ANTINOCICEPTIVE EFFECTS OF ADENOSINE INFUSION IN MAN - ASSESSMENTS INEXPERIMENTALLY-INDUCED PAIN AND IN SURGERY

Acute nociceptive pain in the postoperative phase is, despite extensiv e knowledge of its physiology and optimization of available therapies, still a clinical problem of importance. There is still room for devel opment of new therapies, with the goal of gaining a pain-relieved pati ent without or with as few side-effects as possible, thereby minimizin g postoperative complications. The endogenous compound adenosine is us ed clinically as an antiarrythmic agent and as a vasodilator. In addit ion, it is known to induce pain in humans, when exogenously administer ed. During the last decade, several animal studies have, however, show n that adenosine may exert inhibitory action in nociceptive transmissi on. This thesis set out to study the tentative antinociceptive effect of adenosine in humans. Low and non-hypotensive doses (50-80 mu g . kg (-1). min(-1)) of adenosine were given to healthy volunteers as well a s perioperatively to patients, without causing pain or hypotension. In 10 healthy volunteers, adenosine (50-80 mu g . kg(-1). min(-1)) infus ion increased the heat pain threshold of normal hairy skin, with no im pact on thermal perception thresholds, indicating that adenosine reduc es nociceptive C fiber transmission. In 9 healthy volunteers, a single -blind randomized placebo-controlled crossover treatment with adenosin e (70 mu g . kg(-1). min(-1)), alone or combined with ketamine (0.1 mg . kg(-1)) or morphine (0.1 mg . kg(-1)), reduced experimentally induc ed ischemic pain, with a tendency toward an augmented efficacy when co mbined with morphine. This finding suggests an inhibitory effect of ad enosine on C fiber-induced ongoing pain. Further, a model of cutaneous inflammatory pain, induced by topical mustard oil, was studied using a double-blind randomized crossover techniques in 6 volunteers, where adenosine (50 mu g . kg(-1). min(-1)) attenuated the development of al lodynia around the injured area. The results of the latter two models of experimental pain implicate an inhibitory action on central sensiti zation. The intraoperative isoflurane requirement during treatment wit h adenosine (80 mu g . kg(-1). min(-1)) or placebo, was studied in 145 patients subject to surgery, mainly involving three different pain mo dalities; more superficial (breast surgery, 72 patients), deep somatic /joint-associated (shoulder surgery, 30 patients) and visceral (gyneco logical abdominal surgery, 43 patients) pain. A significant reduction in end-tidal isoflurane concentration was seen during surgery, by appr oximately 20-50%, interpreted as an antinociceptive effect. The reduct ion was especially marked during gynecological abdominal surgery. In a ddition, the postoperative opioid requirement in 115 patients was stud ied and found reduced, by approximately 25%, an interesting result as the opioid-sparing effect extended for 21-24 hours beyond the end of i nfusion. The findings of this thesis are in Line with the. antinocicep tive actions reported from animal studies in acute pain models, and de monstrates an alleviating effect of exogenous adenosine administration in various acute clinical pain states.