The Effects of Topical Cobratoxin in Alleviating Muscular Discomfort A randomized, double-blind, placebo-controlled clinical trial Jay K Udani, MD 1,2 , Michael N Pakdaman, MD 1 1 Medicus Research LLC, Agoura Hills, CA 91361, 2 Medical Director, Northridge Hospital Integrative Medicine Program Purpose To evaluate the efficacy of topical application of Cobrazol in alleviating muscle pain and to compare these effects with a topical placebo product. Introduction Musculoskeletal pain affects approximately 70 million individuals in the US and may arise from muscle, ligaments, bones, or joints 1 . Common pharmacological interventions to help manage musculoskeletal pain include aspirin, acetaminophen, non-steroidal anti-inflammatory drugs (NSDAIDs), opioid analgesics, and muscle relaxants. While widespread, these therapy options pose potential adverse effects including gastrointestinal problems, kidney and liver damage, and drug dependence 2 . Snake venom has been used in many cultures as an natural analgesic. Snake venoms are rich in peptides that have been shown to modulate pain 3 . Animal models have demonstrated the antinociceptive activity of snake venoms, which contain high amounts of neurotoxins targeting nicotinic acetylcholine receptors (NAChR) 4 . cobratoxin (CTX), a post- synaptic neurotoxin isolated from Naja naja atra, has been shown to possess analgesic activity through an opiate independent mechanism. Crotamine, one of the main components in the venom of Crotalus durissus terrificus was also found to have analgesic effects 5 . While the analgesic effects of these products have been well-described, this is the first randomized, double-blind, placebo controlled clinical trial to evaluate the effect of natural topical snake venom in reducing muscle pain. References 1.Patel KV, Guralnik JM, Dansie EJ, Turk DC. Prevalence and impact of pain among older adults in the United States: findings from the 2011 National Health and Aging Trends Study.Pain. 2013 Dec;154(12):2649-57. 2.Raja R, Kingsbury SR, Wise E, Conaghan PG. Primary care approaches to musculoskeletal multiple-site joint pain pharmacological therapy: a survey of general practitioners. Prim Health Care Res Dev. 2014 Jan 22:1-6. 3.Grasset E. The cobra neurotoxin; pharmacology and clinical applications in the treatment of pain. Med Hyg (Geneve) 1952; 10: 55-8. 4.Chen ZX, Zhang HL, Gu ZL, Chen BW, Han R, et. al. A long-form a-neurotoxin from cobra venom produces potent opioid-independent analgesia. Acta Pharmacologica Sinica 2006 April; 27 (4): 402-408. 5.Mancin AC, Soares AM, Andrião-Escarso SH, Faça VM, Greene LJ, Zuccolotto S, Pelá IR, Giglio JR. The analgesic activity of crotamine, a neurotoxin from Crotalus durissus terrificus (South American rattlesnake) venom: a biochemical and pharmacological study. Toxicon. 1998 Dec;36(12):1927-37. Financial Disclosure: Jay K. Udani and Michael N. Pakdaman are employed by Medicus Research. Medicus Research received research funding for this study from Nature’s Innovation, Inc. (Orem, Utah). Michael N. Pakdaman, Jay K. Udani, and Medicus Research do not endorse any brand or product. Medicus Research does not have any financial interests in any supplement or nutritional product manufacturer or distributor. Study Product The active product was Cobrazol (Nature’s Innovation, Inc., Orem, Utah), a homeopathic blend consisting of Naja Tripudians (Asian Cobra Venom), Crotalus Horridus (Southwestern Rattlesnake Venoma), Lachesis Muta (South American Bushmaster Venom), Capsicum Annum, and Arnica Montana. The placebo product was composed of the base ingredients methylcellulose, distilled water, yellow coloring, isopropyl alcohol, and menthol scent. Study participants were instructed to apply the product, either active or placebo, topically to the affected area twice daily for 2 weeks. Study Participants The study aimed to enroll healthy volunteers with occasional muscle discomfort, identified as having pain or discomfort at a level of 5 or greater on a 10-point visual analog scale (VAS) for at least 4 days per week. Clinical Trial Design Healthy volunteers were recruited through online advertising and through our database of clinical trial participants. Study participants were phone screened to identify those with