Dynorphin A(1-13) analgesia in opioid-treated patients with chronic pain. A controlled pilot study

Objective: This pilot study was developed to acquire preliminary data concerning the analgesic efficacy and tolerability of dynorphin A(1-13), a 13 amino acid fragment of the endogenous opioid peptide dynorphin A(1-17), in opioid-treated patients. Design and Setting: Randomised, double-blind, placebo-controlled, graded dose, 3-way crossover pilot study conducted in a comprehensive cancer centre. Patients: Nine chronic pain patients receiving morphine > 150 mg/day for at least 2 weeks, or the equivalent dose of hydromorphone. Interventions: Each patient was given a study treatment on each of 3 successive days after the opioid regimen was stabilised. On each day, a patient received 50% of the usual oral opioid dose when pain was at least moderate, followed 15 minutes later by a brief intravenous infusion of either dynorphin A(1-13) 150 μg/kg, dynorphin A(1-13) 500 μg/kg, or saline placebo. The sequence of administration was randomly ordered. Main Outcome Measures: Pain intensity, pain relief, mood and adverse effects were recorded for 8 hours after each treatment. Blood was sampled for dynorphin levels beginning 15 minutes after the infusion. Results: The data demonstrated linear dose-response trends for most of the parameters evaluated. Using analysis of variance (ANOVA), the differences among lower dose dynorphin A(1-13), higher dose dynorphin A(1-13), and the control were strongest for the sum of pain intensity differences (categorical scale) [p = 0.08], peak relief (p = 0.10), and total mood effect (p = 0.08). Post hoc pairwise comparisons consistently demonstrated the largest differences between the higher dose dynorphin A(1-13) and control. The major adverse effect was flushing. Dynorphin was detected only in the first sample, which was drawn 15 minutes after drug administration. Conclusions: This controlled pilot study identified trends suggesting that a brief intravenous infusion of dynorphin A(1-13) could potentially augment analgesia in opioid-treated patients. Based on this experience, a larger controlled trial is warranted. A 500 μg/kg dose would be an appropriate minimum dose for such studies.