Hiccups unresponsive to therapeutic measures can have a major impact on the quality of life of patients. Occasional bouts of hiccups, which can occur after an expansive meal or fast drinking of cold beverages, are experienced by most human beings and are seldom cause of distress or medical consultation. When first mentioned by Lupton in 1627, “hickop” had already been subject to speculation and investigation for many centuries.1 While Hippocrates and Galen differed in their opinions whether the curious symptom was caused by an ill condition of the stomach or the liver, Shortt in 1833 was the first to suspect an involvement of the phrenic nerve in the generation of hiccups.1 The rhythmic spasms of the diaphragm immediately followed by closure of the glottis occur at a maximal frequency of 60 per minute and are, if not self-limiting, usually stopped by well-known interventions such as holding one’s breath or being scared.2
In rare cases, hiccups can continue for days, months, or even years. Singultus, as hiccups are termed scientifically, is defined as persistent when lasting for longer than 48 hours, and as intractable when being present for 30 days and more.3 The symptom has to be considered a serious medical condition, which can lead to insomnia, exhaustion, and weight loss due to the inability to eat.4 Still, as only a very small fraction of the population is inflicted with intractable hiccups, research in this field is based only on a small number of cases and has not yet led to the discovery of reliable treatment options, let alone the development of a standard of care. The aim of this review is to provide a comprehensive overview of the current state of research on the treatment of intractable hiccups, with respect to the functional anatomy and pathophysiology of the hiccup pathway and a correct diagnostic workup in hiccup patients.
WHY IS HICCUP IMPORTANT TO THE FIELD OF ANESTHESIOLOGY AND INTENSIVE CARE?
While anesthesiologists are quite regularly confronted with acute hiccups in patients during the induction and maintenance of general anesthesia, an intuitive link of anesthesiology to the treatment of chronic singultus does not seem given.5 Still, many aspects of both theoretical background and clinical competence in a setting of perioperative and critical care qualify the anesthesiologist as first carer for patients suffering from chronic hiccups.
Patients with a positive anamnesis for persistent or chronic singultus, even if not presently symptomatic, require particular care and prophylactic measures in an operative setting, as perioperative stress can lead to gastrointestinal irritation and could thus evoke hiccup in these individuals.6 This may entail a risk of regurgitation and aspiration, dangerous especially during the induction of general anesthesia. However, even without a known predisposition, surgical procedures in proximity to structures of the singultus reflex pathway bear a risk of an intraoperative occurrence of singultus, which may not subside after the intervention. For example, an injury or disturbance of the Nervus vagus is a possible complication in intrathoracic or thyroid operations.7–9 Laparoscopic procedures can directly irritate the diaphragm and thus evoke singultus.10 , 11 Timely treatment of this complication, to enable a safe progression of the operation and prevent a postoperative chronification, will fall into the responsibility of the anesthesiologist as caretaker of the patient’s intraoperative stability and well-being. Singultus during surgery may also be caused by anesthesiological intervention, eg, shifts in the electrolyte homoeostasis after volume loading or side effects of intraoperatively applied medication.12–14 Knowledge of the pathophysiological background of hiccup generation and persistence is crucial for an effective therapy in this context. Similar to surgical interventions, persistent singultus can also occur as a complication in invasive procedures performed by the anesthesiologist, like central venous catheterization.15
In the postoperative phase, prolonged singultus may lead to breathing problems especially in a situation in which assisted ventilation is required, entailing longer periods of hospitalization and higher treatment costs.16 , 17 Suphrenic or intrathoracic processes, like an abscess caused by gastrointestinal surgery or a pleural effusion, can be causative for or at least worsen this problem.18 , 19
Persistent hiccup during a stay on an intensive care unit may cause insomnia and weight loss, possibly leading to severe physical exhaustion and thereby interfering with the patient’s recovery process.4
To our knowledge, no medical discipline presently provides a consultancy service for the treatment of perioperative and persistent hiccups on a regular basis; the establishment of a specific field of competence within the field of anesthesiology would seem most expedient. Expertise in the comprehensive evaluation of pathophysiological mechanisms influencing a patient’s condition and, in particular, the knowledge about chronification processes is anesthesiological qualifications that are well needed in the therapy of chronic singultus. Key prerequisites further are the regular implementation of multimodal therapeutic approaches, and not least the familiarity with interventional procedures on peripheral nerves as they are regularly utilized in pain therapy.
A specialized singultus treatment center was established at the Pain Therapy Unit of the Department of Anaesthesiology at the University Hospital Heidelberg, Germany, in 2009; since then, about 240 patients were counseled and treated for chronic hiccups by our anesthesiologists and pain physicians.
A PRIMITIVE REFLEX? ANATOMY OF THE HICCUP PATHWAY AND THE GENERATION OF HICCUP
Search Strategy and Selection Criteria
Sources of information were acquired by a MedLine search for keywords “hiccup,” “singultus,” “persistent hiccup,” “persistent singultus,” “chronic hiccup,” and “chronic singultus.” Peer-reviewed articles in English, German, and French were considered. To provide a comprehensive report on this defined topic, we did not specify a time span.
The involved anatomic structures of the hiccup reflex arc can be divided into an afferent limb, a reflex center, and an efferent limb stimulating the effector musculature. Afferent impulses are transmitted to the hiccup center via the vagal and phrenic nerve, as well as a part of the sympathetic chain arising from the thoracic segments Th6 to Th12.20 , 21 The hiccup reflex center is believed to be located in the hypothalamus, the brainstem, and the cervical spinal cord (segments C3–C5).22 It includes the inspiratory dorsal group of the nucleus tractus solitarii, the ventral group of the nucleus ambiguus in the medullary formatio reticularis, responsible for the Hering-Breuer reflex and containing vagal motoneurons that project to the upper airway, as well as medial and dorsal medullary nuclei for the termination of inspiration.23–25 Several of these nuclei have been suggested to interact, ie, the inspiratory center of the dorsal nucleus tractus solitarii and premotor neurons located in the caudal section of the ventral nucleus ambiguus, projecting to the larynx and the diaphragm.24 , 25 Chronic hiccups in patients with supratentorial lesions suggest the existence of an inhibitory cortical influence that represses the reflex physiologically.26 The efferent limb of the hiccup reflex arc is formed by a complex of structures with mainly respiratory function: the phrenic nerve stimulating the diaphragm, the intercostal nerves to the inspiratory intercostal muscles, as well as direct efferences to the scalenus musculature (responsible for the elevation of the clavicles) and vagal branches to the glottis.20 , 27 , 28 Dopamine and γ-aminobutyric acid (GABA) have been postulated to be of influence in the neurotransmission of the hiccup reflex based on observations made with singultus-inducing and singultus-alleviating therapeutics.21 , 29–31 However, a model of their specific mechanism of action and targeted receptors is yet missing. Figure 1 illustrates the structure of the hiccup reflex arc.
The insignificant effect of hiccups on ventilation implies that hiccups are not a respiratory reflex.20 This is supported by the finding that glottis closure occurs 35 milliseconds after the onset of the diaphragmatic discharge in hiccups, and that any expiratory muscle activity is inhibited for the entire duration of the inspiratory hiccup discharge.1 , 20 Contrary to reflexes known for rhythmic breathing which react increasingly with high partial pressure of alveolar carbon dioxide levels, the frequency of hiccups is reduced.20 A different suggestion states that hiccups are the primarily pathologic result of a dysfunction in the reciprocal inhibition of 2 functional complexes in the pharynx and larynx, the glottis closure complex and the inspiratory complex, responsible for the valve function of the glottis.32
A possible physiologic role for hiccups has been discussed controversially. As hiccups are observed frequently in the fetus from the eighth week of gestation, their occurrence decreasing during childhood and adult life, it has been suggested that they represent a fetal reflex preventing the aspiration of amniotic fluid.33–35 Another study proposes hiccups to be the result of archaic central pattern generators for gill ventilation that persisted during phylogenetic development.36 Intrauterine hiccups could be a mechanism preparing the fetus’ respiratory system for independent breathing after birth; this, however, is contrary to the finding that hiccups have no respiratory function in infants and adults.20 , 33 , 37 , 38 A consistent explanation for the origin and function of hiccups remains yet to be found.
