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Neurontin for Reflex Sympathetic Dystrophy

Off-Label Use Flourishes Despite FDA Ban

Neurontin:  Past and Future

October 2010  –  Tuum Est published a short version of the article below. In it writer Georgena Sil reported her personal encounter with a GP who misprescribed Neurontin for Reflex Sympathetic Dystrophy. Neurontin proved ineffective for her pain but did cause notable side-effects; why then was the GP resentful when Sil ceased the prescription? Sil investigated. Conclusion: Pfizer had a symbiotic marketing strategy with family physicians.

June 2011  –  The Archives of Internal Medicine published a review of a Neurontin Phase IV study called STEPS (Study of Neurontin: Titrate to Efficacy, Profile of Safety). Authors Krumholz et al examined the Neurontin litigation archives. Conclusion: STEPS was not a true research study; it was a seeding trial designed by marketers to push key messages to office-based physicians (forced titration of Neurontin to high dosages, and treatment of off-label conditions).

2018  –  Today, family doctors and neurologists are still urged to prescribe Neurontin for many types of neuropathic pain including Reflex Sympathetic Dystrophy (CRPS Type I). That counsel is echoed by medical journals, health blogs, and the majority of RSD support groups. Among these support groups, a search turns up one laudable exception: American RSDHope.

Clinical Pharmacologist Dr. Thomas Perry warns: Large acute pain trials cast serious doubt on the notion that gabapentin is an efficacious analgesic, as opposed to a soporific drug. But the medical community will not take the lead to end the Neurontin franchise. Perhaps patients can. To that end, Tuum Est developed our Gabapentin Series  [published between now and early 2018].

  • On this page:  Personal report of Sil (expanded)
  • Patient Log: Gabapentin:  Sil contemporaneous observations while taking Neurontin for RSD (includes pain diary, scan results, what didn't work – and what did)
  • Early Clinical Trials and the Seeding Trial:  A clear discussion of Neurontin research
  • Gabapentin Watch:  We will track changes, if any, in attitudes toward prescribing Neurontin found on prominent medical sources online
  • The Pfizer Lockstep Dance:  Animated editorial (let satire stir the world)

The Symbiosis of Dr. Yelland and Pfizer

In 2000, my Saskatoon family physician, Dr. Joel Yelland, eagerly handed me two research papers describing the off-label use of Gabapentin for neuropathic pain. Yelland sounded positive that it would alleviate the Reflex Sympathetic Dystrophy (RSD) in my right foot.

Dr. Yelland had never given me research papers before. It was the other way around – I often brought in to my appointments material I located in the U of S Health Sciences Library. I felt grateful, even honored, that he made the effort this time.

On Dr. Yelland's advice, I tried Gabapentin for three separate periods over two months, with this consistent result: Gabapentin did not improve my RSD pain at all, but did cause side-effects, namely a constant diffuse headache and drowsiness. Throughout the intervals on Gabapentin I also experienced an intense flare of my Lupus Arthritis and had fevers spiking several times a day.

Dr. Yelland became enraged when I could not continue the prescription. Even more disturbing than Yelland's resentment, is the fact that four years earlier the medical world already knew Gabapentin was ineffective for neuropathic pain. Gabapentin is the chemical (or generic) name for Neurontin, a prescription medicine manufactured by Pfizer.

In 1996, a Pfizer employee Dr. David Franklin filed a whistleblower lawsuit on the basis that 88% of the revenue from Neurontin was from off-label uses by year 2000, yet much of the evidence supporting those off-label uses was known to be fabricated.

The lawsuit claimed: Pfizer illegally marketed Neurontin for treatment of ailments not approved by the FDA including migraines, neuropathic pain, and nociceptive pain. The company knew Neurontin was ineffective for those conditions. Despite this, in the early 2000s Pfizer made neuropathic pain a major focus of their marketing strategy.

Source of Yelland’s Rage

In five short years, Pfizer generated $10 billion selling its seizure drug Neurontin for unapproved uses. Pharmaceutical companies try to maximize profit from their best-selling products. But some companies take an illegal shortcut – they market the drug for off-label uses.

