pain is a very good target for therapeutic cannabinoids. Many endocannabinoids, plant cannabinoids and cannabinoid receptors have been linked to pain management or analgesia. After many preclinical studies and clinical trials cannabinoids are emerging as safer and more potent alternatives to opioids in pain management.

Literature Discussion: 

In a mouse study, the endocannabinoid system was found to be required for the analgesic action of acetaminophen (paracetamol); FAAH breaks down acetaminophen to AM404 (first identified as synthetic cannabinoid but also displaying endocannabinoid activity), which in turn blocks re-uptake of Anandamide (Mallet et al., 2008).

MAGL inhibitors showed potential therapeutic action to treat cancer, neurodegenerative diseases, ischemic injuries, inflammation, pain, Anxiety, nausea and drug-withdrawal symptoms (Chen et al., 2012; Kohnz & Nomura, 2014; Mulvihill & Nomura, 2013). The analgesic effect of paracetamol thus seems to be due to increased ambient levels of Anandamide.

Blocking CB1 completely prevents the analgesic action of paracetamol suggesting CB1 is required for analgesia (Bertolini et al., 2006).

Similarly, ibuprofen was found to block the breakdown/hydrolysis of Anandamide (Fowler et al., 1999), which may contribute to the analgesic effect of ibuprofen (and similar substances).

Nox-induced oxyradical stress elicited the activation of DAGLβ in vitro, increasing the biosynthesis of 2-AG (Matthews et al., 2016). DAGLβ modulates pro-inflammatory signaling cascades and its inhibition reduced nociceptive behavior in models of neuropathic and inflammatory pain (Wilkerson et al., 2016).

In mice, inhibition of opioid-degrading enzymes potentiates the analgesic effect of THC, suggesting cross talk or synergy between the opioid- and endocannabinoid systems in pain management (Reche et al., 1998).

In humans, on the other hand, THC was found not so much to enhance the analgesic effect of morphine but to inhibit the experienced discomfort that is normally associated with pain (Roberts et al., 2006).

This would suggest that cannabinoids do no necessarily block pain sensation but rather dissociate negative emotions from the experienced pain.

In a rat model, THC was found to suppress muscle pain via activation of CB1 (Bagüés et al., 2014).

Several synthetic CB2 agonists have been patented for their analgesic properties, indicating a strong role for CB2 in pain management (Murineddu et al., 2012).

TRP receptors (TRPV1-4, TRPA1, TRPM8) are classically known for their role in pain sensation.

TRPs bind to most plant cannabinoids and endocannabinoids with varying affinities (De Petrocellis et al., 2011, 2012), tentatively making TRPs excellent targets and plant cannabinoids excellent substrates for pain management.

More research is required to test the therapeutic potential of cannabinoids in pain.

In patients with Chronic Widespread pain, the endocannabinoid PEA was found to provide homeostatic pain control through the PPARα receptor (Ghafouri et al., 2013).

In mice 2 mg/kg i.p. (like THC and gabapentin) CBD reduced, but did not prevent, neuropathic pain induced by cis-platin (Harris et al., 2016).

The interaction between CBG and the α2 receptor (alpha 2 adrenalin receptor) may prove effective in pain control (Giovannoni et al., 2009).

In rats, blocking GPR55 signaling reduced algesia suggesting GPR55 is a target for pain control (Deliu et al., 2015).

References:

Bagüés, A., Martín, M.I., and Sánchez-Robles, E.M. (2014). Involvement of central and peripheral cannabinoid receptors on antinociceptive effect of tetrahydrocannabinol in muscle pain. Eur. J. Pharmacol. 745C, 69–75.

Bertolini, A., Ferrari, A., Ottani, A., Guerzoni, S., Tacchi, R., and Leone, S. (2006). Paracetamol: new vistas of an old drug. CNS Drug Rev. 12, 250–275.

Deliu, E., Sperow, M., Console-Bram, L., Carter, R.L., Tilley, D.G., Kalamarides, D.J., Kirby, L.G., Brailoiu, G.C., Brailoiu, E., Benamar, K., et al. (2015). The Lysophosphatidylinositol Receptor GPR55 Modulates pain Perception in the Periaqueduactal Grey. Mol. Pharmacol.

