The immune system, a complex network of cells, tissues, and organs, is the body’s primary line of defense against pathogens and disease. Various medications have beneficial effects on the immune system, while others negatively impair it. In the context of surgery, it is especially important to understand these effects, given the physiological stress of surgery. This article will discuss the effect of key perioperative adjuvants on the immune system.
The immune system is divided into innate and adaptive components, where the former provides rapid, non-specific responses and the latter is a specialized immune response that develops over time to recognize specific pathogens and create immunological memory. Innate immunity is comprised of anatomic barriers (i.e., skin) that prevent pathogens from entering, the humoral response (i.e., antimicrobial proteins), and cellular immunity (i.e., macrophages, monocytes, neutrophils, natural killer [NK] cells). By contrast, the key mediators of adaptive immunity are the T and B lymphocytes, which engage in cellular signaling and produce antibodies as needed.1
Perioperative adjuvants, such as benzodiazepines, opioids, and non-steroidal anti-inflammatory drugs, are medications that are commonly administered in combination with other anesthetics to enhance overall sedation, reduce preoperative anxiety, and lower the amount of general anesthetic necessary.2 While these medications are essential for patient comfort and successful anesthesia induction, understanding the impact of perioperative adjuvants on the immune system is vital for optimizing outcomes and minimizing risks, especially in immunocompromised patients.
Benzodiazepines are a class of psychoactive drugs well-known for their depressant effects on the CNS.2 Stimulation of peripheral-type benzodiazepine receptors may influence phagocytosis, chemotaxis, T-cell maturation, oxidative bursts, and cytokine production. Additionally, central-type benzodiazepine receptors have an indirect effect on the hypothalamic-pituitary-adrenal axis, which is known for its role in stress management.3 In a veterinary study, midazolam, an agonist of the peripheral-type benzodiazepine receptor and commonly used sedative for procedures, was administered to adult horses to assess the drug’s effects on immune function. The medication dose-dependently reduced neutrophil and macrophage oxidative bursts, which involves the rapid release of reactive oxygen species in preparation for innate immunological responses. Midazolam also reduced phagocytosis in blood neutrophils and macrophages.4 On the other hand, an in vitro study suggests diazepam, another commonly administered benzodiazepine, stimulates neutrophil
migration and phagocytosis through peripheral-type benzodiazepine receptors. Administration of clonazepam, which binds to central-type benzodiazepine receptors, was found to have no effect on either metric.5,6 Benzodiazepine adjuvants in the perioperative setting have shown varying effects on the immune system, requiring clinicians to consider drug-specific consequences.
Opioids are generally recognized for their immunosuppressive qualities, including suppression of NK cell cytotoxicity, inhibition of macrophage and neutrophil phagocytosis, and other restrictions on innate immunity. Additionally, morphine significantly depresses adaptive immunity, especially regarding B and T cells. In vitro studies indicate heterologous desensitization between opioids, including morphine, oxycodone, and meperidine, and chemokine receptors, which disrupts the communication between innate and adaptive immunity. Opioids like morphine, heroin, and methadone have also been shown to enhance HIV viral replication.7
Non-steroidal anti-inflammatory drugs (NSAIDs) have antipyretic, anti-inflammatory, and antithrombotic properties, and are often administered in the perioperative setting as analgesia adjuvants but suppress parts of the immune system. They work by inhibiting COX-1 and COX-2, enzymes that produce prostaglandins, the chemicals that promote inflammation and pain. By restricting the expression of COX enzymes, NSAIDs like ibuprofen and celecoxib can prevent immunosuppressive cytokine production. COX-2 is associated with the tumor microenvironment, including pro-inflammatory cells like IL-1β, TGFβ, and epidermal growth factor. The upregulation of COX-2 in lung, bladder, pancreas, and prostate cancers can influence cancer cell invasion, angiogenesis promotion, and metastasis.6,8
The immune system is indispensable for maintaining health and defending the body against infections and disease, with both innate and adaptive components working together to mount a coordinated response against pathogens. Administering perioperative adjuvants, such as benzodiazepines, opioids, and NSAIDs, along with other anesthetic agents is a common clinical practice that can improve patient quality of life, manage pain, and enhance sedation. However, these medications can have significant effects on immune function. More research will enhance our understanding of the long-term effects of these adjuvants on immune function and refine strategies for minimizing negative impacts on patient health.
References
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2. Edinoff, Amber N., et al. “Benzodiazepines: Uses, Dangers, and Clinical Considerations.” Neurology International, vol. 13, no. 4, Dec. 2021, pp. 594–607. https://doi.org/10.3390/neurolint13040059
3. Rochard, Pierrick, et al. “Expression of the Peripheral Benzodiazepine Receptor Triggers Thymocyte Differentiation.” Gene Expression, vol. 12, no. 1, June 2018, p. 13. https://doi.org/10.3727/000000004783992170
4. Massoco, C., and J. Palermo-Neto. “Effects of Midazolam on Equine Innate Immune Response: A Flow Cytometric Study.” Veterinary Immunology and Immunopathology, vol. 95, no. 1, Sept. 2003, pp. 11–19. https://doi.org/10.1016/S0165-2427(03)00097-7
5. Marino, Franca, et al. “Diazepam Stimulates Migration and Phagocytosis of Human Neutrophils: Possible Contribution of Peripheral-Type Benzodiazepine Receptors and Intracellular Calcium.” Pharmacology, vol. 63, no. 1, May 2008, pp. 42–49. https://doi.org/10.1159/000056111
6. Ackerman, Robert S., et al. “The Effects of Anesthetics and Perioperative Medications on Immune Function: A Narrative Review.” Anesthesia & Analgesia, June 2021. https://doi.org/10.1213/ANE.0000000000005607
7. Eisenstein, Toby K. “The Role of Opioid Receptors in Immune System Function.” Frontiers in Immunology, vol. 10, Dec. 2019. Frontiers, https://doi.org/10.3389/fimmu.2019.02904
8. Sandler, Alan B., and Steven M. Dubinett. “COX-2 Inhibition and Lung Cancer.” Seminars in Oncology, vol. 31, Apr. 2004, pp. 45–52. https://doi.org/10.1053/j.seminoncol.2004.03.045