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Home , Chloral betaine, Chloral hydrate, Ethchlorvynol, Ethinamate, Glutethimide, Hexobarbital

Postgrad Med J: first published as 10.1136/pgmj.46.535.314 on 1 May 1970. Downloaded from

Pcstgraduate Medical Journal (May 1970) 46, 314-317.

CURRENT SURVEY RUSSELL R. MILLER* DIRK V. DEYOUNG Pharm. D. M.D. Director, Communications Study, Assistant Medical Director, University of Chicago Continental Assurance Company, Chicago JAMES PAXINOS B.S (Pharm.) Assistant Director for Clinical Services, Department ofPharmacy, University of Chicago Hospitals and Clinics THIS review will treat the more commonly prescribed Human hypnotic agents and their -inducing properties. In the past, have been divided into Hypnotic agents that are seldom used (), and non-barbiturates. This classification, drugs that are not singularly soporific but may be based on chemical structure, has little contemporary used either alone or as adjuncts in inducing sleep [e.g. clinical significance since compounds in each group (Equanil, Miltown), have essentially the same qualitative pharmacologic (Librium) and (Valium)] and drugs that properties. Naturally, there are quantitative differ- copyright. have little soporific effect [, ences in onset and duration of action. and methylparafynol (Oblivon, Dormison) (Lasagna, 1954)] will not be discussed. Onset of action Indications Onset is generally rapid with liquid preparations is an extremely common complaint with such as syrup of (Noctec, Somnos), which are confronted. of (Nembutal) and elixir of physicians perpetually Many not as patients have chronic insomnia. In other patients (Seconal). However, liquids are http://pmj.bmj.com/ insomnia is acute but intermittent. Situations in convenient as capsules and since a capsule of sodium which acute insomnia can occur are during or after secobarbital, sodium pentobarbital or chloral plane or train travel, hospitalization in strange and hydrate usually causes drowsiness within about often noisy surroundings or simply having to sleep 30 min, these three compounds give quite satis- in environments that are different or unfamiliar. factory hypnotic results in most patients in capsular There appear to be three basic types of insomnia. form. In one a has in Onset of action is also related to the intrinsic

