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In My Opinion

Thoughts on tolerance, hyperalgesia, and short-acting opioids
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The recent article published in Practical Pain Management, “Appropriate Opioid Dosing for Activities of Daily Living,” by Drs. Forest Tennant and Jeffrey Reinking,1 made several important points which can never be said too often. One is that the goals of opioid treatment for chronic pain, in addition to reduced pain, are improved activities of daily living, decreased time in bed or on a couch, improved mental functioning and improved quality of life. The second is that “the notion that there should be a ceiling or restricted dose of opioids is nonsensical, unscientific, and inhumane.” Despite the belief of some researchers and some regulatory agencies that there is an arbitrary upper limit of opioid that should not be exceeded, there is in fact no clinical evidence of the validity of such a belief.

Also as pointed out by Tennant and Reinking, animal studies have clearly shown that there are genetic differences in the ability of different opioids to provide pain relief in different subjects. Additionally, there are documented differences in the metabolism of the various opioids. For example, persons who are deficient in the enzyme that metabolizes the prodrug codeine to morphine, need much higher doses of codeine in order to get pain relief. There are also differences among subjects in the penetration of various opioids through the blood-brain barrier, and differences among people in absorption of transdermal opioids. The result is that people given the same dose of an opioid can vary in the resulting blood level and in the degree of pain relief. Therefore people can vary widely in the opioid dose they require for adequate pain relief. That opioid-tolerant chronic pain patients can function well, and even drive safely, in the presence of serum levels that may be considered lethal in opioid-naïve patients was shown clearly in Tennant’s ground-breaking study of opioid blood levels.2 When pain is not well-controlled, the limiting factor in further increasing the dose, or alternatively adding a second opioid, is the development of adverse effects such as sedation or constipation. What matters is the patient’s pain relief and functioning, not the dose.


However, there are some points in Tennant’s study that I feel require clarification. When Tennant writes that “chronic pain patients become tolerant to opioids after about 7-10 days,” I believe he means to say that patients become tolerant to the sedative effects of opioids within 7-10 days, which of course is a very good thing. Tolerance generally means getting less effect from a given dose, so it is important to specify which effect you mean. Opioids have several effects on the body – pain relief, sedation, constipation, and nausea (as well as euphoria). It is well recognized that within days of starting an opioid, people develop tolerance to its sedating, nauseating, and euphoria-producing effects. Unfortunately people do not develop tolerance to the constipating effect of opioids, which is why it is important to discuss the need for a pre-emptive bowel program when initiating opioid therapy.

There is controversy in the literature about whether tolerance to pain relief develops. In my clinical practice, which includes many patients treated with opioids for up to 15 years, quite a few have been on stable doses of opioids for years. Other opioid-prescribing clinicians have observed the same thing. Unfortunately there is a dearth of outcome reports in the medical literature. Recently, Tennant3 reported on a series of cases in his practice in whom long-term opioid doses were stable. When patients report increased pain after months or years of opioid treatment, their physician frequently attributes this to the development of tolerance to the pain-relieving effect of the opioids. But, remember, tolerance to all the other effects of opioids develops within days! What is much more likely is that the patient’s disease has progressed or that a new pain-producing problem has appeared.

It is also common for patients to require upward titration when opioids are first initiated. There are usually two reasons for this, and neither one is related to tolerance to the analgesic effect of the drug. First, opioids must be initiated at a very low dose because of the sedation and nausea they may produce. Over a few days, as these effects abate due to tolerance, the dose is then gradually increased until adequate analgesia obtains. It is quite common for the patient to return a short time later and say that their pain level has risen again. At this point, the most likely reason is increased activity. As the pain level diminishes, the patient (hopefully!) begins to spend less time horizontal and engages in more physical activities. Naturally their pain level will then increase, requiring additional upward titration. Within weeks, however, the patient will reach an equilibrium between their level of functioning and the opioid dose. At this point, the dose is likely to stabilize. Clearly, we need more published outcome studies to confirm this common clinical observation.


There are other assertions in Tennant’s article with which I respectfully disagree. These have to do with (1) hyperalgesia and (2) initiation of opioid therapy in opioid-naïve patients. Hyperalgesia, which means increased sensitivity to painful stimuli, is used in two difference contexts in pain medicine. In one context, hyperalgesia refers to the excessive pain often induced by neuropathies or certain chemicals. It is used in this sense in a recent paper describing the hyperalgesia and allodynia produced by injections of capsaicin.4 Another context is the unfounded assertion that some patients who chronically take high-dose opioids develop increased pain with increased doses, or increased sensitivity to noxious stimuli. This is based on studies of laboratory animals, and of people given intrathecal opioids or studied under other unusual conditions.5,6 I am unaware of any studies supporting the existence of this phenomenon in clinical practice with respect to patients chronically on oral or transdermal opioids. The assertion of opioid-induced hyperalgesia has found its greatest usefulness by physicians and regulators looking for justification to limit opioid prescribing and by some cost-conscious insurance companies seeking a medical reason to deny payment for high doses of opioids. Tennant and Reinking write in their article, “Hyperalgesia. . . can clinically exist if a physician overprescribes opioids to a mild pain patient or a person who doesn’t have pain. This situation almost always exists because the physician is unfamiliar with the Controlled Substance Act Schedules.” This statement is not evidence-based; it’s an opinion without a clinical or published basis.

Last updated on: February 21, 2011
First published on: January 1, 2009