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ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 2  |  Page : 73-78

Efficacy of expressed breast milk alone or in combination with paracetamol in reducing pain during ROP screening: A randomized controlled trial


Department of Pediatrics, Goa Medical College, Bambolim, Goa, India

Date of Submission05-Dec-2020
Date of Decision01-Jan-2021
Date of Acceptance06-Jan-2021
Date of Web Publication15-May-2021

Correspondence Address:
Annely D'Lima
Department of Pediatrics, Faculty Block, Goa Medical College, Bambolim - 403 202, Goa
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.jcn_198_20

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  Abstract 


Introduction: Retinopathy of prematurity (ROP) has been widely acknowledged to be the primary cause of preventable childhood blindness in developing countries. However, the procedure for screening is extremely painful. In this study, we attempted to relieve the pain experienced by these babies using breast milk alone or in combination with oral paracetamol. Materials and Methods: A total of 120 preterm neonates were randomized into three groups: (Group A – control group = 40, Group B – breast milk group = 40, and Group C – oral paracetamol + breast milk = 40). Group B received 2 ml expressed breast milk (EBM) through a sterile syringe orally 2 min prior to procedure, Group C received syrup paracetamol, 15 mg/kg 30 min prior to procedure and EBM as in Group B. Pain experienced was measured by the premature infant pain profile (PIPP) score 20 s prior, during and 2 min after procedure. All procedures were video recorded. The video recorder and analyzer were both blinded to the intervention. Results: PIPP scores before the procedure (PIPP 1) in Groups A, B, and C were 4.09 ± 2.44, 3.25 ± 1.71, and 3.45 ± 2.20. Postprocedure PIPP score (PIPP 2) increased to 15.74 ± 2.42 in Group A, 15.44 ± 2.05 in Group B, and 15.83 ± 1.36 in Group C. There was no significant statistical difference in pain scores in the intervention groups (Groups B and C) compared to the control group (Group A), P = 0.724. PIPP scores recorded postprocedure in Groups A, B, and C were, 7.72 ± 3.43, 6.87 ± 3.46, and 7.85 ± 3.37 indicating residual pain. Conclusion: The procedure of ROP screening causes significant pain, with persistence of residual pain in premature neonates. However, there was no statistical difference in the pain scores noted in the intervention Groups B and C in comparison to the control Group A

Keywords: Expressed breast milk, paracetamol, retinopathy of prematurity


How to cite this article:
Naik A, D'Lima A, Sreekumar K, Silveira MP. Efficacy of expressed breast milk alone or in combination with paracetamol in reducing pain during ROP screening: A randomized controlled trial. J Clin Neonatol 2021;10:73-8

How to cite this URL:
Naik A, D'Lima A, Sreekumar K, Silveira MP. Efficacy of expressed breast milk alone or in combination with paracetamol in reducing pain during ROP screening: A randomized controlled trial. J Clin Neonatol [serial online] 2021 [cited 2021 Jun 12];10:73-8. Available from: https://www.jcnonweb.com/text.asp?2021/10/2/73/316183




  Introduction Top


Retinopathy of prematurity (ROP) has been widely acknowledged to be the primary cause preventable childhood blindness in developing countries. Binocular indirect ophthalmoscopy is the best and the only reference examination technique for ROP screening in new-borns. However, this procedure is painful and is known to cause stress and physical debilitation among preterm neonates, especially because of the use of eyelid speculum and scleral indentation.[1] Most of the new-born babies admitted in neonatal intensive care units (NICUs) the world over are subjected to repeated painful procedures, many of which are deemed essential for their survival. This frequent exposure to painful stimuli may affect the neurologic outcome of these neonates. It is a known fact that the more sicker and premature the baby the more number of painful procedures they will be exposed to.[2] It is now, a well-known fact that even the most immature neonates are anatomically and physiologically capable of feeling pain. Early pain experiences have long-term sequelae as a result of changes in the central nervous system and altered responsiveness of the neuroendocrine and immune systems to stress at maturity.[3]

