JP2024020037A - Biomarker of pain and itching - Google Patents
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Abstract
Description
本発明は、表皮生体電位（ｅｐｉｄｅｒｍａｌ ｂｉｏｐｏｔｅｎｔｉａｌ：ＥＢ）を痛み及び／又は痒みのバイオマーカーとして利用する技術に関する。 The present invention relates to a technique that uses epidermal biopotential (EB) as a biomarker for pain and/or itch.
痛みや痒みは苦痛や不快を伴う感覚で、多くの疾患で優先的に治療対象となるべき症状である。これらの感覚は当事者にしか感知しえないことから、常に被験者の自己申告による個々人の感性的な表現で表される。しかしながら、治療の要否や治療薬の選択には、痛みや痒みの定量的評価が求められる。 Pain and itching are sensations associated with pain and discomfort, and are symptoms that should be prioritized for treatment in many diseases. Since these feelings can only be sensed by those involved, they are always expressed as individual emotional expressions based on the subject's self-report. However, quantitative evaluation of pain and itching is required to determine whether treatment is necessary and to select therapeutic agents.
感覚量の定量的評価は難しいが、歴史的に工夫を凝らしたアセスメントツールが臨床の場で開発されてきている。たとえば、痛みのアセスメントツールで臨床の場で用いられているものは、Ｎｕｍｅｒｉｃａｌ Ｒａｔｉｎｇ Ｓｃａｌｅ（ＮＲＳ）、Ｖｉｓｕａｌ Ａｎａｌｏｇｕｅ Ｓｃａｌｅ（ＶＡＳ）、Ｖｅｒｂａｌ Ｒａｔｉｎｇ Ｓｃａｌｅ（ＶＲＳ）、Ｆａｃｅ Ｐａｉｎ Ｓｃａｌｅ（ＦＰＳ）である（非特許文献１）。同様に、痒みの場合にも、ＮＲＳ、ＶＡＳ、ＶＲＳが用いられる（非特許文献２）。ＮＲＳは、痛みを０から１０の１１段階に分け、痛みが全くないのを０、考えられるなかで最悪の痛みを１０として、痛みの点数を問うものである。ＶＡＳは、１００ｍｍの線の左端を「痛みなし」、右端を「最悪の痛み」とした場合、患者の痛みの程度を表すところに印を付けてもらうものである。ＶＲＳは３段階から５段階の痛みの強さを表す言葉を数字の順に並べ（例：痛みなし、少し痛い、痛い、かなり痛い、耐えられないくらい痛い）、痛みを評価するものである。ＦＰＳは、顔のアイコンが良い表情から悪い表情に順に並び、現在の痛みに一番合う顔を選んでもらうことで痛みを評価するものであり、３歳以上の小児の痛み自己評価に有用とされている。 Although quantitative evaluation of sensory quantities is difficult, historically sophisticated assessment tools have been developed in clinical settings. For example, painful assessment tools used in clinical settings are Numerical Rating Scale (NRS), Visual Analogue Scale (VAS), Verbal Rating Scale (VRS), FACE, FACE. SCALE (FPS) (non -patent) Reference 1). Similarly, in the case of itching, NRS, VAS, and VRS are used (Non-Patent Document 2). The NRS measures pain on an 11-point scale from 0 to 10, with 0 representing no pain and 10 representing the worst possible pain. In the VAS, the left end of a 100 mm line represents "no pain" and the right end represents "worst pain," and the patient is asked to mark the area representing the degree of pain. The VRS evaluates pain by arranging words expressing the intensity of pain in three to five levels in numerical order (e.g., no pain, a little pain, pain, a lot of pain, unbearable pain). FPS evaluates pain by arranging facial icons in order from good to bad expressions and asking children to choose the face that best matches their current pain, and is said to be useful for self-assessment of pain in children aged 3 years and older. has been done.
ただし、これらのアセスメントツールは、いずれも一定の数値的な取り扱いはできるものの、被験者個人の自己申告による評価であり、個々人の感じ方や過去の経験的な感覚に依存するところも大きく、被験者間同士の整合性（汎化性）も保証されないことから、客観性が乏しいことが従来から問題となっている。 However, although these assessment tools can handle numerical values to a certain extent, they are evaluations based on the self-reports of individual subjects, and they are highly dependent on the individual's feelings and past experience, and there are differences between subjects. Consistency (generalizability) between them is not guaranteed, so lack of objectivity has long been a problem.
一方、客観的な評価の試みとして、電気生理学的な手法も検討されている。特許文献１には心電波形から評価する方法、特許文献２には、心拍数及び心拍揺らぎから痛みを評価する方法が示されているが、いずれも臨床現場で広く利用するには至っていない。痛みや痒みを客観的に計測し、バイオマーカーとして利用できる新たな手法が求められている。 On the other hand, electrophysiological methods are also being considered as an attempt at objective evaluation. Patent Document 1 discloses a method of evaluating pain from electrocardiographic waveforms, and Patent Document 2 discloses a method of evaluating pain from heart rate and heart rate fluctuations, but neither has been widely used in clinical practice. There is a need for new methods that can objectively measure pain and itching and use them as biomarkers.
現在、痛みと痒みのアセスメントツールとして利用されている自己申告型の手法は、簡便ではあるものの、客観性に乏しいのが課題である。一方、特許文献１に記載の心電波形や心拍数を指標とした評価法は、痛みと心臓の反応に着目したものであるが、原理的に痛みが心機能に影響を与える場合のみの評価手法であり、痛みと心機能の相関性や痛みの検出感度については明示されておらず、臨床的価値については明らかではない。また、特許文献２の心拍数を指標とする評価法では、ストレス要因を痛みと判定する手法であり、心拍数変動と痛みの検出感度や病態との関連性については明らかになっていない。 Although the self-report methods currently used as pain and itch assessment tools are simple, they lack objectivity. On the other hand, the evaluation method using electrocardiogram waveforms and heart rate as indicators described in Patent Document 1 focuses on pain and cardiac reactions, but in principle it can only be evaluated when pain affects cardiac function. It is a method, and the correlation between pain and cardiac function and pain detection sensitivity are not clearly stated, and its clinical value is not clear. Further, the evaluation method using heart rate as an index in Patent Document 2 is a method of determining a stress factor as pain, and the relationship between heart rate fluctuations and pain detection sensitivity and pathological conditions has not been clarified.
このような心機能マーカーを指標として痛みを評価する手法は以下の問題を伴うことが報告されている。心拍数と慢性腰痛患者の痛みの関係について多数の論文を調査した報告（非特許文献３）によれば、慢性腰痛患者で副交感神経の活性が低下して心拍数に影響を与える可能性は一般化できないこと、急性痛や亜急性痛が評価されていないこと、感情的な要素が心拍数に影響を与えること、心疾患がある場合には適用できないことなどである。このように、心拍数や心電波形などの心機能マーカーを指標にした痛み評価は、実用上は限界があるといえる。 It has been reported that this method of evaluating pain using cardiac function markers as an index is accompanied by the following problems. According to a report that investigated numerous papers on the relationship between heart rate and pain in patients with chronic low back pain (Non-Patent Document 3), it is generally accepted that parasympathetic nerve activity decreases in patients with chronic low back pain and that it may affect heart rate. It does not assess acute or subacute pain, emotional factors affect heart rate, and it cannot be applied in patients with cardiac disease. In this way, it can be said that pain evaluation using cardiac function markers such as heart rate and electrocardiographic waveforms as indicators has limitations in practical use.
