NephRxTools

Beta · Literature search and summary

Clinical evidence

Kidney outcomes, measured exposure and efficacy.

Kidney outcomes

Guidance

  • NKF · patient guidance, 2025. Describes topical diclofenac as a potential option in CKD, citing low systemic exposure. Advises professional review and use within label directions. National Kidney Foundation, 2025
  • VA/DoD · CKD guideline discussion, 2025. Suggests that topical NSAIDs may carry less kidney risk than oral NSAIDs, while some risk may remain. This narrative discussion considers trial and observational findings; residual confounding is possible. VA/DoD, 2025

Study findings

  • Roth & Fuller · pooled randomized trials, n = 927. Over 12 weeks in knee osteoarthritis, greater creatinine increases and CrCl decreases were reported with oral diclofenac than with topical solution. Not a dedicated CKD trial. Roth & Fuller, 2011 Older-adult trials and longer follow-up.
  • Teo et al. · retrospective cohort, n = 6,298 with CKD. Any AKI within 30 days: topical NSAIDs versus no NSAID, adjusted odds ratio 1.38 (95% CI 1.18–1.63). Mixed topical NSAIDs; no product-specific estimate. Teo et al., 2023
  • Lim et al., 2021 · retrospective cohort, n = 12,773 aged ≥60 years. AKI and/or hyperkalemia within 30 days: topical NSAIDs versus no NSAID, adjusted odds ratio 1.48 (95% CI 1.31–1.67). In the CKD subgroup, topical versus short-course systemic NSAIDs: adjusted odds ratio 0.74 (95% CI 0.60–0.90). Lim et al., 2021
  • Lim et al., 2022 · retrospective cohort, n = 12,798 aged ≥65 years. AKI and/or hyperkalemia within 30 days: topical NSAIDs versus no NSAID, adjusted odds ratio 1.29 (95% CI 1.15–1.45). Related Singapore data; patient overlap with the earlier analyses is unquantified. Lim et al., 2022
  • Krummel et al. · case report. AKI after topical ketoprofen, followed by improvement after drug withdrawal. Patient with CKD; concomitant enalapril and furosemide. A single report cannot estimate incidence. Krummel et al., 2000

Limitations: Cohort findings are associations, not a causal or Voltaren-specific risk estimate. Cohort extraction is abstract-based; full-text appraisal pending. Related cohorts may overlap and are not pooled. These studies do not establish safety or a dosing/monitoring schedule for active or recent AKI or dialysis. Teo et al., 2023 Lim et al., 2021 Lim et al., 2022

Roth & Fuller · pooled trials in older adults

  • Seven trials, 4–12 weeks; 280 adults aged ≥75 years with knee or hand osteoarthritis. Diclofenac solution 1.5%: n = 138; placebo: n = 39; DMSO control: n = 103. Roth & Fuller, 2012
  • Renal/urinary adverse events were uncommon; no group differences were detected. Blood pressure and renal laboratory changes were also similar. Roth & Fuller, 2012

Limitations: Not a CKD-specific analysis. Small samples and short follow-up cannot establish absence of uncommon kidney harm. Roth & Fuller, 2012

Shainhouse et al. · uncontrolled long-term study

  • 793 adults with knee osteoarthritis used topical diclofenac solution: 40 drops to each painful knee four times daily, for up to 52 weeks. Mean exposure was 204 days; 144 participants used it for 1 year. Shainhouse et al., 2010
  • Creatinine shifted from normal to abnormal in 4.2% of subjects. The abstract reports clinically significant shifts in fewer than 0.3% per laboratory variable. Shainhouse et al., 2010

Limitations: No concurrent control; a laboratory shift is not an adjudicated AKI event. This does not establish CKD progression risk or override Canadian label duration restrictions. Shainhouse et al., 2010

Canadian labels and counselling
Find the exact product and label

Systemic exposure

Study regimens are not prescribing instructions.

Canadian gels · selected studies

  • Voltaren Emulgel 1.16%: 4 g three times daily; 7 days; final morning administration on day 7. Site and area not reported. Haleon Canada ULC, 2026aAUC (0–24 h), geometric mean: 179 ng·h/mL topical versus 1360 ng·h/mL oral. Voltaren diclofenac sodium enteric-coated tablet; 25 mg three times daily. Haleon Canada ULC, 2026a
  • Voltaren Emulgel Extra Strength 2.32%: 2 g twice daily; 7 days; day-7 assessment. Same ankle, ≈400 cm²; non-occlusive. Haleon Canada ULC, 2026bAUC (0–24 h), geometric mean: 67.9 ng·h/mL topical versus 2830 ng·h/mL oral. Voltaren diclofenac sodium 50 mg tablet; release type not specified in the retrieved VOPO summary; 50 mg three times daily. Haleon Canada ULC, 2026b

Healthy-volunteer PK studies, not CKD safety trials. The gel regimens come from separate studies and are not a head-to-head comparison.

