High-dose Benzodiazepine Research Articles

Use of high dose benzodiazepines in alcohol and sedative withdrawal delirium

The authors describe two patients who required massive doses of benzodiazepines to treat complicated alcohol and sedative withdrawal delirium. Some of the factors that contributed to difficulties in management are discussed. Finally, we describe the advantages and disadvantages of high dose pharmacologic management and controversies regarding psychopharmacologic management of such complex patients.

Nicotine, caffeine and alcohol use in high- and low-dose benzodiazepine users

Cigarette smoking, coffee and alcohol use were investigated prospectively in 37 high-dose benzodiazepine (BZD) regular users (HDRU), 87 low-dose BZD regular users (LDRU), 50 low-dose BZD occasional users (LDOU) and in 37 non-BZD users (control subjects). The frequency of smokers was significantly greater in the HDRU than in the other three groups studied. Also, the HDRU consumed a significantly greater number of cigarettes and dose of caffeine per day than the other subjects investigated. Also, alcohol dependence was significantly more frequent in the HDRU. Regression analysis showed a significant positive correlation between the BZD dose and both the cigarettes and the caffeine consumed per day. The findings suggest that BZD should be prescribed with caution in individuals who are heavy smokers or are consuming large amounts of coffee and alcohol.

Guillain Barré syndrome in an ICU masked by prolonged use of diazepam and vecuronium

Many authors have reported secondary neuropathies in intensive care patients due, for example, to sepsis and steroid therapy. A polytrauma patient was admitted to our intensive care unit with quadriplegia and coma which were thought to be due to the prolonged effects of curare and high-dose benzodiazepine administration, respectively. Differential diagnosis included neurological disorders but further investigations revealed Guillain Barre syndrome as the underlying condition for his quadriplegia.

Prospective audit of upper gastrointestinal endoscopy in two regions of England: safety, staffing, and sedation methods.

A prospective audit of upper gastrointestinal endoscopy in 36 hospitals across two regions provided data from 14,149 gastroscopies of which 1113 procedures were therapeutic and 13,036 were diagnostic. Most patients received gastroscopy under intravenous sedation; midazolam was the preferred agent in the North West and diazepam was preferred in East Anglia. Mean doses of each agent used were 5.7 mg and 13.8 mg respectively, although there was a wide distribution of doses reported. Only half of the patients endoscoped had some form of intravenous access in situ and few were supplied with supplementary oxygen. The death rate from this study for diagnostic endoscopy was 1 in 2000 and the morbidity rate was 1 in 200; cardiorespiratory complications were the most prominent in this group and there was a strong relation between the lack of monitoring and use of high dose benzodiazepines and the occurrence of adverse outcomes. In particular there was a link between the use of local anaesthetic sprays and the development of pneumonia after gastroscopy (p < 0.001). Twenty perforations occurred out of a total of 774 dilatations of which eight patients died (death rate 1 in 100). A number of units were found to have staffing problems, to be lacking in basic facilities, and to have poor or virtually non-existent recovery areas. In addition, a number of junior endoscopists were performing endoscopy unsupervised and with minimal training.

Withdrawal symptoms from high dose benzodiazepines in poly drug users

Among poly drug users attending a treatment service, 33 subjects were identified who had experienced withdrawal symptoms from high dose benzodiazepines (median diazepam equivalent 140 mg/day) at a time uncomplicated by simultaneous cessation of other drugs. Symptoms were rated using the Benzodiazepine Withdrawal Symptom Questionnaire (Tyrer et al. (1990) The Benzodiazepine Withdrawal Symptom Questionnaire. J. Affective Disorders, 19, 53–61). The symptoms experienced were similar to those described in studies of withdrawal from low dose benzodiazepines, but more severe. Greater severity of symptoms was significantly associated with high dosage, the use of multiple benzodiazepines and oral rather than injected use. The implications for clinical management are discussed.

Benzodiazepine dependence and withdrawal: identification and medical management.

