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Acute Pain Management in Patients on Opioid Replacement Therapy

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ClinicalTrials.gov Identifier: NCT03933865
Recruitment Status : Active, not recruiting
First Posted : May 1, 2019
Last Update Posted : August 30, 2021
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco

Tracking Information
First Submitted Date  ICMJE December 4, 2018
First Posted Date  ICMJE May 1, 2019
Last Update Posted Date August 30, 2021
Actual Study Start Date  ICMJE October 31, 2018
Estimated Primary Completion Date October 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 30, 2019)
peak change in cold pressor tolerance [ Time Frame: 1 day per session ]
The amount of time (seconds) a participant can keep hand in cold water bath before pain becomes unbearable. The change will be the highest value after study medications have been administered subtracted from the session baseline.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 30, 2019)
  • peak change in cold pressor threshold [ Time Frame: 1 day per session ]
    The time (seconds) at which pain first develops after placing hand in cold water bath. The change will be the highest value after study medications have been administered subtracted from the session baseline.
  • peak change in conditioned pain modulation (CPM) [ Time Frame: 1 day per session ]
    Responses to a brief pressure pain stimulus are evaluated alone and then re-assessed during application of a tonic noxious stimulus (hand in water bath) using validated procedures. The peak change in CPM outcome will be a difference in differences score: the largest value of CPM after study medications have been administered subtracted from CPM at baseline
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 30, 2019)
Peak Drug Liking Visual Analog Scale [ Time Frame: 1 day per session ]
The participant positions an arrow along a line (labeled from 0 to 100) using the keypad to indicate his or her answer of how s/he likes the drug(s) at that moment.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Acute Pain Management in Patients on Opioid Replacement Therapy
Official Title  ICMJE Acute Pain Management in Patients on Opioid Replacement Therapy
Brief Summary This is an outpatient randomized within subject placebo-controlled human laboratory investigation of analgesia (as assessed with quantitative sensory testing; QST) from ketamine alone and in combination with hydromorphone in buprenorphine maintained participants. The goals of this project are to characterize the analgesic, subjective, and physiologic effects of ketamine combined with hydromorphone in patients on buprenorphine maintenance for opioid use disorder.
Detailed Description

Eligible participants will have 8 sessions where they will receive two IM injections.The dose of ketamine will be manipulated (0 mg/kg to 0.4 mg/kg) across sessions. The dose of hydromorphone will either be 0 mg or 8 mg. Therefore, participants will be exposed to ascending doses of ketamine with and without hydromorphone. Order of study medications will be randomized for each participant by an un-blinded statistician and transmitted securely to study pharmacist in charge of medication administration. This study will provide unique information on optimal hydromorphone-ketamine dosing strategies for acute pain management. in buprenorphine maintained patients.

Each session will take place 17 hours after the last buprenorphine dose (trough levels) to control for time since last dose. Sessions will be held on a dedicated unit for human subjects clinical research at Zuckerberg San Francisco General and include two IM injections of study medication given 15 minutes apart by blinded nursing staff. Study sessions will each last approximately 5 hours. Sessions will take place 1-2x weekly and must be separated by at least 72 hours to allow for drug wash-out. QST outcomes will be measured at baseline, as well as 15, 75, 135, and 195 minutes after injection #2 for each session. In addition, abuse liability outcomes will be measured at baseline (if required) and at 15, 75, 135, and 195 minutes after injection #2 for each session.

Blood will be drawn to evaluate baseline buprenorphine /norbuprenorphine levels. Then, PK analyses will be done for ketamine, norketamine and hydromorphone. Blood will be drawn at baseline as well as 15, 75, 135, and 195 minutes after injection #2.

Primary outcome will be analgesia as assessed by QST. The use of various QST measures which assess acute anti-nociception as well as central modification of pain processing will allow us to evaluate whether overall analgesia results from blocking of nociceptor signaling and/or changes to central pain facilitation to better understand the mechanism of ketamine-hydromorphone combinations.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
This is an outpatient randomized within subject placebo-controlled human laboratory investigation of analgesia (as assessed with quantitative sensory testing) from ketamine alone and in combination with hydromorphone in buprenorphine maintained participants.
Masking: None (Open Label)
Masking Description:
Masking: Participant, Investigator, and Outcomes Assessor. The identity of study medication conditions will not be known to investigators, research staff, or patients.
Primary Purpose: Basic Science
Condition  ICMJE
  • Opioid-use Disorder
  • Pain, Acute
Intervention  ICMJE
  • Drug: HYDROmorphone Injectable Solution
    Hydromorphone will be given via intramuscular injection (8 mg)
    Other Name: Dilaudid
  • Drug: Ketamine
    Ketamine will be given via intramuscular injection (0.1, 0.2 or 0.4 mg/kg)
  • Drug: Placebos
    Placebo will be normal saline solution given via intramuscular injection.
Study Arms  ICMJE Buprenorphine Maintained Patients
All participants will be maintained on buprenoprhine for the treatment of opioid use disorder. All participants will be exposed to all 8 study drug combinations
Interventions:
  • Drug: HYDROmorphone Injectable Solution
  • Drug: Ketamine
  • Drug: Placebos
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: August 25, 2021)
1
Original Estimated Enrollment  ICMJE
 (submitted: April 30, 2019)
100
Estimated Study Completion Date  ICMJE November 2023
Estimated Primary Completion Date October 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Males and females aged 18-60 years of age, inclusive.
  2. Maintained on stable buprenorphine/naloxone (Suboxone®) dose for at least 30 days prior to screening, with total daily dose >=4 mg and <=24 mg (Patients may also be on Zubsolv ® equivalent doses >=2.9 and <=17.2 mg). Participant must agree to stay on this dose for duration of study participation.
  3. Urine toxicology screen negative for drugs of abuse but positive for buprenorphine.
  4. Willing and able to speak, read and understand English.
  5. Able and willing to perform/tolerate QST. Persons who can tolerate cold pressor testing for 5 minutes will be disqualified.
  6. Willing to abstain from analgesic medications (other than buprenorphine) for 24 hours prior to each session.
  7. Written informed consent obtained from participant and ability for participant to comply with the requirements of the study.

Exclusion Criteria:

  1. Current alcohol or sedative-hypnotic use disorder as assessed by the Mini International Neuropsychiatric Interview.
  2. Presence of acute or chronic pain as determined by medical history and physical examination and score of 0 on pain VAS at the start of experimental sessions.
  3. Medical or psychiatric condition known to influence QST (e.g. HIV, peripheral neuropathy, Schizophrenia, Raynaud's syndrome).
  4. Women who are pregnant, breastfeeding, or planning on becoming pregnant during course of trial. Women must be using effective birth control and will receive pregnancy tests before each session.
  5. Poor venous access as an IV catheter will be used for blood draws during sessions.
  6. Past history of psychotic disorder (as assessed through MINI).
  7. Uncontrolled hypertension or clinically significant ECG abnormality.
  8. History of allergy or significant adverse reaction to hydromorphone or ketamine.
  9. Significant contraindication to ketamine use (active psychosis, uncontrolled hypertension, past or current ketamine use disorder, cardiovascular disease, glaucoma, active pulmonary infection or disease).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03933865
Other Study ID Numbers  ICMJE Z-1701
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of California, San Francisco
Study Sponsor  ICMJE University of California, San Francisco
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: D. Andrew Tompkins, MD MHS University of California, San Francisco
PRS Account University of California, San Francisco
Verification Date August 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP