Assessment of immunotoxicity of buprenorphine

Abstract

SummaryIn order to use buprenorphine as an analgesic in immunological experiments, we have studied the potential immunotoxicity of buprenorphine. Three-week-old male Wistar Riv: TOX rats were subcutaneously treated with buprenorphine by injection of 0.1, 0.4, or 1.6 mg/kg body weight per day over a period of 4 weeks. Concentrations used were within the range for analgesia in rats. A slight decrease of body weight gain was observed at the highest dose in one but not in a duplicate study. Decreased liver weights were observed in all dose groups. Histopathologically glycogen storage was decreased and fatty vacuolation was found to be increased starting from the lowest dose group. The relative but not absolute weight of the lungs was slightly increased at the lowest dose, this phenomenon was therefore not dosedependent. Histopathologically, a dose-dependent increase in interstitial pneumonia in the lung was found. At the 2 higher dose levels the weight of the adrenal glands was increased. No haematological changes were found, nor were there effects on bone marrow.In one of 2 studies indications of potential immunotoxicity noted were: an increased weight of the thymus, as well as an increased weight of popliteal and mesenteric lymph nodes. No effects on the weight of the spleen were found. Histologically, there were no changes in the lymphoid organs tested. Total immunoglobulin A concentrations in serum were significantly decreased in the highest dose group, whereas IgG concentrations were increased, albeit not statistically significantly. IgM and IgE concentrations showed no alterations.Two types of immune function assays were carried out: determination of natural killer cell activity and of mitogen responsiveness of spleen cells. Whereas natural killer activity was unaffected, increased responses to concanavalin-A, phytohaemagglutinin, pokeweed mitogen as well as lipopolysaccharide were found, although never statistically significant.The results indicate that buprenorphine may have a slight stimulatory influence on the immune system at dose levels that are used for analgesia. The effects on the immune system that were noted were modest. Moreover, they were observed in conjunction with other toxicological effects, and can therefore either be direct or indirect.Keywords Ratj immunotoxicologyj buprenorphine; toxicologyj analgesia Pain and distress caused by experimental procedures should be minimized both for ethical, legal, and scientific reasons. Scientifically, pain and distress represent

Morphine Produces Immunosuppressive Effects in Nonhuman Primates at the Proteomic and Cellular Levels

“…Methadone, for instance, has been variously reported to improve (12), impair (11,13), or have no effect (14) on immune function. Similarly, buprenorphine has been variously reported to improve (15)(16)(17) or to suppress (7,8,13) immune function, or to have no effect at all (10,18). Such conflicting information makes it difficult to establish best practices for medical intervention of opioid abuse.…”

Regulatory immunotoxicology: does the published evidence support mandatory nonclinical immune function screening in drug development?

“…In terms of IFT results from screening tests (not undertaken for morphine and methadone), no decrease in NK-cell activity was detected for buprenorphine although weak mitogen-/antigen-stimulated responses that did not attain statistical significance were observed (Van Loveren et al, 1994). More comprehensive evaluations showed both augmentative and suppressive changes in NK-cell activity following prolonged dietary administration of morphine and methadone, but no effects on PFC activity were noted (Van der Laan et al, 1996).…”

“…Two similar 28-day studies were undertaken in male rats (Van Loveren et al, 1994). Buprenorphine was administered by the intravenous route at 0, 0.1, 0.4, and 1.6 mg/kg/day.…”

Immunotoxicology

“…But, it should be borne in mind that in this guideline 407 some immunotoxic compounds may not be identified as such [39], for instance this concerned the opiate analgesic buprenorphine [40] and the long-acting b2-adrenoreceptor agonist salmeterol [41],which affected serum immunoglobulins in rats. Results of an interlaboratory validation study in the rat using cyclosporin A and hexachlorobenzene showed the importance of updating the 407 protocol with LYM-PHOID ORGAN weights and serum immunoglobulin levels.The study concluded that histomorphological examination of lymphoid tissues resulted in the most reliable and sensitive data to be considered in regulatory toxicology and risk assessment [42].…”