Neurontin (GABAPENTIN) - The Illegal Corporate Creation of a Blockbuster Drug

A March 14, 2002, New York Times article revealed that the manufacturer of the seizure medication gabapentin (NEURONTIN) illegally promoted the drug to prescribing physicians for at least 11 “off-label” (unapproved) medical conditions, using their own employees, euphemistically called “medical liaisons.” Many of the bases for the safety and effectiveness of gabapentin for these 11 unapproved uses appears to have been fabrications by the corporation. This included paying physicians to appear as the authors of medical journal articles on unapproved uses for gabapentin when the articles had actually been written by others working under the direction of the company’s marketing department.

This article is based on the Times story and publicly available court documents from a civil complaint filed by the U.S. government against gabapentin’s manufacturer.

Gabapentin was originally sold by Parke-Davis, a subsidiary of Warner-Lambert, which in turn was a corporation acquired by Pfizer, Inc., in 2000. Gabapentin is currently approved by the Food and Drug Administration (FDA) only as supplementary treatment for a specific type of seizure know as partial seizures after maximum tolerated doses of older drugs are used. This is a relatively small potential market for gabapentin.

The 11 illegally promoted unapproved uses for gabapentin as outlined in the court documents are:

1. Bipolar Disorder. Psychiatrists were told that early results from trials evaluating gabapentin in the treatment of bipolar disorder indicated a 90 percent response rate when the drug was started at 900 milligrams per day and increased to 4,800 milligrams per day. No such results existed. In fact, the only type of clinical trial being conducted at the time was a pilot study. According to the court documents, Parke-Davis was in possession of clinical data indicating that increasing the dose did not increase gabapentin’s effect. The FDA-approved dosage for gabapentin in adults is 900 to 1,800 milligrams per day.

Any data regarding gabapentin in bipolar disorder was anecdotal and of unclear scientific value. Most of the published reports on the use of gabapentin in bipolar disorder had been written and sponsored by Parke-Davis, a fact that was hidden. Medical liaisons of the company were trained to tell psychiatrists that there were no reports of adverse reactions with gabapentin when used in psychiatric illness. In fact, such reports had been given to Parke-Davis by health care professionals but the company attempted to hide this information from physicians.

2. Pain Syndromes, Peripheral Neuropathy, and Diabetic Neuropathy. Parke-Davis medical liaisons were trained and instructed to report that “leaks” from clinical trials demonstrated that gabapentin was highly effective in the treatment of a number of pain syndromes and that a 90 percent response rate in the management of pain was being reported. No such evidence existed. Medical liaisons were trained to claim support for these findings as a result of inside information despite the fact that no such information existed. The only basis for these claims were anecdotal evidence of minimal, if any, scientific value. Many of the published case reports, according to the court papers, had been created and sponsored by Parke-Davis in articles that frequently hid the company’s involvement in the creation of the article. The company’s payment for the creation of these case reports was also concealed.

3. Treatment of Epilepsy alone (as monotherapy). Medical liaisons were strongly encouraged to push neurologists to prescribe gabapentin as the only drug to treat epilepsy, in spite of the fact that studies found it safe and effective only when used in combination with other seizure drugs. Neurologists were told that substantial evidence supported the company’s claim that gabapentin was effective when used alone for seizure. In fact, at the time the court papers were filed, Parke-Davis knew that clinical trials using gabapentin alone in seizure were inconclusive. One of Parke-Davis’ clinical trials showed that gabapentin alone was not effective. The vast majority of patients in the study taking gabapentin were unable to continue with gabapentin alone. In the same study, there was no significant difference between doses of 600, 1,200 or 2,400 milligrams. Nevertheless, Parke-Davis continued to urge doctors to use higher doses than approved by the FDA.

In 1997, the FDA rejected the company’s application for approval of gabapentin as mono-therapy in the treatment of seizures.

4. Reflex Sympathetic Dystrophy (RSD). Physicians were informed that extensive evidence demonstrated the efficacy of gabapentin in the treatment of RSD, a condition of pain and tenderness following traumatic injury to a limb. Again, the only evidence was in anecdotal reports of little or no scientific value. The Parke-Davis medical liaisons were trained to imply that case reports, most of which had been created or sponsored by the company, were actually studies.

5. Attention Deficit Disorder (ADD). Pediatricians were told that gabapentin was effective for the treatment of ADD. No hard data to support this claim existed—only occasional anecdotal evidence. Parke-Davis medical liaisons were trained to report that large numbers of physicians had success in treating ADD with gabapentin, when no such case reports existed.

