Benzodiazepinni olib tashlash sindromi - Benzodiazepine withdrawal syndrome

Benzodiazepinni olib tashlash sindromi
Boshqa ismlarBenzo chekinishi
Diazepam2mgand5mgtablets.JPG
Diazepam ba'zan benzodiazepinni olib tashlashni davolashda ishlatiladi.[1]
MutaxassisligiPsixiatriya
Benzodiazepinlar
Diazepin halqasiga birlashtirilgan benzol halqasining kimyoviy tuzilishi diagrammasi. Boshqa bir benzol halqasi diazepin halqasining pastki qismiga bitta chiziq orqali biriktirilgan. Birinchi benzol halqasiga R7 deb nomlangan yon zanjir biriktirilgan; ikkinchisiga, R2 'bilan belgilangan yon zanjir; va diazepin halqasiga biriktirilgan, ikkita yon zanjir R1 va R2 deb nomlangan.
Benzodiazepinlarning yadro tuzilishi. "R" yorliqlari umumiy joylarni bildiradi yon zanjirlar, bu turli xil benzodiazepinlarga o'ziga xos xususiyatlarini beradi.

Benzodiazepinni olib tashlash sindromi- qisqartirilgan benzo olib qo'yish yoki BZDni olib qo'yish - bu klaster belgilar va alomatlar qabul qilgan odam paydo bo'lganda paydo bo'ladi benzodiazepinlar, tibbiy yoki rekreatsion jihatdan va jismoniy rivojlangan qaramlik, dozani kamaytirish yoki bekor qilishni boshdan kechiradi. Jismoniy qaramlikning rivojlanishi va natijada ularning ba'zilari yillar davomida davom etishi mumkin bo'lgan olib tashlash alomatlari, buyurilgan dori-darmonlarni qabul qilish natijasida kelib chiqishi mumkin. Benzodiazepinning olib tashlanishi uyquni buzilishi, asabiylashish, kuchaygan kuchlanish va tashvish, vahima hujumlari, qo'llarning titrashi, titraganlik, terlash, konsentratsiyadagi qiyinchilik, chalkashlik va kognitiv qiyinchiliklar, xotira muammolari, quruq tortishish va ko'ngil aynish, vazn yo'qotish, yurak urishi, bosh og'rig'i, mushaklarning og'rig'i va qattiqligi, sezgi o'zgarishi, gallyutsinatsiyalar, soqchilik, psixoz,[2] va o'z joniga qasd qilish xavfi ortdi[3][4] (to'liq ro'yxat uchun quyidagi "alomatlar va alomatlar" bo'limiga qarang). Bundan tashqari, ushbu alomatlar mum va susayish uslubi bilan ajralib turadi va zo'ravonlik darajasi to'g'ridan-to'g'ri monotonik tarzda doimiy ravishda pasayish o'rniga kundan-kunga yoki haftadan-haftaga o'zgarib turadi.[5] Ushbu hodisa ko'pincha "to'lqinlar" va "derazalar" deb nomlanadi.

Bu potentsial jiddiy holat bo'lib, murakkab va ko'pincha o'z vaqtida cho'zilib ketadi.[6][7] Kamida uch oy davomida kunlik foydalanish deb ta'riflangan benzodiazepinni uzoq muddatli qo'llash,[8] bog'liqlik xavfining ortishi sababli istalmagan,[9] dozani oshirishi, samaradorligini yo'qotishi, baxtsiz hodisalar va tushish xavfining oshishi, ayniqsa qariyalar uchun,[10] shuningdek, kognitiv,[11] nevrologik va intellektual buzilishlar.[12] Qisqa muddatli foydalanish hipnotiklar, uyquni boshlashda samarali bo'lish bilan birga, uyqusizlik ta'siri tufayli uyquning ikkinchi yarmi yomonlashadi.[13]

Benzodiazepinni olib tashlash og'ir bo'lishi mumkin va hayotni xavf ostiga qo'yadigan alomatlarni keltirib chiqarishi mumkin, masalan, soqchilik,[14] ayniqsa, yuqori dozalarda yoki uzoq muddatli foydalanuvchilarda dozani keskin yoki juda tez pasayishi bilan.[6] Shunga qaramay, dozani bosqichma-bosqich kamaytirilishiga yoki qisqa vaqt ichida foydalanuvchilarga nisbatan past dozalarda bo'lishiga qaramay, pulni olib tashlashga jiddiy javob bo'lishi mumkin,[15] hayvon modellarida bitta katta dozadan keyin ham.[16][17] Shaxslarning ozchilik qismi a uzoq davom etadigan sindrom sindromi alomatlari benzodiazepinlar to'xtaganidan keyin bir necha oy yoki bir necha yil davomida sub-o'tkir darajada saqlanib qolishi mumkin. Uzoq muddatli tortishish sindromini rivojlanish ehtimoli dozani asta-sekin kamaytirish orqali kamaytirilishi mumkin.[18]

Surunkali benzodiazepinlarga ta'sir qilish asab ta'siriga ta'sir qiladi, bu esa preparatning ta'siriga ta'sir qiladi, natijada bag'rikenglik va qaramlik.[19] Doimiy terapevtik dozani qabul qilishiga qaramay, benzodiazepinlarni uzoq muddat iste'mol qilish, ayniqsa dozalar o'rtasida, tortilishga o'xshash alomatlarning paydo bo'lishiga olib kelishi mumkin.[20] Preparat bekor qilinganda yoki dozasi kamaytirilganda, olib tashlash belgilari tana fiziologik moslashuvlarni qaytarguncha paydo bo'lishi va qolishi mumkin.[21] Bular qaytish alomatlari preparat dastlab qabul qilingan alomatlar bilan bir xil bo'lishi mumkin yoki bekor qilish belgilarining bir qismi bo'lishi mumkin.[22] Og'ir holatlarda, tortib olish reaktsiyasi jiddiy psixiatrik va tibbiy holatlarni kuchaytirishi yoki shunga o'xshash bo'lishi mumkin, masalan mani, shizofreniya va, ayniqsa yuqori dozalarda, soqchilik buzilishlar.[23] Ishni to'xtatish alomatlarini tan olmaslik benzodiazepinlarni qabul qilish zarurligi to'g'risida soxta dalillarga olib kelishi mumkin, bu esa o'z navbatida olib tashlash etishmovchiligiga va benzodiazepinlarni qayta tiklanishiga, ko'pincha yuqori dozalarga olib keladi.[23]

