Ondansetron Does Not Reduce Withdrawal in Patients With Physical Dependence on Chronic Opioid Therapy

Abstract

Objectives Individuals taking opioids for an extended period of time may become physically dependent, and will therefore experience opioid withdrawal should they stop taking the medication. Previous work in animal and human models has shown that the serotonin (5-HT3) receptor may be implicated in opioid withdrawal. In this study, we investigated if ondansetron, a 5-HT3-receptor antagonist, could reduce the symptoms of opioid withdrawal after chronic opioid exposure in humans. Methods In this double-blinded, randomized crossover study, thirty-three chronic back pain patients (N=33) were titrated onto sustained-release oral morphine for 30 days. Following titration, participants attended two study sessions, one week apart, in which opioid withdrawal was induced with intravenous naloxone, with or without 8mg intravenous ondansetron pretreatment. Opioid withdrawal symptoms were assessed by a blinded research assistant (objective opioid withdrawal score - OOWS) and by the research participant (subjective opioid withdrawal score - SOWS). Results Clinically significant signs of withdrawal were observed during both the ondansetron (ΔOOWS = 3.58 ± 2.22, p < .0001; ΔSOWS = 12.48 ± 11.18, p < .0001) and placebo sessions (ΔOOWS = 3.55 ± 2.39, p < .0001; ΔSOWS = 12.21 ± 10.72, p < .0001), but no significant differences were seen between the treatment sessions in either the OOWS or SOWS scores. Conclusion We hypothesized that ondansetron would reduce opioid withdrawal symptoms in human subjects, but found no difference in withdrawal severity between ondansetron and placebo sessions. These findings suggest that more investigation may be necessary to determine if 5-HT3-receptor antagonists are suitable treatment options for opioid withdrawal.

Non-Opioid Neurotransmitter Systems that Contribute to the Opioid Withdrawal Syndrome: A Review of Preclinical and Human Evidence

“…For instance, a recent study in a human OUD clinical population showed that response to a precipitated naloxone challenge was significantly associated with withdrawal response in a subsequent double-blind randomized and controlled pharmacotherapy examination (Dunn et al, 2018b). A human laboratory model was also used in some of the empirical human studies reviewed herein (Bisaga et al, 2001;Jain et al, 2011;Chu et al, 2017) and has been regularly used to screen medications for alcohol and tobacco use disorders (Perkins et al, 2008(Perkins et al, , 2013McKee, 2009;McKee et al, 2012). Together, this evidence suggests that a laboratory model could be a promising method for screening candidate opioid withdrawal medications prior to clinical trial investigations.…”

“…Two studies have reported on whether the 5-HT 3 antagonist ondansetron modifies opioid withdrawal severity in humans. The first was a case report that suggested ondansetron might reduce human opioid withdrawal syndrome severity (Wakim, 2012); however, the second was a placebo-controlled within-subject empirical evaluation that found no benefit of ondansetron relative to placebo following naloxone-precipitated withdrawal (Chu et al, 2017).…”

Tapping into 5-HT3 Receptors to Modify Metabolic and Immune Responses

“…5-HT 3 receptor antagonists are also useful in treating alcohol dependence [ 22 , 41 , 238 , 239 , 240 ] but show little clinical usefulness in treating dependencies on other drugs of abuse [ 18 , 241 ]. Since 5-HT 3 receptors are present in the reward center [ 242 ], this differential is unexpected.…”

A Flawed Design Produces Flawed Results

“…A recent study (Chu et al, 2017) in The Journal of Addiction Medicine indicated that ondansetron administration did not reduce naloxone-precipitated opiate withdrawal ( NPOW ) symptoms in chronic opiate users with chronic back pain ( COU/CBP ). However, a study design flaw is responsible for the lack of efficacy, which prevents drawing any conclusions from its results.…”

“…The anti-emetic effect of ondansetron has a rapid onset (<0.5 hour) because it is mediated at sites (5-HTR3 receptor + vagal afferent nerves in the gastrointestinal tract and brainstem) outside of the CNS (Tyers, 1992; Tyers and Freeman, 1992). This was cited (Chu et al, 2017) as a justification for administering naloxone 0.5 hour after ondansetron treatment. However, ondansetron’s effect on NPOW occurs within the CNS (Chu et al, 2009); a peripheral acting opioid antagonist (methynaltrexone) does not precipitate withdrawal (Portenoy et al, 2008; Thomas et al, 2008).…”