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Problems With Benzodiazepines in Elderly Patients

1993; Elsevier BV; Volume: 68; Issue: 8 Linguagem: Inglês

10.1016/s0025-6196(12)60643-0

1942-5546

Steven M. Juergens,

EEG and Brain-Computer Interfaces

For 4 decades, benzodiazepines have been used in clinical practice, and critical examination of these agents continues. Although in some ways they are among the safest psychotropic drugs (that is, overdoses are not lethal), concern about various adverse effects has been increasing. An ambivalent attitude is reflected internationally—Great Britain has removed one triazolobenzodiazepine (triazolam) from the marketplace because of concern about adverse effects, whereas another (alprazolam) has gained approval in the United States for treatment of panic disorder in dosages of up to 10 mg/day. Often, benzodiazepines are prescribed on a long-term basis; 1 to 3% of the population in the Western world have received continuous benzodiazepine therapy for more than 1 year. Most studies consistently find that rates of use of benzodiazepines are substantially higher among female than among male subjects and are higher among older than among younger subjects.1Balter MB Manheimer DI Mellinger GD Uhlenhuth EH A cross-national comparison of anti-anxiety/sedative drug use.Curr Med Res Opin. 1984; 8: 5-18PubMed Google Scholar Frequently, inappropriately large doses of benzodiazepines are prescribed with minimal physician follow-up, especially among elderly patients.2Shorr RI Bauwens SF Landefeld CS Failure to limit quantities of benzodiazepine hypnotic drugs for outpatients: placing the elderly at risk.Am J Med. 1990; 89: 725-732Abstract Full Text PDF PubMed Scopus (49) Google Scholar The problems that arise with the use of benzodiazepines may be subtle. Thus, clinicians, patients, and family members may have difficulty recognizing them or may assume that they are psychopathologic changes rather than drug-induced effects. All benzodiazepines can cause memory-related problems. In most studies, the ability of patients to learn new information is impaired (anterograde amnesia) after benzodiazepine therapy. Apparently, this impairment results from disruption of the transfer of information from temporary, short-term memory to some type of longer term memory storage (the consolidation phase).3Task Force on Benzodiazepine Dependency Benzodiazepine Dependence, Toxicity and Abuse: A Task Force Report of the American Psychiatric Association. American Psychiatric Association, Washington (DC)1990Google Scholar Anterograde amnesia becomes more severe with increased dose, faster absorption, intravenous administration, and higher potency of the benzodiazepines. Tolerance to the anterograde amnesia occurs but is incomplete. In long-term users, transient amnesic effects can occur related to peak benzodiazepine levels after administration.4King DJ Benzodiazepines, amnesia and sedation: theoretical and clinical issues and controversies.Hum Psychopharmacol Clin Exp. 1992; 7: 79-87Crossref Scopus (38) Google Scholar Elderly patients are more sensitive than young patients to the effects of benzodiazepines on memory.3Task Force on Benzodiazepine Dependency Benzodiazepine Dependence, Toxicity and Abuse: A Task Force Report of the American Psychiatric Association. American Psychiatric Association, Washington (DC)1990Google Scholar The report by Rummans and associates in this issue of the Mayo Clinic Proceedings (pages 731 to 737) reveals that the impairment of learning and short- and long-term retention, as measured by the Auditory-Verbal Learning Test, extends into the first week after completion of a tapering of the dose of benzodiazepines to discontinuation in patients who are addicted to benzodiazepines only. Whether the change is permanent or improvement occurs after a longer period is unclear. The patients were tested a mean of 6 to 7 days after completion of a 7- to 10-day tapering protocol with use of chlordiazepoxide and showed no symptoms of withdrawal at the time of testing. In elderly patients, however, the metabolism of longer acting benzodiazepines can last for weeks.3Task Force on Benzodiazepine Dependency Benzodiazepine Dependence, Toxicity and Abuse: A Task Force Report of the American Psychiatric Association. American Psychiatric Association, Washington (DC)1990Google Scholar Results may have been affected by persistent effects of the drug at the time of testing. Some evidence indicates that elderly patients have a considerable improvement in measures of memory and cognitive functioning after discontinuation of benzodiazepine therapy. Family members and staff note that patients who discontinue the use of benzodiazepines are brighter, more energetic, less dysphoric, and substantially more intellectually alert than while receiving the drug.5Larson EB Kukull WA Buchner D Reifler BV Adverse drug reactions associated with global cognitive impairment in elderly persons.Ann Intern Med. 1987; 107: 169-173Crossref PubMed Scopus (292) Google Scholar6Salzman C Fisher J Nobel K Glassman R Wolfson A Kelley M Cognitive improvement following benzodiazepine discontinuation in elderly nursing home residents.Int J Geriatr Psychiatry. 