Alprazolam

Alprazolam

ORGANS AND SYSTEMS Cardiovascular

GENERAL INFORMATION Alprazolam, a triazolobenzodiazepine, has been marketed as an anxiolytic with additional antidepressant properties; an analogue, adinazolam, also has partial antidepressant activity [1] and is useful in panic disorder. Like other benzodiazepines, alprazolam is effective in acute and generalized anxiety; its efficacy in panic disorder [2,3], premenstrual syndrome [4], and chronic pain [5] is complicated by high rates of adverse effects [6]. On the other hand, low-dose alprazolam (1.4 mg/day) is useful and well tolerated in the treatment of anxiety associated with schizophrenia [7]. The value of the Saskatchewan data files in an acute adverse event signalling scheme has been evaluated using two benzodiazepines [8]. The first 20 000 patients taking lorazepam and the first 8525 patients taking alprazolam were followed for 12 months after the initial prescription. The most frequent adverse drug reactions associated with these benzodiazepines were drowsiness, depression, impaired intellectual function and memory, lethargy, impaired coordination, dizziness, nausea and/or vomiting, skin rashes, and respiratory disturbance. Sleep disorders, depression, dizziness and/or vertigo, respiratory depression, gastrointestinal disorders, and inflammatory skin conditions occurred significantly more often during the first 30 days after the initial prescription than during the next 6 months.

DRUG STUDIES 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 [9]. 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 threearm, parallel design, double-blind, randomized, placebocontrolled study [10]. 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. ã 2016 Elsevier B.V. All rights reserved.

Alprazolam has been associated with hypotension [11].
A 76-year-old woman, who had a history of hypertension, val-

vular 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 [12,13]. Disinhibition has been reported as a major problem with alprazolam, particularly in patients with borderline personality disorder [14]. Several case reports have suggested that alprazolam can cause behavioral disinhibition [15], in common with other benzodiazepines that are occasionally used for recreational or criminal purposes [16]. 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 [17]. 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 [18]. 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 expe-

rience 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 [19].

Alprazolam 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, repeatedmeasures 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 [20]. 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 [21]. 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 [22]. Alprazolam 0.5 mg reduced only the speed of attentional performance, although the magnitude of this reduction was large (d ¼ 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 ¼ 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, repeatedmeasures design 16 healthy volunteers took alprazolam 1 mg, L-theanine 200 mg, or placebo [23]. 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 ã 2016 Elsevier B.V. All rights reserved.

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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 [24]. 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 [25]. 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 [26]. 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 [27]. 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

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Alprazolam

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 [28]. 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/m2), alprazolam significantly increased basal growth hormone and blunted the responses to exercise of plasma cortisol, ACTH, AVP, and DHEA [29]. 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.


A woman with paranoid schizophrenia developed catatonia 5

days after the abrupt withdrawal of olanzapine and alprazolam [32]. The catatonic symptoms included mutism, prostration, waxy flexibility, oculogyric movements, and an inability to swallow. Her symptoms disappeared after administration of alprazolam and haloperidol, and there was no recurrence.
A 39-year-old woman had withdrawal symptoms after her dose of alprazolam was reduced [33]. Cognitive symptoms made it almost impossible for her to stop taking alprazolam or to continue psychotherapeutic treatment. The medication was stopped by means of a behavioral experiment, in which both patient and therapist were unaware of the way in which the medication was reduced, after which continuation of treatment became possible.

Pharmacological strategies for withdrawing alprazolam, by switching to a longer-acting agent, have been proposed [34]. The potential interaction of paroxetine 20 mg/day and alprazolam 1 mg/day for 15 days on polysomnographic sleep and subjective sleep and awakening quality has been evaluated in a randomized, double-blind, doubledummy, placebo-controlled, repeated-dose, four-period, crossover study in 22 young subjects with no history of sleep disturbances [35]. There were subjective withdrawal symptoms after abrupt discontinuation of alprazolam, including increased subjective sleep latency and reduced subjective sleep efficiency. Abrupt withdrawal of alprazolam in 26 patients with panic disorder resulted in dysphoric mood, fatigue, low energy, confusion, and raised systolic blood pressure, which were notable as the fall in plasma concentrations approached 50% [36]. In addition, there was a psychomotor deficit, which persisted beyond dose stabilization. An anxiety-prone cognitive affect, measurable before undertaking treatment, may be a risk factor for more severe anxiety on withdrawal. These observations provide a rationale for applying cognitive behavioral therapy when tapering doses of benzodiazepines.

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-

DRUG ADMINISTRATION Drug formulations

Dependence on alprazolam and withdrawal symptoms appear to present greater problems than with other benzodiazepines [31].

