Discussion

Oxymetazoline hydrochloride 0.05 per cent nasal spray (oxymetazoline hydrochloride) is widely accessible to patients worldwide and available over the counter, making it an easy and reliable self-care option for patients seeking quick relief from nasal congestion. Known for its vasoconstrictive and sympathomimetic properties, oxymetazoline hydrochloride effectively reduces local oedema on nasal mucosa via alpha-adrenergic receptors.^{Reference Bickford, Shakib and Taverner14} Although oxymetazoline hydrochloride may provide immediate relief for nasal congestion, data suggest that after long-term use, discontinuation of oxymetazoline hydrochloride may lead to worsened mucosal oedema from compensatory vasodilation known as rebound congestion or rhinitis medicamentosa and reduction in efficacy, or tachyphylaxis. Subsequently, this creates a vicious cycle in which patients become increasingly reliant on larger and more frequent doses of oxymetazoline hydrochloride posing a challenge for patients to wean off it while maintaining symptoms of nasal congestion.^{Reference Graf, Enerdal and Hallén15} For these reasons, patients are typically instructed not to use oxymetazoline hydrochloride for longer than 3 to 14 days.^{Reference Wallace, Dykewicz, Bernstein, Blessing-Moore, Cox and Khan4,Reference Rael, Ramey and Lockey7,Reference Bousquet, Lund, van Cauwenberge, Bremard-Oury, Mounedji and Stevens16}

The exact mechanism of the development of rhinitis medicamentosa or its frequency of development with prolonged use of oxymetazoline hydrochloride is unknown.^{Reference Cingi, Ozdoganoglu and Songu17} Patients with a long history of rhinitis medicamentosa develop inflammation within the mucosa such as epithelial and histological changes.^{Reference Graf, Enerdal and Hallén15} The potential for topical decongestants to cause rhinitis medicamentosa is listed as a side effect in the Physicians’ Desk Reference and prompts limiting usage to twice daily for up to five days.¹⁸ The reports addressing this recommendation are conflicting. Graf et al. discovered how benzalkonium chloride, an ingredient included in the oxymetazoline formulary at the time of the study (1999) for its bactericidal and preservative properties, was observed to worsen rhinitis medicamentosa. Notably, benzalkonium chloride has potentially harmful effects on the nasal mucosa from its risk of damage to nasal cilia.^{Reference Graf, Enerdal and Hallén15} To this day, the preservative is still listed as an inactive ingredient in most oxymetazoline formularies.

In contrast, several other studies have shown lack of rhinitis medicamentosa occurrence when oxymetazoline hydrochloride or xylometazoline has been used for up to eight weeks.^{Reference Baroody, Brown, Gavanescu, DeTineo and Naclerio2,Reference Liu, Zhou, Zeng and Luo19} In addition to these observations, the use of intranasal steroids in guinea pigs has been shown to hasten the recovery from rhinitis medicamentosa associated with cessation of topical decongestants.^{Reference Tas, Yagiz, Yalcin, Uzun, Huseyinova and Adali20} Vaidyanathan et al. demonstrated that healthy human patients who developed rhinitis medicamentosa, primarily mediated by a-adrenoreceptors, could successfully reverse rhinitis medicamentosa with use of intranasal fluticasone propionate.^{Reference Vaidyanathan, Williamson, Clearie, Khan and Lipworth12} The absence of rebound congestion in the intranasal corticosteroid spray and oxymetazoline hydrochloride patients in our study was not surprising because of the adjunct dosing of intranasal corticosteroid spray, though we cannot conclude intranasal corticosteroid spray prevented rhinitis medicamentosa from occurring with prolonged oxymetazoline hydrochloride use as explored in other studies.^{Reference Baroody, Brown, Gavanescu, DeTineo and Naclerio2,Reference Thongngarm, Assanasen, Pradubpongsa and Tantilipikorn5–Reference Rael, Ramey and Lockey7}

Several studies have investigated the potential risk of tachyphylaxis with long-term use of oxymetazoline hydrochloride for relief of nasal congestion. There are data to support that use of oxymetazoline hydrochloride has not been shown to cause tachyphylaxis until it has been used at least three times daily for four weeks.^{Reference Watanabe, Foo, Djazaeri, Duncombe, Mackay and Durham21,Reference Yoo, Seikaly and Calhoun22} This was also demonstrated in two separate studies by Graff et al. and Vaidyanathan et al., in which intranasal corticosteroid spray was primarily used to demonstrate that rhinitis medicamentosa caused by long-term oxymetazoline hydrochloride use was secondary to oedema rather than vasodilation. These studies also demonstrated improvement in rebound congestion after a two-week treatment of intranasal corticosteroid spray therapy alone following prolonged oxymetazoline hydrochloride use and subsequent cessation because of rhinitis medicamentosa.^{Reference Vaidyanathan, Williamson, Clearie, Khan and Lipworth12,Reference Graf, Enerdal and Hallén15}

