單波長紅外線光能對於肌筋膜激痛點之治療效果的探討

行政院國家科學委員會補助專題研究計畫 成果報告 期中進度報告 單波長紅外線光能對於肌筋膜激痛點之治療效果的探討 計畫類別 : 個別型計畫 整合型計畫計畫編號 :NSC 97-2314-B-006-004-MY3 執行期間 : 97 年 08 月 01 日至 100 年 07 月 31 日 執行機構及系所 : 國立成功大學醫學院復健學科 計畫主持人 : 官大紳共同主持人 : 林桑伊 陳若佟計畫參與人員 : 陳珮瑩 楊珺蕙 成果報告類型 ( 依經費核定清單規定繳交 ): 精簡報告 完整報告 本計畫除繳交成果報告外, 另須繳交以下出國心得報告 : 赴國外出差或研習心得報告 赴大陸地區出差或研習心得報告 出席國際學術會議心得報告 國際合作研究計畫國外研究報告 處理方式 : 除列管計畫及下列情形者外, 得立即公開查詢 涉及專利或其他智慧財產權, 一年 二年後可公開查詢 中華民國 100 年 10 月 31 日 1

目 錄 中文摘要 P.3 英文摘要 P.5 研究目的 P.7 文獻探討 P.8 研究方法 P.17 研究結果 P.26 參考文獻 P.32 結論自評 P.36 2

中文摘要 : 單波長紅外線光能對於肌筋膜激痛點之治療效果的探討 肌筋膜疼痛症候群 (MPS) 以肌筋膜激痛點 (MTrP) 的存在為特徵,MTrP 是位於骨骼肌肉裡可觸摸之緊繃肌帶上的局部性過度激活的疼痛點 當 MTrP 被強力地觸壓時, 它會產生局部抽搐反應 (LTR) 與位於該肌肉上之特定的引傳痛型式 在 MTrP 上所記錄到的特徵性肌電圖活動, 現已被稱為是終板雜訊 (EPN), 這是一種不正常型式的終板電位, 來自於神經肌肉交接處之乙醯膽素的過度釋放 目前關於 MTrP 的致病機轉已被認為是與 能量危機理論 有所關聯, 亦即 : 肌纖維之過度負荷, 產生功能失常的終板 (EPN), 進而引起肌纖維的過度收縮 ( 緊繃肌帶 ), 導致了局部區域的缺血反應, 以及痛覺神經傳導介質的敏感化 最近,EPN 出現的頻率也已被顯現出與 MTrP 的激活性有所關聯 目前關於 MTrP 的處置, 已經發展出許多治療性的策略, 諸如 : 物理治療 ( 熱療 冷療 電療 ), 徒手治療 ( 噴療與牽拉 放鬆術 按摩 激痛點壓力放鬆術 ), 激痛點注射, 藥物 等等 單波長紅外線光能儀器 (MIRE), 又稱為 Anodyne 治療系統 (ATS), 是 FDA 於 1994 年認可的一種光能治療 ( 波長為 890 nm), 可以暫時性地增加局部循環, 與降低疼痛 已有研究文獻記載 MIRE 對於糖尿病性的神經病變具有療效, 諸如恢復足部的知覺 降低神經性疼痛 改善平衡能力與傷口的瘉合 然而,MIRE 所具有的止痛與舒張血管的特性, 對於 MTrP 是否具有療效, 則沒有被報告過 為了釐清 MIRE 對於 MTrP 的治療效果, 我們設計了一個隨機對照與雙盲的三年期研究計畫 第一年的計畫, 我們將施加 MIRE 在兔子的肌筋膜激痛點上 (MTrS: 等同於人類的 MTrP), 檢驗 MIRE 是否能降低 EPN 的發生頻率, 以為 MIRE 對於 MTrS 的治療效果提供客觀性的證據 ; 研究結果發現,MTrS 裡 EPN 的發生頻率, 與對照組相互比較,MIRE 治療組的確有顯著降低的趨勢 第二年, 我們將比較 MIRE 與傳統物理治療 ( 熱敷合併電療 ) 對於 MTrS 裡 EPN 發生頻率影 3

響的差異, 以顯現 MIRE 是否較優於一般傳統物理治療的療效 ; 研究結果發現, MIRE 確實比傳統物理治療能夠更為顯著地降低 MTrS 裡 EPN 發生頻率 第三年, 我們將在人體上斜方肌上施加 MIRE 與偽裝之 MIRE( 相同的儀器, 但是沒有能量的輸出 ), 以驗證 MIRE 對於人體 MTrP 的治療成效 研究結果發現, 在視覺纇化量表 (VAS) 壓力疼痛閾值(PPT) 壓力疼痛耐受度(PPTO) 頸部失能指數(NDI) 方面,MIRE 都比控制組呈現出較為顯著的療效 經由此一三年期研究計劃, 我們將能真正驗證 MIRE 對於 MTrP 的治療效果, 同時也能更加釐清我們對於 MPS 之致病機轉的瞭解 關鍵詞 : 肌筋膜疼痛症候群, 肌筋膜激痛點, 終板雜訊, 單波長紅外線光能 (MIRE), Anodyne 治療系統 (ATS) 4

