RE: FDA warning for gabapentin and pregabalin use
Here is the full text.
FDA warns about serious breathing problems with seizure and nerve pain medicines
gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR)
When used with CNS depressants or in patients with lung problems
12-19-2019
What safety concern is FDA announcing?
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 FDAapproved drugs.
What is FDA doing?
We are requiring new warnings about the risk of respiratory depression to be added to the
prescribing information of the gabapentinoids. We have also required the drug
manufacturers to conduct clinical trials to further evaluate their 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. Special
attention will be paid to the respiratory depressant effects during this abuse potential
evaluation.
What are gabapentinoids and how can they help me?
Gabapentinoids are FDA-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.
What should patients and caregivers do?
Patients and caregivers should seek medical attention immediately if you or someone you
are caring for experiences symptoms of respiratory problems, because these can be lifethreatening. Symptoms to watch for include:
• Confusion or disorientation
• Unusual dizziness or lightheadedness
• Extreme sleepiness or lethargy
• Slowed, shallow, or difficult breathing
• Unresponsiveness, which means a 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 inform your health care professional about all the drugs you are taking, including
prescription and over-the-counter (OTC) medicines and other substances such as alcohol.
What should health care professionals do?
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.
What did FDA find?
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 preexisting 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.12-14
*
The cases were reported to the FDA Adverse Event Reporting System (FAERS) database.
What is my risk?
All medicines have side effects even when used correctly as prescribed, but in general the
benefits of taking a medicine outweigh these risks. It is important to know that people
respond differently to all medicines depending on their health, other medicines they are
taking, the diseases they have, genetics, and many other factors. As a result, we cannot
determine the likelihood that someone will experience these side effects when taking
gabapentinoids. Your personal health care professional knows you best, so always tell
them about all other medicines you are taking and if you experience any side effects
while taking your medicines.
How do I report side effects from gabapentinoids?
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.
o 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.
o 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.
o 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.
o 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:
o Confusion or disorientation
o Unusual dizziness or lightheadedness
o Extreme sleepiness
o Slowed, shallow, or difficult breathing
o Unresponsiveness, which means the person doesn’t answer or react normally
or you can’t wake them up
o 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 coadministered 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 coprescribing 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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