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EDITORIALS

Zopiclone: another carriage on the tranquilliser train The sedative-hypnotics-an unlovely appellation for a group of drugs-are having a bad time. These agents enjoyed an unprecedented boom in the 1960s and 1970s, when they were commonly prescribed for disorders that are now perceived to be outside the domain of psychopharmacology. Subsequently there was widespread concern about the risk of dependence, even in prescribed dosage. Despite this poor image, the pharmaceutical industry, far from abandoning this class of drugs, has been inspired to synthesise new compounds with the same efficacy but fewer risks. Zopiclone, a cyclopyrrolone, is a product of this enterprise. This agent is unusual in that it differs chemically from benzodiazepines and barbiturates but has the same pharmacological actions-a sedativehypnotic profile together with anticonvulsant, muscle- relaxant, and antiaggressive properties. It is also unusual in that although it is not a benzodiazepine, it nonetheless binds with benzodiazepine receptors in the central nervous system.1 Absorption is rapid after oral administration (plasma concentrations peak within an hour of ingestion2) and elimination half-life is short (< 4 hours)--an ideal pharmacokinetic combination for a drug that is mainly used to induce sleep. With these credentials, zopiclone should promote the rapid onset of sleep with few or no residual effects on waking. In practice, these predicted advantages have been partly confirmed. There are fewer residual effects than with benzodiazepines of long half-life such as nitrazepam, but no difference by comparison with compounds of shorter half-life such as triazolam.3The hangover response is dose-related: 5 mg of the drug causes virtually no complications whereas 10 mg has a pronounced effect.4Interaction with alcohol is less than with most benzodiazepines5 and memory disturbance is milder.6 Clinical studies have established that 7-5 mg is the optimum dose for most patients, young and old.7-9 In this dose the drug is as effective as other commonly used hypnotics such as nitrazepam and temazepam.10-12 Zopiclone has fewer hangover effects than flurazepam.13There are no studies in which other

hypnotic drugs have been shown to be better than zopiclone in any major respect.14 These issues pale into insignificance by comparison with the risk of dependence. Patients and their doctors are often prepared to put up with many adverse effects if they can be reassured that continued administration does not lead to pharmacological dependence. Unfortunately this reassurance cannot be given with zopiclone-even in normal volunteers there is rebound insomnia (a form of withdrawal symptom) when the drug is withdrawn after three weeks of regular treatment.1s There have been no equivalent studies in patients with insomnia. Similar rebound responses have been observed with discontinuation of

zopiclone after only fourteen days.16 Zopiclone can induce physical dependence in monkeys.17 Apart from two uncontrolled studies in an unusual population of former alcoholics,18,19 the only study of dependence potential of zopiclone in psychiatric patients with insomnia

was an

open

one

in which the absence of

relied entirely on a physician’s assessments.2o There are established methods for evaluating the dependence potential of hypnotic drugs, so it is surprising that the manufacturers have not sponsored adequate studies to assess this aspect. Their claims that zopiclone is not associated with the development of tolerance in long-term use, that there is no need to taper the dose on withdrawal, and that "rebound insomnia is rare and minimal" are inaccurate to the point of being irresponsible. Further assessment of the risks of dependence is essential, especially since zopiclone, like almost all other sedative hypnotics, acts on the inhibitory neurotransmitter gamma aminobutyric acid (GABA) and it is likely that a common GABA-dependent mechanism lies behind withdrawal symptoms with all these drugs.22 Zopiclone may be a useful alternative to other hypnotic drugs and has fewer acute adverse effects than many existing compounds. The absence of adequate data on long-term use, especially the risk of pharmacological dependence, is disturbing and unsatisfactory. Before zopiclone can be regarded as a satisfactory substitute for the most commonly used hypnotic benzodiazepines its long-term risks need to be assessed more thoroughly. Even now far too many people board the tranquilliser train and too few alight when it makes its infrequent stops.

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JC, Boireau A, Garrett C, Julou L. In vitro and in vivo inhibition by zopiclone of benzodiazepine binding to rodent brain receptors. Life Sci 1979; 24: 2417-20. 2. Gaillot J, Heusse D, Houghton GW, Aurele JM, Dreyfus JF. Pharmacokinetics and metabolism of zopiclone. Pharmacology 1983; 27 1. Blanchard

(suppl 2): 76-91. C, Subhan Z, Hindmarch I. Residual effects of zopiclone and benzodiazepine hypnotics on psychomotor performance related to car driving. Drugs Exper Clin Res 1985; 9: 823-29. 4. Lader M, Denny SC. A double-blind study to establish the residual effects of zopiclone in performance in healthy volunteers. Pharmacology 1983; 27 (suppl): 98-108. 5. Seppala T, Nuotto E, Dreyfus JF. Drug-alcohol interaction on driving skills. Pharmacology 1983; 27 (suppl 2): 127-35. 6. Fossen A, Godlibsen OB, Loyning Y, Dreyfus JF. Effect of hypnotics on memory. Pharmacology 1983; 27 (suppl 2): 116-26. 7. Giercksky K-E, Wickstrom E. A dose-response study in situational insomnia with zopiclone, a new tranquilizer. Clin Ther 1980; 3: 21-27. 8. Dehlin O, Rundgren A, Borjesson L, et al. Zopiclone to geriatric patients: a parallel double-blind dose-response clinical trial of zopiclone as a hypnotic to geriatric patients. Pharmacology 1983; 27 (suppl 2): 173-78. 9. Momose T. Effectiveness of zopiclone as a preoperative hypnotic. Pharmacology 1983; 27 (suppl 2): 196-204. 10. Wickstrom E, Giercksky K-E. Comparative study of zopiclone, a novel hypnotic, and three benzodiazepines. Eur J Clin Pharmacol 1980; 17: 3. Harrison

