A Proposed Pilot Study: Acupuncture as an Effective Treatment for Moderate Obstructive Sleep Apnea

Principal Investigator: Connie L. Christie, L.Ac. Dipl. OM

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Abstract: This proposal is a non-randomized pragmatic single-arm pilot study designed to evaluate the feasibility of conducting a clinical trial to determine whether acupuncture provides relief from the symptoms of moderate obstructive sleep apnea (OSA). Ten subjects who have failed OSA treatment using CPAP, based upon an initial sleep assessment, will be diagnosed and treated with a known acupuncture protocol for the diagnosis of Lung, Kidney and/or Spleen vacuity with excess of phlegm and/or blood stasis. They will be given 16 treatments bi-weekly over an 8 week period. The primary outcome objective is to assess the feasibility and utility of using acupuncture to treat OSA in cases unresponsive to or noncompliant with CPAP. The secondary outcome objective is to determine the conditions for a future controlled trial. The primary outcome will be measured by statistically comparing the physical responses of acupuncture treatment on moderate OSA as measured by polysomnography (PSG), Epworth Sleepiness Scale (ESS) and quality of life changes as measured on the Your Health and Well-Being, SF-36v2™ questionnaire. This pilot study will specifically contribute to the body of research on the use of acupuncture for moderate obstructive sleep apnea and also add to the growing evidence base for the effectiveness of complementary medicine in treating modern health concerns.

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Purpose Statement of the Research and Why It Is Needed Obstructive Sleep Apnea (OSA) presents a significant health risk to the general population due to daytime sleepiness resulting in increased motor vehicle and occupational accidents, loss of job productivity, cognitive dysfunction, depression, life threatening cardiac arrhythmias, severe hypoxemia during sleep, and increased risk factors related to cerebrovascular and cardiovascular disease, hypertension, and diabetes (Chesnutt M, 2011) (Pagel JF, 2008). Current treatment approaches include behavior modification, oral devices, continuous positive airway pressure (CPAP) and surgery. While the best treatment option is CPAP, it is not well tolerated by a significant percentage of those for whom it is prescribed, leading to a clear indication of the need for alternative effective treatment options. There has been very little direct research on the effect of acupuncture on obstructive sleep apnea although preliminary research studies between 2002 and 2008 at São Paulo University Hospital in Brazil show some promising results. Additional research is needed to further validate and expand this work.

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Significance This pilot study will specifically contribute to the body of research on the use of acupuncture for moderate obstructive sleep apnea and also add to the growing evidence base for the effectiveness of complementary medicine in treating modern health concerns. Goals and Objectives The overall goal of this pilot study is to evaluate the feasibility of conducting a clinical trial to determine whether acupuncture provides relief from the symptoms of moderate OSA. The primary objective is to assess the feasibility and utility of using acupuncture to treat OSA in cases unresponsive to or noncompliant with CPAP. The secondary outcome objective is to determine the conditions for a future controlled trial. Specific Aims 1. Determine the feasibility of recruiting and retaining subjects for a randomized controlled trial of acupuncture treatment of moderate OSA unresponsive to or noncompliant with CPAP. 2. Determine the sample size for a randomized control trial (RCT). 3. Assess the safety of acupuncture as an intervention for moderate OSA. 4. Observe the physical responses of acupuncture treatment on moderate OSA as measured by polysomnography (PSG), Epworth Sleepiness Scale (ESS) and quality of life changes as measured on the Your Health and Well-Being, SF-36v2™ questionnaire.

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Background Need for Treatment Obstructive sleep apnea has become an increasingly important health concern with consequences for an individual’s health and well-being, as well as an economical and societal burden due to occupational and motor vehicle accidents. (Pagel JF, 2008) (Patil SP, 2007). In 1993, the prevalence of OSA was estimated to be 2% for women and 4% for men (Young T, 1993). Data from a more recent longitudinal study, the Wisconsin Cohort Study, indicated higher numbers for adults between the ages of 30-60, that is, 4-9% for women and 9-24% for men. Although harder to estimate, with the rise in obesity, children are increasingly being tested for sleep apnea at sleep centers. One 2007 study estimated there was a 7% prevalence in adolescents. (Johnson EO, 2006). OSA is a sleep disorder characterized by recurrent episodes of upper airway obstruction (collapsing of the airway) resulting in apneas (a cessation of airflow for 10 seconds or greater), and hypopneas (reduction of airflow associated with oxyhemogoblin desaturation). OSA occurs secondary to functional and mechanical obstruction of the airway during sleep.

The most

prevalent symptom is excessive daytime sleepiness, followed by impaired cognitive function and mood disorder. Predisposing factors for OSA are obesity, male sex, increasing age, genetic predisposition, craniofacial variations, nasal obstruction, large neck circumference, use of alcohol and sedatives, and smoking. (Doghramji P., 2008). The prevalence of OSA is higher in people with the following comorbid conditions: hypertension, coronary artery disease (previous cerebrovascular accident and ischemic heart disease), and diabetes mellitus. (Patil SP, 2007).

