Chronic back pain (CBP) is a major global health concern with often devastating consequences at the individual and societal levels. Approximately 9% of the adult population suffer from CBP, which is more disabling (indexed as disability-adjusted life years) than any other health condition worldwide, with prevalence and burden increasing with age.4 Despite considerable efforts to improve treatment for patients with CBP, common frontline therapies5 are often not significantly more effective than placebos. In addition, the (long-term) consumption of analgesics can lead to severe side effects and addiction as currently discussed in the case of endemic use of opioids in noncancer pain conditions such as CBP.8,28 This lack of effective drug treatment may at least partially explain the rising numbers of surgical and other interventional procedures patients with CBP undergo, despite their only weak evidence for long-term benefit.23 These shortcomings stress that new ways of treating CBP in a safe, efficient, and cost-effective way are urgently needed.
Experimental and randomized controlled trials (RCTs) have shown that placebo treatments can reduce chronic pain including CBP to a significant and clinically relevant degree.7,13 However, the use of placebo treatments in clinical practice is constrained by both, ethical and legal concerns because they are traditionally administered unbeknownst to the patient. Application of placebo pills with full consent of the patient (ie, open-label placebos [OLPs]) circumvents this conflict and has been heralded as a novel way of harnessing the beneficial effects of placebos without deception.18 Initial findings have suggested that OLPs can reduce chronic and acute pain (ie, back pain and episodic migraine) and cancer-related fatigue.6,16,37 So far, studies on OLP effectiveness have focused on patient-reported outcomes, such as pain intensity and functional disability, in patients6 with CBP, while the impact on objective outcome measures has not yet been investigated. This RCT aimed at investigating OLP effects on subjective, patient-reported measures (pain ratings and disability) and objective outcomes (range of motion [RoM] and velocity of spine motion [VoM]) in a large cohort of patients with CBP. Patients were randomly assigned to either receive OLPs twice daily for 3 consecutive weeks in addition to their stable treatment regimen (OLP + treatment as usual [TAU]) or TAU without any additional intervention. All outcome measures were obtained at baseline, before the first OLP administration and on day 21. Patient-reported outcomes were assessed using standardized questionnaires; objective outcomes were obtained by a blinded examiner and recording of spinal mobility parameters.
2.1. Study design
This RCT following a pretest–posttest design was conducted at the Back Pain Center, University Hospital Essen, Germany, between March 27, 2017, and May 29, 2018. For full trial protocol and statistical analysis plans, see supplement (available as supplemental digital content at https://links.lww.com/PAIN/A867). The trial was registered at the German Clinical Trials Center (Study ID DRKS00012712) on July 12, 2017, and updated once on April 7, 2018, before finalization of data acquisition, unblinding and data analysis. The trial was performed in accordance with the Declaration of Helsinki and approved by the local ethics committee (16-7218-BO, Medical Faculty of the University of Duisburg-Essen, Essen, Germany). An explorative follow-up on day 90 focused on time effects of the OLP treatment and included pain intensity and functional disability described below. Side effects were recorded by Generic Assessment of Side Effects in Clinical Trials24 in the OLP + TAU group. For a schematic overview of the study design, see supplementary Figure 2 (available as supplemental digital content at https://links.lww.com/PAIN/A867).
Two hundred twenty-three patients with CBP were screened for study participation by a trained neurologist. Inclusion criteria comprised persistent CBP of a minimum duration of 12 weeks32 and age >18 years. The diagnoses were classified according to the Quebec Task Force Classification for Spinal Disorders.1 Exclusion criteria consisted of any history of malignancy within the past 5 years, psychiatric disorders, and back pain of a mean intensity of the numeric rating scale (NRS) < 4 a week before baseline. Dose and frequency of drug and nondrug treatment at the timepoint of inclusion (referred to as TAU) had to be stable 3 weeks before screening and during the study period. No relevant changes of eligibility criteria were made after trial registration.
