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* From the Department of Anesthesiology, and
the Laboratory for Immunology and Hematology Research, Rabin Medical Centre, Golda Campus (Hasharon), Petah Tiqva, and The Sackler School of Medicine, Tel-Aviv University Ramat Aviv, Israel.
Address correspondence to: Dr. Benzion Beilin, Department of Anesthesia, Rabin Medical Centre, Golda Campus (Hasharon), 7 Keren Kayemet St., Petah Tiqva, 47372, Israel. Phone: 972-3-9372469; Fax: 972-3-9372470; E-mail: beilinb{at}clalit.org.il
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Abstract |
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Methods: Peripheral blood polymorphonuclear cells and monocytes from healthy volunteers were incubated with 5, 10 and 20 µg·mL–1 tramadol, or with 20, 40 and 80 
g·mL–1 morphine. To each tube, 0.05 mL of 5% suspension of latex beads 0.8 µm in diameter was added. After incubation for 60 min the percentage of cells engulfing latex particles and the phagocytic index (number of particles phagocytized by each individual cell) were detected.
Results: Tramadol affected neither the percentage of cells phagocyting latex particles, nor the phagocytic index of both polymorphonuclear cells and monocytes. On the other hand, incubation with 20, 40 and 80 g·mL–1 morphine caused 11%, 14% and 24% decrease in phagocytosis (P < 0.01 – P < 0.001). The percentage of monocytes phagocyting latex particles was lower by 16%, 19% and 12% at the three doses tested (P < 0.01 – P < 0.001). The three doses of morphine caused a dose dependent decrease in the monocyte phagocyting index by 20%, 29% and 35.5% respectively (P < 0.05). The polymorphonuclear phagocyting index was not significantly lower following incubation with the drug (P = 0.053).
Conclusion: The lack of noxious effect of tramadol on the engulfing capacity of phagocytic cells suggests additional benefit to the relatively safe profile of the drug.
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Methods |
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Phagocytosis
Aliquots of cell suspension (0.95 mL) were incubated with 5, 10 and 20 µg·mL–1 of tramadol (tramadol hydrochloride, Grunenthal GmbH, Aachen, Germany) or with 20, 40 and 80 g·mL–1 of morphine (morphine sulfate, Rafa, Jerusalem, Israel). In one set of experiments, cells were incubated with both 5 µg·mL–1 tramadol and 20 g·mL–1 morphine. The dosage of the drugs used in the study was extrapolated from therapeutic concentrations. To each tube, 0.05 mL of 5% suspension of latex beads 0.8 µm in diameter (Sigma, Rohovot, Israel) was added. Incubation was carried on for 60 min at 37°C in a humidified atmosphere containing 5% CO2. Cells incubated without any drug served as controls. Following incubation, the cells were sedimented by centrifugation, washed twice in phosphate buffered saline, smeared on glass slides and stained using the May Grünwald-Giemsa method. The percentage of phagocyting cells and the number of latex particles engulfed by each individual cell (phagocytic index) were detected. At least 100 polymorphonuclear cells and monocytes were counted for each experimental point.
Statistical analysis
The data were evaluated using repeated measures analysis of variance; post-hoc Bonferroni’s correction was applied as appropriate to adjust for multiple comparisons. Results are expressed as mean ± SEM. The level of significance was established at a P value < 0.05.
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g·mL–1 of morphine caused 11%, 14% and 24% inhibition of polymorphonuclears’ engulfing capacity (P < 0.01 – P < 0.001). The percentage of monocytes phagocyting latex particles was lower by 16%, 19% and 12% at the three doses tested (P < 0.01 – P < 0.001).
Following incubation with morphine, the polymorphonuclear phagocyting index was not significantly reduced (F(3,46) = 2.794, P = 0.113), whereas that of monocytes was numerically less but not significantly different from pre-incubation values (F(3,47) = 2.715, P = 0.06). Incubation with 20, 40 and 80 g·mL–1 of morphine was associated with a dose dependent decrease in the monocyte phagocyting index by 20%, 29% and 35.5% respectively (P < 0.05). Incubation of polymorphonuclears or monocytes with both 5 µg·mL–1 tramadol and 20 g·mL–1 of morphine decreased the percentage of polymorphonuclears and monocytes capable for phagocytosis by 15% and 19% respectively (P < 0.02 and P < 0.002). However, the phagocytic index of both cell types did not differ from the values obtained when the cells were incubated separately with each drug.
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Discussion |
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The present study shows that incubation of human peripheral blood phagocytic cells with increasing doses of tramadol affected neither the percentage of cells capable of phagocytosis, nor their phagocytic index. On the other hand, incubation with morphine induced a dose-dependent decrease in phagocytic capacity of both polymorphonuclears and monocytes. It is of interest that incubation with 5 µg·mL–1 of tramadol and 20 g·mL–1 of morphine caused a slight but significant increase in the phagocytic capacity of both polymorphonuclears and monocytes. Although their phagocytic index was not affected, this observation suggests an additive effect of these drugs on phagocyte engulfing ability.
Opiates and opioids have been shown to interact with the immune system14 and their suppressive effect on the phagocyte engulfing capacity has been well documented in a large number of publications.9,14–17 There are several studies attempting to elucidate the mechanism by which opiates alter the engulfing capacity of the phagocytic cells. According to Makman et al.18 human granulocytes possess a morphine-sensitive µ3-receptor subtype that mediates a suppressive effect of the drug on the cell phagocytic capacity. It has been shown that naloxone is able to block this effect.17,18 Similarly, tramadol binds to µ-opioid receptors, but with low affinity.19 Investigations carried out by Tomei et al.15 suggest that the effect of morphine on murine macrophages depends on several factors, such as concentration and exposure time, a fact that may explain the biphasic dose-response curve of the cells to the drug expressed either as inhibition or stimulation of their phagocytic capacity.20 Another possibility is that morphine affects phagocytosis by inducing changes in cell membrane fatty acid composition causing a decrease of its fluidity, which in turn will impair formation of pseudopodia and internalization of pathogens and foreign particles. A decrease in membrane fluidity of the blood-brain barrier tissue due to alteration in cell membrane fatty acid composition has been shown in rabbits following tramadol administration.21 However, this mechanism would be unlikely to explain the findings in our study, since we did not observe impaired phagocytosis after incubation of peripheral blood phagocytic cells with tramadol, at least with the doses used. Based on observations that applied in analgesic doses, tramadol and morphine exert different immune responses in both humans and rodents. Concomitant with a reciprocal effect on natural killer cell activity,19,22,23 it is conceivable that the outcome regarding the engulfing function of the phagocytic cells will proceed through different path-ways. Moreover, and in contrast to other opioids, the analgesic action of tramadol is only partially inhibited by the opioid antagonist naloxone, which suggests the existence of another mechanism of action. The inhibitory effect of opioids on the function of the immune cells and especially on phagocytosis may explain the increased susceptibility to infections in addicts, though this effect has been shown to be reversible.24
In conclusion, the present study shows that incubation of human peripheral blood phagocytic cells with increasing doses of tramadol did not affect their engulfing capacity for latex particles, while this cell function was dose-dependently impaired following incubation with morphine. This observation may be of particular clinical relevance in the selection of anesthetic drugs for immunocompromised patients.
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Footnotes |
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Assessed April 11, 2005. Accepted for publication July 4, 2005. Revision accepted July 11, 2005.
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