Hiccup is a spasmodic, involuntary contraction of the inspiratory (external) intercostal muscles and the diaphragm associated with a strong, sudden inspiration, and abrupt glottic closure. The inspiratory effort does not result in lung volume changes and there are minimal ventilatory effects. Hiccups can be classified by their duration; acute (up to 48 hours), persistent or protracted (longer than 48 hours) and intractable (>1 month) (1).

Hiccup is a primitive reflex that contains three parts. The afferent portion consists of branches of the vagus nerve, the phrenic nerve, and the sympathetic chain from T6–12. The hiccup center is located in the spinal cord between C3 and C5. The efferent limb is primarily the phrenic nerve with involvement of the efferents to the glottis and accessory muscles of respiration (1).

In addition to the neural pathways, numerous anatomic structures are involved in the mechanism of hiccup (epiglottis, larynx, hyoid muscles, superior constrictor of the pharynx, esophagus, stomach, diaphragm, and exterior intercostal, sternocleidomastoid, anterior serratus, and scalene muscles). Given this extensive list, it is not surprising that hiccup has been associated with many conditions affecting the central nervous system (CNS), thorax, mediastinum, and abdominal viscera; although a cause-and-effect relationship has not always been clear. One report listed over 100 causes, the most common being an overdistended stomach (2). Some cancer-related causes of persistent and intractable hiccup are listed in Table 18.1.

Management is usually aimed at inhibiting or interrupting the irritated reflex arc. Nonpharmacologic therapies (3) include
the Valsalva’s maneuver (expiring forcefully against a closed glottis), ocular compression, carotid sinus massage, traction on the tongue, ice water gargles, noxious odors or tastes, breath holding, rebreathing into a paper bag, gagging, drinking from a glass while holding a pencil between the teeth or while bending over head down, taking as many sips of fluid as rapidly as possible without breathing, ingesting granulated sugar, biting a lemon wedge, or inducing emesis. Physical changes that may help stop hiccups include pulling the knees to chest, leaning forward to compress the chest, tapping over the fifth cervical vertebra, or applying ice over the phrenic nerve. Although these measures have not been subjected to controlled clinical trials, most are worth a try. However, many are not practical for these patients, who may be too debilitated to tolerate even simple maneuvers (e.g., holding breath).

Gastric distension being the most common cause of hiccups in patients with cancer, initial treatment should be aimed at relieving the distension and increasing gastric emptying. The insertion of a nasogastric tube may provide quick relief while drug therapy is being provided. Many drugs have been used to treat hiccups (Table 18.2). The literature is based largely on case reports and no definitive clinical evidence is available
to define the standard treatment. The drugs most commonly used are chlorpromazine (25–50 mg through i.v., orally, or rectally three to four times a day) (4), haloperidol (1–5 mg orally three times daily or subcutaneously every 12 hours) (5), nifedipine (10 mg p.o. three times daily) (6), metoclopramide (10 mg p.o. or i.v. every 6 hours) (7), and baclofen (10–20 mg p.o. three times a day) (8). Chlorpromazine is less attractive in patients with cancer due to side effects of hypotension and sedation. Moreover, Baclofen should be given with caution to the elderly due to frequent side effects of sedation, insomnia, dizziness, weakness, ataxia, and confusion (8). Haloperidol may be a better choice for those taking opioids. If hiccups persist, amitriptyline (10 mg three times a day) (9), carbamazepine (200 mg three times a day) (10), diphenylhydantoin (200 mg i.v. and then 100 mg p.o. four times a day) (77), or valproic acid (15 mg/kg/day in divided doses) (11) can be administered. Gabapentin (300 mg p.o. three times daily) has shown efficacy in treating hiccups among patients with cancer. The mechanism of action is probably related to the increase of endogenous γ-aminobutyric acid (GABA) release which plays a role in the modulation of the excitability of the diaphragm and the other inspiratory muscles (12, 13).

Efficacy has been claimed for a variety of drugs that have a peripheral action such as atropine, edrophonium, procainamide, and quinidine. Methylphenidate (10 mg p.o. daily) is reported to be effective in the treatment of hiccups (14).

Various invasive methods have been tried. Gastric aspiration may be useful if overdistension of the stomach is the cause of hiccups. The insertion of a nasogastric tube may also serve a purpose by stimulating the pharynx or causing gagging. High-pressure oxygen inhalation has been tried. Percutaneous stimulation of the phrenic nerve has also been reported. A surgical approach consists of an attack on the phrenic nerve (by a crush technique), usually first attempted on the left. Regardless of treatment, in most cases, hiccups stop because of, or in spite of, therapeutic measures (15, 16).

It is important to remember that hiccups in cancer may be extremely distressing and affect the quality of life by interfering with food intake, causing insomnia, or exacerbating pain and other symptoms. For this reason, it may be advisable to pursue diagnosis and treatment more aggressively than in the general population (17).

