JOURNAL READING

Effect of Opioid-Free Anaesthesia on Perioperative

Period: A Review

Pembimbing:
Dr. M. F. Susanti Handayani, Sp. An

Disusun Oleh :
Adeta Yuniza Mulia
2015730002

KEPANITERAAN KLINIK

STASE ILMU ANESTESI

RUMAH SAKIT UMUM DAERAH CIANJUR

FAKULTAS KEDOKTERAN DAN KESEHATAN

UNIVERSITAS MUHAMMADIYAH JAKARTA

2020

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 Pengaruh Anestesi Bebas Opioid pada Periode Perioperatif: Ulasan

ABSTRAK
Pendahuluan: Anestesi seimbang bergantung pada administrasi opioid pada
periode perioperatif sebagai antinociceptive agen. Tidak ada bukti jelas yang
intraoperatif opioid menghasilkan pengurangan skor nyeri pasca operasi. Anestesi
bebas opioid (OFA), kombinasi berbagai opioid- teknik hemat yang mengarah ke
tidak ada administrasi opioid sistemik, neuraxial atau intracavitary intraoperatif,
muncul dari upaya untuk mengembangkan teknik anti-hyperalgesic untuk
meningkatkan kontrol nyeri pasca operasi. Oleh karena itu, Tujuan dari tinjauan
ini adalah untuk memahami sampai sejauh mana opioid gratis bermanfaat pada
periode perioperatif, lebih khusus dampak analgesik dari teknik ini.
Metode: Basis data elektronik Medline dan PubMed digeledah hingga November
2019. Kami menyertakan meta- analisis, uji coba terkontrol secara acak dan
prospektif Studi menyelidiki hasil rasa sakit membandingkan semua jenis anestesi
umum opioid intra-operatif dengan bebas opioid anestesi umum. Hasil utama
adalah ukuran pertama skor nyeri saat istirahat dan pada 24 jam pasca operasi.
Hasil sekunder termasuk analgesia penyelamatan, intravena (yaitu) setara dengan
konsumsi morfin pada 24 jam pasca operasi, tingkat mual dan muntah pasca
operasi (PONV) dalam 24 jam pertama pasca operasi, tarif menyelamatkan obat
antiemetik, lama tinggal di pasca anestesi unit perawatan (PACU) dan total lama
tinggal di rumah sakit. Sebelas studi diidentifikasi, tiga di antaranya adalah meta-
analisis.
Hasil: Skor nyeri rata-rata saat istirahat dalam ukuran pertama sebagai serta pada
24 jam pasca operasi lebih rendah pada opioid kelompok anestesi gratis (OFA)
daripada anestesi berbasis opioid (OBA). Penggunaan analgesia pasca operasi
penyelamatan dan i.v. setara konsumsi morfin lebih rendah di kelompok OFA.
Tren signifikan secara statistik terhadap a penurunan PONV dan penggunaan obat
antiemetik di antara pasien yang tidak menerima opioid diamati. Lama tinggal
PACU lebih lama dalam kelompok bebas opioid, tetapi hanya tiga dari enam
percobaan yang melaporkan signifikan secara statistik perbedaan. Akhirnya, total
lama tinggal di rumah sakit adalah diselidiki oleh dua percobaan dan serupa antara
kelompok.

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Kesimpulan: OFA, jika dibandingkan dengan OBA, tidak menyajikan hasil yang
lebih rendah mengenai skor nyeri atau konsumsi opioid dalam periode pasca
operasi. Itu juga terkait dengan mual dan muntah pasca operasi berkurang. OFA
Teknik menyajikan tantangan masa depan sebagai dokumentasi obyektif manfaat
jangka pendek dan jangka panjang dan ketidaknyamanan. Penelitian lebih lanjut
dengan metodologi yang kuat uji coba dengan ukuran sampel besar diperlukan
untuk menentukan dengan lebih baik kemanjuran dan keamanan anestesi bebas
opioid strategi.
PENDAHULUAN
Definisi anestesi umum adalah istilah cairan, telah memiliki beberapa definisi.
Anestesi umum adalah awalnya dianggap sebagai empat "A": Analgesia, amnesia,
akinesia (imobilitas) dan kontrol otonom [1]. Konsep ini berkembang menjadi
definisi Umum anestesi sebagai keadaan tidak sadar yang reversibel, imobilitas,
antinociception dan kontrol otonom sistem saraf (ANS), dalam hemodinamik
yang terkontrol stabilitas fisiologis [2]. Hasil penting lainnya yang hanya dapat
dinilai secara retrospektif adalah amnesia, yang diasumsikan ketika pasien tidak
sadar. ini Saat ini percaya bahwa ketika empat hasil lainnya locorementioned di
atas tercapai, kesadaran dengan ingatan jarang terjadi [3,4]. Anestesi seimbang,
strategi yang paling umum digunakan dalam beberapa dekade terakhir, sebagian
besar bergantung pada GABA-A reseptor dan reseptor mu-opioid [3]. Jadi
sekarang latihan didasarkan pada hipnotis untuk induksi dan pada inhalasi eter
atau hipnotis untuk pemeliharaan ketidaksadaran. Relaksan otot diberikan untuk
menghasilkan imobilitas dan opioid adalah yang paling umum digunakan obat
untuk mengelola nosisepsi intraoperatif dan nyeri pasca operasi [2,3]. Opioid dulu
ideal obat untuk memblokir reaksi sistem saraf otonom dan memungkinkan
stabilitas hemodinamik [2,5]. Nociception terkait erat dengan kontrol otonom
sistem saraf sejak gangguan nosiseptif sumber utama ketidakstabilan
hemodinamik, serta, sindrom nyeri kronis pasca operasi [6]. Tingkat
antinociception yang memadai telah tercapai ketika diterapkan rangsangan bedah,
respons klinis seperti peningkatan detak jantung dan tekanan darah tidak lagi
terjadi [2,3,5]. Meskipun demikian, menurut a uji klinis baru-baru ini, meskipun
tidak ada respon klinis, aktivasi nociceptive berlangsung selama jenderal yang

