Placebo evokes analgesia through different pathways
Placebo appears to induce moderate analgesia but have very little effect on the neurologic pain score (NPS), suggesting that the evoked pathways and networks are different from those primarily involved in processing noxious stimuli, a recent meta-analysis has shown.
“[W]e have shown that placebo treatments have only small effects on a cerebral pattern tracking nociceptive pain in what is to our knowledge the largest meta-analysis of single-participant neuroimaging data on this topic to date,” said researchers.
A total of 20 studies were eligible for the meta-analysis, resulting in a sample size of 603 participants, in whom large NPS responses to painful stimulation were reported (standard effect size [g], 2.30; 95 percent CI, 1.92–2.69; p<0.001). [JAMA Neurol 2018;doi:10.1001/jamaneurol.2018.2017]
Following placebo treatment, moderate analgesic effects were reported as measured by pain ratings (g, –0.66; –0.80 to –0.53; p<0.001), corresponding to an 11.3-unit reduction on a 101-point visual analogue scale.
Moreover, the obtained Bayes factor was 9.4x1018 suggested that there was “overwhelming support for the hypothesis of non-null placebo effects on pain ratings,” said researchers.
In contrast, placebo treatment appeared to have a very small significant effect on NPS responses (g, –0.08; –0.15 to –0.01; p=0.03). Placebo effects on NPS rating were 12.1-percent as large as its effects on pain ratings and only 3.7-percent as large as the effect of painful stimulation on NPS.
In an analysis of eligible studies with crossover designs, a non-null correlation was observed between greater placebo analgesia and larger downregulation of NPS (Bayes factor=894.5), though the Pearson coefficient was small (r, 0.23; p<0.001), indicating a significant but weak effect.
“This large-scale meta-analysis of participant-level data revealed that placebo treatments have moderate effects on subjective reports of pain, but minimal effects on responses in the NPS, a central nervous system marker that tracks the intensity of nociceptive pain,” said researchers.
“Our results emphasize that placebo analgesia is a phenomenon not based on a single mechanism but rather multiple mechanisms that have yet to be fully understood,” they added.
The findings also have important implications for assessment of treatments for pain and pain-associated neurophysiology. Because pain is processed in relation to complex personal and cultural factors, self-reported pain may not completely capture the efficacy of administered treatments.
“Whether patients feel better is paramount for overall wellbeing, but it does not guarantee that a treatment impacts the intended physiological mechanisms in the brain and elsewhere in the body,” said researchers, noting that while objective pain measures may not perfectly capture wellbeing, they have some value in evaluating pharmacodynamics efficacy.
The database of Medline was accessed for the present meta-analysis. For inclusion, studies needed to have human brain imaging with evoked pain under intensity-matched placebo and control conditions. Single-participant data were obtained from authors of the eligible studies.
“Further studies are necessary to better understand which aspects of pain processing are affected by placebo treatments, and the significance of those processes for long-term clinical outcomes and wellbeing,” said researchers.
“This work serves as a starting point for the development of brain models that track pain-associated outcomes and other clinical and behavioural endpoints,” they added.