Psychomotor performance of long-term benzodiazepine users before, during, and after benzodiazepine discontinuation.

Long-term (mean, 8 years) users of benzodiazepines (BZs) were administered a small battery of cognitive tests on three occasions (before BZ taper, and 5 and 12 weeks post taper) as part of their BZ discontinuation program. Ninety-six patients had 5-week and 77 patients had 12-week data. For taper successes, BZ-free status was confirmed by weekly BZ plasma level determinations. Age and education, as well as baseline test scores, were used as covariates for all data analyses. Patients who successfully tapered off BZ were able to complete symbol copying (SC) and digit symbol substitution (DSST) tasks faster than patients still taking BZ (p < 0.05). In addition, using an adjective check list, patients with taper success, i.e., BZ-free patients, reported lower levels of mental and physical sedation and higher levels of tranquilization (p < 0.05) than did patients still taking BZ. These results were confirmed in two multiple regression analyses with SC and DSST as the dependent variables. Higher baseline, younger age, and successful taper status (off BZ) were selected as significant independent predictors of SC and DSST scores. In summary, cognitive functions improved for many long-term BZ users after discontinuing their BZ intake.

Nefazodone in major depression: adjunctive benzodiazepine therapy and tolerability.

One hundred sixty-six patients suffering from major depressive disorders were treated for 8 weeks with nefazodone in an open study in dosage ranges from 200 to 600 mg. This report focuses primarily on the first week of therapy and on the concomitant use of several benzodiazepines, one of which is not metabolized by the cytochrome system (temazepam). Triazolam response was further evaluated as a function of two nefazodone dosage regimens provided during the first week of therapy, one group receiving nefazodone 200 mg/day for 7 days, and another group receiving nefazodone 200 mg/day for 3 days, followed by 4 days with 400 mg/day. Finally, a comparison of three different nefazodone dosages, the third being 400 mg from day 1 on, was also carried out. Outcome measures included Hamilton Rating Scale for Depression total and the total of the three Hamilton Rating Scale for Depression insomnia items, as well as global improvement, a daily completed sleep questionnaire, and adverse event assessment. A combination of nefazodone with a benzodiazepine (BZ) caused more sedation than nefazodone alone; triazolam, the BZ with the shortest half-life and the highest dependence on the cytochrome 450 system for its metabolism, caused the least amount of sedation, and alprazolam and diazepam, the two daytime benzodiazepines, caused the most sedation. Triazolam caused significant and identical reduction of insomnia in both nefazodone groups. Compared with nefazodone 200 mg given as monotherapy, insomnia was significantly improved--not only by triazolam, but also alprazolam and diazepam, but not temazepam. The addition of nefazodone raised triazolam plasma levels to almost 500%, the plasma level of desmethyl-diazepam 87%, and that of alprazolam 34%. Temazepam plasma levels remained unchanged. When prescribing nefazodone with a benzodiazepine, one should expect an improved sleep pattern initially, but at the cost of clinically relevant daytime sedation. The prediction that temazepam, the only BZ not dependent on the cytochrome mechanism for metabolism, should be the least sedating, and triazolam, because of its cytochromic metabolism interference with nefazodone should be the most sedating, could not be confirmed. In fact, triazolam 0.25 mg capsules seem to be the safest treatment of choice when one has to combine a benzodiazepine with nefazodone in initial stages of therapy, at least of the four benzodiazepines tested in this study.

Progesterone co-administration in patients discontinuing long-term benzodiazepine therapy: effects on withdrawal severity and taper outcome.

Since recent research has suggested that the major metabolites of progesterone are barbiturate-like modulators of GABAergic function, we undertook a pilot study of the efficacy of micronized progesterone in attenuating withdrawal and facilitating discontinuation in benzodiazepine-dependent patients with a minimum of 1 year of continuous daily use. Forty-three patients taking a mean daily dose of 16.2 mg of diazepam (or its equivalent) were assigned, doubleblind, to treatment with either placebo (n = 13) or progesterone (n = 30). Progesterone was titrated to a mean daily dose of 1983 mg, and was co-administered for 3 weeks, after which the benzodiazepine was tapered by 25% per week. Progesterone (or placebo) was then continued for 4 weeks before being discontinued. There was no progesterone versus placebo difference in the severity of taper withdrawal. Withdrawal checklist change scores were 17.3 for progesterone and 16.5 for placebo (F 0.63; df 2.31; n.s.), and the Hamilton rating scale for anxiety change scores were 7.8 for progesterone and 6.3 for placebo (F 0.22; df 2.30; n.s.). There was no difference in ability to remain drug-free at 12 weeks post-taper, with 57% of progesterone-treated patients, and 58% of placebo-treated patients having a successful outcome.

