One of the most controversial issues in neonatology today is the ap- propriate treatment of proceduralpain in the NICU. Infants in the NICU undergo numerous painful procedures. Policies and practices for the treatment of pain vary from NICU to NICU and from doctor to doctor. Numerous studies have been done to clarify the best methods of re- lieving pain, but the studies themselves are ethically problematic. What is the gold standard? How should we assess pain? When have we learned enough to consider certain practices as proven? Should proven practices be considered as the standard of care, even if we know that they are not widely used? In this ethics column, we asked experts in pain and palliative care to consider a proposed randomized trial for proceduralpain in newborns and to discuss whether an in- stitutional review board should approve the trial. Dr Bellieni is a neo- natologist and bioethicist in Sienna, Italy. Dr Taddio is a pharmacologist at the Hospital for Sick Children in Toronto. Dr Linebarger is Medical Di- rector of the Palliative Care Program at Children ’ s Mercy Hospital in Kansas City.
morphine provides short-term clinical benefits. On the basis of our results, we conclude that morphine does not provide adequate analgesia for ventilated preterm neonates of ⬍ 33 weeks’ gestational age who are exposed to acute pain resulting from multiple procedures, such as heel sticks. These conclusions do not apply to continuous severe pain and should not encourage the reduction of analgesic treatment for ventilated preterm neonates in severe pain, who con- stitute a group at high risk for physiologic instability and long-term effects of pain. In fact, the administra- tion of continuous morphine infusions to preterm neonates does not eliminate the need for other anal- gesic approaches (eg, sucrose) that are effective against acute proceduralpain.
measured by behavioral indicators (i.e., crying, facial reac- tions), physiological indicators (i.e., cortisol levels, heart rate, respiratory rate, oxygen saturation), and contextual indicators (i.e., gestational age). Proceduralpain assess- ment tools are different for full-term and preterm neo- nates. Pain response should be measured in studies by valid and reliable scales for the two populations in order to be included in the meta-analysis of this review, such as the premature infant pain profile (PIPP) adapted to meas- ure pain in neonates from 28 to 40 weeks of gestation (WG), the neonatal infant pain scale (NIPS) from 26 to 47 WG, the neonatal facial coding system (NFCS) from 26 to 47 WG, and the Douleur aigue du nouveau-né [acute pain of the newborn] (DAN) from 24 to 41 WG.
Preterm and critically ill newborns admitted to a NICU undergo re- peated skin-breaking procedures that are necessary for their survival. Sucrose is rapidly becoming the accepted clinical standard nonphar- macologic intervention for managing acute proceduralpain for these infants. Although shown to be safe in single doses, only 4 studies have evaluated the effects of repeated doses of sucrose over relatively short periods of time. None has examined the use of sucrose throughout the NICU stay, and only 1 study evaluated the neurodevelopmental out- comes after repeated doses of sucrose. In that study, infants born at ⬍ 31 weeks’ gestational age and exposed to ⬎ 10 doses per day in the ﬁrst week of life were more likely to show poorer attention and motor development in the early months after discharge from the NICU. Re- sults of studies in animal models have suggested that the mechanism of action of sucrose is through opioid pathways; however, in human infants, little has been done to examine the physiologic mechanisms involved, and the ﬁndings reported thus far have been ambiguous. Drawing from the growing animal literature of research that has ex- amined the effects of chronic sugar exposure, we describe alternative amine and hormone pathways that are common to the processing of sucrose, attention, and motor development. In addition, a review of the latest research to examine the effects of repeated sucrose on pain processing is presented. These 2 literatures each can inform the other and can provide an impetus to initiate research to examine not only the mechanisms involved in the calming mechanisms of sucrose but also in the long-term neurodevelopmental effects of repeated sucrose in those infants born extremely preterm or critically ill. Pediatrics 2010; 125:1042–1047
rangements with their mothers, within 12 to 72 hours of life. With the excep- tion of free-ﬂowing oxygen, none of the infants underwent resuscitation pro- cedures in the delivery room. Further- more, all infants were free of any clin- ical problems, with the exception of physiologic jaundice without the need for phototherapy, at enrollment. For in- clusion, the only previous proceduralpain stimulus received by the neonate was a vitamin K injection soon after birth. Infants were excluded from the study if their mothers had used opi- oids at any time during gestation or labor or had received general anesthe- sia or if the infants had an Apgar score of ⬍ 7 in the ﬁrst or ﬁfth minute of life, had major congenital malformations, or had neurologic problems of any type.
