Treatment of Chronic Hiccups in Cancer Patients: A Systematic Review

Introduction

Hiccups was described by Thomas Lupton in 1627 ¹ as involuntary, synchronous, clonic spasms of the intercostal muscles and diaphragm, which produce a sudden inspiration continued by an abrupt glottic closure that results in a characteristic sound.^2–5 The medical term for hiccups, singultus, is of Latin origin meaning “the act of catching one's breath while sobbing.” ⁶ Its frequency varies from 2 to 60 per minute, with little intraindividual variability,^3,6 occurring more frequently in males.^7,8 Hiccup episodes involve unilateral contraction of the left hemidiaphragm in approximately 80% of cases^6,7 and typically follow a peak inspiration, although it can occur at any moment of the respiratory cycle. ⁸

It is unclear whether hiccups have a function. ⁸ It is generally accepted that it is already present in the fetus after the eighth week of gestation; ³ also observed in the neonate, its frequency reduces over time in adults. ³

Most hiccup episodes are benign, of acute onset, and self limited, typically ceasing within minutes. ⁶ However, the symptom is present in 1% to 9% of advanced cancer patients,^9,10 and described as persistent or intractable. Persistent or intractable hiccups are defined as lasting more than 48 hours or 1 month, respectively;^{6,7,9,11–14} and it is qualified as severe when scored 7 or higher in a scale from 0 (no hiccups) to 10 (the worst hiccups imaginable). ⁹ This symptom can have a detrimental impact on the quality of life, with potential consequences of disturbed sleep, disruption in eating and drinking, speech difficulties, pain, gastrointestinal reflux, anxiety, fatigue, depression, even death.^2,3,15–18

To alleviate this, a large number of treatments have been provided, though none has been found to be completely effective. Moreover, the information that can be found in the literature is mainly based on case reports, which means that more evidence is needed.

The objective of this article is to offer the reader a systematic review of the treatment of this symptom in cancer patients, with an initial discussion of physiology, causes, and diagnosis.

Materials and Methods

A search was conducted in MEDLINE and SCOPUS with no restriction on the time limit in the past up to June 1, 2011. To launch the search the following keywords and combinations were used with mesh terms (MH): “hiccup”[MH] AND (“neoplasms”[MH] OR “palliative care”[MH] OR “hospices”[MH] OR “terminal care”[MH] OR “nursing homes”[MH]). The search was limited to publications related to human beings (“humans”) and only included papers in English, French, and Spanish languages.

Both the search and the selection of the studies were made by two reviewers independently (ACB, GGG). These reviewers also assessed the studies included. The criterion used was inclusion only of papers with abstracts containing information on the treatment of hiccups in cancer patients. Some articles not found with MEDLINE or SCOPUS searches were added from the analysis of references. Levels of evidence for all the studies reviewed are seen in Table 1. ¹⁹

Results

In the MEDLINE search, 81 articles were obtained; from those, 16 met the criteria for review. Three hundred and fifty one articles were obtained from SCOPUS; 18 met the criteria. Of these 18, 12 articles were already selected in MEDLINE, thus only 6 were added. After reviewing the references of the 22 previously selected articles, 10 additional articles were also included, as they provided information about treating hiccups in cancer patients. Both reviewers obtained the same articles in their searches.

Of the 32 selected articles that met the inclusion criteria, 8 were reviews, 5 dealt with hiccups surgical treatment (5 case reports), 17 were about pharmacological treatments (15 case reports and 2 retrospective chart reviews), and 2 referred to nonpharmacological treatment (1 case report and 1 retrospective case series). None of the reviews was systematic but they have all been used to obtain information for the present article.

Physiology

The hiccup reflex arc was first described by Bailey in 1953.^7,20 It is composed of an afferent and an efferent limb and a central hiccup center. ⁶ The afferent pathway consists of the vagus nerve, the phrenic nerve (derived from cervical segments C2–C4), and the sympathetic chain (derived from thoracic segments T6–T12).^2,3,6,8

Hiccup centers are believed to be located in the hypothalamus, the medullary reticular formation, the brainstem near the respiratory centers, the medial and dorsal medullary nuclei, and the cervical spinal cord somewhere between C3 and C5 segments.^2,3,8,21 Several groups of the medullary nuclei have been mentioned as interacting in this center including the dorsal portion of the tractus solitarius (for instance, inspiratory center), the ventral group of the nucleus ambiguous (expiratory center), and the nucleous of the phrenic nerve. ²¹

The efferent pathway of the hiccup arc primarily consists of the phrenic nerve, the primary motor input to the diaphragm. ⁶ Additionally, the external intercostal and the scalenus nerves stimulate contraction of the intercostal and scalene muscles, respectively. ⁶ Shortly after the activation of the hiccups arc, the recurrent laryngeal nerve stimulates closure of the glottis, resulting in the characteristic “hic” sound.^6,22

Etiology

More than 100 underlying diseases are associated with intractable hiccups, ⁷ due to the fact that any process occurring along the anatomical pathway of this reflex arc and the hiccups center can evoke this symptom. ²¹

The most common etiologies of persistent and intractable hiccups are pathologies of the gastrointestinal tract such as gastric distension or gastroesophageal reflux disease, ¹² of the thoracic viscera, and of the central nervous system. Additional etiologies include renal failure; metabolic disorders; and some drugs, in particular corticoids, ⁹ which may cause hiccups by lowering the synaptic transmission threshold in the brainstem.

