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 »  Abstract
 » Introduction
 » Case Report
 » Discussion
 » Conclusion
 »  References

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Table of Contents 
CASE REPORT
Year : 2012  |  Volume : 18  |  Issue : 2  |  Page : 138-140

Gabapentin in the treatment of persistent hiccups in advanced malignancy


Department of Pain Medicine and Palliative Care Services, Kokilaben Dhirubhai Ambani Hospital, Four bungalows, Andheri (West), Mumbai-53, India

Date of Web Publication8-Sep-2012

Correspondence Address:
Mahesh Menon
Department of Pain Medicine and Palliative Care Services, Kokilaben Dhirubhai Ambani Hospital, Four bungalows, Andheri (West), Mumbai-53
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1075.100839

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 » Abstract 

Hiccups are a distressing symptom in advanced malignancies in the setting of palliative care. A case of persistent hiccups treated with oral Gabapentin is presented to highlight the clinical and ethical dilemmas in patients with advanced malignancy. A 70-year-old male with non-small cell cancer of the lung with widespread metastases presented with persistent hiccups. The patient and family sought only symptom relief from home, without hospitalization or further investigations. The hiccups were dramatically relieved by oral Gabapentin, highlighting the recent reports that mention this molecule as being useful for hiccups. Gabapentin is a simple tool that may be utilized by palliative care physicians to relieve hiccups in advanced malignancies.


Keywords: Gabapentin, Persistent hiccups, Hiccups in malignancy


How to cite this article:
Menon M. Gabapentin in the treatment of persistent hiccups in advanced malignancy. Indian J Palliat Care 2012;18:138-40

How to cite this URL:
Menon M. Gabapentin in the treatment of persistent hiccups in advanced malignancy. Indian J Palliat Care [serial online] 2012 [cited 2019 Aug 19];18:138-40. Available from: http://www.jpalliativecare.com/text.asp?2012/18/2/138/100839



 » Introduction Top


We report a case of a patient with advanced non-small cell cancer of the right lung with persistent hiccups. Hiccups are a physiological phenomenon, but can herald an ominous prognosis in the setting of advanced malignancy. [1] Based on the duration of the symptoms, hiccups may be "persistent" (>48 hours) or "intractable" (>1 month). [2] There is a paucity of literature regarding the treatment of hiccups in advanced malignancies. Literature describes the role of Gabapentin in the management of this symptom in advanced malignancy in the form of observational studies. [1],[3],[4] Our case report highlights the application of this drug in the management of advanced hiccups in the Indian palliative care setting. This has implications in the management of patients who may not be able to access palliative care services or advanced interventions because of geographical, socio-economic, or personal barriers.


 » Case Report Top


Mr. A, recently diagnosed with non-small cell cancer of the right lung with multiple metastases, was under treatment from the department of pain medicine and palliative care services for pain, and was fairly asymptomatic with a transdermal fentanyl patch delivering the medicine at 25 micrograms/hour. The new symptom of hiccups, unrelieved for 2 days, was reported by the patient one evening. The hiccups were unresponsive to simple home remedies, medications such as hysocine butyl bromide, both oral and injectable, oral metoclopramide, oral ondansentron, tramadol-paracetamol, tapentadol, oral morphine and alprazolam. These medications were leftover from previous prescriptions given to the patient at various centers prior to our consult. The hiccups had distressed him significantly, accompanied by decreased oral intake, disturbed sleep and mood, and increase in pain during the movement accompanying each hiccup. The morphine addition helped with pain relief only. There was no constipation, no vomiting, nor any new symptom. When the patient reported this symptom, a prescription of oral gabapentin 100 mg was given. Gabapentin was available with the patient as the patient was prescribed it in the past for burning pain, and had stopped it after relief of pain (since 14 days). The hiccups resolved dramatically in 20 minutes, and were absent for 5 hours after which a repeat dose was administered, which resolved the symptoms completely. The patient was advised to take gabapentin in a dose of 100 mg 3 times a day. No other medication was advised since gabapentin had worked well to the patient's satisfaction. The family physician had made a home visit and had advised hospitalization. The patient refused further management for the time and came for a follow- up the next day. On clinical examination, vital parameters were stable, there was mild pallor and sclerae were normal, the abdomen was soft and bowel sounds were audible. There were no significant changes in the cardio-respiratory or neurologic examination. His mood and oral intake had improved. A simple screen was carried out at the patient's request. Blood chemistry was unremarkable. Chest radiographs showed new findings, like a greater loss of volume of right lung, with ipsilateral tracheal shift and diffuse reticulonodular opacities in both lungs, suggestive of lymphangitis carcinomatosa. The diaphragm was tented and flattened, an increase compared with the previous radiograph. He underwent an abdominal ultrasound examination in his hometown- and it has been reported as unremarkable. He has been free of hiccups since the first visit for 1 month with complete resolution of hiccups with gabapentin.


