Chronic PainPhase 1KETA-2011NCT01369680
Oral Ketamine for Control of Chronic Pain in Children
A Phase 1 study testing Ketamine in people with Chronic Pain, run by University of Rochester at 1 site in United States.
Trial summary
The study is a maximum tolerated dose finding study for oral, chronic, daily administration of oral ketamine (by mouth) in children with long-term daily pain. Read more about this study
- Who is it for?
- Ages 8 to 22 years
- Conditions the study is for
- Chronic Pain
- What is being tested?
- Ketamine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- May 2011to Oct 2012
- Phase
- Phase 1
- 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 8 to 22 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Subject, parent, or guardian willing and able to give informed consent
- NRS for pain >4
- Chronic pain, which has been present for >3 months, or persisting longer than is normal for the underlying diagnosis
- Chronic pain related to diagnoses including but not limited to: cancer, rheumatologic disease, sickle cell anemia, cystic fibrosis, pancreatitis, and neuromuscular disease (e.g. Duchenne muscular dystrophy)
- Able to tolerate and cooperate with neurocognitive assessment
- Age 8-22 years old
Who cannot join
- If they are known or suspected to have drug dependence or addiction
- History of psychiatric disorder such as depression, schizophrenia, or bipolar disorder
- History of hypertension
- Unable to cooperate with neurocognitive assessment
- Chronic pain related to chronic abdominal pain syndrome
- Known liver disease or elevation of AST or ALT greater than 3 times the upper limit of normal.
Show all 10Show fewer
- Previous intolerance or allergic reaction to ketamine
- Pregnancy
- Use of CYP3A4 inhibitors or inducers within the 2 week period prior the study drug administration or within 5 half-lives of the respective medication, whichever is longer, until study conclusion.
- Consumption of grapefruit or grapefruit products from at least 2 weeks prior to study drug administration until study conclusion.
Trial locations and contacts
1 site in 1 country.
About this study
The study is a maximum tolerated dose finding study for oral, chronic, daily administration of oral ketamine (by mouth) in children with long-term daily pain.
Read the detailed description
Pain control in children is a major concern when children have chronic diseases, such as cancer and sickle cell disease with frequent pain crises. Additionally, though the traditional pain medications of morphine and acetaminophen are regarded as safe and effective for pain control in children, there are few alternative therapies available when these medications are insufficient. Chronic pain (whether cancer or non-cancer pain) in children has few approved and well tolerated therapeutic options with proven efficacy.
Ketamine is a medication that was first described in 1962[1]. It is an NMDA-R (N-methyl-D-aspartate-receptor) antagonist with dissociative amnestic and analgesic effects[1-2]. Ketamine is particularly successful as a dissociative amnestic for children in the emergent setting as it has little respiratory or cardiac impact, has a short half-life, and has fewer psychomimetic effects in the pediatric population than in adults[1]. Its function is via antagonism and reduction of NMDA-receptors in the afferent pain pathway. In effect, this decreases pain receptors and can dramatically reduce the need for narcotic pain medications for patients with chronic pain.
Unfortunately, with such dissociative effects, ketamine has been a drug of abuse for decades[1,3]. Additionally, there is concern that ketamine may have long-term deleterious effects on cognition for those subjects chronically exposed to IV ketamine[4], especially children whose neural pathways may still be developing[1,5]. These effects may include difficulty with attention and working memory, though the effects appear to be short-term and reversible in adults. However, much of this data is derived from rodent or primate studies, and there is little evidence that there are long-term cognitive effects on humans chronically exposed to ketamine[1]. This lack of data is particularly impactful in the pediatric group.
Ketamine has been evaluated as an analgesic medication for patients with chronic pain that is not resolved with narcotics and gabapentin. There are a number of case reports and small case series that suggest ketamine is a useful medication for control of chronic pain in adults[2,4,6-8]. Additionally, there are case studies that describe lasting (12 week) pain control in adults after 4-10 days of ketamine therapy[7-8]. However, there are, to date, little data that aid a pediatrician in determining if ketamine is a safe and effective option as a chronic, oral therapy for children with chronic pain.
Overall, there are few proven safe and effective medications for use in chronic pain management for children. Ketamine is a well known medication with a well elaborated safety profile, when given intravenously and for short periods of time. There is, as above, emerging data that ketamine is useful for chronic pain control in adults. The question that remains to be answered is whether ketamine is a safe option for chronic use in children, whose brains are significantly more plastic and whose metabolism is different compared with those of adults.
