ABHR gel for refractory nausea and vomiting

The pathophysiology of nausea and vomiting, whether induced by chemotherapy or other causes, is complex. It involves multiple organ systems, including primarily the central nervous system, the gastrointestinal tract and the peripheral nervous system. Multiple neurotransmitters and receptors are involved, including serotonin, neurokinin, dopamine, histamine and muscaric receptors, as well as others. For this reason, one single antiemetic agent is rarely completely effective.

Multiple classes of antiemetic are used in the primary prevention and treatment of nausea and vomiting. The primary ones are 5HT3 antagonists, neurokinin-1 antagonists and dexamethasone. With a combination of these agents, acute and delayed chemotherapy-induced nausea and vomiting is controlled in most patients. Unfortunately, some patients have significant breakthrough nausea and vomiting. In addition, patients with advanced disease not receiving chemotherapy can have refractory nausea and vomiting.

Breakthrough symptoms are usually treated with one or more antiemetics with different mechanisms of action. Commonly chosen agents include prochlorperazine, promethazine, lorazepam, haloperidol, droperidol, metoclopramide and cannabinoids. A newer agent, olanzapine, is showing promise in treating breakthrough symptoms. It inhibits certain serotonin and dopamine receptors.

Some patients have such refractory symptoms that they require multiple antiemetics to control their symptoms. Combinations of antiemetics with different mechanisms of action can have added efficacy. Hospice patients, as well as those who have refractory symptoms, may require alternate routes of administration as well, such as rectally or topically.

Topical method

ABHR in pluronic lecithin organogel (PLO) gel is a formulation of multiple antiemetics compounded into a topical gel. It is not commercially available and must be prepared by a compounding pharmacy. There are multiple combinations and strengths available, so it can be tailored to the patient’s needs. One common formulation is shown in the table. The usual dose would be 1 g (1 mL) applied to the skin of the inner wrists every four to six hours.

The “A” represents lorazepam. The antiemetic mechanism of action of benzodiazepines is not clear, but it inhibits the limbic system and reduces cortical central nervous system input into the vomiting center of the central nervous system. In addition, its action to reduce anxiety is important.

The “B” is diphenhydramine. It works as an antihistamine and anticholinergic agent, and reduces the activity of the vestibular system. In addition, it can reduce extrapyramidal adverse effects from dopamine antagonists.

Lisa K. Lohr

The “H” stands for haloperidol, a potent dopamine antagonist.

The “R” is for metoclopramide. This agent works both as a dopamine antagonist and to improve slowed gastrointestinal transit time. The adverse effects expected from this combination are primarily drowsiness, lethargy, confusion and muscle twitches. However, this combination is actually well tolerated by most patients.

PLO gel is a two-part compounding gel that allows incorporation of hydrophilic and lipophilic components. It is preferable to use the pharmaceutical grade powder formulation of medications, instead of ground-up tablets. The hydrophilic medications would be added to the aqueous pluronic phase, and the lipophilic medications would be added to the organic phospholipid phase. When the two phases are combined, the mixture automatically gels up. This PLO gel enhances the permeability of the skin and improves drug transport and absorption. However, it is unclear exactly what proportion of the dose is absorbed.

Supporting data

Two authors have published results from non-comparative descriptions of case series. One author (Weschules, 2005) described a series of more than 6,000 prescriptions of ABHR gel given to hospice patients. In addition, this study looked at patients also receiving the ABHR compound through different dosage forms, including rectal suppositories, and oral capsules and suspension. ABHR was well tolerated, with few patients (0.5%) discontinuing this agent due to adverse effects. Adverse effects were more common in the elderly. Those adverse effects related to treatment discontinuation included sedation/somnolence, agitation and confusion.

Another group of researchers (Bleicher, 2008) reported the results from two pilot trials studying ABH (no “R”) gel for rescue treatment of chemotherapy-induced nausea and vomiting. Thirty-three patients were given the topical gel in a dose of lorazepam 2 mg/diphenhydramine 25 mg/haloperidol 2 mg. In the first pilot of 23 patients, 74% reported decreased nausea and vomiting, most within 30 minutes of application. In the second pilot of 10 patients, all patients reported that the topical gel was effective, with mean symptoms score dropping substantially. Adverse effects were experienced by a few patients.

Other combinations of antiemetics use dexamethasone with other agents. “BDR” would be diphenhydramine 25 mg/dexamethasone 4 mg to 10 mg/metoclopramide 10 mg. In using this formulation, it is important to remember how much dexamethasone the patient is receiving in total, in regards to possible corticosteroid-related adverse effects.

None of these combinations of antiemetics are commercially available, but they can be compounded not only into topical gels but into rectal suppositories by a compounding pharmacy. In addition, suppositories can be extemporaneously prepared by putting oral tablets/capsules into larger, empty gelatin capsules. They can then be lubricated and administered rectally. Many patients do not like rectal medications and would prefer topical administration if the oral route is not suitable.

In summary, combinations of three or more antiemetics with different mechanisms of action can be prepared for rectal or topical administration when the oral route of administration is not available due to vomiting or bowel obstruction. These products are effective in most, but not all patients. They are well tolerated in most patients, and the adverse effects are similar to the same agents given orally or intravenously.

Lisa K. Lohr, PharmD, BCPS, BCOP, is a Clinical Pharmacist in Oncology and Bone Marrow Transplantation in the Department of Pharmacy Services at the University of Minnesota Medical Center and is a HemOnc Today Editorial Board member.

For more information:

• Bleicher J. J Support Oncol. 2008:6:27-32.
• Moon RB. Int J Pharm Compound. 2006;10:95-98.
• Weschules DJ. J Pall Med. 2005;8:1135-1143.