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

Sponsor

Johns Hopkins University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04973748

Collaborator

University of Maryland (Other)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

The opioid epidemic is a considerable problem in the United States, and prescription opioids significantly contribute to the epidemic.1 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%2 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 open-label conditioning therapy as an adjunct for post-operative pain management in complex head and neck cancer patients. This open-label, randomized controlled trial will specifically compare post-operative opioid consumption and pain scales between patients receiving multimodal analgesia with conditioning therapy and placebo (OLC group) to those receiving multimodal analgesia, alone (Control group). Findings from this study will determine the efficacy of conditioning therapy as an innovative approach to decrease opioid consumption and improve outcomes in head and neck cancer patients and will provide rationale for development of future large scale trials.

Condition or Disease	Intervention/Treatment	Phase
Postoperative Pain Opioid Use	Behavioral: Open Label Conditioning	N/A

Detailed Description

Primary Objective Determine feasibility of open-label randomized controlled trial of conditioning therapy for post-operative pain management in complex head and neck cancer patients.

Rationale: Conditioning therapy with placebo has been studied and shown to be effective for reducing the amount of active medication required for a variety of medical conditions, including corticosteroids for psoriasis and amphetamines for ADHD. A more recent study showed additional promise for acute pain management for spinal cord injury in the inpatient rehabilitation facility setting. While these results provide rationale that conditioning therapy may also be effective for management of acute pain following surgery, trials have not been completed in this clinical setting. Given behavioral factors associated with the development of certain types of HNC, these patients often have poor social support and low socioeconomic status. These factors not only increase the risk for depression and associated opioid depression, but may also complicate adherence to new treatment methods. This pilot study will evaluate the feasibility of conditioning therapy for pain control following complex head and neck cancer surgery with free flap reconstruction in this specific patient population and clinical setting. Specifically, it will provide preliminary data on recruitment, retainment and reasons for participant drop out that will help guide the design of future larger scale trials.

Secondary Objective

Evaluate whether conditioning therapy with placebo decreases short-term and long-term post-operative opioid use following HNC surgery.

Rationale: While the primary aim of this pilot study is to assess feasibility, it has also been designed to include adequate sample size for statistical analysis of trends of post-operative opioid consumption. All study participants will receive standard multimodal analgesia, including opioids, and will have opioid consumption and pain severity documented. Patients in the OLC group will additionally begin conditioning therapy on the first post-operative day (POD 1) and will continue therapy through POD 7. The study is powered to evaluate whether the addition of conditioning therapy leads to a statistically significant decrease in baseline opioid consumption, defined as the change in average daily MME from post-operative days 2-4 to post-operative days 5-7. Data on opioid consumption and pain levels will be tracked through six weeks following surgery. Trends in absolute and change in baseline opioid consumption in each group will also help guide development of future studies and determine if seven days of therapy is adequate to observe an effect on short-term (1 week following surgery) and long-term (3-6 weeks following surgery) opioid consumption.

Background (briefly describe pre-clinical and clinical data, current experience with procedures, drug or device, and any other relevant information to justify the research)

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.1 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.1 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 their peri-operative pain needs.3,4 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%2, of these patients also suffer from psychiatric comorbidities.5,6 These factors inherently increase the risk of opioid dependence7 and studies have shown that chronic opioid use following surgery for HNC is associated with decreased disease free survival.8 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).9 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 to decrease the total dose of active medications required for a clinical response including opioids for pain following spinal cord injury,10 stimulants for ADHD,11 and corticosteroids for psoriasis.4 In the aforementioned study of corticosteroid use in patients with psoriasis, researchers compared the effect of standard therapy to partial dosing with reinforcement (i.e. same number of treatments with patients receiving alternating active ingredient vs placebo). They found comparable rates of symptom control and relapse between these two groups.9 Additionally, in patients receiving partial but equivalent dosing, those who were presented with reinforcement during each treatment had greater control and less relapse of symptoms than those without reinforcement.9

Many of these have been performed as "open-label" studies, where patients were aware of their group assignment and were informed when each placebo treatment was given. On such study by Morales-Quezeda, et al evaluated conditioning therapy for treatment of acute pain following spinal cord surgery in the inpatient rehabilitation facility setting. This open-label study specifically showed that patients with acute spinal cord injury who received interspersed placebo doses (in place of opioid medications) had greater reduction in total opioid consumption from baseline consumption and similar pain control as those who received opioid medications alone.10

These results suggest that conditioning therapy may also benefit HNC patients 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Randomized controlled trialRandomized controlled trial

Masking:

None (Open Label)

Primary Purpose:

Supportive Care

Official Title:

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

Anticipated Study Start Date :

Sep 1, 2022

Anticipated Primary Completion Date :

Jan 1, 2024

Anticipated Study Completion Date :