英文摘要 : The Therapeutic Effect of Monochromatic Infrared Photo Energy (MIRE) on the Myofascial Trigger Point Myofascial pain syndrome (MPS) is characterized by the presence of a myofascial trigger point (MTrP), which is a localized hyperirritable spot in a palpable taut band of skeletal muscle fibers. With an MTrP being strongly palpated, it will produce a local twitch response (LTR) and a referred pain pattern that is specific to that muscle. The characteristic of electromyographic activities recorded from an MTrP locus is regarded as endplate noise (EPN), which is an abnormal pattern of endplate potentials resulting from excessive leakage of acetylcholine in the neuromuscular junction. It is now postulated that the pathogenesis of an MTrP is related to energy crisis theory, that is: muscle fibers overload results in dysfunctional endplates (EPNs), which cause muscle fibers hypercontraction (taut bands) leading to local hypoxemia and sensitization of nociceptive neurotransmitters. Recently, the prevalence of EPNs has been shown to be correlated with the irritability of an MTrP. There are many therapeutic strategies designed for the management of MTrPs, such as: physical modalities (thermotherapy, cryotherapy, electrotherapy); manual therapy (spray and stretch, postisometric relaxation, massage, trigger point pressure release), MTrP injection, medication etc. Monochromatic infrared photo energy (MIRE), also known as Anodyne Therapy System (ATS), is one kind of photon therapy (890 nm of wave length) which had been approved by FDA in 1994 for temporarily increasing local circulation and reducing pain. Literatures have documented that MIRE could be beneficial for diabetic neuropathy, such as restoration of foot sensation, reduction of neuropathic pain, improvement of balance and wound healing. However, the analgesic and vasodilation effects of MIRE on the MTrP have not been reported. Three years of randomized-controlled, doubled-blinded experiments were designed for elucidating the therapeutic effect of MIRE on the MTrP. In the first year, MIRE was applied on an MTrS in a rabbit (equivalent to an MTrP in human) to see if EPNs would be reduced to reveal the objective evidence of therapeutic effect of MIRE. The results showed that MIRE could effectively reduce the EPN prevalence in an MTrS region. In the second year, the effect of MIRE was compared to that of heat combined with electrotherapy to show that if MIRE was superior to the traditional physical therapy for an MTrP. The results showed that MIRE reduced the EPN prevalence more effectively than the traditional physical therapy. In the third year, MIRE vs. sham MIRE (the same device only without power output) was applied on an 5

MTrP in the upper trapezius to examine the therapeutic effects on an MTrP. The results showed that MIRE had significant effect on an MTrP by the measurements of visual analog scale (VAS), pressure pain threshold (PPT), pressure pain tolerance (PPTO), and neck disability index (NDI). Through this 3-year study, we can prove the therapeutic effect of MIRE on an MTrP. The results of this study can also help us to further delineate the pathogenesis of MPS. Keywords: myofascial pain syndrome (MPS), myofascial trigger point (MTrP), endplate noise (EPN), monochromatic infrared photo energy (MIRE), Anodyne therapy system (ATS). 6

The Objective of this Study Monochromatic infrared photo energy (MIRE) has been shown to be beneficial for the restoration of sensation and reduction of pain in diabetic peripheral neuropathy. The vasodilatation effect of MIRE might play a major role in its therapeutic effectiveness. Current animal and human studies have attributed the pathogenesis of an myofascial trigger point (MTrP) to the energy crisis (local hypoxia) hypothesis and spinal cord integration mechanism. The prevalence of endplate noise (EPN) has also been shown to be correlated to the irritability of an MTrP. Through the vasodilatation effect of MIRE to improve the local microcirculation, we hypothesize that MIRE is effective for the management of myofascial pain syndrome (MPS). The objective of this 3-year study was to prove that MIRE could significantly decrease the prevalence of EPN in an myofascial trigger spot (MTrS) in a rabbit skeletal muscle in the first year study, which would be a animal study revealing the objective evidence of the effectiveness of MIRE for MPS, and to prove that MIRE was better than traditional physical therapy (heat therapy combined with electrotherapy) in the second year study, and to prove that MIRE was better than placebo therapy for MTrP in human in the third year study. Through the results of this study, we could verify a new therapeutic strategy for the management of MPS, and also help us to further delineate the pathogenesis of MPS. 7

BACKGROUND AND LITERATURE REVIEW Basic Knowledge of Monochromatic Infrared Photo Energy (MIRE) Monochromatic infrared photo energy (MIRE), known as Anodyne Therapy System (ATS) (Anodyne Therapy LLC, Tampa, FL), is one kind of photon therapy. The ATS delivers MIRE at a wavelength of 890 nm through therapy arrays, which are placed in direct contact with the skin. Each therapy arrays contains 60 superluminous Gallium Aluminum Arsenide (GaAIAs) diodes that pulses at 292 times/s [Burke, 2003]. According to the manufacturer literature, the intense ilumination of the skin by MIRE may non-invasively increase the localized release of nitric oxide (NO) from hemoglobin [Burke, 2003; Maegawa et al., 2000]. Released from nitrosothiols in hemoglobin or from endothelial cells, NO diffuses into smooth muscle cells that line small arteries, veins, and lymphatics. Once being inside the smooth muscle cell, NO binds to guanylate cyclase (GC) and makes GC activated. Activated GC enables the cleavage of two phosphate groups from guanosine triphosphate (GTP), which results in the formation of cyclic guanosine monophosphate (cgmp). cgmp is important to the phosphorylation of myosin. Once myosin phosphorylated, smooth muscle cell myosin will relax, and the vessels will dilated [Moncada & Higgs, 1993]. Through the increased release of NO, MIRE has been reported toresult in beter blood flow, acute delivery of growth factors and white blood cells, fibroblastic differentiation and proliferation, angiogenesis, reduced edema, and mediation of pain [Burke, 2005]. The ATS, which delivers MIRE, has received approval by FDA in 1994 for temporarily increasing local circulation and reducing pain. The ATS has been proposed currently as a treatment modality for several indications, such as: peripheral neuropathy, wound healing, and pain management [Burke, 2005]. Clinical Studies Evaluating the Therapeutic Effectiveness of MIRE Carnegie and Burke (2002) conducted a double-blind, placebo-controlled study of 8 patients (16 limbs) with loss of protective sensation (LOPS). Compared to the placebo group, all actively treated limbs achieved protective sensation, as demonstrated by an increased number of sensation sites. However, this study was limited by the small sample size and by a lack of both randomization sampling. Kochman et al. (2002) had tested the effectiveness of ATS on 49 patients with diabetic peripheral neuropathy (DPN). The results of this study suggest that ATS may provide improved pressure and heat sensitivity in patients with DPN. However, a definitive conclusion from this study could not be derived in the absence of a control group. Goldman (2003) conducted a retrospective study of 9 patients who received 12 ATS 8

