Gabapentin and the Criminal Manipulation of Science, a Decade Later

Health Letter, January 2017

Sarah Sorscher, J.D., M.P.H.

In 2004, Parke-Davis, the manufacturer of gabapentin (NEURON-TIN), pleaded guilty to felony charges for illegal marketing.[1] At the center of its campaign was a coordinated effort to manipulate the scientific literature, publishing selected reports and data to make the drug appear effective for “off-label” uses not approved by the Food and Drug Administration (FDA).[2],[3]

Off-label sales declined after the criminal investigation of the company was publicized by The New York Times in 2002.[4],[5] Yet even today doctors continue to prescribe this dangerous drug for multiple off-label uses.[6] Protect yourself and your loved ones from unnecessary risk by learning which claims about gabapentin (and its two extended-release versions) are supported by sound science and which are not.

Limited Use: Epilepsy and shingles pain

Gabapentin was first approved by the FDA in 1993 to treat partial seizures — a type of epilepsy — as a supplement to other anti-seizure medications.[7] Four years later, the FDA rejected a Parke-Davis application to approve gabapentin as a stand-alone epilepsy treatment.[8],[9]

Three different versions of the drug — gabapentin, gabapentin enacarbil extended-release (HORIZANT) and extended-release gabapentin (GRALISE) — are FDA-approved to treat nerve pain related to shingles, a common skin infection caused by the chicken pox virus.[10],[11],[12] Both gabapentin and gabapentin enacarbil, which converts to gabapentin once in the body,[13] are effective for shingles pain.[14],[15] However, GRALISE showed only minimal effectiveness, proving no better than a placebo in two of three randomized trials.[16] Even in the trial showing some effectiveness, the drug reduced average pain scores only half a point, compared with a placebo, on a 0 to 10 scale, a questionable benefit.

The benefits for each indication must also be weighed against the drug’s many risks:[17],[18],[19] Up to one in five patients taking gabapentin and its variants experience drowsiness, dizziness or loss of muscle control as a side effect, and this may impair their driving ability. Gabapentin and its variants also cause pancreatic cancer in animals. The drug also causes a rare but deadly reaction that can damage multiple organ systems, and it increases the risk of suicide. Risk of side effects is even greater among patients with impaired kidney function, which is common among elderly adults.

Do Not Use: Restless leg syndrome

Gabapentin enacarbil extended release is FDA-approved for restless leg syndrome (RLS) in adults.[20] High doses of gabapentin enacarbil are absorbed more efficiently by the intestine than high doses of gabapentin, potentially resulting in greater side effects.[21]

Gabapentin enacarbil reduces RLS symptoms. Yet an FDA reviewer initially recommended against approving the drug for this use because it caused pancreatic cancer in rats at doses relatively close to those used in humans, outweighing its potential benefit for RLS.[22] We agree with that reviewer and recommend against using this drug for RLS.

Off-label uses

More than 10 years after Parke- Davis pleaded guilty for illegal marketing, misinformation on gabapentin’s off-label uses remains common.

Non-shingles nerve pain

Parke-Davis’ illegal marketing campaign systematically misinformed doctors on the benefits of gabapentin for various types of nerve pain unrelated to shingles, even after the FDA warned that these uses could not be supported with available evidence.[23]

In particular, Parke-Davis misrepresented data to suggest that gabapentin was effective for pain due to complications from diabetes. A company-funded, placebo-controlled trial supporting this use was published with great fanfare in the prestigious Journal of the American Medical Association (JAMA) in 1998.[24],[25] Yet even today, Parke-Davis has yet to publish full results from two additional clinical trials showing no benefit for this type of pain, including one trial three times larger than the JAMA study.[26]

Bipolar disorder

Use of gabapentin to treat bipolar disorder is particularly troubling because anti-epileptic drugs such as gabapentin increase suicide risk. Fortunately, this use became less popular following the publication in 2000 of two placebo-controlled trials showing the drug was no better than a placebo for bipolar symptoms.[27]