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Pathophysiology The pathogenesis of OSA involves neurophysiologic pathways, throat pathophysiology and inflammation, and dysfunctional muscular tension and tonus. Current understanding of the pathophysiologic mechanisms of OSA suggests a balance of anatomic imposed mechanical loads and compensatory neuromuscular responses (Patil SP, 2007). Alterations in upper airway structures such as tonsillar hypertrophy, retrognathia, variations in craniofacial structures, jaw position and acromegaly are known to be associated with OSA (Patil SP, 2007). In addition, obesity, which is considered a major risk for sleep apnea, could narrow and compress the upper airway and contribute to collapsibility (Patil SP, 2007). Normally the pharyngeal dilator muscles maintain pharyngeal patency via reflex pathways from the central nervous system. If anatomically mechanical loads are altered or if the dynamic neuromuscular responses to the upper airway change, then increased pharyngeal collapsibility is possible. During the respiratory cycle, various muscles (tonic muscular activity during expiration and phasic muscular activity during inspiration) stabilize the upper airway while pharyngeal motor output is modulated by several mechanisms: 1) the wake vs sleep state dependent mechanism, 2) response of local mechanoreceptors to negative pressure, and 3) ventilator control mechanisms. Neuromuscular responses affecting the reduction of upper airway muscle activity which occurs with sleep onset are controlled by serotonergic, cholinergic, noradrenergic and histaminergic pathways. OSA patients have been observed to have elevated muscle activity during wakefulness that can be reduced with the application of positive airway pressure (Patil SP, 2007). Individuals not having OSA start with lower muscle activity and have

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no response to the application of positive airway pressure. This suggests that the compensatory muscle activity of OSA patients during wakefulness is then loss during sleep, which leads to upper airway obstruction. In other words, the balance of the anatomically imposed mechanical load during wakefulness is lost during sleep when neuromuscular responses take over. Pathology in the neuromuscular responses has also been observed (Patil SP, 2007). Inflammatory and denervation changes in the upper airway muscular layer of the pharynx occur in patients suffering from OSA (Boyd JH, 2007). One study examining the tissue cells of a control group (n=7) versus the tissue cells of OSA patients (n=11) revealed a three-fold increase of inflammatory cells for OSA patients. Tissue examination also showed OSA patients had significantly increased upper airway mucosa, as well as showing a 5.7 fold increase in intramuscular nerve fibers in OSA patients as compared to the control group. This data suggests OSA patients may be unable to generate adequate muscular dilating forces while asleep (Boyd JH, 2007). Diagnosis OSA is diagnosed with a comprehensive sleep study utilizing polysomnography (PSG), the gold standard. More recently, home portable monitors for diagnosis are gaining in popularity due to lower cost and ease of use, although error rates are significantly higher with the portable monitor (Ballard RD, 2008).

The PSG measures 16 different parameters during sleep.

The most

important measurements are: airflow, respiratory effort, blood oxygen saturation, snoring, apneas, and hypoapneas. The frequency of obstructive events as measured by the PSG is reported as the Apnea-Hypopnea Index Scale (AHI). These are measured as respiratory arousal events per hour.

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An AHI of > 5 and < 15 is diagnosed as mild OSA, an AHI > 15 and < 30 is a diagnosis of moderate OSA and severe OSA is an AHI > 30. There are two validated subjective self-reporting tools utilized in sleep apnea. The Epworth Sleepiness Scale (ESS) rates subjective experiences of daytime sleepiness and alertness. The Multiple Sleep Latency Test (MSLT) measures, in minutes, the time it takes for a person to fall asleep during the day. The importance of diagnosing and treating OSA can be identified by the risks associated with not treating it. The risks of untreated OSA include increased motor vehicle and occupational accidents due to daytime sleepiness, loss of job productivity, social and cognitive dysfunction, reduced vitality, depression, cardiovascular disease, impotence, severe hypoxemia during sleep, hypertension, and diabetes (Chesnutt M, 2011) (Pagel JF, 2008). Standard Treatment Treatment includes behavior modification, oral devices, nasal continuous positive airway pressure (CPAP) and surgery. The optimal treatment is nasal CPAP. CPAP works by providing a continuous positive airway pressure applied via a nasal mask. This low pressure, ranging between 4.5 and 10 cm of oxygen, acts as a splint to keep the nasopharyngeal airway open. CPAP is known to abolish apneas, hypoapneas and snoring as well as improve sleep quality and quantity (Sullivan CE, 1981). Treating OSA may address the chronic associated comorbidities of obesity, hypertension, cardiovascular disease, and cerebrovascular events. One nasal expiratory positive airway pressure (EPAP) device, Provent therapy, is a FDA approved alternative therapy to CPAP for OSA. It consists of disposable, nightly-use nasal devices that create a high expiratory resistance resulting in positive pressure throughout exhalation that keeps the upper

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airway open. It has been shown to significantly reduce AHI with nightly adherence (Berry RB, 2011). Both CPAP and EPAP have adverse effects including dry mouth and throat, breathing discomfort, insomnia, oxygen desaturation, nasal congestion or discomfort and oropharyngeal pain (Berry RB, 2011). The first research to show that training of the upper airway muscles can significantly improve sleep related outcomes including reduction of the AHI was published in 2005 (Puhan MA, 2005). Research has shown that regularly playing the Australian wind instrument, the didgeridoo, is an effective treatment for OSA and is well accepted by subjects. The study showed that after 4 months of playing the didgeridoo for 20 minutes daily 5 days a week there was a significant reduction is daytime sleepiness and AHI in subjects with moderate OSA. The investigators hypothesize that playing the didgeridoo trains the upper airway muscles thereby increasing airway dilation and wall stiffening.

