1 PAIN MANAGEMENT AND BOTULINUM TOXIN - 통증시장현황및보툴리눔독소를중심으로 - 조병성 메디톡스 To whom correspondence should be addressed. E-mail bscho@medy-tox.co.kr snu21@dreamwiz.com 목차 1. Executive Summary 2. 통증 (Pain) 이란? 3. Market potential 4. 통증치료제동향 5. Botulinum Toxin & Pain Management
2 1. Executive Summary 통증 (Pain) 은실제적혹은잠재적인조직손상과관련된불쾌한감각 / 감정적인경험이며, 질병과직간접적인연관성을가진다. 또한심각한 삶의질 에대한손상을가져오기도한다. 특성상대단히주관적이며개인차가심하므로정확히진단하거나효과적으로치료하는것이어렵다. 통증을느끼는감각기관은 Nociceptor라고하며, 교감 / 부교감신경및중추 / 말초신경과상호작용을하여두뇌로신호를전달한다. 발생원인을기준으로크게 2가지타입으로분류되며 (Nociceptive pain과 Neuropathic pain), Nociceptive pain은조직손상이원인이고 Neuropathic pain은신경계의기능장애가원인이다. 질병과관련이있는통증은크게 6가지이며, Post-operative pain( 수술 ), Cancer pain( 암 ), Back pain( 등 ), HIV pain( 후천성면역결핍증 ), Diabetic pain( 당뇨 ), Arthritic pain( 관절염 ) 이다. 특히, Back pain은미국, 일본, 프랑스, 독일등주요선진국에서만도 2억명의잠재환자와 1억명에가까운확진환자가있어가장큰수요를가진다. 전세계적으로 3-6억명이각종통증을경험하고있으며, 향후에도고령화, 비만, 질병등으로통증환자수는증가할전망이다. 진통제로서는크게 4가지분류가있는데, NSAID(Non-Steroid Anti-Inflammation Drug, 비스테로이드성소염제 ), Opioid( 아편 ), Opioid combination( 아편복합제 ), Others group( 기타 ) 으로나뉜다. 주요제약기업들은각종진통제를연구개발중이며, 특히 Neuropathic pain 치료를위한연구가활발히진행중이다. 세계적인진통제시장규모는 2004년에약 33억달러로추정된다. 보툴리눔독소주사제는현재 6개의공식적인적응증과함께수십가지의비공식적인용도 (Off Label Use) 로사용되고있다. 2004년에약 1조원의시장을형성할것으로보이며 ( 미용분야포함 ), 통증분야에서는 Migraine( 편두통 ), Back pain( 등통 ), 치통등에서주로사용된다. 편두통의경우미국에만약 2천 8백만명의환자가있는것으로추정될정도로큰시장이다. 생활환경, 작업환경이주로의자에서생활하는방식이많아짐에따라증가하는추세이다. 보툴리눔독소는한번시술로 3-6개월정도의장기적인치료가가능하다. 또한, 독소가신경말단부위에만작용하고정확한작용메커니즘을가지고있어기존진통제에비해부작용이없고안전성이높다. 이런잇점들로인해보툴리눔독소는 Neuropathic pain의치료에효과적인것으로알려져있다. 또한, 미국에서는편두통과등통에대한임상시험이 2-3상을거치고있어 Efficacy와 Safety가증명되고있다. 향후판매가시작되면진통제로서수요가크게증가할것으로전망된다.
