LAS VEGAS—Interaction between opioids and the immune system is complex in that both trauma and pain can cause immunosuppression, with relief of pain, in part, alleviating this condition. Although definitive human data are lacking, animal studies show strong evidence of opioid immunosuppression, said Joseph V. Pergolizzi, MD, adjunct Assistant Professor of Pharmacology in the Department of Pharmacology at Temple University School of Medicine, Philadelphia, Pennsylvania to attendees of PAINWeek 2014.

“Treatment strategies in the special populations like the elderly might benefit from the avoidance of drugs that have intrinsic immunosuppressive properties,” said Dr. Pergolizzi. Not all opioids share the same immunosuppressive properties. This distinction may help guide providers treating elderly patients with characteristic “immunosenescence,” or decline in immune system responsiveness.

In both animals and humans undergoing surgery, surgical stress result has been shown to activate the hypothalamic- pituitary-adrenal axis and the sympathetic nervous system, leading to suppressed immune function, including natural killer (NK) cell activity, cytokine production, and lymphoproliferation.

Pain is also a stressor that can impair immune functions; notably, NK activity. Decreases in NK activity in the perioperative period and their association with greater rates of cancer recurrence and mortality have been described for cancers of the breast, head and neck, colon and rectum, and lung.

“Opioids, however, have additional direct effects on many aspects of immune function,” Dr. Pergolizzi said. “These effects depend on multiple factors, including structure of the individual opioid agent and dose range used.” Potential mechanisms include modulation of the hypothalamic pituitary axis, stimulation of the sympathetic nervous system, and direct action via mu receptors on immune cells.

Opioids that are immunosuppressive include codeine, methadone, morphine, remifentanil, and fentanyl, he said. Less immunosuppressive agents are buprenorphine, hydromorphone, oxycodone, and tramadol. One study of the effect of the continuous infusion of fentanyl or buprenorphine on immune responses found that for fentanyl, a significant reduction of the immune function was present for all parameters studied, whereas buprenorphine did not affect the immune responses evaluated, he said.

In summarizing the key take-home messages from his presentation, Dr. Pergolizzi said that “both therapeutic and chronic uses of opioids compromise the optimal functioning of the immune system, and overwhelming evidence suggests that opioid use affects both innate immunity and adaptive immunity.”

For that reason, “chronic administration of opioids decreases the proliferative capacity of macrophage progenitor cells and lymphocytes; additionally, the differentiated function of immune cells is significantly affected by opioids. These effects are mediated by either a direct action of opioids on the target cells or by indirect centrally mediated pathways.”

Furthermore, “molecular biological and biochemical characterization suggest that immune cells differentially express classical opioid receptors,” meaning that “not all opioids have the same effect on the immune system.” Although the clinical relevance of these finding remains to be determined, “special populations like the elderly maybe be more susceptible to the immunosuppressive effects of opioids,” he concluded.