Management of Rhinitis Medicamentosa: A Systematic Review

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Management of Rhinitis Medicamentosa:

A Systematic Review

Otolaryngology–

Head and Neck Surgery 1–10

ÓAmerican Academy of Otolaryngology–Head and Neck Surgery Foundation 2018 Reprints and permission:

sagepub.com/journalsPermissions.nav DOI: 10.1177/0194599818807891 http://otojournal.org

Shana M. Zucker

¹

, Blair M. Barton, MD

¹

, and Edward D. McCoul, MD, MPH

^1,2,3

Sponsorships or competing interests that may be relevant to content are dis- closed at the end of this article.

Abstract

Objective.Rhinitis medicamentosa (RM) is a common condition resulting from overuse of topical nasal decongestants.

Despite the prevalence in otolaryngologic practice, a clear treatment protocol has not been established. Our objective was to review the current published literature pertaining to the treatment of RM with the possibility of finding data that support one treatment over another.

Data Sources. PubMed, Embase, Cochrane, and Web of Science databases were examined for patients diagnosed with RM resulting from chronic use of topical nasal decongestants.

Review Methods.The PRISMA standard (Preferred Reporting Items for Systematic Reviews and Meta-analyses) was utilized to identify English-language studies reporting treatment of patients with the primary diagnosis of RM after chronic use of a topical decongestant. Outcome measures of interest included patient-reported symptom relief and objective parameters. MINORS criteria (methodological index for nonrandomized studies) were used to assess the quality of articles.

Results. A total of 350 articles were identified, 9 of which met final inclusion criteria for qualitative analysis. Outcomes defined in each publication were highly varied and relied on several unstandardized measures. The most commonly reported treatment option was topical nasal steroids, although overall there was limited evidence on which to base treatment recommendation.

Conclusions. There is not adequate evidence to develop a standardized treatment protocol for RM. The development of a uniform questionnaire, standard outcomes to be measured, and a method of assessing such outcomes is necessary. Prospective randomized controlled studies are warranted to determine the optimal treatment regimen following diagnosis of RM.

Keywords

rhinitis medicamentosa, chronic rhinitis, nonallergic rhinitis, nasal decongestants, systematic review, rhinomanometry, nasal congestion

Received July 10, 2018; revised August 29, 2018; accepted September 28, 2018.

R

hinitis medicamentosa (RM), also referred to as rebound rhinitis, is a type of nonallergic mucosal inflammation resulting from the overuse of topical nasal decongestants. RM causes patients to experience nasal stuffiness, swelling, discomfort, and mucosal hyperreactiv- ity.^1-3Topical nasal decongestants are indirect sympathomimetic drugs that exert action by promoting vesicular release of norepinephrine from neurons with subsequent stimulation of alpha-adrenergic receptors.⁴Topical nasal decongestants, such as oxymetazoline and phenylephrine, which are available over the counter, result in vasoconstriction and hyper- trophy of the nasal soft tissue.^5-7 Despite a relatively high incidence of RM in up to 9% of patients visiting otolaryngology and allergy clinics, the pathophysiologic mechanism is not well understood.⁸Consequently, management of RM has not been clearly defined, with most physicians advocat- ing for the prompt discontinuation of topical decongestants and application of intranasal steroids and nasal saline.^1-3,5,6

Patients who self-medicate with topical nasal decongestants pose a particular challenge to physicians, as these agents are easily accessible over the counter and characteris- tically provide rapid relief of nasal congestion. As a result, physical dependence can occur, which drives the vicious cycle of continued use of the product in an effort to main- tain nasal patency. Other sinonasal disorders may underlie or coexist with RM, which indicates the importance of obtaining a thorough history to identify overlapping sources

1Department of Otolaryngology–Head and Neck Surgery, School of Medicine, Tulane University, New Orleans, Louisiana, USA

2Department of Otorhinolaryngology, Ochsner Clinic Foundation, New Orleans, Louisiana, USA

3Ochsner Clinical School, School of Medicine, University of Queensland, New Orleans, Louisiana, USA

This article was presented as a poster at the 2018 Triological Combined Sections Meeting; January 18-20, 2018; Scottsdale, Arizona.

Corresponding Author:

Edward D. McCoul, MD, MPH, Department of Otorhinolaryngology, Ochsner Clinic Foundation, 1514 Jefferson Hwy, CT4, New Orleans, LA 70121, USA.