Treatment Challenges Although it is the gold standard, CPAP is not without its drawbacks. CPAP is considered highly effective in only 62% of patients. It is not tolerated by 20to 30 % of patients and its major limitation is poor patient compliance. (Padma A, 2007) (Wright J, 2000). Adequate compliance is defined as CPAP use for at least 4 hours per night, 5 nights a week (Santamaria J, 2007). Using these criteria, compliance rates are between 46-67% (Santamaria J, 2007) (Kribbs NB, 1993). Further, only 50%-75% of patients who were prescribed CPAP continue to use it after one year (Stepnowsky C Jr, 2003). Poor compliance can be due to any of the following: lack of portability, cost, pump noise, mask leaks and discomfort, dry throat and mouth, claustrophobic feelings, local tissue injury to face and nasal bridge, unintentional mask removal, nasal irritation or congestion, epistaxis, rhinitis,

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pressure intolerance and aerophagia (swallowing air causing stomach bloating) (Padma A, 2007) (Hoffstein V, 1992) (Kakkar RK, 2007). Acupuncture: Research and Review Introduction Clinical research has been conducted on acupuncture since the 1950s (White A, 2004). Studies have been published in the United States since the early 1970’s. Older research published in China reported positive results using acupuncture that upon review lacked the rigor and scientific standards to be considered valid and adequate. Good research on acupuncture can be challenging when adhering to the scientific standards for randomized controlled trials, due to biomedical standards not accounting for the unique holistic paradigm of acupuncture. Unlike a drug, acupuncture treatment generally involves an individualized treatment plan based on a specific diagnosis for the individual rather than a “one-size-fits-all” protocol. Further, a satisfactory acupuncture placebo has yet to be developed. The ongoing research challenge addresses the value of acupuncture research using the current biomedical standards of blinded, randomized controlled trials. The question is how to best design an acupuncture study that is similar to the delivery of acupuncture in current clinical practice that utilizes traditional diagnostic methods and applies individualized treatment. (Hammerschlag R, 1998). Acupuncture research tends to achieve positive results when designed as a pragmatic study that examines the effectiveness of acupuncture treatment compared to another form of treatment or no treatment (Kaptchuk TJ, 2010), rather than a comparison to a placebo. In the pragmatic study, isolating a specific mechanism of action is not important.

This type of research is also called

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“whole system” research and provides valuable information on clinical outcomes (Hawe P, 2004).

Importance of Research on Acupuncture and Obstructive Sleep Apnea The question to ask regarding acupuncture and obstructive sleep apnea is whether obstructive sleep apnea could be resolved with acupuncture treatment. There currently is no evidence of that and no research to date has attempted to answer that question. But, preliminary research has shown that acupuncture was better than placebo and that a single session can reduce the negative effects of moderate OSA (Freire AO, 2007) (Friere AO, 2010). What is needed is a double-blind, randomized controlled trial to determine the efficacy of acupuncture in the treatment of OSA, ideally with long-term follow-up to demonstrate if there are lasting results. But first, smaller studies are needed to validate diagnostic methods, identify optimal acupuncture treatment protocols, and document long term follow-up. This proposed pilot study is designed to address the question of whether acupuncture could be an effective treatment for patients who fail CPAP, for any reason. This could lead to additional research to determine how acupuncture compares with CPAP as an effective treatment for OSA.

Acupuncture Research Related to OSA Acupuncture is known to help with somnolence, cognitive impairment, throat diseases, snoring, muscular tension and tonus, and structural issues as well as to affect neurophysiological pathways - all issues associated with OSA. Excessive daytime sleepiness (somnolence) and cognitive impairment such as poor memory and mood disorder are among the most common

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symptoms of OSA. Respiratory issues of the throat, snoring, structural muscular tension and tonus issues as well as dysfunction of neurophysiological pathways are all possible contributors to OSA (Patil SP, 2007) (Boyd JH, 2007) (Woodson T, 1991) (Maciocia G, 2008). Although there has been limited research on acupuncture and OSA, there are a number of studies with positive results for the symptoms of OSA and associated conditions. Most of the research studies conducted on acupuncture and somnolence have been indirect, as the focus has been on treating insomnia. It can be inferred that treating insomnia improves daytime sleepiness. Various research shows positive evidence that acupuncture improves insomnia (Lin Y, 1995) (Li LF, 2010) (Cao HJ, 2009) (Kalavapalli R, 2007). Many studies have been conducted using acupuncture to improve cognitive function, including poor memory and mood disorders. One Cochrane review found over 105 studies for treating the symptoms of vascular dementia which include memory loss and personality disorders, with reported benefits of 70 to 91% for the treatment group. (Peng W, 2007 ). Another study of acupuncture for vascular dementia found significant therapeutic effects on memory when using 5 acupoints, namely, Tanzhong (CV-17), Zhongwan (CV-12), Qihai (CV-6), Zusanli (ST-36) and Xuehai (SP-10) (Yu J, 2006). Three of these points, Tanzhong (CV-17), Zusanli (ST-36) and Xuehai (SP-10) will be used in this pilot study. This study involved 60 hospital in-patients diagnosed with vascular dementia who were randomly assigned to either the treatment group or the control group. Both groups were administered a mini-mental status examination (MMSE), the Hasegewa’s dementia scale revised (HDS-R) and activities for daily living (ADL). Both groups were given medication and acupuncture treatment. However, the treatment group was administered additional acupuncture sessions daily on the aforementioned five acupoints for a