3 2. 통증 (Pain) 이란? 1. 정의 A. 실제적이거나잠재적인조직손상과관련되거나또는그러한손상으로기술된불쾌한감각적이고감정적인경험임. B. An unpleasant sensory and emotional experience associated with actual or potential tissue damage (International Association for the Study of Pain: IASP) 2. 분류 : 통증은발생원인에따라크게 2가지로분류함. 어떤경우는동시에 2가지가발생하기도함. A. Nociceptive pain i. 가장흔한타입이며, 실제로발생한조직의상해를입은부위의통증감지센서인 Nociceptor에의해발생됨. ii. Activation of nociceptors causes the subsequent activation of nociceptive nerve fibers ㄱ. 2 main types: myelinated A-delta nerve fibers and non-myelinated C nerve fibers ㄴ. Myelinated A-delta fibers: transmit pain sensation very rapidly and carry messages that are perceived by the brain as sharp or stabbing pain. ㄷ. Unmyelinated C nerve fibers: carry pain sensation at a much slower rate. ㄹ. The majority of nociceptive pain is a combination of signaling from both fiber types. B. Neuropathic pain i. 주로신경조직의손상혹은장애로인한통증 : pain initiated or caused by a primary lesion or dysfunction in the nervous system (IASP) ii. Nociceptic pain과는원인이다르며다만뇌로의전달경로는동일함. iii. 다양한범위의통증분야를포함하며원인이정확히파악되어있지않은경우도있음. iv. 통증분야의신약개발이활발한영역임. v. 가장흔한예는 diabetic neuropathy( 당뇨 ), cancer pain( 암 ), HIV pain( 후천성면역결핍증 ), back pain( 동통 ), post-operative( 수술후통증 ) 임.
4 <2 가지통증타입의주요발생분포 > 출처 : www.back.com 3. Market potential 1. 통증관련질병을기준으로분류할경우다음과같은 6개분야가주요통증시장임. A. Post-operative pain : 수술후통증 B. Cancer pain: 암에동반되는통증 C. Back pain: 보툴리눔톡신의약품 ( 보톡스계열 ) 의주요타겟시장으로통증분야에서도가장환자수가많아큰성장이예상 D. HIV pain: 후천성면역결핍증에동반되는통증 E. Diabetic neuropathy: 당뇨통증 F. Arthritic (osteoarthritis and rheumatoid arthritis) pain: 골관절염및류마티스관절염 2. 세계주요 7개국 ( 미국, 일본, 프랑스, 독일, 이탈리아, 스페인, 영국 ) 을기준으로한각질병에대한환자수는아래와같음. A. Back pain은근육과신경계의질환으로서주로등쪽에서발생함. B. 주요 7개국시장에서만약 2억명의환자가있을것으로추정되며, 전세계를포함할경우 5억명정도로예상됨.
5 <Trends in prevalence of major pain syndromes, 2000 2007> 3. Key factors to Pain 통증은향후에도지속적으로환자수가늘어날것으로예상되는데, 이는생활환경, 보건, 문화수준이향상되는것과도밀접한관계가있음. A. 고령화 (aging population): 특히 cancer, back, arthritis와관련된통증의주요원인 B. 신약개발으로인한질환치료 (improvement in drugs to treat underlying disease, resulting in greater survival rate: 특히암과 HIV/AIDS의경우, 신약개발로인해치료율이높아지고수명이연장되면서, 통증을겪는기간도길어짐. C. 비만 (increase in obesity): 지속적인비만인구의증가로당뇨인구뿐만아니라, back problems도동시에증가하는양상임. 4. Key unmet needs in the management of pain A. 현재까지의 opioid ( 아편 ) 계열혹은 NSAID(Non-Steroid Anti Inflammatory Drug, 비스테로이드성소염진통제 ) 계열의경우, nociceptive pain의치료에는효과적이나 neuropathic pain의치료에는불충분하였음. B. 따라서아래와같이통증치료제개발에고려되어야하는현재 6가지정도의주요관건이있음. C. 보툴리눔독소의경우, effective treatment, side effect, novel mechanism of action, neuropathic pain 치료관점에서고유의장점이있는통증치료제임.
6 <Unmet needs in the management of pain> 4. 통증치료제동향 1. 주요기업 A. Pain R&D pipeline은세계적인주요제약기업들이진행중이며, 대표적으로는 Johnson & Johnson, AstraZeneca, CeNes, Algos, GSK, Novartis임. <Analysis of pain pipeline by company, 2000>
7 2. 치료제클래스와진행정도에따른연구동향 A. 통증치료제는구조및성분에따라크게 4가지로구분됨. B. 아래에서알수있듯이 NSAID, Opioid 계열이주종인상황에서, 현재는기존과는다른작용메커니즘을가진 Other group에대한연구가활발히진행되고있음. C. 보툴리눔톡신의경우, Other group으로분류됨. D. 최근각광받는 COX-II (Cyclo-Oxygenase II) inhibitor의경우, NSAID 계열에속함. <Analysis of pain pipeline by phase, 2000> 3. Pain drug class에따른시장규모추정 A. 아래자료에서확인할수있듯이, Neuropathic pain drug market은상당히새로운분야임. B. 2000-2001에 NSAID와 Opioid 계열의약물의판매가급증하였음. C. Other analgesics의경우꾸준한성장세가예상됨.
