Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther. 2011;90(6):844-851.
This clinical trial was not randomized or blinded due to the challenges of introducing a placebo vaporized substance.
Human trial (N=24). Thirteen participants used morphine (10 by end of study), 11 participants used oxycodone; final analysis 11 men and 10 women, all Caucasian. Origin of pain: musculoskeletal, not otherwise specified (7); posttraumatic (4); arthritic (2); peripheral neuropathy (2); cancer, fibromyalgia, migraine, multiple sclerosis, sickle cell disease, and thoracic outlet syndrome (1 each). Mean morphine dose was 62 mg twice a day (range=10–200 mg) and the mean oxycodone dose was 53 mg twice a day (range=10–120 mg).
Opioid (and opioid metabolites) pharmacokinetics (PK): Mean plasma concentration–time curves for morphine and oxycodone with and without cannabis treatment, for days 1 and 5, and plasma concentrations at steady state (1, 2, 4, 6, 8, 10, and 12 h after oral opioid administration). Tetrahydrocannabinols (THC) PK: plasma levels at baseline and 3, 10, 30, and 60 min. Objective effects (Rhodes Index of Nausea, Vomiting, and Retching Questionnaire) and subjective effects (self-reports utilizing the Drug Effects Questionaire). Pain scores on days 1 and 5, Mean plasma THC levels; subjective effects AUC12 for opioids.
Primary Outcome Measures
The effects of vaporized cannabis administered 3 times a day on the steady-state pharmacokinetics of sustained-release morphine and oxycodone administered at 12-h intervals.
This is the first human study to show that inhaled cannabis safely potentiates the analgesia of opioids. This effect did not appear to be due to PK influences, rather the authors speculate the effect is due to unknown pharmacodynamic (PD) activity.
Cannabis inhalation with a vaporizer may enhance the analgesia of opioids. In addition, previous research suggest that Cannabis may be useful in attenuating the development of opioid tolerance and dependence.
Don Abrams, MD, a University of California-San Francisco researcher and clinician who brings a rational approach to Cannabis use, is to be credited for forging another path forward in the use of medical marijuana. Although a placebo-controlled study previously showed that oral Δ-9-THC (dronabinol/Marinol®) in patients using opioids augments analgesia,1 this is the first human study to show that inhaled cannabis safely potentiates the analgesia of opioids. The effect does not appear to be pharmacokinetic (PK); rather Abrams and authors speculate that the potentiation of analgesia is due to pharmacodynamic (PD) activity. However, previous studies have demonstrated that THC and cannabidiol (CBD) enhance the penetration of other drugs into the brain.2 In the case of a more complex Cannabis extract that would contain the naturally occurring terpenes (eg, Β-caryophyllene) this could also enhance the THC (and other cannabinoids) penetration of the blood-brain barrier as this is a general property of terpenes.3,4,5
Several studies have shown that morphine and THC share many pharmacological properties, including analgesia, hypothermia, respiratory depression, locomotor depression, and tolerance development, even though the mechanisms of action of these 2 compounds are quite different.6 More recently, a bidirectional cross-tolerance between morphine and THC has been demonstrated in mice.7 Not surprisingly, synergic activities have been demonstrated between cannabinoids and opioids, resulting in significant antinociception.8,9 Besides the distinct cannabinoid and opioid receptors that colocalize in areas of the brain that process pain signals, THC (and possibly other cannabinoids) induce the release of endogenous opioids and endocannabinoids.10 These activities could account for PD synergic activity.
The limitations of the study include low participant number and lack of placebo control (vaporizing a placebo would be extraordinarily challenging). Also it would have been interesting to know the ratio of THC/cannabidiol (CBD). The THC concentration is given as 3.6% (in today’s medical marijuana culture this is a low value). However the CBD concentration is not known, and this compound may be effective in pain.11,12
While treatment of pain with opioids is efficacious, it is accompanied by tolerance and dependence issues.
The use of opioids is accepted as the standard of care in patients with cancer and acute pain, as well as subgroups of patients with chronic nonmalignant pain. And yet there are those who abuse these drugs as well. Increased opioid abuse coincides with a controversial US campaign against the undertreatment of pain that has caused an enormous increase in opioid prescriptions. Americans are only 4.2% of the planet's population, yet they use 80% of the world’s opioid supply.13 While treatment of pain with opioids is efficacious, it is accompanied by tolerance and dependence issues.
Addiction and tolerance to opioids represent a major problem in clinical medicine. It is ironic that another controlled substance may be useful for the tolerance and withdrawal symptoms that develop from chronic use of opioids. Tetrahydrocannabinol and Cannabis spp. have also been shown to be useful for the tolerance that develops from chronic use of opioids,14,15 as well as some of the withdrawal symptoms (murine model).16 Note to the clinician: There are other medicinal plants (with various levels of evidence using extracts or isolates) that have demonstrated attenuation of tolerance and/or withdrawal symptoms to opoids or other hard drugs. These plants include iboga (Tabernanthe iboga),17–21 lobelia (Lobelia inflata),22–25 and ashwagandha (Withania somnifera).26,27
The fact that an Institutional Review Board (IRB) approved a study with opioids and vaporized Cannabis strongly suggest that we as a medical community may be progressing from the times of Anslinger’s Federal Bureau of Narcotics’ highly sensationalized propaganda against marijuana. Instead, we are on the brink of entering a rational approach to understanding Cannabis as a medicinal plant. But it is still not without controversy. Some medical professionals are still blind to the medicinal value of Cannabis spp. The American Society of Addiction Medicine, just over 1 year ago, issued a white paper opposing the value of medical marijuana.28 While there are obvious abuses of the medical marijuana laws, some patients have had their quality of life improved by this medicinal plant.