As the neonates cannot verbally express their pain, they depend on their caregivers to recognize, assess, and manage their pain.[4] Surrogate markers have been studied and widely used to assess the pain experienced by neonates. These include motor responses, facial expressions, cry, and changes in physiologic parameters such as heart rate, blood pressure, oxygen saturation, and respiratory rate. The validated scores for the assessment of pain include the Neonatal Facial Coding System (Craig 1994), Neonatal Infant Pain Scale (Lawrence 1993), or Premature Infant Pain Profile (PIPP) (Stevens 1996).[5]

Many pharmacological and nonpharmacological interventions have been studied to relieve the pain experienced by neonates during the various procedures.[6] Expressed breast milk (EBM),[5] sweet solutions (oral sucrose or glucose solutions),[7] and various drugs such as paracetamol and acetaminophen[8] have been studied in the various clinical trials to relieve procedural pain with equivocal results.

ROP screening in new-borns is an essential procedure and is known to cause severe pain during the procedure with residual pain persisting for up to 30 min after the procedure.[9] In this study, we tried to compare two commonly used methods to relieve procedural pain, namely EBM and paracetamol.


  Materials and Methods Top


A randomized, controlled, clinical trial was carried out in a tertiary level III NICU in West India for a period of 6 months from November 2014 to April 2014. One hundred and twenty preterm infants, with a gestational age (assessed using New Ballard Score) <34 weeks and/or birth weight <1500 gm were enrolled in the study. Sample size calculation was based on a study by E M Boyle et al. A sample size of 30 per group was calculated to allow 80% probability of detecting a three point difference in PIPP score with significance at the 5% level. This was done using N master 2.0 software.[10] The Institutional Ethical Committee approved the study. Written informed consent was obtained from the parents. Infants requiring mechanical ventilation at the time of ROP screening or receiving sedatives or narcotics, neonates not receiving oral feeds, and neonates with congenital anomalies were excluded from this study. The neonates were allocated into three groups using a computer-based randomization process according to their ophthalmologic examination sequence using sealed opaque envelopes. A special staff nurse was assigned for opening the envelopes at the time of examination. The neonates were enrolled only once in the study to avoid the possibility of habituation of pain. Mydriatics were used before eye examination. These were phenylephrine 2.5% and tropicamide 0.5%. One drop of tropicamide was instilled every 10–15 min for four times starting 1 h before the scheduled time for the examination. This was followed by phenylephrine, one drop just before examination. The procedure for screening involved the use of indirect ophthalmoscopy using a 20D lens, and this was performed by an experienced ophthalmologist (all the procedures in this study were done by a senior resident ophthalmology). After instilling a topical anesthetic drop (Proparacaine), a wire speculum was inserted to keep the eye-lids apart, and a scleral indenter was used whenever required. All the neonates were swaddled during the procedure. Group A served as the control group. Group B received 2 ml of EBM administered through a sterile syringe into the baby's mouth 2 min prior to procedure, and Group C received syrup paracetamol at a dose of 15 mg/kg administered 30 min before procedure along with breastmilk as in Group B. The pain scores were calculated using the PIPP score. Physiologic parameters, including heart rate, respiratory rate, and baseline SpO2 were determined in all patients before eye examination and during examination using Masimo7 pulse oximeter by an intern who was blinded to the study groups. The ROP screening examinations were video recorded using an Apple iPad. The video recording taken 20 s before procedure served as baseline (PIPP 1). The other two videos were taken during and 2 min postprocedure and these served as PIPP2 and PIPP 3, respectively. Two neonatologists experienced in the use of PIPP scoring and blinded to the intervention groups determined the pain score by 30-s observation of the neonates', response in the video recording at the beginning of the eye examination and during last 45 s of the eye examination. Video recordings found to be incomplete at this time were discarded. Each video was replayed thrice, and the mean PIPP score was calculated and used for analysis. To avoid interobserver variations, the videos were recorded by single observer who was blinded to the intervention. The PIPP scores were validated by another independent observer who was blinded to the intervention used and found to be comparable. Data were analyzed using the IBM SPSS version 20.0, IBM Corp. Released 2011, IBM SPSS Statistics for Windows version, 20.0 (Armonk, NY, IBM Corp.). Variables were expressed in the percentages and mean ± standard deviation. Data were analyzed with the Chi-square test and one-way analysis of variance. The difference was considered significant for P < 0.05.