Fowler, C.J., Janson, U., Johnson, R.M., Wahlström, G., Stenström, A., Norström, K., and Tiger, G. (1999). Inhibition of Anandamide hydrolysis by the enantiomers of ibuprofen, ketorolac, and flurbiprofen. Arch. Biochem. Biophys. 362, 191–196.

Ghafouri, N., Ghafouri, B., Larsson, B., Stensson, N., Fowler, C.J., and Gerdle, B. (2013). Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder pain correlate with pain intensity and sensitivity. pain 154, 1649–1658.

Giovannoni, M.P., Ghelardini, C., Vergelli, C., and Dal Piaz, V. (2009). Alpha2-agonists as analgesic agents. Med. Res. Rev. 29, 339–368.

Harris, H.M., Sufka, K.J., Gul, W., and ElSohly, M.A. (2016). Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice. Planta Med.

Mallet, C., Daulhac, L., Bonnefont, J., Ledent, C., Etienne, M., Chapuy, E., Libert, F., and Eschalier, A. (2008). endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. pain 139, 190–200.

Matthews, A. T., Lee, J. H., Borazjani, A., Mangum, L. C., Hou, X., & Ross, M. K. (2016). Oxyradical stress increases the biosynthesis of 2-arachidonoylglycerol: involvement of NADPH oxidase. American Journal of Physiology - Cell Physiology, 311(6), C960-C974. https://doi.org/10.1152/ajpcell.00251.2015

Murineddu, G., Asproni, B., and Pinna, G.A. (2012). A survey of recent patents on CB2 agonists in the management of pain. Recent Patents CNS Drug Discov. 7, 4–24.

De Petrocellis, L., Ligresti, A., Moriello, A.S., Allarà, M., Bisogno, T., Petrosino, S., Stott, C.G., and Di Marzo, V. (2011). Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br. J. Pharmacol. 163, 1479–1494.

De Petrocellis, L., Orlando, P., Moriello, A.S., Aviello, G., Stott, C., Izzo, A.A., and Di Marzo, V. (2012). cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiol. Oxf. Engl. 204, 255–266.

Reche, I., Ruiz-Gayo, M., and Fuentes, J.A. (1998). Inhibition of opioid-degrading enzymes potentiates delta9-tetrahydrocannabinol-induced antinociception in mice. Neuropharmacology 37, 215–222.

Roberts, J.D., Gennings, C., and Shih, M. (2006). Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine. Eur. J. Pharmacol. 530, 54–58.  

Wilkerson, J. L., Ghosh, S., Bagdas, D., Mason, B. L., Crowe, M. S., Hsu, K. L., … Lichtman, A. H. (2016). Diacylglycerol lipase β inhibition reverses nociceptive behaviour in mouse models of inflammatory and neuropathic pain. British Journal of Pharmacology, 173(10), 1678-1692. https://doi.org/10.1111/bph.13469

Clinical Trials: 

Many clinical trials have tested the efficacy of cannabinoids to suppress pain with mixed results.

In general a mixture of THC and CBD was found to be most effective.

Moreover, cannabinoids seem more effective in suppressing chronic pain than acute pain.

Finally, cannabinoids can be mixed with other pain medication (opioids, paracetamol, ibuprofen) to produce stronger (synergistic) pain relief.

Positive outcome: cannabinoids were found to synergistically increase the analgesic effect of opioids by 27% (compared to opioids alone) (Abrams et al., 2011).

A mix of THC/CBD (oral spray) was used to suppress pain related to cancer.

In general, the THC/CBD mix provided long-lasting pain relief without desensitization (the need to increase the dose to reach the desired effect) (Johnson et al., 2013).

A THC/CBD mix was also effective against central pain experienced in MS (Rog et al., 2005).

Smoked cannabis was found to significantly reduce pain sensation in chronic neuropathic pain (Ware et al., 2010; Wilsey et al., 2013).

The effect was positively correlated with cannabis dose.

Apart from analgesia, smoked cannabis improved sleep.

Oral THC was found to effectively reduce chronic non-cancer pain in some, but not all, patients (Haroutiunian et al., 2008).

