Quick Answer
Gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR) are not opioids and do not act on opioid receptors, but they do depress the central nervous system. Taken with an opioid, they add to sedation and to the suppression of breathing. The FDA issued a safety warning in December 2019 requiring new respiratory warnings on these products, after reviewing cases in which people died of respiratory depression, all of whom had at least one risk factor such as opioid use, other central nervous system depressants, older age, or reduced lung function.
This combination is often entirely appropriate and deliberately prescribed. The point is not to stop it, but to know that it is a genuine interaction requiring monitoring, and to stop assuming these medicines are pharmacologically neutral. Do not stop gabapentin or pregabalin abruptly, as withdrawal can include seizures. For free and confidential help 24 hours a day, the SAMHSA National Helpline is 1-800-662-4357.
Gabapentin and pregabalin were prescribed widely as a way to reduce opioid doses, which means an enormous number of people now take both together. In December 2019 the U.S. Food and Drug Administration warned that serious breathing difficulties can occur in people using these medicines who have respiratory risk factors, and it named opioid use as one of those risk factors. Most patients taking both have never heard this.
What Gabapentinoids Are and Why So Many People Take Them
Gabapentin and pregabalin are known collectively as gabapentinoids. They are approved for seizure disorders, certain forms of nerve pain including diabetic neuropathy and postherpetic neuralgia, and, for some formulations, restless legs syndrome. Pregabalin is also approved for fibromyalgia.
Their use extends far beyond those approvals. Gabapentin in particular is prescribed off label for back pain, sciatica, anxiety, insomnia, migraine prevention, hot flashes, and alcohol withdrawal. Prescribing rose sharply during the period when opioid prescribing came under scrutiny, precisely because gabapentinoids were seen as a lower risk alternative or an opioid sparing addition.
That reputation is the problem. A medicine understood as the safe alternative is not questioned in the way an opioid is, and patients are rarely counseled about combination risk when it is added to an existing opioid regimen.
The FDA Warning of December 2019
On December 19, 2019, the FDA warned that serious breathing difficulties may occur in patients using gabapentin or pregabalin who have respiratory risk factors. The risk factors named include the use of opioid pain medicines and other drugs that depress the central nervous system, such as anti-anxiety medicines, antidepressants, and antihistamines, as well as conditions that reduce lung function such as chronic obstructive pulmonary disease. Older adults were identified as being at higher risk.
The warning followed a review of case reports submitted to the agency, observational studies, clinical trials, and animal studies. Among 49 case reports of respiratory depression submitted between 2012 and 2017, 12 people died, and every one of them had at least one risk factor.
The FDA required new warnings on the prescribing information for these products and also required manufacturers to conduct clinical trials evaluating the abuse potential of gabapentinoids, particularly in combination with opioids. The agency noted that there is less evidence of serious breathing difficulty in healthy people taking gabapentinoids alone.
Read carefully, that last point is the heart of the matter. The concern is not the medicine by itself. It is the medicine in company.
How a Non-Opioid Ends Up Affecting Breathing
Gabapentinoids do not bind opioid receptors and, despite the name, do not act directly on GABA receptors either. They bind a subunit of voltage-gated calcium channels in the central nervous system, reducing the release of several excitatory neurotransmitters.
The net effect is dampened neuronal excitability. That is what makes them useful for seizures and nerve pain, and it is also what makes them sedating. When neuronal activity is broadly reduced in a brain that is already receiving an opioid signal to breathe less, the two effects compound.
This is a third distinct route to the same endpoint. Opioids reach it through mu receptors, benzodiazepines and alcohol through GABA-A, gabapentinoids through calcium channels. Because the routes are independent, the brain has no compensating mechanism that recognizes the total load.
Why Gabapentin Intensifies Opioid Effects
Beyond additive sedation, there is a further consideration. Gabapentin appears to increase the absorption and subjective effect of some opioids, which is one reason it has acquired value in illicit markets and is reported to be used deliberately to intensify an opioid experience.
This matters for two groups. It matters for people who are misusing substances, because it means the effective opioid exposure can be larger than the amount taken would suggest. And it matters for patients doing everything correctly, because the same pharmacology operates whether or not the intent was recreational.
Gabapentin is also now detected in a meaningful proportion of overdose deaths in surveillance data, almost always alongside opioids rather than alone. That pattern is consistent with a contributing rather than a primary cause, which is exactly what an interaction looks like in the data.
Legal Status: Not a Controlled Substance Everywhere
Pregabalin is a Schedule V controlled substance under federal law in the United States. Gabapentin is not federally scheduled. Some states apply their own controlled-substance or prescription-monitoring requirements, and those requirements can change.
This patchwork has a practical consequence. In a state where gabapentin is not monitored, it may not appear in a prescription monitoring database, which means a clinician reviewing that database can miss it entirely when assessing a patient's total sedative burden. The single most useful thing a patient can do is name it out loud rather than assume the system knows.
