종설접수번호 :09-029(2 차 -0710) 섬유근통증후군 을지대학교의과대학을지대학병원신경과 오건세장상현 Fibromyalgia Syndrome Gun-Sei Oh, MD, Sang-Hyun Jang, MD Department of Neurology, Eulji University Hospital, Eulji University School of Medicine, Daejeon, Korea Fibromyalgia is a chronic pain syndrome of unknown etiology that is characterized by diffuse musculoskeletal pain, fatigue, sleep disturbance, memory disturbance, and exaggerated tenderness over particular paired locations. Fibromyalgia is found in 2% to 4% of the general population and more common in women, with symptoms usually appearing between 20 and 55 years of age. The diagnostic criteria for fibromyalgia syndrome established in 1990 by the American College of Rheumatology (ACR), includes widespread pain for at least 3 months and point tenderness upon the application of a 4 kg weight at 11 or more of the 18 characteristic tender points. The 2010 ACR preliminary diagnostic criteria have been developed, which are strongly correlated with the 1990 ACR criteria and provide an alternative approach to diagnosis. Patients with fibromyalgia syndrome have lower pain thresholds and experience an altered temporal summation to pain stimuli. The sensitization of pain perception occurs in the dorsal horn of patients with fibromyalgia. However, it is unknown whether sensitization is due to increased pain fiber facilitation, or decreased inhibition. Pregabalin is approved by the United States Food and Drug Administration for the management of fibromyalgia patients. Tricyclic antidepressants, cardiovascular exercise, cognitive behavioral therapy and patient education are also effective in reducing the pain experienced by fibromyalgia patients. This article provides an overview of fibromyalgia syndrome, which is currently thought to be partly responsible for chronic diffuse pain. J Korean Neurol Assoc 31(1):1-7, 2013 Key Words: Diagnosis, Fibromyalgia syndrome, Treatment 서론 섬유근통증후군은만성근골격계통증의흔한원인으로근육과힘줄과인대에영향을미치는연조직통증질환중하나이다. 이질환의원인은아직잘모르지만연조직에뚜렷한염증은없는것으로알려져있다. 두통이나과민성대장증후군과같은다른기능성질환처럼아직섬유근통증후군에대해서도논란이많다. 1,2 이질환을앓고있는환자의대부분이신체검사, 검사실검사, 방사선검사에서뚜렷한이상이없다. 따라서이질환은기질적질환이아니라 심리또는정신신체질환으로여기기도한다. 현재병태생리학적기전은중추신경의통증처리과정변화에초점이맞추어져있다. 섬유근통증후군은 19세기중엽프랑스와영국에서섬유염이라는용어로처음사용되었다. 여성에서흔하며나이가들수록발생률이증가한다. 20-50세여성에서유병률은 2% 정도이지만 70대에서는 8% 로증가한다. 3,4 임상특징은전신근골격계통증과피로, 인지또는정동장애가나타나며신체검사에서특정위치에압통점을발견할수있고검사실검사는다른동반질환이없는경우정상이다. Received September 1, 2011 Revised December 6, 2011 Accepted December 6, 2011 *Gun-Sei Oh, MD Department of Neurology, Eulji University Hospital, Eulji University School of Medicine, #95 Dunsanseo-ro, Seo-gu, Daejeon 302-799, Korea Tel: +82-42-611-3429 Fax: +82-42-611-3429 E-mail: gsoh@eulji.ac.kr 본론 1. 임상양상 환자는흔히온몸이아프다고하며감기를자주앓는다고한 J Korean Neurol Assoc Volume 31 No. 1, 2013 1
