A drug called etanercept can restore responsiveness to the pain-relieving effects of morphine in rats that have developed morphine tolerance, reports a study in the February issue of Anesthesia & Analgesia, official journal of the International Anesthesia Research Society (IARS).
The experimental results suggest that etanercept—which blocks the inflammatory cytokine tumor necrosis factor (TNF)-alpha—could provide a useful new approach to "extend the effectiveness" of morphine and related drugs (opioids) for pain control. The lead study author of the new study is Dr. Chih-Shung Wong of Cathay General Hospital, Taipei, Taiwan.
Etanercept Restores Morphine Responses, Blocks Spinal Inflammation
Morphine and other opioid drugs play an important role in the treatment of severe pain. However, the development of tolerance—requiring much higher doses for effective pain control—is an important limiting factor on their use.
The authors designed an experiment to evaluate the effects of etanercept in rats that had been made morphine tolerant. When these animals were treated with etanercept, it restored up to 60 percent of their responsiveness to morphine.
Morphine tolerance was associated with changes in the levels of certain inflammation-promoting proteins, called cytokines. When the animals were treated with etanercept, expression of the inflammatory cytokines was significantly reduced, in particular Tumor necrosis factor-alpha, often called TNF-. These changes were accompanied by reduced levels of activation of specialized spinal cord immune cells, called microglia.
Through its ability to block TNF- etanercept is an effective treatment for rheumatoid arthritis and other inflammatory autoimmune diseases. TNF- is expressed in spinal cord cells, and plays a significant role in the development of several neurological disorders.
The new results show that etanercept can restore much of the pain-relieving effect of morphine in morphine-tolerant rats. Etanercept treatment also reduces expression of inflammation-promoting cytokines, as well as activation of the microglia.
"This suggests that TNF-alpha is an important proinflammatory cytokine that mediates the neuroinflammation associated with morphine tolerance," Dr Shen and colleagues write. The study provides researchers with important new clues regarding the molecular pathways leading to morphine tolerance.
Although much further research is needed, the results also raise the possibility that etanercept could provide a useful new treatment for restoring the pain-relieving effects of morphine in patients who have become morphine-tolerant. This could be an important new tool for the management of patients with severe chronic pain, who are often left with few options for effective pain control once morphine tolerance has developed. Given the new findings on the roles of TNF-alpha and inflammatory cytokines, Dr. Shen and co-authors conclude, "Evaluation of other potent anti-inflammatory drugs for morphine tolerance management is…warranted to further explicate the features of morphine tolerance."
Small Solutions for Big Problems in Drug Discovery and Delivery