Video Essay Transcript:
In 2019, an estimated 10.1 million people aged 12 or older misused opioids (Opioid Crisis Statistics).
The opioid epidemic is the serious and growing problem of increased prescription and abuse of opioids that we have seen over the last 10-20 years in the US. For some, all it takes is one mistake. That one pill can trigger a whole lifetime of addiction, and without proper treatment or awareness, it can lead to severe consequences. Some of the most common types of opioids are Oxycodone, Codeine, Hydrocodone, and Morphine. These are all mostly used in medical settings and are prescribed by doctors, and subsequently, they are also the most abused opioids.
Opioids work by attaching themselves to opioid receptors which are g-coupled proteins that are found on nerve cells in the brain, spinal cord, gut, and other parts of the body. They then block the pain messages that are sent from the body through the spinal cord to the brain. There are 3 types of opioid receptors, mu (MOR), kappa (KOR), and delta (DOR). Each receptor has a different variety of clinical effects when compared to one another. Because of the ongoing opioid epidemic, there has been more research going on in the pharmacological industry to find a non-addictive pain medication, to use instead of current opioids, like oxycodone. The most abused opioids are mostly mu-opioid receptor agonists as this is the only receptor that produces euphoria. This is what creates the “high” that comes with opioids being abused. This is why researchers have been targeting the KOP and DOP as alternatives.
This topic is important as along with the opioid epidemic, many opioids have many life-threatening side effects like respiratory depression, but DOR/KOR agonists do not produce as severe effects. On top of this, the is also an increasing need for non-addictive pain medications and those that can be catered to a specific condition or type of pain. All of these points were tied together through a recent experimental/research study titled, “The mixed kappa and delta-receptor agonist, MP1104, attenuates chemotherapy-induced neuropathic pain,” which was completed to see if the new drug molecule could be used to alleviate pain while also being a non-addictive opioid medication.
The study used mice to test the hypothesis to see if their molecule/the drug, MP1104, could be used to attenuate this type of pain. The mice were given the drug continuously for 23 days to test both its efficacy and to see if it was non-addictive. The researchers used the warm-water tail-withdrawal assay which measures latency through the withdrawal of the mouse’s tail following thermal stimulation and is mediated via spinal cord reflexes as an indicator to assess pain in the mice along with the subject’s basic vitals (Atigari et al. 2020 pg. 2). The dose-response effects for tail-withdrawal were evaluated using an experimental design that was described in previous similar studies (Bohn et al., 2000; Paton et al., 2017). To create chemotherapy-induced neuropathic pain (CINP) in the mice, they were administered paclitaxel, a chemotherapeutic agent, and control mice were given a combination that was mostly 0.9% saline (Atigari et al. 2020 pg. 2-3).
The experiment tested how the drug helped with mechanical allodynia, increased sensitivity to and pain caused by stimuli like light touch, and cold allodynia, an increased sensitivity to and pain caused by normal, non-painful, cool temperatures. These are both neuropathic conditions and side effects that are faced by patients that undergo chemotherapy. To evaluate the administration of MP1104 and its effects on the CINP, the mice were given daily injections of either MP1104, morphine, or the control combination for 23 days. Then on every other day, mechanical and cold allodynia behaviors were measured an hour after injection (Atigari et al. 2020 pg. 3). The other part of this experiment was to test the addictiveness of this drug. To do so, some mice underwent tolerance and withdrawal experiments. In the withdrawal experiment, male CD1 mice were administered twice-daily injections with either morphine or MP1104 for 5 days. Then, Naloxone was administered to trigger withdrawal within the mice (Atigari et al. 2020 pg. 3). They were then evaluated for the number of jumps they could do over 15 min so that the researchers could see if the drug inhibited the mice during the induced “withdrawal period.”
It was concluded that MP1104 did alleviate chemotherapy-induced neuropathic pain in mice and it was also seen to be a non-addictive pain medication in animal trials. As stated in the research article, “In the CINP model, MP1104 was highly potent at attenuating both mechanical and cold allodynia. In addition, MP1104 did not show sedation, anxiogenic effects, naloxone-precipitated withdrawal, cross-tolerance with morphine, or respiratory depression” (Atigari et al. 2020 pg. 2).
When looking at the study from a broader perspective, we see that it can be deemed ethical and justified, aside from animal testing concerns, and it can be repeated by other researchers to confirm the results. Regarding conflicts of interest, the study reported that S. Majumdar, a researcher on the study, is the co-founder of a biopharmaceutical company, but no other conflicts of interest were reported or found. The main limitation of this study is that the drug was tested on mice, so we do not know if it will work in humans or what unforeseen effects it can have. The study could have been improved by increasing the number of days that the mice were given the drug to test if it was a non-addictive medication. In addition, in the main experiment, 164 male mice were used but only eighteen female mice which means that the results could not be as accurate when gender is considered. This was also the case in the tolerance and withdrawal experiments, where 100 male mice were used, but no female mice. Overall, the study was sound and did not have any other major issues.
