Conditioned Open-label Placebos to Facilitate Opioid Reduction in Patients With Subacute or Chronic Pain Pain: a Randomized Controlled Trial

Pain is a major global health problem and is often treated with opioid medication, although risks outweigh the benefits (EFIC, 2022; Goldberg \& McGee, 2011; Sandhu et al., 2018). The administration of an open-label placebo (OLP) treatment, i.e., the placebo treatment with full disclosure of being a placebo, has proven to be an effective treatment in pain syndromes \[i.e., chronic low back pain (Carvalho et al., 2016; Kleine-Borgmann et al., 2019) and irritable bowel syndrome (Kaptchuk et al., 2010)\]. Likewise, meta-analyses reveal that patients in an OLP condition exhibit significantly greater improvement in pain relief than those in a control group (Buergler et al., 2023; von Wernsdorff et al., 2021). Moreover, and of relevance when it comes to the need to reduce opioid medication, OLPs have been shown to be a promising candidate for drug tapering: In line with the conditioning paradigm, the drug as the unconditioned stimulus is paired with the neutral stimulus of an OLP in a learning phase. Then, the OLP alone becomes a conditioned stimulus (Benedetti, 2008; Doering \& Rief, 2012; Martin-Pichora et al., 2011; Price et al., 1999).

A new line of research that indicates that OLPs are effective as an adjunctive treatment for the reduction of drugs have been shown to be feasible for the reduction of active medication in opioid use disorder (Belcher et al., 2019, 2023), acute pain (Bernstein et al., 2019; Flowers et al., 2021; Morales-Quezada et al., 2020; Sezer et al., 2021), chronic posttraumatic pain (Estudillo-Guerra et al., 2021), and ADHD (Sandler et al., 2010; Sandler \& Bodfish, 2008).

Despite these promising findings, there is a lack of trials that examine OLP as adjunctive treatment for the reduction of opioid medication in the subacute and chronic pain population. OLPs are suitable for the controlled reduction of long-acting opioids that are embedded in the planned reduction regimen, and could provide a means of harnessing analgesic placebo effects in patients with subacute and chronic pain, without any loss in pain management efficacy. The major goal of our study is therefore to support participants in their aim to reduce their opioid intake.

• P-Dragees blue Lichtenstein, Placebo dragees (Other): In the intervention group, open-label placebos are administered within the framework of a mind-body management intervention approach, which in turn is consistent with the biopsychosocial model of pain and with a patient-centred approach. The verbal interaction follows the four discussion points: 1. Opioids work by telling the body that participants are not experiencing as much pain; 2. Placebos should be taken every time an opioid is taken which supports the reduction of opioid medication (shown by previous studies); 3. By pairing the pills together the brain will learn to release chemicals like endorphins that cause pain-relief in response to the placebo, just as it does in response to the opioid; 4. At a certain point, placebos might provide adequate pain relief, and the participants might need less opioids. In addition, during the intervention, participants use electronic monitoring (EM) to track medication and OLP intakes.
• Control group (EM) (Other): In the EM control group, the focus lies on the electronic monitoring of the opioid intake. The treatment rationale is designed to facilitate the reduction of opioid medication by promoting a positive attitude towards the implementation of the reduction. The verbal interaction follows the four discussion points: 1. The collection of EM data allows for greater patients' sense of agency over medication treatment; 2. Tracking of opioid medication use supports the reduction of opioid medication (shown by previous studies); 3. The EM is a useful tool, and daily recording of opioid medication intake should be done; 4. At a certain point, EM might provide adequate pain relief, and participants might need less opioids.

Primary outcomes

• Daily opioid consumption (MED): [Daily measure: starts on day 1 after the first intervention visit (baseline, day 0) after randomization and ends on day 42 at the end of the study.]: Cumulative dose (i.e. total amount) of opioid pain medication consumption based on daily morphine equivalent doses (MED). Data is collected in SEMA3 app.