Jan 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Conrol Pain: All patients will continue with standard multimodal analgesia (as above) while inpatient. The nursing staff will assess and document pain severity by Likert scale every 4 hours in EPIC, as is standard of care.	Behavioral: Open Label Conditioning a. Conditioning therapy in OLC group: Patients in the OLC group will receive conditioning therapy with all doses of opioids and placebo. Placebo will be formulated to have the same physical appearance as liquid oxycodone and will be dispensed by the Weinberg inpatient pharmacy and administered by the nursing staff. Given reduced sense of smell and taste and administration of medications via nasogastric or gastric tube, taste of the medication will not be a consideration for formulation of placebo. At all times that oxycodone or placebo medication is administered, the patient will undergo conditioning therapy. As described here, the patient will 1) be given time to note the similar color and appearance of the medications and 2) be given simultaneous exposure to a clove oil Sniffin' sticks, which has been shown to stimulate both olfactory and trigeminal chemoreceptors.
Experimental: Open Label Conditioning Conditioning therapy in the Open label conditioning (OLC) group: Patients in the OLC group will receive conditioning therapy with all doses of opioids and placebo. Given reduced sense of smell and taste and administration of medications via nasogastric or gastric tube, taste of the medication will not be a consideration for formulation of placebo. At all times that oxycodone or placebo medication is administered, the patient will undergo conditioning therapy. As described here, the patient will 1) be given time to note the similar color and appearance of the medications and 2) be given simultaneous exposure to a clove oil Sniffin' sticks, which has been shown to stimulate both olfactory and trigeminal chemoreceptors.	Behavioral: Open Label Conditioning a. Conditioning therapy in OLC group: Patients in the OLC group will receive conditioning therapy with all doses of opioids and placebo. Placebo will be formulated to have the same physical appearance as liquid oxycodone and will be dispensed by the Weinberg inpatient pharmacy and administered by the nursing staff. Given reduced sense of smell and taste and administration of medications via nasogastric or gastric tube, taste of the medication will not be a consideration for formulation of placebo. At all times that oxycodone or placebo medication is administered, the patient will undergo conditioning therapy. As described here, the patient will 1) be given time to note the similar color and appearance of the medications and 2) be given simultaneous exposure to a clove oil Sniffin' sticks, which has been shown to stimulate both olfactory and trigeminal chemoreceptors.

Arm

Intervention/Treatment

Active Comparator: Conrol

Pain: All patients will continue with standard multimodal analgesia (as above) while inpatient. The nursing staff will assess and document pain severity by Likert scale every 4 hours in EPIC, as is standard of care.

Behavioral: Open Label Conditioning

a. Conditioning therapy in OLC group: Patients in the OLC group will receive conditioning therapy with all doses of opioids and placebo. Placebo will be formulated to have the same physical appearance as liquid oxycodone and will be dispensed by the Weinberg inpatient pharmacy and administered by the nursing staff. Given reduced sense of smell and taste and administration of medications via nasogastric or gastric tube, taste of the medication will not be a consideration for formulation of placebo. At all times that oxycodone or placebo medication is administered, the patient will undergo conditioning therapy. As described here, the patient will 1) be given time to note the similar color and appearance of the medications and 2) be given simultaneous exposure to a clove oil Sniffin' sticks, which has been shown to stimulate both olfactory and trigeminal chemoreceptors.

Experimental: Open Label Conditioning

Conditioning therapy in the Open label conditioning (OLC) group: Patients in the OLC group will receive conditioning therapy with all doses of opioids and placebo. Given reduced sense of smell and taste and administration of medications via nasogastric or gastric tube, taste of the medication will not be a consideration for formulation of placebo. At all times that oxycodone or placebo medication is administered, the patient will undergo conditioning therapy. As described here, the patient will 1) be given time to note the similar color and appearance of the medications and 2) be given simultaneous exposure to a clove oil Sniffin' sticks, which has been shown to stimulate both olfactory and trigeminal chemoreceptors.

Behavioral: Open Label Conditioning

Outcome Measures

Primary Outcome Measures

Change in morphine milligram equivalents (MME) between control and open label conditioniong patients [up to 1 week]
Comparison of postoperative day (POD) 2-4 with POD 5-7 MME between groups

Secondary Outcome Measures

Likert pain scale [up to 6 weeks]
Measurement of subjective pain; 0 = no pain, 10 = most intense pain ever experienced.
Functional Pain Scale [up to 6 weeks]
Subjective measurement of how pain affects activities of daily living; 0 = no pain, 10 = intolerable pain where the patient cannot do any activity (even speak) because of pain.
Patient Health Questionnaire-9 (PHQ-9) [weekly up to 6 weeks]
Objectifies degree of depression; 5-9 mild depression, 20-27 severe depression
Zung self-rated anxiety scale (SAS) [weekly up to 6 weeks]
Anxiety Scale; 20-44 Normal range, 75 and above-extreme anxiety

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Head and neck cancer patients undergoing cancer surgery and microvascular reconstruction.
Age 18 years or older
Ability to comprehend and willingness to participate in open-label conditioning study regardless of study group assignment

Exclusion Criteria:

Chronic opioid use prior to HNC diagnosis
Substance use disorder
Contraindication to receiving scheduled Acetaminophen, Ibuprofen, or Opioids
Psychosis, delirium or other significant cognitive impairment preventing participation in study

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Johns Hopkins University
University of Maryland

Investigators

Principal Investigator: Peter S Vosler, MD, PhD, JHU SOM Oto Head and Neck Surgery

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

Johns Hopkins University

ClinicalTrials.gov Identifier:

NCT04973748

Other Study ID Numbers:

IRB00276225

First Posted:

Jul 22, 2021

Last Update Posted:

Aug 11, 2022

Last Verified:

Aug 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Undecided

Plan to Share IPD:

Undecided

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Johns Hopkins University

open label placebo

opioid

postoperative analgesia

placebo

head and neck cancer

Additional relevant MeSH terms:

Head and Neck Neoplasms

Study Results

No Results Posted as of Aug 11, 2022