 » Discussion Top


Hiccups were believed to be a simple spasmodic contraction of the diaphragm, but an experimental study showed that it was more complex, with a patterned motor act involving the diaphragm, intercostals muscles, vocal cords, and glottis. The author proposed the existence in the brain stem of a specific neural circuit capable of generating hiccups. A plethora of stimuli are known to activate this reflex. [5] Persistent hiccups may have devastating effects on the mind and body in such patients. A vicious cycle of sleep disturbance, decreased intake and prolonged exertion, leads to deleterious effects such as fatigue, distress, dehydration, weight loss, and, in extreme cases, death. [6],[7] Since hiccups are perceived as an innocuous symptom, many patients delay reporting them, as in the case of Mr. A unless they are persistent, or intractable. In addition, there are numerous "home remedies" in every cultural context for hiccups. Also, a study of literature reveals very little information about hiccups as opposed to the commonly-addressed physical symptoms in palliative care, like pain, breathlessness, and bowel symptoms, etc. The prevalence of hiccups in malignancy has not been estimated although a review by Porzio et al. revealed the prevalence to be around 3.9 - 4.5%. [3] Chemotherapy itself may cause hiccups, and of particular note for the palliative care physician, corticosteroids and benzodiazepines, which are commonly used adjuncts in these settings, have been reported to be associated with hiccups although no particular drug may be definitively implicated in the etiology. [8],[9] In the review by Martinez, 21 patients out of 24 had at least one identifiable organic etiology, and 13 patients presented two or more possible associated conditions. The most common possible causes were digestive tract disorders, followed by central nervous system diseases. [1] In the case of Mr. A, the findings on the X-ray might suggest irritation of the phrenic nerve and diaphragm on the right side- a possible cause of this new development. In a retrospective review over a 5-year period from a community hospital, it was noted that patients presenting with hiccups as a symptom (of any etiology), were usually male, older than 50 years of age, and with co-morbid conditions. Laboratory investigations did not contribute significantly to management. Such patients mainly underwent an upper GI endoscopy with little benefit. In addition, no treatment showed significant success. [2] This has significant implications, more so in the Indian palliative context in private practice, wherein we are faced with the ethical dilemmas of the financial implication of investigating an end-of-life patient "thoroughly": A repeat PET-CT scan, a chest CT scan with an abdominal CT scan with contrast perhaps? The attitude of the family care physician reflects the urge to "just don't stand there- do something." A recent cross-sectional survey of rural and urban households by Joseph et al. revealed that Indian patients preferred home-based palliative care services, much like in our case. [10] Having discussed the options with the family and with the patient, a decision was made to withhold invasive and expensive investigations, especially since the symptom had resolved, and the prognosis and overall management were unlikely to change. The doctrine of "Patient Autonomy" was respected after having informed the patient about the benefits and risks of management options. [11],[12] Gabapentin has a role in the management of intractable hiccups in view of its favorable tolerability, pain-modulating effects, minimal adverse events, and lack of drug interactions. [4],[13] Gabapentin is believed to act via heterodimeric GABA B receptor activation, NMDA activation, AMPA blocking effects, activating ATP sensitive K channels, or blocking AMPA-receptor-mediated transmission in the spinal cord, binding to the L-α-amino acid transporter, activating ATP-sensitive K+ channels, α2δ subunit of spinal N-type Ca 2+ channels., and its efficacy in hiccups may be attributed to any of its wide range of actions on neural receptors. [14] Observing the rapid onset of its action, one may attribute its effect to rapid ion fluxes and downstream effects affecting neural conduction for instance the action on α2δ subunit of N-type Ca 2+ channels, with a reduction in Ca 2+ permeability, neuronal excitability, and synaptic transmission. Chlopromazine remains the only FDA-approved agent in the United States for this symptom. [13] Martinez et al. reported successful treatment of this symptom with chlorpromazine in 19 out of 24 patients. [1] In our patient, with a history of ischemic heart disease, chlorpromazine carried the risk of QT c interval prolongation, and was not chosen. Gabapentin has a wider scope of application as it has been mentioned as one of the useful agents against neuropathic pains in cancer. [15] The prevalence of neuropathic pain in cancer in a tertiary center in the Indian setting has been reported to be 11.8%. [16] Considering this, gabapentin is a useful tool in cancer patients in the Indian context.

