Systemic Review

The Pathogenesis and Pharmacological Treatment of Hiccups

M. Steger; M. Schneemann; M. Fox

Disclosures

Aliment Pharmacol Ther. 2015;42(9):1037-1050. 

In This Article

Abstract and Introduction

Abstract

Background Hiccups are familiar to everyone, but remain poorly understood. Acute hiccups can often be terminated by physical manoeuvres. In contrast, persistent and intractable hiccups that continue for days or months are rare, but can be distressing and difficult to treat.

Aim To review the management of hiccups, including a systematic review of reported efficacy and safety of pharmacological treatments.

Methods Available articles were identified using three electronic databases in addition to hand searching of published articles. Inclusion criteria were any reports of pharmaceutical therapy of 'hiccup(s)', 'hiccough(s)' or 'singultus' in English or German.

Results Treatment of 341 patients with persistent or intractable hiccups was reported in 15 published studies. Management was most effective when directed at the underlying condition. An empirical trial of anti-reflux therapy may be appropriate. If the underlying cause is not known or not treatable, then a range of pharmacological agents may provide benefit; however, systematic review revealed no adequately powered, well-designed trials of treatment. The use of baclofen and metoclopramide are supported by small randomised, placebo-controlled trials. Observational data suggest that gabapentin and chlorpromazine are also effective. Baclofen and gabapentin are less likely than standard neuroleptic agents to cause side effects during long-term therapy.

Conclusions This systematic review revealed no high quality data on which to base treatment recommendations. Based on limited efficacy and safety data, baclofen and gabapentin may be considered as first line therapy for persistent and intractable hiccups, with metoclopramide and chlorpromazine in reserve.

Introduction

Hiccups are familiar to everyone, but remain a poorly understood phenomenon caused by involuntary, repetitive contractions of the diaphragm and, in many cases, the intercostal muscles (Video S1 https://onlinelibrary.wiley.com/doi/10.1111/apt.13374/suppinfo). The medical term for this condition is 'Singultus', which can be translated from Latin as 'to be caught in the act of sobbing'. The coordinated contraction of the inspiratory musculature leads to a rapid intake of air that is, within a few milliseconds, interrupted by closure of the glottis. It is this that results in the characteristic sound, the 'hic' in hiccups, between 4 and 60 times a minute. In adults, it appears to serve no physiological purpose; however, the frequent observation of hiccups in utero during prenatal ultrasound examinations suggest that it may have a role in training inspiratory muscles in readiness for respiration after delivery.[1,2]

Epidemiology

The classification of hiccups is based on their duration.[3] An acute attack lasts less than 48 h. 'Persistent hiccups' last more than 2 days. 'Intractable hiccups' are present if the attack lasts more than 1 month. The Guinness Book of Records documents the longest period of continuous hiccupping at 69 years and 9 months. This attack was apparently cured, at last, by prayers to St Jude… the patron saint of lost causes! Acute hiccups are a familiar experience that is very common in children but also experienced by adults. It is self-limiting and rarely requires pharmacological treatment because physical manoeuvres exist to foreshorten the attack (see below). The incidence and prevalence of persistent and intractable hiccups in the community has not been studied. A retrospective review of consecutive patients attending a general hospital identified 55 of 100 000 patients that received a primary diagnosis of hiccups.[4] Hiccups are more common in diseases affecting the gastrointestinal or central nervous systems (CNSs). Up to 20% of patients with Parkinson's disease and 10% of patients with reflux symptoms complain of recurrent hiccups compared to approximately 3% of controls.[5,6] Overall, the prevalence in advanced cancer has been reported as 3.9–4.8%.[7] However, in one case series, more than a quarter of patients with oesophageal carcinoma reported at least one attack of hiccups lasting more than 48 h. Irrespective of the underlying condition, when the condition is difficult to control this impacts on patient's quality of life and mood by interfering with eating, social interaction and sleep.

Pathophysiology

Hiccups are spontaneous, myoclonica contractions of the diaphragm and, in many cases, the intercostal musculature. As first proposed by Bailey in 1943, it widely accepted that hiccups are generated by a 'reflex arc' with afferent, central and efferent components (Figure 1).[8] The afferent impulse is carried by the vagus nerve, phrenic nerves or sympathetic nerve fibres (thoracic outflow T6–T12). Areas of the CNS involved in the hiccup response appear to include the upper spinal cord (C3–C5), the brainstem in the medulla oblongata near the respiratory centre, the reticular formation and the hypothalamus. Dopaminergic und gamma-amino-butyric-acid (GABA-ergic) neurotransmitters can modulate this central mechanism. The efferent response of the reflex is carried by the phrenic nerve to the diaphragm that has been observed to contract unilaterally or, less often, bilaterally. Activation of the accessory nerves leads to contraction also of the intercostal muscles. This stereotyped sequence of events is completed by reflex closure of the glottis by the recurrent laryngeal branch of the vagus nerve. Glottal closure is an important protective reflex because, without it, in patients with a tracheotomy hiccups lead to significant hyperventilation.[9]

Figure 1.