In cancer patients several other situations can lead to hiccups, since in these patients not only the neoplasic illness itself is involved, but also unrelated comorbidities; supportive pharmacologic treatments; infectious complications; and/or anticancer therapies, including chemotherapy, radiotherapy, and surgery^{2,3,9,10,23–25} (see Table 2).

Diagnosis

Persistent and intractable hiccups calls for a diagnostic evaluation to exclude treatable causes, ⁶ but no systematic study of chronic hiccup has assessed the benefit of extensive workup. ² In each patient a detailed medical history and physical examination needs to be done, paying more attention to the structures involved in the anatomical arc reflex. ⁶

Past surgical interventions should be inquired into, as well as respiratory and gastrointestinal symptoms; infections; and use of alcohol and medications, especially corticosteroids, benzodiazepines, and barbiturates. ¹⁰

Basic laboratory studies should be conducted to check for electrolyte disturbances including hyponatremia, hypokalemia, and hypocalcemia. Electrocardiography should be considered to exclude coronary artery disease;^2,6,27 and imaging tests should be performed if any element of the history or physical examination suggests an etiology affecting a particular system. Other invasive tests such as lumbar puncture and bronchoscopy, should be considered, depending on the patient's situation.

However, since there are so many causes that can underlie chronic hiccups, a negative medical history and physical examination does not necessarily imply the diagnosis of idiopathic or psychogenic hiccups. ²

Finally, it is important to remember that in the setting of advanced cancer patients, hiccups can be multifactorial—and that depending on the patient's prognosis and functional status, an extensive workup to find the cause can be harmful.

Treatment

The literature reveals a large number of proposed treatments, which suggests the lack of effectiveness of any one therapy.^3,10,21 Treatments can be divided into surgery treatment, nonpharmacological treatment, and pharmacological treatment. With surgical treatment the cause can be resolved and therefore the symptom can be controlled, although it must be taken into consideration that only case reports were found describing surgical treatments. In Table 3 some surgical maneuvers are shown.

Very often in cancer patients the cause cannot be eliminated; nonpharmacological and pharmacological approaches need to be considered. Included in nonpharmacological treatments are folk remedies (see Table 4). To our knowledge, no systematic review or clinical trial exists on these remedies; their safety and efficacy are not well known and should be studied.

Describing nonpharmacological treatments, a retrospective case series about acupuncture and a case report about the use of nebulized saline have demonstrated relief of hiccups in cancer patients (see Table 5), but more studies need to be done to confirm this data.

Discussing pharmacological treatments, the selected articles in the current review are shown in Table 6. There are no RCT or other studies that compare the effectiveness of surgical, nonpharmacologic, and pharmacologic treatment. Information retrieved for each pharmacological agent in hiccups treatment is provided below.

Conclusions

A medical history and clinical exam should be done to try to determine the most feasible cause of hiccup. Addressing chronic hiccup having a well-known and potentially removable cause, surgery should be considered, since it can be an etiological and definite treatment.

Regarding nonpharmacological measures, although there is no evidence of their usefulness and safety, popular remedies are breath holding or drinking in small sips.

In the setting of advanced cancer patients, the etiology is usually multifactorial and the cause irreversible. Then, a pharmacological treatment needs to be attempted, even during the waiting time for a potential curative surgery. Unfortunately, pharmacological effectiveness with these patients is only shown in anecdotal reports and short case series. Papers reporting effectiveness of baclofen describe only eight patients. Usefulness of chlorpromazine and gabapentine is described in retrospective case series of 50 and 44 patients, respectively. The effectiveness of remaining drugs reviewed or combinations is anecdotal, and no conclusion can be drawn.

On the other hand, there is great heterogeneity in the patients included as well as in the doses and methods used to evaluate the efficacy of the different treatments.

The only randomized clinical trial we have found shows the treatment of idiopathic hiccups with baclofen in four patients without cancer. ²⁸ The scarce evidence prevents us from making general recommendations. In order to offer general recommendations, more randomized clinical trials should be done. In the meantime, if treating hiccups in cancer patients is necessary, it is important to consider the patient's general condition to avoid potential side effects.

In some case reports, advanced cancer patients have improved with the use of baclofen and gabapentin; efficacy of chlorpromazine was reported in a cohort of cancer and noncancer patients. From this point of view, baclofen or gabapentin could be considered options. If baclofen is started, it is important to consider paying more attention to elderly patients. Doses of baclofen in the studies seen range from 5 mg every 8 hours to 20 mg every 6 hours. Gabapentin in case reports is started at 300 mg per day and slowly increased up to 900 mg to 1200 mg per day. In some cases, baclofen and gabapentin could be given together. ³⁰ In case the oral route is not available, chlorpromazine has been used, taking into consideration the risk of hypotension and somnolence, with doses of 25 mg every 8 hours. Finally, in refractory hiccups in patients in the last days of life, midazolam could be considered.

Studies about hiccups need to be done to obtain more evidence about its treatment. One worthwhile clinical trial would be comparing the use of baclofen and of gabapentin. A clinical trial comparing chlorpromazine with baclofen and/or gabapentin should be done.