Other options include an array of interventions targeting the phrenic nerve. [17],[18],[19] These procedures have potential risks include local anesthetic toxicity, hematoma formation, and theoretical risk of nerve injury with hemidiaphragmatic palsy. The procedure was explained to the patient and relatives, and was advised to the patient as a back-up plan if the persistent hiccups proved to be intractable to pharmacotherapy. Finally, complementary and alternative medicine also offers treatment for hiccups. [20]


 » Conclusion Top


Gabapentin is useful in the management of persistent hiccups in malignancy and has the advantage of low dosing, gradual titration of dosage, fewer drug interactions, and systemic effects. In addition, it may double up as a useful anti-neuropathic pain agent in malignancy-related pains. Surgical options and procedures for this symptom are best reserved, in the author's opinion, for intractable hiccups where simple measures have failed, or where a symptomatic organic lesion lends itself to intervention.

 
 » References Top

1.Martinez RC, Villamil C. Hiccup: Review of 24 cases. Rev Med Chil 2007;135:1132-8.  Back to cited text no. 1
    
2.Cymet TC. Retrospective analysis of hiccups in patients at a community hospital from 1995-2000. J Natl Med Assoc 2002;94:480-3.  Back to cited text no. 2
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3.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.  Back to cited text no. 3
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4.Tegeler ML, Baumrucker SJ. Gabapentin for intractable hiccups in palliative care. Am J Hosp Palliat Care 2008;25:52-4.  Back to cited text no. 4
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5.Newsom DJ. An experimental study of hiccup. Brain 1970;93:851-72.  Back to cited text no. 5
    
6.Kolodzik PW, Eilers MA. Hiccup (singulutus): Review and approach to management. Ann Emerg Med 1991;20:565-73.  Back to cited text no. 6
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7.Howard RS. Persistent hiccups. BMJ 1992;305:1237-8.  Back to cited text no. 7
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8.Takiguchi Y, Watanabe R, Nagao K, Kuriyama T. Hiccups as an adverse reaction to cancer chemotherapy. J Natl Cancer Inst 2002;94:772.  Back to cited text no. 8
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9.Thompson DF, Landry JP. Drug-induced hiccups. Ann Pharmacother 1997;31:367-9.  Back to cited text no. 9
    
10.Joseph N, S J, Kotian S. A comparative study to assess the awareness of palliative care between urban and rural areas of Ernakulum district, Kerala, India. Indian J Palliat Care 2009;15:122-6.  Back to cited text no. 10
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11.American Medical Association. Code of Medical Ethics; 2006-2007 ed. United States: American Medical Association, 2007: § 8.08 at 227.  Back to cited text no. 11
    
12.Fins JJ. A Palliative Ethic of Care: Clinical Wisdom at Life's End. Sudbury, MA: Jones and Bartlett Publishers; 2006. p. 1-281.  Back to cited text no. 12
    
13.Marinella MA. Diagnosis and management of hiccups in the patient with advanced cancer. J Support Oncol 2009;7:122-7, 130.  Back to cited text no. 13
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14.Cheng JK, Chiou L. Mechanisms of the Antinociceptive Action of Gabapentin. J Pharmacol Sci 2006;100:471-86.  Back to cited text no. 14
    
15.Tassinari D, Drudi F, Carloni F, Possenti C, Santelmo C, Castellani C. Neuropathic pain in oncology. Novel evidence for clinical practice. Recenti Prog Med 2011;102:220-7.  Back to cited text no. 15
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16.Bhatnagar S, Mishra S, Roshni S, Gogia V, Khanna S. Neuropathic pain in cancer patients--prevalence and management in a tertiary care anesthesia-run referral clinic based in urban India. J Palliat Med 2010;13:819-24.  Back to cited text no. 16
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17.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;35:455-7.  Back to cited text no. 17
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18.Calvo E, Fernández-La Torre F, Brugarolas A. Cervical phrenic nerve block for intractable hiccups in cancer patients. J Natl Cancer Inst 2002;94:1175-6.  Back to cited text no. 18
    
19.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.  Back to cited text no. 19
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20.Ge AX, Ryan ME, Giaccone G, Hughes MS, Pavletic SZ. Acupuncture treatment for persistent hiccups in patients with cancer. J Altern Complement Med 2010;16:811-6.  Back to cited text no. 20
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