Ann Allergy Asthma Immunol xxx (2015) 1e8

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Acupuncture for seasonal allergic rhinitis: a randomized controlled trial Charlie Changli Xue, PhD *; Anthony Lin Zhang, PhD *; Claire Shuiqing Zhang, PhD *; Cliff DaCosta, PhD y; David F. Story, PhD *; and Frank C. Thien, MD z * School

of Health Sciences, RMIT University, Bundoora, Victoria, Australia School of Mathematical and Geospatial Sciences, RMIT University, Bundoora, Victoria, Australia z Respiratory and Sleep Medicine Clinical Research Unit, Monash University, Victoria, Australia y

A R T I C L E

I N F O

Article history: Received for publication February 26, 2015. Received in revised form April 24, 2015. Accepted for publication May 23, 2015.

A B S T R A C T

Background: Seasonal allergic rhinitis (SAR) is a common condition with relatively high prevalence in Australia. It causes a significant impact on sufferers’ quality of life (QoL). Meta-analysis has shown that the efficacy of acupuncture for SAR is uncertain. Objective: To evaluate the efficacy and safety of 12 sessions of acupuncture treatment during 4 weeks for SAR in a randomized, subject- and assessor-blinded, sham-controlled trial conducted during the pollen seasons in 2009 through 2011 in Melbourne. Methods: Patients diagnosed with SAR and confirmed allergic to rye grass pollen were randomly allocated to receive real acupuncture (RA) or sham acupuncture (SA) treatment. RA was delivered manually, whereas SA involved superficial needling at non-acupoints without additional stimulation. Severity of SAR symptoms was the primary outcome measurement. Secondary outcomes were QoL, global change, SAR-related medication usage, and adverse events. Analysis of covariance using pollen count as a covariate was used to analyze outcome data. Results: A total of 175 participants were included in this trial. RA was significantly better than SA for decreasing SAR symptom severity (sneezing, mean difference 0.28, 95% confidence interval 0.51 to 0.05; itchiness of ears and palate, mean difference 0.40, 95% confidence interval 0.69 to 0.11) at the end of treatment and improving participants’ QoL at the end of the treatment and follow-up phases. Furthermore, the acupuncture treatment was safe and well tolerated. Conclusion: Four weeks of acupuncture treatment is a safe and effective option for clinical management of SAR in the Melbourne area for patients’ symptom relief and QoL improvement. Ó 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Introduction Seasonal allergic rhinitis (SAR), also known as hay fever, is caused by an immune response to different pollen allergens, including grasses, trees, and weeds, and is characterized by a pattern of symptoms, including sneezing, rhinorrhea, nasal and throat itching, nasal congestion, and postnasal drip. Other symptoms, such as headache and impaired smell and ocular conjunctive irritation, also are associated with SAR.1 SAR is a common condition with a relatively high prevalence in Australia and many other Western countries. In Australia, based on self-reports from the Reprints: Charlie Changli Xue, PhD, Head, School of Health Sciences, RMIT University, Plenty Road, Bundoora, VIC 3083, Australia; E-mail: [email protected]. au. Disclosures: The authors declare no conflict of interest. Funding: The National Health and Medical Research Council (project number 555421).

2007 to 2008 National Health Survey, SAR affects 15.1% of the Australian population.2 The rate reported in Victoria (17.5%) was higher than the rate for all of Australia.2 This condition not only results in a group of symptoms but also is associated with impairments in how patients function in daily life.3,4 It influences patients’ quality of life (QoL) in several important domains, such as sleeping and emotion, decreases sufferers’ work productivities, and limits social activities.4 SAR has significant economic impact owing to direct and indirect costs on the affected persons and their families, on the health care systems, and on the society as a whole.5 Recently, the efficacy and safety of acupuncture for the management of allergic rhinitis has been investigated by many clinical studies,6e13 although the efficacy of acupuncture for SAR is uncertain by meta-analysis.14 Furthermore, most of these used 8 weeks of acupuncture treatment.7e10,12,13 Because airborne grass pollen is the predominant cause of SAR in the Melbourne region,15,16 SAR symptoms would spontaneously resolve after the 2-month pollen

http://dx.doi.org/10.1016/j.anai.2015.05.017 1081-1206/Ó 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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season during late spring and early summer of each year (September to December). Thus, it is necessary to conduct a clinical trial with a shorter period of treatment to reflect the real effect of acupuncture on SAR in the Melbourne region. Therefore, from 2009 through 2011, a phase II, parallel, randomized, single-blinded, sham-controlled clinical trial was conducted to investigate the efficacy and safety of 4 weeks of acupuncture treatment for SAR symptom relief in an adult population. Methods Setting The study was conducted at the Bundoora and metropolitan Melbourne campuses of the School of Health Science, RMIT University, Australia. It was approved by the RMIT University human research ethics committee and registered in the Australian and New Zealand Clinical Trial Registry (ANZCTRN 21609000751279) and filed with the Australian Government Therapeutic Goods Administration before commencement of the trial. The trial period, including treatment and follow-up, was from 2009 through 2011, from October to December each year, which is associated with highest rye grass pollen count in Melbourne.15,16 Sample Size Calculation Guided by the formula of Campbell et al17 in estimating effect size for ordered categorical outcomes in 2-group comparisons, the effect size estimate was calculated using the data for alleviation of symptom severity at the end of the treatment period in the authors’ previous clinical trial.6 The sample size required to yield 90% power with a 2-tailed significance level of 5% was calculated as 60 participants per group. To investigate the treatment effect at the end of treatment and at the end of follow-up and consider dropouts, the potential recruitment was increased to up to 180 participants with SAR.

