Antiemetic therapy for gastroparesis

Phenothiazines

Phenothiazines are the most commonly prescribed antiemetics ( Table 25.1 ). They exert an antiemetic effect by blocking dopamine-2 and 5-HT receptors in the chemoreceptor trigger zone, as well as having weak histamine-1 and muscranic-1 receptor blocking activity. The most commonly used phenothiazines as antiemetics are promethazine and prochlorperazine. Chlorpromazine and perphenazine are first generation antipsychotic medications for bipolar disorder and schizophrenia, and they are used much less as antiemetic agents. Promethazine is commonly dosed at 12.5–25 mg oral tablet every four to six hours as needed for nausea and emesis. Promethazine is inexpensive and widely available. It can be given as a suppository, intramuscular injection, and intravenous infusion. These alternatives to the oral preparation are useful in patients during periods of emesis. Prochlorperazine is usually dosed at 5–10 mg every six to eight hours as needed. Prochlorperazine can be given as oral tablets, intramuscular injection, and intravenous infusion ( Table 25.1 ).

Phenothiazines are effective therapies for acute nausea and vomiting associated with elective surgery, vertigo, motion sickness, and migraine based on randomized controlled trials . However, there are no efficacy data on the use of phenothiazines in chronic nausea and vomiting associated with gastroparesis. Short term, intermittent use of phenothiazines is a reasonable approach. Frequent daily use or high doses of phenothiazines, especially with intravenous dosing, should be avoided. Promethazine has been recognized for its potential for abuse and intentional misuse . It can increase the “high” sensation one gets from opiates .

Phenothiazines penetrate the CNS and frequently cause drowsiness, sedation, and confusion. Patients should be warned against driving, operating machinery, and strenuous activity. Concurrent intake of alcohol and other sedatives should be avoided. Lower doses of promethazine should be used whenever possible, especially in the elderly. Furthermore, both promethazine and prochlorperazine may cause extrapyramidal side effects, such as tardive dyskinesia and dystonia, due to their dopamine antagonism in the basal ganglia . Phenothiazines should be used with caution in patients with dementia, due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and cognitive decompensation.

Venous scarring with promethazine is a well-known adverse event. FDA issued a patient safety bulletin in 2006 for the potential of severe tissue injury due to extravasation of intravenous promethazine. Promethazine should be infused only through a large-bore vein, and the patency of the access site should be checked before administering. The patient should be instructed to report burning or pain during and after the injection. An intravenous port or peripherally inserted central catheter line should be considered if promethazine is ordered for home health use in patients with recurring nausea and vomiting. Subcutaneous injection of promethazine is contraindicated.

Histamine-1 (H1) receptor antagonist

Antihistamines inhibit the action of histamine at the H1 receptor, blocking the stimulation of the emesis pathway that originates from the histamine rich vestibular system. The currently available H1 receptor antagonists for nausea and emesis are listed in Table 25.1 . Dimenhydrinate and meclizine are pure H1 receptor antagonists, while diphenhydramine and hydroxyzine have mixed actions on other receptor subtypes. Diphenhydramine, dimenhydrinate, and meclizine are available over-the-counter. H1 receptor antagonists have been shown to be efficacious in the treatment of acute nausea and vomiting associated with motion sickness and in the postoperative period . There are no data regarding efficacy of H1 receptor antagonist for chronic nausea and emesis associated with gastroparesis. These agents are generally less helpful than other emetics in gastroparesis, since the vestibular system does not play a prominent role in the pathophysiology of emesis associated with gastroparesis. However, the sedative and antiemetic properties of intravenous histamine receptor antagonists may be helpful in the hospitalized patients. Potential side effects of H1 receptor antagonists are usually minor, but include sedation, dizziness, fatigue, and tremor.

Dopamine-2 (D2) receptor antagonist

Two D2 receptor antagonists commonly used in the treatment of gastroparesis are metoclopramide and domperidone, though only metoclopramide is approved in the United States. Dopamine-2 receptor antagonists work on both central (antiemetic effect) and peripheral (prokinetic effect) dopamine receptors. They promote their peripheral prokinetic effects through the blockade of enteric D2 receptors, thereby facilitating the release of acetylcholine known to increase gastric motility by directly mediating smooth muscle contraction . In this chapter, we will focus on the anti-emetic effects of D2 receptor antagonist, as the prokinetic effects will be addressed in a separate chapter of this book.