Chiqib ketish reaktsiyalari to'g'risida xabardor bo'lish, tortib olish zo'ravonligiga qarab individual konus strategiyalari, ishontirish va benzodiazepinni olib tashlashni qo'llab-quvvatlash guruhlariga murojaat qilish kabi muqobil strategiyalarning qo'shilishi bularning barchasi pulni olib chiqishning muvaffaqiyat darajasini oshiradi.[24][25]

Belgilari va alomatlari

Benzodiazepinlar, barbituratlar yoki spirtli ichimliklar, jiddiy tibbiy asoratlarni keltirib chiqarishi mumkin. Ulardan chiqish xavfliroq ekanligi aytilgan opioidlar.[26] Foydalanuvchilar odatda to'xtatish uchun ozgina maslahat va yordam olishadi.[27] Ba'zi olib tashlash alomatlari dastlab dori buyurilgan alomatlar bilan bir xil,[22] va o'tkir yoki uzoq davom etishi mumkin. Uzoq vaqtdan beri simptomlarning paydo bo'lishi yarim hayot benzodiazepinlar uch haftagacha kechiktirilishi mumkin, ammo qisqa muddatli ta'sirchanlardan ajralish alomatlari ko'pincha erta, odatda 24-48 soat ichida namoyon bo'ladi.[28] Semptomlarda yuqori yoki past dozani to'xtatish bilan bog'liq bo'lgan asosiy farqlar bo'lmasligi mumkin, ammo yuqori dozalardan semptomlar og'irroq bo'ladi.[29]

Kunduzgi qayta tiklanish va tiklanishni bekor qilish alomatlari, ba'zida dozani qabul qilish bilan aralashtirib yuborilishi, qaramlik o'rnatilgandan so'ng paydo bo'lishi mumkin. 'Reergentsiya' - bu preparat dastlab buyurilgan alomatlarning qaytishi, aksincha, 'tiklanish' belgilari simptomlarning qaytishi. u uchun dastlab benzodiazepin qabul qilingan, ammo oldingisiga qaraganda ancha kuchli darajada; "dozani olib tashlash" - bu preparatning oldingi dozasi tugashi va butunlay olib tashlashning yangi tsiklining boshlanishi, bu alomatlar keyingi dozani qabul qilishda tarqalib ketadi, ammo bu dozadan keyin yana bir yangi olib tashlash tsikli boshlanadi. tugaydi, shuning uchun har bir dozani bekor qilishning yangi boshlanishi 'dozani oshirib yuborish chekinish 'va agar kerakli davolanish bo'lmasa, aylanada abadiy takrorlanishi mumkin (buning uchun yarim umr ko'rgan benzo, masalan. diazepam, almashtirish mumkin, shuning uchun preparat dozalar orasida eskirmaydi).[30]

Dozani kamaytirish paytida pulni olib tashlash alomatlari birinchi marta paydo bo'lishi mumkin va ular orasida uyqusizlik, xavotirlik, bezovtalik, vazn yo'qotish, bosh aylanishi, tunda terlash, titroq, mushaklarning qisilishi, afazi, vahima qo'zg'ashlari, depressiya, derealizatsiya, paranoya, oshqozon buzilishi, diareya, fotobobi mavjud. va boshqalar, va odatda triazolam singari qisqa muddatli benzodiazepinlarni to'xtatish bilan bog'liq.[23][31] Kunduzgi alomatlar bir necha kundan bir necha haftagacha tunda benzodiazepindan foydalanishni boshlaganidan keyin paydo bo'lishi mumkin[32][33] yoki zopiklon kabi z-dorilar;[34] tortib olish bilan bog'liq bo'lgan uyqusizlik rebound dastlabki darajadan ham yomonroq,[35][36] va tezda yo'q qilingan benzodiazepinlar uchun, shu jumladan triazolam va temazepam, bu 1991 yilgi kichik tadqiqotga ko'ra (n = 18) qisqacha va vaqti-vaqti bilan ishlatilganda ham yuz berishi mumkin.[37]

Dozani asta-sekin yoki keskin qisqartirish paytida quyidagi alomatlar paydo bo'lishi mumkin:

Tez to'xtatish yanada jiddiy sindromga olib kelishi mumkin

Chiqib ketish davom etar ekan, bemorlar tez-tez jismoniy va ruhiy sog'lig'ini yaxshilangan kayfiyat va bilimni yaxshilash bilan yaxshilaydi.

Mexanizm

Asosiy maqola: Benzodiazepinga bog'liqlik § Mexanizm
Shuningdek qarang: Spirtli ichimliklarni olib tashlash sindromi § Kindling va Kindling (sedativ-gipnoz olib tashlash)

Tolerantlik, qaramlik va tushkunlik mexanizmlari bilan bog'liq neyroadaptiv jarayonlar GABAerjik va glutamaterjik tizimlarga ta'sir qiladi.[19] Gamma-aminobutirik kislota (GABA ) markaziy asab tizimining asosiy inhibitör nörotransmitteridir; taxminan GABA dan sinapslarning to'rtdan uchdan bir qismigacha foydalaniladi.[77] GABA xlorid ionlarining kirib kelishida vositachilik qiladi ligandli xlorli kanallar deb nomlangan GABAA retseptorlari. Xlorid asab hujayrasiga kirganda hujayra membranasi potentsiali giperpolyarizatsiyalanadi va shu bilan depolarizatsiyani inhibe qiladi yoki post-sinaptik asab hujayrasining otish tezligini pasaytiradi.[78] Benzodiazepinlar GABA ta'sirini kuchaytiradi,[79] 5-bo'linma retseptorining a va b subbirliklari orasidagi joyni bog'lash orqali[80] shu bilan GABA borligida xlorli kanal ochilish chastotasini oshiradi.[81]

