Alprazolam dependence

Pinna G, Galici R, Schneider HH, et al. Alprazolam dependence prevented by substituting with the beta-carboline abecamil. 

Patterson JF. Withdrawal from alprazolam dependency using clonazepam clinical observations. J Clin Psychiatry 1990 5[Suppl 5] 47-49. 

The benzodiazepines currently available for clinical use vary substantially in pharmacokinetics, acute euphoriant effects, and frequency of reported dependence. It is likely, therefore, than not all benzodiazepines have the same potential for abuse. Diazepam, lorazepam, and alprazolam may have greater abuse potential than chlordiazepoxide and clorazepate (Wolf et al. 1990). Similarly, oxazepam has been reported to produce low levels of abuse (Eliding 1978). Jaffe et al. (1983) found that in recently detoxified alcoholic patients, halazepam produces minimal euphoria even at a supratherapeutic dosage. The development of partial agonist and mixed agonist/antagonist compounds at the benzodiazepine receptor complex may offer an advantage over approved benzodiazepines for use in alcoholic patients. 

Klein E, Uhde TW, Post RM Preliminary evidence for the utility of carbamazepine in alprazolam withdrawal. Am J Psychiatry 143 235—236, 1986 Kouyanou K, Pither CE, Wessely S Medication misuse, abuse and dependence in chronic pain patients. J Psychosom Res 43 497-304, 1997 Kryspin-Exner K [Misuse of bezodiazepine derivatives in alcoholics] (German). Br J Addict Alcohol Other Drugs 61 283-290, 1966 Kryspin-Exner K, Demel 1 The use of tranquilizers in the treatment of mixed drug abuse. Int J Clin Pharmacol Biopharm 12 13-18, 1973... 

Walker BM, Ettenberg A The effects of alprazolam on conditioned place preferences produced by intravenous heroin. Pharmacol Biochem Behav 75 75 80, 2003 Weens EM, Griffiths RR Zolpidem self-injection with concurrent physical dependence under conditions of long-term continuous availability in baboons. Behav Pharmacol 9 285—297, 1998... 

The speciflc clinical use of the numerous available benzodiazepines depends on their individual pharmacokinetic and pharmacodynamic properties. Drugs with a high affinity for the GABAa receptor (alprazolam, clonazepam, lorazepam) have high anxiolytic efficacy drugs with a short duration of action (temazepam) are used as hypnotics to minimise daytime sedative effects. Diazepam has a long half-life and duration of action and may be favoured for long-term use or when there is a history of withdrawal problems oxazepam has a slow onset of action and may be less susceptible to abuse. 

Cytochrome P450 2D6 and 3A4 activities. Saw palmetto extract, administered to healthy volunteers (six men and six women) for 14 days at generally recommended doses, did not alter the disposition of coadministered dextromethorphan and alprazolam primarily dependent on the CYP2D6 or CYP3A4 pathways for elimination b Cytotoxic activity. Extract from saw palmetto, in LNCaP cell culture, produced cell... 

A multitude of studies show that benzodiazepine is effective in the treatment of panic disorder, sometimes freeing patients from panic attacks after six to eight weeks of use. Benzodiazepines tend to work quickly, with a reduction in panic being observed as little as one week after the start of treatment. However, benzodiazepines have the risks of tolerance and dependency. Common benzodiazepines used to treat panic disorder include alprazolam (Xanax) and clonazepam (Klonopin). 

A second issue relating to long-term medication is the effect of withdrawing medication at the end of a period of treatment. Benzodiazepines are associated with discontinuation symptoms, and their repeated use may foster the development of true physiological dependence. In a study of discontinuation of treatment for panic disorder [Rickels et al. 1993) with either alprazolam [n = 27), imipramine [n = 11) or placebo [n = 10), a withdrawal syndrome was observed in almost all patients treated with alprazolam but in few pa-... 

Most sedative drugs, including narcotics and alcohol, potentiate the sedative effects of benzodiazepines. In addition, medications that inhibit hepatic cytochrome P450 (CYP) 3A3/4 increase blood levels and hence side effects of clonazepam, alprazolam, midazolam, and triazolam. Lorazepam, oxazepam, and temazepam are not dependent on hepatic enzymes for metabolism. Therefore, they are not affected by hepatic disease or the inhibition of hepatic enzymes. 

American Psychiatric Association Benzodiazepine Dependence, Toxicity, and Abuse A Task Force Report of the American Psychiatric Association. Washington, DC, American Psychiatric Association, 1990 Cohn JB, Wilcox CS Low-sedation potential of buspirone compared with alprazolam and lorazepam in the treatment of anxious patients a double-blind study. J Clin Psychiatry 47 409 12, 1986 Dolovich LR, Addis A, Vaillancourt JM, et al Benzodiazepine use in pregnancy and major malformations or oral cleft meta-analysis of cohort and case-control studies. BMJ 317 839-843, 1998 Goldberg HL, Finnerty RJ The comparative efficacy of buspirone and diazepam in the treatment of anxiety. Am J Psychiatry 136 1184—1187, 1979 Kupfer DJ, Reynolds CF 111 Management of insomnia. N Engl J Med 336 341-346, 1997... 

Alprazolam has caused a lower incidence of drowsiness, light-headedness and depression than diazepam. Alprazolam, like other benzodiazepines, has the potential for the development of tolerance and withdrawal symptoms, although the incidence is lower than that seen with other benzodiazepines. Alprazolam s potential for drug dependence is less in comparison to other benzodiazepines. 