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dalam anestesi. Karena itu, tidak ada respons klinis bukan indikasi aktivasi
spesifik nosisepsi yang tidak ada [7]. Tidak diragukan lagi, opioid adalah
antinosiseptif yang efektif agen dan salah satu dari tiga pilar anestesi seimbang
adalah pemberian opioid pada perioperatif periode [3,8]. Pendekatan pemberian
opioid sebelum operasi telah digunakan sebagai strategi untuk mengurangi pasca
operasi rasa sakit. Namun, meta-analisis terbaru dari 20 acak uji coba terkontrol
menyimpulkan bahwa tidak ada bukti yang jelas bahwa opioid pencegahan
menghasilkan pengurangan dalam skor nyeri [9]. Diketahui pula bahwa
perioperatif pemberian opioid merupakan predisposisi persisten penggunaan
opioid [10]. Meta-analisis 2014 yang mengevaluasi konsekuensi klinis dosis
opioid intraoperatif, terungkap bahwa opioid dosis tinggi selama operasi
berhubungan dengan meningkatnya persepsi nyeri dan meningkat persyaratan
opioid pasca operasi [11]. Ini dapat dijelaskan oleh dua fenomena terkait:
Toleransi opioid dan hiperalgesia yang diinduksi opioid [12,13]. Toleransi adalah
efek farmakologis yang mengarah untuk kurangnya tanggapan progresif terhadap
administrasi opioid itu bisa diatasi dengan menambah dosis. Hiperalgesia yang
diinduksi opioid adalah proses sensitisasi di mana opioid, secara paradoks,
menyebabkan peningkatan rasa sakit sensitivitas (Opioid Paradox) [8,12].
Neuroadaptation ini proses menyebabkan menyoroti rasa sakit yang ada dan
pemberdayaan pengembangan nyeri kronis [12,13]. Apa saja opioid mampu
berpotensi menginduksi hiperalgesia, terutama opioid kerja pendek [14].
Meskipun opioid adalah antinosiseptif yang paling efektif obat, mereka memiliki
efek samping yang tidak diinginkan, seperti depresi pernapasan, kelemahan otot
faring, mual dan muntah pasca operasi, retensi urin, sembelit, ileum, pruritus,
toleransi dan hiperalgesia yang dapat berkembang menjadi sindrom nyeri kronis
[8,13,15]. Mual dan muntah terutama bertanggung jawab atas keterlambatan
pemulihan pasien, pasien tinggal lama dalam pemulihan area dan, oleh karena itu,
keterlambatan keluarnya rumah sakit. Diketahui juga bahwa opioid merusak pola
tidur dan dapat menyebabkan delirium pasca operasi [16]. Juga pasien menerima
opioid sebagai bagian dari anestesi umum dan meninggalkan rumah sakit dengan
resep opioid, muncul memiliki peningkatan risiko ketergantungan opioid [17]
Karena itu, masih bisa diperdebatkan apakah perioperatif administrasi opioid

