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EVIDENCE-BASED MANAGEMENT OF ACUTE RHINOSINUSITIS WITH
HERBAL PRODUCTS
Samandarova Azizabonu
Bukhara University of innovative education and medicine.
Abstract
: The overuse of antibiotics for unjustified indications such as the management of
acute uncomplicated rhinosinusitis has contributed to the emergence of antibiotic-resistant
strains of bacteria and prompted the need for alternative treatments. This review assesses the
quality of evidence for the management of acute rhinosinusitis with herbal products, with the
goal of positioning them among other treatments and identifying future research directions.
Searches with Nacetylcysteine and mometasone furoate nasal spray (MFNS) were performed
to compare the strength of evidence of herbal products to these conventional products, which
are indicated for acute rhinosinusitis.
Keywords:
Acute rhinosinusitis, Herbal product, Conventional treatment, Antibiotic
Introduction
Acute rhinosinusitis, a common infection of the upper respiratory tract, is associated
with a significant impact on quality of life and high socioeconomic costs [
1
]. Guidance on the
treatment of acute rhinosinusitis is clear. The European position paper on rhinosinusitis and
nasal polyps (EPOS) 2012 recommends antibiotics for sinusitis of bacterial origin only , and
the International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR:RS)
recommends a conservative approach to the use of antibiotics on the grounds that acute
rhinosinusitis even of bacterial origin has a high spontaneous resolution rate. In cases of acute
viral rhinosinusitis, guidelines support the use of topical steroids, antihistamines and
ipratropium bromide (level of evidence Ia), aspirin/non-steroidal anti-inflammatory drug
(level of evidence Ib), and herbal medicines (level of evidence Ib). Systemic steroids,
however, are only rec ommended in complicated sinusitis [2].
Despite the existence of these recommendations on the use of antibiotics, acute
rhinosinusitis is frequently treated with antibiotics, contributing to the global emergence of
antibiotic-resistant strains of bacteria . One way of addressing the overuse of antibiotics in
this scenario is to identify alternative treatments for rhinosinusitis that treat the infection and
control symptoms.
Herbal products first triggered the interest of clinicians in the 1990s, and there has been a
drive to perform fur ther studies on them ever since . Until the 1990s, evidence for the use of
herbal products in acute rhinosinusitis remained largely anecdotal. However, in the past 20
years, randomized controlled trials in rhinosinusitis have been performed with a number of
herbal products . This review aims to assess the level and quality of evidence for the
management of acute rhinosinusitis with herbal products and review their position in the
context of other treatments. To this end, we have selected four herbal products for which
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high-level evidence was available from at least one double-blind randomized clinical trial
involving approximately 100 patients or more, either versus placebo or in comparison with
another active treatment: Sinupret®, Pelargonium sidoides extract, Cyclamen europaeum
(CE), cineole, and GeloMyrtol forte®.
To provide context for these data, we compared the strength of evidence of herbal products
with that of the two synthetic treatments currently indicated for the management of acute
rhinosinusitis, N-acetylcysteine and mometasone furoate. [3].
The structure of the search strings was ‘acute rhinosiusitis’ or ‘acute rhinitis’ or ‘acute
sinusitis’ and ‘[product name]’. The search was intended to identify randomized controlled
trials, however, when none were available, other study types were included.
Sinupret versus placebo Neubauer and März tested the efficacy and toxicity of Sinupret
(BNO 101) in a randomized double-blind placebo-controlled trial . The trial included 160
patients with a diagnosis of acute bacterial sinusitis (n = 81in the Sinupret group and n = 79
in the placebo group).Sinupret or placebo were given as two sugar-coated tablets three times
a day for 2 weeks alongside an antibiotic and a decongestant. Overall, patients in the Sinupret
group had significantly better primary outcomes – radiographic findings and patient
assessment of the therapy at the end of treatment – than patients receiving placebo.Likewise,
patients in the Sinupret group reported a significant improvement in secondary outcomes,
including mucosal swelling, nasal obstruction and headache, compared with patients in the
placebo group. No significant toxicities were reported in either study group. The main
limitation of this trial was the inclusion of male participants only.A meta-analysis by Melzer
et al., including publishedand unpublished data with BNO 101, confirmed the results of the
trial [4].
