Opioid Tolerance

Bottle of Opioid pills

Opioids are used to help manage acute and chronic pain. In the case of chronic pain, long-term opioid use may be necessary. Illicit opioids like heroin are also used for their euphoric effects.

Prolonged use of prescription or illicit opioids can lead to the development of drug tolerance. Tolerance occurs when the body adapts to opioid use, causing previous doses to have a diminished effect. As a result, higher doses of opioids are needed to achieve the desired effects.

Opioid Tolerance Symptoms

The primary symptom of opioid tolerance is the need for higher doses to achieve the same pain relief previously felt with lower doses. Tolerance to the various effects of opioids tends to develop at different rates.

For example, tolerance to the pain-relieving and sedative effects develops much sooner than tolerance to effects like respiratory depression, constipation, and constriction of pupils. As a result, there may be serious adverse effects as higher doses are taken. This includes opioid-induced respiratory depression, which can be fatal.

Causes of Opioid Tolerance

Opioids produce their effects by binding to opioid receptors that are present throughout the central nervous system. These receptors inhibit the enzyme adenylate cyclase, which is present inside neurons. This enzyme coordinates the activity of other molecules in neurons and controls the firing rate of the neurons. Tolerance develops due to changes in adenylate cyclase levels, which decreases the impact of opioids on neuronal firing.

Changes in the expression and responsiveness of opioid receptors also contribute to opioid tolerance. Other factors include changes in the rate of metabolism and the elimination of opioids. Administration of 60 mg/day of morphine for a week is considered to be enough to produce tolerance. Similarly, administration of 30 mg/day of oxycodone or 8 mg/day of hydromorphone for a week is enough to cause tolerance.

Some additional factors that influence the development of opioid tolerance include:

  • Dosage: High doses of opioids can lead to the development of tolerance much sooner than low doses of opioids.
  • Frequency of use: Frequent use of prescription or illicit opioids is more likely to lead to tolerance than occasional use of opioids
  • Duration of use: Prolonged use of opioids is associated with the development of tolerance. In these circumstances, the physician may switch the patient to a different opioid.
  • Type of opioid: There are three different types of opioid receptors: mu, delta, and kappa. Each opioid binds differently to these receptors. In addition, each opioid has a different half-life. Certain opioids are short-acting due to a shorter half-life, and others are long-acting due to a longer half-life. Due to these differences, it takes varying amounts of time to develop tolerance to different opioids.
  • Other factors: Other factors that may influence tolerance include biological factors. These may include genes that influence the sensitivity and expression of opioid receptors as well as the metabolism of opioids. Overall health may also influence the metabolism of opioids, which affects the level of tolerance.

Cross-Tolerance

Prolonged use of one drug can make someone tolerant to other drugs that share a similar structure or mechanism of action. For example, tolerance to morphine may also lead to cross-tolerance for methadone and other opioids.

However, there are multiple opioid receptors in the body, and each individual opioid has different affinities for these receptors. Though cross-tolerance may develop for other opioids, such as morphine tolerance creating a methadone tolerance, it is often incomplete. In other words, the level of methadone tolerance may develop to a lesser extent than morphine tolerance.

Opioid Potentiation

An opioid potentiator is any substance, including food, drugs or herbs, that enhance the effects of an opioid. This may include common food sources, such as orange juice or grapefruit, or other drugs. Other potentiators include central nervous system depressants like:

  • Benzodiazepines
  • Muscle relaxants
  • Antihistamines
  • Alcohol

When used in combination with opioids, these central nervous system depressants can cause respiratory depression, coma and death. Other substances, such as ibuprofen, certain adrenergic agonists, vitamin B and methylphenidate (Ritalin), enhance the pain-relieving effects of opioids. Potentiators like vitamin B complex are even capable of reversing opioid tolerance.

How to Prevent Opioid Tolerance

Besides the treatment of chronic pain, opioids are also used during surgical procedures and for the treatment of cancer-related pain. For these reasons, it is helpful to prevent tolerance to opioids.

One of the most common methods of preventing opioid tolerance is rotating the type of drug used. This involves using a different opioid once tolerance develops to the initial drug. Since cross-tolerance is often incomplete, a different opioid can replace the first opioid and produce the desired effects.

Other methods for lowering or reversing opioid tolerance include using a combination of opioids or using ketamine. The combination of two opioids results in greater pain relief than either opioid alone and prevents the development of tolerance.

Ketamine Infusion

Ketamine is a drug that is generally used as a pain reliever in the emergency room. Ketamine produces its pain-relieving effects by blocking the NMDA (N-methyl-D-aspartate) receptor that is involved in the amplification of pain signals. The NMDA receptor also plays an important role in the development of tolerance to opioids. Because of this, the infusion of ketamine with opioids is effective in reducing or reversing opioid tolerance.

Stem Cell Therapy

Another promising method for the prevention of opioid tolerance is the use of stem cells. Animal studies show that injection of stem cells can prevent and even reverse opioid tolerance in rats and mice. However, the effectiveness of using stem cells to prevent or reverse opioid tolerance in humans is unknown and requires further research.

Getting Help With Opioid Addiction

Prolonged use of opioids can lead to the development of tolerance and dependence on the drug. This can occur even if prescription opioids are taken as directed. The physical dependence on opioids may become severe enough to cause an addiction. Addiction to opioids involves the inability to control opioid use, despite the negative consequences on a person’s physical health and social life.

Stopping opioid use after developing dependence can lead to unpleasant withdrawal symptoms. Although they are not life-threatening, these withdrawal symptoms can cause significant discomfort and lead to a relapse. Treatment at a detox center can help someone cope with the symptoms of opioid withdrawal and prevent a relapse.

Detoxification may involve a gradual taper of opioid doses to prevent uncomfortable withdrawal symptoms. In the case of opioid addiction, treatment at a rehabilitation facility is necessary upon the completion of detox. Effective treatment for opioid addiction involves medicinal approaches and behavioral therapy to address the issues underlying addiction.

If you or a loved one is addicted to heroin or prescription opioids, The Recovery Village Ridgefield can help. Our experienced, accredited medical professionals provide quality care and treatment for substance use disorders and co-occurring mental health conditions. Contact us today to explore treatment options and find a program that can work well for you.

Institute for Chronic Pain. “Tolerance to Opioid Pain Medications.” September 2016. Accessed October 4, 2019.

Dumas, Emily; Pollack, Gary. “Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective.” The AAPS Journal, December 2008. Accessed October 4, 2019.

Bell, Rae; Kalso, Eija. “Ketamine for pain management.” Pain reports, September 2018. Accessed October 4, 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.