type person difficulty only falling on September 29, 2021 by guest. Protected asleep. In a second type, individuals achieve sleep pharmacodynamic nature of the particular hypnotic easily, but have trouble staying asleep. In a third agent. An 'ultra-short acting' such as type, both falling and remaining asleep are physiolo- (Sombulex, Cyclonal) probably has the gically arduous. most prompt onset of action while a 'long-acting' Let us emphasize that chronic insomnia is best barbiturate such as may require treated by attacking the underlying cause, ifapparent. several hours to produce maximal effect (Sharpless, If not evident, the cause (or causes) should be care- 1965a). The reasons for the variability of pharmaco- fully sought by the physician. Lack of sleep associ- dynamic (and thus biochemical) behaviour among ated with somatic pain or with a psychiatric problem, the various hypnotic agents is beyond the scope of for example, may be treated best by prescribing this review (see Shideman, 1961; Sharpless, 1965a, b). , or tranquilizers and/or psychotherapy. * Postdoctoral Fellow, National Library of Medicine, Duration of action U.S. Department of Health Education and Welfare. Duration of effect is Requests for reprints should be addressed to Dr Miller, hypnotic largely dependent Box 96, University ofChicago Hospitals and Clinics, Chicago, on two factors, the intrinsic pharmacodynamic Illinois 60637, U.S.A. characteristics of the drug and the dosage used. Postgrad Med J: first published as 10.1136/pgmj.46.535.314 on 1 May 1970. Downloaded from Current survey 315 Both of these factors should be considered when in some persons following administration of a selecting a hypnotic agent. If a patient requires a barbiturate. However, such an effect appears to be drug with a rapid but brief hypnotic effect, perhaps a rather rare phenomenon. It is said to occur less one of the 'ultra-short acting' barbiturates, ordinarily frequently with than with the barbi- used as intravenous anaesthetics, may be useful. turates. Similarly, the alleged capacity of hypnotics Bush, Berry & Hume (1966) studied oral sodium to produce in patients with pain is rarely hexobarbital (Sombulex, Cyclonal), sodium metho- evident clinically. There seems to be little reason to hexital and sodiumthiopental(nooral preparationsof avoid prescribing hypnotics for patients in pain who the latter two drugs are commercially available) and also have insomnia. Of course, appropriate anal- their results indicate that thesethreedrugs maybe use- gesics should also be prescribed. ful in treatment ofpatients who have difficulty in fall- Gastric irritation is said to be a problem with ingasleep but who, once asleep, do not easily awaken. chloral hydrate but modem dosage forms (capsules, If a patient needs a hypnotic for both inducing syrup) appear to have largely eliminated this side and maintaining sleep, one of the longer acting effect. (Beta-Chlor), a relative of hypnotics in an appropriate dose is indicated. In most chloral hydrate, is said to cause less gastric irrita- patients a 1-0 g dose of chloral hydrate, for example, tion but there is no objective evidence to support will provide adequate sleep but doses of 1-5 g or this claim. 2-0 g may be necessary in some patients. , or residual after waking, is a The older designations of hypnotics as being problem with many of the hypnotics although in 'short-acting', 'medium-acting', 'long-acting', are some patients, e.g. certain hospitalized persons, this clinically and pharmacodynamically meaningless. effect may not be undesirable. The only hypnotics Such labels have no scientific meaning because there not having this side-effect are the 'ultra-short acting' are no valid human data to support them. No con- barbiturate hexobarbital (Sombulex, Cyclonal) and, trolled human studies have been done, showing that for most persons, the non-barbiturate compound specified doses of several hypnotics have different (Valmid). Other barbiturates, although durations of action. Thus, commercial preparations called 'short-acting', are all known to have this side combining a 'short-acting' barbiturate with a effect. The non-barbiturates (Noludar), copyright. 'moderately long-acting' barbiturate (as in ) (Arvynol, Serenesil, Placidyl), meth- are not pharmacologically rational. By increasing or aqualone (Quaalude, Melsed, Melsedin, Paxidorm) decreasing the dosage of such a drug as secobar- and (Doriden), have this side-effect in bital, for instance, the physician can usually obtain some persons, also; there are no well-designed any effect from relatively brief and shallow sedation studies demonstrating their lack of hangover. With to a prolonged and rather profound -like state. all hypnotics hangover can be minimized by titrating each patient's insomnia against different doses of a Dose variability particular drug. http://pmj.bmj.com/ The dose required for a satisfactory hypnotic Various allergic reactions have been noted with effect varies greatly among individual patients. Such the use of all hypnotics. The symptoms usually are variability can be explained in part by individual skin rash, pruritus, and . differences in the of a drug or in the More serious adverse effects have been en- response of individual central nervous systems to a countered. The Registry on Adverse Reactions of the given concentration of the drug. But the necessary American Medical Association has received a num- dose is also related to other differences in a patient's ber of reports of reactions to hypnotic drugs (see condition, such as the degree of or depres- Table 1). A direct causal relationship was not de- on September 29, 2021 by guest. Protected sion present, and to the environment in which he finitely established because these reports come from a must sleep. Thus, the use of a 'standard' dose under variety of sources not subject to follow-up investiga- all circumstances is not rational (or efficacious) tion. The reports may represent only a fraction of therapeutics. A patient should first receive a rela- the reactions which do occur. tively low dose of a hypnotic (e.g. 0-5 g of chloral In addition to the unpublished Registry reports, hydrate or 50 mg of secobarbital or pentobarbital). adverse reactions have also been reported in the If is not achieved, the dose may be doubled literature. Two cases of peripheral neuropathy due or even tripled. It is generally better therapeutics to to glutethimide werereportedbyBartholomew (1961). adjust the dose of a specific drug with which the Cases of thrombocytopenia following the use of physician is familiar to the individual requirements ethinamate have been reported (Sharpless, 1965b). of the patient than to try other drugs. has been cited as a possible cause of aplastic anaemia (New Drugs, 1967). Side-effects Acute intoxication or poisoning with the hypnotics Paradoxical mental excitement reportedly occurs is common. It has been estimated that there are Postgrad Med J: first published as 10.1136/pgmj.46.535.314 on 1 May 1970. Downloaded from 316 Current survey TABLE 1. Reported associations with adverse reactions to hypnotic agents Drug Reaction No. of cases Glutethimide Urticaria 5 Exanthematic rash 17 Peripheral neuropathy, haematuria, weakness, slurred speech, 1 or 2 mental decline, thrombocytopenia, aplastic anaemia with pancytopenia, leukopenia, megaloblastic anaemia, agranulo- cytosis, allergic dermatitis Ethinamate Macular rash 1 Pentobarbital Leukopenia 3 Exanthematic rash 14 Jaundice 8 Dyspnea (cyanotic), thrombocytopenia, haemolytic anaemia, 1 or 2 psychoses, agitation, extrapyramidal reactions, seizures, urticaria Secobarbital Leukopenia 4 Extrapyramidal reactions 3 Urticaria 3 Exanthematic rash 16 Jaundice 4 Aplastic anaemia, thrombocytopenia, seizures, neuropathy, I or 2 confusional state, erythema multiforme Methyprylon Agranulocytosis 1 Ethchlorvynol Numbness of arms, seizures, aplastic anaemia with pancyto- 1 or 2 penia, leukopenia, itching and skin rash, abnormalities Chloral hydrate Urticaria 3 Exanthematic rash 7 Methaqualone Paresthesias, abdominal pain, dilated pupils 1

