Optimising treatment expectations in chronic lower back pain through observing others: a study protocol for a randomised clinical trial

Setting

The study will be part of a collaborative research centre (CRC) project (SFB 289). Therefore, some of the tests will be analysed across all participating projects. This study will be conducted at the University Medical Centre Hamburg-Eppendorf, Germany.

Study aim

The proposed study will evaluate the expectations and effects of OLPs in contrast to active ANAs for the treatment of CLBP. The following are the proposed key questions.

Research aims in the present study are:

  1. Can the effect of treatment expectation on pain be enhanced by observational learning?

  2. Does positive treatment expectation enhance the ANA effects of treatment (main effect of expectation)?

  3. Do the effects of positive expectation and pharmacological treatment combine in an additive or multiplicative (synergistic) manner?

  4. Does the impact of treatment expectation on ANA treatment outcome differ between subjective (pain, perceived limitation in mobility) and behavioural (functional capacity) outcome measures?

Research aims in the present study that are also analysed as part of other projects within the SFB 289/CRC are:

  1. Do individual trait and state variables such as anxiety, comorbid depression and stress-related neuroendocrine measures modulate the effect of treatment expectancy on treatment outcome?

  2. Does the functional and structural connectivity of the prefrontal cortex with pain-related regions at rest predict expectation effects on ANAs treatment outcome?

  3. Do salivary cortisol awakening response and salivary alpha-amylase predict expectations effects on ANAs treatment outcome?

Patient and public involvement

Patients should benefit from clinical studies, and this has been a priority for this project from the outset. The study grew out of the authors’ clinical activity and therapy expertise with chronic pain patients. Therefore, the patients were already involved in the planning phase and were asked whether they would accept the study design, the deception condition and what information they considered necessary to understand the procedure. The patients were able to provide valuable input. We discussed the study in an interview with the chairperson of the German pain organisation ‘UVSD SchmerzLOS’ (independent association of active patients with pain in Germany, ‘Painless’). The ‘UVSD SchmerzLOS’ has also published an interview that introduces the main aspects of the clinical applications of placebo effects in their journal.

The production of the videos for the observational learning for the treatment (ANA or OLP) effects is of high importance for our study. We based the video script on the medical history of one of our patients with CLBP and hired a professional actor to perform in it. We carefully investigated satisfaction with the videos of patients with CLBP and distributed materials by interviewing patients who were not later enrolled in the study. In addition, patients will be asked for in-depth feedback on the materials and study design after their participation in the study. When the results of the study are published, they will be sent to all patients who provided written consent.

Target population

Participants will be eligible or not eligible for the study according to the following criteria:

Inclusion criteria

  • Age≥18 years.

  • Primary symptom CLBP (ICD-10).49

  • Average pain intensity≥4/10 on NRS during past week.

  • Sufficient fluency in German language to understand and respond in German language and questionnaires.

Exclusion criteria

  • Severe acute or chronic mental health condition (eg, psychosis).

  • Chronic diseases with a dominant role in disability (eg, rheumatic disorders, cancer, severe heart diseases).

  • Pain-relevant ‘red flags’6 (eg, tumour, active rheumatologic disorder).

  • Inflammatory or neuropathic back pain.

  • Unstable ANA medication—dose and frequency of ANA treatment should be stable for 3 weeks prior to screening.

  • Regular intake of metamizole (dipyrone).

  • Known allergies or other contraindications for metamizole (dipyrone).

  • Pregnancy and breast feeding.

Notably, if patients are not eligible to participate in the MRI scanning, they will not be excluded from participation for the study itself.

Recruitment

Participants will be recruited via general practitioners, specialised institutions for back pain, orthopaedic surgeons, physiotherapists, pain therapists and all institutions in the Hamburg metropolitan area that treat patients with CLBP.

Relevant contact partners in Hamburg, Germany, will be contacted and informed about the study. They will receive a checklist to be able to do fast screening of the inclusion and exclusion criteria. Thereafter, potential participants will receive a flyer with all the relevant information and contact addresses. After the study team receives the contact information of potential participants, the study physician will assess the inclusion and exclusion criteria.

