Most patients with advanced
cancer experience severe
pain and are often treated with
opiates.
Cancer patients are especially susceptible to
opportunistic infections due to treatment with immunosuppressive and
cytostatic drugs. Since
opiates have been demonstrated to have immunomodulatory effects, it is of clinical importance to evaluate potential differences between commonly used
opiates with regard to their effect on the immune system. The aim of this study was to evaluate the effect of
morphine,
tramadol,
fentanyl and
ketobemidone on the functioning of the immune system with special reference to TNF and
IL-8 release. Method. U-937 cells were preincubated with different concentrations of
opioids followed by stimulation with LPS 100 μg/ml for three hours. The effect of
opioids on the levels of
cytokine mRNA was studied using RT-PCR. Erk and Akt phosphorylation was also measured by Western blot. Results. All
opioids with the exception of
fentanyl were capable of inhibiting TNF release from U-937 cells.
Morphine had no effect on
IL-8 release but the effect of other
opiates was almost the same as the effect on TNF. All
opioids with the exception of
fentanyl were capable of inhibiting production of
mRNA for TNF and
IL-8. The observed effects of
opiates were not always reversible by
naloxone, suggesting that the effects might be mediated by other receptors or through a non-receptor mediated direct effect. Although preliminary evidence suggests the involvement of Erk and Akt pathways, further studies are needed to unravel the intracellular pathways involved in mediating the effects of
opiates. Our data suggests that the order of potency with regard to inhibition of
cytokine release is as follows:
tramadol >
ketobemidone >
morphine >
fentanyl. Conclusion. Further studies are needed to understand the clinical implications of the observed immunosuppressive effects of
tramadol and
ketobemidone and to improve
opioid treatment strategies in patients with
cancer.