The peptide-based drugs, which mimic a natural brain chemical, target the same pain-relieving opioid receptor as morphine.
Researchers at Tulane University and Southeast Louisiana Veterans Health Care System have developed a painkiller that is as strong as morphine but isn’t likely to be addictive and with fewer side effects, according to a new study in the journal Neuropharmacology.
Using rats, scientists compared several engineered variants of the neurochemical endomorphin, which is found naturally in the body, to morphine to measure their effectiveness and side effects. The peptide-based drugs target the same pain-relieving opioid receptor as morphine.
Opium-based drugs are the leading treatments for severe and chronic pain, but they can be highly addictive. Their abuse results in thousands of overdose deaths in the United States annually. They can cause motor impairment and potentially fatal respiratory depression. Patients also build up tolerance over time, increasing the risk for abuse and overdose.
“These side effects were absent or reduced with the new drug,” said lead investigator James Zadina, VA senior research career scientist and professor of medicine, pharmacology and neuroscience at Tulane University School of Medicine. “It’s unprecedented for a peptide to deliver such powerful pain relief with so few side effects.”
In the study, the new endomorphin drug produced longer pain relief without substantially slowing breathing in rats; a similarly potent dosage of morphine produced significant respiratory depression. Impairment of motor coordination, which can be of particular importance to older adults, was significant after morphine but not with the endomorphin drug.
The new drug produced far less tolerance than morphine and did not produce spinal glial cell activation, an inflammatory effect of morphine known to contribute to tolerance.
Scientists conducted several experiments to test whether the drug would be addictive. One showed that although rats would spend more time in a compartment where they had received morphine, the new drug did not affect this behavior. Another test showed that when the press of a bar produced an infusion of drug, the rats only increased efforts to obtain morphine and not the new drug. The tests are predictive of human drug abuse, Zadina said.
Researchers hope to begin human clinical trials of the new drug within the next two years.
Source: Keith Brannon – Tulane University
Image Source: The image is credited to Paula Burch-Celentano, Tulane University.
Original Research: Abstract for “Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine” by James E. Zadina, Mark R. Nilges, Jenny Morgenweck, Xing Zhang, Laszlo Hackler, and Melita B. Fasold in Neuropharmacology. Published online January 2016 doi:10.1016/j.neuropharm.2015.12.024
Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine
Opioids acting at the mu opioid receptor (MOR) are the most effective analgesics, however adverse side effects severely limit their use. Of particular importance, abuse liability results in major medical, societal, and economic problems, respiratory depression is the cause of fatal overdoses, and tolerance complicates treatment and increases the risk of side effects. Motor and cognitive impairment are especially problematic for older adults. Despite the host of negative side effects, opioids such as morphine are commonly used for acute and chronic pain conditions. Separation of analgesia from unwanted effects has long been an unmet goal of opioid research. Novel MOR agonist structures may prove critical for greater success. Here we tested metabolically stable analogs of the endomorphins, endogenous opioids highly selective for the MOR. Compared to morphine, the analogs showed dramatically improved analgesia-to-side-effect ratios. At doses providing equal or greater antinociception than morphine in the rat, the analogs showed reduced a) respiratory depression, b) impairment of motor coordination, c) tolerance and hyperalgesia, d) glial p38/CGRP/P2X7 receptor signaling, and e) reward/abuse potential in both conditioned place preference and self-administration tests. Differential effects on glial activation indicate a mechanism for the relative lack of side effects by the analogs compared to morphine. The results suggest that endomorphin analogs described here could provide gold standard pain relief mediated by selective MOR activation, but with remarkably safer side effect profiles compared to opioids like morphine.
“Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine” by James E. Zadina, Mark R. Nilges, Jenny Morgenweck, Xing Zhang, Laszlo Hackler, and Melita B. Fasold in Neuropharmacology. Published online January 2016 doi:10.1016/j.neuropharm.2015.12.024