Off-label means the symptom you want to treat is not truly an indication for prescribing the drug; the symptom is not listed on the label; no clinical trials support that particular use. FDA approval is not required for off-label treatments, which makes the shortcut alluring as the manufacturer needn't invest money in further research studies.

Where is the line drawn? Doctors are allowed to prescribe medicines for unapproved uses, but pharmaceutical companies may not actively promote or market the medicine for off-label use, and may not use financial inducements or misrepresentation to sell doctors on the idea. However, the consumer group Public Citizen called Neurontin the most complete and well-documented case of off-label promotion to ever come into public view.

The marketing tactics were symbiotic, offering profit to the doctor as well as to Pfizer. In this context we understand Dr. Yelland's rage when Gabapentin (Neurontin) proved ineffective for my case of RSD. Simply: When the written prescriptions ceased, Yelland's financial kickbacks from Pfizer ceased.

Pfizer Lawsuits Well Founded

Dr. David Franklin's Qui Tam lawsuit was well-founded. In 2004 pharmaceutical giant Pfizer paid $430 million to settle the civil and criminal charges for illegal promotion of Neurontin. In 2009, Pfizer paid another fine of $2.3 billion. Pfizer was found guilty of violating racketeering laws in the United States. Violating RICO (the Racketeer Influenced and Corrupt Organizations Act) meant that future jury awards to injured patients were tripled.

By 2010, Pfizer faced 1,200 individual lawsuits over Neurontin. A frequent side-effect reported by plaintiffs was depression and increased thoughts of suicide, caused by a depletion of serotonin. The FDA responded by requiring Neurontin and similar epilepsy medicines to carry warnings of this risk on the label.

Litigation documents said: Pfizer engaged in outright deception of the biomedical community, and suppressed scientific truth. Pfizer stalled or stopped the publication of negative study results; manipulated the design of clinical trials and the data to make the drug look more effective than it was; and using questionable tactics to enhance the drug's image and increase its sales.

All of these practices were highly unethical, harmful to science, wasteful of public resources, and potentially dangerous to the public's health, said Kay Dickersin, Director for the Center for Clinical Trials at Johns Hopkins University. Why did Pfizer risk censure by skewing the data? Clinical Pharmacologist Dr. T. Perry summarized the process succinctly:

It was crucial for the company to exaggerate the purported benefits of Neurontin, push the dose, and play down adverse effects, in order to maximize off-label use for the large population of chronic-pain patients who might at least purchase several months worth of the drug – even if they could not be persuaded to renew their Rx.

Neuropathic Pain:  Skewed Clinical Trials

Pfizer sold Neurontin to treat several conditions for which it does not have FDA approval. One of those conditions was neuropathic pain, a chronic condition resulting from an injury to the nervous system. This was an off-label use of Neurontin; worse, Pfizer encouraged doctors to prescribe it at higher doses than were approved by the FDA. To downplay the lack of effectiveness of Neurontin, Pfizer skewed the results of clinical trials .

Perhaps the most subtle example of manipulated research is the Backonja Study which focused on neuropathic pain. It was planned as a blind study, where Neurontin was tested against a placebo. In research it is crucial that patients don't know which group they're in, to avoid the placebo effect where a patient may declare he feels better simply because he expects he should (hope can engender endorphins), or because he does not want to displease the authority figure of the doctor.

But part of the trial called for very high doses of Neurontin which led to adverse effects (or AEs) such as somnolence or dizziness in half the patients. The side-effects allowed patients to figure out which group they were in — control group or Rx group — so it was no longer a blind study. Due to this and other flaws, a Biostatistician at Berkeley University concluded: The trial provides no basis of any clinical efficacy for Neurontin over placebo in reducing pain in this population.