  Results Top


One hundred and twenty neonates who underwent ROP screening eye examination were included in this study. Twenty-four video recordings were found to be inadequate for the purpose of recording the PIPP score and hence were excluded postrandomization. Two neonates were excluded due to refusal of consent postrandomization. Ninety-four video recordings were then analyzed. A CONSORT-based diagram showing patient flow through each step of the trial is shown in [Figure 1]. Fifty-four infants (54%) were male. Thirty-eight (40.4%) of the neonates were born by ceaserean section and the rest by vaginal delivery. The mean gestation age of studied infants was 33.3 ± 2.1 weeks and their birth weight were 1440 gr ± 300 g. Fifty-three (56.4%) of the neonates included in the study population were small for gestational age. The postconceptional age at the first ophthalmological examination in the entire cohort ranged from 33 to 36 weeks (median age at examination was 16 ± 5.35 days). According to the data displayed in [Table 1], all the three groups were similar at baseline in terms of birth weight, gestational age, and mode of delivery. There was a history of assisted ventilation in 8 (8.5%), 8 (8.5%), and 7 (7.5%) of patients in Groups A, B, and C, respectively (P = 0.52). The mean PIPP scores in three groups are showed in [Table 2]. The duration of examination was 3–5 min in all neonates. There were no adverse effects noted in any of the neonates who underwent the procedure.
Figure 1: Flowchart of the study participants

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Table 1: Characteristics of study population

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Table 2: Pain assessment in study population

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The PIPP scores calculated 20 s before the procedure served as the baseline score (PIPP 1). This score was compared to the PIPP scores recorded during the procedure (PIPP 2) and the PIPP score recorded 2 min after the procedure was complete (PIPP 3). This was done to detect the presence of residual pain following the procedure.

The PIPP score before the examination (PIPP 1) in the control group (Group A) was 4.09 ± 2.44, the EBM group (Group B) was 3.25 ± 1.71, and in the EBM and paracetamol group (Group C) was 3.45 ± 2.20. After the examination, the mean PIPP score (PIPP 2) increased to 15.74 ± 2.42 in Group A, 15.44 ± 2.05 in Group B and 15.83 ± 1.36 in Group C respectively. There was a significant increase (P < 0.05) in the PIPP score during the procedure (PIPP2) in comparison to the PIPP score before the procedure (PIPP1), by the Greenhouse-Geisser test. Furthermore, the PIPP 2 in all the three groups, the control group, Group A as well as the study groups Group B and C was >12. This indicates that the procedure of ROP screening causes severe pain. There was no significant statistical differences noted in the PIPP scores between the control group (Group A) and the intervention groups, Group B and Group C (p, 0.72). The PIPP score following the procedure (PIPP 3) in all the three groups was >7, and this indicates that there was the persistence of slight to moderate pain which lasted for up to 2 min following the procedure. This was statistically significant by the Greenhouse-Geisser test (P < 0.05) indicating the presence of residual pain.


