Model-Based Assessment of the Liver Safety Profile of Acetaminophen to Support its Combination Use with Topical Diclofenac in Mild-to-Moderate Osteoarthritis Pain.
Acetaminophen
Liver safety
Model-based meta-analysis
Osteoarthritis
Pain
Topical diclofenac
Journal
Pain and therapy
ISSN: 2193-8237
Titre abrégé: Pain Ther
Pays: New Zealand
ID NLM: 101634491
Informations de publication
Date de publication:
06 Jan 2024
06 Jan 2024
Historique:
received:
27
08
2023
accepted:
15
11
2023
medline:
7
1
2024
pubmed:
7
1
2024
entrez:
6
1
2024
Statut:
aheadofprint
Résumé
The use of combination therapy of oral acetaminophen and topical diclofenac, having complementary mechanisms of action, is an attractive strategy to enhance the analgesic response in osteoarthritis (OA) pain. While topical diclofenac is considered as well tolerated due to its low systemic exposure, concerns of liver toxicity with acetaminophen at standard analgesic doses remain. Thus, this study aimed to assess the liver safety profile of acetaminophen, particularly in OA management, using a model-based meta-analysis (MBMA). A literature review was conducted using the MEDLINE database to identify randomized clinical trials (RCTs) reporting liver toxicity on acetaminophen use. An MBMA was implemented to assess the deviation from the upper limit of normal (ULN) of alanine aminotransferase or aspartate aminotransferase, namely > 0-1 × ULN, > 1.5-2 × ULN, and > 3 × ULN representing mild, moderate, and severe risk of liver abnormality, respectively. A total of 15 RCTs were included in the MBMA, encompassing over 4800 subjects and exposure to acetaminophen ranging from 2 to 26 weeks. Of the 15 included studies, eight involved patients with OA pain, four involved healthy subjects and three were in patients with conditions such as asthma, glaucoma, chronic pain, and cardiovascular disease. Acetaminophen 1500-4000 mg/day was found to exhibit 23% (95% confidence interval (CI): 17.74-29.20), 1.35% (95% CI: 0.17-2.51) and 0.01% (95% CI: 0.00-0.32) increased risk for mild, moderate, and severe liver injury, respectively, versus placebo. Moreover, at therapeutic doses, no correlation was identified between acetaminophen intake and liver abnormality risk. Overall, our analysis shows that short-term (~ 8-16 weeks) acetaminophen use at therapeutically recommended doses is associated with a low risk of clinically relevant changes in liver enzymes. Given the good tolerability of topical diclofenac, the findings support the safety of the combination of acetaminophen and topical diclofenac, at least over the short term, as treatment for mild-to-moderate OA pain.
Identifiants
pubmed: 38183572
doi: 10.1007/s40122-023-00566-2
pii: 10.1007/s40122-023-00566-2
doi:
Types de publication
Journal Article
Langues
eng
Informations de copyright
© 2024. The Author(s).
Références
Long H, Liu Q, Yin H, et al. Prevalence trends of site-specific osteoarthritis from 1990 to 2019: findings from the Global Burden of Disease Study 2019. Arthritis Rheumatol. 2022;74(7):1172–83.
pubmed: 35233975
pmcid: 9543105
doi: 10.1002/art.42089
Neogi T. The epidemiology and impact of pain in osteoarthritis. Osteoarthritis Cartilage. 2013;21(9):1145–53.
pubmed: 23973124
pmcid: 3753584
doi: 10.1016/j.joca.2013.03.018
Perrot S. Osteoarthritis pain. Best Pract Res Clin Rheumatol. 2015;29(1):90–7.
pubmed: 26267003
doi: 10.1016/j.berh.2015.04.017
van Laar M, Pergolizzi JV Jr, Mellinghoff HU, et al. Pain treatment in arthritis-related pain: beyond NSAIDs. Open Rheumatol J. 2012;6:320–30.
pubmed: 23264838
pmcid: 3527878
doi: 10.2174/1874312901206010320
Raffa RB, Clark-Vetri R, Tallarida RJ, Wertheimer AI. Combination strategies for pain management. Expert Opin Pharmacother. 2003;4(10):1697–708.
pubmed: 14521480
doi: 10.1517/14656566.4.10.1697
WHO. World Health Organization Model List of Essential Medicines. 2021; https://www.who.int/groups/expert-committee-on-selection-and-use-of-essential-medicines/essential-medicines-lists , 2022.