prevention and relief techniques that have been shown to minor procedures in neonates. Facilitated tucking is a developmentally sensitive, non- pharmacological comfort measure that can relieve proceduralpain in very low birth weight (VLBW) infants. Facilitated tucking involves holding a newborn in flexed position with warm hands to offer tactile and thermal sensory stimulation to rocedures. The research studies term improvement in pain sensitivity following pain reduction programmes (Modrcin
Titles and abstracts were reviewed independently by 2 pairs of reviewers (G.L., O.K.; A.S., J.Y.). All disagreements were resolved through consensus or a third reviewer. Published and un- published guidelines were included if they focused on hospitalized or non- hospitalized neonates, infants, chil- dren, or adolescents aged 0 to 18 years and pain assessment or management of acute proceduralpain. Guidelines in languages other than English and un- published hospital-speci ﬁ c guidelines were excluded. For guidelines with . 1 version, only the most updated ver- sions were included.
Participants frequently described anxiety around procedure-related complications (e.g., their child being cut) and their child experiencing greater pain from mul- tiple needle pokes due to unsuccessful procedures. Ef- fectively utilizing analgesia for procedures such as IV insertions and venipuncture can not only substantially improve the pain children experience, it can also im- prove the success rate of procedures and shorten the overall procedure time, highlighting, again, the import- ance of effective knowledge translation in this area . Caregivers shared distressing experiences about proce- dures carried out at non-pediatric urban and rural cen- tres. In a recent survey of pediatric pain management practice and policies in Alberta EDs, it was noted that policies around proceduralpain were lacking . Implementing pain-related policies has been linked with an increase in the number of patients receiving analgesia for procedures in the ED setting . Given 85% of Can- adian children in need of emergency care are seen in non-pediatric EDs, there is an urgent need for KT efforts targeting the general ED setting [47, 48].
age (ELGA), very low gestational age (VLGA), and term-born infants; 2) to examine whether more ex- posure to neonatal skin-breaking procedures (pain) is linked to higher basal cortisol and/or increased cortisol response to novelty at 8 months of age cor- rected for prematurity; and 3) to evaluate whether there is an association between amount of morphine exposure and the effect of early proceduralpain on cortisol responsiveness. We hypothesized that 1) basal cortisol will be higher in ELGA compared with VLGA and term-born infants; 2) ELGA infants will display increased cortisol responses after structured interaction with novel toys at 8 months, whereas VLGA and term-born infants will not show a stress response to novelty and may even find exposure to novelty positive or arousal reducing; 3) among the preterm infants, higher exposure to neonatal skin- breaking procedures will be associated with in- creased basal and challenge cortisol levels at 8 months of age, after controlling for neonatal illness severity; and 4) among the preterm infants, greater neonatal morphine exposure will modulate the long- term effects of exposure to neonatal procedures (ie, will be associated with lower basal and challenge cortisol levels at 8 months, after controlling for neo- natal illness severity). To our knowledge, this is the first study of endocrine stress response (salivary cor- tisol) to novelty in human preterm infants.
This large, unique CMA highlights the need to inform clinicians, researchers, parents of infants, and research ethics boards, as well as funders of research, about their decisions to continue to conduct placebo-controlled trials after decades of research. Had such a CMA analysis been conducted earlier, uptake of sucrose or glucose for proceduralpain management may have occurred sooner, thereby reducing exposure of infants around the world to unnecessary proceduralpain, and reducing wasted resources resulting from unjustified research. Some limitations of this review should be mentioned. The CMA focused only on crying time and composite infant pain intensity scores. However, the effect of sweet solutions on physiologic responses to pain are far less consistent and sweet solutions actually result in an increase in heart rate in some instances. Behavioral responses are
The search strategy will combine subject headings and keywords for concepts: pain, ED procedures and visits, parents, and information needs. The author team includes pain research (SA), systematic review method- ology (LH), and knowledge translation (SS) specialists, as well as a medical research librarian (RF). The team convened to decide on relevant keywords and subject heading to include in the search, including procedures that are common to the ED setting (e.g., venipuncture, IV insertion). Database searches will be limited to English language records published since January 2000. The author team selected 2000 as the start date for the search after conducting a preliminary investigation of systematic reviews on pediatric proceduralpain in the hospital setting. To our knowledge, the earliest system- atic review was conducted in 1999  and reported small sample sizes and inconsistent findings from included studies. Since then, the evidence-base for pediatric pain management has improved significantly [16, 17]. In order to identify parents’ experiences and information needs as they pertain to current practices in pediatric pain care, we will exclude studies published prior to 2000, as these are likely not reflective of the current parental experience.
