To help FDA track safety issues with medicines, we urge patients and health care professionals to report side effects involving gabapentin, pregabalin, or other medicines to the FDA MedWatch program, using the information in the "Contact FDA" box at the bottom of the page.

Facts about Gabapentinoids

• Gabapentinoids include gabapentin and pregabalin. They are FDA-approved to treat a variety of conditions including partial seizures; pain from damaged nerves that follows spinal cord injury, healing of shingles, or diabetes; fibromyalgia; and moderate to severe primary restless legs syndrome.
• Gabapentin is marketed under the brand names Neurontin and Gralise, and as generics. Gabapentin enacarbil is a prodrug of gabapentin marketed under the brand name Horizant.
• Gabapentin is not scheduled by the Drug Enforcement Administration (DEA) as a controlled substance. A human abuse liability evaluation was not conducted when gabapentin was developed in the 1980s and early 1990s.
• Gabapentin is available as a tablet, capsule, solution, and extended-release tablet.
• Pregabalin is marketed under the brand names Lyrica and Lyrica CR, and as generics.
• Pregabalin is a Schedule V controlled substance, which means that among the drugs scheduled by the DEA because of their abuse potential, it has a lower potential for abuse but may lead to some physical or psychological dependence.
• Pregabalin is available as a capsule, solution, and extended-release tablet.
• Common side effects of gabapentinoids include drowsiness, dizziness, blurry or double vision, difficulty with coordination and concentration, and swelling of the hands, legs, and feet.

Additional Information for Patients and Caregivers

• FDA is warning that serious breathing difficulties may occur when gabapentin (Neurontin, Gralise, Horizant) or pregabalin (Lyrica, Lyrica CR) is taken with other medicines that depress the central nervous system (CNS) such as opioids, in those patients who have underlying respiratory problems, or in the elderly. There is less evidence supporting the risk of serious breathing difficulties with gabapentinoids alone in otherwise healthy individuals, and we will continue to monitor this population for additional evidence.
• Respiratory problems can be life-threatening, so seek medical attention immediately if you or someone you are caring for experiences the following symptoms:
  • 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 can't wake them up
  • Bluish-colored or tinted skin, especially on the lips, fingers, and toes
• Always take gabapentinoids as prescribed. Do not take more of the medicine or take it more often than prescribed because doing so can cause serious problems or death.
• Always tell all your health care professionals about all the medicines you are taking, including prescription and over-the-counter (OTC) medicines. It is helpful to keep a list of all your current medicines in your wallet or another location where it is easily retrieved. You can fill out and print a copy of My Medicine Record.
• Read the patient Medication Guide every time you receive a prescription for a gabapentinoid. The Medication Guide will be updated with new or other important information about your medicine. The Medication Guide explains the important things that you need to know. These include the side effects, what the medicine is used for, interactions with other medicines, how to take and store it properly, and other things to watch out for when you are taking the medicine.
• Talk to your health care professional if you have any questions or concerns.
• To help FDA track safety issues with medicines, report side effects from gabapentin, pregabalin, or other medicines to the FDA MedWatch program, using the information in the "Contact FDA" box at the bottom of this page.

Additional Information for Health Care Professionals

• 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.
• To help FDA track safety issues with medicines, report adverse events involving gabapentin, pregabalin, or other medicines to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of this page.

Data Summary

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

Gabapentinoids are increasingly being prescribed for medical uses, and misuse and abuse of these medications are growing. Between 2012 and 2016, the number of patients who filled a gabapentin prescription increased from 8.3 million to 13.1 million annually, and the number of patients who filled a pregabalin prescription increased from 1.9 million to 2.1 million annually.16 Gabapentinoids are commonly co-administered with opioids for prescribed medical uses and abused in combination with opioids. Data collected in 2016 from an office-based physician survey showed that 14 percent and 19 percent of patient encounters involving gabapentin and pregabalin, respectively, also involved opioids.17 Several small cross-sectional studies suggest that in the U.S. and Europe, approximately 15 percent to 26 percent of patients with opioid use disorder (OUD) concomitantly misuse or abuse gabapentin, and approximately 7 percent to 21 percent of patients with OUD concomitantly misuse or abuse pregabalin. However, these studies were small, so the prevalence estimates may not be generalizable to all populations of patients with OUD.17-22

