Abstract
Rationale
Dozens of preclinical studies have reported cannabinoid agonist potentiation of the analgesic effects of μ-opioid agonists.
Objectives
The aim of this study was to determine if a cannabinoid agonist could potentiate opioid analgesia in humans using several laboratory pain models.
Methods
Healthy participants (n = 10) with/out current drug use/pain conditions completed this within-subject, double-blind, placebo-controlled, randomized outpatient study. Nine 8-h sessions were completed during which dronabinol (0, 2.5, 5 mg, p.o.) was administered 1 h before oxycodone (0, 5, 10 mg, p.o.) for a total of 9 test conditions. Outcomes included sensory threshold and tolerance from four experimental pain models (cold pressor, pressure algometer, hot thermode, cold hyperalgesia), along with participant- and observer-rated, performance and physiological effects.
Results
Oxycodone produced miosis (p < 0.05) and analgesic responses (e.g., pressure algometer [p < 0.05]), while dronabinol did not (p > 0.05). Depending on the dose combination, dronabinol attenuated or did not alter oxycodone analgesia; for example, dronabinol (2.5 mg) decreased the analgesic effects of oxycodone (10 mg) on pressure tolerance. Conversely, dronabinol increased oxycodone subjective effects (e.g., drug liking) (p < 0.05); oxycodone (5 mg) ratings of “high” were potentiated by 5 mg dronabinol (p < 0.05; placebo = 1.1 [± 0.7]; 5 mg oxycodone = 4.7 [± 2.2]; 5 mg dronabinol = 9.9 [± 8.4]; 5 mg oxycodone + 5 mg dronabinol = 37.4 [± 11.3]).
Conclusions
This study indicates that dronabinol did not enhance the analgesic effects of oxycodone and increased abuse- and impairment-related subjective effects. These data suggest that dronabinol may not be an effective or appropriate opioid adjuvant; it could potentially increase opioid dose requirements, while increasing psychoactive opioid effects.
Similar content being viewed by others
Reference
Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL (2011) Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Thera 90(6):844–851
Altis K, Schmidtko A, Angioni C, Kuczka K, Schmidt H, Geisslinger G, Lötsch J, Tegeder I (2009) Analgesic efficacy of tramadol, pregabalin and ibuprofen in menthol-evoked cold hyperalgesia. Pain 147(1–3):116–121
American pain society. Pain management and dosing guide. 2016 http://americanpainsociety.org/uploads/education/PAMI_Pain_Mangement_and_Dosing_Guide_02282017.pdf
Babalonis S, Hampson AJ, Lofwall MR, Nuzzo PA, Walsh SL (2015) Quinine as a potential tracer for medication adherence: a pharmacokinetic and pharmacodynamic assessment of quinine alone and in combination with oxycodone in humans. J Clin Pharmacol 55(12):1332–1343
Babalonis S, Lofwall MR, Nuzzo PA, Walsh SL (2016) Pharmacodynamic effects of oral oxymorphone: abuse liability, analgesic profile and direct physiologic effects in humans. Addict Biol 21(1):146–158
Bachhuber MA, Saloner B, Cunningham CO, Barry CL (2014) Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010. JAMA Int Med 174(10):1668–1673
Beaulieu P (2006) Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Can J Anaesth 53(8):769–775
Binder A, Stengel M, Klebe O, Wasner G, Baron R (2011) Topical high-concentration (40%) menthol-somatosensory profile of a human surrogate pain model. J Pain 12(7):764–773
Bloomfield MA, Hindocha C, Green SF, Wall MB, Lees R, Petrilli K, Costello H, Ogunbiyi MO, Bossong MG, Freeman TP (2018) The neuropsychopharmacology of cannabis: a review of human imaging studies. Pharm Thera 195:132-161
Boehnke KF, Litinas E, Clauw DJ (2016) Medical cannabis use is associated with decreased opiate medication use in a retrospective cross-sectional survey of patients with chronic pain. J Pain 17(6):739–744
Bradford AC, Bradford WD (2017) Medical marijuana laws may be associated with a decline in the number of prescriptions for Medicaid enrollees. Health Aff 36(5):945–951
Califf RM, Woodcock J, Ostroff S (2016) A proactive response to prescription opioid abuse. NEJM. 374(15):1480–1485
Campbell G, Hall WD, Peacock A, Lintzeris N, Bruno R, Larance B, Nielsen S, Cohen M, Chan G, Mattick RP, Blyth F (2018) Effect of cannabis use in people with chronic non-cancer pain prescribed opioids: findings from a 4-year prospective cohort study. Lancet Public Health 3(7):e341–e350
Caputi TL, Humphreys K (2018) Medical marijuana users are more likely to use prescription drugs medically and nonmedically. J Addict Med 12(4):295–299
Cichewicz DL (2004) Synergistic interactions between cannabinoid and opioid analgesics. Life Sci 74(11):1317–1324
Cichewicz DL, McCarthy EA (2003) Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. J Pharmacol Exp Ther 304(3):1010–1015