Recognition of the negative consequences of inadequately controlled paediatric pain has generated increased interest in pain assessment and management for young patients . A large portion of this research has focused on reducing the pain of common paediatric procedures, such as routine childhood immunizations, venipuncture, intramuscular in- jections, and dressing changes [9,10]. To our knowledge, there has not yet been a formal attempt to quantify and reduce the amount of pain associated with subcutaneous methotrexate injections in the paediatric rheumatology population. These patients may be particularly vulnerable to the long-term consequences of uncontrolled proceduralpain due to their young ages and relatively long duration of therapy. A recent, large study of children with JIA re- ceiving methotrexate from an average age of 6.1 years, for a median duration of 29 months, found that methotrexate had a detrimental impact on the patients' quality of life . Therefore, there is a need to improve the experience of subcutaneous methotrexate administration. Measuring the amount of pain associated with methotrexate provides a baseline for determining the efficacy of interventions and can aid clinicians in counseling patients and families about to begin therapy.
Abstract: Primary dysmenorrhea (PD) has been the focus of a number of experimental pain studies. Although a number of reviews exist, few have critically evaluated the existing body of research on PD and experimental and proceduralpain. Data from 19 published research articles that include women with PD and responses to an experimental or proceduralpain stimulus (or stimuli) suggest that women with PD may have elevated pain reactivity, as compared to women without PD. This pattern appears to be true across different phases of the menstrual cycle. However, there is an abundance of conflicting findings, which may be due to significant methodological issues such as inconsistent definitions of PD, wide variation in experimental pain methodologies, and inaccurate assessment of the menstrual cycle. Future research should focus on identifying specific symptoms (i.e., pain threshold ratings) to more clearly define what constitutes PD, establish reliable and valid laboratory testing protocols, and assess the menstrual cycle with greater precision.
In this study, respondents had some knowledge about non-pharmacologic strategies for use in the management of proceduralpain in children, especially distraction, which has been found very helpful for children during medical procedures [2,3,14].This has been previously reported . With the emphasis on offering tender loving care to patients during their professional training, it may not be surprising that nurses had better knowledge about these interventions, compared to physicians whose training are mainly geared toward the pharmacologic aspect of care. Nevertheless, pain relief remains the duty of every clinician. This highlights the urgent need of building the capacity of healthcare providers on these simple non-pharmacologic methods for improved service delivery.
There were three sets of questions for the hy- potheses. The first compared the two arms of the prospective study at the final ( . 12 months) data point. The second compared the prospective data with data collected before the prospective study began. For each, age was a covariate. The third hypothesis examined predictors of child distress, incorporating the procedural variables, group and age, at . 12 months from diagnosis. Hypothesis 1: A) The combined intervention group (CI) will re- port lower levels of child and parent distress than the pharmacologic only group (PO). This provides a test of the effect of adding a psychologic inter- vention to the pharmacologic protocol. B) Parent and staff ratings of child and parent distress will decrease during the 18 month period for both groups. C) Parents of younger children will report higher levels of child distress before and during procedures than parents of older children and adolescents, consistent with previous literature (LeBaron S, Zeltzer L. Assessment of acute point anxiety in children and adolescents by self-reports, observer reports, and a behavior checklist. J Con- sult Clin Psychol. 1984;52:729 –738). Hypothesis 2: Children and adolescents with leukemia and their mothers and fathers in the PO and CI groups will have lower levels of child and parent distress than the CC group at .12 months from diagnosis. The rationale is that the introduction of a systematic approach to proceduralpain (pharmacologic or pharmacologic plus psychologic) will result in a lessening of child and parent distress. Hypothesis 3: Child distress (staff and parent ratings) will be positively associated with technical difficulty and
