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The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions
Abstract
From folk medicine and anecdotal reports it is known that Cannabis may reduce pain. In animal studies it has been shown that delta-9-tetrahydrocannabinol (THC) has antinociceptive effects or potentiates the antinociceptive effect of morphine. The aim of this study was to measure the analgesic effect of THC, morphine, and a THC-morphine combination (THC-morphine) in humans using experimental pain models. THC (20 mg), morphine (30 mg), THC-morphine (20 mg THC+30 mg morphine), or placebo were given orally and as single doses. Twelve healthy volunteers were included in the randomized, placebo-controlled, double-blinded, crossover study. The experimental pain tests (order randomized) were heat, cold, pressure, single and repeated transcutaneous electrical stimulation. Additionally, reaction time, side-effects (visual analog scales), and vital functions were monitored. For the pharmacokinetic profiling, blood samples were collected. THC did not significantly reduce pain. In the cold and heat tests it even produced hyperalgesia, which was completely neutralized by THC-morphine. A slight additive analgesic effect could be observed for THC-morphine in the electrical stimulation test. No analgesic effect resulted in the pressure and heat test, neither with THC nor THC-morphine. Psychotropic and somatic side-effects (sleepiness, euphoria, anxiety, confusion, nausea, dizziness, etc.) were common, but usually mild.
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“No significant analgesic effect of dronabinol or morphine-dronabinol combination on heat, pressure or cold tests.Additive effect of morphine on transcutaneous electrical stimulation test Potentiation of analgesia not observed in this experimental pain study”
From Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis (2017) · cites this paper as Naef 2003
Citations
Cites
Method for quantitative estimation of thermal thresholds in patients.
Fruhstorfer, H., Lindblom, U., & Schmidt, W. C. (1976) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.39.11.1071 · Cited by 785
Cannabinoid receptors and pain
Pertwee, R. G. (2001) · Progress in Neurobiology · doi:10.1016/s0301-0082(00)00031-9 · Cited by 741
Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review
Tramèr, M. R., Carroll, D., Campbell, F. A., Reynolds, D. J. M., Moore, R. A., & McQuay, H. J. (2001) · BMJ · doi:10.1136/bmj.323.7303.16 · Cited by 610
Action of cannabidiol on the anxiety and other effects produced by ?9-THC in normal subjects
Zuardi, A. W., Shirakawa, I., Finkelfarb, E., & Karniol, I. G. (1982) · Psychopharmacology · doi:10.1007/bf00432554 · Cited by 608
Cannabidiol: An Overview of Some Pharmacological Aspects
Mechoulam, R., Parker, L. A., & Gallily, R. (2002) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.2002.tb05998.x · Cited by 530
Campbell, F. A., Tramèr, M. R., Carroll, D., Reynolds, D. J. M., Moore, R. A., & McQuay, H. J. (2001) · BMJ · doi:10.1136/bmj.323.7303.13 · Cited by 422
Marijuana and medicine: assessing the science base
(1999) · Choice Reviews Online · doi:10.5860/choice.37-2206 · Cited by 409
The analgesic properties of delta‐9‐tetrahydrocannabinol and codeine
Noyes, R., Brunk, S. F., Avery, D. H., & Canter, A. (1975) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt197518184 · Cited by 378
Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women
Wall, M. E., Sadler, B. M., Brine, D. R., Taylor, H. L., & Perez‐Reyes, M. (1983) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1983.179 · Cited by 346
Cannabis and Cannabis Extracts: Greater Than the Sum of Their Parts?
