Gabapentinoids and Opioids: The Hidden Danger of Combined Respiratory Depression

When doctors prescribe gabapentin or pregabalin for nerve pain, many assume they’re adding a safe, non-addictive option to a pain plan-especially when opioids are involved. But here’s the truth: combining these drugs doesn’t just add up. It multiplies the risk of something deadly-respiratory depression.

What Exactly Is Respiratory Depression?

Respiratory depression means your breathing slows down enough to become dangerous. Your body doesn’t get enough oxygen, carbon dioxide builds up, and your brain stops telling your lungs to work. In severe cases, it leads to coma or death. This isn’t theoretical. Between 2012 and 2017, the FDA recorded 49 cases of respiratory depression linked to gabapentinoids. Of those, 12 ended in death. Every single fatal case involved either an opioid, another CNS depressant, or an existing breathing problem.

Why Gabapentinoids and Opioids Are a Dangerous Mix

Gabapentin and pregabalin were never designed to be painkillers like opioids. They work on nerve signals, not on opioid receptors. But here’s the twist: they still slow down your breathing-even on their own. A small 2016 study with healthy volunteers showed that a single dose of gabapentin caused more breathing pauses during sleep than a placebo. Pregabalin did the same.

When you add opioids into the mix, the effect isn’t just added-it’s amplified. Studies like the one by Myhre et al. found that when people took both pregabalin and remifentanil (a strong opioid), their CO2 levels rose significantly higher than with either drug alone. That’s additive respiratory depression. Your brain gets confused. It’s already being told to slow breathing by the opioid. Then gabapentinoids hit, and the brakes get pressed harder.

Even worse, gabapentinoids might reverse opioid tolerance. Normally, people who take opioids long-term build up a tolerance-they need higher doses to feel the same effect. But gabapentinoids can reset that tolerance, making the same opioid dose suddenly more powerful-and more dangerous.

The Numbers Don’t Lie

A landmark 2017 study in PLOS Medicine looked at over 2 million patients over 16 years. It found that if you were prescribed both an opioid and a gabapentinoid, your risk of dying from an opioid-related cause jumped by 50%. For those on very high doses of gabapentin, the risk nearly doubled-up 98%. That’s not a small increase. That’s a life-or-death spike.

And it’s not rare. In 2017, nearly 1 in 4 new prescriptions for pregabalin came with an opioid. Gabapentin wasn’t far behind. Why? Because doctors were trying to reduce opioid doses. They thought gabapentinoids were a safer alternative. But the data shows that instead of cutting risk, they were creating a new one.

Who’s Most at Risk?

Not everyone who takes these drugs together will have problems. But some people are far more vulnerable:

• Older adults-lung function declines with age, and the brain’s response to depressants weakens.
• People with COPD, sleep apnea, or asthma-their breathing is already compromised.
• Those with kidney problems-gabapentin and pregabalin are cleared by the kidneys. If your kidneys aren’t working well, the drugs build up in your blood, increasing side effects.
• People on high doses-the higher the dose, the greater the risk. The FDA warns that doses above 300 mg of gabapentin or 150 mg of pregabalin per day raise the danger significantly.

What the Regulators Say

In April 2019, the U.S. Food and Drug Administration (FDA) issued a formal warning. All gabapentinoid labels now carry a boxed warning-the strongest type-about the risk of respiratory depression when combined with opioids. The UK’s MHRA did the same. These aren’t gentle suggestions. They’re red flags.

The FDA’s review found that 92% of gabapentinoid-related respiratory depression cases involved either another CNS depressant or a pre-existing breathing issue. In other words, if you’re taking an opioid, you’re already in the danger zone.

Are Gabapentinoids Even Necessary?

Here’s the uncomfortable truth: the evidence that gabapentinoids improve pain control when added to opioids is weak. A 2020 study in JAMA Network Open analyzed over 5.5 million surgical patients. It found that in most cases, gabapentinoids didn’t significantly reduce pain or opioid use after surgery. In some types of surgery, like cardiothoracic procedures, opioid-related respiratory depression hit 17% of patients-even without gabapentinoids. Adding them didn’t help. It only made things riskier.

So why are they still prescribed so often? Because they’re easy. They’re not controlled substances. They don’t cause euphoria. Doctors think they’re safe. But safety isn’t just about addiction. It’s about breathing.

What Should You Do?

If you’re taking gabapentin or pregabalin with an opioid, don’t stop suddenly. That can cause seizures or withdrawal. But do talk to your doctor. Ask these questions:

• Is this combination still necessary?
• Could I try a different pain treatment without this risk?
• What’s my kidney function? Do I need a lower dose?
• Am I on the lowest effective dose of both drugs?

Your doctor should start you on the lowest possible dose of gabapentinoids and increase it slowly-especially if you’re older or have kidney issues. The Medical Letter recommends this approach for anyone with respiratory risk factors.

Alternatives to Consider

If gabapentinoids aren’t working well and carry this risk, what else can help with nerve pain?

• SNRIs like duloxetine or venlafaxine-these antidepressants are FDA-approved for neuropathic pain and don’t cause respiratory depression.
• Topical treatments like lidocaine patches or capsaicin cream-no systemic effects, no breathing risk.
• Physical therapy and nerve blocks-non-drug options that often work better than people expect.
• Cognitive behavioral therapy-helps manage chronic pain without drugs at all.

Bottom Line

Gabapentinoids aren’t harmless. When mixed with opioids, they turn a known risk into a life-threatening one. The data is clear: this combination kills. And it’s not rare. It’s happening in clinics across the country because doctors thought they were being cautious.

If you’re on both, talk to your provider. Ask if the benefits still outweigh the risks. There are safer ways to manage pain. You don’t have to accept this level of danger just because it’s common.