analyzed by an independent statistician who was blinded to the participants’ allocation. Treatment After a 2-week run-in period, the participants were treated by RA or SA treatment 3 times per week for 4 weeks and then followed for 4 weeks. Three registered acupuncturists who had at least 5 years of clinical experience provided RA and SA treatments. To avoid possible bias caused by practitionereparticipant interaction, equal numbers of participants who received RA and SA treatments were randomly allocated to each acupuncturist. Four key acupoints and supplementary acupoints were used for RA treatment. The key (common) acupoints (for all participants) were yingxiang (LI 20, bilateral), yintang (MH-N-3), fenchi (GB 20, bilateral), and hegu (LI 4, bilateral). The supplementary acupoints were determined for each participant according to their CMSDD, such as taiyuan (LU 9, bilateral) for lung qi deficiency, zusanli (ST 36, bilateral) for spleen deficiency, and qihai (CV 6) for kidney deficiency syndrome. For the SA treatment, the points that were needled were located on non-acupoints area beside the real acupoints. When applying acupuncture, Hwato single-use, disposable, presterilized needles 0.22 mm in diameter (Suzhou Medical Appliance factory, Jiangsu Province, China), were used. Needles 30 and 13 mm long were selected for RA and SA treatments, respectively. Different techniques were applied for RA or SA treatment: for RA, the needles were inserted at different depths according to the acupoint location and maintained for 20 minutes with manipulations of the needles applied 3 times (during insertion, between insertion and withdrawal, and at withdrawal); for SA, needles were inserted shallowly and inactive manipulations (simply holding the handle without any stimulation) were applied to make participants unaware of the group allocation. Symptom Relief Medication

Participants Adult participants with SAR 18 to 70 years old residing in the metropolitan area of Melbourne with a history of at least 2 years of typical symptoms of SAR or of perennial allergic rhinitis with seasonal exacerbation and a positive allergen skin prick test (SPT) reaction to rye grass pollen were recruited through public media. The SPT was conducted using grass mix and perennial rye extracts and using saline and histamine (10 mg/mL) as negative and positive controls, respectively. Potential participants’ eligibility was confirmed by SPT and a physician’s examination. A Chinese medicine syndrome differential diagnosis (CMSDD) also was conducted to further determine individual treatment based on syndrome diagnosis. Four types of syndrome were predefined: (1) lung qi deficiency, (2) lung and spleen deficiency, (3) lung and kidney deficiency, and (4) lung, spleen, and kidney deficiency syndromes.6,9 Randomization and Blinding Randomization numbers were prepared by an independent statistician using a computer-generated random assignment procedure. The results of the randomization allocation process were kept in opaque sealed envelopes, with 1 envelope for each participant. The envelopes were opened when participants arrived for their first treatment. All participants were informed that there was a 50% chance of receiving real acupuncture (RA) or sham acupuncture (SA) treatment. The acupuncturists were isolated from outcome assessments and data analysis. To ensure the integrity of participant blinding, the acupuncturists were thoroughly counseled to ensure that they did not discuss any aspect of the treatment procedures with the participants. In addition, trial data were

In this trial, participants were required to cease any existing SAR medication before commencement of the trial and were instructed to use standardized relief medication when needed. The relief medication was the short-acting antihistamine loratadine (Claritin; Schering-Plough Healthcare Products, Inc, Memphis, Tennessee; 10 mg, 1 tablet daily, as needed) and a decongestant nasal spray (Drixine; Bayer Australia Ltd, Pymble, New South Wales, Australia; 0.5 mg/mL, 2 sprays per nostril every 8e12 hours, as needed). These medications are commonly used for the symptomatic treatment for SAR. Participants were advised that if their symptoms become intolerable, then they could take loratadine as the relief medication and that the oxymetazoline nasal spray was to be used only if nasal blockage become unmanageable with loratadine usage. All participants were required to record their relief medication usage during the trial in case report forms (CRFs). The relief medication score was calculated using the following scoring system: 1 tablet of loratadine equaled 1 point and 2 sprays per nostril of oxymetazoline equaled 1 point. Outcome Measurements Symptom severity assessmentdprimary outcome measurement Symptom severity was recorded by the participants in their weekly CRFs during the trial. The participants were required to selfassess the severity of their nasal and non-nasal symptoms. Four nasal symptoms (sneezing, watery rhinorrhea, nasal congestion, and nasal itching) and 4 non-nasal symptoms (ocular itching, watering, redness, itching of the ears, and/or palate) were individually assessed using a 4-point scale (0, no symptoms; 1, mild symptoms, ie, symptoms that are present but not particularly bothersome; 2, moderate symptoms, ie, symptoms that are bothersome but do not

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interfere with daily activities; 3, severe symptoms, ie, symptoms that are bothersome and interfere with daily activities or disturb sleep); the total maximum symptom score is 12 for nasal symptoms and 12 for non-nasal symptoms, as described by Juniper et al.18 The participants were instructed on the recognition of the individual symptoms and their qualification immediately before their baseline assessment.

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Results Participants and Baseline Characteristics and Baseline Symptom Severity

Global change assessment Global change of overall symptoms and QoL was rated by the participants using a 15-point scale (þ7 to 7, with the plus sign indicating a change for the better): 1, 0, and þ1 indicated trivial changes; þ3, þ2, 2, and 3 indicated minimal changes; þ5, þ4, 4, and 5 indicated moderate changes; and þ7, þ6, 6, and 7 indicated major changes. This questionnaire was completed by participants at the end of treatment and at the end of follow-up.

According to the recruitment strategy provided, 292 volunteers were screened from enquiries. The telephone interview and initial assessment excluded 46 volunteers who did not meet the inclusion criteria. Sixty-eight volunteers could not participate owing to time constraints; hence, 175 were included in the trial. They were randomized to the RA (n ¼ 88) or SA (n ¼ 87) group in the first week of treatment after the 2-week run-in period. The numbers of participants included in the RA and SA groups during each year of the 3-year study were 30 (15 and 15), 76 (38 and 38), and 69 (35 and 34), respectively. During the 4-week treatment period, 18 participants in the RA group and 6 in the SA group discontinued owing to time restrictions; during the follow-up period, 3 participants in the SA group lost contact and failed to send back the follow-up CRFs. As a result, 151 participants completed the treatment and 148 participants completed the follow-up assessment (Fig 1). There was no significant difference between the 2 groups with regard to participants’ age, sex, smoking status, duration of SAR morbidity, and family history of SAR. For the 4 CMSDD types, no difference was found between the 2 groups. All demographics of the included participants were comparable (P > .05; Table 1). Furthermore, there was no significant difference between the 2 groups for all symptom severity and QoL assessment scores at baseline.

