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Benzodiazepines and the elderly a review of potential problems
Journal of Subslance Abuse Treamen~, Vol. 8, pp. 35-41, Printed in the USA. All rights reserved.
1991 Copyright
Benzodiazepines
0
0740-5472191 $3.00 + .OO 1991 Pergamon Press plc
and the Elderly
A Review of Potential Problems
MARY H. CLOSSER, Yale School of Medicine,
New Haven,
DO Connecticut
Abstract - This article reviews the literature describing the extent of benzodiazepine use and abuse in the elderly and specific problems attendant upon this use. Unrecognized, undocumented use and abuse of psychoactive drugs is frequent in this population and can lead to serious problems with untreated dependence and withdrawal. The elderly appear to be more sensitive to the effects of benzodiazepines, both because of changed pharmacokinetics and pharmacodynamics with aging and because of altered postreceptor cerebral response. All problems identified with benzodiazepines such as dependence, withdrawal, and cognitive and psychomotor impairment are proportionally greater among the elderly, who can least afford these risks. Review of the literature leads to the conclusion that benzodiazepine prescribing for the elderly should be undertaken with the greatest caution and only with the recognition of all potentially disastrous effects. Keywords-
benzodiazepines; substance dependence; elderly; withdrawal; neuropsychological impairment; memory problems.
tion is expected to expand to 12.5%. Thirty percent of all prescription medications are given to the elderly (Baum, Kennedy, & Forbes, 1984), and twice the incidence of adverse drug reactions and side effects that younger patients have occurs in this population. Many of these medications are psychoactive drugs. In a study of medication use among intermediate-care facility residents (Beers et al., 1988), investigators discovered that more than half of all residents received a psychoactive medication. Twenty percent received a benzodiazepine, 87% of these as a standing order. Suboptimal choice of benzodiazepine was common as 30% received long-acting agents. Of the available sedative-hypnotic drugs, the benzodiazepines are by far the most frequently prescribed, and the elderly receive almost 40% of these prescriptions (Thompson, Moran, & Neis, 1983). Investigation of drug-associated hospital admissions in older patients has shown that up to 10% may be due to benzodiazepines (Grymonpre, Mitenko, Sitar, Aoki, & Montgomery, 1988). Despite increasing evidence that psychoactive drug use in the elderly can be problematic, many elderly persons receive such drug therapy.
INTRODUCTION LESS OFTEN DISCUSSED than broad concerns about benzodiazepines is the more specific issue of benzodiazepine prescribing for the elderly and its corollary problems. Schweizer, Case, and Rickels (1989) note that little is known about problems such as benzodiazepine withdrawal in the elderly, despite the remarkably high prevalence of chronic benzodiazepine use in this population. This article reviews the literature describing the extent of benzodiazepine use and abuse in the elderly and specific problems attendant upon this use.
DEMOGRAPHICS Elderly persons currently account for approximately 11% of the population; by the year 2000, this proporThe author would like to specially thank Kirk Brower, MD, for assistance in the preparation of this manuscript. Requests for reprints should be addressed to Mary H. Closser, DO, Central Treatment Unit, APT Foundation, 9144 Howard, New Haven, CT 06519.
35
M. H. Closer
36
Unrecognized, undocumented use and abuse of psychoactive drugs is frequent in this population (Buchsbaum, Boling, & Groh, 1987) and can lead to serious problems with untreated dependence and withdrawal. In a prospective study of prescribing practices in ambulatory clinics, Buchsbaum et al. noted that internal medicine house officers significantly underrecorded the benzodiazepine medications they prescribed for their elderly patients and the indications for use of these drugs. Miller, Whitcup, Sacks, and Lynch (1985) describe cases of initially unrecognized and untreated benzodiazepine dependence in elderly persons and the polypharmacy that often confuses the picture, noting that extensive, unnecessary work-ups can result from unsuspected drug dependence. Medicine is not the only specialty that tends to miss the diagnosis of benzodiazepine dependence. Whitcup and Miller (1987) retrospectively reviewed 90 psychiatric inpatient records to determine the extent of unrecognized drug dependence and resulting complications. Twenty-one percent were drug dependent; 53% of these were unrecognized and were not detoxified. Of the unrecognized cases, 70% developed significant, serious medical complications requiring transfer to a medicine service. Unrecognized cases were significantly more likely to be older female benzodiazepine abusers; recognized cases, young male alcohol abusers. Among recognized cases of alcoholism in the elderly, benzodiazepine dependence is often a complication. Finlayson, Hurt, Davis, and Morse (1988) described the characteristics of 216 elderly inpatients in an alcohol treatment unit. Fourteen percent also had a drug abuse or dependence diagnosis, and all had been prescribed these medications. Eighty-seven percent of such medications were “minor tranquilizers or hypnotics,” other terminology sometimes used for benzodiazepines. Treatment for both alcohol and drug dependence disorders was required in this group. Other common diagnoses seen in this population were tobacco dependence (67Vo), some form of organic brain syndrome (440/o), and affective disorder (12%). Other investigators believe that concerns regarding the dangers of benzodiazepine dependence in the elderly are exaggerated. In a survey of an ambulatory elderly population (Pinsker & Suljaga-Petchel, 1984), half of the patients said they had never increased use of their benzodiazepine; none who had stopped use noted withdrawal symptoms, and 75% took it “only when needed.” The authors concluded that there was no evidence of addiction in their sample and further, that prolonged use of low-dose benzodiazepine in elderly patients is safe. It is unclear whether or not all criteria for psychoactive substance abuse or dependence were applied in diagnosing this sample. Another objection to their conclusion of benzodiazepine safety is that benzodiazepine use may cause problems in the elderly quite apart from abuse and dependence.
PHARMACOLOGIC
CHANGES
WITH AGING
Controlled studies have documented that the elderly are more sensitive to the effects of benzodiazepines than are the young. Reviews of this topic by Swift (1986) and Cook (1986) describe problems associated with accumulation, tolerance, intensity, and duration of drug response. Single doses of a benzodiazepine produce peak responses twice as great in elderly persons as in younger controls, while plasma drug concentrations were similar. Studies of patients requiring premeditation of diazepam showed that the dose and plasma concentration needed to produce a certain level of sedation decreased by 2 to 3 times between the ages of 20 and 80. Cook reviews speculation that this increase in acute response to single doses of benzodiazepine is likely due to some change in cerebral response instead of changes in pharmacokinetics. There is evidence that benzodiazepines induce greater increases in gamma amino butyric acid (GABA) binding and neuronal inhibition in elderly animals, which may account for this enhanced cerebral response. Differences in cerebral response among elderly patients are significant and complicate studies of the phenomenon. Psychomotor performance studies of regular dosing indicate that the elderly, especially those with dementia, hypoalbuminemia, or chronic renal failure are most at risk for prolonged sedation. Swift describes the changed pharmacokinetics in the elderly, which also affect response: decreased plasma clearance of those benzodiazepines requiring oxidative metabolism, increased volume of distribution of the drug caused by increased proportion of total body fat to lean body mass, and subsequent lowered peak plasma concentration and prolonged plasma half-life. Salzman, Shader, Greenblatt, and Harmatz (1983) describe the pharmacokinetic and clinical differences between multiple dosing of a long half-life (diazepam) and short half-life (oxazepam) benzodiazepine in an elderly sample. Absorption of diazepam was faster and onset of clinical effects more pronounced. Diazepam accumulated extensively, washed out slowly, and sedative effects persisted for 2 weeks after diazepam treatment was discontinued. However, there did not appear to be a difference between clinical degree of sedation during treatment, perhaps because of development of acute tolerance to central nervous system depression. The authors do not make conclusions regarding clinical efficacy of these drugs, but suggest that understanding the elderly patient’s different pharmacokinetics may help in appropriate drug selection in order to minimize side effects such as unwanted sedation or breakthrough of underlying symptoms. In summary, the elderly appear to be more sensitive to the effects of benzodiazepines, both because of changed pharmacokinetics and pharmacodynamics with aging and because of altered postreceptor cere-
Benzodiazepines and the Elderly
37
bral response. Appropriate choice of benzodiazepine cannot be based solely on consideration of elimination half-life, as this is only one factor affecting increased response.
individual titration of chlordiazepoxide to withdrawal symptoms is necessary.
WITHDRAWAL
There is an extensive literature on the neuropsychological effects of benzodiazepines (Bergman, Borg, & Holm, 1980; Golombok, Moodley, 8z Lader, 1988; Hendler, Cimini, Ma, & Long, 1980; Hoehn-Saric 8z McLeod, 1986; Lucki & Rickels, 1986; Lucki, Rickels, 8z Geller, 1985, 1986; Peturrson, Gudjonsson, & Lader, 1983; Smiley, 1987), which describes intellectual, cognitive, and psychomotor impairment as common effects of benzodiazepine treatment. Describing cognitive impairment caused solely by benzodiazepines in the elderly is a more complex problem. These is some controversy regarding the extent of “normal” functional cognitive impairment caused by aging, which, in any case, varies widely among individuals (Zillmer & Ball, 1989). Therefore, studies need to take into account normal patterns of cognitive loss and to carefully compare elderly patients to younger controls matched for other possible causes of impaired performance (e.g., education, previous level of functioning, medications, physical status).
Some reports have indicated that benzodiazepine withdrawal in the elderly may be more difficult than in younger patients. A prospective study of benzodiazepine use and withdrawal in elderly medical inpatients revealed half to be using these drugs (Foy, Drinkwater, March, & Mearrick, 1986). These patients had an increased risk of developing confusion during their hospital stay, especially those whose medications were stopped abruptly. They did not appear to develop other withdrawal symptoms, such as anxiety or insomnia, that are commonly noted in younger patients. The authors conclude that benzodiazepines should not be suddenly discontinued in elderly patients. Most clinicians would add that benzodiazepines should not be suddenly discontinued in any population. Another study of benzodiazepine withdrawal in elderly patients had different findings. Schweizer, Case, and Rickles (1989) compared severity of withdrawal symptoms and clinical outcome in a matched sample of elderly and younger benzodiazepine-dependent patients. The elderly patients showed significantly less severe withdrawal symptoms during a gradual taper and did as well at outcome as did younger patients. The authors speculate that the possible slower clearance of drug in the elderly patients would attenuate withdrawal symptoms (a “self-taper” mechanism). Another speculation derives from conceptualizing benzodiazepine withdrawal as due in part to a drug-discontinuation-induced overactivity or rebound of previously inhibited noradrenergic, serotonergic, and cholinergic neuronal activity. If functional neuronal capacity diminishes with age, benzodiazepine withdrawal might cause less rebound overactivity in elderly persons. Withdrawal from alprazolam is of much recent concern because of its widespread use. Alprazolam’s ability to cause dependence and withdrawal appeared to surprise many clinicians, and its possibly uniquely difficult withdrawal has led to controversy regarding its treatment. Closser, Brower, and Beresford (1990) describe sudden discontinuation of alprzolam, with substitution and subsequent taper of chlordiazepoxide as a rapid, well-tolerated technique for detoxification. They noted that an elderly, alprazolam-dependent woman required less chlordiazepoxide to suppress alprazolam withdrawal symptoms (25 mg chlordiazepoxide for each 1 mg alprazolam) than younger patients. However, they found a range of chlordiazepoxide dosages required in other patients (So-150 mg of chlordiazepoxide to 1 mg alprazolam) and emphasize that
NEUROPSYCHOLOGICAL
Cognitive
IMPAIRMENT
Impairment
Pomara, Deptula, Medel, Block, and Greenblatt (1989) devised a careful study of the effects of single 2.5- and IO-mg doses of diazepam and of chronic bedtime administration on elderly and young subjects. They found that single lo-mg doses impaired recall memory in all subjects; a 2.5-mg dose caused impaired cognition (increased “intrusion errors”) in the elderly only. Regular bedtime dosing of 10 mg caused significant next-day recall memory impairment in both age groups, and 2.5-mg bedtime dosing increased intrusion errors in both groups. The authors concluded that the elderly appear to have an increased sensitivity to some of diazepam’s deleterious cognitive effects. They also noted that partial tolerance appears to develop to the drug’s effects on memory with chronic administration. Drug-induced dementia is certainly the most easily treated form of cognitive impairment and yet is difficult to recognize. Medications can also exacerbate underlying dementia and greatly interfere with functional capacity. Larson, Kukull, Buchner, and Reifler (1987) prospectively assessed adverse drug reactions causing cognitive impairment in outpatients being evaluated for dementia. They found that sedative-hypnotics (especially long-acting benzodiazepines) were the most common drugs associated with cognitive impairments. This association was carefully documented by psychometric testing during drug use and after withdrawal. Although many patients remained demented after drug
M. H. Closer
38 withdrawal, all showed improved functioning with abstinence. Most of their patients had used benzodiazepines for years, and cognitive impairment appeared to develop insidiously as a “late complication” of a drug initially prescribed at a younger age. They also noted that some patients were given additional drugs to treat side effects, for example, neuroleptics given to patients who developed confusion on benzodiazepines. A monograph devoted to the amnestic effects of benzodiazepines extensively reviews clinical and laboratory findings and expresses concern that benzodiazepine-induced amnesia is often unrecognized (Gamzu, 1987; Scharf, Fletcher, & Graham, 1988; Scharf, Saskin, &Fletcher, 1987; Sussman, 1987). This amnesia is of particular concern for elderly users of benzodiazepines, whose memory problems may be exacerbated by the drugs or due to the drugs themselves, but instead are blamed on aging. Memory loss in the elderly is particularly devastating, as they fear progressive deterioration in functioning and loss of self. The drugs may be initially prescribed for treatment of anxiety, but can actually exacerbate the condition by impairing cognitive and motor functioning. These authors note that benzodiazepines, particularly the short-acting triazolam, lorazepam, and alprazolam, cause anterograde amnesia by interfering with the transfer of information from immediate to long-term memory storage. The problem, then, is not with retrieval of memory but with memory storage itself. The amnesia can occur for events transpiring long after peak drug effects have passed, for instance, amnesia for events during the day following bedtime administration of triazolam. Most persons suffering from benzodiazepine-induced amnesia are unaware of their memory losses and impaired learning ability. Unfortunately, these impairments may not be readily apparent during routine clinical interviewing. Specific cognitive screening questions are needed to test memory function and to identify those suffering from anterograde amnesia. Not all benzodiazepines produce the same degree of amnesia clinically. Research involving the benzodiazepine receptor indicates that receptor-binding affinity may account for the differences seen clinically. Memory impairment appears to be most frequent with those benzodiazepines having greatest receptorbinding affinity. Differences in lipophilicity and, hence, volume of distribution may account for the range and protraction of amnestic effects. The drug’s half-life does not determine its amnestic potential, as the amnestic effect lasts well beyond any sedative effect and can occur even when no sedation is noted. Thus, avoidance of the long-acting benzodiazepines in the elderly does not preclude problems, as the shortest-acting benzodiazepines also have the greatest amnestic potential (Scharf et al., 1988). Choice of benzodiazepine, either long-acting or short-acting,
long elimination half-life or short, will depend upon careful consideration of which side effects will be least deleterious to the individual patient.
