Tag: gabapentinoids

05/14/24

Global Concerns with Gabapentinoids

Image by Gustavo Ackles from Pixabay

I saw an unexpected market research report on LinkedIn, Gabapentin Market Size in 2024. Unexpected in the sense that I was surprised that a drug that has been a generic medication since 2004 would have a place in the global market in 2024. The Report, more of a teaser to get you to pay $4900 for the full report from Precision Reports, said the global market is anticipated to rise at a considerable rate between 2024 and 2031. Gabapentin was the 6th most prescribed drug of 2021 and the 10th most prescribed drug of 2022. Not bad for a medication referred to once as “the snake oil of the twentieth century” by a Pfizer executive (See “Twentieth Century Snake Oil”).

Chan et al evaluated the global trends in gabapentinoid (gabapentin and pregabalin, Neurontin and Lyrica respectively) consumption between 2008-2018 from 65 countries and regions globally and showed there was a 17.20% increase in global consumption. “The study shows that despite differences in healthcare system and culture, a consistent increase in gabapentinoid consumption is observed worldwide, with high-income countries remaining the largest consumers.” Approved indications include neuropathic pain, fibromyalgia, restless legs syndrome, generalized anxiety disorder (not in the U.S.), and others. Given their potential for misuse, the authors said there was a need to understand the global consumption of gabapentinoids.

One of the major factors driving the overall increase in gabapentinoid consumption is their wide range of indications. They suggested the need to revisit the appropriateness of off-label gabapentinoid prescriptions as it seems to be based on clinical experience with mixed or limited evidence. Another reason for the increase of gabapentinoid consumption is they are viewed as a safer alternative than opioids and benzodiazepines. This is despite the risk of misuse with or without their concurrent use with opioids or benzodiazepines. “Patients who have a history of opioid, benzodiazepine, or alcohol misuse have been reported as being vulnerable to misuse gabapentinoids.”

The consumption of gabapentinoids has increased significantly over the span of 11 years, from 2008-2018, inclusive. This increasing trend has been consistent among countries from all income levels. High-income countries remained to be the largest consumers of gabapentinoids, whereas upper-middle-income and lower-middle-income countries showed greater growth in consumption. Against the background of this evidence of increasing use, considering both the abuse potential and the mixed evidence for off-label use, further studies are warranted to investigate the implications behind the increase in consumption and if there is a case for international and national regulatory bodies to review existing treatment guidelines and public health policy relating to gabapentinoids.

Patricia Weiser, PharmD described the similarities and differences of gabapentin and pregabalin. They belong to the same class of drugs known as anticonvulsants or antiepileptic drugs (AEDs). They work by mimicking the effects of gamma-aminobutyric acid (GABA). GABA is thought to have a calming effect and reduce nerve activity in the brain, “which is believed to slow down nerve signal involved in seizures and pain.” Pregabalin is more potent than gabapentin on a per-milligram (mg) basis.  She said off-label uses of both include: generalized anxiety disorder, panic disorder, PTSD, OCD, migraine, bipolar disorder and substance use disorder.

Peet et al noted around 95% of gabapentin prescriptions in the U.S. were for off-label pain management use, despite studies questioning its pain management effectiveness and its misuse with concurrent opioid therapy. In 2006, opioid analgesic episodes plateaued between 50 and 56 million episodes before decreasing to 42.1 million in 2018. Gabapentin episodes increased from 1.5 million in 2006 to 8.1 million in 2018. Concurrent opioid analgesic and gabapentin episodes (OACGs) increased from 1.9% in 2006 to 7.6% in 2018, a relative increase of 344%. Between 2006 and 2018, 18.1% of all OACGs consisted of OA and gabapentin episodes beginning in the same week. See the following figure from the Peet et al study.

Despite gabapentin’s questionable effectiveness in pain management, OACG prescribing has increased, with a potential associated increased risk of all-cause and drug-related hospitalizations. Pain specialists were the most frequent OACG prescribers. Differences between specialties may be exacerbated by cases in which gabapentin may have modest impact (eg, chronic and/or neuropathic pain), by the complexity of cases overall, or because opioid prescribing restrictions more severely affect pain management strategies for complex cases. Prescribing patterns for OACG were similar to those for female patients, patients 66 years or older, and counties with high poverty levels, rural populations, and predominantly non-Hispanic White populations, suggesting that increased OACG prescribing may therefore be an unintentional consequence of opioid prescribing restrictions. Better understanding factors associated with these trends, and to what extent they may be mitigated or exacerbated by prescribing policies and/or physician education, will facilitate efforts to address this increasingly common and potentially dangerous clinical practice. Limitations of this study include observing dispensed not written prescriptions, data limited to retail pharmacies, and lacking information on patient clinical status.

