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In 1993, the Food and Drug Administration (FDA) approved the oral prescription drug gabapentin (NEURONTIN) as an add-on treatment for focal (partial) seizures[1] — a type of epilepsy that begins in one side of the brain — and subsequently approved the drug in 2002 to treat pain that occurs as a late complication of shingles (postherpetic neuralgia) in adults.[2] The agency later approved two different formulations of the drug: one (GRALISE) to treat shingles pain[3] and another (HORIZANT)...
In 1993, the Food and Drug Administration (FDA) approved the oral prescription drug gabapentin (NEURONTIN) as an add-on treatment for focal (partial) seizures[1] — a type of epilepsy that begins in one side of the brain — and subsequently approved the drug in 2002 to treat pain that occurs as a late complication of shingles (postherpetic neuralgia) in adults.[2] The agency later approved two different formulations of the drug: one (GRALISE) to treat shingles pain[3] and another (HORIZANT) to treat shingles pain and moderate-to-severe restless leg syndrome in adults.[4]
Most uses off-label
Gabapentin has been a top-selling drug for many years: It was the ninth most commonly prescribed drug in the U.S. in 2016, totaling over 58 million prescriptions that year.[5]
However, most of gabapentin’s prescriptions are for off-label uses (uses not approved as safe and effective by the FDA).[6] A study that used nationally representative data showed that gabapentin had, as of 2001, the highest proportion (83 percent) of off-label prescriptions of all outpatient prescription drugs.[7] Gabapentin’s off-label uses include treatment of anxiety, bipolar disorder, borderline personality disorder, drug and alcohol addiction, insomnia, migraine, neuropathic pain associated with diabetes, and vertigo.[8]
Pfizer, the company that acquired Warner-Lambert (the original maker of gabapentin) and its marketing division (Parke-Davis), agreed to pay a total of $755 million in 2004 and 2014 in criminal and civil settlements with the U.S. federal government for its long-standing illegal promotion of the drug for off-label uses.[9] Furthermore, a 2013 study revealed that information included in publications of industry-sponsored trials supporting the off-label uses of gabapentin was frequently “different” from what was actually described in internal industry reports, suggesting that gabapentin’s maker deliberately manipulated the published literature to make the drug appear more effective than it actually is for its off-label uses.[10]
Limited use: Epilepsy and shingles pain
Although the clinical trials supporting gabapentin’s initial approval showed that the drug is effective as an add-on treatment in people with drug-resistant partial epilepsy, these trials were of short duration (lasting only three months) and did not provide any evidence regarding the long-term effectiveness of this drug.[11]
A clinical trial that directly compared gabapentin with other drugs used for the treatment of partial epilepsy such as lamotrigine (LAMICTAL) and carbamazepine (CARBATROL, EPITOL, EQUETRO, TEGRETOL, TERIL) showed that gabapentin had a higher rate of treatment failure and a lower rate of remission at one year than these other drugs, respectively, due to inadequate seizure control.[12] Importantly, gabapentin is ineffective for a type of seizures called absence seizures[13] and can worsen certain types of generalized seizures.[14]
Two small trials lasting between seven and eight weeks showed that gabapentin reduced, but did not eliminate, shingles pain: Subjects taking the drug had a mean pain score of around four (on a pain scale that ranged from 0 to 10) after treatment, compared with a not much higher pain score of nearly six before treatment.[15]
Despite its modest effectiveness, gabapentin has one advantage: It does not interact with other antiepileptic drugs. Gabapentin, however, is primarily eliminated by the kidneys, so adverse reactions to the drug (see text box below) may be more likely in patients with impaired kidney function.
Do Not Use: Restless leg syndrome
Gabapentin enacarbil extended release (HORIZANT) is approved to treat restless leg syndrome. However, high doses of this formulation are absorbed more efficiently by the intestine than high doses of other gabapentin formulations are, potentially resulting in greater, more serious adverse events.[16]
An FDA medical reviewer initially recommended against approving gabapentin enacarbil extended release because it causes pancreatic cancer in rats at doses relatively close to those used in humans, outweighing its potential benefit for restless leg syndrome. We concur with that reviewer and recommend against using this drug for this indication.[17]
Drug abuse potential
Historically, gabapentin was presumed to not have an abuse potential.[18] However, there is growing evidence to the contrary. For example, a U.S. study showed an almost 3,000 percent increase in the recreational use of gabapentin from 2008 to 2014.[19] Moreover, a 2016 systematic review estimated that misuse of gabapentin occurs in approximately 1 percent of the general population, between 40 percent and 65 percent of gabapentin users with prescriptions for the drug, and between 15 percent and 22 percent of opioid abusers.[20]
The Advisory Council on the Misuse of Drugs, an independent body of experts that advises the U.K. government, has highlighted concerns over the misuse of gabapentin in light of reports of abuse, dependence and involvement of gabapentin in opioid overdoses and opioid-related and other deaths.[21] The council asserts that gabapentin products present a risk of addiction and that the abuse potential of gabapentin is similar to that of tramadol (CONZIP, ULTRAM), a controlled substance in the U.K. and the U.S. Therefore, the council had recommended that gabapentin should be classified as a controlled substance.
