Washington, DC—Gabapentin and pregabalin are approved for treating patients with several specific neurological and neuropathic conditions. Yet off-label use of these gabapentinoids has risen astronomically without much verified benefit, according to past research.

An article in the New England Journal of Medicine pointed out that, in a review of a health and medical care survey involving 350,000 community-living adults from 2002 through 2015, the proportion of participants who used gabapentinoids rose from 1.2% in 2002 to 3.9% in 2015. Most of the increase occurred after 2008, with use increasing among patients with diabetes and those aged 65 years and older. The greatest increases were in patients with five or more chronic conditions and opioid prescriptions.

That is why a new drug-safety communication from the FDA is so concerning.

The agency 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.

Among those factors are use of opioid pain medicines and other drugs that depress the central nervous system (CNS), as well as conditions such as chronic obstructive pulmonary disease that reduce lung function.

Also at higher risk are the elderly, according to the FDA, which points out that the drugs are approved for a variety of conditions, including seizures, nerve pain, and restless legs syndrome.

Use has far outstripped those, however, according to the communication. “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,” the FDA writes. “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.”

Government officials say they will continue to monitor these medicines as part of the routine monitoring of all FDA-approved drugs and are requiring a new warnings about the risk of respiratory depression to be added to the prescribing information of the gabapentinoids.

Drug manufacturers are also being required to conduct clinical trials to further evaluate the drugs’ abuse potential, particularly in combination with opioids, “because misuse and abuse of these products together is increasing, and co-use may increase the risk of respiratory depression.”

The agency advises that gabapentinoids should always be initiated at the lowest dose, and patients should be monitored for symptoms of respiratory depression and sedation when coprescribing gabapentinoids with an opioid or other CNS depressant, such as a benzodiazepine. A similar approach should be taken with patients who have underlying respiratory disease and elderly patients, who are also at increased risk.

“We recognize that incorporating one or more medications with non-drug therapies is the prevailing approach for optimizing analgesia,” the FDA points out. “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.”

The best way to proceed, according to the agency, is to 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.

To reach the conclusions, the FDA reviewed several sources of data, including case reports submitted to the agency or published in the medical literature, observational studies, clinical trials, and animal studies. Reports submitted to the FDA and data from the medical literature show that serious breathing difficulties may occur when gabapentinoids are taken by patients with preexisting respiratory risk factors. Among 49 case reports submitted to the 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 or concomitant use of a CNS depressant.

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