Chronic use of opioids as morphine and tramadol to control pain is associated with several side effects and tolerance to their analgesic effect and dependence. Some of the side effects of opioids can be ameliorated by naloxone, however this is associated with decreased analgesia. Nalbuphine was shown to ameliorate morphine and tramadol psychological dependence. The current study aims to investigate the effect of co-administration of nalbuphine with morphine or tramadol on tolerance to analgesia and physical dependence and the possible involvement of norepinephrine in its effect. Co-admistration of nalbuphine with morphine or tramadol prevented tolerance to analgesia and physical dependence that was observed with each drug alone and this was associated with prevention of the elevation in norepinephrine in the locus coereulus (LC) following naloxone administration. These results emphasize the possible use of nalbuphine in combination with morphine or tramadol to preserve their analgesic effect and to prevent the development of dependence to their effect.