Oral Ketamine for Control of Chronic Pain in Children (KETA-2011)

February 11, 2013 updated by: David Korones, University of Rochester
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

12

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New York
      • Rochester, New York, United States, 14642
        • University of Rochester

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

8 years to 22 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ketamine 0.25 mg/kg/dose
The first three subjects were administered 0.25 mg/kg/dose oral ketamine.
Drug: Ketamine
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.
Other Names:
  • Ketalar
  • Ketamine hydrochloride
Experimental: Ketamine 0.5 mg/kg/dose
The second group of three subjects were administered 0.5 mg/kg/dose oral ketamine.
Drug: Ketamine
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.
Other Names:
  • Ketalar
  • Ketamine hydrochloride
Experimental: Ketamine 1 mg/kg/dose
The third group of three subjects were administered 1 mg/kg/dose oral ketamine.
Drug: Ketamine
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.
Other Names:
  • Ketalar
  • Ketamine hydrochloride
Experimental: Ketamine 1.5 mg/kg/dose
The fourth group of three subjects were administered 1.5 mg/kg/dose oral ketamine.
Drug: Ketamine
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.
Other Names:
  • Ketalar
  • Ketamine hydrochloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Up to 2 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Neurocognitive Effect
Time Frame: 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.
At 14 weeks
Norketamine Cmax (Measured in ng/mL).
Time Frame: 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.
At week 1
Pain Control
Time Frame: 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.
Week 2

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Rochester

Investigators

  • Principal Investigator: David Korones, MD, University of Rochester

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2011

Primary Completion (Actual)

October 1, 2012

Study Completion (Actual)

October 1, 2012

Study Registration Dates

First Submitted

May 23, 2011

First Submitted That Met QC Criteria

June 7, 2011

First Posted (Estimate)

June 9, 2011

Study Record Updates

Last Update Posted (Estimate)

February 15, 2013

Last Update Submitted That Met QC Criteria

February 11, 2013

Last Verified

February 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • KETA-2011

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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