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.
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Figure 1.: Functional diagram of the hiccup reflex arc. Anatomical structures of the hiccup reflex center are located in the hypothalamus, the brainstem, and cervical spinal cord (cervical segments 3–5). The afferent limb is formed by the Nervus (N) vagus, N phrenicus, and a part of the sympathetic chain (thoracic segments 6–12). Efferent structures include the N phrenicus, Nervi (Nn) intercostales, and direct efferences to scalenus musculature.
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
Table 1.: List of Etiologic Causes for Chronic Hiccups
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 catheters15,127Table 2 lists further examples of postinterventional hiccups.
Table 2.: List of Interventional Causes for Persistent 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
Table 3.: List of Pharmaceutical Agents Associated With Intractable Hiccups
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.”136,144–146Table 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.
Figure 2.: Suggested algorithm for a structured diagnostic procedure in hiccup patients. Primary concept should be to determine and specifically eliminate a potential cause for the symptom. Further diagnostics like imaging techniques and laboratory examinations are helpful if a cause is suspected but not directly identified. Symptomatic therapy should be administered only if no underlying pathology can be detected or sufficiently treated.
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
Figure 3.: Strategies for an adapted treatment approach to persistent singultus. The correct therapeutic measures should always be gradually adapted to the patient’s individual needs and symptom severity. As first step, behavioral alterations can already bring alleviation in many cases. A psychological evaluation of every patient is crucial, intervention should be provided early and in combination to any stage of physical therapy. Pharmacological options are available as mono- or combination therapy but should only be applied if specific treatment of an underlying cause fails. Interventional treatment has to be considered as last option in cases with a high level of suffering and insufficient success with other therapeutic approaches.
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, https://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.
Table 4.: Comparative Analysis of Baclofen and Gabapentin Mono- and Combination Therapy
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.
CONCLUSIONS
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.”
SUMMARY POINTS
- 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.
DISCLOSURES
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.
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