Majeed MH, Sherazi SAA, Bacon D, Bajwa ZH. Pharmacological treatment of pain in osteoarthritis: a descriptive review. Curr Rheumatol Rep. 2018;20(12):88.
pubmed: 30465131
doi: 10.1007/s11926-018-0794-5
Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ. 2015;350: h1225.
pubmed: 25828856
pmcid: 4381278
doi: 10.1136/bmj.h1225
Leopoldino AO, Machado GC, Ferreira PH, et al. Paracetamol versus placebo for knee and hip osteoarthritis. Cochrane Database Syst Rev. 2019;2(2):Cd013273.
Mauger AR, Jones AM, Williams CA. Influence of acetaminophen on performance during time trial cycling. J Appl Physiol (1985). 2010;108(1):98–104.
Honvo G, Leclercq V, Geerinck A, et al. Safety of topical non-steroidal anti-inflammatory drugs in osteoarthritis: outcomes of a systematic review and meta-analysis. Drugs Aging. 2019;36(Suppl 1):45–64.
pubmed: 31073923
pmcid: 6509095
doi: 10.1007/s40266-019-00661-0
Shah S, Mehta V. Controversies and advances in non-steroidal anti-inflammatory drug (NSAID) analgesia in chronic pain management. Postgrad Med J. 2012;88(1036):73–8.
pubmed: 22052884
doi: 10.1136/postgradmedj-2011-130291
Huntjens DR, Danhof M, Della Pasqua OE. Pharmacokinetic-pharmacodynamic correlations and biomarkers in the development of COX-2 inhibitors. Rheumatology (Oxford). 2005;44(7):846–59.
pubmed: 15855183
doi: 10.1093/rheumatology/keh627
Taneja A, Oosterholt SP, Danhof M, Della Pasqua O. Biomarker exposure-response relationships as the basis for rational dose selection: Lessons from a simulation exercise using a selective COX-2 inhibitor. J Clin Pharmacol. 2016;56(5):609–21.
pubmed: 26331692
doi: 10.1002/jcph.629
NICE. Osteoarthritis: care and management. Clinical guideline [CG177]. In:2020.
Bruyere O, Honvo G, Veronese N, et al. An updated algorithm recommendation for the management of knee osteoarthritis from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). Semin Arthritis Rheum. 2019;49(3):337–50.
pubmed: 31126594
doi: 10.1016/j.semarthrit.2019.04.008
Bell J, Sethi V, Siddiqui K, Conaghan PG. AB0808 Combination of oral paracetamol and topical NSAIDs for osteoarthritis pain: a systematic scoping review of the literature. In: BMJ Publishing Group Ltd; 2019.
Bariguian Revel F, Fayet M, Hagen M. Topical diclofenac, an efficacious treatment for osteoarthritis: a narrative review. Rheumatol Ther. 2020;7(2):217–36.
pubmed: 32086778
pmcid: 7211216
doi: 10.1007/s40744-020-00196-6
Alchin J, Dhar A, Siddiqui K, Christo PJ. Why paracetamol (acetaminophen) is a suitable first choice for treating mild to moderate acute pain in adults with liver, kidney or cardiovascular disease, gastrointestinal disorders, asthma, or who are older. Curr Med Res Opin. 2022;38(5):811–25.
pubmed: 35253560
doi: 10.1080/03007995.2022.2049551
Conaghan PG, Arden N, Avouac B, Migliore A, Rizzoli R. Safety of paracetamol in osteoarthritis: what does the literature say? Drugs Aging. 2019;36(Suppl 1):7–14.
pubmed: 31073920
pmcid: 6509082
doi: 10.1007/s40266-019-00658-9
Roberts E, Delgado Nunes V, Buckner S, et al. Paracetamol: not as safe as we thought? A systematic literature review of observational studies. Ann Rheum Dis. 2016;75(3):552–9.
pubmed: 25732175
doi: 10.1136/annrheumdis-2014-206914
Dart RC, Bailey E. Does therapeutic use of acetaminophen cause acute liver failure? Pharmacotherapy. 2007;27(9):1219–30.
pubmed: 17723075
doi: 10.1592/phco.27.9.1219
Mandema JW, Cox E, Alderman J. Therapeutic benefit of eletriptan compared to sumatriptan for the acute relief of migraine pain–results of a model-based meta-analysis that accounts for encapsulation. Cephalalgia. 2005;25(9):715–25.
pubmed: 16109054
doi: 10.1111/j.1468-2982.2004.00939.x
Chan P, Peskov K, Song X. Applications of model-based meta-analysis in drug development. Pharm Res. 2022.
