Conditioned Open-label Placebos to Facilitate Opioid Reduction in Patients With Chronic Non-cancer Pain

Chronic Non-cancer Pain Clinical Trial

— ROM  

Official title:

Conditioned Open-label Placebos to Facilitate the Reduction of Opioid Medication (ROM) in Patients With Chronic Non-cancer Pain: a Randomized Controlled Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06350786
• Other study ID #: ROM Study
• Secondary ID: PZ00P1_201972
• Status: Not yet recruiting
• Phase: N/A
• Start date: May 2024
• Est. completion date: July 2025

Study information

• Verified date: April 2024
• Source: University of Zurich
• Contact: Cosima Locher, PhD
• Phone: +41 44 255 12 03
• Email: Cosima.Locher[@]usz.ch
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study aims to evaluate whether the reduction of the daily morphine equivalent dose (MED) in patients with chronic non-cancer pain (CNCP) can be decreased with an open-label placebo (OLP) intervention in comparison to an electronic monitoring (EM) control group. The participants will receive the intervention (OPL or EM) over the duration of six weeks. Diverse psychological and health measures will be assessed with questionnaires over the course of the intervention. Furthermore, evaluation outcomes, qualitative outcomes and safety outcomes will be assessed. It is hypothesized that the OLP-intervention group in comparison to the EM-control group will have a significantly lower consumption of MED over the course of the study. Furthermore, this study aims to evaluate whether the OLP intervention can reduce opioid withdrawal symptoms in comparison to the control group.

Description:

CNCP is a major global health problem and is often treated with opiod medication, although risks outweigh the benefits. Therefore, recent studies suggest that an open-label placebo (OLP) treatment, the placebo treatment with full disclosure of being a placebo, has proven to be an effective, clinically relevant, and evidence-based treatment in CNCP syndromes. Furthermore, a new line of research indicated that OLPs have been shown to be feasible for the reduction of active medication in opioid use disorder. 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 86
• Est. completion date: July 2025
• Est. primary completion date: May 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Signed Informed Consent
• = 18 years of age
• German speaking
• Chronic non-cancer pain = 6 months in duration
• Chronic opioid medication for > 3 months
• 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
• 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 CNCP specific interventions

Related Conditions & MeSH terms

• Chronic Non-cancer Pain

Intervention

Other:
• P-Dragees blue Lichtenstein, Placebo dragees
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: Opioids work by telling the body that participants are not experiencing as much pain; Placebos should be taken every time an opioid is taken which supports the reduction of opioid medication (shown by previous studies); 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; At a certain point, placebos might provide adequate pain relief, and the participants might need less opioids.
• Control group (EM)
In the EM control group, the focus lies on the electronic monitoring (EM) 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: The collection of EM data allows for greater patients' sense of agency over medication treatment; Tracking of opioid medication use supports the reduction of opioid medication (shown by previous studies); The EM is a useful tool, and daily recording of opioid medication intake should be done; At a certain point, EM might provide adequate pain relief, and participants might need less opioids.

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
Cosima Locher	Brown University, University of Basel

References & Publications (7)

Belcher AM, Cole TO, Massey E, Billing AS, Wagner M, Wooten W, Epstein DH, Hoag SW, Wickwire EM, Greenblatt AD, Colloca L, Rotrosen J, Magder L, Weintraub E, Wish ED, Kaptchuk TJ. Effectiveness of Conditioned Open-label Placebo With Methadone in Treatment of Opioid Use Disorder: A Randomized Clinical Trial. JAMA Netw Open. 2023 Apr 3;6(4):e237099. doi: 10.1001/jamanetworkopen.2023.7099. — View Citation

Bernstein MH, Magill M, Weiss AP, Kaptchuk TJ, Blease C, Kirsch I, Rich JD, Becker SJ, Mach S, Beaudoin FL. Are Conditioned Open Placebos Feasible as an Adjunctive Treatment to Opioids? Results from a Single-Group Dose-Extender Pilot Study with Acute Pain Patients. Psychother Psychosom. 2019;88(6):380-382. doi: 10.1159/000503038. Epub 2019 Sep 27. No abstract available. — View Citation