8 <Forecast sales of pain drug class pipelines, 2000 2007> 5. Botulinum Toxin & Pain Management 1. Botulinum Toxin( 보툴리눔독소, 보톡스 ) A. Botox 은보툴리눔독소 A형으로서, 미국 Allergan사가발매하고있음. 신경말단의아세틸콜린분비를억제하여근육의수축을막고 3-6개월정도의마비를유발함. B. 이미사시, 안검경련, 주름등에대한적응증을가지고있어, 2004년에만 8천억원이상의판매가이루어질것으로추정됨. C. 통증분야에서는이미 Back pain, migraine 등의치료에사용되고있음 i. Off-label use: 정식임상시험과허가를받지않은상태로의사들의결정으로사용하는방식 ii. 보톡스의경우많은적응증에있어, 의사들의연구를통해효과가입증이되면정식임상을거쳐정식적응증허가를받는방식으로사업영역확장 ( 주름의경우에도동일 ) D. 미국 Allergan 사는 2-3가지통증과관련된적응증에대한임상시험을진행중이며향후 3년내로허가를받을것으로예상됨. 2. 통증및 Neuropathic pain 환자규모 A. Neuropathic pain의경우, 그정의나원인의다양성으로인해정확히진단되기까지는여러검사가필요함. B. 보톡스의경우특히현재뚜렷한치료법이없는 Neuropathic pain에잘적용되는특성을가지고있음.
9 < 보톡스시장추정 : Back pain 및 Migraine 등질병치료영역 > 2001-2009E ( 단위 : 백만달러 ) * 출처 : Morgan Stanley, 2004 * Headache: migraine ( 편두통 ) 등 * Pain: lower back pain ( 요통 ) 등 * Estimated WW Market Size: 모건스탠리의전세계시장추정치 * AGN Penetration Rate: 추정시장에대한 Allergan사의시장침투율
10 C. Back pain i. Chronic back pain은가장많은만성통증이며, 남녀고르게발생함. ii. Botulinum toxin이강점을가지는 Back pain의경우, 세계주요 7개국에 2억명정도의환자가있으며, 이중확진과치료를받는비율은 50% 정도임. 타국가의발생비율은크게다르지않아쉽게추정가능함. 다만발병시에도국가별로소득수준에따라치료수준이다름. iii. 다양한증상으로인해확진이어려우나, 기간기준으로는 3개월이상지속시만성통증으로분류함. iv. 주요원인 : 나쁜자세, 삠, 염좌, 감염, 염증등 v. Back pain은 Nociceptic/Neuropathic features를동시에가질수있으며, 만성통증은대개 Neuropathic pain임. vi. 만성통증은자체성격으로인해장기치료에적합한보톡스의수요를지속적으로증가시키며독성이적어타약물의장기치료가쉽지않은성격이있음. <Trends in the prevalence of back pain, 2000 2007>
