It was a pleasure reading in the Journal the report by Porzio et al about their success in the treatment of hiccup using gabapentin (http://www.nzma.org.nz/journal/116-1182/605/).1 Their experience with this structurally GABA-related substance is similar to ours: occasionally patients respond to it dramatically.2,3

Unfortunately, more often than not, therapy for chronic idiopathic singultus (CIS) is less straightforward, requiring the use of a combination of drugs. The efficacy of several drug combinations (cisapride, omeprazole and baclofen (COB) with or without gabapentin, or gabapentin alone) has been assessed in several studies.4,5

For practical purposes, idiopathic hiccup can be assumed to have its origin either in the viscera (gastrointestinal tract) or in the central nervous system. Cisapride and omeprazole – through facilitation of gastric emptying and reduction of gastric acid production, respectively – are thought to reduce an assumed afferent input from the periphery to a putative supraspinal hiccup center. Baclofen (a centrally acting GABA-B receptor agonist) and gabapentin (acting mainly via the alpha2-delta subunit of the calcium channel) are thought to reduce excitability and depress reflex hiccup activity.

COB, a ‘broadband therapy’ for this condition, was considered by our group – until the withdrawal of cisapride from the market – to be the empirical therapy of choice, gabapentin being an excellent add-on drug or in some cases replacement drug for baclofen.

While, as always in polypharmacy, it is impossible to assess the exact role of a particular component of the drug combination used, it is fair to say that at least in some cases the selective serotonin 5-HT4-receptor agonist cisapride had an important role. This has led to the search for a replacement gastrokinetic substance to be used, at least in those cases where delayed gastric emptying is felt to be contributory.

The best-known available alternative, the benzamide compound metoclopramide (Reglan), is a mixed dopamine receptor antagonist, 5-HT4-receptor agonist, and cholinesterase inhibitor. It has a long tradition in the treatment of hiccups, going back to the late 1960s.6 However, although adverse reactions are rare, a potential exists for extrapyramidal side-effects to occur, and therefore we prefer to avoid its long-term use. Similar concerns apply to itapride (Ganaton). Mosapride (Gasmotin) is also undesirable because, like cisapride, it prolongs the QT interval.

Two newer drugs deserve mention and consideration as potential gastrokinetic agents in hiccup patients.

Tegaserod (Zelnorm) is a 5-HT4-receptor partial agonist, recently introduced for treatment of constipation in women with irritable bowel syndrome.7 The substance might offer advantages similar to those of cisapride, without the danger of torsade de pointes. Interestingly enough, recent research has revealed that the breathing centre in the brain stem is (at least in part) under serotoninergic control via a subtype of 5-HT4-receptors, opening the possibility that 5-HT4 agonists might also influence hiccupping by activating the rhythm-generating respiratory neurons.8

The ‘afil’ class of selective phosphodiesterase inhibitors (sildenafil, vardenafil, and tadalafil), while certainly not needing any introduction as therapy for erectile dysfunction, have additional useful effects that are less known. Recently, a gastric prokinetic effect of sildenafil was reported, offering a rationale for its inclusion in the group of potential hiccup treatments.9 Even if the gastrokinetic effect of ‘afils’ turns out to be irrelevant, a case report by Peleg and Peleg, entitled ‘Sexual intercourse as potential treatment for intractable hiccups’, gives reason for hope of a cure.10

We certainly look forward to case reports describing the effect (if any) of these types of drugs on chronic hiccup.