treatments with two therapy pads. Re-evaluations of outcome were performed at 12 24 weeks after the final ATS treatment was completed. These studies showed that improved sensation diminished as early as 12 weeks after the therapy ceased. Goldman then concluded that to maintain long-term restoration of sensation, treatment would have to keep ongoing. Kochman (2004) later conducted another experiment to evaluate the clinical effectiveness of combined therapies with ATS and physical therapy. Thirty-eight elderly participants (mean age 78) with confirmed neuropathy and an experience of at least one fall in the past three months were recruited. They had received ATS treatments daily for 30- to 40-minute, which were followed by physical therapy. Physical therapy interventions consisted of static and dynamic balance retraining, neuromuscular re-education, strength training, and stretching of the ankle plantar flexors and hip flexors. In the end of this study, the author concluded that a combined therapy program can improve foot sensation, balance and gait and thus reduce the incidence of falls. However, the results did not clearly reveal the therapeutic gains which would be attributable to physical therapy alone or to an increase in foot sensation resulting from ATS alone. Leonard et al. (2004) recruited 27 patients with diabetes and peripheral neuropathy and divided them into two groups, based on their ability or inability to sense Semmes-Weinstein monofilaments (SWMs) 6.65 at all tested sites (group 1: n=18 vs. group 2: n=9). These patients initially received both active and sham ATS therapy for 40 minutes, three times per week for two weeks. They then received another six active treatments of the same duration administered to both limbs during the following two weeks. The results showed that, for diabetics with LOPS who have not progressed to profound sensory loss, there can be a temporary improvement in sensation with the use of ATS. Pain and balance were reported to be improved in group 1 subjects but was not significantly different in group 2 subjects. The limitation of this study is that it did not measure pain reduction or balance improvement in active compared to sham treatment of individual limbs. In addition, objective measurement for balance impairment, and long-term follow-up after 12 treatments were also lacking. Among the 2239 patients with peripheral neuropathy (PN), while 1395 (62%) having PN due to diabetes, Harkless et al. (2006) found that the mean number (7.1 ± 2.9) of sites insensitive to the SWM 5.07 was decreased to 2.4 ± 2.6 after MIRE treatment. The improvement was 66%. For the 2078 patients having LOPS, which was defined by Medicare as a loss of sensation at two or more sites on either foot, 1106 (53%) no longer suffered LOPS after MIRE treatment. Neuropathic pain with a VAS of 7.2 ± 2.2 points in the 1563 patients was reduced by 4.8 ± 2.4 points after 9

MIRE treatment. It was thus conclude that MIRE treatment is associated with clinical improvement in foot sensation and reduction in neuropathic pain. However, the study by Clifft et al. (2005) had a different conclusion. They recruited 39 subjects with diabetic peripheral neuropathy and randomly assigned them to an active MIRE group or a placebo group. The results revealed that the active MIRE treatment was no more effective than the placebo MIRE. With current available literature, there still is insufficient scientific evidence to fully support the use of MIRE for these proposed indications. Most studies were limited by their lack of randomization, placebo-controlling and double-blinding, as well as long-term follow-up of clinical effectiveness. In addition, most of these experiments were focused on restoration of sensation and wound healing in diabetic peripheral neuropathy. The effect of pain reduction of MIRE on a common muscle pain condition, myofascial pain syndrome, has not being well studied. Current Concept of Myofascial Pain Syndrome Myofascial pain syndrome (MPS) can be traced back to its beginning in 1950s when Travell first described it [Travell & Rinzler, 1952]. MPS is characterized by the presence of a myofascial trigger point (MTrP), which is a localized hyperirritable spot in a palpable taut band of skeletal muscle fibers. It has been reported that many clinical signs could be used to diagnose MPS, such as: (1).localized tender spot in a palpable taut band; (2).consistent and characteristic referred pain (ReP) pattern; (3).local twitch response (LTR); (4).restricted range of stretch; (5).constant low grade or moderate pain with episodic severe pain (exacerbation); (6).weakness without atrophy; (7).spread of pain to other parts of body; (8).referred autonomic phenomena (vasoconstriction, coldness, sweating, pilomotor response, ptosis, hypersecretion, etc.). [Fricton, 1993 & 1994; Gerwin, 1991 & 1992; Hung, 1976 & 1985; Rachlin, 1994; Rosen, 1993; Simon, 1988 & 1990; Simons et al., 1999; Sola & Bonica, 1990; Travell & Simons, 1983 & 1992]. Simons concluded that "spot tendernes, pain recognition," and "taut band" are the most reliable signs and the minimal criteria needed to identify an MTrP, while "referred pain" and "local twitch response" are most useful as confirmatory signs of the MTrP [Simons, 1996]. After reviewing 93 pulications and identified 19 different diagnostic criteria, Tough et al (2007) found tender spot in a taut band, patient painrecognition on tenderspot palpation, predicted pain referal patern, and local twitch response were the most frequently used criteria for the diagnosis of MTrPs. To achieve a higher interrater reliability, Gerwin had strongly emphasized the importance of hands-on training in the diagnosis of an MTrP [Gerwin et al., 1997].. 10

Animal Model for Studies of Myofascial Trigger Points Until now, the morphological evidence for an MTrP has not been fully defined. However, recent electromyographic (EMG) studies on both animal and human subjects have made the pathophysiology of MTrPs much better understood. Hong and Torigoe had developed an animal model and found it was very useful for studying the pathophysiology of an MTrP [Hong and Torigoe, 1994]. In rabbit skeletal muscle, taut bands similar to that in human muscle could be identified by finger palpation. When they squeezed or compressed a certain sensitive site in the palpable taut band, the rabbit would express as if it suffered pain or discomfort (such as screaming, kicking, or withdrawing), which was not observed when the other site was similarly irritated. When they used a needle or a blunt metal probe to stimulate this particular site mechanically (tapping or snapping), localized twitch responses (LTRs) could be observed. These rabbit localized twitch responses (R-LTRs) are similar to human local twitch responses (LTRs) both in the characteristics of visible muscle twitching and in electromyographic (EMG) recording. Both R-LTRs and human LTRs were elicited much easier at this sensitive spot than other sites in the same muscle [Fricton et al., 1985; Hong & Torigoe, 1994; Hong et al., 1995; Simons & Dextor, 1995]. This hyperirritable spot was defined as myofascial trigger spot (MTrS), which is similar to human MTrP. The Sensitive (LTR) Locus and the Active (EPN) Locus of an MTrP In an MTrP region, the minute site from which an LTR can be elicited, either by finger snapping or by needling stimulation, has been defined as a sensitive locus of an MTrP [Hong, 1994]. Since a sensory nerve fiber has been shown nearby the sensitive locus in a primitive histological study [Hong et al., 1996-a], it is very likely that the sensitive locus (LTR locus) is a sensitized nociceptor (or sensitized nociceptors). When the inserting needle encounters a sensitive locus, the nociceptors in this locus will be activated and both local pain and referred pain can be induced. Therefore, a sensitive locus can be regarded as the sensory component of the MTrP. From an animal study for mapping LTR loci [Chang et al., 1998], and from an algometer study and MTrP injections on human subjects [Hong et al., 1996-b], sensitive loci (LTR loci) could be found everywhere in the whole muscle, but most frequently be found in the endplate zone. In 1993, Hubbard and Berkoff reported their findings of the characteristic EMG activities in an MTrP region of the human upper trapezium muscle [Hubbard and Berkoff, 1993]. Simons et al later defined these EMG activities of an MTrP as spontaneous electrical activity (SEA) [Simons et al., 1995-a & 1995-b & 1995-c]. SEA can be recorded from a minute locus of either an MTrP region in human 11

