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Veterinary Therapeutics Summer 2008 (Vol 9, No 2)

Comparative Adrenocortical Suppression in Dogs with Otitis Externa following Topical Otic Administration of Four Different Glucocorticoid-Containing Medications

by Chris Reeder, DVM, Craig Griffin, DVM, DACVD, N. Polissar, PhD, B. Neradilek, MS, Rob Armstrong, DVM, DVSc

    Clinical Relevance

    The safety of using otic formulations is often of concern for practitioners and pet owners alike, with "safe" in this context meaning no adrenocortical suppression. This study evaluated the effect of four glucocorticoid-containing otic formulations on plasma cortisol concentrations, measured by corticotropin stimulation testing (plasma cortisol concentrations before and after corticotropin injection), in dogs presented with otitis externa. Dexamethasone tended to have larger adrenocortical suppression compared with the other three formulations (betamethasone, triamcinolone, and mometasone), but the difference was not statistically significant. The largest difference among the four drugs was observed between dexamethasone and betamethasone (P = .09).

    Introduction

    Otitis externa is a common disease in dogs and a frequent reason for them to be presented for treatment. A survey of dermatologic conditions seen by general practitioners in the United Kingdom from 1998 to 2001 concluded that 795 of 3,707 (21.4%) consultations were dermatology related,1 with the majority (62.6%) of such patients being dogs and the primary presenting problem (22% of presented dogs) being otitis. Otitis externa is a complex disease thought to involve predisposing, primary, and perpetuating factors. Primary causes initiate otic inflammation, which is then maintained by otic pathogens, including Malassezia spp yeast and coagulase-positive Staphylococcus spp bacteria; in the presence of inflammation, otic pathogens tend to be found in greater numbers, and often together, in the external ear canal of dogs with otitis externa. The combination of infection from an inciting cause and the resulting significant inflammation contributes to the disease pathogenesis. The nature of otitis externa often justifies treatment with a combination topical product composed of antibacterial, antifungal, and antiinflammatory agents.2,3 In the United States, many commercially available topical otic products are labeled for the treatment of canine otitis externa.

    Topical corticosteroids are included in otic products because of the importance of controlling inflammation in the management of otitis externa. However, corticosteroids can have adverse side effects. Previous studies have documented systemic effects following administration of topical glucocorticoids in healthy dogs. Zenoble and Kemppainen4 evaluated topical medications (triamcinolone acetate, fluocinonide, or betamethasone valerate or no steroid [control group]) applied to a shaved patch on the lateral thorax of healthy dogs (four groups of five dogs each). All dogs receiving a topical steroid preparation showed a significant decrease in plasma cortisol, as determined by corticotropin stimulation testing, starting after day 2 of treatment and lasting at least 3 weeks after the medication was discontinued. Two previous studies5,6 evaluated topically applied otic medications containing a steroid in combination with other ingredients. Moriello and associates5 evaluated two groups of eight dogs each treated for 7 days with a commercial otic medication containing dexamethasone or triamcinolone, and all dogs developed marked adrenocortical suppression based on corticotropin stimulation testing at the 1-week recheck. Ghubash et al6 also showed adrenocortical suppression in healthy dogs treated with an otic medication containing dexa­methasone (Tresaderm, Merial) based on comparison of corticotropin stimulation testing results before and after 14 days of treatment; however, these authors found that adrenocortical suppression was significantly less in healthy dogs treated with an otic medication containing betamethasone (Otomax, Schering-Plough Animal Health).

    All these studies4-6 evaluated the effects of topical glucocorticoid administration in normal ears; there are no published studies evaluating systemic effects of such treatments in dogs with otitis externa. Inflammation could increase blood flow to the ear canal and change the nature of the epidermal barrier, thereby altering the absorption of a topically applied medication. Thus, one objective of the present study was to evaluate the systemic effects of topically applied glucocorticoids in dogs with otitis externa.