93-99. 11. Pull CB, Dreyfus JF, Brun JP. Comparison of nitrazepam and zopiclone in psychiatric patients. Pharmacology 1983; 27 (suppl 2): 205-09. 12. Wheatley D. Zopiclone: a non-benzodiazepine hypnotic: controlled comparison to temazepam in insomnia. Br J Psychiatry 1985; 146: 312-14. 13. Quadens OP, Hoffman G, Buytaert G. Effects of zopiclone as compared to flurazepam in women over 40 years of age. Pharmacology 1983; 27 (suppl 2): 146-55. 14. Goa KL, Heel RC. Zopiclone: a review of its pharmacodynamic and

pharmacokinetic properties and therapeutic efficacy as an hypnotic. Drugs 1986; 32: 48-65. 15. Dorian P, Sellers EM, Kaplan H, Hamilton C. Evaluation of zopiclone physical dependence liability in normal volunteers. Pharmacology 1983; 27 (suppl 2): 228-34. 16. Lader M, Frcka G. Subjective effects during and on discontinuation of zopiclone and temazepam in normal subjects. Pharmacopsychiatry 1987; 20: 67-71. Yanagita T. Dependence potential of zopiclone studied in monkeys. Pharmacology 1983; 27 (suppl 2): 216-27. 18. Bechelli LP, Navas F, Pierangelo SA. Comparison of the reinforcing properties of zopiclone and triazolam in former alcoholics. Pharmacology 1983; 27 (suppl 2): 235-41. 19. Boissl K, Dreyfus JF, Delmotte M. Studies on the dependence-inducing potential of zopiclone and triazolam. Pharmacology 1983; 27 (suppl 2): 17.

242-47. 20. Kazamatsuri H. A clinical study on dependence liability of zopiclone. IV International Congress of Sleep Research (APSS), Bologna, July 18-22, 1983. 21. Skerritt JH, MacDonald RL. Benzodiazepine receptor ligand actions on GABA responses: benzodiazepines, CL 218872, zopiclone. Eur J Pharmacol 1984; 101: 127-34. 22. Cowen PJ, Nutt DJ. Abstinence symptoms after withdrawal of tranquillising drugs: is there a common neurochemical mechanism? Lancet 1982; ii: 360-62.

Fish oils and diabetic microvascular disease The low incidence of coronary heart disease and thrombosis in Greenland Eskimos has focused attention on their traditional diet-mostly seals, whales, and fish.12 Although these marine creatures have a high cholesterol and fat content, their fat is unique in that it contains large quantities of longchain, highly polyunsaturated omega-3 fatty-acids. In the Eskimo diet these fatty-acids consist largely of eicosapentaenoic acid, (20:5 omega-3) and docosahexaenoic acid (22:6 omega-3) whereas linoleic acid (18:2 omega-6) is the predominant

in the UK and other developed countries.3J Consequently, the possible protective effects of dietary omega-3 fatty acids against atherosclerosis have been studied by examining their actions on prostaglandin metabolism and platelet function.4 Omega-3 fatty-acids inhibit synthesis of arachidonic acid and its incorporation into phospholipids, decrease platelet production of thromboxane Az (a potent vasoconstrictor and inducer of platelet aggregation), and increase production of thromboxane A3 (which largely lacks biological activity) and prostaglandin 13 (an effective antiaggregating substance. Other beneficial actions include decreased plasma lipoprotein concentrations, increased erythrocyte deformability, decreased blood viscosity and blood pressure, and increased thrombolytic activity. 5-7 The finding that death due to heart disease was inversely correlated with fish consumption in a 20-year prospective survey of Dutch men has strengthened the suspicion that these

polyunsaturate western

laboratory findings are clinically important.8 If a single dietary change were to alter many of the mechanisms involved in atherogenesis, that would have considerable implications. This notion was quickly extrapolated to the prevention or delay of diabetic complications, many of which are attributable to microvascular disease.9 New evidence lends support to such a hypothesis in diabetes. Jensen and colleagues using a double-blind crossover design, studied the effects on endothelial permeability, blood and plasma pressure, lipids of 8 weeks’ supplementation of a diabetic diet with cod-liver oil (rich in omega-3 fatty acids) compared with 8 weeks’ supplementation with olive oil in eighteen insulintreated diabetic patients with albuminuria of more than 30 mg/day. With cod-liver oil supplementation there was a significant fall in mean transcapillary escape rate of albumin (compared with the baseline rate) and a reduction in mean blood pressure; no changes occurred with olive oil. The effects of cod-liver oil on transcapillary albumin escape did not correlate with the fall in blood pressure, and glomerular filtration rate, degree of albuminuria, insulin requirements, glycosylated haemoglobin, and blood glucose levels were unchanged during either period of study. However, cod-liver oil supplementation was associated with a significant increase in plasma high-density lipoprotein cholesterol and a significant decrease in the concentration of very-low-density lipoprotein cholesterol and triglyceride; the level of low-density lipoprotein (LDL) cholesterol was unchanged. These researchers conclude that cod-liver oil may have a direct action on vascular permeability that is independent of its beneficial effect on blood pressure. They further suggest that this action results from a decreased transfer of lipoproteins into the vascular wall. On completion of the study all the changes returned to baseline values.

Zopiclone: another carriage on the tranquilliser train.

507 EDITORIALS Zopiclone: another carriage on the tranquilliser train The sedative-hypnotics-an unlovely appellation for a group of drugs-are having...
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