These trends have led to the American Psychiatric Association warning psychiatrists of the risks of prescribing gabapentinoids in “Before You Prescribe Gabapentin, Consider These Risks” in Psychiatric News. Donald Egan noted that while gabapentin was initially marketed as having a low potential for abuse, “a growing body of evidence highlights the potential risks of overprescribing the medication.” Psychiatric News said there were several factors to keep in mind when prescribing gabapentin or with patients who have been prescribed gabapentin by another doctor. In 2004, Pfizer pleaded guilty to multiple counts of illegally promoting the off-label use of gabapentin, which resulted in $430 million in fines.

The increased use of gabapentin with opioids has contributed to a surge of negative health outcomes, including hospitalizations and death. In 2019 the FDA issued a warning about the risks of respiratory depression from gabapentinoids used in combination with CNS depressants such as opioids, antidepressants, and benzodiazepines. Despite the warning, gabapentin prescribing increased. “At least 40% to 65% of individuals with prescriptions for gabapentin and roughly 20% for individuals who misuse opioids report gabapentin misuse.”

Egan suggested gabapentin misuse could be partly driven by dependence and withdrawal symptoms. He said studies have shown that patients who took as little as 400 mg daily for 3 weeks may experience withdrawal symptoms, “including anxiety, pain, nausea, fatigue, and restlessness.” These can begin as soon as 12 hours of stopping, and can last up to 10 days. Implied here is then to taper off of gabapentin and not stop it cold turkey.

In 2022 the CDC published a Morbidity and Mortality Weekly Report (MMWR), noting the number of overdose deaths involving gabapentin between 2019 and 2020. The CDC report said gabapentin was the 7th most prescribed medication in the U.S., as opposed to the 10th most prescribed medication reported above, with 69 million prescriptions dispensed. While data indicated how gabapentin was associated with intentional abuse, less was known about the drug’s role in fatal overdoses. The CDC analyzed data from the State Unintentional Drug Overdose Reporting System (SUDORS).

The data analysis showed that of the 58,362 deaths, 9.7% (5,687) detected gabapentin in the toxicology results. Of those with a positive gabapentin test, “Gabapentin-involved deaths occurred in 2,975 of 5,687 decedents (52.3%).” The percentage of opioid-involved deaths with gabapentin remained high, ranging from 85% to 90%. “The percentage of deaths that involved a prescription opioid declined from 41.9% of deaths with gabapentin detected in the first quarter of 2019 to 33.0% during the last quarter of 2020.”

During 2019–2020, gabapentin detection and involvement in fatal drug overdoses increased, appearing to follow the rising trend in overall overdose deaths during the COVID-19 pandemic. Overall increases were largely driven by increases in synthetic opioids such as illicitly manufactured fentanyls and likely exacerbated by the social and economic consequences of the pandemic. Nearly 90% of drug overdose deaths in which gabapentin was detected also involved an opioid, particularly (and increasingly) illicitly manufactured fentanyls. Although gabapentin testing is recommended as part of comprehensive postmortem toxicology testing protocols for drug overdose death investigations in the United States, gabapentin is not included in the list of substances recommended in an adequate analyte panel and is not uniformly included on death certificates by some certifiers; therefore, overdose deaths involving gabapentin or with gabapentin detected are likely underestimated. Routine gabapentin testing, as part of comprehensive postmortem toxicology testing protocols for drug overdose death investigations, could further elucidate its role in drug overdose deaths. Despite the lack of uniform testing, gabapentin detection and involvement in overdose deaths increased during 2019–2020. These findings highlight the dangers of polysubstance use, particularly co-use of gabapentin and illicit opioids. Persons who use illicit opioids with gabapentin should be educated about the increased risk for respiratory depression and death.

Egan recommended psychiatrists educate their patients on the risks and benefits of gabapentin use, especially the potential for abuse, dependence and overdose. They should screen patients for substance use disorders and other medications, to reconcile any medications they are taking that could lead to adverse interactions. The effectiveness of gabapentin in treatment should be periodically evaluated and stopped if the desired outcomes are not achieved within six months. Finally, he said adverse events related to gabapentin should be reported. “Such information will contribute to a better understanding of the safety profile of the medication and help regulatory agencies take appropriate measures if needed.”

Amidst the emerging evidence of the adverse consequences of over prescribing of gabapentin, there is a pressing need for medical professionals to discuss the prescribing practices involving these medications. These conversations should focus on evidence-based interventions over unsupported off-label applications that do not have data to support their efficacy and may lead to long-term impacts on health. This is not to say that there is not a role for gabapentin in modern medical practice, but rather a need to reevaluate prescribing practices in order to maximize patient care as well as prevent the potential development of a medication-related crisis.

