Pain management is a hugely important aspect of cancer care. An estimated one in three patients experience pain, either from cancer itself or after common treatments such as chemotherapy, radiation, and surgery.
Though the majority of patients are able to find relief, the pain medications that provide it can often come with drawbacks, including side effects and the risk of developing a tolerance to the drugs.
“The good news is that up to 85 percent of cancer patients get relief from relatively simple pain management therapies,” says neurologist Gavril W. Pasternak, who heads a laboratory in the Molecular Pharmacology and Chemistry Program of the Sloan Kettering Institute. “But our goal is to see 100 percent of cancer patients pain free with treatments that are effective and safer than the ones we have now. And the key to that is a better understanding of our body’s pain receptors.”
The Drawbacks of Pain Meds
Opioid analgesics, also known as narcotics analgesics, are used to treat many types of discomfort, including back pain, the pain of childbirth, and cancer-associated pain. These medications, which include morphine, meperidine (Demerol®), methadone, oxycodone, and codeine, can also help anesthetics work more effectively.
However, opioid analgesics can have side effects such as dizziness and breathing problems. In addition, while few cancer patients become addicted to these drugs, some people build up a tolerance to the medications and need increasing amounts to block the pain. Because of this, scientists are continually searching for better medications to control pain without the side effects and complications of opioid analgesics.Back to top
A New Class of Drugs
In a 2011 study, Dr. Pasternak and MSK physician-scientist Ying-Xian Pan reported that a new opioid derivative they generated and studied in the laboratory could be developed into a painkiller that retains the beneficial properties of opioids while avoiding their drawbacks. This investigational compound, IBNtxA, produced powerful analgesic effects without inducing breathing difficulties or physical dependence, or activating the reward pathway in the brain and causing an intense high.
“In fact, IBNtxA worked better than morphine for neuropathic pain — a condition due to nerve damage as seen in peripheral neuropathy — or nerve damage caused by surgery or the tumor itself,” Dr. Pasternak says. “This told us that IBNtxA was working on a different receptor than those targeted by standard opioid analgesics.”
The researchers were able to determine that IBNtxA works through receptors that differ in structure from the receptors through which conventional opioids transmit their effects. Traditional opioid drugs bind to a group of receptors called G-protein coupled receptors (GPCRs). IBNtxA operates through truncated GPCRs, which are smaller than the classical receptors because they lack one of seven structural units called the transmembrane domain.Back to top
Discovering a Target for Pain
“We knew IBNtxA was targeting a truncated GPCR,” Dr. Pasternak says. “The question was, can we prove which one, and how does it work? To do so, we had to take a closer look at how IBNtxA was metabolized in the body.”
The researchers generated strains of mice lacking GPCRs. These mice were unaffected when given both the conventional opioid drug morphine and IBNtxA. The researchers then injected a virus that delivered a specific truncated GPCR receptor called 6TM GPCR into the spinal cords of some of these animals. In those with this restored receptor, the IBNtxA drug had analgesic action — while the morphine continued to have no such effect.
The finding, reported in the Journal of Clinical Investigation, is a major breakthrough in the field of pain therapeutics because it provides scientific proof that the truncated receptor is a valid target for drugs such as IBNtxA.
“First, it identifies a new drug target capable of mediating strong analgesic actions without many of the side effects seen with traditional opioid analgesics,” Dr. Pasternak says. “This has major potential implications in the development of safer analgesics lacking abuse potential.”
Second, the study establishes the pharmacological importance of targeting truncated GPCRs, as newer drugs could potentially work on one of these receptors even more effectively.
“Many in our field did not believe truncated variants, which lack the traditional structure, could be valid targets,” Dr. Pan says. “Our study is the first to establish this family of receptors as potential drug targets. Over 10 percent of GPCR genes produce truncated receptors through a process called alternative pre-mRNA splicing. Our study may open new avenues for development of a wide range of other drugs.”Back to top