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period of 6 weeks. At the end of the 6-week period, both groups were again administered the MMSE, HDS-R and ADL. While both groups improved, the treatment group scores (80% effective rate) were significantly higher than those in the control group (46.7% effective rate), with a significant difference of p< 0.05. Studies on the effectiveness of acupuncture for mood disorders, especially depression, have found acupuncture to be as effective as medication and/or psychotherapy. (Allen J, 1998) (Luo H, 1998). These studies provide evidence that acupuncture has had positive results on the two main symptoms of OSA, those being daytime sleepiness and mood disorder. The following are acupuncture studies that explore some of the pathophysiologic mechanisms of OSA that involve neurophysiologic pathways, throat pathophysiology, and dysfunctional muscular tension and tonus. Research on acupuncture analgesia reveals that acupuncture stimulates nerves that send impulses to the spinal cord and the central nervous system (CNS) which then release neurotransmitter chemicals that block pain signals (Pomeranz B, 1988). It may be possible that acupuncture has CNS effects that would influence the neurophysiologic pathways involved in OSA. Acupuncture analgesia research has also shown that one of the hormones released is adrenocorticotrophic hormone (ACTH). This hormone stimulates the adrenal cortex, releasing cortisol which is known to block inflammation in the body. Inflammation in the pharynx could play a role in pharyngeal occlusion in OSA (Boyd JH, 2007). Research on acupuncture for treatment of the throat has primarily been limited to sore throat, that is inflammation of the throat, and there is extensive literature on the application of acupuncture

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for throat diseases. In Chinese medicine, the throat is described as the “open-the-wind-way” and includes specific points that treat it (Ji ZH, 2012). One study using acupuncture for dysphonia associated with benign pathological tissue changes in the pharynx revealed significant improvement in voice quality of the treatment group (Yiu E, 2006). In this study, 24 participants between 19 and 51 years old, were divided into two groups, a treatment group and a placebo group. Both groups were given acupuncture, but only the treatment group was given acupuncture sessions using points specifically related to throat problems and vocal functions. All participants got 10 sessions within a 20-day period, with a pre- and post-acoustic analysis of their voice range profile, and a perceptual analysis of voice quality and quality of life measurement. A comparison between the two groups showed a significant improvement for the treatment group in measures of voice activity and participation profile (VAPP), self-perceived severity, and emotion scores. The VAPP had a mean change of 33.34, while the emotion scores had a mean change of 18.75, both with a p ≤0.01. Voice quality of breathiness and roughness ratings showed a mean improvement of 1 and 0.25 units respectively, with p values of 0.02 and 0.04. Another more recent Iranian study on postoperative sore throat found promising results using one acupoint, Neiguan (PC-6) (Esmaeili S, 2013). A non-randomized clinical study with 228 subjects undergoing elective surgeries were separated into a treatment group and a control group. The control group was administered acupuncture as described, in addition to the routine medical care both groups received. Postoperatively, the incidence of sore throat was measured and compared, with 14% of the treatment group experiencing a sore throat compared to 29.8% of the control group with a p> 0.05.

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Snoring, like somnolence, has been written about extensively in TCM (Maciocia G, 2008). There is a pattern of insomnia that particularly addresses snoring, that of phlegm-heat. Snoring is considered an excess pattern always involving phlegm (Maciocia G, 2008). One study of 120 subjects, addressing insomnia as a pattern of phlegm and heat, showed a 97% improvement rate. (Cui R, 2003). The acupoints selected were Baihui (GV-20), Shenting (GV-24), Sishencong (EXHN-1), Shenmen (HT-7), Neiguan (PC-6), Zhongwan(CV-12), Fenglong (ST-40) and Gongsun (SP-4). This study was of 120 subjects who were randomly divided into a treatment group and a control group. Each group consisted of a series of outpatients between the ages of 28 and 67 suffering from insomnia, which was diagnosed as interior-stirring by phlegm-heat. A sleep efficiency grading system was adopted and all of the cases in the study were determined to have a sleep efficiency of less than 60%. The treatment group was administered acupuncture with the points described above, plus estazolam 1-2 mg. daily over a period of 10 days, while the control group received estazolam 1-2 mg. with no acupuncture. Both groups were given 3 courses of treatment, after which the effects were evaluated. The measurement for the treatment group was superior at a 96.7% effective rate compared to 86.7% for the control group. Statistical significance was not provided. Three of those acupoints will be used in this proposed study: Baihui (GV-20), Neiguan (PC-6), and Fenglong (ST-40). Acupuncture research studies involving post-stroke treatment and muscle atrophy show that acupuncture affects muscular tension and tonus and well as the nerve pathways of motor function. One randomized controlled study of stroke patients receiving acupuncture showed a beneficial therapeutic effect on motor function (Sallstrom S K. A., 1996). A group of 45 consenting stroke rehabilitation patients with an average age of 57, were randomly assigned to either a control group (21) or an acupuncture group (24). The median time from stroke to

