ASRA Pain Medicine Update

Cannabis has been used for both recreational and medical purposes for several centuries. Hashish, which is a form of cannabis, was found in Egyptian mummies.¹ Cannabis was prohibited in the United States in 1937 and remained relatively unpopular until the 1960s, when its use became in demand among adolescents and young adults.² Use of cannabis has continued to increase since then, especially after 2007. From 2007–2014, reported use increased from 5.8% to 8.4 %. Declining prices, change in public perception, and the awareness of medical cannabis may have contributed to this trend.³

Some studies suggest that CBD is effective for treating neuropathic pain, yet research is still ongoing to determine its efficacy in chronic pain conditions and to elucidate any side effects or hazards associated with its use.

Currently, cannabis is the most popular illicit drug in the United States. A recent survey indicated that recreational use of marijuana remains the most popular indication (89.5%). Marijuana for combined recreational and medical use is also popular (36.1%), followed by medical use alone (10.5%).⁴

Cannabis produces a variety of compounds known as cannabinoids that have not been detected in other plants. Some cannabinoids can be activated to produce the two most well-known cannabinoids: tetrahydrocannabinol (THC) and cannabidiol (CBD).

Use of cannabinoids is also rising because of their increased availability in stores and online. CBD can be found in retailers in all 50 states and in more than 40 countries; however, legislation regulating their use varies between states. CBD oil is made from high CBD and low THC hemp, which makes it different from other medical marijuana products that usually have high concentrations of THC. Treating chronic pain and other medical conditions with THC and CBD oil specifically represents one of the hottest and most controversial topics in the medical field.

The therapeutic effect on chronic pain is thought to be produced by modulation of signal transduction pathways in addition to interactions with the endocannabinoid and serotonin systems. Some studies suggest that CBD is effective for treating neuropathic pain, yet research is still ongoing to determine its efficacy in chronic pain conditions and to elucidate any side effects or hazards associated with its use.

Regardless of whether it is efficacious, many patients with chronic pain who are undergoing interventional pain procedures will be using these products. Physicians must understand the effects of cannabinoids, including CBD, on anticoagulation. Does it place patients at increased risk for bleeding?

Blood coagulation studies indicate that organic cannabis extract and the major cannabinoids, THC and cannabinol (CBN), show considerable antithrombotic activity in vitro. In addition, CBD showed mild anticoagulating effects. Furthermore, the authors demonstrated that 50% clotting times in obese and lean rats treated with cannabis extracts were 1.5- to 2.0-fold greater than their controls (rats not treated with cannabis extracts). The authors also suggested that cannabis may be used in the setting of hypercoagulable states as may exist in patients with diabetes type 2.⁵ In other studies, CBD oil was found to affect platelets and anticoagulants by suppressing their production and thereby potentially increasing bleeding tendencies.⁶

In addition, CBD can interact with warfarin and increase the risk of bleeding complications. CBD is metabolized through the hepatic P450 enzyme system, which warfarin also uses. Both share the same isoforms in their metabolism (CBD acts on CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 and warfarin acts on five of them). CBD can competitively compete with the metabolism of warfarin by occupying the same isoforms, thereby decreasing the degradation of warfarin. Patients on warfarin who will be using cannabis should have their international normalized ratio monitored to detect any interaction between both drugs.^7–10

The problem is even bigger with synthetic cannabis. Synthetic cannabis is a mixture of different plant materials that have been combined with cannabinoids produced in the laboratory. Stores sell the drug under different names such as spice, K2, and fake weed. Synthetic cannabis is not legally regulated, and users should exercise caution when considering whether to use those compounds. For example, an individual in Maryland experienced fatal bleeding after the use of synthetic cannabis which was thought to be laced with brodifacoum (rat poison).¹¹ Dozens of similar cases were identified in Illinois.¹² Brodifacoum blocks the effects of vitamin K, leading to bleeding. Similar cases were identified in other states and the number of fatalities is rising.¹³

Cannabinoids can potentially increase bleeding tendencies through various mechanisms. We need to educate patients who are being considered for interventional pain procedures about this risk. In addition, ASRA should consider adding official recommendations to its guidelines for interventional pain and spine procedures for patients using cannabinoids to better guide physicians in their practices.

References

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6. HealthMag Reviews. Possible CBD oil side effects. From https://www.healthmagreviews.com/cbd-oil-side-effects/ Accessed September 20, 2018.
7. Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012;92(4):414–417. https://doi.org/10.1038/clpt.2012.96
8. Wadelius M, Chen LY, Downes K, et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. J Pharm.2005;5(4):262–270. https://doi.org/10.1038/sj.tpj.6500313
9. Jiang R, Yamaori S, Takeda S, Yamamoto I, Watanabe K. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci.2011;89(5–6):165–170. https://doi.org/10.1016/j.lfs.2011.05.018
10. Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life Sci.2011;88(15–16):730–736. https://doi.org/10.1016/j.lfs.2011.02.017
11. American Academy of Family Physicians. Synthetic cannabinoid poisoning outbreak poses challenges. 2018. https://www.aafp.org/news/health-of-the-public/20180518cannabinoids.html. Accessed September 11, 2018.
12. Illinois Department of Public Health. Synthetic cannabinoids. http://dph.illinois.gov/topics-services/prevention-wellness/medical-cannabis/synthetic-cannabinoids. Accessed September 11, 2018.
13. Linnane, R. Wisconsinites are smoking rat poison. How did we get here? 2018. https://www.jsonline.com/story/news/2018/09/04/wisconsinites-smoking-rat-poison-k-2-spice-synthetic-marijuana/1116686002. Accessed September 11, 2018.