Time course of the enhancement and restoration of the analgesic efficacy of codeine and morphine by Δ9-tetrahydrocannabinol

Williams, I. Jovan; Edwards, Sherita; Rubo, Alex; Haller, Victoria L.; Stevens, David L.; Welch, Sandra P.

doi:10.1016/j.ejphar.2006.04.003

Cited by 29Cannabis and Cannabinoid ResearchPain Management and Opioid UsePain Mechanisms and Treatments

Time course of the enhancement and restoration of the analgesic efficacy of codeine and morphine by Δ9-tetrahydrocannabinol

Williams, I. Jovan, Edwards, Sherita, Rubo, Alex, Haller, Victoria L., Stevens, David L., Welch, Sandra P.·2006·European Journal of Pharmacology

DOI 10.1016/j.ejphar.2006.04.003

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Abstract

Delta9-tetrahydrocannabinol (delta9-THC) synergizes with morphine and codeine by releasing endogenous opioids. These studies determined 1) the duration of enhancement of morphine and codeine by delta9-THC, 2) the effect of (delta9-THC on the time course of fully efficacious doses of the opioids, 3) restoration of efficacy of morphine and codeine by delta9-THC, and 4) duration of restoration. Sub-active combination doses of delta9-THC/morphine or delta9-THC/codeine are equivalent in duration of action and efficacy to high-dose opioids alone. Delta9-THC (20 mg/kg p.o.) significantly restores the antinociceptive effects of both high-dose morphine and codeine (100 and 200 mg/kg p.o., respectively) at later time points at which morphine or codeine was no longer active (360- and 120-min post-administration, respectively). Thus, the cannabinoid/opioid combination might be useful in therapeutics to enhance opioid activity, as well as to restore the efficacy of opioids.

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A low dose of morphine (20 mg/kg) or codeine (30 mg/kg) with a single pre-treatment of an inactive dose of delta-9-THC produced the same efficacy (ED80) as the high doses of each opioid alone.
“A low dose of morphine (20 mg/kg) or codeine (30 mg/kg) with a single pre-treatment of an inactive dose of delta-9-THC produced the same efficacy (ED80) as the high doses of each opioid alone.”
From Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis (2017) · cites this paper as Williams 2006
In Study 1, pre-treatment with delta-9-THC did not enhance the fully efficacious dose of morphine but enhanced low-dose morphine and both doses of codeine, in addition to extending the time course.
“Study 1: Pre-treatment with delta-9-THC did not enhance the fully efficacious dose of morphine but enhanced low-dose morphine and both doses of codeine, in addition to extending the time course.”
From Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis (2017) · cites this paper as Williams 2006
In Study 2, delta-9-THC restored analgesic efficacy after the time that the opioids had ceased being effective on their own (360 mins post dose for morphine and 120 min post dose for codeine).
“Study 2: delta-9-THC restored analgesic efficacy after the time that the opioids had ceased being effective on their own (360 mins post dose for morphine and 120 min post dose for codeine)”
From Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis (2017) · cites this paper as Williams 2006
For codeine, delta-9-THC pre-treatment also increased the duration of action of the ED80 dose of codeine.
“For codeine, delta-9-THC pre-treatment also increased the duration of action of the ED80 dose of codeine”
From Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis (2017) · cites this paper as Williams 2006

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Antinociceptive Synergy between Δ9-Tetrahydrocannabinol and Opioids after Oral Administration
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Potentiation of Δ9-tetrahydrocannabinol-induced analgesia by morphine in mice: involvement of μ- and κ-opioid receptors
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Enhancement mu opioid antinociception by oral delta9-tetrahydrocannabinol: dose-response analysis and receptor identification.
Cichewicz, D. L., Martin, Z. L., Smith, F. L., & Welch, S. P. (1999) · PubMed · Cited by 121 · see citing works
Self-citation
The role of endogenous opioids in enhancing the antinociception produced by the combination of delta 9-tetrahydrocannabinol and morphine in the spinal cord.
Pugh, G., Smith, P. B., Dombrowski, D. S., & Welch, S. P. (1996) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)21168-5 · Cited by 123 · see citing works
Self-citation
Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine
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Authors: Williams, I. J., Edwards, S., Rubo, A., Haller, V. L., Stevens, D. L., & Welch, S. P.
Affiliations: Virginia Commonwealth University (US)
Corresponding author: Welch, Sandra P.
ORCID: Stevens, David L.
Venue: European Journal of Pharmacology
Publisher: Elsevier BV
Published: 2006-06
Volume: 539
Issue: 1-2
Pages: 57-63
ISSN: 0014-2999 (ISSN-L)
DOI: 10.1016/j.ejphar.2006.04.003
OpenAlex: W2131868189
Cited by: 29
References: 57
Citations by year: 2026: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 1 · 2017: 2 · 2015: 1 · 2014: 2 · 2012: 2
FWCI: 2.09
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: European Journal of Pharmacology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5k02da000186-09)
National Institute on Drug Abuse (P01DA009789, DA 05274, DA 09789, K02 DA-00186)
Topics: Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
Keywords: delta-9-tetrahydrocannabinol, morphine, codeine, opioid analgesia, opioid synergy, endogenous opioid release, antinociception, opioid tolerance
MeSH terms: Analgesics, Opioid, Animals, Codeine, Drug Synergism, Male, Mice, Inbred ICR, Morphine, Dronabinol, Analgesics, Non-Narcotic, Mice

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Time course of the enhancement and restoration of the analgesic efficacy of codeine and morphine by Δ9-tetrahydrocannabinol

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