Clinical trial NCT04950660
Conditions: Adolescent Idiopathic Scoliosis
Sponsor: Children's Mercy Hospital Kansas City
Start date: 2019-12-11; Completion date: 2024-08-01
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Prospective, randomized control trial To determine if oral caffeine decreases the frequency of opioid demand in children with adolescent idiopathic scoliosis after their spinal fusion surgery To compare pain scale ratings, number of requests for diazepam, average heart rate, average blood pressure, sex, age, ethnicity, post-op day of discharge, operative time, estimated intraoperative blood loss, remittance post-surgery, length of hospital stay, and segments fused during spinal fusion surgery.

Detailed description:
Because these receptors are so important for modifying pain and inflammation, caffeine has been added as an adjuvant to common analgesics, such as paracetamol, ibuprofen, and aspirin in the belief that it will enhance their analgesic efficacy. Most studies used paracetamol or ibuprofen with 100 mg to 130 mg caffeine, and the most common pain conditions studied were postoperative dental pain, postpartum pain, and headache. There was a small but statistically significant benefit with caffeine used at doses of 100 mg or more, which was not dependent on the pain condition or type of analgesic. Additionally, trials have shown superior efficacy of adding caffeine to ibuprofen instead of administering ibuprofen alone for treating acute pain, reflecting that caffeine is an effective analgesic adjuvant. The addition of caffeine (≥ 100 mg) to a standard dose of commonly used analgesics provides a small but important increase in the proportion of participants who experience a good level of pain relief.

Finally, the beneficial effects of caffeine on aerobic activity and resistance training performance are well documented. Studies have shown that caffeine ingestion resulted in significantly lower levels of soreness compared with placebo (p ≤ 0.05). A further beneficial effect of sustained caffeine ingestion in the days after the exercise bout is an attenuation of delayed onset muscle soreness. Orthopaedic surgery also causes muscle injury, and patients might benefit from caffeine's effect on lowering muscle soreness. Acute caffeine administration also has been shown to demonstrate increases in alertness, contentment, motivation to work, talkativeness, and energy. It also decreases muscle twitches. All of these effects would be beneficial in the post-operative period, especially for Adolescence Idiopathic Scoliosis (AIS) patients undergoing spinal fusion surgery in the orthopaedic department at Children's Mercy Hospital.

Arms: arm 1: Experimental Group: patient group (n = 34) receiving a 100 mg dose of caffeine (1/2 of a 200mg tablet to be taken whole or crushed), taken twice daily. This will be an adjuvant to their standard pain control. arm 2: Control group: patient group (n = 34) receiving placebo compounded to look similar to the caffeine treatment, taken twice daily. This will be an adjuvant to their standard pain control.
Interventions: intervention 1: Caffeine Tablet intervention 2: Placebo
Intervention descriptions: intervention 1: Caffeine is approved by the FDA as a stimulant. A stimulant approved by the United States Food and Drug Administration (FDA) for the treatment to increase mental alertness and in combination with painkiller to treat migraine headaches. It is approved in the form of pill or tablet. intervention 2: Placebo, empty opaque dark blue blank capsule, taken twice daily. This will be an adjuvant to their standard pain control.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
2024 
Can Oral Caffeine Decrease 
Postoperative Opioid Consumption 
following Posterior Spinal Fusion in 
Adolescent Idiopathic Scoliosis? A 
Randomized Placebo-Controlled Trial 
NCT04950660 
08/27/2024 


