July/August 2021

Combating Chronic Pain
By Bonnie Johnson, MS, RDN, HCP
Today’s Geriatric Medicine
Vol. 14 No. 4 P. 22

Cannabis has been known as an effective analgesic for centuries, if not millennia.

It’s no secret, there’s a major health war being fought, and pain is the enemy. A 2018 report revealed that chronic pain was the most common reason adults in the United States seek medical care. The 2016 survey detailed in this report showed that about 20% of American adults—50 million people—were suffering from chronic pain and 8% had experienced pain so severe that it restricted or changed at least one major daily activity.1 The list of currently available treatments for pain is long: prescription and nonprescription drugs, injections, herbal remedies, physical therapy, massage, acupuncture, and surgery, to name a few. Yet traditional treatments for chronic pain have remained relatively unchanged since the 1980s, when pain specialists started using opioids to treat long-term, noncancer pain.2 In the alternative and complementary medicine space, treating pain has become much more of an art, and as cannabis is legalized for medicinal use in more and more states, cannabis has become a powerful tool. Moreover, as opioids lose favor in chronic pain management, even traditional clinicians are interested in the role cannabis may play to diminish opioid use and dose requirements.3

Patients and health care providers alike cite pain as that most common condition for the use of cannabis as medicine. Critically, the 2017 National Academies of Sciences, Engineering, and Medicine report, “The Health Effects of Cannabis and Cannabinoids,” named only three conditions with conclusive or substantial evidence for which cannabis or cannabinoid treatment were effective treatments, and chronic pain was one of them.4 This has resulted in expanded use of cannabinoid treatment in chronic pain as well as research into the mechanisms by which it works and potential new therapeutics based on cannabinoid structures.

Of course, cannabis in the treatment of pain isn’t novel or revolutionary. A cannabis preparation known as “mafeisan” is mentioned in the writing of Hua Tho, a second-century Chinese physician who dissolved cannabis powder in wine and used it as the first recorded general anesthesia for surgery.5 Now, 39 states and Canada have legalized cannabis for medicinal use. In Colorado, where medical cannabis has been legal since 2001, “severe pain” is listed as one of the conditions recognized for legal use. A 2014 survey showed that 94% of medical cannabis identification cardholders in Colorado received their “medical cards” due to “severe pain.”6

More recent surveys show some evidence that individuals are replacing the use of conventional pain medications such as opioids with cannabis. Data from one Michigan medical marijuana dispensary suggest that medical cannabis use in pain patients was associated with 64% reduction in opioid use.7 A larger survey analyzed prescription data from Medicare Part D enrollees in states with medical access to cannabis, results of which suggested a significant reduction in the prescription of conventional pain medications such as opioids.8 Despite all this evidence, the FDA hasn’t approved cannabis for the treatment of pain or any other condition.

Pain
Pain is most often discussed in terms of source, severity, and duration.

Source
Pain generally originates from the following three sources:

• Nociceptive pain is typically the result of tissue injury. Common types of nociceptive pain are arthritis, postinjury, and postsurgical pain.

• Neuropathic pain is caused by nerve irritation. This is associate with conditions such as diabetic or other neuropathy and sciatica.

• Central pain—a name not well agreed-upon—is a third more recently recognized type of pain. It’s caused by a dysfunction of the nervous system without any known origin and can be extremely difficult to treat. One example is pain experienced by patients with fibromyalgia.

Severity
Severity of pain is subjective and varies from patient to patient depending on the following factors:

• signals from injured area, such as inflammation;
• cognitive factors, such as giving attention to the injury;
• contextual factors, such as expectations of pain;
• mood factors, such as existing depression or anxiety;
• chemical factors, such as functioning of the endocannabinoid system; and
• genetics, such as a predisposition for endorphin deficiency.

Duration
In addition, pain responses can be categorized by duration as acute or chronic. Acute pain usually comes on quickly and is caused by something specific, such as a sprained ankle or a paper cut. Acute pain usually lasts fewer than six months, and because it is gone when the underlying cause is gone, a person can go on with life as usual. Chronic pain, on the other hand, is pain that is ongoing, lasting longer than six months, and the underlying cause is difficult to diagnose. People suffering with chronic pain have physical and psychologic effects that can interfere with daily living. Chronic pain can cause muscle tension, fatigue, changes in appetite, depression, anger, and anxiety.