[Hubbard and Berkoff, 1993] or an MTrS in animal model [Simons et al., 1995-a]. Studies have revealed that more SEAs were recorded from an MTrP region than from a non-mtrp region [Simons et al., 1995-a & 1995-b & 1995-c]. The minute locus from which SEA can be recorded is now defined as an active locus of an MTrP [Simons, 1996]. Tracing back old literatures, Wiederholt confirmed this EMG activity as endplate noise (EPN), which was quite similar to SEA [Wiederholt, 1970]. The study by Ito attributed this abnormal pattern of endplate potentials to excessive release of acetylcholine packets [Ito et al., 1974]. Simons later suggested the term EPN rather than SEA be used in MTrP studies because the EPN was exactly the same as SEA recorded from MTrP region [Simons, 2001; Simons et al., 2002]. He concluded that the EPNs found in active loci of MTrPs are abnormal patterns of endplate electrical activity resulting from excessive acetylcholine leakage [Simons et al., 1995-a; Simons et al., 2002]. Our recent animal study also revealed that botulinum toxin type A (BTX-A), a drug capable of blocking the release of acetylcholine from neuromuscular junction, could effectively suppress the prevalence of EPN in rabbit myofascial trigger spots (MTrSs), which further supported Simons conclusion [Kuan et al., 2002: NSC-89-2314-B-006-179]. The Basic Unit of an MTrP During MTrP injection, it has been recommended that the needle should be inserted into multiple sites in the entire MTrP region in order to eliminate its tenderness effectively [Travell & Simons, 1983; Simons et al., 1999]. During our searching for EPN with an EMG needle, we can always find either EPN or LTR, or both, at different loci in an MTrP region, and both EPN and LTR are often associated with a sharp pain sensation that is similar to the patient's usual complaint. Based on these clinical observations and animal studies, Hong has proposed a Multiple Loci Theory for an MTrP, that is, each MTrP is composed of several small sensitive loci [Hong, 1993 & 1994]. In 1998, Hong and Simons further extended the concept of Multiple Loci Theory to the concept of The Basic Unit of an MTrP. It was hypothesized that each MTrP contains many basic units of an MTrP, the MTrP locus. Each MTrP locus consists of a sensory component (a sensitive locus) and a motor component (an active locus) [Hong & Simons 1998; Kuan et al., 1998]. The sensitive locus, from which an ReP or an LTR can be elicited, is probably related to sensitized nerve fibers (nociceptors). The active locus, from which we can record an endplate noise (EPN), which is now considered as abnormal patterns of endplate potentials resulting from excessive leakage of acetylcholine. A sensitive locus is probably in the immediate vicinity of an active locus, and when both structures (sensitive locus and active locus) exist together, they may form an MTrP locus, the 12

basic unit of an MTrP. Therefore, the pathogenesis of MTrPs is probably related to sensitized nociceptors (sensory loci) associated with dysfunctional endplates (active loci) [Hong and Simons, 1998; Kuan et al., 1998]. Pathophysiological Studies of Myofascial Trigger Points The pathogenesis of an MTrP: Energy Crisis For the mechanism about the formation of an MTrP, Travell and Simons have proposed integrated trigger point hypothesis, which has been considered as today s most accepted theory for the pathogenesis of an MTrP [Travell & Simons, 1983; Simons et al., 1999]. According to the hypothesis, an initial muscular overload, either from overuse, trauma, or chronic malpositioning, will lead to a dysfunctional motor endplate. This results in an excessive release of acetylcholine and a prolonged depolarization of the postjunctional membrane. It is then followed by a consecutive release and inadequate reuptake of calcium ions from local sarcoplasmic reticulum, which causes uncontrolled muscle fiber shortening and sustained contraction of sarcomeres. This will impairs local circulation even though the metabolic demand is increased. As local hypoxemia and energy crisis persist, neurovasoactive substances and neurotransmitters from free nerve endings will also be released. Thus a vicious cycle of energy crisis will be formed [Travell & Simons, 1983; Simons et al., 1999]. In a review article, Simons (2004) further substantiate this hypothesis to a 6-step positive-feedback cycle, i.e.: step1: abnormal ACh release; step 2: increased fiber tension; step 3: local hypoxia; step 4: tissue distress; step 5: sensitizing substances; (step 5 : sarcoplasmic reticulum dysfunction); step 6: autonomic modulation (Fig. 1) [Simons, 2004]. Fig. 1: Positive-feedback cycle of a 5- or 6-step integrated hypothesis to explain the etiology of myofascial trigger points. [Simons, 2004] 13