Long-term benzodiazepine users 3 years after participation in a discontinuation program.

OBJECTIVE: Clinical status and use of benzodiazepines and other psychotropic drugs at follow-up were assessed in patients who had been chronically dependent on benzodiazepines and had been referred for participation in a discontinuation study. METHOD: Of 123 benzodiazepine-dependent patients screened for entry into a tapered discontinuation program, 48 had completed the program, 38 had not, and 37 had not undergone drug tapering. Follow-up information was obtained through a structured telephone interview and a mail questionnaire that included a global severity scale assessing anxiety and depression and the Hopkins Symptom Checklist. The time to follow-up was 2.7-5.0 years, and the mean +/- SD interval between screening and follow-up was 2.9 +/- 0.9 years. RESULTS: Outcome at follow-up significantly favored the patients who had completed the discontinuation program; 73% were not using benzodiazepines, compared to 39% in the unsuccessful taper group and 14% in the no-taper group. Moderate or marked anxiety was still reported by 35% of the patients who were taking benzodiazepines and 25% of those who were not. At follow-up, 22% of the patients were being treated with nonbenzodiazepine psychotropic agents, primarily antidepressants. CONCLUSIONS: The high percentage of patients who were benzodiazepine-free at follow-up and the continued anxiety and depression present in many patients suggest that some patients may have been taking benzodiazepines because of chronic or recurrent anxiety or depression, not physical dependence.

Carbamazepine treatment in patients discontinuing long-term benzodiazepine therapy. Effects on withdrawal severity and outcome.

Forty patients with a history of difficulty discontinuing long-term, daily benzodiazepine therapy were randomly assigned, under double-blind conditions, to treatment with carbamazepine (200 to 800 mg/d) or placebo. A gradual taper (25% per week reduction) off benzodiazepine therapy was then attempted. Five weeks after taper, significantly more patients who had received carbamazepine than placebo remained benzodiazepine free, this despite the fact that no statistically significant differences in withdrawal severity could be demonstrated. Patients receiving carbamazepine reported a larger reduction in withdrawal severity than patients receiving placebo, but only at a trend level, and only on the daily patient-rated withdrawal checklist. Eleven patients (28%) required antidepressant therapy for depression or panic when assessed at 12-weeks follow-up. The results of this pilot investigation suggest that carbamazepine might have promise as an adjunctive drug therapy for the benzodiazepine withdrawal syndrome, particularly in patients receiving benzodiazepines in daily dosages of 20 mg/d or greater of diazepam equivalents.

Hepatic perfusion index (HPI) in mesenteric angina and following successful revascularization.

This is a case report of a 45 year old man who had previously undergone a small bowel resection for acute mesenteric ischaemia. He subsequently suffered from mesenteric angina due to stenosis of the origin of the superior mesenteric artery and intermittent claudication due to aorto-iliac atheroma. The patient underwent a successful aorto-bifemoral Y graft and small bowel revascularization with a saphenous vein graft between the Y graft and the accessible proximal portion of the superior mesenteric artery. Before vascular reconstruction, the hepatic perfusion indices (HPI) in both the fasted and fed states were elevated; after mesenteric revascularization the HPI values were substantially lowered. The hepatic perfusion index may, by demonstrating functional abnormality, be useful in the diagnosis of mesenteric ischaemia and also in the assessment of treatment. Further evaluation of HPI in patients with suspected mesenteric ischaemia is therefore required.

Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper.

