|Year : 2016 | Volume
| Issue : 4 | Page : 294-296
Palliative management of intractable hiccups in a patient with an advanced brain tumour
Sami Ayed Alshammary1, Balaji P Duraisamy2, Lobna M. A. Saleem2, Luma Al Fraihat2, Abdullah Altamimi2, Stuart Brown3
1 Comprehensive Cancer Center, Palliative Care Unit, King Fahad Medical City; Centre for Postgraduate Studies in Family Medicine, Ministry of Health, Riyadh, Saudi Arabia
2 Comprehensive Cancer Center, Palliative Care Unit, King Fahad Medical City, Riyadh, Saudi Arabia
3 Department of Palliative Care, Two Worlds Cancer Collaboration Foundation, Abbotsford, Canada; International Network for Cancer Treatment and Research, Brussels, Belgium
|Date of Web Publication||12-Oct-2016|
Sami Ayed Alshammary
Comprehensive Cancer Center, Palliative Care Unit, King Fahad Medical City, Riyadh, Saudi Arabia
Intractable hiccupping is distressing for both patients under palliative care and their families, particularly if the patients have advanced cancer. The lack of clear management guidelines renders hiccup management challenging for health professionals. We report our management of intractable hiccups in a 70-year-old man with a progressive malignant brain tumour who was under palliative care. The hiccups were difficult to control; several drugs were tested before we finally introduced (and upwardly titrated) gabapentin, which appears to be safe when used to manage intractable hiccups.
Keywords: Anti-epileptics, brain tumour, gabapentin, intractable hiccups, palliative care
|How to cite this article:|
Alshammary SA, Duraisamy BP, Saleem LM, Al Fraihat L, Altamimi A, Brown S. Palliative management of intractable hiccups in a patient with an advanced brain tumour. J Health Spec 2016;4:294-6
|How to cite this URL:|
Alshammary SA, Duraisamy BP, Saleem LM, Al Fraihat L, Altamimi A, Brown S. Palliative management of intractable hiccups in a patient with an advanced brain tumour. J Health Spec [serial online] 2016 [cited 2019 Apr 24];4:294-6. Available from: http://www.thejhs.org/text.asp?2016/4/4/294/191913
| Introduction|| |
We report the case of a 70-year-old male with advanced glioblastoma multiforme (WHO Grade IV) of the right temporal lobe. He presented with intractable hiccups more than one month in duration.
Hiccupping is an involuntary physiological reflex involving the respiratory muscles of the chest and diaphragm, mediated by the phrenic and vagus nerves and a central (brainstem) reflex centre.  A single episode can last from a few seconds to as long as several days. Based on the duration, hiccups can be divided into three categories: Acute hiccups that last for up to 48 h, persistent or protracted hiccups that last for more than 48 h and intractable hiccups that last for over a month.  Intractable cases are rare but do occur.
The causes of hiccups in palliative care settings include gastric stasis and distention (the most common causes), gastroesophageal reflux disease (GERD), metabolic disturbances (e.g., uraemia, hypercalcaemia or hyponatremia), infection, local factors causing irritation of the diaphragm or phrenic nerve, hepatic disease/hepatomegaly and cerebral causes (e.g., tumours or metastases). 
The detailed pathophysiology of hiccups remains poorly understood. However, possible causes include irritation of the afferent or efferent nerves of the diaphragm (the phrenic or vagus nerves) or the medullary centres.  Several neurotransmitter pathways of the brainstem and medulla, including those involving dopamine, serotonin, opioids, calcium channels and gamma-aminobutyric acid (GABA) are possibly involved in mediating hiccups. 
There are few reports on the treatment of intractable hiccups in patients with advanced malignancies and under palliative care. However, observational studies have suggested that gabapentin may be useful for management of hiccups in patients with advanced malignancies. ,,] Here, we report on the successful use of gabapentin to treat intractable hiccups in a palliative care setting.
| Case report|| |
We report the case of a 70-year-old man with a 2-year history of advanced glioblastoma multiforme of the right temporal lobe. After partial resection in June 2013, he received 30 fractions of whole-brain radiation until August 2015, with concurrent temozolomide, followed by six cycles of temozolomide. He developed recurrence in June 2015; this was managed using palliative bevacizumab (a single agent) until October of the same year. Unfortunately, disease progression developed, chemotherapy was stopped and the patient was transferred to the palliative care unit of our tertiary hospital for supportive care at home. He presented in January 2016 with intractable hiccups that lasted more than one month in duration. The hiccups were frequent and irritating, which disturbed his sleep and caused severe distress to both him and his family. Simple breath-holding and drinking cold water did not stop the hiccups. Neither abdominal distention nor GERD was apparent, and he experienced regular bowel movements. He was on dexamethasone (oral 2 mg daily). In the clinic, he was started on metoclopramide 10 mg TID (three times per day) with no effect, even after one week. Then he was placed on haloperidol 1.5 mg TID, but again no benefit was apparent. Next, he was started on chlorpromazine 25 mg at night, but this was discontinued after two days because the sedation was intolerable. We decided to admit him in order to give the family some respite and to better monitor his responses to the treatment. Baclofen, codeine, morphine and omeprazole were all tested both singly and in combination but afforded no benefit (although no intolerable side-effects were encountered). Oral gabapentin was begun at 100 mg TID, reviewed every 3 rd day, and was titrated upwardly to a final dose of 300 mg TID. The hiccups stopped, and the patient did not report any side-effects. He was discharged on this dose and reported that he felt well.
