Are hiccups a known side effect of beta-antagonists?/nA patient who had been medicating with metopr

Fråga: Are hiccups a known side effect of beta-antagonists?

A patient who had been medicating with metoprolol 50 mg/d, warfarin 7.5 mg/d, simvastatin 50 mg/d, atorvastatin 20 mg/d, and aspirin 75 mg/d for at least six months experienced an episode of hiccups lasting for 11 days. On suspicion of the hiccups being an adverse drug effect, metoprolol was withdrawn for two days, and the hiccups disappeared. Metoprolol was reinstated, without recurrence of the hiccups.

Sammanfattning: Drug treatment is an uncommon cause of hiccups and there is no convincing evidence that beta-blockers could cause hiccups. Metoprolol is unlikely to be the cause of hiccups in the present case, and the likelihood of a causal relationship is further reduced by a negative rechallenge.

Svar: We found no reports of beta-blocker associated hiccups in Medline, Drugline or standard pharmacological literature. In the Swedish adverse drug reaction register, there are 25 reports of hiccups possibly related to drug therapy (1). Only one of these reports concerned a beta-antagonist, bisoprolol.

Although hiccups are common and have been associated with a large number of pathologic conditions (e.g. encephalitis, tumours of the brain or mediastinum, multiple sclerosis, brainstem lesions, dysnatremia, pericarditis and esophageal diseases), drugs are not a common cause (2, 3). The drugs most commonly associated with hiccups are corticosteroids, benzodiazepines and opioids (3, 4). Although ethanol is frequently discussed as a causal agent, it is not clear whether this occurs by a pharmacologic mechanism or secondary to gastric distension (3).

It has been suggested that hiccups are a physiologic reflex of unknown purpose or a phylogenetic remnant of a breathing control circuit discarded by evolution (2, 3). The neuronal circuit producing them is probably located in the brainstem, and activation of GABA(beta) receptors within this anatomic area has an inhibiting effect on hiccups (3).

Withdrawal of the alpha-adrenergic agonist clonidine has been associated with a withdrawal syndrome characterised by sympathetic over-activity, insomnia, headache, nausea, hypersalivation, and hiccups. There are indications that co-treatment with the non-selective beta-blocker propranolol could worsen these symptoms via an unknown mechanism (5), but this association between beta-antagonists and hiccups could not be considered very convincing. Swedis online (cited 2008-12-29) Straus C, Vasilakos K, Wilson RJ, Oshima T, Zelter M, Derenne JP et al. A phylogenetic hypothesis for the origin of hiccough. Bioessays 2003;25(2):182-188 Thompson DF, Landry JP. Drug-induced hiccups. Ann Pharmacother 1997;31(3):367-369 Drugline no 13493 (year 1997) Drugline no 04566 (year 1085)