Trial Design 
This clinical trial titled “Can Oral Caffeine Decrease Postoperative Opioid Consumption following 
Posterior Spinal Fusion in Adolescent Idiopathic Scoliosis? A Randomized Placebo-Controlled Trial” was 
registered on ClinicalTrials.gov, Protocol ID STUDY00000775, ClinicalTrials.gov ID NCT04950660.  The full 
trial protocol can be accessed at https://clinicaltrials.gov/study/NCT04950660. The Institutional Review 
Board (IRB) approved this prospective, randomized, placebo-controlled, and double-blinded clinical trial.   
Participants 
All eligible adolescent idiopathic scoliosis patients undergoing posterior spinal fusion by two attending 
spine surgeons from December 2019-December 2023 were approached, with an enrollment goal of 68 
total subjects.  Due to the extended time involved, the study was concluded with 51 completed subjects. 
Inclusion criteria were patients aged 12 through 17 years of age who presented for surgical treatment of 
AIS with either of the two treating surgeons.  Additional inclusion criteria were the ability to swallow 
pills (blinded clinical trial using a blank pill capsule), English as the primary language, mental capacity 
sufficient to understand the purpose of the clinical trial, surgery performed via a posterior approach, 
patient assent and at least of one of their biological parents or guardian(s) consenting for the patient to 
participate  Exclusion criteria was a history of obesity (defined by a BMI at or above the 95th percentile), 
weight below 40 kg, any spine diagnosis other than AIS, revision spine surgery, anterior or combined 
approach, admission to PICU (Pediatric Intensive Care Unit), postoperative oxycodone use, specific 
medication allergies (ibuprofen, caffeine, codeine, and/or diazepam), history of renal disease, history of 
a coagulation disorder, history of cardiac dysrhythmia or open heart surgery, history of chronic pain 
syndrome or Complex Regional Pain Syndrome, current use of oral central nervous system stimulant 
(e.g. methylphenidate), age greater than 18 years, children or parents unable to consent, individuals 
with cognitive delays, pregnant females, and prisoners. Caffeine is reported to be toxic when consumed 
in high doses when combined with other oral stimulants1  Therefore, it was decided to exclude patients 
previously prescribed psychostimulants.  The clinical trial was discussed, and informed consent 
obtained, during the preoperative visit.    
Interventions 
The interventional drug (caffeine) used in this clinical trial was prescribed as approved by the United 
States FDA (Food and Drug Administration) for the treatment of postoperative pain in children. We 
extensively reviewed research focused on safe caffeine consumption in pediatrics and followed 
published guidelines in the administration of caffeine as an adjuvant to standard oral pain medications 
after surgery.  This literature review showed that caffeine being administered at the current doses in 
this clinical trial would not be harmful to children or adolescents. Data has been collected in children 
and adolescents using dose–response and placebo-controlled research methods regarding caffeine use. 
Outcomes, such as cardiovascular function, mood, and cognitive performance, have all been measured 
at caffeine doses ranging from 50 to 300 mg 2-4. High caffeine intakes, defined as >5 mg/kg of body 
weight per day, correlated with risk of anxiety and withdrawal symptoms. Lower doses did not 
demonstrate these effects and had positive results with improved cognitive function, antidepressant 
action, and sports performance 5-7.  The goal caffeine consumption for children and adolescents should 
be less than 2.5 mg/kg of body weight per day 8.   


