Miracle hiccough cure gets the attention it deserves

BMJ 2006; 333 doi: https://doi.org/10.1136/bmj.39051.721632.3A (Published 07 December 2006) Cite this as: BMJ 2006;333:1222

Nefopam for chronic persistent hiccups

Editor – I write with reference to Roberts’s and Thomas’s
experiences.1,2 Chronic persistent hiccups is a rare but distressing
condition most frequently associated with serious underlying health
problems of peripheral (esophagogastric irritational noxae, chest tumors,
etc) and central (cerebral ischemia, cerebral expanding lesions
especially in the posterior fossa, etc) causes.3,4 We have previously
reported the effectiveness of nefopam in abolishing acute severe hiccups
in three patients with recent onset of incapacitating, refractory hiccup,
and in the setting of acute postoperative hiccups.5-7 Nefopam (3,4,5,6-
Tetrahydro-5-methyl-l-phenyl-1H-2.5-benoxazocine) is a centrally acting
non-opioid analgesic agent that has anti-shivering properties,
structurally related to antihistamine and anti-parkinsonian drugs
(orphenadrine).8 In this report we present our experience in treating
chronic hiccup with nefopam (Accupan, France). Over 5 years we have
received more than 200 contacts from all over the world patients with
chronic, intractable hiccups or their physicians. This interest led us to
develop a simple diagnostic work-up for chronic intractable hiccups:
esophagogastroduodenoscopy, complete blood count, chest X-ray and if these
investigations yield negative findings, non-invasive brain imaging. Using
this work-up we selected for treatment with nefopam a series of 57
patients (Table) with chronic, intractable hiccups fulfilling stict
inclusion criteria: bouts of hiccups lasting more than 3 weeks, resistant
to vagal and Lam’s maneuvers and unsuccessfully treated with
chlorpromazine, baclofen, nimodipine and lidocaine and in whom
esophagogastroduodenoscopy failed to disclose mucosal disorders.
Of the 57 patients with chronic intractable hiccups enrolled, the median
referral time from hiccup onset was 2 years; 17 patients, all with type II
diabetes mellitus, had undergone coronary artery surgery, 16 had cerebral
disease (previous stroke, intracranial tumor or neurovascular
abnormalities), 8 had neck problems (tumor or neck surgery), 5 had
mediastinal disease (lung tumor or lymphoma), and 11 had no documentable
physical disease but possible psychological problems. Nefopam was
administered i.v. at a dose of 0.25 mg/kg over 10 sec
We defined the cessation of hiccups as no recurrent bouts for at least 4
hours after intravenous nefopam, and reduction of hiccups as a 30%
decrease in the frequency (bouts/min). Intravenous nefopam administration
(0.15 mg/kg at the rate of 1 mg/sec) abolished hiccups in 9/57 patients
(15.7%); and reduced hiccups in 14/57 patients (24.5%) (Table). Nefopam
was more effective in abolishing or reducing hiccups in patients receiving
nefopam within 3 months after the onset of hiccup, and with coexisting
health problems that trigger the central or peripheral nervous system, for
example brain tumors, neck surgery and lymphoma and less effective in
patients with advanced peripheral nerve dysfunction such as long-lasting
and poorly controlled diabetes mellitus.

In this report we describe that off-label use of nefopam, although it
is not a panacea for hiccupping, is safe and effective in abolish or
reducing chronic intractable hiccups of presumably diverse causes. We also
describe simple diagnostic work-up for chronic intractable hiccups, that
allow to identify specific coexisting health problems.

The mechanism of nefopam-induced hiccups suppression remain
uncertain. Although conflicting effects of antiparkinsonian durgs
(dopamine agonist drugs) on hiccups have been reported,9 nefopam probably
does so by inhibiting synaptosomal neurotransmitter uptake, activating the
descending pain-modulating pathways, and exerting a direct muscle relaxant


1 Roberts H. Blood lettering and miraculous cures. BMJ 2006; 333:
2 Thomas RH, Thomas NJ. Miracle hiccough cure gets the attention it
deserves. BMJ 2006;333(7580):1222.
3 Kolodzik PW, Eilers MA. Hiccups (Singults): review and approach to
management. Ann Emerg Med 1991;20:565-73.
4 Park MH, Kim BJ, Koh SB, et al. Lesional location of lateral medullary
infarction presenting hiccups (singultus). J Neurol Neurosurg Psychiatry
5 Bilotta F, Rosa G. Nefopam for severe hiccups. N Engl J Med.
6 Bilotta F, Ferri F, Giovannini F, Pinto G, Rosa G. Nefopam or clonidine
in the pharmacologic prevention of shivering in patients undergoing
conscious sedation for interventional neuroradiology. Anaesthesia.
7 Bilotta F, Pietropaoli P, Rosa G. Nefopam for refractory postoperative
hiccups. Anesth Analg. 2001;93(5):1358-60.
8 Heel RC, Brogden RN, Peaks GE, Speight TM, Avery GS: Nefopam: A review
of its pharmacological properties and therapeutic efficacy. Drugs
9 Sharma P, Morgan JC, Sethi KD. Hiccups associated with dopamine agonists
in Parkinson disease. Neurology 2006;66(5):774.

Table. Demographic characteristics of the Patients


Age – yr

Mean 52.3±8.7
Range 21-88

Sex – no. of patients (%)

Male 42(73)
Female 15(27)

Hiccup duration – yr

Median 2.0
Range 0.1-9

Coexisting disease (patients: total/hiccups cessation/hiccups

Coronary surgery: 17/2/4
Cerebral disease: 16/3/5
Neck disease: 8/1/1
Mediastinal disease: 5/1/2
No evidence of coexisting physical disease: 11/2/2

Patients receiving nefopam within 3 months after the onset of hiccup
(patients: total/hiccups cessation/hiccups reduction) 12/3/4

Competing interests:
None declared

Competing interests: No competing interests

24 February 2007
Federico Bilotta
Consultant Anesthesiologist
Giovanni Rosa
University of Rome
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