Hiccups are a surprisingly common symptom seen in patients with cancer, either during cancer treatment or in the palliative care setting. Hiccups cause the characteristic sound due to involuntary clonic spasms of the diaphragm and intercostal muscles followed by the sudden close of the glottis.
In most cases, hiccups are amusing and annoying, usually stopping within minutes. However, some patients may experience prolonged hiccupping periods of greater than 48 hours (persistent or chronic) or greater than 2 months (intractable). Persistent/intractable hiccups have been reported in up to 10 percent of patients with advanced cancer.
The hiccup reflex is composed of the afferent pathway (through the vagal and phrenic nerves and the sympathetic chain), the central hiccup center (in the hypothalamus), and the efferent pathway (through the phrenic nerve to the diaphragm and the accessory nerves to the intercostal muscles). Although it is poorly understood, neurotransmitters such as dopamine and GABA seem to be involved. Prolonged hiccups seen in patients with cancer seem to be more common in men than in women, and in older patients compared to younger patients.
Prolonged hiccups can have many undesirable consequences. These may include sleep disturbances, fatigue/exhaustion, reduced food and fluid intake, possible aspiration, emotional distress (anxiety and depression), and decreased cognitive function.
Many conditions are thought to promote the development of persistent/intractable hiccups. These include gastric distention; GERD/gastritis; low blood levels of sodium, calcium, and potassium; hyperglycemia; sudden change of temperature; alcohol intake; stroke; brain tumors; pneumonia; head injuries; pericardial and pleural effusions; and many more. Some cancers associated with hiccups include esophageal, colon, lung, pancreatic, liver, renal cancers, as well as leukemias and lymphomas.
Medications have also been thought to be associated with or cause persistent/intractable hiccups. Many of them are used in the treatment of cancer. Chemotherapy agents include cisplatin, cyclophosphamide, carboplatin, docetaxel, paclitaxel, etoposide, gemcitabine, vindesine, and vinorelbine. Of these, cisplatin is the most frequently described chemotherapy agent in case reports. Other non-chemo medications reported are corticosteroids, benzodiazepines, methyldopa, barbiturates, heroin, nicotine, antibiotics, and inhaled anesthesia. More invasive procedures include phrenic nerve block and vagal/phrenic nerve stimulation.
Of these medications, dexamethasone has been reported most frequent as a causative agent in persistent/intractable hiccups. There are several case reports of patients developing prolonged hiccups after chemotherapy administration, including dexamethasone. The patients in these reports often got relief from either substituting methylprednisolone or by withholding the corticosteroid entirely, without sacrificing antiemetic efficacy.
There are many folk remedies for hiccups such as breath-holding, the Valsalva maneuver, acupuncture, rubbing the palate or pharynx with cotton swabs, biting a lemon, breathing into a paper bag, digital rectal massage, eating a spoonful of peanut butter or sugar, and many others.
There is no pharmacological treatment for hiccups that has been studied in-depth. Case reports and case series have cited several medications that have been tried. These include olanzapine, metoclopramide, haloperidol, nifedipine, nimodipine, carvedilol, midazolam, valproic acid, phenytoin, carbamazepine, amantadine, methylphenidate, benzonatate, nebulized lidocaine, and oral viscous lidocaine. Other agents show more promise in relieving hiccups.
Chlorpromazine is the only FDA-approved agent for the treatment of hiccups. Unfortunately, chlorpromazine is not effective for all people, and the adverse effects include excessive sleepiness, confusion, urinary retention, hypotension, and prolongation of the QTc interval. The anti-dopaminergic effect is thought to be the mechanism of action. The usual dose for this indication is 25 mg TID for a few days.
Baclofen is another agent repurposed for the treatment of hiccups. It is a GABA derivative, more commonly used in the treatment of muscle spasms. The usual side effects include sedation, hypotonia, confusion, headache, and nausea/vomiting. In one double-blind, randomized, cross-over trial, baclofen was studied in patients with intractable hiccups. The four male patients were treated with baclofen in a dose of 5 mg PO Q8h for 3 days, then the dose was increased to 10 mg PO Q8h for 3 more days (Am J Gastroenterology 1992;87:1789-1791). These researchers found a statistically significant improvement in hiccup severity. However, the actual hiccup frequency was not improved.
Gabapentin, another GABA analogue, has been described in some case reports and a large case series to have efficacy in treating intractable hiccups. The usual dose cited in these publications starts at 100 mg TID, but can increase to 300-400 mg TID, if needed. The mechanism of action appears to be an alteration of the excitability of the inspiratory muscles. In a published case series, the efficacy rate appeared to range from 10-18 percent (Clinic Neuropharm 2010;33:179-180). These patients tolerated the gabapentin well, except for some sleepiness, which often is mild and resolves on its own. Gabapentin is used frequently in patients with cancer for treating neuropathy and hot flashes, and is generally well-tolerated.
There aren't many studies published in the treatment of hiccups in patients with cancer. In addition to treating any modifiable causes (hypokalemia, GERD, etc.), patients suffering with persistent or intractable hiccups can be offered a few promising treatments. One approach is to change the dexamethasone to methylprednisolone, or to withhold the steroid from the antiemetic plan, perhaps substituting olanzapine if needed. Gabapentin or baclofen would also be a reasonable choice. If baclofen is chosen, it could be started at 5 mg TID, and advancing the dose to 10 mg TID, if needed. Alternatively, gabapentin could be started at 100 mg TID, and then the dose could be increased if needed up to 300-400 mg TID. As uncomplicated chemotherapy-associated hiccups usually resolve in a few days, the patient may not need chronic treatment.
For Further Reading
- Becker DE. Nausea, vomiting, and hiccups: a review of mechanisms and treatment. Anesth Prog 2010;57:150-157
- Calsina-Berna A, Garcia-Gomez G, Gonzalez-Barbotea J, et al. Treatment of chronic hiccups in cancer patients: a symptomatic review. J Pall Med 2012;15:1142-1150
- Kang JH, Bruera E. Hiccups during Chemotherapy: What Should we do? J Pall Med 2015;18:572
- Marinella MA. Diagnosis and management of hiccups in the patient with advanced cancer. J Support Oncol 2009;7:122-127
- Menon M. Gabapentin in the treatment of persistent hiccups in advanced malignancy. Indian J Palliat Care 2012;18:138-140
- Neuhaus T, Ko YD, Stier S. Successful treatment of intractable hiccups by oral application of lidocaine. Support Care Cancer 2012;20:3009-3011
- Porzio G, Aielli F, Verna L, et al. Gabapentin in the treatment of hiccups in patients with advanced cancer: a 5-year experience. Clinic Neuropharm 2010;33:179-180
- Ramirez F, Graham DY. Treatment of intractable hiccup with baclofen: results of a double-blind, randomized, controlled, cross-over study. Am J Gastroenterology 1992;87:1789-1791
LISA LOHR, PHARMD, BCPS, BCOP, is Clinical Oncology Specialist/MTM provider at Masonic Cancer Clinic Fairview/University of Minnesota Health, Minneapolis.