“Few things a doctor does are more important than relieving pain” (1). The clinical use of opioids to treat pain has changed little since the days of Osler, except for the development of many synthetic compounds such as methadone, fentanyl, and alfentanil (1a). Morphine remains the mainstay of clinical treatment in many settings and the prototype opioid whose effects, both desired and undesired, are familiar to clinicians. They recognize that achieving the desired degree of analgesia often leads to tolerance requiring dose escalation accompanied by hypoventilation and decreased gastrointestinal motility. The symptoms of opioid withdrawal in newborns of mothers addicted to heroin, morphine, or methadone are familiar to pediatricians. The clinical problems associated with opioid therapy in pediatrics were reviewed recently by Suresh and Anand (2). Recent investigations have revealed many of the mechanisms involved in these processes, which have lead to potential therapeutic options to reduce tolerance and enhance analgesia.

Several reviews have been published recently that describe and diagram intracellular events associated with opioid analgesia and tolerance (2–6). Discussions of the differences between the proposed mechanisms in these reviews show that our understanding of these processes is still incomplete (7, 8). Some of the disagreements about the mechanisms of opioid analgesia and tolerance reflect the models used in individual studies or differences in study conditions (7, 9). Analgesia and tolerance involve integrated systems within the body that may exhibit autoregulatory changes extending well beyond the events in single cells (9). As Trujillo recounted from Umberto Eco, “for every complex problem, there's a simple solution, and it's wrong (7)!” There are no simple answers to explain the interplay between analgesia and tolerance associated with opioid therapy.

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