Withdrawal from the Study and Rescue Medication

Pollen Count and Relief Medication Score

During the entire trial period, participants were free to withdraw at any stage without having to provide a reason to the authors. All missing data were replaced using the last-datum-carry-forward method for conducting an intention-to-treat analysis.

Data on daily grass pollen counts were divided into 3 categories: grass, other, and total pollen counts. The 3-year weekly total pollen counts during the trial period are presented in Figure 2. Data shown in the figure indicated that pollen counts changed during the trial period, with a peak in treatment week 4. During the trial period, participants were required to record their symptom relief medication usage in their CRFs. The weekly total relief medication scores were compared between the 2 groups at each time point and no significant difference was found (Fig 3).

Quality-of-life assessment The QoL was assessed with the Rhinoconjunctivitis Quality of Life Questionnaire with Standardized Activities,19 which consists of 28 questions clustered in 7 domains: sleep, practical problems, non-nasal and eye symptoms, nasal symptoms, eye symptoms, activities, and emotional function domains. Each question was assessed by the participants, with scores ranging from 0 to 6. In addition, a 7-point scale questionnaire (Spector questionnaire), which contains 14 questions related to allergic rhinitis symptoms and QoL, was adapted for assessing the treatment outcome.20

Adverse Events Participants were provided with an adverse event (AE) record form in the CRFs and they were instructed to record any unexpected signs, symptoms, and feelings during the entire trial period. Details of any AEs were scored using a 3-point scale (1, mild; 2, moderate; 3, severe) to indicate severity. Similarly, all acupuncturists were required to record any observed AEs before, during, and after each treatment session. Pollen Count Data The data for daily grass pollen counts during the trial period were provided by the School of Botany, University of Melbourne. The weekly total pollen count was used as a covariate in the statistical analysis. Credibility of Acupuncture Procedures At the end of the follow-up period, a question to test the credibility of the blinding procedure for RA and SA was included in the CRF. Statistical Analysis Baseline categorical data and demographic characteristics, such as sex and family history, were analyzed by c2 analysis to determine the equivalence of the 2 groups. Analysis of covariance using weekly pollen count as the covariate was applied to analyze weekly outcome data.

Treatment Effects Symptoms Using pollen count data as a covariate, analysis showed that at the end of the treatment phase, symptoms of sneezing and itchiness of the ears and palate in the RA group were significantly less severe than in the SA group, and that at the end of follow-up phase, symptoms of sneezing, total nasal symptoms, and global nasal and non-nasal symptoms in the RA group were significantly less severe than in the SA group (Table 2; full data for Table 2 are presented in eTable 1, available online). Figure 4 presents the trend of symptom severity change using the Spector sneezing score as an example. Quality of life At the end of the treatment phase, the Qol activity and practical domains in the RA group were significantly better than in the SA group. At the end of the follow-up phase, the QoL activity domain, practical domain, and global QoL in the RA group were significantly superior to that in the SA group (Table 2). Global change No significant difference for global change between the 2 groups was found at the end of the treatment phase or at the end of the follow-up phase.

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Assessed for eligibility (n=292)

Excluded (n=114): - Not meeting selection criteria (n=46) - Time restriction (n=68)

Included (n=178) 2 weeks baseline

Treatment 1 Randomised (n=175)

Real acupuncture group (n=88) 4 weeks treatment, 3 times/week

Sham acupuncture group (n=87) 4 weeks treatment, 3 times/week

18 drop-outs Due to time restrictions Real acupuncture group (n=70) 4 weeks follow-up

6 drop-outs Due to time restrictions

Sham acupuncture group (n=81) 4 weeks follow-up

3 drop-outs Due to loss of contact Analysed Intention-to-treat Figure 1: Flow with diagram of trial procedure

Analysed with Intention-to-treat (n=87)

(n=88)

Figure 1. Flow diagram of trial procedure.

Credibility of Blinding

Adverse Events

The credibility of blinding was tested in the CRF of the last week (follow-up week 4). Participants were asked to guess which group they had been allocated to. There was no difference between the 2 groups for the number of participants who guessed the RA group, the SA group, or unsure (c2 ¼ 2.029, P ¼ .363).

There were some mild and moderate AEs reported by participants during the acupuncture treatment period, but there was no significant difference between the RA and SA groups in the proportion of

Table 1 Demographic characteristics of included participants

Age (y), mean  SD Duration of AR (y), mean  SD Men/women Smoking status (current/former/never) Has family history of SAR Chinese medicine differentiation typea

Real acupuncture (n ¼ 88)

Sham acupuncture (n ¼ 87)

Significance

41.75  11.15 20.66  12.21

42.16  11.26 22.40  13.34

t ¼ 0.243 t ¼ 0.896

P ¼ .809 P ¼ .372

39/49 3/32/53

33/54 4/20/63

c2 ¼ 0.737 c2 ¼ 3.769

P ¼ .443 P ¼ .152

35 28/18/20/22

38 37/14/17/19

c2 ¼ 0.274 c2 ¼ 2.203

P ¼ .647 P ¼ .530

Abbreviations: AR, allergic rhinitis; SAR, seasonal allergic rhinitis. a Chinese medicine differentiation types: lung deficiency/lung þ spleen deficiency/ lung þ kidney deficiency/lung þ spleen þ kidney deficiency.

Figure 2. Weekly grass pollen count data of 3 years (2009 through 2011).

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Figure 3. Weekly symptom relief medication score. FLUP, follow-up.

Figure 4. Symptom severity over time (using the Spector sneezing score as an example). FLUP, follow-up.

participants who reported mild or moderate AEs (9.7% vs 8.5%, c2 ¼ 0.126, P ¼ .722; Table 3). All these mild or moderate discomforts were short term, and no medical assistance was required. No serious AE was reported during the treatment and follow-up periods.