Potensializatsiya uzoq muddatli foydalanish bilan ta'minlanganda, neyroadaptatsiyalar paydo bo'ladi, natijada GABAergik reaktsiya pasayadi. GABA sirtining aniqligiA retseptorlari oqsil darajasi retseptorlarning aylanish darajasi kabi benzodiazepin ta'siriga javoban o'zgartiriladi.[82] Javobgarlikni kamaytirishning aniq sababi aniqlanmagan, ammo retseptorlar sonining past regulyatsiyasi faqat ba'zi retseptorlarning joylashgan joylarida, shu jumladan, nigraning pars reticulata; retseptorlari sonini pastga tartibga solish yoki ichki holatga keltirish boshqa joylarda asosiy mexanizm bo'lib ko'rinmaydi.[83] Qabul qiluvchilar konformatsiyasining o'zgarishi, aylanishning o'zgarishi, qayta ishlash yoki ishlab chiqarish stavkalari, fosforillanish darajasi va retseptorlari genlarining ekspressioni, subbirlik tarkibi, GABA va benzodiazepin uchastkalari orasidagi bog'lanish mexanizmlarining pasayishi, GABA ishlab chiqarishning pasayishi va kompensator kabi boshqa farazlar uchun dalillar mavjud. glutamaterjik faollikni kuchayishi.[19][82] Birlashtirilgan model gipotezasi retseptorlarning ichki joylashuvining kombinatsiyasini o'z ichiga oladi, so'ngra retseptorlarning gen transkripsiyasidagi o'zgarishlar uchun yadro faolligini ta'minlaydigan ba'zi retseptorlarning kichik bo'linmalarining imtiyozli degradatsiyasi.[82]

Benzodiazepinlar miyadan tozalanganida, bu neyroadaptatsiyalar "niqobsiz" bo'lib, neyronning beg'araz qo'zg'alishiga olib keladi deb taxmin qilingan.[84][tekshirib bo'lmadi ]Glutamat eng keng tarqalgan qo'zg'atuvchidir neyrotransmitter umurtqali hayvonlarda asab tizimi.[85] Chiqib ketish paytida glutamat qo'zg'atuvchi faolligining oshishiga olib kelishi mumkin sezgirlik yoki yonish CNS, ehtimol bilish va simptomatologiyaning yomonlashishiga olib keladi va har bir keyingi olib tashlash davrini yomonlashtiradi.[86][87][88] Oldindan benzodiazepinlardan voz kechish tarixiga ega bo'lganlar keyingi safar muvaffaqiyatga erishish ehtimoli kamligi aniqlandi.[89]

Tashxis

Og'ir holatlarda, tortib olish reaktsiyasi yoki uzoq davom etishi mani, shizofreniya, kabi jiddiy psixiatrik va tibbiy holatlarni kuchaytirishi yoki o'xshash bo'lishi mumkin. qo'zg'atilgan depressiya, vahima buzilishi, umumiy tashvish buzilishi va murakkab qisman tutilishlar va, ayniqsa yuqori dozalarda, soqchilik kasalliklari.[23] Ishni to'xtatish alomatlarini tan olmaslik benzodiazepinlarni qabul qilish zarurligi to'g'risida yolg'on dalillarga olib kelishi mumkin, bu esa o'z navbatida olib tashlash etishmovchiligiga va benzodiazepinlarni qayta tiklanishiga, ko'pincha yuqori dozalarga olib keladi. Oldindan mavjud bo'lgan buzilish yoki boshqa sabablar odatda yaxshilanmaydi, ammo uzoq davom etadigan alomatlar keyingi oylarda asta-sekin yaxshilanadi.[23]

Semptomlar psixologik sabablarga ega bo'lmasligi mumkin va yaxshi va yomon kunlar bilan intensivlikda o'zgarib, oxir-oqibat tiklanishigacha o'zgarishi mumkin.[90][91]

Oldini olish

Ga ko'ra Britaniya milliy formulasi, benzodiazepinlardan tezroq emas, balki juda sekin chiqib ketish yaxshiroqdir.[28] Dozani kamaytirish tezligi simptomlarning intensivligi va zo'ravonligini minimallashtirish uchun eng yaxshi tarzda amalga oshiriladi. Anekdotal ravishda sekin pasayish darajasi uzoq davom etadigan sindromni rivojlanish xavfini kamaytirishi mumkin.

Uzoq yarim umr benzodiazepinlar kabi diazepam[1] yoki xlordiazepoksid rebound ta'sirini minimallashtirish uchun afzaldir va past dozali shakllarda mavjud. Ba'zi odamlar dozani kamaytirish o'rtasida to'liq barqarorlashmasligi mumkin, hatto pasayish darajasi sekinlashganda ham. Bunday odamlar ba'zida shunchaki davom etishlari kerak, chunki ular bir muncha vaqtgacha ulardan butunlay voz kechmaguncha o'zlarini yaxshi his qilmasliklari mumkin.[92]

Menejment

Xlordiazepoksid, 5 mg kapsül, ba'zan alternativ sifatida ishlatiladi diazepam benzodiazepinni olib tashlash uchun. Diazepam singari, u uzoq vaqtga ega yarim umrni yo'q qilish va uzoq muddatli faol metabolitlar.[6][93]

Benzodiazepinga qaramlikni boshqarish odamning yoshi, komorbidligi va benzodiazepinlarning farmakologik yo'llarini hisobga olishni o'z ichiga oladi.[94] Psixologik aralashuvlar faqat to'xtatilgandan keyin va kuzatuv paytida dozani bosqichma-bosqich kamaytirish orqali kichik, ammo sezilarli qo'shimcha foyda keltirishi mumkin.[95] O'rganilgan psixologik tadbirlar gevşeme mashg'ulotlari, uyqusizlikni kognitiv-xulq-atvorli davolash va iste'mol va alomatlarni o'z-o'zini nazorat qilish, maqsadni belgilash, tashlab ketishni boshqarish va tashvish bilan kurashish edi.[95]

Benzodiazepinni olib tashlashni boshqarishda standart yondashuv mavjud emas.[96]Etarli motivatsiya va to'g'ri yondashuv bilan deyarli har bir kishi benzodiazepinlardan muvaffaqiyatli chiqib ketishi mumkin. Ammo uzoq davom etgan va og'ir sindrom nikohlarning buzilishiga, biznesdagi muvaffaqiyatsizlikka, bankrotlikka, kasalxonaga yotqizilishga va eng jiddiy salbiy ta'sir o'z joniga qasd qilishga olib kelishi mumkin.[3] Shunday qilib, uzoq muddatli foydalanuvchilar o'zlarining xohishlariga qarshi to'xtashga majbur qilinmasligi kerak.[6]

