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 …”

05/5/17

The Evolution of Neurontin Abuse

© smeagorl | 123rf.com

Not long ago a Columbus Ohio television station, Fox 28, noted the Ohio Substance Abuse Monitoring Network (OSAM) issued an alert about a pill doctors say is now being abused by heroin addicts. It’s not an opioid or a benzodiazepine; it’s not even a controlled substance. Yet it was the number one dispensed medication in Ohio in December of 2016, “at a 30 percent higher rate than Oxycodone.” Can’t guess? Would you be surprised to know that drug was Neurontin?

In February of 2017 OSAM published “Neurontin© Widely Sought for Illicit Use.” The OSAM report said Neurontin (gabapentin) was first identified as drug of abuse by law enforcement in January of 2014, in Dayton, Ohio. Over the last three years of reports there has been illicit gabapentin use in seven of eight urban regions in Ohio. See Table 1 in the OSAM bulletin for more information.

Preliminary analysis of OSAM’s most recent data for July to December 2016, found street availability and illicit use of Neurontin® to be moderate to high in six of the eight OSAM regions. In Athens, a participant commented, “It seems like everyone is on Neurontin®.” A law enforcement officer noted, “Enormous Neurontin® abuse right now.”

Gabapentin, known by its brand name of Neurontin®, is an anticonvulsant medication approved by the FDA as adjunctive treatment of partial seizures and to manage neuropathic pain from shingles. It has a variety of touted off label uses, and was referred to as “the snake oil of the 20th century” in an internal Pfizer email.  It is currently seen as having a low abuse profile and is not scheduled as a controlled substance by the DEA. But that may need changing.

It is also used to by opioid users to self-medicate through withdrawal and as a high in itself. One individual in Ohio said his attraction to Neurontin® was that it intensified his methadone: “So if you take your methadone and you go buy 10 Neurontin® and you take all 10, it’s sort of like you tripled your dose.” Others said they get a “semi-euphoric feeling” if they abuse it. Some recent studies: “Abuse and Misuse of Pregabalin and Gabapentin” and “Gabapentin Misuse, Abuse and Diversion: a Systematic Review” said gabapentin is most often abused by individuals with a history of drug abuse, especially opioids. And it is “being misused internationally.”

An article in Pharmacy Times indicated the number of prescriptions written for gabapentin was at an all time high. “According to a report by IMS Health, 57 million prescriptions for gabapentin were written in the United States in 2015, a 42% increase since 2011.” Alone it has a low abuse potential, but when combined with muscle relaxants, opioids of anxiety medications “gabapentin’s potential for abuse and addiction significantly increasing and ultimately gets those individuals high.” A study of Florida inmates found it was being crushed and snorted like cocaine. “Out of 96 prescriptions, only 19 were actually in the hands of an inmate that was actually prescribed that drug.”

An article in Pain News Network noted a study of urine samples from patients being treated at pain clinics found that 22% (70 out of 323) were taking gabapentin without a prescription. Researchers found of those patients taking gabapentin illicitly, 56% were taking it with an opioid; 27% with an opioid and a muscle relaxant or anxiety medications like benzodiazepines. The medical director of ARIA Diagnostics in Indianapolis, Indiana said the high rate of misuse was surprising as well as a wake up call for prescribers. Doctors don’t usually screen for gabapentin abuse when making sure patients are taking medications as prescribed.

Little information exists regarding the significance of Gabapentin abuse among clinical patients. Until recently, it was considered to have little potential for abuse however this review has shown that a significant amount of patients are taking Gabapentin without physician consent. This could be due to the fact that recent studies have revealed that Gabapentin may potentiate the ‘high’ obtained from other central nervous system acting drugs.

In the UK, gabapentin and pregabalin (Lyrica) prescribing is getting scrutinized more closely. At least 38 deaths involving pregabalin and 26 involving gabapentin were reported in the UK between 2012 and the end of 2015. The UK Advisory Council on the Misuse of Drugs (ACDMD) recommended they be reclassified as Class C controlled substances. “Both pregabalin and gabapentin are increasingly being reported as possessing a potential for misuse. When used in combination with other depressants, they can cause drowsiness, sedation, respiratory failure and death.”

Pregabalin may have a higher abuse potential than gabapentin because of its rapid absorption, faster onset of action and higher potency. It also causes a high or elevated mood in users. The side effects can include chest pain, wheezing, changes in vision and less frequently, hallucinations, Gabapentin was said to produce feelings of relaxation, calmness and euphoria. If snorted, its high is similar to using a stimulant.

The use of gabapentin and pregabalin by the opioid abusing population either together or when opioids are unavailable reinforces the behavior patterns of this high-risk population. There is a high risk of criminal behavior stimulated by the wish to obtain gabapentin and pregabalin.

Lyrica (pregabalin) is Pfizer’s top selling drug, with $6 billion in 2014 sales. Pfizer said reclassifying its drugs could harm patients. “Controlling the supply of these products across the whole UK, would be a disproportionate measure that would impact on patients and their quality of life.” An Irish study found pregabalin abuse a “serious emerging problem.” Recreational users in Belfast call the drug “Budweisers because it induces a state similar to drunkenness.” Gabapentin has received more attention as a potential drug of abuse in the US.

In 2012, “Has Gabapentin Become a Drug of Abuse?” appeared in Medscape, but the problem seems to have been somewhat downplayed. The article said: “a small number of postmarketing cases report gabapentin misuse and abuse,” but went on to say the rationale for abuse was unknown. Yet one of cited references for the Medscape article, “Abuse, dependency and withdrawal with gabapentin: a first case report,” did note that consumer websites reported several experiences of gabapentin misuse in order to feel high. “According to these consumer reports, gabapentin effects are close to those of marijuana and can appear with low doses.” Then the article reviewed several articles noting problems with abuse, misuse and withdrawal with gabapentin, essentially what has been reported above. In its conclusion, the article said:

 On the basis of case reports and postmarketing reports, there appears to be potential for abuse, dependency, and withdrawal symptoms associated with gabapentin use. Patients involved in this misuse and abuse were using gabapentin at doses greater than those recommended, to relieve symptoms of withdrawal from other substances, and for uses that are not FDA-approved.Providers should assess patients for drug abuse history when prescribing gabapentin, as well as monitor patients for any signs of misuse or abuse. Prescribers and pharmacists should monitor patients for the development of tolerance, unauthorized escalation of dosing, and requests for early refills or other aberrant behavior. Prescribers should consider requesting testing for the presence of gabapentin in urine drug screens if abuse is suspected.

I’ve personally been hearing reports from individuals in treatment for opioid drug problems consistent with the above information for several years. On one occasion, a woman said after she had told a psychiatrist she has a history of abusing gabapentin, but he prescribed it to her anyway. If you’re interested, a previous article I wrote, “Twentieth Century Snake Oil” reviews a history of Neurontin (gabapentin) that may surprise you. Another article, “The Dark Side of a Pill to Cure Addiction” reviewed mixed findings when gabapentin was used to treat alcohol withdrawal.