Diazepam

Comparative studies

Baclofen can reduce the symptoms of the alcohol withdrawal syndrome and has been compared with diazepam in 37 patients, who were randomized into two groups [ ]. Baclofen 30 mg/day was given orally to 18 patients and diazepam 0.5–0.75 kg/kg/day to 19 patients. The Clinical Institute Withdrawal Assessment was used to evaluate physical symptoms of alcohol withdrawal syndrome. Both baclofen and diazepam significantly reduced the score, and there were no significant differences between the two. When subscales for sweating, tremors, anxiety, and agitation were evaluated singly, baclofen and diazepam both significantly and equally reduced sweating, tremors, and anxiety. Both reduced the agitation score, although diazepam acted slightly more rapidly than baclofen.

Intravenous sodium valproate has been compared with an infusion of diazepam for control of refractory status epilepticus in an open, randomized, study in 40 children with refractory status epilepticus at a tertiary care teaching hospital [ ]. Refractory status epilepticus was controlled by valproate in 80% and by diazepam in 85% of the patients. The median time to control refractory status epilepticus was less with valproate (5 minutes) than diazepam (17 minutes). None of the patients who were given valproate required ventilation or developed hypotension, whereas of those given diazepam 60% required ventilation and 50% developed hypotension after starting the infusion. There were no adverse effects on liver function with valproate.

Placebo-controlled studies

In a double-blind, placebo-controlled, randomized trial in 120 children with spastic cerebral palsy received a bedtime dose of diazepam or placebo [ ]. A bedtime dose of diazepam to reduce hypertonia and muscle spasm, with passive stretching exercises, significantly improved behavior. The diazepam relaxed the muscles making the passive stretching easy, and the movements sustained muscle relaxation during the day. There was a significant improvement in wellbeing, improved activities of daily living, and reduced family burden of caring. There were fewer unwarranted crying spells during the day and less wakefulness during the night. There was no daytime sedation.

Cardiovascular

Cases of inadvertent intra-arterial injection of diazepam have been reported.

• A 51-year-old woman with an acute claustrophobic anxiety attack developed gangrene of the fingers after she was inadvertently given diazepam 10 mg intra-arterially [ ].

• Inadvertent intra-arterial injection of diazepam (2.5 mg in 0.5 ml) has been reported in an 8-year-old girl [ ]. Gangrene resulted and amputation of the 4th and 5th fingers was required.

Gangrene has been previously reported with intra-arterial injection of diazepam and is also well known with other classes of drugs, such as barbiturates and phenothiazines. It appears to be caused by the drug rather than the solvent used in the intravenous formulations.

Respiratory

Respiratory difficulties are a major potential adverse effect of rectal diazepam [ ].

Of 94 children who presented with seizures, 11 had respiratory depression after intravenous or rectal diazepam [ ]. However, this finding was challenged [ , ]. The authors of the second comment stated that this complication does not occur when rectal diazepam gel is used without other benzodiazepines; they also recommended that during long-term therapy families should be instructed not to give rectal diazepam more than once every 5 days or five times in 1 month.

Patients receiving intravenous benzodiazepines must be monitored for respiratory depression, which may demand artificial ventilation during intensive treatment. Diazepam may cause more respiratory depression than lorazepam at equieffective dosages [ ] and is contraindicated in neonates for this reason and because it produces unacceptably prolonged sedation [ ].

Nervous system

In an open study in 104 patients with acute stroke, diazepam 10 mg bd for 3 days was well tolerated [ ].