一方、痒みの電気生理学的な評価に関しては、皮膚のアレルギー反応や皮膚炎の機序を解明するために、実験的外科手術で電極を皮下に刺して刺激剤を注入し、炎症反応や痒みを評価する手法が報告されているが（非特許文献４）、侵襲的評価法であり、あくまでも実験的手法に留まる。以上のように、痛みや痒みを直接的に、かつ非侵襲的に日常医療で使用できるような評価手法やバイオマーカーは報告されていない。 On the other hand, regarding the electrophysiological evaluation of itching, in order to elucidate the mechanism of skin allergic reactions and dermatitis, experimental surgery is used to insert electrodes subcutaneously and inject stimulants to induce inflammatory reactions and itching. Although an evaluation method has been reported (Non-Patent Document 4), it is an invasive evaluation method and remains an experimental method. As described above, no evaluation method or biomarker that can be used directly and non-invasively in daily medical care for pain and itching has been reported.
本発明は、感情や心疾患が影響する心拍や心電位等のサロゲート的な指標によらず、できるだけ直接的に生体表皮から痛み信号と痒み信号を検出し、評価することを課題とする。痛みや痒みは、苦痛や不快を伴うことから、生活の質（Ｑｕａｌｉｔｙ Ｏｆ Ｌｉｆｅ：ＱＯＬ）を左右する重要要素であり、その治療のための薬剤投与においても、適切なバイオマーカーがあれば、薬剤の選択と適正使用に大きく貢献する。 An object of the present invention is to detect and evaluate pain signals and itch signals from the epidermis of a living body as directly as possible, without relying on surrogate indicators such as heartbeat or cardiac potential that are influenced by emotions or heart disease. Pain and itching are important factors that affect quality of life (QOL) because they are accompanied by pain and discomfort, and when administering drugs to treat them, if appropriate biomarkers are available, drug greatly contributes to the selection and proper use of
また、従来の自己申告型の主観的評価に依らず、生体表皮から痛み信号と痒み信号を検出する方法であれば、痛みと痒みの症状把握を客観的に行うことができ、コミュニケーションが取れない患者（乳幼児、小児、認知症患者など）の症状把握にも非常に有用である。 Additionally, without relying on conventional self-reported subjective evaluations, a method that detects pain and itch signals from the epidermis of a living body allows for objective understanding of symptoms of pain and itch, and prevents communication. It is also extremely useful for understanding the symptoms of patients (infants, children, dementia patients, etc.).
一方、医薬品には副作用がつきもので、しばしば問題となる。たとえば、抗がん薬は有効率は２０～３０％程度とされるものの、ほぼ全例に副作用が発生するため、薬剤の恩恵を享受することなく副作用に苦しむ患者は、７０～８０％という計算になる。このため、治療薬が無効の患者は除外し、有効性が期待できる患者層を選択するには、薬剤感受性のバイオマーカーが必要となる。患者に対する医薬品の適正使用ができれば、無用な治療を行わずにすむので、医療経済上も大きな利点がある。最も一般的で数多くの病態に付随する痛みと痒みという感覚を評価できる客観的なバイオマーカーの開発は、医療上の重大な課題であり、その解決が強く求められている。 On the other hand, medicines are often accompanied by side effects, which often pose problems. For example, although anticancer drugs are said to have an efficacy rate of about 20-30%, side effects occur in almost all cases, so it is estimated that 70-80% of patients suffer from side effects without enjoying the benefits of the drug. become. Therefore, drug-sensitive biomarkers are needed to exclude patients for whom therapeutic drugs are ineffective and to select a group of patients who can be expected to be effective. If drugs can be used appropriately for patients, there will be no need for unnecessary treatment, which will have great medical economic benefits. The development of objective biomarkers that can assess the sensations of pain and itching that accompany many of the most common pathological conditions is a critical medical challenge that is desperately needed.
本発明は、痛みや痒みを生じた病態において、皮膚表面に電極を装着して計測される表皮生体電位を痛み及び痒みのバイオマーカーとして利用する技術に関し、以下の発明で構成される。
（１）痛み及び／又は痒みの程度を定量化するためのバイオマーカーであって、接触型電極で計測された表皮生体電位から、統計手法及び／又は機械学習手法を用いた数理モデルで算出されたバイオマーカー。
表皮生体電位によって算出されるバイオマーカーであることから、客観的に痛みや痒みを捉えることができる。
The present invention relates to a technique for utilizing epidermal biopotential measured by attaching electrodes to the skin surface as a biomarker for pain and itching in pathological conditions that cause pain and itching, and is comprised of the following inventions.
(1) A biomarker for quantifying the degree of pain and/or itching, which is calculated from the epidermal biopotential measured with a contact electrode using a mathematical model using statistical methods and/or machine learning methods. Biomarkers.
Since it is a biomarker calculated by epidermal biopotential, it is possible to objectively capture pain and itching.
（２）前記計測された表皮生体電位の変動を求め、周波数パワー値又はＰｏｗｅｒ Ｄｅｎｓｉｔｙ Ｓｐｅｃｔｒｕｍ（ＰＳＤ）値として表し、痒み及び／又は痛み状態を効果量（ｅｆｆｅｃｔ ｓｉｚｅ）で計量化することを特徴とする（１）記載のバイオマーカー。
効果量として表すことにより、データの単位に依存せず、標準化された効果の程度として表すことができる。また、効果量は、サンプルサイズによって変化しない標準化された指標であることから、痛みや痒みの程度を相互比較する際にも非常に有用である。
(2) The variation in the measured epidermal biopotential is determined and expressed as a frequency power value or a Power Density Spectrum (PSD) value, and the itch and/or pain state is quantified in terms of effect size. The biomarker according to (1).
By expressing it as an effect size, it can be expressed as a standardized degree of effect without depending on the unit of data. Furthermore, since the effect size is a standardized index that does not vary depending on the sample size, it is very useful when comparing the levels of pain and itching.
（３）（１）又は（２）に記載のバイオマーカーを薬剤投与の要否の判定、薬剤の選択、薬剤投与効果の観察、服薬期間の設定、鎮痛薬開発時の有効性評価、止痒薬開発時の有効性評価に利用する方法。
本発明のバイオマーカーは、薬剤投与による副作用の程度を客観的に表す指標として用いることができる。また、薬剤の副作用を抑制する薬のスクリーニング、有効性評価にも用いることができる。
(3) Use the biomarkers described in (1) or (2) to determine whether or not to administer a drug, select a drug, observe the effect of drug administration, set the duration of drug administration, evaluate effectiveness when developing analgesics, and treat itching. A method used for efficacy evaluation during drug development.
The biomarker of the present invention can be used as an index that objectively represents the degree of side effects caused by drug administration. It can also be used for screening and evaluating the effectiveness of drugs that suppress their side effects.
（４）前記薬剤が、止痒作用または鎮痛作用を有する薬剤で、電位依存性カルシウムチャネル阻害薬、アデノシン受容体拮抗薬、κオピオイド受容体作動薬、セロトニン・ノルアドレナリン再取り込み阻害剤から選ばれる薬剤であることを特徴とする（３）に記載の方法。
（５）前記薬剤が、プレガバリン、ガバペンチン、ナルフラフィン、ジフェリケファリン、デュロキセチンから選ばれる、少なくとも１種類の薬剤であることを特徴とする（４）に記載の方法。
具体的には、本発明のバイオマーカーによって、上記の止痒作用や鎮痛作用を有する薬剤の評価を行うことができる。
(4) The drug has an antipruritic or analgesic effect, and is selected from voltage-gated calcium channel blockers, adenosine receptor antagonists, κ-opioid receptor agonists, and serotonin/noradrenaline reuptake inhibitors. The method according to (3), characterized in that:
(5) The method according to (4), wherein the drug is at least one drug selected from pregabalin, gabapentin, nalfurafine, difelikephalin, and duloxetine.
Specifically, the biomarkers of the present invention can be used to evaluate drugs having the above-mentioned antipruritic and analgesic effects.