We reviewed data from the FDA Adverse Event Reporting System (FAERS) database and the medical literature1-6 which show that respiratory depression can occur when gabapentinoids are administered in combination with opioids or other central nervous system (CNS) depressants or in patients with underlying respiratory impairment. A small number of reports were in patients only on gabapentinoids. A search of FAERS from January 1, 2012, to October 26, 2017, identified 49 cases of respiratory depression with gabapentinoids. Fifteen cases were reported with gabapentin and 34 cases with pregabalin. Ninety-two percent of the cases reported either a respiratory risk factor, including age-related loss of lung function, or the use of a CNS depressant. Twenty-four percent of the cases resulted in death (n=12). All 12 death cases reported at least one risk factor for developing respiratory depression or concomitant use of a CNS depressant.

Several small randomized trials of healthy volunteers showed that gabapentinoids alone and in combination with opioids depress respiratory function. Myhre et al.7 conducted a small randomized, double-blind, placebo-controlled cross-over trial in 12 healthy volunteers exposed to placebo, pregabalin alone, the opioid remifentanil alone, or a combination of pregabalin plus remifentanil. End-tidal CO2 rose with exposure to the drugs together in an additive way. Piovezan and colleagues8 carried out a small randomized, double-blind, placebo-controlled cross-over trial of eight healthy volunteers. The subjects were older non-obese men without sleep complaints or sleep apnea. Subjects were given a single dose of gabapentin or placebo followed by a sleep study. After a washout period, subjects were again given a single dose of treatment (crossing over to the alternate treatment) followed by another sleep study. The number of hourly apneic episodes during gabapentin exposure exceeded those during placebo exposure.

Observational studies suggest that patients exposed to preoperative gabapentinoids have an increased risk of postoperative respiratory depression compared to those not exposed to gabapentinoids preoperatively. A Mayo Clinic research group published a case-control study describing the relationship between preoperative gabapentin exposure and the risk of postoperative respiratory depression in more than 11,000 arthroplasty patients.9 They defined respiratory depression as apnea, hypopnea, oxyhemoglobin desaturation, or an episode of severe pain despite moderate to profound sedation (i.e., "pain-sedation" mismatch) during recovery in the postanesthesia care unit. In this study, when compared to patients not exposed to preoperative gabapentin, the risk of respiratory depression was increased 60 percent for patients using regional anesthesia (odds ratio [OR] 1.60, 95%

confidence interval [CI] 1.27, 2.02) and 47 percent for those using general anesthesia (OR 1.47, 95% CI 1.26, 1.70) when the preoperative anesthesia regimen included gabapentin doses greater than 300 mg. This same research group conducted another case-control study describing the relationship between preoperative gabapentin exposure and the risk of postoperative respiratory depression in more than 8,000 laparoscopy patients.10 Respiratory depression was defined as apnea, hypopnea, oxyhemoglobin desaturation, pain-sedation mismatch, naloxone administration, failure to extubate, need to reintubate, or non-invasive positive pressure ventilation (NIPPV) use in patients who were not previously prescribed such a device. In this study, preoperative gabapentin increased the risk of postoperative respiratory depression by 26 percent (OR 1.26, 95% CI 1.02, 1.58) compared to those not exposed to preoperative gabapentin.

Animal studies have shown that gabapentinoids can cause respiratory depression alone and in combination with opioids.12-14 Kozer and colleagues12 showed that rabbits given morphine after gabapentin had greater CO2 retention than rabbits given saline after gabapentin. Lyndon and colleagues13 studied the respiratory depressant effects of a high intraperitoneal dose of pregabalin with and without medium dose morphine in six mice. Pregabalin produced a dose-dependent decrease in respiration rate. A pregabalin bolus given alone depressed mouse minute ventilation to the same extent as a morphine bolus given alone. The respiratory depressant effects of morphine and pregabalin were additive, not multiplicative. Collectively, the published animal studies suggest that gabapentinoids have an independent dose-dependent depressive effect on respiration and can augment the respiratory depression caused by opioids.

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