The results from our systematic review demonstrated that in oxymetazoline hydrochloride naïve patients, initiating combination treatment with intranasal corticosteroid spray and oxymetazoline hydrochloride may not only serve as a treatment option for rhinitis medicamentosa but also provide superior relief in nasal congestion symptoms when compared with the use of either agent alone. This was demonstrated by objective and subjective data points.^{Reference Baroody, Brown, Gavanescu, DeTineo and Naclerio2,Reference Thongngarm, Assanasen, Pradubpongsa and Tantilipikorn5–Reference Rael, Ramey and Lockey7} Objective data to indirectly and directly measure nasal volume included nasal peak inspiratory flow and acoustic rhinometry.^{Reference Baroody, Brown, Gavanescu, DeTineo and Naclerio2,Reference Rael, Ramey and Lockey7}

Peak nasal inspiratory flow measures nasal potency indirectly by measuring airflow in a relatively rapid and inexpensive way. In a study by Fuller et al., the authors found nasal peak inspiratory flow to be a useful means for measuring outcomes post-septorhinoplasty. Although the authors acknowledge nasal peak inspiratory flow is not intended for diagnostic purposes, their study has been the largest to assess the relationship between nasal peak inspiratory flow with Nasal Obstruction and Septoplasty Effectiveness Scale scores and demographic data comprising 610 patients with mean age of 36.12 years, similar to the mean ages across the 4 studies in our review.^{Reference Fuller, Gadkaree, Levesque and Lindsay23} Meltzer et al. demonstrated a 65.8 per cent increase in nasal peak inspiratory flow (l/minute) in the intranasal corticosteroid spray and oxymetazoline hydrochloride 3 spray group when compared with the intranasal corticosteroid spray group (40.9 per cent increase) and placebo group (23.2 per cent increase) alone (p < 0.05).^{Reference Meltzer, Orgel, Bronsky, Furukawa, Grossman and LaForce1}

Acoustic rhinometry, developed in the 1970s, measures a cross-sectional area of the internal nose by detecting reflected sound waves; it is reportedly more reliable for measuring the anterior 6 cm of the nasal cavity.^{Reference Bickford, Shakib and Taverner14} Baroody et al. demonstrated larger nasal volumes through acoustic rhinometry (mean + SEM, 15.8 + 1.1 ml) in the intranasal corticosteroid spray and oxymetazoline hydrochloride group compared with placebo (mean + SEM, 12.1 + 0.9 ml) or oxymetazoline hydrochloride (mean + SEM, 12.4 + 0.8 ml) groups alone (p < 0.03).^{Reference Baroody, Brown, Gavanescu, DeTineo and Naclerio2} Overall, the included studies did not show differences amongst quality of life data obtained across these treatment groups when compared with placebo groups. However, Rael et al. found improvement in sleep in the intranasal corticosteroid spray and oxymetazoline hydrochloride cohort compared with the intranasal corticosteroid spray placebo group. Theoretically, this could be explained from increased nasal airflow secondary to decreased oedema, especially since dosing of intranasal corticosteroid spray and oxymetazoline hydrochloride was administered in the evening in their study.^{Reference Rael, Ramey and Lockey7}

All four studies reported improvement in nasal symptoms in the combination treatment groups as compared with monotherapy or placebo groups. We recognise the limitations in that each study utilised different methods for collecting symptom scores, and grading symptoms is highly subjective. We also recognise the possibility of patient bias. Perhaps one of the more clinically relevant findings was that no rebound congestion was reported in the 336 patients treated with dual therapy of prolonged oxymetazoline hydrochloride use after patients were followed for up to 22 days of observation.^{Reference Baroody, Brown, Gavanescu, DeTineo and Naclerio2,Reference Thongngarm, Assanasen, Pradubpongsa and Tantilipikorn5–Reference Rael, Ramey and Lockey7}

Three of the four studies implemented treatment on patients with verified allergic or non-allergic rhinitis symptoms by performing skin prick testing prior to initiating treatment.^{Reference Thongngarm, Assanasen, Pradubpongsa and Tantilipikorn5–Reference Rael, Ramey and Lockey7} In the study by Rael et al., it was explicitly stated that patients on immunotherapy were stabilised for 30 days prior to enrolling in the study. The impact of immunotherapy and other adjunctive treatment such as oral antihistamines was not stratified in these studies.^{Reference Rael, Ramey and Lockey7}

Because of heterogeneity across studies and lack of sub-analyses available, we were unable to perform analyses on whether or not patients across all studies with allergic rhinitis experienced greater benefit than patients with non-allergic rhinitis. Thongngarm et al. found that patients with allergic rhinitis experienced significant reduction in nasal congestion with intranasal corticosteroid spray and oxymetazoline hydrochloride on days 4 to 7, 8 to 14, 15 to 28 and 29 to 42 when compared with placebo groups. Their analysis demonstrated a significant improvement in allergic rhinitis patients compared with non-allergic rhinitis patients (allergic patients, n = 18 and non-allergic patients, n = 7; p < 0.05).^{Reference Thongngarm, Assanasen, Pradubpongsa and Tantilipikorn5} However, this data is limited by the small sample size of 25 patients. Comparing the response of allergic rhinitis to non-allergic rhinitis patients in a larger trial is worthy of further exploration with potential for application to clinical practice.