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inclusion in the study was 40 days, with inclusion criteria consisting of hemiparesis following a first stroke. Both groups received a full complement of multi-disciplinary individually adapted rehabilitation, but the control group received no acupuncture treatments while the acupuncture group received classical acupuncture according to their traditional Chinese medicine diagnosis for 30 minutes 3-4 times weekly for 6 weeks. All participants were administered a neuropsychological screen battery, as well as motor function, ADL and quality of life questionnaires upon entry into the group, and again 6 weeks later. While both groups improved, the results for the acupuncture group were significantly higher, particularly in the quality of life measurements of: 1) emotional reactions--the acupuncture and control groups had respectively, a mean change of 9.3 (p=0.02) and -3.8; 2) sleep--the acupuncture and control groups had respectively, a mean change of 15.2 (p=0.004) and -11.6; 3) pain--the acupuncture and control groups had respectively, a mean change of 12.6 (p=0.004) and 3.4; and 4) physical movement-the acupuncture and control groups had respectively, a mean change of 40.5 (p=0.0001) and 20.7. Another Chinese study with stroke patients found that acupuncture needling significantly improved the muscle strength, muscle tonus, and muscle spasticity in stroke patients (Luo BD, 2010). This was a 30-day study of 106 patients diagnosed with spastic paralysis who were divided into two groups – an observation group who were administered a balanced muscular tension needling method at the side of extensor and flexor of limbs, and a control group, who were administered acupuncture at Jianyu (LI-15), Quchi (LI-11), Waiguan (TH-5), etc . Results from this study showed a total effective rate of 96.3% for the observation group compared to 84.6% in the control group with a p 15 and < 30 events per hour, confirmed by a full PSG study and no prior experience with acupuncture. There were three arms, each with 12 subjects: 1) acupuncture group, 2) placebo group, and 3) control group. The subjects were randomized via a blinded, independent researcher selecting a treatment order on a closed piece of paper out of a box. The acupuncture group received treatment of the following acupoints: Neiguan (PC-6), Lieque (LU-7), Hegu(LI-4), Yingxiang (LI-20), Baihui (GV20),Lianquan ( CV-23), Zusanli (ST-36), Fenglong (ST-40), Sanyinjiao (SP-6) and Zhaohai (KI6). The placebo group received sham acupuncture, that is, needling at non-acupoints with no further details specified. The control group received diet and sleep hygiene counseling. In addition to the PSG study data, there were 2 other measured outcomes: the validated functional scales of EES and the SF-36 lifestyle questionnaire. 26 subjects completed the study. Results from the PSG data showed a significant improvement in the acupuncture group as follows: AHI decreased by 50.5% (P=0.0005), apnea index (AI) decreased by 79% (P=0.0008), the number of respiratory events decreased by 43% (P=0.0008), sleep onset had a 67% shorter latency and sleep efficiency increased by 8%. The sham group showed a significant improvement in only one parameter, sleep efficiency, (14%) while the control group had a significant improvement of 12% in sleep efficiency. The control group experienced significantly greater respiratory events (53%). In addition, the acupuncture group had both a significant improvement in their ESS scores (P=0.028) and the following SF-36 scores: role physical (P=0.016), bodily pain (P=0.017), vitality (P=0.024), and mental health (P=0.005). The sham group had a significant increase in the mental health dimension of the SF-36 (P=0.033) while the control group had a significant negative change in their mental health dimension (P=0.029).

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The second study, a follow up to the 2007 study, demonstrated that both a single manual acupuncture (MA) treatment and a 10 HZ electro-acupuncture (EA) treatment produced significantly reduced AHI and other nocturnal respiratory events evaluated on PSG in moderate OSA patients (Friere AO, 2010). This study was conducted between January 2007 and August 2008, at the São Paulo university hospital. 40 subjects were enrolled in the study. Eligibility was a diagnosis of moderate OSA, AHI > 15 and < 30 events per hour, confirmed by a full PSG study, no prior experience with acupuncture and between 30 to70 years of age. There were four arms, each with 10 subjects: 1) manual acupuncture (MA) group, 2) 2 Hz electroacupuncture (EA), 3) 10 Hz electroacupuncture (EA) and 4) control group. The subjects were randomized (not described) via a blinded, independent researcher. The MA group received treatment of the following acupoints: Kongzui (LU-6), Lieque (LU-7), Hegu(LI-4), Yingxiang (LI-20), Baihui (GV-20),Lianquan ( CV-23), Zusanli (ST-36), Fenglong (ST-40), Zhaohai (KI-6), and the extra point Shanglianguan (EX HN22). The EA groups received the identical acupoints with electrodes placed on Lianquan (CV-23), Shanglianguan (EX HN22), Hegu (LI-4) and Zusanli (ST-36) with frequencies of either 2 or 10 Hz. The control group had no treatment which was not elaborated on in the study. The only outcome measured was PSG data. Each subject obtained a baseline PSG prior to treatment and then again immediately after. Changes in PSG showed a significant improvement in the MA and 10 Hz EA groups, respectively, of AHI (MA: pre 21.9, post 11.2 and EA: 20.6, 9.9), (P=0.005, P=0.005), AI (MA: 5.15, 0.7 and EA: 8.2, 0.3), (P=0.038, P=0.009), and respiratory events (MA: 120.5, 61.0 and EA: 117.0, 56.0), (P=0.039, P=0.014). No significant changes were noted in the 2 Hz electro-acupuncture or control group. The study focused on the lack of motor competence in OSA that the investigators suspected was either the result of an inflammatory

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condition or central mechanism that reduced the airway dilator muscles. They postulated that positive results involved the serotonergic pathways and the anti-inflammatory effects of acupuncture. In addition, they speculated that the 10 Hz EA produced stronger muscle toning than the 2 Hz EA. These two studies present the first English language research suggesting that acupuncture may have a future role in management of moderate OSA.