1992; 7: 89-93Crossref Scopus (102) Google Scholar The increased sensitivity of elderly patients may be due, in part, to a lower baseline performance; thus, an equal decrement in a younger and an older patient would be more noticeable and have more serious consequences in the elderly patient.3Task Force on Benzodiazepine Dependency Benzodiazepine Dependence, Toxicity and Abuse: A Task Force Report of the American Psychiatric Association. American Psychiatric Association, Washington (DC)1990Google Scholar The long-term use of benzodiazepines in elderly patients commonly exacerbates underlying dementia and may cause excessive morbidity. Often, the cognitive impairment seems to develop insidiously as a “late complication” of a drug initially prescribed at a younger age. In some patients, other drugs may be administered to treat side effects of the benzodiazepines—for example, a neuroleptic agent may be prescribed for patients who have confusion from benzodiazepine therapy.5Larson EB Kukull WA Buchner D Reifler BV Adverse drug reactions associated with global cognitive impairment in elderly persons.Ann Intern Med. 1987; 107: 169-173Crossref PubMed Scopus (292) Google Scholar The benzodiazepine-induced memory problems may be unrecognized by patients, family members, or clinicians; thus, the actual incidence of benzodiazepine-related problems is unknown. Patients who have such memory problems may conclude that nothing worth remembering had happened if they are unable to recall events. Alternatively, memory problems may be attributed to aging rather than the pharmaceutical agent. Both short-term and long-term therapy with benzodiazepines also impair cognitive and neuromotor functioning, although the effects of long-term administration have been inconsistent in experimental subjects.3Task Force on Benzodiazepine Dependency Benzodiazepine Dependence, Toxicity and Abuse: A Task Force Report of the American Psychiatric Association. American Psychiatric Association, Washington (DC)1990Google Scholar Sedation, drowsiness, ataxia, incoordination, diplopia, vertigo, and dizziness are common side effects related to dose and individual susceptibility. Tolerance to these effects develops but may be incomplete.3Task Force on Benzodiazepine Dependency Benzodiazepine Dependence, Toxicity and Abuse: A Task Force Report of the American Psychiatric Association. American Psychiatric Association, Washington (DC)1990Google Scholar Impaired visual spatial ability and sustained attention have been found in long-term benzodiazepine users, and patients are unaware of their diminished ability.7Golombok S Moodley P Lader M Cognitive impairment in long-term benzodiazepine users.Psychol Med. 1988; 18: 365-374Crossref Scopus (153) Google Scholar Again, elderly patients seem to be at increased risk of benzodiazepine-induced psychomotor impairment, and the impairment may gradually worsen with stable therapeutic levels. Use of alcohol, high doses of benzodiazepines, and administration of other drugs such as anticholinergic agents are associated with increased sensitivity for cognitive and psychomotor effects.3Task Force on Benzodiazepine Dependency Benzodiazepine Dependence, Toxicity and Abuse: A Task Force Report of the American Psychiatric Association. American Psychiatric Association, Washington (DC)1990Google Scholar These foregoing problems translate into an increased risk of deleterious events. Benzodiazepines may impair specific driving skills, but such effects are inconsistent from person to person and may depend on dose and time of administration. These skills are most affected during benzodiazepine therapy in elderly patients,3Task Force on Benzodiazepine Dependency Benzodiazepine Dependence, Toxicity and Abuse: A Task Force Report of the American Psychiatric Association. American Psychiatric Association, Washington (DC)1990Google Scholar who have a significantly increased risk of injurious motor vehicle accidents and a substantially increased relative risk with high-dose regimens.8Ray WA Fought RL Decker MD Psychoactive drugs and the risk of injurious motor vehicle crashes in elderly drivers.Am J Epidemiol. 1992; 136: 873-883Crossref PubMed Scopus (378) Google Scholar Current users of long half-life benzodiazepines have a significantly increased risk of falling and sustaining a hip fracture; this risk does not dissipate after the first 30 days of therapy, an indication that tolerance to the impairment does not develop.9Ray WA Griffin MR Downey W Benzodiazepines of long and short elimination half-life and the risk of hip fracture.JAMA. 1989; 262: 3303-3307Crossref PubMed Scopus (477) Google Scholar Short half-life benzodiazepines also pose considerable hazards for older patients. During the first few hours after administration, severely incapacitating psychomotor effects increase the risk of falling should patients need to get out of bed for any reason.10Fisch HU Baktir G Karlaganis G Minder C Bircher J Excessive motor impairment two hours after triazolam in the elderly.Eur J Clin Pharmacol. 