Conditioned Open-label Placebo (COLP) for Peri-operative Pain Management in Patients With Head and Neck Cancer

August 22, 2024 updated by: Johns Hopkins University

Open-label Conditioning Therapy for Peri-operative Pain Management in Head and Neck Cancer Patients

The opioid epidemic is a considerable problem in the United States, and prescription opioids significantly contribute to the epidemic. Head and neck cancer (HNC) patients are inherently at increased risk for opioid dependence as surgical treatment can cause significant pain and up to 50% of patients also suffer from psychiatric comorbidities. Novel methods are needed to decrease opioid consumption following HNC surgeries to limit the risk of chronic opioid dependence in these patients. Conditioning therapy with placebo aims to elicit a classically conditioned response to an inactive medication through consistent pairing of the medication with a neutral stimulus (i.e. an odor) and has been shown to be effective for decreasing the amount of active drug require for certain clinical responses, including for acute pain. However, studies have not been completed for the treatment of acute pain in the inpatient post-operative setting. The overall goal of this pilot study is to determine the feasibility and effectiveness of conditioned open-label placebo (COLP) as an adjunct for post-operative pain management in complex head and neck cancer patients. This randomized, controlled, open-label trial will specifically compare post-operative opioid consumption and pain scales between patients receiving multimodal analgesia along with conditioned open-label placebo (COLP group) to those receiving multimodal analgesia, alone (Treatment as usual group). Findings from this study will determine the efficacy of COLP as an innovative approach to decrease opioid consumption and improve pain control in head and neck cancer patients and will provide rationale for development of future large scale trials.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Background:

The opioid epidemic is a considerable problem in the United States, with more than 5 million Americans currently affected by opioid-related substance use disorders. While prescription medications may be thought of as safe and controlled, many opioid-naïve patients report continuing to take prescription opioids for over one year after surgery, and the majority of heroin users report starting with abuse of prescription opioids. At the same time, prescription opioids have more than doubled from 2001-2013 and multiple studies in other surgical specialties suggest that patients receive opioids in excess of the patient's peri-operative pain needs Prior efforts to battle this epidemic have included the increased use of multimodal analgesia, policies to limit the amount of opioids able to be prescribed at one time, and databases to track prescribing habits across health care facilities. While these have had some success, there is significant room for improvement.

Head and neck cancer (HNC) patients represent a unique population in that surgical resection often leads to significant peri-operative pain and disfigurement. A high proportion, up to 50% of these patients also suffer from psychiatric comorbidities. These factors inherently increase the risk of opioid dependence and studies have shown that chronic opioid use following surgery for HNC is associated with decreased disease free survival. Novel methods are needed to minimize opioid risks in this patient population.

Conditioning therapy aims to elicit a classically conditioned, or Pavlovian, response through consistent pairing of a medication with a neutral stimulus (i.e. an odor). Treatment involves reinforcement with simultaneous presentation of a characteristic odor with each dose of active and inactive medication. Prior studies have shown efficacy of conditioning therapy paired with placebo medication to decrease the total dose of active medications required for a clinical response including opioids for pain following spinal cord injury, stimulants for attention deficit hyperactivity disorder, and corticosteroids for psoriasis. Many of these have been performed as "open-label" studies, where patients were aware of group assignment and were informed when each placebo treatment was given.

These results suggest that patients with HNC may also benefit from conditioned open-label placebos by reducing total opioid consumption required for adequate pain control in the peri-operative setting and providing an innovative intervention to potentially decrease the risk of opioid dependence in this patient population.

Primary Objective:

Determine if the addition conditioned open-label placebo (COLP) to standard multimodal analgesia decreases baseline opioid consumption from post-operative day (POD) 2 to 5 in comparison to standard multimodal analgesia alone in patients with head and neck cancer.