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sesuai atau perlu saat ini praktik klinis [18]. Karena kekhawatiran yang timbul
dari penggunaan berlebihan opioid dan efek sampingnya, memiliki strategi baru
muncul untuk mencapai anestesi umum yang seimbang. Itu konsep anestesi
seimbang telah diperluas di Indonesia Untuk memasukkan lebih banyak obat yang
menargetkan neurofisiologis yang berbeda mekanisme [2,3]. Diketahui bahwa
kapan obat anestesi dengan mekanisme yang berbeda digabungkan, mereka
menghasilkan interaksi sinergis, makna yang memaksimalkan penggunaan obat
yang berbeda dengan dosis yang lebih kecil efek yang diinginkan sambil
meminimalkan efek samping. Fenomena ini dikenal sebagai anestesi umum
Multimodal dan telah memungkinkan pengurangan dosis opioid yang digunakan
[3,19]. Selain itu, pendekatan multimodal berpotensi mengurangi neuroadaptation
sentral menjadi opioid [17]. Khawatir tentang efek samping opioid yang
signifikan, strategi untuk anestesi umum seimbang sekarang digunakan agen
antinociceptive berbeda yang menargetkan pusat sistem saraf, seperti
dexmedetomidine [20], dan target kurang spesifik, seperti lidocaine [21], untuk
mengelola komponen anestesi nosiseptif [2]. Ajuvan nonopioid seperti NSAID,
beta-blocker, Antagonis NMDA (ketamin), alpha2-agonists, lidocaine,
gabapentin, dll. dapat mengurangi kebutuhan opioid untuk mencapai antinosisepsi
intraoperatif yang adekuat atau analgesia pasca operasi [8,13]. Namun, kita harus
ingat bahwa mereka harus dipilih berdasarkan pada pasien dan prosedur
farmakologisnya profil paling cocok [22]. Sebagian besar dari obat-obatan ini
dapat mengurangi penggunaan opioid intraoperatif dengan biaya sedasi yang lebih
lama [8]. Karena alasan baru yang ditambahkan setiap tahun untuk pengurangan
penggunaan opioid yang terkait dengan memperluas konsep anestesi multimoda
umum, sebuah konsep baru telah muncul: Bebas opioid anestesi. Anestesi bebas
opioid (OFA) dapat dilakukan didefinisikan sebagai kombinasi dari berbagai
opioid-sparing teknik yang mengarah ke tidak ada administrasi intraoperatif
opioid sistemik, neuraxial, atau intrakaviter [8,14,15]. OFA juga dapat dilakukan
dengan analgesia lokoregional untuk kontrol nyeri yang lebih baik, tetapi tidak
wajib [14]. Strategi ini membantu mengurangi kejadian efek samping dan suku
cadang yang diinduksi opioid opioid sebagai analgesik untuk periode pasca
operasi [16] Ada populasi tertentu yang mendapat manfaat dari penggunaan OFA,

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yaitu pada kecanduan opioid, nyeri kronis sindrom, obesitas, apnea tidur
obstruktif, kanker operasi dan kolorektal ERAS (Gambar 1) [8,13-15]. Meskipun
pemberian opioid perioperatif adalah a praktek umum dan lama, itu dipertanyakan
apakah masih diperlukan dalam praktik saat ini. Karena itu, Tujuan ulasan ini
adalah untuk memahami yang mana memperpanjang opioid gratis bermanfaat
pada periode perioperatif, lebih khusus dampak analgesik bebas opioid anestesi.
Metode
Pencarian untuk ulasan ini dilakukan di PubMed dan Medline hingga 30
November 2019 menggunakan permintaan: (“bebas opioid” [Semua Bidang]
DAN ((((“anestesi” [ Semua Bidang] ATAU "anestesi" [Ketentuan MeSH])
ATAU "anestesi" [ Semua Bidang]) ATAU "anestesi" [Semua Bidang]) ATAU
“Anestesi” [Semua Bidang])) ATAU ((“bebas opioid” [Semua Bidang] ATAU
"non-opioid" [Semua Bidang]) ATAU ("intra-operasi" [Semua Bidang] DAN
((((("analgesik opioid" [Farmakologis Aksi] ATAU "analgesik, opioid"
[Ketentuan MeSH]) ATAU ("analgesik" [ Semua Bidang] DAN “opioid” [Semua
Bidang])) ATAU “opioid analgesik ”[Semua Bidang]) ATAU“ opioid ”[Semua
Bidang]) ATAU“ opioid ”[ Semua Bidang]) ATAU "opioid" [Semua Bidang])))
DAN (((("anestesi" [ Semua Bidang] ATAU "anestesi" [Ketentuan MeSH])
ATAU "Anestesi" [Semua Bidang]) ATAU "anestesi" [Semua Bidang]) ATAU
"anestesi" [Semua Bidang])). Akhirnya, Google Cendekia juga digunakan untuk
mengidentifikasi studi yang relevan yang belum diidentifikasi menggunakan
strategi yang dijelaskan di atas. Hasil dari strategi pencarian ini terbatas pada
meta-analisis, uji coba terkontrol secara acak, prospektif studi dan manusia, yang
ditulis dalam bahasa Inggris atau Portugis. Analisis hanya fokus pada artikel yang
diterbitkan di 5 tahun terakhir (dari 30.11.2014 hingga 30.11.2019). Artikel dalam
bahasa lain, tinjauan sistematis atau literatur, studi retrospektif, laporan kasus,
artikel pendapat pribadi dan surat kepada editor dikeluarkan. Judul dan abstrak
diputar di tahap pertama berdasarkan kriteria inklusi dan eksklusi. Hanya cobaan
itu termasuk pasien dengan anestesi umum dan diselidiki hasil nyeri
membandingkan semua jenis intra-operatif pemberian opioid tanpa opioid
dimasukkan dalam ulasan ini. Kriteria kelayakan hanya diterapkan pada studi
primer.

