Analgesic efficacy and safety of morphine in the Procedural Pain in Premature Infants (Poppi) study: randomised placebo-controlled trial

Abstract

SummaryBackgroundInfant pain has immediate and long-term effects but is undertreated because of a paucity of evidence-based analgesics. Although morphine is often used to sedate ventilated infants, its analgesic efficacy is unclear. We aimed to establish whether oral morphine could provide effective and safe analgesia in non-ventilated premature infants for acute procedural pain.MethodsIn this single-centre masked trial, 31 infants at the John Radcliffe Hospital, Oxford, UK, were randomly allocated using a web-based facility with a minimisation algorithm to either 100 μg/kg oral morphine sulphate or placebo 1 h before a clinically required heel lance and retinopathy of prematurity screening examination, on the same occasion. Eligible infants were born prematurely at less than 32 weeks' gestation or with a birthweight lower than 1501 g and had a gestational age of 34–42 weeks at the time of the study. The co-primary outcome measures were the Premature Infant Pain Profile–Revised (PIPP-R) score after retinopathy of prematurity screening and the magnitude of noxious-evoked brain activity after heel lancing. Secondary outcome measures assessed physiological stability and safety. This trial is registered with the European Clinical Trials Database (number 2014-003237-25).FindingsBetween Oct 30, 2016, and Nov 17, 2017, 15 infants were randomly allocated to morphine and 16 to placebo; one infant assigned placebo was withdrawn from the study before monitoring began. The predefined stopping boundary was crossed, and trial recruitment stopped because of profound respiratory adverse effects of morphine without suggestion of analgesic efficacy. None of the co-primary outcome measures differed significantly between groups. PIPP-R score after retinopathy of prematurity screening was mean 11·1 (SD 3·2) with morphine and 10·5 (3·4) with placebo (mean difference 0·5, 95% CI −2·0 to 3·0; p=0·66). Noxious-evoked brain activity after heel lancing was median 0·99 (IQR 0·40–1·56) with morphine and 0·75 (0·33–1·22) with placebo (median difference 0·25, 95% CI −0·16 to 0·80; p=0·25).InterpretationAdministration of oral morphine (100 μg/kg) to non-ventilated premature infants has the potential for harm without analgesic efficacy. We do not recommend oral morphine for retinopathy of prematurity screening and strongly advise caution if considering its use for other acute painful procedures in non-ventilated premature infants.FundingWellcome Trust and National Institute for Health Research.

Multimodal pain assessment improves discrimination between noxious and non‐noxious stimuli in infants

“…While this time window may not be appropriate for longer procedures, and consideration of other non‐noxious control stimuli is needed, using a data‐driven approach such as the one used here may identify features within physiological responses which are accurate surrogate measures of infant pain. Moreover, in the case of clinical trials of analgesics, including multiple modalities is beneficial in the assessment of safety, as well as efficacy, of a drug …”

“…While this time window may not be appropriate for longer procedures, and consideration of other non-noxious control stimuli is needed, using a data-driven approach such as the one used here may identify features within physiological responses which are accurate surrogate measures of infant pain. Moreover, in the case of clinical trials of analgesics, including multiple modalities is beneficial in the assessment of safety, as well as efficacy, of a drug 41,42. Here, we considered responses to a clinically required heel lance and compared them to responses to a non-noxious control stimulus.These stimuli were closely matched, allowing us to identify features that could discriminate the noxious component of the procedure.…”

A Critical Review on the Relevance of Paracetamol for Procedural Pain Management in Neonates

“…However, as mentioned earlier, in the POPPI study, oral morphine (100 µg/kg) was associated with either a higher incidence of newly occurring apneic events or an increase in the number of such events in the morphineexposed group. Because of these safety-related findings (sufficient evidence of harm), the POPPI study was terminated early (10). Based on the currently available evidence, it seems that a non-pharmacological intervention, based on a bundled developmental care intervention concept, resulted in a clinically relevant reduction in the pain and stress responses and in the time needed to recover (69).…”

“…The reported short-term side effects associated to opioid exposure in preterm neonates include hypoventilation and apnea, low blood pressure, intestinal hypoperistalsis, and bladder dysfunction. Hypoventilation and apnea resulted in prolonged duration [7 (4-20) days in morphine-exposed group compared to 6 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) days in the placebo group, + 1 day of ventilation] (9). Along the same line, Hartley et al recently reported that morphine (single oral, 100 µg/kg dose) in non-ventilated preterm infants, used to facilitate the screening for retinopathy of prematurity (ROP) in the Procedural Pain in Premature Infants (POPPI study) and to blunt the pain response, resulted in a high incidence (8/15 vs. 3/15, relative risk 2.7, number needed to harm = 3) of either newly occurring apneic events or an increase in the number of such events in the morphine-exposed group (10).…”

“…Along the same line, Hartley et al recently reported that morphine (single oral, 100 µg/kg dose) in non-ventilated preterm infants, used to facilitate the screening for retinopathy of prematurity (ROP) in the Procedural Pain in Premature Infants (POPPI study) and to blunt the pain response, resulted in a high incidence (8/15 vs. 3/15, relative risk 2.7, number needed to harm = 3) of either newly occurring apneic events or an increase in the number of such events in the morphine-exposed group (10). Because of these safety-related findings (sufficient evidence of harm), the POPPI study was terminated early (10). The available data on the severity and the incidence of low blood pressure in the different studies also likely reflect differences in morphine doses and subsequent morphine exposure.…”