A new study, published online in Nature Medicine, is the first to discover a cellular signal that selectively causes narcotic tolerance. A reformulation of the common cancer drug imatinib (Gleevec®) managed to eliminate morphine tolerance in rats. Researchers of The University of Texas MD Anderson Cancer Center said the achievement was an important step towards improving the effectiveness of chronic pain management in patients.

Although narcotics like morphine represent the pillar of chronic pain treatment, patients can develop tolerance to the pain-relieving effects of these drugs when taking them for extended periods, and require higher dosages to control pain levels, whilst in some cases narcotics become altogether ineffective.

Leading researcher, Howard B. Gutstein, M.D., professor in the Departments of Anesthesiology/Perioperative Medicine and Biochemistry at MD Anderson declared:

“By suggesting a way to prevent or reverse tolerance in patients, this study could have far-reaching implications for many people suffering with chronic intractable pain.”

Their study revealed that by activating the b- isoform of the platelet-derived growth factor receptor (PDGFR) in animals that were previously not exposed to morphine developed a morphine tolerance.

Imatinib, a common drug for the treatment of certain types of leukemia and gastrointestinal tumors, targets various cellular receptors, including the PDGFR, which is heavily expressed in those cancer cells.

According to the study findings, imatinib not only prevented morphine tolerance, it also totally reversed tolerance in rats that continuously received high morphine doses for several days, in the same way that morphine and other opioids are often administered to chronic pain patients.

Whilst morphine and other opioids function by binding to mu opioid receptors in the brain and spinal cord, researchers have so far not observed Imatinib’s ability to inhibit morphine tolerance in cancer patients taking the drug, as imatinib does not penetrate the nervous system. However, the research team reformulated imatinib by using a simple, clinically approved carrier molecule called Captisol®, which considerably increases drug delivery to the brain.

Gutstein declared:

“What’s particularly exciting is that imatinib already is approved for use in humans, which suggests that we might be able to utilize this discovery to treat patients fairly soon.”

He highlighted that the reformulated imatinib must first undergo efficacy and safety tests in further animal studies, after which it will be tested in humans in a Phase I study.

Gutstein concluded:

“Many patients in severe pain often refuse high doses of opioids because of the side effects, and they desperately need relief. We may be able to quickly translate this discovery and dramatically reduce the suffering endured by the sickest patients, and not just those with cancer.”

Patients who take morphine and other opioids are at risk of various side effects that range from being unpleasant to life threatening in intensity, such as nausea, itching, constipation and breathing depression. Decreasing morphine tolerance could mean that patients can take lower doses for pain relief with fewer side effects.

Written by Petra Rattue