Abstract: The $71 billion global pain relief market is characterized by serious unmet needs for safety, efficacy, and value. Topical pain relief, which comprises 13% of this market, is a safe, effective alternative for many conditions in which systemic administration is either not desirable or unnecessary. Among topical agents, cannabinoids are attractive for their interaction with close to 80 pathways involved in pain and/or inflammation, and their lack of toxicity or addiction potential. More controlled studies are required, though, before topical cannabinoids become widely accepted among pain specialists.
A Call for Formal Clinical Evaluation
The goals of safety and efficacy in pain management underscore the many unmet needs in this medical specialty. The 2019 worldwide pain relief market has been estimated at $71 billion, with projected growth approaching 4% per year through 2027. Topical agents, which target mild to moderate pain, comprise nearly 13% of this market — $8.9 billion. Topical formulations are available to provide immediate, delayed, or long-term delivery of active ingredients. While topical administration is unsuited for treating deep tissue pain, it allows precision targeting of localized pain, systemic safety, rapid onset, and a low risk of tolerance or abuse2.
The topical pharmacopeia includes many agents originally developed as oral or injected dosage forms, including salicylates, non-steroidal anti-inflammatory drugs (NSAIDs), capsaicinoids, corticosteroids, and opioids. For example, while oral corticosteroids are used to treat a wide range of systemic inflammatory disorders, including chronic obstructive pulmonary disease, lupus, inflammatory bowel disease, and skin disorders affecting large areas of the body3, topical versions of these medicines treat localized eczema, contact dermatitis, psoriasis, and hemorrhoids4. Many corticosteroid creams are available over the counter at standardized, safe concentrations or, for more severe diseases, by prescription.
The Oral-Topical Connection
The major benefit of topical drug administration is the ability to treat localized pain while minimizing systemic dosing and side effects. For example, systemic adverse events occur in one-third of patients receiving the steroid clobetasol orally but are absent following topical administration5.
Many other pharmaceutical products have successfully transitioned from oral or injected administration to topical, including antifungals, antibacterials, and — most relevant to this discussion — analgesics.
Some topical analgesics, such as the counter-irritants menthol or camphor, or numbing agents (e.g., lidocaine), have no oral counterpart6. Most agents relieve pain topically through mechanisms similar to their systemic activity. Topical salicylates used for localized conditions such as sprains, arthritis, and muscle aches work similarly (through inhibiting cyclooxyrgenase enzymes) to oral aspirin, which is taken regularly by between 40 and 50 million Americans.
Their long history of safe use as systemic medicines makes salicylate derivatives an attractive agent in health and personal hygiene products. Topical salicylates are widely available over the counter for treating both acute and chronic conditions, including strains or sprains, tendinopathy, muscle aches, osteoarthritis, neuropathic pain, and others8.
Similarly, NSAIDs, originally introduced as oral drugs, have been reformulated for topical administration. A review of clinical studies found several agents that were as safe and effective as their oral counterparts in treating osteoarthritis of the knee9. At the top of the list were topical diclofenac, ibuprofen, ketoprofen, and piroxicam, which were assessed as superior to acetaminophen and as good as oral NSAIDs for pain relief, but with lower adverse event risk significantly compared with oral/systemic formulations.
The Case for Topical Cannabinoids
The search for safe, effective pain relief has frequently turned to “natural” or non pharmaceutical agents. Analgesic capsaicinoids, which are derived from chili peppers, are just one example. QUTENZA® (Averitas Pharma, Inc.), an FDA-approved 8% capsaicin patch, has been used successfully to treat nerve pain10. Many other natural products have been studied too, mostly as oral or aromatherapy agents11.
Cannabinoids represent a novel (from a pharmaceutical development perspective) class of pain relief with potential for both oral and topical administration. Primarily found in cannabis products, cannabinoids act on one or both cannabinoid receptor types: CB1 receptors, found mostly in the brain, limbic system, and the eye12, and CB2 receptors located mostly in immune cells13.
Of the more than 80 cannabinoids tetrahydrocannabinol (THC) is best known for its euphoric effects, while cannabidiol (CBD) is nonpsychotropic14. CBD shows low affinity for CB1 and CB2 receptors responsible for the “high” of THC. Instead, CBD acts as a complex agonist and antagonist on close to 80 distinct molecular targets, including enzymes, ion channels/receptors, G-protein coupled receptors, transporter proteins, and nuclear receptors15. One of these targets is the, which among other effects regulates mood16.
CBD’s activity in so many biological pathways mediating pain, inflammation, and mood is a classic signal of potential “draggability.” Retrospective/observational studies demonstrate that cannabis use improves symptom scores for rheumatic diseases17. One trial examining cannabis use in more than 10,000 patients showed significantly lowered pain among the 20% of subjects who were cannabis users.
The Science
Randomized, controlled clinical trials on cannabis in pain relief tend to be small and do not always examine CBD alone, but combined with other cannabinoids. One small study found decreased reliance on opioid painkillers for cancer patients receiving cannabis during early treatment18.
...“the vast literature on oral-topical switches suggests a possible role for CBD in the alleviation of localized pain”...
