Postoperative Tramadol/Gabapentin/Ibuprofen Versus Tramadol/Placebo/Ibuprofen

Hypotheses

H1: Children who receive scheduled tramadol 1mg/kgQ6h with scheduled gabapentin (3 mg/kg/q6h
dose) and PRN ibuprofen will experience better pain relief than children who receive
scheduled tramadol 1mg/kgQ6h with PRN ibuprofen following tonsillectomy.

H2: Children who receive scheduled tramadol 1mg/kgQ6h with scheduled gabapentin and PRN
ibuprofen will report fewer side effects than children who receive scheduled tramadol
1mg/kgQ6h with PRN ibuprofen following tonsillectomy.

This prospective study will include children ages 4 to 15 that are scheduled to undergo a
tonsillectomy (with or without adenoidectomy) procedure at CHC's Minneapolis campus with one
of the three Children's Ear, Nose, Throat and Facial Plastic Surgery surgeons. The three
surgeons will perform the same standardized surgical technique. The study will be
prospective, randomized, and double-blinded. Neither the patient /caregiver(s) nor the
person(s) evaluating the patient postoperatively will know whether the patient was assigned
to Group 1 or Group 2. A random numbers list will be generated to assign sequential patients
to Group 1 or Group 2 in order to eliminate selection bias due to group assignment or
post-operative evaluation.

To minimize any potential risks associated with either tramadol or gabapentin when
administered to obese children (i.e, children at the 85th percentile BMI or higher) the
medication dose will be capped at a rate representing the 85th percentile for the child's
age, sex and height.

Caregivers will be advised to administer the scheduled tramadol for five days along with
scheduled gabapentin (or placebo) for five days. PRN doses of ibuprofen may be administered
throughout the 10-day study period. For postoperative days 6-10, both groups will be advised
to switch to a PRN regimen of ibuprofen and tramadol.

Caregivers will be advised NOT to administer any study medication if the child shows signs
of over-sedation (respiratory rate lower than normal, slurred speech, etc.) or vomiting as a
result of the study drug, AND will be asked to call the Ear Nose & Throat group in case of
severe pain and or side effects (24/7 contact information will be provided). If the patient
displays signs of severe over-sedation (breathing rate less than 12 breaths/minute,
difficulty or inability to be aroused) parents will be advised to call 911. If in doubt, the
caregiver will be asked to call the 24/7 ENT group phone number.

For all adverse events that arise during the study period, both non-urgent and urgent, the
first point of contact for families will be with Children's Ear Nose & Throat and Facial
Plastic Surgery. If families contact Children's pharmacy with any questions related to
dosing or side effects, pharmacy staff will either contact Children's Ear, Nose & Throat and
Facial Plastic Surgery themselves or refer the family to do so. For severe adverse events
(respiratory depression, over sedation, seizure, etc.) and/or the child is seen by a
physician due to potential drug side effects, the pharmacist will be authorized to break the
blind. If in doubt, the pharmacist can call Children's Ear, Nose & Throat and Facial Plastic
Surgery for guidance.

Staff Assessment and Caregiver Diary

The following patient and clinical information will be collected by research staff:
patient's age, gender, race, diagnosis (apnea or chronic tonsillitis), concomitant
medication use, postoperative pain, and tonsil size rated on a scale of 1 to 4 (see Appendix
I).

The choice of outcome domains and measures in this study is based on a consensus paper
developed by the Pediatric Initiative on Methods, Measurement, and Pain Assessment in
Clinical Trials (PedIMMPACT) expert panel (McGrath et al., 2008). Acute pain domains are
included in the caregiver diary for this study.

A daily diary will be completed by the caregiver and will be used to track the patient's
pain symptoms, side effects, adverse events, and recovery during the first 24 hours and ten
days post-surgery. This diary was developed and modified based on feedback received for the
diary used in the recent clinical trial (Friedrichsdorf, unpublished). In addition, the
research coordinator will contact the caregiver every second day to collect the same data
and insure that the diary is completed. The patient /caregiver data will be compared to
responses provided during the telephone call in order to validate diary entries. Intensity
of pain and discomfort due to pain will be measured utilizing several methods including: a
validated pain scale, documentation of use of analgesics and rescue medications, waking from
sleep, time to ability to eat solid food, and time to return to normal activity. Other
outcome measures include: fluid intake, general satisfaction with treatment, and economic
impact of recovery (e.g., need for additional outpatient care for throat and/or ear pain,
bleeding, nausea, or poor eating).

In this study, pain self-assessment by the children and adolescents will include the Faces
Pain Scale-Revised (FPS-R) (with anchors 0=no pain and 10=highest pain imaginable) for
children ages 4-10 (Hicks et al., 2001), and NRS-11 (with anchors 0=no pain and 10 = highest
pain imaginable) for children ages 11-15 (note: children age 8-10 years will be asked to
choose either the FPS-R or NRS-11, as both scales are validated for use with children in
this middle age range). The designated caregiver participating in the study will receive
training on pain scale administration. The study coordinator or research associate will call
caregivers every two days during the follow-up period to remind them to complete the diary
and return it in the postage-paid envelope provided by research staff.