Finally, it should be stressed again that certainly not all benzodiazepine prescribing to opioid maintenance patients need be long term. McDuff et al. (1993) reported on detoxification from alprazolam, the benzodiazepine most commonly used by their methadone subjects. With methadone dosage usually remaining the same, patients were offered a set reducing course of alprazolam over 11 weeks. Of 22 patients, four refused the treatment and 12 out of 18 subsequently completed detoxification, although timescales in practice proved variable. In a comparative study by Weizman et al. (2003) just over a quarter of benzodiazepine-dependent methadone maintenance patients remained free of benzodiazepines... 

Alprazolam may also relieve tremor at doses of 0.75 to 3 mg/day (357). Because chronic use can lead to habituation or dependence, alprazolam is best used episodically for patients who require only intermittent tremor reduction to prevent social embarrassment or occupational interference. Methazolamide, a carbonic anhydrase inhibitor, has been reported to reduce hand tremor (at doses of 50 to 300 mg/day) in several open studies ( 358, 359). A controlled trial, however, could not confirm the efficacy of this agent in the treatment of tremor but did report that side effects such as paresthesias, sedation, headache, and gastrointestinal symptoms were common (77, 356). 

Withdrawal symptoms are unlikely to occur after only 3 to 4 months of continuous use of a BZD. Early indications of dependence have been noted, however, with reports of withdrawal symptoms after only 6 weeks of continuous use, particularly with the short-acting agents such as alprazolam (23, 24, 228, 229, 230, 231 and 232). 

High-potency benzodiazepines (alprazolam, clonazepam) generally are more effective in panic disorder than low-potency benzodiazepines (diazepam, lorazepam, etc.). Although less research has been done on the low-potency benzodiazepines, it is generally accepted that they frequently result in sedation prior to adequately relieving panic attacks. The reader is referred to the discussion of benzodiazepines in Chapter 8 for a detailed overview of mechanism of action. A critique of the issues of benzodiazepine dependence and appropriate use is given in Chapter 13-... 

Insomnia is a common complaint in the elderly. As people age they require less sleep, and a variety of physical ailments to which the elderly are subject can cause a change in the sleep pattern (e.g. cerebral atherosclerosis, heart disease, decreased pulmonary function), as can depression. Providing sedative hypnotics are warranted, the judicious use of short half-life benzodiazepines such as temazepam, triazolam, oxazepam and alprazolam for a period not exceeding 1-2 months may be appropriate. Because of their side effects, there would appear to be little merit in using chloral hydrate or related drugs in the treatment of insomnia in the elderly. It should be noted that even benzodiazepines which have a relatively short half-life are likely to cause excessive day-time sedation. The side effects and dependence potential of the anxiolytics and sedative hypnotics have been covered elsewhere in this volume (Chapter 9). 

Although the shorter-acting BZs such as Xanax (alprazolam) and Halcion (triazolam) seem to be the most toxic and most prone to cause dependence, any BZ can cause these untoward effects, including the commonly used Klonopin (clonazepam) and Ativan (lorazepam). Overall, the BZs and many related medications used to treat anxiety and insomnia are potentially very brain disabling and spellbinding, and entail much graver risks than commonly recognized by health care providers and their patients. 

Fig. 23. Effects of diazepam, alprazolam and buspirone on drug discrimination in rats trained to discriminate 2 mg/kg i.p. diazepam from saline. Note the dose-dependent generalization of lower doses of diazepam towards responding on die lever associated with the training dose of diazepam, with a similar generalization curve for alprazolam. Buspirone does not generalize to diazepam.

Dependence on alprazolam and withdrawal symptoms appear to present greater problems than with other benzodiazepines (SED-12, 98). 

Benzodiazepine (BZ) intoxication is manifested as slurred speech, poor coordination, swaying, drowsiness, hypotension, nystagmus, and confusion. Signs and symptoms of BZ withdrawal are similar to those of alcohol withdrawal, including muscle pain, anxiety, restlessness, confusion, irritability, haJlucinations, delirium, seizures, and cardiovascular collapse. Withdrawal from short-acting BZs (e.g., oxazepam, lorazepam, alprazolam) has an onset within 12 to 24 hours of the last dose. Diazepam, chlordiazep-oxide, and clorazepate have elimination half-lives (or active metabolites with elimination half-lives) of 24 to greater than 100 hours. So, withdrawal may be delayed for several days after their discontinuation. Sedative-hypnotic dependence is summarized in Table 73-2. 

CANNABIS ANXIOLYTICS AND HYPNOTICS-BZDs-alprazolam, diazepam, midazolam, triazolam Unpredictable changes in plasma concentration. Risk of toxicity or therapeutic failure, particularly of drugs with a narrow therapeutic index Induction or inhibition of CYP3A4-mediated metabolism by cannabis. It is not yet known whether the effects are dependent on the degree of cannabis consumption Be aware. Watch for signs of toxicity, especially when cannabis use abruptly changes... 

If clonazepam can be considered a long-acting alprazolam-like anxiolytic , then alprazolam XR can be considered an even longer-acting clonazepam-like anxiolytic with the potential of improved tolerability features in terms of less euphoria, abuse, dependence, and withdrawal problems, but this has not been proven... 

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