We compared the effect on withdrawal severity and acute outcome of a 25% per week taper of short half-life vs long half-life benzodiazepines in 63 benzodiazepine-dependent patients. Patients unable to tolerate taper were permitted to slow the taper rate. Ninety percent of patients experienced a withdrawal reaction, but it was rarely more than mild to moderate. Nonetheless, 32% of long half-life and 42% of short half-life benzodiazepine-treated patients were unable to achieve a drug-free state. The most difficulty was experienced in the last half of taper. Baseline personality, high Eysenck neuroticism, female sex, and mild-to-moderate alcohol use were found to be more significant predictors of withdrawal severity than the daily benzodiazepine dose or benzodiazepine half-life. These findings suggest that personality factors contribute significantly to the patient's difficulties with gradual benzodiazepine discontinuation of therapeutic doses of benzodiazepines.

Long-term therapeutic use of benzodiazepines. I. Effects of abrupt discontinuation.

We compared the effect of abrupt discontinuation of therapeutic doses of short half-life and long half-life benzodiazepines in 57 benzodiazepine-dependent patients (daily use, greater than 1 year). Despite the use of a mean daily dose of 14.1 mg of diazepam equivalents, there were notable residual symptoms of anxiety and depression present at intake (Hamilton Rating Scale for Anxiety score, 17.0; Hamilton Rating Scale for Depression score, 14.0). Benzodiazepine intake was stabilized for 3 weeks before double-blind assignment to placebo (n = 47), or continued benzodiazepine use (n = 10). Clinical assessments were performed daily, including benzodiazepine plasma levels. Depending on the outcome criteria used, anywhere from 58% to 100% of patients were judged to have experienced a withdrawal reaction, with a peak severity at 2 days for short half-life and 4 to 7 days for long half-life benzodiazepines. Relapse onto benzodiazepines occurred in 27% of patients who were receiving long half-life benzodiazepines and in 57% of patients who were receiving short half-life benzodiazepines. Baseline predictors of relapse were nonpanic diagnoses, a higher benzodiazepine dose, and a higher Eysenck neuroticism score. A short half-life and higher daily doses were associated with greater withdrawal severity, as were personality traits, such as dependency and neuroticism, less education and higher baseline levels of anxious and depressive symptoms. Patients who were able to remain free of benzodiazepines for at least 5 weeks obtained lower levels of anxiety than before benzodiazepine discontinuation. These results provide a detailed picture of the symptoms, time course, and multidimensional determinants of the benzodiazepine withdrawal syndrome.

Aortocaval fistulas and the use of transvenous balloon tamponade.

Six cases of acute aortocaval fistula are reported, which illustrate the difficulties of diagnosis and management in a rare life-threatening condition. Five cases arose from spontaneous rupture of aortic aneurysms and one from trauma. In four cases the diagnosis was made before surgery. Useful diagnostic features included inappropriate jugular venous distension in five patients, lower abdominal and trunk cyanosis in three patients and a palpable thrill in three patients. Preoperative diagnosis permitted attempts to control venous haemorrhage in three cases, one by balloons through the aortic sac and two by transvenous positioning of balloon catheters in the vena cava before aortic opening. The use of transvenous balloon catheters was found to be helpful in reducing haemorrhage. Four patients left hospital alive. Preoperative recognition of the signs of an acute aortocaval rupture and preliminary balloon tamponade appear to be valuable in the management of acute aortocaval fistulas.

Benzodiazepine dependence: management of discontinuation.

This article discusses the management of benzodiazepine (BZ) withdrawal in patients who are chronically benzodiazepine dependent. Gradual benzodiazepine discontinuation is preferable to abrupt discontinuation, particularly for patients on short half-life benzodiazepines. For a small number of patients, replacement of short half-life with long half-life benzodiazepines may also be helpful. Finally, we present new preliminary data from a controlled, double-blind study that suggest that adjunctive use of such drugs as carbamazepine, imipramine, and buspirone may be helpful in managing gradual benzodiazepine discontinuation. Initiating adjunctive medication prior to, and continuing it during and after benzodiazepine discontinuation led to significantly higher discontinuation success rates for carbamazepine (91%), buspirone (85%), and imipramine (79%) than for placebo (58%) (p less than .05). Careful followup for an extended period of time is needed after benzodiazepine discontinuation because, frequently, emerging psychiatric symptoms may again necessitate psychiatric intervention.

Benzodiazepine dependence and withdrawal in elderly patients.

