Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Study of the Treatment of Experimental Pain in Opioid Dependent Persons on Methadone or Buprenorphine Maintenance

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2013 by Johns Hopkins University
Sponsor:
Collaborator:
Information provided by (Responsible Party):
D. Andrew Tompkins, MD, Johns Hopkins University
ClinicalTrials.gov Identifier:
NCT01642030
First received: July 9, 2012
Last updated: August 9, 2013
Last verified: August 2013
  Purpose

Pain is very common in persons with a history of addiction, but few studies have examined the best treatment of pain in this population. This is a study to determine the pain relief provided by intravenous hydromorphone (Dilaudid) or buprenorphine given to persons maintained on stable doses of methadone or buprenorphine. Experimental sessions will require overnight stays on a residential research unit. In these sessions, persons will be exposed to standard experimental pain techniques at baseline and then rate the relief (if any) provided by the study medication when exposed to the same techniques. Persons will be asked to participate in 2 or 3 sessions, each separated by at least 7 days.


Condition Intervention Phase
Opioid Dependence
Pain
Addiction
Drug: Placebo
Drug: Hydromorphone
Drug: Buprenorphine
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Analgesic Effects and Abuse Liability of Intravenous Hydromorphone and Buprenorphine in Pain-free Opioid Dependent Participants

Resource links provided by NLM:


Further study details as provided by Johns Hopkins University:

Primary Outcome Measures:
  • Cold pressor test. [ Time Frame: This will be measured 7 times during each 40-hour session. On average, all sessions will be completed within 4 weeks. ] [ Designated as safety issue: No ]
    The participant places a hand up to the wrist in a circulating water bath maintained at approximately 4 degrees Celsius (up to 5 minutes). The time at which pain develops is the threshold. The time a volunteer's hand remains underwater before pain is unbearable is tolerance.

  • Innocuous stimulation. [ Time Frame: This will be measured 7 times during each 40-hour session. On average, all sessions will be completed within 4 weeks. ] [ Designated as safety issue: No ]
    Participants' thresholds for warmth and touch sensations will be measured bilaterally on the ventral forearm using the FDA approved Medoc thermal stimulator (Ramat Yishai, Israel) and calibrated Von Frey filaments.

  • Pressure pain. [ Time Frame: This will be measured 7 times during each 40-hour session. On average, all sessions will be completed within 4 weeks. ] [ Designated as safety issue: No ]
    An electronic algometer (Somedic; Horby, Sweden) with a 1cm2 hard rubber probe will be used to assess responses to noxious mechanical pressure on the trapezius and forearm. Pressure is gradually increased at a constant rate (30kPA/sec); the average threshold and tolerance across 2 trials will be calculated.

  • Thermal pain. [ Time Frame: This will be measured 7 times during each 40-hour session. On average, all sessions will be completed within 4 weeks. ] [ Designated as safety issue: No ]
    All contact heat stimuli will be delivered using the FDA approved Medoc thermal stimulator (Ramat Yishai, Israel) on the dorsal forearm or dorsum of the foot. The thermode's temperature gradually increases (0.5oC/sec) until no longer tolerated (max 51 degrees Celsius). The average threshold and tolerance across 2 trials will be calculated.

  • Temporal summation. [ Time Frame: This will be measured 7 times during each 40-hour session. On average, all sessions will be completed within 4 weeks. ] [ Designated as safety issue: No ]
    Temporal summation involves rapidly applying a series of identical noxious stimuli in the same area to determine the increase in pain across trials. For temporal summation of thermal pain, 3 sequences of 10 heat pulses each from the FDA approved Medoc thermal stimulator (Ramat Yishai, Israel) will be applied to the dorsal forearm.

  • Diffuse noxious inhibitory controls (DNIC). [ Time Frame: This will be measured 7 times during each 40-hour session. On average, all sessions will be completed within 4 weeks. ] [ Designated as safety issue: No ]
    DNIC refers to the phenomenon of one noxious stimulus inhibiting the pain of a second noxious stimulus. Baseline responses to a brief painful stimulus (e.g., algometer on right trapezius) are evaluated and then re-assessed during application of a tonic noxious stimulus (e.g., cold pressor test with left hand).


Secondary Outcome Measures:
  • Visual analog scales (VAS) of subjective drug effects. [ Time Frame: This will be measured 7 times during each 40-hour session. On average, all sessions will be completed within 4 weeks. ] [ Designated as safety issue: No ]
    VAS are single item questions that assessed subjective drug effects at the time of scale completion. Ratings are entered into a computer by the participant positioning an arrow along a 100 mm line marked at either end with "none" (0) and "extremely" (100).

