This study will be performed in the emergency department (ED) of Shanghai Jiaotong
University Affiliated Sixth People's Hospital in China. This hospital is a tertiary
and teaching hospital that receives approximately 350,000 ED visits annually. The
study was approved by the Ethics Committee of Shanghai Jiaotong University Affiliated
Sixth People’s Hospital. And we used the SPIRIT reporting guidelines, as Figure 1
This study is a single center, double-blinded randomized controlled trial. Figure 2 shows how participants eligible for this trial flow through the study from
recruitment to follow-up. Adult patients with a single acute limb fracture occurring less than one day after
injury and who are indicated for nonoperative treatment will be recruited. They will
be randomly assigned to either the intervention or control group. The intervention
group will receive oral pills of oxycodone (5 mg)/acetaminophen (325 mg), and the
control group will receive pills of acetaminophen (650 mg) only.
The primary outcome measure will be the 11-point Numeric Rating Scale (NRS-11). Secondary outcomes include Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), EuroQol five-dimension questionnaire (EQ-5d), self-rated satisfaction with the analgesia produced by the intervention or control
medication (scale of 0-10), self-reported nighttime sleeping duration, total number
of analgesic intervention or control pills used during the trial, total duration for
taking intervention or control medication. Any remaining analgesic medications will
be collected by the researchers at the end of the trial. Demographic information will
be collected from the medical record.
Adult participants will be recruited prospectively and sequentially as they are admitted
to the ED of Shanghai Jiaotong University Affiliated Sixth People's Hospital. Informed
written consent will be obtained from all participants. All methods and procedures
in this study are in accordance with the Declaration of Helsinki.
Male and female patients, 18 to 100 years old, will be candidate participants. We
will include patients who have an acute limb fracture diagnosed less than one day
after injury. Eligible locations of fractures include foot, ankle, tibia, fibula,
knee, femur, hip, hand, wrist, forearm, elbow, humerus, shoulder, or clavicle. All
candidate participants indicated for nonoperative treatment and be willing to participate
in this study will be enrolled.
Patients with non-limb fractures will be ineligible, or similarly, those who have
multiple fractures involving more than one site. Also, patients with vascular, nerve,
or tendon injuries, and open fractures will be excluded. Patients with a pre-injury
chronic condition requiring frequent pain management such as sickle cell disease,
fibromyalgia, or any neuropathy are not eligible, as are those who have taken methadone
at any time in their life. Patients who are pregnant, verified by urine or serum HCG
testing, will be excluded. Patients who report any adverse reaction or who are allergic
to any of the study medications will be dropped from the study. Patients who have
contraindications, such as peptic ulcer disease, or who report any prior use of recreational
narcotics will be excluded.
Additional exclusion criteria are as follows: medical conditions that might affect
metabolism of opioid analgesics or acetaminophen, such as hepatitis, renal insufficiency
or failure, hypo- or hyperthyroidism, and Addison’s or Cushing’s disease; taking any
medicine that might interact with any of the study medications, such as anticholinergic
drugs, oral contraceptives, loop diuretics, probenecid, or liver enzyme inducers;
unable to communicate properly and answer questions (e.g., patients with a diagnosis
of dementia); physically handicapped people with mobility problems; people with no
fixed domicile and short-term visitors who cannot be easily located; people unwilling
or unable to cooperate with data collectors or researchers.
Randomization and blinding
Stratified blocked randomization will be used to group the participants randomly.
The fracture site will be a stratification factor, with the following blocks: (1)
foot, ankle, tibia, or fibula; (2) knee, femur, or hip; (3) hand; (4) wrist or forearm;
(5) elbow or humerus; (6) shoulder or clavicle. The randomization will be carried
out by an independent research assistant, who will not be involved in the enrollment, intervention, assessment of the participants,
or data analysis. 1226 unique eight-digit random numbers will be generated for each
group (total of 6 groups) by SAS® V.9.4 software. The participants will be assigned randomly to two groups (A and B)
in a 1:1 ratio according to the designated interval (only the research assistant will
know the interval), and the 1226 random numbers will be assigned randomly to the members
of each group. Patients of each group will be further categorized according to fracture
site, and then the assignments will be documented. These 6 documents (also referred
to as the blinding code) contain the participants’ serial numbers (according to their
order of enrollment), random number sequences, and study group assignment; these will
be recorded in duplicate and submitted to the clinical research-responsible unit and
the research assistant for secure storage. Simplified versions of these documents that do not contain the study group will serve
as a reference for allocating study medications to participants.
Each study drug package contains one bottle, and each bottle contains 20 tablets of
either oxycodone/acetaminophen or acetaminophen tablets (according to the blinding code). The immediate release oxycodone will be used in this study. The drugs will be contained within identical unmarked, opaque gel capsules. The capsules
will be topped up with small quantities of lactose to equalize the weight of the capsules.
The shape of the outer packaging and the bottle is exactly the same. A random number
sequence will be attached to the outer packet, and there will be a sealed opaque envelope attached (which is called “emergency
letter”), which contains study group allocation and medication type contained within
the packet. In the event of an emergency, serious adverse reaction, or if the participant
needs to know what kind of treatment he/she is receiving, researchers and the participant
can obtain the information from the emergency letter. If the seal to the emergency
letter is opened and letter is read, the participant will be excluded from the trial.
After data collection is completed, a two-step method is used to reveal group membership.
The first step lists only the treatment group to which each participant belongs (such
as group A or B), but does not indicate which group is the intervention group or the
control group. The second step reveals the treatment received by groups A and B, and
which group is the control group. Statistical data analyst will also be blinded to
After recruitment, each participant will receive a bottle of tablets according to
the random number sequence. The outer package marked with the random number will be
tagged with the subject’s serial number, which will be securely stored by researchers
for 14 days until the participant’s trial is completed.
