Clinical trial NCT01369680: Oral Ketamine for Control of Chronic Pain in Children
Official title: Oral Ketamine for Control of Chronic Pain in Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Chronic Pain
Keywords: Ketamine
Chronic pain
Children
Oral pain medication
Lead sponsor: University of Rochester
Sponsor class: OTHER
First posted: 2011-06-09
Enrollment: 12
Sex: ALL
Minimum age (years): 8
Maximum age (years): 22
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants Tolerating Dose
timeFrame: Up to 2 weeks
Secondary outcomes:
measure: Neurocognitive Effect
timeFrame: At 14 weeks
measure: Norketamine Cmax (Measured in ng/mL).
timeFrame: At week 1
measure: Pain Control
timeFrame: Week 2
Other outcomes:
Locations:
city: Rochester
country: United States
facility: University of Rochester
state: New York
Study officials:
affiliation: University of Rochester
name: David Korones, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Okon T. Ketamine: an introduction for the pain and palliative medicine physician. Pain Physician. 2007 May;10(3):493-500.
citation: Kronenberg 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.
citation: Visser 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.
citation: Wilder 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.
citation: Schwartzman 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.
citation: Sigtermans 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.
citation: Bell 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.
citation: Bredlau 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.