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Nefopam for Refractory Postoperative Hiccups

Bilotta, Federico MD, PhD; Pietropaoli, Paolo MD; Rosa, Giovanni MD

doi: 10.1097/00000539-200111000-00066
ANESTHETIC PHARMACOLOGY: (International Society for Anaesthetic Pharmacology): Review Article

Department of Anesthesia and Intensive Care, University of Rome “La Sapienza”, Rome, Italy

July 9, 2001.

Address correspondence and reprint requests to Federico Bilotta, MD, PhD, via dei Tadolini 13, Rome, 00196, Italy. Address e-mail to

Refractory postoperative hiccups is an uncommon but distressing condition that may cause deleterious effects such as wound dehiscence, infection, fatigue, and dehydration. Hiccups–brief bursts of intense inspiratory activity involving the diaphragm and inspiratory intercostal muscles, with reciprocal inhibition of the expiratory intercostal muscles–might result from structural or functional disturbances of the medulla or of afferent or efferent nerves to the respiratory muscles (1). The first line of management is to reverse or treat any underlying cause such as esophageal obstruction or gastric distention. In most cases, hiccups respond to stimulation of the pharynx or the external auditory meatus, or to vagal maneuvers. Increasing the partial pressure of inspired carbon dioxide (rebreathing) reduces the frequency of hiccups, and reducing carbon dioxide pressure (hyperventilation) increases the amplitude of hiccups (2). Patients with persistent hiccups have been treated with several classes of drugs: chlorpromazine, carbamazepine, nifedipine, nimodipine, baclofen, metoclopramide, haloperidol, ketamine, phenytoin and lidocaine (2–4). All have potentially serious adverse effects and some may be contraindicated in the postoperative setting. Invasive techniques proposed for the control of refractory hiccups include glossopharyngeal nerve block (5) and phrenic nerve block (6). Both procedures reduce vital capacity, may cause dyspnea or hypoxia, and may fail to stop hiccups (7).

We previously reported (8) that severe hiccups in medical patients responds to treatment with nefopam– 3,4,5,6-Tetrahydro-5-methyl-l-phenyl-1H-2.5-benoxazo-cine hydrochloride (Oxadol, Kedrion, Italy)–a nonopioid analgesic drug with shivering suppression properties (9). In this study we describe the use of nefopam in seven patients with postoperative hiccups refractory to standard therapeutic maneuvers: gastric decompression, vagal maneuvers (Valsalva maneuver, carotid and optic compression), pharynx and external auditory meatus stimulation, and carbon dioxide rebreathing. This series includes all cases of refractory postoperative hiccups we observed over the past 2 yr as anesthesiologists in a university hospital.

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Case Reports

All patients were adults undergoing surgical procedures with general anesthesia; some had associated diabetes or arterial hypertension or both and were ASA class I-III (Table 1). None of the patients reported a history of persistent hiccups. In five patients IV nefopam at a dose of 10 mg over 10 s promptly resolved the hiccups; in two patients an additional dose of IV nefopam (10 mg over 10 s) was needed before the hiccups remitted. None of the patients had severe adverse reactions to nefopam; nausea and sweating developed in two patients, but both responded to IV ondansetron 8 mg.

Table 1

Table 1

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Though few patients undergoing surgery will experience refractory hiccups, the few who do may be treated with methods that are unpleasant, invasive, and therefore risky, expensive, time-consuming, and sometimes futile. Most of the drugs proposed have drawbacks in the postoperative setting. Hence the importance of documented evidence that IV infusion of the analgesic drug nefopam will ordinarily suffice to stop recurrent attacks promptly and with minor adverse reactions. Postoperative hiccups have multiple causes: organic or psychological abnormalities, underlying disease, surgical manipulation, and anesthesiological drugs or maneuvers.

The mechanism underlying the hiccups of presumably diverse causes in our seven patients is an interesting but unanswered question. Hiccups result from stimulation of the central or peripheral components of a hiccup reflex arc. As early as 1833 Shortt recognized the relationship between phrenic nerve irritation and hiccups. Bailey in 1943 proposed the existence of a “hiccup center” located in the upper cervical spinal cord. Although the central connection between the afferent and efferent limbs of the hiccup reflex arc cannot be ascribed to a specific anatomic location, it probably involves interactions among brainstem and midbrain areas, including the respiratory center, phrenic nerve nuclei, medullary reticular formation, hypothalamus, and nonspecific anatomic locations in the spinal cord between C3-5. The afferent portion of the hiccup reflex arc comprises the phrenic and vagal nerves and the sympathetic chain arising from T6-12 (10).

Although the mechanisms underlying the analgesic action of nefopam are unclear, nefopam does not bind to opiate receptors but inhibits synaptosomal uptake of several neurotransmitters, including dopamine, norepinephrine, and serotonin (11). In animal studies, nefopam exhibits direct muscle relaxant activity (5 to 10 times as potent as the antiparkinsonian drug orphenadrine) and relatively weak anticholinergic and antihistamine activity (12). Our observation that off-label use of nefopam resolved hiccups of presumably diverse causes suggests that this analgesic drug is effective in treating hiccups of central and peripheral origin. It probably does so by inhibiting synaptosomal neurotransmitter uptake, activating the descending pain-modulating pathways, and exerting a direct muscle relaxant action.

Our experience shows that refractory postoperative hiccups will usually respond to a dose of 10 mg IV nefopam. In two patients in this series we had to administer an additional dose of 10 mg IV. Reported adverse reactions to IV nefopam include pain at the IV site, nausea, and sweating (12). Two of our seven patients suffered from nausea and sweating that responded to IV ondansetron 8 mg.

A limitation of our study is its unblinded nonrandomized design. The difficulty in designing a prospective, randomized, and blinded trial to evaluate the apparent effectiveness and safety of nefopam lies not only in the rarity of the condition but also in identifying a reference standard for comparison with nefopam from among the various treatment regimens for refractory postoperative hiccups.

In conclusion, when standard therapeutic maneuvers fail, IV nefopam will promptly and reliably relieve refractory postoperative hiccups without inducing severe adverse reactions.

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© 2001 International Anesthesia Research Society