1990; 38: 229-232Crossref PubMed Scopus (16) Google Scholar Behavioral disinhibition reactions during treatment with various benzodiazepines have been reported more commonly in elderly than in younger patients. Studies have shown that severe anxiety and depressive psychopathologic symptoms persist in many long-term benzodiazepine users while the therapy is continued. After successful withdrawal from long-term benzodiazepine treatment, however, patients have substantially improved anxiety and depression scores in comparison with baseline values, an implication that long-term use of benzodiazepines may worsen depression and anxiety.11Schweizer E Rickels K Case WG Greenblatt DJ Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper.Arch Gen Psychiatry. 1990; 47: 908-915Crossref Scopus (166) Google Scholar Depression has been noted to emerge during benzodiazepine therapy.3Task Force on Benzodiazepine Dependency Benzodiazepine Dependence, Toxicity and Abuse: A Task Force Report of the American Psychiatric Association. American Psychiatric Association, Washington (DC)1990Google Scholar In addition, deterioration in mood and social behavior in subjects receiving benzodiazepines has been noted by objective raters but not by the subjects themselves; therefore, negative effects may be difficult to elicit by self-report.12Griffiths RR Bigelow GE Liebson I Differential effects of diazepam and pentobarbital on mood and behavior.Arch Gen Psychiatry. 1983; 40: 865-873Crossref PubMed Scopus (87) Google Scholar The withdrawal symptoms are another complicating factor in the use of benzodiazepines (Table 1). More than 90% of long-term users (8 to 12 months or longer) of benzodiazepines experience withdrawal symptoms (“new” time-limited symptoms that are not part of the original anxiety state) even if the withdrawal process is slow.11Schweizer E Rickels K Case WG Greenblatt DJ Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper.Arch Gen Psychiatry. 1990; 47: 908-915Crossref Scopus (166) Google Scholar13Rickels K Schweizer E Weiss S Zavodnick S Maintenance drug treatment for panic disorder. II. Short- and long-term outcome after drug taper.Arch Gen Psychiatry. 1993; 50: 61-68Crossref Scopus (83) Google Scholar Slow withdrawal, however, is associated with less severe problems than is abrupt discontinuation.3Task Force on Benzodiazepine Dependency Benzodiazepine Dependence, Toxicity and Abuse: A Task Force Report of the American Psychiatric Association. American Psychiatric Association, Washington (DC)1990Google Scholar Gradual tapering of the dose of alprazolam after long-term treatment of panic disorder results in pronounced rebound of panic and anxiety symptoms above pretreatment levels in more than 50 to 90% of patients, depending on how the symptoms are measured.13Rickels K Schweizer E Weiss S Zavodnick S Maintenance drug treatment for panic disorder. II. Short- and long-term outcome after drug taper.Arch Gen Psychiatry. 1993; 50: 61-68Crossref Scopus (83) Google Scholar The incidence of withdrawal symptoms apparently is less in short-term users (less than 6 to 8 months) of benzodiazepines—although symptoms can develop within weeks, especially if large doses of high-potency agents are used. High-potency, quickly eliminated benzodiazepines seem to cause the most severe withdrawal syndrome.Table 1Commonly Observed Symptoms Associated With Withdrawal of BenzodiazepinesFrom Roy-Byrne PP. Benzodiazepines: dependence and withdrawal. In: Roy-Byrne PP, Cowley DS, editors. Benzodiazepines in Clinical Practice: Risks and Benefits. Washington (DC): American Psychiatric Press, 1991: 138. By permission. AnxietyIrritabilityInsomniaFatigueHeadacheMuscle twitching or achingTremor, shakinessSweatingDizzinessDifficulties with concentration*Symptoms more likely to represent true withdrawal rather than an exacerbation or return of original anxiety.Nausea, loss of appetite*Symptoms more likely to represent true withdrawal rather than an exacerbation or return of original anxiety.Observable depression*Symptoms more likely to represent true withdrawal rather than an exacerbation or return of original anxiety.Depersonalization, derealization*Symptoms more likely to represent true withdrawal rather than an exacerbation or return of original anxiety.Increased sensory perception (smell, light, taste, touch)*Symptoms more likely to represent true withdrawal rather than an exacerbation or return of original anxiety.Abnormal perception or sensation of movement* Symptoms more likely to represent true withdrawal rather than an exacerbation or return of original anxiety. Open table in a new tab The inability of patients on long-term benzodiazepine therapy to discontinue use of the drug because of withdrawal symptoms is of concern. Even with a slow withdrawal procedure for 1 month, more than a third of the subjects are unable to discontinue therapy.11Schweizer E Rickels K Case WG Greenblatt DJ Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper.Arch Gen Psychiatry. 1990; 47: 908-915Crossref Scopus (166) Google Scholar13Rickels K Schweizer E Weiss S Zavodnick S Maintenance drug treatment for panic disorder. II. Short- and long-term outcome after drug taper.Arch Gen Psychiatry. 