Mandema JW, Gibbs M, Boyd RA, Wada DR, Pfister M. Model-based meta-analysis for comparative efficacy and safety: application in drug development and beyond. Clin Pharmacol Ther. 2011;90(6):766–9.
pubmed: 22089340
doi: 10.1038/clpt.2011.242
Maringwa J, Sardu ML, Hang Y, et al. Characterizing effects of antidiabetic drugs on heart rate, systolic and diastolic blood pressure. Clin Pharmacol Ther. 2021;109(6):1583–92.
pubmed: 33280092
doi: 10.1002/cpt.2130
Qin L, Zhang N, Ishigami J, et al. Dyskalemia risk associated with fixed-dose anti-hypertensive medication combinations. J Hum Hypertens. 2021.
Witjes H, Khatri A, Diderichsen PM, Mandema J, Othman AA. Meta-analyses of clinical efficacy of risankizumab and adalimumab in chronic plaque psoriasis: supporting evidence of risankizumab superiority. Clin Pharmacol Ther. 2020;107(2):435–42.
pubmed: 31502263
doi: 10.1002/cpt.1624
Marshall S, Madabushi R, Manolis E, et al. Model-informed drug discovery and development: current industry good practice and regulatory expectations and future perspectives. CPT Pharmacometrics Syst Pharmacol. 2019;8(2):87–96.
pubmed: 30411538
pmcid: 6389350
doi: 10.1002/psp4.12372
FDA Guidance. Meta-analyses of randomized controlled clinical trials to evaluate the safety of human drugs or biological products guidance for industry. Drug Safety. 2018.
Al-Busafi SA, Hilzenrat N. Mild hypertransaminasemia in primary care. ISRN hepatology. 2013;2013: 256426.
pubmed: 27335825
pmcid: 4890914
doi: 10.1155/2013/256426
Ozer J, Ratner M, Shaw M, Bailey W, Schomaker S. The current state of serum biomarkers of hepatotoxicity. Toxicology. 2008;245(3):194–205.
pubmed: 18291570
doi: 10.1016/j.tox.2007.11.021
Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354(7):731–9.
pubmed: 16481640
doi: 10.1056/NEJMra052270
O’Neil CK, Hanlon JT, Marcum ZA. Adverse effects of analgesics commonly used by older adults with osteoarthritis: focus on non-opioid and opioid analgesics. Am J Geriatr Pharmacother. 2012;10(6):331–42.
pubmed: 23036838
pmcid: 3529168
doi: 10.1016/j.amjopharm.2012.09.004
Freo U, Ruocco C, Valerio A, Scagnol I, Nisoli E. Paracetamol: a review of guideline recommendations. J Clin Med. 2021;10(15).
Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Rheumatol. 2020;72(2):220–33.
pubmed: 31908163
pmcid: 10518852
doi: 10.1002/art.41142
Zeng C, Wei J, Persson MSM, et al. Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: a systematic review and network meta-analysis of randomised controlled trials and observational studies. Br J Sports Med. 2018;52(10):642–50.
pubmed: 29436380
doi: 10.1136/bjsports-2017-098043
Craig DG, Bates CM, Davidson JS, Martin KG, Hayes PC, Simpson KJ. Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced hepatotoxicity. Br J Clin Pharmacol. 2012;73(2):285–94.
pubmed: 22106945
pmcid: 3269587
doi: 10.1111/j.1365-2125.2011.04067.x
Stanos SP, Galluzzi KE. Topical therapies in the management of chronic pain. Postgrad Med. 2013;125(4 Suppl 1):25–33.
pubmed: 24547601
doi: 10.1080/00325481.2013.1110567111
Wadsworth LT, Kent JD, Holt RJ. Efficacy and safety of diclofenac sodium 2% topical solution for osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled, 4 week study. Curr Med Res Opin. 2016;32(2):241–50.
pubmed: 26506138
doi: 10.1185/03007995.2015.1113400
Barbosa CD, Balp MM, Kulich K, Germain N, Rofail D. A literature review to explore the link between treatment satisfaction and adherence, compliance, and persistence. Patient Prefer Adherence. 2012;6:39–48.
pubmed: 22272068
pmcid: 3262489
doi: 10.2147/PPA.S24752
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012.
Mitchell SJ, Kane AE, Hilmer SN. Age-related changes in the hepatic pharmacology and toxicology of paracetamol. Current gerontology and geriatrics research. 2011;2011: 624156.
pubmed: 21765826
pmcid: 3135080
doi: 10.1155/2011/624156
Le Couteur DG, McLean AJ. The aging liver. Drug clearance and an oxygen diffusion barrier hypothesis. Clinical pharmacokinetics. 1998;34(5):359–373.
