Palonosetron and hydroxyzine pre-treatment reduces the objective signs of experimentally-induced acute opioid withdrawal in humans: a double-blinded, randomized, placebo-controlled crossover study

Abstract

Background Treatments for reducing opioid withdrawal are limited and prone to problematic side effects. Laboratory studies, clinical observations, and limited human trial data suggest 5-HT3-receptor antagonists and antihistamines may be effective. Objectives This double-blind, crossover, placebo-controlled study employing an acute physical dependence model evaluated whether (i) treatment with a 5-HT3-receptor antagonist (palonosetron) would reduce opioid withdrawal symptoms, and (ii) co-administration of an antihistamine (hydroxyzine) would enhance any treatment effect. Methods At timepoint T=0, healthy (non-opioid dependent, non-substance abuser) male volunteers (N=10) were pre-treated with either a) placebo, b) palonosetron IV (0.75 mg), or c) palonosetron IV (0.75 mg) and hydroxyzine PO (100 mg) in a crossover study design. This was followed at T=30 by intravenous morphine (10mg/70kg). At T=165, 10mg/70kg naloxone IV was given to precipitate opioid withdrawal. The objective opioid withdrawal score (OOWS) and subjective opioid withdrawal score (SOWS) were determined 5 and 15 minutes after naloxone administration (T=170, 180, respectively). Baseline measurements were recorded at T=-30 and T=-15. Results Comparison of average baseline OOWS scores with OOWS scores obtained fifteen minutes after naloxone was significant (p=0.0001). Scores from fifteen minutes post-naloxone infusion showed significant differences in OOWS scores between treatment groups: placebo, 3.7 ± 2.4; palonosetron, 1.5± 0.97; and palonosetron with hydroxyzine, 0.2 ± .1333. Conclusions Pretreatment with palonosetron significantly reduced many signs of experimental-induced opioid withdrawal. Co-administration with hydroxyzine further reduced opioid withdrawal severity. These results suggest that 5-HT3 receptor antagonists, alone or in combination with an antihistamine, may be useful in the treatment of opioid withdrawal.

A Flawed Design Produces Flawed Results

“…The COU/CBP results are in stark contrast to two prior studies (Chu et al, 2009; Erlendson et al, 2017), which demonstrated that treatment of healthy volunteers with either of two structurally distinct 5-HT3 antagonists substantially reduced (and often eliminated) NPOW symptoms. In these studies, the 5-HT3 antagonists were administered 2.5 hours before naloxone; but naloxone was administered only 0.5 hour after ondansetron in the COU/CBP study.…”

Optimizing a therapy for opiate use disorders: Characterizing ondansetron pharmacokinetics in blood and brain

“…not altered by ondansetron treatment. Although ondansetron administration caused a 20% reduction in NOWS symptom severity, its efficacy in the setting of a chronic OUD was far less than was observed in our prior mouse and human studies 10,11 where administration of 5HT 3A R receptor antagonists significantly inhibited or completely ablated all experimentally induced opioid withdrawal responses exhibited by the subjects.…”

Opioid misuse in gastroenterology and non-opioid management of abdominal pain

“…Preoperative gabapentin administration has been shown to significantly ( P < 0.001) reduce postoperative opioid consumption in a meta-analysis of 1,793 patients who underwent abdominal, genitourinary, orthopaedic or thoracic surgery 110 . In a study of experimentally induced opioid withdrawal, co-administration of palonosetron (a 5-hydroxytryptamine receptor 3 (5-HT 3 ) antagonist) with hydroxyzine reduced the severity of withdrawal 111 . In addition, a Cochrane review published in 2017 identified buprenorphine as more effective than alternatives (for example, clonidine or lofexidine) in terms of severity of withdrawal, duration of treatment and likelihood of completing treatments 112 .…”