（６）感覚量の異常、痛み、痒みを生じる病態を評価する方法であって、前記病態の原因が神経因性疼痛、線維筋痛症、中枢性神経障害性疼痛、多発性硬化症、自己免疫疾患、がん、糖尿病神経障害、又は抗がん薬投与時の手足のしびれ、痒み、感覚障害、若しくは手足症候群によるものであって、（１）又は（２）に記載のバイオマーカーによって評価することを特徴とする評価方法。
本発明のバイオマーカーによって、種々の疾患、あるいは薬剤の副作用によって生じる感覚量の異常、痛み、痒みを客観的に評価することができる。
(6) A method for evaluating a pathological condition that causes an abnormality in the amount of sensation, pain, or itching, the cause of the pathological condition being neuropathic pain, fibromyalgia, central neuropathic pain, multiple sclerosis, Immune disease, cancer, diabetic neuropathy, or numbness, itching, sensory disturbance in the hands and feet during administration of anticancer drugs, or hand-foot syndrome, and evaluated by the biomarker described in (1) or (2). An evaluation method characterized by:
Using the biomarker of the present invention, it is possible to objectively evaluate sensory abnormalities, pain, and itching caused by various diseases or side effects of drugs.
本発明者らは、痛みまたは痒みが生じている状態のＥＢを生体表皮で計測するために、皮膚に非侵襲的に装着できる接触型の電極と生体電位の計測デバイスを採用し、計測されたデータから心電位の影響を排除した変化量の抽出技術を開発し、そこから痛み及び／又は痒みのバイオマーカーを開発できることを明らかにした。さらに標準薬物を用いて痛みや痒み刺激を誘発させた状態で、鎮痛薬と止痒薬がそれぞれ薬効が前記バイオマーカーで客観的に可視化できることを明らかにし、本発明を完成させた。これによって、従来、自己申告による主観的な半定量化評価であるＮＲＳ、ＶＡＳ、ＶＲＳ、ＦＰＳ等で欠如していた客観性を担保でき、かつ心機能マーカーを利用した間接的で限定的な代替評価法に比べて、利便性が高く有用な痛み及び／又は痒みの評価技術を提供することができる。 The present inventors adopted a contact type electrode that can be attached non-invasively to the skin and a bioelectrical potential measurement device to measure EB in a state where pain or itching occurs on the biological epidermis. We developed a technique for extracting changes from data that excludes the influence of cardiac potential, and demonstrated that it is possible to develop biomarkers for pain and/or itch from this data. Furthermore, the present invention was completed by demonstrating that the medicinal efficacy of analgesics and antipruritics can be objectively visualized using the aforementioned biomarkers while inducing pain and itching stimuli using standard drugs. As a result, it is possible to ensure the objectivity that was lacking in conventional self-reported subjective semi-quantitative evaluations such as NRS, VAS, VRS, FPS, etc., and it is an indirect and limited alternative to using cardiac function markers. It is possible to provide a more convenient and useful pain and/or itching evaluation technique than other evaluation methods.
以下にデータを示しながら具体的に説明するが、本発明はこれらに限定されるものではない。 The present invention will be specifically explained below while showing data, but the present invention is not limited thereto.
［動物モデルと計測システム］
本発明の創出には動物モデルを用いた。被験動物は、皮膚に計測用の電極を貼るためにヘアレスマウス（Ｈｏｓ：ＨＲ－１、ＳＰＦ、オス、日本エスエルシー）を用い、マウスに薬剤を投与した後のＥＢを計測した。ヘアレスマウスは体毛がないため、体表のどの部位にでも非侵襲的に電極を装着することが可能であり、本試験では、頭部と背部の２か所を選び、それぞれ頭部ＥＢと背部ＥＢを計測した。図１にマウスＥＢ計測時にＥＢ計測デバイスを装着した様子を模式的に示した。評価システムの構成は、ＥＢを計測するＥＢ計測デバイスと、入出力、データ解析を行う制御部からなる。ＥＢ計測デバイスの電極はＥＢを計測できる電極であれば、その形態を問わない。制御部は操作タブレット、ＰＣ等どのようなものを用いてもよい。また、ＥＢ計測デバイスと制御部は無線制御でも有線制御でも構わず、システム全体も同様の機能を有した構成であれば、いずれでもよい。 本試験で用いたＥＢ計測システムは、ＰＧＶ株式会社が開発したパッチ式脳波計を利用した。システム全体を構成するブロック図を図２に示す。
[Animal model and measurement system]
An animal model was used to create the present invention. As test animals, hairless mice (Hos: HR-1, SPF, male, Japan SLC) were used to attach measurement electrodes to the skin, and EB was measured after administering the drug to the mice. Hairless mice have no body hair, so it is possible to non-invasively attach electrodes to any part of the body surface. EB was measured. FIG. 1 schematically shows how the EB measurement device is attached when measuring mouse EB. The evaluation system consists of an EB measurement device that measures EB, and a control section that performs input/output and data analysis. The electrodes of the EB measurement device may have any form as long as they can measure EB. The control unit may be any device such as an operation tablet or a PC. Further, the EB measuring device and the control unit may be controlled by wireless or wired, and the entire system may have any configuration as long as it has similar functions. The EB measurement system used in this test utilized a patch-type electroencephalogram developed by PGV Corporation. A block diagram configuring the entire system is shown in Figure 2.
本評価システムの計測部は、伸縮性の高い柔軟電極シート（接触型電極）と、小型軽量でありながら高精度・低ノイズで脳波計測が出来る仕様の小信号計測デバイスから構成される。接触型電極はパッチ式電極で、そのまま体表の複数個所の皮膚表皮に貼ることができ、同時計測できる。電極は、伸縮性を有するシート上に形成されて密着性が高く体表に装着される。ＥＢ計測の電極（頭部、背部、対照）はケーブルでＡ／Ｄコンバーターに接続され、計測電圧のアナログ値をデジタル値に変換する。デジタル信号は各機能ブロックを制御するマイクロコントローラーを介して、ストレージに記録される。マイクロコントローラーは、制御コマンドの受信・ＥＢデータの送信等をＢｌｕｔｏｏｔｈ無線通信で行うＢＬＥモジュールに接続され、操作タブレットから制御される。ストレージに記録されたＥＢデータはタブレットで受信し、タブレットのインターネット回線を通じて外部のクラウドサーバーに送信することができる。クラウドサーバーにはデータ解析ソフトウェアが搭載されており、ここでデータ解析が行われ、解析結果はユーザーに報告される。 The measurement section of this evaluation system consists of a highly stretchable flexible electrode sheet (contact electrode) and a small-signal measurement device that is small and lightweight and capable of measuring brain waves with high precision and low noise. Contact electrodes are patch-type electrodes that can be applied directly to the skin epidermis at multiple locations on the body surface, allowing for simultaneous measurements. The electrodes are formed on a stretchable sheet and are attached to the body surface with high adhesion. The electrodes for EB measurement (head, back, control) are connected to an A/D converter with a cable, which converts the analog value of the measured voltage into a digital value. Digital signals are recorded in storage via microcontrollers that control each functional block. The microcontroller is connected to a BLE module that receives control commands, transmits EB data, etc. using Bluetooth wireless communication, and is controlled from an operating tablet. The EB data recorded in the storage can be received by the tablet and sent to an external cloud server via the tablet's internet line. The cloud server is equipped with data analysis software, which performs data analysis and reports the analysis results to users.
本システムの接触型電極とデータ集積回路は、頭蓋骨によるシールドを超えて伝わる１μＶ以下の脳内神経細胞の非常に微細な活動電位をも計測できる感度を有しており、体表から各種生体信号を包括的に計測収集できる。したがって、脳波電位に限らず、筋電位や心電位、その他の部位の生体信号も包括的にＥＢとして計測することができる。 The contact electrodes and data integrated circuits of this system are sensitive enough to measure even the very minute action potentials of nerve cells in the brain of 1 μV or less that are transmitted beyond the shield of the skull, and various biological signals transmitted from the body surface. can be measured and collected comprehensively. Therefore, not only electroencephalogram potentials but also myocardial potentials, cardiac potentials, and biological signals from other parts can be comprehensively measured as EB.