Email: [email protected]

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of nasal obstruction or inflammation.^3-5,7-9 Patients with allergic rhinitis, septal deviation, or upper respiratory infec- tions often elect to use over-the-counter topical nasal decongestants, putting themselves at higher risk for developing RM.⁴Despite the recognition of RM as a clinical entity for several decades, an widely accepted protocol of treatment to wean patients off these medications has yet to be established.¹⁰

A variety of medical and surgical treatments are poten- tially available to treat patients with RM. We aimed to sum- marize the available evidence in the literature about the treatment of RM, which might form the basis for a standardized protocol for treatment and a guide for future research.

Outcomes of interest included improved breathing and reduced decongestant use among patients with RM.

Methods

A comprehensive review of the English-language literature was performed from the following electronic bibliographic databases: PubMed, EMBASE, the Cochrane Library, and Web of Science (science and social science citation index).

Search criteria included all occurrences in the title or abstract of the following terms: (1)rhinitis medicamentosa, rebound rhinitis, chronic rhinitis, or atrophic rhinitis and (2) nasal decongestant and (3) nasal steroids or turbinate reduction. Inclusion criteria for the literature search were defined with the PICOS approach (population, intervention, control, outcome, study design). Search criteria included adults.18 years of age described as having RM, rebound rhinitis, chronic rhinitis, or atrophic rhinitis as a result of the chronic use of topical nasal decongestant medications.

Interventions included, but were not limited to, nasal steroid treatment or turbinate reduction and were compared with a control. Outcomes measured in our search were improvement of breathing and related symptoms. Study designs included case-control, case series with chart review, prospective cohorts, and randomized controlled trials. A systematic search was performed and reported in accordance with the PRISMA standard (Preferred Reporting Items for Systematic Reviews and Meta-analyses;Figure 1).

Two reviewers (S.M.Z., B.M.B.) performed eligibility assessment of data in a standardized manner. In the initial screening, the abstract of every citation was reviewed for relevance to the treatment of RM in human patients.

Irrelevant citations and case reports were excluded and duplicate records subsequently removed. The full text of the remaining citations was obtained and reviewed in full.

Noneligible studies were excluded—specifically, those that did not provide data on treatments or outcomes and those that did not distinguish between patients with RM and those with other forms of rhinitis. One full-text article was excluded because the authors published 2 articles about the same patients in a prospective cohort: the original report¹⁰ and a 1-year follow-up.¹¹ The 1-year follow-up study was selected for inclusion in the qualitative synthesis. The other remaining studies were included for qualitative analysis.

Despite the use of the exclusion criterion of patients .18

years old, 3 of our qualifying studies each included 1 under- age patient in the study cohort.^12-14

The MINORS criteria (methodological index of nonrandomized studies) were used by 2 independent reviewers (S.M.Z., B.M.B.) to appraise the quality of the selected articles (Table 1). The MINORS criteria form a validated test that was developed as a tool to assess the quality and risk of bias of observational studies.¹⁵ The qualifying articles were reviewed and scored out of a maximum of 16 (if the study was nonrandomized) or a maximum of 24 (in the case of a comparative study). The items are scored as 0 (not reported), 1 (reported but inadequate), or 2 (reported and adequate).¹⁵

Extracted data from full-text articles included study setting, design, population, participant demographics and baseline characteristics, criteria for patient collection, details of the intervention and control conditions, recruitment and completion rates, and outcomes and times of measurement, as well as sponsorship by pharmaceutical companies. The principal summary measures were patient reports of symptom relief, nasal airflow, thickness of nasal mucosa, and ability to discontinue use of topical vasoconstrictors without relapse. The risk of bias was assessed at the study level by examining each study for design, the stated purpose for the study, and the source of patient data collection. The risk of bias at the evidence level was determined for each study to provide an estimate of strength and study design.

Quantitative data were assessed for suitability of pooling into a meta-analysis.

Results

The initial database query identified 345 articles, which were screened for relevance to the treatment of RM (Figure 1). Article reference lists were also screened, yield- ing an additional 5 relevant articles. Duplicates were removed, followed by articles meeting exclusion criteria, then those not adequately fulfilling inclusion criteria. One additional article¹⁰ was excluded because the authors had published 2 reports, 1 year apart, on the same 10-patient prospective case cohort; the 1-year follow-up¹¹was selected for inclusion, while the original article was deemed ineligi- ble to avoid data duplication.