Challenges

Research on acupuncture and obstructive sleep apnea is really in a beginning stage. While the preliminary research from Brazil is exciting and inspires further inquiry, both studies have some issues. The 2007 study may be difficult to replicate. Also, in that study, patient safety was questioned as OSA-diagnosed patients were denied treatment…that is, they were given placebos, and in the case of the control group, no treatment. The control group had a greater number of respiratory events and their AHI index deteriorated.

The investigators dismissed any ethical

concerns due to the general lack of funds in the Brazilian health care system to care for its population but it would be difficult to replicate this study in another country such as the United States.

Another concern this author has about the Brazilian studies, is the lack of rationale for treatment and choice of treatment points. There was no traditional diagnosis using a Chinese medicine disease mechanism or syndrome pattern, nor were the acupoints chosen from any explained rationale. The study states that acupoints were selected individually due to specific characteristics of each point. Although the study showed significant positive results, it is unknown whether the results were optimal since Chinese Medicine principles were not applied.

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Treatment Protocol Rationale The limited literature and research on OSA and acupuncture add additional challenges to designing a study that adequately presents diagnostic patterns of OSA and then follows an optimal acupuncture treatment protocol. This study proposes to treat OSA as disharmonious patterns of Qi vacuity with phlegm stasis. The vacuity can be Lung, Kidney or Spleen, or any combination of these three. The treatment protocol for these patterns was derived from Bob Flaws online course, “Sleep Apnea Treated with Chinese Medicine” (Flaws B, 2003). The protocol consists of a core group of acupoints that focus on vacuity and phlegm stasis and limited additional points to be utilized, depending on other presenting symptoms of Liver Qi stagnation, blood stasis, and Stomach organ involvement. The proposed acupoints are listed in Table 1. Six of the core acupoints: Neiguan (PC-6), Lieque (LU-7), Baihui (GV-20), Lianquan (CV-23), Sanyinjiao (SP-6), Fenglong (ST-40) were utilized in both the 2007 and 2010 Brazilian studies. And the core acupoint, Shanglianquan (EX HN22) was utilized in the 2010 Brazilian study. This author has found the diagnosis of Qi vacuity and phlegm, often with Liver Qi stagnation and/or blood stasis, to be congruent with clinical observation and peer consultations. The root disease mechanism of OSA can be shown to originate in vacuity. The upper airway collapses due to this vacuity. This could be Lung, Kidney or Spleen vacuity or any combination of these three and a branch excess of phlegm and/or blood stasis. According to Chinese medicine theory, respiration is governed by the Lungs and Kidneys. The Lungs also govern the Qi of the entire body. The Lungs downbear the Qi while the Kidney Qi grasps the downbeared Lung Qi. Cessation of breathing is caused by vacuity in the Lungs as

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they are responsible for inhalation and exhalation. Lung Qi is supported by the Spleen which upbears the Qi to the Lungs. During obstructive sleep apnea either there is not enough Lung Qi to move the breath or there is an obstruction in the free flow of Lung Qi. Lung Qi can be vacuous if there is not enough Spleen Qi or Kidney Qi. Spleen Qi provides the post-heaven Qi and the Kidneys support the pre-heaven Qi. Liver Qi stagnation can further obstruct the free flow of Lung Qi by either invading the Stomach or causing counterflow or by transforming into heat which ascends and disrupts the Lung Qi. Phlegm is commonly present in obstructive sleep apnea (Flaws B., 2005). When the Spleen is vacuous, it fails to move and transform dampness thus engendering phlegm. The lungs then store the phlegm. Phlegm turbidity is also engendered when Qi and blood become obstructed and stagnate. Qi is needed to circulate the blood in the body. If the blood cannot move normally and uninhibited through the body, as when Qi is vacuous or stagnates, there will be blood obstruction and stagnation known as blood stasis.

Research Design and Methods Research Goals and Aims The research goal is to assess the effectiveness of an 8-week acupuncture protocol on symptoms of moderate obstructive sleep apnea (OSA). Specific Aim 1: Assess self-reported daytime sleepiness pre and post acupuncture treatment using the Epworth Sleepiness Scale (ESS).

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Specific Aim 2: Assess self-reported health and well-being pre and post acupuncture treatment using the SF-36V2™ . Specific Aim 3: Assess polysomnography (PSG) changes from pre to post acupuncture treatment. Specific Aim 4: Gather information about the feasibility of a large scale randomized clinical trial using acupuncture to treat moderate OSA. Overview This proposed pilot study is a non-randomized, pragmatic single arm study. The goal is to use the results from this pilot study to plan a randomized controlled trial to assess the feasibility, utility and safety of using an acupuncture protocol as a therapeutic intervention for treating OSA. This study proposal utilizes a TCM diagnosis with an individualized treatment plan and evaluation of the effectiveness of an acupuncture protocol as provided in a normal clinical practice. In order to support methodological rigor and reproducibility, the treatment protocol is restricted to a fixed set of acupuncture points with a limited selection of additional points as needed and no other treatments of any kind. The treatment protocol assumes a traditional Chinese medicine (TCM) diagnosis that includes Lung, Spleen and/or Kidney organ deficiencies and an excess of phlegm. This is based on the Chinese medicine etiology of OSA occurring through the above organ deficiencies, with phlegm being the result of the deficiencies. If a patient has a different TCM diagnosis, he or she will not be included in the study. The study is non-randomized and single arm because it is preliminary research to determine if further study and resources are warranted.

