Pharmacological modulation of experimental phasic and tonic muscle pain by morphine, alfentanil and ketamine in healthy volunteers.
BACKGROUND
Muscle pain is a major clinical problem but the underlying mechanisms and its pharmacological modulation need further investigation. This study on 15 volunteers evaluates if two experimental muscle pain models are sensitive to micro -receptor agonists and to an N-methyl-D-aspartate (NMDA)-receptor antagonist.


METHODS
In the left tibialis anterior, intramuscular electrical (IMES) pain thresholds were determined for single (SPTmuscle) and five (RPTmuscle) repeated stimuli. Also pain to suprathreshold stimulation at 150% of RPTmuscle, 10 s, was assessed on a visual analog scale (VAS) as AUCimes (area under the VAS curve). In the right TA muscle, pain intensity on infusion of 0.5 ml of hypertonic saline, 5% (AUCsaline) and pain distribution indicated as local and referred were evaluated. Pain variables were assessed before, during and after intravenous infusions of morphine (10 microg x kg-1 min-1, 10 min), alfentanil (target-controlled infusion, plasma concentration; 60 ng ml-1, 60 min) and ketamine (10 microg x kg-1 min-1, 60 min). All data were normalized to baseline pain values (before drug infusions were initiated) and compared with placebo (midazolam, 2 microg x kg-1 min-1, 10 min).


RESULTS
SPTmuscle increased (log mean values +/- SD, mA) with morphine (0.11 +/- 0.17, P < 0.05), alfentanil (0.28 +/- 0.24, P < 0.001) and ketamine (0.19 +/- 0.18, P < 0.01) as compared with placebo (-0.03 +/- 0.12). Alfentanil and ketamine also increased RPTmuscle (0.25 +/- 0.21, P < 0.01 and 0.21 +/- 0.19, P < 0.05, respectively) as compared with placebo (0.00 +/- 0.17). Pain to IMES (AUCimes) was reduced (median values [25th-75th percentiles], cm x s) by alfentanil and ketamine (-19.7 [-14.6 - -29.6] and-12.8 [-8.3 - -27.8], P < 0.05, respectively) vs. placebo (-0.8 [1.6 - -12.3]). Similar drug effects were seen when pain to infusion of hypertonic saline (AUCsaline) was assessed (alfentanil:-388 [-99 - -677] and ketamine:-326 [-227 - -573], P < 0.05 compared with placebo: 150 [449--240]). Ketamine also reduced the size of the local pain area (-58.4 [-21.2 - -176.1], < 0.05) as compared with placebo (-0.4 [70.6 - -13.4]). The frequency of referred pain was also lower when ketamine was given (3/13, P < 0.05) vs. placebo (9/14).


CONCLUSIONS
The study demonstrates that experimental muscle pain induced in humans by electrical stimulation and infusion of hypertonic saline is sensitive to pharmacological modulation similar to preclinical animal tests and clinical trials. The data suggest that these models can be valuable tools in analgesic drug development.
Schulte
H
H
Department of Anaesthesia and Intensive Care, Huddinge University Hospital, Stockholm, Sweden. helene.schulte@cfss.ki.se
Graven-Nielsen
T
T
Sollevi
A
A
Jansson
Y
Y
Arendt-Nielsen
L
L
Segerdahl
M
M
D000328:Adult; D015760:Alfentanil / Q000494:pharmacology*; D004558:Electric Stimulation; D005260:Female; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000502:physiology*; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000502:physiology; D012462:Saline Solution, Hypertonic
D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D012462:Saline Solution, Hypertonic; D015760:Alfentanil; D007649:Ketamine; D009020:Morphine