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Hasil utama yang akan dievaluasi adalah yang pertama ukuran skor nyeri saat
istirahat dan 24 post operasi jam. Hasil sekunder gembira dengan nyeri akut
termasuk butuhkan untuk penyelamatan analgesia dan intravena (yaitu) ekuivalen
konsumsi morfin pada 24 jam pasca operasi. Hasil sekunder lain yang dicari
adalah tingkat mual dan muntah pasca operasi (PONV) dalam 24 jam pertama
pasca operasi, tingkat obat antiemetik, dan hasil terkait sumber daya rumah sakit
termasuk panjang tinggal di unit perawatan pasca-anestesi (PACU) dan total lama
tinggal di rumah sakit. Karakteristik percobaan yang diekstraksi meliputi:
Prosedur bedah, rejimen opioid intra-operatif, obat yang digunakan untuk
perawatan anestesi dan jenis pasca operasi analgesia. Secara singkat, Risiko Bias
dari Cochrane Collaboration Alat untuk uji coba terkontrol secara acak digunakan
untuk menilai kualitas metodologi masing-masing secara acak percobaan [23].
Tidak ada upaya untuk menghubungi penulis klarifikasi tentang item Risiko Bias.
Hasil selektif pelaporan dinilai berdasarkan hasil yang diuraikan di bagian Metode
tetapi tidak dilaporkan dalam Hasil bagian. Jika dalam studi apa pun data
ditemukan tidak lengkap, upaya dilakukan untuk menghubungi penulis yang
sesuai via email untuk data yang relevan. Dalam sebuah penelitian, rasa sakit skor
disajikan dalam format grafis [24]. Karena itu, perangkat lunak online
(https://apps.automeris.io/ wpd /) digunakan untuk mengekstrak poin data. Hasil
dilaporkan sebagai tabel dan hasil yang relevan untuk setiap studi dirangkum.
Semua opioid dulu dikonversi menjadi dosis equianalgesic dari i.v. morfin untuk
analisis (mis. morfin 10 mg = morfin oral 30 mg = i.v. pethidine 75 mg = i.v.
piritramide 7,5 mg) [25,26]. Skor nyeri dilaporkan sebagai penilaian visual, verbal
atau numerik skala diubah menjadi analog 0-10 standar skala untuk evaluasi
kuantitatif. Efektivitas komparatif dilaporkan sebagai proporsi pasien dengan hasil
atau sebagai skor rata-rata. Nilai p <0,05 dianggap signifikan.
Hasil
Dari 1.415 studi yang diidentifikasi oleh literatur kami pencarian, 11 memenuhi
kriteria inklusi, mewakili total 3483 pasien (2975 dari meta-analisis dan 508 dari
uji coba) [24,27-36]. Diagram alir mengikuti PRISMA pedoman menunjukkan
proses pencarian dan pemilihan literatur (Gambar 2). Menurut penilaian kami
mengikuti Cochrane Alat Kolaborasi Risiko Bias (Gambar 3), mayoritas uji coba

