P&T News: February 1994, Vol. 14, No. 8
Michelle Fouts, R.Ph. and John Rachow, M.D.
Peer Review Status: Internally
Reviewed
The elderly are large consumers of sleep aids. From 1990 through 1991, 38% of the prescriptions filled for benzodiazepine hypnotics were for patients 65 years of age or older.5 Ried et al examined the use of psychotropic drugs in a community-dwelling cohort of elderly patients. They reported that 30.6% of the study population used psychotropic medications; hypnotics represented 23% of the psychotropic medication.6 During 1989, there were 651 million tablets/capsules of benzodiazepine hypnotics dispensed in the United States; this represented a 65% increase in sales since 1981.5
Evaluation and Treatment of Insomnia
Since insomnia has many causes, the indications for treatment are
dependent on the etiology. A thorough medical evaluation is essential
prior to initiating treatment. Indications for therapy will be driven
by the underlying cause and severity of symptoms.
Nonpharmacologic therapy or establishment of good "sleep hygiene" can be used as adjuncts to treatment of the specific cause of insomnia and as primary treatment when the cause in unclear. Nonpharmacologic therapy should be attempted before prescribing a hypnotic and concomitantly with pharmacologic therapy. Good sleep hygiene includes the scheduling of naps, adherence to regular retiring and rising times, and mild sleep restriction to promote better sleep quality. Environmental strategies include a bed used only for sleeping, a comfortable bedroom temperature, avoidance of heavy evening meals, restriction of fluid intake in the evening, and gentle exercise with a relaxation period before bedtime.7
Hypnotic Drugs
Historically, a number of medications have been used to induce sleep.
Barbiturates, chloral hydrate, and glutethimide had been used
routinely for sleep until the introduction of the benzodiazepine
flurazepam (Dalmane®) in the late 1960s. The benzodiazepines were
a major clinical advancement in safety. Lower addiction potential and
fewer drug interactions caused by the induction of hepatic enzymes
and displacement of other medications from protein binding sites were
additional advantages over the earlier medications. Since the
introduction of flurazepam, there has been further progress with the
marketing of benzodiazepines with shorter durations of action such as
oxazepam (Serax®), temazepam (Restoril®), and triazolam
(Halcion®). The benzodiazepines, however, also have some
drawbacks to their use including central nervous system (CNS)
depression, rebound insomnia, drug accumulation, disinhibition, and
severe withdrawal symptoms with prolonged use. Most recently, a new
nonbenzodiazepine hypnotic, zolpidem (Ambien®), has been
introduced which may prove to be an effective agent with fewer
significant adverse effects than the benzodiazepines. However,
further studies are needed to establish the place of zolpidem in
therapy.
Pharmacokinetic Considerations
The elderly population provides a special challenge to the physician
treating insomnia with a pharmacological approach. CNS-active
medications tend to be lipid soluble. This factor becomes important
in the elderly because with advancing age, lean body mass decreases
and adipose tissue mass increases.9 This phenomenon leads to an
increased volume of distribution for lipid soluble medications. Also
in the elderly, drug clearance is probably of greater significance
when choosing a hypnotic agent. The benzodiazepines and zolpidem are
metabolized by the liver. The phase I oxidative pathway of metabolism
is impaired in the elderly, which may lead to decreased drug
clearance and increased drug accumulation. The long-acting
benzodiazepines are metabolized via this pathway. The phase II
glucuronide-conjugative pathway does not appear to be affected by
aging.9, 10 The short-acting benzodiazepines and zolpidem are
metabolized via the glucuronide-conjugative pathway.
