Opioid-Induced Hyperalgesia: Why Long-Term Opioid Use Can Make Pain Worse

It sounds impossible: you’re taking more opioids to control your pain, but it’s getting worse. Not just a little - your whole body feels more sensitive. A light touch hurts. The same movement that used to cause mild discomfort now feels sharp and burning. You’re not imagining it. This isn’t tolerance. It’s something else: opioid-induced hyperalgesia.

What Exactly Is Opioid-Induced Hyperalgesia?

Opioid-induced hyperalgesia (OIH) is a paradoxical reaction where long-term opioid use makes your nervous system more sensitive to pain instead of less. It’s not the same as tolerance, where you need higher doses to get the same pain relief. With OIH, your pain threshold drops. Things that never hurt before - like a blanket on your skin or a gentle bump - now trigger real pain. The pain also spreads. If you originally had lower back pain, now your legs, hips, or even arms might start hurting too.

This isn’t rare. Studies show it happens in 2% to 10% of people on long-term opioid therapy. It’s more common with high doses, especially when given through IV or injections. People with kidney problems are at higher risk because opioid metabolites build up in the body. Morphine-3-glucuronide and hydromorphone-3-glucuronide - byproducts of these drugs - can directly stimulate pain pathways in the spinal cord.

How Does Opioid Use Turn Pain Up Instead of Down?

Your nervous system doesn’t just shut down pain signals when opioids are around. It fights back. Here’s how:

• NMDA receptors wake up. Opioids bind to brain and spinal cord receptors, but they also trigger a chain reaction that activates NMDA receptors - the same ones involved in chronic nerve pain. This turns up the volume on pain signals.
• Dynorphin gets released. This natural brain chemical, usually linked to stress and depression, increases when opioids are present. Dynorphin makes nerve cells more excitable, sending more pain signals.
• Descending pain pathways flip. Normally, your brain sends signals down the spine to quiet pain. With OIH, those signals become louder, not quieter. The rostral ventromedial medulla - a brain region that controls pain - starts promoting pain instead of blocking it.
• Your genes matter. Some people have a version of the COMT gene that breaks down dopamine and norepinephrine slower. This leads to higher levels of these chemicals in the brain, which can amplify pain sensitivity. If you’ve always been more sensitive to pain, you might be at higher risk for OIH.

These changes create central sensitization - the same process seen in fibromyalgia and chronic headaches. Your nervous system becomes stuck in overdrive. Even after the original injury heals, the pain keeps going.

How Do You Know It’s OIH and Not Just Tolerance?

Doctors often confuse OIH with tolerance. But there are key differences:

Comparing Opioid Tolerance and Opioid-Induced Hyperalgesia

Feature	Opioid Tolerance	Opioid-Induced Hyperalgesia
Pain pattern	Same location, worsening intensity	Pain spreads beyond original area
Response to touch	No change	Allodynia - light touch causes pain
Effect of dose increase	Temporary relief	Pain gets worse
Effect of dose reduction	Pain returns	Pain may improve
Response to non-opioid meds	Minimal effect	Often improves with gabapentin, ketamine

If your pain gets worse every time your doctor increases your dose, and you start feeling pain in new places, OIH should be suspected. The only way to be sure? Rule out everything else - new injuries, disease progression, depression, or withdrawal.

What Happens If You Just Keep Increasing the Dose?

It’s a trap. You increase the dose to fight the pain. The pain gets worse. You increase again. The cycle continues. More opioids mean more NMDA activation, more dynorphin, more central sensitization. You end up on dangerously high doses - sometimes over 200 mg morphine equivalents per day - with no real relief.

In surgical patients, studies show those given high doses of opioids during surgery need 20-30% more pain meds afterward. That’s OIH in action. The drug meant to prevent pain ends up making it harder to control.

How Is OIH Treated?

The first step is counterintuitive: reduce the opioid dose. Yes, you read that right. Lowering the dose - even slowly - can reduce the hyperalgesic signal. Many patients report less pain within days or weeks after tapering.

The second step is switching opioids. Not all opioids are the same. Methadone is a top choice because it blocks NMDA receptors, just like ketamine. One study found patients on methadone needed 40% less pain medication after surgery compared to those on morphine or oxycodone.

Other options include:

• Ketamine - given in low doses (0.1-0.5 mg/kg/hour), it blocks NMDA receptors and can break the pain cycle. Used in clinics under supervision.
• Gabapentin or pregabalin - these calm overactive nerves by targeting calcium channels. Doses range from 900-3600 mg/day for gabapentin, 150-600 mg/day for pregabalin.
• Magnesium sulfate - an IV infusion can help reduce acute hyperalgesia, especially in hospital settings.
• Cognitive behavioral therapy (CBT) - helps retrain how your brain processes pain signals. Works best with medication changes.

Physical therapy is also important. Gentle movement helps reset your nervous system’s sensitivity. Avoiding fear-based avoidance of activity can reduce the brain’s pain amplification.

Why Is OIH Still Controversial?

Some doctors don’t believe it’s real. They say, “It’s just uncontrolled pain.” But animal studies since 1971 show it clearly. Human studies confirm it too - especially in cancer pain, post-surgery recovery, and chronic pain patients.

The problem? It’s hard to prove in a single patient. There’s no blood test. No scan. No clear biomarker. Diagnosis relies on pattern recognition: worsening pain with dose increases, spread of pain, allodynia.

A 2020 survey found only 35% of pain specialists felt confident diagnosing OIH. That’s a problem. Patients get labeled as “drug-seeking” or “non-compliant” when they’re actually experiencing a biological side effect of their treatment.

What Should You Do If You Suspect OIH?

If you’re on long-term opioids and your pain is getting worse despite higher doses:

1. Track your pain. Note where it hurts, how intense it is (1-10 scale), and whether light touch triggers it.
2. Don’t increase your dose on your own. Talk to your doctor.
3. Ask: “Could this be opioid-induced hyperalgesia?”
4. Request a review of your opioid regimen. Ask about switching to methadone or adding gabapentin.
5. Consider a pain specialist if your current doctor dismisses your concerns.

OIH isn’t a sign of weakness. It’s a sign your nervous system has been rewired. And like any rewiring, it can be undone - with the right approach.

Looking Ahead: What’s Next for OIH?

Researchers are working on better ways to spot OIH early. Some are testing genetic markers like COMT variants to predict who’s at risk. Others are developing new drugs that block pain without triggering NMDA activation - like kappa-opioid agonists.

For now, the best defense is awareness. If you’re on opioids for more than a few months, know the signs. If pain worsens with higher doses, it’s not just tolerance. It might be your body fighting back.