4-week follow-up, no benefit was found for relieving nasal obstruction. For QoL, the RA treatment was more effective than the SA treatment for improving participants’ QoL, specifically on the activity and practical domains related to SAR in the treatment and follow-up phases. More importantly, the treatment was beneficial for improving participants’ global QoL at the end of the follow-up phase. These results suggested that, compared with the SA control, the RA treatment of this study not only induced instantaneous effects on relieving SAR symptoms and improving QoL but also brought about long-lasting effects for another 4 weeks after the treatment phase and the long-lasting effects were greater than the instantaneous effects. Considering that SAR had an impact on the QoL of the patients beyond only nasal symptoms, these findings suggest that acupuncture has an advantage over specific (and especially topical) medications, which have more limited effect. Based on these findings, the RA treatment administered in this trial is recommended to be administered pre-seasonally for symptom control during the peak pollen season.

Discussion Summary of Findings This was a randomized, single-blinded, sham-controlled trial including 3 cohorts conducted during the pollen seasons of 2009 through 2011. A total of 175 participants with SAR were included during those 3 years. All participants were diagnosed with 1 of 4 types of CMSDD and received the RA or SA treatment accordingly. Twelve treatment sessions were completed within 4 weeks. The RA treatment used in this study achieved a greater effect than SA treatment for sneezing and itching symptoms at the end of the 4week treatment; however, for nasal symptoms (sneezing, runny nose, itchy nose, and total nasal symptoms) at the end of the

Table 2 Treatment effects (using pollen count as the covariate)a Questionnaire

Items

End of treatment RA group, mean (SD)

Juniper 4 point symptom scores

RQLQ(S) questionnaire Spector 7 point questionnaire

SA group, mean (SD)

End of follow-up Mean difference (95% CI)

RA group, mean (SD)

ANCOVA resultsb F1,172

P value

SA group, mean (SD)

Mean difference (95% CI)

ANCOVA resultsb F1,172

P value

Sneezing score

1.61 (0.87)

1.89 (0.70)

0.28 (0.51 to 0.05)

5.496

.020c

1.30 (0.85)

1.49 (0.86)

0.19 (0.44 to 0.06)

2.093

.150

Itchiness of ears and palate score Activity domain

0.81 (0.90)

1.21 (1.04)

0.40 (0.69 to 0.11)

7.654

.006c

0.57 (0.71)

0.78 (0.90)

0.21 (0.45 to 0.03)

2.806

.096

6.78 (5.56)

8.62 (4.71)

1.84 (3.37 to 0.31)

5.551

.020

d

4.69 (4.25)

6.58 (4.64)

1.89 (3.21 to 0.57)

7.792

.006d

Practical domain Sneezing score

7.00 (5.48) 3.27 (1.69)

8.64 (4.88) 3.80 (1.48)

1.64 (3.18 to 0.10) 0.53 (1.00 to 0.06)

4.475 4.823

.036d .029c

4.80 (4.37) 2.55 (1.40)

6.55 (5.19) 3.28 (1.56)

1.75 (3.17 to 0.33) 0.73 (1.17 to 0.29)

5.761 10.770

.017d .001c

Runny nose score Itchy nose score Total nasal symptom score Global nasal and non-nasal symptoms Global quality of life

3.32 (1.81) 2.68 (1.71) 3.40 (1.61)

3.59 (1.73) 3.01 (1.70) 3.70 (1.60)

0.27 (0.79 to 0.25) 0.33 (0.84 to 0.18) 0.30 (0.78 to 0.18)

0.994 1.624 1.573

.320 .204 .211

2.53 (1.55) 2.01 (1.26) 2.55 (1.42)

3.06 (1.72) 2.50 (1.44) 3.01 (1.54)

0.53 (1.02 to 0.04) 0.49 (0.89 to 0.09) 0.46 (0.90 to 0.02)

4.493 5.866 4.303

.035c .016c .040c

4.32 (1.53)

3.90 (1.49)

0.42 (0.03 to 0.87)

3.373

.068

4.87 (1.39)

4.26 (1.57)

0.61 (0.17e1.05)

7.425

.007d

4.15 (1.52)

3.86 (1.38)

0.29 (0.14 to 0.72)

1.824

.179

4.86 (1.40)

4.41 (1.42)

0.45 (0.03e0.87)

4.427

.037d

Abbreviations: ANCOVA, analysis of covariance; CI, confidence interval; RA, real acupuncture; RQLQ(S), Rhinoconjunctivitis Quality of Life Questionnaire with Standardized Activities; SA, sham acupuncture. a Full data are presented in eTable 1 (available online). b Performed on adjusted mean values. c Symptom severity of the RA group was significantly less than that of the SA group. d The quality of life of the RA group was significantly better than that of the SA group.

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Table 3 Adverse events Adverse events

Real acupuncture (n ¼ 88)

Sham acupuncture (n ¼ 87)

Pain at needling area during treatment Pain at needling area after treatment Bruise Sensitive needling area after alcohol swab Numbness and weakness at local area after needling Feeling tired after needling Feeling nauseous after needling Headache possibly related to acupuncture Low mood possibly related to acupuncture Constipation possibly related to acupuncture All adverse events reported during treatment and follow-up Participants who reported adverse events, n (%)

1 mild 7 mild, 6 moderate 7 mild 4 moderate 2 moderate 1 mild 1 mild 1 mild, 1 moderate 0 0 18 mild, 13 moderate 17 (9.7)

0 2 mild, 2 moderate 1 mild 2 mild 0 0 0 4 mild, 2 moderate 1 moderate 1 moderate 9 mild, 6 moderate 15 (8.5)

Conversely, although some mild or moderate discomforts caused by needling were reported by participants from the 2 groups, there was no medical assistance required for managing such AEs. In addition, the RA group tended to have more AEs than the SA group. This might be caused by the difference in needling technique applied in the RA vs SA treatment. However, there was no difference between the 2 groups in the number of participants who reported AEs and there were no dropouts because of the AEs. Therefore, one can conclude that the RA treatment was safe and well tolerated. Previously, the authors’ research group conducted a small-scale sham-controlled pilot trial using syndrome-based acupuncture treatment 3 times a week for 4 weeks of participants with SAR6 and a sham-controlled trial with the same treatment twice a week for 8 weeks of participants with persistent allergic rhinitis.9 These 2 studies proved acupuncture was effective and safe for the management of allergic rhinitis. The present study confirmed those previous findings.

