Gabapentinoids and Opioids: The Hidden Danger of Combined Respiratory Depression

When you take gabapentin or pregabalin for nerve pain, and your doctor adds an opioid for stronger relief, it might feel like a smart move-two drugs working together to control pain. But what if that combination is quietly slowing your breathing? This isn’t a rare accident. It’s a documented, life-threatening interaction that’s been hiding in plain sight for years.

The Real Risk You’re Not Talking About

Gabapentinoids-medications like gabapentin (Neurontin, Horizant) and pregabalin (Lyrica)-were never meant to be dangerous on their own. They’re used for epilepsy, fibromyalgia, and nerve pain. But research shows they can suppress breathing even when taken alone. When mixed with opioids like oxycodone, hydrocodone, or fentanyl, that risk doesn’t just add up-it multiplies.

In 2019, the U.S. Food and Drug Administration (FDA) issued a formal warning after analyzing over 5,000 adverse event reports. They found 49 cases of serious respiratory depression linked to gabapentinoids. Of those, 92% happened when the patient was also taking another CNS depressant-usually an opioid. And 12 of those cases ended in death. Every single fatal case involved either an opioid, another sedative, or a pre-existing breathing problem like COPD or sleep apnea.

This isn’t just theory. A landmark 2017 study in PLOS Medicine tracked more than 16 years of prescription data and found that people taking both gabapentin and an opioid had a 50% higher chance of dying from an opioid overdose. If they were on high doses of gabapentin, that risk jumped to nearly double.

How Does This Actually Happen?

It’s not just that both drugs make you sleepy. The mechanism is more complex-and more dangerous.

Gabapentinoids affect the brain’s control of breathing by reducing the response to carbon dioxide buildup. Normally, when CO2 rises in your blood, your brain tells you to breathe faster. Gabapentinoids blunt that signal. Opioids do the same thing. Together, they silence the body’s natural safety alarm.

There’s also a pharmacokinetic twist: opioids slow down how fast your stomach empties. Since gabapentin is mainly absorbed in the upper small intestine, that delay means more of it gets into your bloodstream at once. Higher blood levels = higher risk.

A small but telling study gave healthy volunteers pregabalin and remifentanil (a fast-acting opioid) separately and together. When taken alone, each drug slightly raised carbon dioxide levels during sleep. When combined? The rise was additive-meaning the effect wasn’t just stronger, it was predictable and dangerous in a way that’s hard to reverse.

Who’s Most at Risk?

This isn’t a risk that affects everyone equally. Certain people are far more vulnerable:

• People over 65-aging lungs and slower metabolism make them more sensitive to CNS depression.
• Those with kidney problems-both gabapentin and pregabalin are cleared by the kidneys. If your kidneys aren’t working well, the drugs build up.
• Patients with COPD, sleep apnea, or asthma-any condition that already compromises breathing becomes exponentially riskier.
• People on high doses-doses above 1,800 mg/day of gabapentin or 300 mg/day of pregabalin carry significantly higher risk.
• Post-surgical patients-one study of over 5.5 million surgical patients found respiratory depression rates as high as 72% in general surgery when gabapentinoids were added to opioids.

Even if you’re young and healthy, don’t assume you’re safe. A 2018 study showed that gabapentin alone increased the number of apnea episodes during sleep by nearly 50% compared to placebo. That’s not something you’d notice until it’s too late.

Why Are Doctors Still Prescribing This Combo?

The answer is complicated. In the mid-2010s, as opioid prescribing guidelines tightened, doctors scrambled for alternatives. Gabapentinoids were seen as a safe, non-addictive way to reduce opioid doses. Many believed they’d help with pain without adding respiratory risk.

But here’s the problem: the evidence that gabapentinoids actually improve pain control when added to opioids is weak. A 2020 analysis in JAMA Network Open concluded that adding gabapentinoids to opioids offers no real advantage in pain relief after surgery. In fact, it might just be adding risk without benefit.

Despite the FDA warning, co-prescribing hasn’t dropped. In 2017, nearly 1 in 4 new gabapentinoid prescriptions came with an opioid. That’s still happening today. Many prescribers don’t realize how serious this interaction is-or they assume the patient is fine because they’re not “high-risk.”

What Should You Do?

If you’re taking both a gabapentinoid and an opioid, here’s what matters:

1. Don’t stop either drug suddenly. Stopping gabapentinoids can cause seizures. Stopping opioids can trigger withdrawal. Talk to your doctor first.
2. Ask if you really need both. Is the pain worse than the risk? Are there alternatives like physical therapy, NSAIDs, or non-opioid nerve pain meds like duloxetine?
3. Check your kidney function. A simple blood test for creatinine clearance can tell you if your dose needs to be lowered.
4. Start low, go slow. If you must start gabapentinoids, begin at the lowest possible dose. The Medical Letter recommends this for everyone, especially older adults.
5. Watch for signs of trouble. Slowed breathing, confusion, extreme drowsiness, or waking up gasping for air are red flags. If you live alone, consider a pulse oximeter to monitor oxygen levels at night.

The Bigger Picture

This isn’t just about two drugs. It’s about how we treat chronic pain-and how easily we accept risk when the solution seems simple. Gabapentinoids were marketed as a safer alternative, but safety isn’t just about addiction potential. It’s about whether a drug keeps you alive.

Regulators have sounded the alarm. The FDA, the UK’s MHRA, and major medical societies all agree: combining these drugs is dangerous. But real change won’t happen until patients and doctors start asking harder questions.

If you’re on this combo, you’re not alone. But you’re also not powerless. Ask your doctor: Is this combination necessary? What’s the evidence for benefit? What’s the real risk to my breathing? You deserve a clear answer.

What’s Next?

The medical community is slowly catching up. Some hospitals now use electronic alerts to flag gabapentinoid-opioid combinations. Others require a signed risk acknowledgment before prescribing both. But until these practices become standard, the burden falls on you.

Don’t assume your doctor knows the full risk. Don’t assume your condition makes you immune. And don’t assume that because you’ve been on this combo for months, it’s safe. Respiratory depression doesn’t come with warning signs-it comes with silence.

If you’re taking both drugs, talk to your doctor today. Ask for a full review of your pain management plan. And if you feel your breathing is slower than usual, or you’re waking up tired even after a full night’s sleep-don’t wait. Get help now.