Metoclopramide has been available in the US since 1974 and is indicated for the treatment of diabetic gastroparesis and symptomatic gastroesophageal reflux disease. It is the only drug approved by the FDA for the management of symptoms related to diabetic gastroparesis. It has a short half-life (60–90 minutes), has a rapid onset of action within minutes when given intravenously or intramuscularly, and it is well-absorbed. It can be administered orally in either tablet or solution form with 5–10 mg BID to QID 30 minutes prior to meals and at bedtime. It is recommend to titrate to the lowest effective dose with a maximum not to exceed 40 mg/day in 4 divided doses . Intramuscular (IM), intravenous (IV), intranasal, and rectal formulations are available ( Table 25.1 ). For IV administration, a maximum of 30 mg/day in 3 divided doses is recommended. An intraperitoneal formulation has been utilized for patients on peritoneal dialysis . For patients with refractory nausea and vomiting limiting any absorption by oral administration, subcutaneous (sc) injections of metoclopramide 10 mg (2 mL) administered every 6 hours for 3 days resulted in subjective and objective improvement in both GI symptoms and gastric stasis in patients with gastroparesis . Additionally, administering metoclopramide sq provided peak levels at 30 minutes with serum concentration levels comparable to that of IV administration. Subcutaneous metoclopramide use is recommended for patients who have demonstrated no side effects in the past but whose nausea and vomiting is not being adequately controlled. Subcutaneous metoclopramide at 5–10 mg doses (1–2 cc’s) BID or TID can supplement oral metoclopramide and guarantee absorption to gain symptom control thus avoiding emergency room visits and their accompanying economic burden. Side effect potential does need to be monitored.

Metoclopramide readily crosses the blood-brain barrier and has inhibitory effects on 5-HT3 and D2 receptors on the medullary chemoreceptor trigger zone in the brain which explains its antiemetic activity . Blocking D2 receptors in the striatopallidal and nigrostriatal pathways may lead to extrapyramidal movements similar to those seen in patients with Parkinson’s disease known as tardive dyskinesias. Tardive dyskinesia, a potentially irreversible clinical manifestation, is characterized by involuntary movements of the face, tongue, lips, extremities, and choreoathetoid movements of the body . Consequently, prolonged use of metoclopramide is limited by its CNS side effects. Because of this, the FDA issued a black box warning in 2009 and limited its use to no more than 12 weeks . Metoclopramide should be avoided in patients with Parkinson’s as it may exacerbate Parkinsonian symptoms, and it is contraindicated in patients with seizures since metoclopramide lowers the seizure threshold. It is estimated that the risk of developing tardive dyskinesia is rare and can develop in <1% of patients with onset usually seen within 24–48 hours after starting metoclopramide (mostly parenterally) . The risk is greater in the elderly, females, and patients with renal impairment. Interestingly, genetic factors may play a role in the development of this side effect, and should be avoided if there is a family history of metoclopramide-induced movement disorder . If an acute dystonic reaction develops, administration of anticholinergics (i.e. diphenhydramine 25–50 mg IV or IM) in combination with benzodiazepines (i.e. diazepam 2–10 mg IV or IM) may provide immediate relief . Other side effects reported in up to 35% of patients, include fatigue, drowsiness, irritability, and depression . Galactorrhea, irregular menses, and breast tenderness can also develop related to prolactin release. In diabetic gastroparesis, it is recommended limiting the use of metoclopramide to severe refractory cases since there are now safer alternatives for control of nausea and emesis such as 5-HT3 or NK1 receptor antagonists . Additionally, clinicians should always discuss with their patients all expected side effects expected with metoclopramide along with documentation of this discussion in the medical record.

Domperidone is another D2 receptor antagonist with both central and peripheral effects. However, domperidone does not have the significant CNS side effects seen with metoclopramide because it does not readily crosses the blood-brain barrier – nor does it have cholinergic effects, a side effect seen in other prokinetic agents . Another difference is that domperidone is not a 5-HT4 agonist. Although extensively utilized throughout the world for treatment of gastroparesis since it was first developed in 1978, domperidone is not approved in the U.S. due to rare reports of cardiotoxicity from QTc prolongation after IV administration of high doses . To put this into perspective, because of the low oral bioavailability of domperidone (13–17%) , oral doses over 1000 mg/day would correlate with the IV doses administered to patients when cardiotoxicity was reported . Currently, domperidone is no longer available in IV form. When the FDA evaluated domperidone in 1989, they determined that there were not enough patients enrolled in controlled clinical trials to make a statistically significant evaluation, and therefore the agency withheld approval of this drug without attempt to pursue further trials . Physicians may prescribe domperidone only if they apply for an FDA-approved Investigational New Drug (IND) protocol, a compassionate clearance program for patients with refractory GI symptoms of gastroparesis or other functional GI disorders who have failed standard treatment .

Domperidone is rapidly absorbed with peak plasma concentrations occurring at approximately 10 for oral formulations . The pharmacokinetics are linear over a dose range of 10–40 mg . Its half-life is 7–9 hours in healthy subjects . Domperidone has low bioavailability by oral route (13–17%) and high by IM route (90%) likely due to first-pass effect in the liver and gut wall metabolism . It has a short half-life (60–90 minutes). The pharmacodynamics that explain its effective prokinetic effects includes its ability to enhance antroduodenal contractions, improve esophageal motor function, accelerate gastric emptying, and improve peristalsis across the pylorus . Dosing normally begins at 10 mg before meals and at bedtime and can be titrated up to 80–120 mg/day until symptom control is achieved. The most common side effects are due to hyperprolactinemia (i.e. galactorrhea, irregular menses, breast tenderness).