supported the hypothesis-, sucrose was ineffective in calming methadone ex- posed infants suffering from withdrawal symptoms, adding evidence to the as- sociation among sweet taste, an intact endogenous opioid system, and analge- sia. Until recently, this was the only study examining effects of sucrose in infants with antenatal opioid exposure. From these studies demonstrating calming effects of sucrose on crying infants, the research questions turned to whether sucrose reduced pain if given before painful procedures. In the ﬁ rst published report of a placebo- controlled RCT of sucrose for proceduralpain in newborn infants, sucrose sig- ni ﬁ cantly reduced crying during a heel lance and resulted in a more rapid return to a calm state compared to water. 48 Additionally, the combination
conducted within the first week of life and studies conducted at .36 weeks’ conceptional age (gestational age plus postnatal age). Each analysis model included base values, procedural invasive- ness (mild, moderate, and high), gestational age category, and the interaction of gestational age category with invasiveness. (Analy- ses of behavioral state during the first week of life and .36 weeks’ conceptional age include only two levels of procedural invasive- ness [mildly and moderately invasive procedures] because of a paucity of usable data for those infants born . 36 weeks’ gesta- tional age). To increase precision, the models also included whether supplemental oxygen, mechanical ventilation, and/or medications were provided at the time of study, as well as data on race, gender, and severity of IVH. To examine the effects of extrauterine development, a repeated measures ANOVA com- pared the heart rate and behavioral state responses of infants born at ,28 weeks’ gestational age during four conceptional age time periods: , 28, 28 to 31, 32 to 36, and . 36 weeks’ conceptional age. These analysis models included the same covariates as in the previous analyses but substituted conceptional age for gestational age categories. Mean proceduralpain ratings by clinicians ex- tracted from our previous study were compared with the subjects’ physiologic and behavioral responses (difference scores) to those same procedures using correlation analyses. A regression analysis model (PROC REG; SAS Institute, Cary, NC) was used to examine whether clinician’s proceduralpain ratings predicted the magni- tude of physiologic and behavioral state responses. All statistical analyses were performed with SAS.
Since invasive procedures such as corticosteroid injec- tions, anaesthetic injections, and dry needling are carried out frequently in rheumatology [15,16], it is important to better understand which factors influence proceduralpain, and how it can be managed effectively. Some pro- cedures for the management of induced pain have been established in rheumatology department, but not vali- dated and published, and most approaches to date have used empirical treatment. The results of studies on the use of topical lidocaine-prilocaine cream (EMLA) before vascular puncture and corticosteroid injections are con- tradictory [17-19]. It therefore seemed pertinent to eval- uate pain linked to different procedures in rheumatology, and how this pain is currently managed.
Despite the use of local anesthesia or premedication, invasive procedures are still an unpleasant experience for the child. In addition to treating disease-related pain, the usefulness of managing procedure-related pain has become obvious. More speciﬁcally, there is a need for new and safe anal- gesic/sedative therapeutic methods that are, if possible, easy to adminis- ter. The premixed equimolar mixture of 50% oxygen and nitrous oxide inha- lation (EMONO), already indicated in the pediatric setting for conducting brief painful procedures, is a straight- forward, effective, and rapidly revers- ible analgesic method, without major adverse effects. This method is widely used in pediatric outpatient settings for minimally invasive procedures. 3
It is acknowledged that this small-scale pilot study has some limitations. First, blinding of participants, health care professionals, and research team was not possible due to the nature of the intervention. In addition, it was very difficult to standardize the pharmacological treatment from one ses- sion to another. Although patients received the treatment according to a preestablished protocol, the doses could be adjusted by the pain clinic if they felt that the child was too anxious or distressed before the procedure. Moreover, the same analgesics could have different effects among patients or even with the same patient from one session to another, creating high heterogeneity in sedation levels and analgesia. On the other hand, the burn surface area was mostly small (mean total body surface area = 5% ± 4%), limiting the findings within this population. It is difficult to predict how children with more extensive burns would react to an intervention using distraction or whether they would be able to interact with a videogame as they might require a higher level of sedation during the procedure. Finally, given the young age of the participants, it was not possible to measure the sense of presence in infants and young children. The sense of presence is related to immersion and is an essential component of VR distraction that distinguishes it, along with interaction, from other forms of distraction such as playing video games or watching a television screen. 60,61 As the sense of presence is