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.

Dissociable neural responses related to pain intensity, stimulus intensity, and stimulus awareness within the anterior cingulate cortex: a parametric single-trial laser functional magnetic resonance imaging study.

Neuroimaging studies have demonstrated activations in the anterior cingulate cortex (ACC) related to the affective component of pain, but not to stimulus intensity. However, it is possible that the low spatial resolution of positron emission tomography, as used in the majority of these studies, obscured areas coding stimulus intensity. We revisited this issue, using a parametric single-trial functional magnetic resonance imaging design, and investigated pain, stimulus intensity, and stimulus awareness (i.e., pain unrelated) responses within the ACC in nine healthy volunteers. Four different stimulus intensities ranging from warm to painful (300-600 mJ) were applied with a thulium yttrium-aluminum granite infrared laser in a randomized order and rated by the subjects on a five point scale (P0-P4). Pain-related regions in the ventral posterior ACC showed a response that did not distinguish between innocuous trials (P0 and P1) but showed a positive linear relationship with the blood oxygenation level-dependent contrast signal for painful trials (P2-P4). Regions in the dorsal anterior ACC along the cingulate sulcus differentiated between P0 (not perceived) and P1 but exhibited no additional signal increase with P2; these regions are related to stimulus awareness and probably to cognitive processing. Most importantly, we identified a region in the dorsal posterior ACC showing a response that discriminated between nonpainful trials (P0 and P1); therefore, this region was simply related to basic sensory processing and not to pain intensity. Stimulus-related activations were all located adjacent to the cingulate motor area, highlighting the strategic link of stimulus processing and response generation in the posterior ACC.