controlled trial (RCT) of acupuncture for allergic rhinitis in Australia. To blind participants, a sham control using superficial needling on non-acupoints was adopted. The acupuncturist was the only individual who was not blinded to the treatment and the participants were unlikely to know the group assignment. Pollen count data were clearly higher at the end of the treatment and during the follow-up period compared with the baseline. Thus, the last-datum-carryforward method was used to deal with missing data and dropouts. Acupuncture treatments were modified by taking CMSDD into consideration, which was to mimic real clinical practice situations. This study focused on participants with SAR. To recruit a reasonably large number of participants, the trial was conducted continuously for 3 years during the same season. In the Melbourne area, SAR symptoms are often largely influenced by the pollen count. Therefore, 3 years of pollen count data were collected and these data were used as a covariate for each participant in the present data analysis. Medication for relief of allergic rhinitis symptoms was allowed in this study but limited to loratadine and a decongestant nasal spray. This approach enabled the medication usage data to be accurately calculated and analyzed. One limitation of this study is the selection of control methods. In clinical research, RCTs are considered the gold standard for evaluating the effectiveness of interventions.60 When conducting RCTs on acupuncture, different control methods have been used, including sham or placebo acupuncture, usual care, an active treatment, a waiting list, or no treatment.61 In theory, an inert placebo control would differentiate the specific effect of a therapy from a nonspecific placebo effect. However, it is difficult to design an inert placebo control for a physical intervention such as acupuncture.62 Therefore, selecting an appropriate control procedure for clinical studies of acupuncture is a critical challenge.63 Sham needling, involving a superficial needle insertion at the wrong acupoints or non-acupoints, might induce a nonspecific effect greater than that of a perfect inert placebo.64 Neuroscience studies have confirmed that sham needling is not physiologically inert.65,66 Since the first innovative invention of the placebo acupuncture needle was introduced in 1998,67 attempts at designing a perfect placebo acupuncture device have been ongoing. However, thus far, no optimal placebo for acupuncture research seems to exist. Furthermore, some recent studies have investigated the costeffectiveness of acupuncture treatment68,69 and suggested that acupuncture is cost-effective in the management of allergic rhinitis in Germany. Whether such a finding on cost-effectiveness can be extended to the Australia population was not investigated in this trial.

Potential Mechanisms of Acupuncture for SAR Allergic rhinitis involves an allergic inflammatory response and an IgE-mediated hypersensitivity reaction. There is a complicated interaction among inflammatory cells, cytokines released by those cells, proinflammatory neuropeptides, and neurotrophins. In particular, nerve endings are exposed after the integrity of the nasal epithelium is compromised, which leads to the release of substance P and calcitonin gene-related peptide.21,22 The use of acupuncture for allergic rhinitis in clinical practice has been recommended in a recently published clinical practice guideline by the American Academy of OtolaryngologyeHead and Neck Surgery,23 although a previous clinical guideline did not support its use.24 A recent review article pointed out that allergic rhinitis symptom relief caused by acupuncture treatment might be related to the anti-inflammatory effects induced by acupuncture.22 These antiinflammatory effects could be associated with multiple physiologic pathways, including the hypothalamusepituitaryeadrenal axis,25e28 sympathetic pathways,27,28 and possibly parasympathetic cholinergic pathways.29e32 Other relevant antiinflammatory effects of acupuncture include antihistamine effects33e36 and downregulation of proinflammatory cytokines37e43 and proinflammatory neuropeptides.44,45 Acupuncture also has been proved to down-regulate neurotrophins,46e51 suppress the expression of cyclo-oxygenases 1 and 2 and inducible nitric oxide during experimentally induced inflammation, and suppress other reactions related to anti-inflammatory actions.52e59 Strength and Limitation of This Study

Implication for Clinical Practice and Further Research

The present study was conducted according to a rigorous methodologic protocol, with the largest sample in a randomized

It is worth noting that the 4-week acupuncture treatment induced a long-lasting treatment effect until the end of the 4-week