Psychomotor
Impairment
Falls by the elderly are a significant source of morbidity and mortality. Injury is the sixth leading cause of death in the elderly, and most fatal injuries are caused by falls. There are many intrinsic risk factors for falling (Tinetti & Speechley, 1989), one of which is the use of medications including benzodiazepines. The deleterious effect of benzodiazepines on motor performance in the elderly has been related to increased risk of falling and to hip fracture. A prospective study of risk factors for falls in ambulatory elderly patients showed that continuous use of benzodiazepines appeared to increase the risk of falling, and any use of benzodiazepines was related to multiple falls in persons who fell (Sorock & Shimkin, 1988). They noted that the risk of falling caused by continuous benzodiazepine use appears to be higher in patients with loss of proprioceptive sensation in the toes. The authors discuss evidence for a direct effect of benzodiazepines on the cerebellum, which results in ataxia and loss of coordination, likely caused by impairment of motor responses to loss of balance. Sedation and hypotension also contribute to impairment of motor function. They caution clinicians to review carefully the use of these drugs in elderly patients and to taper the drugs cautiously when no longer essential. Several studies have assessed the risk of hip fracture in elderly persons who receive psychotropic drugs. Ray, Griffin, Schaffner, Baugh, and Melton (1987) performed a case-control study of elderly patients with hip fractures who used psychotropics and those who did not. A significantly increased risk of hip fracture was found with the use of long elimination halflife drugs (hypnotic-anxiolytics, antidepressants, and neuroleptics). The principal authors later specifically investigated the risk of hip fracture in elderly users of long and short elimination half-life benzodiazepines (Ray, Griffin, & Downey, 1989). Current users of long half-life elimination benzodiazepines had a 70% greater risk of hip fracture than patients taking no psychotropic drug. This increased risk persisted after the first 30 days of therapy, indicating no development of tolerance to psychomotor impairment. As in their earlier article, the authors emphasize that long half-life benzodiazepines should be used with great caution in the elderly. Another significant cause of injuries in the elderly is automobile accidents. Impaired vision and hearing can impair driving skills; the added sedation and cognitive impairment caused by benzodiazepines may increase the number of accidents in this population. This public is aware today of the importance of alco-
Benzodiazepines and the Elderly
ho1 in causing automobile accidents, but is much less aware of the role of other drugs. In a prospective study, Skegg, Richards, and Doll (1979) discovered a highly significant association between the use of “minor tranquilizers” and the risk of serious automobile accident. The number of elderly persons in this study was small, but one might speculate that their risk would be even greater.
SLEEP DISORDERS
Many elderly persons suffer from insomnia or other sleep disorders; and benzodiazepines are frequently prescribed for this indication. The prevalence of insomnia increases with age and with the presence of medical disorders (Gillin & Byerley, 1990), making hospitalized elderly the largest consumers of benzodiazepine hypnotics. Despite recommendations that hypnotics be utilized only as adjunctive treatment for insomnia on a short-term basis, long-term prescribing of these medications is common. Patients invariably complain of worsening of their sleep disorder during withdrawal of the hypnotic, leading them to object strenuously to its discontinuation and their physicians to continue prescribing. Gillin, Spinweber, and Johnson (1989) review evidence for rebound insomnia after discontinuation of benzodiazepine hypnotics and conclude that the risk is greater with short half-life as compared with the long half-life benzodiazepines. Of importance is that this rebound insomnia (withdrawal) may occur even at low, therapeutic doses, particularly with short-acting benzodiazepines because of the development of tolerance and dependence. This may lead to increasing doses or selection of a longer-acting benzodiazepine, which increases the risk of toxicity from accumulation in the elderly. The pharmacological dependence worsens with continued use if escalating doses of the short-acting preparations are used to offset rebound insomnia (actually, withdrawal insomnia). Schneider-Helmert (1988) investigated in the sleep laboratory the effectiveness of benzodiazepines as hypnotics in low-dose dependent elderly insomniacs. He discovered that benzodiazepine-dependent subjects has equally short, but qualitatively worse, sleep when compared to drug-free insomniacs. Slow-wave and REM sleep were both suppressed in benzodiazepine users. However, drug users typically overestimated their total sleep time when given hypnotics. This overestimation of sleep time is likely the result of anterograde amnesia and confuses patients’ assessments of the drug’s effectiveness and of rebound insomnia. True withdrawal insomnia does occur during discontinuation of benzodiazepine hypnotics (see earlier), but this amnesia makes the symptom appear even worse. Clinicians would be well advised to taper benzodi-
39
azepine hypnotics on discontinuation as they would normally taper anxiolytics. Greenblatt, Harmatz, Zinny, and Shader (1987) studied the effects of sudden or gradual discontinuation from triazolam on withdrawal insomnia (“rebound sleep disorder”). Abrupt withdrawal subjects experienced prolonged sleep latency, reduced sleep duration, and increased awakenings compared to subjects who received a taper over 4 nights. This taper method is recommended as a means to help prevent continued drug use caused by rebound insomnia in patients who would otherwise wish to stop.
