Painkillers like Vicodin, Oxycontin, and morphine provide vital relief for people suffering from debilitating pain, but could potentially lead to dependence, addiction, or a developed tolerance to the drugs's beneficial effects.

Synthetic opioids like hydrocodone, the primary ingredient in Vicodin, and oxycodone, also known as Oxycontin, dull the sensation of pain by binding to targets called opioid receptors in the pain-sensing nerve cells of the brain and spinal cord. With regular use, however, the body builds up tolerance to opioids, requiring increasingly higher doses for the same painkiller effect.

A new study from researchers at the University of Michigan Medical School and Bristol-Myers Squibb Company identifies a mechanism by which painkiller drugs might be altered so that lower doses are needed to be effective, decreasing the risk of tolerance, addiction, and other undesirable side effects.

"We 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 drug's positive impact without increasing negative side effects," said co-author Dr. John Traynor, a pharmacology professor at U-M Medical School.

Traynor said that the research, published in the journal Proceedings of the National Academy of Sciences (PNAS) on June 10, is still in very early stages, but that identifying the compounds could "revolutionize" pain treatment.

The researchers explained that conventional painkiller drugs target the "orthosteric," or primary, site of the mu-opioid receptor in pain-sensing neurons, which also results in undesirable side effects like constipation, respiratory suppression, and drug tolerance.

In the new study, based on both mouse and cell models, the research team found compounds that bind to a different "allosteric," or regulatory, site on the mu-opioid receptor, which was previously unknown.

"The 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," said Traynor.

The compounds seem to bind to the receptor in such a way that it enhances the effects of painkillers like morphine, which means lower drug doses could provide the same pain relief.

"What's particularly exciting is that these compounds could potentially work with the body's own natural painkillers to manage pain," said Traynor.

If the research translates to animal studies and later clinical trials in humans, less addictive next-generation painkillers could eventually replace current prescription drugs like Vicodin and Oxycontin, which have a high risk of unpleasant side effects and withdrawal symptoms.

The Centers for Disease Control and Prevention (CDC) recently announced that deaths from overdoses of prescription painkillers have reached epidemic levels, with over 16,000 such American deaths reported in 2010 — more than those from heroin and cocaine combined.