Sometimes the effects of opioids on the gastrointestinal tract are therapeutic, but more often they are problematic and undesirable. All of the commonly used opioid agonists, such as morphine, meperidine, and fentanyl, can produce spasm of gastrointestinal smooth muscle. This may cause various side effects, including constipation, biliary colic, and delayed gastric emptying. Constipation occurs when intestinal transit time is increased due to a loss of normal peristalsis and increased sphincter tone. It can be a particularly debilitating problem in patients who require chronic opioid treatment because very little tolerance develops to this stimulant effect. Increased biliary pressure occurs when the gall bladder contracts against a closed or narrowed sphincter of Oddi. Passage of gastric contents into the proximal duodenum is delayed because there is increased tone at the gastroduodenal junction. This last effect is particularly important for anesthesiologists because analgesic premedication may increase the risk of aspiration or delay the absorption of orally administered drugs. All of these effects may be reversed or prevented with naloxone, but this is usually undesirable because the analgesic effects also will be antagonized.
The article by Murphy et al. in this issue of Anesthesiology  shows that selectively antagonizing the peripheral effects of morphine can prevent nearly all of the decrease in gastric emptying. The study design is simple and concise: Morphine is given to volunteers, either alone or with N-methyl naltrexone, a permanently charged competitive antagonist that cannot cross the blood-brain barrier. The rate of emptying is then measured with two validated techniques, bioimpedance and acetaminophen absorption. It should be clear that the existence of a peripheral opioid effect was never really in doubt because animal studies have long suggested that central nervous system and peripheral mechanisms are involved in opioid gastrointestinal effects.  Peripheral opioid effects clearly play a major role in the colon: For years, the most effective treatments for severe diarrhea have been loperamide and diphenoxylate, two poorly absorbed opioids. N-methyl naltrexone has already been shown to antagonize the inhibitory effects of morphine on human intestine in vitro  and in vivo.  It is true that different mechanisms may be involved in gastric emptying and intestinal peristalsis, but the complex apparatus of the enteric nervous system (including opioid receptors and opioid peptides) extends through both areas.
The value of this study, then, is the demonstration that peripheral antagonism may be a clinically useful treatment for this particular opioid side effect. A single dose of morphine produced significant effects in these healthy volunteers: The stomach took four times as long to empty plain water, and there was a threefold decrease in the peak plasma concentration of acetaminophen. The antagonist prevented these changes at a dose that is unlikely to produce toxicity or to reverse analgesia. 
Where does this leave us? N-methyl naltrexone is an investigational drug, and it has been given “orphan” status by the Food and Drug Administration. The results of this limited study are clear but not definitive. We will eventually need to have data on a range of antagonist doses and the onset and duration of antagonism. We also need to see the effect of the antagonist alone on gastric emptying-perhaps it will reverse endogenous opioid tone in the stomach! Most importantly, we need to define the clinical populations at risk who might benefit from the prophylactic or therapeutic use of this new drug.
Carl E. Rosow, M.D., Ph.D.
Associate Professor of Anaesthesia, Harvard Medical School; Anesthetist, Department of Anesthesia and Critical Care; Massachusetts General Hospital; 55 Fruit Street; Boston, Massachusetts 02114–2696
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