Gabapentinoid Drug Use Is Exploding Despite Poor Safety and Efficacy Profiles

In 1993, the Food and Drug Administration (FDA) approved gabapentin (under the brand name NEURONTIN) as an add-on treatment for focal (partial) seizures — a type of epilepsy that begins in one side of the brain — and subsequently approved the drug in 2002 to treat the long-term pain that occurs as a late complication of shingles (postherpetic neuralgia) in adults.[1] The agency later approved two different formulations of the drug: one (sold under the brand name GRALISE) to treat postherpetic neuralgia[2] and another (sold under the brand name HORIZANT) to treat such shingles pain and restless legs syndrome in adults.[3]

Pregabalin (LYRICA) is chemically very similar to gabapentin and was initially approved by the FDA in 2004 for postherpetic neuralgia[4] and neuropathic pain related to diabetic neuropathy (nerve damage).[5] The agency subsequently approved the drug for partial-onset seizures; neuropathic pain due to spinal cord injury; and fibromyalgia, a condition characterized by muscle pain, stiffness and fatigue.[6]

Together gabapentin and pregabalin are classified as gabapentinoids as they are chemically similar to gamma-aminobutyric acid (GABA), a natural substance in the brain that blocks certain nerve signals.

Marked increases in the prescribing of gabapentinoids, particularly for uses not approved by the FDA (so-called off-label uses), indicate that these drugs are widely overprescribed and misused in the U.S. A major cause of this overprescribing was illegal off-label marketing over many years by Pfizer, the manufacturer of Neurontin and Lyrica, which resulted in payment of hundreds of millions of dollars in fines assessed by the U.S. Department of Justice.[7],[8] Three recently published studies characterized the growth and extent of gabapentinoid overuse during the past two decades.

Extensive off-label use

The first study, which was published in 2019 in the Journal of Clinical Medicine, examined a nationally representative sample of outpatient visits to non-federally employed physicians to assess trends in gabapentinoid use from 2003 to 2016.[9] The study revealed that the number of visits that involved the prescribing of a gabapentinoid nearly quadrupled from 2003 to 2016 (9 to 35 gabapentinoid-related visits per 1,000 visits, respectively). Most of this increase was due to a rise in gabapentin prescribing. The study also showed that for an astounding 97% of all gabapentinoid-related visits, the prescriber had not included an FDA-approved indication for such use among the first three diagnoses listed on the corresponding medical claim, suggesting a high rate off-label prescribing.

The second study, which was published in 2020 in the journal Supportive Care in Cancer, assessed trends in the use of gabapentinoids by adult cancer patients in the U.S. using data from the annual Medical Expenditure Panel Survey — a large-scale federal survey of a nationally representative sample of families and individuals, their medical providers (including doctors, hospitals and pharmacies) and employers across the U.S. regarding the use of specific health services, including prescription drugs — from 2005 to 2015.[10] Importantly, these drugs are not approved for treating cancer-related pain syndromes. Gabapentinoid use for pain was found in 5.6% of cancer patients nationally in 2015, which represented a 2.4-fold increase since 2005. In 2005, the total number of gabapentinoid prescriptions filled by U.S. adults with cancer was approximately 1.2 million, and by 2015 the number of such prescriptions had increased to about 3.5 million. The study researchers noted that “Gabapentinoid use for cancer pain is off-label with conflicting evidence for benefit.”

The third study, which was conducted by the Institute of Safe Medication Practices (ISMP) and published in the organization’s Quarter Watch newsletter in 2019, analyzed data from the 2016 Medical Expenditure Panel Survey.[11] One goal of the study was to measure current patterns of gabapentinoid use in comparison with other psychoactive drugs. The ISMP researchers found that an estimated 10 million adults in the U.S. used a gabapentinoid during 2016, including 8.7 million taking gabapentin and 1.6 million taking pregabalin (some patients took both). Notably, gabapentin was more widely prescribed than the most commonly used antidepressant (sertraline [ZOLOFT]) and the most popular benzodiazepine (alprazolam [XANAX]). Moreover, gabapentin was the second most frequently used psychoactive drug, ranking behind only the opioid combination of acetaminophen/hydrocodone.