HICCUPS AS A SYMPTOM OF UNDERLYING ILLNESS
Considering the involvement of anatomical structures with diverse primary functions in the hiccup reflex arc, it is not surprising that a vast number of pathological conditions has been associated with persistent hiccups. If examined for common characteristics, causative illnesses seem to induce hiccups either by spatial compromise along the course of vagal, phrenic, or intercostal nerve branches (tumors, vascular malformations, pregnancy), alternatively, irritation due to inflammation (esophagitis, pericarditis, encephalitis) or other pathologies of adjoining organs (myocardial infarction, asthma).2 , 39–41 Systemic infections, as well as electrolyte disturbances associated with several metabolic disorders such as diabetes mellitus and renal failure, have been described as causes of chronic hiccups.2 , 42 Traumatic lesions or functional impairment of the neuronal network of the hiccup reflex arc (due to neurologic diseases such as Parkinson’s disease and multiple sclerosis) may also present with singultus.22 , 43 In not a few cases, hiccups are not a symptom of physical but psychological distress or disorder.44 Most commonly reported as an underlying cause of intractable hiccups are illnesses within the gastrointestinal tract, the central and peripheral nervous system, and the thoracic viscera. In many patients though, a definite culprit for hiccupping is difficult to identify. The immediate connection between a pathology and singultus is not always clear, and hiccups have been associated with farfetched causes, such as glaucoma.45 An overview of conditions found causative for persistent hiccups can be deferred from Table 1.
PHARMACOLOGICAL OR INTERVENTIONAL TREATMENT AS CAUSE OF PERSISTENT HICCUPS
Parallel to illnesses that involve structures of the hiccup pathway, interventions undertaken in close proximity of the reflex’s center, its afferences or efferences can provoke persistent hiccups. Recurring cases of hiccups after brain surgery suggest a clinical significance of the symptom in this context.123 , 124 Hiccups have also been reported to occur after various interventions within the gastrointestinal tract; to be noted, with respect to relevance in the clinical routine, is the occurrence of persistent hiccups as a complication of everyday procedures such as gastroscopy.10 , 126 Less common inducers of hiccup include cardiac electrodes and central venous catheters15 , 127 Table 2 lists further examples of postinterventional hiccups.
Pharmacological agents targeting receptor types and interfering within the neuronal mechanism of the singultus reflex are a likely trigger of chronic singultus. Thus, hiccups secondary to treatment with dopamine agonists of high D3 receptor affinity have been reported, whereas benzodiazepine-induced hiccups are likely transmitted by GABA.136 , 137 Corticoids have been suggested to lower the threshold of synaptic transmission in the midbrain and therefore facilitate the stimulation of the hiccup reflex arc; progesterone derivatives likely act in a similar way.138 , 139 Hiccups during combination chemotherapy with cisplatin and dexamethasone may be induced by a synergistic effect, with cisplatin causing serotonin release from enterochromaffine cells and vagal afferents.140 Cases of hiccups after general or local anesthesia have been reported, but ascertaining whether the anesthetic agent or the procedure itself caused the symptom is often difficult.14 , 141 Epidural injections of anesthetics may cause persistent hiccups solely due to change in the cerebrospinal fluid volume.142 Hiccups during the postoperative period can complicate the recovery phase through sleep disturbance, exhaustion, and wound dehiscence.143
Interestingly, agents that are utilized in the treatment of chronic hiccups are sometimes found themselves to be cause of the symptom. Atropine, local anesthetics, and benzodiazepines such as midazolam, for example, have been reported to play this “double-role.”136 , 144–146 Table 3 provides a summary of pharmaceuticals associated with persistent hiccups.
DIAGNOSTIC STRATEGIES IN HICCUP PATIENTS
In some cases, a connection between intractable hiccups and a preexistent infliction is easily drawn and the symptom can be sufficiently controlled by treatment of the underlying problem. If the cause is less clear, a patient presenting with persistent hiccups should receive an extensive workup that addresses all probable causes of the symptom. A careful anamnesis of past or current infections, preexisting illnesses, and previous interventions, especially within the gastrointestinal and nervous system, is essential. The patient’s regular medication should be checked for agents known to induce singultus, especially corticosteroids, benzodiazepines, chemotherapeutics, and dopamine agonists. Alcohol and drug consumption habits should be assessed. In respect of the strong association of persistent hiccups with malignant diseases, it should be evaluated whether the patient has an increased risk for cancer due to familial, environmental, or behavioral factors. Furthermore, it can be helpful to assess whether the patient remembers a starting point or an assumed cause for the hiccupping, as well as for factors alleviating or aggravating the symptom. Reevaluation of measures previously taken against the hiccups can be indicative in planning a therapeutic strategy.
The physical examination should put an emphasis on neurologic, gastrointestinal and respiratory function, and symptoms suggesting a dysfunction of these systems. Myocardial infarction, stroke, and, less acutely, auricular irritation should be eliminated as probable causes of the hiccup. Basic laboratory tests for electrolyte balances, renal function, and troponin T levels, as well as an electrocardiographic examination should be performed in every patient. Further diagnostic procedures (eg, imaging, lumbar puncture) should be initiated depending on the individual situation.
It is important to consider that hiccups seldom have a definite, singular organic cause. Especially in advanced cancer patients, a group among which persistent singultus is not an uncommon symptom, the hiccup can often be multifactorial. General suggestions for a therapeutic approach to singultus patients are lined out in Figure 2.
BREAKING THE CYCLE: APPROACHES FOR THE THERAPY OF PERSISTENT HICCUP
A vast collection of folk remedies against hiccups has emerged from centuries of attempted cure, including the most peculiar procedures such as traction of the tongue, pulling the knees up to the chest, prayer, and drinking from the opposite side of a glass. Not few approaches have made their way into scientific publication; for example, there are descriptions of sexual intercourse or the swallowing of granulated sugar having stopped the hiccupping.173 , 174 Suggesting a trial of one of the several harmless approaches that have been listed to detail by other authors should always precede treatment with potentially more toxic alternatives when dealing with a patient initially presenting with hiccups.1 , 21
Finding ways to terminate the hiccups has been a subject of widespread study on nonpharmacological and medication-based treatment that has revealed successful approaches to some extent. The “perfect method” has not been found to this day, leading to a confusing plurality of anecdotal suggestions that often merely apply to a subgroup of hiccup patients. Structured guidelines have yet to be developed. A suggestion for the therapeutic approach to persistent singultus is presented in Figure 3.
Pharmacological Treatment: Single Drug Approaches
As one of the earlier pharmaceutics shown to have an effect in the relief of chronic hiccups, chlorpromazine still is the only drug approved by the U.S. Food and Drug Administration for the treatment of singultus. Two case series with 50 and 24 patients, respectively, support its benefit in hiccups, which is likely mediated by a dopamine blockade in the hypothalamus.21 , 175 , 176 However, a substantial number of other studies on the efficacy of chlorpromazine are negative.83 , 177 , 178 Haloperidol and olanzapine have been suggested to counteract hiccups through similar mechanisms, the latter possibly also exerting an antiserotonergic effect leading to decreased motoneuron excitability.179–181 However, patients treated with those antipsychotics should be monitored closely for side effects, which can include sedation, faintness, palpitations, tachycardia, extrapyramidal symptoms, and skin rash.175 , 180 Experience in a randomized controlled study on 36 singultus patients treated with the parasympathomimetic and antidopaminergic gastroprokinetic metoclopramide (MCP) shows this dopaminergic D3 receptor antagonist and serotonergic 5-hydroxytriptamine receptor agonist to be effective in abolishing intractable hiccups.182 Common unfavorable effects in this study included dizziness, upset mood, fatigue, and constipations.182 More severe adverse effects such as dyskinesia, supraventricular tachycardia, and the malignant neuroleptic syndrome are rarely seen, making MCP a comparatively safe treatment option.60 , 83 However, the majority of reports on successful treatment of chronic hiccups are based on studies with few case numbers and reliable conclusions on the tolerability and efficacy are impossible. Nefopam, an analgesic structurally related to antihistamines and antiparkinsonian medication, has been introduced for the treatment of intractable hiccups. It is assumed that nefopam acts as a muscle relaxant, activates descending pain-modulating pathways and inhibits synaptosomal neurotransmitter uptake, thus diminishing hiccups.9 Likewise and presumably by blocking dopamine and norepinephrine reuptake, methylphenidate has shown a therapeutic effect in anesthetized subjects, but also in a lung cancer patient presenting with singultus.183 , 184 Studies with anticonvulsants such as carbamazepine, phenytoin, and valproic acid have shown their effectiveness in treating chronic singultus possibly due to sodium channel blockade and membrane potential stabilization.177 , 185 , 186 Nevertheless, toxic side effects and a narrow therapeutic window make them a less favorable drug of choice; plasma levels should be monitored and alternative treatment should be considered.19 , 177 Nifedipine was successfully tried in a case study of 7 hiccup patients but should be prescribed with caution, as it is prone to show hypotensive side effects.178 The newer nimodipine, which acts through the same mechanism blocking pre- and postsynaptic L-type calcium channels in the hiccup reflex arc, shows better central nervous system penetration and might therefore be preferred.187 Lidocaine, a sodium channel blocker with membrane-stabilizing effects, can be effective against hiccups when administered systemically.188 Its administration into the nasal cavity in nebulized form seems a promising way to avoid high plasma concentrations while treating singultus effectively, although a mere mechanical effect for this mean of administration cannot be ruled out.189 Contradictory to the reports of benzodiazepines inducing hiccups, midazolam can also be successful in treating them.190 Its general sedative and anticonvulsant effects may make this drug especially suitable for end-of-life care. Further drugs reported to be effective in cases of intractable singultus are the α1/β-receptor antagonist carvedilol, as well as antidepressive agents like for instance amitriptyline and sertraline.191–193 An overview over pharmaceutical agents purported to be capable of curing hiccups and their postulated mechanisms of action in this regard is provided in Supplemental Digital Content, Appendix, http://links.lww.com/AA/B866.
