DURHAM, N.C. — A drug developed over 20 years ago to treat cancer could help patients living with crippling pain, according to new research. A team from Duke University says kenpaullone switches on a gene that douses chronic inflammation.
Experiments on mice and humans found it was remarkably successful at alleviating nerve injury and bone tumor symptoms. Researchers are hopeful clinical trials will see equally successful results in humans suffering a host of conditions.
According to the CDC, around one in five U.S. adults deals with chronic pain. Major causes include arthritis or spinal damage. Study authors say new drugs and other therapies to alleviate chronic pain also need to be safe — meaning the fewer side-effects the better.
“It is especially important that they be non-addictive and non-sedative, while being effective against nerve injury pain and cancer pain, preferably with a minimal time to official approval,” says lead author Professor Wolfgang Liedtke.
“Because chronic pain, like many chronic diseases, has an important root in genetic switches being reprogrammed in a bad way, a disease modifying treatment for chronic pain should reset the genetic switches, not just cover up the pain,” the researcher at the Duke Cancer Institute adds in a university release.
Fighting pain at the genetic level
Prof. Liedtke practiced pain medicine for the last 17 years at Duke University and is now an executive at Regeneron Pharmaceuticals in New York.
“I just cannot sleep anymore because turning in bed hurts, my spine hurts laying down, and sitting up to sleep hurts even more,” one bone cancer patient says in a media release.
“During daytime, I have constant brain fog, interrupted by pain that within minutes gets worse 10-out-of-10, against a background of constant burning pain which gets worse toward the afternoon and evening. I hurt more when I go to the bathroom. The pain medication makes my brain fog worse. I feel like a zombie. I am badly constipated and itch all over.”
Similarly, those with chronic nerve injury damage caused by diabetes, side-effects of medication, or severe shingles describe their lives as misery. Prof. Liedtke and the team sought better treatments by surveying the “junkyard of cancer drugs” with the potential to be repurposed. They tested over 1,000 compounds contained in two libraries of the National Cancer Institute.
In addition to stopping cells from multiplying, many reset maladaptive genetic switches in non-dividing nerve cells. In mice with bone cancer, kenpaullone was found to stop pain caused by nerve constriction. It triggered a gene called Kcc2, which expels chloride from neurons. Low levels silence signaling between cells — reducing pain.
In all forms of chronic pain studied in experimental animals and human spinal cord models, Kcc2 disappeared from neurons making up the primary pain gate. Prof. Liedtke notes that kenpaullone appears to be an effective remedy for challenging-to-treat pain.
What can kenpaullone help prevent?
Study authors report that the pain relief in patients was profound and long-lasting. It also displayed the signs of impacting gene regulation.
“At this stage, we knew we had met the basic requirement of our screen of shelved cancer drugs, namely identified Kcc2 gene expression-enhancers, and demonstrated that they are analgesics in valid preclinical pain models,” Prof. Liedtke explains.
Further tests yielded “resoundingly affirmative results.” They showed Kenpaullone affects spinal cord processing of pain. It also reduces nerve injury-induced elevation of chloride levels in pain-relaying neurons.
The researchers discovered the underlying mechanism. Kenpaullone inhibits a pain relaying enzyme called GSK3-beta that turns off a gene called delta-CAT.
Study authors conclude that these findings suggest kenpaullone and similarly-acting kinase-inhibitory compounds (as well as delta-CAT gene therapy) all have the potential to become a new line of treatment for chronic pain sufferers. This includes people dealing with nerve injury pain and cancer bone. They believe kenpaullone will also work on other forms of chronic pain associated with low Kcc2 expression.
Researchers add this approach to pain management may also be helpful in treating neurological and psychiatric disorders which may use the same mechanism to trigger the disease.
The study appears in the journal Nature Communications and identified three other highly promising drugs that could carry out similar functions.
South West News Service writer Mark Waghorn contributed to this report.