Kathy Sykora

Withdrawal reaction after long-term therapeutic use of benzodiazepines.

We conducted a double-blind, placebo-controlled trail in which 40 patients who had undergone long-term therapy with benzodiazepines were switched to placebo or to diazepam in a dose approximately equivalent to their usual dose of the benzodiazepine; the dose of diazepam was then tapered during an eight-week period. Patients were assessed clinically and psychologically and had weekly sessions of behavioral therapy. The subjects who received placebo had more symptoms, assessed their symptoms as more severe, and stopped taking the study drug at a higher rate than those receiving the tapering doses of diazepam. The subjects in the placebo group also had symptoms shortly after being switched to placebo, whereas those in the diazepam group had symptoms much later. Some withdrawal symptoms were distinct from those of anxiety (e.g., tinnitus, involuntary movement, and perceptual changes). Withdrawal symptoms occurred earlier in patients who had received short-acting benzodiazepines than in those who had received long-acting benzodiazepines. Symptoms gradually disappeared over a four-week period in both the placebo and the diazepam groups. Serial determination of plasma benzodiazepine concentrations was a useful way to assess compliance, treatment outcome, and relapse during withdrawal. We conclude that a clinically important, mild, but distinct withdrawal syndrome occurs after discontinuation of long-term therapeutic use of benzodiazepines.

The serotonin uptake inhibitor citalopram attenuates ethanol intake

No effective drug for decreasing ethanol intake is available for clinical use. Our previous studies showed that zimeldine decreased ethanol intake in rats and nondepressed alcohol abusers. However, zimeldine was withdrawn from the market because of serious toxicity. We tested citalopram, a selective serotonin uptake inhibitor, in 39 male nondepressed early‐stage problem drinkers (aged 19 to 61 years). Subjects were randomly allocated to receive either citalopram, 20 (n = 20) or 40 (n = 19) mg/day orally, or placebo in a double‐blind, crossover trial. Citalopram administration and ethanol intake were assessed by self‐report and objectively. Citalopram, 20 mg/day, did not show an effect. However, citalopram, 40 mg/day, decreased the number of drinks consumed (F1,17 = 5.27; P < 0.05) and increased the number of abstinent days (F1,17 = 13.18; P < 0.005). The effect is probably through modulation of the neurobiologic mechanisms regulating ethanol intake. Our results suggest a new pharmacologic approach to decrease ethanol intake.

Zimelidine‐induced variations in alcohol intake by nondepressed heavy drinkers

The effect of zimelidine, a specific serotonin‐reuptake inhibitor, on alcohol intake was tested in 13 healthy male, nondepressed heavy drinkers who were randomly allocated to receive zimelidine or placebo in a double‐blind, crossover experiment. There were five 2‐wk experimental periods (baseline, placebo 1 and 2, and zimelidine 1 and 2). Treatment was discontinued in three subjects due to a suspected adverse reaction and three other subjects dropped out. Thus, 13 subjects participated in at least two experimental drug periods and only 10 participated in all the periods. In the 13 subjects zimelidine increased the days of abstinence and decreased the daily number of drinks consumed, whereas in the 10 subjects only the number of days of abstinence increased. Subjects did not report aversive alcohol‐sensitizing reactions. Spielberger state‐anxiety test scores and depression scores (Montgomery/Asberg and Hamilton) were low at the beginning and throughout the study. Our data suggest that zimelidine modifies alcohol intake by a different mechanism than previously tested drugs, possibly by modulating the central neural mechanism that controls drinking of alcohol.

Diazepam loading: Simplified treatment of alcohol withdrawal

Alcohol withdrawal therapy can be simplified with a loading dose of diazepam, taking advantage of the kinetic tapering afforded by the drugs long t½s and its metabolites, and of the effectiveness of nonpharmacologic maneuvers. In a double‐blind trial, 50 inpatients in moderate to severe alcohol withdrawal received 20 mg oral diazepam and supportive care (n = 25) or placebo and supportive care (n = 25) every 2 hr until they were asymptomatic. Fifty‐six percent of patients responded to placebo within 5 ± 2.9 hr (mean ± SD), whereas 72% responded to initial diazepam within 6.3 ± 3.9 hr. Patients treated with diazepam had more rapid and greater improvement than those treated with placebo. Patients who did not respond to six doses of diazepam received further (unblinded) diazepam, 20 mg, every 1 to 2 hr. All patients who did not initially respond (n = 18) improved after more diazepam. Thus all patients who received diazepam (n = 36), during the experimental phase or subsequently, were effectively treated. There were no adverse effects. The median number of 20‐mg diazepam doses to treat alcohol withdrawal were three, given over a period of 7.6 hr (range = 1 to 12 and 0.33 to 45 hr). Complications occurred only in those who received placebo during the experimental phase, indicating that delay in therapy may be responsible for the appearance of complications in alcohol withdrawal.