- Conditions
- Chronic Pain
- Being tested
- Ketamine
- Keywords
- Ketamine, Chronic pain, Children, Oral pain medication
- Medical subject headings
- Chronic Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
KetamineDrug
Also called Ketalar, Ketamine hydrochloride
Drug will be given orally three times a day at doses escalating from 0.25mg/kg/dose to 1.5mg/kg/dose in cohorts of 3. Each subject will be administered study drug for 2 weeks.
| Study group | Role | What they receive |
|---|---|---|
| Ketamine 0.25 mg/kg/dose | Experimental | The first three subjects were administered 0.25 mg/kg/dose oral ketamine. Receives: Drug: Ketamine |
| Ketamine 0.5 mg/kg/dose | Experimental | The second group of three subjects were administered 0.5 mg/kg/dose oral ketamine. Receives: Drug: Ketamine |
| Ketamine 1 mg/kg/dose | Experimental | The third group of three subjects were administered 1 mg/kg/dose oral ketamine. Receives: Drug: Ketamine |
| Ketamine 1.5 mg/kg/dose | Experimental | The fourth group of three subjects were administered 1.5 mg/kg/dose oral ketamine. Receives: Drug: Ketamine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants Tolerating Dose
According to CTCae any dose causing grade 2 or worse toxicity will be an untolerated dose. Tolerability is defined as ability to take the medication for 2 weeks without having a grade 2 or worse toxicity.
Measured: Up to 2 weeks
Secondary outcomes (3)
Neurocognitive Effect
Baseline neurocognitive testing will be done before study drug is given. Subjects will be reassessed for any changes in neurocognitive scores at end of dosing (week 2) and at three weeks off study drug (week 14). Significant changes were measured at week 14 compared to baseline. Week 2 was measured to inform future studies.
The neurocognitive scores are standardized scores with a mean of 100; low scores correlate with low neurocognitive function, while high scores correlate with high function. A significant change is defined as greater than or equal to 10% decrease in scores.
Measured: At 14 weeks
Norketamine Cmax (Measured in ng/mL).
Pharmacokinetic testing will be done during chronic ketamine administration on subjects consenting to additional testing one week into study drug administration. This is to further describe the activity of ketamine in the blood of children when administered chronically and to enable comparison of any clinical effect or toxicity with steady state levels of ketamine in children.
Measured: At week 1
Pain Control
Subjects will be assessed for clinically significant change in pain scores during and after study drug administration. Significant change in pain scores were determined at week 2, though week 14 scores were collected as well.
Participants with a 2 point (or greater) decrease in pain scores compared to baseline were considered to have responded. The NRS scale was used, the scale ranges from 0-10, with 10 being the most pain.
Measured: Week 2
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jun 2011 (estimated)
- Study startMay 2011
- Primary completionOct 2012
- Study completionOct 2012
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 (9)Papers the sponsor has linked to this study.
- Other trials for Chronic PainStudies of the same condition, open and under way.
- More trials run by University of RochesterThe 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 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Rochester
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, David Korones, University of Rochester
- Investigators
- David Korones, MD, Principal investigator, University of Rochester
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01369680
- Sponsor's protocol ID
- KETA-2011
- Acronym
- KETA-2011
- Status last verified
- Feb 2013
- First submitted
- 23 May 2011
- Last updated
- 15 Feb 2013
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Green SM, Cote CJ. Ketamine and neurotoxicity: clinical perspectives and implications for emergency medicine. Ann Emerg Med. 2009 Aug;54(2):181-90. doi: 10.1016/j.annemergmed.2008.10.003. Epub 2008 Nov 6.
PubMed 18990467Okon T. Ketamine: an introduction for the pain and palliative medicine physician. Pain Physician. 2007 May;10(3):493-500.
PubMed 17525784Kronenberg RH. Ketamine as an analgesic: parenteral, oral, rectal, subcutaneous, transdermal and intranasal administration. J Pain Palliat Care Pharmacother. 2002;16(3):27-35. doi: 10.1080/j354v16n03_03.
PubMed 14640353Visser E, Schug SA. The role of ketamine in pain management. Biomed Pharmacother. 2006 Aug;60(7):341-8. doi: 10.1016/j.biopha.2006.06.021. Epub 2006 Jul 5.
PubMed 16854557Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, Gleich SJ, Schroeder DR, Weaver AL, Warner DO. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009 Apr;110(4):796-804. doi: 10.1097/01.anes.0000344728.34332.5d.
PubMed 19293700Schwartzman RJ, Alexander GM, Grothusen JR, Paylor T, Reichenberger E, Perreault M. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain. 2009 Dec 15;147(1-3):107-15. doi: 10.1016/j.pain.2009.08.015. Epub 2009 Sep 23.