6. Restless Leg Syndrome (RLS). This is another condition in which company medical liaisons were trained to refer to a growing body of evidence relating to the RLS, when no such scientific data existed. The only reports were anecdotal, the majority of which had been sponsored or created by Parke-Davis.

7. Trigeminal Neuralgia. The company represented gabapentin as a treatment for trigeminal neuralgia, a syndrome of severe bursts of facial pain, when no scientific data supported this claim; only occasional anecdotal reports. No evidence was available that gabapentin was as effective as currently available less expensive painkillers.

8. Post-Hepatic Neuralgia (PHN). This is a syndrome of severe pain following a herpes virus infection. Physicians were told that 75 to 80 percent of all PHN patients were successfully treated with gabapentin. Again, no clinical trial data supported such a claim.

9. Essential Tremor Periodic Limb Movement. No scientific data supported Parke-Davis’ claim that gabapentin was effective for this disorder, just anecdotal reports of dubious scientific value.

10. Migraine. Claims that gabapentin was effective in the treatment of migraine headache were made by company medical liaisons and were alleged to be based on early results from clinical trials. Pilot studies had been suggested and undertaken, but no early results existed to support these claims. The data were purely anecdotal and most case reports were either created or sponsored by Parke-Davis.

11. Drug and Alcohol Withdrawal Seizures. It was suggested by the company that gabapentin be used in the treatment of drug and alcohol withdrawal seizures despite the lack of any evidence supporting the use of the drug for these conditions.

Parke-Davis’ concocted uses for gabapentin turned the drug into a “blockbuster.” A blockbuster is the Wall Street description for any drug that sold $1 billion per year or more. In 2000, the company reported that gabapentin had earned $1.3 billion. As much as 78 percent of these sales were for uses without evidence that gabapentin was safe and effective. In 2001 a market research firm estimated that gabapentin sales totaled $1.7 billion.

The court papers offer a remarkable insight into the ethics (or lack thereof) of a major multinational pharmaceutical company. A senior marketing executive at Parke-Davis was quoted during a teleconference as saying to medical liaisons:

Pain management, now that’s money. Monotherapy, that’s money. We don’t want to share these patients with everybody, we want them on Neurontin only. We want their whole drug budget, not a quarter, not half, the whole thing....That’s where we need to be holding their hand and whispering in their ear: “Neurontin for pain, Neurontin for monotherapy, Neurontin for everything” ... I don’t want to hear that safety crap either, have you tried Neurontin, every one of you should take one just to see there is nothing [that the drug is safe], it’s a great drug.

Pfizer has scored about $3.0 billion in gabapentin sales over the short term of the past two years, 2000 and 2001. The company may also reap a long term benefit from sales of the drug. Physicians’ prescribing practices, also known as prescribing habits, are not likely to be cured of the gabapentin habit just by The New York Times article. In addition, as of March 28, 2002 the National Library of Medicine listed 729 English language articles published in the medical literature on gabapentin use in humans. Of course, not all these articles are corporate creations but the disturbing point is that there may not be any attempt to purge the medical literature of these company-contrived studies, leaving patients, even years from now, at risk of exposure to gabapentin for inappropriate uses.

There is nothing new in the Parke-Davis gabapentin escapade and the company’s drug promotion. Over 30 years ago Senator Gaylord Nelson (D-WI) held a series of hearings on problems with the drug industry. In a 1969 hearing it was learned that drug companies employed physicians and scientists to prepare articles for medical journals. In those days these “kept” scientists and doctors were known in the trade as “the stable.” With time comes status inflation, and now these individuals are called “medical liaisons.”

The last serious Congressional hearings on the promotional practices of the pharmaceutical industry were held in 1990. During these hearings, Dr. Sidney Wolfe, co-founder of the Health Research Group, played a central role in exposing widespread bribing of doctors by drug companies.

Recent events have properly raised the question whether federal watchdogs have become lap dogs, lazy dogs or just sleeping dogs when it comes to the public interest. The degree of vigilance of the FDA watchdog over the pharmaceutical industry is directly in the hands of the United States Congress. Judging by the amount of time that has lapsed since Congress has held meaningful hearings on either the drug industry or the FDA, it looks as if the “top dog” (Congress) got some bones and went to sleep.

What You Can Do

If you or a family member are taking gabapentin for one of the 11 unapproved, often apparently concocted, uses listed above, you and the prescribing doctor should evaluate the need for gabapentin.