生体各所で誘導される感覚量は、脳で感知されるが、感覚の発生部位と感知部位の両方で計測されることが望ましい。従来から、体表から計測する生体電位は、脳波（ｅｌｅｃｔｒｏｅｎｃｅｐｈａｌｏｇｒａｍ：ＥＥＧ）、心電位（ｅｌｅｃｔｒｏｃａｒｄｉｏｇｒａｍ：ＥＣＧ）、筋電位（ｅｌｅｃｔｒｏｍｙｏｇｒａｍ：ＥＭＧ）などの臓器別に分類されて取り扱われているが、本発明者らは、生体反応はマルチモーダルで、多様な生体電位が同時に発生されるので、痛みや痒みを病態として捉えるときには、特定臓器の電位を抽出するのではなく、複数の生体信号の総和を生体表面でＥＢとして捉え、その中から痛みや痒みに特徴的な電位に注目することが望ましいと考えた。本試験ではこの考えで評価を実施したが、特にＥＣＧは電位が高いので、妨害信号と見なして本システムの心電位除去フィルターで除去し、心機能マーカーの影響を無視してデータ解析を行った。 The amount of sensation induced in various parts of the body is sensed by the brain, but it is desirable to measure it at both the site where the sensation occurs and the site where it is sensed. Conventionally, biopotentials measured from the body surface have been classified and handled by organ, such as electroencephalogram (EEG), electrocardiogram (ECG), and electromyogram (EMG). et al., biological reactions are multimodal and various biological potentials are generated simultaneously, so when treating pain or itching as a pathological condition, rather than extracting the potential of a specific organ, we consider the sum of multiple biological signals on the biological surface. We thought it would be desirable to consider this as EB and focus on potentials that are characteristic of pain and itching. In this study, evaluation was conducted based on this idea, but since ECG has a particularly high potential, it was treated as an interfering signal and removed using the electrocardiogram removal filter of this system, and the data was analyzed ignoring the influence of cardiac function markers. .
計測・収集した電位波形の解析は、本システム用に独自開発した数理モデルからなる信号処理プログラムで実施した。本プログラムは、前処理・特徴量変換・効果量導出のプロセスから構成される。前記数理モデルは、統計手法及び／又は機械学習手法を用いたモデルで構築されている。ＥＢを計測した際の電位の変動は、フィルターによるノイズ低減処理（前処理）を経て周波数パワー値に変換され、当該周波数パワー値は、周波数で除したＰｏｗｅｒ Ｄｅｎｓｉｔｙ Ｓｐｅｃｔｒｕｍ（ＰＳＤ）値に変換される（特徴量変換）。このように、周波数パワー値やＰＳＤといった周波数情報に変換することによって、特定の周波数における変化量をデジタルバイオマーカーとして扱うことができる。 Analysis of the measured and collected potential waveforms was performed using a signal processing program consisting of a mathematical model originally developed for this system. This program consists of the processes of preprocessing, feature value conversion, and effect size derivation. The mathematical model is constructed using a statistical method and/or a machine learning method. The potential fluctuation when measuring EB is converted to a frequency power value through noise reduction processing (preprocessing) by a filter, and the frequency power value is converted to a Power Density Spectrum (PSD) value divided by the frequency. (Feature transformation). In this way, by converting into frequency information such as a frequency power value or PSD, the amount of change in a specific frequency can be treated as a digital biomarker.
痒みや痛みの状態の異なる個体グループの間において、周波数における変化量の違いを定量比較するためには、、データの単位に依存せず、標準化された効果の程度を表す指標である「効果量」（ｅｆｆｅｃｔ ｓｉｚｅ）と呼ばれる指標でグループ間の特徴量の差を計量化し出力する。効果量は感覚量を定量化するには好ましい概念である。 In order to quantitatively compare differences in the amount of change in frequency between groups of individuals with different itching and pain conditions, it is necessary to use the ``effect size'', which is an index that does not depend on the unit of data and expresses the degree of standardized effect. The difference in feature amounts between groups is quantified and output using an index called "effect size." Effect size is a preferred concept for quantifying sensory magnitude.
本手法で得られた特徴量で、痒みや痛みの予測を行うことも可能である。予測モデル構築時には、時間不変の特徴を抽出するＣｏｎｖｏｌｕｔｉｏｎａｌ Ｎｅｕｒａｌ Ｎｅｔｗｏｒｋ（ＣＮＮ：畳み込みネットワーク）用いた特徴ネットワークとＢｉｄｉｒｅｃｔｉｏｎａｌ ｌｏｎｇ ｓｈｏｒｔ－ｔｅｒｍ ｍｅｍｏｒｙ（ＢｉｄＬＳＴＭ）を用いたシーケンスネットワークで構成されている（非特許文献５、非特許文献６）。 It is also possible to predict itching and pain using the feature values obtained using this method. When constructing a predictive model, it consists of a feature network using a Convolutional Neural Network (CNN) to extract time-invariant features and a sequence network using Bidirectional long short-term memory (BidLSTM) (Non-Patent Document 5). , Non-Patent Document 6).
痛みと痒みに係る評価薬剤は、薬理学的作用が確立している薬剤を標準薬として用いた。刺激剤は抗マラリア薬として臨床で使用されているクロロキン（マウス投与量１００μｇ／ｋｇ、５０μＬ ｓ．ｃ．／ｓｉｔｅ）で、マウス後根神経節ＭｒｇｐｒＡ３受容体を介して痛みと痒みの両方を誘導することが知られている（非特許文献７）。抑制剤の鎮痛薬は神経因性疼痛治療薬として臨床で使用されているプレガバリン（マウス投与量１０ｍｇ／ｋｇ、５０μＬ ｓ．ｃ．／ｓｉｔｅ）を用い、抑制剤の止痒薬は難治性そう痒症治療薬として臨床で使用されているナルフラフィン（マウス投与量１０μｇ／ｋｇ、５０μＬ ｓ．ｃ．／ｓｉｔｅ）を用いた。これら３つの薬剤はいずれもヒトにおける臨床で効果が検証されているため、本試験における標準薬として扱うことができる。 For evaluation drugs related to pain and itching, drugs with established pharmacological effects were used as standard drugs. The stimulant is chloroquine (mouse dose 100 μg/kg, 50 μL s.c./site), which is clinically used as an antimalarial drug, and induces both pain and itching via the mouse dorsal root ganglion MrgprA3 receptor. It is known that (Non-Patent Document 7). The suppressant analgesic used was pregabalin (mouse dose 10 mg/kg, 50 μL sc/site), which is used clinically as a neuropathic pain treatment drug, and the suppressant antipruritic drug was used to treat intractable pruritus. Nalfurafine (mouse dose: 10 μg/kg, 50 μL s.c./site), which is used clinically as a drug for treating the disease, was used. All three drugs have been clinically verified to be effective in humans, so they can be used as standard drugs in this study.
痛みと痒みを誘発する刺激剤と、鎮痛作用と止痒作用をもつ抑制剤を組み合わせて用いて解析を行い、ＥＢの中から特徴的な信号を抽出することにより、痛み及び/又は痒みのバイオマーカーとして同定することが可能となった。各薬剤は、各投与条件で１群４匹のマウス背部体側部の皮下に投与し、投与後１０分間、頭部ＥＢと背部ＥＢをそれぞれ観測した。頭部ＥＢは脳波を含む中枢系のＥＢを計測し、背部ＥＢは薬剤投与部位に近い筋電位や皮下の細胞の興奮電位を直接計測する意味がある。 By performing analysis using a combination of a stimulant that induces pain and itch and a suppressant that has analgesic and antipruritic effects, and extracting characteristic signals from EB, we will be able to identify the bioscience of pain and/or itch. It became possible to identify it as a marker. Each drug was subcutaneously administered to the dorsal sides of four mice per group under each administration condition, and the head EB and dorsal EB were observed for 10 minutes after administration. The head EB measures central system EB including brain waves, and the back EB measures directly the myoelectric potential and excitatory potential of subcutaneous cells near the drug administration site.