Benzodiazepines
The benzodiazepines exert their effects through stimulation of the
gamma-aminobutyric-acid (GABA)-receptor complex in the CNS. All
benzodiazepines are capable of producing anxiolytic, sedative,
hypnotic, skeletal muscle relaxant, and anticonvulsant effects at
equipotent doses.11 The important differences between benzodiazepines
result from the pharmacokinetic properties of the individual
compounds (Table 1).12
All the benzodiazepines are metabolized by the liver. Those that are metabolized via the phase I oxidative pathway [e.g., diazepam (Valium®), chlordiazepoxide (Librium®)] have active metabolites. Some of the active metabolites actually have longer half-lives than the parent compound. Diazepam, for example, has a half-life of 20 to 50 hours, desmethyldiazepam, one of its major active metabolites, has a half-life of 30 to 200 hours. Oxazepam, lorazepam (Ativan®), temazepam, triazolam and zolpidem are handled by the phase II pathway and have no active metabolites. As a result, they have short half-lives (Table 1).
Chronic administration of diazepam, chlordiazepoxide, and flurazepam has been associated with an increased incidence of CNS adverse effects in the elderly.13-16 These side effects include daytime drowsiness, fainting, ataxia, confusion, diminished psychomotor performance, impaired reaction time, incoordination, and anterograde amnesia.
Two separate studies by Ray et al demonstrated an increased relative risk of hip fracture in a group of Canadian elderly using benzodiazepines with long half-lives (> 24 hours).17, 18 The patients using benzodiazepines with long half-lives had a 70% greater risk of hip fracture than patients not taking psychotropic medications.18 Sorock et al also showed an increased relative risk of falling in a cohort of community-dwelling senior citizens using benzodiazepines on a daily basis. However, there was no significant increased risk of falling for subjects using benzodiazepines as needed.19 Sobel et al studied the institutionalized elderly and discovered a significantly higher use of sedative hypnotics in those patients suffering falls as compared to patients not having falls.20
Triazolam, a benzodiazepine with a shorter half-life, has also caused difficulties in the elderly, 21,22 Greenblatt et al demonstrated an increase level of sedation and psychomotor impairment in healthy elderly patients compared to healthy young adults taking equivalent doses of triazolam. Pharmacokinetic data in the same study indicated that the elderly subjects had higher serum levels of triazolam for a given dose.21 Temazepam, marketed a few years before triazolam. Additionally, the authors reported an increased incidence of adverse behavioral reactions to triazolam in patients 65 years of age or older who were receiving doses greater than 0.125 mg.22
The choice of benzodiazepine for use in the elderly is strongly influenced by the pharmacokinetic properties of the individual agents. All the benzodiazepines are equally effective;12 but due to the markedly increased risk of serious adverse effects in the elderly patient population, it is reasonable to preferentially prescribe agents with shorter duration of action using the smallest effective dose. This strategy will lessen the drug accumulation that is seen in agents with longer half-lives. Even though the benzodiazepines with short half-lives are preferred in the elderly, they are also more likely to cause withdrawal syndromes if taken chronically and then abruptly discontinued.
Zolpidem
Zolpidem is a nonbenzodiazepine hypnotic which is an imidazopyridine
derivative. Zolpidem preferentially binds to the omega-1 subtype of
the benzodiazepine receptor. This specificity is thought to be
responsible for its lack of anxiolytic, skeletal muscle relaxant, and
anticonvulsant activity at hypnotic doses.23 Zolpidem does not
disrupt the physiological pattern of sleep with doses less than 20
mg, a theoretical advantage over the benzodiazepines.24, 25
Zolpidem is rapidly absorbed from the gastrointestinal tract and has a quick onset of action (peak concentration is achieved 1.6 hours after administration). It is metabolized by the liver via the glucuronide-conjugative pathway and has no active metabolites. The elimination half-life of zolpidem is 2.5 to 3 hours, which contributes to its relatively short duration of action.26
The adverse effects associated with zolpidem in clinical trials have been relatively mild, and have included headache, drowsiness, confusion, nausea, vomiting, malaise, feeling of drunkenness, leg cramps, and nightmares.24, 26-29 Fairweather et al and Scharf et al investigated the effect of zolpidem on psychomotor performance in geriatric patients and found no consistent deleterious effects on daytime performance. 27, 29 However, CNS depression (dysphoria, confusion, ataxia, fatigue, and drowsiness), CNS disinhibition, and nightmares have occurred at a significantly high incidence with doses of 20 mg versus 10 mg or placebo. Zolpidem 20 mg compared to triazolam 0.5 mg had similar rates of adverse drug reactions. High-dose zolpidem (20 and 30 mg) also increased the fall rate in the elderly patients.30
Annseau et al reported two cases of psychotic reactions in young adults receiving their first dose of zolpidem; these reactions were similar to those previously reported with triazolam.31 Cavallaro et al reported two cases involving the development of tolerance and withdrawal phenomena associated with zolpidem.32 These reports suggest that zolpidem may share common features and risk factors for side effects and tolerance development with the short half-life benzodiazepines.30-32
Zolpidem has shown hypnotic activity with as little as 5 mg in both normal volunteers and the elderly. 24, 27, 29 There is only minimal improvement in hypnotic activity above 10 mg; however, adverse effects are dose-related and increase markedly with doses greater that 10 mg.29, 30 The recommended starting dose for elderly or debilitated patients is 5 mg.26
A disadvantage of zolpidem is its cost. The 5 mg and 10 mg tablets cost $1.00 and $1.25 each, respectively. These costs are considerably more expensive than triazolam ($.32 per 0.125 mg), oxazepam ($0.06 per 10 mg), temazepam ($0.03 per 15 mg), and lorazepam ($0.02 per 0.5 mg), which are generically available. (Note: UIHC acquisition costs are reported). Medication costs are an important point to consider when prescribing for elderly patients on fixed incomes.
Antihistamines
The antihistamines (e.g., diphenhydramine, hydroxyzine) are used
frequently as hypnotics and represent 10% of the market share in the
United States.5 In addition, antihistamines are available
over-the-counter and are frequently found in combination cold, sinus,
and allergy preparations. Recently, antihistamines have also been
combined with pain relievers and marketed as night time pain
medication (e.g., Tylenol PM®). Due to their significant
anticholinergic activity and subsequent risk of orthostatic
hypotension and CNS depression, these agents should be used with
caution in the independent-living elderly. Any medication with
anticholinergic activity should be avoided in patients with dementia
and it will exacerbate confusion.
Miscellaneous Hypnotic Agents
Chloral hydrate has been utilized for its hypnotic effects for
decades. It is metabolized to the active form of trichloroethanol.
Chloral hydrate has an onset of action in 20 to 60 minutes, and the
half-live of trichloroethanol is 7 to 9.5 hours. The drawbacks of
chloral hydrate include its ability to displace anticonvulsants and
warfarin from protein binding sites. Chloral hydrate also causes a
high incidence of confusion, agitation, and disorientation in the
elderly,33 therefore, its use as a routine hypnotic is not
recommended.
Antidepressant medications have also been utilized for their sedating properties in patients with possible depression. Trazadone (Desyrel®) and the tricyclic antidepressants improve sleep due to their sedating effects. The tricyclic antidepressants, however, should be used with caution in the elderly population due to their anticholinergic properties. If a tricyclic antidepressant is indicated, agents with lower anticholinergic side effect profiles (e.g., nortriptyline, desipramine) are preferred.
Conclusions
The goal in the treatment of insomnia in all patients is not only
uninterrupted sleep but, more importantly, improved quality of life
for the patient and family. 4, 7 Hypnotic medications should not be
the mainstay for the management of most causes of disturbed sleep.4
Treatment of the underlying cause, in conjunction with improving
sleep hygiene, is imperative to appropriate and long-term successful
treatment of insomnia. Therefore, symptomatic treatment of insomnia
should be limited to a short course, preferably 7 to 10 days, with
frequent reevaluation if the agent is to be used for more than two to
three weeks. Hypnotics should not be prescribed in quantities
exceeding a one-month supply.