Dyspepsia consists of episodic or persistent symptoms that include abdominal pain or discomfort, postprandial fullness, abdominal bloating, belching, early satiety, anorexia, nausea, vomiting, heartburn, and regurgitation. There is considerable overlap between this constellation of symptoms and those of gastroesophageal reflux disease (GERD), biliary tract disease, irritable bowel syndrome, and chronic pancreatitis. This condition is reported in approximately 25% of the population each year, but most do not seek medical care (18, 19).

Results of upper GI endoscopy in 3667 general medical patients with dyspepsia were as follows: normal (34%), gastroesophageal reflux (24%), inflammation (20%), ulcer (20%), and cancer (2%) (18). Dyspepsia is divided into two categories: organic dyspepsia and functional dyspepsia. Patients in the first group have anatomical abnormalities (e.g., peptic ulcer disease, GERD, gastric, or esophageal cancer). Patients in the second category have symptoms for which no focal lesion can be found (Table 18.3). Recent studies have shown potential associations between specific pathophysiologic disturbances and functional dyspeptic symptoms. Delayed gastric emptying reported in approximately 30% of patients with functional dyspepsia is associated with postprandial fullness, nausea, and vomiting. Impaired gastric accommodation present in 40% of patients with functional dyspepsia is found to be associated with early satiety. Hypersensitivity to gastric distension is observed in 37% of patients with functional dyspepsia and is associated with postprandial pain, belching, and weight loss. Psychosocial factors have also been identified as pathophysiologic mechanisms (20, 21).

Dysmotility-like dyspepsia, or gastroparesis, is commonly seen in patients with cancer due to autonomic nervous system dysfunction, use of anticholinergic drugs, or opioids. It is associated with symptoms of bloating, abdominal distension, flatulence, and prominent nausea. Patients with this condition tend to have premature satiety with resultant epigastric heaviness or fullness even after the consumption of small meals (22). The diagnosis of paraneoplastic dyspepsia requires a high index of clinical suspicion. A panel of serologic tests for paraneoplastic autoantibodies, scintigraphic gastric emptying, and esophageal manometry are useful as first-line screening tests. Nuclear scintigraphy is considered the gold standard for diagnosing and quantifying delayed gastric emptying. Seropositivity for type 1 antineuronal nuclear antibody, Purkinje cell cytoplasmic antibody, or N-type calcium channel-binding antibodies has been detected in patients with paraneoplastic gastroparesis but its diagnostic value is under investigation (23).

Recent studies have linked gastroparesis to disruption of the interstitial cell of Cajal (ICC). These are fibroblast-like cells, which have been identified in the gut by electron microscopy and by immunohistochemistry for Kit protein. Generating electrical slow waves, the ICC are intercalated between the intramural neurons and the effector smooth muscular cells to form a gastroenteric pacemaker system. It has been recently found that loss of the ICC causes dysmotility-like symptoms in vivo. A loss of these cells has been detected in patients with paraneoplastic gastroparesis (24).

Other causes of cancer-induced dyspepsia include gastric cancer or lymphoma, gastritis secondary to radiotherapy chemotherapy, gastric compression secondary to intra-abdominal tumor, hepatomegaly, splenomegaly, ascites, or gastric outlet obstruction due to tumor. Medications that have been associated with dyspepsia include acarbose, alcohol, alendronate, codeine, iron, metformin, nonsteroidal anti-inflammatory drugs, erythromycin, potassium, corticosteroids, and theophylline. Dosage reduction or discontinuation of the offending agent may relieve dyspepsia.

The management of organic dyspepsia should be directed at the cause. Treatment may be based on previous history (e.g., obstructing lesion responding to primary tumor treatment) or recent endoscopy findings. In functional dyspepsia, treatment should be based on symptoms (Table 18.3). Nutrition support in gastroparesis begins with encouraging smaller volume, low-fat, low-fiber meals and, if necessary, liquid caloric supplements. Metoclopramide is now the prokinetic drug of choice (25). Controlled-release metoclopramide (20–80 mg q12h) is effective in ameliorating symptoms of the cancer-induced dyspepsia such as nausea, vomiting, loss of appetite, and bloating (26).

Moreover, subcutaneous administration of metoclopramide is an important method, allowing for continued guaranteed
absorption. Low-dosage erythromycin also has a prokinetic role, either alone or in combination with metoclopramide. Domperidone, a centrally acting antiemetic and prokinetic, is not available in US markets. Antiemetics should be used for nausea, which is a very severe debilitating symptom. There should be a low threshold for placing a jejunal feeding tube either by laparoscopy or mini-laparotomy. Parenteral nutrition should be used only briefly during hospitalization and not encouraged or sustained in an outpatient. Most excitingly, the era of gastric electrical stimulation has arrived for patients not responding to standard medical therapy. The dramatic decrease in nausea and vomiting, as well as a sustained evidence of improved quality of life, gastric emptying, nutritional status, and decreased hospitalizations by this device are documented by long-term follow-up of more than a year (27). Gastric pacemaker has been studied in patients with diabetes-induced gastroparesis but not in cancer. Further research is needed in patients with cancer-induced gastroparesis (28, 29).

