Plain English Summary
Background and study aims
Pain in babies has negative consequences, both immediately and in the longer term. As babies cannot describe their pain the measurement and treatment of pain is difficult and, compared to adults and older children, pain is undertreated in this group. Given that a baby requiring intensive care will experience an average of 12 painful procedures per day and, the youngest and sickest babies may experience 50 procedures per day, this is a serious clinical issue that urgently needs to be addressed. The aim of this study is to test whether morphine can provide effective pain relief in babies during invasive medical procedures. While morphine is frequently given to adults when they experience pain, it is not known whether morphine provides effective pain relief for acute pain in babies. An example of a painful procedure that is frequently and regularly performed on premature babies is an eye exam that tests for Retinopathy of Prematurity – this is a disease which if untreated can lead to permanent blindness. Although the exam is considered to be painful and can result in unstable breathing and heartbeat for up to 24 hours after the exam, the pain relief currently provided during this procedure has limited efficacy. Here, we want to see if morphine can provide effective pain relief for babies undergoing this exam.
Who can participate?
Infants that were born at less than 32 weeks gestation or with a birth weight or less than 1501g. They must be in-patients at the John Radcliffe Hospital in Oxford and be between 34-42 weeks gestational age when undergoing the test.
What does the study involve?
Participants are randomly allocated into one of two groups. Those in group 1 are given morphine during an eye exam testing for Retinopathy of Prematurity. Those in group 2 are given a placebo during the same procedure. Clinical pain assessment tools are used to measure pain experienced. Newly developed brain imaging techniques are also used to see how morphine can affect pain related brain activity.
What are the possible benefits and risks of participating?
We cannot guarantee any direct benefits. At present we don’t know whether giving a pain relieving medication (morphine) reduces the pain and discomfort caused by eye exams and blood tests. We are carrying out this study to help doctors make the right decisions about the care of preterm babies in the future. Morphine is a pain-relieving drug that is routinely used in children and adults to treat acute pain. Morphine is routinely used in the neonatal unit to sedate babies when they are ventilated, although to-date few studies have been carried out where morphine has been administered to babies to provide pain relief prior to invasive procedures. The dose of morphine (100 μg/kg) will be administered by mouth and has been approved by the neonatal pharmacist. Although morphine can have effects on breathing rate and blood pressure, a study that used twice this dose did not report any adverse side effects. We do not anticipate that the babies will experience these side effects and they will be monitored very closely by the staff on the neonatal unit
Where is the study run from?
John Radcliffe Hospital, Department of Paediatrics (UK)
When is the study starting and how long is it expected to run for?
January 2015 to November 2019
Who is funding the study?
1. National Institute for Health Research, EME (UK)
2. Wellcome Trust (UK)
Who is the main contact?
Dr Rebeccah Slater
Trial website
Additional identifiers
EudraCT number
2014-003237-25
ClinicalTrials.gov number
Protocol/serial number
19317
Study information
Scientific title
A blinded randomised placebo controlled trial investigating the efficacy of morphine analgesia for procedural pain in infants
Acronym
POPPI: procedural pain in premature infants
Study hypothesis
The aim of this study is to test whether morphine can provide effective pain relief in babies during invasive medical procedures.
Ethics approval
The Northampton Research Ethics Committee, 23/07/2015, ref.: 15/EM/0310
Study design
Blinded, placebo-controlled, parallel-group randomised clinical trial
Primary study design
Interventional
Secondary study design
Clinical trial of an investigational medicinal product (CTIMP)
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use contact details to request a participant information sheet
Condition
Topic: Children; Subtopic: Pain
Intervention
As of 02/09/2016:
1: Morphine Sulphate: 10ml of the IMP will be supplied in amber glass bottle at a concentration of 200 μg/ml. This will provide a dose of 100 μg/kg which will be administered orally by sterile oral/enteral 3ml syringe.
2: Placebo (inactive solution): The placebo (inactive solution) will be supplied in identical packaging but will contain only the carrier solution.