  Discussion Top


The PIPP scores in all the three groups that is the control and the intervention groups were comparable. These findings indicate that EBM given 2 min before the procedure alone or in combination with paracetamol given 30 min before the procedure do not abolish pain responses during ROP examination in preterm infants. These findings were similar to the study done by A Sener Taplak and Erdem which revealed comparable PIPP scores in the control and study groups during the ROP examination.[11] A study done by Ribeiro et al. which assessed the efficacy of 2 ml of breast milk versus 0.5 ml/kg of 25% glucose both given 2 min before the ROP examination showed that heart rate and the crying time during the procedure and the salivary cortisol 60 min following the procedure did not vary significantly between the breast milk and glucose groups.[12] Rosali et al. in their study showed that PIPP scores were significantly less (P < 0.05) in the group that received EBM during the procedure and this difference persisted even at 5 min after the procedure in comparison to the control group.[13] Seifi et al. in their study compared the efficacy of oral acetaminophen versus oral sucrose with placebo. Their results showed that the group that received sucrose had significantly lower PIPP score compared with the acetaminophen or sterile water treated groups at the beginning of eye examination but not at its termination. These findings indicate that sucrose does not abolish pain responses during ROP examination in preterm infants.[14] O'Sullivan et al. assessed sucrose and sterile water combined with non nutritive sucking and swaddling in total of 40 infants undergoing primary ophthalmologic examination, and they concluded that pain scores remained consistently high and appropriate pain relief for ROP remains a challenge.[15] Bozlak and Dolgun compared the nonpharmacologic methods of swaddling with orally administered 0.2 ml of 24% sucrose, swaddling with orally administered breast milk, and swaddling with orally administered distilled water all of which were implemented immediately before the ROP examination. No significant differences in PIPP scores were found across the three groups.[16] Gal et al. assessed whether the addition of sucrose 24% to topical anesthetic improved procedural pain control during the ROP eye examination. It was seen that patients experienced significantly less pain at speculum insertion with sucrose than with placebo, although the post procedure pain was same in both the groups. Hence, he concluded that oral sucrose may reduce the immediate pain response in premature infants undergoing eye examination for ROP.[17]

There are several studies comparing different doses and routes of sweet solution (sucrose, 25% dextrose and EBM) administration with sterile water as pain relieving measures for various procedures performed in the NICU. The analgesic effect of sweet solutions is probably due to the link that exists between the oro-gustatory effects of sweet solution given orally and the endogenous opioid pathway.[18] A Cochrane review concludes that sucrose reduces procedural pain from heel-lance and venepuncture in neonates, with minimal to no side effects. The dose range for reducing pain varies from 0.012 to 0.12 g (0.05 ml to 0.5 ml of 24% solution) of sucrose.[7]

In our study, the setting being a government run hospital, we preferred the use of breastmilk as it was easily available, at no added cost and associated with no adverse effects. Furthermore, a recent Cochrane review states that breastmilk may provide pain relief during a single painful procedure.[5] One of the potential mechanisms by which EBM may have a nociceptive effect is because of its sweetness due to the presence of lactose. Furthermore, compared to artificial formulas, breast milk contains a higher concentration of tryptophan, a precursor of melatonin and melatonin is shown to increase the concentration of beta endorphins which may provide pain relief.[5] The Cochrane meta-analysis included healthy term neonates or stable late preterm neonates,[5] however, there was no meta-analysis including preterm neonates who are subjected to repeated painful procedures during hospitalization; for them, the ideal analgesic has not yet been identified. Hence, in this study, we attempted to study the efficacy of breastmilk in preterm neonates given 2 min before the procedure alone or in combination with paracetamol given 30 min before the procedure as a pain-relieving measure during ROP screening, and we concluded that breastmilk alone or in combination with paracetamol does not provide any pain relief.