Unlike other pain medications, cannabis has been shown to be effective for all types of chronic pain. In fact, a recent systematic review of a meta-analysis of cannabinoid use for the treatment of chronic pain examined 28 randomized trials among 2,454 patients and showed that, compared with placebo, cannabinoids were associated with greater reduction in pain and greater average reduction in numerical pain ratings.9 As noted in the 2017 National Academies report mentioned earlier, the evidence from current research provides a basis for the medical use of cannabis in the treatment of chronic pain in adults.4

The use of cannabinoids to treat acute pain has proven less successful in trials.10 One recent systematic review concluded, “On the basis of the available randomized controlled trial evidence, cannabinoids have no role in the management of acute pain.”11 However, this may overstate the findings by not recognizing the limitations, similar to those of other cannabinoid trials: small sample sizes, limited duration of treatment, and lack of uniformity of measurement of pain outcomes.

The effects of cannabinoid medicine on pain are mediated through the source of the pain.

Nociceptive Pain
Nociceptive pain results from tissue damage. It’s sometimes referred to as inflammatory pain because when the injury occurs, the damaged tissue releases signals to recruit immune cells, including some inflammatory factors, to start the repair of the damage. These cells release more messengers that activate receptors on nerves that send signals up the spinal cord to the brain, initiating the sensation of pain. Nociceptive pain can be reduced in two ways: by blocking the inflammatory process at the site of the injury or by controlling the effects of pain signals traveling to the brain. Cannabidiol (CBD), tetrahydrocannabinol (THC), and potentially other cannabinoids, can dampen pain through both these pathways. They both have strong anti-inflammatory effects that work at the site of the injury. THC exerts an anti-inflammatory effect by activating the CB2 receptors on immune cells, which control the pain-inducing signals released in response to injury. CBD acts directly on inflammatory signals and shifts the activation of macrophage repair cells from proinflammatory to anti-inflammatory type.12 THC can also modulate pain at the spinal cord and brain directly by binding with CB1 receptors, which increases opioid receptor activation and reduces the sensation of pain.13 CBD influences pain processing by increasing levels of the endogenous “bliss molecule” anandamide, which directly activates CB1 receptors. Beyond its action within the endocannabinoid system, CBD has been shown to enhance the activity of the brain’s primary inhibitory neurotransmitter gamma-aminobutyric acid, which may also dampen pain signals.14

Neuropathic Pain
Neuropathic pain is different from nociceptive pain in that it’s a result of damage to the body’s nervous system, from pinching of nerves or damage from a range of diseases such as multiple sclerosis, diabetes, or HIV. Chemotherapy is another common cause of neuropathic pain due to its damaging effects on the body. Neuropathic pain is especially difficult to treat because it doesn’t result from inflammation that can be remediated with over-the-counter nonsteroidal anti-inflammatory medications such as ibuprofen. The mechanism by which cannabis works in chemotherapy-induced pain is through the activation of serotonin receptors by CBD-rich cannabis preparations.15 Sciatica is an example of neuropathic pain, as well, which involves pinching of the sciatic nerve, causing pain in the lower back and down the leg. In sciatica, there appears to be an increase in CB1 receptors in the spinal cord that, if activated, reduces pain. CB1 receptors can be activated by THC, and the activity enhanced by the ability of CBD to help control anandamide activity.16

Activating CB1 receptors appears to be the primary pathway by which cannabinoids affect the pain signaling pathway in both nociceptive and neuropathic pain. However, overactivation of CB1 receptors with THC can eventually lead to weaker effects. Research suggests the use of a 1 to 1 ratio of THC and CBD in a cannabis preparation may impede the body’s tolerance to THC and/or CB1 activation.17

Central Pain
Central pain is a relatively new term in the field of pain treatment and has yet to be agreed upon by those who diagnose and treat it. It’s pain with no known origin, and it can be very difficult to treat. The classic example of central pain is that experienced by patients with fibromyalgia. While the pain pathway is clear—it arises from a dysfunction in the way pain signals travel to the brain and are processed—the root cause is unknown. Because the diagnosis and treatment are so diverse, research into the effects of cannabis on central pain is difficult to find. However, in a recent study of a small group patients using cannabis to treat fibromyalgia, all participants reported pain symptom improvement, and one-half stopped taking other medications to treat pain.18

CBD for Pain
Despite the intense interest in CBD as a pain reliever, there are few published studies of pure CBD product for pain in humans. Even without such evidence, millions of Americans are using CBD products to treat pain. All other studies have examined THC alone or a combination of THC and CBD. However, it’s accepted that CBD inhibits and/or changes the production of certain inflammatory signals.12 Other studies indicate that CBD can reduce inflammation in both the retina19 and small bowel,20 which shows that it may be promising for the treatment of pain caused by retinal and inflammatory bowel diseases. Several preclinical (rat) studies show that CBD reduces pain and inflammation in models of neuropathic pain due to arthritis.21 Because chronic pain is often associated with depression and anxiety, the use of CBD also appears to relieve pain symptoms by improving mood through the activation of serotonin receptors.22