Who Is at Higher Risk
- Anyone taking an opioid, particularly at higher doses or with extended release formulations
- Anyone also taking a benzodiazepine, sleep aid, muscle relaxant, sedating antihistamine, or drinking alcohol
- Adults aged 65 and older, in whom clearance is slower and sensitivity greater
- People with COPD, asthma, sleep apnea, or any condition that reduces lung function
- People with reduced kidney function, because gabapentinoids are cleared by the kidneys and can accumulate to unexpectedly high levels
- Anyone whose opioid tolerance has recently fallen, such as after a hospital stay, a period of abstinence, or incarceration
Kidney function deserves emphasis, because it is the variable most often missed. Unlike most opioids, which are handled by the liver, gabapentinoids depend on the kidneys. A person whose kidney function declines with age or illness can accumulate the drug at an unchanged dose.
Warning Signs to Watch For
The FDA advises seeking immediate medical attention for the following, which can be life threatening.
- Confusion or disorientation
- Unusual dizziness or lightheadedness
- Extreme sleepiness or lethargy
- Slowed, shallow, or difficult breathing
- Unresponsiveness
- Bluish tinted skin, especially on the lips, fingers, and toes
These signs are most likely in the days after a gabapentinoid is started, after a dose increase, or after any other sedating medication is added to the regimen.
Why Gabapentinoids Cannot Be Stopped Abruptly Either
Gabapentin and pregabalin produce physical dependence with regular use, and abrupt discontinuation can cause a withdrawal syndrome that includes anxiety, insomnia, sweating, nausea, pain, and in some cases seizures. The seizure risk is particularly relevant for anyone taking a gabapentinoid for a seizure disorder in the first place.
As with every other combination in this series, the correct response to learning about the interaction is a conversation with a prescriber or pharmacist, not an abrupt change made alone.
Frequently Asked Questions
My doctor prescribed both. Does that mean it is safe?
It usually means the clinical benefit was judged to outweigh the risk, which is a reasonable and common decision. The combination is frequently used precisely to allow a lower opioid dose. What the prescription does not guarantee is that the risk was discussed, that every other sedating medicine is known to that prescriber, or that anyone has checked kidney function recently. Those are fair things to ask about at the next appointment.
Is pregabalin more dangerous than gabapentin with opioids?
Pregabalin is absorbed more predictably and is more potent by weight, and it is federally scheduled while gabapentin is not, which reflects a judgment about abuse potential. Both carry the same FDA respiratory warning. The more useful question is not which is riskier but what the total sedative load looks like across everything a person takes.
Can gabapentin help with opioid withdrawal?
It is sometimes used as part of a supportive medication regimen during withdrawal to address anxiety, restlessness, and sleep, and there is a clinical rationale for that. It is not a treatment for opioid dependence in itself, and it carries its own dependence potential. This is a decision for a clinician managing the withdrawal, not something to arrange independently.
Why is gabapentin controlled in some states but not others?
Federal and state scheduling are separate systems. Gabapentin remains unscheduled federally, while some states apply their own controlled-substance or prescription-monitoring requirements. Because those rules change, a pharmacist or the relevant state authority is the best source for the current local requirement.
Does gabapentin show up on a standard drug test?
Not usually. Standard panels do not include gabapentinoids, and detecting them requires a test ordered specifically. This is one more reason that a spoken account of everything being taken is more reliable than any record a clinician can pull.
I take gabapentin for nerve pain and only occasionally take an opioid. Is that a problem?
It is a situation worth flagging rather than an emergency. Occasional opioid use often means lower tolerance, and the days when both are in the body are the days that matter. It is worth asking a pharmacist how the two are likely to interact for you specifically, and worth telling anyone at home what to watch for on those days.
Where can I get help if I am dependent on gabapentin, opioids, or both?
Gabapentinoid dependence is a recognized clinical problem and there are established approaches to tapering it safely, particularly when it exists alongside opioid dependence. The SAMHSA National Helpline is free, confidential, and available at any hour: 1-800-662-4357. Additional educational information is available at getdetox.com and opioidtreatmentfinder.com.
Related Guides
- Opioid drug interactions: which combinations are dangerous and why
- Opioids and benzodiazepines
- Opioids and alcohol
Sources
- U.S. Food and Drug Administration, drug safety communication on serious breathing problems with gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR) when used with central nervous system depressants or in patients with lung problems, December 19, 2019
- U.S. Food and Drug Administration, boxed warning requirement for opioid analgesics and central nervous system depressants, August 2016
- Drug Enforcement Administration, drug scheduling
- National Institute on Drug Abuse, opioids research topics
- Centers for Disease Control and Prevention, overdose prevention
- Substance Abuse and Mental Health Services Administration, National Helpline