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memiliki risiko bias yang tidak jelas. Upaya dilakukan untuk hubungi tiga penulis
[24,34,35], tetapi tidak ada yang menyediakan data tambahan yang diminta.
Karakteristik penelitian termasuk dalam hal ini Studi ditunjukkan pada Tabel 1.
Semua studi utama termasuk total pasien mulai dari 40 hingga 80. Mengenai jenis
operasi, tiga uji coba dimasukkan pasien dijadwalkan untuk kolesistektomi
laparoskopi [24,27,35], dua untuk operasi bariatrik [33,36] dan empat untuk
berbagai jenis operasi elektif [28,31,32,34]. Dua studi termasuk semua jenis
ransum operasi opeasi [29,30].
Tiga percobaan menyelidiki remifentanil sebagai intra-operatif rejimen opioid
[28,31,32], dua fentanyl yang dieksplorasi [24,35], satu sufentanil [33]; dua
percobaan membandingkan fentanyl dan remifentanil ke grup kontrol [27,34].
Semua termasuk uji coba diberikan anestesi volatil untuk mempertahankan
anestesi kecuali dua yang diberikan propofol [27,34].
Skor Nyeri
Tabel 2 menunjukkan hasil primer dan sekunder minat pada semua studi
termasuk. Dalam tiga penelitian, pasien melaporkan nyeri menggunakan skor
skala analog visual (VAS) [24,28,33], dua penelitian menggunakan skor nilai
numerik (NRS) untuk mengukur rasa sakit [27,31]. Keduanya sistem penilaian
berkisar antara 0 hingga 10. Tiga meta analisis yang digunakan a skala analog 0-
10 standar [29,30,36]. Dalam dua penelitian, ukuran pertama skor nyeri saat
istirahat tidak dilaporkan [34,35]. Lima studi juga tidak melaporkan skor nyeri
pada 24 jam pasca operasi [27,32,34-36]. Selanjutnya, Elsaye, dkk. [24]
menunjukkan skor nyeri pada bentuk grafik saja. Dengan demikian, jumlahnya
diekstrapolasi untuk penelitian ini sebagai penulis tidak merespon. Skor nyeri
rata-rata saat istirahat di langkah pertama adalah secara statistik lebih rendah (p
<0,05) dalam anestesi bebas opioid (OFA) daripada di anestesi berbasis opioid
(OBA) di enam studi [24,27,30,31,33,36] dan skor nyeri rata-rata pada 24 jam
pasca operasi juga secara statistik lebih rendah dalam lima studi [24,27,30,31,33].
Persyaratan Analgesia
Penggunaan analgesia pasca operasi tambahan adalah dilaporkan lebih rendah
pada kelompok OFA dalam lima artikel, tetapi hanya dua dari mereka yang
melaporkan perbedaan yang signifikan secara statistik dalam jumlah pasien yang

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membutuhkan pertolongan analgesia [24,27]. Empat percobaan menemukan
persyaratan yang jauh lebih rendah setara dengan konsumsi morfin yang setara
dengan intravena pada 24 jam pasca operasi dalam kelompok bebas opioid
[30,31,33,36].
Mual dan Muntah Pasca Operasi (PONV)
Insiden PONV dilaporkan pada semua kecuali satu belajar [31]. Delapan dari
sepuluh studi yang membandingkan kejadian PONV dalam kelompok opioid
versus non-opioid mengamati tren signifikan secara statistik menuju penurunan di
PONV di antara pasien yang tidak menerima opioid [24,28-30,33-36].
Penggunaan obat antiemetik secara signifikan lebih rendah pada kelompok bebas
opioid di empat dari lima penelitian [27,28,34,35].
Lama tinggal
Dalam semua penelitian, lama tinggal di post-anestesi unit perawatan (PACU)
lebih lama dalam kelompok bebas opioid, tetapi hanya tiga dari enam percobaan
yang melaporkan signifikan secara statistik perbedaan [27,28,30]. Akhirnya, total
lama menginap di rumah sakit diselidiki oleh dua percobaan dan serupa antara
kelompok [33,35].
Diskusi
Ulasan ini menyelidiki efek bebas opioid anestesi, dibandingkan dengan anestesi
berbasis opioid pada nyeri pasca operasi, tingkat mual pasca operasi dan muntah
serta lama tinggal di PACU dan total lama tinggal di rumah sakit. Salah satu dari
tiga pilar anestesi seimbang adalah administrasi opioid pada periode perioperatif
sebagai agen antinociceptive [3,8]. Namun, pasca operasi rasa sakit tetap menjadi
masalah nyata dan ada tidak ada bukti jelas bahwa opioid intraoperatif
menghasilkan pengurangan skor nyeri [9]. Memang, pusat gugup sensitisasi
sistem dapat disebabkan oleh nosiseptif Menanggapi trauma bedah yang
mengakibatkan pasca operasi hyperalgesia [8,14]. Karena itu, orang akan
melakukannya mengatakan bahwa memblokir respons nosisepsi dengan
intraoperatif opioid, bisa jadi solusi untuk mencegahnya sakit parah pasca operasi
[14]. Namun, manajemen nyeri pasca operasi adalah a sistem yang lebih
kompleks. Sebuah meta-analisis 2014 itu mengevaluasi konsekuensi klinis
intraoperatif dosis opioid mengungkapkan bahwa opioid dosis tinggi selama