Compare studied formulations and regimensAUC, Cmax, reported absorption and study limitations

Application site and formulation

Shah et al. · ketoprofen gel at three sites

  • Randomized crossover; 24 healthy men. Ketoprofen gel 3%: 1 g (30 mg) every 6 hours for 25 doses over 100 cm² of back, arm or knee. Reference: 0.5 mL ketoprofen solution 60 mg/mL on the back. Shah et al., 1996
  • Reported relative bioavailability versus the topical solution: back 0.90 ± 0.50; arm 1.08 ± 0.63; knee 0.74 ± 0.38. Knee Cmax was lower than arm/back. Urinary recovery of total enantiomers ranged from 5.41% to 9.10% of dose. Shah et al., 1996

Limitations: The abstract does not identify the ± statistic. These are topical-reference comparisons, not oral-relative percentages or diclofenac site-conversion factors. Shah et al., 1996

Moreira & Liu · diclofenac/menthol gel

  • Crossover study; 18 healthy adults. Diclofenac sodium 1% + menthol 3% gel, 4 g four times daily for 3 days, compared with Voltaren sodium gel 1% at the same regimen and oral diclofenac 50 mg three times daily. Moreira & Liu, 2017
  • AUC48–72 relative to oral: tube 16.1% (90% CI 12.2–21.1%); roll-on 14.4% (90% CI 11.0–19.0%). Greater diclofenac exposure was reported with the combination than with the comparator gel. Moreira & Liu, 2017

Limitations: Dose normalization and application area were not established from the abstract. Vehicle differences prevent attributing the effect to menthol alone; no transfer to Canadian gels or compounds. Moreira & Liu, 2017

Salicylate absorption and safety reports

Human absorption studies and reports of interactions and toxicity.

Methyl vs trolamine salicylate

  • Studied preparations: 12 healthy adults; 5 g/application of methyl salicylate 12.5% ointment twice daily for 4 days, or trolamine salicylate 10% cream twice daily for 1 day. Thigh application area: 10 cm², as reported in the abstract. Morra et al., 1996
  • Serum salicylic acid: Methyl salicylate: Cmax 2–6 mg/L after application seven (day 4). Undetectable after trolamine application. Morra et al., 1996
  • 24-hour urinary recovery: Total salicylate and principal metabolites relative to applied dose: methyl salicylate 15.5% on day 1, approximately 22% on days 2–4; trolamine 1.4% on day 1. Urinary recovery is not an oral-relative AUC percentage. Undetectable serum levels do not mean zero absorption. Morra et al., 1996
  • Source limitation: English abstract: day-1 recovery 15.5%; translations: 15.7%. Full-text tables not verified. Morra et al., 1996

Methyl salicylate during heat and exercise

  • Human study: In 6 healthy volunteers, methyl salicylate absorption was more than threefold higher during exercise in heat than under control conditions. Systemic availability was assessed using plasma salicylate and urinary salicyluric acid over 8 hours. Danon et al., 1986
  • Limitations: This experimental finding is not a multiplier for another product, body site or application pattern. The retrieved abstract does not specify the applied dose, vehicle or area. Danon et al., 1986

Results apply to the studied preparations and regimens; exposure in renal impairment and equivalent oral doses were not established.

Interactions and toxicity

Yip et al. · warfarin interaction series

  • Eleven patients receiving warfarin had elevated INR after substantial topical methyl salicylate use; three had bleeding manifestations. Yip et al., 1990

Limitations: Selected cases without an exposed-population denominator. These reports describe a possible interaction; they do not estimate its frequency or establish effects with all anticoagulants. Yip et al., 1990

Joss & LeBlond · warfarin interaction case

  • A patient with previously stable warfarin anticoagulation had INR 12.2 after daily application of a methyl-salicylate-containing gel to the knees for 8 days. Joss & LeBlond, 2000

Limitations: The retrieved abstract does not establish the applied amount or exact formulation. The case cannot define a safe quantity. Joss & LeBlond, 2000

Tabatabai et al. · systemic toxicity case

  • An older adult reportedly used a 3-ounce tube of methyl salicylate 30% / menthol 10% cream on the back over 2 days. Serum salicylate was 41.4 mg/dL. Skin was intact and renal function described as near normal. Tabatabai et al., 2025

Limitations: Additional oral or chronic exposure could not be excluded. This is a toxicity report, not a therapeutic-use PK estimate or a KaLaya-specific result. Tabatabai et al., 2025

Find salicylate products and label cautions

Efficacy and alternatives

Findings apply to the studied formulations and pain conditions.

Derry et al. · salicylate rubefacients

  • The Cochrane review found insufficient dependable evidence to support salicylate-containing rubefacients for acute injuries or chronic musculoskeletal pain. Derry et al., 2014

Limitations: Search through August 2014. This concerns efficacy, not a quantified kidney risk or every current multicomponent product. Derry et al., 2014

Brutcher et al. · compounded creams

  • Randomized trial; 399 patients with localized chronic pain. The tested mixtures included ketoprofen for nociceptive pain and diclofenac for mixed pain. No significant improvement over placebo in average pain-score reduction was found at 1 month. Brutcher et al., 2019

Limitations: Different mixtures and heterogeneous pain conditions; not an InflaFlex trial. Systemic exposure and CKD safety were not established. Brutcher et al., 2019

US lidocaine patch 5% · measured absorption

  • Fifteen healthy volunteers wore three patches (2,100 mg lidocaine total) for 12 hours on 420 cm² of intact back skin. Bryant Ranch Prepack, 2024
  • Label-reported dose absorbed: 64 ± 32 mg; expected absorbed fraction: 3 ± 2%; Cmax: 0.13 ± 0.06 mcg/mL. Bryant Ranch Prepack, 2024

Limitations: This record concerns the studied US 5% patch. It does not establish CKD safety or exposure from Canadian creams, sprays, 4% patches or compounds. Bryant Ranch Prepack, 2024

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