    Mometasone furoate is a potent glucocorticoid approved in the United States for use in humans as both topical and inhaled products. It is a 16a-methyl analogue of beclomethasone that has higher glucocorticoid receptor affinity compared with other common glucocorticoids.7 An in vitro study in humans found that mometasone furoate has 22, 7, 5, and 1.5 times greater glucocorticoid receptor affinity compared with dexamethasone, triamcinolone acetonide, budesonide, and fluticasone proprionate, respectively.7 Despite this potency, mometasone furoate has no significant adrenocortical suppression compared with other topically applied glucocorticoids in humans,8 and it has been found to cause no significant adrenocortical suppression after inhalation therapy at 400 µg/day for 14 days in people with mild to moderate asthma. However, higher dosages (800 and 1,600 µg/day) caused adrenocortical suppression in humans based on 24-hour serum and urinary cortisol concentrations.9 Asthmatic patients administered inhaled mometasone furoate at 400 µg/day for 14 days had a significantly smaller decrease in serum and urine cortisol levels than did patients treated with beclomethasone.10

    Mometasone furoate is the glucocorticoid component of Mometamax (Intervet/Schering-Plough Animal Health), a topical otic preparation licensed in the United States for treatment of canine otitis externa using once-daily administration for 7 days. Manufacturer safety data have shown that topical administration of this product in healthy dogs does not cause greater systemic effects than does treatment with betamethasone.11 However, no studies are available in dogs with preexisting otitis externa, and the second objective of this study was to investigate possible differences between systemic effects of topical Mometamax and older commercially available products.

    Materials and Methods

    This was a randomized, double-blinded, 7-day study with no placebo group. This study was designed to follow FDA suggested dosing guidelines for each of the medications tested.

    Animals

    Owners of dogs referred to a specialty dermatology practice and confirmed to have bilateral otitis externa were offered the opportunity to enroll their pets in this study. All dogs were privately owned, and owners provided informed consent for their dogs to be included in the study. Animal care and use committee approval was not required because the study was conducted by a private veterinary referral hospital. Dogs of either sex (neutered or intact but not pregnant or nursing) between the ages of 8 months and 10 years and weighing 2 to 60 kg were eligible for enrollment (see Table 1 for summary data for the enrolled dogs). Typical clinical signs were erythema of the external ear canal, head shaking, pawing at the ears, and otic odor or discharge. All dogs received an otoscopic examination; to be enrolled in the study, dogs were required to have bilateral intact tympanic membranes (no tears seen), no more than 25% stenosis of the vertical ear canal, no "cobblestone appearance" to the ear canal epithelium, and no calcification of the ear canal cartilage. Additionally, enrolled dogs were required to have no history of polyuria, polydipsia, polyphagia, or other systemic disease with two exceptions: Dogs with hypothyroidism could be enrolled provided they were stable under treatment for the past year, and dogs with atopic dermatitis that were being treated with allergen-specific immunotherapy for at least the past 8 months could also be enrolled. Dogs were excluded if they had been treated with oral antihistamines, oral antibiotics, oral antifungals, or topical otic medications within the 2 weeks before enrollment; oral glucocorticoids within 8 weeks before enrollment; or injectable glucocorticoids within 10 weeks before enrollment.

    Clinical Evaluation

    At the start of the study, each dog received a full physical examination and an otoscopic examination using a handheld otoscope and a clean otoscopic cone for each ear. Ear cytology was performed on both ears of each dog to evaluate and classify the etiology of the otitis externa (i.e., bacterial, yeast, or only allergic). A cotton-tipped applicator was used to collect material from the level of the vertical and horizontal canal; the applicator was gently rolled onto a glass microscope slide, which was then heat-fixed and stained with a modified Wright's stain (Medical Chemical Corp., Torrance, CA). Baseline (day 0) and posttreatment (day 7) serum chemistry panels, complete blood counts (CBCs), and thyroid panels were obtained for all dogs. Dogs with abnormal results on day 0 (prestudy baseline) were not included in the study.

