PAin SoluTions In the Emergency Setting (PASTIES)—patient controlled analgesia versus routine care in emergency department patients with non-traumatic abdominal pain: randomised trial

Study design

The study comprised two contemporaneous multicentre, open label, randomised trials of PCA versus routine care. Patients presenting to the emergency department requiring intravenous analgesia and admission to hospital, with either traumatic musculoskeletal injury or non-traumatic abdominal pain, were potentially eligible for inclusion. Key outcome measures were collected at baseline and then hourly for 12 hours. Although two separate trials were completed (one of patients presenting with traumatic musculoskeletal injuries, the other of patients with non-traumatic abdominal pain), both were based on the same protocol, which is outlined briefly below. Nevertheless, we have considered them as two separate trials because they were powered separately. This paper reports the trial of patients with non-traumatic abdominal pain.

Participants

Eligible patients were adults presenting to the emergency department with non-traumatic abdominal pain requiring intravenous opioid analgesia and hospital admission for at least 12 hours from the time of enrolment. We excluded patients with chronic pain and those with opiate tolerance; a full list of exclusion criteria is available in table 1 of the protocol paper.22 Study participants were patients who met the eligibility criteria and were willing and able to give informed consent.

Study recruitment

Patients underwent initial assessment and management, including initial pain relief, according to local policy. A research nurse screened patients on their arrival at the emergency department. After initial assessment and pain management, a research nurse approached them and gave them an information sheet detailing the study. If patients were happy to discuss the study further, any questions were answered at this stage. Patients were then fully assessed against the inclusion and exclusion criteria before written informed consent was obtained from those who were willing and able to participate. Patients who declined to take part were not obliged to give a reason, but the research nurse recorded any reasons given.

Study procedures and data collection

After informed consent was obtained, the first study pain score was recorded using a visual analogue scale, and the participant was randomised (using a secure web based randomisation system) to receive either PCA or routine care.

Participants in both groups then received instructions on how to complete subsequent visual analogue scale scores, which were entered into a mini flipchart (the participant was instructed to turn the page of the flipchart after an entry was made, so the previous score was not visible for comparison). Participants were asked to record their pain scores on deep breathing. Electronic timers (Casio F-91W digital watches) issued a bleep every hour as a reminder to the participant to complete the hourly score, but this bleep was not typically loud enough to wake the participant from sleep. The visual analogue scale was presented as a 10 cm horizontal line with verbal anchors at each end of “no pain” and “worst pain possible.” Participants were instructed to select the point along the line (and mark this point with a pen with a single vertical line) that reflected their current pain perception. Participants recorded visual analogue scale pain scores at 60 minute intervals over a 12 hour period. Participants were also instructed on how to record periods asleep, retrospectively, on the booklet by using a tick box on each page.

Most other outcome data were collected for 12 hours from the point at which the first study pain score was completed. Opioid use was recorded from the prescribed drugs administered as recorded on the patient’s drug chart during the study period (including that prescribed pre-admission). We used study observation charts, based on standard hospital charts, for all study participants; these were completed as part of routine care by emergency department nurses in the emergency department and then by ward nurses after inpatient ward admission. Observations followed the standard of care in each centre. Typically, this involved observations hourly for four hours, two hourly for eight hours, and four hourly thereafter. In practice, this meant hourly vital signs in the emergency department and two hourly vital signs for the rest of the study period. Observations included heart rate, blood pressure, respiratory rate, oxygen saturations, oxygen flow rate, sedation score, and nausea score (0-2). A research nurse reviewed the observation charts after the 12 hour study period and transcribed out of range results into the study case report form.

Where possible, at the end of the 12 hour study period (or the following morning as appropriate), a research nurse visited participants in both groups to facilitate collection of study data. The final page of the data collection booklet included a five point pain management satisfaction score ranging from “perfectly satisfied” to “not satisfied at all.” Following the participant’s discharge, the research nurse obtained the length of stay in hospital and final diagnosis at discharge from the patient administration system (or equivalent) and recorded them in the case report form.

Interventions

Participants allocated to receive routine care were prescribed intravenous morphine while in the emergency department and oral morphine (or subcutaneous/intramuscular for those nil by mouth) when transferred to the hospital ward. Participants randomised to the PCA group received instruction from the research nurse in how to operate the PCA device, which was set up by the emergency department nurses and started with a 1 mg morphine bolus and a five minute lockout. PCA was continued for a minimum period of 12 hours; in practice, the clinical team reviewed ongoing requirement for PCA the following morning. Participants in both groups were prescribed multi-modal analgesia in addition, including paracetamol and a non-steroidal anti-inflammatory drug (unless contraindicated), and were also prescribed antiemetics as required.

Primary outcome measure

The primary outcome measure was the total pain experienced over the 12 hour study period, as captured by the hourly completion of a visual analogue pain rating scale. We derived this by plotting data as a graph of visual analogue scale pain against time and calculating the area under the curve for each participant. This is a measure of overall pain experienced during the study period.23

Secondary outcome measures

Secondary outcome measures included total opioid dose, out of range vital signs, patients satisfaction with pain management, proportion of study period in moderate/severe pain (that is with visual analogue scale >4.4 cm), proportion of study period spent sleeping, and length of hospital stay.