CLINICAL
EXAMPLES
A delirious 71-year-old widower living in a supervised apartment was brought into the emergency room by the building manager, who insisted that the patient had been drinking. The widower was known to have been attending AA meetings regularly with the assistance of local AA members, who denied seeing the man intoxicated before. He was admitted to a detoxification unit, where he was seen to be disoriented with marked impairment in immediate and short-term memory. He angrily denied any use of alcohol or medications; breathalyzer testing was negative, and urine screening revealed the presence of benzodiazepine. Search of his apartment by the building manager revealed a nearly empty bottle of triazolam. The patient’s delirium and memory impairments gradually cleared over 4 days during a careful, low-dose diazepam substitution and taper. He later recalled having taken only two pills from his newly renewed supply of sleeping pills, which he angrily refused to call “medication.” “ That isn’t a drug - I need it to sleep! ” After a 3-week rehabilitation stay, the patient was sleeping soundly without any hypnotics and had a much better understanding of his addictions. A 59-year-old professor was self-referred for inpatient detoxification from alprazolam when she became concerned about addiction. She had seen an article in a newspaper about alprazolam and was quite frightened by the story. She had been prescribed diazepam for 2 years for anxious symptoms and had required hospitalization for its discontinuation; a new psychiatrist prescribed alprazolam, which she now had been taking for 24 months and was unable to stop despite repeated attempts. She felt herself to be less able to think and had missed significant amounts of time from work when trying to detoxify herself. Alprazolam was discontinued, and chlordiazepoxide 25 mg was administered orally every 4 hours as needed to suppress withdrawal symptoms for the first 24 hours. This substitution established an equivalence ratio for this patient of 25 mg chlordiazepoxide-1 mg alprazolam. A gradual taper of chlordiazepoxide over the
M. H, Glosser
next 14 days was well-tolerated, and the patient was able to participate in rehabilitation, where she learned new techniques for dealing with her anxiety and somatic complaints. Younger patients undergoing alprazolam detoxification by this chlordiazepoxide substitution and taper method exhibited equivalence ratios of from 50: 1 up to 150: 1 chlordiazepoxide:alprazolam (Closser et al., 1990). DISCUSSION All problems identified with benzodiazepines are proportionally greater among the elderly, who can least afford these risks. Although abuse and dependence may be relatively rare phenomena in persons who do not abuse other drugs, these are not the only clinical problems with benzodiazepine use. Review of the literature leads to the inescapable conclusion that benzodiazepine prescribing for the elderly should be undertaken with the greatest caution and only with the recognition of all the above described potentially disastrous effects. The elderly are likely to respond to substance abuse treatment for benzodiazepine dependence as well as, or better than, younger patients. There is no consensus regarding the necessity of inpatient detoxification, but certainly an elderly patient with other medical problems will require careful assessment and observation. Treating clinicians are well advised to seek evidence of previous substance abuse and concurrent abuse of other substances, such as alcohol. Simultaneous use of alcohol and a benzodiazepine exacerbates problems associated with both drugs and complicates withdrawal from each. Among patients with other psychiatric diagnoses prompting initial benzodiazepine prescription, strong therapeutic alliance with the treatment provider will improve outcome and may be the only treatment needed for the original complaint. Careful assessment of the elderly patient’s medical, psychiatric, and social history will allow for important, appropriate interventions and help prevent unnecessary disability. REFERENCES Baum, C., Kennedy, D.L., & Forbes, M.B. (1984). Drug use in the United States in 1981. JAMA, 241, 1293. Beers, M., Avorn, J., Soumerai, S.B., Everitt, D.E., Sherman, D.S., & Salem, S. (1988). Psychoactive medication use in intermediate-care facility residents. JAMA, 260, 3016-3020. Bergman, H., Borg, S., & Holm, L. (1980). Neuropsychological impairment and exclusive abuse of sedatives or hypnotics. Amer-
ican Journal of Psychiatry, 137, 215-217. Buchsbaum, D.G., Boling, P., & Groh, M. (1987). Residents’ underdocumentatiqn in elderly patients’ records of prescriptions for benzodiazepine. Journal of Medical Education, 62, 438-440. Closser, M.H., Brower, K.J., & Beresford, T.P. (1990). Treatment
of alprazolam withdrawal tion of chlordiazepoxide
with substitution and gradual reduc(Abstract]. Alcoholism: Clinical and Experimental Research, 14, 136. Cook, P.J. (1986). Benzodiazepine hypnotics in the elderly. Acta
Psychiatrica Scandinavica, 332, 149-158. Finlayson, R.E., Hurt, R.D., Davis, L.J., & Morse, R.M. (1988). Alcoholism in elderly persons: A study of the psychiatric and psychosocial features of 216 inpatients. Mayo Clinic Proceed-
ings, 63, 761-768. Foy, A., Drinkwater, V., March, S., & Mearrick, P. (1986). Confusion after admission to hospital in elderly patients using benzodiazepines. British Medical Journal, 293, 1072. Gamzu, E.R. (1987). The role of benzodiazepines in amnesia: Laboratory predictors. Journal of Clinical Psychiatry Monograph,
5, 8-13. Gillin, J.C., & Byerley, W.F. (1990). The diagnosis and management of insomnia. New England Journal of Medicine, 322, 239-248. Gillin, J.C., Spinweber, C.L., & Johnson, L.C. (1989). Rebound insomnia: a critical review. Journal of Clinical Psychopharmacol-
ogy, 9, 161-172. Golombok, S., Moodley, P., & Lader, M. (1988). Cognitive impairment in long-term benzodiazepine users. Psychological Medicine, 18, 365-374. Greenblatt, D. J., Harmatz, J.S., Zinny, M.A., & Shader, RI. (1987). Effect of gradual withdrawal on the rebound sleep disorder after discontinuation of triazolam. New England Journal
of Medicine, 317, 722-728. Grymonpre, R.E., Mitenko, P.A., Sitar, D.S., Aoki, F.Y., & Montgomery, P.R. (1988). Drug-associated hospital admissions in older medical patients. Journal of the American Geriatric Soci-
ety, 36, 1092-1098. Hendler, N., Cimini, C., Ma, T., & Long, D. (1980). A comparison of cognitive impairment due to benzodiazepines and to narcotics. American Journal of Psychiatry, 137, 828-830. Hoehn-Saric, R., & McLeod, D.R. (1986). Physiological and performance responses to diazepam: Two types of effects. Psy-
chopharmacology Bulletin, 22, 439-443. Larson, E.B., Kukull, W.A., Buchner, D., & Reifler, B.V. (1987). Adverse drug reactions associated with global cognitive impairment in elderly persons. Annals of Internal Medicine, 107,
169-173. Lucki, I., & Rickels, K. (1986). The behavioral effects of benzodiazepines following long-term use. Psychopharmacology Bulle-
tin, 22, 424-433. Lucki, I., Rickels, K., & Geller, A.M. (1985). Psychomotor performance following the long-term use of benzodiazepines. Psy-
chopharmacology Bulletin, 21, 93-96. Lucki, I., Rickels, K., & Geller, A.M. (1986). Chronic use of benzodiazepines and psychomotor and cognitive test performance.
Psychopharmacology, 88, 426-433. Miller, F., Whitcup, S., Sacks, M., & Lynch, P.E. (1985). Unrccognized drug dependence and withdrawal in the elderly. Drug and Alcohol Dependence, 15, 177-179. Peturrson, H., Gudjonsson, G.H., & Lader, M.H. (1983). Psychometric performance during withdrawal from long-term benzodiazepine treatment. Psychopharmacology, 81, 345-349. Pinsker, H., & Suljaga-Petchel, K. (1984). Use of benzodiazepines in primary-care geriatric patients. Journal of the American Geri-
atric Society, 32, 595-597. Pomara, M., Deptula, D., Medel, M., Block, R.I., & Greenblatt, D.J. (1989). Effects of diazepam on recall memory: Relationship to aging, dose, and duration of treatment. Psychopharmacology Bulletin, 25, 144-148. Ray, W.A., Griffin, M.R., & Downey, W. (1989). Benzodiazepines of long and short elimination half-life and the risk of hip fracture. Journal of the American Medical Association, 262,
3303-3307.