오건세장상현 다. 이외에두통, 손발저림, 수면장애, 설사, 변비, 빈뇨, 식욕부진, 구갈, 어지럼, 시야흐림, 비특이적인가슴통증, 구역, 구토, 같은다양한신체증상을호소한다. 조금만무리를하여도쉽게피로를느끼며, 통증이악화된다. 아침에손발이뻣뻣한느낌이있으며자고일어나도상쾌한느낌이없어잠을자지않은것같다고한다. 대부분환자에게인지및정동장애가동반된다. 전형적인경우에는집중력장애로빠른사고전환에어려움을느낀다. 5 우울증과불안증이약 30-50% 에서동반되며편두통이나긴장형두통이약 50-80% 에서동반된다. 1-3,6 2. 진단섬유근통증후군의진단기준은크게 2가지가있다. 하나는 1990 년발표된미국류마티스협회 (American College of Rheumatology: ACR) 의분류기준이고나머지하나는 2010년발표된예비진단기준이다. 7,8 섬유근통증후군을진단하기위한 ACR 분류기준이대부분의임상또는치료연구에서사용되어왔으나임상에서사용하기에는어려움이있다. 반면예비진단기준은 1990년 ACR분류기준과좋은상관성을보이고진료실에서도쉽게사용될수있다. 섬유근통증후군의진단은일차적으로전신통증에근거를 두고있다. 환자는만성근육통과관절통을호소하나신체검사나검사실검사에서관절과근육에염증의증거는없으나신체검사에서특정연조직부위에다발압통점이특징적으로존재한다. 9 18군데특정해부학적위치를 4 kg의압력으로압박하였을때 11군데이상에서압통이있으면진단할수있다 (Fig.). 그러나 11군데미만에서압통점이있는경우에도섬유근통증후군에합당한병력이있고다른중요원인을배제하면진단할수있다. 압통점은통증인식이항진된것을의미하므로섬유근통증후군의진단을위해필요한압통점의정확한숫자는다소가변적일수있다. 섬유근통증후군의 ACR분류기준은많은환자를대상으로한연구에서유용성이증명되었으며임상연구와역학연구에서일차적으로사용되어야만한다. 그러나대부분의의사가압통점을검사하는방법에익숙하지않으므로일부연구자는섬유근통증후군진단기준에서압통점검사를사용하지않고증상에의해서만진단하는것을선호하고있다. 8,10 따라서압통점검사를배제한 ACR 예비진단기준은비전문가가섬유근통증후군을정확하게진단하는데도움이될수있다. 11 2010년발표된 ACR의예비진단기준은압통점검사없이섬유근통증후군의특징적인증상의심각도를척도화하여진단하도록고안되었다. 이진단기준은 1990년 ACR 분류기준 Occiput: suboccipital muscie insertions Low cervical: anterior aspects of the intertransverse spaces at C5-C7 Tarpezius: midpiont of the upper border Supraspinatus: above the medial border of the scapular spine Gluteal: upper outer quadrants of buttocks Second Rib: second costochondral junctions Lateral Epicondyle: 2 cm distal to the epicondyles Greater trochanter: posterior to the trochanteric prominence Knee: medial fat pad proximal to the joint line Figure. Tender points in fibromyalgia. Locations of 9 bilateral tender point sites to be palpated for testing the Americal College of Rheumatology 1990 criteria for the classification of fibromyalgia (text book of neurology. 2nd ed. 2012). 2 대한신경과학회지제 31 권제 1 호, 2013
섬유근통증후군 Table. Fibromyalgia diagnostic criteria Criteria A patient satisfies diagnostic criteria for fibromyalgia if the following 3 conditions are met: 1) Widespread pain index (WPI) 7 and symptom severity (SS) scale score 5 or WPI 3 6 and SS scale score 9. 2) Symptoms have been present at a similar level for at least 3 months. 