FDA warning: gabapentinoids and respiratory depression

The FDA just came out with a significant warning about respiratory depression with the use of gabapentinoids (gabapentin and pregabalin), see https://www.fda.gov/news-events/fda-brief/fda-brief-fda-requires-new-warnings-gabapentinoids-about-risk-respiratory-depression

-- they recommend avoiding pairing an opioid with any CNS depressant, including with a gabapentinoid, benzodiazepine, sedating antidepressant, sedating antipsychotic, antihistamine, or other product, because of the risk of respiratory depression (see https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-serious-breathing-problems-seizure-and-nerve-pain-medicines-gabapentin-neurontin ). If prescribing a gabapentinoid, it is important to start with low doses, titrate carefully, and inform patients of the respiratory risk.
    -- in the 5 years from 2012-2017, there were 49 cases of respiratory depression associated with gabapentinoids, 92% of whom had either a respiratory risk factor, including just age-related loss of lung function, or used a CNS depressant; 15 cases reported were reported with gabapentin and 34 cases with pregabalin
        -- gabapentinoids have been reported to cause serious respiratory problems in those with pre-existing respiratory risk factors, with 12 deaths reported to the FDA in the past 5 years (undoubtedly, this is underreported).
        -- also 3 observational studies have found respiratory depression in those on gabapentinoids given prior to surgery, and this result is been confirmed in animal studies. For example, a large Mayo Clinic study with 11,000 patients undergoing arthroplasty found a 60% increased risk of respiratory depression in those on gabapentin undergoing regional anesthesia and a 47% increased risk for those getting general anesthesia
-- the dose of gabapentinoids should be reduced in those with renal impairment
-- gabapentinoids should be tapered if they are to be decreased or discontinued

Commentary:
-- from 2012 to 2016, the number of patients filling gabapentin prescriptions increased from 8.3 million to 13.1 million annually, and for pregabalin from 1.9 million to 2.1 million annually
-- gabapentinoids are often given as adjuvants for pain control with opioids, a 2016 study finding the combination in 14% on gabapentin and 19% on pregabalin; and in small studies 15-26% of those with opioid use disorder concomitantly misuse gabapentin and 7-21% pregabalin
    -- it should be noted, that prior guidelines have suggested using such drugs as gabapentinoids as an adjunct to decrease opioid dosages (see http://gmodestmedblogs.blogspot.com/2016/03/new-cdc-guidelines-for-opiate.html)

--there have been a few blogs related to the gabapentinoids:
--http://gmodestmedblogs.blogspot.com/2018/09/gabapentanoids-plus-opioids-higher.html which documents an increased opioid-related death rate with co-prescription with either pregabalin or gabapentin, based on an Ontario population-based nested case control study
--and a couple finding minimal benefit from gabapentinoids in pain:
    --http://gmodestmedblogs.blogspot.com/2017/08/gabapentinoids-not-indicated-for.html found not much benefit but significant adverse effects of prescribing gabapentanoids for chronic low back pain (not neuropathic pain)
        --this blog also quotes an article in statnews about the high co-usage of opiates with gabapentin, the enhanced euphoria from gabapentin taken with opiates, and gabapentin’s ability to block the effects of meds used for addiction treatment
    --http://gmodestmedblogs.blogspot.com/2017/04/diabetic-peripheral-neuropathy-and-more.html , though gabapentanoids are often prescribed for neuropathy, this systematic review for diabetic peripheral neuropathy pain found that pregabalin had a “small” effect size and there was none for gabapentin, though there was large benefit from duloxetine and venlafaxine. Of note, for pain indications, the FDA has approved gabapentin only for postherpetic neuralgia and pregabalin for that, as well as diabetic neuropathy, fibromyalgia, and neuropathic pain from spinal cord injury.

So, another concern about gabapentinoids. It does seem that the potential benefits (which may be significantly over-rated) may be dwarfed by the potential harms (leading to the FDA warning). Though all drugs have potential serious adverse effects (and the actual mortality or severe respiratory depression from gabapentinoids has not been found in large numbers of people, per above), I personally have been favoring either tricyclics (eg nortripyline or desipramine) or SNRIs (either venlafaxine or duloxetine) with good success, especially for neuropathic pain but also as adjuvant analgesics for regular pain syndromes. But, if prescribing gabapentinoids, the clinician should carefully assess risk for respiratory depression, especially in those on CNS depressants or with baseline respiratory depression (including older age). And the patient should be warned of the possibility of severe respiratory depression.

geoff​

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