The Placebo Effect in Pain Therapies

Abstract

Pharmacological strategies for pain management have primarily focused on dampening ascending neurotransmission and on opioid receptor-mediated therapies. Little is known about the contribution of endogenous descending modulatory systems to clinical pain outcomes and why some patients are mildly affected while others suffer debilitating pain-induced dysfunctions. Placebo effects that arise from patients' positive expectancies and the underlying endogenous modulatory mechanisms may in part account for the variability in pain experience and severity, adherence to treatment, distinct coping strategies, and chronicity. Expectancy-induced analgesia and placebo effects in general have emerged as useful models to assess individual endogenous pain modulatory systems. Different systems and mechanisms trigger placebo effects that highly impact pain processing, clinical outcomes, and sense of well-being. This review illustrates critical elements of placebo mechanisms that inform the methodology of clinical trials, the discovery of new therapeutic targets, and the advancement of personalized pain management.

Keywords: conditioning; dose-extending placebos; expectation; modeling; nocebo; opioids; vasopressin.

Figures

Figure 1

Schematic representation of the psychophysiological mechanisms of placebo effects. Verbal suggestions (e.g., anticipation of a benefit), firsthand therapeutic experience of pain reduction (e.g., experiential learning and conditioning), observation of others (e.g., social learning), contextual and treatment cues (e.g., seeing a treatment), and interpersonal interactions (e.g., patient-clinician relationship) contribute to create expectancies that can trigger a set of psychoneurobiological changes. At the neural levels, placebo effects result in the release of neuropeptides (e.g., opioids) and the modulation of brain areas involved in the transmission of pain signaling and the formation of expectancies. Areas such as the spinal cord, RVM, PAG, mThal, ACC, SII-dpINS, and aINS (red) show reduced activation when placebo effects are observed. The generation of expectancies involves an increased activation of frontal areas including the vmPFC and dlPFC with a descending modulation of the NAc–VS, PAG, the spinal cord, and RVM (blue). PAG, the spinal cord, and RVM play a dual function with both increased and decreased activity (purple). The generated placebo effects influence responses to pharmacological, integrative, psychological, and surgical interventions (155). Abbreviations: aINS, anterior insula; ACC, anterior cingulate cortex; dlPFC, dorsolateral prefrontal cortex; mThal, medial thalamus; NAc–VS, nucleus accumbens–ventral striatum; PAG, periaqueductal gray; RVM, rostroventral medulla; S1, primary somatosensory area; SII–dpINS, secondary somatosensory area and dorsal posterior insula; vmPFC, ventromedial prefrontal cortex. Figure adapted from Reference .

Figure 2

Opioids and placebo effects. A placebo (red) given after consecutive administrations of morphine occurring (a) 1 day or (b) 1 week apart induces a morphine-like effect on pain endurance, indicating that the placebo acts as a dose-extending agent despite the washout and the half-life of opioids. Data taken from References and . Figure adapted from Reference .

Figure 3

Arginine vasopressin and placebo analgesic effects. (a,b) Vasopressin induces a significant increase in placebo effects as compared to oxytocin, saline, and no treatment. The effect size is significantly larger (Cohen’s δ = 0.603) in women as compared with a smaller and nonsignificant effect of vasopressin on placebo effects in men. In women, (c) dispositional anxiety and (d) the significant acute salivary cortisol changes correlate negatively with the magnitude of vasopressin-induced enhancement of placebo effects. Red-green refers to the difference in pain reports when two distinct visual cues are presented as part of the placebo manipulation. The VAS runs from 0 = no pain to 10 = maximum tolerable pain. Abbreviation: VAS, Visual Analog Scale. Data from Reference .

Figure 4

Reduction of pain (primary outcome) in a hypothetical clinical trial that compares two treatments, a and b, and a placebo, c. The treatments a and b are two classes of analgesics. The no-intervention arm, x, is needed to detect a genuine placebo effect, i.e., the difference between the placebo arm, c, and the no-treatment arm, x.