2.3. Informed consent and randomization
All patients gave written informed consent to study participation and received monetary compensation for participation. Patient screening was performed before randomization. As part of the informed consent procedure, all patients were shown a video providing standardized information about the placebo effect in general and recent research findings on potential beneficial effects of open-label placebo application before randomization. The video had been produced by a US television network (CBS New York, CBS2's Dick Brennan reports, Seen at 11, April 11, 2016; see supplement, available as supplemental digital content at https://links.lww.com/PAIN/A867), was modified and translated into German, and introduced by the principal investigator of the study (U.B., for full wording and video file see supplement, available as supplemental digital content at https://links.lww.com/PAIN/A867). One hundred twenty-seven eligible patients with CBP were randomly assigned to the open-label placebo group (OLP + TAU; N = 67) or the TAU group (TAU; N = 60) by a prepared 1:1-balanced randomization list (http://www.randomizer.org/). The random allocation sequence was generated by a blinded laboratory member, enrollment was performed by an unblinded physician (J.K.-B.), and all outcomes were assessed by a blinded examiner (A.H.). Owing to the inherent characteristic of the open-label placebo treatment, patients were aware of their group allocation and not blinded to treatment. Patients were asked to keep their group allocation confidential in presence of any study personnel.
Patients in the OLP + TAU group received open-label placebo capsules containing microcrystalline cellulose (Zeebo Effect, LLC, South Burlington, Vermont) twice a day for 21 days. All patients were informed that the capsules did not contain any active ingredients. Capsule intake was recorded on a daily basis in a patient diary. All TAU group patients were offered the same OLP treatment upon completion of the study to increase compliance and compensate for possible negative effects as described previously.6
2.5. Assessment of patient-reported outcomes
A composite pain intensity score (mean of minimum, maximum, and average pain intensity during the last 7 days on an 11-point NRS [0-10, anchors: “no pain at all”–“unbearable pain”6]) was assessed as primary outcome at baseline (day 0), day 11, and day 21 after randomization in a patient diary.
As secondary outcomes, subjective and objective measures of pain-related disability were assessed. The Oswestry Disability Index (ODI)12 used patient ratings to capture perceived disability in 10 predefined domains (eg, ability to care for oneself, ability to walk, social live, ability to travel, etc; subjective, standardized measure), and the Patient-Specific Functional Scale (PSFS) 30 requires patients to assess their ability to perform physical activities deemed relevant by the patient (subjective, nonstandardized measure). Additional secondary subjective outcomes included self-reported measures of depression, anxiety, and stress (Depression Anxiety Stress Scales [DASS]20). As exploratory outcomes, treatment credibility and expectancy (Credibility and Expectancy Questionnaire [CEQ] 10) were assessed in the OLP + TAU group. In addition, the number of days when patients requested rescue medication and the amount of rescue medication needed were documented.
2.6. Assessment of objective outcomes
Objective outcome measures included the range and velocity of spine mobility (Epionics Medical GmbH; Epionics SPINE, Berlin, Germany) as well as the Back Performance Scale29 (BPS), a blinded observer-rated assessment of 5 predefined mobility-related activities (eg, sock test, pick-up test, and lift test; objective, standardized measure) and were assessed as secondary outcomes by a blinded experimenter (A.H.) following a standardized protocol.9,33 For measurement of range and velocity of spine mobility, 2 flexible sensors placed over the left and right spina iliaca posterior superior (placed parallel to the lumbar spine) recorded surface-bending movement in 12 same-sized segments. Acceleration sensors on both ends of the sensors measured the direction in relation to gravitation (see supplement, available as supplemental digital content at https://links.lww.com/PAIN/A867; Figure 3). The procedure is validated for CBP and shows a high test–retest reliability.9,31
2.7. Statistical analysis
Analyses were performed on an intention-to-treat basis without any exclusions other than major protocol violation, consent withdrawal, and major technical failures. Linear mixed-model analyses were run using the software R (The R Project for Statistical Computing, Version 3.4.1, The R Foundation, https://www.r-project.org/). Sample size for the primary outcome was calculated based on the results of Carvalho et al.6 expecting moderate effect sizes using a standardized package for RStudio.