The hospital investigational drug study (IDS) pharmacy provided either a treatment dose or placebo 
dose of caffeine to be given to the patient and was also in charge of randomization for the study.  The 
experimental group received a 100 mg dose of caffeine (1/2 of a 200mg tablet) twice daily. The control 
group received a placebo dose that was compounded to look identical to the caffeine (capsule), also 
taken twice daily.  Both the active and placebo doses were given at the time of transition off the patient-
controlled analgesia (PCA) at 0900 on POD 1.   
Randomization 
The clinical trial subjects, clinician, and researcher were all blinded to the group assignments.  IDS 
pharmacy utilized an internet randomization generator to create the code. The code used numbers 1-4 
to create groups, and odd numbers were assigned to the experimental/caffeine group. Subjects were 
randomized the day prior to dosing.  If a subject was randomized but did not become a study participant 
(i.e. did not receive a dose of medication), IDS pharmacy did not reuse the randomization code; the next 
line on the randomization table was utilized.  The doses were concealed in teal, opaque capsules.  Empty 
capsules were used for placebo doses.  Capsules were sent to the inpatient floor in 24-hour batches.  IDS 
pharmacy staff did not enter the randomization assignment into REDCap until after the patient was 
discharged and chart recordings were finalized.    
Postoperative Pain Management Protocol 
The standard postoperative spinal fusion medications for patients with AIS at the clinical trial's initiation 
became the control pain pathway for the clinical trial with the addition of the placebo versus active 
caffeine dosages.  To reduce bias, the Anesthesia Pain Service standardized their intra-operative and 
post-operative analgesia.  During surgery, intrathecal (IT) preservative-free morphine was given after 
spine exposure.  After surgery, a PCA was then utilized until post-operative day (POD) 1.  The medication 
in the PCA was standardized to hydromorphone on demand only.  An oral dose of gabapentin was used 
pre-operatively and was continued three times daily until POD 3.  In the recovery room, a clonidine 
patch was placed and continued until discharge.   Intravenous (IV) ketorolac and acetaminophen 
scheduled was used until transition off the PCA on POD 1.  Patients were routinely transitioned off the 
PCA to oral pain medications the morning of POD 1 (defined as 0900-2359).  IDS caffeine dosed at 100 
mg twice daily (at 0900 and 1700) was ordered and provided as either a treatment or placebo dose 
based on their randomization. The drug was cut to fit into empty capsules in a dark color to mask the 
contents by the IDS pharmacist.  The placebo capsules were empty.  
Post-operative oral transition medications were also standardized (Table 1). The POD 1 transition opioid 
was hydrocodone/acetaminophen offered at 2 dose ranges (lower and higher).  The lower dose was 
0.15mg/kg (rounded down) to the nearest pill size (5mg or max of 7.5mg) given for moderate pain (VAS 
score of 0-5). A higher dose measured at 0.2mg/kg (rounded down) to the nearest pill size (7.5mg or 
max of 10mg) for severe pain was ordered for severe pain (VAS score of 6-10).   
Data Collection 
Data from the EMR (electronic medical record) consisted of patient demographic variables as well as 
surgical variables (duration of operative time, estimate of intraoperative blood loss, and spinal segments 
fused).  The primary outcome variable was postoperative oral opioid consumption, with secondary 
outcomes including postoperative pain scores, number of requests for diazepam, average heart rate, 
average systolic blood pressure, and length of hospital stay (LOS).  Opioid consumption was 
standardized to milligram of morphine equivalents (MME).  To control variability of MME, based on 


patient weight, a point system was derived and was measured daily until discharge. The lower dose of 
opioid counted as one point, and the higher dose was counted as two points. Total MME/kg/day was 
also calculated and recorded daily.  Patients were on scheduled ibuprofen (~10mg/kg) from transition 
off PCA until discharge.  All patients had diazepam (equal to or less than 0.05mg/kg) ordered as needed 
for muscle spasms.  Standardization of post-operative analgesia also included oral gabapentin (5mg/kg) 
TID continued through POD 3.  An outline of the anesthesia pain standardization pathway and 
postoperative pain medication pathway for this clinical trial are detailed in Table 1.  Pain scores were 
obtained per nursing standard using the Visual Analog Scale (VAS).  The primary outcomes were the 
number of demands (total points) for oral opioids from transition off PCA until discharge and total 
MME/kg/day.     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early study evaluation revealed multiple study participants being disqualified related to the research 
team missing details on inclusion and exclusion criteria.  Subsequently, a member of the research team 
was assigned solely to review each patient candidate’s chart to ensure study compatibility before being 
approached for the study.  Clinician error in following the research protocol was also noted, therefore 
the caffeine study participant label was added to the operating room (OR) time out, and an email was 
sent to OR scheduling, anesthesia staff, and inpatient floor charge nurses within 2 days before the 
scheduled surgery.  On the day of surgery, a standard study email outlining the nursing pain 
management protocol was sent out to all nursing staff involved with caring for the patient in attempts 
to avoid breeches in protocol. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Methods and Sample Size 
A review of post-surgical patients of the 2 senior surgeons that were managed from February 2018-
January 2019 was conducted.   Similar inclusion/exclusion criteria recorded daily opioid demand via the 
point system and whether caffeine had been prescribed was analyzed.  This data determined a sample 
size of 34 in each group, yielding 80% power to detect a difference in group means of 3.  This assumed a 
common standard deviation of 4.3 and was based on a two-group t-test with a significance level of 0.05. 
 