  • Pupil diameter. [ Time Frame: This will be measured at baseline and every 15 minutes during experimental pain testing. Testing will occur during 10 hours of each 40-hour session. Sessions will be separated by at least 7 days. ] [ Designated as safety issue: No ]
    This will be assessed with a digital pupilometer (Neuroptics, Inc.) in constant room lighting.

  • Number of participants with adverse events. [ Time Frame: This will be measured 7 times during each 40-hour session. On average, all sessions will be completed within 4 weeks. ] [ Designated as safety issue: Yes ]
  • Profile of Mood States. [ Time Frame: This will be measured 7 times during each 40-hour session. On average, all sessions will be completed within 4 weeks. ] [ Designated as safety issue: No ]
    This scale consists of 72 adjectives commonly used to describe momentary mood states. Participants rate from 0 (not at all) to 5 (extremely).

  • Vital Signs. [ Time Frame: This will be measured at baseline and every 15 minutes during experimental pain testing. Testing will occur during 10 hours of each 40-hour session. Sessions will be separated by at least 7 days. ] [ Designated as safety issue: Yes ]
    These include blood pressure, pulse, respiration rate, oxygen saturation, and skin temperature.

  • Trait pain catastrophizing. [ Time Frame: This will be measured once during the screening visit. ] [ Designated as safety issue: No ]
    Pain catastrophizing scale (PCS) will be done at screening to measure trait levels of catastrophizing.

  • Situational pain catastrophizing. [ Time Frame: This will be measured 7 times during each 40-hour session. On average, all sessions will be completed within 4 weeks. ] [ Designated as safety issue: No ]
    This construct compromises the sum of 6 questions measuring the 3 primary dimensions of catastrophizing: rumination, magnification, and helplessness.


Estimated Enrollment: 100
Study Start Date: August 2013
Estimated Study Completion Date: August 2015
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Methadone Maintenance Drug: Placebo
Intravenous injection of approximately 5 mL administered via slow push over 5 minutes. Given 4 injections during the session with each injection separated by 1.5 hours.
Other Name: Normal Saline
Drug: Hydromorphone
Intravenous injection of approximately 5 mL administered via slow push over 5 minutes. Given 4 injections during the session with each injection separated by 1.5 hours.
Other Name: Dilaudid
Buprenorphine Maintenance Drug: Placebo
Intravenous injection of approximately 5 mL administered via slow push over 5 minutes. Given 4 injections during the session with each injection separated by 1.5 hours.
Other Name: Normal Saline
Drug: Hydromorphone
Intravenous injection of approximately 5 mL administered via slow push over 5 minutes. Given 4 injections during the session with each injection separated by 1.5 hours.
Other Name: Dilaudid
Drug: Buprenorphine
Intravenous injection of approximately 5 mL administered via slow push over 5 minutes. Given 4 injections during the session with each injection separated by 1.5 hours.
Other Names:
  • Suboxone
  • Subutex

  Hide Detailed Description

Detailed Description:

This research is being done to learn how to better treat pain in people maintained on opioid medications, like methadone and buprenorphine (Suboxone ®, Subutex ®). People who take opioid medications for long periods of time are known to experience pain differently; and, regular amounts of medications may not be enough to treat the pain of these individuals. Additionally, many people with a history of addiction are afraid of taking opioid pain relievers, like morphine or hydromorphone (Dilaudid ®), for fear of relapse.

This study will help guide the medical community on better pain treatment for people prescribed buprenorphine or methadone. Investigators also want to determine the risk for relapse in people who receive opioid pain relievers for the treatment of acute pain.

Healthy people aged 18-55 who are maintained on buprenorphine or methadone for the treatment of opioid dependence may take part in this study. Participants must be free of illicit drug use and be on a stable dose of methadone or buprenorphine. Initial screening will occur over the phone and then select participants will be scheduled for an in-person screening at the BPRU.

If a participant meets all criteria and agrees to participate, he or she will be enrolled into the study. Enrolled participants will have 2 or 3 sessions involving overnight stays on the Behavioral Pharmacology Research Unit (BPRU) residential unit.

  • If participants are on methadone, they will have 2 sessions
  • If participants are on buprenorphine, they will have 3 sessions.

Sessions will each last for about 40 hours and involve identical procedures. That means participants will stay 2 nights on the BPRU residential unit for each session, and these sessions will be at least a week a part. Most people will complete all sessions within 1 month.

During sessions participants will experience the following:

Day 1 - Admission to the BPRU residential unit

  • Participants will take an alcohol breath test and provide a urine sample to check for drug use (and pregnancy if female). These tests must be negative to be admitted.
  • Vital signs will be measured.
  • Participants will receive their normal dose of methadone or buprenorphine.