Migraines

Parke-Davis withheld publication of data from two clinical trials showing that the drug was ineffective at preventing migraines, and the company modified the published results of a third failed trial to make the drug appear effective.[28] A systematic review published in 2013 that included unpublished data (discovered during litigation) concluded that gabapentin is not effective for prevention of migraines,[29] yet some doctors continue to recommend the drug for migraines where other drugs have failed.[30]

Attention deficit hyperactivity disorder (ADHD)

Parke-Davis marketed gabapentin heavily for ADHD, even though it has not been tested for this use in published clinical trials.[31],[32] The drug’s side effects include hostility and concentration problems in children, making this use particularly inappropriate.[33]

What You Can Do

Do not use any version of gabapentin for off-label uses, as the scientific evidence for the drug remains disturbingly tainted by misinformation, even a decade after the manufacturer pleaded guilty to criminal marketing.

NEURONTIN or generic gabapentin should be used only for treatment of partial seizures in combination with other anti-seizure medications, and for moderate to severe shingles pain.

We recommend that you do not use HORIZANT or GRALISE. These products are more expensive but no more effective (and GRALISE is probably less effective) than generic gabapentin for treating shingles pain, and they are not FDA-approved for treating seizures.

References

[1] Department of Justice. Press release: Warner-Lambert to pay $430 million to resolve criminal and civil health care liability relating to off-label promotion. May 13, 2004. https://www.justice.gov/archive/opa/pr/2004/May/04_civ_322.htm. Accessed July 6, 2016.

[2] In re Neurontin marketing and sales practices litigation. Civil Action No. 04- cv-10739-PBS. 2011 WL 3852254. August 31, 2011.

[3] Vedula SS, Bero L, Scherer RW, Dickerson K. Outcome reporting in industry- sponsored trials of gabapentin for off-label uses. N Engl J Med. 2009;361(20):1963-1971.

[4] Petersen M. Whistle-blower says marketers broke the rules to push a drug. New York Times. March 14, 2002. http://www.nytimes.com/2002/03/14/business/whistle-blower-says-marketers- broke-the-rules-to-push-a-drug.html?pagewanted=all. Accessed July 6, 2016.

[5] In re Neurontin marketing and sales practices litigation. Civil Action No. 04- cv-10739-PBS. 2011 WL 3852254. August 31, 2011.

[6] UpToDate. Gabapentin: Drug information (Lexicomp). Accessed June 14, 2016.

[7] Parke-Davis. Label: gabapentin (NEURONTIN). September 2015. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=ee9ad9ed-6d9f-4ee1-9d7f- cfad438df388&type=pdf&name=ee9ad9ed-6d9f-4ee1-9d7f-cfad438df388. Accessed July 6, 2016.

[8] In re Neurontin marketing and sales practices litigation. Civil Action No. 04-cv-10739-PBS. 2011 WL 3852254. August 31, 2011.

[9] United States of America ex rel David Franklin v. Pfizer, (AMENDED COMPLAINT). Civil Action No. 96- 11651-PBS (undated). https://www.citizen.org/sites/default/files/1638attach.pdf. Accessed July 6, 2016.

[10] XenoPort Inc. Label: gabapentin enacarbil, extended release (HORIZANT). July 2013. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=4c486fc7-c8c4-4c6c-b30c- 366dabaeaadd&type=pdf&name=4c486fc7-c8c4-4c6c-b30c-366dabaeaadd. Accessed July 6, 2016.

[11] Parke-Davis. Label: gabapentin (NEURONTIN). September 2015. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=ee9ad9ed-6d9f-4ee1-9d7f- cfad438df388&type=pdf&name=ee9ad9ed-6d9f-4ee1-9d7f-cfad438df388. Accessed July 6, 2016.

[12] Depomed, Inc. Label: gabapentin (GRALISE). September 2015. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=7d12b4e9-ed44-43c0-9e46- f6c195300f03&type=pdf&name=7d12b4e9-ed44-43c0-9e46-f6c195300f03. Accessed June 20, 2016.

