Genetic biomarkers of placebo response: what could it mean for future trial design?

For many classes of medications, such as analgesics, antidepressants, angina treatments, antihistamines and nonsteriodal asthma prophylaxis, well-designed, randomized, placebo-controlled trials (RCTs) often show no difference between drug and placebo [1]. As a consequence, RCTs commonly use various ‘enrichment’ strategies that can selectively exclude participants based on pretreatment response to placebo (placebo run-in) or include them if they respond to drug (predictive enrichment) [2,3]. The enriched subset of patients is then randomized to drug or placebo. By presumably depleting placebo responders – or enriching for drug responders – it is expected that the trial will show a larger drug–placebo difference, thus increasing power while decreasing sample size. Many potential threats to the validity of enrichment strategies have been proposed. For example, placebo run-in subjects may experience unblinding side effects once shifted to active drug [4] and, conversely, patients pre-treated with drug then randomized to placebo can experience withdrawal relapse creating a bias against placebo [3]. Probably the most severe criticism is that empirical studies of placebo run-in methodologies generally fail to show any improved ability to detect drug–placebo differences [5]. Given the limitations of current enrichment strategies, coupled with the recent increases in clinical trial costs and placebo-response rates [6,7], identifying placebo-response biomarkers to guide enrichment could prove to be a valuable strategy. Research into the neurological basis of the placebo response was launched by the discovery that placebo-induced analgesia could be blocked by the opioid antagonist naloxone [8]. Today there is converging evidence that opioid receptors and dopamine-reward circuitry form part of the neurological placebo-response pathway [9,10]. With potential mechanisms in sight, the search for genetic biomarkers of placebo response is now a feasible proposition. We recently provided evidence that COMT, an enzyme that plays a key role in prefrontal and midbrain dopamine tuning, may be a biomarker of placebo response in irritable bowel syndrome [11]. The COMT Val18Met single nucleotide polymorphism is a G-to-A transition that results in a valine-to-methionine substitution [12]. The methionine form of the enzyme is three to four-times less efficient at catabolizing dopamine than the valine form. Consequently Met/Met homozygotes have higher levels of prefrontal dopamine relative to Val/Met and Val/Val. Met/Met individuals have a greater tendency to seek and appreciate rewards [13] as well as to confirm new information based on their prior beliefs (confirmation bias) [14]. We recently demonstrated that Met/Met individuals have significantly greater placebo responses than Val/Met and Val/Val and that the response is highest when treated by a warm, caring practitioner.