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FDA Warns About Serious Breathing Problems with Gabapentin and Pregabalin

The U.S. Food and Drug Administration (FDA) is warning that serious breathing difficulties may occur in patients using gabapentin (Neurontin, Gralise, Horizant) or pregabalin (Lyrica, Lyrica CR) who have respiratory risk factors. These include the use of opioid pain medicines and other drugs that depress the central nervous system, and conditions such as chronic obstructive pulmonary disease (COPD) that reduce lung function. The elderly are also at higher risk.

Gabapentin and pregabalin are FDA-approved for a variety of conditions, including seizures, nerve pain, and restless legs syndrome.

Our evaluation shows that the use of these medicines, often referred to as gabapentinoids, has been growing for prescribed medical use, as well as misuse and abuse. Gabapentinoids are often being combined with CNS depressants, which increases the risk of respiratory depression. CNS depressants include opioids, anti-anxiety medicines, antidepressants, and antihistamines. There is less evidence supporting the risk of serious breathing difficulties in healthy individuals taking gabapentinoids alone. We will continue to monitor these medicines as part of our routine monitoring of all FDA-approved drugs.

Gabapentinoids are approved to treat a variety of conditions including partial seizures and nerve pain from spinal cord injury, shingles, and diabetes. Other approved uses include fibromyalgia and restless legs syndrome. Gabapentin was first approved in 1993 and pregabalin was first approved in 2004. Gabapentin is marketed under the brand names Neurontin and Gralise, and also as generics. Gabapentin enacarbil is marketed under the brand name Horizant. Pregabalin is marketed under the brand names Lyrica and Lyrica CR, and also as generics. Pregabalin is a Schedule V controlled substance, which means it has a lower potential for abuse among the drugs scheduled by the Drug Enforcement Administration (DEA), but may lead to some physical or psychological dependence.

Health care professionals should start gabapentinoids at the lowest dose and monitor patients for symptoms of respiratory depression and sedation when co-prescribing gabapentinoids with an opioid or other central nervous system (CNS) depressant such as a benzodiazepine. Patients with underlying respiratory disease and elderly patients are also at increased risk and should be managed similarly.

We recognize that incorporating one or more medications with non-drug therapies is the prevailing approach for optimizing analgesia. However, pairing an opioid with any CNS depressant – a gabapentinoid, benzodiazepine, sedating antidepressant, sedating antipsychotic, antihistamine, or other product – will increase the risk of respiratory depression. Shifting treatment from one CNS depressant to another may pose similar risks. Be aware of the potential additive effects of all these CNS depressants and plan accordingly, by starting with low doses, titrating carefully, and informing patients of the potential for CNS and respiratory depression and their symptoms. The gabapentinoid prescribing information already includes guidance for health care professionals to caution patients about dizziness, somnolence, and the potential for impaired ability to operate a car or complex machinery.

We reviewed several sources of data, including case reports submitted to FDA or published in the medical literature, observational studies, clinical trials, and animal studies.

Reports submitted to FDA and data from the medical literature show that serious breathing difficulties can occur when gabapentinoids are taken by patients with pre-existing respiratory risk factors.1-6, 8 Among 49 case reports submitted to FDA over the 5-year period from 2012 to 2017, 12 people died from respiratory depression with gabapentinoids, all of whom had at least one risk factor. This number includes only reports submitted to FDA,* so there may be additional cases about which we are unaware.

We also reviewed the results of two randomized, double-blind, placebo-controlled clinical trials in healthy people, three observational studies, and several studies in animals. One trial showed that using pregabalin alone and using it with an opioid pain reliever can depress breathing function.7,8 The other trial showed gabapentin alone increased pauses in breathing during sleep. The three observational studies at one academic medical center showed a relationship between gabapentinoids given before surgery and respiratory depression occurring after different kinds of surgeries.9-11 We also reviewed several animal studies that showed pregabalin alone and pregabalin plus opioids can depress respiratory function.

FDA is warning that serious, life-threatening, and fatal respiratory depression has been reported with the gabapentinoids, gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR). Most cases occurred in association with co-administered central nervous system (CNS) depressants, especially opioids, in the setting of underlying respiratory impairment, or in the elderly. Our evaluation of respiratory depression with the gabapentinoids provides some evidence contrary to the widely held belief that gabapentinoids lack drug interactions and have wide therapeutic indices. Published studies demonstrate these drugs can behave in an additive way to potentiate central nervous system (CNS) and respiratory depression. When co-prescribing gabapentinoids with another CNS depressant, particularly an opioid, or in patients with underlying respiratory impairment, initiate the gabapentinoid at the lowest dose. Adjust the dose of both gabapentin and pregabalin in patients with renal impairment and patients undergoing hemodialysis, because both drugs are excreted by the kidneys. Monitor for symptoms of respiratory depression and sedation, especially when co-prescribing gabapentinoids with an opioid or other CNS depressant such as a benzodiazepine or when prescribing to patients with underlying respiratory impairment, or elderly patients. The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants, including the gabapentinoid. Gabapentinoids used for analgesia or seizure control should be tapered prior to discontinuation. See the prescribing information for specific tapering guidance. Encourage patients to read the Medication Guide they receive with each gabapentinoid prescription, which explains the safety risks and provides other important information.

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