With further mechanical stress or other aggravating (perpetuating) factors added, a latent MTrP will become to be an active MTrP. The active MTrP may recover by itself as long as further muscular overload is avoided, may persist without progression, or may become aggravated (i.e.,. increased pain intensity and spread to other sites) if they are not treated appropriately or if the perpetuating factors are present [Hong and Simons, 1998]. The pathogenesis of an MTrP: Spinal Cord Mechanism Based on LTR studies, the MTrP mechanism is supposed to be closely related to spinal cord integration [Hong and Torigoe, 1994; Hong et al., 1995]. In rabbit skeletal muscle, the EMG activities of LTRs were almost disappeared after lidocaine block or transection of the innervating nerve [Hong and Torigoe, 1994]. The rabbit LTRs were unobtainable immediately after spinal cord transection at a level high above the lower motor neurons of that muscle, and then nearly completely recovered approximately 2.5 hours later (spinal shock period) [Hong et al., 1995]. These animal studies revealed that the rabbit LTRs are obviously mediated through the spinal cord, and supraspinal structures are not essential. For the other component of an MTrP, the active (EPN) locus, Hong demonstrated that there was no obvious change in EPN after transection of peripheral nerve or spinal cord up to one hour in an animal study [Hong and Yu,1998]. It appears that EPN is not directly related to the spinal cord mechanism. However, EPN persisted for only one day after nerve transection and then disappeared on the second day, and remained disappeared till the end of that study (up to one month). The result showed that humoral mechanism (acetylcholine release) plays a major role in the occurrence of EPN in the MTrP region, while neural mechanism (direct nerve impulse) is not important [Kuan et al., 2001; NSC 89-2320- B006-030]. By applying the stain with horseradish peroxidase (HRP), the most widely used agent for neuronal tract-tracing techniques, Kuan et al. (2007) have demonstrated both motor and sensory connections between an MTrS in the rabbit skeletal muscle and its spinal cord [Kuan et al., 2007-a; NSC 92-2314- B-006-074]. In a recent human study, the prevalence of EPN has been shown to be highly correlated with the irritability of that MTrP [Kuan et al.,. 2007-b; 2007]. In summary, the pathogenesis of MTrPs is probably related to an integrative mechanism in the spinal cord in response to sensitized sensory nerve fibers (nociceptors) associated with dysfunctional endplates. The Management of MTrPs There are many therapeutic strategies designed for the management of MPS. 14

Many of them have been claimed effective, but none has been proven to be conclusive. Before starting our treatment, it is important to first find out the underlying pathologies such as tendonitis, disc lesions, etc. and the perpetuating factors for an MTrP which include mechanical stress, nutritional inadequencies, metabolic and endocrine inadequencies, chronic infections, or psychologic factors [Fricton, 1994; Gerwin, 1993]. These underlying pathologies and perpetuating factors should be managed and corrected to make the treatment of MPS successful and also to avoid the recurrence of MTrPs. The therapeutic methods of MTrPs included physical modalities (thermotherapy, cryotherapy, electrotherapy, laser therapy); manual therapy (stretching, manipulation, therapeutic exercise, spray and stretch, postisometric relaxation, trigger point pressure release), MTrP injection (dry needling, local ansthetics, botulinum toxin), medication (NSAID, muscle relaxants) etc. [Hong et al., 2003]. Physiotherapy puts its focus on restoration of the muscle to its normal length, and the joint to its full range of motion. Home programs emphasize on self-stretching techniques, maintaining proper posture, therapeutic exercises and other physical medicine modalities [Travell & Simons, 1983; Simons et al., 1999]. The effectiveness of electrotherapy on the treatment of MTrPs has been documented [Graff-Radford et al., 1989; Hou et al., 2002; Hsueh et al., 1997; Lee et al., 1997; Tanrikut et al., 2003]. A study on MTrP treatment by Graff-Radford et al. (1989) suggested that low frequency electrical stimulation was not effective, and high frequency therapy is effective for MTrP pain relief but not effective to change the MTrP sensitivity. Combined therapy with ultrasound and electrotherapy may have better results than single therapy [Lee et al., 1997]. Hsueh et al. (1997) indicated that electrical nerve stimulation is better than electrical muscle stimulation for pain relief, but electrical muscle stimulation is better than electrical nerve stimulation for relief of muscle tightness. Laser therapy has been suggested as a needless (painless) acupuncture. The electromagnetic energy form laser may penetrate through the skin to the MTrP, causing the stimulation which is similar to dry needling [Kleinkort and Foley, 1984]. Snyder-Mackler et al. (1986) found an increase in skin resistance after laser therapy and suggested that it was a sympathetically mediated effectiveness. However, the effectiveness of laser therapy on MTrPs is still controversial [Snyder-Mackler et al., 1986; Lin et al., 2000; Wang,1995; Waylonis et al., 1988]. MTrP injection, either with dry needling or with lidocaine (0.5%), might be one of the most effective technique for the treatment of MPS. It is essential to elicit LTRs (similar to Teh-Chi in acupuncture) during MTrP injection to obtain an immediate and complete pain relief [Hong, 1993 & 1994; Hong & Simons, 1993]. Chu 15

emphasized the importance of muscle twitching (LTR) and she developed the electrical twitch obtaining intramuscular stimulation (ETOIMS), which was shown to have better pain-relieving effect for MPS [Chu J, 2000 & 2002]. The mechanism of MTrP injection for pain control is still not clear. It is postulated that the strong pressure stimulation of needling to the MTrP units can probably provide very strong neural impulses to the dorsal horn cells in the spinal cord to break the vicious cycle of MTrP circuit [Hong, 2002]. 16

MATERIALS AND METHODS General Design Three years of randomized-controlled, doubled-blinded experiments were designed for elucidating the therapeutic effect of MIRE on the MTrP. In the first year, MIRE was applied on an MTrS in a rabbit (equivalent to an MTrP in human) to see if EPNs would reduced to reveal the objective evidence of therapeutic effect of MIRE. In the second year, the effect of MIRE was compared to that of heat combined with electrotherapy to show if MIRE was superior to the traditional physical therapy for an MTrS. In the third year, patients with definite diagnosis of MPS were recruited. MIRE vs. sham MIRE (the same device only without power output) was applied on the MTrP in the upper trapezius to verify the therapeutic effect of MIRE on human. 1st year: Animal study of MIRE on MTrS Rabbits random One side biceps femoris The other side biceps femoris 2 weeks MIRE 2 weeks Sham MIRE 1 week 1 week EPN mapping before immediately one week after later 2nd year: Animal Study of MIRE v.s Traditional PT on MTrS Rabbits random Group A 2 weeks MIRE 1 week Group B 2 weeks Traditional PT (HP & ES) 1 week EPN mapping before immediately one week after later 17