In The Truth About Drug Companies, Marcia Angell documented how gabapentin (Neurontin) grew from its original approval as a secondary treatment for epilepsy into a blockbuster drug by encouraging doctors to use it to treat common, but vague conditions like pain and anxiety. The problem of drug-related deaths and gabapentin has been a concern since at least 2022 when Public Citizen filed a petition with the FDA and DEA to make gabapentin a federally controlled substance, requesting it be placed as a Schedule V drug, where pregabalin (Lyrica) is scheduled. There has been no federal action yet, despite the increase of deaths associated with both drugs. The petition noted that for each increase of 100,000 gabapentinoid prescriptions, the number of deaths increase by approximately 5% (See Exhibit 5 for a graph representating this increase). While both gabapentin and pregabalin are scheduled as controlled substances in the United Kingdom, the U.S. has yet to do so with gabapentin.

05/24/22

The Truth About Gabapentin

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Gabapentin has been peddled as a treatment for problems as diverse as hot flashes, itchy skin, postoperative pain, and social phobia. That is in addition to its approved uses for partial seizures, nerve pain following shingles and moderate-to-severe restless leg syndrome. In November of 2021, GoodRx listed gabapentin as the sixth-most prescribed medication in the U.S. Not surprisingly, in a 1999 email the Marketing Director for Pfizer at the time called gabapentin “the snake oil of the twentieth century,” claiming it had been successful with “just about everything they have studied.”

Pfizer has paid $945 million to resolve lawsuits against the off-label marketing of gabapentin. For a number of years, gabapentin has been known as a drug of abuse—alone or in combination with other drugs. A 2017 study in the journal Addiction by Lyndon et al (discussed below) noted combining gabapentin (Neurontin) or pregabalin (Lyrica) with opioids increased the risk of acute overdose death. The researchers referred to concomitant use of gabapentinoids and heroin as an emerging public health problem.

It is important that doctors and their patients are aware that the combination of opioids with gabapentin or pregabalin potentially increases the risk of acute overdose death through either reversing tolerance or by an additive effect of the drugs to depress respiration.

In 2019 the FDA acknowledged the risk of serious breathing problems with gabapentin and pregabalin and added a warning to their prescribing information. The FDA also required manufacturers to conduct clinical trials to further evaluate their abuse potential, particularly in combination with opioids. “Misuse and abuse of these products together is increasing, and co-use may increase the risk of respiratory depression.” Despite these concerns, gabapentin is still not a Scheduled drug by the DEA, while pregabalin, coming to market in 2004, is a Schedule V controlled substance.

However, Campbell et al reported in “Gabapentin controlled substance status” that seven state boards of pharmacy have independently reclassified gabapentin as a Schedule V drug.  Twelve states have implemented prescription monitoring programs and three states are deliberating gabapentin’s future controlled/monitored status. The United Kingdom reclassified gabapentin in 2019, placing it in the same controlled substance schedule as barbiturates, buprenorphine, and tramadol. Despite the lawsuits and FDA-limitations, gabapentin prescriptions dispensed from 2011 to 2017 increased two-fold—from 33.4 million to 64.8 million.

Case reports indicate that gabapentin is abused for a variety of reasons, but the most common listed are for euphoria, potentiating the high from opiates, reduction of alcohol cravings, a cocaine-like high, as well and sedation or sleep. Individuals at the highest risk for abusing gabapentin include those with opioid abuse, mental illness, or previous history of prescription drug abuse. Postmortem toxicology analyses have directly linked gabapentin as a cause of death, but most deaths observed occurred with concomitant use with opiates or benzodiazepines. Gabapentin when combined with these agents appears to be lethal at lower serum gabapentin concentrations than gabapentin alone.

Medical Xpress confirmed that most prescriptions for gabapentin were approved for off-label use. A newly published study, “Outpatient Off-Label Gabapentin Use for Psychiatric Indications,” found that more than 99% were for off-label uses. Amie Goodin, a coauthor of the study, said they had anticipated a lot of off-label use, but were surprised at the magnitude of use.

Out of more than 200,000 patient records, just over 5,700 involved a gabapentin prescription. That corresponds to nearly 130 million visits nationally between 2011 and 2016.The vast majority of those prescriptions were off-label, and most patients were also on other prescription drugs. In nearly one-third of cases, those additional medications included a CNS depressant. Antidepressants were the most common type of CNS depressant, followed by opioid painkillers and benzodiazepines. Of all office visits where off-label gabapentin was in the record, about 5% of patients had a depression diagnosis, and 3.5% had an anxiety disorder.

