New findings provide vital step towards exploring pain medications that may
lower risks of prescription drug abuse and side effects of painkillers

ANN ARBOR, Mich. ‹ For patients managing cancer and other chronic health
issues, painkillers such as morphine and Vicodin are often essential for
pain relief. The body¹s natural tendency to develop tolerance to these
medications, however, often requires patients to take higher doses ­
increasing risks of harmful side effects and dependency.

Now, new research from the University of Michigan Health System and a major
pharmaceutical company has identified a novel approach to moderate and
severe pain therapy that paves the way for lower dosage painkillers. The
findings appear in Proceedings of the National Academy of Sciences of the
United States of America.

Drugs such as hydrocodone (the main ingredient of Vicodin) and oxycodone
(Oxycontin) are often the best options for the treatment of moderate to
severe pain for patients facing medical conditions ranging from a wisdom
tooth extraction to cancer. The drugs bind to specific molecules (opioid
receptors) on nerve cells in the brain and spinal cord to prevent the
feeling of pain.

³We have for the first time discovered compounds that bind to an alternative
site on the nerve opioid receptors and that have significant potential to
enhance the drug¹s positive impact without increasing negative side
effects,² says co-author John Traynor, Ph.D., professor of pharmacology at
the U-M Medical School.

³We are still in the very early stages of this research with a long way to
go, but we believe identifying these compounds is a key step in
revolutionizing the treatment of pain. This opens the door to developing
pain relief medications that require lower doses to be effective, helping
address the serious issues of tolerance and dependence that we see with
conventional pain therapy.²

Conventional drug treatments for pain work by targeting the so-called
orthosteric site of the opioid receptor that provides pain relief. Targeting
this site, however, is a double-edged sword because it is also responsible
for all of the drug¹s unwanted side effects, such as constipation and
respiratory depression. Tolerance also limits chronic use of the drugs
because higher doses are required to maintain the same effect.

Using cell systems and mouse brain membranes, researchers have identified
compounds that bind to a physically distinct and previously unknown
³allosteric² site on the opioid receptor- a site that fine-tunes the
activity of the receptor. Not only do these compounds act at a location that
hasn¹t been studied as a drug target before but they bind to the receptor in
a new way to enhance the actions of morphine ­ which means lower doses can
have the same impact.

³The newly-discovered compounds bind to the same receptor as morphine but
appear to act at a separate novel site on the receptor and therefore can
produce different effects. What¹s particularly exciting is that these
compounds could potentially work with the body¹s own natural painkillers to
manage pain,² Traynor says.

³We know that conventional strong pain medications ultimately increase the
risk of withdrawal symptoms and addiction, which is an especially serious
issue with the current prescription drug abuse epidemic in our country. The
implications of this work, if it translates to animal studies and then to
humans, are highly significant to this area of study.²

Additional authors: Andrew Alt, Ph.D., Neil Burford Ph.D., Mary J Clark
M.A., Samuel Gerritz Ph.D, Martyn Banks Ph.D., Jonathan O¹Connell Ph.D., Tom
Wehrman, Ph.D.

Funding: Partially supported by National Institutes of Health grant MH083754

Disclosures: None

Reference: ³Discovery of Positive Allosteric Modulators and Silent
Allosteric Modulators of the Mu Opioid Receptor,² Proceedings of the
National Academy of Sciences of the United States of America.

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