McPartland, J. M., & Russo, E. B. (2001) · Journal of Cannabis Therapeutics · doi:10.1300/j175v01n03_08 · Cited by 321
Arendt‐Nielsen, L., Brennum, J., Sindrup, S. H., & Bak, P. (1994) · European Journal of Applied Physiology · doi:10.1007/bf00376776 · Cited by 303
Self-citationMeasurements of human pressure-pain thresholds on fingers and toes
Brennum, J., Kjeldsen, M., Jensen, K., & Jensen, T. S. (1989) · Pain · doi:10.1016/0304-3959(89)90240-6 · Cited by 293
Analgesic Effect of Delta‐9‐Tetrahydrocannabinol
Noyes, R., Brunk, S. F., BARAM, D. A., & Canter, A. (1975) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1975.tb02348.x · Cited by 272
Antipsychotic effect of cannabidiol.
Zuardi, A. W., Morais, S. L., Guimarães, F. S., & Mechoulam, R. (1995) · PubMed · Cited by 264
Marihuana, the Forbidden Medicine
Grinspoon, L., & Bakalar, J. B. (1993) · doi:10.1038/scientificamerican1269-17 · Cited by 227
Comparison of the subjective effects of Δ 9 -tetrahydrocannabinol and marijuana in humans
Wachtel, S. R., ElSohly, M. A., Ross, S. A., AMBRE, J. J., & de Wit, H. (2002) · Psychopharmacology · doi:10.1007/s00213-002-1033-2 · Cited by 210
Smith, F. L., Fujimori, K., Lowe, J., & Welch, S. P. (1998) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(97)00583-2 · Cited by 154
Effect of racemic mixture and the (S+)-isomer of ketamine on temporal and spatial summation of pain
Arendt‐Nielsen, L., Nielsen, J., Petersen‐Felix, S., Schnider, T. W., & Zbinden, A. M. (1996) · British Journal of Anaesthesia · doi:10.1093/bja/77.5.625 · Cited by 147
Self-citationThe Enhancement of Morphine Antinociception in Mice by Î9-Tetrahydrocannabinol
Smith, F. (1998) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(98)00012-4 · Cited by 146
Brenneisen, R., Egli, A., ElSohly, M. A., Henn, V. S., & Spiess, Y. (1996) · PubMed · Cited by 134
Self-citationPain relief with oral cannabinoids in familial Mediterranean fever
Holdcroft, A., Smith, M., Jacklin, A., Hodgson, H. J. F., Smith, B., Newton, M., & Evans, F. J. (1997) · Anaesthesia · doi:10.1111/j.1365-2044.1997.139-az0132.x · Cited by 129
Cichewicz, D. L., Martin, Z. L., Smith, F. L., & Welch, S. P. (1999) · PubMed · Cited by 121
Who is Using Cannabis as a Medicine and Why: An Exploratory Study
Ogborne, A. C., Smart, R. G., Weber, T. R., & Timney, C. B. (2000) · Journal of Psychoactive Drugs · doi:10.1080/02791072.2000.10400245 · Cited by 120
Morphine and ibuprofen compared using the cold pressor test
Jones, S. F., McQuay, H. J., Moore, R. A., & Hand, C. W. (1988) · Pain · doi:10.1016/0304-3959(88)90156-x · Cited by 119
Antinociceptive, subjective and behavioral effects of smoked marijuana in humans
Greenwald, M. K., & Stitzer, M. L. (2000) · Drug and Alcohol Dependence · doi:10.1016/s0376-8716(99)00128-3 · Cited by 119
Cannabinoid CB1 receptor upregulation in a rat model of chronic neuropathic pain
Siegling, A., Hofmann, H. A., Denzer, D., Mauler, F., & De Vry, J. (2001) · European Journal of Pharmacology · doi:10.1016/s0014-2999(01)00798-1 · Cited by 108
Raft, D. D., Gregg, J. M., Ghia, J. N., & Harris, L. S. (1977) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt197721126 · Cited by 103
Petersen‐Felix, S., Luginbühl, M., Schnider, T. W., Curatolo, M., Arendt‐Nielsen, L., & Zbinden, A. M. (1998) · British Journal of Anaesthesia · doi:10.1093/bja/81.5.742 · Cited by 101
Self-citationVivian, J. A., Kishioka, S., Butelman, E. R., Broadbear, J., Lee, K. O., & Woods, J. H. (1998) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)37642-6 · Cited by 98
The Selective Cannabinoid Antagonist SR 141716A Blocks Cannabinoid-Induced Antinociception in Rats
Lichtman, A. H., & Martin, B. R. (1997) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(96)00121-9 · Cited by 92
Are poor metabolisers of sparteine/debrisoquine less pain tolerant than extensive metabolisers?
