost any type of pain; and their “experience is supported by national prescribing data.” They suspected “that clinicians who are desperate for alternatives to opioids have lowered their threshold for prescribing gabapentinoids to patients with various types of acute, subacute, and chronic noncancer pain.”
They noted that past marketing practices of gabapentin (Neurontin) also help explain the growing use of gabapentinoids for various types of pain. After Neurontin was approved as an antiseizure medication in 1993, the manufacturer engaged in an extensive (and illegal) marketing campaign to increase off-label prescribing of Neurontin for pain. “Research had suggested that the drug had analgesic properties, but postherpetic neuralgia was the only pain-related indication for which there was sufficient evidence from clinical trials to justify FDA approval.” The company (Pfizer and its subsidiaries) eventually admitted to improper off-label marketing and paid $897 million in three separate cases (criminal and civil) of marketing for off label unapproved uses. Also see “Twentieth Century Snake Oil” and “The Evolution of Neurontin Abuse.”
Goodman and Brett thought there were several reasons to be concerned with the trend to prescribe gabapentinoids as supposedly safer alternatives to opioids. First, there was no reasonably robust evidence to support the use of gabapentinoids for off-label use. They found that most recently published studies of gabapentinoids for pain examined single-dose or short-course gabapentinoids for mitigating postoperative pain, “an indication that isn’t relevant to general outpatient practice.”
Relatively few clinical trials have assessed the use of gabapentinoids in the common pain syndromes for which they are prescribed off-label — and many of those trials were uncontrolled or inadequately controlled and of short duration. Among the few well-conducted, properly controlled, double-blind studies, results have been mixed at best. In a recent rigorously conducted placebo-controlled trial, pregabalin was ineffective for patients with painful sciatica.
Second, the side effects with gabapentinoids are not trivial ones. Sedation and dizziness are fairly common; and some patients have cognitive difficulties while taking these drugs. In a sciatica trail, 40% of patient taking pregabalin reported dizziness, as compared to 13% of those taking a placebo. The adverse effects are reversible and not always severe; and they are reversible when the drugs are discontinued. However, gabapentinoids are often taken with other medication with central nervous system side effects. “Such polypharmacy might affect neurologic function in subtle but clinically important ways.”
Third, evidence suggests that some patients misuse, abuse, or divert gabapentin and pregabalin. Some users describe euphoric effects, and patients can experience withdrawal when high doses are stopped abruptly. The likelihood of gabapentinoid abuse is reportedly heightened among current or past users of opioids and benzodiazepines. Whether misuse and abuse of gabapentinoids will become an important public health issue remains to be seen. [That is the FDA concern noted in the opening paragraph]
Fourth, “the indiscriminate off-label use of gabapentinoids reinforces the tendency to view the treatment of pain through a pharmacologic lens.” Goodman and Brett thought appropriate pain management of acute and chronic pain management should examine how the patient’s pain is affecting activity and function and set ‘realistic goals that may include coping with or mitigating pain,” but not necessarily eliminating it. “Writing a prescription and moving on is much easier and less stressful for clinicians.” And nonpharmacologic approaches may be unavailable or unaffordable for many patients.
Nevertheless, clinicians shouldn’t assume that gabapentinoids are an effective approach for most pain syndromes or a routinely appropriate substitute for opioids. Although gabapentinoids offer an alternative that is potentially safer than opioids (and presumably more effective in selected patients), additional research is needed to more clearly define their role in pain management.
Gabapentin can enhance the euphoria caused by opioids, including methadone or buprenorphine; and it staves off drug withdrawals. These factors make it an attractive supplement for individuals misusing or abusing opioid or benzodiazepines. In large enough quantities, it can also have its own euphoric effect. There can be withdrawal symptoms. And reports of misuse and abuse of gabapentinoids are increasing.
There is also no “reasonably robust evidence” for off-label pain relief at this time. It may be a matter of medical professionals looking at the treatment of pain through a pharmacologic lens (with the encouragement of pharmaceutical companies). More research is needed into the efficacy of gabapentinoids in pain management. Adverse effects can be problematic, especially if a gabapentinoid is taken with other medications with central nervous system side effects. Given the history of deceit and exaggerated claims made with gabapentin, let’s be cautious of how we use it. Remember that “fools rush in …”