［データ解析］
接触型電極で計測した単一チャンネルの波形データを高速フーリエ変換（ｆａｓｔ Ｆｏｕｒｉｅｒ ｔｒａｎｓｆｏｒｍ）し、横軸に周波数（Ｈｚ）、縦軸に信号パワー（μＶ２）で表した。ＡＩ解析では、各投与条件における薬剤投与前後の周波数スペクトルの違いを確認した。薬剤投与前後において、１分間のデータを基準値として抽出し、１０秒毎にスペクトルを抽出し平均化処理を行うこと（エポック）で投与前後のデータを取得した。
[Data analysis]
Single-channel waveform data measured with a contact electrode was subjected to fast Fourier transform, and the horizontal axis represents frequency (Hz) and the vertical axis represents signal power (μV 2 ). In the AI analysis, differences in frequency spectra before and after drug administration under each administration condition were confirmed. Before and after drug administration, data for 1 minute were extracted as a reference value, and spectra were extracted every 10 seconds and averaged (epoch) to obtain data before and after administration.
本試験では周波数帯域０～６０ＨｚのＥＢを観測したが、この周波数帯域は、脳波ではδ波（ｄｅｌｔａ，１～４Ｈｚ、徐波）、θ波（ｔｈｅｔａ，４～７Ｈｚ、徐波）、α波（ａｌｐｈａ，８～１３Ｈｚ）、β波（ｂｅｔａ，１５～３０Ｈｚ、速波）、γ波（ｇａｍｍａ，３０～８０Ｈｚ）に分類され、特にδ波からβ波の帯域（０～３０Ｈｚ）が広く精神神経系病態の分析に用いられている。本発明の予備試験で、無刺激剤である生理食塩水を投与した場合には、マウス個体差によると思われるＥＢの信号が０～３０Ｈｚで変則的に観測された。このため、定型的な脳波領域に拘ることなく、共通な特徴量を抽出すべきことから、個体差の大きな０～３０Ｈｚは解析対象とせずに、３０Ｈｚ以上の高周波数帯域を対象とすることにした。したがって、一般的な脳波解析（ＥＥＧ）の低周波帯域と心電波形解析（ＥＣＧ）が排除された形の３０～６０Ｈｚの周波数帯の包括的ＥＢで評価することが本発明の特徴でもある。 In this test, we observed EB in the frequency band 0 to 60 Hz, but this frequency band includes delta waves (delta, 1 to 4 Hz, slow waves), theta waves (theta, 4 to 7 Hz, slow waves), and alpha waves in the brain waves. (alpha, 8 to 13 Hz), beta waves (15 to 30 Hz, fast waves), and gamma waves (gamma, 30 to 80 Hz). In particular, the band from δ waves to beta waves (0 to 30 Hz) is widely used by the mind. It is used to analyze pathological conditions of the nervous system. In a preliminary test of the present invention, when physiological saline, which is a nonstimulant, was administered, EB signals were observed irregularly in the range of 0 to 30 Hz, which seems to be due to individual differences between mice. For this reason, since common features should be extracted without being concerned with typical brain wave regions, we decided to target high frequency bands of 30 Hz and above, rather than 0-30 Hz, which has large individual differences, as the target of analysis. did. Therefore, it is a feature of the present invention that evaluation is performed using comprehensive EB in the frequency band of 30 to 60 Hz, excluding the low frequency band of general electroencephalogram analysis (EEG) and electrocardiogram waveform analysis (ECG).
［信号パワー値の統計的有意差検定］
統計解析は、対照薬剤と評価薬剤の２群間の比較を観測周波数１０Ｈｚ帯域ごとに実施し、信号パワー値についてＷｉｌｃｏｘｏｎの順位和検定の符号順位検定で行った。その結果、表１にまとめたように、条件１～３の評価薬剤単剤では、各周波数帯域で有意差は認められなかったが（ＥＢに有意な影響を与えなかった）、条件５のプレガバリンの投与後にクロロキンを投与した場合に、背部ＥＢの３０～４０Ｈｚ（ハッチ部分）の信号パワー値に統計的有意差（ｐ＜０．０５）が認められた。これは、薬剤投与部位とＥＢ観測部位が近い背部の部位でクロロキンの薬理作用（痛み誘導）にプレガバリンの薬理作用（鎮痛）が大きく影響を与えたことを示唆しており、３０～４０Ｈｚの周波数帯域がバイオマーカーとして、プレガバリンの鎮痛作用が可視化できたものと考えられる。
[Statistical significance test of signal power values]
Statistical analysis was performed by comparing the two groups of the control drug and the evaluation drug for each observation frequency band of 10 Hz, and the signed rank test of the Wilcoxon rank sum test was performed on the signal power values. As a result, as summarized in Table 1, no significant difference was observed in each frequency band for the evaluation drugs alone in conditions 1 to 3 (no significant effect on EB), but pregabalin in condition 5 When chloroquine was administered after the administration of chloroquine, a statistically significant difference (p<0.05) was observed in the signal power values of 30 to 40 Hz (hatched area) in the dorsal EB. This suggests that the pharmacological action (analgesic) of pregabalin greatly influenced the pharmacological action (pain induction) of chloroquine in the dorsal region where the drug administration site and the EB observation site are close, and It is thought that the analgesic effect of pregabalin could be visualized using the band as a biomarker.
［効果量（Ｃｏｈｅｎ’ｓ ｄ）による判定］
効果量は、データの差、影響、相関、連関といった「効果」の比較する指標で、大きく分けると「ｄ族」と「ｒ族」があり、ｄ族の効果量は差の大きさを表し、ｄ族の効果量には「Ｃｏｈｅｎのｄ」と「Ｈｅｄｇｅｓのｇ」がある。効果量は、データの差、影響、相関、連関といった「効果」を比較する指標である。効果量は、相関の強さを表すｒ、差の大きさを表すｄなどを指標にすることができるが、本試験では、生物学的反応の効果量（ｅｆｆｅｃｔ ｓｉｚｅ）を判定するために、Ｃｏｈｅｎ’ｓ ｄの効果量による判定を行った。Ｃｏｈｅｎ’ｓ ｄの効果量による判定は、データの単位に依存せず、標準化された効果の程度を表す指標で、サンプルサイズによって変化しない標準化された指標であるから、本試験のようにマウスに個体差があり、サンプルデータの中の平均値が異なる場合の解析には適している。平均値が異なっても標準偏差が異なると効果に差異があるとされ、下式で示される。
[Judgment based on effect size (Cohen's d)]
Effect size is an index that compares "effects" such as data differences, influences, correlations, and associations.It can be roughly divided into "d group" and "r group."The effect size of group d indicates the size of the difference. , the effect size of the d group includes "Cohen's d" and "Hedges'g". Effect size is an index that compares "effects" such as data differences, influences, correlations, and associations. The effect size can be expressed using r, which represents the strength of the correlation, and d, which represents the size of the difference, but in this study, in order to determine the effect size of the biological response, Judgment was made based on the effect size of Cohen's d. Judgment based on Cohen's d effect size does not depend on the unit of data and is an index representing the standardized degree of effect, and it is a standardized index that does not change depending on the sample size. It is suitable for analysis when there are individual differences and the average values in the sample data are different. Even if the average value is different, if the standard deviation is different, it is said that there is a difference in the effect, which is shown by the following formula.