The ISMP team noted that gabapentinoids were rarely used alone. Strikingly, half of all patients using these drugs reported taking three or more psychoactive drugs, and one-quarter took five or more. Of additional concern, 35% of gabapentinoid users also reported taking an opioid, and 18% regularly used a benzodiazepine or similar drug. Such drug combinations are potentially unsafe because they increase the risk of drug overdose and depressed breathing through their effects on the central nervous system.[12]

Adverse effects[13],[14]

Common adverse effects of gabapentinoids include dizziness, drowsiness, fatigue, impaired ability to drive or operate heavy machinery, swelling in the arms and legs, and problems with coordination. Less common adverse effects include the following:

• A rare, potentially fatal disorder call Drug Reaction with Eosinophilia and Systemic Symptoms or DRESS (also known as multiorgan sensitivity) that can lead to fever; rash; swollen lymph glands; and inflammation in the liver, kidneys, heart and other organs (for gabapentin only)
• Severe allergic reactions, including anaphylaxis and angioedema, that may lead to swelling of the mouth, lips and tongue; difficulty breathing; and low blood pressure
• Suicidal thoughts and behavior
• Seizures precipitated by abruptly stopping the drugs
• Depressed breathing

Our recommendations

Public Citizen’s Health Research Group has designated both gabapentin and pregabalin as Limited Use. We recommend patients use generic versions of gabapentin, which are much cheaper than Neurontin, and limit use of the drug to the treatment of partial-onset seizures and moderate-to-severe postherpetic neuralgia. We advise against using Gralise or Horizant for postherpetic neuralgia because they are expensive and there are no adequate studies that show them to be more effective than generic gabapentin. We recommend against using Horizant for restless legs syndrome because less toxic remedies (for example, regular exercise) exist and the long-term effectiveness of Horizant for this use has not been demonstrated.

We also advise limiting use of pregabalin as add-on therapy to other drugs to treat partial-onset seizures. We recommend against using pregabalin for nerve pain disorders or fibromyalgia because there is insufficient evidence showing that the drug’s benefits outweigh its risks for such uses.

Finally, do not use gabapentinoids for any off-label indications. Although such uses are common, they are not evidence-based, and they expose patients to unacceptable risks. Be especially warry of using gabapentinoids at the same time as other drugs that depress breathing, such as benzodiazepines and opioids, because the overlapping use of such medications places you at increased risk of overdose and death.
 

References

[1] Pfizer. Label: gabapentin (NEURONTIN). April 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021446s040,%20022488s017lbl.pdf. Accessed August 7, 2020.

[2] Almatica Pharma. Label: gabapentin (GRALISE). April 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022544s026lbl.pdf. Accessed August 7, 2020.

[3] Arbor Pharmaceuticals. Label: gabapentin (HORIZANT). April 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022399s010lbl.pdf. Accessed August 6, 2020.

[4] Food and Drug Administration. Letter to Pfizer Global Research and Development approving NDA 21-723. December 30, 2004. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/21723ltr.pdf. Accessed August 7, 2020.

[5] Food and Drug Administration. Letter to Pfizer Global Research and Development approving NDA 21-446. December 30, 2004. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/21446ltr.pdf. Accessed August 7, 2020.

[6] Pfizer. Drug label: pregabalin (LYRICA). April 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021446s040,%20022488s017lbl.pdf. Accessed August 6, 2020.

[7] Department of Justice. Warner-Lambert to pay $430 million to resolve criminal & civil health care liability relating to off-label promotion. May 13, 2004. http://web.archive.org/web/20041205003748/www.usdoj.gov/opa/pr/2004/May/04_civ_322.htm. Accessed August 20, 2020.

[8] Department of Justice. Justice department announces largest health care fraud settlement in Its history. September 2, 2009. https://www.justice.gov/opa/pr/justice-department-announces-largest-health-care-fraud-settlement-its-history. Accessed August 20, 2020.

[9] Zhou L, Bhattacharjee S, Kwoh KL, et al. Trends, patient and prescriber characteristics in gabapentinoid use in a sample of United States ambulatory care visits from 2003 to 2016. J Clin Med. 2019; 9(1):83.

[10] Fauer AJ, Davis MA, Choi SW, et al. Use of gabapentinoid medications among US adults with cancer, 2005–2015. Support Care Cancer. 2020;28(1):5-8.

[11] Institute for Safe Medication Practices. Unsafe use of GABA analog drug. Quarter Watch. March 27, 2019.

[12] Food and Drug Administration. Drug safety communication: FDA warns about serious breathing problems with seizure and nerve pain medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR) when used with CNS depressants or in patients with lung problems. December 19, 2019. https://www.fda.gov/media/133681/download. Accessed August 7, 2020.

[13] Pfizer. Label: gabapentin (NEURONTIN). April 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021446s040,%20022488s017lbl.pdf. Accessed August 6, 2020.

[14] Pfizer. Drug label: pregabalin (LYRICA). April 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021446s040,%20022488s017lbl.pdf. Accessed August 6, 2020.