Intravenous dextromethorphan to human volunteers: relationship between pharmacokinetics and anti-hyperalgesic effect.
The aim of this study was to investigate the effect of dextromethorphan (DM) 0.5 mg/kg administered intravenously (i.v.) on hyperalgesia and pain after a tissue injury in human volunteers, and to describe the relationship between pharmacokinetic and pharmacodynamic data. The heat-capsaicin sensitisation model, a well-established experimental hyperalgesia model was induced in 24 healthy, male volunteers aged 21-35 years. The subjects received i.v. DM 0.5 mg/kg or isotonic saline on two separate study sessions. The primary outcome measure from 0 to 3 h was reduction in area of established secondary hyperalgesia. Secondary outcome measures were reduction in area of secondary hyperalgesia in response to brief thermal stimulation, heat pain detection thresholds and painfulness after tonic heat pain. Blood samples were collected throughout the study to describe the relationship between pharmacokinetic and pharmacodynamic data. Intravenous DM 0.5 mg/kg significantly reduced areas of established secondary hyperalgesia with an average of 39% (P<0.05). Development of secondary hyperalgesia was substantially prevented by DM (P<0.05). No significant effect was seen on either heat pain detection thresholds or after tonic heat pain. The pharmacokinetic-pharmacodynamic relationship showed a large inter-subject variation with a mean delay in effect of nearly 2 h in relation to peak serum concentration. The results strongly indicate that DM is an anti-hyperalgesic drug. The delay in effect may be explained by several mechanisms and suggests that timing of DM administration is an essential factor for using the drug in clinical settings.
Duedahl
Tina H
TH
The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark Department of Anesthesiology and Intensive Care Medicine, Herlev University Hospital, Herlev, Denmark The Pharmacological Laboratory, Glostrup University Hospital, Glostrup, Denmark Department of Anesthesiology, Glostrup University Hospital, Glostrup, Denmark.
Dirks
Jesper
J
Petersen
Kamilla B
KB
Romsing
Janne
J
Larsen
Niels-Erik
NE
Dahl
Jorgen B
JB
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002211:Capsaicin; D018592:Cross-Over Studies; D003915:Dextromethorphan / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D003917:Dextrorphan / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy*; D007262:Infusions, Intravenous / Q000379:methods; D008297:Male; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome
D018691:Excitatory Amino Acid Antagonists; D003917:Dextrorphan; D003915:Dextromethorphan; D002211:Capsaicin