Hypnotics in the elderly

Bayer AJ, Bayer EM, Pathy MSJ, et al. A double-blind controlled study of chlormethiazole and triazolam as hypnotics in the elderly. Acta Psychiatr Scand 1986 73[Suppl 329] 104-111. 

Janicak PG, Ayd FA Jr. Sedative-hypnotics in the elderly population. In Nelson JC, ed. Geriathc psychopharmacoiogy. New York Marcel Dekker, 1997. 

Soldatos CR, Dikcos DG (1993) Efficacy and rebound of five hypnotics in the elderly a critical review. In L Vellas, JL Albarede (eds) Sleep disorders and insomnia in the elderly. Serdi, Paris, 209-221... 

ANTICONVULSANT, HYPNOTIC and SEDATIVE properties. It is used in some countries as a hypnotic in the elderly, for preoperative medication and in the managment of withdrawal from alcohol. 

Zolpidem, chemically unrelated to benzodiazepines or barbiturates, acts selectively at the y-aminobutyric acidA (GABAA)-receptor and has minimal anxiolytic and no muscle relaxant or anticonvulsant effects. It is comparable in effectiveness to benzodiazepine hypnotics, and it has little effect on sleep stages. Its duration is approximately 6 to 8 hours, and it is metabolized to inactive metabolites. Common side effects are drowsiness, amnesia, dizziness, headache, and GI complaints. Rebound effects when discontinued and tolerance with prolonged use are minimal, but theoretical concerns about abuse exist. It appears to have minimal effects on next-day psychomotor performance. The usual dose is 10 mg (5 mg in the elderly or those with liver impairment), which can be increased up to 20 mg nightly. Cases of psychotic reactions and sleep-eating have been reported. 

The consequences of benzodiazepine use in the elderly may be severe. Benzodiazepines are common in drug poisoning suicides in the elderly (Carlsten et al. 2003). This is especially apparent for the hypnotics flunitrazepam and nitrazepam. Benzodiazepines are also associated with an increased risk of motor vehicle crashes in the elderly (Hebert et al. 2007). 

Several histamine HI antagonists, e.g. hydroxyzine, promethazine, and mepyramine, display considerable sedative effects and they are sometimes used as sedative/hypnotics. Symptoms after withdrawal are usually less severe than those seen with the above mentioned hypnotics and sedatives. Especially in the elderly caution with these agents is warranted as. 

Nevertheless, the GABAergic properties of benzodiazepines remain their most important clinical application. Over the past 30 years, the most widely used benzodiazepine drug has been diazepam (1.6). It is an anxiolytic, sedative, and muscle relaxant the anxious, depressed person becomes more outgoing and relaxed. There have been many diazepam analogs. Oxazepam (4.177) and lorazepam (4.178) have similar effects. Temazepam (4.179), flunitrazepam (4.180), and flurazepam (4.181) are useful sedative-hypnotics. Clonazepam (4.182) is a clinically useful anticonvulsant. Brotizolam (4.183), a novel benzodiazepine analog, seems to be an effective sedative-hypnotic. Midazolam (4.184) is an imidazolo-benzodiazepine that is water soluble and thus easily injectable. It is a hypnotic sedative with marked amnestic (i.e., memory loss) properties and is used in dentistry, endoscopic procedures, and induction to anesthetics in the elderly and in... 

Table 12-7 lists considerations regarding sleep disruption in the elderly, and Table12-8 lists considerations regarding BZD hypnotics in this population.

Zopiclone is relatively well tolerated (137). The most common adverse reaction is taste alteration. A postmarketing analysis of 10,000 cases revealed that zopiclone has a relatively low incidence of side effects (about 8%) (138). Like BZDs, zopiclone has a dose-related hangover effect (139). Rebound insomnia has occurred after short-term use (5 to 14 days) but does not appear to be as severe, even after abrupt withdrawal (140, 141). Abuse, tolerance, and physical and psychological dependence have been reported with zopiclone (142). Zopiclone has been shown to be as effective a hypnotic as triazolam in the elderly ( 143). More comparisons with short to medium half-life BZDs for the treatment of insomnia are needed to show that zopiclone has an advantage over the BZDs. 

Sedatives and hypnotics as a group, and BZDs in particular, are frequently implicated in drug-related hospital admissions in the elderly ( 333, 334). This group is at particular risk for abrupt drug discontinuation when hospitalized, with resulting withdrawal symptoms that may be unrecognized as such and attributed to other health problems (313, 335, 336 and 337). BZD hypnotics should not be routinely prescribed in the hospital unless the patient has a demonstrated sleep disorder ( 338). Even then, reassurance that restless sleep is normal in such a situation may obviate the need for a hypnotic ( 330). 

