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

Overview

This study aims to evaluate whether the reduction of the daily morphine equivalent dose (MED) in patients with subacute and chronic pain 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.

Detailed description

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.

Interventions

• 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: 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 (show
• Other Control group (EM)
  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 (sho

Primary outcome measures

• Daily opioid consumption (MED): [Time frame: 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 outcome measures (10)

• Subjective opioid withdrawal symptoms [Time frame: 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.]
• Pain severity [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 Opioid Analgesics Beliefs Scale - Cancer [Time frame: 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.]
• Treatment Expectancy 1 [Time frame: One-time assessment: measured on day 0 at the first intervention visit (baseline).]
• Treatment Expectancy 2 [Time frame: One-time assessment: measured on day 0 at the first intervention visit (baseline).]
• Placebo pill count [Time frame: 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 [Time frame: 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.]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Switzerland · 1 center

• University Hospital Zurich, Department of Consultation-Liaison Psychiatry and Psychosomati — Zurich

Publications

• EFIC. (2022, May 12). What is the definition of pain? European Pain Federation. https://europeanpainfederation.eu/history/what-is-pain/
• Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC Clinical Practice Guideline for Prescribing Opioids for Pain - United States, 2022. MMWR Recomm Rep. 2022 Nov 4;71(3):1-95. doi: 10.15585/mmwr.rr7103a1. PMID 36327391
• Paice JA, Bohlke K, Barton D, Craig DS, El-Jawahri A, Hershman DL, Kong LR, Kurita GP, LeBlanc TW, Mercadante S, Novick KLM, Sedhom R, Seigel C, Stimmel J, Bruera E. Use of Opioids for Adults With Pain From Cancer or Cancer Treatment: ASCO Guideline. J Clin Oncol. 2023 Feb 1;41(4):914-930. doi: 10.1200/JCO.22.02198. Epub 2022 Dec 5. PMID 36469839
• Sandler AD, Bodfish JW. Open-label use of placebos in the treatment of ADHD: a pilot study. Child Care Health Dev. 2008 Jan;34(1):104-10. doi: 10.1111/j.1365-2214.2007.00797.x. PMID 18171451
• Sandler AD, Glesne CE, Bodfish JW. Conditioned placebo dose reduction: a new treatment in attention-deficit hyperactivity disorder? J Dev Behav Pediatr. 2010 Jun;31(5):369-75. doi: 10.1097/DBP.0b013e3181e121ed. PMID 20495473
• 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. PMID 31563914
• Belcher AM, Cole TO, Greenblatt AD, Hoag SW, Epstein DH, Wagner M, Billing AS, Massey E, Hamilton KR, Kozak ZK, Welsh CJ, Weintraub E, Wickwire EM, Wish ED, Kaptchuk TJ, Colloca L. Open-label dose-extending placebos for opioid use disorder: a protocol for a randomised controlled clinical trial with methadone treatment. BMJ Open. 2019 Jun 21;9(6):e026604. doi: 10.1136/bmjopen-2018-026604. PMID 31230007
• 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. PMID 37043203

Identifiers

NCT: NCT06350786 · ROM Study · PZ00P1_201972

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