11 D. 편두통 (Migraine) i. 편두통은뇌속의동맥의경련으로인해뇌혈류가감소하여발생함 Spasm of arteries in the head, reducing blood flow to the brain). ii. 미국의경우, 편두통환자가 2천 8백만명정도로큰시장임. E. Tension Headache( 두통 ) i. 두통의 90% 는등과어깨부위의근육통에의해유발됨. ii. 보통스트레스에의해발생함. F. 치통 i. 이빨과관련된통증은뇌와가까운거리에있어더민감하고자극이강한특성 이있음. ii. 또한치과치료의경우장기적인치료를필요하는경우가많아타진통제에비해 장기간효력지속이가능한보툴리눔독소를진통제로사용하고있음. iii. 당사의경우, B형보툴리눔독소주사제를진통제로개발하는연구과제를보건 복지부의지원으로수행중임. G. 기타적용분야 i. Fissure: 병리 열창 ( 裂瘡 ) 갈라짐 ii. Anismus iii. Cervical dystonia: 목주변의근긴장 iv. Occupational dystonia(for example, writer s cramp) <Defining the diagnosed pain patient population, 2000>
12 3. 보툴리눔독소및통증분야개발현황 A. 보툴리눔독소의약품의경우, Neuropathic pain 치료를위한새로운작용메커니즘 (Novel mechanisms of action) 으로분류되고있음. i. 따라서시장에진출시적절한규모를형성할것으로예상됨. B. 현재보톡스 (Botox ) 의경우, Low back pain에대한적응증확대를위해임상3상시험의막바지단계에있고 2006년에시장출시허가를획득할수있을것으로예상됨. 이경우, 2004년다한증 (Hyperhidrosis) 에이어, 6번째치료적응증을가지는것이됨. i. 그리고, Tension headache에대한임상 2상시험을진행중임. 4. 임상시험사례 A. 보톡스의경우, myofascial pain syndrome ( 근근막증후군 : 筋筋膜症候群 ) 과 chronic muscle spasm의치료에효과적인것으로증명되었음 ( 첨부1: Porta, 2000). i. 2년간의조사에의하면상당한증상치료효과보임. ii. 지속기간 : 2.5-3.6개월 iii. 효과발생시기 : 시술후 1주일부터통증완화됨. iv. 1년후통증정도 : 대상자의 10% 정도는 1년후완전히통증이사라짐이관찰됨. v. 부작용 : 아주낮음. 근근막증후군 [ 筋筋膜症候群, Myofascial Pain Syndrome] 근육이수축되어통증이유발되는현상. 근육과근육을싸고있는막에서유래된통증이라는의미에서붙여진이름으로근근막통증증후군, 근막통증증후군이라고도한다. 근육이란적절한수축과이완을통해서근육자체의기능을유지하고있다. 그런데여러가지원인, 특히부자연스럽거나긴장된자세의반복에의하여장기간에걸쳐근육이과긴장된상태에놓여있게되면근육은자체의탄력성을잃어버리고쉽게수축되며결국에가서는수축된상태로계속남게된다. 이렇게되면근육은딱딱한띠처럼느껴지게된다. 일단근육이수축된상태로있게되면근육내에분포하는신경이눌리게되고혈관이압박됨으로인하여근육내에서생긴통증물질들이배출되지못하고근육내에축적된다. 그러면근육수축으로근육이부착된골막이자극을받음으로통증이유발된다. 통증유발부위는근육이있는모든부위에생길수있으나주로목, 어깨, 등, 허리, 엉덩이, 뒷무릎에발생된다. 검사상특별한이상이나타나지않는근근막증후군은짧은시간내에생기는현상이아니고오랜기간의잠복기를가진후비로소증상으로나타나는것이므로물리요법이나약물복용으로좋아지지않는경우가많다. 따라서무엇보다도중요한것은적절한운동을통하여효과적으로풀어주어더이상의비정상적인근육의수축을막아야한다.
