Gabapentinoids and Opioids Together: What You Need to Know About Respiratory Risks

When doctors combine gabapentin or pregabalin with opioids for pain relief, they’re trying to do something smart: use less opioid to cut down on addiction risk and side effects. It made sense on paper. But over the last few years, the story has changed. Now, we know this combo can quietly shut down breathing-especially in vulnerable people-and the consequences can be deadly.

Why This Combo Was Ever a Good Idea

Gabapentin (Neurontin) and pregabalin (Lyrica) were never meant to be painkillers. They started as seizure drugs. But doctors noticed something interesting: patients on these meds after surgery often needed less morphine or oxycodone. Studies showed opioid use dropped by 20-30% when gabapentinoids were added. That sounded like a win. Less opioid meant fewer constipation issues, less nausea, and lower risk of dependence. By 2017, prescriptions for this combo had jumped 64% in the U.S. alone.

The logic was simple: if you can reduce opioid doses without losing pain control, why not? Especially in post-op settings, where patients are already at risk for complications. Hospitals started using gabapentinoids routinely after joint replacements, spine surgeries, and even C-sections. It became standard practice-until the data started turning against it.

The Hidden Danger: Slowed Breathing

The real problem isn’t that gabapentinoids cause respiratory depression on their own. They rarely do. But when they team up with opioids, something dangerous happens. Both drugs hit the brainstem-the part that controls breathing-and they do it in different ways.

Opioids slow down the brain’s response to rising CO2 levels. Gabapentinoids do the same, but through a separate pathway. When you add them together, the effect isn’t just added-it’s multiplied. Think of it like two people pulling on the same rope. Neither one is strong alone, but together, they can snap it.

A 2017 study in PLOS Medicine found that opioids slow down gut movement, which lets more gabapentinoid get absorbed into the bloodstream. That means your body ends up with up to 44% more of the drug than expected. Higher levels = higher risk. And it’s not just about dose. Even standard doses-like 300 mg of gabapentin three times a day-can become dangerous when paired with opioids in people with sleep apnea, COPD, or kidney problems.

Who’s at Highest Risk?

Not everyone who takes this combo will have trouble breathing. But some people are sitting on a ticking clock. The FDA and other agencies now list these as high-risk groups:

• People over 65
• Those with chronic lung disease (COPD, asthma)
• Patients with obstructive sleep apnea
• Anyone with kidney impairment (creatinine clearance under 60 mL/min)
• People already on high opioid doses
• Those taking other sedatives like benzodiazepines or alcohol

A 2022 UK analysis found that patients with sleep apnea who got gabapentinoids along with opioids had a 2.3 times higher risk of dying from respiratory failure. And it’s not just the elderly. A Reddit post from an anesthesiologist described a 58-year-old man with mild COPD who needed naloxone after just 20 mg of morphine and 300 mg of gabapentin-both considered low doses. He wasn’t an addict. He wasn’t overdosing on purpose. He just got unlucky with the combo.

What the Data Really Shows

Here’s where things get confusing. Some studies say the risk is rare. Others say it’s serious. Why the contradiction?

A 2020 JAMA Network Open study of over 16,000 patients found that while the combo increased the chance of opioid-related harm, the absolute risk was still low-so low that you’d need to treat more than 16,000 people before one serious event occurred. That sounds reassuring. But here’s the catch: those 16,000 patients were mostly healthy, younger adults. The real danger shows up in the groups we don’t study much-older people, those with lung disease, cancer patients.

A 2022 systematic review in Frontiers in Pharmacology found that in cancer patients, the combo was linked to higher death rates. Why? Because cancer patients often have weakened lungs, are on high opioids, and are frail. They’re the ones who don’t make it into big trials-and the ones who die when the breathing slows.

The American Geriatrics Society’s Beers Criteria, updated in 2019, says outright: avoid this combo. The UK’s NICE guidelines, updated in 2023, say the same for chronic back pain. And the CDC’s 2022 opioid guidelines now warn: “Avoid prescribing gabapentinoids with opioids when possible.”

Real-World Changes Are Already Happening

Hospitals aren’t waiting for more studies. They’re changing protocols.

Dr. R. Smith, an orthopedic surgeon in Australia, told a medical forum that since his hospital stopped giving gabapentinoids to opioid-treated patients with sleep apnea, code blue respiratory events dropped by 40%. That’s not a fluke. That’s a life-saving change.

Prescriptions are falling too. In the U.S., gabapentinoid prescriptions peaked at 67 million in 2018. By 2021, they dropped to 61 million. Co-prescribing with opioids fell by 12% in just two years, according to Express Scripts. The FDA forced drugmakers to add a boxed warning in 2019-the strongest kind. Manufacturers now have to run new clinical trials to prove the safety of this combo. Results aren’t due until 2025.

What Should You Do If You’re on This Combo?

If you’re taking gabapentin or pregabalin with an opioid, don’t panic. But do pay attention.

• Watch for signs: Unusual drowsiness, confusion, slow or shallow breathing, or waking up gasping for air at night.
• Don’t skip doses: Stopping gabapentinoids suddenly can cause seizures or worsen pain. Talk to your doctor first.
• Ask about alternatives: Is there another painkiller you can use? Could physical therapy or nerve blocks help instead?
• Get monitored: If you’re having surgery, tell your anesthesiologist you’re on this combo. They need to know to adjust your opioid dose and monitor you closely.
• Know your kidney function: If you’re over 60 or have diabetes, ask for a simple blood test to check your creatinine clearance. If it’s low, your gabapentinoid dose needs to be cut.

The Bottom Line

Gabapentinoids aren’t evil. They help some people with nerve pain. Opioids aren’t evil either-they relieve terrible pain when used correctly. But together, they create a risk that’s hard to predict and deadly when it happens.

The safest approach now is this: avoid the combo unless absolutely necessary. If you need it, use the lowest possible doses, monitor closely, and never take it without medical supervision. The goal isn’t to eliminate pain relief-it’s to get there without risking your breathing.

What’s Coming Next

Researchers are working on better ways to predict who’s at risk. A new risk calculator, expected in mid-2024, will use 12 factors-age, kidney function, opioid dose, BMI, sleep apnea history-to give each patient a personalized risk score. Early results show it can spot high-risk patients with 87% accuracy.

There’s also work on new versions of gabapentinoids that don’t cross into the brain as easily. If they work, they could give pain relief without the breathing risk. Until then, caution is the only proven tool we have.