Benzodiazepines and the Elderly Ray, W.A., Griffin, M.R., Schaffner, W., Baugh, D.K., & Melton, L.J. (1987). Psychotropic drug use and the risk of hip fracture. New England Journal of Medicine, 316, 363-369. Salzman, C., Shader, R.I., Greenblatt, D.J., & Harmatz, J.S. (1983). Long v short half-life benzodiazepines in the elderly. Archives of General Psychiatry, 40, 293-297. Scharf, M.B., Fletcher, K., & Graham, J.P. (1988). Comparative amnestic effects of benzodiazepine hypnotic agents. Journal of Clinical Psychiatry, 49, 134-137. Scharf, M.B., Saskin, P., & Fletcher, K. (1987). Benzodiazepine-induced amnesia: Chnical and laboratory findings. Journal of Clinical Psychiatry Monograph, 5, 14-17. Schneider-Helmert, D. (1988). Why low-dose benzodiazepine-dependent insomniacs can’t escape their sleeping pills. Acta Psychiatrica Scandinavica, 78, 706-711. Schweizer, E., Case, W.G., & Rickels, K. (1989). Benzodiazepine dependence and withdrawal in elderly patients. American Journal of Psychiatry, 146, 529-53 1. Skegg, D.C.G., Richards, S.M., & Doll, R. (1979). Minor tranquillizers and road accidents. British Medical Journal, 1, 917-919. Smiley, A. (1987). Effects of minor tranquillizers and antidepres-
41 sants on psychomotor performance. Journal of Clinical Psychiatry, 48 (Suppl.), 22-28. Sorock, G.S., & Shimkin, E.E. (1988). Benzodiazepine sedatives and the risk of falling in a community-dwelling elderly cohort. Archives of Internal Medicine, 148, 2441-2444. Sussman, N. (1987). Benzodiazepines and memory: A clinical perspective. Journal of Clinical Psychiatry Monograph, 5, 4-7. Swift, C.G. (1986). Special problems relating to the use of hypnotics in the elderly. Acta Psychiatrica Scandinavica Supplement, 73, 92-98. Thompson, T.L., Moran, M.G., & Nies, AS. (1983). Psychotropic drug use in the elderly, Part 1. New England Journal of Medicine, 308, 134-138. Tinetti, M.E., & Speechley, M. (1989). Prevention of falls among the elderly. New England Journal of Medicine, 320, 1055-1059. Whitcup, S.M., & Miller, F. (1987). Unrecognized drug dependence in psychiatrically hospitalized elderly patients. Journal of the American Geriatric Society, 35, 297-301, Zillmer, E.A., & Ball, J.D. (1989). Behavioral gerontology: Cognitive changes associated with normal and abnormal aging. Resident and Staff Physician, 35, 79-85.
1991 Copyright
Benzodiazepines
0
0740-5472191 $3.00 + .OO 1991 Pergamon Press plc
and the Elderly
A Review of Potential Problems
MARY H. CLOSSER, Yale School of Medicine,
New Haven,
DO Connecticut
Abstract - This article reviews the literature describing the extent of benzodiazepine use and abuse in the elderly and specific problems attendant upon this use. Unrecognized, undocumented use and abuse of psychoactive drugs is frequent in this population and can lead to serious problems with untreated dependence and withdrawal. The elderly appear to be more sensitive to the effects of benzodiazepines, both because of changed pharmacokinetics and pharmacodynamics with aging and because of altered postreceptor cerebral response. All problems identified with benzodiazepines such as dependence, withdrawal, and cognitive and psychomotor impairment are proportionally greater among the elderly, who can least afford these risks. Review of the literature leads to the conclusion that benzodiazepine prescribing for the elderly should be undertaken with the greatest caution and only with the recognition of all potentially disastrous effects. Keywords-
benzodiazepines; substance dependence; elderly; withdrawal; neuropsychological impairment; memory problems.
tion is expected to expand to 12.5%. Thirty percent of all prescription medications are given to the elderly (Baum, Kennedy, & Forbes, 1984), and twice the incidence of adverse drug reactions and side effects that younger patients have occurs in this population. Many of these medications are psychoactive drugs. In a study of medication use among intermediate-care facility residents (Beers et al., 1988), investigators discovered that more than half of all residents received a psychoactive medication. Twenty percent received a benzodiazepine, 87% of these as a standing order. Suboptimal choice of benzodiazepine was common as 30% received long-acting agents. Of the available sedative-hypnotic drugs, the benzodiazepines are by far the most frequently prescribed, and the elderly receive almost 40% of these prescriptions (Thompson, Moran, & Neis, 1983). Investigation of drug-associated hospital admissions in older patients has shown that up to 10% may be due to benzodiazepines (Grymonpre, Mitenko, Sitar, Aoki, & Montgomery, 1988). Despite increasing evidence that psychoactive drug use in the elderly can be problematic, many elderly persons receive such drug therapy.
INTRODUCTION LESS OFTEN DISCUSSED than broad concerns about benzodiazepines is the more specific issue of benzodiazepine prescribing for the elderly and its corollary problems. Schweizer, Case, and Rickels (1989) note that little is known about problems such as benzodiazepine withdrawal in the elderly, despite the remarkably high prevalence of chronic benzodiazepine use in this population. This article reviews the literature describing the extent of benzodiazepine use and abuse in the elderly and specific problems attendant upon this use.
DEMOGRAPHICS Elderly persons currently account for approximately 11% of the population; by the year 2000, this proporThe author would like to specially thank Kirk Brower, MD, for assistance in the preparation of this manuscript. Requests for reprints should be addressed to Mary H. Closser, DO, Central Treatment Unit, APT Foundation, 9144 Howard, New Haven, CT 06519.
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M. H. Closer
36
Unrecognized, undocumented use and abuse of psychoactive drugs is frequent in this population (Buchsbaum, Boling, & Groh, 1987) and can lead to serious problems with untreated dependence and withdrawal. In a prospective study of prescribing practices in ambulatory clinics, Buchsbaum et al. noted that internal medicine house officers significantly underrecorded the benzodiazepine medications they prescribed for their elderly patients and the indications for use of these drugs. Miller, Whitcup, Sacks, and Lynch (1985) describe cases of initially unrecognized and untreated benzodiazepine dependence in elderly persons and the polypharmacy that often confuses the picture, noting that extensive, unnecessary work-ups can result from unsuspected drug dependence. Medicine is not the only specialty that tends to miss the diagnosis of benzodiazepine dependence. Whitcup and Miller (1987) retrospectively reviewed 90 psychiatric inpatient records to determine the extent of unrecognized drug dependence and resulting complications. Twenty-one percent were drug dependent; 53% of these were unrecognized and were not detoxified. Of the unrecognized cases, 70% developed significant, serious medical complications requiring transfer to a medicine service. Unrecognized cases were significantly more likely to be older female benzodiazepine abusers; recognized cases, young male alcohol abusers. Among recognized cases of alcoholism in the elderly, benzodiazepine dependence is often a complication. Finlayson, Hurt, Davis, and Morse (1988) described the characteristics of 216 elderly inpatients in an alcohol treatment unit. Fourteen percent also had a drug abuse or dependence diagnosis, and all had been prescribed these medications. Eighty-seven percent of such medications were “minor tranquilizers or hypnotics,” other terminology sometimes used for benzodiazepines. Treatment for both alcohol and drug dependence disorders was required in this group. Other common diagnoses seen in this population were tobacco dependence (67Vo), some form of organic brain syndrome (440/o), and affective disorder (12%). Other investigators believe that concerns regarding the dangers of benzodiazepine dependence in the elderly are exaggerated. In a survey of an ambulatory elderly population (Pinsker & Suljaga-Petchel, 1984), half of the patients said they had never increased use of their benzodiazepine; none who had stopped use noted withdrawal symptoms, and 75% took it “only when needed.” The authors concluded that there was no evidence of addiction in their sample and further, that prolonged use of low-dose benzodiazepine in elderly patients is safe. It is unclear whether or not all criteria for psychoactive substance abuse or dependence were applied in diagnosing this sample. Another objection to their conclusion of benzodiazepine safety is that benzodiazepine use may cause problems in the elderly quite apart from abuse and dependence.