A modified-release formulation of alprazolam (Xanax XR) has been studied in a randomized, open, singledose, two-period crossover study in healthy volunteers, 12 adolescents (13–17 years) and 12 adults (20–45 years), who took single doses of 1 or 3 mg [37]. At both doses, mean plasma concentration-time profiles of alprazolam, a-hydroxyalprazolam, and 4-hydroxyalprazolam were similar in adolescents and adults. Parent–metabolite ratios were similar in the two age groups and were consistent with those previously reported. The most common adverse event was somnolence, which was dose-related. Based on the similar pharmacokinetic profiles, the doses of Xanax XR should be similar in adolescents and adults.

Drug withdrawal

Drug overdose

exposed areas (photosensitivity) due to alprazolam [30]. A photopatch test was negative, but an oral photochallenge test with UVA irradiation was positive after he had taken alprazolam for 17 days.

LONG-TERM EFFECTS Drug dependence

Withdrawal alprazolam.

symptoms

have

been

ã 2016 Elsevier B.V. All rights reserved.

described

with

The effects of alprazolam overdose have been reported [38,39].

Alprazolam
A 28-year-old African–American man took alprazolam 12 mg.

He denied using alcohol, other prescription medications, overthe-counter medications, or illicit drugs. He denied any suicidal intent. He stated that he had taken this large dose because his usual dose of 1–2 mg had failed to relieve his anxiety. He was drowsy and his heart rate was 58/minute. He had marked firstdegree atrioventricular block, with a PR interval of 500 ms.
A 30-year-old woman, with a history of depression, was found dead after taking an unknown quantity of alprazolam, tramadol, and alcohol. At autopsy, only slight decomposition and diffuse visceral congestion were observed. Blood concentrations of alprazolam, alcohol, and tramadol were 0.21 mg/l, 1.29 g/kg, and 38 mg/l respectively.

The relative toxicity of alprazolam compared with other benzodiazepines has been assessed from a database of consecutive poisoning admissions to a regional toxicology service [40]. There were 2065 admissions for single benzodiazepine overdose: alprazolam 131 overdoses, diazepam 823 overdoses and other benzodiazepine 1109 overdoses. The median length of stay for alprazolam overdoses was 19 hours, which was 1.27 times longer than for other benzodiazepines. Of patients with alprazolam overdoses, 22% were admitted to ICU, which was 2.06 times more likely than with other benzodiazepines. Flumazenil was given to 14% of alprazolam patients and 16% were ventilated, which was significantly more than for other benzodiazepine overdoses (8% and 11% respectively). Of those with alprazolam overdoses 12% had a Glasgow Coma Scale score under 9, compared with 10% for other benzodiazepines. The authors concluded that alprazolam was significantly more toxic after overdose than other benzodiazepines.

DRUG–DRUG INTERACTIONS See also HIV protease inhibitors; Alliaceae

Alcohol In common with other benzodiazepines, alprazolam produces additional impairment of performance when it is taken together with alcohol [41]. The combination can also produce behavioral disturbance and aggression [16,42].

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Alprazolam pre-treatment significantly attenuated the discriminative stimulus effects of amfetamine, and some of the self-reported drug effects. The authors suggested that future human laboratory-based studies should compare the behavioral effects of amfetamine alone and after pre-treatment with alprazolam, using other behavioral arrangements, such as drug self-administration. They also suggested that benzodiazepines with lower abuse potential (for example oxazepam) might also attenuate the behavioral effects of amfetamine.

Dextropropoxyphene Inhibition of alprazolam metabolism by dextropropoxyphene has been reported [45].

Ketoconazole In a double-blind, crossover, pharmacokinetic and pharmacodynamic study of the interaction of ketoconazole with alprazolam and triazolam, two CYP3A4 substrate drugs with different kinetic profiles, impaired clearance by ketoconazole had more profound clinical consequences for triazolam than for alprazolam [46].

Miocamycin Hydroxylation of miocamycin metabolites is mainly performed by CYP3A4. Some macrolide antibiotics cause drug interactions that result in altered metabolism of concomitantly administered drugs by the formation of a metabolic intermediate complex with CYP450 or competitive inhibition of CYP450 [47]. The resulting interactions can cause rhabdomyolysis (associated with the coadministration of some statins, for example lovastatin or simvastatin), hypoprothrombinemia (associated with warfarin), excessive sedation (associated with certain benzodiazepines, for example alprazolam, diazepam, midazolam, or triazolam), ataxia (associated with carbamazepine), and ergotism (associated with ergotamine).

Moclobemide Alosetron In an open, randomized, crossover study in 12 healthy men and women, alosetron 1 mg bd did not affect the pharmacokinetics of a single oral dose of alprazolam 1 mg [43].


A 44-year-old man developed the serotonin syndrome after

taking moclobemide and alprazolam for 1 year [48]. The symptoms developed after 4 days of extreme heat, which was thought to have contributed.

