Chronic Pain
Conditions
Keywords
Ketamine, Chronic pain, Children, Oral pain medication
Brief 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.
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.
Interventions
DRUGKetamine
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.
Sponsors
University of Rochester
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
8 Years to 22 Years
Healthy volunteers
No
Inclusion criteria
* 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
Exclusion criteria
* 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. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Tolerating Dose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neurocognitive Effect | At 14 weeks | 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. |
| Norketamine Cmax (Measured in ng/mL). | At week 1 | 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. |
| Pain Control | Week 2 | 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. |
Countries
United States
Participant flow
Recruitment details
Recruitment began in June 2011 and closed in April 2012. Patients were referred by their primary pain physician.
Participants by arm
| Arm | Count |
|---|---|
| Ketamine 0.25 mg/kg/Dose Cohort of three participants treated at 0.25 mg/kg/dose oral ketamine. | 3 |
| Ketamine 0.5 mg/kg/Dose Cohort of three participants treated at 0.5 mg/kg/dose oral ketamine. | 3 |
| Ketamine 1 mg/kg/Dose Cohort of three participants treated at 1 mg/kg/dose oral ketamine. | 3 |
| Ketamine 1.5 mg/kg/Dose Cohort of three participants treated at 1.5 mg/kg/dose oral ketamine. | 3 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Ketamine 0.25 mg/kg/Dose | Ketamine 0.5 mg/kg/Dose | Ketamine 1 mg/kg/Dose | Ketamine 1.5 mg/kg/Dose | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 2 Participants | 3 Participants | 3 Participants | 3 Participants | 11 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 3 participants | 3 participants | 3 participants | 3 participants | 12 participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 2 Participants | 1 Participants | 9 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 3 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 | 2 / 3 | 3 / 3 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 1 / 3 | 1 / 3 | 0 / 3 | 0 / 3 |
Outcome results
Primary
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.
Time frame: Up to 2 weeks
Population: Number of participants was determined through negotiation with the FDA for safety of all participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ketamine 0.25 mg/kg/Dose | Number of Participants Tolerating Dose | 3 participants |
| Ketamine 0.5 mg/kg/Dose | Number of Participants Tolerating Dose | 3 participants |
| Ketamine 1 mg/kg/Dose | Number of Participants Tolerating Dose | 3 participants |
| Ketamine 1.5 mg/kg/Dose | Number of Participants Tolerating Dose | 1 participants |
Secondary
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.
Time frame: At 14 weeks
Population: All participants not lost to follow-up were analyzed
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ketamine 0.25 mg/kg/Dose | Neurocognitive Effect | 0 participants |
| Ketamine 0.5 mg/kg/Dose | Neurocognitive Effect | 0 participants |
| Ketamine 1 mg/kg/Dose | Neurocognitive Effect | 0 participants |
| Ketamine 1.5 mg/kg/Dose | Neurocognitive Effect | 0 participants |
Secondary
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.
Time frame: At week 1
Population: All participants consenting for pharmacokinetics were analyzed. No participants in ketamine 1.5 mg/kg/dose group consented for pharmacokinetics.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ketamine 0.25 mg/kg/Dose | Norketamine Cmax (Measured in ng/mL). | 37.5 ng/mL |
| Ketamine 0.5 mg/kg/Dose | Norketamine Cmax (Measured in ng/mL). | 135 ng/mL |
| Ketamine 1 mg/kg/Dose | Norketamine Cmax (Measured in ng/mL). | 250 ng/mL |
Secondary
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.
Time frame: Week 2
Population: Number of participants for analysis was determined in negotiation with the FDA for safety of all participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ketamine 0.25 mg/kg/Dose | Pain Control | 3 participants |
| Ketamine 0.5 mg/kg/Dose | Pain Control | 0 participants |
| Ketamine 1 mg/kg/Dose | Pain Control | 2 participants |
| Ketamine 1.5 mg/kg/Dose | Pain Control | 0 participants |