Buspirone may be an effective anxiolytic in the elderly patient and less likely than BZDs to produce excessive sedation ( 352, 353, 354 and 355). Dizziness, however, may be a problem. Zolpidem or zaleplon, particularly in lower doses (i.e., 2.5 to 5.0 mg at bedtime) may be viable alternatives ( 356). The elimination half-life of these two agents is approximately 3 hours in the elderly. Although it has sleep-enhancing properties similar to BZD hypnotics, it is less likely to alter sleep architecture. Whereas antidepressants and b -blockers may be useful alternatives in younger patients, no data document their effectiveness for anxiety in elderly patients ( 307). Although antipsychotics may be helpful in reducing severe agitation, their side effect profile makes them unsuitable for use in subjective anxiety states ( 300, 307). 

In the elderly there is a consistent increase in the maximum plasma concentration and the ti/2 of zolpidem. This is related to a reduced volume of distribution associated with a decrease in clearance [36], As with other hypnotics that are extensively degraded in the liver and show high protein binding, the pharmacokinetics of zolpidem is altered in patients with liver disease. Accordingly, in patients with hepatic insufficiency receiving zolpidem, the Cmax and the ti/2 are consistently increased [36, 37], In patients with renal insufficiency the disposition rate of zolpidem is decreased compared with that of age-matched healthy adults (Tab. 3). 

Trewin VF, Lawrence CJ, Veitch GB (1992) An investigation of the association of benzodiazepines and other hypnotics with the incidence of falls in the elderly. J Clin Pharm Ther 17 129-133... 

Many benzodiazepines have been introduced over the past 35 years as hypnotic medications. The early ones, such as nitrazepam and flurazepam, were long acting (Tab. 1). Indeed, they were so long acting that residual effects were inevitable the next day, and substantial accumulation could occur, especially in the elderly. The next generation of benzodiazepines included the medium acting compounds, such as temazepam, lormetazepam, and loprazolam. Short-acting benzodiazepines were brotizolam and the extensively studied triazolam. 

Studies in the elderly have been carefully reviewed by Soldatos and his colleagues [27]. Some deterioration in the soundness of sleep has been detected but the amount of rebound insomnia following zopiclone discontinuation is relatively weak. Although one would certainly expect rebound in a hypnotic with a half-life of around 5 h, the frequency and severity of such rebound seems definitely less than those observed with comparative benzodiazepines such as triazolam and temazepam [28],... 

Insomnia is a common complaint in the elderly. As people age they require less sleep, and a variety of physical ailments to which the elderly are subject can cause a change in the sleep pattern (e.g. cerebral atherosclerosis, heart disease, decreased pulmonary function), as can depression. Providing sedative hypnotics are warranted, the judicious use of short half-life benzodiazepines such as temazepam, triazolam, oxazepam and alprazolam for a period not exceeding 1-2 months may be appropriate. Because of their side effects, there would appear to be little merit in using chloral hydrate or related drugs in the treatment of insomnia in the elderly. It should be noted that even benzodiazepines which have a relatively short half-life are likely to cause excessive day-time sedation. The side effects and dependence potential of the anxiolytics and sedative hypnotics have been covered elsewhere in this volume (Chapter 9). 

Bayer et al. (1986) conducted a 9-week, double-blind controlled study of triazolam and another hypnotic, chlormethiazole, in the elderly with sleep disturbances. They found daytime withdrawal effects from triazolam but not chlormethiazole. At week 3, significantly more... 

The most frequent adverse effect which occurs in at least one-third of patients is drowsiness, often accompanied by incoordination or ataxia. Problems with driving, operating machinery, or falls can result, particularly in the elderly, and can be an important source of morbidity, loss of physical function, and mortality (47,48). Memory impairment, loss of insight, and transient euphoria are common paradoxical reactions of irritability or aggressive behavior have been well documented (11) and appear to occur more often in individuals with a history of impulsiveness or a personality disorder (40), and in the context of interpersonal stress and frustration (49). Tolerance to the sedative and hypnotic effects generally occurs more rapidly than to the anxiolytic or amnestic effects (1). 

Drugs that act on the central nervous system appear to produce an exaggerated response in relation to that expected from the plasma concentration, and sedatives and hypnotics may have a pronounced hangover effect. These drugs are also more likely to depress respiration because vital capacity and maximum breathing capacity are lessened in the elderly. 

Clomethiazole is structurally related to vitamin B 1 (thiamine) and is a hypnotic, sedative and anticonvulsant. It is comparatively free from hangover it can cause nasal irritation and sneezing. Dependence occurs and use should always be brief. When taken orally, it is subject to extensive hepatic first-pass metabolism (which is defective in the elderly and in liver damaged alcoholics who get higher peak plasma concentrations), and the usual t) is 4 h (with more variation in the old than the young) it may also be given i.v. 

The S enantiomer of hexobarbital possesses three- to fourfold greater hypnotic activity than its antipode (4). However, in the elderly population, the clearance of R-hexobarbital, but not that of S-hexobarbital, is substantially reduced (23). Administration of the S enantiomer, therefore, will produce a more predictable clearance than that of the racemate. Also, as the safety profile of the less active enanticaner is unknown, one cannot rule out the possibility of its involvement in the overall toxicity of hexobarbital. For a related barbiturate, pentobarbital, it has been suggested that despite its weaker pharmacological activities, sedation with the R enantiomer is accompanied by symptrans of hyperexcitability (24). 

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