A total of 9 articles were included for analysis. Risk of bias was assessed, and overall study quality was heteroge- neous, with 4 randomized controlled trials and 5 noncontrolled studies (Table 1). MINORS scores ranged from 9 to 12 (out of 16) for the noncontrolled studies and 18 to 20 (out of 24) for the controlled studies (Table 2).

Data from the included studies are summarized inTable 3. The RM treatment regimens included nasal steroids, nasal steroids with oxymetazoline hydrochloride, oral ATP (adenosine triphosphate), a laser diode, and a kinetic oscillator. Outcome data included patient reports of symptom relief, nasal volume, peak inspiratory flow, nasal flow and resistance, minimal cross-sectional area, thickness of nasal mucosa, histamine sensitivity, and ability to discontinue use of topical vasoconstrictors without relapse. Findings were

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positive across all studies: regardless of the intervention, patients experienced improvement in each study’s measured parameters. However, the patient age range, observation period, and number of patients in the intervention differed across publications. Furthermore, outcome measures and treatment protocols were inconsistent across the included publications. As such, quantitative pooling was unable to be performed in this review due to heterogeneity of outcome measures across interventions.

Discussion

RM is a pervasive and frustrating condition for patients and physicians alike, without a consensus on treatment type or treatment duration. The lack of standard regimen is directly linked to the uncertainty, as reflected in the literature, of the pathophysiologic mechanism underlying RM. One proposal holds that the chronic vasoconstriction causes hypoxemia and subsequent ischemia of the nasal mucosa, resulting in impaired function and congestion.^7,9 Alternatively, fatigue of the overstimulated alpha- and beta-adrenergic vasoconstrictor mechanisms may occur, resulting in reactive hypere- mia and edema, as well as tachyphylaxis and decreased sensitivity to endogenous catecholamines, defined as a

decreasing therapeutic response necessitating a higher dosage of medication to attain the same benefit.^4,7,9 A third proposal is that increased parasympathetic activity intended to counter the sympathomimetic drugs may alter vasomotor tone, resulting in increased vascular permeability and edema.⁴ Histologic, pharmacokinetic, and pathophysiologic studies are necessary to better understand the mechanism of RM, which would lead investigators to more targeted treatments.

Of the interventions assessed, 1 eligible publication assessed oral ATP; 1 used a kinetic oscillator device; and 1 utilized a laser diode treatment. The most commonly used treatment among the included studies was intranasal steroids.12,13,16-22

Whereas the pathophysiology of the condition of RM is not fully understood, the mechanism of action is most well understood for nasal steroids. The conclusion of Vaidyanathan et al may be a good starting point in better understanding the pathophysiology of the condition, as their results showed statistical significance in reversal of tachyphylaxis in response to fluticasone.¹⁹It has been established that the use of nasal steroids results in activation of beta- adrenergic receptors, resulting in a cascade that inhibits endothelial adherence of leukocytes and the subsequent Figure 1.Flow diagram of study screening and selection. RM, rhinitis medicamentosa.

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activation of prostaglandin synthesis, thereby promoting res- olution of the edematous state of the nasal mucosa.^1,23,24It is believed that the edema, rather than vasodilation, is the component of RM that is responsible for the hallmark nasal obstruction.^1,23Treatment of RM fails because the symptom of chronic obstruction results in relapse to abuse of decongestants; therefore, subjects whose obstruction is relieved exhibit lower rates of returning to topical decongestant use^1,23with nasal mucosa that reverts to normal.^24-27

Clinical trials in the mid-1970s developed the use of dexamethasone as an intranasal steroid treatment, with decreasing frequency over 2 to 4 weeks.^3,12,28 Since then, administration of corticosteroids has been established as a first-line therapy for allergic rhinitis,²⁹but with a more con- crete understanding of the pathophysiology of RM, a more appropriate and specific pharmacologic intervention could be developed.^1,6,7,9,17 Contrary to previous studies, which pointed to immediate cessation of topical nasal decongestants,^3,21 findings in this review point to the potential for an alternative management plan.