3) The patient does not have a disorder that would otherwise explain the pain. Ascertainment 1) WPI: note the number areas in which the patient has had pain over the last week. In how many areas has the patient had pain? Score will be between 0 and 19. Shoulder girdle, left Hip (buttock, trochanter), left Jaw, left Upper back Shoulder girdle, right Hip (buttock, trochanter), right Jaw, right Lower back Upper arm, left Upper leg, left Chest Neck Upper arm, right Upper leg, right Abdomen Lower arm, left Lower leg, left Lower arm, right Lower leg, right 2) SS scale score: Fatigue Waking unrefreshed Cognitive symptoms For the each of the 3 symptoms above, indicate the level of severity over the past week using the following scale: 0 = no problem 1 = slight or mild problems, generally mild or intermittent 2 = moderate, considerable problems, often present and/or at a moderate level 3 = severe: pervasive, continuous, life-disturbing problems Considering somatic symptoms in general, indicate whether the patient has: * 0 = no symptoms 1 = few symptoms 2 = a moderate number of symptoms 3 = a great deal of symptoms The SS scale score is the sum of the severity of the 3 symptoms (fatigue, waking unrefreshed, cognitive symptoms) plus the extent (severity) of somatic symptoms in general. The final score is between 0 and 12. * Somatic symptoms that might be considered: muscle pain, irritable bowel syndrome, fatigue/tiredness, thinking or remembering problem, muscle weakness, headache, pain/cramps in the abdomen, numbness/tingling, dizziness, insomnia, depression, constipation, pain in the upper abdomen, nausea, nervousness, chest pain, blurred vision, fever, diarrhea, dry mouth, itching, wheezing, Raynaud s phenomenon, hives/welts, ringing in ears, vomiting, heartburn, oral ulcers, loss of/change in taste, seizures, dry eyes, shortness of breath, loss of appetite, rash, sun sensitivity, hearing difficulties, easy bruising, hair loss, frequent urination, painful urination, and bladder spasms (Arthritis Care & Research 2010;62:600-610). 에는포함되어있지않은인지문제와신체증상의중요성을인식하여평가에포함시키고있다. 이예비진단기준은 1990년 ACR 분류기준과좋은상관성을보였다. 따라서이새로운진단기준은압통점검사에익숙하지않은비전문가나복잡한환자에게유용하게사용할수있다. 또한모집단을대상으로한만성전신통증연구에서도유용하게사용할수있을것이다. 이예비진단기준은최소한 3개월동안통증과신체증상이지속되고 (cognitive symptom) 정도, 그리고일반적인신체증상의수를수치로추정한값이다. 증상심각도척도점수의총합은 0점부터 12 점까지있다 (Table). 전체인구중약 10% 에서만성전신통증이있으며이들중대부분은통증을설명할만한특별한질병이나구조적인이상을갖고있지않다. 12 이들중많은수가섬유근통증후군진단에합당한증상과징후를갖고있는것으로알려져있다. 13 이러한통증을설명할만한다른질환이없는경우전신통증지 표 (wide pain index) 와증상심각도척도 (symptom severity scale) 를조합하여진단하도록되어있다. 전신통증지표는신체를 19 군데로구분하여통증부위를수치로계산하는것이고, 증상심각도척도점수 (symptom severity scale score) 는피로 (fatigue) 정도, 상쾌하지않은각성 (waking unrefreshed) 정도, 인지증상 3. 병태생리학섬유근통증후군의발병기전은통증처리과정의변화가원인으로알려져있으므로정상통증경로를간략하게설명하겠다. 통각정보가일차구심신경을경유하여척수후각에존재하는이 J Korean Neurol Assoc Volume 31 No. 1, 2013 3
