Oxycodone Tolerance

woman with her hand on her head after taking too much oxycodone

Oxycodone (brand name OxyContin) is a powerful opioid that is commonly prescribed to treat moderate to severe pain. Unfortunately, regular oxycodone use, even as prescribed, can rapidly lead to the development of tolerance and physical dependence.

Before getting into the details of oxycodone tolerance and its consequences, it may be helpful to define a few terms:

  • Tolerance: refers to a physical change in the brain that occurs when a drug is consistently present, making it necessary to increase the amount of drug taken or increase the frequency of dosing to achieve the desired effect
  • Dependence: develops when the brain adapts to the presence of a drug so that if the drug is suddenly not present physical and psychological withdrawal symptoms are experienced. Although withdrawal symptoms are uncomfortable, they are manageable.
  • Addiction: is an extension of dependence, and is characterized by compulsive drug-seeking behavior despite negative consequences

Oxycodone Tolerance Symptoms

The hallmark characteristic of oxycodone tolerance is the need for higher doses to achieve the desired effect. Oxycodone is often prescribed for pain management, so someone who has successfully used oxycodone but who experiences a resurgence of pain is exhibiting symptoms of tolerance.

Cross Tolerance

Someone who regularly used oxycodone and developed a tolerance will find that they have a reduced sensitivity to other opioids as well. This change is called opioid cross-tolerance and develops because opioids have similar pharmacological properties, meaning that they interact with many of the same targets in the brain and produce similar effects.

The opioid family has a few subtypes of opioids, which have somewhat different mechanisms of action (known as pharmacodynamics). This difference means oxycodone-induced opioid tolerance will have slightly different degrees of tolerance to other opioids, depending on the specific pharmacodynamics of the subtype.

Causes Of Oxycodone Tolerance

The precise mechanism that underlies the development of oxycodone tolerance is very complex and there are still aspects of it that scientists are working to understand. However, there are some factors that reliably predict tolerance development, including:

  • Dosage: Higher doses more rapidly induce tolerance.
  • Frequency of use: Increased dosing frequency causes tolerance to develop faster.
  • Duration of use: Longer durations of use are associated with higher levels of tolerance.
  • Interactions with other drugs: Most legal and illegal drugs affect one or more key metabolic pathways in the body that could affect opioid metabolism. Over-the-counter, prescription and illicit drugs can all interact with oxycodone, sometimes with fatal consequences. If you are prescribed oxycodone, tell your doctor about any other drugs you may take concurrently.
  • Other factors: Genetic differences are a major factor in how quickly someone will develop oxycodone tolerance, as are metabolism, mental and physical health, age, gender and even diet.

Oxycodone Potentiation

A potentiator is a substance that increases the effect of oxycodone. Potentiators can work by inhibiting breakdown or prolonging the amount of time oxycodone is available for use in the body. Some potentiators work by affecting complementary pathways, which enhances the effect of oxycodone. Potentiating oxycodone can be very dangerous and may increase the risk of overdose.

Oxycodone potentiators include:

  • Grapefruit juice: blocks oxycodone metabolism, meaning that oxycodone will be available at higher concentrations and for longer amounts of time than it would be normally. Grapefruit juice combined with oxycodone is also associated with a risk for respiratory depression, which can be lethal. Notably, other citric fruits may have similar effects (e.g., limes or oranges).
  • Anti-allergy medicines: including diphenhydramine (the active ingredient in Benadryl), can inhibit oxycodone metabolism and increase its effects.
  • Cimetidine: is an antacid that is used to treat heartburn. Like diphenhydramine, cimetidine increases the effects of oxycodone.
  • Over-the-counter herbal remedies: like valerian root (for sleeplessness) and St. John’s Wort (for depression/mental wellbeing) can enhance the effects of oxycodone.

How To Prevent Oxycodone Tolerance

The best way to prevent oxycodone tolerance is to take the lowest effective dose and to take it as infrequently as possible — following the approval of a doctor. People who are prescribed oxycodone to manage chronic pain should discuss opioid rotation with their healthcare provider, which can delay (but not prevent) tolerance. However, there is currently no reliable way to prevent the development of oxycodone tolerance among people who regularly use oxycodone.

Ethanol For Tolerance Reversal

The combined effects of oxycodone and alcohol (ethanol) are often profoundly dangerous, and 22% of deaths caused by opioids in 2010 involved alcohol. People who co-abuse opioids and alcohol indicate that alcohol increases the effects of opioids, which leads researchers to evaluate whether alcohol can stop or even reverse opioid tolerance.

Studies in mice support the hypothesis: After maintaining mice on oxycodone for enough time for them to develop dependence, researchers administered alcohol 30 minutes before oxycodone and found that the effectiveness of oxycodone was significantly higher than it was in an oxycodone-dependent mouse without alcohol. Interestingly, the researchers found that alcohol did not change the concentration of oxycodone in the brain, indicating that the two drugs are interacting neuronally; that is, they affect brain cells in ways that cause the cells to behave differently, rather than simply affecting the amount of oxycodone that is available for the cells to use.

These are very preliminary findings and have a long way to go before they are translated into human medicine. Under no circumstances are these findings supportive of people testing alcohol and oxycodone combinations on themselves. These lab-based studies used precisely measured doses that were administered to mice. Equating doses between mice and humans is not a simple weight-based ratio — there are complex calculations that are used to account for metabolic differences between species. People should always consult their doctor for advice on adjusting their medications or for seeking new treatment options.

Getting Help With Oxycodone Addiction

Even among addictive opioids, oxycodone stands apart as being dangerous if taken for more than a couple of weeks. Even when used exactly as directed, tolerance and dependence rapidly set in, which can cause people to misuse and abuse their prescription. Thankfully, oxycodone addiction treatment is available.

People struggling to manage an oxycodone use disorder should look for a quality rehab program that can address every aspect of recovery, from the initial evaluation to long-term aftercare. The staff should be a multidisciplinary team that has experience in helping people successfully treat opioid addiction.

If you or a loved one struggle with oxycodone addiction or another type of opioid addiction, The Recovery Village Ridgefield can help. Contact The Recovery Village Ridgefield to speak with a representative who can detail the initial steps of addiction treatment and how you can take the first steps toward a healthier future.

Dumas, Emily; Pollack, Gary. “Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective.” The AAPS Journal, November 2008. Accessed September 26, 2019.

National Institute on Drug Abuse. “The Neurobiology of Drug Addiction.” January 2007. Accessed September 26, 2019.

McCance-Katz, Elinore; et al. “Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: a review.” The American Journal on Addictions, April 2012. Accessed September 26, 2019.

Bailey, David G; Dresser, George; Arnold, Malcolm. “Grapefruit and medication interactions: forbidden fruit or avoidable consequences?” CMAJ, 2012. Accessed September 26, 2019.

The Centers for Disease Control and Prevention. “Alcohol Screening and Brief Intervention for People who Consume Alcohol and Use Opioids.” Accessed September 26, 2019.

Jacob, Joanna; et al. “Ethanol Reversal of Tolerance to the Antinociceptive Effects of Oxycodone and Hydrocodone.” The Journal of Pharmacology and Experimental Therapeutics, July 2017. Accessed September 26, 2019.

Medical Disclaimer: The Recovery Village aims to improve the quality of life for people struggling with a substance use or mental health disorder with fact-based content about the nature of behavioral health conditions, treatment options and their related outcomes. We publish material that is researched, cited, edited and reviewed by licensed medical professionals. The information we provide is not intended to be a substitute for professional medical advice, diagnosis or treatment. It should not be used in place of the advice of your physician or other qualified healthcare provider.

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