Hiccup with aripiprazole plus benzodiazepines resolving with pregabalin and/or benzodiazepine switch/discontinuation. four case reports

Hiccup lasting for more than 2 days is termed protracted and hiccup lasting for more than 2 months is termed intracta- ble; hiccup is associated with high mortal- ity.1 The neurochemistry associated with hiccup is unknown. However, it is believed that dopamine facilitates the hiccup, whereas γ-aminobutyric acid (GABA) reduces it through GABAB receptors but may2 in- crease it through GABAA receptors. In fact, antiparkinsonian medication induces it,3 whereas dopamine receptor blockers and the GABAB agonist baclofen are used in its treatment.4,5 Alternative proposed treatments include the dihydropyridine L-type calcium channel blocker, nimodipine,6 and the α2δ subunit of voltage-gated calcium channels ligands gabapentin7 and pregaba- lin.8,9 Gabapentin and pregabalin are active on L-, N-, P-, and R-type calcium channels. Summarizing the previous data, D2 dopa- mine and GABAA receptor facilitation acti- vates the hiccup reflex in combination with voltage-gated calcium ions, whereas GABAB receptor activation, dopamine D2 inhibi- tion, and voltage-gated calcium channel blockade inhibit the reflex. Calcium ion channel inhibition is able to block hiccup; however, the mechanism is currently un- known. Interestingly, dopaminergic firing of ventral tegmental area dopamine neu- rons is supported by N-type channels,10 and both N- and P-type channel–mediated calcium ion influx facilitate somatodendri- tic and terminal dopamine release.11 In addi- tion, GABAB receptors directly inhibit voltage-gated calcium ion channels,12 whereas GABAA receptor activation in- creases intracytosol calcium in astrocytes through L- and T-type voltage-gated cal- cium channels.13 D2 dopamine receptor–blocking anti- psychotics should theoretically decrease the risk for hiccup, but aripiprazole is a par- tial D2 receptor agonist at lower doses; thus, it may be expected to increase it. Adding a benzodiazepine to aripiprazole might fur- ther increase the risk for hiccup. We describe 4 cases of patients who developed hiccup after taking aripiprazole and benzodiazepines; the symptom improved after discontinuation of one of the drugs or after adding a voltage-gated calcium ion blocker.