PHARMACOLOGIC
CHANGES
WITH AGING
Controlled studies have documented that the elderly are more sensitive to the effects of benzodiazepines than are the young. Reviews of this topic by Swift (1986) and Cook (1986) describe problems associated with accumulation, tolerance, intensity, and duration of drug response. Single doses of a benzodiazepine produce peak responses twice as great in elderly persons as in younger controls, while plasma drug concentrations were similar. Studies of patients requiring premeditation of diazepam showed that the dose and plasma concentration needed to produce a certain level of sedation decreased by 2 to 3 times between the ages of 20 and 80. Cook reviews speculation that this increase in acute response to single doses of benzodiazepine is likely due to some change in cerebral response instead of changes in pharmacokinetics. There is evidence that benzodiazepines induce greater increases in gamma amino butyric acid (GABA) binding and neuronal inhibition in elderly animals, which may account for this enhanced cerebral response. Differences in cerebral response among elderly patients are significant and complicate studies of the phenomenon. Psychomotor performance studies of regular dosing indicate that the elderly, especially those with dementia, hypoalbuminemia, or chronic renal failure are most at risk for prolonged sedation. Swift describes the changed pharmacokinetics in the elderly, which also affect response: decreased plasma clearance of those benzodiazepines requiring oxidative metabolism, increased volume of distribution of the drug caused by increased proportion of total body fat to lean body mass, and subsequent lowered peak plasma concentration and prolonged plasma half-life. Salzman, Shader, Greenblatt, and Harmatz (1983) describe the pharmacokinetic and clinical differences between multiple dosing of a long half-life (diazepam) and short half-life (oxazepam) benzodiazepine in an elderly sample. Absorption of diazepam was faster and onset of clinical effects more pronounced. Diazepam accumulated extensively, washed out slowly, and sedative effects persisted for 2 weeks after diazepam treatment was discontinued. However, there did not appear to be a difference between clinical degree of sedation during treatment, perhaps because of development of acute tolerance to central nervous system depression. The authors do not make conclusions regarding clinical efficacy of these drugs, but suggest that understanding the elderly patient’s different pharmacokinetics may help in appropriate drug selection in order to minimize side effects such as unwanted sedation or breakthrough of underlying symptoms. In summary, the elderly appear to be more sensitive to the effects of benzodiazepines, both because of changed pharmacokinetics and pharmacodynamics with aging and because of altered postreceptor cere-
Benzodiazepines and the Elderly
37
bral response. Appropriate choice of benzodiazepine cannot be based solely on consideration of elimination half-life, as this is only one factor affecting increased response.
individual titration of chlordiazepoxide to withdrawal symptoms is necessary.
WITHDRAWAL
There is an extensive literature on the neuropsychological effects of benzodiazepines (Bergman, Borg, & Holm, 1980; Golombok, Moodley, 8z Lader, 1988; Hendler, Cimini, Ma, & Long, 1980; Hoehn-Saric 8z McLeod, 1986; Lucki & Rickels, 1986; Lucki, Rickels, 8z Geller, 1985, 1986; Peturrson, Gudjonsson, & Lader, 1983; Smiley, 1987), which describes intellectual, cognitive, and psychomotor impairment as common effects of benzodiazepine treatment. Describing cognitive impairment caused solely by benzodiazepines in the elderly is a more complex problem. These is some controversy regarding the extent of “normal” functional cognitive impairment caused by aging, which, in any case, varies widely among individuals (Zillmer & Ball, 1989). Therefore, studies need to take into account normal patterns of cognitive loss and to carefully compare elderly patients to younger controls matched for other possible causes of impaired performance (e.g., education, previous level of functioning, medications, physical status).
Some reports have indicated that benzodiazepine withdrawal in the elderly may be more difficult than in younger patients. A prospective study of benzodiazepine use and withdrawal in elderly medical inpatients revealed half to be using these drugs (Foy, Drinkwater, March, & Mearrick, 1986). These patients had an increased risk of developing confusion during their hospital stay, especially those whose medications were stopped abruptly. They did not appear to develop other withdrawal symptoms, such as anxiety or insomnia, that are commonly noted in younger patients. The authors conclude that benzodiazepines should not be suddenly discontinued in elderly patients. Most clinicians would add that benzodiazepines should not be suddenly discontinued in any population. Another study of benzodiazepine withdrawal in elderly patients had different findings. Schweizer, Case, and Rickles (1989) compared severity of withdrawal symptoms and clinical outcome in a matched sample of elderly and younger benzodiazepine-dependent patients. The elderly patients showed significantly less severe withdrawal symptoms during a gradual taper and did as well at outcome as did younger patients. The authors speculate that the possible slower clearance of drug in the elderly patients would attenuate withdrawal symptoms (a “self-taper” mechanism). Another speculation derives from conceptualizing benzodiazepine withdrawal as due in part to a drug-discontinuation-induced overactivity or rebound of previously inhibited noradrenergic, serotonergic, and cholinergic neuronal activity. If functional neuronal capacity diminishes with age, benzodiazepine withdrawal might cause less rebound overactivity in elderly persons. Withdrawal from alprazolam is of much recent concern because of its widespread use. Alprazolam’s ability to cause dependence and withdrawal appeared to surprise many clinicians, and its possibly uniquely difficult withdrawal has led to controversy regarding its treatment. Closser, Brower, and Beresford (1990) describe sudden discontinuation of alprzolam, with substitution and subsequent taper of chlordiazepoxide as a rapid, well-tolerated technique for detoxification. They noted that an elderly, alprazolam-dependent woman required less chlordiazepoxide to suppress alprazolam withdrawal symptoms (25 mg chlordiazepoxide for each 1 mg alprazolam) than younger patients. However, they found a range of chlordiazepoxide dosages required in other patients (So-150 mg of chlordiazepoxide to 1 mg alprazolam) and emphasize that
NEUROPSYCHOLOGICAL
Cognitive
IMPAIRMENT
Impairment
Pomara, Deptula, Medel, Block, and Greenblatt (1989) devised a careful study of the effects of single 2.5- and IO-mg doses of diazepam and of chronic bedtime administration on elderly and young subjects. They found that single lo-mg doses impaired recall memory in all subjects; a 2.5-mg dose caused impaired cognition (increased “intrusion errors”) in the elderly only. Regular bedtime dosing of 10 mg caused significant next-day recall memory impairment in both age groups, and 2.5-mg bedtime dosing increased intrusion errors in both groups. The authors concluded that the elderly appear to have an increased sensitivity to some of diazepam’s deleterious cognitive effects. They also noted that partial tolerance appears to develop to the drug’s effects on memory with chronic administration. Drug-induced dementia is certainly the most easily treated form of cognitive impairment and yet is difficult to recognize. Medications can also exacerbate underlying dementia and greatly interfere with functional capacity. Larson, Kukull, Buchner, and Reifler (1987) prospectively assessed adverse drug reactions causing cognitive impairment in outpatients being evaluated for dementia. They found that sedative-hypnotics (especially long-acting benzodiazepines) were the most common drugs associated with cognitive impairments. This association was carefully documented by psychometric testing during drug use and after withdrawal. Although many patients remained demented after drug
M. H. Closer
