Benzodiazepines in the Treatment of Alcoholism: Future Directions


The above treatment recommendations emphasize that minimal signs and symptoms of ethanol withdrawal can generally be treated without pharmacotherapy. The repeated experience of untreated ethanol withdrawals, however, may produce a “kindling” effect over time. Kindling is the “progressive increase in neural responsivity produced by spaced and repeated epileptogenic stimulation of certain brain structures.”

The kindling hypothesis suggests that each additional episode of withdrawal will elicit increasingly severe signs and symptoms. Preclinical studies in which the severity of the ethanol withdrawal syndrome increased in rats subjected to repeated episodes of ethanol withdrawal or following kindling induced by electroshock, metrazol injections, or amygdaloid stimulation indicate that such a process may take place.

In addition, a retrospective study in alcoholics reported that periods of heavy drinking and dependence on ethanol were associated with an exacerbation of agoraphobia and social phobias, and that subsequent periods of abstinence were associated with substantial improvements in these phobic anxiety states. A recent study demonstrated that patients with panic disorder and alcohol dependence do not distinguish panic attacks from withdrawal symptoms on a symptom checklist. It is suggested that panic attacks as well as other symptoms of anxiety may be “kindled” by ethanol withdrawal thereby increasing in severity with each additional withdrawal episode. The effect of this kindling may be evident for prolonged periods, with a continuation of spontaneous anxiety symptoms despite abstinence.

The effects of repeated withdrawal episodes may not be limited to periods of abstinence lasting several days. Persons with alcohol dependence often become maintenance drinkers, ingesting alcohol to ameliorate the early symptoms of withdrawal. Upon awakening, for instance, many alcoholics may experience symptoms such as tremor or nausea and ingest an “eye-opener.” Nightly episodes of withdrawal may therefore also be involved in a kindling phenomenom.

The repeated effects of withdrawal may also produce significant pathology aside from the putative effects of kindling. Markedly elevated levels of cortisol, for example, have been reported early during the ethanol withdrawal syndrome, when blood alcohol levels are still detectable. As noted above, high levels of corticosteroids have been associated with various CNS symptoms as well as neuronal damage. Repeated and prolonged elevations of cortisol during withdrawal may result in hippocampal damage and the development of an organic brain syndrome, the alcoholic dementia.

Signs and symptoms of mild ethanol withdrawal, or even subclinical withdrawal, may therefore be “priming” the alcoholic for future episodes of increasingly severe withdrawal or anxiety disorders, or result in the development of other CNS pathology. This would suggest that all episodes of ethanol withdrawal should be treated aggressively. The clinical significance of withdrawal-induced kindling and other CNS damage will require a longitudinal, labor-intensive, multicenter study. Subjects with alcohol dependence and mild symptoms of ethanol withdrawal could be treated with placebo or pharmacotherapy, with the severity of withdrawal being determined by various biochemical, physiological, and behavioral measures. Long-term follow-up would be essential in order to quantitate the severity of subsequent withdrawal episodes, anxiety symptoms, and other alterations in CNS function.

Although the various medications recommended above for the treatment of ethanol withdrawal are all efficacious, each has its own limitations and disadvantages. Other medications that may more effectively and safely treat ethanol withdrawal are presently being investigated. Alprazolam, a short-acting triazolobenzodiazepine, has a high affinity at central benzodiazepine receptors. Some studies have suggested that alprazolam has potent inhibitory effects on noradrenergic activity, which may be less evident with other benzodiazepines. Alprazolam, but not diazepam, has been reported to activate the brain alpha2-adrenoceptors involved in rat growth hormone secretion. In normal controls, yohimbine, an a2-adrenoceptor antagonist, blocked the effects of single-dose alprazolam-induced decreases in plasma MHPG and blood pressure. In contrast, diazepam did not block effects of yohimbine. Long-term treatment of patients with panic disorder with alprazolam significantly reduced baseline plasma MHPG and blunted the yohimbine-induced increases in plasma MHPG, anxiety, nervousness, and blood pressure. Alprazolam has also been reported to be a successful therapeutic agent in the treatment of panic disorder, a syndrome partially characterized by overactivity of the noradrenergic system. Alprazolam may also have a more potent effect than other benzodiazepines on HPA axis activity, markedly decreasing corticosteroid levels. As depressive symptoms are commonly noted during the ethanol withdrawal syndrome, the reported antidepressant properties of alprazolam may also offer additional advantages over other benzodiazepines in the treatment of ethanol withdrawal. Alprazolam may therefore decrease withdrawal signs and symptoms through multiple mechanisms: enhancing the GABA-induced chloride influx into neurons, decreasing noradrenergic overactivity, and reducing elevations of cortisol. Although Wilson and Vulcano reported no difference in the clinical efficacy of alprazolam compared with chlordiazepoxide, withdrawal severity was rated retrospectively, no physiological or biochemical variables were obtained, and no placebo group was included. Further work in this area is required.


Selections from the book: “Recent Developments in Alcoholism. Volume 7. Treatment Research: Alcoholics Anonymous. The Family. Serotonin and Preference. Clinical Pharmacology.” Edited by Marc Galanter. An Official Publication of the American Medical Society on Alcoholism, the Research Society on Alcoholism, and the National Council on Alcoholism. 1989.