| Discussion|| |
Hiccups are frequent in general populations and are usually benign and transient. Intractable hiccups point to a possible organic cause that is usually serious. Although no specific pathophysiological mechanism has been identified, a hiccup reflex arc has been described: The afferent limb (including the phrenic, vagus and sympathetic nerves) transmits somatic and visceral sensory signals to a central processing unit in the midbrain and the efferent limb travels in the motor fibres of the phrenic nerves to the diaphragm and (via accessory nerves) to the intercostal muscles. ,,
The central processing of hiccups remains poorly understood, but may not be confined solely to the medulla, perhaps also involving other regions of the central nervous system between the brainstem and cervical spine.  The central hiccup component usually refers to chemoreceptors that are probably located in the periaqueductal grey matter and subthalamic nuclei.
The incidence of hiccups in a given community is difficult to estimate as most episodes are transient. Sufferers may take over-the-counter medicines or home remedies, or simply wait until symptoms resolve spontaneously. Most sufferers will not seek medical attention.
Persistent hiccups can have unpleasant effects including fatigue, dehydration, weight loss, wound dehiscence and death (in extreme cases).  Our patient experienced sleep deprivation and social embarrassment, fatigue and anxiety attributable to his intractable hiccups. He made many visits to the emergency room and clinic and took various pharmaceuticals, without any relief.
The palliative care team aimed to control his symptoms quickly, while performing the minimal number of investigative procedures and minimising the possible side-effects of medication. The focus was on improving his quality of life.
The patient was satisfied, and his hiccups were fully controlled. He was discharged home and was able to return to his usual activities. No side-effects were reported by him or his family. He was followed up by home care and over the telephone.
It is important to note that, immediately after the brain tumour resection, the patient was on levetiracetam 500 mg twice daily to control seizures. The palliative care team briefly considered whether increasing the levetiracetam dose would be better than adding gabapentin to control the hiccups. However, the literature lacks any evidence supporting the use of levetiracetam for hiccup management. Given the urgent need, the team decided to add gabapentin.
The patient stopped taking both gabapentin and levetiracetam for about two weeks in April 2016 due to difficulty swallowing and the hiccups recurred (but without seizures). He was readmitted for reassessment. He had deteriorated neurologically, and imaging (computed tomography of the brain) confirmed further progression of the disease. He was recommenced on syrups of levetiracetam and gabapentin at the previous doses. He was discharged on titration of gabapentin at 1200 mg/day in good health.
Gabapentin, an anti-epileptic drug commonly used for neuropathic pain management in patients with cancer and under palliative care, may effectively treat hiccups by increasing endogenous GABA-mediated inhibition of inspiratory muscle action, , reducing calcium influx by inhibiting voltage-operated calcium channels in the presynaptic terminals of respiratory muscles or both of these mechanisms. Furthermore, it also increases the levels of serotonin (an important neurotransmitter) in the nucleus raphe magnus of the medulla, which is the most likely source of GABAergic inhibitory inputs to the hiccup reflex arc.
Gabapentin should thus be considered a treatment for intractable hiccups in palliative care settings, particularly if central causes are suspected. The drug is associated with minimal adverse effects and is safe, inexpensive and readily available in several formulations.
| Conclusion|| |
This case report reinforces previous reports on the efficacy of gabapentin used to treat established hiccups that are resistant to other drugs. Gabapentin may be particularly useful if the hiccups are caused by brain tumours. Further work is needed to establish treatment guidelines for the management of persistent hiccups.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Marinella MA. Diagnosis and management of hiccups in the patient with advanced cancer. J Support Oncol 2009;7:122-7, 130.
Regnard C. Hiccup. In: Oxford Textbook of Palliative Medicine. 3 rd
ed. Oxford: Oxford University Press. 2004. p. 477-9.
Woelk CJ. Managing hiccups. Can Fam Physician 2011;57:672-5, e198-201.
Martínez Rey C, Villamil Cajoto I. Hiccup: Review of 24 cases. Rev Med Chil 2007;135:1132-8.
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;33:179-80.
Tegeler ML, Baumrucker SJ. Gabapentin for intractable hiccups in palliative care. Am J Hosp Palliat Care 2008;25:52-4.
Becker DE. Nausea, vomiting, and hiccups: A review of mechanisms and treatment. Anesth Prog 2010;57:150-6.
Hansen BJ, Rosenberg J. Persistent postoperative hiccups: A review. Acta Anaesthesiol Scand 1993;37:643-6.
Takahashi T, Murata T, Omori M, Tagaya M, Wada Y. Successful treatment of intractable hiccups with serotonin (5-HT) 1A receptor agonist. J Neurol 2004;251:486-7.
Kolodzik PW, Eilers MA. Hiccups (singultus): Review and approach to management. Ann Emerg Med 1991;20:565-73.
Fraser CL, Arieff AI. Nervous system complications in uremia. Ann Intern Med 1988;109:143-53.
De Deyn PP, D′Hooge R, Van Bogaert PP, Marescau B. Endogenous guanidino compounds as uremic neurotoxins. Kidney Int Suppl 2001;78:S77-83.