Conditioned open-label placebo for opioid reduction after spine surgery: a randomized controlled trial

Abstract

Placebo effects have traditionally involved concealment or deception. However, recent evidence suggests that placebo effects can also be elicited when prescribed transparently as "open-label placebos" (OLPs), and that the pairing of an unconditioned stimulus (eg, opioid analgesic) with a conditioned stimulus (eg, placebo pill) can lead to the conditioned stimulus alone reducing pain. In this randomized control trial, we investigated whether combining conditioning with an OLP (COLP) in the immediate postoperative period could reduce daily opioid use and postsurgical pain among patients recovering from spine surgery. Patients were randomized to COLP or treatment as usual, with both groups receiving unrestricted access to a typical opioid-based postoperative analgesic regimen. The generalized estimating equations method was used to assess the treatment effect of COLP on daily opioid consumption and pain during postoperative period from postoperative day (POD) 1 to POD 17. Patients in the COLP group consumed approximately 30% less daily morphine milligram equivalents compared with patients in the treatment as usual group during POD 1 to 17 (-14.5 daily morphine milligram equivalents; 95% CI: [-26.8, -2.2]). Daily worst pain scores were also lower in the COLP group (-1.0 point on the 10-point scale; 95% CI: [-2.0, -0.1]), although a significant difference was not detected in average daily pain between the groups (-0.8 point; 95% CI: [-1.7, 0.2]). These findings suggest that COLP may serve as a potential adjuvant analgesic therapy to decrease opioid consumption in the early postoperative period, without increasing pain.

Trial registration: ClinicalTrials.gov NCT04574388.

Figure 1.

Patients consenting to participation completed baseline questionnaires and were randomized to either the treatment as usual (TAU) or conditioned open-label placebo (COLP) group. Study staff visited patients in both groups twice daily while inpatient and contacted once daily after hospital discharge to collect daily reports on their analgesics taken and pain scores. Patients in the COLP group also reported how many placebo pills were taken each day. On POD 1, COLP patients began the “pairing” regime by taking one open-label placebo pill each time they took an opioid analgesic. On POD 2, COLP patients were instructed to begin taking 3 daily scheduled placebo pills in addition to the placebo pills paired with each opioid analgesic (“pairing 1 scheduled”). All patients were asked to continue recording daily analgesic consumption and pain scores, with COLP patients also continuing the “pairing 1 scheduled” regime, until their postoperative follow-up appointment (approximately 17 days after surgery). DA, daily assessments; POD, postoperative day; QST, quantitative sensory testing; R, randomization; S, surgery.

Figure 2.

CONSORT study flow diagram. Patients were approached and recruited from the anesthesia preoperative clinic. Of the 144 patients assessed for eligibility, 51 patients were enrolled and randomized to either the TAU (n = 25) or COLP (n = 26) group. Before beginning COLP treatment, 2 participants withdrew because of anxiety about the upcoming surgery, and one participant became ineligible because of postoperative complications necessitating intensive care unit admission postoperatively. After beginning allocated treatment, 4 patients in the COLP group and 3 in the TAU group withdrew. There were 41 patients included in the final analysis (TAU: n = 22 and COLP: n = 19). COLP, conditioned open-label placebo; POD, postoperative day; TAU, treatment as usual.

Figure 3.

Daily opioid analgesic consumption in the postoperative period. Daily opioid consumption during the postoperative period was calculated by converting all opioids to morphine milligram equivalents (MMEs) for both inpatient (approximately POD 1–3) and outpatient (approximately POD 4–17) periods. (A) Daily opioid consumption was compared between groups over time. Overall, patients randomized to COLP consumed significantly less opioids daily from POD 1 to POD 17 compared with patients in the TAU group (Wald x²: 5.93, P = 0.015). (B) Timelines of daily opioid consumption for individual patients in the TAU group (EMM: 43.1, 95% CI: [33.4, 52.9]). On POD 7, 94% of patients in the TAU group were taking opioids, with 75% of TAU patients still taking opioids on POD 14. (C) Timelines of daily opioid consumption for individual patients in the COLP group (EMM: 28.6, 95% CI: [21.1, 36.2]). On POD 7, 68% of patients in the COLP group were taking opioids, with 53% of COLP patients still taking opioids on POD 14; CI, confidence interval; COLP, conditioned open-label placebo; EMM, Estimated Marginal Mean; POD, postoperative day; TAU, treatment as usual.

Figure 4.

Daily pain scores in the postoperative period. Patients provided daily reports of their worst pain and average pain experienced in the previous 24 hours. (A) Patients in the COLP group reported significantly lower worst daily pain scores in the postoperative period compared with patients in the TAU group (COLP EMM: 5.9, 95% CI: [5.2, 6.6] vs TAU EMM: 6.9, 95% CI: [6.3, 7.6]; Wald x²: 4.50, P = 0.034). (B) Patients’ average daily pain (BPI mean) experienced in the previous 24 hours was not significantly different between groups (COLP EMM: 4.4, 95% CI: [3.8, 5.0] vs TAU EMM: 5.1, 95% CI: [4.4, 5.7]; Wald x²: 2.39, P = 0.122). BPI, Brief Pain Inventory; CI, confidence interval; COLP, conditioned open-label placebo; EMM, Estimated Marginal Mean; POD, postoperative day; TAU, treatment as usual.

Figure 5.

Exploratory analysis of treatment moderation by baseline patient characteristics. Interactions between treatment and baseline characteristics were assessed using the PROCESS macro in SPSS, which assesses for significant moderation of treatment effect by other variables. (A) Significant treatment x baseline pain interaction, suggesting a greater benefit of COLP among patients with higher reported baseline pain. (B) Significant treatment x sex interaction, with COLP associated with lower opioid consumption predominantly among female patients. (C and D) Significant treatment x age interaction, with COLP associated with decreased pain (C) and opioid consumption (D) among younger patients. (E) Significant treatment x TSP interaction, suggesting a greater benefit of COLP among patients higher baseline TSP. (F and G) Significant treatment x fibromyalgianess interaction, with COLP associated with lower pain (F) and daily opioid consumption (D) among patients with higher baseline fibromyalgianess scores. COLP, conditioned open-label placebo; POD, postoperative day; TAU, treatment as usual; TSP, temporal summation of pain.