Primary care physicians prescribe benzodiazepines for the treatment of anxiety. Although most patients use the benzodiazepines appropriately, some patients experience benzodiazepine abuse, addiction, or physical dependence, each one of which is a distinct syndrome. Benzodiazepine dependence, which relates to the development of tolerance and an abstinence syndrome, can be produced by three disparate benzodiazepine use patterns. These distinct benzodiazepine use patterns can in turn create distinct withdrawal syndromes. High-dose benzodiazepine use between 1 and 6 months can produce an acute sedative-hypnotic withdrawal syndrome. In contrast, low-dose therapeutic range benzodiazepine use longer than 6 months can produce a prolonged, subacute low-dose benzodiazepine withdrawal syndrome. Daily, high-dose benzodiazepine use for more than 6 months can cause a combination of an acute high-dose benzodiazepine withdrawal and a prolonged, subacute low-dose withdrawal syndrome. In addition, patients may experience syndrome reemergence. A literature search was conducted using the medical subject headings benzodiazepines, substance abuse, substance dependence, substance withdrawal syndrome, and benzodiazepines adverse effects. The years 1970 to the present were reviewed. Medical management for acute benzodiazepine withdrawal includes the graded reduction of the current benzodiazepine dosage, substitution of a long-acting benzodiazepine, and phenobarbital substitution. However, the medical management of benzodiazepine dependence does not constitute treatment of benzodiazepine addiction. Primary care physicians can accept complete, moderate, or limited medical responsibility regarding patients with substance use disorders. However, all physicians should provide diagnostic and referral services.

Novel approaches to the pharmacotherapy of schizophrenia

AbstractNumerous attempts to extend the pharmacotherapy of schizophrenia beyond conventional neuroleptics are reviewed. Clozapine and melperone are atypical neuroleptics that produce few extrapyramidal side effects during acute usage and possible less tradive dyskinesia with prolonged use. Decreasing dopamingeric activity with a tyrosine hydroxylase inhibitor or dopamine autoreceptor agonists may also be of value. Neuroleptics that block voltage‐sensitive calcium channels or calcium channel blockers per se have been advocated for treatment of negative symptoms or the deficit state. Among other possible clinical approaches reviewed are: beta adrenergic blockers, clonidine, tryptophan, 5‐hydroxytryptophan, fenfluramine, GABA drugs, including high dose benzodiazepines, lithium, carbamazepine, opioid agonists and antagonists, gamma‐endorphins, TRH analogs and vasopressin. Most studies indicate these agents produce inconsistent or slight‐to‐modest benefits, either in comparison with standard neuroleptic drugs or inaddition to neuroleptics, in groups of schizophrenic patients, including some double blind placebo‐controlled trials. Those individuals who do respond sometimes, but not always, fail to relapse when the experimental drug is discontinued or fail to respond to it in subsequent trials. Consistent with the presumed heterogeneity of schizophrenia, there is some evidence supporing non‐neuroleptic drug treatment for specific schizophrenic subtypes. The various stages of this usually life‐long disorder, together with the possible mutability of the underlying etiological factors over time, requires the utmost care in clinical trials.

Diazepam tapering in detoxification for high-dose benzodiazepine abuse.

The clinical characteristics and management of patients who abuse high doses of benzodiazepines are not well described. In a prospective open study, 23 subjects who abused high doses of benzodiazepines were admitted for detoxification. Urine or blood test results confirmed benzodiazepine use in all but one subject and multiple drug use in eight (35%). Median benzodiazepine dose was 150 mg (range 40 to 500 mg) of diazepam equivalent. Initial plasma concentrations (diazepam: median = 1245 ng/ml; desmethyldiazepam: median = 2961 ng/ml) were 400% to 800% higher than usual therapeutic concentrations. For detoxification, subjects were given a loading dose of diazepam equal to approximately 40% their reported daily consumption. This was followed with daily tapering of diazepam by 10%. This regimen resulted in a slow and gradual decline in drug concentrations. Withdrawal symptoms were assessed daily. Sixteen subjects completed detoxification in the hospital without complications. One subject became paranoid and confused on day 7 of withdrawal. This was attributed to a too-low initial loading dose and too-rapid tapering, which resulted in rapid drug elimination. Gradual reduction of diazepam dose appears to be an effective and safe approach for detoxifying abusers of high doses of benzodiazepines.

The authors reply

Benzodiazepines (BZDs) rarely cause respiratory depression and death. On the other hand, high-dose BZDs may lead to profound sedation and diminished brainstem functions that mimic other structural brain lesions as described in our case: a 70-year-old unresponsive woman. She was hypothermic and had rapid shallow breathing. Her Glasgow Coma Scale score was E1V1M4, with pinpoint pupils and absent corneal, oculocephalic and oculovestibular reflexes. Other physical exams, laboratory testing and brain imaging were unremarkable. After two doses of 0.4 mg naloxone and intravenous thrombolytics were given, there were no significant responses, and the diagnosis remained a mystery. The cause of her unconsciousness was uncovered when her husband found empty bags of 80 tablets of alprazolam and lorazepam. Her consciousness and brainstem reflexes improved dramatically after 0.25 mg of intravenous flumazenil. The blood for BZDs concentration showed alprazolam 268 ng/mL (20–40 ng/mL), lorazepam 861 ng/mL (20–250 ng/mL) and their metabolites.