Opioids - Over the horizon

There are a number of interesting long-term avenues to follow. For example, BU 08028 is a mu receptor agonist, related to buprenorphine, but is also an agonist to the nociceptin receptor, which could help reduce side-effects. Tests show it can relieve pain in macaque monkeys yet when they had the chance to take as much of the drug as they wanted, they didn’t abuse it. Signs of painful withdrawal also seem reduced [Ref 1].

Syntrix Pharma has Omnitran (desmetramaol) in Phase II. This is an improved version of popular opioid Tramadol for Neuropathic Pain. Half of Tramadol patients cannot optimally metabolise the drug and Omnitran can eliminate these metabolic issues by delivering the active Tramadol metabolite directly without any metabolic exacerbations.

It might also be possible to make better opioids that selectively activate a sub-type of the mu receptor. For example IBNtxA (3-iodobenzoyl-6β-naltrexamide), a naltrexone derivative has already been tested in animal models.

In addition, researchers have identified six piperidine-based mu receptor agonists that can provide effective pain relief with fewer respiratory problems than conventional opioids. And others are investigating G protein-coupled receptor agonists such as the recently tested drug, RB-64, suggesting that such therapies may side-step some of the side-effects usually seen with molecules that target the kappa opioid receptor [Ref 2].

In 2016, researchers discovered PZM 21, a drug that’s selective for the mu-opioid receptors and which produces no respiratory depression and other physical side effects, yet still produces long- lasting affective analgesia. Data suggests it seems to offer less addictive liability [Ref 6] but this will await confirmation. The drug is being investigated by Epiodyne.

Syntrix Pharma has Omnitran (desmetramaol) in Phase II. This is an improved version of popular opioid Tramadol for Neuropathic Pain. Half of Tramadol patients cannot optimally metabolise the drug and Omnitran can eliminate these metabolic issues by delivering the active Tramadol metabolite directly without any metabolic exacerbations. It might also be possible to make better opioids that selectively activate a sub-type of the mu receptor. For example IBNtxA (3-iodobenzoyl-6β-naltrexamide), a naltrexone derivative has already been tested in animal models. In addition, researchers have identified six piperidine-based mu receptor agonists that can provide effective pain relief with fewer respiratory problems than conventional opioids. And others are investigating G protein-coupled receptor agonists such as the recently tested drug, RB-64, suggesting that such therapies may side-step some of the side-effects usually seen with molecules that target the kappa opioid receptor [Ref 2].

In 2016, researchers discovered PZM 21, a drug that’s selective for the mu-opioid receptors and which produces no respiratory depression and other physical side effects, yet still produces long- lasting affective analgesia. Data suggests it seems to offer less addictive liability [Ref 3] but this will await confirmation. The drug is being investigated by Epiodyne.

Clearly there are a number of potential avenues of research to follow. There are also new funding initiatives that should encourage promising candidates. For example, in 2018 the FDA launched an innovation challenge to spur the development of medical devices, including diagnostic tests and digital health technologies to help combat the opioid crisis. Over 250 applications were received, which bodes well for this crisis. And President Trump has called for $13 billion in additional funding over the next two years for the Department of Health and Human Services to tackle the problem.

Read the three other pats in this series here: Opioids: The war on drugs, Opioids: the future and challenging the epidemic, Replacement therapies for opioid drugs in pain treatment.

References
Ref 1 “A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates” Huiping Ding et al. PNAS September 13, 2016 113 (37) E5511-E5518; https://doi.org/10.1073/pnas.1605295113. https://www.epgonline.org/global/journals/a-novel-orvinol-analog--bu08028--as-a-safe-opioid-analgesic-without-abuse-liability-in-primates-.html
Ref 2 “The G protein-biased κ-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo.” White KL et al. J Pharmacol Exp Ther. 2015 Jan; 352(1):98-109. doi: 10.1124/jpet.114.216820. Epub 2014 Oct 15. https://www.epgonline.org/uk/journals/the-g-protein-biased---opioid-receptor-agonist-rb-64-is-analgesic-with-a-unique-spectrum-of-activiti.html
Ref 3 “Management of Opioid Addiction With Opioid Substitution Treatments: Beyond Methadone and Buprenorphine” Florence Noble et al. Front. Psychiatry, 18 January 2019 | https://doi.org/10.3389/fpsyt.2018.00742. https://www.epgonline.org/global/journals/management-of-opioid-addiction-with-opioid-substitution-treatments--beyond-methadone-and-buprenorphi.html