Twin Research and Human Genetics

Articles

Opioid Pharmacogenomics Using a Twin Study Paradigm: Methods and Procedures for Determining Familial Aggregation and Heritability

Martin S. Angsta1 c1, Nicholas G. Phillipsa2, David R. Drovera3, Martha Tinglea4, Jeffrey L. Galinkina5, Uwe Christiansa6, Gary E. Swana7, Laura C. Lazzeronia8 and J. David Clarka9

a1 Department of Anesthesia, Stanford University School of Medicine, United States of America. ang@stanford.edu

a2 Department of Anesthesia, Stanford University School of Medicine, United States of America.

a3 Department of Anesthesia, Stanford University School of Medicine, United States of America.

a4 Department of Anesthesia, Stanford University School of Medicine, United States of America.

a5 Department of Anesthesiology, Children's Hospital, University of Colorado at Denver Health Science Center, Aurora, United States of America.

a6 Department of Anesthesiology, Children's Hospital, University of Colorado at Denver Health Science Center, Aurora, United States of America.

a7 Center for Health Sciences, SRI International, Menlo Park, CA, United States of America.

a8 Department of Psychiatry and Behavioral Sciences and of Pediatrics, Stanford University School of Medicine, United States of America.

a9 Department of Anesthesia, Stanford University School of Medicine, United States of America; Department of Anesthesia, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States of America.

Abstract

Opioids are the cornerstone medication for the treatment of moderate to severe pain. However, analgesic opioid requirements and the propensity to suffer from aversive opioid effects, including fatal respiratory depression and addiction, vary widely among patients. The factors underlying the substantial response variance remain largely unknown and need clarification for using opioids more effectively in appropriately selected patients. This ongoing study takes advantage of the twin paradigm to estimate the genetic and environmental contributions to inter-individual differences in opioid responses. Evidence of significant heritability will justify more detailed and extensive genomic studies. The enrollment target is 80 monozygotic and 45 dizygotic twin pairs who undergo a target-controlled infusion of the opioid alfentanil and saline placebo in sequential but randomized order. In a laboratory-type setting, well-defined pharmacodynamic endpoints are measured to quantify pain sensitivity, analgesic opioid effects, and aversive opioid effects including respiratory depression, sedation and reinforcing affective responses. First results obtained in 159 participants provide evidence for the feasibility and utility of this interventional study paradigm to estimate familial aggregation and heritability components of relevant drug effects. Areas highlighted in this report include recruitment strategies, required infrastructure and personnel, selection of relevant outcome measures, drug infusion algorithm minimizing pharmacokinetic variability, and considerations for optimizing data quality and quantity without hampering feasibility. Applying the twin paradigm to complex and potentially harmful studies comprehensively characterizing pharmacological response profiles is without much precedent. Methods and first results including heritability estimates for heat and cold pain sensitivity should be of interest to investigators considering similar studies.

(Received April 08 2010)

(Accepted July 30 2010)

Keywords

  • pharmacogenomics;
  • pharmacodynamics;
  • opioid;
  • alfentanil;
  • twin;
  • heritability;
  • familial aggregation;
  • heat pain;
  • cold pressor pain;
  • pain sensitivity;
  • quantitative sensory test;
  • analgesia;
  • respiratory depression;
  • sedation;
  • nausea;
  • pruritus;
  • liking;
  • positive affective response

Correspondence:

c1 Address for correspondence: Martin S. Angst, MD, Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, USA.

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