Cichewicz DL, Martin ZL, Smith FL, Welch SP (1999) Enhancement mu opioid antinociception by oral delta9-tetrahydrocannabinol: dose-response analysis and receptor identification. J Pharmacol Exp Ther 289(2):859–867
Compton P, Kehoe P, Sinha K, Torrington MA, Ling W (2010) Gabapentin improves cold-pressor pain responses in methadone-maintained patients. Drug Alcohol Depend 109(1–3):213–219
Congressional Research Service (2018). The opioid epidemic and the Food and Drug Administration: legal authorities and recent agency action. Updated December 27, 2018. https://fas.org/sgp/crs/misc/R45218.pdf
Cooper ZD, Bedi G, Ramesh D, Balter R, Comer SD, Haney M (2018) Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability. Neuropsychopharmacology 43:2046–2055
Dowell D, Haegerich TM, Chou R (2016) CDC guideline for prescribing opioids for chronic pain — United States, 2016. MMWR Recomm Rep 65(RR-1):1–49. https://doi.org/10.15585/mmwr.rr6501e1
Fattore L, Spano M, Melis V, Fadda P, Fratta W (2011) Differential effect of opioid and cannabinoid receptor blockade on heroin-seeking reinstatement and cannabinoid substitution in heroin-abstinent rats. Br J Pharmacol 163(7):1550–1562
Fraser HF, Van Horn GD, Martin WR, Wolbach AB, Isbell H (1961) Methods for evaluating addiction liability. (A) “Attitude” of opiate addicts toward opiate-like drugs. (B) a short-term “direct” addiction test. J Pharmacol Exp Ther 133:371–387
Greco R, Demartini C, Zanaboni AM, Piomelli D, Tassorelli C (2018) Endocannabinoid system and migraine pain: an update. Front Neurosci 12:172
Greenwald MK, Stitzer ML (2000) Antinociceptive, subjective and behavioral effects of smoked marijuana in humans. Drug Alcohol Depend 59(3):261–275
Haghparast A, Shamsizadeh A, Samandari R, Omranifard A, Vaziri A, Razavi Y (2014) Cannabinoid receptors in the basolateral amygdala are involved in the potentiation of morphine rewarding properties in the acquisition, but not expression of conditioned place preference in rats. Brain Res 1565:28–36
Haney M, Malcolm RJ, Babalonis S, Nuzzo PA, Cooper ZD, Bedi G, Gray KM, McRae-Clark A, Lofwall MR, Sparenborg S, Walsh SL (2016) Oral cannabidiol does not alter the subjective, reinforcing or cardiovascular effects of smoked cannabis. Neuropsychopharmacology 41(8):1974–1982
Hill SY, Schwin R, Goodwin DW, Powell BJ (1974) Marihuana and pain. J Pharmacol Exp Thera 188(2):415–418
Khan MIA, Walsh D, Brito-Dellan N (2011) Opioid and adjuvant analgesics: compared and contrasted. Am J Hosp Palliat Care 28(5):378–383
Kinsey SG, Long JZ, Cravatt BF, Lichtman AH (2010) Fatty acid amide hydrolase and monoacylglycerol lipase inhibitors produce anti-allodynic effects in mice through distinct cannabinoid receptor mechanisms. Pain 11(12):1420–1428
Kraft B, Frickey NA, Kaufmann RM, Reif M, Frey R, Gustorff B, Kress HG (2008) Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers. Anesthesiology. 109(1):101–110
Li JX, Koek W, France CP (2012) Interactions between Delta(9)-tetrahydrocannabinol and heroin: self-administration in rhesus monkeys. Behav Pharmacol 23(8):754–761
Lile JA, Kelly TH, Charnigo RJ, Stinchcomb AL, Hays LR (2013) Pharmacokinetic and pharmacodynamic profile of supratherapeutic oral doses of Δ9-THC in cannabis users. J Clin Pharmacol 53(7):680–690
Lucas P, Walsh Z, Crosby K (2016) Substituting cannabis for prescription drugs, alcohol and other substances among medical cannabis patients: the impact of contextual factors. Drug Alcohol Rev 35(3):326–333
Maguire DR, France CP (2016) Effects of daily delta-9-tetrahydrocannabinol treatment on heroin self-administration in rhesus monkeys. Behav Pharmacol 27(2–3 Spec Issue):249–257
Maguire DR, France CP (2018) Reinforcing effects of opioid/cannabinoid mixtures in rhesus monkeys responding under a food/drug choice procedure. Psychopharmacology 3:1–9
Maguire DR, Yang W, France CP (2013) Interactions between μ-opioid receptor agonists and cannabinoid receptor agonists in rhesus monkeys: antinociception, drug discrimination, and drug self-administration. J Pharmacol Exp Ther 345(3):354–362
McLeod DR, Griffiths RR, Bigelow GE, Yingling JE (1982) An automated version of the digit symbol substitution test (DSST). Behav Res Methods Instrum Comput 14:463–466
Moulin DE, Clark AJ, Gilron I, Ware MA, Watson CP, Sessle BJ (2007) Pharmacological management of chronic neuropathic pain—consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag 12(1):13–21
Naef M, Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Zbinden A, Brenneisen R (2003) The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain 105(1–2):79–88
Narang S, Gibson D, Wasan AD, Ross EL, Michna E, Nedeljkovic SS, Jamison RN (2008) Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain 9(3):254–264
Olesen AE, Andresen T, Staahl C, Drewes AM (2012) Human experimental pain models for assessing the therapeutic efficacy of analgesic drugs. Pharmacol Rev 64(3):722–779