38 withdrawal, all showed improved functioning with abstinence. Most of their patients had used benzodiazepines for years, and cognitive impairment appeared to develop insidiously as a “late complication” of a drug initially prescribed at a younger age. They also noted that some patients were given additional drugs to treat side effects, for example, neuroleptics given to patients who developed confusion on benzodiazepines. A monograph devoted to the amnestic effects of benzodiazepines extensively reviews clinical and laboratory findings and expresses concern that benzodiazepine-induced amnesia is often unrecognized (Gamzu, 1987; Scharf, Fletcher, & Graham, 1988; Scharf, Saskin, &Fletcher, 1987; Sussman, 1987). This amnesia is of particular concern for elderly users of benzodiazepines, whose memory problems may be exacerbated by the drugs or due to the drugs themselves, but instead are blamed on aging. Memory loss in the elderly is particularly devastating, as they fear progressive deterioration in functioning and loss of self. The drugs may be initially prescribed for treatment of anxiety, but can actually exacerbate the condition by impairing cognitive and motor functioning. These authors note that benzodiazepines, particularly the short-acting triazolam, lorazepam, and alprazolam, cause anterograde amnesia by interfering with the transfer of information from immediate to long-term memory storage. The problem, then, is not with retrieval of memory but with memory storage itself. The amnesia can occur for events transpiring long after peak drug effects have passed, for instance, amnesia for events during the day following bedtime administration of triazolam. Most persons suffering from benzodiazepine-induced amnesia are unaware of their memory losses and impaired learning ability. Unfortunately, these impairments may not be readily apparent during routine clinical interviewing. Specific cognitive screening questions are needed to test memory function and to identify those suffering from anterograde amnesia. Not all benzodiazepines produce the same degree of amnesia clinically. Research involving the benzodiazepine receptor indicates that receptor-binding affinity may account for the differences seen clinically. Memory impairment appears to be most frequent with those benzodiazepines having greatest receptorbinding affinity. Differences in lipophilicity and, hence, volume of distribution may account for the range and protraction of amnestic effects. The drug’s half-life does not determine its amnestic potential, as the amnestic effect lasts well beyond any sedative effect and can occur even when no sedation is noted. Thus, avoidance of the long-acting benzodiazepines in the elderly does not preclude problems, as the shortest-acting benzodiazepines also have the greatest amnestic potential (Scharf et al., 1988). Choice of benzodiazepine, either long-acting or short-acting,
long elimination half-life or short, will depend upon careful consideration of which side effects will be least deleterious to the individual patient.
Psychomotor
Impairment
Falls by the elderly are a significant source of morbidity and mortality. Injury is the sixth leading cause of death in the elderly, and most fatal injuries are caused by falls. There are many intrinsic risk factors for falling (Tinetti & Speechley, 1989), one of which is the use of medications including benzodiazepines. The deleterious effect of benzodiazepines on motor performance in the elderly has been related to increased risk of falling and to hip fracture. A prospective study of risk factors for falls in ambulatory elderly patients showed that continuous use of benzodiazepines appeared to increase the risk of falling, and any use of benzodiazepines was related to multiple falls in persons who fell (Sorock & Shimkin, 1988). They noted that the risk of falling caused by continuous benzodiazepine use appears to be higher in patients with loss of proprioceptive sensation in the toes. The authors discuss evidence for a direct effect of benzodiazepines on the cerebellum, which results in ataxia and loss of coordination, likely caused by impairment of motor responses to loss of balance. Sedation and hypotension also contribute to impairment of motor function. They caution clinicians to review carefully the use of these drugs in elderly patients and to taper the drugs cautiously when no longer essential. Several studies have assessed the risk of hip fracture in elderly persons who receive psychotropic drugs. Ray, Griffin, Schaffner, Baugh, and Melton (1987) performed a case-control study of elderly patients with hip fractures who used psychotropics and those who did not. A significantly increased risk of hip fracture was found with the use of long elimination halflife drugs (hypnotic-anxiolytics, antidepressants, and neuroleptics). The principal authors later specifically investigated the risk of hip fracture in elderly users of long and short elimination half-life benzodiazepines (Ray, Griffin, & Downey, 1989). Current users of long half-life elimination benzodiazepines had a 70% greater risk of hip fracture than patients taking no psychotropic drug. This increased risk persisted after the first 30 days of therapy, indicating no development of tolerance to psychomotor impairment. As in their earlier article, the authors emphasize that long half-life benzodiazepines should be used with great caution in the elderly. Another significant cause of injuries in the elderly is automobile accidents. Impaired vision and hearing can impair driving skills; the added sedation and cognitive impairment caused by benzodiazepines may increase the number of accidents in this population. This public is aware today of the importance of alco-
Benzodiazepines and the Elderly
ho1 in causing automobile accidents, but is much less aware of the role of other drugs. In a prospective study, Skegg, Richards, and Doll (1979) discovered a highly significant association between the use of “minor tranquilizers” and the risk of serious automobile accident. The number of elderly persons in this study was small, but one might speculate that their risk would be even greater.
SLEEP DISORDERS
Many elderly persons suffer from insomnia or other sleep disorders; and benzodiazepines are frequently prescribed for this indication. The prevalence of insomnia increases with age and with the presence of medical disorders (Gillin & Byerley, 1990), making hospitalized elderly the largest consumers of benzodiazepine hypnotics. Despite recommendations that hypnotics be utilized only as adjunctive treatment for insomnia on a short-term basis, long-term prescribing of these medications is common. Patients invariably complain of worsening of their sleep disorder during withdrawal of the hypnotic, leading them to object strenuously to its discontinuation and their physicians to continue prescribing. Gillin, Spinweber, and Johnson (1989) review evidence for rebound insomnia after discontinuation of benzodiazepine hypnotics and conclude that the risk is greater with short half-life as compared with the long half-life benzodiazepines. Of importance is that this rebound insomnia (withdrawal) may occur even at low, therapeutic doses, particularly with short-acting benzodiazepines because of the development of tolerance and dependence. This may lead to increasing doses or selection of a longer-acting benzodiazepine, which increases the risk of toxicity from accumulation in the elderly. The pharmacological dependence worsens with continued use if escalating doses of the short-acting preparations are used to offset rebound insomnia (actually, withdrawal insomnia). Schneider-Helmert (1988) investigated in the sleep laboratory the effectiveness of benzodiazepines as hypnotics in low-dose dependent elderly insomniacs. He discovered that benzodiazepine-dependent subjects has equally short, but qualitatively worse, sleep when compared to drug-free insomniacs. Slow-wave and REM sleep were both suppressed in benzodiazepine users. However, drug users typically overestimated their total sleep time when given hypnotics. This overestimation of sleep time is likely the result of anterograde amnesia and confuses patients’ assessments of the drug’s effectiveness and of rebound insomnia. True withdrawal insomnia does occur during discontinuation of benzodiazepine hypnotics (see earlier), but this amnesia makes the symptom appear even worse. Clinicians would be well advised to taper benzodi-
39
azepine hypnotics on discontinuation as they would normally taper anxiolytics. Greenblatt, Harmatz, Zinny, and Shader (1987) studied the effects of sudden or gradual discontinuation from triazolam on withdrawal insomnia (“rebound sleep disorder”). Abrupt withdrawal subjects experienced prolonged sleep latency, reduced sleep duration, and increased awakenings compared to subjects who received a taper over 4 nights. This taper method is recommended as a means to help prevent continued drug use caused by rebound insomnia in patients who would otherwise wish to stop.