In HIV patients with neuropathic pain that did not respond to conventional pain medication, smoked cannabis provided effective in 46% of patients (compared to 18% for placebo)(Ellis et al., 2009).

Oral cannabis extract was found to effectively reduce post-operative pain (Holdcroft et al., 2006).

  Negative outcome: One clinical trial has tested the efficacy of smoked cannabis on pain relief in patients with Cluster Headache.

Cannabis did not prove effective in this study (Leroux et al., 2013).

THC was found not to reduce pain sensitivity in Irritable Bowel Syndrome (Klooker et al., 2011).

Contrary to results with chronic pain, smoked cannabis was not effective at suppressing acute pain in humans (Kraft et al., 2008).

Literature:

Abrams, D.I., Couey, P., Shade, S.B., Kelly, M.E., and Benowitz, N.L. (2011). cannabinoid-opioid interaction in chronic pain. Clin. Pharmacol. Ther. 90, 844–851.

Chen, R., Zhang, J., Wu, Y., Wang, D., Feng, G., Tang, Y.-P., … Chen, C. (2012). Monoacylglycerol lipase is a therapeutic target for Alzheimer’s disease. Cell Reports2(5), 1329-1339. https://doi.org/10.1016/j.celrep.2012.09.030

Ellis, R.J., Toperoff, W., Vaida, F., van den Brande, G., Gonzales, J., Gouaux, B., Bentley, H., and Atkinson, J.H. (2009). Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 34, 672–680.

Haroutiunian, S., Rosen, G., Shouval, R., and Davidson, E. (2008). Open-label, add-on study of tetrahydrocannabinol for chronic nonmalignant pain. J. pain Palliat. Care Pharmacother. 22, 213–217.

Holdcroft, A., Maze, M., Doré, C., Tebbs, S., and Thompson, S. (2006). A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management. Anesthesiology 104, 1040–1046.

Johnson, J.R., Lossignol, D., Burnell-Nugent, M., and Fallon, M.T. (2013). An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J. pain Symptom Manage. 46, 207–218.

Klooker, T.K., Leliefeld, K.E.M., Van Den Wijngaard, R.M., and Boeckxstaens, G.E.E. (2011). The cannabinoid receptor agonist delta-9-tetrahydrocannabinol does not affect visceral sensitivity to rectal distension in healthy volunteers and IBS patients. Neurogastroenterol. Motil. Off. J. Eur. Gastrointest. Motil. Soc. 23, 30–35, e2.

Kohnz, R., & Nomura, D. K. (2014). Chemical Approaches to Therapeutically Target the Metabolism and Signaling of the endocannabinoid 2-AG and Eicosanoids. Chemical Society reviews43(19), 6859-6869. https://doi.org/10.1039/c4cs00047a

Kraft, B., Frickey, N.A., Kaufmann, R.M., Reif, M., Frey, R., Gustorff, B., and Kress, H.G. (2008). Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers. Anesthesiology 109, 101–110.

Leroux, E., Taifas, I., Valade, D., Donnet, A., Chagnon, M., and Ducros, A. (2013). Use of cannabis among 139 cluster headache sufferers. Cephalalgia Int. J. Headache 33, 208–213.

Mulvihill, M. M., & Nomura, D. K. (2013). Therapeutic Potential of Monoacylglycerol Lipase Inhibitors. Life sciences92(8-9), 492-497. https://doi.org/10.1016/j.lfs.2012.10.025

Rog, D.J., Nurmikko, T.J., Friede, T., and Young, C.A. (2005). Randomized, controlled trial of cannabis-based medicine in central pain in Multiple Sclerosis. Neurology 65, 812–819.

Ware, M.A., Wang, T., Shapiro, S., Robinson, A., Ducruet, T., Huynh, T., Gamsa, A., Bennett, G.J., and Collet, J.-P. (2010). Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ Can. Med. Assoc. J. J. Assoc. Medicale Can. 182, E694–E701.

Wilsey, B., Marcotte, T., Deutsch, R., Gouaux, B., Sakai, S., and Donaghe, H. (2013). Low-dose vaporized cannabis significantly improves neuropathic pain. J. pain Off. J. Am. pain Soc. 14, 136–148.

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