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follow-up. This suggests that, in clinical practice, to prevent unbearable SAR symptoms, acupuncture treatments could be administered a few weeks before the peak pollen season. In contrast, acupuncture 3 times a week proved bearable and safe for SAR management in the present study. For further acupuncture RCTs on allergic rhinitis, placebo control and cost-effectiveness analysis should be considered. In conclusion, 4-week Chinese medicine syndrome-modified acupuncture treatment is a safe and effective option for clinical management of SAR in the Melbourne area for patients’ symptom relief and QoL improvement. Acknowledgments The authors thank Ms Mira An, Dr Yuan Di, Dr Jo Shergis, Dr Hsiewe Ying Tan, and Mr Thomas Keech for their assistance in delivering the acupuncture treatment and the conduct of the clinical trial. Supplementary Data Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.anai.2015.05.017. References [1] Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol. 2001;108(suppl):S147eS334. [2] Australian Institute of Health and Welfare. Allergic Rhinitis (‘Hay Fever’) in Australia. Canberra: Australian Institute of Health and Welfare; 2011. [3] Kirmaz C, Aydemir O, Bayrak P, Yuksel H, Ozenturk O, Degirmenci S. Sexual dysfunction in patients with allergic rhinoconjunctivitis. Ann Allergy Asthma Immunol. 2005;95:525e529. [4] Juniper EF. Rhinitis and quality of life: nothing to be sneezed at! Expert Rev Pharmacoecon Outcomes Res. 2001;1:121e123. [5] Bousquet J, Khaltaev N, Cruz AA, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization). Allergy. 2008;63(suppl 86):8e160. [6] Xue CC, English R, Zhang JJ, Da Costa C, Li CG. Effect of acupuncture in the treatment of seasonal allergic rhinitis: a randomized controlled clinical trial. Am J Chin Med. 2002;30:1e11. [7] Magnusson AL, Svensson RE, Leirvik C, Gunnarsson RK. The effect of acupuncture on allergic rhinitis: a randomized controlled clinical trial. Am J Chin Med. 2004;32:105e115. [8] Ng DK, Chow PY, Ming SP, et al. A double-blind, randomized, placebocontrolled trial of acupuncture for the treatment of childhood persistent allergic rhinitis. Pediatrics. 2004;114:1242e1247. [9] Xue CC, An X, Cheung TP, et al. Acupuncture for persistent allergic rhinitis: a randomised, sham-controlled trial. Med J Aust. 2007;187:337e341. [10] Xue CC, Zhang CS, Yang AW, et al. Semi-self-administered ear acupressure for persistent allergic rhinitis: a randomised sham-controlled trial. Ann Allergy Asthma Immunol. 2011;106:168e170. [11] Choi SM, Park JE, Li SS, et al. A multicenter, randomized, controlled trial testing the effects of acupuncture on allergic rhinitis. Allergy. 2013;68: 365e374. [12] Brinkhaus B, Ortiz M, Witt CM, et al. Acupuncture in patients with seasonal allergic rhinitis: a randomized trial. Ann Intern Med. 2013;158:225e234. [13] Zhang CS, Xia J, Zhang AL, et al. Ear acupressure for perennial allergic rhinitis: a multicenter randomized controlled trial. Am J Rhinol Allergy. 2014;28: e152e157. [14] Lee MS, Pittler MH, Shin BC, Kim JI, Ernst E. Acupuncture for allergic rhinitis: a systematic review. Ann Allergy Asthma Immunol. 2009;102:269e279. [15] Ong EK. Forecasting the onset of the grass pollen season in Melbourne (Australia). Aerobiologia. 1997;13:43e48. [16] de Morton J, Bye J, Pezza A, Newbigin E. On the causes of variability in amounts of airborne grass pollen in Melbourne, Australia. Int J Biometeorol. 2011;55:613e622. [17] Campbell MJ, Julious SA, Altman DG. Estimating sample sizes for binary, ordered categorical, and continuous outcomes in two group comparisons. BMJ. 1995;311:1145e1148. [18] Juniper EF, Stahl E, Doty RL, Simons FE, Allen DB, Howarth PH. Clinical outcomes and adverse effect monitoring in allergic rhinitis. J Allergy Clin Immunol. 2005;115(suppl 1):S390eS413. [19] Juniper EF, Thompson AK, Ferrie PJ, Roberts JN. Validation of the standardized version of the Rhinoconjunctivitis Quality of Life Questionnaire. J Allergy Clin Immunol. 1999;104:364e369. [20] Spector SL, Nicklas RA, Chapman JA, et al. Symptom severity assessment of allergic rhinitis: part 1. Ann Allergy Asthma Immunol. 2003;91:105e114. [21] Dykewicz MS, Hamilos DL. Rhinitis and sinusitis. J Allergy Clin Immunol. 2010; 125(suppl 2):S103eS115.

7

[22] McDonald JL, Cripps AW, Smith PK, Smith CA, Xue CC, Golianu B. The antiinflammatory effects of acupuncture and their relevance to allergic rhinitis: a narrative review and proposed model. Evid Based Complement Alternat Med. 2013;2013:591796. [23] Seidman MD, Gurgel RK, Lin SY, et al. Clinical practice guideline: allergic rhinitis. Otolaryngol Head Neck Surg. 2015;152(suppl):S1eS43. [24] Brozek JL, Bousquet J, Baena-Cagnani CE, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol. 2010;126: 466e476. [25] Zhang A, Li RX, Wang Y, et al. Corticosterone mediates electroacupunctureproduced anti-edema in a rat model of inflammation. BMC Complement Altern Med. 2007;7:27. [26] Li A, Lao L, Wang Y, et al. Electroacupuncture activates corticotrophinreleasing hormone-containing neurons in the paraventricular nucleus of the hypothalamus to alleviate edema in a rat model of inflammation. BMC Complement Altern Med. 2008;8:20. [27] Kim HW, Kang SY, Yoon SY, et al. Low-frequency electroacupuncture suppresses zymosan-induced peripheral inflammation via activation of sympathetic post-ganglionic neurons. Brain Res. 2007;1148:69e75. [28] Kim HW, Uh DK, Yoon SY, et al. Low-frequency electroacupuncture suppresses carrageenan-induced paw inflammation in mice via sympathetic post-ganglionic neurons, while high-frequency EA suppression is mediated by the sympathoadrenal medullary axis. Brain Res Bull. 2008; 75:698e705. [29] Kavoussi B, Ross BE. The neuroimmune basis of anti-inflammatory acupuncture. Integr Cancer Ther. 2007;6:251e257. [30] Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458e462. [31] Tracey KJ. The inflammatory reflex. Nature. 2002;420:853e859. [32] Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergic antiinflammatory pathway: a missing link in neuroimmunomodulation. Mol Med. 2003;9:125e134. [33] Belgrade MJ, Solomon LM, Lichter EA. Effect of acupuncture on experimentally induced itch. Acta Derm Venereol. 1984;64:129e133. [34] Lundeberg T, Bondesson L, Thomas M. Effect of acupuncture on experimentally induced itch. Br J Dermatol. 1987;117:771e777. [35] Pfab F, Hammes M, Bäcker M, et al. Preventive effect of acupuncture on histamine-induced itch: a blinded, randomized, placebo-controlled, crossover trial. J Allergy Clin Immunol. 2005;116:1386e1388. [36] Pfab F, Huss-Marp J, Gatti A, et al. Influence of acupuncture on type I hypersensitivity itch and the wheal and flare response in adults with atopic eczemada blinded, randomized, placebo controlled, crossover trial. Allergy. 2010;65:903e910. [37] Petti FB, Liguori A, Ippoliti F. Study on cytokines IL-2, IL-6, IL-10 in patients of chronic allergic rhinitis treated with acupuncture. J Trad Chin Med. 2002;22: 104e111. [38] Rao YQ, Han NY. Therapeutic effect of acupuncture on allergic rhinitis and its effects on immunologic function. Zhongguo Zhen Jiu. 2006;26:557e560. [39] Shiue HS, Lee YS, Tsai CN, Hsueh YM, Sheu JR, Chang HH. DNA microarray analysis of the effect on inflammation in patients treated with acupuncture for allergic rhinitis. J Altern Complement Med. 2008;14:689e698. [40] Zheng MF, Lin C, Zheng LP, He FR. Effects of acupuncture-moxibustion on monocyte Th1/Th2 cytokine in peripheral blood of patients with perennial allergic rhinitis. J Acupunct Tuina Sci. 2010;8:85e88. [41] Fang JQ, Liu F, Shao XM, Wu YY. Effect of electroacupuncture on carrageenaninduced inflammation, IL-1beta and TNF-alpha concentrations and their mRNA expressions in toe tissue in rats. Zhen Ci Yan Jiu. 2007;32:224e228. [42] Joos S, Schott C, Zou H, Daniel V, Martin E. Immunomodulatory effects of acupuncture in the treatment of allergic asthma: a randomized controlled study. J Altern Complement Med. 2000;6:519e525. [43] Carneiro ER, Xavier RAN, Castro MAPD, Nascimento CMOD, Silveira VLF. Electroacupuncture promotes a decrease in inflammatory response associated with Th1/Th2 cytokines, nitric oxide and leukotriene B4 modulation in experimental asthma. Cytokine. 2010;50:335e340. [44] Li YM, Zhuang LX, Lai XS, Jiang GH. Effects of electroacupuncture on plasma vasoactive intestinal peptide and substance P in perennial allergic rhinitis patients. Zhen Ci Yan Jiu. 2007;32:136e138. [45] Ai MK, Guan XM, Zhu CG, Vacca LL. The influence of electroacupuncture and morphine on substance P (SP), enkephalin (ENK) and acetylcholine esterase (AChE) in the spinal cord of rats. Zhen Ci Yan Jiu. 1986;11:96-105, 95. [Article in Chinese]. [46] Zhang SP, Zhang JS, Yung KY, Zhang HQ. Nonopioid-dependent antiinflammatory effects of low frequency electroacupuncture. Brain Res Bull. 2004;62:327e334. [47] Kim HW, Roh DH, Yoon SY, et al. The anti-inflammatory effects of low- and high-frequency electroacupuncture are mediated by peripheral opioids in a mouse air pouch inflammation model. J Altern Complement Med. 2006;12: 39e44. [48] Zhang RX, Lao L, Wang X, et al. Electroacupuncture attenuates inflammation in a rat model. J Altern Complement Med. 2005;11:135e142. [49] Yonehara N, Imai Y, Chen JQ, Takiuchi S, Inoki R. Influence of opioids on substance P release evoked by antidromic stimulation of primary afferent fibers in the hind instep of rats. Regul Peptides. 1992;38:13e22. [50] Kondo I, Marvizon JCG, Song B, et al. Inhibition by spinal m- and d-opioid agonists of afferent-evoked substance P release. J Neurosci. 2005;25: 3651e3660.

