People with pain differ in how they respond to opioids, both in the degree of analgesic relief they feel and in whether they experience aversive or reinforcing drug effects. While the conventional wisdom is that this variability has a genetic basis, how large a role genetics plays has been unclear—until now. Using a classic twin study paradigm applied for the first time to an investigation of opioid responses, J. David Clark and colleagues at Stanford University School of Medicine in California, US, report significant heritability of opioid analgesic and non-analgesic effects on heat and cold-pressor pain thresholds, respiratory rate, nausea, and drug disliking; other effects with low heritability such as drug liking, pruritus, and sedation showed significant familial aggregation, suggestive of shared environmental determinants. The new findings set the stage for more detailed molecular genetic studies aiming to identify the specific genes and pathways controlling opioid responses, and also create optimism that physicians could one day target opioids to patients most likely to experience pain relief and least likely to suffer side effects or to abuse the drugs.
The results on the heritability of opioid analgesia appear in the July 2012 issue of the journal Pain, while those concerning aversive and reinforcing opioid effects debut in the July 2012 issue of the journal Anesthesiology.
The rationale for a twin study
Opioids are a mainstay of treatment for chronic pain, but interindividual variability in responses to the drugs makes it difficult for physicians to make appropriate treatment decisions for their patients. “People have very different degrees of pain relief, different side effects, and different propensities to go on and abuse the drugs,” first author Martin Angst told PRF. “We can’t predict who will do well, and who will do poorly, and we don’t know what the contributing factors are,” he said.
That genes account for this wide trait variability has long been the assumption of pharmacogenomic studies of opioids in humans (for recent reviews see Stamer and Stüber, 2007; Oertel and Lötsch, 2008; Walter and Lötsch, 2009; Kambur and Männistö, 2010), but those investigations have provided disappointing results: The various single-nucleotide polymorphisms linked to opioid responses thus far account for very little of the observed differences among individuals. “One of the major motivations of our study,” Angst told PRF, “was to make sure that interindividual differences in opioid responses are significantly due to genetics before engaging in larger, difficult-to-conduct, and expensive human studies trying to dissect the molecular genetics underlying such differences.”
Twin studies allow researchers to estimate heritability of different traits, but previous twin studies of pain had focused primarily on clinical conditions like migraine or back pain, and relied mostly on information provided on questionnaires; only three prior twin studies had examined heritability of experimental pain phenotypes, and none looked at opioid responses (MacGregor et al., 1997; Nielsen et al., 2008; Norbury et al., 2007). For the first such twin study, Angst and coworkers performed a randomized, double-blind, placebo-controlled, crossover investigation on 81 identical (monozygotic) and 33 fraternal (dizygotic) twin pairs, ages 18-70. Half of the twin pairs received a single dose of the short-acting, μ-opioid receptor agonist alfentanil, followed by saline placebo, while the other half received the infusions in reverse order. A computer-controlled infusion paradigm ensured an alfentanil plasma concentration of 100 ng/mL, a level previously reported to provide clinically relevant analgesic effects. The investigators then measured baseline pain sensitivities and analgesic effects using experimental heat and cold-pressor pain models, and also assessed adverse effects. In addition, they gauged the impact of covariates, including demographic variables such as gender and age, as well as anxiety, depression, sleep, and blood pressure, on opioid responses.
The key findings
In their report published in Pain, Angst and colleagues found significant heritability (49 percent) for baseline cold-pressor pain tolerance (time to withdrawal), in line with previous findings from Christopher Sivert Nielsen, Norwegian Institute of Public Health, Oslo, Norway, and colleagues (Nielsen et al., 2008). In terms of the analgesic response to opioids, they discovered that genes explained from 12-60 percent of the variability in traits they examined. “That opioid analgesia is under considerable genetic control is perhaps not surprising, but documentation in humans has been long overdue,” Nielsen wrote in a Commentary accompanying the report (Nielsen, 2012). “Hopefully, these results will contribute to a broader appreciation that individual differences in pain and analgesia are real, and not just a result of some patients exaggerating their pain and others being stoic,” he wrote.
Still, Angst stresses that heritability estimates varied widely among traits. The study’s most prominent finding, for instance, indicated that genetic factors explained 60 percent of an opioid-induced elevation in the cold-pressor pain threshold (time to pain). However, heritability of an opioid-induced increase in heat pain threshold, another response they observed, reached only a modest 12 percent. Those findings, Angst said, “educate researchers as to which opioid responses should or should not be studied in the context of genetics.” Furthermore, the investigators found no significant heritable component for the analgesic effect of alfentanil on cold-pressor pain tolerance, but rather significant familial aggregation (30 percent), suggesting that shared environmental influences might be more important. (Because familial aggregation includes both shared environmental influences and genetic effects, there remains a possibility for some role for genetics even in the face of low heritability. However, the small sample size of the study prevented the researchers from further breaking down the familial effects).
In their report published in Anesthesiology, Angst and coworkers also found significant heritability for aversive and reinforcing opioid effects: 59 percent for nausea, 36 percent for drug disliking, and 30 percent for respiratory depression. The high heritability of nausea is of particular importance, since nausea is one of the most common and troublesome complications that patients experience while on opioids. Also intriguing is the heritability of drug disliking, which the authors suggest could serve as a phenotype in future studies to gauge the likelihood of opioid abuse.
In contrast, other aversive and reinforcing opioid effects with low heritability had significant familial effects, including pruritus (38 percent familial effect), dizziness (32 percent), sedation (29 percent), and drug liking (26 percent), again revealing the importance of shared environmental determinants, according to Roger Fillingim, University of Florida, Gainesville, US. “[P]reexisting environmental influences may contribute importantly to opioid responses, raising the possibility that prediction models incorporating both genetic and environmental factors may account for a broader range of opioid effects, which would potentially strengthen personalized treatment efforts,” Fillingim wrote in a Commentary accompanying the Anesthesiology report (Fillingim, 2012).
Questions for future research
Whether the current findings, from subjects receiving opioids under carefully controlled laboratory conditions, ultimately push personalized medicine forward will depend on whether they also apply to clinical pain in the real-world environment of physician offices. It is also unclear whether the twin study’s results from the acute setting have relevance for chronic opioid use. On the epidemiological front, while the researchers found that the covariates of gender and age were most consistently associated with opioid responses, how those and other covariates interact with genetic factors remains uncertain.
Furthermore, though Angst and colleagues studied opioid analgesic and non-analgesic effects separately, understanding the relationship between both types of effects will not only help target treatment—to those likely to experience both effective analgesia and few side effects—but could also point towards more complicated fundamental biology, according to Marshall Devor, Hebrew University of Jerusalem in Israel. “If the amount of analgesia and number of side effects do not correlate with one another, different genes, and different opioid mechanisms, might be involved—that would be interesting,” Devor said.
Angst reports that his team is currently preparing a manuscript that will precisely address this issue. “Preliminary analysis indicates that the correlations are weak, if they exist at all,” he said.
Regardless of the link, if any, between opioid pain-relieving and adverse effects, the current twin study gives new direction to the endeavor of finding genes that underlie opioid response heritability by defining measurable phenotypes with a clear genetic basis. Angst is pursuing funding to use such phenotypes in larger samples of healthy adult volunteers in order to dissect the underlying genetics. He and others suspect that traits like opioid analgesic response involve many different genes, and that gene-gene interaction is likely to be important. That means his and others’ efforts won’t be easy or quick. The current findings do provide reassurance that the genes are, in fact, out there—researchers just need to find them now.
Karl Gruber is a Ph.D. candidate in genetics at Heinrich Heine University in Düsseldorf, Germany, and a freelance science writer.
