Efficacy of Gabapentin in Treating Pain in Children With SNI (Gabapentin Trial)
Efficacy of Gabapentin in Treating Pain in Children With SNI (Gabapentin Trial)
Children born with severe brain-based developmental disabilities frequently experience
 persistent unexplained periods of pain and irritability, often compounded by a limited
 capacity to communicate their distress. The investigators call this entity Pain and
 Irritability of Unknown Origin (PIUO). The rationale of this trial is to identify the
 clinical effect size of gabapentin in reducing and resolving pain in children with
 developmental brain disorders, specifically those with severe neurological impairment (SNI).
Background

 Children with SNI may experience nociceptive-inflammatory pain as a result of their specific
 medical condition or procedures. Often, however, it is not clear what underlies the pain
 behavior as there is no clear inciting noxious event. The investigators define this entity of
 pain without an obvious source as Pain and Irritability of Unknown Origin (PIUO).

 The investigators' work to date has developed an efficient, focused clinical pathway to
 evaluate children with SNI for all potential sources of nociceptive-inflammatory pain. Using
 this approach the "unknown" element of pain in these children is reduced and a source of PIUO
 may be found in individual cases, increasing the potential for treatment. Nevertheless there
 are children, who at the end of a thorough evaluation guided by a clinical pathway, will
 still have PIUO. These children may benefit from adjuvant analgesics such as gabapentin.

 The evidence base supporting the use of gabapentin for pain and irritability in infants and
 children with neurological impairment rests on case series publications describing a limited
 number of retrospective cases. The lack of prospective, randomized studies, even for this
 commonly used medication, underpins the rationale for this trial.

 Objectives

 The primary objective of the pilot trial is to evaluate the clinically significant difference
 of gabapentin to decrease pain and irritability in children with SNI, when the source of pain
 and irritability is attributed to neurological dysregulation (nociplastic pain), as measured
 by parent-reported pain scores.

 The investigators will compare the gabapentin versus placebo along an escalating dose range
 for both individual subjects and for the group. The investigators will aggregate the results
 of the completed N-of-1 trials across all subjects to estimate the group level comparative
 effectiveness of gabapentin in reducing pain and irritability.

 Outcomes from this study will help with designing larger randomized control trials,
 especially with sample size and power calculations. It will also provide prospective
 information on drug effect.

 Trial Design

 This trial uses a single randomized multiple-measures cross-over design (N-of-1), with
 results aggregated over several subjects. This design is well-suited to outcomes that are
 highly specific to each individual and not amenable to precise measurement across a large
 cohort. The heterogenous nature of pain and irritability responses in children are more
 likely to be personally specific and characteristic, rather than generalizable.

 Subjects will switch between gabapentin (G) and placebo (P) in a randomized order. The
 sequence of whether G precedes P (GP) or P precedes G (PG) will be randomized by the study
 pharmacist, and neither the clinician nor the subject (parent/caregiver) will know the
 sequence. Each subject will serve as their own control and experiment, allowing for a finer
 assessment of the treatment efficacy within each patient.

 The primary variable assessed is the child's pain score. Pain and irritability will be
 measured using the Non-Communicating Children's Pain Checklist - Revised (NCCPC-R) at
 specified intervals throughout the randomized sequence of G : P. Additional measures of
 parent/caregiver burden and impact on their daily function will be undertaken weekly with the
 PROMIS-57, a tool adapted to measure the impact of the child's pain and irritability on
 parental functioning. Other measures will be of usual, known side effects (e.g., sedation)
 and of any unexpected adverse events.
Inclusion Criteria:

 -  Children aged 6 months to 18 years with SNI (from any cause) with unexplained pain and
 irritability and whose cognitive or communication impairments prevent determination of
 pain location, cause, and type will be eligible to participate.

 -  Eligible children will have cognitive impairment or be non-verbal and have severe
 levels of disability equivalent to Gross Motor Functional Classification System
 (GMFCS) scores of 3, 4 or 5 as well as Communication Function Classification System
 (CFCS) level 4 or 5.

 -  Eligible children will score >3 on two scales administered via an Eligibility
 Screening that measures persistence and distress level the child is experiencing as
 well as identifies the type of pain and irritability as PIUO - with no obvious cause
 or explanation. The score of >3 on the scale measuring pain persistence and distress
 level confirms that the child is experiencing pain and irritability more than "a
 little" on "some days".

 -  The will be evidence of a comprehensive evaluation of PIUO in the child's medical
 history, showing no evidence for treatable sources (nociceptive-inflammatory) of pain
 and/or irritability symptoms.

 Exclusion Criteria:

 -  Children not within the specified age range

 -  Children with communication capabilities and cognitive development to localize their
 pain.

 -  Participants whose pain and or irritability is diagnosed through completion of the
 PIUO Pathway during the enrollment phase of the trial.

 -  Patients with a known hypersensitivity/allergy to the study medication

 -  Patients who are actively participating in another experimental therapy study for pain
 and/or irritability.

 -  Patients who are a poor medical risk because of other systemic diseases or active
 uncontrolled infections.

 -  Patients who score A or B on the Pain Survey

 -  Patients who have an active source of nociceptive-inflammatory pain at the time of
 enrolment (e.g., post-operative pain)

 -  Patients with active renal disease, known renal impairment or glomerular filtration
 rate < 60 mL/min/1.73 m2 (if known).

 -  Patients with known significant hepatic impairment at the discretion of the
 investigator.

 -  Patients with clinically relevant abnormal ECG (if available) at the discretion of the
 investigator.

 -  Patients with diagnosis of sickle cell disease.

 -  Parents who do not speak one of Canada's two official languages (English or French)