Nefazodone Amfetamine Six healthy volunteers learned to recognize the effects of oral D-amfetamine 15 mg and then the effects of a range of doses of D-amfetamine (0, 2.5, 5, 10, and 15 mg), alone and after pre-treatment with alprazolam (0 and 0.5 mg), were assessed [44]. Amfetamine alone functioned as a discriminative stimulus and produced stimulant-like self-reported drug effects related to dose. Alprazolam alone did not have amfetamine-like discriminative stimulus effects, nor did it increase ratings of sedation or impair performance. ã 2016 Elsevier B.V. All rights reserved.

Nefazodone is a weak inhibitor of CYP2D6 but a potent inhibitor of CYP3A4 and it increases plasma concentrations of drugs that are substrates of CYP3A4, such as alprazolam, astemizole, carbamazepine, ciclosporin, cisapride, terfenadine, and triazolam.

Oral contraceptives Oral contraceptives alter the metabolism of some benzodiazepines that undergo oxidation (alprazolam,

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Alprazolam

chlordiazepoxide, and diazepam) or nitroreduction (nitrazepam) [49]. Oral contraceptives inhibit enzyme activity and reduce the clearances of these drugs. There is nevertheless no evidence that this interaction is of clinical importance. It should be noted that for other benzodiazepines that undergo oxidative metabolism, such as bromazepam or clotiazepam, no change has ever been found in oral contraceptive users. Some other benzodiazepines are metabolized by glucuronic acid conjugation. The clearance of temazepam was increased when oral contraceptives were administered concomitantly, but the clearances of lorazepam and oxazepam were not [50]. Again, it is unlikely that this is an interaction of clinical importance.

sequences (paroxetine þ alprazolam placebo, alprazolam þ paroxetine placebo, paroxetine þ alprazolam, and paroxetine placebo þ alprazolam placebo) in randomized order [54]. There was no pharmacodynamic interaction at steady state. The most commonly reported adverse event was drowsiness, with a higher incidence when alprazolam was used, both alone and in combination with paroxetine.

Sertraline Sertraline (50–150 mg/day) had no effects on alprazolam metabolism in a randomized, double-blind, placebocontrolled study in 10 healthy volunteers [55].

Ritonavir The inhibitory effect of ritonavir (a viral protease inhibitor) on the metabolism of alprazolam, a CYP3A-mediated reaction, has been investigated in a double-blind study [51]. Ten subjects took alprazolam 1.0 mg plus either low-dose ritonavir (four doses of 200 mg) or placebo. Ritonavir reduced alprazolam clearance by 60%, prolonged its half-life, and magnified its benzodiazepine agonist effects, such as sedation and impairment of performance.

Selective serotonin reuptake inhibitors (SSRIs)

Troleandomycin Troleandomycin inhibits the metabolism of ecabapide and alprazolam by inhibition of CYP3A4 [56,57].

Venlafaxine The effects of venlafaxine on the pharmacokinetics of alprazolam have been investigated in 16 healthy volunteers. Steady-state venlafaxine 75 mg bd did not inhibit CYP3A4 metabolism of a single dose of alprazolam 2 mg [58].

Fluoxetine A within-subject, double-blind, placebo-controlled, parallel design has been used to measure the effects of citalopram (20 mg/day) and fluoxetine (20 mg/day) on the pharmacokinetics and pharmacodynamics of alprazolam (1 mg/day) [52]. Fluoxetine significantly impaired the metabolism of a single oral dose of alprazolam 1 mg, leading to prolongation of the half-life and an increased AUC, whereas citalopram did not. Neither SSRI significantly affected the pharmacodynamic effects of alprazolam. This experiment suggests differential effects of citalopram and fluoxetine on alprazolam kinetics.

FOOD–DRUG INTERACTIONS Grapefruit juice There have been two studies of the effects of repeated ingestion of grapefruit juice on the pharmacokinetics and pharmacodynamics of both single and multiple oral doses of alprazolam in a total of 19 subjects [59]. Grapefruit juice altered neither the steady-state plasma concentration of alprazolam nor its clinical effects.

REFERENCES

Fluvoxamine The effects of co-administration of fluvoxamine on plasma concentrations of alprazolam have been studied in 23 Japanese outpatients [53]. All patients were taking fluvoxamine (25–100 mg/day) either before or after monotherapy with alprazolam (0.4–1.6 mg/day). Co-administration with fluvoxamine produced on average a 58% increase in plasma alprazolam concentrations. However, there were wide variations in the plasma concentrations of alprazolam. The interaction was attributed to the CYP2C19 genotype.

Paroxetine In a double-blind, double-dummy, placebo-controlled, repeated-dose (15 days), 4-period crossover study, each of 25 young adult volunteers received each of four treatment ã 2016 Elsevier B.V. All rights reserved.

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