算出される数値は標準偏差を単位として平均値がどれだけ離れているか（正の効果、負の効果）を表し、以下のように、絶対値ではｄが０．８０を超えると「大きな効果」と解釈される。 The calculated value indicates how far apart the average values are (positive effect, negative effect) using standard deviation as a unit, and as shown below, in absolute value, if d exceeds 0.80, it is a "large effect". It is interpreted as
ｄ＝０．０１ → 非常に小さな効果量
ｄ＝０．２０ → 小さな効果量
ｄ＝０．５０ → 中程度の効果量
ｄ＝０．８０ → 大きな効果量
ｄ＝１．２０ → 非常に大きな効果量
ｄ＝２．００ → 極めて大きな（ｈｕｇｅ）効果量
d=0.01 → Very small effect size d=0.20 → Small effect size d=0.50 → Medium effect size d=0.80 → Large effect size d=1.20 → Very large effect Amount d=2.00 → Huge effect size
Ｃｏｈｅｎ’ｓ ｄの効果量の判定結果を表２にまとめた。効果量が大きいと判定された絶対値ｄ＝０．８０を超えた条件をハッチ部分で示した。痛み及び痒みの刺激剤のクロロキン（条件３）は単剤で一貫して正の効果（痛み及び痒みの誘発の反映）を示しており、刺激を生体に与えていることが示唆される。それに対して抑制剤の止痒薬ナルフラフィンを前投与（条件４）すると、クロロキンがもたらす正の効果が反転して併用効果は負の効果で表現された。同様に抑制剤である鎮痛薬プレガバリンを前投与（条件５）すると、クロロキンの正の効果が併用効果では負の効果量に反転していることが示された。これらの結果は、クロロキンの痒み誘発がナルフラフィンの止痒作用によって抑制されたこと、またクロロキンの痛み誘発がプレガバリンの鎮痛作用によって抑制されたことを反映していると解釈できる。これらのクロロキンが誘発する感覚刺激に対する鎮痛薬と止痒薬の抑制効果は、３０～６０Ｈｚの周波数帯で観測された。特に条件５の３０～４０Ｈｚ周波数帯での抑制効果は、ＥＢ信号パワー値の統計的有意差が認められた条件と一致しており、その効果量も大きかった。これらの結果は、ＥＢにおける３０～６０Ｈｚの周波数帯がバイオマーカーとして利用できることを示唆している。 The results of determining the effect size of Cohen's d are summarized in Table 2. Conditions in which the absolute value d was determined to be large and exceeded d=0.80 are indicated by hatched areas. Chloroquine (Condition 3), a pain and itch stimulant, consistently shows positive effects (reflecting the induction of pain and itch) as a single agent, suggesting that it provides stimulation to living organisms. On the other hand, when the antipruritic drug nalfurafine was preadministered (condition 4), the positive effect of chloroquine was reversed, and the combined effect was expressed as a negative effect. Similarly, when the analgesic pregabalin, which is a depressant, was preadministered (condition 5), it was shown that the positive effect of chloroquine was reversed to a negative effect size in the combined effect. These results can be interpreted as reflecting that the itch induction of chloroquine was suppressed by the antipruritic effect of nalfurafine, and that the pain induction of chloroquine was suppressed by the analgesic effect of pregabalin. These suppressive effects of analgesics and antipruritics on chloroquine-induced sensory stimulation were observed in the frequency range of 30-60 Hz. In particular, the suppressive effect in the 30-40 Hz frequency band under condition 5 was consistent with the condition in which a statistically significant difference in the EB signal power value was observed, and the effect size was large. These results suggest that the 30-60 Hz frequency band in EB can be used as a biomarker.
効果量による評価法では、痒みや痛みが生じている病態に治療薬（抑制剤）を投与した場合の薬理効果もＥＢの効果量によって可視化できる。この評価のための実験的作業仮説は、以下の３点である。 In the evaluation method based on the effect size, the pharmacological effect when a therapeutic drug (suppressant) is administered to a pathological condition that causes itching or pain can also be visualized based on the effect size of EB. The experimental working hypotheses for this evaluation are the following three points.
（１）クロロキンは、痛みと痒みの誘発作用があり、細胞に対して興奮系に働き、電気生理学上で高周波数帯といわれる３０Ｈｚ以上で正の効果量を導く。
（２）鎮痛作用のあるプレガバリン（抑制剤）の投与後にクロロキンを投与すると、クロロキンの痛み誘導は抑制され、負の効果量を導く。
（３）止痒作用のあるナルフラフィン（抑制剤）の投与後にクロロキンを投与すると、クロロキンの痒み誘導は抑制され、負の効果量を導く。
(1) Chloroquine has the effect of inducing pain and itching, acts on the excitatory system of cells, and leads to a positive effect level at frequencies above 30 Hz, which is said to be a high frequency band in terms of electrophysiology.
(2) When chloroquine is administered after the administration of pregabalin (an inhibitor), which has an analgesic effect, the pain induction of chloroquine is suppressed, leading to a negative effect size.
(3) When chloroquine is administered after administration of nalfurafine (an inhibitor), which has antipruritic effects, the itch induction of chloroquine is suppressed, leading to a negative effect amount.
試験の結果を表２に示す。クロロキンは刺激剤で本来は正の効果量を示すが、止痒薬のナルフラフィンを前投与してある場合、または鎮痛薬のプレガバリンを前投与してある場合には、クロロキンを投与しても抑制剤による併用効果で負の効果量に反転し、結果として抑制効果が強く表現され、作業仮説に一致する結果が得られた。 The results of the test are shown in Table 2. Chloroquine is a stimulant and originally shows a positive effect level, but if the antipruritic drug nalfurafine has been pre-administered or the analgesic drug pregabalin has been pre-administered, even if chloroquine is administered, the effect will not be suppressed. The effect size was reversed to negative due to the combination effect of the drug, and as a result, the inhibitory effect was strongly expressed, and results consistent with the working hypothesis were obtained.
この作業仮説と表２の実施例の結果を合わせて図示すると、図３及び図４となる。すなわち、図３は単剤の効果を示しており、「痛みと痒みの誘発作用を有する刺激剤のクロロキンは、細胞に興奮を与え、正の効果量の傾向をもち、抑制剤として鎮痛作用をもつプレガバリンと止痒作用をもつナルフラフィンは、細胞の興奮を抑えるので、負の効果量の傾向をもつ」という作業仮説に対して、頭部ＥＢでも背部ＥＢでも仮説を支持する傾向が見られた。 This working hypothesis and the results of the examples shown in Table 2 are illustrated in FIGS. 3 and 4. In other words, Figure 3 shows the effect of a single drug. Chloroquine, a stimulant that induces pain and itch, excites cells, tends to have a positive effect size, and has an analgesic effect as a suppressant. Regarding the working hypothesis that "pregabalin, which has antipruritic properties, and nalfurafine, which has an antipruritic effect, tend to have a negative effect size because they suppress cell excitability," there was a tendency to support the hypothesis in both head EB and dorsal EB. .
図４は、刺激剤と抑制剤の併用効果を見たものであるが、「鎮痛薬プレガバリンまたは止痒薬ナルフラフィンを前投与して、その後にクロロキンを投与すると、クロロキンの正の効果量は抑制され、抑制剤の併用時の効果量は負の方にシフトする」という作業仮説に対して、頭部ＥＢでも背部ＥＢでも仮説を支持する結果が得られた。 Figure 4 shows the combined effect of a stimulant and a depressant. ``If the analgesic drug pregabalin or the antipruritic drug nalfurafine is preadministered, and then chloroquine is administered, the positive effect size of chloroquine is suppressed. Regarding the working hypothesis that ``the effect size when combined use of inhibitors shifts to the negative side,'' results supporting the hypothesis were obtained for both head EB and dorsal EB.
