The findings suggest that patients benefited from placebo treatment to a greater degree than healthy individuals did and that studies on healthy individuals may underestimate the magnitude of the placebo analgesic effect in patients. Patients' clinical pain and experimentally induced pain respond to placebo to the same degree.

Fear was induced by the anticipation of electric shock in order to investigate whether fear reduced the effectiveness of a placebo intervention on reported pain and the acoustic startle reflex. Thirty-three subjects participated in a 3 Condition (Natural History [NH], Placebo [P], Placebo+Fear [PF])×3 Test (Pretest, Posttest 1, Posttest 2) within-subject design, tested on 3 separate days. Measures of fear were fear of pain (FOP), measured by the Fear of Pain Questionnaire (FPQ-III); fear-potentiated startle; and a self-report measure that assessed the effectiveness of the fear induction procedure. In the pain intensity data, there was a trend towards a placebo effect. This trend was abolished by induced fear, and was most pronounced in subjects who were highest in measures of fear. The placebo manipulation also caused a reduction in startle reflex amplitude. This effect was abolished by induced fear, and was strongest amongst high FOP subjects. In conclusion, induced fear abolished placebo analgesia, and this effect was strongest in subjects who had high scores on measures of fear.

The placebo effect is considered the core example of mind-body interactions. However, individual differences produce large placebo response variability in both healthy volunteers and patients. The placebo response in pain, placebo analgesia, may be dependent on both the opioid system and the dopaminergic system. Previous studies suggest that genetic variability affects the function of these 2 systems. The aim of this study was therefore to address the interaction between the single nucleotide polymorphisms opioid receptor mu 1 (OPRM1) rs1799971 and catechol-O-methyltransferase (COMT) rs4680 on placebo analgesia. Two hundred ninety-six healthy volunteers participated in a repeated-measures experimental design where thermal heat pain stimuli were used as pain stimuli. Participants were randomized either to a placebo group receiving placebo cream together with information that the cream would reduce pain, or to a natural history group receiving the same pain stimuli as the placebo group without any application of cream or manipulation of expectation of pain levels. The results showed that the interaction between OPRM1 rs1799971 and COMT rs4680 was significantly associated with the placebo analgesic response. Participants with OPRM1 Asn/Asn combined with COMT Met/Met and Val/Met reported significant pain relief after placebo administration, whereas those with other combinations of the OPRM1 and COMT genotypes displayed no significant placebo effect. Neither OPRM1 nor COMT had any significant influence on affective changes after placebo administration. As shown in this study, genotyping with regard to OPRM1 and COMT may predict who will respond favorably to placebo analgesic treatment.

Higher levels of fear have been shown to partly explain individual differences in placebo analgesic responding. The catechol-O-methyltransferase (COMT) rs4680 Val158Met polymorphism has been associated with both increased placebo analgesia and increased fear-related behavior, in what appears to be inconsistent findings in the literature. The aim of the study was therefore to investigate placebo analgesia and fear-related processes with regard to the COMT genotype, to sort out whether the Met-allele is associated with increased placebo analgesia or increased fear of pain (FOP). A 3 Group (Emla, placebo and natural history) by 5 Test (2 pretest, 3 posttests) mixed design was used (N = 223). A contact heat-evoked stimulator was used to induce pain, and FOP was quantified with the Fear of Pain Questionnaire-III. Saliva was obtained for genotyping. As expected, we observed a significant interaction of test by group (P < 0.01), with lower pain report in the placebo group compared with the natural history group (P < 0.01). There was a main effect of the COMT genotype on fear of medical pain (P = 0.032), and Met-allele carriers reported significantly higher fear of medical pain compared with the Val-allele (P = 0.044). We observed no effect of the COMT genotype on mean pain-level report or placebo analgesia. Thus, we conclude that the Met-allele seems to be associated with the negative emotional process of fear, but not with placebo analgesia.