Baclofen and Gabapentin.
Within recent years and because the “perfect antihix drug” is still missing, approaches to the sufficient treatment of hiccups have become focused on 2 pharmaceutical agents, gabapentin and baclofen. A Medline search restricted to case reports published in English between 1999 and 2015 revealed 16 reports of studies on the therapy of hiccups with baclofen including 1 randomized controlled study, and 11 results for the therapy with gabapentin or pregabalin. This suggests that these drugs are of high current interest within this confined field of research.
Medline Search Algorithms
("Hiccup"[MeSH Terms] OR "Hiccup"[All Fields]) AND ("Gabapentin"[Supplementary Concept] OR "Gabapentin"[All Fields])
("Hiccup"[MeSH Terms] OR "Hiccup"[All Fields]) AND ("Baclofen"[Supplementary Concept] OR "Baclofen"[All Fields])
The GABA type B receptor agonist baclofen likely acts through reduced release of dopamine in the central nervous system.194 It may also mediate an inhibitory effect via presynaptic hyperpolarization of the hiccup reflex arc in the spinal cord.21 , 131 In a randomized controlled study with 30 participants (N = 15 in intervention and placebo control groups), Zhang et al195 investigated the antihiccup effectiveness of baclofen, which was given at 10 mg 3 times a day for 5 days. The relative risk for cessation of hiccups in the intervention group compared with controls was 7, the relative risk for symptom improvement was 0.2, and the relative risk of no treatment effect was 0.06. Because the study was limited to stroke patients who had been suffering from persistent hiccups (<1 month duration) that were not associated with other pathologic conditions known to cause chronic singultus, conclusions on a more general patient collective are difficult.
Baclofen has consistently led to full cessation of hiccups within the first 6 days of treatment in 34 of 35 further cases that we included in our review of the literature. In 1 case series of 7 patients, hiccup in 3 patients could be cured by administration of a single dose.194 The reported doses ranged between 5 and 40 mg daily in 1–4 fractions, a common dosage was 5–10 mg twice or 3 times daily. Suggestions of a dose between 15 and 75 mg/d or a maximum of 80 mg/d, respectively, can be found in the literature.131 , 196 One case report contrarily describes the occurrence of hiccup-like respiratory patterns with long-term baclofen therapy in a cerebral palsy patient, which resolved when the baclofen dosage was reduced from 20 to 10 mg daily.197 However, the relevance of this case may be questionable, as the spasms could not clearly be identified as hiccup as opposed to diaphragmatic myoclonic or vocal tics. Baclofen has a half-life of 4.5–6.8 hours in healthy subjects, and is excreted via renal metabolism with a glomerular clearance proportional to the creatinine clearance.198 , 199 Side effects of baclofen can be severe, especially in high-risk patients. Muscle weakness with difficulty of walking, disturbance of consciousness and severe respiratory depression with need of mechanical ventilation occurred in patients suffering from renal failure, a kidney-transplant patient treated with a combination of olanzapine and baclofen developed extrapyramidal symptoms and a swollen tongue that may have been related to either of the drugs.180 , 198 , 199 In other hemodialysis patients, baclofen was administered at a reduced dosage (2.5–5 mg 3 times a day) without notable side effects.198 Zhang et al195 reported no serious side effects in their trial.
Gabapentin, a GABA analog that is inactive at N-methyl-D-aspartate receptors, has been postulated to act on the α2δ subunit of presynaptic voltage-dependent calcium channels, resulting in the inhibition of diaphragmatic and inspiratory musculature excitability.200 , 201 Studies with H3-gabapentin revealed specific binding sites in the brain only, suggesting gabapentin to act mainly within the central nervous system.201 Gabapentin has a half-life of 5 to 9 hours and is excreted renally, making it a safe drug with regard to possible interactions within the hepatic metabolism, but requiring caution when given to patients with renal failure.202 The bioavailability of gabapentin decreases with increasing dose, from 60% at 300 mg to 40% at 400 mg.203 Review of the published case reports revealed effectiveness of treatment (improvement or cessation of hiccups) in 81 of 83 cases; the duration of therapy until full cessation of hiccups, if accomplished, could range from immediate up to 6 months. Treatment was administered for 6 months at the longest, and in most cases, the dosage was tapered down over 3–4 weeks at the end of treatment to prevent withdrawal symptoms. Gabapentin was given at doses between 200 and 1200 mg daily in 1 to 4 fractions, with 300–400 mg 3 times a day being the most common dosage. Gabapentin seems to be generally well tolerated; only 13 accounts of sleepiness are reported in the literature. Potential side effects include dizziness, somnolence, fatigue, ataxia, peripheral edema, and, less commonly, painful gynecomastia and hypoglycemia.203 Gabapentin has been shown to be effective even in low doses in a heart-transplant patient who developed serious side effects with baclofen therapy, thus representing a potential option in situations where drug elimination or side effects cause difficulty.204 Pregabalin, a newer GABA analog with similar pharmacokinetic properties but higher potency might also prove to be a preferred option in this context, as it demonstrated efficacy against hiccups in relatively small doses of 300–450 mg/d.202
Although baclofen has a 10-year advance in having been subject to clinical research in intractable hiccups according to our Medline search (first description published in 1988205 compared with the first mentioning of gabapentin against hiccups in 1999),30 it seems that both drugs are among the most effective at aborting the symptom, having stopped the symptom in a number of cases where other drugs did not help.205 , 206 Comparative examination of the reported results seems to imply that gabapentin is slightly less prone to procure serious side effects than baclofen. The possibility of low-dose application makes gabapentin or pregabalin favorable in singultus patients with impaired constitution. Further studies have to be performed to confirm this notion. In our clinical experience, the occurrence of adverse drug reactions, dose ranges, and the dose-dependency of the wanted effect often differ significantly even between hiccup patients with similar medical profile.
Pharmacological Treatment: Combination Therapy
Both baclofen and gabapentin have been used in combination therapies with omeprazole and/or cisapride, 2 additional agents commonly prescribed for intractable hiccups.202 , 207 , 208 Successful accounts were made of approaches with baclofen in combination with olanzapine or with chlorpromazine (1 patient each); approaches with gabapentin, propranolol, and clonazepam, or pregabalin, chlorpromazine and pantoprazole, respectively, were also reported to abolish hiccups in 2 other patients.133 , 180 , 202 , 209 Notably, the drugs were used at doses comparable with those considered in monotherapy; therefore, the advantage of combination therapy seems doubtable in cases where monotherapy is efficient. Petroianu et al208 published a case series of 4 patients that were either treated with cisapride, omeprazole, and gabapentin or cisapride, omeprazole, baclofen, and gabapentin. One patient’s hiccups fully ceased with the cisapride, omeprazole, and gabapentin therapy; the other patients showed similar (1 patient) or better (2 patients) outcome when treated with all 4 agents. The comparative results of the performed Medline literature research can be deferred from Table 4. The concept of combination therapy with adjuvants such as omeprazole and cisapride appears promising but further evaluation is needed.
