In Sweden, mainly as a traditional therapy, a mixture of equal parts of Desentol and Lepheton is of

Fråga: In Sweden, mainly as a traditional therapy, a mixture of equal parts of Desentol and Lepheton is often prescribed to coughing children but also in conditions like laryngitis and pseudo croup. Some parents now have understood that Lepheton contains ethylmorphine and have expressed thoughts whether this mixture could cause addiction or abuse due to its content? The mixture is even administered to children at an age of only 7-8 months.

Sammanfattning: Ethylmorphine is metabolized to morphine to a significant extent. Seven ADR reports on ethylmorphine in Sweden concern psychiatric side effects, hallucinations being the most frequent one. Abuse or addiction have not been reported but Cocillana-etyfin is a consistent object of prescription forgeries in Sweden, indicating that ethylmorphine is subject to drug abuse. No such reports have been found for Lepheton/Desentol. The crucial question whether ethylmorphine and codeine could in any way increase the risk of narcotic abuse later in life cannot be answered.

Svar: The extempore mixture Desentol/Lepheton, which was introduced during the 1960s, contains diphenhydramine (an antihistamine) 3.72 mg/ml and ethylmorphine chloride 0.82 mg/ml + ephedrine chloride 2.05 mg/ml. The mixture and related mixtures have previously been subject to two Drugline questions focusing on addiction/abuse during the years 1982-1992 (1,2). The half-life of ethylmorphine is 2-3 hours. According to the Swedish PDR (FASS), Lepheton is not recommended to children <2 years and the dosing for children 2 years of age is 2.5 ml x 3 (6 mg ethylmorphine/day). Three to five years, 5 ml x3 and 6-10 years, 7.5 ml x3 (18 mg/day) (3). However, in a department of ear, nose and throat the recommendation is: three months to one year, 2.5 ml x3, one to three years, 5 ml x3, 3-10 years, 10 ml x3, > 10 years, 15 ml x3 (37 mg/day) (4). It is important to observe that there is no documentation demonstrating any effect of the treatment with the mixture in children with laryngitis or pseudo croup. Ethylmorphine is also available in the mixture Cocillana-etyfin, which contains ethylmorphine hydrochloride 2.5 mg/ml + spir fortis 103 mg/ml + senegae 7.8 mg/ml, and the mixture Cosylan, which contains ethylmorphine 1.7 mg/ml + spir fortis 0.046 ml/ml. Recommended dose of Cocillana-etyfin: children 2-5 years 2.5 ml x3-4 (15-20 mg ethylmorphine/day), 6-12 years 5 ml x3-4 (37.5-50 mg/day), adults 5-10 ml x3-4 (37.5-100 mg/day).

Ethylmorphine has been reported to cause psychiatric adverse drug reactions (ADRs). During the period 1973-1995 SADRAC (Swedish Adverse Drug Reactions Advisory Committee) has received seven psychiatric reports - the last one in 1994 - associated with the treatment of ethylmorphine describing 11 reactions (7 for Lepheton and 4 for Cocillana-etyfin): hallucination (n=4), "psychiatric influence" (n=2), agitation, nightmares, confusion, depression and loss of memory (one of each), but no report describing addiction or abuse. With respect to Desentol, there are two psychiatric reports - hallucination and "psychiatric influence" - but both of these patients were concomitantly treated with Lepheton (5).

The risk of developing addiction or abuse due to the content of ethylmorphine - as with codeine - has been discussed earlier (1,2). No documented reports concerning addiction or abuse were found. However, it is important to observe that addiction and abuse are generally not regarded as ADRs and are rarely reported as side effects to SADRAC or WHO (6). A thorough literature search has been performed covering recent pharmacologic handbooks and the databases Medline and Swedis. Ethylmorphine has effects that are the same as codeine and is N-demethylated like codeine in a minor fraction to morphine. In a Norwegian study of four subjects - two women, 52 and 55 kg and two men, 75 and 85 kg - were given a single dose of 75 mg ethylmorphine (45 ml Cosylan). Blood samples were analyzed one, three, six, 12 and 24 hours after intake. Detectable concentrations of morphine, normorphine, ethylmorphine, M3G and M6G were found in all of the four subjects. Morphine could be detected up to six hours after intake with a peak for all persons one hour after the oral administration. The concentration of morphine in serum was not high (30 nmol/l, total maximal sum of morphine and metabolites in serum = 610 nmol/l), one fifth to one tenth of the Cmax seen after 10 mg morphine intravenously, or corresponding to Cmax after 10 mg orally (7). The corresponding figures with respect to 50 mg codein for maximal free morphine, totaled sum of free morphine, and metabolites in serum in extensive hydroxylators were 20 and 295 nmol/l respectively. Recovered doses of codeine as free and conjugated morphine were six per cent in extensive and 0.4 per cent in poor hydroxylators (8). Thus, a significant amount of morphine is formed from both ethylmorphine and codeine. Ethylmorphine might therefore be expected to have the same potential for addiction and abuse as the structural analogue codeine.

In studies focusing on prescription forgeries, ethylmorphine, mainly as Cocillana-etyfin, is a consistent finding in Sweden (6). In a top-10-list, Cocillana-etyfin was the 6th (n=125) most common drug in 1982-1986. Interestingly no reports of Lepheton/Desentol have been found in this surveillance. If this is related to the considerably lower sales (about one in 8) as compared to Cocillana-etyfin, or the use in lower doses of ethylmorphine, or the antihistaminic compound in Desentol prohibiting the use of higher doses of the Lepheton/Desentol combination, is not clear. In relation to the prescribing, however, codeine is more frequently found among prescription forgeries than ethylmorphine (6). 1 Drugline nr 03162 (year 1982)

2 Drugline nr 07710 (year 1990)
3 FASS 1995
4 Drugline nr 09607 (year 1992)
5 Drugline nr 08445 (year 1991)

6 Bergman U, Dahl-Puustinen M-L: Use of prescriptions forgeries in a drug abuse surveillance network. Eur J Clin Pharmacol 1989; 36: 621-623 7 Ripel Å, Christophersen AS, Björnboe A, Mörland J: Morphine formation after intake of ethylmorphine. Pharmacol Toxicol 1992; 70: 28-29 8 Yue QY, Hasselström J, Svensson JO, Säwe J: Pharmacokinetics of codeine and its metabolites in Caucasian health volunteer: comparisons between extensive and poor hydroxylators of debrisoquine. Br J Clin Pharmacol 1991; 31: 635-642