The above data are unpublished information from the Registry on Adverse Reactions of the copyright. Council on Drugs of the American Medical Association. 15,000 barbiturate poisonings in the To be truly addicted to a hypnotic agent, that is every year. The signs and symptoms of barbiturate physiologically dependent, one must take large doses poisoning are chiefly referred to the central nervous over a long period of time (Shideman, 1961). The and the cardiovascular systems. For appropriate large dose requirement distinguishes the hypnotics treatment of poisoning the reader is referred to other from the opiates. Thus, the use of therapeutic doses sources for detailed information (Arena, 1967; of a barbiturate for a period ofyears will not produce http://pmj.bmj.com/ Done, 1969; Gleason et al., 1969). ordinarily. Tolerance and dependence Interaction Tolerance to, and upon, Many agents are known to interact with hypnotics barbiturates and most non-barbiturates have been to produce a greater degree of physiological depres- noted. It is not known if tolerance to hypnotics in sion than would be obtained with a hypnotic alone. ordinary night-time doses is a significant problem. Among such interacting compounds are , Sharpless (1965a) feels that it is and he advises calcium salts, tranquilizers, (Myanesin, on September 29, 2021 by guest. Protected caution in prescribing hypnotics for patients with Tolserol), and thiamine (Shideman, 1961). The exact chronic insomnia. He believes that in such cases the physiological and biochemical nature and causes of possible consequences of persistent insomnia must these interactions are not understood. Patients who be weighed against the possible dangers of the regularly take hypnotics are often taking daytime regular and habitual use of hypnotic drugs. 'No or some of the other agents mentioned general rule can be given. The danger of severe above. Together, they probably can lead to physio- physical dependence and addiction is over- logic dependence. Lasagna (1967) cautions against emphasized; more pertinent is the question whether stopping all drugs suddenly and completely in such regular use of barbiturates and other hypnotics may patients since an abstinence syndrome (or 'with- not tend to obscure or exacerbate the condition drawal syndrome') can rapidly and fulminantly underlying the insomnia, thus establishing a vicious occur. The patient's drug intake should be slowly cycle in which the patient becomes psychologically reduced at the rate of 100 mgsecobarbital-equivalent/ dependent on or "habituated" to, the drug' (Sharp- day. less, 1965a). Hypnotics can also prolong the action of other Postgrad Med J: first published as 10.1136/pgmj.46.535.314 on 1 May 1970. Downloaded from