On March 7, 2022, Medscape announced that Public Citizen filed a petition with the FDA and the DEA to make gabapentin a federally controlled substance. The nonprofit group requested that gabapentin come under the DEA’s Schedule V category, where Lyrica is scheduled. The authors argued the risks with gabapentin warranted more safety measures. Classifying gabapentin as a Schedule V drug would make tracking its use and misuse easier and put into place educational and limitation requirements to lessen the risks of addiction, overdose and death.

The Public Citizen petition said there was substantial evidence of widespread misuse of gabapentin, partly because of the extraordinary levels of off-label prescribing. “Both gabapentin and pregabalin have been empirically linked to the opioid overdose epidemic as drugs that potentiate the activity of these oftentimes deadly analgesics.”  There were five systematic reviews summarizing evidence of the harms associated with gabapentin abuse, misuse and diversion.

One review by Smith et al, “Gabapentin misuse, abuse, and diversion: A systematic review,” concluded from their review that gabapentin was “primarily misused for recreational purposes, self-medication, or intentional self-harm, and was used alone or in combination with other substances, especially opioids, benzodiazepines, or alcohol.”

In summary, findings from the present review suggest that gabapentin is misused/abused internationally for recreation, self-medication, or self-harm, with an array of subjective experiences. Substance abuse populations, especially individuals with a history of or current opioid misuse, appear to be at particular risk for misuse/abuse. Further studies to identify risk factors for gabapentin misuse and to characterize gabapentin’s abuse liability are recommended.

Another systematic review by Evoy et al in 2021, “Abuse and Misuse of Pregabalin and Gabapentin: A Systematic Review Update,” confirmed the findings of their 2017 systematic review, that gabapentin and pregabalin are increasingly being misused in order to self-medicate and produce rewarding effects, such as euphoria, relaxation, or disassociation. “Most concerning was the finding of increased evidence of associated patient harm, including increased hospital utilization and opioid-related overdose risk.”

Lyndon et al examined trends in drug-related deaths involving gabapentin in England and Wales from 2004 to 2015 in, “Risk to heroin users of poly-drug use of pregabalin or gabapentin.” They found that prescriptions for gabapentin and pregabalin increased around 24% per year during the study period, from 1 million in 2004 to 10.5 million in 2015. There were concurrent increases in drug-related deaths involving gabapentin and pregabalin; 79% of which involved opioids. “For each increase of 100,000 gabapentinoid prescriptions, the number of deaths increased by approximately 5%.” See the following graphs in the Public Citizen petition.

Postmortem studies in some U.S. jurisdictions have noted an increase in gabapentin-related overdoses. In “Prevalence of gabapentin in drug overdose postmortem toxicology testing results,” Slavova et al found 22% of decedents tested positive for gabapentin. “Among the 3,360 drug-overdose decedents who tested positive for opioids, 880 (26%) also tested positive for gabapentin. Conversely, among the 931 decedents who tested positive for gabapentin, 876 (94%) also tested positive for opioids.”

Buttram et al found in “Law Enforcement-derived data on gabapentin diversion and misuse, 2002-2015” that there were 407 cases of gabapentin diversion reported in 41 states from 2002 to 2015. The gabapentin diversion rate rose steadily from zero in the first quarter of 2002 to a rate comparable to the diversion rate of OxyContin in 2015.

The Public Citizen petition concluded by noting the evidence presented in the petition clearly fulfilled the DEA criteria for scheduling gabapentin:

  1. There is evidence that individuals are taking gabapentin in amounts sufficient to create a hazard to their health and to the community.
  2. There is significant diversion of gabapentin from legitimate drug channels.
  3. Individuals are taking gabapentin on their own initiative rather than on the basis of medical advice from a practitioner.

I’m hopeful the FDA and the DEA will respond to the petition by scheduling gabapentin. I’ve been disturbed with what I’ve seen happen with gabapentin since I first read The Truth About Drug Companies. Marsh Angell described how Neurontin (gabapentin) was transformed from an add-on medication when other anti-seizure drugs failed, into a blockbuster, with sales of $2.7 billion in 2003 by getting doctors to prescribe it for unapproved uses. About 80% of the prescriptions that year were for off-label use. “In fact, Neurontin has become a sort of all-purpose restorative for chronic discomfort of almost any type—yet there is almost no good published evidence that it works for most of these conditions.”

For more information on gabapentin and pregabalin, see “Twentieth Century Snake Oil,” “The Evolution of Neurontin Abuse,” “Foolishness with Gabapentin,” “Gabapentinoids Perpetuate Addiction” on this website.