Quite in contrast to the many explanatory attempts regarding the mechanisms of action of the various agents that were tested in treatment studies, hardly any reasoning for treatment failure can be found in the existing literature on singultus pharmacotherapy. In some studies, the primary dose seemed simply too low; satisfying results were achieved when the dosage of the respective drug was increased.132 The intensified treatment evoked intolerable side effects in other cases, making it impossible to define an adequate therapeutical window.34 , 203 Oneschuk et al207 speculated that the treatment with MCP may not have proven efficient in their study because the drug was not given enough time to act before baclofen was added. Gabapentin was not effective in 2 patients in a palliative situation who were sedated with midazolam, although the character of the implied inhibitory interaction in this setting was not clearly explained by the authors.210 Unsatisfying therapy results in a study on baclofen, which did not reduce the hiccup’s frequency while decreasing its intensity, might have been owed to an insensitive recording method (an audiotape).34 Petroianu et al206 detected an interesting correlation, showing that treatment failure most frequently occurred in patients who had been exposed to the drug of choice before and thus, perhaps desensitized. They also suspected poor compliance in singultus patients, who often possess a long history of medical consultations and treatment attempts, to be a limiting factor. Notably, neither of the 2 existing publications on randomized controlled pharmacotherapy trials for chronic hiccups contains an explanation for unsuccessful cases within the study setting.182 , 195
Nonpharmacological and Interventional Treatment
Apart from trying to tackle the hiccupping systemically, approaches that are based on local intervention within the hiccup reflex arc at the central or peripheral level should be considered. If a tumor inflicts nervous structures involved in the generation of hiccups, surgical resection can bring relief.24 , 104 Blockade by injection of local anesthetics (eg, lidocaine 1.5% solution) into the cervical epidural space or in close proximity to the phrenic nerve was successful in curing hiccups.106 , 211 Radiofrequency ablation of the phrenic nerve and transoesophageal diaphragmatic pacing were also described to be effective.212 , 213 Ultrasound permits accurate application of the injectate or electrodes next to the phrenic nerve.214 , 215 Furthermore, successful blockade can be confirmed by electrostimulation of the targeted nerve.216 One report describes the successful intervention in a hiccup patient by stimulation of the vagal nerve.217
Another wide field of interest addresses acupuncture as a promising means of treating singultus. However, as most publications refer to only small number of cases and mostly provide no comparison to a control group, the informative value of studies on this subject has to be seen critically. To this day, the only 4 randomized controlled trials that met the criteria to be assessed in a Cochrane review compared the effectiveness of different acupuncture techniques, though risk of bias was high in all studies and meta-analysis was impossible due to structural differences.218 Although pharmacopuncture, the injection of pharmacological or herbal agents into acupoints, was reviewed as a possible alternative for treating hiccups in cancer patients, guidelines and evidence on safety for this procedure are missing and the method should be considered critically.219
Which of the 3 therapeutic principles of pharmacological treatment, interventional procedures or acupuncture shows the best in curing hiccups, or whether any combination of the 3 might be superior to treatment with 1 means alone remains unclear. In a recent systematic review and meta-analysis, Choi et al220 found acupuncture treatment to be slightly more effective against hiccups compared to intramuscular injection or oral therapy with conventional medication, but only 4 randomized controlled trials met the inclusion criteria and a high risk of bias was found in all studies. Although numerous cases and many case series have been reported suggesting a wide variety of treatment options for chronic singultus, randomized and controlled studies of larger scale are needed.
Chronic hiccups constitute a medical problem that concerns only a minor fraction of the patients that frequent our hospitals and practices. Yet, for those affected, it can be a source of great distress, exhaustion, and despair; it can lead to exacerbation of other preexisting conditions and significantly impair the quality of life. Despite well over a century of clinical research on this topic, we still lack the knowledge how to treat persistent hiccups systematically and sufficiently. The reason for this is most likely found in a missing attribution of chronic hiccups to a single medical discipline. Because causes for the symptom can origin from a dysfunction of very different organ systems, ideal diagnostic workup and therapy in hiccup patients can be achieved only by means of effective cooperation between specialists. Due to a missing infrastructure in the clinical management of these patients, we also suspect a high number of unreported cases of intractable hiccups.
Working in a competence center for hiccup treatment, our clinical experience with singultus patients differs significantly from findings presented in the literature, suggesting that conclusions drawn from case reports/series are not necessarily applicable to the everyday patient presenting with singultus. Experience from randomized controlled studies or large-scaled observational studies would be necessary to draw reliable conclusions on the efficacy of pharmacological and nonpharmacological interventions. A both thorough and wide-ranging diagnostic workup is of great importance to reveal and eliminate possible underlying causes for the hiccups, and with them, the symptom itself. Special treatment center would help to gather experiences with hiccup patients, to establish treatment standards, to give structured advise to peripheral practitioners, and gain new insights from research on larger patient collectives.
Taking all these factors into consideration, we can only conclude that chronic singultus truly has to be regarded as “an underestimated problem.”
- Chronic hiccups are a pathological condition with serious consequences such as depression, weight loss, insomnia, and severe exhaustion.
- Chronic hiccups are often associated with illnesses of the upper gastrointestinal tract or the central nervous system, but can also have a solely psychological background.
- Baclofen, gabapentin, and MCP are drugs of current research interest in the therapy of chronic hiccups, but evidence from large-scale studies is yet missing.
- Guidelines on the interdisciplinary clinical management of chronic hiccup patients have not yet been established, but would benefit the treatment of those patients.
Name: Eva K. Kohse, MD.
Contribution: This author was involved in literature search, drafting, and editing.
Name: Markus W. Hollmann, MD, PhD, DEAA.
Contribution: This author was involved in drafting and editing.
Name: Hubert J. Bardenheuer, MD.
Contribution: This author was involved in editing.
Name: Jens Kessler, MD.
Contribution: This author was involved in literature search, drafting, and editing.
This manuscript was handled by: Ken B. Johnson, MD.
1. Lewis JH. Hiccups: causes and cures. J Clin Gastroenterol. 1985;7:539–552.
2. Samuels L. Hiccup; a ten year review of anatomy, etiology, and treatment. Can Med Assoc J. 1952;67:315–322.
3. Kolodzik PW, Eilers MA. Hiccups (singultus): review and approach to management. Ann Emerg Med. 1991;20:565–573.
4. Launois S, Bizec JL, Whitelaw WA, Cabane J, Derenne JP. Hiccup in adults: an overview. Eur Respir J. 1993;6:563–575.
5. Kranke P, Eberhart LH, Morin AM, Cracknell J, Greim CA, Roewer N. Treatment of hiccup during general anaesthesia or sedation: a qualitative systematic review. Eur J Anaesthesiol. 2003;20:239–244.
6. Wilmore DW, Smith RJ, O’Dwyer ST, Jacobs DO, Ziegler TR, Wang XD. The gut: a central organ after surgical stress. Surgery. 1988;104:917–923.
7. Varaldo E, Ansaldo GL, Mascherini M, Cafiero F, Minuto MN. Neurological complications in thyroid surgery: a surgical point of view on laryngeal nerves. Front Endocrinol (Lausanne). 2014;5:108.
8. Mom T, Filaire M, Advenier D, et al. Concomitant type I thyroplasty and thoracic operations for lung cancer: preventing respiratory complications associated with vagus or recurrent laryngeal nerve injury. J Thorac Cardiovasc Surg. 2001;121:642–648.
9. Bilotta F, Pietropaoli P, Rosa G. Nefopam for refractory postoperative hiccups. Anesth Analg. 2001;93:1358–1360.
10. Grifoni E, Marchiani C, Fabbri A, et al. A case of persistent hiccup after laparoscopic cholecystectomy. Case Rep Surg. 2013;2013:206768.
11. Strate T, Langwieler TE, Mann O, Knoefel WT, Izbicki JR. Intractable hiccup: an odd complication after laparoscopic fundoplication for gastroesophageal reflux disease. Surg Endosc. 2002;16:1109.
12. Pines A, Goldhammer E, Frankl O. [Hiccup as a presenting symptom of hypokalemia]. Harefuah. 1982;102:65–66.
13. Thorne MG. Hiccup and heart block. Br Heart J. 1969;31:397–399.
14. Landers C, Turner D, Makin C, Zaglul H, Brown R. Propofol associated hiccups and treatment with lidocaine. Anesth Analg. 2008;107:1757–1758.
15. Sav T. Hiccups, a rare complication arising from use of a central venous catheter. Hemodial Int. 2010;14:337–338.
16. Baumann A, Weicker T, Alb I, Audibert G. Baclofen for the treatment of hiccup related to brainstem compression. Ann Fr Anesth Reanim. 2014;33:e27–e28.
17. Pajot S, Geeraerts T, Leblanc PE, Duranteau J, Benhamou D. Hiccup during weaning from mechanical ventilation: the use of nefopam. Br J Anaesth. 2007;99:748–749.
18. Kim JJ, Sa YJ, Cho DG, Kim YD, Kim CK, Moon SW. Intractable hiccup accompanying pleural effusion: reversible clipping of an intrathoracic phrenic nerve. Surg Laparosc Endosc Percutan Tech. 2013;23:357–359.