Nonpharmacologic intervention in acute alcohol withdrawal

The importance of nonpharmacologic and pharmacologic interventions in the treatment of alcohol withdrawal is not known. A randomized, double‐blind, placebo‐controlled trial was conducted with 41 patients in alcohol withdrawal in an emergency department. The patients received either supportive care (10 min of standardized assessments, reassurance, reality orientation, and nursing care an hour) with three doses of sublingual lorazepam 2 mg every 2 hr (21 patients, drug group) or supportive care with three doses of sublingual placebo every 2 hr (20 patients, no‐drug group). Immediately before each drug dose, the clinical course of alcohol withdrawal was assessed hourly by the Clinical Institute Withdrawal Assessment for Alcohol (CIWA‐A). Interraters reliability in using CIWA‐A was high. After each assessment, supportive care was given for 10 min before each dose. After completion of a 7‐hr initial phase, patients were discharged and reassessed daily for 5 days. Thirty‐seven patients (90.2%) improved in the initial phase. Treatment failures (CIWA‐A > 10) were more common in the patients treated without drug (3/20, 15%) than in those treated with drug (1/21, 4.8%). Overall variations in intergroup CIWA‐A scores during the initial phase were not significant. The rate of improvement of CIWA‐A scores over the first 2 hr after drug was slightly faster in patients receiving lorazepam than in the control group. CIWA‐A scores were the same during follow‐up. These results indicate that most outpatients in mild to moderate alcohol withdrawal without medical complications improve without drug therapy in the emergency department setting.

A clinical scale to assess benzodiazepine withdrawal.

The objective, sensitive, and reliable quantitation of withdrawal symptoms is essential to assess physical dependence on drugs. Data collected from 23 patients abusing high doses of benzodiazepines (mean diazepam dose equivalents, 150 mg/day; range, 40–500) and from 40 long-term therapeutic users randomized to receive either placebo (N = 19) or diazepam (N = 21; mean diazepam dose equivalents, 15 mg/day; range, 5–40; mean duration of use, 72 months; range, 6–240) were analyzed. Information on the type and severity of symptoms was obtained from several assessment instruments. In the high-dose abuse group, plasma benzodiazepine concentrations were measured daily and the 3 consecutive days of greatest relative daily fall were considered the critical withdrawal period. Selection of the 22 items of the Clinical Institute Withdrawal Assessment-Benzodiazepines (CIWA-B) was based on statistically significant differences between baseline and critical withdrawal periods in high-dose subjects and between symptoms associated with placebo and diazepam in low-dose subjects, using contingency tables and logistic regression analysis. Of the 104 symptoms measured by the assessment instruments, 22 symptoms were found to distinguish withdrawal from prewithdrawal. These symptoms were selected based on significant differences (t-test, p ranged between <0.05 and <0.001) on type and severity of symptoms between baseline and the clinical withdrawal period in high-dose subjects, and on differences (cH2: P ranged between <0.05 and <0.001) in type of symptoms in placebo and diazepam subjects during the first week of withdrawal among the longterm therapeutic users of benzodiazepines. From these 22 symptoms, we constructed the CIWA-B, a scale of 20 five-point items and two additional values. We propose the CIWA-B as an instrument to assess and monitor benzodiazepine-like withdrawal.

New thyroxine treatment in older adults beginning lithium therapy: implications for clinical practice.

OBJECTIVEnThe authors sought to determine the incidence of lithium-induced hypothyroidism in a population-based cohort of older adults beginning lithium therapy and thereby to inform clinical guidelines on the frequency of monitoring necessary in this group.nnnMETHODSnThe authors conducted a population-based observational cohort study using four administrative databases that contained information on over 1.3 million older adults in Ontario who receive universal healthcare coverage in terms of physician services, drugs, and hospitalizations. Over an 18-month period, they studied adults age>or=65 who were newly prescribed lithium or valproate, monitoring subjects for initiation of T4 therapy (as a proxy for hypothyroidism) while they continued their lithium use.nnnRESULTSnThe authors identified 1,705 new users of lithium and 2,406 new users of valproate with similar baseline characteristics. Lithium users were significantly more likely to be treated with T4 than were valproate users. The rate of T4 treatment per 100 person-years was 5.65 in the lithium group and 2.70 in the valproate group.nnnCONCLUSIONnT4 treatment was initiated in almost 6% of lithium-treated patients, suggesting the possibility that hypothyroidism developed twice as frequently among these patients as would be expected among a mixed-age population. Increased vigilance and continued monitoring of thyroid functioning for at least 2 years is necessary in older adults beginning lithium therapy.