12/24/19

Gabapentinoids Perpetuate Addiction

 

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Quest Diagnostics generated more than $7.7 billion in revenue in 2017 by offering diagnostic testing services for cancer, cardiovascular disease, infectious disease, neurological disorders and employment and drug testing. The company recently published a report of prescription drug misuse in the U.S. based on analysis of clinical drug monitoring through Quest and a survey of 500 primary care physicians. It found that gabapentin was emerging as an alternative pain therapy to opioids while its misuse rose 40% in one year—13.4% in 2018 from 9.6% in 2017. “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 presented findings from over 4.4 million drug monitoring tests for patients in all 50 states and the District of Columbia from 2011 through 2018. Physicians thought gabapentin was a less risky alternative to opioids and are less concerned about its potential for misuse. The survey found that in an effort to avoid prescribing opioids, 78% of physicians prescribed gabapentin to their patients with chronic pain and 85% had done so in the past six months. Sixty-three percent believed less than 10% of patients prescribed gabapentin misuse it. Concern for the potential of gabapentin misuse was significantly lowers than opioids, benzodiazepines and amphetamines. See the graphic from the Quest report.

When taken alone and as prescribed, there is less of a risk for misuse or addiction. Yet taking gabapentin with other medications such as muscle relaxants, opioids and anxiety medications can produce a high. Vice reported the FDA has only approved gabapentin for treating seizures and nerve pain from shingles, but its reach extends far beyond those two conditions. It is prescribed for migraines, fibromyalgia, hot flashes, depression, bipolar disorder, restless leg syndrome, anxiety, and a variety of other nerve and chronic pain issues. Jordan Covvey, an assistant professor of pharmacy at Duquesne University, said “It’s the ‘lets’ just throw something at the wall and hope that it magically sticks’ drug.” She added that a lot of damage could be happening with that sort of strategy.

Recent studies have questioned gabapentin’s use as a benign catch-all drug and documented its potential for misuse. There is an increased risk of death when it is combined with opioids and a worrying correlation with suicide. Despite the concerns, its use continues to rise. IMS reported gabapentin prescriptions increased from 39 million in 2012 to 64 million in 2016, making it the 10th most prescribed medication. Lyrica (pregabalin), another gabapentinoid, ranked 8th by invoice spending.

In 2017 Christopher Goodman and Allan Brett said in the New England Medical Journal that gabapentinoids (gabapentin and pregabalin) were being overprescribed. The FDA approved gabapentinoids for treating postherpetic neuralgia (gabapentin and pregabalin), fibromyalgia (pregabalin), and neuropathic pain associated with diabetes or spinal cord injuries (pregabalin). But they are being increasingly prescribed for almost any type of pain.

We found that most recently published clinical 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.

An estimated 95% of gabapentin prescriptions are for off-label use. According to Joe Ross, a researcher on pharmaceutical policy, there are no well-designed, placebo-controlled clinical trials for several of its off-label uses. Some have one or two studies, but the results are either modest or inconsistent. “Only about 20 percent of gabapentin’s off-label uses have data supporting them.” See the Vice article and “Twentieth Century Snake Oil” for a description of how Parke-Davis, the company that brought Neurontin (gabapentin) to market spent millions of dollars on a deceptive marketing campaign to promote gabapentin’s off-label use. Doctors were said to reach for gabapentin in situations where someone is difficult to treat.

Another concern noted by Goodman and Brett was the misuse and abuse of gabapentin and pregabalin. They cited “Abuse and Misuse of Pregabalin and Gabapentin,” which said an increasing number of patients are self-administering higher than recommended doses of gabapentinoids to achieve euphoric highs. “In the general population, a 1.6% prevalence of gabapentinoid abuse was observed, whereas prevalence ranged from 3% to 68% among opioid abusers.” They concluded the evidence suggests particularly in individuals with a history of opioid abuse, gabapentinoids have a potential for abuse. Another study of opioid users in Kentucky reported 15% of participants used gabapentin specifically “to get high” in the past six months. This was a 165% increase from the year before.

Peckham, Ananickal and Sclar said the abuse potential of gabapentin was well documented and it was highly sought after for use in potentiating opioids. While the US was in the midst of an opioid epidemic, the national focus has overshadowed the growing diversion and concomitant abuse of prescription medications like gabapentin to potentiate an opioid high. “Gabapentin presents as an opportunistic prescription drug of abuse, given its relatively low cost and non-schedule status at the federal level.”

They reported that 24% of patients with sustained co-prescription of gabapentin and opioids had at least three prescription claims exceeding the established dosage thresholds. “This is of particular concern, as abuse of gabapentin in concert with opioids has been associated with a fourfold increased risk of respiratory depression, the primary cause of death in opioid-related overdose.” Research suggested that when gabapentin exceeded a dose of 900 mg, it could lead to a 60% increase in the odds of opioid-related death relative to the abuse of opioids alone.