- Narang S, Gibson D, Wasan AD, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain. 2008;9(3):254-264.
- Reid MJ, Bornheim LM. Cannabinoid-induced alterations in brain disposition of drugs of abuse. Biochem Pharmacol. 2001;61(11):1357-1367.
- Liu R, Zhang L, Lan X, et al. Protection by borneol on cortical neurons against oxygen-glucose deprivation/reperfusion: involvement of anti-oxidation and anti-inflammation through nuclear transcription factor kappaappaB signaling pathway. Neurosci. 2011;176:408-419.
- Nokhodchi A, Sharabiani K, Rashidi MR, Ghafourian T. The effect of terpene concentrations on the skin penetration of diclofenac sodium. Int J Pharm. 2007;335(1-2):97-105.
- Tas C, Ozkan Y, Okyar A, Savaser A. In vitro and ex vivo permeation studies of etodolac from hydrophilic gels and effect of terpenes as enhancers. Drug Deliv. 2007;14(7):453-459.
- Rapaka RS, Sorer H. Discovery of Novel Opioid Medications. Rockville, MD: National Institute on Drug Abuse;1994.
- Thorat SN, Bhargava HN. Evidence for a bidirectional cross-tolerance between morphine and delta 9-tetrahydrocannabinol in mice. Eur J Pharmacol. 1994;260(1):5-13.
- Vigano D, Rubino T, Vaccani A, et al. Molecular mechanisms involved in the asymmetric interaction between cannabinoid and opioid systems. Psychopharmacol. 2005;182(4):527-536.
- Cox ML, Haller VL, Welch SP. Synergy between delta9-tetrahydrocannabinol and morphine in the arthritic rat. Eur J Pharmacol. 2007;567(1-2):125-130.
- Welch SP. Interaction of the cannabinoid and opioid systems in the modulation of nociception. Int Rev Psychiatry. 2009;21(2):143-151.
- Booz GW. Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. Free Radic Biol Med. 2011;51(5):1054-1061.
- Costa B, Trovato AE, Comelli F, Giagnoni G, Colleoni M. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur J Pharmacol. 2007;556(1-3):75-83.
- Wang J, Christo PJ. The influence of prescription monitoring programs on chronic pain management. Pain Physician. 2009;12(3):507-515.
- Vigano D, Rubino T, Parolaro D. Molecular and cellular basis of cannabinoid and opioid interactions. Pharmacol Biol Behav. 2005;81(2):360-368.
- Cichewicz DL, Welch SP. Modulation of oral morphine antinociceptive tolerance and naloxone-precipitated withdrawal signs by oral Delta 9-tetrahydrocannabinol. J Pharmacol Exp Ther. 2003;305(3):812-817.
- Lichtman AH, Sheikh SM, Loh HH, Martin BR. Opioid and Cannabinoid Modulation of Precipitated Withdrawal in Δ9-Tetrahydrocannabinol and Morphine-Dependent Mice. J Pharmacol Exp Ther. 2001;298(3):1007-1014.
- Onaivi ES, Ali SF, Chirwa SS, et al. Ibogaine signals addiction genes and methamphetamine alteration of long-term potentiation. Ann NY Acad Sci. 2002;965:28-46.
- Leal MB, Michelin K, Souza DO, Elisabetsky E. Ibogaine attenuation of morphine withdrawal in mice: role of glutamate N-methyl-D-aspartate receptors. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27(5):781-785.
- Parke LA, Burton P, McDonald RV, Kim JA, Siegel S. Ibogaine interferes with motivational and somatic effects of naloxone-precipitated withdrawal from acutely administered morphine. Prog Neuropsychopharmacol Biol Psychiatry . 2002;26(2):293-297.
- Alper KR, Lotsof HS, Frenken GM, Luciano DJ, Bastiaans J. Treatment of acute opioid withdrawal with ibogaine. Am J Addictions. 1999;8(3):234-242.
- Luciano D. Observations on treatment with ibogaine. Am J Addictions. 1998;7(1):89-90.
- Eyerman DJ, Yamamoto BK. Lobeline attenuates methamphetamine-induced changes in vesicular monoamine transporter 2 immunoreactivity and monoamine depletions in the striatum. J Pharmacol Exp Ther. 2005;312(1):160-169.
- Harrod SB, Dwoskin LP, Crooks PA, Klebaur JE, Bardo MT. Lobeline attenuates d-methamphetamine self-administration in rats. J Pharmacol Exp Ther. 2001;298(1):172-179.
- Miller DK, Crooks PA, Teng L, et al. Lobeline inhibits the neurochemical and behavioral effects of amphetamine. J Pharmacol Exp Ther. 2001;296(3):1023-1034.
- Wilhelm CJ, Johnson RA, Lysko PG, Eshleman AJ, Janowsky A. Effects of methamphetamine and lobeline on vesicular monoamine and dopamine transporter-mediated dopamine release in a cotransfected model system. J Pharmacol Exp Ther. 2004;310(3):1142-1151.
- Kasture S, Vinci S, Ibba F, et al. Withania somnifera prevents morphine withdrawal-induced decrease in spine density in nucleus accumbens shell of rats: a confocal laser scanning microscopy study. Neurotoxic Res. 2009;16(4):343-355.
- Kulkarni SK, Ninan I. Inhibition of morphine tolerance and dependence by Withania somnifera in mice. Journal of ethnopharmacology. 1997;57(3):213-217.
- American Society of Addiction Medicine. American Society of Addiction Medicine Rejects Use of 'Medical Marijuana. PR Newswire (http://s.tt/1bGOT);2011.