In a multicenter, double-blind study, 310 patients with generalized anxiety disorder were treated for 6 weeks with abecarnil (mean daily dose 12 mg), diazepam (mean daily dose 22 mg), or placebo in divided doses for 6 weeks [ ]. Those who had improved at 6 weeks could volunteer to continue double-blind treatment for a total of 24 weeks. Slightly more patients who took diazepam (77%) and placebo (75%) completed the 6-week study than those who took abecarnil (66%). The major adverse events during abecarnil therapy were similar to those of diazepam, namely drowsiness, dizziness, fatigue, and difficulty in coordination. Abecarnil and diazepam both produced statistically significantly more symptom relief than placebo at 1 week, but at 6 weeks only diazepam was superior to placebo. In contrast to diazepam, abecarnil did not cause withdrawal symptoms. The absence of a placebo control makes it difficult to interpret the results of another study of the use of abecarnil and diazepam in alcohol withdrawal, which appeared to show comparable efficacy and adverse effects of the two drugs [ ].

The mechanism of rare extrapyramidal effects with diazepam is unexplained [ ].

A study has been conducted to clarify whether subjective sleepiness in older people accurately reflects a benzodiazepine-related reduction in psychomotor function [ ]. Placebo or diazepam 5 or 10 mg were given orally in a single-blind crossover manner to eight healthy young men (mean age 20 years) and placebo and diazepam 5 mg to seven healthy older men (mean age 61 years). The following were monitored every 20 minutes from 10.00 h until 16.00 h (the drug having been given at 12.00 h): plasma drug concentration, choice reaction time as an objective measure of psychomotor function, and the Stanford Sleepiness Scale as a measure of subjective sleepiness. The pharmacokinetics of diazepam did not differ significantly between the two groups. Diazepam 10 mg in the young men produced significant increases in both the choice reaction time and sleepiness score. Diazepam 5 mg had no significant effect on sleepiness in either group but did produce a significant increase in choice reaction time only in the older subjects, matching that in the young subjects given diazepam 10 mg. The older subjects suffered from dissociation between subjective sleepiness and objective psychomotor impairment after diazepam. Older individuals may underestimate the detrimental effects of benzodiazepines on brain function.

Neuromuscular function

Muscle rigidity after high-dose opioids can be reduced by the benzodiazepines midazolam and diazepam [ ].

Psychiatric

The effects of diazepam on word list recall, prospective memory, sustained attention and subjective ratings of arousal have been studied in 48 healthy participants, aged 19–35 years, who took oral diazepam mean dose 0.19 mg/kg or placebo in a double-blind study [ ]. Retrospective memory and prospective memory were assessed by free recall of unrelated word lists and by instructing participants to ask for a hidden belonging at the end of the session. Sustained attention was measured by multiple trials of a digit cancellation task and subjective arousal was assessed by self-ratings of drowsiness. Diazepam impaired performance on all measures. Diazepam reduced prospective memory performance associated with reduced subjective arousal, but unrelated to sustained attention. This is the first report of the effects of benzodiazepines on prospective remembering and further supports the view that the arousal/attentional system is composed of partially independent subsystems that have differential relationships to memory.

Psychiatric

A fugue-like state with retrograde amnesia has been associated with diazepam [ ].

• A 23-year-old military officer on active duty took diazepam 5 mg tds and ibuprofen for back spasms. Three days later he was found sitting in a church, having assumed a previous role from his past life. He identified the date as 14 months before and his memory before that time was intact. However, he had no memory of events during the previous 14 months. There were no symptoms suggesting a schizophrenic disorder and his mental function was normal. His symptoms resolved within 24 hours of withdrawal of diazepam, except for amnesia of the event. He assumed his correct identity and was aware of the correct date. He had taken ibuprofen in the past with no adverse effects and this was his first exposure to a benzodiazepine. No other medications were involved and a full medical review found no cause for his symptoms other than diazepam use.

Healthy men and women (n = 46) were randomly assigned to placebo or diazepam 5 or 10 mg in a double-blind, between-groups design to examine the effect of diazepam on self-aggressive behavior under controlled laboratory conditions [ ]. The participants were then provided with the opportunity to self-administer electric shocks during a competitive reaction time task. Self-aggression was defined by the intensity of shock chosen. Diazepam 10 mg was associated with higher average shocks than placebo and a greater likelihood of attempting to self-administer a shock that they were led to believe was severe and painful. There were sedative effects, but diazepam did not impair memory, attention, concentration, pain threshold, or reaction-time performance. The authors concluded that clinically relevant doses of diazepam may be associated with self-aggressive behavior without significantly impairing basic cognitive processes or psychomotor performance.