Heartburn is the most common GI complaint in the western population; 33–44% of the population complain of heartburn at least monthly and 7–13% may have it daily (30). Heartburn is a retrosternal burning sensation that usually radiates proximally from the xiphoid process to the neck. It is caused by reflux of the gastric content into the esophagus. GERD occurs when the amount of gastric content that refluxes into the esophagus exceeds the normal limit, causing symptoms with or without esophagitis. Although there is no clear evidence that GERD is more common in those with cancer, certain conditions in this population may increase their risk, such as intra-abdominal lesions, which increase pressure on the stomach. In addition to the typical symptoms (heartburn, regurgitation, dysphagia), abnormal reflux can cause atypical symptoms such as coughing, chest pain, and wheezing and also damage to the lungs (pneumonia, asthma, idiopathic pulmonary fibrosis), vocal cords (laryngitis, cancer), ear (otitis media), and teeth (enamel decay). Approximately 50% of patients with reflux develop esophagitis, which is classified on the basis of severity.

The most important pathophysiologic factor in GERD is frequent transient relaxation of the lower esophageal sphincter (LES). Other factors include anatomic disruption of the LES as in hiatal hernia, transient increase in intra-abdominal pressure, abnormal esophageal peristalsis with impaired clearance of acid, and gastroparesis.

A number of foods, drugs, and neurohumoral factors reduce basal LES pressure, making patients prone to gastroesophageal reflux and heartburn (Table 18.4). Avoiding these foods and medications often constitutes the initial treatment of GERD. Some common agents that increase LES pressure include a protein meal, bethanechol, metoclopramide, and α-adrenergic agonists.

Heartburn is most frequently noted within 1 hour of eating, particularly after the largest meal of the day. Wine drinkers may have heartburn after hearty consumption of red wine but not after white wine. Lying down, especially after a late meal, causes heartburn within 1–2 hours; in contrast to peptic ulcer disease, heartburn does not awaken the person in the early morning. Heartburn may be accompanied by regurgitation, a bitter acidic fluid in the mouth that is common at night or when the patient bends over. The regurgitated material comes from the stomach and is yellow or green, suggesting the presence of bile. It is important to distinguish regurgitation from vomiting. The absence of nausea, retching, and abdominal contractions suggests regurgitation rather than vomiting. Furthermore, the regurgitation of bland material is atypical for acid reflux disease and suggests the presence of an esophageal motility disorder (i.e., achalasia) or delayed gastric emptying.

Many disorders cause epigastric or substernal pain similar to heartburn, making it important to determine the cause in each patient. Causes include collagen-vascular disorders, scleroderma, mixed connective tissue disorders, raised intra-abdominal pressure, gastroparesis, nasogastric tube, prolonged recumbent position, persistent vomiting, pregnancy, hypothyroidism, Zollinger-Ellison syndrome, medications, and some surgical procedures (e.g., myotomy, esophagogastrectomy).

Treatment is a stepwise approach. The goal is to control symptoms, to heal esophagitis, and to prevent recurrent esophagitis or complications. The treatment is based on lifestyle modification and control of gastric acid secretion. Lifestyle modification includes losing weight, avoiding precipitating factors such as chocolate, spicy food, alcohol, citrus juice, and tomato-based products. Ask the patient to eat several small meals during the day and avoid large ones, and elevate the head of the bed. Antacids are effective in mild symptoms if given after each meal and at bedtime. More aggressive therapy includes H₂ receptor blockers, sucralfate, or omeprazole. Metoclopramide works very well in GERD among patients with cancer who commonly have gastroparesis. It increases the LES
pressure and enhances gastric emptying. Long-term therapy is usually necessary. Approximately 80% of patients have a recurrent but nonprogressive GERD that is controlled with medications. In 20% of patients the disease is progressive and severe complications may occur, such as strictures or Barrett’s esophagus. Laparoscopic fundoplication or other palliative procedures should be considered and discussed with patients having cancer. Over the past decade, a new noninvasive endoscopic technique, called Enteryx, has been developed to treat GERD (31). This procedure involves the injection of a compound called ethylene polyvinyl alcohol into the LES, just within the stomach. The injection is done with guidance from real-time x-ray. The compound is in liquid form outside the body, but when it comes into contact with the tissues inside the body, it turns into an expanding, spongy material. The procedure may cause a sore throat or chest pain. Although this treatment resulted in highly significant improvement at 6 and 12 months, longer follow-up is needed to better assess the duration of efficacy of these positive effects.