19. Marinella MA. Diagnosis and management of hiccups in the patient with advanced cancer. J Support Oncol. 2009;7:122–127, 130.
20. Davis JN. An experimental study of hiccup. Brain. 1970;93:851–872.
21. Friedman NL. Hiccups: a treatment review. Pharmacotherapy. 1996;16:986–995.
22. McFarling DA, Susac JO. Hoquet diabolique: intractable hiccups as a manifestation of multiple sclerosis. Neurology. 1979;29:797–801.
23. al Deeb SM, Sharif H, al Moutaery K, Biary N. Intractable hiccup induced by brainstem lesion. J Neurol Sci. 1991;103:144–150.
24. Amirjamshidi A, Abbassioun K, Parsa K. Hiccup and neurosurgeons: a report of 4 rare dorsal medullary compressive pathologies and review of the literature. Surg Neurol. 2007;67:395–402.
25. Arita H, Oshima T, Kita I, Sakamoto M. Generation of hiccup by electrical stimulation in medulla of cats. Neurosci Lett. 1994;175:67–70.
26. van Durme CM, Idema RN, van Guldener C. Two rare complications of glioblastoma multiforme: persistent hiccup and acquired haemophilia A. Neth J Med. 2008;66:286–288.
27. Kahrilas PJ, Shi G. Why do we hiccup? Gut. 1997;41:712–713.
28. Loft LM, Ward RF. Hiccups. A case presentation and etiologic review. Arch Otolaryngol Head Neck Surg. 1992;118:1115–1119.
29. Chang FY, Lu CL. Hiccup: mystery, nature and treatment. J Neurogastroenterol Motil. 2012;18:123–130.
30. Moretti R, Torre P, Antonello RM, Nasuelli D, Cazzato G. Treatment of chronic: new perspectives. Eur J Neurol. 1999;6:617.
31. Ray P, Zia Ul Haq M, Nizamie SH. Aripiprazole-induced hiccups: a case report. Gen Hosp Psychiatry. 2009;31:382–384.
32. Askenasy JJ. About the mechanism of hiccup. Eur Neurol. 1992;32:159–163.
33. Brouillette RT, Thach BT, Abu-Osba YK, Wilson SL. Hiccups in infants: characteristics and effects on ventilation. J Pediatr. 1980;96:219–225.
34. Walker P, Watanabe S, Bruera E. Baclofen, a treatment for chronic hiccup. J Pain Symptom Manage. 1998;16:125–132.
35. Miller FC, Gonzales F, Mueller E, McCart D. Fetal hiccups: an associated fetal heart rate pattern. Obstet Gynecol. 1983;62:253–255.
36. Straus C, Vasilakos K, Wilson RJ, et al. A phylogenetic hypothesis for the origin of hiccough. Bioessays. 2003;25:182–188.
37. Dunn PM. Fetal hiccups. Lancet. 1977;2:505.
38. Fuller GN. Hiccups and human purpose. Nature. 1990;343:420.
39. Douthwaite AH. Intractable hiccuping in acute myocardial infarction. Br Med J. 1971;2:709.
40. Hemachudha T, Phanthumchinda K, Indrakoses A, Wilde H. Intractable hiccups (singultus) as presenting manifestation of Japanese encephalitis. J Med Assoc Thai. 1984;67:621–623.
41. Pooran N, Lee D, Sideridis K. Protracted hiccups due to severe erosive esophagitis: a case series. J Clin Gastroenterol. 2006;40:183–185.
42. Chou CL, Chen CA, Lin SH, Huang HH. Baclofen-induced neurotoxicity in chronic renal failure patients with intractable hiccups. South Med J. 2006;99:1308–1309.
43. Yardimci N, Benli S, Zileli T. A diagnostic challenge of Parkinson’s disease: intractable hiccups. Parkinsonism Relat Disord. 2008;14:446–447.
44. Theohar C, McKegney FP. Hiccups of psychogenic origin: a case report and review of the literature. Compr Psychiatry. 1970;11:377–384.
45. Carmichael C. Glaucoma presenting as hiccups. JAMA. 1989;261:702.
46. Kumar A, Dromerick AW. Intractable hiccups during stroke rehabilitation. Arch Phys Med Rehabil. 1998;79:697–699.
47. Mandalà M, Rufa A, Cerase A, et al. Lateral medullary ischemia presenting with persistent hiccups and vertigo. Int J Neurosci. 2010;120:226–230.
48. Tiedt HO, Wenzel R. Persistent hiccups as sole manifestation of right cortical infarction without apparent brainstem lesion. J Neurol. 2013;260:1913–1914.
49. Jansen PH, Joosten EM, Vingerhoets HM. Persistent periodic hiccups following brain abscess: a case report. J Neurol Neurosurg Psychiatry. 1990;53:83–84.
50. Ward BA, Smith RR. Hiccups and brainstem compression. J Neuroimaging. 1994;4:164–165.
51. de la Fuente-Fernandez R. [Hiccup and dysfunction of the inferior olivary complex]. Medicina Clinica. 1998;110:22–24.
52. Hahn A, Neubauer BA. Epileptic diaphragm myoclonus. Epileptic Disord. 2012;14:418–421.
53. Ponnusamy A, Rao G, Baxter P, Field P. Ictal hiccup during absence seizure in a child. Epileptic Disord. 2008;10:53–55.
54. Wilson J, Manners BT, Robins DG, Erdohazi M. Persistent hiccup as a presenting feature of Alexander’s leucodystrophy. Dev Med Child Neurol. 1981;23:660–661.
55. Sugimoto T, Takeda N, Yamakawa I, et al. Intractable hiccup associated with aseptic meningitis in a patient with systemic lupus erythematosus. Lupus. 2008;17:152–153.
56. Connolly JP, Craig TJ, Sanchez RM, Sageman WS, Osborn RE. Intractable hiccups as a presentation of central nervous system sarcoidosis. West J Med. 1991;155:78–79.
57. Eisenächer A, Spiske J. Persistent hiccups (singultus) as the presenting symptom of medullary cavernoma. Dtsch Arztebl Int. 2011;108:822–826.
58. Seyama H, Kurita H, Noguchi A, Shiokawa Y, Saito I. Resolution of intractable hiccups caused by cerebellar hemangioblastoma. Neurology. 2001;57:2142.
59. Stotka VL, Barcay SJ, Bell HS, Clare FB. Intractable hiccough as the primary manifestation of brain stem tumor. Am J Med. 1962;32:312–315.
60. Gupta VK. Metoclopramide for migraine-associated hiccup. Int J Clin Pract. 2006;60:604–605.
61. de Seze J, Zephir H, Hautecoeur P, Mackowiak A, Cabaret M, Vermersch P. Pathologic laughing and intractable hiccups can occur early in multiple sclerosis. Neurology. 2006;67:1684–1686.
62. Riphagen J, Modderman P, Verrips A. Hiccups, nausea, and vomiting: water channels under attack! Lancet. 2010;375:954.
63. Seki T, Hida K, Lee J, Iwasaki Y. Hiccups attributable to syringobulbia and/or syringomyelia associated with a Chiari I malformation: case report. Neurosurgery. 2004;54:224–226.
64. Gilani SM, Danforth RD. Intractable hiccups: a rare presentation of phrenic nerve schwannoma. Eur Ann Otorhinolaryngol Head Neck Dis. 2012;129:331–333.
65. Kumral E, Acarer A. Primary medullary haemorrhage with intractable hiccup. J Neurol. 1998;245:620–622.
66. Hongliang X, Xuemei C, Shizhao H, Chaofeng L. Acupuncture and cupping for treatment of hiccup in cases of cerebrovascular accident. J Tradit Chin Med. 2006;26:175–176.
67. Gambhir S, Singh A, Maindiratta B, Jaeger M, Darwish B, Sheridan M. Giant PICA aneurysm presenting as intractable hiccups. J Clin Neurosci. 2010;17:945–946.
68. Li ML, Gupta A, Thomas P, Richards AJ. Basilar artery aneurysm: an unusual cause of intractable hiccups. Hosp Med. 2000;61:868–869.
69. Souadjian JV, Cain JC. Intractable hiccup. Etiologic factors in 220 cases. Postgrad Med. 1968;43:72–77.
70. Badawi RA, Birns J, Ramsey DJ, Kalra L. Hiccups and bilateral carotid artery dissection. J R Soc Med. 2004;97:331–332.
71. Meher S, Churasia P, Tandon M, Singh D. Vertebral artery dissection and intractable hiccups: an uncommon presentation. Neurol India. 2012;60:108–109.