A further finding of this review, albeit understated, is the importance of patient education. Only 2 studies highlighted the importance of informing patients of the cause of their rhinitis, which is the overuse of topical nasal decongestants, and that limiting the frequency and duration of these medications is central to avoiding development of RM.^11,16 Reviews describing RM highlighted the significance of properly informing patients of the risk of abusing topical decongestants, emphasizing that this crucial piece of com- munication could help prevent the development of RM alto- gether. These reviews further suggested that, given both patient-reported and objective measures of nasal pressure, administration of these medications should be limited to a controlled medical setting.^7,16 Such discussion of patient education is hardly touched on in the included studies, and limiting the use of topical decongestants to a medical center was not suggested.

The selectivity of the inclusion and exclusion criteria greatly affects the ability to qualitatively assess the findings of these publications as a whole. The inclusion of patients with perennial allergic rhinitis in 1 study weakens the broader conclusions that can be drawn.¹⁷ Furthermore, inclusion criteria of daily overuse of topical nasal decongestants ranged from minimum 1 month,¹² 3 months,¹⁸ 4 months,²¹ minimum 1 year,¹⁴ and minimum 15 months.²⁰ One study included patients whose use of topical nasal decongestants ranged from 3 to 15 years, with dose per day ranging from daily use to 15 times a day.¹⁶ One study defined overuse as administration 5 times a day, and the duration of these doses ranged from 2 weeks to .10 years.¹³ One study included exclusively healthy patients in whom RM was induced with oxymetazoline and treated by administering nasal steroids 3 times a day for 2 weeks and then 2 times a day for 3 more days.¹⁹The exclusion criteria, however, were generally comparable.

The outcomes examined included patient reports of symptom relief, peak nasal inspiratory flow, nasal flow and Table1.MINORS:MethodologicalIndexofNonrandomizedStudies.a Author(Year)

MINORS Score

Clearly Stated Aim

Inclusionof Consecutive Patients Prospective Collection ofData Endpoints Appropriate Unbiased Assessment ofEndpoint Appropriate Follow-up Period

Lossto Follow-up \5%

Prospective Calculation ofSample

Adequate Control Group

Contemporary Groups Baseline Equivalence ofGroups

Adequate Statistical Analyses Halle

´n

(1997)16 18212212202202 Ferguson(2001)17 20222222202202 Juto(2014)18 19212212102222 Vaidyanathan(2010)19 18112211202222 Wang(1991)13 1021121210———— Caffier(2008)14 1222221210———— Baldwin(1975)12 1222220220———— Graf(1997)11 1121221120———— Bende(1996)20 921220200———— a Dashesindicatenonrandomizedstudy(ie,16maximumscorevs24forcomparativestudy).

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resistance, peak inspiratory flow, minimal cross-sectional area, thickness of mucosa, histamine sensitivity, patient ability to discontinue use of topical nasal decongestants without relapse, and histological examination. The 2 most common measures were objective patient report of symptom relief and nasal flow and resistance. Given the complementary role for subjective and objective measures—specifically, objective measures that are accurate and replicable—we propose that the outcomes to be measured would ideally include (1) a standardized subjective patient symptom score, (2) nasal flow and resistance, and (3) histological changes.

Simplifying or ensuring that future studies measure these 3 outcomes, with the same indices, would reduce variability and yield results that could provide standardized practice recommendations.

The heterogeneity of reporting patient symptom scores stands out as a key issue from this systematic review. Of the included studies, 6 incorporated patient reports of symptom relief as 1 of their primary outcomes, yet all 6 utilized different methods. In 1 study, patients reported their daily

‘‘nasal congestion’’ scores on a visual analog scale of 1 to 10 in both the morning and the evening over the course of the 6-week trial¹⁷; another study used a visual analog scale of 1 to 100 to estimate ‘‘nasal stuffiness’’ before treatment and at 6 and 12 months after the treatment period.²¹ Other studies reported quotes of patients describing their ‘‘sinuses opening up,’’¹²queried patient ‘‘need’’ for topical decongestants at 2 and 6 months after the treatment period,²⁰used a visual analog scale of 1 to 10 to report nasal airflow as well as patient satisfaction at pre- and posttherapeutic time points,¹⁷ and required patients to keep a diary symptom score based on summing scales of 0 to 4 in the categories of stuffiness, itching, and secretion.¹⁴ The heterogeneity in assessments of the hallmark symptom of RM highlights a deficiency in the current literature. The employment of common measures and a validated disease-specific tool would enhance validity and comparability.

