Chronic Pain, Hyperalgesia, Pain
Conditions
Keywords
Pain, Chronic pain, Opioid induced hyperalgesia, Opioid therapy
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.
Interventions
DRUGKetamine
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.
DRUGPlacebos
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.
Sponsors
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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. \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Temperature of Pain Threshold | 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 | 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 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Opioid - Ketamine Subjects who have chronic pain conditions treated with an opioid regimen will be randomized to receive a ketamine treatment during the study. | 16 |
| Opioid - Placebos Subjects who have chronic pain conditions treated with an opioid regimen will be randomized to receive a placebo treatment during the study. | 18 |
| Non-opioid - Ketamine This group will include subjects who have chronic pain conditions but not on an opioid regimen over the last 3 months. Subjects in this group will be randomized to receive a ketamine treatment. | 22 |
| Non-opioid - Placebos This group will include subjects who have chronic pain conditions but not on an opioid regimen over the last 3 months. Subjects in this group will be randomized to receive a placebo treatment. | 23 |
| Total | 79 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Physician Decision | 4 | 4 | 2 | 6 |
| Overall Study | Subject had scheduling issues | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Opioid - Ketamine | Opioid - Placebos | Non-opioid - Ketamine | Non-opioid - Placebos | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 18 Participants | 22 Participants | 23 Participants | 79 Participants |
| Sex: Female, Male Female | 10 Participants | 8 Participants | 15 Participants | 13 Participants | 46 Participants |
| Sex: Female, Male Male | 6 Participants | 10 Participants | 7 Participants | 10 Participants | 33 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 16 | 0 / 18 | 0 / 22 | 0 / 23 |
| serious Total, serious adverse events | 0 / 16 | 0 / 18 | 0 / 22 | 0 / 23 |
Outcome results
Primary
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.
Time frame: Baseline at visit 1, post inufsion at visit 1, and at visit 2 which was 1 week after visit 1
Population: Only subjects who experienced pain relief after the infusion were scheduled for visit 2. This is why the overall # of participants analyzed differs from the # of baseline participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Opioid - Ketamine | Change in Duration of Supra-threshold Pain Tolerance | -5.22 seconds | Standard Deviation 9.96 |
| Opioid - Placebos | Change in Duration of Supra-threshold Pain Tolerance | 13.81 seconds | Standard Deviation 19.55 |
| Non-opioid - Ketamine | Change in Duration of Supra-threshold Pain Tolerance | -1.91 seconds | Standard Deviation 7.32 |
| Non-opioid - Placebos | Change in Duration of Supra-threshold Pain Tolerance | -0.39 seconds | Standard Deviation 13.25 |
p-value: 0.004Kruskal-Wallis
Primary
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.
Time frame: Baseline at visit 1, post inufsion at visit 1, and at visit 2 which was 1 week after visit 1
Population: Only subjects who experienced pain relief after the infusion were scheduled for visit 2. This is why the overall # of participants analyzed differs from the # of baseline participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Opioid - Ketamine | Change in Temperature of Pain Threshold | -0.02 Degrees Celsius | Standard Deviation 0.79 |
| Opioid - Placebos | Change in Temperature of Pain Threshold | -0.61 Degrees Celsius | Standard Deviation 1.79 |
| Non-opioid - Ketamine | Change in Temperature of Pain Threshold | -0.61 Degrees Celsius | Standard Deviation 1.15 |
| Non-opioid - Placebos | Change in Temperature of Pain Threshold | -0.77 Degrees Celsius | Standard Deviation 1.04 |
p-value: 0.274Kruskal-Wallis
Primary
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.
Time frame: Baseline at visit 1, post inufsion at visit 1, and at visit 2 which was 1 week after visit 1
Population: Only subjects who experienced pain relief after the infusion were scheduled for visit 2. This is why the overall # of participants analyzed differs from the # of baseline participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Opioid - Ketamine | Change in Temperature of Pain Tolerance | -0.06 Degrees Celsius | Standard Deviation 1.46 |
| Opioid - Placebos | Change in Temperature of Pain Tolerance | 0.52 Degrees Celsius | Standard Deviation 1.33 |
| Non-opioid - Ketamine | Change in Temperature of Pain Tolerance | -0.42 Degrees Celsius | Standard Deviation 1.95 |
| Non-opioid - Placebos | Change in Temperature of Pain Tolerance | -0.19 Degrees Celsius | Standard Deviation 1.03 |
p-value: 0.552Kruskal-Wallis