Exploration of Immunology

Table 1. Differential immunomodulatory effects of commonly used opioids in humans and translational models.

Opioid	Predominant immune profile*	Relative direction/magnitude	Reported immune effects (human/translational)	Mechanistic considerations
Morphine	Immunosuppressive	Moderate–strong	↓ NK cell activity; ↓ T-cell proliferation; Impaired macrophage function	Strong MOR agonism; HPA axis activation; High CNS penetration
Fentanyl	Immunosuppressive	Moderate	↓ NK cell cytotoxicity; Reduced lymphocyte responsiveness	Potent MOR agonist; Central pathways
Methadone	Immunosuppressive	Mild–moderate	Modest reduction in NK cell activity	Long-acting MOR agonist; Central effects
Oxycodone	Minimally immunosuppressive	Mild and transient	Limited or transient suppression of cellular immunity	MOR agonist with lower immunosuppressive profile
Tramadol	Immune-preserving/potentially immunostimulatory	Mild enhancement	↑ NK cell activity; ↑ IL-2; Preserved T-cell responses	Weak MOR agonist; SNRI activity
Buprenorphine	Immune-preserving	Neutral	Preserved NK and T-cell function	Partial MOR agonist; κ-antagonism; Biased signaling

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↓: decrease; ↑: increase; NK: natural killer; MOR: mu-opioid receptor; HPA axis: hypothalamic-pituitary-adrenal axis; CNS: central nervous system; IL-2: interleukin-2; SNRI: serotonin-norepinephrine reuptake inhibitor. *: Immune effect profiles are derived primarily from human observational and perioperative studies, supported by translational and mechanistic data. The magnitude and causality of opioid-induced immune modulation in humans remain incompletely defined. Key references [7, 25, 26, 27].

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Author contributions

LDV: Conceptualization, Writing—original draft, Writing—review & editing, Visualization, Supervision. TL: Writing—original draft, Writing—review & editing, Visualization. FAL: Writing—original draft. SM: Writing—original draft. All authors read and approved the submitted version.

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