A second useful outcome for studying RM is analysis of nasal flow and resistance. Current evidence suggests that rhinomanometry would be the most precise, accurate, and relevant objective test for RM, with high reliability.^30-32

Furthermore, given that RM is a condition in which swelling and congestion are key physical findings, the ability of rhinomanometry to measure transnasal flow and pressure make it an appropriate functional examination.³¹Additionally, acoustic rhinometry, which evaluates changes in airway dimensions and geometry,^31,32 is highly correlated with rhinomanometry and was found to produce comparable results; as such, these measures could be used complementarily,^30,32 which would facilitate standardization of objective outcomes.

Finally, further examination of histologic changes was one of the least common outcomes assessed, yet it has the potential to deepen the understanding of the pathophysiology of RM.^8,33 Recent findings suggest that patients with RM have alterations including, but not limited to, reduced cilia cell counts, changes in cilia ultrastructure, and rupture of the basal layer, each of which predisposes a patient to interstitial edema.^9,30,31Additionally, ultrastructural changes to the endothelial cells of capillaries of the submucosal sinu- soid venous plexuses suggestive of increased permeability is indicative of edema.^20,30 Using these 3 ideal outcomes and common methods would allow for better comparison and potential pooling of results.

It is important to note that the strength of the conclusions drawn from this systematic review depends on the quality of the evidence of the studies, as reflected in the assessment with MINORS criteria. Notably, while the loss to follow-up was predominately reported and adequate, the majority of the studies had inadequate reporting of patient selection, and none of the included studies prospectively calculated a sample size. Further significant limitations include that 3 of the 4 randomized studies were subject to potential conflict of interest, as they were supported by pharmaceutical and pharmaceutical device companies.^16-18 Additionally, 2 studies combined information in such a way that only vague inferences can be made about their findings. Specifically, 1 article included patients with either RM or perennial allergic rhinitis but did not distinguish their outcomes in the presen- tation of the data,¹⁷whereas the second article administered 2 different treatments and likewise presented all patients as 1 group.¹³ Another publication experienced patient dropout but made assumptions about the data.¹⁹ This limits the Table 2.Itemized Assessment of Risk of Bias for Studies Included in Systematic Review.

Author (Year) Direction of Inquiry Randomization Blinding Handling of Lost Data Basis for Treatment Allocation

Halle´n (1997)¹⁶ Prospective Yes Yes NA Randomized

Ferguson (2001)¹⁷ Prospective Yes NA Excluded Randomized

Juto (2014)¹⁸ Prospective Yes Yes Excluded Randomized

Vaidyanathan (2010)¹⁹ Prospective Yes Yes Excluded Randomized

Wang (1991)¹³ Prospective (case series) No NA NA NA

Caffier (2008)¹⁴ Prospective (case series) NA NA NA Standard protocol

Baldwin (1975)¹² Prospective (case series) NA NA NA Standard protocol

Graf (1997)¹¹ Prospective (case series) NA NA NA Standard protocol

Bende (1996)²⁰ Prospective (case series) NA NA NA Standard protocol

Abbreviation: NA, not applicable.

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Table3.StudyDataAvailableforQualitativeAnalysis. Author(Year)Design Age,Mean (Range),y Control: Treatment,nControlTreatment Outcomes Reviewed MethodsofOutcome AnalysisFindings Halle

´n (1997)16 RCT3310:10Placebonasal sprayqd for14d

Fluticasone propionatenasal spray,200mgqd for14d Patientreportsof symptomrelief, nasalvolume, PNIF,MCA, thicknessofnasal mucosa Nasalmucosalswelling andMCArecorded withrhinostereometry, acousticrhinometry, andpeakinspiratory flowmeter;nasal stuffiness(estimatedon VAStwicedaily)

Meanreductionwith rhinostereometry: 1.2mm Meanincreasein MCA:0.27cm2 PNIFmean improvement:121 min Morningsymptom scores:reducedby Eveningsymptom scores:reducedby Improvement statisticallysignificant vsplaceboafter1 2wk Ferguson(2001)17 RCT37.210:9Placebonasal spray