Heard K, Green JL, Anderson V, Bucher-Bartelson B, Dart RC. A randomized, placebo-controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration. BMC Pharmacol Toxicol. 2014;15:39.
pubmed: 25047090
pmcid: 4118644
doi: 10.1186/2050-6511-15-39
Maeda M, Tanaka R, Aso M, et al. Hepatic adaptation to therapeutic doses of acetaminophen: an exploratory study in healthy individuals. Clin Ther. 2020;42(7):1276–1291 e1271.
Pincus T, Koch GG, Sokka T, et al. A randomized, double-blind, crossover clinical trial of diclofenac plus misoprostol versus acetaminophen in patients with osteoarthritis of the hip or knee. Arthritis Rheum. 2001;44(7):1587–98.
pubmed: 11465710
doi: 10.1002/1529-0131(200107)44:7<1587::AID-ART282>3.0.CO;2-X
Altman RD, Zinsenheim JR, Temple AR, Schweinle JE. Three-month efficacy and safety of acetaminophen extended-release for osteoarthritis pain of the hip or knee: a randomized, double-blind, placebo-controlled study. Osteoarthritis Cartilage. 2007;15(4):454–61.
pubmed: 17142063
doi: 10.1016/j.joca.2006.10.008
Bradley JD, Brandt KD, Katz BP, Kalasinski LA, Ryan SI. Comparison of an antiinflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med. 1991;325(2):87–91.
pubmed: 2052056
doi: 10.1056/NEJM199107113250203
Doherty M, Hawkey C, Goulder M, et al. A randomised controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain. Ann Rheum Dis. 2011;70(9):1534–41.
pubmed: 21804100
doi: 10.1136/ard.2011.154047
Ganetsky M, Berg AH, Solano JJ, Salhanick S. Inhibition of CYP2E1 with propylene glycol does not protect against hepatocellular injury in human acetaminophen daily-dosing model. J Clin Pharmacol. 2019;59(1):131–8.
pubmed: 30151903
doi: 10.1002/jcph.1299
Herrero-Beaumont G, Ivorra JA, Del Carmen TM, et al. Glucosamine sulfate in the treatment of knee osteoarthritis symptoms: a randomized, double-blind, placebo-controlled study using acetaminophen as a side comparator. Arthritis Rheum. 2007;56(2):555–67.
pubmed: 17265490
doi: 10.1002/art.22371
Ioannides SJ, Siebers R, Perrin K, et al. The effect of 1 g of acetaminophen twice daily for 12 weeks on alanine transaminase levels–A randomized placebo-controlled trial. Clin Biochem. 2015;48(10–11):713–5.
pubmed: 25899926
doi: 10.1016/j.clinbiochem.2015.04.011
Mohamed N, Meyer D. Intraocular pressure-lowering effect of oral paracetamol and its in vitro corneal penetration properties. Clin Ophthalmol. 2013;7:219–27.
pubmed: 23390358
pmcid: 3564461
doi: 10.2147/OPTH.S38473
Pincus T, Koch G, Lei H, et al. Patient Preference for Placebo, Acetaminophen (paracetamol) or Celecoxib Efficacy Studies (PACES): two randomised, double blind, placebo controlled, crossover clinical trials in patients with knee or hip osteoarthritis. Ann Rheum Dis. 2004;63(8):931–9.
pubmed: 15082468
pmcid: 1755088
doi: 10.1136/ard.2003.020313
Parra D, Beckey NP, Stevens GR. The effect of acetaminophen on the international normalized ratio in patients stabilized on warfarin therapy. Pharmacotherapy. 2007;27(5):675–83.
pubmed: 17461702
doi: 10.1592/phco.27.5.675
Prior MJ, Harrison DD, Frustaci ME. A randomized, double-blind, placebo-controlled 12 week trial of acetaminophen extended release for the treatment of signs and symptoms of osteoarthritis. Curr Med Res Opin. 2014;30(11):2377–87.
pubmed: 25121804
doi: 10.1185/03007995.2014.949646
Temple AR, Benson GD, Zinsenheim JR, Schweinle JE. Multicenter, randomized, double-blind, active-controlled, parallel-group trial of the long-term (6–12 months) safety of acetaminophen in adult patients with osteoarthritis. Clin Ther. 2006;28(2):222–35.
pubmed: 16678643
doi: 10.1016/j.clinthera.2006.02.004
Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006;296(1):87–93.
pubmed: 16820551
doi: 10.1001/jama.296.1.87