Olfson M, Wall MM, Liu SM, Blanco C (2017) Cannabis use and risk of prescription opioid use disorder in the United States. Am J Psychiatry 175(1):47–53
Redmond WJ, Goffaux P, Potvin S, Marchand S (2008) Analgesic and antihyperalgesic effects of nabilone on experimental heat pain. Curr Med Res Opin 24(4):1017–1024
Roberts JD, Gennings C, Shih M (2006) Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine. Eur J Pharmacol 530(1–2):54–58
Schrepf A, Harper DE, Harte SE, Wang H, Ichesco E, Hampson JP, Zubieta JK, Clauw DJ, Harris RE (2016) Endogenous opioidergic dysregulation of pain in fibromyalgia: a PET and fMRI study. Pain. 157(10):2217–2225
Solinas M, Panlilio LV, Tanda G, Makriyannis A, Matthews SA, Goldberg SR (2005) Cannabinoid agonists but not inhibitors of endogenous cannabinoid transport or metabolism enhance the reinforcing efficacy of heroin in rats. Neuropsychopharmacology 30(11):2046–2057
Staahl C, Olesen AE, Andresen T, Arendt-Nielsen L, Drewes AM (2009) Assessing analgesic actions of opioids by experimental pain models in healthy volunteers - an updated review. Br J Clin Pharmacol 68(2):149–168
United States Food and Drug Administration. Statement by FDA Commissioner Scott Gottlieb, M.D., on the agency’s ongoing work to forcefully address the opioid crisis. 2018. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm618831.htm
Varrassi G, Fusco M, Skaper SD, Battelli D, Zis P, Coaccioli S, Pace MC, Paladini A (2018) A pharmacological rationale to reduce the incidence of opioid induced tolerance and hyperalgesia: a review. Pain Ther 7(1):59–75
Wallace M, Schulteis G, Atkinson JH, Wolfson T, Lazzaretto D, Bentley H, Gouaux B, Abramson I (2007) Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology 107(5):785–796
Walsh SL, Nuzzo PA, Lofwall MR, Holtman JR Jr (2008) The relative abuse liability of oral oxycodone, hydrocodone and hydromorphone assessed in prescription opioid abusers. Drug Alcohol Depend 98:191–202
Walter C, Oertel BG, Lötsch J (2015) THC may reproducibly induce electrical hyperalgesia in healthy volunteers. Eur J Pain 19(4):516–518
Welch SP (2009) Interaction of the cannabinoid and opioid systems in the modulation of nociception. Int Rev Psychiatry 21(2):143–151
Welch SP, Eads M (1999) Synergistic interactions of endogenous opioids and cannabinoid systems. Brain Res 848(1–2):183–190
Acknowledgments
Grants from the National Center for Research Resources and National Center for Advancing of Translational Sciences (KL2TR000116-04 [SB]; UL1TR001998 [UK CTSA]) and the University of Kentucky Center for Clinical and Translation Science provided support for this research. We thank Anne Estrup Olesen (Aalborg University Hospital, Denmark) for feedback on the experimental pain protocols; the staff at the University of Kentucky (UK) Center on Drug and Alcohol Research for research support: Amanda Kopca, Matthew Taylor, and Victoria Vessels; the UK Investigational Pharmacy for preparing study medication; and Dr. Samy-Claude Elayi for patient support.
Funding
This study was funded by grants from the National Center for Research Resources and National Center for Advancing of Translational Sciences (KL2TR000116-04 [SB]; UL1TR001998 [UK CTSA]).
Author information
Authors and Affiliations
Contributions
Shanna Babalonis, Michelle Lofwall, Paul Sloan, and Sharon Walsh were responsible for the study concept and design. Shanna Babalonis directly supervised the conduct of the study, interviewed and consented the participants, directed the statistical analyses, and wrote the manuscript. Michelle Lofwall and Laura Fanucchi conducted medical interviews and physical examinations and reviewed laboratory results. Michelle Lofwall, Paul Sloan, and Laura Fanucchi provided medical coverage and edited the manuscript. Paul Nuzzo trained the staff, provided technical support services, supervised daily operations, and conducted data analyses. Sharon Walsh, Michelle Lofwall, Paul Sloan, Laura Fanucchi, and Paul Nuzzo provided critical revisions of the manuscript for important intellectual content.
Corresponding author
Ethics declarations
The study was approved by the University of Kentucky Institutional Review Board and was conducted in accordance with the Helsinki guidelines for ethical research. A Certificate of Confidentiality was obtained from the U.S. Food and Drug Administration (FDA).
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Babalonis, S., Lofwall, M.R., Sloan, P.A. et al. Cannabinoid modulation of opioid analgesia and subjective drug effects in healthy humans. Psychopharmacology 236, 3341–3352 (2019). https://doi.org/10.1007/s00213-019-05293-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-019-05293-1