오건세장상현 차구심신경세포에폭주된다. 14,15 이들이차구심신경세포로부터통증상행경로가시작되는데이중척수시상로를통하여시상의배측기저복합체 (ventrobasal complex of thalamus) 를경유하여체성감각피질 (somatosensory cortex) 의일차몸감각부위 (SI) 와이차몸감각부위 (SII) 에종지하는경로는주로국소화와감각 -식별(sensory-discriminative) 기능을처리하고, 또다른경로인척수망상체로는앞띠다발피질 (anterior cingulate cortex) 편도 (amygdala) 에동기- 정동 (motivational-affective) 정보를전달한다. 16-19 후각에서통각처리과정은말초뿐만아니라, 중추로부터오는하행경로에의해서도조절을받는다. 20 수도관주위회백질은팔곁핵 (parabrachial nucleus) 뿐만아니라, 연수에위치한큰솔기핵 (nucleus raphe magnus, NRM) 과도연결되어있다. 21 큰솔기핵의기능은입쪽배안쪽연수 (rostral ventromedial medulla; RVM) 내에있는주위구조물에의해지배를받는다. 입쪽배안쪽연수 (RVM) 는큰솔기핵 (NRM) 과거대세포망상핵 (nucleus reticularis gigantocellularis) 의배쪽에있는주위망상체 (reticular formation) 가포함된부위이다. 입쪽배안쪽연수부위로부터나온정보가등가쪽섬유단 (dorsal lateral funiculus) 을경유하여후각으로전달된다. 22 입쪽배안쪽연수는억제경로와촉진경로를갖고있어등뿔통각처리과정에서통증을억제하기도하고촉진시키기도한다. 입쪽배안쪽숨뇌는 on세포, off세포, neutral 세포로구성되어있다. On세포는유해자극의전달을촉진시키는역할을하며, 아편유사작용제 (opioid agonist) 는이세포의활성도를억제하는것으로알려져있다. Off 세포는유해자극의전달을억제하는역할을하며, 아편유사작용제가이세포의활성도를항진시킨다. 23 통증조절망은통각전달경로로부터직접또는간접입력을받는다. 통증조절망은시상하부와편도, 앞띠다발피질, 앞섬 (anterior insula) 을포함한변연앞뇌 (limbic forebrain) 와긴밀한고리를형성하여공포, 주의력, 기대 (expectancy) 와같은고급요소가통증처리에영향을미칠수있도록한다. 24 섬유근통환자는정상인에비해통증역치가감소되어있다. 그러나말초조직에서는뚜렷한이상이없으나, 기능자기공명뇌영상에서는섬유근통증후군환자와정상인사이에차이가있는것으로보고되었다. 25 섬유근통증후군환자에서통증이비정상적으로증가하는것은이상시간가중 (abnormal temporal summation) 즉 wind-up과연관이있다는보고가있다. 26 통증자극시정상인에서는뇌로부터시작되는하행억제경로가척수반응을억제하는것으로알려져있으나섬유근통환자에서는이러한하행억제경로가제대로작동하지않는보고가 있다. 27,28 또한통증을촉진시키는하행경로가섬유근통과같은만성통증증후군에서어떠한역할을할수도있다. 29 교세포 (glial cell) 는통증신호를항진시키며교세포의활성화를억제시키면통증악화를막을수있다. 30,31 그러나섬유근육통의발병기전에서교세포의역할에대해서는아직더연구가필요하다. 따라서섬유근통의발병기전은현재까지는중추통증전달기전에이상으로생각된다. 4. 검사섬유근통증후군은검사실검사나영상검사에서이상이발견되는경우는거의없다. 따라서검사는섬유근통을유발하는다른질환을감별하기위하여한다. 잠재염증질환을감별하기위하여전혈구계산 (complete blood count), 적혈구침강속도 (erythrocyte sedimentation rate), C 반응단백질 (C-reactive protein) 을우선확인한다. 항핵항체 (antineuclear antibody), 류마티스인자 (rheumatoid factor) 와같은혈청검사는병력과신체검사에서염증질환이나전신류마티스질환이의심되는경우에만한다. 갑상선질환이나염증근육질환이의심되는환자에서갑상선기능검사와크레아틴키나제 (creatine kinse) 검사가각각필요하다. 바이러스검사나비타민 D 수치검사가도움이된다는증거는없다. 섬유근통이있는모든환자는자세한병력을조사하여일차수면장애나정동장애가동반되어있는지확인하여야한다. 또한수면무호흡과수면중주기사지운동장애가있는지알아보고의심되면수면다원검사가필요하다. 섬유근통환자중최소 1/3에서처음진단당시에정동장애가있으므로우울증과불안증증상에대한문진이꼭필요하다. 섬유근통증후군환자에서자율신경계장애가알려져있으나혈압과심박확인이외에다른적당한선별검사가없다. 자율신경계장애가의심되는환자는틸트테이블검사 (Tilt-table test) 와같은객관적인검사가필요하다. 5. 감별진단섬유근통증후군의비특이적인증상은많은다른질환에서비슷하게나타날수있으므로자세한병력과신체검사, 선별된검사실검사가꼭필요하다. 주요감별질환은다음과같다. 류마티스관절염, 전신홍반루푸스과같은염증류마티스질환 : 32 골관절염, 허리척추협착증과같은비염증근골격질환 : 과민성대장증후군, 만성피로증후군, 측두하악기능장 4 대한신경과학회지제 31 권제 1 호, 2013
섬유근통증후군 애, 여성외음부통 (vulvodynia), 과민방광같은기능신체증후군 (functional somatic syndrome): 33,34 근막통증증후군과같은국소통증증후군. 35 6. 치료섬유근통증후군은만성통증질환으로치료에어려움이있다. 환자와가족에게이질환에대한병인, 진단, 치료가불확실하다는것을교육시키고만성적인경과를거치지만진행하지않는다는것을주지시키는것이중요하다. 7 우울증, 하지불안증후군, 수면무호흡, 국소근골격계질환 ( 윤활낭염, 건염 ) 이존재하면같이치료해야한다. 섬유근통증후군치료에서가장효과적인치료약은항우울제이다. 9 미국에서 FDA에의해승인된약물은항우울제인 duloxetine, milnacipran과항뇌전증약인 pregabalin이다. 약물치료는일반적으로저용량으로시작하여점차증량시킨다. 