BANS,32mg/sprayPatientreportsof symptomrelief, nasalvolume, MCA

Subjective:patients recordednasal congestionscoreson 10-pointVASAMandPM (meanusedfor statisticalanalysis); objective:nasalvolume andminimalcross- sectionalareaby acousticrhinometry

Significantlyless congestedand subjectivesymptom improvementvs placebo Nasalairway objectivelywas improvedvsplacebo butnottostatistical significance MCAsignificantly decreased Juto(2014)18 RCT4035:36Device maintained stable pressure without oscillation

Kineticoscillation stimulation: mechanical vibrationsat50 Hz Patientreportsof symptomrelief, PNIF

RQSS,diarysymptom score,PNIFMedianRQSS stuffinessmeasur from2to1(onscale of0to3) Vaidyanathan(2010)19 RCT3319:19Fluticasone,200mg BIDfor3d; placeboatdays1, 14,17

Fluticasone,200mg BIDfor3d;oral prazosin,1mg,at days1,14,17 PNIF,NARPNIF,NAR, oxymetazolinedose- responsecurve

Significantdecrease PNIFafterday1 Significantincrease NARafterdays1, 14,17 (continued)

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Table3.(continued) Author(Year)Design Age,Mean (Range),y Control: Treatment,nControlTreatment Outcomes Reviewed

MethodsofOutcome AnalysisFindings Wang(1991)13 Prospective clinical investigation

17-50NA:22 (1),8(2)

NA(1)Topical dexamethasone ortriamcinolone innormalsaline for1-2wk, followedby normalsalineas regularnasal drops;(2)oral ATP,20mg,3 timesdaily PNIF,NARNasalmucusclearance timemeasurement, grossappearanceof nasalmucous membrane,optical microscopyappearance ofsampletakenfrom junctionofanteriorand middlethirdsofinferior turbinate,and rhinomanometry

Nasalmucus clearancetime shortenedinvarying degreesthroughout cohort Caffier(2008)14 Prospective clinical investigation

44(15-72)NA:42NAVideo-endoscopic inferiorturbinate reductionwitha diodelaser

Patientreportsof symptomrelief, PNIF,NAR, abilityto discontinue vasoconstrictors withoutrelapse Shortterm:NAR,patient satisfactionratingon VAS;longterm:inferior turbinate photodocumentation, recurrentneedfor decongestants

NAR:significant improvement SubjectiveVAS: significant improvement 88%patients successfullystopped decongestantabuse after6mo,74%after 1y Baldwin(1975)12 Caseseriesreport14-60NA:22NADexamethasone administeredby Decadron Turbinaire apparatus:0.084 mgm,with diminishing frequencyover4 wk

Patientreportsof symptomrelief, MCA,patient abilityto discontinue vasoconstrictors withoutrelapse Completecessationof topicalvasoconstrictors inanyform,reliefof symptoms,returnof appearanceofnasal mucosato‘‘normal’’

Allpatients discontinueduseof topical vasoconstrictors within2wkof treatmentregimen withoutrelapseat mofollow-up (continued)

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Table3.(continued) Author(Year)Design Age,Mean (Range),y Control: Treatment,nControlTreatment Outcomes Reviewed

MethodsofOutcome AnalysisFindings Graf(1997)11 1-yfollow-upof prospective clinical investigation

30.3(18-42)NA:10NABudesonidespray, 400mg/d,for6 wkduring decongestant withdrawal Patientreportsof symptomrelief, MCA

MCA,decongestiveeffect ofoxymetazoline, histaminesensitivity measuredwith rhinostereometry; symptomscorefor nasalstuffiness

Histaminesensitivity: stillincreasedafter mobutnotafter1 Decongestiveeffect oxymetazoline: increasedafter6m (indicativeof reversibletolerance) Norelapsetolong- termuseduring1-y follow-up Bende(1996)20 Casecohort30NA:11NABANS,8000mg/d, for2mo

Patientreportsof symptomrelief, NAR

NARatrestandafter exercise,beforeand aftertreatment;need fortopicalnasal decongestants2and6 moaftertreatment period

Statisticallysignificant differenceintotal NARatrestbefor andaftertreatment (38.064.3) Nostatistically significantdifference intotalNARafter exercisebeforeand aftertreatment Abbreviations:ATP,adenosinetriphosphate;BANS,budesonideaqueousnasalspray;BID,twiceperday;MCA,minimalcross-sectionalarea;NA,notapplicable;NAR,nasalairwayresistance;PNIF,peaknasalinspira- toryflow;qd,daily;RCT,randomizedcontrolledtrial;RQSS,RhinitisQuestionnaireSymptomScore;VAS,visualanalogscale.

