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By Shaifali Bhalla

Shaifali Bhalla-finalChronic pain is an important public health problem that often goes undertreated. Although opioids are the most commonly used agents to manage chronic pain, effective treatment is difficult due to development of drug tolerance, dependence, abuse, and withdrawal. Therefore, there is still a critical need to identify alternative and innovative solutions to meet both treatment needs of patients and the desired level of safety expected of modern drug therapies.

We have found that endothelin-A (ETA) receptor antagonists enhance morphine and oxycodone analgesia ETA receptor antagonist coadministered with morphine (PDF) increased analgesia by 85%, which lasted longer (five hours compared to two hours with morphine alone). Oxycodone (PDF) analgesia was increased by 61.72% with ETA receptor antagonist pretreatment. We have also demonstrated that ETA receptor antagonists mitigate opioid tolerance in animal (PDF) and cellular (PDF) models of tolerance by recoupling of G proteins. When animals were chronically treated with opioids alone, analgesia was significantly reduced, indicating that tolerance had developed. However, ETA receptor antagonists restored morphine and oxycodone analgesia (66.67% and 56% increases, respectively) in these animals.


According to the Journal of the American Medical Association (PDF) and reports from the National Council on Alcoholism and Drug Dependence Inc., the number of teenagers, young adults, and pregnant women who are addicted to opioids, as well as the infants born with opioid withdrawal symptoms, has jumped in the past decade. Further, The New York Times reported that people who previously might not have used heroin or the needle are more likely to use prescription opiates, and this has the potential to become a national or international issue. As of 2010, over 12 million Americans reported using prescription pain medications for nonmedical purposes without having obtained a prescription. The World Health Organization also estimates that two million people in the United States alone are addicted to prescription opiates. We have found exciting evidence that ETA receptor antagonist minimizes withdrawal symptoms such as weight loss, severe hypothermia, and jumping behavior associated with naloxone-precipitated opioid withdrawal.

This is the first report to indicate that selective blockade of ETA receptors in the brain reduces morphine and oxycodone withdrawal symptoms. Current treatments include using other opioids such as methadone and buprenorphine, opioid antagonists such as naltrexone, and a2-adrenergic receptor agonists such as clonidine. Upon further studies, it is possible that this novel approach may reduce withdrawal symptoms in patients who are dependent upon opiates and help address the public health concern of addiction.

Shaifali Bhalla, Ph.D., is an associate professor of pharmaceutical sciences at Midwestern University Chicago College of Pharmacy. Her laboratory focuses on the role of central endothelin receptor system and neurovascular remodeling in opioid tolerance and withdrawal.