Haddan tashqari tez chiqib ketish, tushuntirishning etishmasligi va odamlarni vaqtincha olib tashlash alomatlarini boshdan kechirayotganiga ishontirmaslik, ba'zi odamlarda vahima va aqldan ozishdan qo'rqishlarini kuchayishiga olib keldi, ba'zi odamlar travmadan keyingi stress buzilishlariga o'xshash holatni rivojlantirdilar. natija. Sekin-asta chiqib ketish rejimi, oilangiz, do'stlaringiz va tengdoshlaringizning ishonchi bilan natijani yaxshilaydi.[6][18] 2015 yilgi Cochrane sharhiga ko'ra, kognitiv xulq-atvor terapiyasi plyus konus qisqa muddatda to'xtashga erishishda samarali bo'ldi, ammo olti oydan keyin ta'siri aniq emas edi.[97]

Dori vositalari

Ba'zi bir o'rnini bosuvchi farmakoterapiya va'da qilgan bo'lsa-da, ulardan foydalanishni ta'minlash uchun mavjud dalillar etarli emas.[95] Ba'zi tadkikotlar shuni ko'rsatdiki, o'rnini bosuvchi farmakoterapiyani birdaniga almashtirish faqat dozani bosqichma-bosqich kamaytirishga qaraganda unchalik samarasiz edi va faqat uchta tadqiqot melatonin qo'shishning afzalliklarini topdi,[98] paroksetin,[99] trazodon,[100] yoki valproat[100] dozani bosqichma-bosqich kamaytirish bilan birgalikda.[95]