Study design

This study is based on a fully balanced within-subject and between-subject placebo study design (figure 1). Treatment outcome will be assessed at the subjective (pain rating, limitation in mobility) and objective behavioural (functional capacity) levels. For this purpose, active ANA, OLP and expectation (positive=high vs neutral=low) will be fully crossed. In addition, a control group (natural history; NH) will complement the design. The NH group will receive no intervention (no treatment, no videos). Treatment expectation (high/low) will be induced through observational learning of treatment benefits in a standardised video showing either positive or neutral treatment effects in another patient.

Figure 1
Figure 1

Study design. ANA, analgesic; DTI, diffusion tensor imaging; NH, natural history; OLP, open label placebo; rsFMRI, resting state functional MRI.

The study includes three visits over the course of 3 months, including a follow-up after 3 months. The baseline assessment of pain includes perceived limitation in functional capacity, treatment expectation and further psychological assessment. If patients meet the inclusion criteria, they will be fully informed about the study and asked to provide written informed consent. All patients will be reminded to continue with their usual care (eg, current medication), and they will be informed that they will be randomised to receive either an approved and widely used non-opioid ANA or a placebo, or they will be assigned to the control group. Participants will also be informed that both the active ANA and the placebo have shown beneficial effects for CLBP in previous studies, with varying responses between individuals.36 39

After providing written consent, participants will complete a questionnaire and do certain physical exercises to assess baseline values. To assess and analyse predicting variables, patients will undergo rsfMRI scanning, 3D-MPRage T1-weighted sequence (T1), DTI and neuroendocrine measures (salivary cortisol awakening response and salivary alpha-amylase) at rest within 1 week after enrolment in the study. After the baseline assessment, patients will be randomly allocated to one of the five study groups. Participants will be randomised using block randomisation stratified by gender (ratio 1:1) to allocate the participants to one of the five study arms (ANA/high, ANA/low, OLP/high, OLP/low and NH). A member of staff who will not be involved in the trial will prepare sealed envelopes.

Once the study psychologist has obtained informed consent and baseline data regarding medical background, pain and physical capacity, participants can choose a random sealed envelope, and the intervention and treatment will commence accordingly.

Before the corresponding medical treatment is started, participants will undergo a treatment expectation modulation by watching a brief (10 min) video that is part of the general standardised study information. Alterations in treatment expectation will be assessed immediately after the intervention. On the following day, patients will start their treatment (ANA or OLP) at home. The NH group will be assessed in the same manner as the four experimental groups, but they will not undergo modulation of expectancy (video) or receive ANA treatment (ANA or OLP). Participants in the NH group will be offered ANA or OLP after completion of the main observation period (3 months) and after participating in the study.

In addition to the treatment, patients will be given a pain diary and questionnaires to complete within the 3 week phase. Patients will be contacted once a week and encouraged to update their pain diaries. At the follow-up sessions (at 3 weeks and 3 months), the assessment tools used for the baseline assessment will be repeated. Participants will be contacted to remind them of their appointments.

Blinding

The researcher conducting the primary data analysis will be blinded to group allocation. Due to the nature of the study, the researcher conducting the intervention will not be blinded to group allocation. Therefore, the possibility of an experimenter effect cannot completely be excluded but should be minimised due to the study design.

Intervention

After providing written informed consent for participation in the study and the fMRI scanning, the participants will be randomly assigned to one of the five study groups and receive treatment-specific information that is largely similar for the ANA and OLP treatment (figure 2).

Figure 2
Figure 2

Treatment information. ANA, analgesic; OLP, open label placebo; NH, natural history.

Video-based treatment expectation manipulation

On randomisation to the study medication and the substance-specific/adjusted verbal information, patients will be asked to carefully watch a 10 min video that will be introduced as part of the general standardised study information. Patients in the high expectation groups will watch a video in which an actor introduced as a fellow patient describes and demonstrates the improvement in their back pain and pain-related functional impairments, following ANA or OLP treatment. In the first part of the video, the patient executes a number of different movements with visible signs of discomfort (pretreatment). In the second part, the same movements are repeated, but the patients shows no signs of discomfort (posttreatment). The videos are identical except for the treatment, which will be either an ANA or an OLP. Participants in the neutral expectation groups, ‘OLP/low expectation’ and ‘ANA/low expectation’, will watch a control video of the same length, in which the same actor will provide neutral information regarding CLBP without any reference to the course of treatment. The age of the fellow patient is approximately 60 years, which best reflects the mean age of this patient group.39