According to John Abramson of Harvard Medical School: Pfizer commissioned other studies to test where Neurontin could alleviate neuropathic pain. All results were negative, showing that Neurontin was no better than a placebo in treating neuropathic pain. These were not the Seeding Trials, which were concocted later. These early studies were high-level, performed to a high standard (double-blind, randomized, and controlled).

Pfizer knew about the early well-designed studies, the FDA knew about them, and Pfizer's own consultants looked at them and advised: this Rx doesn’t work for neuropathic pain.”

Expanded FDA-Label Too Expensive, Pfizer Takes Shortcut

The FDA approves each prescription medicine for a well-defined set of diseases. Each medicine that is sold bears its own individual FDA-approved label. Doctors are free to prescribe a medicine for uses not specified on the label, but the FDA forbids promotion of those off-label uses.

The court found: Neurontin's manufacturers decided not to seek an expanded FDA label for the drug, an expensive process requiring solid proof from clinical trials. Instead, the company boosted sales through aggressive promotional strategies, even when scientific studies had demonstrated that it was not effective, the Justice Department said.

Pfizer could not bury those strategies forever. The company was convicted of sanitizing documents. The case: A Pfizer sales representative altered documents, then backdated the alterations on his computer, to delete the evidence of promotion of Neurontin for uses and dosages for which it was not indicated or approved.

U.S. Attorney Michael Sullivan, chief prosecutor for the Boston Federal District, observed:

Pfizer’s illegal and fraudulent promotion scheme corrupted the information process relied upon by doctors in their medical decision making, thereby putting patients at risk.

Pfizer Policy on Public Disclosure

After a company merger in 2000, when pharmaceutical giant Pfizer acquired Parke-Davis, a policy manual emerged titled Pfizer Policy on Public Disclosure. The document defines itself as: Global directive to address and constrain the communication of study results; the authorship of medical articles; and investigator access to clinical data. These policies formally blocked investigators and medical journals from access to the clinical research database. Significant excerpts:

Closed Database: As owners of the study database, Pfizer has discretion to decide who will have access. Generally, study databases are only made available to regulatory authorities.

Limited Statistical Power: Pfizer reserves the right not to release all exploratory study results, or to make the designs of clinical trial protocols available publicly, because: (1) they are often proprietary to Pfizer; (2) due to their limited statistical power, they serve primarily to generate or preliminarily test hypotheses that may be more thoroughly evaluated in future trials.

Journals Access Synopsis Only: If requested by a medical journal on review of a manuscript for publication, Pfizer will provide via the author, a synopsis of the clinical trial protocol with the understanding that such documents are confidential and should be returned to Pfizer.

Authors Access Selective Results: All authors, from within Pfizer or external, will be given the relevant statistical tables, figures, and reports needed to support the planned publication. Pfizer sometimes employs staff to help analyze and interpret data, and to produce manuscripts and presentations.

Constraint on Publication: Pfizer reserves the right to ask to defer publication of individual site results. Pfizer has the right to review any of the manuscripts, presentations, or abstracts that originate from our studies, or that use our data, before they are submitted for publication.

Multi-Site Clinical Trials: Individual investigators in multi-site trials will have access to their own subject's data and may have the randomization code at the end of the trial. This code matches a patient to their treatment (active med or placebo). Pfizer will make a summary of the full study available to each investigator.

Full Database Withheld: Pfizer does not ordinarily provide investigators with the database for the full study. We will provide access to relevant data at an agreed location and will respond to reasonable requests for additional analyses. For multi-site trials, Pfizer will also permit investigators to review relevant statistical tables, figures, and reports for the entire study at a designated Pfizer facility.

FURTHER READING

Survey of Neurontin Early Clinical Trials

Research:  Bias and the Sunshine Act

Law:  Pfizer Curbed and Convicted

Fourth Estate:  Dutiful Warnings About Neurontin

Whistleblower Experience with BigPharma

Georgena S. Sil
Saskatoon, Canada
Physicist & Technical Writer
Alumnus: University of British Columbia
TuumEstContact@protonmail.com

Copyright © 2008-2018 Georgena Sil. All Rights Reserved.