  • Antipsikotiklar odatda benzodiazepinni olib tashlash bilan bog'liq psixoz uchun samarasizdir.[54][101] Benzodiazepinni olib tashlash paytida antipsikotiklardan saqlanish kerak, chunki ular olib tashlash alomatlarini kuchaytiradi, shu jumladan konvulsiyalar.[28][102][103][104] Biroz antipsikotik moddalar pul olish paytida boshqalardan ko'ra xavfli bo'lishi mumkin, ayniqsa klozapin, olanzapin yoki past kuch fenotiyazinlar (masalan, xlorpromazin ), ular pastga tushganda soqchilik chegarasi va pulni olib tashlash oqibatlarini yomonlashtirishi mumkin; agar ishlatilsa, juda ehtiyot bo'lish kerak.[105]
  • Barbituratlar benzodiazepinlarga o'zaro chidamli va odatda ulardan qochish kerak; ammo fenobarbital foydalanish mumkin, chunki u nisbatan xavfsiz,[106] pastga qarang.
  • Benzodiazepinlar yoki to'xtatilgandan keyin, hatto vaqti-vaqti bilan o'zaro ta'sirga chidamli dori-darmonlardan saqlanish kerak. Ular orasida benzodiazepinlar Z-dorilar, shunga o'xshash harakat mexanizmiga ega. Buning sababi shundaki, benzodiazepinlarga nisbatan bag'rikenglik shaxsiy biokimyoga bog'liq holda olib tashlanganidan keyin to'rt oydan ikki yilgacha davom etadi. Benzodiazepinlarga qayta ta'sir qilish odatda tolerantlik va benzodiazepinni olib tashlash sindromini qayta faollashishiga olib keldi.[107][108]
  • Bupropion, asosan antidepressant va chekishni to'xtatish vositasi sifatida ishlatiladigan benzodiazepinlardan yoki boshqa sedativ-gipnozlardan (masalan, alkogoldan) to'satdan chiqib ketishni boshdan kechirayotgan odamlarda, soqchilik xavfi ortishi sababli kontrendikedir.[109]
  • Buspirone ko'payish to'xtatilishning muvaffaqiyat darajasini oshirishi aniqlanmadi.[8]
  • Kofein uning ogohlantiruvchi xususiyati tufayli olib tashlash alomatlarini yomonlashtirishi mumkin.[6] Kamida bitta hayvonlarni o'rganish ba'zi birlarini ko'rsatdi benzodiazepin saytining modulyatsiyasi soqchilik chegarasini pasayishiga olib keladigan kofein bilan.[110]
  • Karbamazepin, an antikonvulsant, benzodiazepinni olib tashlashni davolash va davolashda ba'zi foydali ta'sirlarga ega ekanligi ko'rinadi; ammo tadqiqotlar cheklangan va shu sababli mutaxassislarning benzodiazepinni olib tashlash uchun foydalanish bo'yicha tavsiyalar berish qobiliyati hozircha mumkin emas.[107]
  • Etanol, asosiy spirt spirtli ichimliklar, hatto engil va mo''tadil foydalanish ham, ehtimol, shuning uchun olib tashlash etishmovchiligining muhim bashoratchisi ekanligi aniqlandi o'zaro faoliyat bag'rikenglik benzodiazepinlar bilan.[6][107][111]
  • Flumazenil bag'rikenglikni qaytarishni va retseptorlarning ishini normallashtirishni rag'batlantirishi aniqlandi. Shu bilan birga, benzodiazepinni olib tashlashni davolashda uning rolini namoyish qilish uchun randomizatsiyalangan sinovlar shaklida qo'shimcha tadqiqotlar o'tkazish kerak.[112] Flumazenil regulyatsiyani rag'batlantiradi va aksini qaytaradi ajratish ning benzodiazepin retseptorlari uchun GABAA retseptorlari, shu bilan bag'rikenglikni qaytarish va olib tashlash alomatlari va relaps stavkalarini kamaytirish.[113][114] Mumkin bo'lgan xavf bilan taqqoslaganda cheklangan tadqiqotlar va tajriba tufayli flumazenilni zararsizlantirish usuli munozarali bo'lib, faqat tibbiy nazorat ostida statsionar tartibda amalga oshirilishi mumkin.
Flumazenil 4-266 hafta davomida benzodiazepinlardan xoli bo'lgan bemorlarda dushmanlik va tajovuzkorlik tuyg'ularini kamaytirishda platsebodan ko'ra samaraliroq ekanligi aniqlandi.[115] Bu flumazenilning benzodiazepinning uzaygan semptomlarini davolashda rolini taklif qilishi mumkin.
Lader va Morton tomonidan benzodiazepin retseptorlari antagonisti - flumazenilning benzodiazepinni olib tashlash alomatlariga ta'sirini o'rganish bo'yicha tadqiqot olib borildi. Tadqiqot sub'ektlari bir oydan besh yilgacha benzodiazepinsiz edi, ammo ularning barchasi doimiy ravishda olib tashlanish ta'sirini turli darajalarda qayd etishdi. Doimiy alomatlar orasida bulutli fikrlash, charchoq, bo'yin tarangligi, depersonalizatsiya, kramplar va tebranish va xarakteristikasi sezgir benzodiazepinni olib tashlash alomatlari, ya'ni pinalar va ignalarni his qilish, terining yonishi, og'riq va tanadagi buzilish sub'ektiv hissiyotlari. 0,2-2 mg flumazenil bilan davolash vena ichiga a-da ushbu alomatlarni kamaytirishi aniqlandi platsebo - nazorat ostida o'rganish. Bu benzodiazepin retseptorlari antagonistlari neytral va klinik ta'sirga ega bo'lmaganligi sababli qiziqish uyg'otadi. Tadqiqot muallifi, ehtimol, benzodiazepinni ilgari ishlatilganligi va keyinchalik bag'rikenglik GABA-BZD retseptorlari majmuasining konformatsiyasini teskari agonist konformatsiya va antagonist flumazenil benzodiazepin retseptorlarini asl sezgirligiga qaytaradi. Ushbu tadqiqotda Flumazenil uzoq davom etgan benzodiazepinni olib tashlash sindromi uchun muvaffaqiyatli davo ekanligi aniqlandi, ammo qo'shimcha tadqiqotlar talab etiladi.[116] Shvetsiyadagi professor Borg tomonidan olib borilgan tadqiqotlar uzoq davom etadigan kasallikdan aziyat chekadigan bemorlarda ham xuddi shunday natijalarni keltirib chiqardi.[38] 2007 yilda, Hoffmann – La-Rosh flumazenil ishlab chiqaruvchilari uzoq davom etadigan benzodiazepinni olib tashlash sindromi mavjudligini tan oldilar, ammo bu holatni davolash uchun flumazenilni tavsiya qilmadilar.[117]
  • Ftorxinolon antibiotiklar[118][119][120] CNS toksikligi bilan kasallanishni umumiy populyatsiyada 1% dan, benzodiazepinga qaram populyatsiyada yoki ulardan voz kechayotganlarda 4% gacha oshirishi qayd etilgan. Ehtimol, bu ularning GABA antagonistik ta'sirining natijasidir, chunki ular benzodiazepin retseptorlari joylaridan benzodiazepinlarni raqobatdosh ravishda siqib chiqarishi aniqlangan. Ushbu antagonizm susayishdan oldin bir necha hafta yoki bir necha oy davom etishi mumkin bo'lgan o'tkir siqilish belgilarini kuchaytirishi mumkin. Semptomlarga depressiya, tashvish, psixoz, paranoya, og'ir uyqusizlik, parateziya, tinnitus, yorug'lik va tovushga yuqori sezuvchanlik, titroq, holat epileptikus, o'z joniga qasd qilish fikrlari va o'z joniga qasd qilish harakati. Ftorxinolon antibiotiklari benzodiazepinni olib tashlashga bog'liq yoki unga bog'liq bemorlarda kontrendikedir.[6][121][122][123][124] NSAID ba'zi yumshoq GABA antagonistik xususiyatlariga ega va hayvonlarni tadqiq qilish shuni ko'rsatadiki, ba'zilari benzodiazepinlarni bog'lanish joyidan siqib chiqarishi mumkin. Shu bilan birga, ftorxinolonlar bilan birgalikda qabul qilingan NSAIDlar GABA antagonizmini, GABA toksikligini, tutilishlarni va boshqa jiddiy salbiy ta'sirlarni sezilarli darajada ko'payishiga olib keladi.[125][126][127]
  • Imidazenil benzodiazepinni olib tashlashni boshqarish bo'yicha bir qator tadqiqotlar olib borgan, ammo hozirda uni olib tashlashda foydalanilmaydi.[128]
  • Imipramin to'xtatilishning muvaffaqiyat darajasini statistik ravishda oshirishi aniqlandi.[8]
  • Melatonin kattalashtirish uyqusizlikka chalingan odamlar uchun to'xtatish muvaffaqiyat darajasini statistik ravishda oshirishi aniqlandi.[8]
  • Fenobarbital, (a barbiturat ), "detoks" yoki boshqa statsionar muassasalarda tez chiqib ketish paytida tutilishlarning oldini olish uchun ishlatiladi sovuq kurka. Fenobarbitaldan keyin bir-ikki haftalik konus keladi, ammo fenobarbitaldan sekin konusga afzallik beriladi.[23] Taqqoslash ishida benzodiazepinlardan foydalangan holda tezkor konus fenobarbital tezkor konusdan ustun ekanligi aniqlandi.[129][130]
  • Pregabalin benzodiazepinni olib tashlash simptomlarining og'irligini kamaytirishga yordam berishi mumkin,[131] va qayt qilish xavfini kamaytiradi.[132]
  • Progesteron benzodiazepinning chiqarilishini boshqarish uchun samarasiz deb topildi.[112]
  • Propranolol to'xtatilishning muvaffaqiyat darajasini oshirishi aniqlanmadi.[8]
  • SSRI antidepressantlarning benzodiazepinni olib tashlashni davolashda ahamiyati kamligi aniqlandi.[133]
  • Trazodone to'xtatilishning muvaffaqiyat darajasini oshirishi aniqlanmadi.[8]