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Sixteen subjects will be recruited with moderate OSA who have failed a prescribed treatment of CPAP. Prior to receiving the study treatment, all subjects will be required to provide PSG data to be used as a baseline for comparison with a follow up PSG at the end of the 8 week treatment period. Subjects will be diagnosed and treated with an acupuncture protocol by one of three licensed acupuncturists. The subjects will receive acupuncture bi-weekly for 8 weeks. At the completion of 8 weeks of acupuncture treatment, the subjects will undergo a post-treatment PSG study evaluation of the participant’s response to treatment.

This will also include pre and post

treatment assessments of the ESS and the SF-36v2™ questionnaires. Pre to post treatment changes in PSG, ESS and SF-36v2™ will be statistically analyzed. Participants a. Recruitment, Consent and Initial Screening Prior to any contact with potential subjects, Institutional Review Board (IRB) approval will be obtained. Participants will be recruited through outpatient pulmonary centers and private physician offices in the Los Angeles area via flyers (Appendix 1). Subjects are eligible to participate if they have a diagnosis of moderate OSA confirmed through a PSG study and have failed CPAP. Failure of CPAP is determined by either the patient having notified their physicians that they are unable to comply with CPAP (for any reason) or if their physician has found through analyzing their respiratory data that they are non-compliant. Individuals who respond to the flyers will be initially screened by phone. If they meet the initial screening criteria as defined below under, “Inclusion and Exclusion Criteria”, an initial interview will be arranged. Screened potential subjects will be asked to come into the Los Angeles clinic for an initial interview to further evaluate for inclusion and exclusion criteria. At that time, the subjects

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will be provided with information on the study purpose and process. This will include the requirements and the risks of participation such as the possible risks of acupuncture: pain, bleeding, infection, fainting, hematomas and pneumothorax as detailed in the consent form (Appendix 2). Potential subjects will be given the opportunity to ask questions before signing the consent form which includes their agreement to comply with the treatment plan and scheduled appointments. Once the consent form is signed, each participant will be assigned a numeric code that will be used on all data collection materials for the duration of the study. Next, each participant will be assigned to one of the three listed research practitioners in the city of their choice, and an initial diagnosis and treatment visit will be scheduled. Subjects will not be paid for their participation but will receive a total of 16 free acupuncture treatment sessions over an eight week period. Treatment will be provided at three private clinics in Whittier, San Pedro, and Los Angeles, CA by three licensed acupuncturists, also known as the research practitioners. Each acupuncturist has at least 5 years of experience. Participants will be instructed to continue to be compliant with their personal physician’s instructions and all prescribed medications, but asked to agree not to introduce any new form of treatment, herb or nutritional supplement during their eight week acupuncture treatment. If at any time during the treatment a participant needs additional medical treatment for their OSA, they will be referred to their primary care provider and removed from the study. b. Randomization No randomization is required as it is a single arm. All patients in the study will be given the core acupuncture treatment and additional points per presenting TCM pattern as determined by the treating research practitioner.

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c. Inclusion and Exclusion Criteria Inclusion criteria are subjects, male and female, between the ages of 18 and 70 who have a diagnosis of moderate OSA, which is a score of ≥15 to ≤30 Apnea Hypopnea Index (AHI) events per sleep hour as diagnosed through a PSG study. In addition, each subject must have been prescribed CPAP as treatment and due to non-compliance, no longer utilizing it. By limiting eligibility to this population, the study does not attempt to persuade or deny any subject prescribed standard OSA treatment. Exclusion criteria are:  

            

pregnant or nursing women alcohol use greater than daily use of 1 drink for women or 2 drinks for men. One drink is defined as either: 12 fluid ounces of beer, 5 fluid ounces of wine or 1.5 fluid ounces of distilled alcohol. morbid obesity, defined as BMI ≥ 40 significant lung disease neurological disease mental impairments facial structural abnormalities central sleep apnea severe sleep apnea mild sleep apnea use of psychotropic medications use of sleeping medications use of recreational drugs or marijuana oropharyngeal surgeries current use of oral devices for OSA

Confidentiality Subject confidentiality will be maintained per patient HIPAA standards.

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Treatment Protocol a. Treatment Protocol Rationale The limited literature and research on OSA and acupuncture are challenges to designing a study that adequately presents diagnostic patterns of OSA and then follows an optimal corresponding TCM acupuncture treatment protocol. This study proposes to treat OSA as disharmonious patterns of Qi vacuity with phlegm stasis. The vacuity can be Lung, Kidney or Spleen, or any combination of these three. The treatment protocol for these patterns was derived from a Chinese comparison study (Flaws B., 2003). The protocol consists of a core group of acupoints that focus on vacuity and phlegm stasis with additional points utilized depending on other presenting symptoms, primarily Liver Qi stagnation, blood stasis and Stomach organ involvement. This author has found the diagnosis of Qi vacuity and phlegm, often with Liver Qi stagnation and/or blood stasis, to be congruent with clinical observation and collegial consultations. The proposed points are listed in Table 1.

