Double-Blind, Randomized, Placebo-Controlled Trial of Metoclopramide for Hypersalivation Associated With Clozapine

Abstract

Hypersalivation is a frequent, disturbing, and uncomfortable adverse effect of clozapine therapy that frequently leads to noncompliance. The aim of this study was to examine the efficacy of metoclopramide (dopamine D2 antagonist, antiemetic medication) as an option for management of hypersalivation associated with clozapine (HAC). A 3-week, double-blind, placebo-controlled trial was conducted in university-based research clinics from January 2012 to May 2014, on 58 inpatients treated with clozapine who were experiencing hypersalivation. The subjects were randomly divided into placebo and metoclopramide groups. The starting dose was 10 mg/d. Participants who did not respond were up-titrated 10 mg/d weekly to a total of 30 mg/d during the third week. The number of placebo capsules was increased accordingly up to 3 capsules per day. Primary outcome was the change from baseline to the end of study in the severity of hypersalivation as measured with the Nocturnal Hypersalivation Rating Scale and the Drooling Severity Scale. Secondary outcomes included Clinical Global Impression of Improvement scale and adverse effect scales. Significant improvement on the Nocturnal Hypersalivation Rating Scale was demonstrated in the metoclopramide group from the end of the second week (P < 0.004), and on the Drooling Severity Scale (P < 0.02) in the third week. Clinical Global Impression-Improvement scale scores revealed major improvement. Twenty subjects (66.7%) treated with metoclopramide reported significant decline or total disappearance of HAC in comparison to 8 patients (28.6%) who received placebo (P = 0.031). No adverse effects to metoclopramide were reported. Metoclopramide was found to be safe and effective for the treatment of HAC.

A retrospective case notes review of the effectiveness and tolerability of metoclopramide in the treatment of clozapine-induced hypersalivation (CIH)

“…The mechanism of metoclopramide in reducing hypersalivation is not clearly defined. Substituted benzamide derivatives do not have adrenergic antagonistic, anticholinergic, or adrenomimetic properties [ 4 ]. Previous trials with this group of drugs with high selective binding to the dopamine D 2 /D 3 receptors have shown efficacy in treating CIH [ 20 ].…”

“…In addition, metoclopramide stimulates gastric motility and exerts its prokinetic effect by antagonising dopamine mediated relaxation effect on gastrointestinal smooth muscle [ 3 ]. Besides the anti-emetic and prokinetic effects of metoclopramide, it is believed that the peripheral activity of the drug can reduce secretion of saliva, and hence it has been considered as a treatment option for clozapine-induced hypersalivation (CIH) also known as sialorrhea [ 4 ].…”

“…A 3-week, double-blind, placebo-controlled trial found that metoclopramide administered at 10 – 30 mg/day, was a safe and effective agent in the treatment of CIH, demonstrating significant improvement on the Nocturnal Hypersalivation Rating Scale, the Drooling Severity Scale, and the Clinical Global Impression-Improvement scale [ 4 ]. While no adverse effects were reported in the study, some of the common side effects that may occur with metoclopramide treatment include diarrhoea, asthenia, drowsiness, hypotension, movement disorders, and parkinsonism [ 11 ].…”

Thrombocytopenia associated with clonidine in a case of clozapine-induced sialorrhea

“…Botulinum toxin, metoclopramide, and tricyclic antidepressants are additional agents that have varying degrees of evidence for the management of clozapine-induced sialorrhea. [10][11][12] a 2A Adrenergic receptor agonists, such as clonidine, have also been reported in case reports 2,13,14 to be effective at managing clozapine-induced sialorrhea. Clonidine is generally well tolerated, but it is imperative that clinicians monitor a patient's blood pressure if clonidine is used concomitantly with clozapine.…”

Tropicamide ophthalmic solution reduces clozapine-induced sialorrhea: a case report

“…The treatment options suggested in CIS are glycopyrrolate, biperiden [5], amisulpride augmentation [6], scopolamine (hyoscine) butylbromide [7], and low-dose amitriptyline [8]. In a recent study, metoclopramide was found effective and safe in CIS [9]. All systemic agents that are used for sialorrhea may increase clozapine's side effects such as blood pressure changes, constipation, and arrhythmias or may have a negative impact on cognition [5].…”