72. Stine RJ, Trued SJ. Hiccups: an unusual manifestation of an abdominal aortic aneurysm. JACEP. 1979;8:368–370.
73. Wagner MS, Stapczynski JS. Persistent hiccups. Ann Emerg Med. 1982;11:24–26.
74. Trapp JD. An unusual cause of intractable hiccups: a hair in the external auditory canal. South Med J. 1963;56:325–326.
75. Gigot AF, Flynn PD. Treatment of hiccups. JAMA. 1952;150:760–764.
76. Burdette SD, Marinella MA. Pneumonia presenting as singultus. South Med J. 2004;97:915.
77. De Santis M, Martins V, Fonseca AL, Santos O. Large mediastinal thoracic duct cyst. Interact Cardiovasc Thorac Surg. 2010;10:138–139.
78. Rachid B, Amine B, Aziz C, Ali AM. Giant viable hydatid cyst of the lung revealed by hiccups. Pan Afr Med J. 2012;13:48.
79. Hulbert NG. Hiccoughing (hiccup or singultus). Practitioner. 1951;167:286–289.
80. Lin YC. Acupuncture for persistent hiccups in a heart and lung transplant recipient. J Heart Lung Transplant. 2006;25:126–127.
81. Alifano M, Morcos M, Molina T, Regnard JF. An unusual cause of hiccup: costal exostosis. Treatment by video-assisted thoracic surgery. Eur J Cardiothorac Surg. 2003;23:1056–1058.
82. Cymet TC. Retrospective analysis of hiccups in patients at a community hospital from 1995-2000. J Natl Med Assoc. 2002;94:480–483.
83. Madanagopolan N. Metoclopramide in hiccup. Curr Med Res Opin. 1975;3:371–374.
84. Davenport J, Duong M, Lanoix R. Hiccups as the only symptom of non-ST-segment elevation myocardial infarction. Am J Emerg Med. 2012;30:266.e1–266.e2.
85. Gasparini M, Regoli F, Ceriotti C, Gardini E. Images in cardiovascular medicine. Hiccups and dysphonic metallic voice: a unique presentation of Twiddler syndrome. Circulation. 2006;114:e534–e535.
86. Celik T, Kose S, Bugan B, Iyisoy A, Akgun V, Cingoz F. Hiccup as a result of late lead perforation: report of two cases and review of the literature. Europace. 2009;11:963–965.
87. Redondo-Cerezo E, Viñuelas-Chicano M, Pérez-Vigara G, et al. A patient with persistent hiccups and gastro-oesophageal reflux disease. Gut. 2008;57:763, 771.
88. Shay SS, Myers RL, Johnson LF. Hiccups associated with reflux esophagitis. Gastroenterology. 1984;87:204–207.
89. Mulhall BP, Nelson B, Rogers L, Wong RK. Herpetic esophagitis and intractable hiccups (singultus) in an immunocompetent patient. Gastrointest Endosc. 2003;57:796–797.
90. Seeman H, Traube M. Hiccups and achalasia. Ann Intern Med. 1991;115:711–712.
91. Kaufmann HJ. Hiccups: an occasional sign of esophageal obstruction. Gastroenterology. 1982;82:1443–1445.
92. Khorakiwala T, Arain R, Mulsow J, Walsh TN. Hiccups: an unrecognized symptom of esophageal cancer? Am J Gastroenterol. 2008;103:801.
93. Burcharth F, Agger P. Singultus: a case of hiccup with diaphragmatic tumour. Acta Chir Scand. 1974;140:340–341.
94. Orr CF, Rowe DB. Helicobacter pylori hiccup. Intern Med J. 2003;33:133–134.
95. McElreath DP, Olden KW, Aduli F. Hiccups: a subtle sign in the clinical diagnosis of gastric volvulus and a review of the literature. Dig Dis Sci. 2008;53:3033–3036.
96. van Heuven PF, Smeets PM. Behavioral control of chronic hiccupping associated with gastrointestinal bleeding in a retarded epileptic male. J Behav Ther Exp Psychiatry. 1981;12:341–345.
97. Hong L, Zhao Y, Zhang X, et al. Reversal effect of electroacupuncture on the symptom of intractable hiccups in hepatitis B virus carriers. J Pain Symptom Manage. 2008;35:335–336.
98. Chand EM, Nasir A, Pascal RR. Pathologic quiz case: refractory hiccups in a man after liver transplantation for hepatitis C. Arch Pathol Lab Med. 2003;127:248–250.
99. Marino RA. Baclofen therapy for intractable hiccups in pancreatic carcinoma. Am J Gastroenterol. 1998;93:2000.
100. Oster MW. Cancer of the pancreas. N Engl J Med. 1980;302:232.
101. Rosenberger J, Veseliny E, Bena L, Roland R. A renal transplant patient with intractable hiccups and review of the literature. Transpl Infect Dis. 2005;7:86–88.
102. Porzio G, Aielli F, Narducci F, et al. Hiccup in patients with advanced cancer successfully treated with gabapentin: report of three cases. N Z Med J. 2003;116:U605.
103. Morris L, Marti J, Ziff D. Intractable hiccoughs in pregnancy. J Obstet Gynaecol. 2004;24:474.
104. Cheng MH, Twu NF, Fuh JL, Wang PH. Intractable hiccups as an unusual presentation of a uterine leiomyoma: a case report. J Reprod Med. 2005;50:954–956.
105. Su WH, Lee WL, Cheng MH, Yen MS, Chao KC, Wang PH. Typical and atypical clinical presentation of uterine myomas. J Chin Med Assoc. 2012;75:487–493.
106. Calvo E, Fernández-La Torre F, Brugarolas A. Cervical phrenic nerve block for intractable hiccups in cancer patients. J Natl Cancer Inst. 2002;94:1175–1176.
107. Krahn A, Penner SB. Use of baclofen for intractable hiccups in uremia. Am J Med. 1994;96:391.
108. Lazarevic V, Hägg E, Wahlin A. Hiccups and severe hyponatremia associated with high-dose cyclophosphamide in conditioning regimen for allogeneic stem cell transplantation. Am J Hematol. 2007;82:88.
109. Ramirez FC, Graham DY. Hiccups, compulsive water drinking, and hyponatremia. Ann Intern Med. 1993;118:649.
110. Hardo PG. Intractable hiccups—an early feature of Addison’s disease. Postgrad Med J. 1989;65:918–919.
111. Madu AE, Oliver L. Non-ketotic hyperglycinaemia: case report and review of medical literature. J Matern Fetal Neonatal Med. 2013;26:537–539.
112. Ahmed F, Ganie MA, Shamas N, Wani M, Parray I. Hiccup: an extremely rare presentation of thyrotoxicosis of Graves’ disease. Oman Med J. 2011;26:129–130.
113. Delèvaux I, André M, Marroun I, Lamaison D, Piette JC, Aumaître O. Intractable hiccup as the initial presenting feature of systemic lupus erythematosus. Lupus. 2005;14:406–408.
114. Shelburne SA 3rd, Visnegarwala F, Adams C, Krause KL, Hamill RJ, White AC Jr. Unusual manifestations of disseminated Histoplasmosis in patients responding to antiretroviral therapy. Am J Med. 2005;118:1038–1041.
115. Lin LF, Huang PT. An uncommon cause of hiccups: sarcoidosis presenting solely as hiccups. J Chin Med Assoc. 2010;73:647–650.
116. Albrecht H, Stellbrink HJ. Hiccups in people with AIDS. J Acquir Immune Defic Syndr. 1994;7:735.
117. D’Alessandro DJ, Dever LL. Baclofen for treatment of persistent hiccups in HIV-infected patients. AIDS. 1997;11:1063–1064.
118. MACHTOU C. [Case of hiccup in epidemic influenza]. Rev Otoneuroophtalmol. 1955;27:306–307.
119. Sinha BM. Hiccough as one of the forms of malignant malaria. Antiseptic. 1948;45:121.
120. Bolognesi M, Bolognesi D. Complicated and delayed diagnosis of tuberculous peritonitis. Am J Case Rep. 2013;14:109–112.
121. Friedland JS. Hiccups, toxoplasmosis, and AIDS. Clin Infect Dis. 1994;18:835.
122. Berlin AL, Muhn CY, Billick RC. Hiccups, eructation, and other uncommon prodromal manifestations of herpes zoster. J Am Acad Dermatol. 2003;49:1121–1124.
123. Carlisi E, Bossi D, Zaliani A, Dalla Toffola E. Persistent hiccup after surgical resection of a brainstem arteriovenous malformation: a case successfully treated with gabapentin during rehabilitation. Case report. Eur J Phys Rehabil Med. 2012;48:289–291.