밤중에 tricyclic antidepressant (TCA) 를저용량 (25-50 mg) 으로시작하거나 cyclobenzaprine 10 mg으로시작하고필요하면낮에는단순진통제를사용한다. 36-39 그러나 TCA는부작용때문에특히노인에서사용에제한이있으므로수면문제가많은섬유근통환자는취침시저용량 pregabalin (25-30 mg) 으로시작하여 300-450 mg/day까지증량한다. 40,41 Pregabalin은우울증에는효과가없다. 42 피로감을많이호소하는환자와우울증이동반된경우에는아침에 duloxetine이나 milnacipran로시작하여전자는 60-120 mg/day까지후자는 100-200 mg/day까지점차증량시킨다. 42,43 일부환자에서는다제요법 (polypharmacy) 에더효과적이므로아침에저용량선택세로토닌 / 노르에피네프린재흡수억제제 (SNRI) 와취침시저용량 pregabalin를사용한다. 따라서치료는개인의증상에따라달라져야한다. NSAID (nonsteroidal anti-inflammatory drug) 는일차선택약제로추천되지않지만 tramadol은중추신경계작용약물과같이사용하면효과가있을수있다. 44 빨리걷기, 자전거타기, 수영, 수중유산소운동과같은저충격유산소운동 (low-impact aerobic activity) 이효과가있으며한번에최소한 30분이상, 일주일에 3번이상운동해야한다. 45-47 인지행동요법과유산소운동을같이하면더효과적이다. 48,49 결론 만성근육통과관절통을앓고있는환자중신체검사나검사실검사에서뚜렷한염증이없는경우섬유근통증후군가능성을 염두에두어야한다. 신체검사에서특정연조직부위에다발압통점을찾는것이중요하지만, 임상에서압통점의숫자가섬유근통증후군진단에꼭필요한것은아니다. 섬유근통증후군에특이한진단검사가아직없으므로꼭필요한검사만하여야한다. 따라서처음에는잠재염증을배제하기위하여전혈구계산와급성기반응물질 ( 적혈구침강속도, C 반응단백질 ) 을검사하고, 필요에따라다른검사를추가해야한다. 임상적으로다른질환의동반이의심되는경우해당질환에대한검사가필요하며특히수면장애와정동장애의동반여부를꼭감별해야한다. 그리고섬유근통증후군환자들에서항상통증의근원을찾으려는노력을해야한다. 특히염증류마티스질환과비염증근골격계통증의동반여부가치료방향을결정하는데중요하므로반드시감별해야한다. 치료는증상에맞추어개별화되어야하고향후섬유근통증후군의병인과치료에대한다각적인연구가필요하겠다. REFERENCES 1. Goldenberg DL. Fibromyalgia syndrome. An emerging but controversial condition. JAMA 1987;257:2782-2787. 2. Goldenberg DL. Fibromyalgia syndrome a decade later: what have we learned?. Arch Intern Med 1999;159:777-785. 3. Weir PT, Harlan GA, Nkoy FL, Jones SS, Hegmann KT, Gren LH, et al. The incidence of fibromyalgia and its associated comorbidities: a population-based retrospective cohort study based on International Classification of Diseases, 9th Revision codes. J Clin Rheumatol 2006;12:124-128. 4. Bannwarth B, Blotman F, Roué-Le Lay K, Caubère JP, André E, Taïeb C. Fibromyalgia syndrome in the general population of France: a prevalence study. Joint Bone Spine 2009;76:184-187. 5. Glass JM. Cognitive dysfunction in fibromyalgia and chronic fatigue syndrome: new trends and future directions. Curr Rheumatol Rep 2006;8:425-429. 6. Marcus DA, Bernstein C, Rudy TE. Fibromyalgia and headache: an epidemiological study supporting migraine as part of the fibromyalgia syndrome. Clin Rheumatol 2005;24:595-601. 7. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33:160-172. 8. Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res 2010;62:600-610. 9. Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. JAMA 2004;292:2388-2395. 10. Katz RS, Wolfe F, Michaud K. Fibromyalgia diagnosis: a comparison of clinical, survey, and American College of Rheumatology criteria. Arthritis Rheum 2006;54:169-176. J Korean Neurol Assoc Volume 31 No. 1, 2013 5
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