Dissociation of Morphine Analgesia and Sedation Evaluated by EEG Measures in Healthy Volunteers

Aim: The analgesic effects of morphine (CAS 57-27-2) in clinical use are well described. Sedation is discussed as a relevant side-effect, mostly based on data recorded in normal subjects without pain. The aim of this study was to quantify and to evaluate electrophysiologically the analgesic and sedative effects of morphine for the first time using an experimental pain model.

Methods: Analgesic and sedative effects of a low dose of morphine sulfate (CAS 6211-15-0; 10 mg i.v.) were determined using a standard phasic pain model (intracutaneously administered electrical pulses) in a placebo-controlled design with seven healthy subjects. Five blocks (1 block = 80 stimuli) of painful stimuli were applied, covering a period of 3 h. Analgesia was assessed by subjective pain ratings and by pain-related brain potentials. Sedation was determined by the power spectra of the spontaneous EEG, by auditory evoked potentials (AEP), reaction times and mood scales.

Results: In all subjects the pain related variables were suppressed maximally 2 h after morphine administration (p < 0.01 versus placebo), indicated by a decrease of the pain ratings by about 45% and of the pain related brain potentials by about 50%. Interestingly, no effect on any sedation variable was found (p > 0.05).

Conclusion: The lack of sedative effects in the presence of marked analgesia was surprising in comparison with results of previous studies. It is concluded that the experimental pain increased the arousal level thus counteracting morphine-induced sedation. This may explain why other studies found relevant sedation after morphine application in the absence of pain. This underlines that sedative effects of analgesic drugs should be evaluated in the presence of pain. In relation to other analgesics (meperidine, pentacozine, nortilidine, flupirtine and tramadol) evaluated by exactly the same experimental protocol, morphine exhibited a potent analgesia with the smallest sedative effects of all.