Opium has been used for thousands of years to treat pain. When the morphine alkaloid was identified as the active ingredient in opium, pharmacologic production of opiates became possible. Widespread use and abuse of opiates led to strict regulatory controls. By the 1940s, a physician’s prescription was required to obtain opiates legally in the United States. Ballantyne and Mao review some new ideas about opiates that have come out of bench-top and clinical research and their possible implications for the management of chronic pain.

The authors begin their review by noting that most of the literature on opioid therapy is composed of uncontrolled case series of short duration. They also address some older concepts about opiates that have not been confirmed by more recent research. For example, recent findings do not support the belief that neuropathic pain is opioid resistant. Neuropathic pain is relatively difficult to treat, however, and may require higher dosages to achieve analgesia.

A number of consensus statements regarding management of opioid therapy are cited for reference. The authors suggest that opiate dosage increases beyond initial titration should be “introduced with extreme caution” and point to accumulating evidence showing that dosages need to be limited “to maintain both efficacy and safety.”

Prolonged use of opiates leads to tolerance (i.e., higher dosages are needed to maintain equivalent pain relief over time). This tolerance involves opioid-receptor changes at the cellular level as well as psychologic factors. Prolonged opiate use also has been linked to increased pain sensitivity in both bench-top and clinical research studies.

Chronic opiate use may have risks beyond inadequate pain relief. Suppression of both adrenal and gonadal hormone production has been linked to opioid therapy. Opioidrelated receptors have been found on immune cells and may explain some of the immunosuppressive effects associated with chronic opiate use.

The authors note that when opiates provide good pain relief at stable doses, the pain therapy guidelines are relatively easy to follow. When patients have more complex problems and inadequate relief, however, physicians may be inclined to consent to requests for increased opiate dosages. The review authors suggest that, given the risks cited, these patients in particular may benefit from efforts to limit the opioid dosage. Evidence supporting a ceiling dosage for opiate treatment is growing, but no hard number is preferred. The review authors note that a daily dosage limit of 180 mg of morphine or morphine equivalent was used in most of the controlled studies.

Because each opioid acts differently at the opioid receptor, rotating the type of opiate used is suggested as a means of decreasing the opiate dosage needed. According to the authors, rotating to methadone works particularly well, reducing the opiate dosage by as much as one half. Some pain authorities have voiced concern, however, regarding methadone’s prolonged half-life, which may lead to drug accumulation and high plasma levels.

If efforts to limit dosage escalation fail, the authors suggest weaning the patient from opioid therapy. After two to three months without opiates, a “true assessment” of pain may be accomplished, and opioid therapy can be restarted at “much lower doses.”

editor’s note: Although this review amply demonstrates the authors’ extensive knowledge of opiate pharmacology and pain pathophysiology, few of the supposedly new insights offered regarding pain therapy reflect what I see in my office practice. The authors’ assertion that opiate therapy simply should be withdrawn if physician-oriented treatment goals are not met may explain why so few chronic pain patients are treated at specialized pain centers, and why so many patients end up returning to their family physician’s office despite referral. The many patients with chronic pain whom I have seen over the years do appear to have increased pain sensitivity. They also appear to be sensitive and fragile in more areas than just the perception of pain, and I doubt their opiate dosage alone is the explanation.

Raising expectations and helping these vulnerable patients avoid harm by sticking to “one doctor, one pharmacy, one amount” is good common-sense clinical advice. Promptly turning them away if the going gets tough and forcing opiate rotations or reductions in dosages, however, sound like measures to increase physician comfort rather than patient pain relief. Most of the harm I have seen occur in patients with chronic pain does not relate to opiate side effects but rather to the risky measures patients take to obtain pain medicines when no reliable supply is available from a single physician who will follow them over the long run.—B.Z.