Study Entry: Single Randomisation only
Initial:
1. Morphine Sulphate: 2 ml of the IMP will be supplied at a concentration of 200 µg/ml. This will provide a dose of 100 µg/kg which will be administered orally by syringe
2. Placebo (inactive solution): The placebo (inactive solution) will be supplied in identical syringes but will contain only the carrier solution
Study Entry : Single Randomisation only
Intervention type
Other
Phase
Phase II
Drug names
Primary outcome measure
Current as of 04/02/2016:
1. Clinical pain score measured using the Premature Infant Pain Profile-revised (PIPP-R) 30 seconds after ROP screening
2. Magnitude of nociceptive-specific brain activity evoked by heel lance
Previous:
1. Clinical pain score measured using the Premature Infant Pain Profile (PIPP) 1 minute after ROP screening
2. Magnitude of nociceptive-specific brain activity evoked by heel lance
Secondary outcome measures
Current as of 04/02/2016:
1. Clinical stability in the 6-hour and 24-hour period following the start of the clinical intervention. The clinical intervention is defined as the heel lance followed by rhe ROP screening.
2. Premature infant pain profile-revised (PIPP-R) score and amplitude of nociceptive reflex withdrawal activity following heel lance
3. Drug safety will be assessed by calculating the number of incidences of apnoea that require intervention using NeoPuff or ‘bag and mask’ and the number of incidences of hypotension that require treatment with inotropes in the 24-hour period following the administration of the IMP or placebo.following ROP screening
Previous:
1. Clinical stability in the 6-hour and 24-hour period after ROP screening
2. Premature infant pain profile (PIPP) score and amplitude of nociceptive reflex withdrawal activity following heel lance
3. Drug safety will be assessed by calculating the number of incidences of apnoea that require intervention using NeoPuff or ‘bag and mask’ and the number of incidences of hypotension that require treatment with inotropes in the 24-hour period following ROP screening
Overall trial start date
01/01/2015
Overall trial end date
01/11/2019
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Participants will be in-patients on the neonatal unit at the John Radcliffe Hospital, Oxford
2. Infants born less than 32 weeks’ gestation or birth weight <1501 g
3. At the time of study, infants will be between 34 and 42 weeks gestational age (GA) and will be studied if they require a clinical heel lance and retinopathy of prematurity (ROP) screening on the same test occasion. We will study infants during a single ROP examination when they are greater than or equal to 34 weeks’ gestation
4. Infants for whom parents/guardians have consented to inclusion in the trial.; Upper Age Limit 42 weeks
Lower Age Limit 34 weeks
5. Senior clinician considers inclusion in trial to be medically appropriate (added 04/02/2016)
Participant type
Patient
Age group
Child
Gender
Both
Target number of participants
Planned Sample Size: 156; UK Sample Size: 156
Participant exclusion criteria
1. Intraventricular haemorrhage > grade II
2. Short bowel syndrome
3. Receiving nil by mouth due to documented gut pathology
4. Received opiates in the last 72 hours
5. Received other analgesics or sedatives in the last 24 hours
6. Previously documented episode of morphine sensitivity
7. Congenital malformation or genetic condition known to affect neurological development
8. Senior clinician considers inclusion in trial to be medically appropriate
9. Born to mothers who regularly use opiates during pregnancy or while breastfeeding or expressing breast milk
Recruitment start date
01/09/2016
Recruitment end date
01/06/2019
Locations
Countries of recruitment
United Kingdom
Trial participating centre
John Radcliffe Hospital
Department of Paediatrics
University of Oxford
Level 2, Children's Hospital
Oxford
OX3 9DU
United Kingdom
Funders
Funder type
Government
Funder name
National Institute for Health Research, EME
Alternative name(s)
NIHR
Funding Body Type
government organisation
Funding Body Subtype
Federal/National Government
Location
United Kingdom
Funder name
Wellcome Trust
Alternative name(s)
Wellcome
Funding Body Type
private sector organisation
Funding Body Subtype
international
Location
United Kingdom
Results and Publications
Publication and dissemination plan
The plan to publish the results of the study in a peer-reviewed medical journal after we have acquired and analysed the data.
Intention to publish date
01/11/2019
Participant level data
Not expected to be available
Basic results (scientific)
Publication list
2016 protocol: http://www.thelancet.com/doi/story/10.1016/html.2016.01.19.2536