The next steps for this study would be for the researchers to repeat it to make sure that the results are reliable. If they find that the drug does not work, they will need to modify it and then start from the beginning with testing in mice. If the molecule does work, they would need to find funding and apply for or start a clinical trial so that they can test if the results hold up in human subjects. This study is particularly important as it has many larger implications. Not only can it lead to the start of clinical trials for MP1104, but it can also inspire other researchers to create similar molecules that can be used to treat other kinds of pain, like pain associated with migraines or back pain. This study was also a huge step when it comes to combating the opioid epidemic. Research within the topic of looking for opioid alternatives and non-addictive solutions to treating pain is growing and this study will play an important role in educating other scientists and paving the way for even more similar studies that could one day, slowly resolve the opioid epidemic.
References:
Al-Hasani R, Bruchas MR. 2020. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology. 115:1363–1381. doi:10.1097/aln.0b013e318238bba6
Atigari DV, Paton KF, Uprety R, Váradi A, Alder AF, Scouller B, Miller JH, Majumdar S, Kivell BM. 2020. The mixed kappa and delta opioid receptor agonist, MP1104, attenuates chemotherapy-induced neuropathic pain. Neuropharmacology. 185:108445. doi:10.1016/j.neuropharm.2020.108445
Bohn, L.M., Gainetdinov, R.R., Lin, F.T., Lefkowitz, R.J., Caron, M.G., 2000. μ-Opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence. Nature 408, 720–723. https://doi.org/10.1038/35047086.
Google, Creative Commons License
How opioid drugs activate receptors. 2018 Jun 5. NIH https://www.nih.gov/news-events/nih-research-matters/how-opioid-drugs-activate-receptors
Image of Mu, Kappa, Delta Opioid Receptor. [Digital Image]. 2018. PDB-101. https://pdb101.rcsb.org/motm/217
Image of Pill Bottles. [Digital Photograph] 2016. Montgomery Advertiser. https://www.montgomeryadvertiser.com/story/news/2016/05/31/pill-bottle-drive-supports-third-world-countries/85187792/
Image of U.S. Filled with Opioid Drawings. [Digital Image]. Vox. https://www.vox.com/2018/9/26/17901778/opioid-epidemic-solutions-policy-explainers
Nagelhout JJ. 2016. Opioid agonists and antagonists. Anesthesia Key. https://aneskey.com/opioid-agonists-and-antagonists/
National Institute on Drug Abuse (NIDA/NIH). 7 Nov. 2017. Anyone Can Become Addicted to Drugs. YouTube. https://www.youtube.com/watch?v=wCMkW2ji2OE
Opioid Crisis Statistics. HHS.gov. https://www.hhs.gov/opioids/about-the-epidemic/index.html
Opioid Epidemic by the Numbers. [Digital Infographic]. HHS.gov. https://www.hhs.gov/opioids/about-the-epidemic/index.html
Opioids In the Body. [Digital Infographic]. 2017. New Jersey Monthly. https://njmonthly.com/articles/science/opioids-in-the-body/
Overall view of the µ-OR structure. [Digital Image]. 2012. Nature. https://www.nature.com/articles/nature10954
Paton, K.F., Kumar, N., Crowley, R.S., Harper, J.L., Prisinzano, T.E., Kivell, B.M., 2017. The analgesic and anti-inflammatory effects of Salvinorin A analogue β-tetrahydropyran Salvinorin B in mice. Eur. J. Pain 21, 1039–1050. https://doi.org/10.1002/ejp.1002.
Pexels.com, For Free and Fair Reuse
Solving the Opioid Crisis In America. [Digital Infographic]. 2017. AHIP. https://www.ahip.org/solving-the-opioid-crisis-in-america/
Vanderah TW. 2010. Delta and kappa opioid receptors as Suitable drug targets for pain. The Clinical Journal of Pain. 26. doi:10.1097/ajp.0b013e3181c49e3a
@drmingko. Opioid Drug Side Effects. [Digital Infographic]. 2017. Stanford Pain Medicine Twitter. https://twitter.com/stanfordpain/status/868595931633135616
Featured Image Source:
Image of U.S. Filled with Opioid Drawings. [Digital Image]. Vox. https://www.vox.com/2018/9/26/17901778/opioid-epidemic-solutions-policy-explainers