Many of these studies combine THC with CBD, which confounds the issue of which compound is responsible for the effect. For example, a double-blind, placebo-controlled study on fibromyalgia found a statistically significant decrease in pain scores, concluding that “phytocannabinoids can be a low-cost and well-tolerated therapy to reduce symptoms and increase the quality of life of patients with fibromyalgia.”19
Another small study with multiple sclerosis patients of an oral spray containing both THC and CBD found “improved spasticity and pain in secondary progressive MS patients.”20
Recognizing the confusion inherent in such studies, Australian researchers have undertaken the largest, most comprehensive test of CBD alone. These investigators will analyze safety and efficacy data in a dose-ranging study of CBD alone in patients with advanced cancer undergoing palliative care21.
A previous study examining the effects of oral CBD and three other cannabinoids (excluding THC) found that 53% of patients were able to reduce or eliminate opioids22.
Very few studies examining topical CBD for pain exist but results from several high-quality trials are encouraging. One small crossover study using a commercial CBD oil on 29 patients with peripheral neuropathy concluded that “the transdermal application of CBD oil can achieve significant improvement in pain and other disturbing sensations in patients with peripheral neuropathy. The treatment product was well tolerated and may provide a more effective alternative compared to other current therapies in the treatment of peripheral neuropathy.”23
Another preclinical trial in a rat knee osteoarthritis model24 used CBD gels of various concentrations. The study found that treated animals recovered to near-baseline activity. Perhaps more significant, from the perspective of pharmaceutical development, is that plasma CBD concentrations were linear with respect to loading dosage. The authors concluded that “topical CBD application has therapeutic potential for relief of arthritis pain-related behaviors and inflammation without evident side effects.”
Another double-blind, placebo-controlled study of 60 patients with myofascial pain25 randomized subjects to receive either topical CBD or a placebo, applied twice daily. Muscle activity was measured on days 0 and 14. At study’s end, 14 of those receiving CBD showed decreased masseter muscle activity of 11% (right masseter muscles) and 13% (left), while the decrease in the control group averaged 1.7%; pain intensity also decreased in the treatment group by 70.2%, compared with just under 10% for the control group, a highly significant difference.
Most recently, a small, randomized, double-blind crossover study in humans examined the effectiveness of a topical CBD preparation for treating neuropathic pain of the lower extremities26. Investigators found “a statistically significant reduction in intense pain, sharp pain, cold and itchy sensations in the CBD group,” and no adverse events. The authors wrote that transdermal CBD “may provide a more effective alternative compared to other current therapies in the treatment of peripheral neuropathy.”
On aggregate, these preclinical and clinical cannabinoid studies make a strong case for the formal, large-scale study of CBD for relieving mild-to-serious chronic pain in patients currently relying on conventional oral pain relief, especially those who depend on opioids to conduct activities of daily living. Additionally, the vast literature on oral-topical switches suggests a possible role for CBD in the alleviation of localized pain resulting from injury, disease, or medical interventions (e.g., surgery, radiation).
Real-World Results
A 2020 review27 of CBD in rheumatology care lamented the lack of formal clinical evidence supporting adoption of CBD in standard healthcare practice. The authors note CBD’s status, as defined by the World Health Organization, as safe and lacking abuse potential but noted that unregulated manufacturing practices have led to inconsistent product quality. The authors recommend that patients “obtain a product with certification of Good Manufacturing Practices, initiate treatment with a nighttime low dose and have defined outcome goals within a reasonable time frame.”
This advice is framed against the backdrop of already high acceptance of and satisfaction with topical CBD preparations among various patient groups28, particularly among patients undergoing palliative care. This study found that 24% of patients already used CBD, either topically or through vaping, and that these users reported improvements in pain.
My chiropractic practice has experience using both topical and ingestible CBD-based products. Among the products with which we are most familiar, the Helix Professional Pain Relief with CBD product has resulted in many positive outcomes. This product is available in two strengths, and each comes in a 2 oz and 4 oz tube. Helix CBD products are manufactured to the highest Good Manufacturing Practices standards and are only available through pain care specialists. Healthcare practitioners interested in trying this product should visit www.helix4pain.com and request product samples.
Our patients have also experienced positive outcomes with sublingual and ingestible CBD treatments. Haleigh’s Hope manufactures several such products, which may be found at https://haleighshope.com/shop/.
Conclusion
The case for formal investigation of topical CBD treatments for mild to moderate pain is based on the myriad of interactions between CBD and human biology, promising preclinical and clinical studies, the search for nonaddictive alternatives to opioids, and the desire for oral-to-topical switches to treat pain while reducing potential side effects, compared with systemic administration.
That CBD, particularly as a topical treatment, satisfies safety requirements for new drugs is established science. All that remains is the wifi to venture outside the box of conventional drug development and conduct more clinically relevant studies.
With a private practice in Fairfield, NJ for more than 30 years, Dr. Joseph D. Salamone, D.C., DAAPM, FRCCM, founded the American Academy of Hospital Chiropractors where he was one of four in the country to be on call in the emergency room. Dr. Salamone's professional memberships include the National Chiropractic Research Honor Society, Association of New Jersey Chiropractors, American Chiropractic Association, American Academy of Pain Management, American Academy of Hospital Chiropractors, and the Council on Sports Injuries and Physical Fitness. He completed the Masters Certification Program in Spinal Bio-mechanics and Whiplash Acceleration/ Deceleration injuries and is board certified and licensed to practice in New Jersey, New York, Pennsylvania, and Michigan. You may email Dr. Salamone at [email protected], call 973-464-0311 or visit www.drjosephsalamone.com.
For references please visit www.bit.ly/4407Salamone