13 B. 또한, chronic back pain의완화에도효과적인것으로밝혀짐 (Royal, 1999). i. Allergan에의해수행된임상시험에서좋은결과보임. ii. 만성동통에 240 unit의보톡스를주사한결과, 6주후상당한개선효과보임. 5. Marketing Factors A. 보툴리눔의약품의통증에대한임상시험은이미몇경우에있어성공적으로수행되었을뿐만성공적으로진행중임. 이를통해보톡스계열의의약품의 efficacy와 safety가증명되었고시장 ( 의사 ) 의신뢰를확보하였음. B. 향후에도적응증확대와시장침투율을높여수요를증가할것으로예상됨. C. 더구나보톡스의약품은세계적으로도잘알려져있어의사와환자들에게친숙한상태이며, 통증치료제로서의허가시많은미디어의주목을받아쉽게알려질것으로예상됨. 6. Satisfaction of Unmet Needs A. 앞서언급된 Myofascial Pain Syndrome은 NSAID와같은기존진통제로서는잘치료되지않는 chronic neuropathic pain임. 따라서이런 neuropathic pain 치료를위해서는새로운메커니즘의약품이필요한상황이며결과적으로보톡스와같은의약품이개발됨. B. Chronic back pain의경우에도많은 unmet needs가있음. Chronic back pain의경우아직정확한원인이규명되지않아이에따른약물개발의패러다임이없는상황임. 특히, low back pain의경우임상적으로매우다양하고난치성의환자들이많음. C. 보톡스의경우, 전체적인 Neuropathic pain에대해서는중간정도의강점을가지고있으며, 특히, Myofascial Pain Syndrome과 low back pain에대해서는상당히우수한강점을가진것으로보임. <Botox satisfaction of unmet needs>
14 7. SWOT analysis of Botox A. 보톡스계열의약품은진통제시장에서유효성, 안전성, 인지도등에서강점이있어충분히시장에서자리잡을것으로예상됨. <Key factors in the relative success of Botox>
15 < 첨부 1> A comparative trial of botulinum toxin type A and methylprednisolone for the treatment of myofascial pain syndrome and pain from chronic muscle spasm. Pain. 2000 Mar;85(1-2):101-5. Porta M. Pain Centre, Department of Neurology, Policinico San Marco, 24020, Zingonia/Bergamo, Italy. Myofascial pain syndrome (MPS) is a common illness, characterised by acute or chronic focal pain, muscle stiffness and fatigue. The pathophysiology of MPS remains unclear. Previous preliminary studies have demonstrated therapeutic efficacy of the muscle relaxant botulinum toxin type A (BTX-A) in the treatment of MPS. A single-centre, randomised trial compared the effects of BTX-A with the steroid methylprednisolone (both administered intramuscularly with 0.5% bupivacaine), in 40 patients suffering from chronic myofascial pain in the piriformis, iliopsoas or scalenus anterior muscles. Thirty days after receiving an injection of either BTX-A or steroid followed by post-injection physiotherapy, pain severity had decreased significantly from baseline in both treatment groups, with no significant difference between the two treatment groups. However, the baseline pain score was significantly higher in the BTX-A treatment group compared with the steroid group (7.9 vs. 7.3), and the reduction in pain score between baseline and 30 days post-injection was greater in the BTX-A group compared with the steroid group (- 3.9 vs. -3.5; P=0.06). At 60 days post-injection, the pain severity score for the BTX-Atreated patients was statistically significantly lower than the pain score for the steroidtreated population (2.3 vs. 4.9). Furthermore, the reduction in pain score in the BTX-A group at 60 days post-injection was greater than at 30 days (-5.5 vs. -3.9), whereas the effect of the steroid had begun to wane. These results indicate the superior efficacy of BTX-A (Botulinum Toxin Type A) over conventional steroid treatment in patients suffering from MPS, when combined with appropriate physiotherapy. Publication Types: Clinical Trial Randomized Controlled Trial PMID: 10692608 [PubMed - indexed for MEDLINE]
16 Neurobiological basis for the use of botulinum toxin in pain therapy. J Neurol. 2004 Feb;251 Suppl 1:I1-7 Mense S. Institut fur Anatomie und Zellbiologie III, Universitat Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany. mense@urz.uni-heidelberg.de The various serotypes of botulinum toxin (BoNT) exert their action by inhibiting the exocytosis of acetylcholine (ACh) on cholinergic nerve endings. BoNT cleaves proteins (e.g. SNAP-25 or VAMP) that are necessary for the docking of the ACh vesicle to the presynaptic membrane. Without docking, no ACh can be released into the synaptic cleft and the innervated structure is paralyzed. This article focuses on the neuromuscular endplate. The main targets of BoNT therapy are states of muscle hyperactivity such as contractures (in the physiological sense), or spasm and focal dystonias. CONTRACTURES: The "integrated hypothesis" of the formation of myofascial trigger points suggests that a lesion of a muscle damages the endplate so that excessive ACh is released. This causes a local contracture (partial contraction of a muscle fiber) underneath the endplate. The