Investigating Pain Caused by Rattlesnake Envenomation and the Possible Analgesic Effects of Antivenom

Abstract

Approximately 5.8 billion humans reside at or live near (~1 hour) a snake’s habitat, causing most of the world population to be at risk to encounter a snakebite. According to the World Health Organization (WHO), approximately 400,000 people worldwide experience snake envenomations per year, and of that population, more than 148,000 people die as a result. The Centers for Disease Control and Prevention (CDC) reports that in the U.S. there are between of 5,000 - 8,000 venomous snakebite cases per year with approximately 7 deaths. Pit vipers, that include rattlesnakes, copperheads, and cottonmouths, are the largest group of venomous snakes in the U.S. and Fifty to fifty-five percent of snake envenomations in the U.S. are as a consequence of rattlesnake bites. In Arizona, there are approximately 250 cases of rattle snakebites reported annually. Pain, due to snake venom, is an understudied subject and further investigation might lead to a better understanding of its development during an envenomation. Non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are rarely used to treat the pain associated to an envenomation as they present a significant risk of bleeding due to risk of platelet aggregation inhibition, a problem of great concern in patients who develop coagulopathy or thrombocytopenia due to the snake bite. For this reason, opioids such as morphine, oxycodone, hydromorphone, and fentanyl are commonly used to reduce pain in snake bite victims. However, the overuse of opioids could potentially lead to adverse symptoms post-discharge of a snake envenomated victim as well as contribute to the worrisome opioid epidemic happening in the U.S. According to the CDC, between 2017-2018, 2 out of every 3 opioid deaths are related to synthetic opioids. Antivenom, which includes Crotiladae polyvalent immune Fab (ovine) antivenom (CROFAB), immunized in sheep and the Crotiladae equine immune F(ab’)2 (equine) (ANAVIP), immunized in horses, is a crucial therapy during a rattlesnake envenomation. Antivenom has never been evaluated for any analgesic effects it may have. Using descriptive variables, we attempted to evaluate possible analgesic effects of CROFAB or ANAVIP after rattlesnake envenomation using retrospective data obtained from the Arizona Poison and Drug Information Center between the years 2018 and 2019. We found that most pain symptoms observed during a rattlesnake envenomation can be linked to snake venom Phospholipase A2 and snake venom metalloproteinase. We also observed that males suffered more envenomations compared to females between 2018 and 2019. Finally, while we obtained inconclusive data, specifically in effectively quantifying pain objectively, we still suggest that antivenom may have analgesic effects during envenomation cases where pain is not severe. The findings of this retrospective study both in terms of analgesia with either one of the anti-venoms or differential effect of either CROFAB or ANAVIP antivenom needs to be confirmed with a prospective controlled study. The differential effect of different types of antivenom might be artificially inflated due to the larger number of patients in the CROFAB group. Finally, the lack of need of opiate or opioids in management of envenomation also needs to be further evaluated in a prospective study.