Alprazolam

Comparative studies

In a randomized, crossover, open study of the control of nausea and vomiting in 19 patients with operable breast cancer, granisetron alone was compared with granisetron plus alprazolam [ ]. Alprazolam increased the efficacy of granisetron. The addition of alprazolam did not increase the incidence of adverse reactions to granisetron, but neither the adverse effects nor their frequencies were specified.

Placebo-controlled studies

Alprazolam 0.25 mg or 1 mg has been evaluated in 47 otherwise healthy subjects, selected for a moderate to high degree of anxiety before oral surgery in a three-arm, parallel design, double-blind, randomized, placebo-controlled study [ ]. There were 27 adverse events in the interval between dosing and surgery: 2, 10, and 15 events each with placebo, alprazolam 0.25 mg and alprazolam 1 mg respectively. The most common events were drowsiness with placebo and drowsiness, dizziness, lightheadedness, and nausea with alprazolam. There were also single reports of trembling, feeling cold, anxiety, panic attacks, a desire to smoke, increased appetite, sleepiness, and dry mouth with alprazolam. There were no serious adverse events and no subject withdrew from the study because of adverse events.

Cardiovascular

Alprazolam has been associated with hypotension [ ].

• A 76-year-old woman, who had a history of hypertension, valvular heart disease (mitral regurgitation) with chronic atrial fibrillation, chronic obstructive airways disease, diverticular disease of the sigmoid colon, and generalized anxiety disorder, developed severe hypotension with a tachycardia after taking alprazolam for 7 days. She also had severe weakness, depressed mood, and impaired gait and balance, without clinical features of neuromuscular disease.

Psychological, psychiatric

Rapid and sometimes serious mood swings to mania or depression, and other adverse effects, including enuresis, aggression, impaired memory, sedation, and ataxia, can occur in patients with panic disorder treated with alprazolam [ , ].

Disinhibition has been reported as a major problem with alprazolam, particularly in patients with borderline personality disorder [ ]. Several case reports have suggested that alprazolam can cause behavioral disinhibition [ ], in common with other benzodiazepines that are occasionally used for recreational or criminal purposes [ ]. In one study, covering the period January 1989 to June 1990, the medical records of 323 psychiatric inpatients treated with alprazolam, clonazepam, or no benzodiazepine were reviewed [ ]. The frequencies of behavioral disturbances were not significantly different in the different groups, suggesting that alprazolam does not have unique disinhibitory activity and that disinhibition with benzodiazepines may not be an important clinical problem in all psychiatric populations. The study design did not allow the establishment of a relation between the prescription of the benzodiazepine and worsening behaviors, and the findings need to be interpreted conservatively, because it was a retrospective review of a heterogeneous population.

Agoraphobia/panic disorder occurred in 31 patients, 15 of whom had originally been treated with alprazolam and 16 with placebo, had been previously followed during an 8-week treatment period, and had alprazolam-induced memory impairment [ ]. These patients were reviewed 3.5 years after treatment to determine whether the memory impairment persisted. Those who had used alprazolam performed as well as those who had taken placebo on the memory task and other objective tests. The performances in both groups were similar to pretreatment values. However, there were differences in subjective ratings: those who had used alprazolam rated themselves as less attentive and clear-headed and more incompetent and clumsy. Memory impairment found while patients were taking alprazolam did not persist 3.5 years later.

Abrupt withdrawal of alprazolam after prolonged treatment of panic disorder is associated with panic attacks.

• A 77-year-old married woman with panic attacks did not experience them while she took alprazolam 0.5 mg bd for 5 months; however, the attacks recurred after an increase in dose to 0.5 mg qds [ ].

The authors suggested that the duration of action of alprazolam is too brief to prevent rebound anxiety with administration four times a day, but this explanation is highly speculative. This case illustrates the potential severity of alprazolam rebound and how its long-term use can exacerbate the symptoms for which it was originally administered.