[13] Food and Drug Administration. Medical Review(s): Gabapentin enacarbil (HORIZANT). April 5, 2011. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022399Orig1s000MedR.pdf. Accessed July 7, 2016.

[14] Food and Drug Administration. Medical Review(s): gabapentin (NEURONTIN). May 24, 2002. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-397.pdf_Neurontin_Medr_P1.pdf. Accessed July 7, 2016.

[15] Zhang L, Rainka M, Freeman R, et al. A randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of gabapentin enacarbil in subjects with neuropathic pain associated with postherpetic neuralgia (PXN110748). J Pain. 2013;14(6):590-603.

[16] Food and Drug Administration. Medical Review(s): gabapentin extended release (GRALISE). December 7, 2010.http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022544Orig1s000MedR.pdf. Accessed July 7, 2016.

[17] Parke-Davis. Label: gabapentin (NEURONTIN). September 2015. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=ee9ad9ed-6d9f-4ee1-9d7f- cfad438df388&type=pdf&name=ee9ad9ed-6d9f-4ee1-9d7f-cfad438df388. Accessed July 6, 2016.

[18] Depomed, Inc. Label: gabapentin (GRALISE). September 2015. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=7d12b4e9-ed44-43c0-9e46- f6c195300f03&type=pdf&name=7d12b4e9-ed44-43c0-9e46-f6c195300f03. Accessed June 20, 2016.

[19] XenoPort Inc. Label: gabapentin enacarbil, extended release (HORIZANT). July 2013. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=4c486fc7-c8c4-4c6c-b30c- 366dabaeaadd&type=pdf&name=4c486fc7-c8c4-4c6c-b30c-366dabaeaadd. Accessed July 6, 2016.

[20] XenoPort Inc. Label: gabapentin enacarbil, extended release (HORIZANT). July 2013. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=4c486fc7-c8c4-4c6c-b30c- 366dabaeaadd&type=pdf&name=4c486fc7-c8c4-4c6c-b30c-366dabaeaadd. Accessed July 6, 2016.

[21] Food and Drug Administration. Medical Review(s): Gabapentin enacarbil (HORIZANT). April 5, 2011. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022399Orig1s000MedR.pdf. Accessed July 7, 2016.

[22] Ibid.

[23] In re Neurontin marketing and sales practices litigation. Civil Action No. 04-cv-10739-PBS. 2011 WL 3852254. August 31, 2011.

[24] Backonja M, Beydoun A, Edwards K, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: A randomized controlled trial. JAMA. 1998;280(21):1831-1836.

[25] In re Neurontin marketing and sales practices litigation. Civil Action No. 04-cv-10739-PBS. 2011 WL 3852254. August 31, 2011.

[26] Ibid.

[27] Fullerton CA, Busch AB, Frank RG. The rise and fall of gabapentin for bipolar disorder. A case study on off-label pharmaceutical diffusion. Medical Care. 2010;48(4):372-379.

[28] In re Neurontin marketing and sales practices litigation. Civil Action No. 04-cv-10739-PBS. 2011 WL 3852254. August 31, 2011.

[29] Linde M, Mulleners WM, Chronicle EP, McCrory DC. Gabapentin or pregabalin for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev. 2013:CD010609.

[30] Garza I, Schwedt TJ. Chronic migraine. UpToDate. Updated May 12, 2015. www.uptodate.com. Accessed July 6, 2016.

[31] Mack A. Examination of the evidence for off-label use of gabapentin. J Managed Care Pharm. 2003;9 (6):559-568.

[32] United States of America ex rel David Franklin v. Pfizer (AMENDED COMPLAINT). Civil Action No. 96- 11651-PBS (undated). https://www.citizen.org/sites/default/files/1638attach.pdf. Accessed July 6, 2016.

[33] Parke-Davis. Label: gabapentin (NEURONTIN). September 2015. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=ee9ad9ed-6d9f-4ee1-9d7f- cfad438df388&type=pdf&name=ee9ad9ed-6d9f-4ee1-9d7f-cfad438df388