In the absence of federal efforts to reclassify gabapentin as a controlled substance, a small number of US states have implemented a number of regulatory approaches to mitigate diversion and abuse. Primary strategies include the reclassification of gabapentin as a controlled substance and mandating the reporting of the prescribing and/or dispensing of gabapentin to a state-level PDMP. These efforts are progressive both nationally and globally, as gabapentin is not classified as a controlled substance in Europe despite previous European reports of gabapentin abuse, nor is it a controlled substance in Australia or Canada.While state-level efforts to combat the diversion and abuse of gabapentin, and thus the opioid epidemic, are to be commended, such efforts are not a substitute for a strategic national approach. Given the growing empirical evidence surrounding both the diversion and abuse of gabapentin, we call for reclassification as a controlled substance at the federal level and implementation of a national pharmacovigilance program. Additionally, future research is needed to identify the degree of regulatory oversight needed to effectively detect and mitigate gabapentin abuse.

A study published in Clinical Toxicology examined the misuse and toxicology trends associated with gabapentin and baclofen, using data gleaned from the National Poison Data System (NPDS). From 2013 to 2017 all gabapentin exposures increased by 72.3%. All fifty states saw an increase in exposure to gabapentin. The authors also noted that misuse and diversion of gabapentin has been well-documented. Intentional suicide attempts with gabapentin increased by 80.5%. The authors noted the increased exposures coincided with reductions in opioid prescribing. They speculated the increases may represent an unintended consequence of the need for effective pain management and the migration away from opioid use.

Vice reported that while gabapentin is not classified as a controlled substance at the federal level, 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. In January of 2019 Michigan classified gabapentin as a Schedule 5 substance, which is the same scheduling as cough medicines with codeine. Virginia did the same in July of 2019 and Alabama followed in November of 2019.

Then on December 19, 2019, the FDA released a drug safety communication warning of serious breathing difficulties may occur patients using gabapentinoids with opioids or other drugs that depress the central nervous system, such as anti-anxiety medications, antidepressants, and antihistamines. Individuals with respiratory risk factors that reduce lung function (i.e., COPD: chronic obstructive pulmonary disease) and the elderly are also at higher risk. They are requiring new warnings about the risk of respiratory depression be added to the prescribing information of gabapentinoids.

We have also required the drug manufacturers to conduct clinical trials to further evaluate their abuse potential, particularly in combination with opioids, because misuse and abuse of these products together is increasing, and co-use may increase the risk of respiratory depression. Special attention will be paid to the respiratory depressant effects during this abuse potential evaluation.

There is even less evidence that gabapentin is helpful with mental health disorders. In 2000, a randomized, placebo-controlled trial showed gabapentin did not work better than placebo for bipolar disorder; one study found it was worse than placebos when treating bipolar mania. The British Medical Journal published a study in June of 2019 that found gabapentinoids were associated with increased risk of suicidal behavior and unintentional overdoses in adolescents and young adults (15-24 years old). There were no clear associations with suicidal behavior in those aged 55 and older.

Participants in the other age bands showed heterogeneous associations, with increased hazards of suicidal behaviour, unintentional overdoses, and head/body injuries, and no associations with road traffic incidents or offences and arrests for violent crimes. When analysing gabapentinoids separately, pregabalin use was associated with increased hazards of all outcomes, whereas there were decreased or no associations for gabapentin.

At the Eastern Division StartWell Event 2019 held by the Royal College of Psychiatrists (RC Psych), The President of the RC Psych, Wendy Burn tweeted the following slide from one of the presentations:

Her tweet said: “We are going to have to face the issue of dependence on antidepressants,” but notice that gabapentinoids are also listed. This was a replication of the “Prescribed medicines review: summary” for Gov.UK, which found that 1.4 million people (3% of the adult population of Britain) had received, and had dispensed, a gabapentinoid. This was an increase of 2.9% to 3.3% of the adult population. The number of patients continuously on a gabapentinoid in the UK  from April 2015 to March of 2018 was 160,000.

From the time Neurontin (gabapentin) was approved by the FDA in 1994, there have been reports of intentional off-label use, promoted by the pharmaceutical company that brought it to market. Neurontin has been off-patent since 2004, but it seems the off-label use and now misuse of gabapentin has continued, and even grown. It has become a cheap (less than $1 per pill) way to potentiate the high of opioids and is now sold by drug dealers alongside of your opioid-of-choice. It has been even touted as a possible treatment for alcohol dependence. This so-called “cure” for addiction has been turned on its head and been demonstrated to intensify the high from opioids and perpetuate, but not cure, addiction.