Current survey 317 non-hypnotic drugs. An example is methaqualone's Our choice of a hypnotic agent for patients who prolongation of the action of methscopolamine (New need a drug both to fall and stay asleep is either Drugs, 1967). chloral hydrate, pentobarbital or secobarbital. Of these three drugs, we have a slight preference for Contraindications chloral hydrate because it appears less likely to The barbiturates are completely contraindicated cause tolerance and dependence, and to have a lower in patients with a personal or familial history ofacute incidence of side-effects, particularly hangover. intermittent porphyria, because these drugs stimulate Secobarbital and pentobarbital seem to be indis- certain liver enzymes that can cause a precipitous tinguishable from each other in almost every pharma- and dangerous rise in the level of porphyrins. Several cologic or pharmacodynamic respect. When pre- of the barbiturates and chloral hydrate are known to scribing any of these three drugs, adequate dosage cross the placental barrier readily and are found in should be used. With chloral hydrate, 1-5 or 2-0 g foetal tissue. If hypnotics are considered for adminis- are often required. Owens & Marshall (1955) have tration to pregnant women, the possibility of risk of shown that the usual adult dose-1-0 g-may be foetal respiratory and central depres- inadequate for some persons. With secobarbital and sion must be carefully weighed against the expected pentobarbital, the usual dose is 100 mg; however, therapeutic benefits to the mother. All hypnotics 150 and 200 mg doses may be necessary in some should be administered with caution and initially in patients. reduced doses to patients with hepatic damage. The We do not recommend the newer non-barbiturates specific dangers ascribed to use of barbiturates and because little is known about their pharmacology and chloral hydrate in patients with hepatic disease seem toxicology. Some workers (and pharmaceutical to have been over-emphasized in the past. The manufacturers) have claimed that these drugs have traditional textbook caution concerning chloral a lower incidence of side-effects and a lower addic- hydrate's use in cardiac patients has not been tion potential than the barbiturates but such claims justified by actual clinical experience (Medical Letter, have not been conclusively verified. All of the non- 1960). barbiturate drugs are also more expensive than For more complete information on side-effects, chloral hydrate, secobarbital or pentobarbital, copyright. toxicity, interactions and contraindications, the particularly when any of these three drugs are pre- reader is referred to the product literature for the scribed by generic name. / drug in which he is interested. In general, much less is known about the pharmacology and toxicology of References / the non-barbiturates. ARENA, J.M. (Ed.) (1967) Advances in the treatment of poisoning. Modern Treatment, 4, No. 4. /Conclusions BARTHOLOMEW, A.A. (1961) Letter. British Medical Journal,

There are few data on which to base a 2, 1570. http://pmj.bmj.com/ objective BUSH, M.T., BERRY, G. & HUME, A. (1966) Ultra-short acting recommendation of drugs of choice for insomnia, barbiturates as oral hypnotic agents in man. Clinical because there is a remarkable paucity ofwell-designed Pharmacology and Therapy, 7, 373. comparative clinical studies showing that a given DONE, A.K. (1969) Pharmacologic principles in the treatment is more effective and has fewer side- of poisoning. Pharmacology for Physicians, 3, No. 7. hypnotic agent GLEASON, M.N., GOSSELIN, R.E., HODGE, H.C. & SMITH, effects than other hypnotic agents. With few excep- R.P. (1969) Clinical Toxicology of Commercial Products. tions, there is little difference between the ability of Williams & Wilkins, Baltimore. the various to the central LASAGNA, L. (1954) A comparison of hypnotic agents.

hypnotic agents depress on September 29, 2021 by guest. Protected nervous and the in their Journal of Pharmacology and Experimental Therapy, 11, 9. system, agents vary only LASAGNA, L. (1967) The pharmacological basis for the effect- onset and duration of action and the dosage required ive use ofhypnotics. Pharmacology for Physicians, 1, No. 2. to produce sleep. The incidence ofside-effects appears MEDICAL LETTER ON DRUGS AND THERAPEUTICS (1960) to be approximately equal for all hypnotic agents, British Medical Journal, 2, 104. clinical seems to indicate that New Drugs (1967) American Medical Association, Chicago. although experience OWENS, A.H. & MARSHALL, E.K. (1955) Further studies on the most troublesome side-effect, hangover, is lower metabolic fate of chloral hydrate and trichloroethanol. with chloral hydrate than with all of the other agents Bulletin of the John Hopkins Hospital, 96, 320. (not including the 'ultra-short acting' barbiturate SHARPLESS, S.K. (1965a) Hypnotics and sedatives. I. The hexobarbital). barbiturates. The Pharmacological Basis of Therapeutics (Ed. by L. S. Goodman and A. Gilman), 3rd ed., Macmillan, For patients who need a hypnotic only to help New York. them get to sleep, hexobarbital is a useful drug. SHARPLESS, S.K. (1965b) Hypnotics and sedatives. II. Miscel- Unfortunately, there has been little clinical experience laneous agents. The Pharmacological Basis of Therapeutics with this Ethinamate is another (Ed. by L. S. Goodman and A. Gilman), 3rd ed., Mac- drug. compound millan, New York. that acts rapidly (about 30 min) and only for a SHIDEMAN, F.S. (1961) Clinical pharmacology of hypnotics relatively short time (about 3-4 hr). and sedatives. Clinical Pharmacology and Therapy, 2, 313.