The studies included in the meta analysis also had a predominantly male population,
limiting the application of the findings to a broader population.Similar benefits of Sinupret
(BNO 1016) were reportedin patients with acute viral rhinosinusitis, in a robustly designed
double-blind randomized controlled trial .In contrast to the trial conducted by Neubauer and
März,patients did not receive treatments for acute rhinosinusitis other than the study drug,
and there was a higher proportion of women than men in both treatment groups [5].
This trial randomized 386 patients (n = 194 in the Sinupret group and n = 192 in the
placebo group). Patients received two tablets of Sinupret 80 mg or placebo, three
times daily for 15 days. In the intent-to-treat (ITT) population (n = 190 in each group), the
number of patientsconsidered to be healed (investigator-assessed major symptom score [MSS]
≤ 1) was significantly higher in the Sinupret group than in the placebo group (48.4%
vs.35.8%; p = 0.0063) at the end of treatment. The numberneeded to treat (NNT) for patients
to have MSS ≤ 1 at theend of treatment was eight in the ITT. This result wascorroborated by
patient-assessed MSS, the 20-item questionnaire sino-nasal outcome test (SNOT-20) German
adapted version (GAV), and ultrasonography imaging.The incidence of adverse events was
similar between the two groups. The per-protocol (PP) analysis of the trial gave results
concurrent with the ITT analysis [6].
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In summary, adequately powered randomized trials have demonstrated superiority of
Sinupret versus placebo in patients with bacterial or viral rhinosinusitis.Trials of Sinupret in
bacterial sinusitis almost exclusively included male patients, while trials of Sinupret in viral
sinusitis included a mixed-gender study population.Sinupret versus other treatments A
limited number of studies have provided evidence on the efficacy and safety of Sinupret
versus synthetic treatments. The literature search identified one open-label study comparing
Sinupret Forte with intranasal fluticasone furoate . Sinupret Forte (one tablet) was given
three times a day while fluticasone
furoate (two puffs in each nostrils) was given once a day for 14 days. Both Sinupret and
intranasal fluticasone in duced a similar improvement in MSS and SNOT-20 as
evaluated by the investigator at Day 14. Patients in the Sinupret Forte group did not report
any adverse events.In the fluticasone group, one patient reported epistaxisand two patients
reported nasal itching. The conclusions of the study are limited by its relatively small size
and open-label design.Another study compared a combination of Sinupret and Cinnabaris 3X
with synthetic treatment, including antibiotics, secretolytics and sympathomimetics in
patients presenting with acute sinusitis or an acute exacer bation of a chronically relapsing
sinusitis [
7
].
Overall, robust head-to-head comparisons of Sinupret with conventional treatments are
currently not available.Published studies lack statistical power or were not de signed to show
either differences or equivalence between treatments, thereby limiting the strength of
conclusions.
Cyclamen europaeum (CE)
CE extract has been used for a long time in Southeast Europe for the management of
nasopharyngeal diseases. However, the first randomized trials assessing theefficacy and
safety of this product in acute rhinosinusitis became available very recently only . In
itscurrent formulation, the aqueous/alcohol CE extractcontains the saponin fraction [
8
]. When
administered intranasally, the extract causes a rapid, abundant and often painful discharge of
mucus through a cholinergicreflex lasting for about 30 min . The literature search identified
two double-blind randomized trials comparing CE nasal spray with matching placebo in
acute rhinosinusitis. These two trials were subsequently included in a Cochrane meta-analysis
aiming to assess the efficacy and safety of CE nasal spray in acute rhinosi nusitis. Studies
with CE extract are summarized in Overall, both trials have reported a consistent lack of
effect of nasal CE on sinusitis symptoms and did not have adequate statistical power to
provide robust con clusions about the safety and efficacy of CE nasal spray.It is also possible
that the immediate irritative effect of CE might have compromised the blinding of treatment
in both trials. [9].
