The patient is a 10-year-old boy, who during the last months has been examined due to a suspected,

Fråga: The patient is a 10-year-old boy, who during the last months has been examined due to a suspected, however unconfirmed, lactose intolerance. He was admitted to the emergency department with abdominal pains after intake of 5 ml Cocillana-etyfin (containing ethylmorphine hydrochloride 2.5 mg/ml + spir fortis 103 mg/ml + senegae 7.8 mg/ml). The level of S-amylase on admission was 37 ukat/L (reference value < 22 ukat/L), the following day 10 ukat/L. Is it possible that the limited dose of Cocillana-etyfin can cause an increase of S-amylase level or even pancreatitis?

Sammanfattning: Morphine/ethylmorphine, also in minimal dose, can cause spasm of the sphincter of Oddi, abdominal pains and elevated serum amylase levels. Whether a pancreatitis can be precipitated by the intake of ethylmorphine in minimal doses cannot be answered based on the information available.

Svar: It is well known that morphine and other opioids can induce spasm of the sphincter of Oddi (1,2). Experimentally it has been shown that even subanalgesic doses of morphine (2.5-10 ug/kg iv) can cause spasm in the biliary tract with an increase of the intraluminal pressure (3). The effect is reversed by the morphine antagonist naloxone (3,4).

Although a thorough literature search has been performed, no studies have been found focusing on the effects of ethylmorphine and the biliary system; nor are there any cases with "elevated serum amylase" or pancreatitis reported to the Swedish ADR-function (SADRAC, 5). Concerning morphine there is one report from 1995 in the Swedish ADR-system, describing a 84-year-old woman who developed a pancreatitis. The frequency of biliary spasm among patients treated with opiates has only been examined for fentanyl. In a study of 100 patients undergoing gallstone operations the subjects were concomitantly given on average 400 ug fentanyl intravenously. Although most of these patients had been complaining of biliary pain/spasm earlier, only 3 per cent developed biliary spasm visualized by X-ray showing that the contrast medium could not pass through the biliary ducts to the duodenum.

In a Norwegian study including four subjects - two women, 52 and 55 kg and two men, 75 and 85 kg - were given single oral doses of 75 mg ethylmorphine. Detectable concentrations of morphine, normorphine, ethylmorphine, M3G and M6G were found in all of the subjects. The formation of morphine from ethylmorphine is dependent on CYP2D6 for which genetic polymorphism has been reported. Thus pronounced interindividual differences exist in the population in the amount of morphine formed after ethylmorphine (7,8). In the present case the young patient is said to have taken 5 ml of Cocillana-etyfin which is equivalent to 12.5 mg ethylmorphine. However, it is unknown if the boy had taken more than this rather low dose. If his possible lactose intolerance is taken into account, and the symptoms of the present case are related to as low doses of morphine as 2.5-10 ug/kg (equivalent with 8.8-35 nmol/kg), it has been judged possible that even such a low dose of ethylmorphine as 0.25 mg/kg can cause his abdominal pains and an elevation of S-amylase. However, it would be interesting to know more about the influence of ethylmorphine itself on the gastrointestinal tract but, despite a repeated and wider literature search, no references have been found. 1 Drugline nr 08605 (year 1992)

2 Goodman and Gilman, The pharmacological basis of therapeutics. Pergamon Press, New York. 1996; 9th ed: 532
3 Arndorfer RC: Effects of morphine on the human sphincter of Oddi. Gut 1988; 29: 1402-1407
4 Bird KJ, Narcotic-induced choledochoduodenal sphincter spasm reversed by naloxone. Anaesthesia 1986; 41: 1120-1123
5 SADRAC 1996

6 Jones RM, Detmer M, Hill AB, Bjoraker DG, Pandit U: Incidence of choledochoduodenal sphincter spasm during fentanyl-supplemented anesthesia. Anesth Analg 1981; 60: 638-640 7 Ripel Å, Christophersen AS, Broneboe A, Morland J: Morphine formation after intake of ethylmorphine. Pharmacol Toxicol 1992; 70: 228-229 8 Rane A, Modin AR, Gerdin E: Ethylmorphine O-deethylation cosegregates with the debrisoquin genetic metabolic polymorphism. Clin Pharmacol Ther 1992; 52: 257-264