3rd year: Human Study of MIRE vs. Sham MIRE on MTrP Patients with MTrP random Group A Group B 2 weeks MIRE 2 weeks Sham MIRE 1 week 1 week Outcome Measurement (VAS, PPT,PPTO, NDI) Before immediately after one week later Experimental Protocol: THE FIRST YEAR: Animal Study of MIRE on MTrS Animal Preparation Twenty adult New Zealand rabbits (3~5 Kg) were recruited. These rabbits were kept alone in a large cage, with a 12-hr alternating light-dark cycle, sawdust bedding, and free access to food and water. The procedures related to animal experiments in this study were approved by National Cheng Kung University Institutional Animal Care and Use Committee. Before anesthesia, we used finger palpation to find the most tender spot in a rabbit femoris biceps muscle. The rabbit usually expressed its painful reaction by withdrawaling its limb, turning its head, or screaming, etc. This tender region might contain the MTrS, and was marked for intervention. Then the rabbit was anesthetized with an intra-muscular injection of Ketamine 0.05 mg/gbw [Moulder et al., 1978]. When the animal was anesthetized, the skin was shaved across the lateral aspect of the posterior thighs bilaterally and the animal was placed on a thermostatically controlled circulating-water heating pad with the temperature adjusted to 37 0 C. Subsequent intravenous injection of Pentothal at 0.0lg/ml was given every 20-30 minutes to maintain the anesthetic level so that most of the spinal reflexes were preserved. Respiration and rectal temperature were monitored every 15 minutes, and heart rate and oxygen saturation were monitored every 5 minutes. Identification of a Myofascial Trigger Spot (MTrS) The skin of the lateral thigh of the rabbit was incised to expose the biceps 18

femoris muscle. We slipped a finger beneath the biceps femoris muscle, which was separated posteriorly from the semi-membranosus muscle. The biceps femoris muscle was grasped between the fingers from behind the muscle and was palpated by gently rubbing (rolling) to find a taut band. A taut band felt like a clearly delineated "rope" of muscle fibers roughly 2-3 mm or more in diameter. The fibers of the taut band were unmistakably firmer in consistency than the surrounding muscle so that the band could be snapped between the fingers (like plucking a guitar string). Along the taut band, the location where snapping palpation produced the most vigorous localized twitch response (LTR) was the myofascial trigger spot (MTrS). Electromyographic Recording Setting A 4-channel NICOLET Viking IV electromyographic (EMG) unit was used for our study. The high-cut frequency filter was set at 1,000 Hz and the low-cut at 100 Hz. The gain was generally set at 20 V per division for recordings. At the usual sweep speed of 10 ms per divisions, one screen presented 100 ms of record. A 37-mm, disposable, monopolar needle electrode was connected to channel 1 of the preamplifier box of the EMG unit and was used to search the intramuscular electrical activity (EPN). The control needle electrode, which was connected to channel 2, was inserted into a normal muscle (non-taut band, non-mtrs) tissue. A clip used for the surface electrode was attached onto the nearby skin. It was served as the common reference electrode by connecting it to both channels through a "Y" connector. The ground electrode was clipped to another site of nearby skin (Figure 1). Room temperature was maintained at 21+ l 0 C. Fig. 1: Location and connections of electrodes for EPN recording. 19

Search for Endplate Noise (EPN) in the MTrS Region The search needle was inserted parallel to the direction of the muscle fibers into the region of the MTrS at an angle of approximately 45 0 ~ 60 0 to the surface of the muscle. After the initial insertion to a point just short of the depth of the MTrS, the needle was advanced very slowly. Each advance was made through the least possible distance (usually 1-2 mm for one advancement) by simultaneously rotating the needle to facilitate smooth entry through the muscle tissue. Large advances were avoided because of the minute size of an EPN locus and the likelihood of inducing an R-LTR instead of finding a locus of EPN. When the needle approached an EPN locus, the continuous distant electrical activity (EPN) could be heard. The needle was then pressed laterally in four directions (forward and back, right and left), one of which often resulted in appearance of EPN. If not, the needle was advanced a minimum distance, which then usually resulted in appearance of EPN. A site was an EPN locus when EPN was identified if: 1). noise- like potentials were persist continuously for more than 3 screens (300 ms); 2). the potentials had an amplitude of > 10 V (which werre more than twice the instrumentation noise level of 4 V that were observed in control recordings taken at the beginning and upon completion of each track); 3). the adjacent control channel was not recording potentials greater than instrumentation noise level. The Prevalence of EPN in an MTrS Region (EPN Mapping) There were 8 advancements of needling (each advancement about 1 mm) in one needling track in an MTrS region. When the recording electrode approached its end of advancement, it was withdrawn to the subcutaneous level, but not out of the skin, and then re-inserted the electrode into another track (about 1 mm adjacent to the previous track). There were totally 5 tracks investigated in one MTrS region (Figure 2). These 5 tracks were explored to complete exploration of a pyramidal space. This allowed for the exploration of 40 different loci in the region of one MTrS region. All the EPN loci found in these 40 searching loci in an MTrS region were recorded for later data analysis. 20

MTrP region Taut Band EPN locus Fig. 2. Active needle electrode advancement in an MTrP region for searching for EPN locus. Experimental Protocol The prevalence of EPN loci in an MTrS (EPN mapping) was assessed in the biceps femoris on both sides. For each rabbit, one side of biceps femoris muscle was randomly selected for intervention with MIRE, and the other side was for sham MIRE (control data). The procedures mentioned above were performed by an investigator who was blind to the side of intervention (MIRE vs. sham MIRE). EPN mappings were assessed before, immediately after the 2-week course of intervention. After EPN mapping, the incision wound was sutured and the rabbit was kept alive. After one week, the EPN mapping were followed again in both sides. Data Analysis For each MTrS, the prevalence of EPN was defined as the percentage of total occurrences of EPN among 40 searched sites. The mean and standard deviation of the prevalence of EPN within each MTrS in either side before MIRE, immediately after MIRE, and one week after MIRE were calculated. The paired t test was used to compare the values between the control and experimental sides. Repeated-measured ANOVA was used to compare the values before MIRE intervention, immediately after MIRE intervention, and one week after MIRE intervention. A p value of less than 0.05 was considered statisticaly significant. 21

