<b><i>Background:</i></b> Increasing evidence for the efficacy of analgesic placebo effects in laboratory studies with healthy persons raises the question whether placebos could be used to improve the treatment of pain patients. Expectancies play a central role in shaping analgesic placebo but also nocebo effects. <b><i>Objectives:</i></b> We investigated to what extent a sham opioid infusion (saline solution) produces sustained clinically relevant placebo and nocebo effects in chronic back pain patients. <b><i>Methods:</i></b> Fifty-nine patients received the sham opioid infusion applied via a large drain dressing and were compared to 14 control patients without intervention (natural history, NH) while experimental pain stimuli were applied. All subjects were told that the infusion would decrease pain although in rare cases pain increase would be possible (induction of expectancy). In addition, conditioning was introduced where the participants either experienced a decrease in experimental pain (<i>n</i> = 17; placebo conditioning), an increase (<i>n</i> = 21; nocebo conditioning), or no change (<i>n</i> = 21, no conditioning). <b><i>Results:</i></b> Compared to the NH group, all infusion groups showed positive treatment expectancies and significantly (<i>p</i> < 0.001) reduced clinical back pain (primary outcome) and pain-related disability (secondary outcome, assessed by self-reported functional capacity and perceived impairment of mobility). Even the nocebo conditioned group experiencing increased experimental pain developed positive treatment expectancies followed by reduced pain experience. Positive treatment expectancies and relief in clinical back pain were significantly positively correlated (<i>r</i> = 0.72, <i>p</i> < 0.01). <b><i>Conclusions:</i></b> These findings suggest that it may be beneficial to explicitly shape and integrate treatment expectancies into clinical pain management.
Complex regional pain syndrome (CRPS) typically develops after fracture or trauma. Many of the studies so far have analyzed clinical and molecular markers of CRPS in comparison with healthy or pain controls. This approach, however, neglects mechanisms occurring during physiological trauma recovery. Therefore, we compared the clinical phenotype, sensory profiles, patient-reported outcomes, and exosomal immunobarrier microRNAs (miRs) regulating barrier function and immune response between CRPS and fracture controls (FCs) not fulfilling the CRPS diagnostic criteria. We included upper-extremity FCs, acute CRPS I patients within 1 year after trauma, a second disease control group (painful diabetic polyneuropathy), and healthy controls. Fracture controls were not symptoms-free, but reported some pain, disability, anxiety, and cold pain hyperalgesia in quantitative sensory testing. Patients with CRPS had higher scores for pain, disability, and all patient-reported outcomes. In quantitative sensory testing, ipsilateral and contralateral sides differed significantly. However, on the affected side, patients with CRPS were more sensitive in only 3 parameters (pinprick pain and blunt pressure) when compared to FCs. Two principal components were identified in the cohort: pain and psychological parameters distinguishing FC and CPRS. Furthermore, the immunobarrier-protective hsa-miR-223-5p was increased in plasma exosomes in FCs with normal healing, but not in CRPS and healthy controls. Low hsa-miR-223-5p was particularly observed in subjects with edema pointing towards barrier breakdown. In summary, normal trauma healing includes some CRPS signs and symptoms. It is the combination of different factors that distinguish CRPS and FC. Fracture control as a control group can assist to discover resolution factors after trauma.
We could show that placebo responses to both acute and chronic pain are high in pain treatment settings and that treatment history modulates this effect. Different mechanisms might underlie placebo responses to acute and chronic pain. Our findings highlight the necessity of considering placebo responses and treatment history in the treatment of chronic pain. WHAT DOES THIS STUDY ADD?: Placebo analgesia following verbal information of potent pain relief is high in chronic pain patients in a clinical setting. It is modulated by treatment history. Different mechanisms might underlie placebo analgesia to acute and chronic pain.
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