I have been monitoring and expressing concern about the use and misuse of gabapentinoids for several years. It seems to me the federal government should take the next step and Schedule gabapentin, particularly now that it has become an adjunct to an opioid high. For more on concerns with gabapentinoids, see “Twentieth Century Snake Oil,” “The Dark Side of a Pill to Cure Addiction,” “Foolishness with Gabapentin,” Risky Alcoholism Treatment,” and “The Evolution of Neurontin Abuse.”

07/31/18

Risky Alcoholism Treatment

Pregabalin/Lyrica graffiti in Berlin; licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.

The patent on Pfizer’s blockbuster drug, Lyrica (pregabalin) is running out; it is due to expire in December of 2018. More than six generics companies have lined up tentative approval to sell copies, according to Fierce Pharma. In an apparent effort to keep its blockbuster sales up despite the coming generics, Pfizer rolled out a longer-acting formula in 2017—Lyrica CR. In 2016 Lyrica generated $3.13 billion in sales in the U.S., a 26% increase over the year before. And despite the recent FDA concern that gabapentinoids like pregabalin having a potential for abuse, Pfizer is pushing ahead with a clinical trial to get pregabalin approved for treating alcohol dependence. The Phase 4 clinical trial by Pfizer, “Pregabalin for Alcohol Dependence,” should be completed just as Lyrica’s patent expires in December of 2018.

Gabapentinoids like pregabalin and gabapentin (Neurontin) produce euphoria at high doses. Their effects are similar to alcohol and benzodiazepines. And there is a clear abuse potential. Tolerance develops rapidly with repeated use and withdrawal symptoms have been reported. The U.K. is in the process of reclassifying gabapentin and pregabalin as Class C controlled substances because of evidence they can be abused.

An article on the British website for The Independent newspaper said the British Medical Association has called for pregabalin to be made a controlled substance in the same class as Valium, GHB and steroids. Yasir Abbasi, a consulting psychiatrist said pregbalin dependency was “very widespread, all over the UK.” He added it has an effect similar to Valium. “It sedates you and takes the edge off.” It has become a “massive” problem in prisons, where it is a very tradeable and desirable commodity. “When it goes off patent, and there are cheaper versions available, people will start buying it more and more, particularly over the internet.”

BuzzFeed described how Lyrica (pregabalin) is overprescribed and misused in a Greek refugee camp (Vial) in order to treat rampant depression, anxiety and PTSD. Although psychotherapy is supposed to be done concurrently with the medication, it’s impossible to do so under the circumstances. There are only one psychiatrist and one psychologist working at the camp. The UN refugee agency running the camp denied any knowledge of a Lyrica problem. However, others said the going rate on the camp’s black market for a 300mg Lyrica pill is $5.

A Syrian woman who has lived in Vial for months said: “The people here are desperate, they are suffering, and that [Lyrica] is something that makes them feel comfortable and happy. So they can stay here. They must take this medicine, so they can be patient here.” A former psychology student from Syria who was in the Vial camp was quoted as saying:

“Some people get the pill from the doctor, some from anybody here,” said T., a former psychology student from Syria who arrived in Vial in the spring of 2017. But the wait for an appointment with the doctor can be long. “Life here is hard. Some people take the pill. One, then two, three, four.” T. continued to count on his fingers, all the way up to 10 — “This is bad.” He said the medicine helped them relax and switch off for a bit. “They do not take them as medicine,” he said. “They take it like drugs.”

Along with baclofen, pregabalin and gabapentin (Neurontin) are analogues of the neurotransmitter gamma-aminobutyric acid (GABA). Many GABA analogues are used as anticonvulsants, sedatives and anti-anxiety drugs. According to Carleton Erickson in The Science of Addiction, alcohol affects GABA and a few other receptors to produce its intoxicating and behavioral effects. The GABA association between alcohol and these GABA analogues is simultaneously what attracts researchers to investigate their potential use as treatments for alcohol use disorder and what underlies their adverse effects.

In February of 2018, FDA Commissioner Scott Gottlieb commented on the FDA’s ongoing investigation into the misuse and abuse of gabapentinoids such as gabapentin (Neurontin) and pregabalin (Lyrica). “We’re concerned that the misuse and abuse of these drugs may result in serious adverse events such as respiratory depression and death. We want to understand changes in how patients are using these medicines.” Among the actions taken by the FDA is to review websites where opioid users exchange methods for misusing or abusing gabapentinoids. While this abuse does not yet appear to be widespread, the FDA hopes to stay ahead of any potential problem and is willing to take forceful action, if necessary.

