PainNCT00833755

Effect of Ketamine on Opioid-Induced Hyperalgesia

A study testing Ketamine in people with Pain and Chronic Pain, run by Massachusetts General Hospital at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 18 to 65 years
Conditions the study is for: Pain, Chronic Pain, Hyperalgesia
What is being tested?: Ketamine
Type of treatment: Injection or infusion
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 79 participants
Where: 1 siteUnited States
Study dates: Sep 2008to Apr 2016
Phase: Interventional
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 65 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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.
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.

Who cannot join

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.

Show all 11Show fewer

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.
-

Trial locations and contacts

1 site in 1 country.

United States1 site

Massachusetts General Hospital
Boston, Massachusetts, 02114

Other trials in United States

About this study

Read the 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.

Conditions: Pain, Chronic Pain, Hyperalgesia
Being tested: Ketamine, Placebos
Keywords: Pain, Chronic pain, Opioid induced hyperalgesia, Opioid therapy
Medical subject headings: Pain, Chronic Pain, Hyperalgesia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

KetamineDrug
Also called Ketalar
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.
PlacebosDrug
Also called Saline
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.

Study groups in NCT00833755
Study group	Role	What they receive
Opioid - Ketamine	Active comparator	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. Receives: Drug: Ketamine
Non-opioid - Ketamine	Active comparator	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. Receives: Drug: Ketamine
Opioid - Placebos	Placebo comparator	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. Receives: Drug: Placebos
Non-opioid - Placebos	Placebo comparator	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. Receives: Drug: Placebos

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: Baseline at visit 1, post inufsion at visit 1, and at visit 2 which was 1 week after visit 1
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.
Measured: Baseline at visit 1, post inufsion at visit 1, and at visit 2 which was 1 week after visit 1
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.
Measured: Baseline at visit 1, post inufsion at visit 1, and at visit 2 which was 1 week after visit 1

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Sep 2008Apr 2016

First posted2 Feb 2009 (estimated)
Study startSep 2008
Primary completionMay 2013
Study completionApr 2016

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (2)Papers the sponsor has linked to this study.
Other trials for PainStudies of the same condition, open and under way.
More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase N/A
Primary purpose: Health services research
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind
Who is masked: Participant, Care provider, Investigator
Enrolment: 79 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00833755
Sponsor's protocol ID: 2008P 000879
Status last verified: Jul 2020
First submitted: 29 Jan 2009
Last updated: 23 Jul 2020
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
Individual data sharing: No

Publications

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.
PubMed 28842370
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.
PubMed 28802882

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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All Pain trials

Study at a glance

From the registry record, last updated by the sponsor on 23 Jul 2020. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Effect of Ketamine on Opioid-Induced Hyperalgesia
ClinicalTrials.gov ID: NCT00833755
Acronym / sponsor ID: 2008P 000879
Conditions: Pain, Chronic Pain, Hyperalgesia
Keywords: Pain, Chronic pain, Opioid induced hyperalgesia, Opioid therapy
Study type: Interventional
Recruitment status: Completed
Enrolment: 79 participants (actual)
Lead sponsor: Massachusetts General HospitalUniversity, hospital or other
Study start: Sep 2008
Primary completion: May 2013 (actual)
Study completion: Apr 2016 (actual)
First posted: 2 Feb 2009 (estimated)
Results: Posted 16 Jan 2017

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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.

Study design

Primary purpose: Health services research
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind (participant, care provider, investigator)
Number of arms: 4

Arm	Type	Receives
Opioid - Ketamine	Active comparator	Drug: KetamineThis 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.
Non-opioid - Ketamine	Active comparator	Drug: KetamineThis 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.
Opioid - Placebos	Placebo comparator	Drug: PlacebosThis 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.
Non-opioid - Placebos	Placebo comparator	Drug: PlacebosThis 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.

Who may qualify

Ages: 18 to 65 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (5 listed)

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.
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.

Key exclusion criteria (11 listed)

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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
KetamineAlso: KetalarTo 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.	Drug	Non-opioid - Ketamine, Opioid - Ketamine
PlacebosAlso: SalineTo 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.	Drug	Non-opioid - Placebos, Opioid - Placebos

Primary outcome

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.

Results and safety

Results posted to the registry on 16 Jan 2017, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Opioid - Ketamine	16	12
Opioid - Placebos	18	13
Non-opioid - Ketamine	22	20
Non-opioid - Placebos	23	17

Primary outcome: 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. Mean (Standard Deviation). Unit: Degrees Celsius

Measure	Opioid - Ketamine n = 7	Opioid - Placebos n = 2	Non-opioid - Ketamine n = 4	Non-opioid - Placebos n = 3
Value	-0.02 (0.79)	-0.61 (1.79)	-0.61 (1.15)	-0.77 (1.04)

Opioid - Ketamine vs Opioid - Placebos vs Non-opioid - Ketamine vs Non-opioid - Placebos: p = 0.274, Kruskal-Wallis

Population analysed: 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.

Primary outcome: 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. Mean (Standard Deviation). Unit: Degrees Celsius

Measure	Opioid - Ketamine n = 7	Opioid - Placebo n = 2	Non-opioid - Ketamine n = 4	Non-opioid - Placebos n = 3
Value	-0.06 (1.46)	0.52 (1.33)	-0.42 (1.95)	-0.19 (1.03)

Opioid - Ketamine vs Opioid - Placebo vs Non-opioid - Ketamine vs Non-opioid - Placebos: p = 0.552, Kruskal-Wallis

Primary outcome: 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. Mean (Standard Deviation). Unit: seconds

Measure	Opioid - Ketamine n = 7	Opioid - Placebos n = 2	Non-opioid - Ketamine n = 4	Non-opioid - Placebos n = 3
Value	-5.22 (9.96)	13.81 (19.55)	-1.91 (7.32)	-0.39 (13.25)

Opioid - Ketamine vs Opioid - Placebos vs Non-opioid - Ketamine vs Non-opioid - Placebos: p = 0.004, Kruskal-Wallis

Adverse events

Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Opioid - Ketamine	0 of 16 (0%)	0 of 16 (0%)	Not reported
Opioid - Placebos	0 of 18 (0%)	0 of 18 (0%)	Not reported
Non-opioid - Ketamine	0 of 22 (0%)	0 of 22 (0%)	Not reported
Non-opioid - Placebos	0 of 23 (0%)	0 of 23 (0%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 23 Jul 2020.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 28842370Luna 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.
Derived from this study: PubMed 28802882Maher 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.
MGH Center for Translational Pain ResearchLink provided by the sponsor.
Individual participant dataSharing planned: No

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Jianren Mao, M.D., Ph.D. principal investigator

Massachusetts General Hospital

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A study testing Ketamine in people with Pain and Chronic Pain, run by Massachusetts General Hospital at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 Jan 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00833755, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jul 2020.