All participants will be instructed to take one pill of study medication on an as-needed
basis, but to take it no more frequently than once every 4 hours. Any analgesic other than unblinded oxycodone which is administered as a rescue analgesic,
is prohibited during the trial. We will complete his/her follow-up unceasingly once a participant took a rescue analgesic,
and some extra outcomes including the number of rescue analgesic used and total duration
for taking this medication will be recorded. Participants will be encouraged to complete follow-ups, and they will have access
to the research team anytime to discuss any issues or concerns during the trial. It
will be explained to them that they can discontinue the intervention at any time during
the trial. Demographic information of participants who withdraw from the study after
randomization and their reasons for withdrawal will be collected.
Pain intensity will be assessed by an 11-point numeric rating scale (NRS-11), where
“0” is no pain and “10” is worst possible pain imaginable. Administration of the NRS-11
can be conducted over the phone or in person by a hospital staff data collector. By
contrast, VAS scoring can be administered only during in-hospital visits. The NRS-11
is as effective as the VAS in assessing acute pain.
Anxiety, depression, and health status and quality of life will be assessed with the
following assessment tools. The Self-Rating Anxiety Scale (SAS) is a 100-point test
(20 items) that assesses the degree of anxiety. A higher score means greater anxiety.
The Self-Rating Depression Scale (SDS) is also a 100-point test (20 items). It assesses
the degree of depression. A higher score means that the patient is more depressed.
The EuroQol (EQ-5d) is a health description questionnaire that assesses health status
and quality of life. It contains two questionnaires comprising five dimensions (mobility,
self-care, usual activities, pain/discomfort, and anxiety/depression). Along with
the EQ-VAS, EQ-5d can evaluate patients’ health status and quality of life.
The primary outcome will be the between-group difference in decline in NRS pain scores
from the baseline to 1, 3, 7, and 14 days after randomization. Secondary outcomes
include the between-group difference in change in scores on the SAS, SDS, and EQ-5d from the baseline to 14 days after randomization, and on a custom in-house developed question on the patient’s satisfaction with the medication (0-10) at 14 days after randomization. For the latter, “0” is very dissatisfied and “10”
is very satisfied. Other secondary outcomes are the between-group difference in change
in the quality and duration of sleep, number of study medications used, duration that analgesics were taken, and adverse events.
The Additional file 1 presents a complete summary of data collected during the trial. Baseline information
will be obtained from the participant, including demographic characteristics, sleep
quality during the most recent month at the follow-up, and past medical history before
he or she is recruited. General medical examinations will be also conducted by the
researcher. The results of the NRS scores will be reported by participants at 0, 1,
3, 7, and 14 days after randomization. The SAS, SDS, and EQ-5d questionnaires will
be completed by participants at 0 and 14 days after randomization during in-hospital
visits. A nighttime sleeping diary will be recorded by the participants, and then
submitted to researchers at 14 days after randomization too. Participants will record
the number and the times that analgesic drugs were taken. Adverse events will also
be recorded throughout this trial. At the end of trial, we will ask participants which
analgesic drugs they believe they took and record it.
The sample size was calculated by using the following parameters. An overall 2-sided
significance level of 0.05, power of 90% will be calculated. In line with previous
studies, only if the between-group change difference of NRS scores is reached 1.3
unit or great, it seems as clinically significant in pain, and the standard deviation of the difference in NRS scores between the two groups
was 6.4 points from our prior work. Using these parameters, we calculated a primary
sample size of 511 patients per group, giving a total of 1022 patients. Taking into
account factors like patients loss-to-follow-up and participant withdrawal during
the trial, it is reasonable to increase the sample size by 20%. Therefore, a total
number of 1226 participants will be recruited.
All analyses will be carried out using SPSS V.16.0 (SPSS Inc. Released 2007. SPSS
for Windows, Version 16.0. Chicago, SPSS Inc). We will perform an intention-to-treat analysis including all randomized participants, whether or not they obeyed the allocation. Baseline characteristics will be summarized by treatment
groups. The results from the trial will be presented as comparative summary statistics
(difference in proportions or means), with 95% CIs.
Changes in NRS pain scores (primary outcome); SAS, SDS, and EQ-5d scores; sleep loss;
and the number of times analgesic drugs were taken in the two groups will be compared
with t-student tests, according to their respective fracture site. The incidence of
adverse events in the two groups will be presented as proportions and will be compared
using χ2/Fisher’s exact test.
Safety and adverse event reporting
We will record all adverse events observed by researchers or participants that occurs
within the14 days of randomization, whether they could be related to the study medication
or not. Once adverse events occur, participants will cease study medications and we
will try our best to collect their data. If serious adverse events occur, the investigator
will complete the serious adverse event report form (SAE) immediately, and inform the research group within 24 hours. If
it isn’t a life-threating event and is thought to be an accident related to the study
medication, we will notify the research ethics committee (REC) within 15 days. The research ethics committee will be notified within 7 days
for a life-threatening event. All these adverse events will be reported to the ethics
review committee at the next meeting. All participants who experienced adverse events
will be followed up until the end of the trial.
Patient and public involvement
In a pilot study, we selected patient representatives to help develop and refine our research project. Because of their complaints about
the obvious deterioration of sleep after a fracture, we added “change of sleep quality
and duration” as an indicator to evaluate it as a contributor to analgesic efficacy.
The idea of treating the fracture sites as a stratification factor also came out of
the pilot study.