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 (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. Results: 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. Conclusions: 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.

KEYWORDS:

• Palonosetron
• hydroxyzine
• opioid withdrawal
• antihistamine, 5HT3 antagonist

Acknowledgements

We are thankful for the assistance of Dr. Ming Zheng (Stanford University) with the statistical analysis of these data.

Clinical trial registration

clinicaltrials.gov Identifier: NCT00661674

Funding

This study was supported by the Stanford University School of Medicine Department of Anesthesia. This work was supported by the Stanford Department of Anesthesiology, Pain and Perioperative Medicine. LC was also supported by grants from the National Institute for Drug Abuse (NIDA, K02 DA033348-01A1) and the National Institute of General Medical Sciences (NIGMS, K23 GM071400). GP was supported by a research award (1R01 HDO70795-01A1) from the NIH/National Institute for Childhood Development.

There are no sources of funding, direct or indirect, or connection of any researchers with the tobacco, alcohol, pharmaceutical or gaming industries or any body substantially funded by one of those organizations. There are no contractual constraints to disclose.

Additional information

Funding

This study was supported by the Stanford University School of Medicine Department of Anesthesia. This work was supported by the Stanford Department of Anesthesiology, Pain and Perioperative Medicine. LC was also supported by grants from the National Institute for Drug Abuse (NIDA, K02 DA033348-01A1) and the National Institute of General Medical Sciences (NIGMS, K23 GM071400). GP was supported by a research award (1R01 HDO70795-01A1) from the NIH/National Institute for Childhood Development. There are no sources of funding, direct or indirect, or connection of any researchers with the tobacco, alcohol, pharmaceutical or gaming industries or any body substantially funded by one of those organizations. There are no contractual constraints to disclose.