Rationale:

Patients with head and neck cancer will be enrolled in this randomized, controlled, open-label trial. All study participants will receive standard multimodal analgesia, including opioids, and will have daily opioid consumption and pain severity documented following surgery. Patients in the COLP group will additionally receive conditioning (i.e. exposure to clove oil) with each active oxycodone dose on POD 1-5 and a scheduled placebo oxycodone paired with conditioning (i.e. exposure to clove oil) 3 times per day on POD 2-5. The chance in baseline opioid consumption from POD 2 to 5 will be compared between groups.

Secondary Objectives:

Determine if the addition conditioned open-label placebo (COLP) to standard multimodal analgesia leads to a reduction in pain severity following surgery and persistent opioid use at 6-months following surgery in comparison to standard multimodal analgesia alone in patients with head and neck cancer.

Rationale:

Following surgery, patients complete daily surveys on pain severity. The investigators will compare these pain scales between COLP and TAU groups to determine if there is a difference in pain severity between treatment groups. The investigators will also analyze long-term effects of the intervention with COLP. After the second week following surgery, opioid consumption will continue to be recorded by nursing (if inpatient) or with patient reported surveys (after discharge) through 6 months after surgery. While COLP may have immediate effects on opioid consumption during therapy, the goal of this aim is to determine if short-term therapy can result in long-term changes in behavior.

Study Type

Interventional

Enrollment (Actual)

9

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients receiving pre-operative evaluation for head and neck cancer in the Otolaryngology - Head and Neck Surgery Department at Johns Hopkins Hospital
  • Scheduled for surgery for resection of and/or reconstruction following resection of a head and neck tumor between November 15, 2022 - May 15, 2024, with expected inpatient admission of at least 5 days after surgery.
  • Age 18 years or older
  • Ability to comprehend and willingness to participate in open-label conditioning portion of study regardless of study group assignment
  • Ability to participate in study for 1 week prior to surgery and 6 months following surgery at time of enrollment

Exclusion Criteria:

  • Past medical history of substance use disorder
  • Chronic pain (defined as pain lasting >3 months) or chronic opioid use (for >3 months).
  • Contraindication to receiving acetaminophen, ibuprofen, oxycodone, or hydromorphone
  • New gabapentin prescription started <2 weeks prior to surgery
  • Psychosis, delirium or other significant cognitive impairment preventing participation in study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Supportive Care
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Treatment as usual (TAU)

Standard pain regimen with scheduled acetaminophen and ibuprofen, oxycodone as needed for moderate-to-severe pain, and intravenous hydromorphone as needed for breakthrough pain.

Surveys about pain levels, opioid consumption, side effects of opioids, understanding of placebo effect and symptoms of depression.
Behavioral: Surveys about pain, opioid use and depression symptoms

Surveys before surgery: Within 1 week prior to surgery, patients complete surveys about pain levels, opioid consumption, understanding of placebo effect and symptoms of depression.

Surveys after surgery: Through 6-months after surgery, patients complete surveys about pain levels, opioid consumption, side effects of opioids and symptoms of depression.
Experimental: Conditioned open-label placebo (COLP)

Standard pain regimen with scheduled acetaminophen and ibuprofen, oxycodone as needed for moderate-to-severe pain, and intravenous hydromorphone as needed for breakthrough pain.

Conditioning (i.e. exposure to clove oil scent) with each dose of oxycodone medication on post-operative day (POD) 1-5.

Scheduled placebo oxycodone medication paired with conditioning (i.e. exposure to clove oil scent) 3 times per day on POD 2-5.

Surveys about pain levels, opioid consumption, side effects of opioids, understanding of placebo effect and symptoms of depression.
Behavioral: Surveys about pain, opioid use and depression symptoms

Surveys before surgery: Within 1 week prior to surgery, patients complete surveys about pain levels, opioid consumption, understanding of placebo effect and symptoms of depression.

Surveys after surgery: Through 6-months after surgery, patients complete surveys about pain levels, opioid consumption, side effects of opioids and symptoms of depression.