124. Prakash PS, Prabhakar H. Transient hiccups and stridor after surgery for brain-stem tumor. J Neurosurg Anesthesiol. 2007;19:288–289.
125. de Bie RM, Speelman JD, Schuurman PR, Bosch DA. Transient hiccups after posteroventral pallidotomy for Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1999;67:124–125.
126. Tey HK, Talley NJ. Use of cricoid pressure to facilitate gastric insufflation and stop hiccoughs during gastroscopy. Gastrointest Endosc. 1996;44:760–761.
127. Doshi H, Vaidyalingam R, Buchan K. Atrial pacing wires: an uncommon cause of postoperative hiccups. Br J Hosp Med (Lond). 2008;69:534.
128. Karian JM, Buchheit WA. Intractable hiccup as a complication of ventriculoperitoneal shunt: case report. Neurosurgery. 1980;7:283–284.
129. Sacher F, Monahan KH, Thomas SP, et al. Phrenic nerve injury after atrial fibrillation catheter ablation: characterization and outcome in a multicenter study. J Am Coll Cardiol. 2006;47:2498–2503.
130. Tang Y, Asthana A, Lubel J. Unusual cause of hiccup and abdominal pain after gastric variceal obliteration. Gastroenterology. 2013;144:e1–e2.
131. Turkyilmaz A, Eroglu A. Use of baclofen in the treatment of esophageal stent-related hiccups. Ann Thorac Surg. 2008;85:328–330.
132. Ong AM, Tan CS, Foo MW, Kee TY. Gabapentin for intractable hiccups in a patient undergoing peritoneal dialysis. Perit Dial Int. 2008;28:667–668.
133. Homer JR, Davies JM, Amundsen LB. Persistent hiccups after attempted interscalene brachial plexus block. Reg Anesth Pain Med. 2005;30:574–576.
134. Zhang Y, Jiang H, Wei L, Yu H. Persistent hiccup caused by peripherally inserted central catheter migration. J Anesth. 2011;25:625–626.
135. Madani M. Complications of laser-assisted uvulopalatopharyngoplasty (LA-UPPP) and radiofrequency treatments of snoring and chronic nasal congestion: a 10-year review of 5,600 patients. J Oral Maxillofac Surg. 2004;62:1351–1362.
136. Arroyo-Cózar M, Grau Delgado J, Gabaldón Conejos T. Hiccups induced by midazolam during sedation in flexible bronchoscopy. Arch Bronconeumol. 2012;48:103.
137. Lester J, Raina GB, Uribe-Roca C, Micheli F. Hiccup secondary to dopamine agonists in Parkinson’s disease. Mov Disord. 2007;22:1667–1668.
138. Cersosimo RJ, Brophy MT. Hiccups with high dose dexamethasone administration: a case report. Cancer. 1998;82:412–414.
139. Pertel P, Till M. Intractable hiccups induced by the use of megestrol acetate. Arch Intern Med. 1998;158:809–810.
140. Liaw CC, Wang CH, Chang HK, et al. Cisplatin-related hiccups: male predominance, induction by dexamethasone, and protection against nausea and vomiting. J Pain Symptom Manage. 2005;30:359–366.
141. Moses JA, Ramachandran KP, Surendran D. Treatment of hiccups with instillation of ether into nasal cavity. Anesth Analg. 1970;49:367–368.
142. Kanniah SK. Acute transient hiccups after epidural injection of levobupivacaine. Int J Obstet Anesth. 2009;18:193–194.
143. Hansen BJ, Rosenberg J. Persistent postoperative hiccups: a review. Acta Anaesthesiol Scand. 1993;37:643–646.
144. Kanaya N, Nakayama M, Kanaya J, Namiki A. Atropine for the treatment of hiccup after laryngeal mask insertion. Anesth Analg. 2001;93:791–792.
145. McAllister RK, McDavid AJ, Meyer TA, Bittenbinder TM. Recurrent persistent hiccups after epidural steroid injection and analgesia with bupivacaine. Anesth Analg. 2005;100:1834–1836.
146. Wilcock A, Twycross R. Midazolam for intractable hiccup. J Pain Symptom Manage. 1996;12:59–61.
147. Smith HS, Busracamwongs A. Management of hiccups in the palliative care population. Am J Hosp Palliat Care. 2003;20:149–154.
148. Surendiran A, Krishna Kumar D, Adithan C. Azithromycin-induced hiccups. J Postgrad Med. 2008;54:330–331.
149. Seibert D, Al-Kawas F. Trimethoprim-sulfamethoxazole, hiccups, and esophageal ulcers. Ann Intern Med. 1986;105:976.
150. Takiguchi Y, Watanabe R, Nagao K, Kuriyama T. Hiccups as an adverse reaction to cancer chemotherapy. J Natl Cancer Inst. 2002;94:772.
151. Ifran A, Kaptan K, Beyan C. Intractable hiccups may develop with cyclophosphamide infusion. Am J Hematol. 2004;77:319–320.
152. Javot L, Scala-Bertola J, Petitpain N, Trechot P, Pere P, Gillet P. Methotrexate-induced hiccups. Rheumatology (Oxford). 2011;50:989–990.
153. Lee GW, Oh SY, Kang MH, et al. Treatment of dexamethasone-induced hiccup in chemotherapy patients by methylprednisolone rotation. Oncologist. 2013;18:1229–1234.
154. MacGregor EG, Villalobos R, Perini L. Hiccups with betamethasone dipropionate. J Rheumatol. 2000;27:819–820.
155. Barriocanal Barriocanal AM, Vaqué Cabañas A, Pérez-Andrés R, Olivé Marques A. [Hiccups crisis following paramethasone intraarticular injection]. Med Clin (Barc). 2005;125:158.
156. Iijima M, Uchigata M, Ohashi T, Kato H. Intractable hiccups induced by high-dose intravenous methylprednisolone in a patient with multiple sclerosis. Eur J Neurol. 2006;13:201–202.
157. Dickerman RD, Jaikumar S. The hiccup reflex arc and persistent hiccups with high-dose anabolic steroids: is the brainstem the steroid-responsive locus? Clin Neuropharmacol. 2001;24:62–64.
158. Bagdure DN, Reiter PD, Bhoite GR, Dobyns EL, Laoprasert P. Persistent hiccups associated with epidural ropivacaine in a newborn. Ann Pharmacother. 2011;45:e35.
159. Lauterbach EC. Hiccup and apparent myoclonus after hydrocodone: review of the opiate-related hiccup and myoclonus literature. Clin Neuropharmacol. 1999;22:87–92.
160. Loomba V, Gupta M, Kim D. Persistent hiccups with continuous intrathecal morphine infusion. Clin J Pain. 2012;28:172–174.
161. Winstead DK. Hiccups following ingestion of oral chlordiazepoxide. Am J Psychiatry. 1976;133:719.
162. Browne TR, Feldman RG, Buchanan RA, et al. Methsuximide for complex partial seizures: efficacy, toxicity, clinical pharmacology, and drug interactions. Neurology. 1983;33:414–418.
163. Cooney C, Buckley J. Prolonged singultus as a result of barbiturate toxicity. Ir Med J. 1987;80:290–291.
164. Weksler N, Stav A, Ovadia L, et al. Lidocaine pretreatment effectively decreases the incidence of hiccups during methohexitone administration for dilatation and curettage. Acta Anaesthesiol Scand. 1992;36:772–774.
165. Solla P, Congia S, Secchi L, Perra E, Cannas A. Clozapine-induced persistent hiccup in a patient with Alzheimer’s disease. Clin Neurol Neurosurg. 2006;108:615–616.
166. Miyaoka H, Kamijima K. Perphenazine-induced hiccups. Pharmacopsychiatry. 1999;32:81.
167. Gerschlager W, Bloem BR. Hiccups associated with levodopa in Parkinson’s disease. Mov Disord. 2009;24:621–622.
168. Cheng YM, Lin WA, Yang HN. Risperidone-induced hiccups in a youth with Down syndrome. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:641–642.
169. Marai I, Levi Y. [The diverse etiology of hiccups]. Harefuah. 2003;142:10–13, 79.
170. Paul B, Trovato JA, Thompson J, Badros AZ, Goloubeva O. Efficacy of aprepitant in patients receiving high-dose chemotherapy with hematopoietic stem cell support. J Oncol Pharm Pract. 2010;16:45–51.
171. Bolliger CT, van Biljon X, Axelsson A. A nicotine mouth spray for smoking cessation: a pilot study of preference, safety and efficacy. Respiration. 2007;74:196–201.
