Opioids appear to exert a peripheral effect by gaining access to peripheral opioid receptors. It has been proposed that inflammatory processes and highly osmotic substances could alter the perineural barrier, thereby allowing easy access to opioid receptors. Although local anesthetics do not have osmotic activity, they are highly active on neural tissue and appear to work synergistically with opioids when administered for major conduction blockade. We therefore evaluated, in a double-blind fashion, the combination of lidocaine plus morphine in an attempt to provide a scientific basis for the use of a combination of morphine plus local anesthetics in the periphery. Seven thermal stimuli in 2 degrees C increments (range 40-52 degrees C) were delivered in a random sequence by a computer-controlled thermistor to one of three pretreated sites on 10 volunteers' forearms: reference site (no injection), lidocaine site (0.1-mL intradermal injection of lidocaine 0.5%), or lidocaine plus morphine site (0.1 mL of 0.5 mg of morphine plus lidocaine 1%). Pain responses to the thermal stimuli were rated by the volunteers using the method of magnitude estimation. Pain scores indicated that the combination of lidocaine plus morphine was not more effective than lidocaine alone in attenuating the heat-induced pain. Twenty and 120 min after injection, scores at the lidocaine plus morphine site were 37% and 20% greater than those at the lidocaine site. The addition of morphine to lidocaine did not result in an improvement in the analgesic efficacy and actually had an antianalgesic effect.