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operasi dikaitkan dengan peningkatan persepsi rasa sakit dan peningkatan opioid
pasca operasi persyaratan [11]. Hiperalgesia yang diinduksi opioid, juga disebut
Opioid Paradox, adalah proses sensitisasi dimana opioid, secara paradoksal,
menyebabkan peningkatan sensitivitas nyeri [8,11,12]. Proses neuroadaptasi ini
menyebabkan penyorotan nyeri yang ada dan pemberdayaan nyeri kronis
pengembangan [12,13]. Semua opioid berpotensi hiperalgesia yang diinduksi,
terutama dengan aksi pendek opioid seperti remifentanil. Selanjutnya proses ini
tergantung dosis, dan relevansi klinisnya paling jelas dalam prosedur yang sangat
menyakitkan [14,37]. Anestesi bebas opioid timbul dari upaya ini untuk
mengembangkan teknik anti-hiperalgesik untuk meningkatkan kontrol nyeri pasca
operasi. Teknik ini didasarkan pada dua prinsip: Pertama, opioid menyebabkan
sensitisasi saraf pusat sistem dan karenanya penggunaannya harus diminimalkan;
kedua, ada obat lain dengan mekanisme berbeda aksi yang juga memiliki
kekuatan analgesik yang baik [8,14,5,38]. Maka, dengan menggabungkan
berbagai obat itu bertindak pada reseptor yang berbeda, efek analgesiknya adalah
ditingkatkan yang mengarah ke pengurangan penggunaan opioid. Ini Strategi
membantu mengurangi kejadian opioid yang diinduksi efek samping, mengurangi
kejadian opioid- diinduksi hiperalgesia dan menyuntikkan opioid sebagai
analgesik untuk periode pasca operasi [5,8,14,38]. Sebuah meta-analisis yang
relevan oleh Frauenknecht, et al. mengevaluasi penggunaan opioid intra-operatif
dengan kontrolnya adalah tanpa opioid (saline normal) [29]. Meskipun kelompok
kontrol tanpa opioid dapat dipanggil OFA, penting untuk memperjelas teknik
OFA itu didasarkan pada penggabungan berbagai non-opioid teknik sebagai
bagian dari rencana analgesia multi-modal. Namun demikian, Frauenknecht, et al.
meta-analisis menunjukkan bahwa tidak ada perbedaan yang signifikan antara
skor nyeri pasca operasi dan morfin konsumsi anestesi inklusif-opioid kelompok
dibandingkan dengan kelompok yang diberi saline normal. Dengan kata lain,
penelitian ini menunjukkan bahwa opioid- anestesi berdasarkan tidak menawarkan
keuntungan yang signifikan untuk hasil nyeri pasca operasi [29]. Uji coba yang
termasuk dalam ulasan ini mengungkapkan rasa sakit itu skor saat istirahat dalam
ukuran pasca operasi pertama juga pada 24 jam pasca operasi lebih rendah pada
opioid kelompok anestesi gratis bila dibandingkan dengan opioid kelompok. Juga,

 Page 10 of 11 
anestesi bebas opioid bila dibandingkan dengan anestesi berbasis opioid dikaitkan
dengan lebih rendah i.v. persyaratan setara morfin dalam 24 pasca operasi jam dan
permintaan analgesia penyelamatan yang lebih rendah. Grape, dkk. meta-analisis
menunjukkan bahwa dexmedetomidine anestesi bebas opioid lebih unggul
anestesi berbasis opioid remifentanil dengan perbaikan hasil nyeri dalam periode
segera pasca operasi dan hingga 24 jam pasca operasi, serta, persyaratan yang
lebih rendah dari i.v. ekuivalen morfin [30]. Clonidine, juga alfa-2-agonis,
digunakan dalam satu percobaan yang dilaporkan skor nyeri yang secara statistik
lebih rendah pada pasca operasi segera periode dan 24 jam pasca operasi di OFA
grup [31]. Singh, et al. meta-analisis mengenai pasien yang menjalani
pembedahan bariatric menyimpulkan bahwa pasien yang menerima
dexmedetomidine membutuhkan opioid 33% lebih sedikit 24 jam pertama setelah
operasi dibandingkan dengan kontrol [36] Efek analgesik yang berkepanjangan
dari dexmedetomidine mungkin jelaskan temuan ini. Dexmedetomidine sangat
selektif alfa-2-agonis yang memiliki ansiolitik, simpatolitik, dan sifat analgesik.
Telah digunakan sebagai opioid pengganti dalam berbagai intervensi bedah karena
telah telah terbukti menurunkan skor nyeri pasca operasi, opioid konsumsi, dan
risiko merugikan terkait opioid acara [39,40]. Pengurangan rasa sakit pasca
operasi oleh dexmedetomidine dapat dijelaskan dengan aktivasi alfa-2-
adranoreceptores yang menghambat pelepasan zat P dari tanduk punggung, yang
mengarah ke pengurangan nosiseptif input [28,40]. Selain hasil utama kami,
anestesi bebas opioid dikaitkan dengan pengurangan pasca operasi mual dan
muntah. Juga, penggunaan penyelamatan antiemetik obat secara signifikan lebih
rendah pada bebas opioid grup [27,28,34,35]. Demikian juga tiga meta-analisis
termasuk dalam ulasan ini juga dilaporkan jauh lebih rendah kejadian PONV
dalam 24 jam pasca operasi [29,30,36].
Tidak hanya penggunaan opioid pasca operasi, tetapi juga intraoperatif
administrasi adalah faktor risiko untuk pasca operasi mual dan muntah [29].
Sementara PONV dianggap sebagai efek tidak menyenangkan tetapi melekat dari
jenderal berbasis opioid anestesi, pasien menilai muntah sebagai hasil utama harus
dihindari pada periode pasca operasi, ke depan nyeri pasca operasi [41]. PONV
bertanggung jawab atas sistem konsumsi sumber daya termasuk lama tinggal yang