8

C.C. Xue et al. / Ann Allergy Asthma Immunol xxx (2015) 1e8

[51] Cabioglu MT, Cetin BE. Acupuncture and immunomodulation. Am J Chin Med. 2008;36:25e36. [52] Bai YH, Lim SC, Song CH, et al. Electro-acupuncture reverses nerve growth factor abundance in experimental polycystic ovaries in the rat. Gynecol Obstet Invest. 2004;57:80e85. [53] Stener-Victorin E, Lundeberg T, Cajander S, et al. Steroid induced polycystic ovaries in rats: effect of electro-acupuncture on concentrations of endothelin-1 and nerve growth factor (NGF), and expression of NGF mRNA in the ovaries, the adrenal glands, and the central nervous system. Reprod Biol Endocrinol. 2003;1:33. [54] Manni L, Lundeberg T, Holmang A, Aloe L, Stener-Victorin E. Effect of electroacupuncture on ovarian expression of a(1)- and b(2)-adrenoceptors, and p75 neurotrophin receptors in rats with steroid-induced polycystic ovaries. Reprod Biol Endocrinol. 2005;3. [55] Manni L, Albanesi M, Guaragna M, Barbaro Paparo S, Aloe L. Neurotrophins and acupuncture. Auton Neurosci. 2010;157:9e17. [56] Aloe L, Manni L. Low-frequency electro-acupuncture reduces the nociceptive response and the pain mediator enhancement induced by nerve growth factor. Neurosci Lett. 2009;449:173e177. [57] Lee JH, Jang KJ, Lee YT, Choi YH, Choi BT. Electroacupuncture inhibits inflammatory edema and hyperalgesia through regulation of cyclooxygenase synthesis in both peripheral and central nociceptive sites. Am J Chin Med. 2006;34:981e988. [58] Zhang RX, Li A, Liu B, et al. IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats. Pain. 2008;135:232e239. [59] Zhang YQ, Ji GC, Wu GC, Zhao ZQ. Excitatory amino acid receptor antagonists and electroacupuncture synergetically inhibit carrageenan-induced behavioral hyperalgesia and spinal fos expression in rats. Pain. 2002;99: 525e535.

