Tolerance and Hyperalgesia: Complications of Opioid Use

Both tolerance and hyperalgesia are difficulties encountered by patients who are prescribed opioids. Both conditions can be seen in pain patients and in people with addiction.

Drug tolerance means the body requires a higher dose of drug to achieve the same effect. In the case of a pain patient, that means it takes more opioid to achieve the same amount of pain control. In an opioid addict, it means the addict requires more of the drug to achieve a “high,” or euphoria. However, as the addiction progresses, many addicts are no longer able to get high, but use opioids to prevent painful withdrawal. Tolerance occurs due to changes that the body makes in response to the presence of the drug.

Scientists think that the presence of opioids results in decreased activation of the mu receptors. One theory is the cell actually “swallows” the opioid receptor so that it’s no longer available, on the outside of the cell, to be stimulated by an opioid.

Hyperalgesia isn’t the same as tolerance, but somewhat similar. Hyperalgesia is an increased sensitivity to pain. In other words, little pains feel like big pains. Allodynia, a related condition, means feeling pain in response to things that aren’t usually painful. For example, a touch on the arm may become painful to someone with allodynia.

Hyperalgesia doesn’t only occur with long-term opioid use. Nerve damage of any kind can cause both hyperalgesia and allodynia. In these cases, anti-convulsant medications are used in an effort to stabilize the nerves that transmit pain messages. 

A recent study compared the pain thresholds of four groups of people: normal controls, chronic pain patients medicated with methadone, chronic pain patients medicated with morphine, and patients on methadone for opioid addiction. All three groups were studied with the cold pressor test. In this test, a subject is asked to submerge a hand in ice water, and record the length of time until the subject feels such bad pain that he must remove his hand from the ice water. Normal controls, not taking any opioids, averaged around 31 seconds. Chronic pain patients on methadone tolerated the pain for 20 seconds. Chronic pain patients on morphine were able to endure the pain about the same length of time at 19 seconds. Methadone-maintained patients with addiction were also able to tolerate an average of 19 seconds. (1) This study seems to indicate that patients on opioids for either pain or addiction treatment both develop hyperalgesia. 

So what’s the difference between hyperalgesia and tolerance? In hyperalgesia, there’s increased sensitivity to pain, but with tolerance, there’s decreased sensitivity to opioids. (2) This difference is important, because if the opioid dose is raised in a patient with hyperalgesia, the patient’s pain may actually worsen. But a patient with tolerance would likely improve with a dose increase.

How many patients on opioids develop hyperalgesia? We don’t know, as there are no controlled studies of this problem as yet. We do know that tolerance often occurs in pain patients. For patients on methadone to treat addiction, tolerance does not seem to develop to the blocking effect of methadone, meaning once a patient is at a dose of methadone sufficient to treat all withdrawal symptoms, he usually doesn’t have to keep increasing the dose over time. Of course, other changes, like new medications, weight fluctuations, and changes in physical activity may change methadone blocking dose requirement in these patients, but this is different from tolerance.

Why does this occur in some people but not others? This may be genetically determined, at least in part. There are three basic opioid receptor types, mu kappa, and delta. To complicate things further, within each of these groups, there are subtypes. Our genes determine which subtype of mu receptor predominates in one person as opposed to another. One opioid may stimulate one sort of mu receptor more than another. (This may be why when switching from one opioid to another, the patient isn’t completely tolerant to the new opioid.) Some scientists believe some configurations of subtypes of opioid receptors make a person more likely to develop hyperalgesia.

What can be done to prevent or treat hyperalgesia? Many patients actually have improved pain control after they are gradually tapered from opioids.

Because the body isn’t completely cross tolerant to different opioids, switching opioids helps some patients. Of course for patients being treated for addiction, there are only two medications that can be legally used: methadone and buprenorphine.

 Some pain medicine doctors advocate using low-dose opioid blockers along with a full opioid. The blockers may have effects at opioid receptors besides just the mu receptor, and these other receptors, like the kappa receptor, may play an important role in hyperalgesia and tolerance since some research shows this improves pain outcomes.

Other types of brain receptors may also play a role in pain and hyperalgesia. For example, there’s evidence that the NMDA receptor is involved in development of tolerance and hyperalgesia.

Some doctors add non-opioid medications like anticonvulsants to opioids in an effort to minimize opioid doses needed. At present there’s a lack of strong evidence to support this practice, though it’s a reasonable method to try.

This is a relatively new area of study, and hopefully in the future we’ll have a better idea of why hyperalgesia, tolerance, and allodynia occur, how to treat them, and even how to prevent them.

  1. Hay JL, White JM, et. al., “Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients.” Journal of Pain, 2009, Mar;10(3):316-22.
  2. DuPen, Anna, Shen, Danny, Ersek, Mary; “Mechanisms of Opioid-Induced Tolerance,” Pain Management Nursing 2007; 8(3):113-121.

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