Therapeutic Potential of Ibuprofen-Paracetamol Combination for Use in Children
Children suffer frequent episodes of illness leading to more primary care visits as compared to any other age group.(1) It is getting emphasized that, for febrile children without any indication of a serious underlying condition, there is a need to treat symptoms of fever along with a focus on comforting the child, rather than only achieving normothermia .(2) This implies the need to relieve the clinical inflammatory state i.e. the pain which is often associated with fever (2)
Paracetamol and ibuprofen are the most widely prescribed medications for the management of fever and pain in children.(3) Ibuprofen is cited as the most studied nonsteroidal anti-inflammatory drug in the management of pain associated with inflammation in children; with durable evidence of efficacy and a good safety profile (4). The clinical utility and therapeutic potential of Ibuprofen plus Paracetamol combination treatment in routine practice settings is reviewed through comprehensive and recently available scientific evidence.
Rationale for Use of Ibuprofen plus Paracetamol Combination in Pyrexia-Pain associated Syndromes
Pain & Inflammation deserve as much attention as Pyrexia in Children: Unlike fever, which is often over-treated in children, pain is frequently underestimated and under-treated in this population. Acute pain is a frequent symptom of pediatric illnesses. Children are particularly vulnerable to suboptimal pain management. Untreated pain in childhood has been reported to lead to short-term sequels like slower recovery and long-term implications such as anxiety, hyperesthesia, and fear of medical care. This is also due to the challenges in the evaluation of pain and fear of using anti-inflammatory drugs(5)
Ibuprofen and Paracetamol: Most Experienced Anti-pyretic & Analgesic Agents in Children: Ibuprofen and paracetamol are the most commonly prescribed analgesics. For fever, paracetamol is the most commonly used agent in pediatric patients. For pain, ibuprofen is the most commonly utilized mediation among children followed by paracetamol. For inflammation, again, ibuprofen is the most commonly used agent in this patient population(2)
Ibuprofen plus Paracetamol Combination: Antipyretic, Weakness & Pain Relieving Potential
Ibuprofen has demonstrated a good safety profile and has been found effective for mild-moderate pain of different origins in children. It has been cited in the scientific literature that in case of fever or pain, ibuprofen should be considered the choice of drug, in a clinical context where there is inflammatory pathogenesis .(5) The antipyretic efficacy of paracetamol is well established. Ibuprofen, as an antipyretic has shown the rapid onset of action within just 15 minutes, effectiveness lasting up to 8 hours; along with relief of malaise derived from the body's temperature rise, especially in the first 24 hours(6)
Specific Scope of Ibuprofen in Sore throat, Pharyngotonsillitis & Acute Otitis Media: In infections or clinical presentations associated with a greater inflammatory component, as in exudative pharyngotonsillitis, or when lymphadenitis is associated, ibuprofen is preferred due to its anti-inflammatory properties(5). In fever or pain co-existing states, ibuprofen should be considered where there is inflammatory pathogenesis, such as acute pharyngotonsillitis and acute otitis media. The advantage of ibuprofen over other NSAIDs is its best-demonstrated tolerability and safety in children.(5)
Benefits of Considering Ibuprofen plus Paracetamol Combination in High-Grade Pyrexia
Ibuprofen plus Paracetamol Combination: Faster Relief of Fever in the First 24 hours: The PITCH trial was an individually randomized, blinded, three-arm trial conducted in England. It included 156 children aged between 6 months and 6 years with axillary temperatures of at least 37.8°C and up to 41.0°C. The treatment intervention comprised of three treatment groups - paracetamol plus ibuprofen, paracetamol alone, or ibuprofen alone. The results of the study reported that, for less time with fever over 24 hours, paracetamol plus ibuprofen were superior to paracetamol (4.4 hours; p<0.001) and to ibuprofen (2.5 hours; p=0.008). Combined therapy cleared fever 23 minutes (2 to 45; P=0.025) faster than paracetamol alone. It was thus concluded that to maximize the time that children spend without fever, healthcare providers and caregivers should use ibuprofen first and consider using paracetamol plus ibuprofen over 24 hours .(7)
Ibuprofen plus Paracetamol Combination: Quicker Reduction in body temperature among Indian Children with Infection associated Pyrexia: An Indian study published by Vyas F et, al was an investigator blinded, randomized, comparative, parallel clinical trial conducted in 99 febrile children, aged between 6 months - 12 years of age.
These children suffered from fever (mean temperature > 38.70 C) which was associated with upper & lower respiratory tract infections, bronchiolitis, malaria, enteric fever, viral illness, and urinary tract infections. They were allocated to three treatment arms - first group received paracetamol 15 mg/kg, second group received ibuprofen 10 mg/kg and third group received both paracetamol and ibuprofen - all as a single dose through oral route. Patients were followed up at intervals of 1, 2, 3, and 4 hours post-dose by tympanic thermometry.
The results indicated the rate of fall of temperature was highest in the paracetamol and ibuprofen combination group. Also, the number of afebrile children any time post-dose until 4 hours was highest in the combination group. The difference between combination and paracetamol was significant for the 1st hour (P = 0.04). The mean reduction in temperature at 4 hours post-treatment was 2.190 C, recorded as the highest reduction in the ibuprofen plus paracetamol-based combination group.