[60] Akobeng A. Understanding randomised controlled trials. Arch Dis Child. 2005; 90:840e844. [61] MacPherson H, Altman DG, Hammerschlag R, et al. Revised standards for reporting interventions in clinical trials of acupuncture (STRICTA): extending the CONSORT statement. J Evid Based Med. 2010;3:140e155. [62] Fregni F, Imamura M, Chien HF, et al. Challenges and recommendations for placebo controls in randomized trials in physical and rehabilitation medicine: a report of the international placebo symposium working group. Am J Phys Med Rehabil. 2010;89:160e172. [63] Birch S. Clinical research on acupuncture. Part 2. Controlled clinical trials, an overview of their methods. J Altern Complement Med. 2004;10:481e498. [64] Kaptchuk TJ, Stason WB, Davis RB, et al. Sham device v inert pill: randomised controlled trial of two placebo treatments. BMJ. 2006;332: 391e397. [65] Kong J, Kaptchuk TJ, Polich G, et al. An fMRI study on the interaction and dissociation between expectation of pain relief and acupuncture treatment. Neuroimage. 2009;47:1066e1076. [66] Harris RE, Zubieta JK, Scott DJ, Napadow V, Gracely RH, Clauw DJ. Traditional Chinese acupuncture and placebo (sham) acupuncture are differentiated by their effects on mu-opioid receptors (MORs). Neuroimage. 2009;47: 1077e1085. [67] Streitberger K, Kleinhenz J. Introducing a placebo needle into acupuncture research. Lancet. 1998;352:364e365. [68] Kim SY, Lee H, Chae Y, Park HJ, Lee H. A systematic review of cost-effective analysis alongside randomised controlled trials of acupuncture. Acupunct Med. 2012;30:273e285. [69] Witt CM, Brinkhaus B. Efficacy, effectiveness and cost-effectiveness of acupuncture for allergic rhinitisdan overview about previous and ongoing studies. Auton Neurosci. 2010;157:42e45.

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8.e1

eTable 1 Symptom scores at baseline, at end of treatment, and at end of follow-up Baseline

Juniper sneezing score Juniper blocked nose score Juniper runny nose Juniper itchy nose Juniper itchy eyes score Juniper watery eyes score Juniper redness of eyes Juniper itchiness of ears and palate RQLQ activity domain RQLQ sleep domain RQLQ non-nasal eye symptoms domain RQLQ practical domain RQLQ nasal symptom domain RQLQ eye symptom domain RQLQ emotional domain RQLQ 28-item total score Spector sneezing score Spector runny nose score Spector congestion score Spector itchy nose score Spector postnasal drip score Spector total nasal symptom score Spector eye symptom score Spector throat symptom score Spector chronic cough score Spector ear symptom score Spector headache score Spector mental function score Spector global nasal and non-nasal symptoms scorea Spector global quality-of-life scorea Global change score

End of treatment

End of follow-up

Real (n ¼ 88)

Sham (n ¼ 87)

Real (n ¼ 88)

Sham (n ¼ 87)

Real (n ¼ 88)

Sham (n ¼ 87)

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

1.48 1.49 1.35 1.08 1.14 0.88 0.78 0.73 6.48 4.74 13.24 6.96 8.94 5.85 6.95 53.16 3.00 2.90 3.19 2.44 2.64 3.24 2.59 2.28 1.78 1.69 2.22 2.16 4.47 4.26 N/A

0.67 0.79 0.81 0.83 0.81 0.84 0.64 0.79 3.97 4.06 9.05 4.19 4.97 4.76 5.29 30.92 1.41 1.44 1.48 1.41 1.54 1.36 1.39 1.31 1.23 1.08 1.38 1.47 1.33 1.40 N/A

1.55 1.45 1.41 1.17 1.05 0.68 0.69 0.89 6.80 4.89 12.25 7.89 9.21 5.57 7.54 54.13 3.26 3.03 3.12 2.64 2.36 3.28 2.43 2.31 1.63 1.95 1.87 2.03 4.24 4.21 N/A

0.70 0.88 0.85 0.83 0.72 0.68 0.59 0.89 4.18 4.67 10.47 4.82 5.74 4.40 6.10 35.08 1.39 1.48 1.61 1.48 1.60 1.46 1.18 1.38 1.20 1.25 1.14 1.30 1.30 1.25 N/A

1.61 1.51 1.56 1.19 1.40 1.13 0.98 0.81 6.78 5.43 12.16 6.99 9.18 7.31 6.83 54.69 3.27 3.32 3.30 2.68 2.99 3.40 3.10 2.41 2.02 1.69 1.97 2.29 4.32 4.12 0.62

0.87 0.95 0.96 1.02 0.99 0.99 0.94 0.90 5.56 5.31 9.90 5.48 6.34 6.82 6.07 41.72 1.69 1.81 1.77 1.71 1.70 1.61 1.63 1.50 1.65 1.14 1.28 1.55 1.53 1.32 3.37

1.89 1.66 1.80 1.41 1.50 1.07 0.97 1.21 8.62 5.79 13.72 8.64 10.72 8.22 8.68 64.01 3.80 3.59 3.45 3.01 2.85 3.70 3.47 2.51 2.01 1.93 2.07 2.47 3.90 3.68 0.76

0.70 0.98 0.85 0.95 0.86 0.95 0.92 1.04 4.71 4.83 11.38 4.88 5.92 6.26 6.55 39.33 1.48 1.73 1.80 1.70 1.75 1.60 1.65 1.72 1.39 1.35 1.43 1.54 1.49 1.28 3.36

1.30 1.26 1.19 0.92 0.97 0.70 0.63 0.57 4.69 3.83 9.05 4.80 6.69 4.27 5.13 38.45 2.55 2.53 2.57 2.01 2.28 2.55 2.31 1.91 1.77 1.45 1.69 1.81 4.87 4.86 1.20

0.85 0.87 0.87 0.86 0.83 0.76 0.76 0.71 4.25 4.19 8.22 4.37 5.02 4.12 4.90 31.45 1.40 1.55 1.46 1.26 1.40 1.42 1.30 1.26 1.36 0.85 0.99 1.14 1.39 1.40 3.03

1.49 1.30 1.37 1.03 1.01 0.66 0.53 0.78 6.57 4.61 9.72 6.55 8.10 5.34 6.67 47.56 3.28 3.06 2.97 2.50 2.34 3.01 2.59 2.16 1.87 1.63 1.78 1.99 4.26 4.41 0.96

0.86 0.96 0.93 0.82 0.88 0.80 0.76 0.90 4.64 4.48 9.82 5.19 5.92 5.01 6.13 35.52 1.56 1.72 1.62 1.44 1.59 1.54 1.60 1.58 1.53 1.07 1.39 1.47 1.57 1.42 3.55

Abbreviation: N/A, not applicable; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire. For these symptom scores, a higher score indicates improvement and a lower score indicates worsening; for all other scores, a lower score indicates improvement and a higher score indicates worsening. a