This meta-analysis found an overall low risk of selection,performance and detection bias in
the two studies in cluded. The authors also emphasized the need for fur ther randomized
controlled trials to evaluate the efficacy of this treatment for acute rhinosinusitis [10].
Baseline characteristics suchas age, gender, weight, symptoms-sum-score, allergy and
smoking status, were balanced between the two Comparative studies of herbal products Data
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from head-to-head comparisons can help guide treatment decisions and help clinicians to
make evidence based decisions. Equivalence or superiority of one product versus another
cannot be assumed based on cross-study comparisons and must rely on direct, comparative
data.The literature search identified one randomized trial and one non-interventional study
comparing herbal medicines [11].
Tesche and colleagues conducted a double-blind randomized trial comparing a herbal
preparation containing five components, possibly resembling Sinupret, with cineole .Of note,
this study did not clearly state using Sinupret when refering to the composition of the
preparation. Furthermore,no placebo group was included in the study. The study recruited a
total of 150 patients across three centres, with 75patients randomized to each treatment group.
Likewise, cineole induced a greater improvement than the other preparation in each
individual component of the symptom
sum score at Days 4 and 7. Improvement at Day 7 in redness of mucosa, oedema and dryness
was greater with cineole than with the other preparation, confirming the effect observed on
the symptom-sum score. Two patients in the cineole group and three patients in the other
group reported mild side effects.Sinupret (BNO 1016) was compared with GeloMyrtol in
anon-interventional parallel group study [12].The study reported comparable effectiveness of
the two treatments on acute rhinosinusitis symptoms, with amore rapid recovery of facial
pain with GeloMyrtol than with Sinupret. However, the study presents a significant number
of weaknesses in its design and methodological approach. For example, the design is closer
to that of a randomized controlledtrial, and the analysis lacks the statistical support of a
randomized trial such as predetermined endpoints [13].
Overall, there are few head-to-head studies of herbal products. Only one randomized
double-blind trial has compareda herbal preparation containing five components resembling
Sinupret with cineole, while another study comparing GeloMyrtol with Sinupret is associated
with serious methodological flaws. There is a need for further randomized comparative trials
with herbal products to differentiate and delineate the properties of each
product.Conventional treatments for acute rhinosinusitis Mometasone furoate nasal spray
versus placebo or amoxicillin Mometasone furoate nasal spray (MFNS) has been usedsince
1998 for the management of inflammatory diseases of the nose [14].
Mometasone furoate is a glucocorticosteroid indicated for rhinitis and acute rhinosinusitis
in some countries, as well as several other conditions including asthma, skin disorders, and
phimosis . In acute rhinosinusitis, the anti-inflammatory properties of mometasone furoate
are thought to mediate its benefi cial effects . The literature search identified three clinical
trials of mometasone furoate in acute rhinosinusitis,one Cochrane meta-analysis, and two
exploratory analyses of the same trial. However, symptoms such as rhinorrhea, post-nasal
drip, or cough were not significantly different between the MFNS and placebo groups. In
both treatment groups, most adverse events were mild or moderate.Minimizing the systemic
activity of intranasal steroids is an important consideration to reduce the risk of hypo
thalamic pituitary adrenal (HPA) axis suppression. The differences between the three groups
persisted from baseline to Day 21. Likewise, individual symptom scores such as congestion,
facial pain, rhinorrhea and post-nasal drip showed greater improvement with MFNS than
with placebo.Most adverse events were mild or moderate in intensity,
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but included headache and epistaxis [15].
