fb pixel
Close this search box.

International Callers Dial 1-310-205-0808

Close this search box.

International Callers Dial 1-310-205-0808

Understanding Opioid Tolerance

Table of Contents

What is Opioid Tolerance?

The definition of opioid tolerance is the failure to maintain a steady dose of the drug over time in order to sustain the desired pharmacological effect. In other words, the user needs to increase the drug dosage to feel the initial pharmacological effect. Although tolerance can occur with a wide variety of drugs, it is more prominent with opioids. Over the past two decades, research on opioid tolerance shifted toward the central nervous system (CNS) because tolerance is not just a cellular phenomenon. It is crucial to understand the neurobiological adaptations associated with opioid tolerance to find safer ways to manage pain.
Tolerance and dependence on opioids are very common side-effects of long-term opiate use. While the mechanisms of tolerance and dependence are not fully understood, it is known that receptor down-regulation causes desensitization and plays a role in a user’s tolerance of opiates.  Additionally, activation of other receptors in the nervous system may also play a role in a user’s tolerance to opiates.  As a result, patients may need more medication to reach the same levels of pain relief.


Down-regulation is a mechanical process for cells to cope with the increase of an external variable.  If there is an increase in intake of a specific molecule, there will be a cellular decrease in the number of receptors to molecules.  For instance, over time, the number of opiate receptors will decrease on a cell’s surface for long-term prescription painkiller users.  As individuals continue to take their regular dose of painkillers, like Oxycodone, fentanyl, and all forms of hydrocodone, there will be fewer opiate receptors for the compounds to bind to, causing less of an effect of the drug.  When this occurs, the body starts becoming desensitized to the drug, which usually causes users to increase their dosage.  Down-regulation is an example of a cell’s negative feedback mechanism, a self-regulating response to changes in the body, usually due to external influences like chemicals or hormones.


Up-regulation is another cellular mechanism that takes part in the body’s tolerance and dependence on opiates.  Up-regulation occurs when an external variable, which has been provided to the body for a long period of time, is removed, and the cell increases the number of receptors.  For example, when an opiate dependency patient seeks treatment and stops using opiates, the opiate receptors in their brains will increase to receive more opiates.  This often leads to withdrawal symptoms and cravings because the body does not have enough opiates to fill the opiate receptors.  Receptor up-regulation and down-regulation can vary in time from minutes to weeks, and the reversal process of these two mechanisms can take months.

How to Treat Opioid Tolerance

In the last decade, we as a society have seen a tremendous increase in the number of opioid-tolerant patients due to the opioid crisis. Sadly enough, it is reported that as many as 15% of all surgery patients going into surgery in the US are already receiving opioid drugs. Furthermore, the number of patients on medication maintenance therapy (MAT) with long-acting opioids such as methadone or buprenorphine-based drugs such as Suboxone is also rising, which poses a challenge to healthcare providers. While using MAT drugs can help with addiction, it does nothing for opioid tolerance, sometime it even worsens the condition.
Although opioid drugs are recognized as the most potent and efficacious class of analgesics, they have recently been degraded to a second-choice therapy for pain management. The primary reason behind this change in prescribing habits is the potential side effects and tolerance that often occur after repeated dosing.
If you or a loved one struggles with tolerance or dependence on opioid drugs, we urge you to contact a medical expert of your family physician.  For more information on choosing an opiate detox program for yourself or a loved one, please feel free to contact our office directly.   Waismann Method® is a safe and proven detox treatment for those suffering from opioid use disorder. Waismann Treatment™ utilizes the most advanced medical techniques available.
Developing an opioid tolerance can be scary, but it does not mean that you are addicted to drugs or that you can’t medically reverse it. Give us a call today. Let us listen to your concerns and help guide you towards a  healthy solution.

More To Explore

Brain Injury After Overdose: A Hidden Epidemic

The opioid crisis is one of the most pressing public health emergencies in both the United States and Canada. However, beneath the surface lies an under-recognized consequence: brain injuries...