The Effect of Chronic Pain on Delay Discounting in Methadone Patients

The epidemic of opioid overdose deaths continues to rise, killing more persons in 2017 than HIV/AIDS at the height of that epidemic. Medication assisted treatment, including methadone and buprenorphine, is the standard of care for the treatment of opioid use disorder (OUD). However, chronic pain can reduce treatment efficacy during medication assisted treatment and is associated with illicit substance relapse, dropout, and subsequent overdose. Mechanisms by which chronic pain may influence the impulsive decision making (e.g., drug relapse) in persons with OUD have not been well characterized. A better understanding is needed of decision-making in this population. Two factors that can influence decisions to use drugs are impulsivity and acute opioid withdrawal. This proposal will test how chronic pain is associated with increases in impulsive decision making in OUD, whether impulsive decision making is greater when undergoing opioid withdrawal, and how catastrophizing may modify the association between withdrawal and impulsive decision making in patients with chronic pain and OUD. An ideal population for this developmental research project are methadone maintained patients, who show high treatment attendance rates and will therefore assure study efficiency and reliable completion.

Study Overview

• Status: Terminated
• Conditions: Opioid-use Disorder; Chronic Pain Syndrome
• Intervention / Treatment: Drug: Naloxone Hydrochloride; Drug: Placebo

Detailed Description

This is an outpatient Phase 1 clinical trial investigating the effect of naloxone precipitated withdrawal on delay discounting. Eligible participants will undergo two experimental sessions presented in random order. One session will involve the measurement of delay discounting 30 minutes after double-blind intramuscular (IM) administration of placebo (normal saline) and the other will have the exact same procedures performed after double-blind IM administration of naloxone (0.1 mg). Injections will occur 2 hours after methadone dosing (peak levels). Study sessions will last 2 hours and involve pain and opioid withdrawal measures assessed at baseline and 15 minute intervals after injections. The participant should be back to baseline and free of withdrawal by the end of the study session. Sessions will occur at least 48 hours apart.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94110
      • Zuckerberg San Francisco General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female adults aged 18-65
• Stable methadone dose (at least 21 days) verified by contacting participant's opioid treatment program
• Understand and speak English
• Urine toxicology screen negative for drugs of abuse and positive for methadone
• Participants must be without signs of intoxication as evidenced by ability to receive full dose of methadone prior to research activities.
• Presence of chronic pain (>3 months) for the Pain group and absence of pain for the No Pain group.

Exclusion Criteria:

• Unstable psychiatric illness as assessed by the Mini International Neuropsychiatric Interview (e.g. active suicidal ideation, psychosis)
• Unstable medical illness as assessed by the study's independent medical monitor (e.g. uncontrolled hypertension, recent myocardial infarction, recent stroke, unstable angina) that may be affected by precipitated withdrawal
• Prescription opioid use besides methadone
• Acute pain process unrelated to chronic pain
• Women who are pregnant or lactating
• Known allergy to naloxone

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pain Group; Patients with chronic pain who are maintained on methadone for opioid use disorder	Drug: Naloxone Hydrochloride; An intramuscular (IM) injection of naloxone will be given.; Other Names: Narcan; Drug: Placebo; An IM injection of 0.9% normal saline will be given.
Placebo Comparator: No Pain Group; Patients who are maintained on methadone for opioid use disorder but who do not have chronic pain.	Drug: Naloxone Hydrochloride; An intramuscular (IM) injection of naloxone will be given.; Other Names: Narcan; Drug: Placebo; An IM injection of 0.9% normal saline will be given.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Delay discounting of money rate (k)	Delay discounting is the relative preference for smaller sooner over larger later rewards, an aspect of impulsivity. Most individuals would prefer an immediate $100 over $100 delayed by 1 year. However, when faced with the choice between receiving $95 now versus $100 in 1 year, preferences for the delayed reward may increase. By assessing such choices across multiple delays, delay discounting quantifies the devaluation of rewards over time, which allows for an index of overall discounting rate (k).	k will be calculated from the same series of discounting questions that will be asked once each session at approcimately 30 minutes after study IM medication administration.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Study Session Peak Pain Visual Analog Scale (VAS)	Current pain level rated on 0-100 VAS. This is the validated pain scale typically used by clinicians in an outpatient or inpatient clinical visit to represent current level of pain. Higher ratings indicate worse pain severity.	Peak Pain VAS will be the highest rating during each 2 hour study session.
Peak Clinical Opiate Withdrawal Scale (COWS) Rating	The COWS is an 11-item validated clinician administered scale that quantifies level of opioid withdrawal. The range of scores is 0-48, with higher scores indicating greater withdrawal severity. The peak COWS rating will be the highest measurement in the session after study drug administration.	Peak COWS rating will be the highest rating during each 2 hour study session.
Peak Subjective Opiate Withdrawal Scale (SOWS) Rating	The SOWS is a 16 item validated self-administered scale for grading opioid withdrawal symptoms. The range of scores is 0-64, with higher scores indicating greater withdrawal severity. The peak SOWS rating will be the highest measurement in the session after study drug administration.	Peak SOWS rating will be the highest rating during each 2 hour study session.
Peak Increase from baseline Pupil Diameter	Pupil diameter (mm) will be measured via digital pupillometer in standard room lighting at baseline and then throughout the study session after study drug administration. The peak increase from baseline value will be the largest increase from baseline pupil diameter measured after study drug administration.	Peak increase from baseline pupil diameter will be the largest increase from baseline pupil diameter measured during each 2 hour study session.

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Johns Hopkins University
• Investigators: Principal Investigator: D. Andrew Tompkins, MD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2020
• Primary Completion (Actual): October 6, 2022
• Study Completion (Actual): October 6, 2022

Study Registration Dates

• First Submitted: June 12, 2020
• First Submitted That Met QC Criteria: July 13, 2020
• First Posted (Actual): July 16, 2020

Study Record Updates

• Last Update Posted (Actual): October 10, 2022
• Last Update Submitted That Met QC Criteria: October 6, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: delay discounting; impulsivity; pain catastrophizing
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Pain; Neurologic Manifestations; Narcotic-Related Disorders; Chronic Pain; Opioid-Related Disorders; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Narcotic Antagonists; Naloxone
• Other Study ID Numbers: Z-1902

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Data will be made available to the public through presentation at scientific meetings and research publications in peer-reviewed journals. I have routinely kept an open policy to share data with the scientific and medical community upon request, and this policy will be continued with the present project.
• IPD Sharing Time Frame: Data will become available after publication of the main study results.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No