Statsionar davolanish

Statsionar giyohvand moddalarni zararsizlantirish yoki reabilitatsiya qilish rekreatsion foydalanishdan farqli o'laroq, dori-darmonlarni qabul qilish paytida bardoshli yoki qaram bo'lib qolganlar uchun moslamalar mos kelmasligi mumkin. Bunday statsionar yo'llanmalar suiiste'mol qilmaydiganlar uchun shikast etkazishi mumkin.[23]

Prognoz

Shuningdek qarang: Uzoq muddatli sindrom sindromi

2006 yil meta-tahlil bosqichma-bosqich parvarishlash samaradorligi uchun dalillarni topdi: minimal aralashuv (masalan, maslahat xati yuboring yoki to'xtatish to'g'risida maslahat berish uchun ko'plab bemorlar bilan uchrashing), so'ngra birinchi urinish muvaffaqiyatsiz bo'lsa, faqatgina ko'paytirmasdan tizimli qisqartirilgan to'xtatish.[8] Kognitiv xulq-atvor terapiyasi vahima buzilishi, melatonin uyqusizlik va umumiy uzoq muddatli benzodiazepindan foydalanish uchun flumazenil yoki natriy valproat uchun to'xtatish muvaffaqiyat ko'rsatkichlarini yaxshiladi.[8] O'n yillik kuzatuv shuni ko'rsatdiki, uzoq muddatli foydalanishdan muvaffaqiyatli chiqib ketganlarning yarmidan ko'pi ikki yildan keyin ham betaraf bo'lgan va agar ular ushbu holatni ikki yil ichida saqlab qolishsa, ular buni saqlab qolishgan o'n yillik kuzatuvda davlat.[10] Bir tadqiqot shuni ko'rsatdiki, benzodiazepinlarni uzoq muddatli ishlatishdan bir yil voz kechgandan so'ng, kognitiv, nevrologik va intellektual buzilishlar normal holatga qaytgan.[134]

Oldindan psixiatrik tashxis qo'yganlar, ikki yillik kuzatuvda asta-sekin konusdan shunga o'xshash muvaffaqiyat ko'rsatkichlariga ega edilar.[92][135] Benzodiazepinlardan foydalanish antidepressantlardan ko'proq foydalanishga olib kelmadi.[136]

Pulni qaytarib olish jarayoni

Qisqa yoki oraliq ta'sir etuvchi benzodiazepinlardan intensivligi tufayli chiqib ketish juda qiyin bo'lishi mumkin tiklanish dozalar o'rtasida sezilgan alomatlar.[6][137][138][139] Bundan tashqari, qisqa muddatli benzodiazepinlar kuchli intensiv sindromni keltirib chiqaradi.[140] Shu sababli, to'xtatish ba'zida avval an o'rnini bosish bilan amalga oshiriladi ekvivalent dozasi shunga o'xshash uzoqroq ta'sirga ega qisqa ta'sirli benzodiazepinning diazepam yoki xlordiazepoksid. To'g'ri ishlatmaslik ekvivalent miqdor jiddiy tortib olish reaktsiyasini keltirib chiqarishi mumkin.[141] A bilan benzodiazepinlar yarim hayot 24 soatdan ortiq xlordiazepoksid, diazepam, clobazam, klonazepam, xlorazepin kislotasi, ketazolam, medazepam, nordazepam va prazepam. Yarim ishlash muddati 24 soatdan kam bo'lgan benzodiazepinlar alprazolam, bromazepam, brotizolam, flunitrazepam, loprazolam, lorazepam, lormetazepam, midazolam, nitrazepam, oksazepam va temazepam.[10] Natijada ekvivalent dozani asta-sekin kamaytiradi.

Konsensus bir necha hafta davomida dozani asta-sekin kamaytirishdir, masalan. Diazepamning kuniga 30 mg dan ortiq dozalari uchun 4 yoki undan ko'p hafta,[1]odamning alomatlarga toqat qilish qobiliyati bilan belgilanadigan tezlik bilan.[142]Tavsiya etilgan pasayish stavkalari har hafta yoki undan ko'proq vaqt davomida boshlang'ich dozaning 50% gacha o'zgarib turadi,[143]har 2 haftada sutkalik dozaning 10-25% gacha.[142]Masalan, Xezer Eshton protokolida qo'llanilgan pasayish darajasi diazepamning 0,5 mg yoki 2,5 mg dozasida yakuniy doza bilan kamayishiga zo'ravonligi va ta'siriga qarab, har ikki-to'rt haftada qolgan dozaning 10% ni yo'q qilishni talab qiladi. xlordiazepoksid.[6]Ko'pgina odamlar uchun 4-6 hafta yoki 4-8 hafta davomida to'xtatish mos keladi.[144]Chiqib ketish jarayoni odam uchun "kasal markazida" bo'lishiga yo'l qo'ymaslik uchun ko'p oylar davomida uzoq muddatli pasayishdan saqlanish kerak.[107]

Muddati

Oxirgi dozani qabul qilgandan so'ng, pulni olib tashlashning o'tkir bosqichi, odatda, taxminan ikki oy davom etadi, ammo chekish belgilari, hatto past dozani qo'llagan taqdirda ham, ushbu davrda asta-sekin yaxshilanadigan olti oydan o'n ikki oygacha davom etishi mumkin,[29][92] ammo, klinik jihatdan ahamiyatli chekinish alomatlari yillar davomida davom etishi mumkin, garchi asta-sekin pasayib ketsa.

Sakkiz hafta davomida benzodiazepin alprazolamni qabul qilgan bemorlarning klinik tekshiruvi alprazolam to'xtaganidan sakkiz hafta o'tgach ham davom etgan xotira etishmovchiligining uzaygan alomatlarini keltirib chiqardi.[145]

Uzoq muddatli sindrom sindromi

Uzoq muddatli sindirish sindromi bir necha oy yoki hatto yillar davomida saqlanib turadigan alomatlarga ishora qiladi. Benzodiazepinlardan voz kechadigan odamlarning ozchilik qismi, ehtimol 10% dan 15% gacha, a uzoq davom etadigan sindrom sindromi ba'zida bu og'ir bo'lishi mumkin. Alomatlar tinnitusni o'z ichiga olishi mumkin,[57][146] psixoz, kognitiv nuqsonlar, oshqozon-ichak traktining shikoyati, uyqusizlik, paresteziya (karıncalanma va karaxtlik), og'riq (odatda oyoq-qo'llarda va ekstremitalarda), mushaklarda og'riq, zaiflik, kuchlanish, og'riqli titroq, titroq xurujlari, jirkanchliklar, bosh aylanishi va blefarospazm[18] va ushbu alomatlar oldindan mavjud bo'lmagan tarixsiz ham paydo bo'lishi mumkin. Dozani kamaytirish yoki benzodiazepinlarni qabul qilishni to'xtatish paytida paydo bo'ladigan tinnitus benzodiazepinlarni tavsiya etish bilan yumshatiladi. Bosh aylanishi ko'pincha eng uzoq davom etadigan tortishish belgisi sifatida qayd etiladi.