Randomisation, allocation concealment, and blinding

Randomisation (one to one) to either PCA or routine care was done via a secure web based randomisation system. Research team members accessing the randomisation website did not know the allocation for an individual patient until the relevant details were entered and recruitment confirmed.

As pain experience over subsequent hours may be affected by the time of day of recruitment (those starting the trial later in the day would be scoring their pain during night hours when they may spend a greater proportion of time asleep), randomisation was stratified by time of the first recorded pain score (morning or afternoon/evening), as well as by recruitment centre. Blinding was not possible for this study owing to the nature of the intervention.

Sample size

We derived the primary outcome by plotting data as a graph of visual analogue scale pain against time and calculating an area under the curve for each participant. This is a measure of overall pain experienced during the study period.23

Very few studies have considered the question of what reduction in area under the curve might be a clinically significant analgesic effect. One study by Camu et al showed that a 20% reduction in the area under the curve for pain on movement was associated with a 26% absolute increase in the proportion of patients reporting their global rating of pain relief as very good or excellent (P=0.01).24 Conservatively, therefore, we chose a difference in area under the curve of 15% between PCA and routine care groups as being of clinical significance. On a standardised area under the curve (scoring between 0 and 100), we expected the routine care group to have an average score of about 40 units, so 15% equates to a six point reduction. A standard deviation can be estimated from the research by Camu et al as about 15 units. On the basis of these assumptions, and using a two tailed, two sample t test, with a type 1 error rate of 0.05, a sample size of 100 patients per group provides sufficient power (80%) to detect a between group difference of 15%.

Statistical analyses

We report and present data according to the relevant CONSORT statement.25 The primary analyses were all pre-specified in a detailed statistical analysis plan approved by the Data Monitoring Committee before the analyses started. They followed an intention to treat approach, with the intent to treat population defined as all participants who completed the baseline and at least one subsequent pain visual analogue scale. Primary analyses were adjusted for the stratification factors (centre and time of baseline pain score (morning or afternoon/evening)) as fixed effects; we also present unadjusted analyses. We present 95% confidence intervals for between group differences, with the significance level for hypothesis testing set at 5%.

We used the area under the curve approach to capture the primary outcome measure of total pain experienced and compared it between PCA and routine care groups by using analysis of covariance, including the two stratification variables and the baseline pain score as covariates. We did this analysis blinded to the allocated group. We calculated the area under the curve by using the “trapezoidal” rule, using straight lines to join visual analogue scale scores and calculating the area under them for the 12 hour period. In general, where one or more hourly pain scores were not recorded, we imputed values by linear interpolation if scores were recorded either side and by last observation carried forward if scores were missing at the end of the 12 hour period, except that such final scores were recorded as zero if the participant was discharged (or self discharged). These conventions were agreed with the Trial Steering Committee and Data Monitoring Committee in a detailed strategy; a member of the Trial Management Group, blinded to participants’ allocated group wherever possible, categorised reasons for missing data.

We similarly compared continuous secondary outcomes between the two groups by using analysis of covariance, with adjustment for the two stratification variables. Given that some visual suggestion of potential violations of the linear model assumptions existed, we also produced bootstrapped confidence intervals for the between group differences for each outcome measure. In each instance, little difference existed between the normal based and bootstrapped confidence intervals; for simplicity, we present only the normal based confidence intervals.

For the analysis of participants’ satisfaction with pain management, we recoded the five point scale (ranging from “perfectly satisfied” to “not at all satisfied”) into two categories, combining “perfectly satisfied” and “very satisfied” into one category and the others into a second category. We used binary logistic regression to determine the odds ratio and 95% confidence interval for the group effect, with adjustment for the stratification variables.

Sensitivity analyses

We did two pre-specified sensitivity analyses of the primary outcome measure: the first scored pain as zero for periods of sleep (sensitivity 1); the second imputed missing pain scores due to transfers to theatre by using linear interpolation from the last recorded pain score to zero at the 12 hour time point (sensitivity 2).

At the request of the Data Monitoring Committee, we also did two further sensitivity analyses. The first of these included the data from the four participants in the hospital that was excluded in the primary analyses (see below; sensitivity 3). The second excluded 35 participants whose baseline pain score seemed to be recorded after randomisation. Data validation checks showed this possibility for some patients, although verification was not straightforward as different sources were used to record the times of baseline pain score and randomisation. We considered that if the baseline pain score had a recorded time of more than five minutes after the recorded time of randomisation, this probably indicated that the score was recorded after randomisation; these are the 35 cases that were excluded in sensitivity 4.

Patient involvement

During the design of this study, a patient representative contributed to the development of the grant application and, later, to the study protocol and participant facing documentation after funding had been awarded. We also had a patient representative on the Trial Steering Committee, who helped to oversee progress of the trial and provided a patient’s perspective on aspects of trial conduct. A lay summary of the study findings will be made available to participants at www.medicalresearchplymouth.org.uk.