Most adverse events were mild or moderate and considered to be related to study drugs.
Exploratory analyses of this trial showed that MFNS twice daily was associated with better
quality of life scores than placebo and more minimal symptom days than placebo or
amoxicillin . Improved efficacy with the higher dose of MFNS was confirmed in a Cochrane
meta-analysis [16].
N-acetylcysteine versus placebo Currently, the two main indications for N-acetylcysteine
are chronic obstructive pulmonary disease and paracetamol overdose . It is also of potential
interest for the management of acute rhinosinusitis due to its antimicrobial activity, ability to
interfere with biofilm formation, and its mucolytic and antioxidant action [17].
The authors found that N acetylcysteine did not affect the Lund-Mackay scoreused for
radiologic staging of sinusitis and it was concluded that the addition of N-acetylcysteine to
conventional treatment has no benefits in acute sinusitis.In another trial, where only the
investigators wereblinded to treatment, N-acetylcysteine was comparedwith ambroxol,
another secretolytic agent [18]. In the ITT population, the improvement in sinusitis-related
symptoms was greater in the N-acetylcysteine group than in the ambroxol group.The authors
reported a higher proportion of patients with improvement at the end of treatment in the N
acetylcysteine group (82.67%) than in the ambroxolgroup (50.67%) (p < 0.0001). At Months
3 and 6, the number of rhinosinusitis exacerbations after the previous episode was also lower
in the N-acetylcysteine group than in the ambroxol group. The proportion of patients
reporting adverse events was lower in the N acetylcysteine group (18.67%) than in the
ambroxol group (52%). The main limitations of this study relate to its open-label design, the
lack of clearly defined end points, and the lack of comparability of both treatment groups at
baseline.Overall, evidence for the use of N-acetylcysteine in acute rhinosinusitis is limited to
small-scale clinical trialswhose designs do not enable firm conclusions on the efficacy of N-
acetylcysteine in this indication[19].
Conclusion
A range of herbal products have been evaluated for treating acute rhinosinusitis in
randomized clinical trials.Sinupret is supported with the strongest evidence base,including
adequately powered multicenter clinical trials,followed by EPs 7630, which is supported by
smallerstudies. Across the range of other herbal products, including CE nasal spray,
GeloMyrtol, and cineole, only one randomized trial is available at best for each product.
Furthermore, each trial identified in this review was
conducted in a single country without power calculations and a small number of participants.
Ideally, ad equately powered international multicenter trials wouldbe required to confirm or
discredit findings and provide further credibility for these products[20].Among synthetic
treatments described in this review,MFNS is supported with the strongest evidence.
Interestingly, the evidence for Sinupret appears to be as
strong as that for synthetic treatments, such as MFNS.Although cross-trial comparisons
cannot be a substitutefor direct comparisons, clinical trials of Sinupret and MFNS suggest
comparable efficacy of these two products. However, patients may prefer the herbal over
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the‘steroid’ approach.The choice between synthetic treatment or herbal medicine is made
difficult by the lack of comparative studies of herbal products with conventional
medicines.Indeed, most trials conducted with herbal products have been placebo-controlled
trials. Currently, only one underpowered study comparing Sinupret with fluticasone furoate is
available [21].
Equally, there are not enough data of sufficient quality available to
guide anevidence-based approach when choosing between different herbal products. To the
best of our knowledge, only one head-to-head comparison of herbal products isavailable,
stressing the need for further prospective trials comparing herbal products [22]. A separate
study comparing Sinupret with GeloMyrtol does not allow a firm conclusion to be drawn on
the efficacy of either product,due to its design [23].
Sinupret (BNO 1016) is the sole herbal product forwhich evidence from well-designed,
randomized controlled studies with sufficient power is available. In the context of antibiotics
misuse, selected herbal medicines are promising alternatives to conventional treatments and
should be considered for the management of acute uncomplicated rhinosinusitis[24].
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