A new orally-administered treatment, Targin (Mundipharma), available in Germany since 2006 and now throughout Europe, combines the opioid oxycodone with its antagonist naloxone in an oral prolonged-release formulation. The combination achieves effective analgesia without compromising bowel function, says Dr Kevin Smith, Mundipharma’s Head of European Clinical Pharmacology, and is indicated for severe pain, which can be adequately managed only with opioid analgesics. The opioid antagonist naloxone is added to counteract OIC by blocking the action of oxycodone at opioid receptors locally in the gut.
Speaking in London at Targin’s European launch, pain specialist Dr Gerhard Muller-Schwefe, Head of the Pain Clinic in Goppingen, Germany and President of the German Association for Pain Relief for the past 12 years, explained oxycodone blocks pain by binding to endogenous opiate receptors in the brain and spinal cord. But it also binds to these receptors in the periphery, notably in the intestine, where it inhibits peristalsis and stimulates fluid uptake from the bowel. ‘The result is a good reduction in pain but usually severe constipation also. It has never been possible to design an opioid that functions only in the CNS,’ he explained. When naloxone is administered intravenously, it immediately antagonises the effects of opioids in the gut and CNS, starting at a low dose. However, when oxycodone and naloxone are administered together orally, in a prolonged release preparation, naloxone has a very different mode of action, he explained. It is able to act locally in the intestine, where it competes successfully against oxycodone in binding to receptors on the gut wall, leaving bowel motility intact. But its very low systemic availability (less than 3% is absorbed) effectively leaves oxycodone unopposed in achieving its central nervous system-induced analgesic effects.
Clinical trials supporting the product’s development have been extensive, he said. ‘Pain intensity measured over 28 days shows no difference is made to pain control regardless of how big a dose of oral naloxone (10 to 40mg) is administered orally alongside oxycodone.’
Double-blind studies, comparing the oral combination of naloxone and oxycodone against oxycodone alone, show no difference between them in analgesic efficacy. Almost three quarters of patients completed an extended year-long study suggesting pain was effectively managed regardless of which treatment was administered. ‘Approximately 30% of patients taking opioids alone quit on account of side effects, with constipation being the worst,’ Dr Muller-Schwefe commented. In the same study, the bowel function index measuring difficulty in defecation and feelings of incomplete bowel evacuation showed a significant reduction in scores with the combined treatment compared to oxycodone alone. Improvement in bowel function was seen within one week, showing constipation is successfully treated, as well as prevented, by the two drugs in combination.