Pain sensitivity and opioid analgesia: a pharmacogenomic twin study

Abstract

Opioids are the cornerstone medication for the management of moderate to severe pain. Unfortunately, vast inter-individual differences in dose requirements complicate their effective and safe clinical use. Mechanisms underlying such differences are incompletely understood, are likely multifactorial, and include genetic and environmental contributions. While accumulating evidence suggests that variants of several genes account for some of the observed response variance, the relative contribution of these factors remains unknown. This study used a twin paradigm to provide a global estimate of the genetic and environmental contributions to inter-individual differences in pain sensitivity and analgesic opioid effects. Eighty one monozygotic and 31 dizygotic twin pairs successfully underwent a computer-controlled infusion with the μ-opioid agonist alfentanil in a single occasion, randomized, double-blind and placebo-controlled study design. Pain sensitivity and analgesic effects were assessed with experimental heat and cold pressor pain models along with important covariates including demographic factors, depression, anxiety, and sleep quality. Significant heritability was detected for cold pressor pain tolerance and opioid-mediated elevations in heat and cold pressor pain thresholds. Genetic effects accounted for 12-60% of the observed response variance. Significant familial effects accounting for 24-32% of observed variance were detected for heat and cold pressor pain thresholds and opioid-mediated elevation in cold pressor pain tolerance. Significant covariates included age, gender, race, education, and anxiety. Results provide a strong rationale for more detailed molecular genetic studies to elucidate mechanisms underlying inter-individual differences in pain sensitivity and analgesic opioid responses. Such studies will require careful consideration of the studied pain phenotype.

Figure 1

Two hundred and twenty eight monozygotic and dizygotic twins successfully underwent a computer-controlled infusion with the mu-opioid agonist alfentanil in a single occasion, randomized, double-blinded and placebo-controlled study paradigm. Baseline assessments included covariates affecting pain perception, sensitivity to experimental heat and cold pressor pain, vital signs, and blood draws. Fifty percent of twin pairs were allocated to receive alfentanil first and saline placebo second, while the other fifty percent of twin pairs received alfentanil and saline placebo in reversed order. The alfentanil target concentrations for both treatment sequences are depicted in the graph. A concentration of 100ng/ml produces significant analgesic effects in patients suffering from postoperative pain. Analgesic drug effects and vital signs were assessed in identical fashion during both stages of the infusion protocol.

Figure 2

Pain sensitivity was assessed with aid of a heat and cold pressor pain model. Heat pain sensitivity was measured by determining the minimum thermode temperature evoking pain while in contact with skin (threshold). Cold pressor pain sensitivity was determined by measuring the time to the onset of pain (threshold) and the time to intolerable pain (tolerance), while the hand and parts of the forearm were immersed in ice water (re-circulated and kept at 1–2°C). Results are ranked from smallest to largest along the x-axis. The inter-individual differences in heat pain sensitivity varied widely and covered a range greater than 10°C. Similarly, inter-individual differences in cold pressor pain sensitivity varied widely and covered more than a ten-fold range. The solid and dashed lines indicate the median and the interquartile range, respectively.

Figure 3

Administration of alfentanil resulted in significant analgesic effects to heat and cold pressor pain (p<0.001). Results are ranked from smallest to largest along the x-axis. Analgesic effects varied widely among study subjects. Analgesic effects to heat pain were absent in some subjects but resulted in a maximum elevation the heat pain threshold of up to 5.7°C in others. Similarly, analgesic effects to cold pressor pain were absent in some subjects but resulted in an elevation of the cold pressor pain threshold and cold pressor pain tolerance to the cut-off value of 180s. The solid and dashed lines indicate the median and the interquartile range, respectively.