Even when a hypnotic is clearly indicated, it may be counterproductive in improving the quality of life for the patient and family duet to adverse effects or excess sedation form accumulation of long half-life benzodiazepines.13-15 The elderly are particularly sensitive to the effects of accumulation due to changes in pharmacokinetics associated with aging.9 Several medications are available with documented efficacy and pharmacokinetic profiles that improve the likelihood of accomplishing treatment goals. There are several short half-live benzodiazepines available including oxazepam, lorazepam, temazepam, and triazolam (Table 1). The new nonbenzodiazepine hypnotic, zolpidem, may also be a suitable alternative to the traditional benzodiazepines, but its place in therapy remains to be established.
|
TABLE 1. Pharmacokinetic and Dosing Information for Benzodiazepines and Zolpidem | |||
|
Medication |
Half-Life (Hours) |
Half-Life of Active Metabolites (Hours) |
Recommended Geriatric Hypnotic Dose |
|
Lorazepam* |
10-20 |
not applicable |
0.5-2 mg |
|
Oxazepam* |
3-21 |
not applicable |
10-15 mg |
|
Temazepam |
10-20 |
not applicable |
15 mg |
|
Triazolam* |
1.6-5.4 |
not applicable |
0.125 mg |
|
Zolpidem |
1.5-4 |
not applicable |
5 mg |
|
Diazepam* |
20-50 |
30-200 |
NR |
|
Flurazepam* |
72 |
47-100 |
NR |
|
Quazepam |
25-41 |
70-75 |
NR |
|
Chlordiazepoxide* |
5-30 |
30-200 |
NR |
|
___________ | |||
References
1. Hosp Community Psychiatry. 1990;47:743-4.
2. Sleep. 1980;3:119-220.
3. Med Clin North Am. 1985;69:1123-52.
4. Treatment of sleep disorders in older people. NIH Consens Dev Conf
Consens Statement. 1990;8(3):1-22.
5. Pharmacological Reviews. 1992;44:151-347.
6. Am J Public Health. 1990;80:1349-53.
7. J Clin Psychiatry. 1992;53(Suppl6):23-8.
8. J Am Geriatr Soc. 1982;30:25-50.
9. N Engl J Med. 1982;306:1081-8.
10. N Engl J Med. 1983;309:354-8.
11. AHFS drug information 93. Bethesda, MD: American Society of
Hospital Pharmacist; 1993:1409.
12. J Clin Psychiatry. 1992;53(Suppl 6):7-13.
13. N Engl J Med. 1973;288:277-80.
14. Clin Pharmacol Ther. 1977;21:355-61.
15. Drug Intell Clin Pharm. 1985;19:37-40.
16. Ann Intern Med. 1987;107:169-73.
17. JAMA. 1989;262:3303-7.
18. N Engl J Med. 1987;316:363-9.
19. Arch Intern Med. 1988;148:2241-4.
20. Drug Intell Clin Pharm. 1983;17:539-42.
21. N Engl J Med. 1991;324:1691-8.
22. Arch Intern Med. 1991;151:2003-8.
23. J Pharmacol Exp Ther. 1986;237:649-58.
24. J Clin Psychopharmacol. 1989;9:9-14.
25. Eur J Clin Pharmacol. 1989;36:461-6.
26. Ambien package insert. Searle. Skokie, IL: 1993 May.
27. Eur J Clin Pharmacol. 1992;43:597-601.
28. J Int Med Res. 1992;20:162-70.
29. J Clin Psychiatry. 1991;52:77-83.
30. Imidazopyridines in sleep disorders: a novel experimental and
therapeutic approach. New York: Raven Press;1988:351-61.
31. Lancet. 1992;339:809.
32. Lancet. 1993;342:374-5.
33. Psychotropic drug handbook. 6th Ed. Cincinnati:Harvey Whitney
Books Co;1991:173.
Angie Kuehl, R.Ph.