Sindrup, S. H., Poulsen, L. K., Brøsen, K., Arendt‐Nielsen, L., & Gram, L. F. (1993) · Pain · doi:10.1016/0304-3959(93)90229-i · Cited by 83
Self-citationEnggaard, T. P., Poulsen, L. K., Arendt‐Nielsen, L., Hansen, S. H., Bjørnsdottir, I., Gram, L. F., & Sindrup, S. H. (2001) · Pain · doi:10.1016/s0304-3959(01)00267-6 · Cited by 79
Self-citationThe influence of anxiety and pain sensitivity on experimental pain in man
von Graffenried, B., Adler, R. H., Abt, K., Nüesch, E., & Spiegel, R. (1977) · Pain · doi:10.1016/0304-3959(77)90137-3 · Cited by 73
Nahas, G. G. (1999) · Humana Press eBooks · doi:10.1007/978-1-59259-710-9_79 · Cited by 68
Quantitative sensory examination in human epidural anaesthesia and analgesia: effects of lidocaine
Brennum, J., Arendt‐Nielsen, L., Secher, N. H., Jensen, T. S., & Bjerring, P. (1992) · Pain · doi:10.1016/0304-3959(92)90005-v · Cited by 61
Self-citationFeng, S., ElSohly, M. A., Salamone, S. J., & Salem, M. Y. (2000) · Journal of Analytical Toxicology · doi:10.1093/jat/24.6.395 · Cited by 56
Hill, S. Y., Schwin, R., Goodwin, D. W., & Powell, B. J. (1974) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)29765-8 · Cited by 55
Antiemetic efficacy of smoked marijuana
Gordh, A. S., Schuster, A., & de Wit, H. (2001) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(01)00533-0 · Cited by 51
Gyr, E., Brenneisen, R., Bourquin, D., Lehmann, T., Vonlanthen, D., & Hug, I. P. (2000) · International Journal of Clinical Pharmacology and Therapeutics · doi:10.5414/cpp38486 · Cited by 50
Self-citationRemifentanil inhibits muscular more than cutaneous pain in humans
Curatolo, M., Petersen‐Felix, S., Gerber, A., & Arendt‐Nielsen, L. (2000) · British Journal of Anaesthesia · doi:10.1093/bja/85.4.529 · Cited by 48
Self-citationComparison of Five Experimental Pain Tests to Measure Analgesic Effects of Alfentanil
Luginbühl, M., Schnider, T. W., Petersen‐Felix, S., Arendt‐Nielsen, L., & Zbinden, A. M. (2001) · Anesthesiology · doi:10.1097/00000542-200107000-00009 · Cited by 45
Self-citationEffects of Moderate and High Doses of Marihuana on Thermal Pain: A Sensory Decision Theory Analysis
Clark, W. C., Janal, M. N., Zeidenberg, P., & Nahas, G. G. (1981) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1981.tb02608.x · Cited by 43
Marijuana-Produced Changes in Pain Tolerance. Experienced and Non-Experienced Subjects
Milstein, S. L., MacCannell, K. L., Karr, G., & Clark, S. (2017) · International Pharmacopsychiatry · doi:10.1159/000468188 · Cited by 40
Absorption, Distribution, and Biotransformation of the Cannabinoids
Harvey, D. J. (1999) · Humana Press eBooks · doi:10.1007/978-1-59259-710-9_10 · Cited by 39
Analgesic action of i.v. morphine-6-glucuronide in healthy volunteers
Buetler, T. M., Wilder‐Smith, O. H. G., Wilder‐Smith, C. H., Aebi, S. P., Cerny, T., & Brenneisen, R. (2000) · British Journal of Anaesthesia · doi:10.1093/oxfordjournals.bja.a013391 · Cited by 35
Self-citationZeidenberg, P., Clark, W. C., Jaffe, J., Anderson, S. W., Chin, S., & Malitz, S. (1973) · Comprehensive Psychiatry · doi:10.1016/0010-440x(73)90040-0 · Cited by 34
