Intravenous (IV) acetaminophen was approved by the U.S. Food and Drug Administration (FDA) in children two years of age and older for the management of mild to severe pain with or without opioids [10,11]. It has a quick onset of action, good analgesic efficacy and practically no side effect in the dose of 10 mg/ kg/dose 8 hourly [12-14] with varied reports of opioid sparing effects [14,15]. IV diclofenac is the current standard of care for management of skeletal VOCs in SCD as opiates have limited availability with the need to monitor for respiratory depression severe constipation and opioid dependence which develops with frequent use. Oral NSAIDs are associated with gastric side effects and non-response with regular usage. This study aimed to compare the efficacy of IV acetaminophen and IV diclofenac sodium in the management of skeletal VOCs among children with SCD.

The present single blind randomized controlled trial was conducted in the department of Pediatrics, VIMSAR, from October, 2016 to November, 2017 after approval from the institutional ethics committee. A pilot study was conducted for first two months (October, 2016 to November, 2016) for calculation of sample size. The inclusion criteria were children with SCD (confirmed by HPLC) of age between 6 months to 14 years of age with onset of symptoms of skeletal VOCs with in last 24 hour not relieved by home-based care. Children who were critically ill, with other serious complications (like acute chest syndrome, splenic sequestration, stroke, overwhelming sepsis, osteomyelitis, arthritis), these requiring any add-on analgesics during the study, and with hepatic or renal impairment were excluded. All enrolled children received standard management of skeletal VOCs and hydration therapy at 1.5 times of maintenance fluid at the emergency room [5].

The pilot study was done with 40 patients who were randomized by Clinical Trial Data Analyzer v1.0 software into intervention (IV acetaminophen) arm and control (IV diclofenac sodium) arm. Undiluted IV acetaminophen 10 mg/kg/dose 8 hourly [16], and diluted IV diclofenac sodium 1mg/kg/dose (1 mg diclofenac sodium in 2 mL of normal saline) 8hrly [17], were used. IV acetaminophen (1mL/10　mg) (Fresenius Kabi India Pvt. Ltd.) and IV diclofenac sodium (1mL/75 mg) (Troikaa Pharmaceuticals Ltd.) were used.

Initial pain score using age appropriate pain scale according to WHO guidelines [18-20] was assessed at 0 hour before administration of drug. A 50% reduction in pain score at 24 hours after first dose since in 14 (70%) and 7 (35%) in the intervention and control arm, respectively. Sample size estimation by n master v2 (BRTC, CMC, Vellore) assuming non–inferiority margin of 10%, alpha error of 5% and power of 80% was calculated as 43 in each arm. The minimum sample size required was 48 in each arm for 10% loss to follow-up.

Computer generated randomization (mixed block randomization) in 1:1 ratio was done by a faculty members not involved in the study. Allocation concealment was done with double opaque sealed envelope by a nurse. Blinding was done for the patient and/or caregiver. The patient enrolment was started from December, 2016 after taking written and informed consent from the parents or caregivers. Drugs were administered by the nurse in the prescribed dosages [21,22] in syringe pump over 30 minutes.

Pain score was assessed at 0, 1 and 24 hours after the administration of the drugs in both arms. The baseline characteristics like age in years, gender, hemoglobin (gm/dL), HPLC for HbS (%), reticulocyte count (%), duration of hydroxyurea use (months), previous hospitalization for skeletal VOCs in last 1 year and units of blood transfusion received were recorded. The pain score at 0, 1 and 24 hour, number of children with 50% reduction in pain score at 24 hours and total number of doses needed to relieve pain after 24 hours of drug administration were recorded in a predesigned case report format. Patients were followed up till adequate pain relief and/or regimen modification. Adequate pain relief was defined as an agreement between the patient and the investigator that the pain was tolerable or completely resolved and no further IV analgesics was needed. The patient was discharged home after of a pain free interval of 12 hour. Patients without adequate pain relief, requiring add-on drug like ketorolac and/or morphine were excluded from the study as per exclusion criteria.