To investigate potential changes in outcome measures over the course of the study and between groups, separate analyses were performed for the following dependent variables: pain intensity (composite pain intensity score, see above), functional disability (ODI, PSFS, and BPS), objective movement analysis (range and velocity of motion) as well as depression, anxiety, and stress (DASS subscales), and the number of days when patients requested rescue medication. All analyses included the factors group and time and the interaction of both factors group × time as fixed effects. A random intercept and random slope for subjects were included as random effects. Timepoints baseline, day 11, and day 21 were included into the model investigating the composite pain intensity score. All other models only included baseline and day 21 as timepoints. Exploratory analysis of day 90 (follow-up) comprised pain intensity ratings (baseline, day 11, day 21, and day 90) and ODI scores (baseline, day 21, and day 90) of the OLP + TAU group only. All models were tested for homoscedasticity, normal distribution of the residuals, and the raw data to model fit. To test for a potential influence of treatment expectation in the OLP + TAU group, correlational analyses were performed between CEQ scores (comprising expectancy and credibility ratings) and changes in pain intensity over the 21 days (eg, Δ pain intensity = day 21 pain intensity − day 0 pain intensity) using the Pearson correlation coefficient. Results of normalized data are listed in Supplementary Table 1 and shown in Supplementary Figure 1 (available as supplemental digital content at https://links.lww.com/PAIN/A867).
3.1. Patients and randomization
One hundred twenty-two patients with CBP completed the trial and were included in the statistical analyses (OLP + TAU: N = 63, TAU: N = 59, Fig. 1). Groups did not significantly differ in age, sex, and pain intensity at baseline (see Table 1 for baseline characteristics; see Supplementary Tables 2–4 for detailed characteristics, available as supplemental digital content at https://links.lww.com/PAIN/A867). A significant baseline group difference was found for body mass inde (BMI) with higher values in the OLP + TAU group.
3.2. Primary outcome
Estimated parameters are given in mean ± SEM. The analysis for changes in pain (indexed by the change in pain intensity composite score over the course of the study) depending on group assignment revealed a significant group × time interaction. This interaction was driven by a significant decrease in pain intensity over the course of 21 days in the OLP group but no significant changes in pain intensity in the TAU group (estimated parameters: OLP + TAU = −0.62 ± 0.23, TAU = 0.11 ± 0.17, P = 0.001, d = −0.44; Fig. 2A). This interaction effect was already significant after 11 days (estimated parameters: OLP + TAU=−0.60 ± 0.24, TAU=−0.12 ± 0.17, P = 0.04, d = −0.27). Including the BMI as a covariate into the model to account for BMI group differences did not improve the model fit (Δ Akaike Information Criterion: 5.1, P = 0.33).
3.3. Secondary outcomes
Analysis of subjective disability (ODI) revealed a significant interaction between group × time. A significant decrease in disability ratings over the course of the 21 days was found in the OLP + TAU group as compared to no significant changes in the TAU group (estimated parameters: OLP + TAU=−3.21 ± 1.59, TAU = 0.65 ± 1.15, P = 0.02, d = −0.45, Fig. 2B). Changes in the PSFS showed a trend for an increase in pain specific function over time (main effect time; estimated parameters: OLP + TAU = 0.94 ± 0.41, TAU = 0.55 ± 0.30, P = 0.06, d = −0.35), which did not significantly differ between groups. Analysis of the BPS revealed a significant improvement in back performance over time (main effect time; estimated parameters: OLP + TAU = −0.90 ± 0.33, TAU = −0.72 ± 0.24, P = 0.003, d = −0.57) with no significant difference between groups (see supplement, available as supplemental digital content at https://links.lww.com/PAIN/A867; Figure 4). Linear mixed-model analyses investigating the range and velocity of motion showed no significant difference between groups or changes over time (all P > 0.05; Fig. 3).
The analysis of the DASS Depression subscale revealed a significant group × time interaction. This interaction was driven by a significant decrease in depression over 21 days in the OLP + TAU group and no significant changes in the TAU group (estimated parameters: OLP + TAU=−1.07 ± 0.55, TAU = 0.37 ± 0.39, P = 0.01, d = −0.50, Fig. 2C). The DASS Stress subscale showed a trend towards a group × time interaction (estimated parameters: OLP + TAU = −1.72 ± 0.73, TAU = −0.47 ± 0.52, P = 0.09, d = −0.32) with a stronger decrease in stress in the OLP + TAU group than the TAU group (see Supplementary Figure 5, available as supplemental digital content at https://links.lww.com/PAIN/A867). Analysis of the DASS Anxiety subscale showed no significant differences between groups and timepoints.
