Advertisement

A Secondary Analysis from a Randomized Trial on the Effect of Plasma Tetrahydrocannabinol Levels on Pain Reduction in Painful Diabetic Peripheral Neuropathy

      Highlights

      • These results suggest a therapeutic window with THC and pain reduction.
      • Extreme low and high levels have a negative association with pain intensity.
      • There was a minor linear effect of THC on cognitive testing.

      Abstract

      This report examines the association between tetrahydrocannabinol (THC) plasma levels and pain response in a secondary analysis of data from a recent diabetic neuropathy study that demonstrated a dose-dependent reduction in spontaneous and elicited pain at specific time points. A randomized, double-blinded, placebo-controlled crossover study was conducted in sixteen patients with painful diabetic peripheral neuropathy. Subjects participated in four sessions, separated by 2 weeks, during each of which they were exposed to one of four conditions: placebo, or 1%, 4%, or 7% THC dose of cannabis. Baseline assessments of spontaneous and evoked pain were performed. Subjects were then administered aerosolized cannabis or placebo and pain intensity and cognitive testing at specific time points for 4 hours. A blood sample was drawn from the left antecubital vein for plasma assay of total THC at 0, 15, 30, 45, 60, 150, and 240 minutes. Associations were made between pain intensity, cognitive impairment and THC plasma levels in this secondary analysis. Results suggested a U-shaped relation whereby pain ratings are greatest at extreme (low and high) levels of THC. The therapeutic window appeared to fall between 16 ng/mL and 31 ng/mL THC plasma level. There was a significant linear effect of THC on only one out of the three cognitive tests. These findings stress the importance of measuring cannabinoid plasma levels when performing future research.
      Perspective: This analysis correlating plasma THC levels and pain reduction in diabetic neuropathy suggest a therapeutic window. Low and high THC levels had a negative association (no reduction) and THC levels within the window had a positive association (reduction). There was a minor negative linear effect of THC on cognitive function.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Braida D.
        • Pozzi M.
        • Cavallini R.
        • Sala M.
        Conditioned place preference induced by the cannabinoid agonist CP 55,940: Interaction with the opioid system.
        Neuroscience. 2001; 104: 923-926
        • Cheer J.F.
        • Kendall D.A.
        • Marsden C.A.
        Cannabinoid receptors and reward in the rat: A conditioned place preference study.
        Psychopharmacology (Berl). 2000; 151: 25-30
        • Clark W.C.
        • Janal M.N.
        • Zeidenberg P.
        • Nahas G.G.
        Effects of moderate and high doses of marihuana on thermal pain: A sensory decision theory analysis.
        J Clin Pharmacol. 1981; 21: 299S-310S
        • Eisenberg E.
        • Ogintz M.
        • Almog S.
        The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: A phase 1a study.
        J Pain Palliat Care Pharmacother. 2014; 28: 216-225
        • Fleiss J.L.
        The Design and Analysis of Clinical Experiments.
        John Wiley and Sons, Inc., New York1999 (Wiley Classics Library Edition)
        • Foltin R.W.
        • Fischman M.W.
        • Byrne M.F.
        Effects of smoked marijuana on food intake and body weight of humans living in a residential laboratory.
        Appetite. 1988; 11: 1-14
        • Gronwall D.M.
        Paced auditory serial-addition task: A measure of recovery from concussion.
        Percept Mot Skills. 1977; 44: 367-373
        • Haj C.G.
        • Sumariwalla P.F.
        • Hanus L.
        • Kogan N.M.
        • Yektin Z.
        • Mechoulam R.
        • Feldmann M.
        • Gallily R.
        HU-444, a novel, potent anti-inflammatory, nonpsychotropic cannabinoid.
        J Pharmacol Exp Ther. 2015; 355: 66-75
        • Hartman R.L.
        • Brown T.L.
        • Milavetz G.
        • Spurgin A.
        • Pierce R.S.
        • Gorelick D.A.
        • Gaffney G.
        • Huestis M.A.
        Cannabis effects on driving longitudinal control with and without alcohol.
        J Appl Toxicol. 2016; 36: 1418-1429
        • Hayes A.F.
        • Preacher K.J.
        Quantifying and testing indirect effects in simple mediation models when the constituent paths are nonlinear.
        Multivariate Behav Res. 2010; 45: 627-660
        • Hill S.Y.
        • Schwin R.