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conclusions that can be drawn about the effectiveness of the findings.

Although the results from these publications cannot be quantitatively pooled, the reported subjective patient experience, as well as objective examination of nasal function, suggests that further investigation of RM is needed. Doing so with consistently selected and evaluated outcomes and performing prospective randomized controlled trials would be a significant contribution to the understanding of the condition, as well as its diagnosis and optimal treatment. The findings of this study conclude that there is no consensus on the best medical therapy for the treatment of RM. Despite this finding, the most common medication used today to treat RM continues to be intranasal corticosteroids.

Conclusion

There is not adequate evidence to conclusively suggest a standardized treatment protocol for RM. Given the significant variability in study design and outcomes reported across the relevant publications, it is recommended that uniform objective and patient-centered outcome measures be adopted for future study. Additional high-level evidence is needed to determine the optimal management strategy for patients diagnosed with RM.

Acknowledgments

Laura Wright, MLIS, MPH, research support librarian.

Author Contributions

Shana M. Zucker, acquisition and analysis of data, drafting of manuscript, final approval, accountable for all aspects; Blair M.

Barton, acquisition and analysis of data, drafting of manuscript, final approval, accountable for all aspects; Edward D. McCoul, conception and design, interpretation of results, revision of manuscript, final approval, accountable for all aspects.

Disclosures

Competing interests:None.

Sponsorships:None.

Funding source: American Academy of Otolaryngology—Head and Neck Surgery Foundation Cochrane Scholars Grant.

References

1. Graf P. Rhinitis medicamentosa: a review of causes and treatment.Treat Respir Med. 2005;4:21-29.

2. Graf P. Long-term use of oxy- and xylometazoline nasal sprays induces rebound swelling, tolerance, and nasal hyper- reactivity.Rhinology. 1996;34:9-13.

3. Black MJ, Remsen KA. Rhinitis medicamentosa. Can Med Assoc J. 1980;122:881-884.

4. Graf P. Adverse effects of benzalkonium chloride on the nasal mucosa: allergic rhinitis and rhinitis medicamentosa. Clin Ther. 1999;21:1749-1755.

5. Dykewicz MS, Fineman S, Skoner DP, et al. Diagnosis and management of rhinitis: complete guidelines of the Joint Task Force on Practice Parameters in Allergy, Asthma and

Immunology. American Academy of Allergy, Asthma, and Immunology.Ann Allergy Asthma Immunol. 1998;81:478-518.

6. Wallace DV, Dykewicz MS, Bernstein DI, et al. The diagnosis and management of rhinitis: an updated practice parameter.

J Allergy Clin Immunol. 2008;122(2):S1-S84.

7. Mortuaire G, de Gabory L, Francois M, et al. Rebound congestion and rhinitis medicamentosa: nasal decongestants in clinical practice. Critical review of the literature by a medical panel. Eur Ann Otorhinolaryngol Head Neck Dis. 2013;130:

137-144.

8. Ramey JT, Bailen E, Lockey RF. Rhinitis medicamentosa.

J Investig Allergol Clin Immunol. 2006;16:148-155.

9. Passali D, Salerni L, Passali GC, Passali FM, Bellussi L. Nasal decongestants in the treatment of chronic nasal obstruction:

efficacy and safety of use.Expert Opin Drug Saf. 2006;5:783- 790.

10. Graf P, Hallen H. Effect on the nasal mucosa of long-term treatment with oxymetazoline, benzalkonium chloride, and placebo nasal sprays.Laryngoscope. 1996;106:605-609.

11. Graf PM, Hallen H. One year follow-up of patients with rhinitis medicamentosa after vasoconstrictor withdrawal. Am J Rhinol. 1997;11:67-72.

