Endomorphin Analog Analgesics: An Alternative to Opioids?

Endomorphin Analog Analgesics: An Alternative to Opioids? – Florence Chaverneff, Ph.D. – May 12, 2016

James Zadina, PhD, of Tulane University School of Medicine, presented data at the session on novel opioid analgesics, which showed reduced adverse events compared to morphine.

Dr Zadina’s laboratory is dedicated to developing improved pain treatments, the inadequacy of which oftentimes results in opioid abuse. In his opinion, an issue in the field of opioid research is that scientists have been trying to ‘tweak’ very old compounds derived from opium.  

His laboratory’s approach, on the other hand, has been to use molecules from the brain.  

n 1997, Dr Zadina isolated two tetrapeptides called endomorphins. These endogenous compounds are very selective for the µ-opioid receptor – the best place to alleviate pain.

His group has been modifying their structures to render them more metabolically stable and achieve their goal of developing compounds with an analgesic power equivalent to that of morphine, but reducing adverse events.

Dr Zadina and his colleagues investigated whether milder adverse events were observed by administration of one of their endomorphin analogs, compared to morphine.

Morphine administration produced CPP and self-administration, whereas the endomorphin analog did not show significant results with either test, despite prolonged access.

Respiratory depression causes fatal overdoses; morphine led to 35% inhibition of respiration, which was unaffected by use of analogs.

Morphine also produced a 38-fold shift in tolerance, which increases the risks of adverse events, when, under the same conditions, their compound showed a 14-fold shift.

Finally, morphine led to 30% motor impairment and 2 hours of antinociception when their lead compound did not affect motor behavior and prolonged antinociception to 4 hours.

Dr Zadina’s endomorphin analog has several other advantages:

  • it is peripherally active, which is unusual for a peptide,
  • penetrates the blood brain barrier,
  • has a longer half-life than its parent compound, and
  • can be effective, not only by intrathecal administration, but also when injected intravenously

In summary, the authors noted a reduction or absence by the endomorphin analog, relative to morphine, of

  • abuse liability,
  • respiratory depression,
  • tolerance,
  • inflammatory response,
  • motor and cognitive impairment, and
  • equal or greater potency and duration of action against neuropathic, post-operative, and peripheral nerve injury.

These compounds, through selective µ-opioid receptor activation, could provide a safer alternative to opioids in treating three major types of pain.

I have much more faith in such medicines derived from our innate mechanism of pain control provided by our endorphins, which are essentially our bodies’ internal version of opioid pain relievers. (see Opioids, Endorphins, and Getting High)

Tweaking these molecules seem much safer than trying to start with a biochemical reaction related to pain (i.e. sodium channels) and then design a molecule to interfere with it.

By starting with a molecule already present and operative in our bodies, the number of unknown adverse effects and long-term risks might be reduced.

Reference

1.  Zadina J, Nilges MR, Morgenweck J, et al. Novel opioid analgesics with reduced abuse liability, respiratory dpression, tolerance and impairment of motor function are effective in multiple models of pain.
Presented at: APS 2016. May 11-14, 2016; Austin, Tx.  

2. Zadina, J.E., Hackler, L., Ge, L.-J., and Kastin, A.J. A potent and selective endogenous agonist for the µ-opiate receptor. Nature. 386:499-502, 1997.  

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