    Corticotropin Stimulation Testing

    A compounded form of corticotropin gel (2.2 U/kg administered in the epaxial muscle) was used for the corticotropin stimulation test. The gel form of corticotropin for adrenal stimulation has been well validated in previous studies and is commonly used for such testing.12-15 Whole blood samples were collected from all dogs immediately before and 2 hours after corticotropin administration on days 0 and 7. All blood samples were allowed to clot for 10 to 20 minutes before being centrifuged (1,957 xg) for 5 minutes; serum was then withdrawn and refrigerated at 4°C for up to 12 hours. An independent commercial laboratory performed the cortisol analysis using a standardized kit radioimmunoassay evaluated for use in dogs (Diagnostic Products Corp., Los Angeles, CA).16

    Medications

    After completion of the corticotropin stimulation testing procedure, each dog's ears were flushed with Cerumene (Vétoquinol) and reexamined with the handheld otoscope.

    Each dog was randomly assigned to a treatment group and prescribed one of four topical ear medications:

    • Mometamax (gentamicin sulfate, mometasone furoate monohydrate, and clotrimazole)
    • Panolog (nystatin, neomycin sulfate, thio­strepton, and triamcinolone acetonide; Fort Dodge Animal Health)
    • Tresaderm (thiabendazole, dexamethasone, and neomycin sulfate)
    • DVMax (gentamicin sulfate, betamethasone valerate, and clotrimazole; IVX Animal Health [generic for Otomax])

    Briefly, as each patient was enrolled, it was assigned a number in sequence (i.e., 1, 2, 3, and so on). The study statistician prepared sealed envelopes with the treatment assignment (A, B, C, or D) in randomized order. The veterinary technician assigned to this project opened the next lettered envelope for the patient to obtain treatment assignment. The investigators were not involved in dispensing or discussing the medications with the owners and were blinded to which medication was dispensed to each patient. Each medication was repackaged into a 15-ml dropper bottle that provided prescribing information only (no product labeling). Owners were instructed about how to instill the medications and potential side effects. If a patient had any adverse side effects, the owner was instructed to contact the veterinary technician assigned to this project. If necessary, the technician would ask the investigator about the proper course of action and would be unblinded only if absolutely necessary owing to the specific side effect noted. Owners were instructed to instill the medication into each ear according to the product label directions. Specific dosages prescribed were:

    • Mometamax: 4 drops for dogs weighing <30 lb or 8 drops for dogs weighing >30 lb administered once daily
    • Panolog: 4-6 drops twice daily
    • Tresaderm: 5-7 drops twice daily
    • DVMax: 4 drops for dogs weighing <30 lb and 8 drops for dogs weighing >30 lb administered twice daily

    Based on this, the calculated dose range for each group was:

    • Mometasone: 0.007-0.02 mg/kg once daily
    • Triamcinolone: 0.002-0.03 mg/kg twice daily
    • Dexamethasone: 0.004-0.024 mg/kg twice daily
    • Betamethasone: 0.006-0.03 mg/kg twice daily

    Statistics

    Univariate and multivariate analyses were used to examine associations between predictor variables and the two outcome variables: (1) the day 7 two-hour corticotropin stimulation testing value and (2) the difference between the day 7 and day 0 corticotropin values at 2 hours (day 7 minus day 0). In addition to type of medication, the other predictor variables included sex, reproductive status (neutered versus intact), breed size (small, ≤20 lb; large, >20 lb), ear conformation (pendulous versus nonpendulous), age, weight, and the day 0 two-hour corticotropin stimulation testing value.

    In the univariate analysis, mean values of the two corticotropin outcome variables were compared among groups using the two-sample t-test (comparing two groups of dogs) or one-way analysis of variance (three or more groups). As the primary planned study analysis, mean values of the outcome variables between Mometamax and each of the other drugs were compared. The two null hypotheses that all four drugs had equal mean values for each of the two outcome variables were tested, and additional post hoc analysis comparing all pairs of drugs was conducted. CIs and P values for the six pairwise comparisons were adjusted for multiple comparisons using Tukey's method.17 Associations between continuous predictor variables, such as age, and the outcome variables were determined using linear regression.

    Using clinical ranges, the day 7 two-hour corticotropin stimulation testing values were categorized as falling below, within, or above the normal range, and the proportions of dogs in these categories were compared among the four medications. Statistical significance was determined using the Fisher exact test.

