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Is there an infectious origin of narcolepsy?
424
Deaths of heroin addicts starting methadone maintenance
on
SIR,-Dr Drummer and colleagues (Jan 13, p 108) report that a substantial number of heroin addicts died within days of entering a methadone maintenance programme. It is important to identify the cause of these deaths. The deaths were unlikely to be due solely to the opioid effect of methadone given orally in opioid-tolerant subjects. Methadone is closely related to dextropropoxyphene, which despite its low opioid potency may cause fatal poisoning when taken in overdose.1,2 Death in such cases can be attributed to the membrane stabilising activity of dextropropoxyphene.3-5We have used the reduction in the motility of Tetrahymena pyriformis as an indicator of membrane stabilising activity, and have confirmed the work of Seernarf who showed that methadone can block nerve conduction because of its membrane stabilising activity. The drug concentrations needed to reduce swimming speed to 50% of control (EC5o) for morphine, diamorphine, dextropropoxyphene, and methadone were 23-0, 7-0, 0-45, and 0 17 mmol/1, respectively. We therefore suggest that the reported deaths were mainly due to accumulation of methadone over several days resulting in death from complications such as cardiac arrhythmias or cardiovascular collapse.3,4Accumulation is likely to have occurred because of the long elimination half-life of methadone (mean 55 h after a single dose and 22-25 h during chronic dosage8,9). In some of these cases the membrane stabilising activity of dextropropoxyphene or alcohol may have interacted with that of methadone, potentiating its toxicity, while, as Drummer et al point out, hepatic impairment could have contributed to a lethal outcome by causing high systemic concentrations of methadone. Poisons Unit,
Guy’s Hospital,
CHANGHAO WU
London SE1 9RT, UK
JOHN A. HENRY
1. Finkle BS.
Self-poisoning with dextropropoxyphene and dextropropoxyphene compounds: the USA experience. Hum Toxicol 1984; 3: 115S-134S. 2. Anon. Death with dextropropoxyphene. London: Committee on Safety of Medicines. Curr Probl 1985; no. 14 (Feb). 3. Henry JA, Cassidy SL. Membrane stabilising activity: a major cause of fatal poisoning. Lancet 1986; i: 1414-17. 4. Amsterdam EA, Rendig SV, Henderson GL, Mason DT. Depression of myocardial contractile function by propoxyphene and norpropoxyphene. J Cardiovasc Pharmacol 1981; 3: 129-38. 5. Holland DR, Steinberg MI. Electrophysiologic properties of propoxyphene and norpropoxyphene in canine conducting tissue in vitro and in vivo. Toxicol Appl Pharmacol 1979, 47: 123-33. 6. Cassidy SL, Henry JA, Roberts AM. Determination of membrane-stabilising potency of drugs by video analysis of protozoan motility. Toxic in Vitro 1989; 3: 18187. 7. Seeman P. The membrane actions of anesthetics and tranquilizers. Pharmacol Rev 1972; 24: 583655. 8. Inturrisi CE, Verebely K. The levels of methadone in the plasma in methadone maintenance. Clin Pharmacol Ther 1972; 13: 633-37. 9. Verebely K, Volavka J, Mulé S, Resnick R. Methadone in man: pharmacokinetic and excretion studies in acute and chronic treatment. Clin Pharmacol Ther 1975; 18: 180-90.
Is there
an
infectious
origin of narcolepsy?
SiR,—The striking association between narcolepsy and HLAhas raised high expectations for an explanation of the aetiology and pathogenesis of the disease.’ Professor Guilleminault and colleagues (Dec 9, p 1376) have, however, pointed out that the HLA-DR2 haplotype is neither sufficient nor necessary to the development of narcolepsy. Besides genetic factors, infectious agents have been discussed as possible causes. Raised levels of streptococcal antibodies have been reported in narcolepsy and in idiopathic hypersomnia.23 Since these findings could be important in the pathogenesis of these diseases, we have investigated a cohort of patients with narcolepsy/cataplexy (group A, n = 100), classified according to Matsuki et al,patients with other types ofhypersomnia (group B, n 57); and healthy controls (group C, n = 107). HLA DR2/DQwlwas present in all but 2 (98%) of the 100 narcolepsy patients, and in 17/55 (31%) with hypersomnia. In all individualls, antibodies to streptolysin 0 (ASO) and streptodornase B (ADB) were measured with commercially available reagents (Fujizoki, Tokyo, and Behring, Marburg,
DR2/DQwl
ASO values (lUjml) in patients with narcolepsy (A, n=100), hypersomnia (B, n=57) and normal controls (C, n=107). -
or
=median values.