Nöropsikologik omillarni sinab ko'rgan tadqiqotda psixofiziologik belgilar normal holatdan farq qiladi va uzoq muddatli sindirish sindromi uzoq muddatli foydalanish natijasida kelib chiqqan asl yatrogenik holat degan xulosaga keldi.[147] Doimiy simptomlarning sabablari - bu doimiy ta'sir ko'rsatadigan retseptorlarning o'zgarishi, giyohvandlik vositasi tomonidan kelib chiqadigan va preparatdan ajralib turadigan psixologik omillar, ehtimol ba'zi hollarda, ayniqsa yuqori dozada foydalanuvchilar, miyaning strukturaviy shikastlanishi yoki tizimli neyronlarning shikastlanishi kabi farmakologik omillarning kombinatsiyasi.[18][148] Semptomlar vaqt o'tishi bilan yaxshilanishda davom etmoqda, ko'pincha odamlar hatto yillar davomida qobiliyatsiz bo'lganidan keyin ham o'zlarining normal hayotlarini tiklaydilar.[6]

Sekin olib chiqish darajasi uzoq muddatli yoki og'ir tortib olish holati xavfini sezilarli darajada kamaytiradi. Uzoq muddatli olib tashlash alomatlari yaxshi kunlar va yomon kunlar bilan belgilanishi mumkin. Uzoq muddatli tortishish paytida alomatlar vaqti-vaqti bilan ko'payganda, fiziologik o'zgarishlar, shu jumladan bo'lishi mumkin kengaygan o'quvchilar shuningdek qon bosimi va yurak urish tezligining oshishi.[23] Semptomlarning o'zgarishi tolerantlikni qaytarish jarayonida GABA uchun retseptorlari sezgirligining o'zgarishi tufayli taklif qilingan.[6] A meta-tahlil benzodiazepindan foydalanish tufayli ko'plab sohalarda kognitiv buzilishlar olti oylik bekor qilinganidan keyin yaxshilanishlarni ko'rsatdi, ammo aksariyat sohalarda sezilarli darajada buzilishlar doimiy bo'lishi mumkin yoki ularni qaytarish uchun olti oydan ko'proq vaqt talab qilinishi mumkin.[149]

Uzoq muddatli alomatlar ko'p oylar yoki bir necha yil davomida susayib boraveradi. Uzoq muddatli benzodiazepinni olib tashlash sindromi uchun vaqtdan tashqari ma'lum davo yo'q,[18] ammo, flumazenil preparati 4-26 hafta davomida benzodiazepinlardan xoli bo'lgan bemorlarda dushmanlik va tajovuzkorlik tuyg'ularini kamaytirishda platsebodan ko'ra samaraliroq ekanligi aniqlandi.[115] Bu flumazenilning benzodiazepinning uzaygan semptomlarini davolashda rolini taklif qilishi mumkin.

Epidemiologiya

Chiqib ketish sindromining og'irligi va davomiyligi turli xil omillar, jumladan, torayish tezligi, foydalanish muddati va dozalari hajmi va mumkin bo'lgan genetik omillar bilan belgilanadi.[6][150] Oldingi benzodiazepinlardan voz kechish tarixiga ega bo'lganlar a sezgir yoki yondi markaziy asab tizimi kognitiv va simptomatologiyaning yomonlashishiga olib keladi va har bir keyingi tortishish davrini yomonlashtiradi.[86][87][88][151]

Maxsus populyatsiyalar

Pediatriya

Onadan benzodiazepinlarni qabul qilganida, ba'zida og'ir bo'lgan neonatal tortishish sindromi paydo bo'lishi mumkin, ayniqsa uchinchi trimestr. Alomatlar kiradi gipotoniya, apnoe afsunlar, siyanoz, nogiron metabolik sovuq stressga javoblar va soqchilik. Neonatal benzodiazepinni olib tashlash sindromi tug'ilgandan keyin bir necha oydan keyin davom etishi haqida xabar berilgan.[152]

Chiqib ketish sindromi taxminan 20% da kuzatiladi pediatrik intensiv terapiya bo'limi bolalari benzodiazepinlar yoki opioidlar bilan infuziya qilinganidan keyin.[153] Sindromga ega bo'lish ehtimoli infuziyaning umumiy davomiyligi va dozasi bilan bog'liq, ammo davomiyligi muhimroq deb hisoblanmoqda.[154] Chiqib ketishni davolash odatda infuziya bir haftadan ko'proq davom etgan bo'lsa, 3- dan 21 kungacha bo'lgan davrda sutdan ajratishni o'z ichiga oladi.[155] Semptomlar orasida titroq, qo'zg'alish, uyqusizlik, aql bovar qilmaydigan yig'lash, diareya va terlash mavjud. Hammasi bo'lib, ellikdan ortiq pulni olib tashlash alomatlari ushbu sharh maqolasida keltirilgan.[153][156] Kuchli abstinentsiya sindromi bo'lgan yangi tug'ilgan chaqaloqlarning alomatlarini yumshatishga qaratilgan atrof-muhit choralari juda oz ta'sir ko'rsatdi, ammo engil holatlarda tinch uyqu muhitini ta'minlash yordam berdi.[153]