THE SECOND YEAR: Animal Study of MIRE vs. Traditional Physical Therapy (tpt) on MTrS Experimental Protocol: MIRE vs Traditional PT The procedures of animal preparation, EMG machine setting, localization of an MTrS, EPN mapping were also the same as the procedures in the first year study. The collected rabbits were randomized into two groups. Group A received MIRE intervention. Group B receive traditional physical therapy (tpt) intervention. The protocol of MIRE intervention consisted of a daily 40 minutes treatment, three times per week for 2 weeks (total six treatments). The tpt program consisted of heat and electrotherapy. Hot packing with 37 0 C was first applied over the MTrS region for 15~20 minutes. The machine (Einmal Elektrode) used for electrotherapy had two applicators connected to the negative and the positive stimulating outputs. Each applicator was a surface electrode and was attached to the muscle where an MTrS located. The type of current was a combination of medium-frequency AC current (80%) and Galvanic (DC) current (20%) at a frequency of 50~100 Hz modulations. The electrotherapy last for 20 minutes. The prevalences of EPN in an MTrS region were performed before the intervention, immediately after the 2-week course of the intervention, and one week after the completion of the intervention. Data Analysis The calculations of data analysis were the same as the first year study. The Third Year: MIRE vs. Sham MIRE on Human Patients Patients with MPS were recruited from our outpatient department. The inclusion criteria were: patients had the diagnosis of MPS with definite MTrPs; they should be 18 years of age or older, and they were able to free communication. The MTrP was identified based on the following criteria, as recommended by Simons [Simons et al., 1999]: (1) a localized tender spot in a palpable taut band of muscle fibers, (2) recognized pain (as the usual clinical complaint) when the tender spot was compressed, and (3) characteristic and consistent referred pain. Patients who had the following conditions should be excluded, such as: (1) acute or serious medical problems, (2) malignancy, (3) sensory deficiency over the body part where MTrPs located, (4) coagulopathy or any other bleeding disorder, (5) taking medication of anti-coagulation or anti-thrombolytics, (5) serum hepatitis B or acquired immunodeficiencysyndrome, (6) cognitive impairment or psychiatric disorder, (7) 22

pregnant or likely to be pregnant. All the included patients signed the informed consents as approved by the human subject research committee of the National Cheng Kung University Hospital. Outcome Measurements Subjective Pain Intensity (Visual Analog Scale; VAS) MTrPs were localized by the examiner s finger palpation, and were marked with indelible ink and recorded on a pain diagram. The pain intensity of an MTrP were subjectively assessed by means of a visual analog scale (VAS). It was a card with an uncalibrated scale ranging from 0 to 10 on one side, and a corresponding 10-cm ruler on the other side. Each centimeter represented one pain level, with 0 representing no pain at rest or during movement, and 10 representing the worst pain ever experienced in one s life.the patient subjectively estimated his/her pain level by moving the pointing device along the uncalibrated scale. By referring the pointing on the uncalibrated scale side to the other 10-cm ruler side, the exact value of subjective pain intensity was then obtained. Pressure Pain Threshold (PPT) The pressure pain thresholds (PPT) of an MTrP were measured by a pressurethreshold algometer, which was developed by Fischer [Fischer, 1986 & 1987]. This algometer had been proved to be valid and reliable [Ohrbach and Gale, 1989; Reeves et al., 1986]. A well-trained assistant who was blinded to the treatment program performed the PPT measurement. The assistant explained thoroughly the examining procedures to the patient, and then placed the patient in a comfortable sitting position and encouraged to maintain complete relaxation. The algometer was applied on the marked MTrP site with the metal rod perpendicular to the surface of the skin. The assistant compressed the algometer to the skin gradually at a speed of approximately 1 2 mm/sec. As soon as the patient began to feel pain or discomfort and say yes, the compression of the algometer was stopped. The reading of the pressure (kg/cm 2 ) at this moment was regarded as the pressure pain threshold (PPT). The patient was required to remember this level of pain or discomfort and to apply the same criterion for the following measurements. Three repetitive measurements at an interval of 30 60 secs were performed at each MTrP site. The average value of the three readings was used for data analysis. Pressure Pain Tolerance (PPTO) The algometer was applied on the marked MTrP site with the metal rod perpendicular to the surface of the skin. The examiner compressed the algometer to 23

the skin gradually at a speed of approximately 1 2 mm/sec. The compression of the algometer was stopped when the patient showed that he could not tolerate more the compression. The reading of the pressure (kg/cm 2 ) at this moment was regarded as the pressure pain tolerance (PPTO). Three repetitive measurements at an interval of 30 60 seconds were performed at each MTrP site. The average value of the three readings was used for data analysis. Neck Disability Index (NDI) Neck disability index (NDI) were recorded by the questionnaire to the patient before the intervention of MIRE, immediately after the 2-week intervention, and one week after completion of the intervention (M 2 ). Experimental Protocol: MIRE vs. Sham MIRE The machine delivering monochromatic infrared photo energy (MIRE) which we used in this study was the Anodyne Therapy System (ATS) (Anodyne Therapy LLC, Tampa, FL). The ATS consisted of a base power unit and therapy pads, which contained 60 infrared (890 nm) gallium aluminum arsinide diodes. The output of photo energy of ATS unit was preset at 1.3 J/cm 2 /min. For sham MIRE, the diodes were inactivated so that no infrared photo energy was emitted. Furthermore, heaters preset at 37 C were inserted into therapy pads. Therefore, both the evaluators and the patients were hardly able to discriminate MIRE from sham MIRE either visually or by temperature. The included patients were randomized into two groups. Group A received MIRE intervention. Group B received sham MIRE intervention. The interventional protocol consisted of a daily 40 minutes treatment, three times per week for 2 weeks (total six treatments). The outcome measurements (VAS, PPT, PPTO, NDI) were performed before the intervention, immediately after the 2-week course of intervention, and one week after the completion of the intervention. Data Analysis The mean and standard deviation of the values measured for pain intensity, pressure pain threshold, and pressure pain tolerance, neck disability index were calculated. The paired Student s t test will be used to assess the differences between the data before and after the intervention. The differences in VAS, PPT, PPTO, NDI after intervention were further normalized as follows: percentage of changes = [(data after intervention - data before intervention)/data before intervention] x 100%. After data normalization, as described above, the differences in the changes of VAS, PPT, PPTO, NDI between the experimental and the control group were compared with 24

paired t test. A P value less than 0.05 was considered statisticaly significant. 25

