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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: 7.39). 11/2011; 90(6):844-51. DOI: 10.1038/clpt.2011.188
Source: PubMed

ABSTRACT 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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    • "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.
    Pharmacology Biochemistry and Behavior 10/2012; 103(3). DOI:10.1016/j.pbb.2012.10.002 · 2.82 Impact Factor
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    • "The CB1 receptor is one of the most ubiquitously expressed G-protein coupled receptors in the central nervous system, and the results of this study confirm this widespread distribution. Our results in PAG were consistent with previous reports that demonstrated somatodendritic (Abrams et al., 2011), axonal/terminal (Tsou et al., 1998), and astrocytic (Abramoff et al., 2004; Mukhopadhyay et al., 2010) CB1 receptor immunolabeling in the CNS. Although cannabinoids are well known as retrograde messengers (Hohmann et al., 2005; Welch, 2009), the large number of somatodendritic profiles we observed suggests that the CB1 receptor may have additional functions in the PAG. "
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    ABSTRACT: The periaqueductal gray (PAG) is part of a descending pain modulatory system that, when activated, produces widespread and profound antinociception. Microinjection of either opioids or cannabinoids into the PAG elicits antinociception. Moreover, microinjection of the cannabinoid 1 (CB1) receptor agonist HU-210 into the PAG enhances the antinociceptive effect of subsequent morphine injections, indicating a direct relationship between these two systems. The objective of this study was to characterize the distribution of CB1 receptors in the dorsolateral and ventrolateral PAG in relationship to mu-opioid peptide (MOP) receptors. Immunocytochemical analysis revealed extensive and diffuse CB1 receptor labeling in the PAG, 60% of which was found in somatodendritic profiles. CB1 and MOP receptor immunolabeling were co-localized in 32% of fluorescent Nissl-stained cells that were analyzed. Eight percent (8%) of PAG neurons that were MOP receptor-immunoreactive (-ir) received CB1 receptor-ir appositions. Ultrastructural analysis confirmed the presence of CB1 receptor-ir somata, dendrites and axon terminals in the PAG. These results indicate that behavioral interactions between cannabinoids and opioids may be the result of cellular adaptations within PAG neurons co-expressing CB1 and MOP receptors.
    Neuroscience 04/2012; 213:191-200. DOI:10.1016/j.neuroscience.2012.03.038 · 3.33 Impact Factor
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    ABSTRACT: Depuis quelques décennies, il existe un regain d’intérêt pour le cannabis médical. Les avancées à la fin du xxe siècle ont rendu possible l’étude scientifique du cannabis et ses mécanismes d’action. Sur le plan politique, certains pays, comme le Canada et les États-Unis, ont modifié leurs lois pour que le traitement médical par les cannabinoïdes soit possible. Les cannabinoïdes comme le dronabinol, le Sativex et le Nabilone ont été testés dans le traitement des douleurs aiguës ou chroniques. C’est surtout dans les douleurs chroniques associées au cancer, à l’infection par le VIH et à la sclérose en plaques que le traitement par les cannabinoïdes semble le plus prometteur. Des études de plus grande envergure et de plus longue durée sont nécessaires pour déterminer les effets indésirables au long cours, ainsi que le risque de mésusage et d’addiction.
    Douleur et Analgésie 06/2012; 25(2). DOI:10.1007/s11724-012-0294-8 · 0.09 Impact Factor

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