さらに、同一薬剤条件でも、頭部ＥＢと背部ＥＢで効果量が異なる場合は、部位特異的な応答と考えることができる。このことは、生体表皮の異なる部位に複数の接触型電極を装着し、痛みや痒み、あるいは痺れや感覚鈍麻などの感覚量の異常を部位別に比較して、感覚量異常部位の特定につなげることができることを示している。本発明では、複数の部位から同時にＥＢを計測できることも特徴で、従来、たとえばＶＡＳ評価では、痛みや痒みの部位を別途申告することが行われてきたが、この作業を同時に処理することを可能とする。 Furthermore, even under the same drug conditions, if the effect size differs between head EB and back EB, it can be considered as a site-specific response. This means that by attaching multiple contact electrodes to different parts of the body's epidermis, we can compare abnormalities in the amount of sensation, such as pain, itching, numbness, and hypoesthesia, by area, and identify areas with abnormal amounts of sensation. It shows that it is possible. Another feature of the present invention is that it is possible to measure EB from multiple sites at the same time. Conventionally, for example, in VAS evaluation, areas of pain or itching were reported separately, but it is now possible to process this task at the same time. shall be.
［効果量の１Ｈｚごとの解析］
上記の通り、Ｃｏｈｅｎ’ｓ ｄの効果量による判定が、高い検出力をもつことが分かったことから、１Ｈｚ刻みで、ＰＳＤ値（パワー値）を積分し、効果量の最も大きな周波数を調べた。その結果、頭部ＥＢでは５４Ｈｚと５６Ｈｚ、背部ＥＢでは４５Ｈｚと５６Ｈｚが抽出された（表３）。したがって、ＥＢの周波数帯は３０～６０Ｈｚのなかでも、４０～６０Ｈｚに絞ってバイオマーカーを設定することも好ましい。ここで注目すべきは、周波数５６Ｈｚで頭部ＥＢと背部ＥＢに共通傾向があったことで、頭部ＥＢと背部ＥＢにおける細胞の興奮周波数が同期していることが示唆される（同じ刺激には生体は同じ反応の周波数で応答すると想定される）。
[Analysis of effect size per 1 Hz]
As mentioned above, it was found that the determination based on Cohen's d effect size has high detection power, so we integrated the PSD value (power value) in 1 Hz increments and examined the frequency with the largest effect size. . As a result, 54 Hz and 56 Hz were extracted from the head EB, and 45 Hz and 56 Hz were extracted from the back EB (Table 3). Therefore, it is also preferable to narrow down the EB frequency band to 40 to 60 Hz and set a biomarker within the 30 to 60 Hz frequency band. What should be noted here is that there was a common tendency for head EB and dorsal EB at a frequency of 56 Hz, suggesting that the excitation frequencies of cells in head EB and dorsal EB are synchronized (when the same stimulus It is assumed that living organisms respond at the same response frequency).
これによって、５６Ｈｚの周波数は痛みと痒みのバイオマーカーとなる可能性が示されたが、止痒薬ナルフラフィンとの併用時にクロロキンの正の効果量から負の効果量への転換程度が大きいことから、５６Ｈｚの周波数は痒みの方に鋭敏なバイオマーカーとしての利用の可能性が期待できる。 This showed that the 56Hz frequency may be a biomarker for pain and itch; however, the degree of conversion from positive to negative effect size of chloroquine was large when used in combination with the antipruritic drug nalfurafine. , the frequency of 56 Hz can be expected to be used as a sensitive biomarker for itching.
［病態の有無による薬物の応答性］
本発明は、痒みと痛みに係るＥＢのバイオマーカーの同定とその利用であり、患者の病態把握、薬物感受性評価と患者選択にも利用できる。本発明のバイオマーカーを用いれば、痛みと痒みの症状把握を客観的に行うことができ、コミュニケーションが取れない患者（乳幼児、小児、認知症患者など）の症状把握にも有用である。
[Drug responsiveness depending on the presence or absence of pathological condition]
The present invention relates to the identification and utilization of EB biomarkers related to itching and pain, and can also be used to understand the disease state of patients, evaluate drug sensitivity, and select patients. By using the biomarker of the present invention, it is possible to objectively understand the symptoms of pain and itching, and it is also useful for understanding the symptoms of patients who are unable to communicate (infants, children, dementia patients, etc.).
一方、医薬品は薬効を持つと同時に程度の差はあれ、副作用も併せ持つ。副作用を最小限にして、治療効果を引き出す条件を見つけることや、そもそも治療効果が得られない患者には投薬しないという選択が必要である。こうした医薬品の選択と投与タイミング、患者と病態の選択という医薬品の適正使用に係る管理は医療現場で常に求められている。痛みや痒みなどの感覚異常に対する適切なバイオマーカーがあれば、医薬品の適正使用の実現のために利用することができる。 On the other hand, while medicines have medicinal effects, they also have side effects, albeit to varying degrees. It is necessary to find conditions that minimize side effects and elicit therapeutic effects, and to choose not to administer medication to patients for whom therapeutic effects cannot be obtained in the first place. Management regarding the proper use of medicines, such as the selection of medicines, the timing of their administration, and the selection of patients and pathological conditions, is always required in the medical field. If there are appropriate biomarkers for sensory abnormalities such as pain and itching, they can be used to realize the appropriate use of pharmaceuticals.
本試験で用いた標準薬の添付文書によれば、プレガバリン（商品名：リリカ）では有効率は３０％程度で副作用である浮動性めまいと傾眠の発生率が３０％程度と報告され、止痒薬のナルフラフィン（商品名：レミッチ）では有効率は７０％程度で不眠症の副作用発生率が１５％程度と報告されている。このように、薬物応答性は患者により異なるので、無症状時や初回投与時の薬物応答性と痛みや痒みの発生時の薬物応答性を本発明のバイオマーカーで調べることにより、患者個々人の薬物応答性が可視化できる。 According to the package insert of the standard drug used in this study, pregabalin (trade name: Lyrica) is reported to have an efficacy rate of about 30% and an incidence of side effects of dizziness and somnolence of about 30%. The drug nalfurafine (trade name: Remitch) is reported to have an efficacy rate of about 70% and a side effect rate of insomnia of about 15%. As described above, drug responsiveness differs depending on the patient, so by examining drug responsiveness when asymptomatic or at the time of first administration and when pain or itching occurs using the biomarker of the present invention, drug responsiveness for each patient can be determined. Responsiveness can be visualized.
図４には、マウスにおけるプレガバリンとナルフラフィンの頭部ＥＢと背部ＥＢで計測された応答性を示した。単剤投与は無症状で投与した状態を反映し、併用時は有症状時（クロロキンによる痛み及び痒みの誘発時）の応答性を効果量で示してある。図４に示すように、無症状時（単剤投与時）にはプレガバリンもナルフラフィンも、５０～６０Ｈｚ周波数帯でｄ＞０．８の正の効果量を示し、何らかの薬理作用を発揮することが示されており、これらは副作用につながる反応である可能性も示唆される。クロロキンで痛みと痒みの刺激を与えた有症状時（併用投与時）には、３０～６０Ｈｚの周波数帯域で治療効果につながる負の効果量が示されている。このように、無症状時と有症状時の薬物応答性を本発明のバイオマーカーによって調べることにより、患者個々人の薬物応答性を知ることができ、治療薬の選択、投薬タイミングの設定、臨床試験における患者層の選択などに利用することができる。この手法は、副作用回避と医薬品の適正使用に大きく貢献するものである。 Figure 4 shows the responsiveness of pregabalin and nalfurafine measured in the head EB and dorsal EB in mice. Single drug administration reflects the state in which the drugs are administered without symptoms, and when used in combination, the response during symptomatic conditions (when pain and itching are induced by chloroquine) is shown as the effective amount. As shown in Figure 4, both pregabalin and nalfurafine have a positive effect size of d>0.8 in the 50-60 Hz frequency band when asymptomatic (when administered as a single drug), suggesting that they exert some pharmacological action. This suggests that these may be reactions that lead to side effects. When chloroquine stimulates pain and itching during symptomatic conditions (when administered in combination), a negative effect level leading to a therapeutic effect has been shown in the frequency range of 30 to 60 Hz. In this way, by examining drug responsiveness during asymptomatic and symptomatic states using the biomarkers of the present invention, it is possible to know the drug responsiveness of individual patients, which can be used to select therapeutic drugs, set dosage timing, and conduct clinical trials. It can be used to select patient groups in This method greatly contributes to the avoidance of side effects and the proper use of pharmaceuticals.
