title: 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: 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.
  
  
  
  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.
  
  
  
  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 (10 mg/70kg). At T = 165, 10 mg/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.
  
  
  
  Comparison of average baseline OOWS scores with OOWS scores obtained 15 minutes after naloxone was significant (p = 0.0001). Scores from 15 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 ± 0.1333.
  
  
  
  Pretreatment with palonosetron significantly reduced many signs of experimentally-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.
authors.affiliation: a Department of Anesthesia , Stanford University School of Medicine , Stanford , CA , USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Erlendson
authors.affiliation: a Department of Anesthesia , Stanford University School of Medicine , Stanford , CA , USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: D'Arcy
authors.affiliation: a Department of Anesthesia , Stanford University School of Medicine , Stanford , CA , USA.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Encisco
authors.affiliation: a Department of Anesthesia , Stanford University School of Medicine , Stanford , CA , USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Yu
authors.affiliation: a Department of Anesthesia , Stanford University School of Medicine , Stanford , CA , USA.
authors.forename: Lorena
authors.initials: L
authors.lastname: Rincon-Cruz
authors.affiliation: a Department of Anesthesia , Stanford University School of Medicine , Stanford , CA , USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Peltz
authors.affiliation: a Department of Anesthesia , Stanford University School of Medicine , Stanford , CA , USA.
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
authors.affiliation: a Department of Anesthesia , Stanford University School of Medicine , Stanford , CA , USA.
authors.forename: Larry F
authors.initials: LF
authors.lastname: Chu
mesh_terms: D018592:Cross-Over Studies; D004311:Double-Blind Method; D004357:Drug Synergism; D064368:Healthy Volunteers; D006801:Humans; D006919:Hydroxyzine / Q000627:therapeutic use*; D007546:Isoquinolines / Q000627:therapeutic use*; D008297:Male; D009020:Morphine / Q000009:adverse effects / Q000037:antagonists & inhibitors; D009270:Naloxone / Q000494:pharmacology; D000077924:Palonosetron; D011812:Quinuclidines / Q000627:therapeutic use*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D007546:Isoquinolines; D011812:Quinuclidines; D006919:Hydroxyzine; D009270:Naloxone; D000077924:Palonosetron; D009020:Morphine
keywords: Palonosetron; antihistamine, 5HT3 antagonist; hydroxyzine; opioid withdrawal