Administration and Dose
The chemical complexity of cannabis makes it difficult to identify the best dose, strain, and method of administration for treating chronic pain. Most patients report that inhaled, sublingual, or oral consumption of cannabis works, but finding the right dose is difficult. Over time, the effects of cannabis weaken because the body builds tolerance, making it more difficult for THC to activate the CB1 receptors. For long-term cannabis treatment, it’s possible to reduce this tolerance by using a product with a balanced THC to CBD ratio.17

For most patients, the most effective dose is the lowest amount of cannabis required to reduce pain symptoms. One study showed that low doses of cannabis provided little relief and moderate doses produced good pain relief, but high doses actually increased pain levels.23,24 Therefore, taking less and carefully increasing the dose until the optimal effectiveness is reached decreases the potential for developing tolerance and minimizes intoxication.5

Cannabis and Opioids
There’s a considerable amount of interest in the impact cannabis use may have on opioid use in the treatment for chronic pain. Some clinical data indicate that cannabis may reduce the dose of opioid medicines required to treat severe pain.5 In one double-blind, placebo-controlled trial, low-dose cannabis and low-dose oxycodone were administered to patients independently and in combination. The study found that when taken alone, neither had a significant impact on pain scores; however, when taken together, patients were able to both tolerate high-pain stimuli as well as experience substantial levels in pain reduction.25

Sativex
While sparingly approved in the United States, it’s worth mentioning the oral-mucosal spray Sativex, generically known as nabiximols. This is a whole-plant cannabis extract with a 1 to 1 ratio of THC to CBD and contains other cannabinoids, terpenoids, and flavonoids. It’s FDA-approved as a prescription treatment for symptomatic relief of spasticity in adult patients with multiple sclerosis who haven’t responded well to other therapy. Globally, Sativex is approved in the United Kingdom and Spain, and in Canada it’s specifically approved for the treatment for neuropathic pain in adults with multiple sclerosis and as a pain reliever in adult patients with advanced cancer suffering from moderate to severe pain that’s resistant to strong opioids.26,27 Research into Sativex and similar therapeutics could provide valuable data into the efficacy of cannabinoid therapies for additional conditions, provide a basis for more cannabinoid-based pharmacotherapies, as well as provide substantiation for traditional methods of cannabis medicine.

Conclusion
The debate regarding pros and cons associated with the use of medical cannabis will carry on well beyond the deliberations into expanded legalization which will hopefully result in more and more clinical research. In the meantime, if there’s one condition for which cannabis should be considered as a more mainstream treatment, it’s chronic pain. While questions remain about proper dose and administration, safety and efficacy are more conventionally accepted, and patients should and will demand that clinicians know more about cannabis and the treatment of chronic pain.

— Bonnie Johnson, MS, RDN, HCP, is a registered dietitian nutritionist, food industry consultant, speaker, and certified cannabis consultant. She spends much of her volunteer time educating a variety of audiences about the benefits and potential risks of using cannabis to treat chronic pain, anxiety, insomnia, and other ailments. As a consultant, she works with the food and cannabis industries to bring science-based education to health care professionals and category-changing products to market.

References
1. Dahlhamer J, Lucas J, Zelaya, C, et al. Prevalence of chronic pain and high-impact chronic pain among adults–United States, 2016. MMWR Morb Mortal Wkly Rep. 2018;67(36):1001-1006.

2. Collier R. A short history of pain management. CMAJ. 2018;190(1):E26-E27.

3. Campbell G, Hall W, Peacock A. Effect of cannabis use in people with chronic non-cancer pain prescribed opioids: findings from a 4-year prospective cohort study. Lancet Public Health. 2018;3(7):e341-e350.

4. National Academies of Sciences, Engineering, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. https://www.nap.edu/read/24625/chapter/1. Published 2017.

5. Backes M. Cannabis Pharmacy. New York, NY: Black Dog and Leventhal Publishers; 2017:245-249.

6. Light MK, Orens A, Lewandowski B, Pickton T; The Marijuana Policy Group. Market size and demand for marijuana in Colorado. https://www.colorado.gov/pacific/sites/default/files/
Market%20Size%20and%20Demand%20Study,%20July%209,%202014%5B1%5D.pdf. Accessed December 21, 2020.

7. Boehnke KF, Litinas E, Clauw DJ. Medical cannabis use is associated with decreased opiate medication use in a retrospective cross-sectional survey of patients with chronic pain. J Pain. 2016;17(6):739-744.

8. Bradford AC, Bradford WD. Medical marijuana laws reduce prescription medication use in Medicare part D. Health Aff (Millwood). 2016;35(7):1230-1236.

9. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015; 313(24):2456-2473.

10. Ahmad S, Hill KP. Medical Marijuana: A Clinical Handbook. Philadelphia, PA: Wolters Kluwer; 2021:357-361.

11. Stevens A, Higgins M. A systematic review of the analgesic efficacy of cannabinoid medications in the management of acute pain. Acta Anaesthesiol Scand. 2017;61(3):268-280.

12. Klein, TW. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol. 2005;5(5):400-411.

13. Cossu G, Ledent C, Fattore L, et al. Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse. Behav Brain Res. 2001;118(1):61-65.

14. Bakas T,van Nieuwenhuijzen P, Devenish S, McGregor I, Arnold J, Chebib M. The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAA receptors. Pharmacol Res. 2017;119:358-370.

15. Ward SJ, McAllister SD, Kawamura R, Murase R, Neelakantan H, Walker EA. Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT1A receptors without diminishing nervous system function or chemotherapy efficacy. Br J Pharmacol. 2014;171:636-645.

16. Siegling A, Hofmann HA, Denzer D, Mauler F, De Vry J. Cannabinoid CB(1) receptor upregulation in a rat model of chronic neuropathic pain. Eur J Pharmacol. 2001;415(1):R5-R7.

17. Russo EB, Guy GW, Robson PJ. Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex®, a cannabis‐based medicine. Chem Biodivers. 2007;4(8):1729-1743.

18. Habib G, Artul S. Medical cannabis for the treatment of fibromyalgia. J Clin Rheumatol. 2018;24(5):255-258.

19. Liou GI, Auchampach JA, Hillard CJ, et al. Mediation of cannabidiol anti-inflammation in the retina by equilibrative nucleoside transporter and A2A adenosine receptor. Invest Ophthalmol Vis Sci. 2008;49(12):5526-5531.

20. Picardo S, Kaplan GG, Sharkey KA, Seow CH. Insights into the role of cannabis in the management of inflammatory bowel disease. Therap Adv Gastroenterol. 2019;12:1756284819870977.

21. Hammell DC, Zhang LP, Ma F, et al. Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis. Eur J Pain. 2016;20(6):936-948.

22. Gregorio DD, McLaughlin RJ, Posa L, et al. Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. Pain. 2019;160(1):136-150.

23. Wallace M, Schulteis G, Atkinson J, et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology. 2007;107(5):785-796. 

24. Wallace M, Furnish T. What steps should be taken to integrate marijuana into pain regimens? Pain Manag. 2015;5(4):225-227.

25. Cooper, Z, Bedi G, Ramesh D. Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability. Neuropsychopharmacology. 2018;43(10):2046-2055.

26. ElSohly MA, Radwan MM, Gul W, Chandra S, Galal A. Phytochemistry of Cannabis sativa L. Prog Chem Org Nat Prod. 2017;103:1-36.

27. Government of Canada. Information for health care professionals: cannabis (marihuana, marijuana) and the cannabinoids: dried or fresh plant and oil administration by ingestion or other means: psychoactive agent. https://www.canada.ca/content/dam/hc-sc/documents/services/drugs-medication/cannabis/information-medical-practitioners/information-health-care-professionals-cannabis-cannabinoids-eng.pdf. Published October 2018.

PAIN + CANNABIS + THE ENDOCANNABINOID SYSTEM
• Anandamide and 2-arachidonoylglycerol are produced by injured tissues via distinct biochemical pathways.

• Anandamide mobilizes in response to inflammation and nerve injury and modulates nociceptive signals by activating local CB1 receptors.

• THC acts directly on CB2 receptors on immune cells to control inflammation and the pain-inducing signals released in response to injury.

• CBD acts directly on inflammatory signals and shifts the activation of macrophage repair cells from pro-inflammatory to anti-inflammatory type.

• THC acts directly on CB1 receptors in the spinal cord and brain to increases opioid receptor activation and reduce pain.

• CBD slows down the natural degradation of anandamide so it can bind with CB1 and CB2 receptors to interrupt or changed pain signals.

— Sources: Klein TW. Cannabinoid-Based Drugs as Anti-Inflammatory Therapeutics. Nat Rev Immunol. 2005;5(5):400-411; Cossu G, Ledent C, Fattore L, et al. Cannabinoid CB1 Receptor Knockout Mice Fail to Self-Administer Morphine but Not Other Drugs of Abuse. Behav Brain Res. 2001;118(1):61-65.