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Effect of Ketamine on Opioid-Induced Hyperalgesia

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ClinicalTrials.gov Identifier: NCT00833755
Recruitment Status : Completed
First Posted : February 2, 2009
Results First Posted : January 16, 2017
Last Update Posted : July 23, 2020
Sponsor:
Information provided by (Responsible Party):
Jianren Mao, MD, PhD, Massachusetts General Hospital

Tracking Information
First Submitted Date  ICMJE January 29, 2009
First Posted Date  ICMJE February 2, 2009
Results First Submitted Date  ICMJE September 20, 2016
Results First Posted Date  ICMJE January 16, 2017
Last Update Posted Date July 23, 2020
Study Start Date  ICMJE September 2008
Actual Primary Completion Date May 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 17, 2016)
  • Change in Temperature of Pain Threshold [ Time Frame: Baseline at visit 1, post inufsion at visit 1, and at visit 2 which was 1 week after visit 1 ]
    We measured the change in pain threshold using Quantitative Sensory Testing (QST). QST refers to a set of quantitative testing of individual responses to mechanical, thermal, and/or electrical stimulation. In this study, pain threshold was the thermal stimulation intensity (in°C) first perceived as painful. To measure this, a contact thermode was attached onto the dorsal surface of the forearm. By pressing a computer mouse button, each subject was able to stop stimulation when they first perceived a painful stimulation from the thermode as the temperature increased 1°C/s. This test was repeated 3 times and an average temperature was calculated. The temperatures could range from a minimum of 0°C to 53°C.
  • Change in Temperature of Pain Tolerance [ Time Frame: Baseline at visit 1, post inufsion at visit 1, and at visit 2 which was 1 week after visit 1 ]
    Using QST, we measured the change in pain tolerance which was the maximum thermal stimulation intensity (in °C) tolerable. In this test, the subject was instructed to press the computer mouse to stop stimulation when the thermode reached the maximal tolerable temperature. This test was repeated 3 times and an average temperature was calculated. The temperatures could range from a minimum of 0°C to 53°C.
  • Change in Duration of Supra-threshold Pain Tolerance [ Time Frame: Baseline at visit 1, post inufsion at visit 1, and at visit 2 which was 1 week after visit 1 ]
    Using QST, we detected the duration (seconds) of tolerance to supra-threshold heat pain stimulation. In this test, subjects were asked to tolerate, as long as he or she could, heat stimulation preset at 47°C for a maximum of 60 seconds. They were given the computer mouse to stop the test if they reached their limit before 60 seconds. If they stopped the test before the 60 seconds, the time that they stopped it was recorded. This test was repeated 3 times and an average duration was calculated. The duration could range from a minimum of 0 seconds to a maximum of 60 seconds.
Original Primary Outcome Measures  ICMJE
 (submitted: January 30, 2009)
Intravenous ketamine, an NMDA receptor antagonist, could be used to differentiate between opioid-induced hyperalgesia and opioid tolerance. [ Time Frame: After completion of study. ]
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of Ketamine on Opioid-Induced Hyperalgesia
Official Title  ICMJE Effect of Ketamine on Opioid-Induced Hyperalgesia
Brief Summary The purpose of this study is to compare pain threshold, pain tolerance, and wind up, as measured by QST, before and after a single dose of ketamine infusion under two clinical conditions: chronic pain patients on opioid therapy and chronic pain patients without opioid therapy.
Detailed Description

We hypothesize that:

  1. Chronic pain patients on chronic opioids would have a lower pain threshold and lower pain tolerance when compared to opioid naïve patients (patients with chronic pain with non-opioids treatment)., as measured by QST in a non-affected neutral limb;
  2. Chronic pain patients on chronic opioids would have an increased response to painful stimulation, so called "windup" as demonstrated by QST;
  3. Both "wind-up" and altered pain threshold and tolerance would be indicative of the presence of opioid-induced hyperalgesia;
  4. Intravenous ketamine, an NMDA receptor antagonist, could be used to differentiate between opioid-induced hyperalgesia and opioid tolerance.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Health Services Research
Condition  ICMJE
  • Pain
  • Chronic Pain
  • Hyperalgesia
Intervention  ICMJE
  • Drug: Ketamine
    To compare pain threshold, pain tolerance, and wind up, as measured by QST, before and after a single dose of ketamine infusion under two clinical conditions: chronic pain patients on opioid therapy and chronic pain patients without opioid therapy.
    Other Name: Ketalar
  • Drug: Placebos
    To compare pain threshold, pain tolerance, and wind up, as measured by QST, before and after a single dose of ketamine infusion under two clinical conditions: chronic pain patients on opioid therapy and chronic pain patients without opioid therapy.
    Other Name: Saline
Study Arms  ICMJE
  • Active Comparator: Opioid - Ketamine
    This group consists of 16 subjects who have chronic pain conditions treated with an opioid regimen. Subjects were randomized to receive a ketamine treatment during the study. They were given an intravenous infusion of ketamine (0.05mg/kg) diluted in 50 ml normal saline over 30 minutes.
    Intervention: Drug: Ketamine
  • Active Comparator: Non-opioid - Ketamine
    This group consists of 22 subjects who have chronic pain conditions but were not on an opioid regimen over the last 3 months. Subjects were randomized to receive a ketamine treatment during the study. They were given an intravenous infusion of ketamine (0.05mg/kg) diluted in 50 ml normal saline over 30 minutes.
    Intervention: Drug: Ketamine
  • Placebo Comparator: Opioid - Placebos
    This group consists of 18 subjects who have chronic pain conditions treated with an opioid regimen. Subjects were randomized to receive a placebo treatment during the study. They were given an intravenous infusion of 50 ml normal saline over 30 minutes.
    Intervention: Drug: Placebos
  • Placebo Comparator: Non-opioid - Placebos
    This group consists of 23 subjects who have chronic pain conditions but were not on an opioid regimen over the last 3 months. Subjects were randomized to receive a placebo treatment during the study. They were given an intravenous infusion of 50 ml normal saline over 30 minutes.
    Intervention: Drug: Placebos
Publications *

*   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 Completed
Actual Enrollment  ICMJE
 (submitted: November 17, 2016)
79
Original Estimated Enrollment  ICMJE
 (submitted: January 30, 2009)
136
Actual Study Completion Date  ICMJE April 2016
Actual Primary Completion Date May 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria for Group 1

  1. Subject will be between ages 18 to 65 years.
  2. Subject has a chronic pain condition for at least three months. This requirement is set in order to avoid the clinical uncertainty of an unstable pain condition and to minimize the study variation. Subjects should have a VAS pain score at 4 or above at the time of study.
  3. Subject is on a chronic opioid treatment regimen (e.g., morphine, fentanyl, oxycodone, methadone, hydromorphone, hydrocodone) for at least three months. There should have been no changes in the type and amount of opioid dose for at least one month. Only patients with a minimal daily dose of at least 60 mg morphine equianalgesic dose will be included.

Inclusion Criteria for Group 2

  1. Subject who meets the criteria #1 & #2 as listed for Group 1.
  2. Subject has not been on an opioid regimen for the last three or more months.

Exclusion Criteria for all groups:

  1. Subject has an altered sensation at the skin site of QST (one of upper extremities).
  2. Subject has scar tissue or acute injury at the skin site of QST.
  3. Subject has neurological disease or a condition causing upper extremities or generalized polyneuropathy, such as diabetic neuropathy, alcoholic neuropathy, AIDS neuropathy, multiple sclerosis, amyotrophic lateral sclerosis, and post-stroke residual neurological deficits.
  4. Subject has a diagnosis of renal or liver failure.
  5. Subject has a diagnosis of unstable angina, congestive heart failure, cardiac arrythmias or myocardial infarction within 1 year.
  6. Subject is allergic to ketamine.
  7. Subject had recent therapy that may influence QST results, e.g., neuroablative procedure involving upper extremities within six-months or peripheral neurolytic block involving upper extremities within two-months.
  8. Subject has a confirmed diagnosis of and is under the care of a psychiatrist for major depression disorder, eating disorder; alcohol or drug dependence; or attention deficit hyperactivity disorder. Subject has any history of a confirmed diagnosis of bipolar disorder, schizophrenia, anxiety disorder or a psychotic disorder
  9. Subject is tested positive on drug urine screening test.
  10. Subject is pregnant or breast-feeding.

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Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older 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 NCT00833755
Other Study ID Numbers  ICMJE 2008P 000879
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Jianren Mao, MD, PhD, Massachusetts General Hospital
Study Sponsor  ICMJE Massachusetts General Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jianren Mao, M.D., Ph.D. Massachusetts General Hospital
PRS Account Massachusetts General Hospital
Verification Date July 2020

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