muscle pain or discomfort. The study included three in-clinic visits, consisting of an initial screening visit, a baseline visit, and a follow-up visit. During the screening visit, a comprehensive history and physical examination were performed. Areas of muscle pain rated ≥ 5 on a 10- point VAS for pain severity were documented. Up to three areas of muscle pain would be followed throughout the study. Upon discharge from the screening visit, daily diaries were dispensed and a one-week run-in period was used to identify individuals who complained of pain for at least 4 days per week. Additionally, participants consuming analgesics or products aimed to relieve muscle pain were required to undergo a 2-week washout period prior to randomization. At the baseline visit, study participants were randomized to receive either active study product or placebo. A 14-day supply of study product was dispensed, as well as daily pain and product compliance diaries. Study participants returned for a final follow-up visit where daily diaries were collected, allowing for assessment of daily pain levels as well as product compliance throughout the course of the study. Results Thirty five subjects were screened and 23 were randomized to receive Cobrazol or placebo. 20 subjects completed the study, 12 from the active group and 8 from the placebo group. The average pain level at the baseline visit was 5.83 in the active group and 5.88 in the placebo group. From the baseline visit to the 2-week follow-up visit, the average pain level had decreased by 32% to 3.96 (p=0.001, within-group) and by 8.5% to 5.38 in the placebo group (p=0.381, within-group) (Figure 1). Additionally, within-groups analysis of daily diary data in the active group revealed significant reductions in pain from baseline to week 1 at multiple body sites in the active group only (Figure 2). From baseline to week 2, a reduction in morning neck pain by 35.8% was noted in the active group, compared to a 16.7% reduction in the placebo group (Figure 3). Conclusion This is the first randomized, double-blind, placebo-controlled clinical trial evaluating the efficacy of topical snake venom in relief of muscle pain. Our study found that a combination of various snake venoms were effective when compared to placebo in reducing chronic musculoskeletal pain and discomfort. 5.83 3.96 5.88 5.38 3 4 5 6 Baseline Week 2 Average Pain Level on 10-Point VAS (Recorded in-clinic) Active Placebo * Figure 1: This graph represents the average levels noted in clinic on a 10- point visual analog scale (VAS). Within-group analysis demonstrated a significant decline (*) in the average pain among those in the active group (p=0.001). There was no significant change in the placebo group (p=0.381). Figure 3: Data on the 10-point visual analog scale for pain was recorded for each designated body location on a daily basis. Between-groups comparison of evening neck pain data reveals a significant difference between product and placebo (*) at week 1 (p=0.022) and week 2 (p=.0.027). 4.91 3.48 3.15 5.24 4.78 4.37 3 4 5 6 Baseline Week 1 Week 2 Average Evening Neck Pain (per daily diary) Active Placebo * Active Group Placebo Group Body Region and Time of Day Daily Pain Scale % Change from Baseline to Week 1 p-value Daily Pain Scale % Change from Baseline to Week 2 p-value Daily Pain Scale % Change from Baseline to Week 1 p-value Daily Pain Scale % Change from Baseline to Week 2 p-value Neck – Morning -18.14 % 0.047 -24.22 % 0.007 -4.04 % 1.000 -9.33 % 0.219 Neck – Evening -29.17 % 0.002 -35.83 % 0.0004 -8.89 % 0.073 -16.59 % 0.014 Joint – Morning -16.53 % 0.267 -23.91 % 0.001 -10.92 % 0.754 -24.61% 0.754 Joint – Evening -17.19 % 0.004 -23.97 % 0.001 -13.69 % 0.754 -26.37% 0.021 Back – Morning -11.86 % 0.060 -21.34% 0.001 -10.52 % 0.044 -16.36% 0.020 Back – Evening -21.49 % 0.013 -29.75 % 0.003 -16.49 % 0.180 -21.24% 0.015 Figure 2: Within-groups analysis of the change in 10-point visual analog scale (VAS) pain scores recorded in the daily diaries. Note the significant reductions in week 1 for neck-morning, neck-evening, joint-evening, and back-evening in the active group. There were no significant reductions in pain scores at week 1 among the placebo group. View publication stats View publication stats