Capgras syndrome has been attributed to diazepam.

• A 78-year-old man with a long history of generalized anxiety disorder had benefited from diazepam for at least 30 years [ ]. During the 6 months before evaluation, he developed a fixed delusion that his sister-in-law had disguised herself as his wife and had replaced her at home. His anxiety symptoms remained at baseline and cognitive function was unimpaired on detailed testing. Medications included diazepam 5 mg bd, paroxetine 40 mg/day, levothyroxine, rabeprazole, ranitidine, and finasteride. The dose of diazepam was tapered and withdrawn and risperidone 0.5 mg qds was started. Within 10 days, the Capgras delusion had completely resolved and he readily recognized his wife during visits.

Endocrine

Gynecomastia, with raised estradiol, has been reported in men taking diazepam [ ].

Acute diazepam administration causes a reduction in plasma cortisol concentrations, consistent with reduced activity of the hypothalamic–pituitary–adrenal axis, especially in individuals experiencing stress. However, the effects of chronic diazepam treatment on cortisol have been less well studied, and the relation to age, anxiety, duration of treatment, and dose are poorly understood. In a double-blind, placebo-controlled, crossover study, young (19–35 years, n = 52) and elderly (60–79 years, n = 31) individuals with and without generalized anxiety disorder took diazepam 2.5 or 10 mg for 3 weeks [ ]. The elderly had significant reductions in plasma cortisol concentrations compared with placebo, both after the first dose and during chronic treatment, but the younger subjects did not. A final challenge with the same dose did not produce any significant cortisol effects in either group and the cortisol response in the elderly was significantly reduced compared with the initial challenge. These results are consistent with the development of tolerance to the cortisol-reducing effects of diazepam. The effect was more apparent in the elderly, was not modulated by generalized anxiety disorder or dosage, and was not related to drug effects on performance and on self-ratings of sedation and tension.

Skin

Cutaneous adverse effects of diazepam are rare. The incidence was 0.4 per 1000 in the Boston Collaborative Surveillance Program [ ].

• A 50-year-old woman was referred to hospital for chronic depression with alcohol dependence [ ]. There was no history of drug allergy. She was given oral thioridazine 100 mg/day and diazepam 10 mg qds. After 2 days she noticed an erythematous eruption on her ankles. Thioridazine was withdrawn, but the eruption became more erythematous and affected both extremities and flanks within a few hours. She was given methylprednisolone 80 mg/day. The next day the eruption became bullous and she became pyrexial (39.4 ° C). Urea and creatinine concentrations were normal. Blood cultures were negative. A skin biopsy showed bullous vasculitis with numerous eosinophils in the dermis. Diazepam was then withdrawn, the pyrexia resolved, and the skin lesions healed, although post-inflammatory ulcers persisted on both ankles for 2 months. A lymphocyte blast transformation test was positive for diazepam.

Sweet’s syndrome has been attributed to diazepam [ ].

• A 70-year-old white man, with no significant preceding medical history, developed an acute painful rash, a fever (38.4 ° C), and severe arthralgia 5 days after starting to take diazepam 10 mg bd for lumbar muscular contracture due to hard physical exercise. He had taken no other medications. There were well-defined purple-red skin plaques, surmounted by vesicular and hemorrhagic blisters. He had a leukocytosis. Sweet’s syndrome was confirmed by punch biopsy of a lesion. Diazepam was withdrawn, and prednisolone 30 mg/day was given for 2 weeks and then tapered. The patient improved quickly and the eruption cleared in 10 days.