Ondansetron does not inhibit the analgesic effect of alfentanil
Petersen‐Felix, S., Arendt‐Nielsen, L., BAK, P., Bjerring, P., Breivik, H., SVENSSON, P., & Zbinden, A. M. (1994) · British Journal of Anaesthesia · doi:10.1093/bja/73.3.326 · Cited by 28
Self-citationBourquin, D., Bundeli, P., Lehmann, T., & Brenneisen, R. (1999) · Journal of Liquid Chromatography & Related Technologies · doi:10.1081/jlc-100102050 · Cited by 13
Self-citationTetrahydrocannabinol zur Therapie chronischer Schmerzen
Elsner, F., Radbruch, L., & Sabatowski, R. (2001) · Der Schmerz · doi:10.1007/s004820170024 · Cited by 11
Cannabinoids and the Control of Chemotherapy-Induced Nausea and Vomiting
Gralla, R. J. (1999) · Humana Press eBooks · doi:10.1007/978-1-59259-710-9_59 · Cited by 10
Effects of moderate and high doses of marihuana on thermal pain: a sensory decision theory analysis
Clark, W. C., Janal, M. N., Zeidenberg, P., & Nahas, G. G. (1982) · Pain · doi:10.1016/0304-3959(82)90124-5 · Cited by 10
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Ben Amar, M. (2006) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2006.02.001 · Cited by 543
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Pertwee, R. G. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2008.00048.x · Cited by 436
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Borgelt, L. M., Franson, K. L., Nussbaum, A. M., & Wang, G. S. (2013) · Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.1187 · Cited by 423
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Russo, E. B., & Marcu, J. P. (2017) · Advances in pharmacology · doi:10.1016/bs.apha.2017.03.004 · Cited by 403
Metadata
- Authors
- Naef, M., Curatolo, M., Petersen-Felix, S., Arendt-Nielsen, L., Zbinden, A., & Brenneisen, R.
- Affiliations
- University of Bern (CH)
- University Hospital of Bern (CH)
- Corresponding author
- Brenneisen, Rudolf
- ORCID
- Curatolo, Michele
- Venue
- Pain
- Published
- 2003-09
- Volume
- 105
- Issue
- 1
- Pages
- 79-88
- ISSN
- 0304-3959 (ISSN-L)
- OpenAlex
- W2091487276
- Cited by
- 209
- References
- 52
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 14 · 2023: 12 · 2022: 4 · 2021: 15 · 2020: 12 · 2019: 7 · 2018: 17 · 2017: 11 · 2016: 7 · 2015: 6 · 2014: 5 · 2013: 7 · 2012: 13
- FWCI
- 6.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pain (publishedVersion)
- PubMed (publishedVersion)
- VBN Forskningsportal (Aalborg Universitet) (submittedVersion)
- Funders
- Novartis Foundation
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
- Keywords
- delta-9-tetrahydrocannabinol, morphine, analgesia, experimental pain, antinociception, hyperalgesia, transcutaneous electrical stimulation, cannabis, opioid analgesics, adverse effects, pharmacokinetics
- MeSH terms
- Adult, Analgesics, Opioid, Cold Temperature, Double-Blind Method, Drug Combinations, Transcutaneous Electric Nerve Stimulation, Female, Hot Temperature, Humans, Male, Morphine, Pain, Palliative Care, Pressure, Dronabinol, Pain Threshold, Cross-Over Studies, Analgesics, Non-Narcotic
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