Homiladorlik

Xavotirlari tufayli benzodiazepinlarni yoki antidepressantlarni to'satdan to'xtatish teratogen dorilarning ta'siri jiddiy asoratlarni keltirib chiqarish xavfi yuqori, shuning uchun tavsiya etilmaydi. Masalan, benzodiazepinlarni yoki antidepressantlarni keskin chiqarib yuborish ekstremal alomatlarni keltirib chiqarish xavfi yuqori, shu jumladan o'z joniga qasd qilish g'oyasi va agar mavjud bo'lsa, asosiy buzilishning qaytishi. Bu kasalxonaga yotqizilishiga va potentsial ravishda o'z joniga qasd qilishga olib kelishi mumkin. Bir tadqiqotga ko'ra, o'z dori-darmonlarini to'satdan to'xtatgan yoki juda tez toraytirgan onalarning uchdan bir qismi «chidab bo'lmas alomatlar» tufayli o'z joniga qasd qilishgan. Bitta ayolda tibbiy abort, endi u dosh berolmasligini sezganligi sababli va yana bir ayol benzodiazepinlardan ajralish alomatlari bilan kurashish uchun spirtli ichimliklarni ishlatgan. O'z-o'zidan abort qilish shuningdek, psixotrop dori-darmonlarni, shu jumladan benzodiazepinlarni keskin olib tashlash natijasida paydo bo'lishi mumkin. Tadqiqot natijalariga ko'ra, shifokorlar odatda to'satdan og'ir oqibatlarga olib kelishini bilishmaydi chekinish ning psixotrop benzodiazepinlar yoki antidepressantlar kabi dorilar.[75]

Qariyalar

Benzodiazepinga qaram bo'lgan keksa yoshdagi odamlarni olib tashlashni o'rganish juda kam asoratlar bilan amalga oshirilishi mumkin va uxlash va bilim qobiliyatlarini yaxshilashga olib kelishi mumkin. Muvaffaqiyatli ishdan bo'shatilgandan 52 hafta o'tgach, kognitiv holatning 22% yaxshilanishi va ijtimoiy faoliyat yaxshilanganligi aniqlandi. Benzodiazepinlarda qolganlar kognitiv qobiliyatlarning 5% pasayishiga duch kelishdi, bu odatdagi qarishda kuzatilganidan tezroq bo'lib tuyuldi, demak benzodiazepinlarni qabul qilish qancha ko'p bo'lsa, bilish effektlari shunchalik yomonlashadi. Semptomlarning ba'zi bir yomonlashishi benzodiazepinni iste'mol qilishni to'xtatishning birinchi oylarida kuzatilgan, ammo 24 haftalik kuzatuvda benzodiazepinlarda qolganlarga nisbatan keksa yoshdagi odamlar aniq yaxshilandi. 24 va 52 haftalik kuzatuvlarda uyquning yaxshilanishi kuzatildi. Mualliflarning fikriga ko'ra, benzodiazepinlar uzoq vaqt davomida uyqudagi muammolar uchun samarali emas edi, faqat olib tashlash bilan bog'liq bo'lganlarni bostirishdan tashqari uyqusizlikni tiklash. Ishdan bo'shatilgandan keyin 24 va 52 xafta orasida yaxshilanishlar ko'plab omillar, jumladan, uyquni yaxshilash va bir nechta bilim va ishlash qobiliyatlarini yaxshilagan. Benzodiazepinlarga sezgir bo'lgan ba'zi bilim qobiliyatlari, shuningdek yoshi, masalan epizodik xotira yaxshilanmadi. Biroq, mualliflar, 3,5 yillik kuzatuvida hech qanday xotira buzilishini ko'rsatmagan va ba'zi xotira funktsiyalari surunkali benzodiazepinni qayta tiklashdan uzoqroq vaqt talab qilishi va keksa odamlarning kognitiv funktsiyalarini yanada takomillashtirish 52 haftadan keyin sodir bo'lishi mumkinligi haqida taxmin qilgan yosh bemorlarda o'tkazilgan tadqiqotni keltirdilar. chekinish. Benzodiazepindan foydalanishni to'xtatgandan so'ng yaxshilanishlarni ko'rish uchun 24 hafta davom etganining sababi, miyaning benzodiazepinsiz muhitga moslashishi uchun zarur bo'lgan vaqt bilan bog'liq edi.[157]

24-haftada sezilarli yaxshilanishlar aniqlandi, shu jumladan ma'lumotni qayta ishlash aniqligi yaxshilandi, ammo benzodiazepinlarda qolganlarda pasayish kuzatildi. 52 haftalik kuzatuvda keyingi yaxshilanishlar qayd etildi, bu benzodiazepinning abstinentsiyasi bilan davom etayotgan yaxshilanishlarni ko'rsatmoqda. Benzodiazepinlar bilan shug'ullanadigan yoshroq odamlar vizual fazoviy xotirada kognitiv yomonlashuvni boshdan kechirmoqdalar, ammo kognitiv ta'sirga qariyalar kabi zaif emaslar.[157] Benzodiazepinlardan xoli keksa bemorlarda reaktsiyaning yaxshilangan vaqtlari 52 xaftada qayd etildi. Bu keksa yoshdagi odamlarda, ayniqsa benzodiazepin iste'molchilarida yo'l-transport hodisalari xavfi ortishi sababli avtomashinani boshqarishda muhim ahamiyatga ega.[157] 24 haftalik kuzatuvda odamlarning 80% benzodiazepinlardan muvaffaqiyatli chiqib ketishdi. Muvaffaqiyatning bir qismi platsebo buzilgan sud jarayoni uchun ishlatiladigan usul psixologik qaramlik keksa bemorlar bir necha hafta oldin asta-sekin kamayishini tugatganligini va faqat platsebo tabletkalarini iste'mol qilishganini anglaganlarida, benzodiazepinlarda. Bu ularni tabletkasiz uxlashlariga ishontirishga yordam berdi.[157]

Mualliflar, shuningdek, farmakologiyaning o'xshashligi va yangisini ta'sir qilish mexanizmi haqida ogohlantirdilar benzodiazepin Z dorilar.[157]

The yarim umrni yo'q qilish diazepam va xlordiazepoksid, shuningdek boshqa yarim umr ko'rish benzodiazepinlari yoshi kattalarga qaraganda qariyalarda ikki baravar ko'p. Ko'pgina shifokorlar benzodiazepin dozasini keksa bemorlarda yoshga qarab sozlamaydilar.[158]

Shuningdek qarang

Adabiyotlar

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