Peer Review Status: Reviewed by Mary B. Ross, R.Ph.,
M.B.A
Background
Nicotine transdermal patches are FDA labeled for the relief of
nicotine withdrawal symptoms as an aid to smoking cessation. The
patches are available from a variety of manufacturers (Habitrol®
-Ciba Geigy, Nicoderm® - Marion Merrell Dow, Nicotrol® -Park
Davis, Prostep® -Lederle), with varying nicotine content and
recommended duration of wear. The product currently stock at UIHC is
Nicoderm®, which is available in 21 mg, 14 mg, and 7 mg
strengths.
The most recent audit conducted from June 1, 1993 to August 31, 1993 showed a change in prescribing habits for nicotine patches when compared to a similarly-conducted 1992 audit. There was a 44% decrease in totally number of prescriptions written for nicotine patches (from 172 to 96), and a corresponding decrease in the number of patients receiving patch prescriptions. The number of nicotine prescriptions written with specific directions increased from 50% to 93% during the reaudit period. A duration of use was indicated in 93% of nicotine prescriptions during the reaudit period, compared to 51% in the initial audit period.
Prescribing Guidelines
The manufacturer's recommended dosing schedule is as follows:
The need for dosage adjustment should be assessed during the first two weeks of therapy. It should be stressed to patients that they should completely stop smoking when initiating nicotine patch therapy to avoid adverse effects. Clinical trials have shown that patients who are unable to stop smoking after 4 weeks of initial therapy are unlikely to stop with further patch treatment. It is probably best to discontinue treatment in these patients.
The patch should be applied only once daily to non-hairy, clear, dry site on the upper body or upper outer arm. The patch should be removed after 24 hours, and a new patch reapplied to an alternate skin site. Skin sites should not be reused for a least one week. Used patches retain a reservoir of nicotine and should be kept away from the reach of small children and pets.
The entire duration of therapy should be 3 to 12 weeks, depending upon the size of the initial dose. Use of the patches for longer than 3 months has not been studied and is not recommended.
Patients are more likely to successfully quit smoking if they participate in formal smoking cessation programs. UIHC has a support program for persons interested in smoking cessation. Both individual counseling and support group meetings are available, with emphasis on behavior modification and nicotine replacement in selected individuals. Use of nicotine patches within recommended dosing guidelines and in collaboration with support programs is the safest and most effective regimen for the patient.
The results of the second nicotine audit show encouraging results regarding safe and appropriate prescribing of nicotine patches. Prescribers are encouraged to be explicit with prescription directions, and pharmacists are asked to ensure that the patient is properly educated on the use of these products. Additionally, health professionals should encourage patients to participate in formal smoking cessation programs in conjunction with nicotine patch use.
Drugs Added to Stock
LODOXAMIDE Ophthalmic Solution: 0.1%, 10 ml Lodoxamide (Alomide® - Alcon) ophthalmic solution is a mast cell stabilizer indicated for the treatment of allergic conjunctivitis and keratitis. It will be used in place of cromolyn ophthalmic solution which has not been available from the manufacturer for several years.
PROGESTERONE Intrauterine Devise Progesterone (Progestasert ® - Alza) intrauterine device provides contraception for a 12-month duration.
RIMANTADINE Tablets: 100 mg Oral Syrup: 50 ml per 5 ml Rimantadine (Flumadine® - Forest) is an antiviral agent indicated for the prophylaxis and treatment of illness caused by influenza A.
RISPERIDONE Tablets: 1 mg, 2 mg, 3 mg, 4 mg Risperidone (Risperdal® - Janssen) is a neuroleptic agent indicated for the management of psychotic disorders. the prescribing of resperidone is restricted to Psychiatry and Neurology.
Drugs Deleted from Stock
COLCHICINE INJECTION Discontinued by the manufacturer. Colchicine tablets are available.
FACTOR IX COMPLEX (ALPHANINE®) AFFINITY PURIFIED INJECTION It has been replaced with a more highly purified solvent detergent product, (Alphanine®SD).