Embedded in an excellent review of acute pain management for the opioid tolerant patient1is an error that has been faithfully transmitted in the medical literature for the past 50 yr by diverse authors. The 1956 edition of Goodman and Gilman’s pharmacology textbook contains the following unreferenced statement: “. . . tolerance does not develop to the excitatory responses elicited by the opium alkaloids. Also the actions on the bowel and the pupil persist, and the morphine addict thus manifests constipation and miosis.”2The only studies that have professed to support this statement came from the Addiction Research Center in Lexington, Kentucky, where unconsenting federal prisoners were given addictive doses of methadone3or morphine4and then withdrawn from the drugs to study the physiologic responses to long-term opioid therapy. These studies did not find any differences during long-term opioid treatment in the tolerance to decreased respiratory rate and miosis. Nevertheless, this statement has been regularly transmitted, in one form or another, through all of the subsequent editions of Goodman and Gilman’s pharmacology textbooks, even in chapters written by other authors. The unreferenced statement also appears in several other pharmacology textbooks, as well as in the other reference given to Stoelting and Dierdorf.5 

Meanwhile, several excellent human studies6–9have shown that tolerance does indeed develop to the miotic effects of μ-opioid agonists. It is not our intent to review these studies because it can be readily observed that patients taking large doses of opioids over a long term do not have miotic pupils, unless they are measured in bright light or have other conditions that produce miosis. Certainly, however, as the opioid dose is escalated above the usual dose, the pupil constricts, just as these patients can also experience oversedation and respiratory depression.

Why measure dark pupil size? It makes no sense to measure the pupil diameter in ambient light because opioids do not interfere with the light reflex. Therefore, a patient looking directly at the room light might have a pupil size of 3 mm. This patient might not even be taking opioids, but the pupil would be termed miotic . The effect of lighting intensity on the miotic effect of opioids has been studied and revealed that dark pupil size should be used to assess the effect of opioids on the pupil.10If a subject is given a standard dose of morphine in bright daylight, the pupil changes from 2.5 mm to 2.2 mm, and the change would not be noticeable, but the same pupil would constrict from 6 mm to 3 mm if the measurements were taken in the dark.

With this information in mind, proper dark pupil measurement can be of value in opioid-tolerant patients. Other classes of drugs, such as benzodiazepines or anticonvulsants, can produce sedation, and with patients using these agents, the constricting pupil is a useful confirmatory sign of opioid toxicity. Furthermore, as the authors1suggest, a dilated pupil at the end of a case can mean inadequate opioid has been given to provide a pain-free emergence. However, with the idea that the pupil does not become tolerant to the miotic effects of opioids, the observation of pupil size in tolerant patients at that time would have no value at all.

* University of California, San Francisco, San Francisco, California. larsonm@anesthesia.ucsf.edu

Mitra S, Sinatra R: Perioperative management of acute pain in the opioid-dependent patient. Anesthesiology 2004; 101:212–27
Goodman L, Gilman A: The Pharmacological Basis of Therapeutics. New York, McMillan, 1956
New York
Martin W, Jasinski D, Haertzen C, Kay D, Jones B, Mansky P, Carpenter R: Methadone: A reevaluation. Arch Gen Psychiatry 1973; 28:286–95
Martin W, Jasinski D: Physiological parameters of morphine dependence in man: Tolerance, early abstinence, protracted abstinence. J Psychiatr Res 1969; 7:9–17
Stoelting R, Dierdorf S: Anesthesia and Co-existing Disease. New York, Livingston, 1988
New York
Senay E, Shick J: Pupillography response to methadone challenge: Aid to diagnosis of opioid dependence. Drug Alcohol Depend 1978; 3:133–8
Higgins S, Stitzer M, McCaul M, Bigelow G, Liebson I: Pupillary response to methadone challenge in heroin users. Clin Pharmacol Ther 1985; 37:460–3
Tress K, El-Sobky A, Aherne W, Piall E: Degree of Tolerance and the relationship between plasma morphine concentration and pupil diameter following intravenous heroin in man. Br J Clin Pharmacol 1978; 5:299–303
Tress K, El-Sobky A: Pupil responses to intravenous heroin (diamorphine) in dependent and non-dependent humans. Br J Clin Pharmacol 1979; 7:213–7
Weinhold L, Bigelow G: Opioid miosis: Effects of lighting intensity and monocular and binocular exposure. Drug Alcohol Depend 1993; 31:177–81