Cannabinoid–Opioid Interaction in Chronic Pain

Division of Hematology-Oncology, San Francisco General Hospital, University of California, San Francisco, San Francisco, California, USA.
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.9). 11/2011; 90(6):844-51. DOI: 10.1038/clpt.2011.188
Source: PubMed


Cannabinoids and opioids share several pharmacologic properties and may act synergistically. The potential pharmacokinetics and the safety of the combination in humans are unknown. We therefore undertook a study to answer these questions. Twenty-one individuals with chronic pain, on a regimen of twice-daily doses of sustained-release morphine or oxycodone were enrolled in the study and admitted for a 5-day inpatient stay. Participants were asked to inhale vaporized cannabis in the evening of day 1, three times a day on days 2-4, and in the morning of day 5. Blood sampling was performed at 12-h intervals on days 1 and 5. The extent of chronic pain was also assessed daily. Pharmacokinetic investigations revealed no significant change in the area under the plasma concentration-time curves for either morphine or oxycodone after exposure to cannabis. Pain was significantly decreased (average 27%, 95% confidence interval (CI) 9, 46) after the addition of vaporized cannabis. We therefore concluded that vaporized cannabis augments the analgesic effects of opioids without significantly altering plasma opioid levels. The combination may allow for opioid treatment at lower doses with fewer side effects.

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Available from: Starley Shade, Oct 05, 2015
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    • "They conclude that combining smaller doses of cannabis and opioids resulted in positive analgesic effects with fewer side effects than a larger dose of either drug alone. Abrams et al. (2011) also found that among chronic pain patients who were treated with opioids, vaporized cannabis augments the analgesic effects of opioids, which may allow for opioid treatment at lower doses with fewer side effects. Similar to clinical and experimental research, data from a community-based study of people who have been prescribed opioids for chronic non-cancer pain found that cannabis use for pain relief purposes was common and that study participants reported greater pain relief in combination with opioids than when opioids were used alone (Degenhardt et al., 2014). "

    Full-text · Article · Nov 2015
    • "It is well established that cannabinoids increase the potency of morphine to produce antinociception in rodents (Cichewicz 2004; Cox et al. 2007; Massi et al. 2001; Smith et al. 1998; Welch and Stevens 1992; Welch et al. 1995) and monkeys (Li et al. 2008; Maguire et al. 2013). In pain patients, cannabinoids enhance the analgesic effectiveness of opioids (Abrams et al. 2011; Narang et al. 2008), suggesting that small doses of opioids might be used when combined with cannabinoids . By reducing the dose of opioids needed for therapeutic effects, cannabinoids might increase the margin of safety of opioids, as long as they do not also enhance adverse effects. "
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    ABSTRACT: Opioids remain the drugs of choice for treating moderate to severe pain, although adverse effects limit their use. Therapeutic utility might be improved by combining opioids with other drugs to enhance analgesic effects, but only if adverse effects are not similarly changed. Cannabinoids have been shown to enhance the antinociceptive potency of opioids without increasing other effects; this study examined whether the effectiveness of cannabinoids is altered in morphine-dependent monkeys. Four monkeys received up to 10 mg/kg morphine twice daily. Changes in the antinociceptive effects of opioid receptor agonists (morphine, U50,488) and cannabinoid receptor agonists (WIN 55,212, CP 55,940, and Δ(9)-tetrahydrocannabinol [THC]) were determined by measuring the latency for monkeys to remove their tails from 40, 50, 54, and 58 °C water. Before treatment, all drugs increased tail withdrawal latency from warm (54 °C) water. Chronic morphine treatment decreased the potency of each drug; the magnitude of rightward shift in dose-effect curves was greatest for morphine, WIN 55,212 and CP 55,940 with at least sixfold shifts for each drug during treatment. Discontinuation of morphine treatment resulted in signs that are indicative of withdrawal, including increased heart rate, decreased daytime activity, and tongue movement. Tolerance developed to the antinociceptive effects of morphine and cross-tolerance developed to cannabinoids under conditions that produced modest physical dependence. Compared with the doses examined in this study, much smaller doses of opioids have antinociceptive effects when given with cannabinoids; it is possible that tolerance will not develop to chronic treatment with opioid/cannabinoid mixtures.
    No preview · Article · Jul 2015 · Psychopharmacology
    • "Recent clinical data suggest that combined opioid/cannabinoid therapy is a viable option for efficacious pain relief, particularly in patients already undergoing opioid therapy (Abrams et al., 2011). Determining the neural mechanisms underlying bi-directional enhanced antinociception between opioids and cannabinoids is essential in developing drug and treatment protocols that safely and effectively manage pain. "
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    ABSTRACT: Co-administration of opioids and cannabinoids can enhance pain relief even when administered on different days. Repeated systemic administration of morphine has been shown to enhance the antinociceptive effect of tetrahydrocannabinol (THC) administered 12h later, and repeated microinjection of the cannabinoid receptor agonist HU-210 into the ventrolateral periaqueductal gray (PAG) has been shown to enhance the antinociceptive effect of morphine administered 1day later. The primary objective of the present study was to test the hypothesis that this cannabinoid/opioid interaction is bidirectional. Experiment 1 showed that microinjection of morphine into the ventrolateral PAG of male Sprague-Dawley rats twice daily for 2days enhanced the antinociceptive effect of HU-210 measured 1day later. In Experiment 2, twice daily systemic injections of THC enhanced the antinociceptive effect of morphine administered 1day later. These results complement the previously mentioned studies by showing that morphine and cannabinoid interactions are bidirectional and that the ventrolateral PAG plays an important role in this effect. In contrast to the PAG, repeated administration of HU-210 or the cannabinoid receptor agonist, WIN 55,212-2, into the RVM had a neurotoxic effect. Rats became ill following repeated cannabinoid administration whether given alone or with morphine. Presumably, this neurotoxic effect was caused by the high cannabinoid concentration following RVM microinjection because rats did not become ill following repeated systemic THC administration. These findings indicate that alternating opioid and cannabinoid treatment could produce a longer lasting and more potent analgesia than either compound given alone.
    No preview · Article · Oct 2012 · Pharmacology Biochemistry and Behavior
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