FDA Warns of Serious Breathing Problems with Use of Gabapentin and Pregabalin

On Dec. 19, 2019, the Food and Drug Administration (FDA) warned that serious breathing problems may occur in patients using the seizure and nerve pain drugs gabapentin (GRALISE, HORIZANT, NEURONTIN) or pregabalin (LYRICA) who have respiratory risk factors.[1]

These risk factors include use of opioid analgesics and other drugs that can depress breathing through their effects on the central nervous system (CNS) (for example, benzodiazepine sedatives like diazepam [VALIUM]), as well as pulmonary disorders that reduce lung function, such as chronic obstructive pulmonary disease (COPD). Elderly patients also have a higher risk of breathing problems when taking gabapentin or pregabalin.

Overview of gabapentin and pregabalin

Gabapentin, sold under the brand name Neurontin, is approved by the FDA to treat partial-onset seizures — a type of epilepsy that begins in one side of the brain — and nerve pain that occurs as a late complication of shingles (a condition called postherpetic neuralgia) in adults.[2] The agency also has approved two additional forms of the drug: one (sold under the brand name Gralise[3]) to treat postherpetic neuralgia and another (sold under the brand name Horizant[4]) to treat postherpetic neuralgia and moderate-to-severe restless legs syndrome in adults.

Pregabalin is approved by the FDA to treat partial-onset seizures; nerve pain due to diabetic neuropathy, postherpetic neuralgia and spinal cord injury; and fibromyalgia, a condition characterized by muscle pain, stiffness and fatigue.[5]

Public Citizen’s Health Research Group has designated both drugs as Limited Use.

We advise limiting use of generic gabapentin to the treatment of partial-onset seizures and moderate-to-severe postherpetic neuralgia. We recommend against using Gralise or Horizant for postherpetic neuralgia because they are expensive and there are no studies that show them to be more effective than generic gabapentin. Do not use Horizant for restless legs syndrome.

We also advise limiting use of pregabalin to treatment of partial-onset seizures. We recommend against using pregabalin for nerve pain disorders or fibromyalgia. Be aware that pregabalin must not be stopped suddenly because seizures may occur. When discontinuing the drug, the dose should be gradually tapered over a week.

FDA warning[6]

The FDA noted that use of gabapentin and pregabalin for prescribed medical reasons has grown in recent years, as have misuse and abuse of these drugs. Between 2012 and 2016, the number of patients who filled a prescription for gabapentin increased from approximately eight million to 13 million annually, and the number of patients who filled a prescription for pregabalin increased from 1.9 million to 2.1 million annually. Importantly, these drugs often are prescribed for uses not approved by the FDA. According to the FDA, gabapentin and pregabalin are frequently taken concomitantly (at the same time) with opioids for prescribed medical uses and often are abused together with opioids.

The FDA based its December alert on a review of data from several sources demonstrating that serious breathing problems can occur when patients with respiratory risk factors use gabapentin or pregabalin. These data sources included reports submitted to the agency’s adverse event reporting system, as well as results of randomized, placebo-controlled clinical trials in healthy individuals, observational studies in humans and experiments in animals.

From January 2012 to October 2017, 49 cases of depressed breathing in people taking gabapentin (15 cases) or pregabalin (34 cases) were reported to the FDA. In 45 of the cases (92%), including all 12 cases that resulted in death, the patient had at least one respiratory risk factor, including use of an opioid or another CNS depressant drug or age-related decline in lung function.

Data from several small randomized, placebo-controlled trials in healthy individuals that were reviewed by the FDA revealed that use of gabapentin or pregabalin alone or in combination with an opioid causes depressed breathing. Similarly, results of observational studies showed that patients exposed to gabapentin prior to surgery were more likely to experience respiratory depression after surgery than those not exposed to the drug.

Finally, experiments in animals demonstrated that both gabapentin and pregabalin administered alone and in combination with opioids depress breathing. The FDA concluded that published animal studies “suggest that [gabapentin and pregabalin] have an independent dose-dependent depressive effect on respiration [breathing] and can augment the respiratory depression caused by opioids.”

In response to this information, the FDA is requiring the addition of new warnings to the product labeling of all gabapentin and pregabalin drug products. The agency also has ordered manufacturers of these products to conduct additional clinical trials to further evaluate the drugs’ abuse potential, particularly when combined with opioids.

What You Can Do

If you are taking gabapentin or pregabalin, you should avoid concomitant use of opioid medications or other CNS depressants, particularly if you are elderly or have COPD or another lung disease. You should never take these medications at higher doses or more frequently than prescribed because doing so could cause serious breathing problems or death.

You also should seek immediate medical attention if you or someone you are caring for develops the following symptoms, which may be indicative of depressed breathing:

• Confusion or disorientation
• Unusual dizziness or lightheadedness
• Extreme sleepiness
• Slowed, shallow or difficult breathing
• Unresponsiveness, which means the person doesn’t answer or react normally or you cannot wake them up
• Bluish-colored skin, especially on the lips, fingers and toes.

References

[1] 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 January 15, 2020.

[2] Pfizer. Label: gabapentin (NEURONTIN). September 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=092ea243-ec15-406e-bb40-4fe092035c70. Accessed January 15, 2020.

[3] Depomed. Label: gabapentin (GRALISE). September 2015. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=7d12b4e9-ed44-43c0-9e46-f6c195300f03. Accessed January 15, 2020.

[4] Arbor Pharmaceuticals. Label: gabapentin enacarbil (HORIZANT). October 2016. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=4c486fc7-c8c4-4c6c-b30c-366dabaeaadd. Accessed January 15, 2020.

[5] Pfizer. Label: pregabalin (LYRICA). June 2019. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=60185c88-ecfd-46f9-adb9-b97c6b00a553. Accessed January 15, 2020.

[6] 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 January 15, 2020.