Drug Res (Stuttg) 2017; 67(02): 119-126
DOI: 10.1055/s-0042-118861
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Skin Irritation and Sensitization Potential of Fixed-Dose Combination of Diclofenac 1% and Menthol 3% Topical Gel: Results of Two Phase I Patch Studies

Dongzhou Jeffery Liu
1   Clinical Development, GSK, Collegeville, PA, USA
Agron Collaku
2   Biostatistics Department, GlaxoSmithKline Consumer Healthcare, Parsippany, NJ, USA
Jonathan S. Dosik
3   TKL Research Inc., Fair Lawn, NJ, USA
› Author Affiliations
Further Information

Publication History

received 17 June 2016

accepted 10 October 2016

Publication Date:
25 November 2016 (online)



Phase I, randomized, controlled patch studies were conducted to evaluate skin sensitization and irritation potential of a new gel formulation containing 1% diclofenac and 3% menthol as a fixed-combination product.


In study A, healthy volunteers were exposed to 4 test patches containing 1% diclofenac+3% menthol, diclofenac, menthol, or placebo gels during an induction (nine 48 to 72-h applications) and challenge phase (one 48-h application). Some subjects were re-challenged to evaluate suspected sensitization. Study B participants underwent 21 consecutive 24-h patch applications of the 4 treatments from study A, 0.2% sodium lauryl sulfate (positive control), 0.9% saline, and a marketed gel (1% diclofenac, Voltaren). Application sites were visually scored by blinded observers for skin sensitization/irritation.


In study A, 77% of participants showed minimal erythema and signs of glazing and peeling with 1% diclofenac+3% menthol by the end of the induction phase, which diminished during the challenge phase. Similar patterns were seen with menthol gel. Only 1 subject exhibited possible sensitization to 1% diclofenac+3% menthol. In study B, mean cumulative irritation score with 1% diclofenac+3% menthol was significantly higher (P<0.0001) vs. reference treatments; however, the positive control failed to produce the expected level of irritation. No treatment-related adverse events were reported.


The sensitization and irritation potential of 1% diclofenac+3% menthol was greater than with the reference treatments. Comparison with positive control was not possible because it did not produce irritation under semiocclusive patch conditions.

  • References

  • 1 Balduini FC, Tetzlaff J. Historical perspectives of lateral ankle sprain. Clin Sports Med 1982; 1: 3-12
  • 2 Kelly JD. Persistent ankle pain after ankle sprain. J Back Musculoskel Rehabil 1992; 2: 47-54
  • 3 Mitchell JA, Warner TD. Cyclo-oxygenase-2: pharmacology, physiology, biochemistry and relevance to NSAID therapy. Br J Pharmacol 1999; 128: 1121-1132
  • 4 Vane J. The mechanism of action of anti-inflammatory drugs. Int J Clin Pract Suppl 2003; 135: 2
  • 5 Vane JR. Aspirin and other anti-inflammatory drugs. Thorax 2000; 55: S3-S9
  • 6 Hla T, Neilson K. Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci U S A 1992; 89: 7384-7388
  • 7 Smith WL, Meade EA, Dewitt DL. Pharmacology of prostaglandin endoperoxide synthase isozymes-1 and -2. Ann New York Acad Sci 1994; 714: 136-142
  • 8 McAdam BF, Mardini IA, Habib A. et al. Effect of regulated expression of human cyclooxygenase isoforms on eicosanoid and isoeicosanoid production in inflammation. J Clin Invest 2000; 105: 1473-1482
  • 9 Henry D, Lim LL-Y, García Rodriguez LA. et al. Variability in risk of gastrointestinal complications with individual nonsteroidal anti-inflammatory drugs: results of a collaborative meta-analysis. Br Med J 1996; 312: 1563-1566
  • 10 Evans JMM, McMahon AD, McGilchrist MM. et al. Topical non-steroidal anti-inflammatory drugs and admission to hospital for upper gastrointestinal bleeding and perforation: record linkage case control study. Br Med J 1995; 311: 22-26
  • 11 Zhang W, Doherty M. EULAR recommendations for knee and hip osteoarthritis: a critique of the methodology. Br J Sports Med 2006; 40: 664-669
  • 12 Galeotti N, Di Cesare Mannelli L, Mazzanti G. et al. Menthol: a natural analgesic compound. Neurosci Lett 2002; 322: 145-148
  • 13 Haeseler G, Maue D, Grosskreutz J. et al. Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol. Eur J Anaesthesiol 2002; 19: 571-579
  • 14 Canadian Chiropractor . Topical analgesics [Internet]. Simcoe, Canada: Canadian Chiropractor; 2011. [cited 2015 December 4] http://www.canadianchiropractor.ca/content/view/2299/
  • 15 Miyatake S, Ichiyama H, Kondo E. et al. Randomized clinical comparisons of diclofenac concentration in the soft tissues and blood plasma between topical and oral applications. Br J Clin Pharmacol 2008; 67: 125-129
  • 16 Voltaren gel FDA drug approval package [Internet] [cited 2015 December 4] http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/Voltaren_022122.cfm
  • 17 Berger RS, Bowman JP. A reappraisal of the 21-day cumulative irritation test in man. J Toxicol Cutaneous Ocul Toxicol 1982; 1: 109-115
  • 18 Zhai H, Maibach HI. Skin occlusion and irritant and allergic contact dermatitis: an overview. Contact Dermatitis 2001; 44: 201-206
  • 19 Agner T, Serup J. Sodium lauryl sulphate for irritant patch testing – a dose-response study using bioengineering methods for determination of skin irritation. J Invest Dermatol 1990; 95: 543-547
  • 20 Hsieh LF, Hong CZ, Chern SH et al. Efficacy and side effects of diclofenac patch in treatment of patients with myofascial pain syndrome of the upper trapezius. J Pain Symptom Manage 2010; 39: 116–125