    A multivariate linear regression model was built to test the association between medication and the day 7 two-hour corticotropin stimulation testing value, with adjustment for other important predictor variables. Only variables with P < .1 in the univariate analysis were considered for selection into the multivariate model. Variables were selected into the multivariate model using backward elimination (with P < .05 for retention in the model). Medication was then added into the final multivariate model.

    P < .05 was used to designate statistical significance. All calculations were carried out in R Statistical Software, version 2.5.0 (R Foundation for Statistical Computing, Vienna, Austria).

    Results

    A total of 46 dogs were evaluated for enrollment into the study, and 40 were enrolled. The other 6 dogs were not enrolled because their baseline chemistry panel, CBC, thyroid panel, or corticotropin stimulation test results were outside normal limits.

    The 40 dogs enrolled into the study had a mean age of 4.2 years and mean weight of 51.5 lb; 65% were females, and 78% were neutered (Table 1). There were 63% large-breed dogs, and 43% of dogs had pendulous ears (Table 1). The number of dogs assigned to each treatment group was:

    • Mometamax: 9 (23%)
    • Panolog: 12 (30%)
    • Tresaderm: 8 (20%)
    • DVMax: 11 (28%)

    Ear cytology was evaluated first on low power (100×) to visualize larger aggregations of debris and inflammatory cells and then on high power (1,000× using oil immersion). Bacteria, yeast, keratinocytes, and inflammatory cells were counted in 10 high-power fields. All dogs had some level of yeast or bacteria in their ear canals (data not shown; unrelated to the purpose of the study other than as inclusion criteria for otitis externa). The results of day 7 serum chemistry panels, CBCs, and thyroid panels did not markedly differ from baseline day 0 values; statistical analysis was not performed for pre- versus posttreatment values for these parameters because they were intended to be used as inclusion criteria. No patient had any adverse side effects from any medication during the course of this study. Individual results for day 7 two-hour corticotropin stimulation testing are listed in Table 2 .

    Comparison of mean values of day 7 two-hour corticotropin stimulation testing values showed no statistically significant differences between sexes or pertaining to reproductive status (intact versus neutered), breed size, or ear conformation and no statistically significant association with age or weight (Table 3). Baseline 2-hour corticotropin stimulation testing was strongly related to day 7 two-hour corticotropin stimulation testing (Table 3). Based on the univariate analysis, no statistically significant differences were seen between Mometamax and Panolog or DVMax (Table 3); however, there was a marginally significant difference between Mometamax and Tresaderm (Mometamax, 12.2 ± 1.0 mg/dl; Tresaderm, 9.1 ± 3.7 mg/dl; P = .052). No statistically significant differences were found between any of the groups with regard to categoric or continuous predictor values (Table 3).

    In the post hoc comparison of mean day 7 two-hour corticotropin values between all pairs of drugs (Table 4), relatively small differences in means among DVMax, Panolog, and Mometamax were noted, with P values all close to 1. However, the mean corticotropin stimulation testing value for Tresaderm was considerably lower than the mean for each of the other three drugs, although only one (Tresaderm versus DVMax) of the three differences of individual drugs compared with Tresaderm was marginally or statistically significant (P = .09 for the comparison of day 7 values; P = .03 for the comparison of changes between day 0 and day 7).

    Plasma cortisol concentration was suppressed below the normal range (8 to 17 mg/dl) at the day 7 two-hour corticotropin stimulation testing in 0%, 9%, 17%, and 50% of dogs treated with Mometamax, DVMax, Panolog, and Tresaderm, respectively (Table 5). Values above the normal range at the day 7 two-hour corticotropin stimulation testing were noted in 9% of DVMax- and 17% of Panolog-treated dogs. There was a statistically significant difference between Mometamax and Tresaderm (P = .03, Fisher exact test) when comparing the percentage of dogs in or out of the normal range for the day 7 two-hour corticotropin stimulation testing.