Secondary outcomes

• Subjective opioid withdrawal symptoms [Measured three times: on day 0 at the first intervention visit (baseline), on day 7, and on day 42 at the end of the study.]: Subjective opioid withdrawal will be assessed with the Subjective Opiate Withdrawal Scale (SOWS). The intensity of the withdrawal symptoms is rated by the patient on a scale between 0 (= not at all) and 4 (= extremely), the scores for individual symptoms are added to a total sum score, which can range from 0 to 64. The secondary endpoint will be the subjective opioid withdrawal score at study end (t3).
• Pain severity [Measured three times: on day 0 at the first intervention visit (baseline), on day 7, and at the end of the study on day 42.]: Pain severity is assessed using the ICD-11 specifiers or 'extension codes'. The index combines patient-assessed ratings of pain intensity, pain-related distress and pain-related interference. Each of these ratings is assessed on an 11-point NRS rating scale, and these are mapped into the following categories depending on the NRS score: none = NRS 0, mild = NRS 1 - 3, moderate = NRS 4 - 6 and severe = NRS 7 - 10.
• Pain disability [Measured three times: on day 0 at the first intervention visit (baseline), on day 7, and at the end of the study on day 42.]: Pain disability is assessed using the pain disability index (PDI) to determine the subjective degree of self-reported impairment caused by the pain problem in everyday life. Seven domains of life are assessed: (1) family and domestic responsibilities, (2) recreation, (3) social activities, (4) occupation, (5) sexual life, (6) self-care and (7) essential activities. The scale ranges from 0 "no impairment" (minimum) - 10 "full impairment" (maximum).
• Anxiety [Measured three times: on day 0 at the first intervention visit (baseline), on day 7, and at the end of the study on day 42.]: Anxiety is assessed using the German version of the GAD-7. It is a brief instrument for assessing self-reported generalized anxiety disorder (GAD) symptoms with seven items asking about the main diagnostic criteria of GAD according to the DSM-IV and the ICD-10 criteria. The questions refer to the past two weeks. The scale ranges from "not at all" (minimum); "On some days"; "On more than half of the days"; "almost every day" (maximum).
• Depression [Measured three times: on day 0 at the first intervention visit (baseline), on day 7, and at the end of the study on day 42.]: Depression is assessed using Patient Health Questionnaire (PHQ-D) consisting of nine items referring to the past two weeks. The German version of the PHQ was derived from the 'Prime MD Patient Health Questionnaire' and is based on the criteria of the DSM-IV. The scale ranges from "not at all" (minimum); "On some days"; "On more than half of the days"; "almost every day" (maximum).
• Pain Opioid Analgesics Beliefs Scale - Cancer [Measured three times: on day 0 at the first intervention visit (baseline), on day 7, and at the end of the study on day 42.]: The POABS-CA in the German version measures pain opioid beliefs based on two components with 10 items and a 5-point Likert scale ranging from 0 ("strongly disagree") to 4 ("strongly agree"). The higher the score, the more negative was the opinion about the use of opioid analgesics for cancer pain, and the stronger was the belief that pain should be endured.
• Treatment Expectancy 1 [One-time assessment: measured on day 0 at the first intervention visit (baseline).]: Expectation measures will be measured in analogy to the most relevant outcomes. First, subjectively expected amount (dose) of opioid medication taken will be examined. For this, the following item will be used at the end of the study "How much opioid medication do you think you will be taking at the end of the study?" The item is answered by naming the type of medication, frequency and amount (dose) of medication.
• Treatment Expectancy 2 [One-time assessment: measured on day 0 at the first intervention visit (baseline).]: Expectation measures will be measured in analogy to the most relevant outcomes. Second, to measure the expected withdrawal symptoms at the end of the study, items from the SOWS questionnaire will be used, which are expanded with instructions regarding the expectation.
• Placebo pill count [Daily measure: starts 1 day after the first intervention visit (baseline, day 0) after randomization and ends on day 42 at the end of the study.]: The intake of placebo pills by the OLP-group will be electronically monitored using survey provided by the app SEMA3. For statistical analysis a ratio will be calculated. A value of the ration close to 1 indicated a more accurate data entry of the placebo pill intake.
• Opioid adherence [Daily measure: starts 1 day after the first intervention visit (baseline, day 0) after randomization and ends on day 42 at the end of the study.]: Opioid adherence trajectories will be measured with the app SEMA3 in both groups. In the EM control group, a print of the actual data report from the app (i.e. graph reflecting the pattern of opioid medication intake) will be the basis for the EM-Feedback.

