Replacing Opioids: Developing drugs to treat pain
Adam Tozer PhD
At high doses opioids cause respiratory depression leading to death.
In America, in 2014, more than 28,000 people died from opioid overdose, and at least half of these deaths involved prescription opioids.1 The cost to the American economy for treating drug addiction is over $55 billion in health and social costs per year2 and over $20 billion in emergency department and hospital care for opioid poisonings.3
Time for policy change?: using neuroscience to tackle America's opioid epidemic
Historically, only patients suffering from cancer pain or recovering from operations were prescribed opioid drugs4. Since 1995, patients suffering from severe acute and chronic pain have been prescribed opioid drugs to relieve their pain. However, patients soon find they need to up their dose as they build a tolerance to the drugs.
This, coupled with aversive withdrawal symptoms such as nausea and heightened pain sensitivity when not on their medication, contribute to the addictive nature and dangerous risk of overdose with these drugs. On top of the addiction and withdrawal symptoms, even safe prolonged use can lead to liver damage and cause constipation.
Despite these dangers, over 27 opioid drugs and 40+ combinations are currently available by prescription, such as, Morphabond, Demerol, Sublimaze and combinations like Vicodin, Tylenol and Percocet. The large array of brands and combinations highlights the use of opioids in the treatment of varied conditions in comparison to their original use for cancer pain and surgery recovery.
Researching alternatives to opioid medication
Other pain drugs and different types of treatment are available. And there are also many ongoing strategies for non-opioid pain drug discovery and development, such as Pfizer and Lilly’s Tanezumab, a monoclonal antibody treatment for chronic pain which has just been granted a fast track designation by the FDA.
Learn more: FDA fast tracks Tanezumab
Research into the mechanisms underlying pain perception to design better drugs and target new pathways to replace the use of opioids is ongoing in academic and industrial labs across the globe.
Live drawn video from Armando Hasundugan explains how we sense and perceive pain.
One class of pain receptor, called G-protein coupled receptors (GPCRs), exist on the surface of pain neurons. They respond to circulating pain mediators produced by acute injury or chronic inflammatory signals and activate pain neurons to signal painful stimuli.
Despite a lot of research into GPCRs as targets for painkillers, most have failed in clinical trial.
Recently Nigel Bunnett’s group at Columbia University uncovered the probable reason for this. As the GPCR receptors, such as the neurokinin receptor (NPK1), are activated on the surface of the cell they are internalized, where they continue to act. Inhibitors of their action are rendered useless as they are restricted to the outside of the cell whilst the signaling continues internally. The group went on to describe how a type of molecule called cholestanols disrupted this internal signaling and significantly improved pain sensation in rats.
Read more: novel non-opioid painkillers work inside cells
Another way drugs are being developed is by engineering blockers of neuronal activity found in nature to target pain neurons and prevent pain signals getting through to the brain. For example, work to utilize spider venoms5 and cone snail toxins6 as pain medications are proving successful. Rg1A4 is an adapted cone snail toxin molecule that inhibits a specific pain receptor that underlies chemotherapy-induced neuropathic pain. The researchers showed that Rg1A4 prevented the pain hypersensitivity caused by chemotherapy in a rodent model, meaning even cancer pain could be treated without the use of opioids in the future.
Read: Developing pain drugs from snail toxins
Medical marijuana could replace opioid medication
The endocannabinoid system is an important signaling mechanism in the body and brain. Whilst cells naturally produce molecules to activate this system, endocannabinoid receptors are also activated by derivatives of the Cannabis sativa plant. The endocannabinoid receptors CB1 and CB2 are found on neurons involved in pain signaling and this underlies cannabis’ historical use as a painkiller. A recent review paper7 details what is currently known about the cannabinoid system and its role in pain sensation, highlighting the benefits of exploiting the endocannabinoid system to inhibit specific pain pathways to produce pain-relieving effects. However, the scientists also caution that the complexity of the system makes it difficult to target a pain specific pathway without causing side-effects such as memory and cognitive impairment, and tolerance and addiction.
That said, there is clinical evidence to support medical marijuana as an alternative treatment to opioids for pain among sufferers. A clinical review of 28 randomized control trials suggested medical marijuana produced positive results for treating pain, and also the spasticity caused by multiple sclerosis8. The review concludes by urging discussion between physicians and patients to ensure patients will benefit from its use. Given that the risk of death by overdose is completely removed in using medical marijuana and a finding that medical marijuana may actually reduce opiate medication use9 in chronic pain sufferers, what limits its prescription or uptake might now be doctors’ own knowledge base and skepticism. As Dr David Casarett explains in his TED talk:
In this TED talk, David Casarett asks: What if mainstream health care operated more like a medical marijuana dispensary?
It is widely accepted that America is suffering from an opioid epidemic4. Large numbers of patients are increasing their doses of prescription opioid medication and putting themselves at risk of overdose. New methods and strategies to treat acute and chronic pain are needed to replace opioids and are being developed. Whether the solution to the epidemic lies in snail venom, antibodies or marijuana the threat to life is real and must be addressed soon.
1. Rudd, R.A., Aleshire, N., Zibbell, J.E. and Gladden, R.M., 2016. Morbidity and Mortality Weekly Report.
2. Birnbaum, H.G., White, A.G., Schiller, M., Waldman, T., Cleveland, J.M. and Roland, C.L., 2011. Societal costs of prescription opioid abuse, dependence, and misuse in the United States. Pain Medicine, 12(4), pp.657-667.
3. Inocencio, T.J., Carroll, N.V., Read, E.J. and Holdford, D.A., 2013. The Economic Burden of Opioid‐Related Poisoning in the United States. Pain medicine, 14(10), pp.1534-1547.
4. Curbing prescription opioid dependency. (2017). Bulletin of the World Health Organization, 95(5), pp.318-319.
5. Saez, N.J., Senff, S., Jensen, J.E., Er, S.Y., Herzig, V., Rash, L.D. and King, G.F., 2010. Spider-venom peptides as therapeutics. Toxins, 2(12), pp.2851-2871.
6. Romero, H.K., Christensen, S.B., Mannelli, L.D.C., Gajewiak, J., Ramachandra, R., Elmslie, K.S., Vetter, D.E., Ghelardini, C., Iadonato, S.P., Mercado, J.L. and Olivera, B.M., 2017. Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain. Proceedings of the National Academy of Sciences, p.201621433.
7. Woodhams, S.G., Chapman, V., Finn, D.P., Hohmann, A.G. and Neugebauer, V., 2017. The cannabinoid system and pain. Neuropharmacology. Hill, K.P., 2015. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: a clinical review. Jama, 313(24), pp.2474-2483.
8. Hill, K.P., 2015. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: a clinical review. Jama, 313(24), pp.2474-2483.
9. Boehnke, K.F., Litinas, E. and Clauw, D.J., 2016. Medical cannabis use is associated with decreased opiate medication use in a retrospective cross-sectional survey of patients with chronic pain. The Journal of Pain, 17(6), pp.739-744.