    Among the non-medication predictor variables considered, the day 0 two-hour corticotropin stimulation testing value was the only variable to be retained in the multivariate model for the day 7 two-hour corticotropin outcome variable. The comparison of the drugs in the multivariate analysis confirmed the findings from the univariate analysis. Namely, after adjustment for the day 0 two-hour corticotropin stimulation testing variable, there was still a marginally significant difference in mean response between the Mometamax and Tresaderm groups (P = .06) and relatively small and statistically nonsignificant differences between Mometamax and the other groups (Table 6).

    Discussion

    All dogs affected with otitis externa and treated with Mometamax had normal corticotropin stimulation testing results after 1 week of topical treatment, which is consistent with previous human studies.8,9 At least one dog in each group treated with the other topical glucocorticoids did develop adrenocortical suppression, although the difference between Mometamax and each of the other groups was not statistically significant except for Tresaderm in individual dogs. This result conflicts with a previous study that found that all dogs treated topically with Panolog for 7 days had significant adrenocortical suppression.5 This may be related to the overall larger daily dose of glucocorticoid. Ghubash et al also saw significant adrenocortical suppression in dogs treated with topical Panolog.6 The substantial, marginally significant adrenocortical suppression seen in this study after 7 days of treatment with Tresaderm versus Mometamax is similar to previous findings in studies evaluating dexamethasone compared with other topical glucocorticoids.4,6 The elevated cortisol from the day 7 two-hour corticotropin stimulation testing results seen in three dogs (two dogs in the Panolog group and one in the DVMax group) were likely stress induced. Cross-reactivity could have occurred between the glucocorticoids in these products and cortisol, leading to a false elevation in cortisol in response to corticotropin stimulation testing. It is possible the vehicle in each medication may have caused an increase or a decrease in transepidermal penetration, a phenomenon previously discussed by Ghubash et al.6 Inflammation may alter the epidermal barrier function and increase the absorption of topically applied glucocorticoids, thereby increasing the likelihood of posttreatment adrenocortical suppression.

    In this study of dogs with otitis externa, the results for dogs receiving Tresaderm topically applied according to the manufacturer's recommendations are virtually the same as the results seen in a previous study in healthy dogs receiving the same product.6 This suggests that drug absorption is similar in dogs with inflamed ears and healthy dogs; however, corticotropin stimulation testing is a very imprecise measure of cutaneous absorption and more reflects systemic uptake. Additionally, the study by Ghubash et al6 used 10 drops of Tresaderm (0.02 to 0.19 mg of dexamethasone/kg) twice daily compared with the dose used in this study (5 to 7 drops or 0.004 to 0.024 mg of dexamethasone/kg twice daily), which is five to eight times lower. Furthermore, Ghubash et al used a dose of Otomax equivalent to 0.011 to 0.047 mg of betamethasone/kg twice daily and observed no adrenocortical suppression in any dogs treated with this product for 14 days.6 In our study, the total daily dose of betamethasone was 0.006 to 0.03 mg/kg, or about 1.5 to 1.8 times lower than the study by Ghubash et al.6 Both that study and our study used manufacturer recommended dosing; the range in the dosing contributed to the large difference in the milligram amount of glucocorticoid product applied.

    Further controlled work using larger groups of dogs is needed to determine whether otic inflammation changes the risk for adrenocortical suppression associated with topical glucocorticoid treatment of otitis externa. A larger sample size would also allow a better appreciation of the true adrenocortical suppression associated with Tresaderm, as this may have been somewhat related to chance in the smaller sample size we used. Dogs with ulcerated ears were excluded from this study, and it is possible that more severe changes associated with otitis externa could have additional influence on the risk for adrenocortical suppression.

    Conclusion

    Only the topical otic treatment containing dexamethasone created marginally significant adrenocortical suppression compared with the other treatment groups. The clinical impression is that the dexamethasone-containing product also induced substantial adrenocortical suppression in individual dogs, although no statistical significance can be assumed from such small numbers. All dogs treated with Mometamax at the manufacturer's recommended dose had normal corticotropin stimulation testing results, while half of the dogs treated with Tresaderm and some dogs in the Panolog and DVMax groups had corticotropin stimulation testing results outside the normal range at the completion of treatment. This phenomenon may have been a result of once-daily rather than twice-daily dosing. The study did not investigate whether otic inflammation altered the risk of adrenocortical suppression following topical glucocorticoid therapy. Larger sample sizes along with a comparison between dogs with and without otitis externa are needed to evaluate the possibility of whether otic inflammation increases glucocorticoid absorption.

