morphine-6-glucuronide and Synovitis

To describe the pharmacokinetics of intra-articularly (IA) administered morphine.. Experimental randomized, cross-over study.. Eight adult healthy mixed breed horses aged 6.5 +/- 2.3 (mean +/- SD) years and weighing 535 +/- 86 kg.. Unilateral radiocarpal synovitis was induced by IA injection of 3 microg lipopolysaccharide (LPS) on two occasions (right and left radiocarpal joint, respectively) separated by a 3-week wash-out period. Treatments were administered 4 hours post-LPS-injection: Treatment IA; preservative free morphine IA (0.05 mg kg(-1)) plus saline intravenous (IV) and treatment IV; saline IA plus preservative free morphine IV (0.05 mg kg(-1)). Concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide (M6G) were determined repeatedly in serum and synovial fluid (SF) by high-performance liquid chromatography mass spectrometry, at 2 and 4 hours and then at 4 hours intervals until 28 hours post-treatment.. Injection of LPS elicited a marked and comparable synovitis in all LPS-injected radiocarpal joints. IA administered morphine was detectable in SF of all eight joints 24 hours post-treatment and in 6/8 joints 28 hours post-treatment. The terminal half-life of morphine in SF was estimated to be 2.6 hours. IA administration of morphine resulted in mean serum concentrations of morphine below 5 ng mL(-1) from 2 to 28 hours after treatment.. Intra-articularly administered morphine remained within the joint for at least 24 hours. At the same time only very low serum concentrations of morphine and M6G were detected. The present results suggest that IA morphine at 0.05 mg kg(-1) may be used for IA analgesia lasting at least 24 hours and give strong support to the theory that previously observed analgesic and anti-inflammatory effects of IA morphine in horses are most likely to be mediated peripherally.

Topics: Analgesics, Opioid; Animals; Cross-Over Studies; Female; Horse Diseases; Horses; Injections, Intra-Articular; Lipopolysaccharides; Male; Morphine; Morphine Derivatives; Synovial Fluid; Synovitis

Intra-articular morphine (5 mg in 25 ml) was administered to patients for post-operative analgesia following arthroscopic knee surgery. At various time intervals, 30 min to 4 h post morphine, venous blood samples were taken in order to determine plasma levels of morphine and its primary metabolites, morphine-3-glucuronide and morphine-6-glucuronide. Measurable amounts of morphine and morphine-3-glucuronide were found in the plasma of 7/10 patients whereas morphine-6-glucuronide was detected in only 2/10 patients. The plasma levels of morphine were lower than that regarded sufficient for post-operative analgesia in all but two patients, indicating a possibility of peripheral analgesia. In addition, synovial biopsy samples were assayed for the presence of opioid binding sites. Tissue samples from 11 different patients were analysed and 6/11 exhibited specific binding of [3H]naloxone, indicating the presence of opioid binding sites/receptors. The receptor type (i.e. mu-, delta- or k-) is at present unknown. Taken together, these data provide evidence that locally administered opiates can act on specific opioid receptors in the synovium to mediate analgesia.

Topics: Adult; Analgesia; Arthroscopy; Female; Humans; Knee; Male; Morphine; Morphine Derivatives; Pain, Postoperative; Radioligand Assay; Receptors, Opioid; Synovitis