Data Requirements and Data Maintenance

All paper forms will be stored in a locked file cabinet located in the Pain and Palliative
Care department office. Data will be entered into Excel on a secure, password-protected
Children's server and will be exported to SPSS for analysis. The study coordinator will
maintain all paper and electronic data.

Risks/Benefits

Risks There is no additional medical risk associated with post-surgical pain management
above and beyond the usual risks. Neither tramadol nor gabapentin pose any known additional
safety risk. However, because little has been published in the pediatric literature about
these two medications and their application in the postoperative setting, the researchers
will form a small Data and Safety Monitoring Committee comprised of Children's staff members
who are not part of the study. This committee will be responsible for reviewing serious
adverse events as requested by the researchers (e.g., pharmacist, pain expert, etc.). As
with any study, there is a risk of loss of confidentiality due to the possibility that
people outside the study (e.g., staff, other families) may become aware of the child's
participation in the study. The researchers will make every effort to ensure patients'
privacy through use of private rooms for all research-related activities. Paper research
forms will be stored in the Pain and Palliative Care office in a locked file cabinet, and
all electronic data will be stored on a password-protected file on the Children's server.

Benefits There is a possibility that children who receive tramadol plus gabapentin with PRN
ibuprofen during the recovery period will report better pain control, fewer side effects, or
both than the children who receive tramadol plus PRN ibuprofen only. Future children and
their families may benefit from the knowledge gained from the study in terms of improved
pain management during the post-tonsillectomy recovery period.

Analysis

Analysis Plan

The following outcomes will be measured at two, four and 24 hours post-surgery, and then
daily for the duration of the follow-up period:

- Pain: Faces Pain Scale-Revised (FPS-R) or Numerical Rating Scale (NRS-11)

- Postoperative pain: Parents' Postoperative Pain Measure (PPPM)

- Pre/Postoperative medication use, including any rescue medications

- Patient- and caregiver-reported side effects

- Sleep: difficulty falling asleep or difficulty waking

- Fluid intake

- Number of patients requiring outpatient care for complications of tonsillectomy
including, but not limited to: throat and/or ear pain, bleeding, nausea

- Parent global satisfaction with treatment, recorded as 0-10 (0=Very Dissatisfied to
10=Very Satisfied) on a visual analog scale.

Descriptive statistics will be used to describe the participants and measurement results
including frequency distribution for categorical data such as gender and any sleep problem
(Yes/No), and mean (standard deviation) or median (range) for continuous data such as age,
fluid intake, pain intensity score and parent global satisfaction with their child's
recovery.

The number of days with pain intensity score greater than 4 will be compared between the
tramadol/ibuprofen group and tramadol/gabapentin/ibuprofen group using a two-sample t-test
or Mann-Whitney test. The PPPM scores and parental global satisfaction with their child's
recovery between two groups will be compared using the two-sample t-test or Mann-Whitney
test as well. Eta correlation coefficients will be calculated to examine the relationship
between PPPM score and the pain intensity score. Chi-square test or Fisher's exact test will
be used to compare the categorical data between two groups such as percent of patients
having any postoperative office visit due to pain/bleeding/nausea and any side effects
happened during the postoperative 10 days. A logistic regression model will be fit with
'patients having >2 days of pain score of > 4' as the dependent variable and other factors
such as patient age, procedure, medication as independent variables in order to identify
clinical factors predictive of postoperative pain following tonsillectomy in children.

Sample Size

Group sample sizes of 30 and 30 achieve 80% power to detect a difference of 2 in days with
pain score > 4 between the Tramadol group and the Gabapentin group with estimated group
standard deviations of 2.7 and with a significance level of 0.05 using a two-sided
two-sample t-test. Assuming a 20% dropout, at least 36 patients will be needed in each
group. The researchers plan to enroll at least 80 parents.

Environment

The study will take place on Children's Minneapolis campus. Data will be stored in the Pain,
Palliative and Integrative Medicine office, currently located in the Medical Doctor's
Building. This study will make use of CHC's outpatient pharmacy services in order to ensure
proper dispensing and blinding.

Inclusion Criteria:

- Child must be scheduled to undergo tonsillectomy (with or without adenoidectomy)

- Child must be between the ages of 4 and 15 at the time of enrollment.

- Child and caregiver must be English-speaking

- The same caregiver (e.g., mother) must agree to complete all study assessments with
child to ensure consistency

Exclusion Criteria:

- Child cannot self-assess pain due to conditions such as developmental delays,
chromosomal abnormalities, or other syndromes

- Child had significant adverse effects to tramadol, gabapentin and/or ibuprofen in the
past

- Child has a known underlying seizure disorder (not febrile seizure)

- Child has known underlying renal or liver dysfunction (with creatinine, aspartate
aminotransferase /alanine aminotransferase, more than twice above normal value for
age, respectively)

- Child is taking an selective serotonin reuptake inhibitor (SSRI), norepinephrine
reuptake inhibitor (SNRI), monoamine oxidase inhibitor (MAOI) or tricyclic