Aversive and reinforcing opioid effects: a pharmacogenomic twin study.
BACKGROUND
The clinical utility of opioids is limited by adverse drug effects including respiratory depression, sedation, nausea, and pruritus. In addition, abuse of prescription opioids is problematic. Gaining a better understanding of the genetic and environmental mechanisms contributing to an individual's susceptibility to adverse opioid effects is essential to identify patients at risk.


METHODS
A classic twin study paradigm provided estimates for the genetic and familial (genetic and/or shared environment) contribution to acute adverse and affective opioid responses, all secondary outcomes of a larger dataset. One hundred twenty-one twin pairs were recruited in a single occasion, randomized, double-blind, and placebo-controlled study. The μ-opioid receptor agonist alfentanil and saline placebo were administered as target-controlled infusions under carefully monitored laboratory conditions. Measured outcomes included respiratory depression, sedation, nausea, pruritus, drug liking, and drug disliking. Demographic information was collected, and aspects of mood and sleep were evaluated.


RESULTS
Significant heritability was detected for respiratory depression (30%), nausea (59%), and drug disliking (36%). Significant familial effects were detected for sedation (29%), pruritus (38%), dizziness (32%), and drug liking (26%). Significant covariates included age, sex, race, ethnicity, education, mood, and depression. Covariates affected sedation, pruritus, drug liking and disliking, and dizziness.


CONCLUSIONS
This study demonstrates that large-scale efforts to collect quantitative and well-defined opioid response data are not only feasible but also produce data that are suitable for genetic analysis. Genetic, environmental, and demographic factors work together to control adverse and reinforcing opioid responses, but contribute differently to specific responses.
Department of Anesthesia, Stanford University School of Medicine, Stanford, California 94305-5117, USA. ang@stanford.edu
Martin S
MS
Angst
Laura C
LC
Lazzeroni
Nicholas G
NG
Phillips
David R
DR
Drover
Martha
M
Tingle
Amrita
A
Ray
Gary E
GE
Swan
J David
JD
Clark
D000328:Adult; D015760:Alfentanil / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D023281:Genomics; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D017450:Receptors, Opioid, mu / Q000235:genetics; D012054:Reinforcement, Psychology; D012119:Respiration / Q000187:drug effects
D000701:Analgesics, Opioid; D006993:Hypnotics and Sedatives; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D015760:Alfentanil