PubMed 19783371Sigtermans MJ, van Hilten JJ, Bauer MCR, Arbous SM, Marinus J, Sarton EY, Dahan A. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain. 2009 Oct;145(3):304-311. doi: 10.1016/j.pain.2009.06.023. Epub 2009 Jul 14.
PubMed 19604642Bell RF. Ketamine for chronic non-cancer pain. Pain. 2009 Feb;141(3):210-214. doi: 10.1016/j.pain.2008.12.003. Epub 2009 Jan 6. No abstract available.
PubMed 19128879Bredlau AL, McDermott MP, Adams HR, Dworkin RH, Venuto C, Fisher SG, Dolan JG, Korones DN. Oral ketamine for children with chronic pain: a pilot phase 1 study. J Pediatr. 2013 Jul;163(1):194-200.e1. doi: 10.1016/j.jpeds.2012.12.077. Epub 2013 Feb 10.
PubMed 23403253
Study at a glance
From the registry record, last updated by the sponsor on 15 Feb 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Oral Ketamine for Control of Chronic Pain in Children
- ClinicalTrials.gov ID
- NCT01369680
- Acronym / sponsor ID
- KETA-2011 / KETA-2011
- Conditions
- Chronic Pain
- Keywords
- Ketamine, Chronic pain, Children, Oral pain medication
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- University of RochesterUniversity, hospital or other
- Study start
- May 2011
- Primary completion
- Oct 2012 (actual)
- Study completion
- Oct 2012 (actual)
- First posted
- 9 Jun 2011 (estimated)
- Results
- Posted 11 Feb 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The study is a maximum tolerated dose finding study for oral, chronic, daily administration of oral ketamine (by mouth) in children with long-term daily pain.
Detailed description
Pain control in children is a major concern when children have chronic diseases, such as cancer and sickle cell disease with frequent pain crises. Additionally, though the traditional pain medications of morphine and acetaminophen are regarded as safe and effective for pain control in children, there are few alternative therapies available when these medications are insufficient. Chronic pain (whether cancer or non-cancer pain) in children has few approved and well tolerated therapeutic options with proven efficacy.
Ketamine is a medication that was first described in 1962[1]. It is an NMDA-R (N-methyl-D-aspartate-receptor) antagonist with dissociative amnestic and analgesic effects[1-2]. Ketamine is particularly successful as a dissociative amnestic for children in the emergent setting as it has little respiratory or cardiac impact, has a short half-life, and has fewer psychomimetic effects in the pediatric population than in adults[1]. Its function is via antagonism and reduction of NMDA-receptors in the afferent pain pathway. In effect, this decreases pain receptors and can dramatically reduce the need for narcotic pain medications for patients with chronic pain.
Unfortunately, with such dissociative effects, ketamine has been a drug of abuse for decades[1,3]. Additionally, there is concern that ketamine may have long-term deleterious effects on cognition for those subjects chronically exposed to IV ketamine[4], especially children whose neural pathways may still be developing[1,5]. These effects may include difficulty with attention and working memory, though the effects appear to be short-term and reversible in adults. However, much of this data is derived from rodent or primate studies, and there is little evidence that there are long-term cognitive effects on humans chronically exposed to ketamine[1]. This lack of data is particularly impactful in the pediatric group.
Ketamine has been evaluated as an analgesic medication for patients with chronic pain that is not resolved with narcotics and gabapentin. There are a number of case reports and small case series that suggest ketamine is a useful medication for control of chronic pain in adults[2,4,6-8]. Additionally, there are case studies that describe lasting (12 week) pain control in adults after 4-10 days of ketamine therapy[7-8]. However, there are, to date, little data that aid a pediatrician in determining if ketamine is a safe and effective option as a chronic, oral therapy for children with chronic pain.
