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Pharmacological modulation of experimental phasic and tonic muscle pain by morphine, alfentanil and ketamine in healthy volunteers.
Acta Anaesthesiol Scand 2003; 47(8):1020-30AA

Abstract

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).

CONCLUSION

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.

Authors+Show Affiliations

Department of Anaesthesia and Intensive Care, Huddinge University Hospital, Stockholm, Sweden. helene.schulte@cfss.ki.seNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12904196

Citation

Schulte, H, et al. "Pharmacological Modulation of Experimental Phasic and Tonic Muscle Pain By Morphine, Alfentanil and Ketamine in Healthy Volunteers." Acta Anaesthesiologica Scandinavica, vol. 47, no. 8, 2003, pp. 1020-30.
Schulte H, Graven-Nielsen T, Sollevi A, et al. Pharmacological modulation of experimental phasic and tonic muscle pain by morphine, alfentanil and ketamine in healthy volunteers. Acta Anaesthesiol Scand. 2003;47(8):1020-30.
Schulte, H., Graven-Nielsen, T., Sollevi, A., Jansson, Y., Arendt-Nielsen, L., & Segerdahl, M. (2003). Pharmacological modulation of experimental phasic and tonic muscle pain by morphine, alfentanil and ketamine in healthy volunteers. Acta Anaesthesiologica Scandinavica, 47(8), pp. 1020-30.
Schulte H, et al. Pharmacological Modulation of Experimental Phasic and Tonic Muscle Pain By Morphine, Alfentanil and Ketamine in Healthy Volunteers. Acta Anaesthesiol Scand. 2003;47(8):1020-30. PubMed PMID: 12904196.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological modulation of experimental phasic and tonic muscle pain by morphine, alfentanil and ketamine in healthy volunteers. AU - Schulte,H, AU - Graven-Nielsen,T, AU - Sollevi,A, AU - Jansson,Y, AU - Arendt-Nielsen,L, AU - Segerdahl,M, PY - 2003/8/9/pubmed PY - 2004/1/24/medline PY - 2003/8/9/entrez SP - 1020 EP - 30 JF - Acta anaesthesiologica Scandinavica JO - Acta Anaesthesiol Scand VL - 47 IS - 8 N2 - 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). CONCLUSION: 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. SN - 0001-5172 UR - https://www.unboundmedicine.com/medline/citation/12904196/Pharmacological_modulation_of_experimental_phasic_and_tonic_muscle_pain_by_morphine_alfentanil_and_ketamine_in_healthy_volunteers_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&amp;sid=nlm:pubmed&amp;issn=0001-5172&amp;date=2003&amp;volume=47&amp;issue=8&amp;spage=1020 DB - PRIME DP - Unbound Medicine ER -