In a placebo-controlled, within-subject, repeated-measures study of the effects of alprazolam on human risk-taking behavior, 16 adults were given placebo or alprazolam 0.5, 1.0, and 2.0 mg [ ]. Alprazolam produced dose-related changes in subjective effects and response rates and dose-dependently increased selection of the risky response option. At a dose of 2.0 mg there was an increased probability of making consecutive risky responses following a gain on the risky response option. Thus, alprazolam increased risk-taking under laboratory conditions. In agreement with previous studies, the observed shift in trial-by-trial response probabilities suggested that sensitivity to consequences (for example oversensitivity to recent rewards) may be an important mechanism in the psychopharmacology of risky decision making. Additionally, risk-seeking personality traits may predict the acute effects of drugs on risk-taking behavior.

In a double-blind, crossover, placebo-controlled study in 12 healthy men of the impact of alprazolam 0.25 and 1.00 mg on aspects of action monitoring, i.e. the monitoring of response conflict and the detection and correction of errors by means of neurophysiological measures, alprazolam significantly reduced the amplitude of the error-related negativity (ERN) and therefore affected brain correlates of error detection [ ]. It increased reaction time and the latencies of lateralized readiness potentials (LRP), thereby affecting motor preparation. It had no effect on amplitude differences in the N2 amplitude component between congruent and incongruent trials, and therefore did not disturb conflict monitoring on correct trials. Alprazolam did not disturb post-error adjustments of behavior.

The cognitive effects of a single dose of alprazolam 0.5 or 1 mg on measures of psychomotor function, visual attention, working memory, planning, and learning have been assessed in 36 healthy adults in a double-blind, parallel-group study [ ]. Alprazolam 0.5 mg reduced only the speed of attentional performance, although the magnitude of this reduction was large (d = 0.8). At a dose of 1.0 mg, there was impairment of psychomotor function, equivalent to that seen for attentional function at the lower dose. In addition, there was moderate impairment (d = 0.5) in working memory and learning. These results suggest that low-dose alprazolam primarily alters visual attentional function. At the higher dose psychomotor functions also became impaired, and it is likely that a combination of these led to the observed moderate impairment of higher-level executive and memory processes.

In a double-blind, placebo-controlled, repeated-measures design 16 healthy volunteers took alprazolam 1 mg, l -theanine 200 mg, or placebo [ ]. The acute effects of alprazolam and l -theanine were assessed under relaxed conditions and in experimentally induced anxiety. Subjective self-reports of anxiety were obtained during both task conditions before and after drug treatment. The results showed some evidence for a relaxing effect of l -theanine during the baseline condition. Alprazolam did not have any anxiolytic effects compared with placebo on any of the measures during the relaxed state. Neither l -theanine nor alprazolam had any significant anxiolytic effects during experimentally induced anxiety. Adverse events were not reported.

In a double-blind, placebo-controlled, crossover study 18 healthy male volunteers took a single dose of alprazolam 0.75 or 1.75 mg or placebo in randomized order [ ]. Performance on cognitive tests included immediate and delayed recall, digit symbol substitution, critical flicker fusion, and choice reaction time as well as subjective ratings. Alprazolam impaired cognitive performance and subjective sedation in a dose-dependent manner.

The effects of extended-release (XR) alprazolam 1 mg and immediate release (IR) alprazolam 1 mg on actual driving ability and cognitive function have been investigated in a double-blind, placebo-controlled, three-way crossover study in 18 healthy volunteers aged 20–45 years [ ]. At 4 hours after the dose, the subjects performed a standardized driving test on a primary highway in normal traffic. Cognitive and psychomotor tests were assessed at 1, 2.5, and 5.5 hours. Memory function was measured after 1 hour. Both formulations severely impaired driving performance at 4–5 hours. The magnitude of impairment in the driving test observed with alprazolam XR was about half that observed with alprazolam IR. Laboratory test results were in line with the driving data. The acute impairing effects of alprazolam XR 1 mg on driving and psychomotor functions were generally less than the IR equivalent, but still of sufficient magnitude to increase the risk of traffic accidents.