It was concluded that Paracetamol and ibuprofen combination caused quicker temperature reduction than either paracetamol or ibuprofen alone. The clinical implication of this study was to consider the use of this combination for quicker reduction of body temperature among Indian children suffering from a wide spectrum of infections.(8)
Efficacy of Ibuprofen and Paracetamol in the Most Common Acute Pain Syndromes in Children: Ibuprofen and Paracetamol have reported efficacy in children with sore throat, ear pains and acute otitis media, adenoid-tonsillectomy pains, toothaches, headaches, minor surgery pains, and musculoskeletal pains(4)
A large meta-analysis published by Tan E et al, towards the end of 2020, aimed to compare acetaminophen with ibuprofen for the short-term treatment of fever or pain in children younger than 2 years. It included 19 studies with 2,41,138 children under 2 years, and concluded that ibuprofen, compared with acetaminophen, was associated with reduced temperature at less than 4 hours and 4 to 24 hours; and less pain at 4 to 24 hours, with equivalent safety(3).
Use of Ibuprofen and Paracetamol – Guideline Testimonies
Both agents are generally well tolerated and given equal status in both national and international guidelines.(2) It is noteworthy that the American Academy of Otolaryngology-Head and Neck Surgery Foundation Clinical Practice Guideline update on tonsillectomy in children recommends that clinicians should recommend ibuprofen, acetaminophen, or both for pain control after tonsillectomy. This recommendation is graded as a 'strong' where the benefits clearly exceed the safety concerns(9)
Practical Pointers for Clinician
√ In pediatric population, unlike fever, which is often overtreated, pain remains poorly estimated and hence, undertreated.
√ Paracetamol and ibuprofen are the most widely prescribed medications for management of fever and pain in children (4)
√ Ibuprofen and Paracetamol combination leads to quicker and superior fever reduction among Indian children with infection and pain syndromes associated with viral infections, respiratory tract infections, malaria, enteric fever, and urinary tract infections.
√ Ibuprofen and Paracetamol are also clinically effective in sore throat, ear pains, adenoid-tonsillectomy pains, toothaches, headaches, musculoskeletal pains, and minor surgery pains.
√ Ibuprofen especially benefits pain-associated with clinically inflammatory conditions in children like acute pharyngotonsillitis and acute otitis media
References
Adapted from
1. McCormick A, Fleming D, Charlton J (1995) Morbidity statistics from general practice. Fourth national study. HMSO, London, pp 1991–1992
2. Kanabar DJ. A clinical and safety review of paracetamol and ibuprofen in children. Inflammopharmacology. 2017 Feb;25(1):1-9. doi: 10.1007/s10787-016-0302-3. Epub 2017 Jan 6. PMID: 28063133; PMCID: PMC5306275.
3. Tan E, Braithwaite I, McKinlay CJD, Dalziel SR. Comparison of Acetaminophen (Paracetamol) With Ibuprofen for Treatment of Fever or Pain in Children Younger Than 2 Years: A Systematic Review and Meta-analysis. JAMA Netw Open. 2020 Oct 1;3(10):e2022398. doi: 10.1001/jamanetworkopen.2020.22398. PMID: 33125495; PMCID: PMC7599455.
4. Poddighe D, Brambilla I, Licari A, Marseglia GL. Ibuprofen for Pain Control in Children: New Value for an Old Molecule. Pediatr Emerg Care. 2019 Jun;35(6):448-453. doi: 10.1097/PEC.0000000000001505. PMID: 29912084.
5. Barbagallo M, Sacerdote P. Ibuprofen in the treatment of children's inflammatory pain: a clinical and pharmacological overview. Minerva Pediatr 2019;71:82-99. DOI: 10.23736/S0026-4946.18.05453-1
6. Narayan K, Cooper S, Morphet J, Innes K. Effectiveness of paracetamol versus ibuprofen administration in febrile childdren: A systematic literature review. J Paediatr Child Health 2017;53:800–7.
7. Hay AD, Costelloe C, Redmond NM, Montgomery AA, Fletcher M, Hollinghurst S, Peters TJ. Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): randomised controlled trial. BMJ. 2008 Sep 2;337:a1302. doi: 10.1136/bmj.a1302. Erratum in: BMJ. 2009;339:b3295. PMID: 18765450; PMCID: PMC2528896.
8. Vyas, Falgun Indravadan et al. "Randomized comparative trial of efficacy of paracetamol, ibuprofen and paracetamol-ibuprofen combination for treatment of febrile children." Perspectives in clinical research vol. 5,1 (2014): 25-31. doi:10.4103/2229-3485.124567
9. Mitchell RB, Archer SM, Ishman SL, Rosenfeld RM, Coles S, Finestone SA, Friedman NR, Giordano T, Hildrew DM, Kim TW, Lloyd RM, Parikh SR, Shulman ST, Walner DL, Walsh SA, Nnacheta LC. Clinical Practice Guideline: Tonsillectomy in Children (Update)-Executive Summary. Otolaryngol Head Neck Surg. 2019 Feb;160(2):187-205. doi: 10.1177/0194599818807917. PMID: 30921525.
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