Review of the robust literature using acute drug injection paradigms points clearly to the conclusion that morphine is immunosuppressive. In contrast, studies of the effect of subacute or chronic administration of morphine on immune function is limited, with variable results. In some cases tolerance to the immunosuppressive effects of the drug is clearly demonstrated, but in other cases, selected immune parameters do not demonstrate tolerance. Discrepancies in findings may result from differences in species or route and manner of drug administration. Even fewer studies (total of 10) have been published on the effects of withdrawal on immune function. Most immune parameters tested are suppressed following drug withdrawal. Recovery time to baseline response levels varies in the studies. In the single report of withdrawal in humans, immune function was suppressed for up to 3 years. It is clearly established that withdrawal suppresses capacity of murine spleen cells to make an ex vivo antibody response, which contrasts with evidence of polarization of the lymphocytes towards a Th2 phenotype. Several laboratories have shown that subacute and chronic exposure to morphine, as well as drug withdrawal, sensitize to the lethal effects of bacterial lipopolysaccharide. Underlying sepsis, combined with morphine-induced hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis, may be occult variables modulating immune responses during opioid administration and withdrawal. As episodes of withdrawal are common among drug abusers, more intensive investigation is warranted on the effects of withdrawal on immune function, on mechanisms of immune modulation, and on sensitization to infection.

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