Other outcomes

• Rationale credibility [One-time assessment: measured on day 42 at the end of the study.]: The rationale credibility of the OLP intervention will be assessed in the OLP group at study end. The following questions will be assessed: "How credible did you find the explanation of why placebo treatment can work?", "During the study, did you believe that these were placebo tablets that did not contain a pharmacologic agent?", "Did you find the explanation of why the placebo intervention may work helpful?", "How helpful did you find the explanation of why placebo treatment can work?". Answers will be rated on a Likert scale ranging from 0 = Not at all to 4 = Extremely.
• Placebo understanding [One-time assessment: measured on day 42 at the end of the study.]: The understanding of placebo will be assessed in both study groups (OLP and control group) at study end using a questionnaire which assesses responders' attitudes regarding non-specific therapies. The first three items of this questionnaire specifically assess the placebo understanding and will be used for this study. The scales differ for the different items. Scale question 1: "I have never heard of the term"; "I have heard the term before, but I do not know"; "A placebo is ... (open question)" Scale question 2: "For me the term is rather positive" "For me the term is neutral, neither positive nor negative"; "For me the term is rather negative"; "I do not know" Scale question 3. "Yes, very often"; "Yes, but rarely"; "No"; "I do not know" Additionally participants are asked, if their understanding of placebos might have changed across the study. Scale: "Yes, to the positive because ... (open question)"; Yes, to the negative because ... (open question)"; "No"; "I do not know"
• Patient Provider Connection [One-time assessment: measured on day 42 at the end of the study.]: The Patient Provider Connection is a subscale of the German version of the Healing Encounters and Attitudes List (HEAL) which can be used independently from the six subscales. The seven items are rated on a five-point Likert scale ranging from "not at all" to "very strong" assessing participants' attitudes towards patient-provider connection as a non-specific treatment effect. The scale ranges from 0 "not at all" (minimum) to "very much" 4 (maximum)
• Medication history [Measured two times: on day 0 at the first intervention visit (baseline) and on day 42 at the end of the study.]: Participants' non-opioid medication intake will be assessed by asking the participants about the medication's name, dosage, and reason for intake. Participants will also be asked about the date of prescription.
• Primary treating physicians' acceptability of the OLP approach: [One-time assessment, measured before study start: on day -14, prior to the first intervention visit (baseline, day 0).]: Before the start of the study the primary treating physicians will be asked about their acceptability of the OLP approach from patient and physicians point of view. All items will be rated on a five- or seven-point Likert scale.
• Primary treating physicians' treatment expectancies [One-time assessment, measured before study start: on day -14, prior to the first intervention visit (baseline, day 0).]: The primary treating physicians will be given the same questionnaire on treatment expectations as the participants. They will be asked about their subjective expectation of their patients' use of opioid medication and their subjective expectation of their patients' withdrawal symptoms at the end of the study. In addition, the primary treating physicians will be asked to assess their patients' motivation to reduce opioid pain medication. Motivation will be assessed with the following questions on a satisfaction ruler ranging from 0 % to 100 %: 1. "How satisfied is your patient currently with his opioid medication?", 2. "How confident are you that your patient can change her/his use of opioid medication?".
• Qualitative Outcomes [One-time assessment: measured at the end of the study on day 42.]: The qualitive outcomes will be assessed with an audio recorded semi-structured interviews and will consist of general questions about placebos and core question about the experience of the OLP intervention, acceptability of the OLP approach and prerequisites, ideas and concerns regarding practical OLP implementation.
• Additional Symptoms [Measured two times: on day 7 after the first intervention visit (baseline) and on day 42.]: Participants answer three questions regarding additional symptoms that might have occurred since the last visit at the study site. The questions are the following: * "How have you been since the last visit?" (open answer format) * "Did you have certain symptoms?" (yes/no) * If the participant answered yes in question 2, a follow up question will be displayed: "Please describe the symptoms you had in detail." (open answer format)

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Signed Informed Consent
* ≥ 18 years of age
* German speaking
* Pain lasting ≥ 4 weeks, including subacute pain (4-12 weeks) and chronic pain (>12 weeks)
* Opioid medication for pain management for ≥ 4 weeks
* Oral intake of opioid medication
* Motivation for opioid reduction
* Participants have a primary treating physician who performs the reduction of the opioid medication
* Having access to a computer or tablet with an email-account

Exclusion Criteria:

* Having psychotic symptoms
* Suicidality
* Cognitive impairment to everyday life
* Planned surgery within the next two months that is expected to affect opioid intake
* Known illegal drug or harmful alcohol consumption
* Intolerance of the ingredients of the placebo pill (e.g., lactose, sucrose, corn-starch)
* Serious health problems that make study participation impossible
* Simultaneous participation in other studies with investigational drugs or pain specific interventions

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• Cosima Locher, PhD, Principal investigator, USZ