12. Baldwin RL. Rhinitis medicamentosa (an approach to treatment).J Med Assoc State Ala. 1975;47:33-35.

13. Wang JQ, Bu GX. Studies of rhinitis medicamentosa. Chin Med J (Engl). 1991;104:60-63.

14. Caffier PP, Frieler K, Scherer H, Sedlmaier B, Goktas O.

Rhinitis medicamentosa: therapeutic effect of diode laser inferior turbinate reduction on nasal obstruction and decongestant abuse.Am J Rhinol. 2008;22:433-439.

15. Slim K, Nini E, Forestier D, Kwiatkowski F, Panis Y, Chipponi J. Methodological index for non-randomized studies (MINORS): development and validation of a new instrument.

ANZ J Surg. 2003;73:712-716.

16. Halle´n H, Enerdal J, Graf P. Fluticasone propionate nasal spray is more effective and has a faster onset of action than placebo in treatment of rhinitis medicamentosa. Clin Exp Allergy. 1997;27(5):552-558.

17. Ferguson BJ, Paramaesvaran S, Rubinstein E. A study of the effect of nasal steroid sprays in perennial allergic rhinitis patients with rhinitis medicamentosa.Otolaryngol Head Neck Surg. 2001;125:253-260.

18. Juto JE, Axelsson M. Kinetic oscillation stimulation as treatment of non-allergic rhinitis: an RCT study.Acta Otolaryngol.

2014;134:506-512.

19. Vaidyanathan S, Williamson P, Clearie K, Khan F, Lipworth B. Fluticasone reverses oxymetazoline-induced tachyphylaxis of response and rebound congestion. Am J Respir Crit Care Med. 2010;182:19-24.

20. Bende M. Treatment of rhinitis medicamentosa. Am J Rhinol.

1996;10:323-325.

21. Graf P. Rhinitis medicamentosa: aspects of pathophysiology and treatment.Allergy. 1997;52(40)(suppl):28-34.

22. Fernandez-Salvador C, Kram Y, Wei JM, et al. Long-term combined oxymetazoline and intranasal steroids. Otolaryngol Head Neck Surg. 2017;157(1)(suppl):P192.

(10)

23. Elwany S, Abdel-Salaam S. Treatment of rhinitis medicamentosa with fluticasone propionate—an experimental study. Eur Arch Otorhinolaryngol. 2001;258:116-119.

24. Malm L. Pharmacological background to decongesting and anti-inflammatory treatment of rhinitis and sinusitis. Acta Otolaryngol Suppl. 1994;515:53-55.

25. Graf P, Halle´n H, Juto J-E. The pathophysiology and treatment of rhinitis medicamentosa.Clin Otolaryngol. 1995;20:224-229.

26. Pipkorn U, Pukander J, Suonpaa J, Makinen J, Lindqvist N.

Long-term safety of budesonide nasal aerosol: a 5.5-year follow-up study.Clin Allergy. 1988;18:253-259.

27. Kully BM. The use and abuse of nasal vasoconstrictor medications.JAMA. 1945;127:307-310.

28. Saunders WH, Gardier RW. Pharmacotherapy in Otolaryngology. St Louis, MO: Mosby; 1976:51-52.

29. Bousquet J, Van Cauwenberge P, Khaltaev N; Aria Workshop Group, World Health Organization. Allergic rhinitis and its

impact on asthma.J Allergy Clin Immunol. 2001;108(5):S147- S334.

30. Pallanch J, Jorissen M. Objective assessment of nasal function.

In: Flint PW, Haughey BH, Robbins KT, et al, eds.Cummings Otolaryngology–Head and Neck Surgery E-book. 6th ed. New York, NY: Elsevier Health Sciences; 2014:644-657.

31. Hilberg O, Jackson AC, Swift DL, Pedersen OF. Acoustic rhinometry: evaluation of nasal cavity geometry by acoustic reflection.J Appl Physiol (1985). 1989;66:295-303.

32. Lal D, Gorges ML, Ungkhara G, Reidy PM, Corey JP.

Physiological change in nasal patency in response to changes in posture, temperature, and humidity measured by acoustic rhinometry.Am J Rhinol. 2006;20:456-462.

33. Knipping S, Holzhausen HJ, Goetze G, Riederer A, Bloching MB. Rhinitis medicamentosa: electron microscopic changes of human nasal mucosa.Otolaryngol Head Neck Surg. 2007;136:

57-61.