 Page 11 of 11 
lama di kedua area pemulihan dan rumah sakit dan akhirnya, meningkat biaya
pelayanan kesehatan [29]. Faktor risiko yang memengaruhi kejadian mual dan
muntah bersifat multifaktorial dan termasuk jenis anestesi, jenis operasi dan
karakteristik pasien [42]. Oleh karena itu, suatu rejimen bebas opioid harus
dipertimbangkan, terutama pada pasien berisiko tinggi, di antara strategi untuk
mencegah PONV. Namun, beberapa uji coba tidak memberikan informasi tentang
profilaksis rutin terhadap PONV atau penyelamatan antiemetik obat-obatan
[24,31,33,36]. Tidak jelas apakah meningkat kejadian PONV pada kelompok
berbasis opioid dapat sepenuhnya dikaitkan dengan administrasi opioid versus
kurangnya profilaksis. Lama tinggal di unit perawatan pasca anestesi (PACU)
lebih lama dalam kelompok bebas opioid, tetapi hanya tiga studi menunjukkan
hasil yang signifikan secara statistik [27,28,30]. Total lama tinggal di rumah sakit
hanya diselidiki oleh dua uji coba dan serupa antara kelompok. Sultana, dkk.
mengklaim bahwa alpha-2-agonis sistemik jangan memperpanjang waktu
pemulihan [15]. Meskipun demikian, banyak uji coba melaporkan secara statistik
tinggal lebih lama di pasca anestesi unit perawatan dalam kelompok bebas opioid
[27,28,30]. Ini terkait dengan fakta bahwa dexmedetomidine memiliki panjang
waktu paruh (2-2,5 jam), dengan demikian terkait dengan pemulihan yang lambat
[27,37,39,40]. Ada batasan penting untuk ulasan ini. Pertama, ulasan kami
didasarkan pada sejumlah studi, sebagian besar memiliki bias bawaan. Kedua,
studi termasuk hadir heterogenitas yang besar. Karena itu, tidak mungkin
membentuk subkelompok mengenai rejimen opioid intraoperatif, obat
pemeliharaan dan jenis operasi untuk analisis lebih lanjut. Akhirnya, kita tidak
dapat menarik kesimpulan yang kuat tentang dampak anestesi bebas opioid pada
total panjang tinggal di rumah sakit. Karena itu, literatur yang ada akan mendapat
manfaat dari uji coba tambahan untuk lebih menentukan dampak dari setiap
strategi anestesi pada sistem kesehatan sumber daya.
Kesimpulan
Meskipun tren saat ini mendukung individual modalitas anestesi dan semakin
banyak penyedia mempraktikkan anestesi bebas opioid, ada yang mengherankan
sedikit data. Ada populasi khusus itu manfaat dari penggunaan OFA, yaitu
kecanduan opioid, sindrom nyeri kronis, pasien obesitas tidak sehat, obstruktif

 Page 12 of 11 
apnea tidur, operasi kanker dan perut operasi. Namun, kontraindikasi untuk
penggunaan OFA kurang jelas. Ada bukti bahwa anestesi bebas opioid, kapan
dibandingkan dengan anestesi berbasis opioid, tidak ada hasil yang lebih rendah
mengenai skor nyeri atau konsumsi opioid dalam periode pasca operasi. Itu juga
terkait dengan mual dan muntah pasca operasi berkurang. Namun, banyak obat
yang digunakan dalam teknik ini seperti ketamin dan gabapentin juga memiliki
kecanduan substansial potensial dan juga dapat menyebabkan kesulitan jangka
panjang [38]. Anestesi bebas opioid hadir sebagai masa depan menantang
dokumentasi obyektif dari keduanya manfaat dan ketidaknyamanan jangka
pendek dan jangka panjang menggunakan ukuran sampel besar dan
pengembangan yang memadai pemantauan nosisepsi intraoperatif. Di Untuk
mengklarifikasi beberapa pertanyaan, pasca operasi dan percobaan Anestesi Bebas
Opioid (POFA), prospektif Studi acak, satu-buta, multisenter sekarang sedang
berlangsung (NCT03316339), merekrut 400 pasien [43]. Hasilnya akan
memberikan informasi mengenai keamanan teknik anestesi bebas opioid.
Kesimpulannya, penelitian lebih lanjut dengan metodologi yang kuat uji coba
dengan ukuran sampel besar diperlukan untuk lebih baik menentukan kemanjuran
dan keamanan bebas opioid strategi anestesi.