contracture compresses small blood vessels, and the tissue becomes ischemic. Ischemia leads to the release of bradykinin (BKN) and sensitization or excitation of nociceptors. BoNT is a causal therapy in these cases, because it stops the excessive ACh release. SPASM: Reflex spasm in a given muscle can be induced by nociceptive input from neighboring joints or muscles. If the force generated by a spasm is relatively high, it will compress the large blood vessels supplying the muscle. The final effect again is ischemia. In this case a drop in ph may accompany the ischemia and BKN are known to be effective stimulants for muscle nociceptors. DYSTONIA: In cases of weak dystonias, a compression of blood vessels is unlikely. However, the tonic contraction will cause a lowering of ph and a release of ATP. Muscle cells contain ATP at concentrations sufficient to excite muscle nociceptors. In cases of spasm and dystonia, BoNT can abolish the pain by relaxing the muscle. Since many patients report alleviation of their pain before the muscle relaxing effect of BoNT has set in, a direct analgesic action of BoNT is being discussed. Most hypotheses rest on the assumption that BoNT inhibits not only the exocytosis of ACh but also of their neurotransmitters. Such an action could be analgesic if the release of neuropeptides from nociceptive nerve endings is prevented. This way, BoNT could alleviate the pain of neuropathies and various types of headache where neurogenic inflammation plays a role. Another site of an analgesic action could be the postganglionic sympathetic nerve ending that uses norepinephrine and ATP as transmitters. Norepinephrine is known to increase cases of chronic pain, and ATP is a
17 stimulant of muscle nociceptors. If BoNT inhibits the release of these transmitters, it could be analgesic in cases of sympathetically maintained pain including the complex regional pain syndrome. Publication Types: Review Review, Tutorial PMID: 14991335 [PubMed - indexed for MEDLINE] A focused review of the use of botulinum toxins for low back pain. Clin J Pain. 2002 Nov-Dec;18(6 Suppl):S155-62. Difazio M, Jabbari B. Department of Neurology, Uniformed Services University, Bethesda, Maryland 20814, USA. Chronic low back pain is the second most common illness reported by patients in the United States and accounts for substantial morbidity and health-care resource utilization. Many back and spine stressors can contribute to tissue injury, resulting in acute or chronic pain. In response to injury, biochemical processes that cause inflammation and nerve sensitization increase pain levels and contribute to a cycle of reactivity that further heightens patients' sensitivity to pain stimuli. Treatment of back pain depends on its severity, duration, and underlying cause. Traditional therapeutic options include exercise, oral anti-inflammatory or analgesic medication, antidepressants, physical therapy and, in severe cases, surgery. Unfortunately, dissatisfaction with treatment of back pain is common. Oral medications may not completely alleviate symptoms, and opioid analgesics must be used with caution because of their addictive properties. Surgery does not always produce relief and, in some cases, may even exacerbate the problem. Botulinum toxin, which has already been shown to alleviate pain associated with cervical dystonia and other conditions characterized by muscle spasticity, is now being studied for the treatment of back pain. Preliminary evaluations have shown that this treatment is safe and has the advantage of providing local relief directly to the site of injury or pain, without causing systemic side effects. Initial data from small trials also suggest that botulinum toxin is effective, alleviating back pain in selected patients. On the basis of
18 these promising results, additional study in larger trials is warranted. Publication Types: Review Review, Tutorial PMID: 12569963 [PubMed - indexed for MEDLINE] 본글의저작권은 " 생물학연구정보센터 BioWave" 에있습니다. 일부내용인용시 " 생물학연구정보센터 BioWave (http://bric.postech.ac.kr/webzine) Vol. 6 No. 17" 으로정보출처를밝혀야합니다. 전체내용에대한인용시생물학연구정보센터의사전허락 (mail: biowave@bric.postech.ac.kr Tel: 054-279-8197~8) 을받으신후전재가가능합니다. ( 단. 원저작자의경우는정보출처만밝히시면됩니다.)