The clinical efficacy of domperidone has been well documented in the literature. American Gastroenterology Association recognizes domperidone as an important treatment option for gastroparesis . Long term treatment with domperidone 20 mg QID for an average of 23 months has resulted in significant reduction in GI symptoms and hospitalizations, accelerated gastric emptying to normal, and enhanced quality of life . In a multicenter, two-phase withdrawal study involving over 200 insulin-dependent diabetic patients showed that domperidone 20 mg QID provided significant improvement in upper GI symptoms and quality of life with a good tolerability profile . Other studies have shown clinical effectiveness of domperidone in patients with gastroparesis . In a recent study by McCallum et al. to assess the cardiac safety and clinical efficacy of high dose domperidone in 21 patients with refractory gastroparesis followed over a median of 12 months, treatment response was positive with 80% reporting >50% improvement in symptoms . Average dose was 65 mg daily and 33% of patient received doses ≥80 mg/day titrated up to 120 mg/day. At 120 mg/day, three patients had a prolonged QTc interval on EKG without adverse cardiac effects. Two of these patients did not meet criteria for treatment response and therefore domperidone was discontinued, while the other patient continued at 80 mg/day without recurrence of QTc prolongation for 20 more months. High-dose domperidone was deemed a safe and effective treatment in patients with refractory gastroparesis. These data are consistent with a recent comprehensive literature review on domperidone which concluded that overall studies do not substantiate cardiac adverse events in patients receiving oral domperidone, even at higher doses .

Clinical trials are currently in process for future dopamine antagonists without cardiac toxicity. TAK-906 is a promising D2/D3 antagonist compound currently in phase 2 trials, and its efficacy and safety are being tested on patients with symptomatic idiopathic or diabetic gastroparesis . TAK-906 does not have any evidence of cardiac toxicity based on animal and phase IA studies in normal subjects providing an advantage over domperidone. A multi-center, double-blind, placebo-controlled trial is to be conducted worldwide with plans to enroll approximately 280 patients who will be followed for approximately 17 weeks with completion date of study estimated to be in late 2020.

CIN-102 is another domperidone-like agent currently undergoing randomized, double-blind clinical trials to evaluate its safety, tolerability, and effect on gastric emptying in adults with diabetic gastroparesis . CIN-102 is a deuterated form of domperidone in which 4 hydrogen atoms on the aromatic ring have been substituted with deuterium atoms. This change in molecular structure lowers its peak plasma concentration and allows for similar antiemetic effects to those of domperidone but without QTc prolonging consequences. A phase 2 trial plans to enroll 60 participants who will be given three different oral doses of CIN-102 twice daily for 14 days versus placebo in three separate cohorts with estimated study completion date later in 2020.

NG 101 is another potent, selective, peripherally-restrictive dopamine D2/D3 receptor antagonist under development for the treatment of gastroparesis. For decades, this agent has been safely used in Europe for the treatment of acute nausea. Clinical trials to date shows that NG 101 has potent antiemetic properties and also increases gastric motility but does not cross the blood-brain barrier nor alter cardiac rhythms . These domperidone-like agents currently under investigation are exciting novel therapies that show potential promise and will hopefully positively benefit the lives of many patients with intractable gastroparesis in the near future.

In summary, domperidone is considered a safe, effective, and well-tolerated antiemetic and prokinetic agent in the management of patients with gastroparesis who have exhausted other therapeutic options. Although domperidone has the potential to prolong QTc with increased risk of arrhythmias, so too do other approved therapies for gastroparesis such as ondansetron, promethazine, and azithromycin as well as many other medications used in non-GI areas. One recommendation is to obtain a baseline electrocardiogram and serum potassium prior to starting domperidone, as well as at 3-month intervals during treatment, with a QTc of >450 ms in males and >470 ms in females and/or significant sustained hypokalemia serving as contraindications to either starting this drug or continuing therapy .

Muscarinic receptor antagonist

Similar to H1 receptor antagonist, muscarinic receptor antagonist blocks the stimulation of the emesis pathway that originates from the vestibular system. Scopolamine is a nonselective muscarinic antagonist, producing both peripheral and central effects. Oral and intravenous administration of scopolamine is limited by very short half-life and does-dependent adverse side effects . Transdermal scopolamine is the only formulation available in the US. When transdermal scopolamine patch is applied to the postauricular skin, an initial priming dose saturates the skin and plasma level can be detected within 4 hours, and subsequent scopolamine is delivered at an approximately constant rate over 3 days .

Efficacy of scopolamine has been demonstrated in meta-analysis of randomized controlled trials for the prevention of motion sickness and postoperative nausea and vomiting . There are no prospective study utilizing scopolamine for nausea and emesis associated with gastroparesis. It’s reasonable to try a short course of transdermal scopolamine patch in selected patients with daily emesis who are unable to tolerate an oral antiemetic. However, adverse side effects of scopolamine are common, related to its central and peripheral anticholinergic effects, such as drowsiness, blurred vision, dry mouth, dizziness, bradycardia and urinary retention. Additionally, scopolamine as an anticholinergic agent, may have a very small effect – if any at all – in delaying gastric emptying .