Back to resultsEffect of Ketamine on Opioid-Induced Hyperalgesia
Primary Purpose
Pain, Chronic Pain, Hyperalgesia
Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Ketamine
Placebos
Sponsored by
About this trial
This is an interventional health services research trial for Pain focused on measuring Pain, Chronic pain, Opioid induced hyperalgesia, Opioid therapy
Eligibility Criteria
Inclusion Criteria for Group 1
- Subject will be between ages 18 to 65 years.
- 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.
- 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
- Subject who meets the criteria #1 & #2 as listed for Group 1.
- Subject has not been on an opioid regimen for the last three or more months.
Exclusion Criteria for all groups:
- Subject has an altered sensation at the skin site of QST (one of upper extremities).
- Subject has scar tissue or acute injury at the skin site of QST.
- 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.
- Subject has a diagnosis of renal or liver failure.
- Subject has a diagnosis of unstable angina, congestive heart failure, cardiac arrythmias or myocardial infarction within 1 year.
- Subject is allergic to ketamine.
- 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.
- 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
- Subject is tested positive on drug urine screening test.
Subject is pregnant or breast-feeding.
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Sites / Locations
- Massachusetts General Hospital
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Active Comparator
Active Comparator
Placebo Comparator
Placebo Comparator
Arm Label
Opioid - Ketamine
Non-opioid - Ketamine
Opioid - Placebos
Non-opioid - Placebos
Arm Description
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.
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.
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.
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.
Outcomes
Primary Outcome Measures
Change in Temperature of Pain Threshold
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
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
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.
Secondary Outcome Measures
Full Information
NCT ID
NCT00833755
First Posted
January 29, 2009
Last Updated
July 21, 2020
Sponsor
Massachusetts General Hospital
1. Study Identification
Unique Protocol Identification Number
NCT00833755
Brief Title
Effect of Ketamine on Opioid-Induced Hyperalgesia
Official Title
Effect of Ketamine on Opioid-Induced Hyperalgesia
Study Type
Interventional
2. Study Status
Record Verification Date
July 2020
Overall Recruitment Status
Completed
Study Start Date
September 2008 (undefined)
Primary Completion Date
May 2013 (Actual)
Study Completion Date
April 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Massachusetts General Hospital
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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:
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;
Chronic pain patients on chronic opioids would have an increased response to painful stimulation, so called "windup" as demonstrated by QST;
Both "wind-up" and altered pain threshold and tolerance would be indicative of the presence of opioid-induced hyperalgesia;
Intravenous ketamine, an NMDA receptor antagonist, could be used to differentiate between opioid-induced hyperalgesia and opioid tolerance.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pain, Chronic Pain, Hyperalgesia
Keywords
Pain, Chronic pain, Opioid induced hyperalgesia, Opioid therapy
7. Study Design
Primary Purpose
Health Services Research
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
79 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Opioid - Ketamine
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Non-opioid - Ketamine
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Opioid - Placebos
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
Non-opioid - Placebos
Arm Type
Placebo Comparator
Arm Description
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 Type
Drug
Intervention Name(s)
Ketamine
Other Intervention Name(s)
Ketalar
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebos
Other Intervention Name(s)
Saline
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change in Temperature of Pain Threshold
Description
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.
Time Frame
Baseline at visit 1, post inufsion at visit 1, and at visit 2 which was 1 week after visit 1
Title
Change in Temperature of Pain Tolerance
Description
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.
Time Frame
Baseline at visit 1, post inufsion at visit 1, and at visit 2 which was 1 week after visit 1
Title
Change in Duration of Supra-threshold Pain Tolerance
Description
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.
Time Frame
Baseline at visit 1, post inufsion at visit 1, and at visit 2 which was 1 week after visit 1
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria for Group 1
Subject will be between ages 18 to 65 years.
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.
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
Subject who meets the criteria #1 & #2 as listed for Group 1.
Subject has not been on an opioid regimen for the last three or more months.
Exclusion Criteria for all groups:
Subject has an altered sensation at the skin site of QST (one of upper extremities).
Subject has scar tissue or acute injury at the skin site of QST.
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.
Subject has a diagnosis of renal or liver failure.
Subject has a diagnosis of unstable angina, congestive heart failure, cardiac arrythmias or myocardial infarction within 1 year.
Subject is allergic to ketamine.
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.
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
Subject is tested positive on drug urine screening test.
Subject is pregnant or breast-feeding.
-
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jianren Mao, M.D., Ph.D.
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
28842370
Citation
Luna IE, Kehlet H, Jensen CM, Christiansen TG, Lind T, Stephensen SL, Aasvang EK. The Effect of Preoperative Intra-Articular Methylprednisolone on Pain After TKA: A Randomized Double-Blinded Placebo Controlled Trial in Patients With High-Pain Knee Osteoarthritis and Sensitization. J Pain. 2017 Dec;18(12):1476-1487. doi: 10.1016/j.jpain.2017.07.010. Epub 2017 Aug 24.
Results Reference
derived
PubMed Identifier
28802882
Citation
Maher DP, Zhang Y, Ahmed S, Doshi T, Malarick C, Stabach K, Mao J, Chen L. Chronic Opioid Therapy Modifies QST Changes After Ketamine Infusion in Chronic Pain Patients. J Pain. 2017 Dec;18(12):1468-1475. doi: 10.1016/j.jpain.2017.07.008. Epub 2017 Aug 10.
Results Reference
derived
Learn more about this trial
Effect of Ketamine on Opioid-Induced Hyperalgesia
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