above 200 IU/ml were seen in 48% of group A and in 30% of group B, but also in 36% of healthy controls (figure). 10% of group A, 4% of group B, and 19% of group C had raised ADB values (over 200 IU/ml). The respective figures above 300 IU were 23%,18%, and 16% for ASO, and9%,2%,and 11 % for ADB. Median vlaues did not differ significantly in the three groups. No correlation was found between streptococcal antibodies and the presence of HLA-DR2 in the patient groups. Hence, in accordance with the findings of Billiard et al2 and Montplaisir et al3 raised ASO and ADB values were seen in patients with narcolepsy and in those with hypersomnia. Compared with the control group ASO values were slightly but not significantly increased in narcoleptics whereas ADB values were lower in both groups of patients. Thus we cannot confirm that streptococcal infections may be implicated in the aetiology and pathogenesis of narcolepsy or hypersomnia, but do not exclude a role for infectious agents other than streptococci in narcolepsy.
respectively). ASO values
Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, D-6300 Giessen, West Germany
G. MUELLER-ECKHARDT
Neurological Hospital and Sleep Disorder Unit, Schwalmstadt
K. MEIER-EWART
Institute for Medical Microbiology, Justus Liebig University, Giessen
H. G. SCHIEFER
=
1. Honda Y, Juji T, eds. HLA and narcolepsy, Berlin. Springer Verlag, 1988. 2. Billiard M, Laaberki MF, Reygrobellet C, et al. Elevated antibodies to streptococcal antigens in narcoleptic subjects Sleep Res 1989; 18: 201 3. Montplaisir J, Poirier G, Lapierre O, Montplaisir S. Streptococcal antibodies in
narcolepsy and idiopathic hypersomnia. Sleep Res 1989; 18: 271. K, Honda Y, Juji T Diagnostic criteria for narcoplepsy frequencies. Tissue Antigens 1987, 30: 155-60.
4 Matsuki
and HLA-DR2
Deaths of heroin addicts starting methadone maintenance
on
SIR,-Dr Drummer and colleagues (Jan 13, p 108) report that a substantial number of heroin addicts died within days of entering a methadone maintenance programme. It is important to identify the cause of these deaths. The deaths were unlikely to be due solely to the opioid effect of methadone given orally in opioid-tolerant subjects. Methadone is closely related to dextropropoxyphene, which despite its low opioid potency may cause fatal poisoning when taken in overdose.1,2 Death in such cases can be attributed to the membrane stabilising activity of dextropropoxyphene.3-5We have used the reduction in the motility of Tetrahymena pyriformis as an indicator of membrane stabilising activity, and have confirmed the work of Seernarf who showed that methadone can block nerve conduction because of its membrane stabilising activity. The drug concentrations needed to reduce swimming speed to 50% of control (EC5o) for morphine, diamorphine, dextropropoxyphene, and methadone were 23-0, 7-0, 0-45, and 0 17 mmol/1, respectively. We therefore suggest that the reported deaths were mainly due to accumulation of methadone over several days resulting in death from complications such as cardiac arrhythmias or cardiovascular collapse.3,4Accumulation is likely to have occurred because of the long elimination half-life of methadone (mean 55 h after a single dose and 22-25 h during chronic dosage8,9). In some of these cases the membrane stabilising activity of dextropropoxyphene or alcohol may have interacted with that of methadone, potentiating its toxicity, while, as Drummer et al point out, hepatic impairment could have contributed to a lethal outcome by causing high systemic concentrations of methadone. Poisons Unit,
Guy’s Hospital,
CHANGHAO WU
London SE1 9RT, UK
JOHN A. HENRY
1. Finkle BS.
Self-poisoning with dextropropoxyphene and dextropropoxyphene compounds: the USA experience. Hum Toxicol 1984; 3: 115S-134S. 2. Anon. Death with dextropropoxyphene. London: Committee on Safety of Medicines. Curr Probl 1985; no. 14 (Feb). 3. Henry JA, Cassidy SL. Membrane stabilising activity: a major cause of fatal poisoning. Lancet 1986; i: 1414-17. 4. Amsterdam EA, Rendig SV, Henderson GL, Mason DT. Depression of myocardial contractile function by propoxyphene and norpropoxyphene. J Cardiovasc Pharmacol 1981; 3: 129-38. 5. Holland DR, Steinberg MI. Electrophysiologic properties of propoxyphene and norpropoxyphene in canine conducting tissue in vitro and in vivo. Toxicol Appl Pharmacol 1979, 47: 123-33. 6. Cassidy SL, Henry JA, Roberts AM. Determination of membrane-stabilising potency of drugs by video analysis of protozoan motility. Toxic in Vitro 1989; 3: 18187. 7. Seeman P. The membrane actions of anesthetics and tranquilizers. Pharmacol Rev 1972; 24: 583655. 8. Inturrisi CE, Verebely K. The levels of methadone in the plasma in methadone maintenance. Clin Pharmacol Ther 1972; 13: 633-37. 9. Verebely K, Volavka J, Mulé S, Resnick R. Methadone in man: pharmacokinetic and excretion studies in acute and chronic treatment. Clin Pharmacol Ther 1975; 18: 180-90.
Is there
an
infectious
origin of narcolepsy?
SiR,—The striking association between narcolepsy and HLAhas raised high expectations for an explanation of the aetiology and pathogenesis of the disease.’ Professor Guilleminault and colleagues (Dec 9, p 1376) have, however, pointed out that the HLA-DR2 haplotype is neither sufficient nor necessary to the development of narcolepsy. Besides genetic factors, infectious agents have been discussed as possible causes. Raised levels of streptococcal antibodies have been reported in narcolepsy and in idiopathic hypersomnia.23 Since these findings could be important in the pathogenesis of these diseases, we have investigated a cohort of patients with narcolepsy/cataplexy (group A, n = 100), classified according to Matsuki et al,patients with other types ofhypersomnia (group B, n 57); and healthy controls (group C, n = 107). HLA DR2/DQwlwas present in all but 2 (98%) of the 100 narcolepsy patients, and in 17/55 (31%) with hypersomnia. In all individualls, antibodies to streptolysin 0 (ASO) and streptodornase B (ADB) were measured with commercially available reagents (Fujizoki, Tokyo, and Behring, Marburg,
DR2/DQwl
ASO values (lUjml) in patients with narcolepsy (A, n=100), hypersomnia (B, n=57) and normal controls (C, n=107). -
or
=median values.
above 200 IU/ml were seen in 48% of group A and in 30% of group B, but also in 36% of healthy controls (figure). 10% of group A, 4% of group B, and 19% of group C had raised ADB values (over 200 IU/ml). The respective figures above 300 IU were 23%,18%, and 16% for ASO, and9%,2%,and 11 % for ADB. Median vlaues did not differ significantly in the three groups. No correlation was found between streptococcal antibodies and the presence of HLA-DR2 in the patient groups. Hence, in accordance with the findings of Billiard et al2 and Montplaisir et al3 raised ASO and ADB values were seen in patients with narcolepsy and in those with hypersomnia. Compared with the control group ASO values were slightly but not significantly increased in narcoleptics whereas ADB values were lower in both groups of patients. Thus we cannot confirm that streptococcal infections may be implicated in the aetiology and pathogenesis of narcolepsy or hypersomnia, but do not exclude a role for infectious agents other than streptococci in narcolepsy.
respectively). ASO values
Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, D-6300 Giessen, West Germany
G. MUELLER-ECKHARDT
Neurological Hospital and Sleep Disorder Unit, Schwalmstadt
K. MEIER-EWART
Institute for Medical Microbiology, Justus Liebig University, Giessen
H. G. SCHIEFER
=
1. Honda Y, Juji T, eds. HLA and narcolepsy, Berlin. Springer Verlag, 1988. 2. Billiard M, Laaberki MF, Reygrobellet C, et al. Elevated antibodies to streptococcal antigens in narcoleptic subjects Sleep Res 1989; 18: 201 3. Montplaisir J, Poirier G, Lapierre O, Montplaisir S. Streptococcal antibodies in
narcolepsy and idiopathic hypersomnia. Sleep Res 1989; 18: 271. K, Honda Y, Juji T Diagnostic criteria for narcoplepsy frequencies. Tissue Antigens 1987, 30: 155-60.
4 Matsuki
and HLA-DR2