［対象となる薬剤と適応症］
本発明によって、痛みと痒みのバイオマーカーは、ＥＢを計測時に３０～６０Ｈｚの周波数帯域で特定されることが示された。従来、痛みまたは痒みの指標が生体電位の周波数帯域または特定周波数で示された報告は見当たらず、本発明によって初めて開発された指標である。
[Target drugs and indications]
The present invention has shown that pain and itch biomarkers are identified in the frequency band of 30 to 60 Hz when measuring EB. Conventionally, there has been no report in which an index of pain or itching is shown in a biopotential frequency band or a specific frequency, and this is the index developed for the first time by the present invention.
このバイオマーカーは、頭部ＥＢと背部ＥＢで共通して観察されたことから、中枢性の反応と末梢性の反応の両方に利用することが可能で、本バイオマーカーの計測で正の効果量で大きい場合に治療薬を処置する判断に利用できる。 Since this biomarker was commonly observed in head EB and dorsal EB, it can be used for both central and peripheral responses, and the measurement of this biomarker has a positive effect size. It can be used to decide whether to administer therapeutic drugs if the amount of the disease is large.
痛みや痒みは当事者しか感知できず、患者の訴えによって、医師が治療薬を処方することになるため、投薬の判断が患者の主観的な訴えに依存している状況になり、薬物依存や過剰投与、無用な投与につながる危険性があるが、本バイオマーカーを利用すれば、客観的な指標によって、適正な治療薬の処方の要否が判断できる。 Pain and itching can only be felt by those involved, and doctors prescribe therapeutic drugs based on patient complaints. This creates a situation in which medication decisions are dependent on patients' subjective complaints, which can lead to drug dependence and overuse. Although there is a risk of unnecessary administration, by using this biomarker, it is possible to determine whether or not to prescribe an appropriate therapeutic drug using an objective index.
また、本発明によるバイオマーカーは、治療薬の選択にも利用できる。臨床上は、神経因性に作用する薬剤を適用する際の判断に特に有用で、具体的には、電位依存性カルシウムチャネル阻害薬、アデノシン受容体拮抗薬、κオピオイド受容体作動薬、セロトニン・ノルアドレナリン再取り込み阻害剤（ＳＮＲＩ）などで、たとえば、プレガバリン、ナルフラフィン、ジフェリケファリン、デュロキセチンから選ばれる、少なくとも１種類の薬剤が挙げられる。 Furthermore, the biomarker according to the present invention can also be used to select therapeutic agents. Clinically, it is particularly useful in determining the application of drugs that act neuropathically, including voltage-gated calcium channel blockers, adenosine receptor antagonists, kappa opioid receptor agonists, serotonin receptor agonists, Examples of the norepinephrine reuptake inhibitor (SNRI) include at least one drug selected from pregabalin, nalfurafine, difelikephalin, and duloxetine.
本バイオマーカーを適用し得る疾患は、痒みまたは痛みを生じる病態や感覚異常を生じる病態であれば疾患を問わないが、神経因性疼痛、線維筋痛症、中枢性神経障害性疼痛、多発性硬化症、自己免疫疾患、がん、糖尿病神経障害などが対象となる。 This biomarker can be applied to any disease as long as it causes itching or pain or abnormal sensation, but neuropathic pain, fibromyalgia, central neuropathic pain, Targets include sclerosis, autoimmune diseases, cancer, and diabetic neuropathy.
さらに、部位別のＥＢ計測によって効果量を調べることができるので、治療薬によって末梢組織に起こる副作用である、抗がん薬投与時の手足のしびれ、痒み、感覚異常、手足症候群などのモニタリングに利用するのも有用である。 Furthermore, since the effect size can be investigated by measuring EB for each site, it is useful for monitoring side effects that occur in peripheral tissues due to therapeutic drugs, such as numbness, itching, paresthesia, and hand-foot syndrome in the hands and feet during administration of anticancer drugs. It is also useful to use
以上、本発明の実施形態によれば、以下の効果を奏することができる。従来技術では、痒みや痛みという感覚的症状の計量化と可視化は難しく、実用化技術は見当たらず、痛みや痒みの治療技術を開発しようとする場合、痛み刺激に対する逃避行動や痒みに対する掻破行動などの行動薬理学的な間接的評価に頼らざるを得ない状況にあった。本発明によるバイオマーカーは、表皮下の細胞における痒みや痛みの刺激に対する生体の直接的な反応であるＥＢの変動を、生体表皮上で接触型電極で捉えて、統計手法または機械学習手法によって効果量を算出することによって、痛みや痒みの感覚量を計量化し、可視化するものである。これによって、痛みと痒みの治療技術と治療薬の開発、化学物質の痛みの及び痒み誘発作用の評価に広く利用できる技術を提供する。
As described above, according to the embodiment of the present invention, the following effects can be achieved. With conventional technology, it is difficult to quantify and visualize sensory symptoms such as itching and pain, and no practical technology has been found.When trying to develop treatment technology for pain and itching, it is necessary to develop techniques such as escape behavior in response to painful stimuli, scratching behavior in response to itching, etc. The situation was such that we had no choice but to rely on indirect behavioral pharmacological evaluation. The biomarker according to the present invention captures fluctuations in EB, which is a direct response of the living body to itch and pain stimuli in cells under the epidermis, using a contact electrode on the living body's epidermis, and uses statistical methods or machine learning methods to produce effects. By calculating the amount, the perceived amount of pain and itching can be quantified and visualized. This provides a technology that can be widely used in the development of pain and itch treatment techniques and therapeutic drugs, and in the evaluation of the pain and itch-inducing effects of chemical substances.
Claims (6)
接触型電極で計測された表皮生体電位から、統計手法及び／又は機械学習手法を用いた数理モデルで算出されたバイオマーカー。 A biomarker for quantifying the degree of pain and/or itching,
A biomarker calculated from the epidermal biopotential measured with a contact electrode using a mathematical model using statistical methods and/or machine learning methods.
周波数パワー値又はＰｏｗｅｒ Ｄｅｎｓｉｔｙ Ｓｐｅｃｔｒｕｍ（ＰＳＤ）値として表し、
痒み及び／又は痛み状態を効果量（ｅｆｆｅｃｔ ｓｉｚｅ）で計量化することを特徴とする請求項１記載のバイオマーカー。 Determining the variation in the measured epidermal biopotential,
Expressed as a frequency power value or Power Density Spectrum (PSD) value,
The biomarker according to claim 1, characterized in that the itching and/or pain state is quantified by an effect size.
前記病態の原因が神経因性疼痛、線維筋痛症、中枢性神経障害性疼痛、多発性硬化症、自己免疫疾患、がん、糖尿病神経障害、又は抗がん薬投与時の手足のしびれ、痒み、感覚障害、若しくは手足症候群によるものであって、
請求項１又は２に記載のバイオマーカーによって評価することを特徴とする評価方法。
A method for evaluating a pathological condition that causes an abnormality in the amount of sensation, pain, or itching, the method comprising:
The cause of the condition is neuropathic pain, fibromyalgia, central neuropathic pain, multiple sclerosis, autoimmune disease, cancer, diabetic neuropathy, or numbness of the hands and feet during administration of anticancer drugs, Due to itching, sensory disturbance, or hand-foot syndrome,
An evaluation method characterized by evaluation using the biomarker according to claim 1 or 2.
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