3.4. Exploratory outcomes
The analysis of the number of days where patients requested rescue medication (ie, nonsteroidal anti-inflammatory drugs [NSAID]) indicated an overall increase over the course of the trial (main effect time; estimated parameters: OLP + TAU = 7.39 ± 2.73, TAU = 8.82 ± 1.91, P < 0.001, d = 1.05). In addition, we found a trend towards a main effect of group with a lower number of days with rescue medication in the OLP + TAU group (estimated parameters: OLP + TAU = 4.07 ± 2.42, TAU = 5.47 ± 1.71, P = 0.09, d = −0.25). However, only 49 patients of the 122 patients enrolled in the study (TAU group N = 30 [50.8%], OLP + TAU group N = 19 [30.1%]) requested analgesics during the study period at least once, and only 26 patients (TAU group N = 11 [18.6%], OLP + TAU group N = 15 [23.8%]) requested NSAIDs daily (see Supplementary Table 2, available as supplemental digital content at https://links.lww.com/PAIN/A867). The increase in demands of rescue medication, which was observed independently of group allocation, might be a result of the awareness of being enrolled in a clinical trial and the potentially associated increased self-awareness.22 Results of this analysis should therefore be interpreted with caution. No significant correlation was found between the CEQ expectancy and credibility and the changes in pain intensity over the course of 21 days in the OLP + TAU group. Standardized assessment of side effects revealed mild symptoms (ie, constipation and reduced appetite) attributed to the open-label placebo use in 7 out of 63 cases (11.1%). Exploratory follow-up analysis of the OLP + TAU group from day 21 to day 90 revealed a persistent analgesic main effect time (estimated parameters: day 21 = 4.64 ± 0.25, day 90 = 4.63 ± 0.19, P = 0.96). Moreover, follow-up analysis of ODI scores of the OLP + TAU group showed a constantly improved functional disability from day 21 to day 90 (main effect time; estimated parameters: day 21 = 25.97 ± 1.64, day 90 = 26.50 ± 1.68, P = 0.74). For exploratory follow-up analysis of the TAU group, see supplement (available as supplemental digital content at https://links.lww.com/PAIN/A867).
This RCT investigated the effect of a 3-week OLP treatment on patient-reported and objective outcomes in patients with CBP. Open-label placebos in combination with TAU significantly reduced pain (primary outcome), disability, and symptoms of depression and stress (secondary outcomes) in our cohort of 122 patients. Furthermore, OLP treatment showed a trend towards a reduced demand for analgesic rescue medication (exploratory outcomes). Remarkably, the analgesic effect of a 3-week OLP treatment was still present at day 90. Although both groups showed an improvement of restriction in mobility-related activities (Back Performance Scale), and in contrast to the positive effects on subjective outcome measures, OLPs had no effect on objective measures of spine mobility, that is, range of motion and VoM.
This is the largest study to date to demonstrate that OLP treatment effectively reduces pain and disability in patients with CBP. The results corroborate those of Carvalho et al.,6 who reported clinically relevant effects of OLPs on CBP in a smaller cohort of 83 patients. Pain and pain-related disability are the major complaints of patients with CBP, and their patient-reported assessment is the gold-standard outcome in trials on CBP.11 Our study indicates that OLPs can effectively reduce the key complaints of CBP. Remarkably, the effect size of OLP treatment on back pain (d = −0.44) was comparable with that of NSAID reported in another trial (ie, etoricoxib, d = 0.32).2
Placebo effects have been documented in various physiological systems and medical conditions,27 but are particularly strong for pain and depression, where up to 70% of overall treatment effects can be attributed to placebo effects.21,25 Their systematic exploitation therefore is highly desirable in the treatment of both conditions. However, until recently, it has been presumed that placebo treatments can have therapeutic benefits only if patients are unaware that they are treated with a placebo. In line with encouraging pilot investigations of OLP treatment in other pain conditions (eg, irritable bowel syndrome),17 episodic migraine,16 and cancer-associated fatigue,37 our study indicates that patients can benefit from placebo treatments even if they know that the substance administered lacks an active ingredient.