Several studies have been conducted to assess the efficacy of breastmilk as an analgesic for procedural pain. It was found to decrease pain experienced during the procedure in studies done by Sahoo JP et al.[18] and Upadhyay and Gupta.[19] The procedures performed in these studies, however, were venipunctures. A meta-analysis concluded that neonates undergoing single painful procedure (heel lancing) should be provided breastfeeding for analgesia when possible, compared to positioning/pacifier/holding and swaddling.[5]

There is limited data on the use of breastmilk as a pain-relieving measure for ROP screening. A higher concentration of dextrose (25%), however, has been found to be significantly associated with a reduction in pain.[20]

The Cochrane results for paracetamol compared with sterile water to reduce pain associated with eye examinations performed to ascertain the presence of ROP were conflicting: one study found a reduction in the PIPP score during the examination for paracetamol versus water, whereas another study did not find a significant reduction in PIPP scores in the first or last 45 s of eye examination. The PIPP scores were higher during eye examination for the paracetamol group than for the sucrose group. The paucity and low quality of existing data do not provide evidence for the effectiveness of paracetamol for neonates exposed to painful procedures such as heel lance and eye-examination.[8] In our study, the results revealed that there was no added benefit of oral paracetamol as a pain-relieving measure during eye-examination. In a study done by Seifi et al., there was no difference in the PIPP score between the control and acetaminophen group; however, the group which received oral sucrose had a significantly lower PIPP score.[14] Kabataş et al. compared oral paracetamol given at a dose of 15 mg/kg with a placebo and found that the intervention group had a significantly lower mean PIPP score during eye examination, following insertion of the speculum (Group 1:12 [9–13] vs. Group 2:14 [13–15], P 0.001). There were no significant differences between the groups with regard to crying, tachycardia/bradycardia, and desaturation. Hence, they concluded that oral paracetamol modestly reduces pain scores during eye examinations.[21]

The neonates experienced severe pain with a PIPP score of >12. This was comparable to the study performed by Rosali et al., in which during the procedure, the babies in both the groups perceived severe pain with PIPP scores of 12.7 ± 1.7 in the intervention group and scores of 15.3 ± 1.78 in the control group.[13] A study by Boyle et al. also demonstrated that ROP examination causes severe pain with PIPP scores of >12 across all the groups.[10] Nesargi et al. in their study also found the mean PIPP scores during the procedure in Group I (proparacaine) to be 15.5 ± 2.06 and Group II (25% dextrose) to be 14.2 ± 1.8 at the first screening.[20]

The PIPP score following the procedure (PIPP 3) in all the three groups was >7 and this indicates that there was persistence of slight to moderate pain which lasted for up to 2 min following the procedure. This was similar to the study of Mehta et al. which assessed the PIPP scores at 1 min and 5 min following the procedure. The PIPP scores recorded at 1 min were between 10 and 12 in both study groups, and the scores recorded at 5 min were between 5 and 6 which indicates the persistence of residual pain following examination.[22]


  Conclusion Top


The procedure of ROP screening causes significant pain in premature neonates which is demonstrated by PIPP scores of >12 across all groups.

There were no significant statistical differences noted in the PIPP scores between the control groups and the intervention groups, Group B and Group C. This indicates that breastmilk alone or in combination with paracetamol is inadequate to relieve the severe pain associated with the procedure of ROP screening.

The PIPP score following the procedure in all the three groups was >7, and this indicates that there was the persistence of slight to moderate pain which lasted for up to 2 min following the procedure.

Acknowledgment

The authors would like to thank Ms. Pallavi Nachinolkar, Lecturer in Biostatistics, Department of Community Dentistry, Goa Dental College for her help with the data analysis.

The resident doctors and consultants in the Department of Ophthalmology who performed the ROP screening.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Costa M, Eckert G, Fortes B, Fortes Filho J, Silveira R, Procianoy R. Oral glucose for pain relief during examination for retinopathy of prematurity: A masked randomized clinical trial. Clinics 2013;68:199-203.  Back to cited text no. 1
    
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Boyle EM, Freer Y, Khan-Orakzai Z, Watkinson M, Wright E, Ainsworth JR, et al. Sucrose and non-nutritive sucking for the relief of pain in screening for retinopathy of prematurity: A randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2006;91:166-8.  Back to cited text no. 10
    
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12.
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