Suicide risk
Based on evidence from clinical trials, the FDA in 2008 required the makers of gabapentin, along with those of 10 other antiepileptic medications, to include a warning in their labeling and develop medication guides to inform patients of the risk of suicidal thoughts or actions associated with the drugs.[22]
- Sudden death in patients with epilepsy
- Severe, possibly life-threatening allergic (anaphylactic) reaction and angioedema that result in difficulty breathing; swelling of the lips, throat and tongue; and low blood pressure requiring emergency treatment
- High eosinophil count (a type of white blood cell), associated with fever, rash and swelling of the lymph nodes, in addition to inflammation of the liver, kidney, heart or muscles
- Dizziness, drowsiness, somnolence, sedation and significant driving impairment
- Lack of coordination, which can result in falls or injuries
- Seizures that do not stop if the drug is discontinued abruptly
- Neuropsychiatric adverse reactions — including emotional instability, hostility, aggression, impaired concentration, restlessness and hyperactivity — in children aged 12 and under
What You Can Do
Generic gabapentin and Neurontin may be used only for the treatment of partial seizures in combination with other antiepileptic drugs and for minimizing moderate-to-severe shingles pain. We do not recommend using Gralise or Horizant for shingles pain because they are expensive and there are no studies that show them to be more effective than generic gabapentin. Do not use Gralise or Horizant for epilepsy, and do not use Gralise for restless leg syndrome. Do not use any gabapentin formulation for off-label uses.
References
[1] Parke-Davis Division of Pfizer Inc. Label: gabapentin (NEURONTIN). October 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020235s064_020882s047_021129 s046lbl.pdf. Accessed January 8, 2018.
[2] Fullerton CA, Busch AB, Frank RG. The rise and fall of gabapentin for bipolar disorder: a case study on off-label pharmaceutical diffusion. Med Care. 2010;48(4):372-379.
[3]Depomed, Inc. Label: gabapentin (GRALISE). September 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7d12b4e9-ed44-43c0-9e46- f6c195300f03. Accessed January 8, 2018.
[4] Arbor Pharmaceuticals. Label: gabapentin (HORIZANT). October 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c486fc7-c8c4-4c6c-b30c- 366dabaeaadd. Accessed January 8, 2018.
[5] Symphony Health. Top 200 drugs – 2016. https://symphonyhealth.com/wp-content/uploads/2017/04/Top-200-Drug-List-2016.pdf. Accessed January 8, 2018.
[6] Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: a systematic review. Addiction. 2016;111(7):1160-1174.
[7] Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office- based physicians. Arch Intern Med. 2006;166(9):1021-1026.
[8] Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: a systematic review. Addiction. 2016;111(7):1160-1174.
[9] Staton T. Pfizer adds another $325M to neurontin settlement tally. Total? $945M. Jun 2, 2014. https://www.fiercepharma.com/sales- and-marketing/pfizer-adds-another-325m-to-neurontin-settlement-tally-total-945m. Accessed January 8, 2018.
[10] Vedula SS, Li T, Dickersin K. Differences in reporting of analyses in internal company documents versus published trial reports: comparisons in industry-sponsored trials in off-label uses of gabapentin. PLoS Med. 2013;10(1):e1001378.
[11] Al-Bachari S, Pulman J, Hutton JL, et al. Gabapentin add-on for drug- resistant partial epilepsy. Cochrane Database Syst Rev. 2013;Jul 25(7):CD001415.
[12] Marson A, Al-Kharusi A, Alwaidh M, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet. 2007;369(9566):1000-1015.
[13] Tenney JR, Jain SV. Absence epilepsy: older vs newer AEDs. Curr Treat Options Neurol. 2014;16(5):10-14.
[14] Schachter SC. Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects. UpToDate. August 21, 2017.
[15] Parke-Davis Division of Pfizer Inc. Label: gabapentin (NEURONTIN). October 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020235s064_020882s047_021129 s046lbl.pdf. Accessed January 8, 2018.
[16] Food and Drug Administration. Application number 022399Orig1s000: Medical review(s) of gabapentin enacarbil (HORIZANT). April 5, 2011. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022399Orig1s000MedR.pdf. Accessed January 8, 2018.
[17] Gabapentin and the criminal manipulation of science, a decade later. September 2016. Worst Pills, Best Pills News. /newsletters/view/1054. Accessed January 8, 2018.
[18] Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: a systematic review. Addiction. 2016;111(7):1160-1174.
[19] Smith RV, Lofwall MR, Havens JR. Abuse and diversion of gabapentin among nonmedical prescription opioid users in Appalachian Kentucky. Am J Psychiatry. 2015;172(5):487-488.
[20] Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: a systematic review. Addiction. 2016;111(7):1160-1174.
[21] Advisory Council on the Misuse of Drugs. Letter to U.K.’s minster for preventing abuse and exploitation re. pregabalin and gabapentin advice. January 14, 2016. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/491854/ACMD_ Advice_-_Pregabalin_and_gabapentin.pdf. Accessed January 8, 2018.
[22] Food and Drug Administration. Information for healthcare professionals: Suicidal behavior and ideation and antiepileptic drugs. January 31, 2008. https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProv iders/ucm100192.htm. Accessed January 8, 2018.
[23] Parke-Davis Division of Pfizer Inc. Label: gabapentin (NEURONTIN). October 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020235s064_020882s047_021129 s046lbl.pdf. Accessed January 8, 2018.
