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Alprazolam, also known under the trade names Xanax (not to be confused with Zantac), Xanor, Alprax, and Niravam, is a short-acting drug of the benzodiazepine class. It is primarily used to treat moderate to severe anxiety disorders (e.g., social anxiety disorder) and panic attacks, and is used as an adjunctive treatment for anxiety associated with moderate depression. It is also available in an extended-release form, Xanax XR, both of which are now available in generic form. Alprazolam possesses anxiolytic, sedative, hypnotic, anticonvulsant, and muscle relaxant properties.

Alprazolam has a fast onset of symptom relief (within the first week); it is the most commonly misused benzodiazepine, however the majority of prescribed users do not develop a substance use disorder. Tolerance to the therapeutic effects of alprazolam is controversial with one view being that alprazolam is ineffective with long term use and the other view being that tolerance to the therapeutic effects does not occur. A physical dependence commonly occurs as a result of alprazolam treatment, typified by a withdrawal and rebound symptoms necessitating a gradual reduction in dosage to minimise withdrawal effects when discontinuing. Withdrawal symptoms similar in character to those noted with sedative-hypnotics and alcohol have occurred following discontinuance of benzodiazepines, including alprazolam. The symptoms can range from mild dysphoria and insomnia to a major syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors and convulsions. In the USA, alprazolam is a schedule IV controlled substance under the Controlled Substances Act.

History

Alprazolam was first synthesized by David Hines (now a part of Pfizer). It is covered under U.S. Patent 3,987,052, which was filed on October 29, 1969, granted on October 19, 1976 and expired in September 1993. Alprazolam was released in 1981. The first approved indication was panic disorder. Upjohn took this direction at the behest of a young psychiatrist David Sheehan. Sheehan's suggestion was to use the new distinction the DSM-III created in the classification of anxiety disorders between generalized anxiety disorder (GAD) and panic disorder in order to market alprazolam specifically for the latter. Panic disorder was, at that point, perceived to be rare and treatable only with tricyclic antidepressants; benzodiazepines were thought to be ineffective. However, from his clinical experience, Sheehan knew panic disorder to be both widespread among the populace and responsive to benzodiazepines. He suggested to Upjohn that marketing alprazolam for panic disorder would both cover new diagnostic territory and emphasize the unique potency of this drug. Sheehan describes that the first group of patients treated by alprazolam was so impressed by its action that the company knew outright that this drug was going to be a hit. A few of those patients actually pooled their money and purchased stock in Upjohn. Several months later, when alprazolam was approved by the United States Food and Drug Administration, they sold out and made a profit.

Alprazolam has an exceptional history insofar as soon after its introduction a number of case reports were published in the medical literature of severe withdrawal symptom-related case reports of psychoses, seizures, and intense rebound anxiety upon discontinuation of alprazolam. Several studies found that initial treatment of panic disorder with alprazolam was significantly superior but after 8 weeks of use alprazolam lost its effectiveness and was no more effective than placebo. It was found that behavioural therapy and the drug imipramine however, proved superior to both placebo and alprazolam. It has been argued that placebo is superior than alprazolam after 8 weeks of use due to lack of rebound withdrawal effects and side effects. Controversy exists in that there are allegations that the drug manufacturer suppressed these negative findings regarding lack of sustained efficacy.

Indications

The main medical uses for alprazolam include:

Panic disorder

Alprazolam is FDA-approved for the short-term treatment (up to 8 weeks) of panic disorder, with or without agoraphobia. Alprazolam is very effective in treating moderate to severe anxiety, essential tremor, and panic attacks. Physicians that elect to prescribe alprazolam for longer than 8 weeks should be aware that continued efficacy has not been systematically demonstrated beyond 8 weeks' use, as tolerance to alprazolam's effects may occur after 8 weeks and necessitate discontinuation or physician-directed dose escalation. However, patients with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit. The physician should periodically reassess the usefulness of the drug for the individual patient. Alprazolam is recommended for treatment resistant cases of panic disorder where there is no history of tolerance or dependence.

Anxiety disorder

Alprazolam is indicated for the management of anxiety disorder (a condition corresponding most closely to the APA Diagnostic and Statistical Manual DSM-III-R diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Alprazolam is recommended for the short-term treatment (2–4 weeks) of severe acute anxiety.

Alprazolam is sometimes prescribed for anxiety with associated depression. There is some evidence for antidepressant treatment of clinical depression in outpatient settings; evidence for inpatients is lacking. The antidepressant effects of alprazolam may be due to its effects on beta-adrenergic receptors. Other benzodiazepines are not known to have antidepressant activity. Studies show that any antidepressant action of alprazolam is questionable and generally weak in comparison to those of antidepressant medications. In contrast, while alprazolam in acute or short-term treatment may have some antidepressant properties, there is evidence that up to a third of long-term users of alprazolam may develop depression.

Side-effects

Although the side-effect profile of alprazolam is, in general, benign, side-effects may occur in some patients and are more likely the higher the dosage taken. Some side-effects may disappear with continued treatment. If signs of an allergic reaction occur - such as hives; difficulty breathing; swelling of face, lips, tongue, or throat - medical attention should be sought immediately. Medical attention should also be sought immediately if signs of jaundice appear: yellowing of the skin or eyes. Other side-effects that may occur are as follows:

• drowsiness, dizziness, lightheadedness, fatigue, unsteadiness and impaired coordination, vertigo
• skin rash, respiratory depression, constipation
• disinhibition
• suicidal ideation (rare)
• urinary retention (infrequent)
• hallucinations (rare)
• ataxia, slurred speech
• short-term memory loss and impairment of memory functions
• anterograde amnesia and concentration problems
• Change in libido
• dry mouth (infrequent)
• increase in appetite
• jaundice (very rare)

Paradoxical Reactions

Although unusual, if the following paradoxical reactions occur, the prescribing physician or other healthcare professional should be alerted and the medication gradually discontinued:

• muscle twitching and tremor
• aggression
• rage, hostility
• mania, agitation, hyperactivity and restlessness

Physical dependence and withdrawal

Alprazolam, like other benzodiazepines, binds to specific sites on the GABA_A gamma-amino-butyric acid receptor. When bound to these sites, which are referred to as benzodiazepine receptors, it modulates the effect of GABA A receptors and, thus, GABAnergic neurons. Long-term use causes adaptive changes in the benzodiazepine receptors, making them less sensitive to stimulation and less powerful in their effects.

Not all withdrawal effects are evidence of true dependence or withdrawal. Recurrence of symptoms such as anxiety may simply indicate that the drug was having its expected anti-anxiety effect and that, in the absence of the drug, the symptom has returned to pretreatment levels. If the symptoms are more severe or frequent, the patient may be experiencing a rebound effect due to the removal of the drug. Either of these can occur without the patient's actually being drug-dependent.

Alprazolam and other benzodiazepines may also cause the development of physical dependence, tolerance, and benzodiazepine withdrawal symptoms during rapid dose reduction or cessation of therapy after long-term treatment. There is a higher chance of withdrawal reactions if the drug is administered in a higher dosage than recommended, or if a patient stops taking the medication altogether without slowly allowing the body to adjust to a lower-dosage regimen.

In 1992, Romach and colleagues reported that dose escalation is not a characteristic of long-term alprazolam users, and the majority of patients indicated that alprazolam continued to be effective, suggesting that tolerance to the anti-anxiety effect is limited.

If a patient feels the need to end treatment with alprazolam, he/she should consult his/her physician before discontinuing