Overall, there are few proven safe and effective medications for use in chronic pain management for children. Ketamine is a well known medication with a well elaborated safety profile, when given intravenously and for short periods of time. There is, as above, emerging data that ketamine is useful for chronic pain control in adults. The question that remains to be answered is whether ketamine is a safe option for chronic use in children, whose brains are significantly more plastic and whose metabolism is different compared with those of adults.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Ketamine 0.25 mg/kg/dose | Experimental | Drug: KetamineThe first three subjects were administered 0.25 mg/kg/dose oral ketamine. |
| Ketamine 0.5 mg/kg/dose | Experimental | Drug: KetamineThe second group of three subjects were administered 0.5 mg/kg/dose oral ketamine. |
| Ketamine 1 mg/kg/dose | Experimental | Drug: KetamineThe third group of three subjects were administered 1 mg/kg/dose oral ketamine. |
| Ketamine 1.5 mg/kg/dose | Experimental | Drug: KetamineThe fourth group of three subjects were administered 1.5 mg/kg/dose oral ketamine. |
Who may qualify
- Ages
- 8 to 22 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (6 listed)
- Subject, parent, or guardian willing and able to give informed consent
- NRS for pain >4
- Chronic pain, which has been present for >3 months, or persisting longer than is normal for the underlying diagnosis
- Chronic pain related to diagnoses including but not limited to: cancer, rheumatologic disease, sickle cell anemia, cystic fibrosis, pancreatitis, and neuromuscular disease (e.g. Duchenne muscular dystrophy)
- Able to tolerate and cooperate with neurocognitive assessment
Key exclusion criteria (10 listed)
- If they are known or suspected to have drug dependence or addiction
- History of psychiatric disorder such as depression, schizophrenia, or bipolar disorder
- History of hypertension
- Unable to cooperate with neurocognitive assessment
- Chronic pain related to chronic abdominal pain syndrome
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: Ketalar, Ketamine hydrochlorideDrug will be given orally three times a day at doses escalating from 0.25mg/kg/dose to 1.5mg/kg/dose in cohorts of 3. Each subject will be administered study drug for 2 weeks. | Drug | Ketamine 0.25 mg/kg/dose, Ketamine 0.5 mg/kg/dose, Ketamine 1 mg/kg/dose, Ketamine 1.5 mg/kg/dose |
Primary outcome
Number of Participants Tolerating Dose
Time frame: Up to 2 weeks
According to CTCae any dose causing grade 2 or worse toxicity will be an untolerated dose. Tolerability is defined as ability to take the medication for 2 weeks without having a grade 2 or worse toxicity.
3 secondary outcomes
Neurocognitive Effect
Time frame: At 14 weeks
Norketamine Cmax (Measured in ng/mL).
Time frame: At week 1
Pain Control
Time frame: Week 2
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Feb 2013.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 18990467Green SM, Cote CJ. Ketamine and neurotoxicity: clinical perspectives and implications for emergency medicine. Ann Emerg Med. 2009 Aug;54(2):181-90. doi: 10.1016/j.annemergmed.2008.10.003. Epub 2008 Nov 6.
- Background: PubMed 17525784Okon T. Ketamine: an introduction for the pain and palliative medicine physician. Pain Physician. 2007 May;10(3):493-500.
- Background: PubMed 14640353Kronenberg RH. Ketamine as an analgesic: parenteral, oral, rectal, subcutaneous, transdermal and intranasal administration. J Pain Palliat Care Pharmacother. 2002;16(3):27-35. doi: 10.1080/j354v16n03_03.
- Background: PubMed 16854557Visser E, Schug SA. The role of ketamine in pain management. Biomed Pharmacother. 2006 Aug;60(7):341-8. doi: 10.1016/j.biopha.2006.06.021. Epub 2006 Jul 5.
- Background: PubMed 19293700Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, Gleich SJ, Schroeder DR, Weaver AL, Warner DO. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009 Apr;110(4):796-804. doi: 10.1097/01.anes.0000344728.34332.5d.
- Background: PubMed 19783371Schwartzman RJ, Alexander GM, Grothusen JR, Paylor T, Reichenberger E, Perreault M. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain. 2009 Dec 15;147(1-3):107-15. doi: 10.1016/j.pain.2009.08.015. Epub 2009 Sep 23.
- Background: PubMed 19604642Sigtermans MJ, van Hilten JJ, Bauer MCR, Arbous SM, Marinus J, Sarton EY, Dahan A. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain. 2009 Oct;145(3):304-311. doi: 10.1016/j.pain.2009.06.023. Epub 2009 Jul 14.
- Background: PubMed 19128879Bell RF. Ketamine for chronic non-cancer pain. Pain. 2009 Feb;141(3):210-214. doi: 10.1016/j.pain.2008.12.003. Epub 2009 Jan 6. No abstract available.
- Derived from this study: PubMed 23403253Bredlau AL, McDermott MP, Adams HR, Dworkin RH, Venuto C, Fisher SG, Dolan JG, Korones DN. Oral ketamine for children with chronic pain: a pilot phase 1 study. J Pediatr. 2013 Jul;163(1):194-200.e1. doi: 10.1016/j.jpeds.2012.12.077. Epub 2013 Feb 10.
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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.
David Korones, MD principal investigator
University of Rochester
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Ketamine in people with Chronic Pain, run by University of Rochester 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 6 inclusion and 10 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 15 Feb 2013. 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. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 Feb 2013). 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?
Number of Participants Tolerating Dose (time frame: Up to 2 weeks). 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 NCT01369680, which also lists 9 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 15 Feb 2013.