Evidence for pregabalin abuse dates back to at least July of 2010, when a case report by Grosshans et al. was published in The American Journal of Psychiatry, “Pregabalin Abuse, Dependence, and Withdrawal.” At the time of the person’s admission, he was consuming 7,500 mg of pregabalin per day; 600 mg is the maximum recommended dose. He had a history of alcohol and cannabis abuse, but had been abstinent from heroin for seven years. Two years before his admission, he began using high doses of pregabalin and it quickly became habit. He developed tolerance and withdrawal symptoms. They did a gradual taper of pregabalin over 12 days, but he complained of a heavy craving for pregabalin and discontinued treatment. He relapsed immediately upon returning home. “Further attempts to motivate him for detoxification” failed and he continued to take pregabalin.

A case report of pregabalin dependence appeared in the Turkish Journal of Psychiatry. A 34 year-old man reported frequently using 7,800 mg of pregabalin daily. The most he’d used at one time was 15,600 mg. In the three years prior to his admission, his longest period of abstinence was three days. “When he tried to stop using pregabalin he experienced pessimism, aggression, anxiety, suicidal ideation, fatigue, excessive sleep, loss of appetite, palpitations, tremors, and vomiting.” Pregabalin use negatively effected his work and his family relationships.

Despite the promising reports on pregabalin use for treating substance dependence, 198 adverse events related to substance abuse and dependence, of which 16 were associated with pregabalin, occurred between 1980 and 2009 according to the Swedish National Register of Adverse Drug Reactions (SWEDIS).

Another case study report in the Indian Journal of Psychiatry by Ashwini et al. reported on yet another case study of pregabalin dependence and an attempted suicide. He was initially prescribed pregablin for neuropathic jaw pain and experienced euphoria and increased energy after taking his medication. After three years of continuous use, he was using 3,000 mg of pregabalin per day and would experience withdrawal if he missed his doses. He attempted suicide twice.” Our case highlights the abuse potential of pregabalin and risk of self-harm behavior with its continuous use.” The researchers recommended all clinicians remain vigilant and mindful of the potential for abuse or dependence, even if their patients are not showing any drug seeking behavior.

Case reports are not the only evidence of concerns with gabapentinoids. JAMA published a study by Patorno et al. looking at the increased risk of suicidality (attempts and completions) and violent death with a range of anticonvulsant drugs, including gabapentin and pregabalin. “Gabapentin treatment was significantly associated with higher risk of suicidal events and combined suicidal acts or violent deaths in adults and young adults.” Similar findings were not seen with pregabalin. However, it had only been on the market since 2005 (only patients who began taking an anticonvulsant between July 2001 and December 2006 were included in the study). It wasn’t as widely used at the time of the study as gabapentin and it had one of the shortest reported therapy times. The median time of use for all the anticonvulsants in the study was 60 days. Pregabalin would likely be used for a much longer time period in alcohol misuse treatment.

In “Misuse and Abuse of Pregabalin and Gabapentin: Cause for Concern?” Fabrizio Schifano wrote how gabapentinoids have been increasingly reported as having a potential for misuse and a relation to fatalities and a growing black market reported from “a range of countries.” He advised physicians thinking of prescribing gabapentinoids to carefully evaluate whether a previous history of drug abuse exists. Pregabalin has a higher potency (six times that of gabapentin), quicker absorption rates (within one hour) and greater bioavailability than gabapentin. Schifano suggested that while one could conclude the distinct pharmacokinetic advantages of pregabalin would mean an improved therapeutic effect, “[it] may explain as well why pregabalin is anecdotally perceived as more ‘powerful’ by drug misusers.”

Schifano did note that pregabalin, if used at therapeutic levels, “may present with beneficial effects” for alcohol misuse treatment. Similarly, he pointed to how gabapentin has been indicated in the treatment of drug addictions. Nevertheless, “A better assessment/clarification of gabapentinoid misuse potential levels is indeed of interest.”

The epidemiology of gabapentinoid misuse needs further detailed and urgent assessment, and consideration of gabapentin/pregabalin testing in urine drug screens should be routinely considered. Further empirical studies with gabapentinoids should be encouraged, focusing on a better assessment of their addictive liability levels across a range of dosages and in individuals with a previous substance misuse history.

Gabapentin has already become a drug of abuse in its own right. See “Foolishness with Gabapentin” and “The Evolution of Neurontin Abuse.” It’s often used to potentiate the euphoric effects of opioid drugs—both legal and illegal ones. The authors of “Abuse and Misuse of Pregabalin and Gabapentin” said: “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.” Over four years ago I expressed concern with using gabapentin to treat alcohol dependence in “The Dark Side of a Pill to Cure Addiction.” The same concern exists today with pregabalin: “well meaning researchers and clinicians could be putting the very people they seek to help at risk with the solutions they propose.”

04/6/18

Foolishness with Gabapentin

© Fabrizio Troiani | 123rf.com

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 …”