RESULTS The Results of the First Year Study: MIRE on an MTrS Thirteen adult New Zealand rabbits (3~5 Kg) were recruited, one was dead during this experiment. Compared to the control group, the prevalence of EPN in the MTrS regions in the experimental group significantly decreased after the intervention of MIRE. One week after the cessation of the MIRE, the EPN in the experimental group increased again, but still below the level of the beginning. The means of prevalence of EPNs in the experimental group before the intervention of MIRE, immediately after the intervention of MIRE, one week after the intervention of MIRE were: 13.8, 7.3, and 10.3, respectively. On the other hand, those data for the control group were: 10.5 (before MIRE), 9.1(immediately after MIRE), and 10.8 (one week after MIRE). The results revealed that the prevalence of EPN in an MTrS could be effectively decreased by the intervention of MIRE. MIRE on EPN Prevalence 20 18 16 14 12 10 8 6 4 2 0 Pre-MIRE Post-MIRE 1 wk later Rabbit_02 Rabbit_03 Rabbit_04 Rabbit_05 Rabbit_06 Rabbit_07 Rabbit_08 Rabbit_09 Rabbit_10 Rabbit_11 Rabbit_12 Rabbit_13 26

16 14 12 10 8 6 4 2 0 Control side Pre-MIRE Post-MIRE 1 wk later Rabbit_02 Rabbit_03 Rabbit_04 Rabbit_05 Rabbit_06 Rabbit_07 Rabbit_08 Rabbit_09 Rabbit_10 Rabbit_11 Rabbit_12 Rabbit_13 The Results of the Second Year Study: MIRE vs tpt on an MTrS Twelve adult New Zealand rabbits (3~5 Kg) were recruited. Compared to the control group, the prevalence of EPN in the MTrS regions in the experimental group significantly decreased after the intervention of MIRE. The EPN in the experimental group increased again one week after the cessation of the MIRE, but still below the level of the beginning. The means of prevalence of EPNs in the experimental group before the intervention of MIRE, immediately after the intervention of MIRE, one week after the intervention of MIRE were: 13, 8, and 9, respectively. On the other hand, those data for the control group were: 11 (before MIRE), 11 (immediately after MIRE), and 10 (one week after MIRE). The results revealed that the prevalence of EPN in an MTrS could be decreased by the intervention of MIRE much more than hot packing combined with electrotherapy (traditional physical therapy). 27

The Experimental (MIRE) Group The Control (Hot Packing with Electrotherapy) Group 28

The Results of the Third Year Study: MIRE vs sham MIRE on an MTrP Fifty-two patients (10 male, 42 females, mean age: 45.1 years old) were recruited. After 2 weeks of MIRE intervention, the mean values of VAS of the experimental group were decreased from 5.62 (M 0 ) to 3.17 (M 1 ), and then increased to 3.46 (M 2 ). The changes of VAS of the experimental group were more significant than those in the control group, which were 4.34 (M 0 ); 2.56 (M 1 ), and 3.33 (M 2 ) [Fig. 2]. The mean values of PPT in the experimental group were increased from 2.36 (M 0 ) to 2.84 (M 1 ), and then decreased to 2.82 (M 2 ); the mean values of PPT in the control group were 2.11 (M 0 ), 1.73 (M 1 ), 1.67(M 2 ) [Fig. 3]. The mean values of PPTO in the experimental group were increased from 4.01 (M 0 ) to 4.40 (M 1 ), and then increased to 4.47 (M 2 ); the mean values of PPTO in the control group were 2.93 (M 0 ), 2.42 (M 1 ), 2.27 (M 2 ) [Fig. 4]. The mean values of NDI in the experimental group were decreased from 22.8% (M 0 ) to 13.9% (M 1 ), and then to 13.1% (M 2 ); the mean values of NDI in the control group were 25.8% (M 0 ), 19.3% (M 1 ), and 19.3% (M 2 ) [Fig. 5]. Application of monochromatic infrared photo energy (MIRE) on the myofascial trigger point (MTrP) in the upper trapezius. 29

6.00 5.62 6.00 5.00 5.00 4.34 4.00 3.00 3.17 3.46 4.00 3.00 2.56 3.33 2.00 2.00 1.00 1.00 0.00 1 2 3 0.00 1 2 3 Experimental Group Control Group Fig 2. Visual Analog Scale (VAS) between the experimental group and the control group * 1: before the intervention of MIRE (M 0 ); 2: immediately after the 2-week intervention (M 1 ); 3: one week after completion of the intervention (M 2 ). 3.00 2.50 2.00 1.50 2.36 2.84 2.82 3.00 2.50 2.00 1.50 2.11 1.73 1.67 1.00 1.00 0.50 0.50 0.00 1 2 3 0.00 1 2 3 Experimental Group Control Group Fig 3. Pressure Pain Threshold (PPT) between the experimental group and the control group * 1: before the intervention of MIRE (M 0 ); 2: immediately after the 2-week intervention (M 1 ); 3: one week after completion of the intervention (M 2 ). 30

5.00 4.50 4.00 3.50 3.00 2.50 2.00 1.50 1.00 0.50 0.00 4.40 4.47 4.01 1 2 3 5.00 4.50 4.00 3.50 3.00 2.50 2.00 1.50 1.00 0.50 0.00 2.93 2.42 2.27 1 2 3 Experimental Group Control Group Fig 4. Pressure Pain Tolerance (PPTO) between the experimental group and the control group * 1: before the intervention of MIRE (M 0 ); 2: immediately after the 2-week intervention (M 1 ); 3: one week after completion of the intervention (M 2 ). 30 25 20 22.8 30.0 25.0 20.0 25.8 19.3 19.3 15 13.9 13.1 15.0 10 10.0 5 5.0 0 1 2 3 0.0 1 2 3 Experimental Group Control Group Fig 5. Neck Disability Index (NDI) between the experimental group and the control group * 1: before the intervention of MIRE (M 0 ); 2: immediately after the 2-week intervention (M 1 ); 3: one week after completion of the intervention (M 2 ). 31