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Endorphin Analogs May Offer Alternative to Opioids

April 29, 2016
Creating an analgesic devoid of unwanted side effects may seem like a pipe dream, but new research into analogs derived from natural compounds in the body have made bold progress.

Developing a pain treatment that can provide effective analgesia and avoid unwanted side effects still stands as the holy grail of pain pharmacology, but researchers may be getting close. The key could lay in a neurochemical already naturally produced in the body—endorphins. 

In a new study recently published in Neuropharmacology,1 researchers at Tulane University and Southeast Louisiana Veterans Health Care System found promising results testing a set of engineered variants of endomorphins on rats. Compared to morphine, the new drugs not only provided similar or superior analgesia, but they also showed noticeably less side effects, including decreased respiratory depression, reduced impairment of motor coordination, and even lack of addictive qualities.

"It's unprecedented for a peptide to deliver such powerful pain relief with so few side effects," said James Zadina, PhD, lead author of the study and a professor of medicine at Tulane University in New Orleans, Louisiana. The research could open up exciting possibilities for the future of pain pharmacology, where endorphin analogs could become the new “gold standard” of pain management.

Today's main treatments for acute and chronic pain provide analgesia by acting on the mu opioid receptor (MOR). In many cases, these drugs provide valuable anti-nociception. However, serious side effects can limit their use and put patients in danger of addiction, overdose, and death.

“There is clearly an unmet need for analgesics that can rise to the same efficacy level as opioids but without the undesirable baggage that comes with this important class of medications,” Jeffrey Fudin, PharmD, DAAPM, FCCP, FASHP, a clinical pharmacy specialist, told Practical Pain Management.

If a novel compound could reproduce the useful pain-relief properties of MOR-agonists and still avoid the addictive properties, respiratory depression, tolerance, constipation, and other side effects infamous to this drug class, such an alternative would be invaluable for pain management, said Dr. Fudin.

Endomorphins, a New Avenue for Analgesia

Endomorphins (EM) are potent, selective MOR agonists that for some time have been considered potential morphine competitors given their “promising profile” of strong analgesic properties that belay the unwanted side effects associated with other MOR agonists, the researchers described.

While naturally produced in the body, researchers have been trying to synthesize potent EM analogs that can achieve optimized, drug-like properties.2-6 In the study, Dr. Zadina et al synthesized 4 of their own cyclized, D-amino acid-containing EM analogs, and found that in many cases, the analogs actually outperformed morphine in numerous ways.

For instance, a series of standard tail flick (TF) tests on male mice and rats showed the analogs provided potent, long-lasting analgesia after intravenous (IV), subcutaneous (SC), and oral administration, with i.v. being the most effective method, producing a Percent Maximum Possible Effect (%MPE) for 240 minutes. Some of the analogs even outperformed morphine in the duration of their analgesia, remaining active up to 5 hours after i.v. administration of 5.6 mg/kg doses (analog 4).

Reducing Side Effects

“Endomorphin analogs do present an interesting option, particularly considering that they can now be pharmaceutically manipulated for enhanced stability and extended half-lives by adding a glycine extension,” Dr. Fudin told Practical Pain Management.

EM analogs also showed significantly better side effect profiles compared to morphine. In some cases, certain side effects like respiratory inhibition were completely abolished, even.

Respiratory depression, a notorious, potentially-fatal side effect of today’s opioids, is frequently caused by ingesting large doses of a pain killer or taking such drugs in combination with other depressants. Dr. Zadina et al found all 4 analog types not only outperformed morphine in antinociception duration, they all showed very little respiratory depression by comparison.

In fact, analog 4 in particular showed no respiratory depression at all and yet outperformed morphine the most in terms of analgesia duration. “The results indicate that the EM analogs are clearly more effective and safer analgesics than morphine,” the authors wrote.

Abuse liability is another major concern with opioid pain management. In 2014, the National Survey on Drug Use and Health found nearly 2 million Americans abused or were dependent on prescription opioids.7 Place preference testing showed a marked difference between the analog compounds and morphine, where 3-days of morphine conditioning produced noticeable place preference in the rats, while conditioning with the analogs did not, even at doses above and below full antinociception.

Impaired motor coordination can be another dangerous danger associated with MOR agonists. Because of these drugs’ effects on the Central Nervous System, doctors typically warn patients initially prescribed chronic opioids to refrain from operating vehicles or heavy machinery for some time.8

Again, analog 4 was particularly successful at providing the greatest duration of antinociception and the least motor impairment compared to morphine, which had much higher measurements of motor impairment. Analogs 2 and 4 were so successful, they achieved a 5-fold and 8.6-fold better therapeutic ratio relative to morphine, respectively.

It could have been possible the analogs’ relative immunity to respiratory depression and impaired motor coordination was because the drugs were not entering the Central Nervous System (CNS) effectively, the authors noted. However, successful administration of the antagonist naloxone methiodide proved the analogs indeed activated CNS receptors.

Patients who require long term opioid use frequently face the challenges of tolerance, as well. This can place them at risk of inadequate pain management and overdose. EM analogs could be the future drug of choice for circumventing tolerance issues in chronic opioid patients.

In a tolerance test following a 7-day cumulative intrathecal  administration, EM analogs showed a 14-fold shift in potency, compared to the sizeable 38-fold shift by morphine. None of the analogs produced spinal glial cell activation either, a known inflammatory effect associated with tolerance. Analog 4 also out-produced hyperalgesia compared to morphine.

This study was supported financially by a Senior Research Career Scientist Award and Merit Review Award from the Department of Veterans Affairs, as well as grants from the Department of Defense, Office of Naval Research, and Louisiana Board of Regents. A Board of Regents predoctoral fellowship was awarded to study coauthor Mark R. Nilges. Study lead author Dr. Zadina and coauthor Laszlo Hackler are inventors on patents covering the compounds characterized in this study, which are assigned under joint agreement to The Department of Veterans Affairs and Tulane University School of Medicine.

Last updated on: May 2, 2016
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