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What Clinicians Need to Know About New FDA Respiratory Warnings on Gabapentin and Pregabalin Products

March 25, 2020
New warnings link this drug class to respiratory depression and abuse potential.

with Jeffrey Fudin, PharmD


The FDA issued a warning in December 2019 that serious breathing difficulties may occur in patients using gabapentin (Neurontin, Gralise, Horizant) or pregabalin (Lyrica, Lyrica CR) who have respiratory risk factors.1 The risk factors include the use of opioid analgesics and other drugs that depress the central nervous system (CNS) and conditions such as chronic obstructive pulmonary disease (COPD) that reduce lung function.

While most clinicians are probably not surprised by the FDA’s warning, they may be unaware of the extent to which gabapentinoids could contribute to respiratory issues, according to Jeffrey Fudin, PharmD, and PPM co-editor-at-large. “With higher scrutiny and diminished availability of opioids and benzodiazepines, we will see a progressive uptick of other substances that are available for diversion and abuse or misuse,” Dr. Fudin said. Gabapentinoids are often prescribed or combined with CNS depressants, such as opioids, anti-anxiety medications, antidepressants, and antihistamines.

Gabapentinoids, especially gabapentin, are easier to obtain than opioids or benzodiazepines, and laws about their possession are not as stringent. (Image: iStock)

Gabapentin and pregabalin are FDA-approved for a variety of conditions, including seizures, neuropathic pain syndromes, and restless legs syndrome. From 2012 to 2016, gabapentin prescribing increased by 64% in the United States.2 Pregabalin has been classified as a Schedule V controlled substance since its release in 2005, indicating that it has some potential for abuse. Although gabapentin is not currently classified as a controlled substance in most states, its abuse potential is still being investigated.

Gabapentinoids, especially gabapentin, are easier to obtain than opioids or benzodiazepines, and laws about their possession are not as stringent. In high doses, however, they offer substance abusers comparable effects as those provided by certain controlled substances, especially in combination with other agents. “Consider what substance abusers of opioids and benzodiazepines desire, compared to, say, what gabapentin and the muscle relaxant baclofen might offer,” Dr. Fudin said.

Opioids can provide sedation, euphoria, and other effects attributable to secondary activity of gaba-amino butyric acid (GABA). Gabapentinoids are structurally similar to GABA and may amplify a “high” feeling when used in combination with opioids. Therefore, the use of gabapentinoids in a population already receiving opioids may lead to a greater risk of abuse for both substances.

Gabapentin and pregabalin block the alpha-2-delta subunit on voltage-gated calcium channels located in the synaptic cleft, which activates neuronal GABA-B receptors. Baclofen also activates the GABA-B receptors, making it useful to treat muscle spasms, but also enhancing the sedative, euphoric effects of gabapentinoids.

Benzodiazepines are used for their sedative-hypnotic, anti-anxiety, and relaxation properties. They nonselectively bind to and activate all receptor subtypes, including GABA-A and GABA-B and impact alpha subunits including types 1, 2, 3, and 5. Alpha 1 activity is linked to sedating effects, alpha 2 and 3 are linked to anxiety, and alpha 5 is linked to cognitive effects such as memory and motor skills. Baclofen has comparable pharmacology to the benzodiazepines and is very similar to GABA. Specifically, baclofen is a GABA agonist at the GABA-B receptors and acts as a muscle relaxant, especially for the treatment of spasms arising within the brain and spinal cord.

Dr. Fudin says he has seen an increase of gabapentin misuse and abuse among patients overall because of its sedative-hypnotic effects as well as a dissociative effect that also occurs with other drugs that enhance dopamine and thereby induce euphoria. Gabapentin may be easily obtained in large quantities undetected because it does not need to be reported to a prescription drug monitoring program in most states. “Community pharmacists have reported instances of early refills and gabapentinoid use beyond prescribed doses and at shortened intervals,” he said. “Clinicians will need to be more diligent in questioning their patients initially and at routine urine screening, and they may want to add gabapentin, pregabalin, and even various natural substances such as kratom or tianeptine to their urine testing orders, if not routinely, perhaps once per year in patients with an elevated risk of polysubstance abuse.”

Clinicians should also encourage patients taking both gabapentinoids and opioids to keep naloxone on hand in case of an emergency. “If the opioid can be reversed with naloxone, the gabapentinoid would have minimal effect on respiratory drive,” said  Dr. Fudin.

Adding a sedative-hypnotic when someone is already taking a gabapentinoid together with an opioid increases the risk of opioid-induced respiratory depression. From a pharmacological perspective, the following additional drugs pose the greatest danger:

  • Benzodiazepines, barbiturates, z-drugs such as zolpidem for insomnia, and meprobamate, which is a metabolite of carisoprodol
  • Sedating antidepressants, particularly tricyclics such as amitriptyline
  • Sedating skeletal muscle relaxants, particularly carisoprodol, because of their effect on the descending activating system, which is similar to that of barbiturates.

In addition, Dr. Fudin advises clinicians to warn patients that starting or stopping any prescription medication could potentially elevate blood levels of their current medications. This applies to OTC products as well, such as sedating antihistamines or antivertigo agents, as they may potentiate a drug-drug interaction or increase sedation.

Besides increased use of gabapentinoids, Dr. Fudin warns that use of substances such as kratom, cathinones (bath salts), tianeptine, cannabidiol (CBD), and tetrahydrocannabinol (THC) may also be on the rise. “It wouldn’t surprise me if we see increased abuse of high-dose dextromethorphan for its hallucinogenic properties and more ketamine diversion as well, both of which block N-methyl-D-aspartase (NMDA) receptors,” he said.  


More on the abuse potential of gabapentinoids.

Last updated on: March 25, 2020
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