        • Goodwin D.W.
        • Powell B.J.
        Marihuana and pain.
        J Pharmacol Exp Ther. 1974; 188: 415-418
        • Holdcroft A.
        • Smith M.
        • Jacklin A.
        • Hodgson H.
        • Smith B.
        • Newton M.
        • Evans F.
        Pain relief with oral cannabinoids in familial Mediterranean fever.
        Anaesthesia. 1997; 52: 483-486
        • Jensen B.
        • Chen J.
        • Furnish T.
        • Wallace M.
        Medical marijuana and chronic pain: A review of basic science and clinical evidence.
        Curr Pain Headache Rep. 2015; 19: 50
        • Miller J.W.
        • Stromeyer W.R.
        • Schwieterman M.A.
        Extensions of the Johnson-Neyman technique to linear models with curvilinear effects: derivations and analytical tools.
        Multivariate Behav Res. 2013; 48: 267-300
        • Moghtaderi A.
        • Bakhshipour A.
        • Rashidi H.
        Validation of Michigan neuropathy screening instrument for diabetic peripheral neuropathy.
        Clin Neurol Neurosurg. 2006; 108: 477-481
        • Portenoy R.K.
        • Ganae-Motan E.D.
        • Allende S.
        • Yanagihara R.
        • Shaiova L.
        • Weinstein S.
        • McQuade R.
        • Wright S.
        • Fallon M.T.
        Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: A randomized, placebo-controlled, graded-dose trial.
        J Pain. 2012; 13: 438-449
        • Raft D.
        • Gregg J.
        • Ghia J.
        • Harris L.
        Effects of intravenous tetrahydrocannabinol on experimental and surgical pain. Psychological correlates of the analgesic response.
        Clin Pharmacol Ther. 1977; 21: 26-33
        • Ramaekers J.G.
        • Moeller M.R.
        • van Ruitenbeek P.
        • Theunissen E.L.
        • Schneider E.
        • Kauert G.
        Cognition and motor control as a function of Delta9-THC concentration in serum and oral fluid: Limits of impairment.
        Drug Alcohol Depend. 2006; 85: 114-122
        • Reilly D.
        • Didcott P.
        • Swift W.
        • Hall W.
        Long-term cannabis use: Characteristics of users in an Australian rural area.
        Addiction. 1998; 93: 837-846
        • Reitan R.M.
        • D. L.A.
        Neuropsychology: Current Status and Application.
        Winston and Sons, Washington, DC1974
        • Schwope D.M.
        • Bosker W.M.
        • Ramaekers J.G.
        • Gorelick D.A.
        • Huestis M.A.
        Psychomotor performance, subjective and physiological effects and whole blood Delta(9)-tetrahydrocannabinol concentrations in heavy, chronic cannabis smokers following acute smoked cannabis.
        J Anal Toxicol. 2012; 36: 405-412
        • Tetrault J.M.
        • Crothers K.
        • Moore B.A.
        • Mehra R.
        • Concato J.
        • Fiellin D.A.
        Effects of marijuana smoking on pulmonary function and respiratory complications: A systematic review.
        Arch Intern Med. 2007; 167: 221-228
        • Wallace M.
        • Schulteis G.
        • Atkinson J.H.
        • Wolfson T.
        • Lazzaretto D.
        • Bentley H.
        • Gouaux B.
        • Abramson I.
        Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers.
        Anesthesiology. 2007; 107: 785-796
        • Wallace M.S.
        • Marcotte T.D.
        • Umlauf A.
        • Gouaux B.
        • Atkinson J.H.
        Efficacy of inhaled cannabis on painful diabetic neuropathy.
        J Pain. 2015; 16: 616-627
        • Ware M.A.
        • Wang T.
        • Shapiro S.
        • Robinson A.
        • Ducruet T.
        • Huynh T.
        • Gamsa A.
        • Bennett G.J.
        • Collet J.P.
        Smoked cannabis for chronic neuropathic pain: A randomized controlled trial.
        CMAJ. 2010; 182: E694-E701
        • Wilsey B.
        • Marcotte T.
        • Deutsch R.
        • Gouaux B.
        • Sakai S.
        • Donaghe H.
        Low-dose vaporized cannabis significantly improves neuropathic pain.
        J Pain. 2013; 14: 136-148
        • Wilsey B.
        • Marcotte T.
        • Tsodikov A.
        • Millman J.
        • Bentley H.
        • Gouaux B.
        • Fishman S.
        A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain.
        J Pain. 2008; 9: 506-521
        • Wilsey B.L.
        • Deutsch R.
        • Samara E.
        • Marcotte T.D.
        • Barnes A.J.
        • Huestis M.A.
        • Le D.
        A preliminary evaluation of the relationship of cannabinoid blood concentrations with the analgesic response to vaporized cannabis.
        J Pain Res. 2016; 9: 587-598