Epibatidine: A Possible Solution to the Opioid Epidemic

By: Morgan Hampton

To what lengths would you go to alleviate pain? Would you risk long-term physical and mental reliance? Imagine that was your only option for relief. This is a problem that many patients face when over-the-counter painkillers stop working. One of humanity’s greatest pursuits is the alleviation of pain. The United States has taken this desire and capitalized on it, creating the Opioid Epidemic. Opioids are highly addictive drugs that were found to be very effective at relieving pain, beginning in the 1800s. Unfortunately, the side effects are arguably incomparable to the short-term relief that opioids provide. Many patients are left with severe withdrawal symptoms and reliance on opioids, leading to addiction and potential overdose. Scientists are working to develop new methods of pain relief without the risk of addiction. One possible solution lies in the forests of Ecuador and Peru: Anthony’s Poison Arrow Frog (Epipedobates anthonyi). Epibatidine, a poison found on the skin of the small amphibian, could replace opioids' role in pain relief. 

Figure 1. Epipedobates anthonyi / Anthony’s Poison Arrow Frog

The opioid epidemic has been on the rise since the 1990s. Derived from the opium poppy - a flower native to northern Africa and Europe - opioids have been in use since the 1800s and were said to be a “safe and effective way to alleviate […] suffering” (Lyden, Binswanger, 2019). Opioid use can cause a variety of neurobiological effects from changes in cell biology to alterations in behavior (Grant, 2020). Between the years 1999 and 2019, 500,000 United States citizens died from an overdose of opioids (Centers for Disease Control and Prevention), and currently, opioid usage is responsible for approximately “one hundred deaths per day in the United States” (Grant, 2020). Opioids are detrimental to both addicts and the U.S. economy. In 2017, the “economic cost of the U.S. opioid epidemic [...] was estimated at $1,021 billion” (Luo, 2021). This includes the cost of “opioid use disorder estimated at $471 billion and “fatal opioid overdose estimated at $550 billion” (Luo, 2021). 

With the severity of the opioid epidemic, many scientists are working to develop new drugs that could replace these addictive painkillers. One of these drugs shows great promise: epibatidine. This drug is secreted by Anthony’s Poison Arrow Frog and was found to be “200 times more potent than morphine on a weight basis” (Garraffo, 2009). Classified as an analgesic - a painkilling medicine - epibatidine is extremely effective at relieving pain. Though later found to be toxic, epibatidine is now used to develop similarly effective painkillers. Could epibatidine and other epibatidine-based analgesics help slow the opioid epidemic by replacing addictive painkillers? Epibatidine is a promising alternative to opioids as it appears to be non-addictive. The brain contains multiple types of protein molecules that process, transfer, and react to chemical signals. These proteins are called receptors and each is assigned to process specific substances. Opioid receptors bind to our bodies' natural opioids called endorphins, which provide feelings of pleasure, reduce stress, aid with pain, and can improve one's mood.

Figure 2. Structure of a Nicotinic Acetylcholine receptor

Opioids from outside sources such as methamphetamine, oxycodone, and fentanyl mimic our bodies' natural endorphins, which is what makes them so addictive. Epibatidine acts on nicotinic acetylcholine receptors, or nAChRs for short, rather than opioid receptors (Grant, 2020). Nicotinic acetylcholine receptors are involved in transmitting pain signals. When Epibatidine binds to these receptors, these signals are inhibited, reducing pain in the body. A study of epibatidine’s effects on mice conducted by Dr. John Daly concluded that the “analgesia was not dependent on an opioid receptor” and that the drug's site of action was “shown to be a nicotinic receptor” (Garraffo, 2009). Drugs that act on nicotinic receptors tend to be less addictive, while still providing effective pain relief; “In contrast to morphine, repeated treatment with ABT-594 [epibatidine] did not appear to elicit opioid-like withdrawal or physical dependence” (Bannon et. al., 1998). 

The main concerns with using epibatidine, or using the compound as a base to create other nonaddictive painkillers, are synthesis and safety. Similar to other high-potency drugs such as fentanyl, scientists struggle to find a safe dosage for epibatidine. The analgesic has been shown through multiple trials on mice to cause seizures, paralysis, muscular issues, and even death when it is overly administered. Scientists are turning toward other methods of synthesis to create safer versions of epibatidine. Side effects could potentially be managed by altering the dosage of the drug or by changing components of the epibatidine compound to make it less potent - as seen through research done at Abbott Laboratories, which “synthesized a neuronal nACh[R] agonist named ABT-594 [...] derived from the epibatidine structure” (Salehi et. al. 2019). “A number of different types of epibatidine analogs have been presented” (Carroll, 2009), all exhibiting similar effectiveness to epibatidine. While epibatidine itself can be toxic, these derivatives show fewer threatening side effects and promise possible use as replacements for opioids. 

Epibatidine’s nonaddictive feature could pose a solution to our current opioid epidemic. As the Opioid Epidemic continues to take over the US, the need for a new and nonaddictive painkiller like epibatidine is pressing. As epibatidine becomes safer to use, the drug could be used not only as a replacement for opioids but also as a potential treatment for other medical issues. Epibatidine may be a treatment for “Alzheimer’s disease, Parkinson’s disease, Tourette’s syndrome, depression, schizophrenia, and pain” (Micheal Decker, 2001). Other research proposes that a number of synthetic methods used to synthesize epibatidine could “provide compounds that have potential for treating nicotine addiction” (Carroll, 2009). Epibatidine, being non addictive, could be a solution to the opioid epidemic, both preventing users from addiction and reliance on these drugs and helping reduce the economic costs that come with widespread addiction and overdose. Tucked away in the slopes of the Andes mountains and tropical rainforests of South America, the powerful painkiller derived from the skin of Anthony’s Poison Arrow Frog has the potential to improve and save both millions of lives and billions of dollars in the future.

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