Behavioral: Conditioned open-label placebo (COLP)

Placebo oxycodone will be formulated to have the same physical appearance as liquid oxycodone and will be dispensed by the inpatient pharmacy and administered by the nursing staff. At all times that oxycodone or placebo medication is administered on post-operative day (POD) 1-5, the patient will undergo conditioning via exposure to a clove oil scent:

  1. Conditioning (i.e. exposure to clove oil scent) with each dose of oxycodone medication on POD 1-5.
  2. Scheduled placebo oxycodone medication paired with conditioning (i.e. exposure to clove oil scent) 3 times per day on POD 2-5.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in baseline daily morphine milligram equivalents (MME/day)
Time Frame: once after surgery up to 1 week
Comparison of average daily MME on POD 5 to average daily MME on POD 2 between TAU and COLP groups.
once after surgery up to 1 week

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Pain assessed by Visual Analogue Scale
Time Frame: daily after surgery up to 2 weeks, then weekly daily after surgery up to 1 month, then monthly daily after surgery up to 3 months, then once daily after surgery up to 6 months
Measurement of subjective pain; 0 = no pain to 100 = most intense pain ever experienced.
daily after surgery up to 2 weeks, then weekly daily after surgery up to 1 month, then monthly daily after surgery up to 3 months, then once daily after surgery up to 6 months
Change in Pain as assessed by the Functional Pain Scale
Time Frame: daily after surgery up to 2 weeks, then weekly daily after surgery up to 1 month, then monthly daily after surgery up to 3 months, then once daily after surgery up to 6 months
Subjective measurement of how pain affects activities of daily living; 0 = no pain to 10 = intolerable pain where the patient cannot do any activity (even speak) because of pain.
daily after surgery up to 2 weeks, then weekly daily after surgery up to 1 month, then monthly daily after surgery up to 3 months, then once daily after surgery up to 6 months
Change in Depression as assessed by the Patient Health Questionnaire-9 (PHQ-9)
Time Frame: weekly daily after surgery up to 1 month, then monthly daily after surgery up to 3 months, then once daily after surgery up to 6 months
Objectifies degree of depression; 0-4: none/minimal, 5-9: mild, 10-14: moderate, 15-19: moderately severe, 20-27: severe
weekly daily after surgery up to 1 month, then monthly daily after surgery up to 3 months, then once daily after surgery up to 6 months
Change in Numerical Opioid Side Effects (NOSE)
Time Frame: daily after surgery up to 2 weeks, then weekly daily after surgery up to 1 month, then monthly daily after surgery up to 3 months, then once daily after surgery up to 6 months
Subjective measurement of severity of side effects related to opioid use; 0 = not present to 10 = as bad as you can imagine.
daily after surgery up to 2 weeks, then weekly daily after surgery up to 1 month, then monthly daily after surgery up to 3 months, then once daily after surgery up to 6 months
Persistent opioid consumption at 6 months after surgery
Time Frame: once after surgery up to 6 months
Proportion of patients with opioid consumption 6 months after surgery between TAU and COLP groups.
once after surgery up to 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Johns Hopkins University

Collaborators

University of Maryland
American Academy of Otolaryngology-Head and Neck Surgery Foundation

Investigators

  • Principal Investigator: Carole Fakhry, MD, JHU SOM Oto Head and Neck Surgery

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 7, 2023

Primary Completion (Actual)

June 28, 2024

Study Completion (Actual)

June 28, 2024

Study Registration Dates

First Submitted

July 9, 2021

First Submitted That Met QC Criteria

July 13, 2021

First Posted (Actual)

July 22, 2021

Study Record Updates

Last Update Posted (Actual)

August 23, 2024

Last Update Submitted That Met QC Criteria

August 22, 2024

Last Verified

August 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB00276225

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Aggregate data (i.e. counts/averages), will be shared after appropriate request. Individual de-identified data will not be shared given small number of participants in this trial.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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