To date, the mechanisms underlying the effectiveness of open-label placebo are still unclear. Expectations induced by information provided to the patient, which are known to be the key determinant of placebo effects in experimental trials, involve complex neurobiological mechanisms including opioidergic pain modulatory pathways.34 In our study, the induction of positive expectations during the informed consent procedure (ie, “previous studies have suggested positive effects of OLPs,” and “placebo effects have been associated with endogenous pharmacology”) and the prospect of “trying something new,” often after previous treatment failures, could have boosted the placebo effect in the OLP group and may have induced disappointment in patients randomized to TAU. However, expectations (as assessed at the beginning of the trial) were not significantly associated to the observed treatment effect. Although this finding does not support a direct effect of expectancy in mediating the effect of OLPs, this certainly does not rule out the contribution of subconscious expectations that have been documented to elicit placebo effects in experimental studies.5,14,15,26,38 Furthermore, patients' treatment expectations are not a stable construct. Patients' interpretation of spontaneous variations in pain intensity may have induced or reinforced positive expectations and thereby led to further pain reduction in the sense of a self-fulfilling prophecy. This might have contributed to the OLP treatment effect.3 More research regarding the psychological and neurobiological mechanisms underlying the efficacy of OLPs, such as Bayesian and predictive coding, and embodied cognition18 but also potentially involved neural mechanisms and neurotransmitter is needed.
Despite the overall encouraging results, our study also points towards the limitations of this treatment approach. So far, OLPs have only been tested in conditions where subjective, patient-reported symptoms, such as pain, depressive symptoms, and fatigue, are used to assess treatment outcome. Our study is the first to demonstrate that OLP treatment does not significantly affect objective therapeutic outcomes (here, the RoM and VoM). This dissociation between effects on subjective vs objective treatment outcomes yields interesting insights from a mechanistic point of view and may suggest the limits of this therapeutic approach for conditions with primarily objective treatment outcomes, such as cardiovascular or immunological diseases.
The results of our study have to be interpreted in the light of several limitations: First, the duration of the trial (3 weeks) was rather short, and trials of a longer duration are needed to explore the sustainability and long-term effects of OLPs, as are suggested by our follow-up data obtained at 3 months. Moreover, a longer trial duration might have unmasked objective outcome changes. However, the observed dispersion of placebo efficacy on subjective and objective outcomes is in line with previous studies.19,35,36 Second, our sample was recruited with the explicit understanding that all participants would receive open-label treatment, which might predominantly have attracted those with a positive attitude towards this kind of treatment approach. Our sample might therefore not be representative of the general population of patients with CBP. However, this type of recruitment bias is inherent to any type of RCT. Third, given that only a minority of our participants were on a stable regiment of analgesic medication (26 [21.3%]), conclusions regarding the potential of OLPs to reduce analgesic medication have to be treated with caution. It is nonetheless important to note that our analysis of patients with stable medication points towards a potential benefit from OLP treatment.
Together, our trial indicates that OLPs can have significant and clinically relevant therapeutic effects on CBP. OLPs are safe, well tolerated, and cost-effective, and their therapeutic potential for chronic pain conditions should be further investigated in larger-scale multicenter studies.
The authors have no conflicts of interest to declare.
Appendix A. Supplemental digital content
Supplemental digital content associated with this article can be found online at https://links.lww.com/PAIN/A867.
Supplemental video content
Video content associated with this article can be found online at https://links.lww.com/PAIN/A867.
The authors thank B. Weltermann and O. Müller for support with patient recruitment, M. Zunhammer, L. Kerkmann, and A. Hashim for technical assistance, and T. Spisak for valuable comments on the article. This work was supported by the German Research Foundation (FOR-1328) and the Foundation for the Science of the Therapeutic Encounter.
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