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 like oxycodone or hydrocodone for extra relief, you might think you’re getting better pain control. But what you’re really doing is stacking two drugs that can quietly shut down your breathing-sometimes with deadly results. This isn’t theoretical. It’s happening in clinics, hospitals, and homes across the U.S. right now.

What Are Gabapentinoids?

Gabapentinoids include gabapentin (Neurontin, Gralise) and pregabalin (Lyrica). They were originally developed for epilepsy but are now widely used for chronic nerve pain-diabetic neuropathy, postherpetic neuralgia, fibromyalgia. Many patients find them helpful. But unlike typical painkillers, these drugs don’t just dull pain. They directly affect the central nervous system, slowing brain activity in ways that can suppress breathing.

Even when taken alone, gabapentinoids can cause respiratory depression. A 2019 FDA review found 49 cases of serious breathing problems linked to these drugs between 2012 and 2017. Twelve of those cases ended in death. And every single fatal case involved at least one risk factor: older age, kidney problems, lung disease, or another CNS depressant.

Why Opioids Make It Worse

Opioids-like morphine, fentanyl, oxycodone-work by binding to receptors in the brainstem that control breathing. Gabapentinoids do something similar, though through different pathways. When you take both, their effects add up. It’s not just 1 + 1 = 2. It’s more like 1 + 1 = 3.

A 2017 study published in PLOS Medicine looked at over 1.6 million opioid users. It found that people taking gabapentin along with opioids had a 50% higher risk of dying from an opioid-related cause. For those on high doses of gabapentin, the risk nearly doubled. That’s not a small increase. That’s a life-threatening one.

And it’s not just about dose. Even low doses of gabapentin can become dangerous when paired with opioids. One small study gave healthy volunteers a single dose of gabapentin before sleep. The number of breathing pauses (apneas) more than doubled compared to placebo. Imagine that happening to someone with sleep apnea, COPD, or just older lungs.

Who’s at Highest Risk?

This isn’t a risk for everyone-but it’s a serious one for specific groups:

• People over 65: Lung function naturally declines with age. The brain’s ability to respond to low oxygen drops too.
• Those with kidney disease: Both gabapentin and pregabalin are cleared by the kidneys. If kidneys aren’t working well, the drugs build up in the blood, increasing side effects.
• Patients with COPD, asthma, or sleep apnea: Their breathing is already compromised. Adding these drugs pushes them closer to failure.
• People on high-dose opioids: Especially those recently started on opioids or recently increased in dose.
• Post-surgical patients: One study found respiratory depression occurred in up to 72% of general surgery patients given gabapentinoids alongside opioids.

And here’s the kicker: many of these patients aren’t told about the risk. Doctors often assume gabapentinoids are safe because they’re not opioids. But they’re not harmless. They’re CNS depressants-just different ones.

The Hidden Mechanism: More Than Just Additive Effects

It’s not just that both drugs slow breathing. There’s another layer. Gabapentinoids may reverse opioid tolerance. That means someone who’s been on opioids for months and has built up resistance to their sedative effects might suddenly become sensitive again when gabapentin is added. Their body, which thought it could handle the opioid, now can’t.

There’s also a pharmacokinetic twist. Opioids slow down gut movement. Gabapentin is absorbed mainly in the upper small intestine. When gut motility slows, gabapentin lingers longer in its absorption zone. That means more of it gets into your bloodstream than expected. You might be taking the same dose, but your body is getting a higher, more dangerous level.

Why Are Doctors Still Prescribing This Combo?

In 2017, nearly one in five new opioid prescriptions came with a gabapentinoid. Why? Because in the wake of the opioid crisis, doctors were pushed to reduce opioid doses. Gabapentinoids seemed like a safe alternative-something to “spare” patients from higher opioid amounts.

But the evidence for pain relief from gabapentinoids in combination with opioids is weak. A 2020 analysis of over 5.5 million surgical patients found no clear benefit. In fact, the added risk of respiratory depression often outweighs any small gain in pain control.

Still, the habit sticks. Many prescribers don’t realize how dangerous the combo is. Or they assume the patient is young and healthy. Or they think, “I’ve prescribed this before, and nothing happened.” But one time is all it takes.

What Should You Do?

If you’re on gabapentin or pregabalin and also taking an opioid:

1. Don’t stop either drug suddenly. Withdrawal from gabapentin can cause seizures. Stopping opioids abruptly can trigger severe pain or withdrawal symptoms.
2. Talk to your doctor. Ask: “Is this combo necessary? Are there safer alternatives?”
3. Ask about non-CNS depressant options. For nerve pain, consider duloxetine, amitriptyline (at low doses), topical lidocaine, or physical therapy.
4. Check your kidney function. If your creatinine clearance is below 60 mL/min, your gabapentinoid dose likely needs adjustment.
5. Start low, go slow. If you’re new to gabapentinoids, your doctor should begin with the lowest possible dose and increase it over weeks, not days.

And if you live alone, or care for someone elderly or with breathing problems, consider keeping naloxone on hand. It won’t reverse gabapentinoid-induced depression-but it can help if opioids are also involved.

The Bottom Line

Gabapentinoids aren’t harmless. They’re not just “mild” nerve pain meds. When combined with opioids, they create a perfect storm for respiratory failure. The FDA, the UK’s MHRA, and major medical journals have all sounded the alarm. Yet the practice continues.

If you’re prescribed both, don’t assume you’re safe. Ask questions. Demand evidence. Push for alternatives. Your breathing is worth it.