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Table 1. Acupuncture Treatment Points Core Acupuncture Points Point

Function

Needle Depth

Danzhong (CV-17)

open the chest Qi

0.5 to 1 cun

Neiguan (PC-6)

quiet the spirit, promote sleep

1 to 1.5 cun

Baihui (GV-20)

quiet the spirit, promote sleep, lift the Qi

0.5 to 1 cun

Sanyinjiao (SP-6)

tonify Spleen

1 to 1.5 cun

Fenglong (ST-40)

resolve phlegm

1 to 1.5 cun

Taixi ( KI-3)

tonify Kidneys

0.5 to 1 cun

Lieque (LU-7)

Tonify Lungs, clear throat obstructions

0.5 – 1 cun

Lianquan (CV-23)

local, disinhibit the throat Qi

0.5 to 1.2 cun

Shanglianquan (EX HN22)

local, disinhibit the throat Qi

0.5 to 1.2 cun

Additional points utilized depending on presenting symptoms Taichong (LV-3)

soothe the Liver Qi

0.5 to 1.5 cun

Xingjian (LV-2)

clear Liver heat

0.5 cun

Neiting (ST-44)

clear Stomach heat

0.5 to 1 cun

Jiexi (ST-41)

move stagnated Stomach Qi

0.5 cun

Zusanli (ST-36)

tonify the Stomach, clear counterflow Qi

1 to 1.5 cun

Xuehai (SP-10)

Move blood stasis

1 to 1.5 cun

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b. Initial Consultation Examination At the initial visit each subject will be asked to fill out the study intake forms (Appendix 3) and to complete the Epworth Sleepiness Scale (Appendix 4) and the SF-36v2™ questionnaires (Appendix 5). Each participant will then be evaluated by the treating research practitioner and given a TCM diagnosis. In order to continue with treatment, a single or multiple organ pattern of Lung, Spleen and Kidney deficiency with an excess of phlegm must be present. If this pattern is not present, then the subject will be disqualified from the study. Following this initial consultation, eight weeks of twice-a-week treatments will be scheduled. c. Study Procedure Subjects will be treated twice a week for 8 weeks for a total of 16 treatments. Needles to be used are 0.18 mm x 30mm, spring type, disposable, sterilized Acuzone brand, made in Korea. All subjects will receive the core acupoints (see Table 1) bi-laterally and up to three additional acupoints from Table 1 as prescribed by the research practitioner. The research practitioner will record the actual acupoints needled and type of manual stimulation for each treatment. Needles will be retained for 30 minutes. Each needle will be inserted to the minimal depth specified in Table 1 and “de Qi” obtained. Tonification and sedation of an acupoint will occur with angular manual needling respectively, in the direction of the channel and in the opposite direction of the channel. Minimal sites needled will be 14 if only using the core treatment, with a maximum of 20 needled sites if using any additional points. No other treatments such as moxibustion, cupping, electrical stimulation or manual therapy will be given during any treatment. All acupoint locations will be measured with an elastic cun band for precision using the location as described in Peter Deadman’s text, A Manual of Acupuncture.

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Evaluation of each participant at baseline will include initial PSG data, and the two subjective functional questionnaires: Epworth Sleepiness Scale and Your Health and Well-Being SF-36v2™ . Two weeks after the final treatment, subjects will return to the clinic to fill out post-treatment ESS, Your Health and Well-Being SF-36v2™ , and the VAS on satisfaction. Participants will be scheduled with Los Angeles Sleep Study Institute, Los Angeles, CA for a post-treatment sleep study. Outcome Measurements (Pre and Post Treatment) Sociodemographic & Clinical Data All sociodemographic and clinical data will be collected and included in the final report. Primary Outcome AHI from polysomnography sleep study data. This data includes measurements of airflow, respiratory effort, blood oxygen saturation, snoring, apneas and hypopneas. Secondary Outcomes 1. Epworth Sleepiness Scale developed by Johns and validated in 1991 (Johns MW, 1991). It is a self-administered questionnaire that is widely used for patients with OSA. It provides a simple standardized method of measuring an individual’s level of daytime sleepiness. The 8-item questionnaire assesses situations of daytime sleepiness using a scale of 1 to 5. The summation of the scores, ranging from 0 – 24, result in a single measurement of daytime sleep propensity. A score of 10 or more is considered sleepy and a potential referral to a sleep specialist. A score of 18 or more is very sleepy.

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2. Your Health and Well-Being SF-36v2™ . This is a validated generic health survey of 36-items that yields an 8-scale profile of functional health and well-being (Ware, 1993). This 12-item questionnaire assesses state of health and well-being using a rating of a 5 level response scale. The results are grouped as physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. The scale has demonstrated good psychometric properties for physical and mental health summaries. Licensed use has been requested from Quality Metric Incorporated. 3. Satisfaction. Subject satisfaction with the results of the study will be recorded using the Visual Analog Scale (VAS). The VAS data is recorded on a scale of 0mm – not satisfied to 100mm -- completely satisfied. 4. Adverse events. Any adverse events will be recorded and included in the published results. Adverse events can include but are not limited to the following: pain following treatment, minor bruising, infection, needle sickness; and in the rare case, a broken needle. Statistical Power Utilizing the AHI change for pre- to post- acupuncture treatment of moderate OSA from the 2010 Brazilian study (Friere AO, 2010), a power calculation (STATA10) determined that a minimum of 10 subjects will be needed to achieve a statistical power of 90%.

Data Management and Statistical Analysis All patient data sheets will be kept confidential and in a locked office. A unique patient study ID but no patient names will be placed on the data forms. Study identifiers kept in a study logbook will be assigned to each patient to protect their confidentiality. When undergoing statistical analysis, the forms will be transferred to the primary investigator’s locked office. Patient

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identifiers will be stored separately from the data files on the primary investigators password protected computer. No one but the study team will have access to this identifier list. Data of continuous variables will be compared with a t-test, while categorical variable proportions will be compared with a chi-square test. A p value of