Opioids are powerful analgesics in both human and veterinary medicine. Opioid receptor agonists and antagonists also modulate the immune system by interacting with central nervous system and immune cell opioid receptors. Certain opioids (morphine, fentanyl, methadone, and codeine) are more immunosuppressive than others (hydromorphone, tramadol, hydrocodone, and oxycodone). Buprenorphine produces little to no negative immune alteration, and may enhance immune function. Morphine and fentanyl both carry a hydroxyl group and demonstrate the strongest immunomodulatory effects; however, the mechanism of this structural difference and its effect on immune response is unknown. Immunomodulatory mechanisms include centrally mediated suppression of natural killer cell activity, reduction in lymphocyte proliferation and interferon activity, and direct stimulation of immune-cell receptors. Systemic administration of morphine, which crosses the blood brain barrier, suppressed lymphocyte activity in the central nervous system. Acute administration of exogenous opioids primarily affects immune function through the sympathetic nervous system, while chronic administration may activate the hypothalamic–pituitary–adrenal axis. Certain opioids have been associated with elevated infection rates in humans and in animal models. Morphine promoted intestinal bacterial translocation into the peritoneal cavity in a mouse model, inducing sepsis. Conversely, buprenorphine and opioid antagonists provide beneficial effects in sepsis in murine models. Buprenorphine improved mean arterial blood pressure, pH, and base excess in endotoxemic rats and attenuated the development of fever. Other studies support the potential role of opioids in increased susceptibility to infectious diseases in intravenous drug users. For example, heroin attenuates the immune system and may serve as a cofactor in the pathogenesis of HIV infection. Veterinary studies are limited, but opioids with minimal immunomodulatory properties (buprenorphine, hydromorphone, tramadol, oxycodone, and oxymorphone) should be chosen for critically ill patients or those with increased risk for sepsis.

Commentary: This fascinating report emphasizes the intuitive need to exercise caution while selecting drugs for individual cases. However, there is little clinical evidence evaluating the impact of opioids on patient outcome in animals with increased risk for sepsis. Additional research evaluating this topic is required in the veterinary population. Many narcotics are not readily available due to depletion of stock and manufacturing difficulties. As a result, our clinical decisions regarding drug therapy may be primarily influenced by availability or affordability rather than the finer points of possible immunomodulation. It is imperative to remember that multimodal analgesia should include other drug classes and modalities, including nerve blocks. This ensures that the lowest effective opiate doses are administered to patients, thereby reducing the potential for harmful effects.—Heather Troyer, DVM, Diplomate ABVP (Canine & Feline Practice)

Immunomodulatory effects of opioids. Odunayo A, Dodam JR, Kerl ME, DeClue AE. J VET EMERG CRIT CARE 20:376-385, 2010.