Opioid-use Disorder, Chronic Pain Syndrome
Conditions
Keywords
delay discounting, pain catastrophizing, impulsivity
Brief summary
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.
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.
Interventions
An intramuscular (IM) injection of naloxone will be given.
DRUGPlacebo
An IM injection of 0.9% normal saline will be given.
Sponsors
Johns Hopkins University
National Institute on Drug Abuse (NIDA)
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
The participant, investigator, medical personnel administering study drug, and outcomes assessor will be blinded to drug being administered.
Intervention model description
This proposal is a randomized double-blind placebo controlled Phase 1 clinical trial / human laboratory study
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Delay Discounting of Money Rate (k) | k will be calculated from the same series of discounting questions that will be asked once each session at approximately 30 minutes after study medication administration. | 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). Delay Discounting of money rate has no units and values can go from 0-infinity. A larger discount rate indicates that a future reward is devalued more, and is associated with more impulsive behavior. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Study Session Peak Pain Visual Analog Scale (VAS) | Peak Pain VAS will be the highest rating during each 2 hour study session. | 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 Clinical Opiate Withdrawal Scale (COWS) Rating | Peak COWS rating will be the highest rating during each 2 hour study session. | 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 Subjective Opiate Withdrawal Scale (SOWS) Rating | Peak SOWS rating will be the highest rating during each 2 hour study session. | 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 Increase From Baseline Pupil Diameter | Peak increase from baseline pupil diameter will be the largest increase from baseline pupil diameter measured during each 2 hour study session. | 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. |
Countries
United States
Participant flow
Recruitment details
We began study recruitment in January 2020 (Q2) after IRB approval was received. The first study participant screening session was on January 21, 2020. UCSF halted all non-essential clinical research in March 2020 and we were unable to conduct research activities on a full 5 day a week schedule until one year later, with some periods during winter surges when we had to again shut down all research activities.
Participants by arm
| Arm | Count |
|---|---|
| Pain Group Patients with chronic pain who are maintained on methadone for opioid use disorder
Naloxone Hydrochloride: An intramuscular (IM) injection of naloxone will be given.
Placebo: An IM injection of 0.9% normal saline will be given. | 6 |
| No Pain Group Patients who are maintained on methadone for opioid use disorder but who do not have chronic pain.
Naloxone Hydrochloride: An intramuscular (IM) injection of naloxone will be given.
Placebo: An IM injection of 0.9% normal saline will be given. | 4 |
| Total | 10 |
Baseline characteristics
| Characteristic | Pain Group | Total | No Pain Group |
|---|---|---|---|
| Age, Continuous | 53.83 years STANDARD_DEVIATION 10.98 | 47.6 years STANDARD_DEVIATION 12.26 | 38.25 years STANDARD_DEVIATION 7.46 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 8 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 5 Participants | 8 Participants | 3 Participants |
| Region of Enrollment United States | 6 participants | 10 participants | 4 participants |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 3 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 4 | 0 / 4 |
| other Total, other adverse events | 1 / 6 | 2 / 6 | 1 / 4 | 0 / 4 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 4 | 0 / 4 |
Outcome results
Primary
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). Delay Discounting of money rate has no units and values can go from 0-infinity. A larger discount rate indicates that a future reward is devalued more, and is associated with more impulsive behavior.
Time frame: k will be calculated from the same series of discounting questions that will be asked once each session at approximately 30 minutes after study medication administration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pain Group | Delay Discounting of Money Rate (k) | Naloxone Session | -1.65 k-value | Standard Deviation 1.17 |
| Pain Group | Delay Discounting of Money Rate (k) | Placebo Session | -1.91 k-value | Standard Deviation 0.56 |
| No Pain Group | Delay Discounting of Money Rate (k) | Placebo Session | -2.11 k-value | Standard Deviation 1.11 |
| No Pain Group | Delay Discounting of Money Rate (k) | Naloxone Session | -2.16 k-value | Standard Deviation 0.92 |
Secondary
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.
Time frame: Peak COWS rating will be the highest rating during each 2 hour study session.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pain Group | Peak Clinical Opiate Withdrawal Scale (COWS) Rating | Placebo | 1.8 score on a scale | Standard Deviation 0.98 |
| Pain Group | Peak Clinical Opiate Withdrawal Scale (COWS) Rating | Naloxone | 2.5 score on a scale | Standard Deviation 2.6 |
| No Pain Group | Peak Clinical Opiate Withdrawal Scale (COWS) Rating | Placebo | 2.75 score on a scale | Standard Deviation 0.5 |
| No Pain Group | Peak Clinical Opiate Withdrawal Scale (COWS) Rating | Naloxone | 3 score on a scale | Standard Deviation 2.4 |
Secondary
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.
Time frame: Peak increase from baseline pupil diameter will be the largest increase from baseline pupil diameter measured during each 2 hour study session.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pain Group | Peak Increase From Baseline Pupil Diameter | Placebo | 0.06 millimeters | Standard Deviation 0.08 |
| Pain Group | Peak Increase From Baseline Pupil Diameter | Naloxone | 0.31 millimeters | Standard Deviation 0.44 |
| No Pain Group | Peak Increase From Baseline Pupil Diameter | Placebo | 0.03 millimeters | Standard Deviation 0.07 |
| No Pain Group | Peak Increase From Baseline Pupil Diameter | Naloxone | 0.07 millimeters | Standard Deviation 0.09 |
Secondary
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.
Time frame: Peak SOWS rating will be the highest rating during each 2 hour study session.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pain Group | Peak Subjective Opiate Withdrawal Scale (SOWS) Rating | Placebo | 3.2 score on a scale | Standard Deviation 2.6 |
| Pain Group | Peak Subjective Opiate Withdrawal Scale (SOWS) Rating | Naloxone | 2.7 score on a scale | Standard Deviation 2.9 |
| No Pain Group | Peak Subjective Opiate Withdrawal Scale (SOWS) Rating | Placebo | 2.8 score on a scale | Standard Deviation 2.1 |
| No Pain Group | Peak Subjective Opiate Withdrawal Scale (SOWS) Rating | Naloxone | 3.8 score on a scale | Standard Deviation 2.1 |
Secondary
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.
Time frame: Peak Pain VAS will be the highest rating during each 2 hour study session.
Population: There was missing data for one participant with chronic pain in the placebo session.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pain Group | Study Session Peak Pain Visual Analog Scale (VAS) | Placebo | 25.2 score on a scale | Standard Deviation 22.9 |
| Pain Group | Study Session Peak Pain Visual Analog Scale (VAS) | Naloxone | 28.2 score on a scale | Standard Deviation 25.4 |
| No Pain Group | Study Session Peak Pain Visual Analog Scale (VAS) | Placebo | 0 score on a scale | Standard Deviation 0 |
| No Pain Group | Study Session Peak Pain Visual Analog Scale (VAS) | Naloxone | 0.25 score on a scale | Standard Deviation 0.5 |