Statistical analyses: Per protocol analysis was done and analysis was performed using SPSS v25 (IBM Corp.) and Dxt v 1.0 (BRTC, CMC Vellore). Data normalcy was tested using Shapiro Wilki and Kolmogorov–Smirnov test. Continuous data were expressed in mean and standard deviation. Categorical data were expressed in proportions. Independent t-test or unpaired t-test was done to compare two continuous variables. Categorical variables were compared by Fischer exact test. Comparison of categorical outcome like 50% reduction in pain score in 24 hours between intervention and control arm were expressed in terms of relative risk (RR), absolute risk reduction (ARR) and number need to treat (NNT). For all statistical purposes, P < 0.05 was considered to be significant.

The flow of the study is shown in Fig. 1. The mean (SD) age was 8.33(3.2) years, Hb S 67.4 (6.4) %, hemoglobin 7.76 (1.4) g/dL units of blood transfusion received 3.04 (1.94) units and reticulocyte count 2.47 (0.82)%. The baseline characteristics were comparable between both groups (Table I).

Fig. 1 Consort flow chart.

The RR (95% CI), ARR (95% CI) and NNT for 50% reduction in pain score after 24 hours of drug administration was 3.6 (2.02-6.33), -0.56 (-0.69-0.36) and -2, respectively. The mean (SD) number of drug doses needed to relieve pain after 24 hours of administration in intervention arm and control arm were [6 (4) and 8 (4); P= 0.011]. The mean (SD) fall in pain score at 1 hour was 1.51 (0.5) among intervention arm and in control arm it was 1.06 (0.5), P<0.001. Eight (17.4%) patients developed local phlebitis at the site of infusion among diclofenac group who were managed conservatively. No other major side effects were noticed in either group.

In this study, IV acetaminophen had 3.6 times increased chance of 50% decrease in pain score after 24 hours of drug administration as compared to IV diclofenac sodium for the management of skeletal VOCs among children with SCD. The fall in pain score after 1 hour of administration of first dose was faster among acetaminophen group as compared to the IV diclofenac group.

This was a single blinded hospital-based study in which reporting bias could not be minimized. This study included only pediatric patients and the results cannot be extrapolated for all age groups. Blood level of the drugs and safety profile were not assessed.

There are different modalities of drugs used in management of skeletal VOCs in SCD ranging from acetaminophen, ketorolac, diclofenac to opioids (low and high potency) [5-7,21] which primarily depends upon severity of pain [3]. Earlier studies have shown the role of IV acetaminophen in managing postoperative analgesia [22,23], and in reducing pain of skeletal VOCs in SCD [16].

In the present study, IV acetaminophen had faster pain relief than IV diclofenac sodium as also corroborated earlier [23]. The use of IV acetaminophen for postoperative analgesia decreased the duration of hospitalization, use of opioid, opioid-related complication rates and costs [24-26].

Few cases developed mild local phlebitis at the site of diclofenac infusion even after dilution in the present study as also reported previous studies [8,11]. The incidence of local phlebitis was higher (22%) in another study [26], probably due to discrepancies in age and of drug administration.

To conclude, IV acetaminophen can be used as an effective option for management of skeletal VOCs in sickle cell disease in children as compared to IV diclofenac sodium. The findings of the current research will add to the analgesic use of IV acetaminophen.

Ethics approval: Veer Surendra Sai Institutional Research and Ethics Committee (VIREC); No: 2015/P-I-RP/128, dated 15 November, 2015.

Contributors: PCP: conceptualization and critical inputs to manuscript writing; NRM: data collection and writing the manuscript; NRM, CP and BKN: data collection, analysis and critical inputs to manuscript writing; SKP: supervision of the work and revision of manuscript.

Funding: None; Competing interests: None stated.