What Is Opiate Potentiation?

Opiate potentiation refers to the enhancement of opiate or opioid effects by another substance. Using potentiators to increase the effects of opiates is dangerous and can cause life-threatening side effects.
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Deliberately trying to enhance the high from opioids can have devastating consequences. Opiates and opioids are drugs used to relieve pain. They include codeine, morphine and heroin.

When these drugs are misused they can cause euphoria and relaxation. Some people mix opioids with substances to potentiate, or increase, the effects of the drugs. Potentiators can increase the pleasurable effects of opioids, but they also increase the risk of serious side effects.

Grapefruit juice, gabapentin and Benadryl are among the most commonly used opioid potentiators. They can turn a small dose of an opioid into a fatal dose.

Non-narcotic pain medications include:

Alcohol and benzodiazepines, such as Xanax or Klonopin, are among the riskiest drugs to take while you’re on opioids. Each substance causes slowed breathing and drowsiness. When they’re combined with opioids, they can make you pass out and stop breathing.

Risks of Opioid Potentiation

All prescription drugs should be taken with caution, but opioids should be taken with extreme caution. Opiates and opioids kill more people each year than car accidents.

When used as prescribed by a doctor, the prescription drugs are relatively safe. However, it’s important to talk to your health care provider about all of the medications you’re taking. Your doctor is unlikely to prescribe the same dose of an opioid if he or she knows you’re taking a drug that potentiates its effects.

Risks of opioid potentiation include:

  • Impaired judgement
  • Loss of motor function
  • Confusion
  • Delirium
  • Coma
  • Weak pulse
  • Memory problems
  • Changes to tolerance
  • Dependence

These side effects increase the risk of accidental injury. You shouldn’t drive a car or use machinery when you begin an opioid prescription or change your dosage. You should never perform these activities if you’re trying to potentiate the effects of an opioid.

Grapefruit Juice

Grapefruit juice is one of the most well-known legal substances people use to potentiate hydrocodone, oxycodone and other opioids. The juice changes the way the body metabolizes, or breaks down, certain opioids.

Drinking grapefruit juice while taking opioids can make a larger portion of the drug reach the brain. It can also make opioids stay in your system for longer periods of time.

A 2010 study published in the journal Basic & Clinical Pharmacology & Toxicology investigated the effects of mixing grapefruit juice and oxycodone. The researchers concluded that grapefruit juice “increases the concentrations and effects of oxycodone.”

Hydromorphone, morphine and oxymorphone are not metabolized in the same way, according to a 2009 review published in Pain Medicine. Grapefruit juice is unlikely to have a significant effect on metabolism of those drugs.


Gabapentin (Neurontin) and pregabalin (Lyrica) are prescription drugs used to treat nerve pain and other conditions. Some people use the nerve-pain drugs to potentiate the effects of opioids.

A 2014 study in Europe surveyed people attending six different rehabs. Twenty-two percent of patients reported misusing gabapentin or pregabalin, and 38 percent of those patients said they used the drugs to potentiate the effects of methadone.

Experts aren’t sure of the exact manner in which opioids interact with gabapentin and pregabalin. But a 2017 study published in the journal Addiction concluded that gabapentin and pregabalin increase the risk of overdose among people who use heroin. The authors of the study think the drugs affect a person’s tolerance and cause an extra effect on slowed breathing.

Diphenhydramine (Benadryl)

In general, doctors try to avoid prescribing opioids alongside other sedatives. Diphenhydramine, the active ingredient in the antihistamine Benadryl, is used to relieve symptoms of allergies and hay fever. Its side effects include drowsiness and dizziness.

A 1985 study of rats concluded diphenhydramine potentiated the pain-relieving effects of the opiate morphine. More recent studies found antihistamines can relieve pain. But experts don’t clearly understand how antihistamines and opioids affect one another.

People who want to potentiate opioids often try Benadryl because of its availability. But it’s unclear how effective the antihistamine is at increasing the effects of opioids. The drugs may have a synergistic effect on sedation, meaning the sedative effects of both drugs together are greater than the effects of either drug separately. But more evidence is needed to know for sure, according to a 2010 review published in The American Journal on Addictions.

People use several substances to potentiate the effects of opiates, and many of these substances interact with the drugs to cause dangerous side effects. You should never attempt to increase or potentiate the effects of an opiate or opioid without consulting a doctor.

Chris Elkins, MA
Senior Content Writer, DrugRehab.com
Chris Elkins worked as a journalist for three years and was published by multiple newspapers and online publications. Since 2015, he’s written about health-related topics, interviewed addiction experts and authored stories of recovery. Chris has a master’s degree in strategic communication and a graduate certificate in health communication.
Kim Borwick, MA
Editor, DrugRehab.com

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