Has hydroxyzine been associated with withdrawal symptoms or dependence?

Fråga: Has hydroxyzine been associated with withdrawal symptoms or dependence?

Sammanfattning: Though there are reports of withdrawal symptoms and recreational use (not necessarily indicative of dependence) of first-generation antihistamines. However, the vast clinical experience of these old drugs indicates that neither dependence nor rebound phenomena are problems of major clinical importance.

Svar: As an anxiolytic agent, hydroxyzine is frequently preferred to the benzodiazepines because of the propensity of the latter to cause physical dependence and potentially dangerous withdrawal symptoms. According to the manufacturer of hydroxyzine the drug does not cause dependence (1). Other first-generation antihistamines (e.g. tripelennamine, cyclizine and diphenhydramine) have been subject to recreational use, and are considered to have abuse potential (2, 3). The drug effects sought might include potentiation of co-administered opioids, as well as hallucinatory effects of the drugs per se when administered in high doses (4, 5). Of note, the use of these drugs for non-therapeutic purposes does directly imply that they are liable to cause dependence. In fact, given that hydroxyzine is a D1 and D2 receptor blocker, it would not be expected to cause dependence, since presently dominant pathogenetic models understand dependence to have dopaminergic stimulation as its basis.

A text book on adverse drug reactions states that termination of prolonged first-generation antihistamine therapy could (at least theoretically) cause withdrawal dyskinesia (resembling tardive dyskinesia) similar to that evoked by abrupt withdrawal of phenothiazine antipsychotics (3). These sources do not reference any cases. We could only find very few reports of H1-blocker drug withdrawal, which, given the extensive use of these, support that such must be a rare event indeed.

In the Swedish adverse drug reaction registry, there is one report of hydroxyzine addiction (causal relationship with drug withdrawal deemed probable, no clinical information available) and three reports of a hydroxyzine withdrawal syndrome. No clinical information regarding the withdrawal syndrome was supplied and the causal relationship to hydroxyzine withdrawal was deemed unclassifiable (6). In addition, there is some evidence that tolerance against the sedative and antihistaminergic/antiallergic effects of histamine-H1 antagonists could develop during continuous therapy (7). Since tolerance against receptor antagonists usually involves up-regulation of receptors or second-messenger systems, drug withdrawal could theoretically evoke symptoms of increased histamine H1 activity, e.g. skin rash or anxiety.