Given the subjective improvement across all four studies in patients with both allergic and non-allergic rhinitis with no reports of life threatening adverse effects, tachyphylaxis or rebound congestion, we propose that the combination of oxymetazoline hydrochloride and intranasal corticosteroid spray may be considered for use as a treatment option for patients entering a season triggering severe allergic rhinitis symptoms as they seek extra relief when symptoms are not controlled with intranasal corticosteroid spray alone.^{Reference Baroody, Brown, Gavanescu, DeTineo and Naclerio2,Reference Thongngarm, Assanasen, Pradubpongsa and Tantilipikorn5–Reference Rael, Ramey and Lockey7} Recent literature on the combination treatment of intranasal corticosteroid spray with inhaled antihistamine has encouraged the practice of combining intranasal spray modalities for targeting different receptor pathways and the release of the first FDA approved intranasal formulation of its kind: Dymista® (azelastine hydrochloride antihistamine and fluticasone intranasal steroid).^{Reference Debbaneh, Bareiss, Wise and McCoul24,Reference Ratner, Hampel, Van Bavel, Amar, Daftary and Wheeler25} Currently, there are no published studies comparing the use of intranasal corticosteroid spray and oxymetazoline hydrochloride to intranasal corticosteroid spray and inhaled antihistamine, or a treatment course utilising a combination of oxymetazoline hydrochloride with both intranasal corticosteroid spray and inhaled antihistamine.

The theory of combining intranasal corticosteroid spray and oxymetazoline hydrochloride to synergistically target nasal mucosa receptors may be especially beneficial for patients presenting with moderate to severe nasal congestion or facing seasonal changes that cause an exacerbation of allergic rhinitis symptoms. Because oxymetazoline hydrochloride can provide prompt decongestive properties to the nasal mucosa, it may allow for increased nasal volume and surface area for the intranasal corticosteroid to effectively target the nasal mucosa.^{Reference Baroody, Brown, Gavanescu, DeTineo and Naclerio2,Reference Meltzer, Bernstein, Prenner, Berger, Shekar and Teper6,Reference Vaidyanathan, Williamson, Clearie, Khan and Lipworth12,Reference Eskiizmir, Hircin, Ozyurt and Unlu26} Although the effects of intranasal steroids can be observed as early as 12 hours after administration, the maximum efficacy may take as long as 12 weeks.^{Reference Bridgeman27,Reference Penttilä, Poulsen, Hollingworth and Holmström28} The delay in maximal effect often prevents patients from instant gratification from the benefit of intranasal corticosteroids.^{Reference Penttilä, Poulsen, Hollingworth and Holmström28} Meanwhile, oxymetazoline hydrochloride is a non-selective alpha adrenergic agonist, which leads to vasoconstriction of nasal vessels resulting in decreased oedema and prompt relief of nasal congestion with a nearly instantaneous onset of action within 5 to 10 minutes and resulting in increased diameter and airflow.^{Reference Baroody, Brown, Gavanescu, DeTineo and Naclerio2}

Theoretically, for patients with suboptimal response to intranasal corticosteroid spray and inhaled antihistamine therapy, the addition of oxymetazoline hydrochloride at the onset of treatment could be beneficial. However, further research on dual therapy oxymetazoline hydrochloride with either intranasal corticosteroid spray or intranasal antihistamine versus monotherapy is needed. There is potential for the role of oxymetazoline hydrochloride in providing relief for patients with seasonal allergy exacerbations, upper respiratory infections or severe allergic reactions refractory to monotherapy nasal spray, and further studies such as randomised controlled trials are recommended. Our study demonstrated that the combination of intranasal corticosteroid spray and oxymetazoline hydrochloride has beneficial effects beyond those of intranasal corticosteroid spray alone.

In the authors’ opinion, the selection of which intranasal spray combination would be a better fit to a patient depends on the clinical condition. For example, combination oxymetazoline hydrochloride and intranasal corticosteroid spray would be a better fit for a patient suffering from non-allergic rhinitis, whereas other options will better suit a patient with allergic rhinitis. These are considerations recommended by the authors.

We acknowledge several limitations in our review. Unfortunately, the studies included are short term, which fail to evaluate long-term outcomes or any potential long-term adverse effects. Therefore, caution is needed when choosing to commence a patient on oxymetazoline hydrochloride as the risk of rhinitis medicamentosa with continued use cannot be addressed with the current data. The data amongst the studies were heterogenous, and therefore we were unable to perform a meta-analysis. Control groups across studies varied, which also limited our ability to compare studies (i.e. combinations of intranasal corticosteroid spray and oxymetazoline hydrochloride and placebo groups as referenced in Table 1). Studies also varied in follow up time from 7 to 22 days as well as follow up questioning and reporting of symptoms. Nasal congestion is arguably subjective in nature and variable throughout the day, and although we acknowledge the objective measurements in two studies, these tests may be variable and user dependent. Quality of life scores may be dependent on time of day and associated with timing of medication administration. The adjunct of oral antihistamines and other modalities such as immunotherapy may serve as confounding variables in the individual studies. Not all studies discussed adjunctive treatment as exclusion criteria.