    Acknowledgments

    We thank Intervet/Schering-Plough Animal Health for funding this study and Dr. Chris Pappas for his support. We are also grateful to Mountain-Whisper-Light Statistical Consulting for providing the statistical analysis and give special thanks to Drs. Wayne Rosenkrantz, Rusty Muse, Joel Griffies, and Colleen Mendelsohn for their support.

    Downloadable PDF

    This study was funded by Intervet/Schering-Plough Animal Health, Summit, NJ.

    1. Hill PB, Lo A, Eden CA, et al. Survey of the prevalence, diagnosis and treatment of dermatological conditions in small animals in general practice. Vet Rec 2006;158(16):533-539.

    2. Cafarchia C, Gallo S, Capelli G, Otranto D. Occurrence and population size of Malassezia spp. in the external ear canal of dogs and cats both healthy and with otitis. Mycopathologia 2005;160(2):143-149.

    3. Saridomichelakis MN, Farmaki R, Leontides LS, Koutinas AF. Aetiology of canine otitis externa: a retrospective study of 100 cases. Vet Dermatol 2007;18(5):341-347.

    4. Zenoble RD, Kemppainen RJ. Adrenocortical suppression by topically applied corticosteroids in healthy dogs. JAVMA 1987;191(6):685-688.

    5. Moriello KA, Fehrer-Sawyer SL, Meyer DL, Feder B. Adrenocortical suppression associated with topical otic administration of glucocorticoids in dogs. JAVMA 1988;193(3):329-331.

    6. Ghubash R, Marsella R, Kunkle G. Evaluation of adrenal function in small-breed dogs receiving otic glucocorticoids. Vet Dermatol 2004;15(6):363-368.

    7. Fardon TC, Lee DK, Haggart K, et al. Adrenal suppression with dry powder formulations of fluticasone propionate and mometasone furoate. Am J Respir Crit Care Med 2004;170(9):960-966.

    8. Prakash A, Benfield P. Topical mometasone. a review of its pharmacological properties and therapeutic use in the treatment of dermatological disorders. Drugs 1998;55(1):145-163.

    9. Affrime MB, Kosoglou T, Thonoor CM, et al. Mometasone furoate has minimal effects on the hypothalamic-pituitary-adrenal axis when delivered at high doses. Chest 2000;118(6):1538-1546.

    10. Chrousos GP, Ghaly L, Shedden A, et al. Effects of mometasone furoate dry powder inhaler and beclomethasone dipropionate hydrofluoroalkane and chlorofluorocarbon on the hypothalamic-pituitary-adrenal axis in asthmatic subjects. Chest 2005;128(1):70-77.

    11. Freedom of Information Summary. NADA 141-177. Mometamax Otic Solution for Dogs. Available at www.fda.gov/cvm/FOI/141-177.pdf; accessed May 2008.

    12. Feldman E, Nelson R. Canine and Feline Endocrinology and Reproduction. 3rd ed. St Louis: Saunders; 2004:464-483.

    13. Watson AD, Church DB, Emslie DR, et al. Plasma cortisol responses to three corticotrophic preparations in normal dogs. Aust Vet J 1998;76(4):255-257.

    14. Kemppainen RJ, Behrend EN, Busch KA. Use of compounded adrenocorticotropic hormone (ACTH) for adrenal function testing in dogs. JAAHA 2005;41(6):368-372.

    15. Ettinger S, Feldman E. Textbook of Veterinary Internal Medicine. 6th ed. St Louis: Saunders; 2005:1599-1600.

    16. Singh AK, Jiang Y, White T, Spassova D. Validation of nonradioactive chemiluminescent immunoassay methods for the analysis of thyroxine and cortisol in blood samples obtained from dogs, cats, and horses. J Vet Diagn Invest 1997;9(3):261-268.

    17. Braun H. The Collected Works of John W. Tukey. Vol 8. New York: Chapman and Hall; 1994.

    References »

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