172. Calsina-Berna A, García-Gómez G, González-Barboteo J, Porta-Sales J. Treatment of chronic hiccups in cancer patients: a systematic review. J Palliat Med. 2012;15:1142–1150.
173. Peleg R, Peleg A. Case report: sexual intercourse as potential treatment for intractable hiccups. Can Fam Physician. 2000;46:1631–1632.
174. Engleman EG, Lankton J, Lankton B. Granulated sugar as treatment for hiccups in conscious patients. N Engl J Med. 1971;285:1489.
175. Friedgood CE, Ripstein CB. Chlorpromazine (thorazine) in the treatment of intractable hiccups. J Am Med Assoc. 1955;157:309–310.
176. Martínez Rey C, Villamil Cajoto I. [Hiccup: review of 24 cases]. Rev Med Chil. 2007;135:1132–1138.
177. Jacobson PL, Messenheimer JA, Farmer TW. Treatment of intractable hiccups with valproic acid. Neurology. 1981;31:1458–1460.
178. Lipps DC, Jabbari B, Mitchell MH, Daigh JD Jr.. Nifedipine for intractable hiccups. Neurology. 1990;40:531–532.
179. Korczyn AD. Hiccup. Br Med J. 1971;2:590–591.
180. Thompson AN, Ehret Leal J, Brzezinski WA. Olanzapine and baclofen for the treatment of intractable hiccups. Pharmacotherapy. 2014;34:e4–e8.
181. Alderfer BS, Arciniegas DB. Treatment of intractable hiccups with olanzapine following recent severe traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2006;18:551–552.
182. Wang T, Wang D. Metoclopramide for patients with intractable hiccups: a multicentre, randomised, controlled pilot study. Intern Med J. 2014;44:1205–1209.
183. Maréchal R, Berghmans T, Sculier P. Successful treatment of intractable hiccup with methylphenidate in a lung cancer patient. Support Care Cancer. 2003;11:126–128.
184. Vasiloff N, Cohen DD, Dillon JB. Effective treatment of hiccup with intravenous methylphenidate. Can Anaesth Soc J. 1965;12:306–310.
185. McFarling DA, Susac JO. Letter: Carbamazepine for hiccoughs. JAMA. 1974;230:962.
186. Petroski D, Patel AN. Letter: Diphenylhydantoin for intractable hiccups. Lancet. 1974;1:739.
187. Hernández JL, Fernández-Miera MF, Sampedro I, Sanroma P. Nimodipine treatment for intractable hiccups. Am J Med. 1999;106:600.
188. Boulouffe C, Vanpee D. Severe hiccups and intravenous lidocaine. Acta Clin Belg. 2007;62:123–125.
189. Neeno TA, Rosenow EC 3rd. Intractable hiccups. Consider nebulized lidocaine. Chest. 1996;110:1129–1130.
190. Moro C, Sironi P, Berardi E, Beretta G, Labianca R. Midazolam for long-term treatment of intractable hiccup. J Pain Symptom Manage. 2005;29:221–223.
191. Stueber D, Swartz CM. Carvedilol suppresses intractable hiccups. J Am Board Fam Med. 2006;19:418–421.
192. Stalnikowicz R, Fich A, Troudart T. Amitriptyline for intractable hiccups. N Engl J Med. 1986;315:64–65.
193. Vaidya V. Sertraline in the treatment of hiccups. Psychosomatics. 2000;41:353–355.
194. Mirijello A, Addolorato G, D’Angelo C, et al. Baclofen in the treatment of persistent hiccup: a case series. Int J Clin Pract. 2013;67:918–921.
195. Zhang C, Zhang R, Zhang S, Xu M, Zhang S. Baclofen for stroke patients with persistent hiccups: a randomized, double-blind, placebo-controlled trial. Trials. 2014;15:295.
196. Guelaud C, Similowski T, Bizec JL, Cabane J, Whitelaw WA, Derenne JP. Baclofen therapy for chronic hiccup. Eur Respir J. 1995;8:235–237.
197. Srivastava S, Hoon A, Ogborn J, Johnston M. Acute onset rhythmic hiccup-like respirations secondary to oral baclofen toxicity. Pediatr Neurol. 2014;51:252–254.
198. Hadjiyannacos D, Vlassopoulos D, Hadjiconstantinou V. Treatment of intractable hiccup in haemodialysis patients with baclofen. Am J Nephrol. 2001;21:427–428.
199. Choo YM, Kim GB, Choi JY, et al. Severe respiratory depression by low-dose baclofen in the treatment of chronic hiccups in a patient undergoing CAPD. Nephron. 2000;86:546–547.
200. Hernández JL, Pajarón M, García-Regata O, Jiménez V, González-Macías J, Ramos-Estébanez C. Gabapentin for intractable hiccup. Am J Med. 2004;117:279–281.
201. Moretti R, Torre P, Antonello RM, Ukmar M, Cazzato G, Bava A. Gabapentin as a drug therapy of intractable hiccup because of vascular lesion: a three-year follow up. Neurologist. 2004;10:102–106.
202. Jatzko A, Stegmeier-Petroianu A, Petroianu GA. Alpha-2-delta ligands for singultus (hiccup) treatment: three case reports. J Pain Symptom Manage. 2007;33:756–760.
203. Thompson DF, Brooks KG. Gabapentin therapy of hiccups. Ann Pharmacother. 2013;47:897–903.
204. Page RL 2nd, Luna M, Brieke A, Lindenfeld J. Low-dose gabapentin for intractable hiccups in a heart transplant recipient. Prog Transplant. 2011;21:340–343.
205. Burke AM, White AB, Brill N. Baclofen for intractable hiccups. N Engl J Med. 1988;319:1354.
206. Petroianu G, Hein G, Petroianu A, Bergler W, Rüfer R. Idiopathic chronic hiccup: combination therapy with cisapride, omeprazole, and baclofen. Clin Ther. 1997;19:1031–1038.
207. Oneschuk D. The use of baclofen for treatment of chronic hiccups. J Pain Symptom Manage. 1999;18:4–5.
208. Petroianu G, Hein G, Stegmeier-Petroianu A, Bergler W, Rüfer R. Gabapentin ‘add-on therapy’ for idiopathic chronic hiccup (ICH). J Clin Gastroenterol. 2000;30:321–324.
209. Alonso-Navarro H, Rubio L, Jiménez-Jiménez FJ. Refractory hiccup: successful treatment with gabapentin. Clin Neuropharmacol. 2007;30:186–187.
210. Porzio G, Aielli F, Verna L, Aloisi P, Galletti B, Ficorella C. Gabapentin in the treatment of hiccups in patients with advanced cancer: a 5-year experience. Clin Neuropharmacol. 2010;33:179–180.
211. Sato S, Asakura N, Endo T, Naito H. Cervical epidural block can relieve postoperative intractable hiccups. Anesthesiology. 1993;78:1184–1186.
212. Kang KN, Park IK, Suh JH, Leem JG, Shin JW. Ultrasound-guided pulsed radiofrequency lesioning of the phrenic nerve in a patient with intractable hiccup. Korean J Pain. 2010;23:198–201.
213. Andres DW. Transesophageal diaphragmatic pacing for treatment of persistent hiccups. Anesthesiology. 2005;102:483.
214. Kessler J, Schafhalter-Zoppoth I, Gray AT. An ultrasound study of the phrenic nerve in the posterior cervical triangle: implications for the interscalene brachial plexus block. Reg Anesth Pain Med. 2008;33:545–550.
215. Renes SH, van Geffen GJ, Rettig HC, Gielen MJ, Scheffer GJ. Ultrasound-guided continuous phrenic nerve block for persistent hiccups. Reg Anesth Pain Med. 2010;35:455–457.
216. Okuda Y, Kamishima K, Arai T, Asai T. Combined use of ultrasound and nerve stimulation for phrenic nerve block. Can J Anaesth. 2008;55:195–196.
217. Payne BR, Tiel RL, Payne MS, Fisch B. Vagus nerve stimulation for chronic intractable hiccups. Case report. J Neurosurg. 2005;102:935–937.
218. Moretto EN, Wee B, Wiffen PJ, Murchison AG. Interventions for treating persistent and intractable hiccups in adults. Cochrane Database Syst Rev. 2013;1:CD008768.
219. Cheon S, Zhang X, Lee IS, Cho SH, Chae Y, Lee H. Pharmacopuncture for cancer care: a systematic review. Evid Based Complement Alternat Med. 2014;2014:804746.
220. Choi TY, Lee MS, Ernst E. Acupuncture for cancer patients suffering from hiccups: a systematic review and meta-analysis. Complement Ther Med. 2012;20:447–455