Anatomy of the hiccups reflux arc (after Bailey 1943). Pathology affecting the brain, diaphragm, thoracic or abdominal viscera can stimulate vagal or phrenic afferents the activate the diffuse 'hiccup center' in the midbrain, brainstem and proximal cervical cord (Table 1). This triggers repetitive myoclonic contractions of the diaphragm and other respiratory muscles via the phrenic and the intercostal nerves (motor efferents coloured red). Immediately afterwards activation of the recurrent laryngeal nerve (RLN) closes the glottis, producing the characteristic «hic» in hiccups.

Causes of Hiccups

Any process that affects the afferent, central or efferent components of the proposed reflex arc can trigger hiccups. The most common cause is distension of the stomach by a large meal or carbonated drinks. The reflex can be triggered also by hot chilli pepper, alcohol, smoking and other irritants to the gastrointestinal or pulmonary tracts. Hiccups can also be triggered by over-excitement or anxiety, especially if accompanied by over-breathing or air swallowing (aerophagia).

Patients with persistent or intractable hiccups should be investigated to identify organic pathology. Over 100 possible associations have been described in the literature; however, many of these are based only on individual case reports. Table 1 provides an overview of pathology that has been reliably linked to this condition. Relatively common CNS causes of hiccups include cerebrovascular disease, brain tumours and intracranial injury; however, it is very rare for hiccups to be the single, presenting symptom of serious neurological disease.[2] Peripheral causes are dominated by gastrointestinal diseases. Reflux oesophagitis and the presence of a large hiatus hernia are often cited as causes of persistent hiccups;[10] however, reflux can be the effect as well as the cause of hiccups.[11] Manometry and pH-impedance monitoring have shown that hiccups can inhibit normal oesophageal motility, reduce lower oesophageal sphincter pressure and alter the normal anatomy of the oesophago-gastric junction, all of which favour gastro-oesophageal reflux (GERD; Figure 2). Cardio-vascular disease such as myocardial ischaemia, pericarditis and aortic aneurysm have been associated with persistent hiccups, as have nasal, pharyngeal and laryngeal conditions including the presence of foreign bodies in the external auditory canal. Other causes linked to hiccups through effects on neural function include alterations to the electrolyte balance, uraemia and hyperglycaemia, plus a range of toxins and recreational drugs. Hiccups are also a recognised side effect of medications such as benzodiazepines, opiates and steroids. The problem can appear after surgery or endoscopy due to the use of sedation, oro-pharyngeal intubation or distention of the stomach during the procedure. Psychogenic causes should not be overlooked in patients with anxiety disorders, acute stress or excitement. However, this should be considered a 'diagnosis of exclusion' in persistent hiccups, especially if repetitive diaphragmatic contractions persist during sleep.

Figure 2.

Oesophageal function before and during an acute attack of hiccups in a patient with hiatus hernia and gastro-oesophageal reflux disease. High resolution manometry demonstrates characteristic short contractions of the crural diaphragm during hiccups. Note suppression of peristalsis and lower oesophageal sphincter function. This patient had recurrent episodes of hiccups responded to medical anti-reflux therapy. UES, upper oesophageal sphincter; LES, lower oesophageal sphincter; CD, crural diaphragm.

Investigation

Searching for the cause of hiccups can be a challenge due to the long course of afferent and efferent nerves and the diffuse central processing of the 'reflex arc'. The medical and surgical history should explore possible triggers for hiccups and document the frequency and duration of the condition. A thorough list of prescribed and over-the-counter medications, alcohol, smoking and recreational drug intake should be taken. The physical survey should include the ears, nose, neck and throat plus a full chest, abdominal and neurological examination. In addition to routine laboratory and imaging, computer tomography of the head, chest and abdomen is performed early to detect pathology along the course of the vagal and phrenic nerves. An upper gastrointestinal endoscopy is indicated. If no pathology is visualised, then an oesophageal manometry and a 24-h pH-impedance reflux study should be considered as GERD may be the most common trigger of hiccups.[10] If neurological symptoms or signs are identified, then Magnetic Resonance Imaging of the head and neck is the most sensitive method to identify CNS pathology including brainstem and cranial nerves.

Therapy

Whenever possible, the treatment of hiccups should be directed at the underlying cause of the condition. If no specific pathology has been identified, or no definitive treatment is possible, then a wide range of physical (Table 2) and pharmacological treatments have been described for the treatment of hiccups. The large number of medications proposed for this indication is a clear indication, first, of the lack of knowledge concerning the underlying pathophysiology of this condition and, second, that no one approach is effective in the majority of cases. Notwithstanding the above, recent years have seen new trials and case series enter the literature. Regulatory bodies have also published new recommendations concerning the use of pharmacological agents for this indication.

aMyoclonic contractions are automatic contractions of a muscle or group of muscles leading to organised movement of a limb or, as in the case of hiccups, other body parts. This is distinct from fasciculations that are disorganised contractions of muscle fibres that do not produce movement.

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