Why Opioids Can Stop Working

By Drs. David Niesel and Norbert Herzog

The epidemic of opioid abuse and the resulting increases in overdoses and deaths have been front and center in the news for quite some time. Now a little appreciated effect called hyperalgesia, an increased sensitivity to pain, can make these drugs less effective for chronic pain leading people to take higher and higher doses seeking relief, increasing the chance of addiction. Opioids can actually prolong and amplify pain rather than relieving it.

Opioids are pain relieving drugs that include hydrocodone, oxycodone, morphine, codeine and other related drugs including illegal ones such as heroin. They are prescribed to relieve pain from a variety of conditions. Opioids act by binding to proteins called opioid receptors located in the brain, spinal column, digestive tract and other organs. Once attached to these receptors, they reduce the perception of pain. However, they can cause drowsiness, nausea, constipation and mental confusion but can also dangerously depress respiration at higher doses.

Surprisingly, opioids can remodel the nervous system to amplify pain signals even after the original injury has healed leaving animals more sensitive to pain. Similarly, people who take opioids prior to surgery typically experience more pain. In an attempt to understand this hyperalgesia and the role of the immune system in it, scientists used an animal model of chronic pain as the result of traumatic nerve injury. Control animals underwent a sham surgery that didn't induce the nerve injury. Ten days after the surgery, the injured animals were divided into two groups, one group was given morphine for 5 days while the second did not and both were compared to control uninjured animals. Over the next 3 months, the animals' threshold for pain was reassessed.

The group of injured animals that had not received morphine had pain sensitivities similar to uninjured rats. The animals that had received morphine retained higher pain sensitivities for 12 weeks before they returned to the sensitivities of the uninjured animals. Even after their original injuries had healed the morphine treated animals continued to experience elevated levels of pain. Uninjured animals later given morphine experienced reduced pain tolerance that returned to normal levels in about a week. So why is the recovery of the pain tolerance of injured opioid treated animals prolonged?

The authors propose that there are two hits on cells in the central nervous system or CNS called microglia that are the primary immune cells of the CNS that respond to infections and injury. The first "hit" is the injury, in this case to a nerve, which activates microglia-initiating inflammation. This is done by signals that are released from injured or dying cells. These signals warn the body of the injury and recruit the immune system to deal with it. Opioids given after an injury represent a second "hit" exaggerating the nerve inflammation by amplifying the signaling, accounting for the persistence of pain. Although it still must be determined if this phenomenon occurs in humans, these results may have far reaching implications. These experiments point to possible new strategies in the management of acute pain with opioids and prevent the long-term consequences to pain perception.

Medical Discovery News is hosted by professors Norbert Herzog at Quinnipiac University, and David Niesel of the University of Texas Medical Branch. Learn more at www.medicaldiscoverynews.com.