CLINICAL
EXAMPLES
A delirious 71-year-old widower living in a supervised apartment was brought into the emergency room by the building manager, who insisted that the patient had been drinking. The widower was known to have been attending AA meetings regularly with the assistance of local AA members, who denied seeing the man intoxicated before. He was admitted to a detoxification unit, where he was seen to be disoriented with marked impairment in immediate and short-term memory. He angrily denied any use of alcohol or medications; breathalyzer testing was negative, and urine screening revealed the presence of benzodiazepine. Search of his apartment by the building manager revealed a nearly empty bottle of triazolam. The patient’s delirium and memory impairments gradually cleared over 4 days during a careful, low-dose diazepam substitution and taper. He later recalled having taken only two pills from his newly renewed supply of sleeping pills, which he angrily refused to call “medication.” “ That isn’t a drug - I need it to sleep! ” After a 3-week rehabilitation stay, the patient was sleeping soundly without any hypnotics and had a much better understanding of his addictions. A 59-year-old professor was self-referred for inpatient detoxification from alprazolam when she became concerned about addiction. She had seen an article in a newspaper about alprazolam and was quite frightened by the story. She had been prescribed diazepam for 2 years for anxious symptoms and had required hospitalization for its discontinuation; a new psychiatrist prescribed alprazolam, which she now had been taking for 24 months and was unable to stop despite repeated attempts. She felt herself to be less able to think and had missed significant amounts of time from work when trying to detoxify herself. Alprazolam was discontinued, and chlordiazepoxide 25 mg was administered orally every 4 hours as needed to suppress withdrawal symptoms for the first 24 hours. This substitution established an equivalence ratio for this patient of 25 mg chlordiazepoxide-1 mg alprazolam. A gradual taper of chlordiazepoxide over the
M. H, Glosser
next 14 days was well-tolerated, and the patient was able to participate in rehabilitation, where she learned new techniques for dealing with her anxiety and somatic complaints. Younger patients undergoing alprazolam detoxification by this chlordiazepoxide substitution and taper method exhibited equivalence ratios of from 50: 1 up to 150: 1 chlordiazepoxide:alprazolam (Closser et al., 1990). DISCUSSION All problems identified with benzodiazepines are proportionally greater among the elderly, who can least afford these risks. Although abuse and dependence may be relatively rare phenomena in persons who do not abuse other drugs, these are not the only clinical problems with benzodiazepine use. Review of the literature leads to the inescapable conclusion that benzodiazepine prescribing for the elderly should be undertaken with the greatest caution and only with the recognition of all the above described potentially disastrous effects. The elderly are likely to respond to substance abuse treatment for benzodiazepine dependence as well as, or better than, younger patients. There is no consensus regarding the necessity of inpatient detoxification, but certainly an elderly patient with other medical problems will require careful assessment and observation. Treating clinicians are well advised to seek evidence of previous substance abuse and concurrent abuse of other substances, such as alcohol. Simultaneous use of alcohol and a benzodiazepine exacerbates problems associated with both drugs and complicates withdrawal from each. Among patients with other psychiatric diagnoses prompting initial benzodiazepine prescription, strong therapeutic alliance with the treatment provider will improve outcome and may be the only treatment needed for the original complaint. Careful assessment of the elderly patient’s medical, psychiatric, and social history will allow for important, appropriate interventions and help prevent unnecessary disability. REFERENCES Baum, C., Kennedy, D.L., & Forbes, M.B. (1984). Drug use in the United States in 1981. JAMA, 241, 1293. Beers, M., Avorn, J., Soumerai, S.B., Everitt, D.E., Sherman, D.S., & Salem, S. (1988). Psychoactive medication use in intermediate-care facility residents. JAMA, 260, 3016-3020. Bergman, H., Borg, S., & Holm, L. (1980). Neuropsychological impairment and exclusive abuse of sedatives or hypnotics. Amer-
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Benzodiazepines and the Elderly Ray, W.A., Griffin, M.R., Schaffner, W., Baugh, D.K., & Melton, L.J. (1987). Psychotropic drug use and the risk of hip fracture. New England Journal of Medicine, 316, 363-369. Salzman, C., Shader, R.I., Greenblatt, D.J., & Harmatz, J.S. (1983). Long v short half-life benzodiazepines in the elderly. Archives of General Psychiatry, 40, 293-297. Scharf, M.B., Fletcher, K., & Graham, J.P. (1988). Comparative amnestic effects of benzodiazepine hypnotic agents. Journal of Clinical Psychiatry, 49, 134-137. Scharf, M.B., Saskin, P., & Fletcher, K. (1987). Benzodiazepine-induced amnesia: Chnical and laboratory findings. Journal of Clinical Psychiatry Monograph, 5, 14-17. Schneider-Helmert, D. (1988). Why low-dose benzodiazepine-dependent insomniacs can’t escape their sleeping pills. Acta Psychiatrica Scandinavica, 78, 706-711. Schweizer, E., Case, W.G., & Rickels, K. (1989). Benzodiazepine dependence and withdrawal in elderly patients. American Journal of Psychiatry, 146, 529-53 1. Skegg, D.C.G., Richards, S.M., & Doll, R. (1979). Minor tranquillizers and road accidents. British Medical Journal, 1, 917-919. Smiley, A. (1987). Effects of minor tranquillizers and antidepres-
41 sants on psychomotor performance. Journal of Clinical Psychiatry, 48 (Suppl.), 22-28. Sorock, G.S., & Shimkin, E.E. (1988). Benzodiazepine sedatives and the risk of falling in a community-dwelling elderly cohort. Archives of Internal Medicine, 148, 2441-2444. Sussman, N. (1987). Benzodiazepines and memory: A clinical perspective. Journal of Clinical Psychiatry Monograph, 5, 4-7. Swift, C.G. (1986). Special problems relating to the use of hypnotics in the elderly. Acta Psychiatrica Scandinavica Supplement, 73, 92-98. Thompson, T.L., Moran, M.G., & Nies, AS. (1983). Psychotropic drug use in the elderly, Part 1. New England Journal of Medicine, 308, 134-138. Tinetti, M.E., & Speechley, M. (1989). Prevention of falls among the elderly. New England Journal of Medicine, 320, 1055-1059. Whitcup, S.M., & Miller, F. (1987). Unrecognized drug dependence in psychiatrically hospitalized elderly patients. Journal of the American Geriatric Society, 35, 297-301, Zillmer, E.A., & Ball, J.D. (1989). Behavioral gerontology: Cognitive changes associated with normal and abnormal aging. Resident and Staff Physician, 35, 79-85.