Endocrine

Alprazolam can alter dehydroepiandrosterone and cortisol concentrations. Of 38 healthy volunteers who received a single intravenous dose of alprazolam 2 mg over 2 minutes (phase I), 15 of 25 young men (aged 22–35 years) and all 13 elderly men (aged 65–75 years) responded to alprazolam and agreed to participate in a crossover study of placebo and alprazolam infusion to plateau for 9 hours [ ]. Plasma samples at 0, 1, 4, and 7 hours were assayed for steroid concentrations. Alprazolam produced significant increases in dehydroepiandrosterone concentrations at 7 hours in both the young andelderly men; significant reductions in cortisol concentrations; no change in dehydroepiandrosterone-S concentrations. These results suggest that alprazolam modulates peripheral concentrations of dehydroepian drosterone and that dehydroepiandrosterone and/or dehydroepiandrosterone-S may have an in vivo role in modulating GABA receptor-mediated responses.

The acute and chronic effects (3 weeks) of alprazolam and lorazepam on plasma cortisol have been examined in 68 subjects (aged 60–83 years), who took oral alprazolam 0.25 or 0.50 mg bd, or lorazepam 0.50 or 1.0 mg bd, or placebo according to a randomized, double-blind, placebo-controlled, parallel design [ ]. Plasma cortisol concentrations were significantly affected compared with placebo, but only by the 0.5 mg dose of alprazolam. During the first and last days of treatment, there was a significant fall in cortisol at 2.5 hours after alprazolam compared with placebo. The predose cortisol concentrations increased significantly during chronic alprazolam treatment, and there were correlations between the cortisol changes and changes in depression, anxiety, and memory scores. These findings suggest that even a short period of chronic treatment with alprazolam, but not lorazepam, may result in interdose activation of the hypothalamic–pituitary–adrenal axis in the elderly, consistent with drug withdrawal. If confirmed, this effect may contribute to an increased risk for drug escalation and dependence during chronic alprazolam treatment.

In a parallel, double-blind, placebo-controlled study in 13 elderly women and 12 elderly men, alprazolam 0.5 mg bd for 3 weeks caused significant rises in inter-dose morning plasma cortisol concentrations in the women but not in the men [ ]. In addition, higher morning plasma cortisol concentrations were significantly associated with better cognitive performance. The authors concluded that elderly women had greater inter-dose activation of the hypothalamic–pituitary–adrenal axis during treatment with therapeutic doses of alprazolam than men, but they stated that this could have been related to drug withdrawal.

In a double-blind, crossover, placebo-controlled study of the effects of alprazolam 5 mg and dehydroepiandrosterone (DHEA) 100 mg/day, alone and in combination, on hypothalamic–pituitary–adrenal axis activity in 15 men (aged 20–45 years; body mass index 20–25 kg/m ² ), alprazolam significantly increased basal growth hormone and blunted the responses to exercise of plasma cortisol, ACTH, AVP, and DHEA [ ]. DHEA and alprazolam in combination significantly increased the growth hormone response to exercise. The authors concluded that DHEA and alprazolam up-regulate growth hormone during exercise, perhaps by blunting a suppressive (HPA axis) system and potentiating an excitatory (glutamate receptor) system.

Skin

Alprazolam, which is lipid-soluble, can cause photosensitivity after a long duration of administration.

• A 65-year-old man developed pruritic erythema on sun-exposed areas (photosensitivity) due to alprazolam [ ]. A photopatch test was negative, but an oral photochallenge test with UVA irradiation was positive after he had taken alprazolam for 17 days.

Drug dependence

Dependence on alprazolam and withdrawal symptoms appear to present greater problems than with other benzodiazepines [ ].