Buergler S, Sezer D, Gaab J, Locher C. The roles of expectation, comparator, administration route, and population in open-label placebo effects: a network meta-analysis. Sci Rep. 2023 Jul 22;13(1):11827. doi: 10.1038/s41598-023-39123-4. — View Citation

Estudillo-Guerra MA, Mesia-Toledo I, Schneider JC, Morales-Quezada L. The Use of Conditioning Open-Label Placebo in Opioid Dose Reduction: A Case Report and Literature Review. Front Pain Res (Lausanne). 2021 Jul 12;2:697475. doi: 10.3389/fpain.2021.697475. eCollection 2021. — View Citation

Flowers KM, Patton ME, Hruschak VJ, Fields KG, Schwartz E, Zeballos J, Kang JD, Edwards RR, Kaptchuk TJ, Schreiber KL. Conditioned open-label placebo for opioid reduction after spine surgery: a randomized controlled trial. Pain. 2021 Jun 1;162(6):1828-1839. doi: 10.1097/j.pain.0000000000002185. — View Citation

Morales-Quezada L, Mesia-Toledo I, Estudillo-Guerra A, O'Connor KC, Schneider JC, Sohn DJ, Crandell DM, Kaptchuk T, Zafonte R. Conditioning open-label placebo: a pilot pharmacobehavioral approach for opioid dose reduction and pain control. Pain Rep. 2020 Jul 20;5(4):e828. doi: 10.1097/PR9.0000000000000828. eCollection 2020 Jul-Aug. — View Citation

Sezer D, de Leeuw M, Netzer C, Dieterle M, Meyer A, Buergler S, Locher C, Ruppen W, Gaab J, Schneider T. Open-Label Placebo Treatment for Acute Postoperative Pain (OLP-POP Study): Study Protocol of a Randomized Controlled Trial. Front Med (Lausanne). 2021 Nov 5;8:687398. doi: 10.3389/fmed.2021.687398. eCollection 2021. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Rationale credibility	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.	One-time assessment: measured on day 42 at the end of the study.
Other	Placebo understanding	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"	One-time assessment: measured on day 42 at the end of the study.
Other	Patient Provider Connection	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)	One-time assessment: measured on day 42 at the end of the study.
Other	Medication history	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.	Measured two times: on day 0 at the first intervention visit (baseline) and on day 42 at the end of the study.
Other	Primary treating physicians' acceptability of the OLP approach:	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.	One-time assessment, measured before study start: on day -14, prior to the first intervention visit (baseline, day 0).
Other	Primary treating physicians' treatment expectancies	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?".	One-time assessment, measured before study start: on day -14, prior to the first intervention visit (baseline, day 0).
Other	Qualitative Outcomes	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.	One-time assessment: measured at the end of the study on day 42.
Other	Additional Symptoms	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)	Measured two times: on day 7 after the first intervention visit (baseline) and on day 42.
Primary	Daily opioid consumption (MED):	Cumulative dose (i.e. total amount) of opioid pain medication consumption based on daily morphine equivalent doses (MED). Data is collected in SEMA3 app.	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.
Secondary	Subjective opioid withdrawal symptoms	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).	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.
Secondary	Pain severity	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.	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.
Secondary	Pain disability	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).	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.
Secondary	Anxiety	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).	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.
Secondary	Depression	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).	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.
Secondary	Pain Opioid Analgesics Beliefs Scale - Cancer	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.	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.
Secondary	Treatment Expectancy 1	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.	One-time assessment: measured on day 0 at the first intervention visit (baseline).
Secondary	Treatment Expectancy 2	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.	One-time assessment: measured on day 0 at the first intervention visit (baseline).
Secondary	Placebo pill count	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.	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.
Secondary	Opioid adherence	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.	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.