Because of the protracted study time and change in pain management practice to the benefit of the 
patients, we concluded this clinical trial at 51 patients (CONSORT Flow Diagram).      
 A biostatistician performed statistical analysis on this trial. Descriptive statistics were generated, 
including 95% confidence intervals (CI).  The caffeine/experimental and control groups were compared 
using independent samples t-tests for continuous variables and Fisher’s Exact tests for categorical 
variables.  Statistical analyses were performed using SAS v 9.4 (SAS Institute, Inc., Cary, NC) with a 
significance level set at 0.05. 
Results 
There were 24 patients in the caffeine group (mean 14.3+/-1.5 years, 91.7% female) and 27 in the 
control group (mean 14.8+/- 1.4 years, 88.9% female).  Patient demographic variables are shown in 
Table 2.   There were no differences in patient demographic variables between groups.  The mean 
number of levels fused were similar between groups (caffeine: 9.9 vs 10.5; P=0.28) with comparable 
operative times (caffeine: 231 minutes vs 246 minutes; P=0.25). The total cohort had an average 
hospital LOS of 2.5 days.  There were no documented complications, adverse events, or adverse drug 
reactions related to caffeine usage in this study.  Only one patient developed a complication following 
surgery, a superficial wound dehiscence that was successfully treated without surgical intervention. 
There were no unplanned reoperations in either study group.  
 
Comparison of Primary Outcome Measures 
The mean length of stay was comparable between study groups with 50% (N=12) of caffeine patients 
and 55.6% (N=15) being discharged home on postoperative day (POD) 2 (Table 3).  Mean daily VAS pain 
scores were statistically similar between study groups as well as the mean daily VAS score with slightly 
lower pain scores in the caffeine cohort.  Postoperative mean total oral opioid usage (measured in 
Table 2: Demographic, Clinical, and Surgical Characteristics of the Caffeine and Control 
Groups 
Demographics 
n 
Caffeine 
n 
Control 
p-
value 
95% CI 
mean (sd) 
mean (sd) 
Female, n (%) 
24 
22(91.7) 
27 
24 (88.9) 
1.00 
  
Race, n (%) 
24 
  
26 
  
0.24 
White 
  
20 (83.3) 
  
19 (73.1) 
  
Black 
  
0 (0) 
  
3 (11.5) 
  
Hispanic 
  
1 (4.2) 
  
3 (11.5) 
  
Other 
  
3 (12.5) 
  
1 (3.9) 
  
Age 
24 
14.25 (1.5) 
27 
14.81 (1.4) 
0.16 
-0.23 - 1.36 
Weight 
24 
53.80 (8.2) 
27 
54.72 (7.1) 
0.67 
-3.38 - 5.21 
Any Complications 
24 
0 (0) 
26 
0 (0) 
 
Operative Time (minutes) 
24 
230.92 (49.6) 
27 
246.15 (43.4) 
0.25 
-10.93 - 41.40 
Number of Segments Fused 
24 
9.92 (2.1) 
27 
10.52 (1.9) 
0.28 
-0.51 - 1.71 
Patient data was segmented into subgroups to enable a detailed analysis. These demographic subgroups 
were the following defined metrics: sex, race, age, complications, duration of operative time, estimate of 
intraoperative blood loss and spinal segments fused.  
 