1993; 50: 61-68Crossref Scopus (83) Google Scholar Once therapy is begun, a cycle of dependence, withdrawal, continued treatment, and further dependence may develop. In comparison with young patients, elderly patients may have a less severe withdrawal syndrome associated with gradual tapering of the dose, possibly because the slower clearance of the drug in elderly patients attenuates withdrawal symptoms.14Schweizer E Case WG Rickels K Benzodiazepine dependence and withdrawal in elderly patients.Am J Psychiatry. 1989; 146: 529-531Crossref PubMed Google Scholar Addiction to benzodiazepines is another adverse consequence of their use. The current report by Rummans and colleagues highlights a group of patients addicted to benzodiazepines only. Two patterns of benzodiazepine abuse and dependence are most prominent—patients who use only benzodiazepines for long periods and those who use benzodiazepines in the context of multidrug abuse. In general, patients who use benzodiazepines only are considerably older and take comparatively lower daily doses but have more difficulty with discontinuation because of withdrawal symptoms.15Busto U Sellers EM Naranjo CA Cappell HD Sanchez-Craig M Simpkins J Patterns of benzodiazepine abuse and dependence.Br J Addict. 1986; 81: 87-94Crossref PubMed Scopus (79) Google Scholar In prescribing benzodiazepines, one needs to weigh carefully the potential therapeutic benefit against the risk of developing physical dependence, acute and chronic toxic reactions, and addiction. In most patients, use should be short term (less than 2 to 4 months) with as low a dose as is effective. Longer use should regularly be reevaluated to ensure that continued benzodiazepine therapy is appropriate and without problems. DuPont16DuPont RL A practical approach to benzodiazepine discontinuation.J Psychiatr Res. 1990; 24: 81-90Abstract Full Text PDF Scopus (14) Google Scholar reported a checklist to determine the appropriateness of continued benzodiazepine use: (1) the diagnosis, distress, and disability warrant the use; (2) the benzodiazepine is yielding an acceptable therapeutic response with appropriate doses and no other drug or alcohol addiction; (3) no benzodiazepine-induced problem is evident; and (4) a family member or significant other can confirm the effectiveness of benzodiazepine use and the absence of impairment and addiction. Identifying problems is easier in patients who use benzodiazepines in the context of addiction to multiple drugs or alcohol (or both) or in patients who escalate the dose of benzodiazepines. Frequently, the adverse consequences of addiction are obvious in their lives. Diagnosing benzodiazepine-related problems in patients who receive therapeutic doses of the drug is more difficult. Evidence of toxicity (that is, memory difficulties, psychomotor effects, benzodiazepine-induced depression or anxiety, or behavioral disinhibition) may be subtle, unobtrusive, or attributed to other causes; hence, the physician, family members, friends, or patients may be unaware that the problems are caused by benzodiazepines. When patients on benzodiazepine therapy continue to have psychiatric symptoms or problems that could be ascribed to the drug, the benzodiazepine is potentially causative. For assessment of the cause of the problems or symptoms, often the only approach available is to taper the dose and ultimately discontinue the treatment. Beyond detoxification, little has been written about the treatment for benzodiazepine dependence. Treatment decisions depend on the diagnosis. If a diagnosis of dependence on a psychoactive substance—a benzodiazepine only or in conjunction with alcohol or a multidrug dependence—is established on the basis of the revised third edition of the Diagnostic and Statistical Manual of Mental Disorders from the American Psychiatric Association, therapy for chemical dependence is favored in combination with other psychiatric treatments if comorbid conditions are present. If physical dependence exists without other adverse effects, the clinician and the patient can decide whether to continue treatment or to detoxify from benzodiazepines and attempt alternative treatments, if necessary, for comorbid conditions. If benzodiazepines may be a factor in exacerbating the patient's problem, withdrawal is preferred, and observation off benzodiazepine therapy should be continued for at least 6 weeks to allow the effects of withdrawal or rebound to be distinguished from recurrence of the psychiatric symptoms. Benzodiazepines are unique in that they are the only addicting drug used routinely in medical practice. Elderly patients are particularly susceptible to development of complications. These medications are effective, but close monitoring by a physician is necessary.3Task Force on Benzodiazepine Dependency Benzodiazepine Dependence, Toxicity and Abuse: A Task Force Report of the American Psychiatric Association. American Psychiatric Association, Washington (DC)1990Google Scholar The potential for occurrence of physical dependence, adverse effects, and addiction must be weighed and respected.