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?