MME) had lower usage in the caffeine cohort for POD1 but there were no significant differences 
between study groups (caffeine 18.6 vs control 21.6, P = 0.19).  After standardizing opioid usage for 
patient weight (MME/kg), there was decreased mean oral opioid usage in the caffeine study group for 
POD1 (caffeine 0.35 vs control 0.40, P = 0.19) and mean daily total oral opioid usage over the hospital 
stay (caffeine 0.32 vs control 0.37, P = 0.1), but these differences were not statistically significant (Figure 
1).  The mean total oral MME/kg for the hospital stay was 0.83 for the caffeine group and 0.92 in the 
control group, P=0.40.  Utilizing the Mann-Whitney test, median oral MME/kg for the hospital stay was 
0.74 in the caffeine group and 0.90 in the control group (difference 0.16).  In assessing the mean total 
oral MME usage of the hospital stay, the caffeine cohort had 5 MME less total opioid consumption 
(caffeine 45.0 vs control 50.6, P = 0.38, Table 3). 
Table 3: Summary of Primary Outcomes Variables, Subdivided by Study Group. 
 
Caffeine (Mean) 
N=24 
Control (Mean) 
N=27 
 
P-Value 
Length of Stay (days±SD) 
2.53±0.6 
2.47±0.5 
 
0.68 
VAS Pain (±SD) 
POD1 
POD2 
POD3 
 
3.2±1.6 
3.38±1.7 
3.8±1.2 
 
3.27±1.6 
3.5±1.5 
3.8±1.2 
 
0.54 
0.74 
0.92 
Mean Daily VAS (±SD) 
3.33±1.65 
 
3.51±1.48 
 
0.69 
 
Total Opioid Usage (MME) 
POD1 
POD2 
POD3 
 
18.6 
20.3 
13.75 
 
21.6 
22.5 
13.9 
 
0.19 
0.48 
0.89 
 
Total Opioid Usage (MME) 
for Hospital Stay 
 
45.0 
 
50.6 
 
 
0.38 
Total MME/kg for Hospital 
Stay 
0.83 
0.92 
0.40 
• 
SD- standard deviation; MME=morphine milliequivalent; VAS=visual analog pain score 
‘ 
 
 
 
 
 
 
 


Figure 1. Graphic Summary of Narcotic Usage, Measured in Morphine 
Milliequivalents/Kilogram (MME/Kg), Subdivided by Study Group Over 
Various In-Hospital Time-Points. 
*MME= morphine milligram equivalents.  Mean MME/kg in each group for postoperative days 1, 2 
and 3.  The last column is the total MME/KG/Day for each group.  The caffeine group had 5 MME less 
opioid use, the equivalent of 5 mg of hydrocodone. 
 
Secondary Outcome Variables 
 Caffeine usage was not associated with an elevation in heart rate or blood pressure but there was a 
decrease in mean heart rate for POD2 (caffeine:77.5±10.4 vs control 84.6±13.9; P=0.04) (Table 4).  
Additionally, there were no differences in the mean number of diazepam requests between study 
groups (caffeine:1.15±0.7 vs control:1.13±0.7; P=0.9) 
Table 4.  Summary of Mean Blood Pressure and Heart Rate Between Study 
Groups in the Acute Postoperative Period. 
 
POD 1 
POD2 
POD3 
Mean for 
Hospital Stay 
Heart Rate (bpm +/- SD) 
 
 
 
 
Caffeine 
83.0 (14.6) 
77.5 (10.4) 
76.0(8.7) 
78.8 (10.3) 
Control 
85.1 (12.8) 
84.6 (13.9) 
79.3 (13.8) 
83.8 (12.4) 
P-Value 
0.59 
0.04 
0.48 
0.12 


Systolic Blood Pressure 
(mmHg  +/- SD) 
 
 
 
 
Caffeine 
98.2 (7.6) 
97.2 (6.2) 
101.7 (11.6) 
98.3 (6.5) 
Control 
103.1 (8.7) 
98.8 (13.9) 
101.3 (5.7) 
101.4 (6.6) 
P-Value 
0.04 
0.44 
0.92 
0.09 
* POD=Postoperative day; bpm=beats per minute; SD=standard deviation