05/5/17

The Evolution of Neurontin Abuse

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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.

06/9/14

The Dark Side of a Pill to Cure Addiction

On December 23, 2013, The Wall Street Journal published an article with the provocative title: “A Pill to Cure Addiction?” The article was generally upbeat and positive about the research done at the Scripps Research Institute in La Jolla, California—a well known and reputable research institution. The original research article, “Gabapentin Treatment for Alcohol Dependence” is available in JAMA Internal Medicine. A news release by The Scripps Research Institute, “Clinical Trial Indicates Gabapentin Is Safe and Effective for Treating Alcohol Dependence,” is available on their website.

The study found that “gabapentin significantly improved the rates of abstinence and no heavy drinking.” In the placebo group, the abstinence rate was 4.1%, 11.1% in the 900mg dose group, and 17.0% in the 1800mg dose group. The no heavy drinking rate was 22.5% in the placebo group, 29.6% in the 900mg dose group and 44.7% in the 1800mg dose group.  See the JAMA Internal Medicine abstract for the above data. The subjects who took the highest dose of gabapentin either stopped drinking altogether (17%) or refrained from heavy drinking (45%).

Barbara Mason, the lead researcher, reported in the Scripps Research Institute news release that the high-dose group refrained from heavy drinking twice as often (45% to 23%) and entirely abstained four times as often (17% to 4%) as the placebo group. Patients who received the lower, 900mg dose of gabapentin showed intermediate benefits. She concluded: “I think that we can now have confidence in the pharmacological effect of this drug.”

The WSJ article reflected this positive, upbeat attitude towards gabapentin as a treatment alternative for alcoholism. It also elaborated on the neurochemical mechanism gabapentin is theorized to influence—the brain’s stress response system—specifically CRF (corticotropin-releasing factor). Alcohol or drug use is thought to trigger the brain’s release of CRF in order to help the brain return to normal after the heightened sensation of pleasure from the chemical high. So years of drinking or drug taking are thought to make the brain more sensitive to CRF.

CRF is sometimes referred to as a “misery neurotransmitter.” It is thought to cause the anxiousness felt by addicts, which they “treat” by drinking again or taking more drugs. It also is believed to play a role in the difficulties that alcoholics and addicts have when trying to quit, particularly during situations that heighten feelings of tension and stress.

The neurochemical research into CRF and CRF-related neurotransmitters has an exciting and promising future into this so-called “dark side of addiction.” It seems to have something to say about the acute withdrawal and post acute withdrawal symptoms alcoholics and drug addicts must wrestle with and overcome to establish abstinence. But there is a dark side to gabapentin, the drug proposed to treat this dysregulation of the brain’s stress response system.

A previous blog, “Twentieth Century Snake Oil,” related the sordid, illegal history of how gabapentin became such widely prescribed drug for not just epilepsy and pain, but a slew of non-approved uses such as: anxiety, post traumatic stress, headaches and insomnia. In 2008 the FDA also mandated that anticonvulsant drugs such as gabapentin carry warning labels about the increased risk of suicidal thoughts and behaviors.  A 2010 study confirmed that gabapentin and other anitconvulsants could be associated with an increased risk of suicidal acts or violent deaths.

An article in Psychiatric Times, “The Link Between Substance Abuse, Violence, and Suicide,” indicated that individuals with a substance use disorder are almost six times more likely to report a lifetime suicide attempt than those without a substance use disorder. Emerging research also suggested that a greater severity of recent drinking is associated with the greater likelihood of suicide attempts and successes. Co-occurring alcohol and drug use may also predict a greater likelihood of suicide.

The study by the Scripps Howard Research Institute did not report any serious side effects among the treated patients. But was the presence of serious side effects actively assessed within the study or were they simply noted if reported by the subjects? It should also be pointed out that within the group with the most promising response to the gabapentin treatment, 38% of the subjects were still drinking heavily while using high doses of gabapentin; and another 45% were drinking to some extent while using gabapentin. This alone is clearly contraindicated in the FDA approved Medication Guide for Neurontin (gabapentin).

Medication assisted forms of recovery are all the rage in addiction treatment and research these days. My fear is that well meaning researchers and clinicians could be putting the very people they seek to help at risk with the solutions they propose. This study does not alleviate that fear. Let’s stay tuned for future developments.

Do you think that gabapentin should be used as a treatment for addiction?

06/4/14

Twentieth Century Snake Oil

My wake up call to the deceptive practices of some pharmaceutical companies came when I read The Truth About Drug Companies by Marcia Angell in 2004. Angell speaks credibly to the issue since she is a former editor-in-chief of the prestigious The New England Journal of Medicine. One example that stayed with me over the years because of its sheer, incredible audacity was how Neurontin was made into a multi-billion dollar selling drug.

In 1994 Neurontin was approved by the FDA as a secondary treatment for epilepsy—to be used when patients failed to respond to other anti-seizure drugs. The patent was due to expire in 1998 (it eventually received a two year extension). So the company began to target doctors to prescribe it for unapproved, off-label uses, “mainly common but vague conditions like pain and anxiety, and also as the sole treatment for epilepsy.”

Although doctors are legally permitted to prescribe an FDA approved drug for any use whatsoever, it is illegal for a drug company to market a drug for off-label uses. According to Angell, what Parke-Davis did was to pay academic experts to put their names on flimsy research papers that showed the drug worked for certain off-label conditions. This “research” typically fell below the standard required by the FDA for an approval of the drug for a particular condition.

Angell said the studies were small and poorly designed. “Some of the articles contained no new data at all, just favorable comments about Neurontin.” Parke-Davis hired medical education and communication companies to prepare the articles and paid academic researchers to put their names on the articles as authors. Once the articles were published in academic journals, “medical liaisons” would visit doctor’s offices to answer questions about the research.

Parke-Davis also sponsored educational meetings and conferences. The “authors” of the papers would describe the positive results of the drug’s off-label uses. Not only were the speakers paid, “but often the doctors in the audience were paid” as consultants. This was to get around the anti-kickback laws. “Consultant meetings were sometimes little more than vacations for potential high prescribers of Neurontin.”

The result was Neurontin becoming a blockbuster drug, with over 2 billion in sales for 2003. “About 80 percent of prescriptions that year were for unapproved uses—conditions like bipolar disorder, post-traumatic stress, disorder, insomnia, restless legs syndrome, hot flashes, migraines, and tension headaches.” In fact, Neurontin became an all-purpose restorative for chronic discomfort. An internal company e-mail described Neurontin as “the ‘snake oil’ of the twentieth century.”

A generic version of Neurontin (gabapentin) went on sale in August of 2004. The website Drugs.com reported that Neurontin sales in 2004 were approximately $2 billion dollars. In 2005, sales dropped to $259.4 million. It dropped from the 10th best selling drug in 2004 to the 123rd best selling drug in 2005. By 2006, Neurontin had dropped out of the top 200 best selling drugs.

In May of 2004 the pharmaceutical manufacturer Warner-Lambert, of which Parke-Davis was then a division, agreed to pay $430 million to resolve criminal charges and civil liabilities in connection with its “illegal and fraudulent promotion of unapproved uses” for Neurontin. See the Department of Justice announcement here. Part of the global agreement was that Pfizer, Inc., the owner of Warner-Lambert since June of 2000, agreed to training and supervision of its marketing and sales staff to ensure that “any future off-label marketing conduct is detected and corrected on a timely basis.”

In December of 2013, the U.S. Supreme Court upheld a $142 million award to the Kaiser Foundation Health Plan by Pfizer for marketing Neurontin for unapproved uses. The court also allowed two other lawsuits against Pfizer to proceed. A key factor in the court’s decision apparently was an analysis by Meredith Rosenthal of the Harvard School of Public Health. “Her analysis found that marketing Neurontin for such unapproved uses as bipolar disorder, neuropathic pain and migraines caused physicians to write 43 million off-label prescriptions.” She further calculated that 99.4 percent of the prescriptions for bipolar disorder were caused by illegal marketing.

The two outstanding lawsuits noted above now seem be settled. In April of 2014 Pfizer agreed to pay $190 million to settle a lawsuit that was first filed in 2002.  The lawsuit claimed the pharmaceutical company took several steps to delay the entry of Neurontin into the generic drug market. According to a Reuters news article, along with other delay tactics, Pfizer allegedly filed “sham patent infringement lawsuits.” And just announced on May 30th, 2014 in this report by Bloomberg, Pfizer agreed to pay $325 million to settle a lawsuit brought by health-care providers claiming that Pfizer marketed Neurontin for unapproved uses. In both settlements, Pfizer did not admit to any wrongdoing.

So why does the history of unapproved marketing of Neurontin (gabapentin) rent so much space in my head and this blog? The Wall Street Journal recently ran an article titled “A Pill to Cure Addiction?” on “new medicines” that are being tested to help people quit drug and alcohol habits. The “new drug,” touted as a possible cure for addiction, is gabapentin.

Do you think that Neurontin sounds like it could be the “snake oil” of the twentieth century?