Day 2 - Experimental pain testing

  • On each session day, a nurse will insert an IV catheter on the arm or hand not involved with pain testing.
  • Investigational drug or placebo will be given in random order. During each pain testing session, participants will receive 4 doses of the same investigational drug or placebo. If participants are on methadone, they will not receive buprenorphine injections as these could cause opioid withdrawal symptoms. Participants will not be told which drug or placebo they are getting and the research staff will not know the assignment either.
  • Participants will have 7 rounds of experimental pain testing, each lasting about 45 minutes and consisting of the same pain procedures. A trained technician will show participants each of the pain testing procedures and practice with them until participants learn what is involved and how to respond. Participants will be asked to complete 4 different types of standard pain tests during each session. Participants may stop these procedures at any point by telling the technician that they wish to stop.

    1. One type of test will produce pain by a device that will be pressed against the skin on the shoulder and arm. This produces pressure, similar to pressing a finger against the skin. Participants will be asked to indicate when the pain from the pressure reaches certain levels of intensity.
    2. Another type of test will produce pain by a small device that gives off heat. An investigator will put this device on a participant's forearm and it will increase in temperature. Some of these temperatures will cause participants to experience pain, and they will be asked to rate the pain produced by different intensities of heat.
    3. The third type of pain test will involve placing a hand in very cold water and leaving it there for as long as possible, or until reaching a time limit. Participants will be asked to rate the pain that they feel from the cold water and they may remove their hand from the water at any time.
    4. In addition to pain tests, investigators will also test the ability to detect touch, warmth, and cold sensations. To test for touch sensitivity, a series of very fine threads or thread-like objects will be applied to the forearm and investigators will ask participants to communicate when first noticing any sensation. To test for warmth and cold sensitivity, the same device used to test heat pain sensitivity will be placed on the arm. Participants will be asked to let the investigator know when they first notice the sensation of warmth or cold.

At times, participants will experience more than one type of pain at the same time.

  • Participants will answer questions about their experiences, including questions about how the study drug or placebo makes them feel and about any problems with the study drug or placebo.
  • Staff will take a participant's vital signs and take a picture of the eye repeatedly over each session.
  • Unless participants experience symptoms of opioid withdrawal (for example - nausea, vomiting, diarrhea or loose stools, body aches, and goosebumps), they will not be given the daily dose of methadone or buprenorphine on pain testing day (Day 2).

Day 3 - Discharge

  • Vital signs will be measured and a picture of the eye will be taken.
  • Participants will answer questions about their experiences from Day 2, including questions about any lasting drug effects and about any problems with the study drug or placebo.
  • Participants will receive their normal dose of methadone or buprenorphine and be discharged from the residential unit.
  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. age 18-55;
  2. diagnosis of opioid dependence
  3. urine toxicology negative for drugs of abuse but positive for opioid maintenance agent;
  4. stable buprenorphine (12-16 mg) or methadone (80-100 mg) dose for the past 30 days;
  5. absence of acute/chronic pain;
  6. able and willing to perform/tolerate pain procedures;
  7. able to communicate in English.

Exclusion Criteria:

  1. current illicit substance use at screening or during trial (including cannabis use);
  2. current diagnosis of alcohol dependence;
  3. acute or chronic pain;
  4. medical or psychiatric condition known to influence pain testing;
  5. current use of prescribed or over the counter analgesic agents;
  6. previous allergic reaction to hydromorphone or buprenorphine;
  7. women who are pregnant, lactating or planning to get pregnant during the course of the trial.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01642030

Contacts
Contact: Jessica Harras 410-550-9494 jharras2@jhmi.edu
Contact: D. Andrew Tompkins, M.D. 410-550-5953

Locations
United States, Maryland
Behavioral Pharmacology Research Unit Recruiting
Baltimore, Maryland, United States, 21224
Contact: Jessica Harras    410-550-9494    jharras2@jhmi.edu   
Principal Investigator: D. Andrew Tompkins, M.D.         
Sponsors and Collaborators
Johns Hopkins University
Investigators
Principal Investigator: D. Andrew Tompkins, M.D. Johns Hopkins University
  More Information

No publications provided

Responsible Party: D. Andrew Tompkins, MD, Assistant Professor, Johns Hopkins University
ClinicalTrials.gov Identifier: NCT01642030     History of Changes
Other Study ID Numbers: 1203, K23DA029609
Study First Received: July 9, 2012
Last Updated: August 9, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Johns Hopkins University:
Quantitative sensory testing
Cold pressor test
Opioid dependence
Methadone maintenance
Buprenorphine maintenance
Abuse liability
DNIC
Temporal Summation

Additional relevant MeSH terms:
Opioid-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Substance-Related Disorders
Buprenorphine
Hydromorphone
Methadone
Analgesics
Analgesics, Opioid
Antitussive Agents
Central Nervous System Agents
Central Nervous System Depressants
Narcotic Antagonists
Narcotics
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Respiratory System Agents
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014