Severity of withdrawal symptoms and clinical outcome were compared in 19 elderly and 22 younger benzodiazepine-dependent patients matched for benzodiazepine half-life, dosage, and duration of treatment. During gradual taper of benzodiazepine doses, the elderly patients showed significantly less severe withdrawal symptoms on several clinical measures and a comparably favorable outcome. Approximately half of each group remained benzodiazepine free for at least 4 weeks. Both groups of patients tolerated drug discontinuation without serious consequences such as seizures or psychosis. Tapered benzodiazepine withdrawal did not appear to be more risky for the elderly group than for the younger patients.

Long-term treatment of anxiety and risk of withdrawal. Prospective comparison of clorazepate and buspirone.

Risk of withdrawal was investigated in a prospective, double-blind comparison of clorazepate dipotassium, a benzodiazepine with a long half-life, and the nonbenzodiazepine buspirone hydrochloride in the long-term treatment of anxious outpatients. Patients were treated with therapeutic doses of clorazepate dipotassium (15 to 60 mg/d) or buspirone hydrochloride (10 to 40 mg/d) for six continuous months before their tranquilizer therapy was blindly and abruptly stopped. There was a significant increase in symptom severity consistent with a withdrawal reaction for the clorazepate group but not the buspirone group. For the clorazepate group, there was a suggestion that previous discontinuous exposure to benzodiazepines might sensitize patients to subsequent withdrawal effects. For the buspirone group, a higher dropout rate raised questions about patient satisfaction with therapy in this rather chronically anxious population.

The uncontrolled case report: a double-edged sword.

The advantages and disadvantages of uncontrolled case reports are reviewed using two cases of false-positive reactions to drugs as illustrative examples.

Gepirone in anxiety: a pilot study.

Ten patients suffering from generalized anxiety disorder were treated, after a single-blind placebo washout week, with the nonbenzodiazepine anxiolytic gepirone in a 6-week open label trial. Mean Hamilton Anxiety scores improved from 24.8 to 7.1 (p less than 0.01). Other physician- and patient-rated scales showed comparable improvement on a mean maximal dose of 41 mg of gepirone. The medication appeared to be nonsedating and well tolerated. The anxiolytic effect of the medication was very marked in several cases, and gepirone appears to have promise as an anxiolytic agent.

Brotizolam, a triazolothienodiazepine, in insomnia.

Sixty-three outpatients with chronic insomnia were treated for 3 weeks under double-blind conditions with either brotizolam (n = 29) at a dose of 0.25 mg or 0.5 mg or placebo (n = 34). A 3-day placebo period preceded and followed the double-blind treatment phase. Brotizolam consistently produced significantly more sleep improvement than placebo but also more adverse effects. In those patients switched abruptly from brotizolam to placebo, rebound insomnia was observed, being most marked at the first post-brotizolam placebo night.

A double-blind comparative trial of zimelidine, amitriptyline, and placebo in patients with mixed anxiety and depression.

We performed a randomized, double-blind clinical trial comparing the efficacy and safety of zimelidine with amitriptyline and placebo in outpatients with major depression, in particular patients with mixed anxiety/depressive symptomatology. Overall, amitriptyline was more effective than zimelidine and placebo after 4 weeks of treatment. However, when those patients with more severe depression were specifically examined, both antidepressants were equal in efficacy and superior to placebo. We also found no evidence for a greater likelihood of a zimelidine-induced peripheral neuropathy in this study. The present results suggest that zimelidine may be more effective in the treatment of severely depressed patients, rather than those with more mild mixed anxiety/depressive syndromes.

One-year follow-up of anxious patients treated with diazepam.

A 1-year follow-up was conducted on patients who had participated in a 6-month diazepam maintenance study. Of 180 patients contacted, 131 patients (73%) responded. Observed relapse rate was 63%, and Hopkins Symptom Checklist (HSCL) scores at follow-up were significantly higher for relapsed than for nonrelapsed patients. Two thirds of all relapsed patients sought some kind of medical, social, or psychiatric help, frequently including medication. Patients who were the most improved at the end of the diazepam maintenance trial consistently had the lowest HSCL scores at the time of follow-up. The implication of these findings for the management of chronic anxious patients is discussed.