Treatment: active ANA versus OLP

The non-opioid metamizole (dipyrone) will be used for the active ANA treatment, as it is generally well-tolerated and has no known central nervous system side effects that could interfere with treatment expectation. According to the guidelines,50 51 metamizole (dipyrone) can be used to treat CLBP at the lowest effective dose and for as short a duration as possible when non-steroidal anti-inflammatory drugs are contraindicated or not effective, which applies to the majority of patients with CLBP who present at tertiary referral centres such a university clinic. Metamizole (dipyrone) and OLP will be provided as film-coated tablets with an identical appearance. Patients randomised to the ANA group will receive 3×2 tablets (=3000 mg), and the OLP groups will receive the same number of placebo tablets. The NH group will receive no treatment other than the medication already prescribed before the trial. To rule out the possibility of agranulocytosis, blood samples will be taken from all patients before the study and after the 3-week intervention.

Outcome measures

Treatment outcome will be assessed at the subjective (pain rating, perceived limitation in mobility) and observed (physical capacity) levels 3 weeks and 3 months after randomization and compared with the baseline assessment. The following variables will be recorded (table 1).

Table 1

Outcome measures

Sample size calculations

Our previous studies have shown large to even larger effects from placebo interventions in patients with CLBP with similar paradigms, d=1.8338 and d=1.56.9 Furthermore, the existing OLP studies in patients with back pain have revealed lower, but still substantial, effects on pain and reported disability with d=0.4439 and d=0.76.36 Accordingly, we expect a difference in the effect on primary outcome (pain intensity) between high and low expectation conditions, and this difference is expected to exceed an effect size of Cohen’s d=0.40. This effect should be shown for at least the pre–post comparison. The corresponding power analysis was based on F statistics for the calculation of analyses of variance (ANOVA) with repeated measures (interaction effect of within and between factor, effect sizes of d=0.4, α=0.05, power 1-ß=0.9, 5 groups, 2 assessments with G*Power).52 This requires 125 participants, and with consideration of the expected drop-out rates, a cell size of 30 participants (N=150) per group is considered sufficient.

Statistical analysis

Between and within differences in clinical outcomes and group allocation will be studied for the different outcome measures with ANOVA tests. The data will be analysed as intention to treat by a researcher blinded to group allocation. Exploratory post hoc analysis will be applied in the event that significant main results are found. The analyses will be performed with IBM SPSS Statistics software V.27.0 (IBM Corp) and data will be reported as means with 95% CIs, unless otherwise specified. Greenhouse-Geisser or Huynh-Feldt correction for the F test will be used to adjust the df for deviation from sphericity, if necessary. For all performed analyses, two-sided P values of p<0.05 will be considered statistically significant.

Outlook and perspective

CLBP is highly prevalent, and it is a major cause of decreased quality of life and disability. The number of prescriptions for opioid medications for CLBP has increased dramatically.10 This trend has been accompanied by significantly increased levels of prescription opioid overdoses, abuse, addiction and diversion.10 Therefore, strategies that exploit the potential of expectation to enhance ANA treatment outcomes are urgently needed. If the observation of treatment benefits prove to enhance the response to OLP and/or active ANA treatment, this could have fundamental implications for routine clinical care, as it may be used as an ethically acceptable53 and cost-effective add-on or an alternative to current treatment modalities. The balanced placebo design used in this study will also shed light on the as yet unexplored question of whether the effects of expectation and of the drug combine in an additive or multiplicative manner. The insights gained in this study will pave the way for future studies that evaluate whether and how these results generalise to other (chronic) pain conditions and ANA treatments. The thorough clinical and psychological assessment in combination with brain imaging (rsfMRI, DTI, T1) and neuroendocrine measures also promises to identify subgroups of patients who are particularly likely to benefit from such interventions and can be systematically targeted in defined patient subgroups in future studies. The brain imaging performed in this study can lay the foundation for not only identifying predictors but also the mechanisms underlying the beneficial effects of expectation in patients in future funding periods, as these may differ fundamentally from those in healthy volunteers.

Ethics and dissemination

The study has been approved by the Hamburg Medical Ethics Council. The results of this trial will be reported in relevant academic journals and conferences.