 Page 13 of 11 
ISSN: 2377-4630

Basto and Machado. Int J Anesthetic

Anesthesiol 2020, 7:104
DOI: 10.23937/2377-4630/1410104
International Volum
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Anesthetics and Anesthesiology

Review ARTicle

Effect of Opioid-Free Anaesthesia on

Perioperative Period: A Review
Tatiana Basto1 and Humberto S Machado1,2,3*
1
Instituto Ciências Biomédicas Abel Salazar, University of Porto, Portugal
Check for
2
Serviço de Anestesiologia, Centro Hospitalar Universitário do Porto, Portugal updates
3
Center for Clinical Research in Anesthesiology, Centro Hospitalar Universitário do Porto,
Portugal

*Corresponding author: Humberto S Machado, MD, MSc, PhD, Serviço de Anestesiologia,

Centro Hospitalar Universitário do Porto, Largo Professor Abel Salazar, 4099-001 Porto,
Portugal, Tel: +351935848475
Abstract
Introduction: Balanced anaesthesia relies on the adminis-
tration of opioids in the perioperative period as antinocicep-
tive agents. There is no clear evidence that intraoperative
opioids result in reduction of postoperative pain scores.
Opioid-free anaesthesia (OFA), combination of various opi-
oids-sparing techniques leading to no administration of
intraoperative systemic, neuraxial or intracavitary opioids,
arises from the attempt to develop anti-hyperalgesic tech-
niques to improve postoperative pain control. Therefore, the
aim of this review is to understand to which extend is opioid
free beneficial in the perioperative period, more specifically
the analgesic impact of this technique.
Methods: The electronic databases Medline and PubMed
were searched until November 2019. We included me- ta-
analyses, randomized controlled trials and prospective
studies investigating pain outcomes comparing any type of
intra-operative opioid general anaesthesia with opioid-free
general anaesthesia. The primary outcome was first mea-
sure of pain score at rest and at 24 postoperative hours.
Length of stay PACU was longer in the opioid free group, but
only three of six trials reported a statistically significant
difference. Finally, total length of stay in the hospital was
investigated by two trials and was similar between groups.
Conclusion: OFA, when compared with OBA, does not
present inferior results regarding pain scores or opioid con-
sumption in the postoperative period. It is also associated
with reduced postoperative nausea and vomiting. The OFA
technique presents as future challenges an objective docu-
mentation of both its short-term and long-term benefits and
inconveniencies. Further research with robust methodolog-
ical trials with large sample sizes are required to better de-
termine the efficacy and safety of opioid-free anaesthetic
strategy.
Keywords
Opioid-free anaesthesia, General anaesthesia, Analgesia,
Opioid, Perioperative period, Multimodal treatment
 Page 14 of 11 
nous (i.v.) morphine consumption equivalents at 24h post-
operatively, rates of postoperative nausea and vomiting
(PONV) within the first 24 postoperative hours, rates of
rescue antiemetic drugs, length of stay in post-anaesthesia
care unit (PACU) and total hospital length of stay. Eleven
studies were identified, three of which are meta-analysis.
Results: Mean pain scores at rest in the first measure as well
as at 24 postoperative hours were lower in the opioid free
anaesthesia (OFA) group than in opioid based an- aesthesia
(OBA). Use of rescue postoperative analgesia and i.v. I
morphine consumption equivalents were lower in the OFA
group. A statistically significant trend toward a decrease in n
PONV and use of antiemetic drugs among patients who did t
not received opioids was observed.
r
o
d
u
c
t
i
o
n
The definition of
general anaesthesia is a
fluid term, having had
several definitions. General
anaesthesia was initially
considered to be the four
“A’s”: Analgesia, amnesia,
akinesia (immobility) and
autonomic control [1]. This
concept evolves into the
definition of General
anaesthesia as a reversible
state of unconsciousness,
immobility,
antinociception and
control of autonomic
nervous system (ANS),
within a controlled
hemodynam- ic
physiological stability [2].
Another essential outcome
that can only be
retrospectively assessed is
amnesia, which is assumed
when patients are
unconscious. It is currently
believed that when the
other four outcomes

Citation: Basto T, Machado HS (2020) Effect of Opioid-Free

Anaesthesia on Perioperative Period: A Review. Int J Anesthetic
Anesthesiol 7:104. doi.org/10.23937/2377-4630/1410104
Accepted: April 18, 2020: Published: April 20, 2020

 Page 15 of 11 
Copyright: © 2020 Basto T, et al. This is an open-access article
distributed under the terms of the Creative Commons Attribution
License, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original author and
source are credited.

 Page 16 of 11 
DOI: 10.23937/2377-4630/1410104 ISSN: 2377-4630
acting opioids [14].
mentioned above are achieved, awareness with recall
rarely occurs [3,4].
Balanced anaesthesia, the most common strategy
used in the last decades, relies mostly upon the GABA-
A receptor and mu-opioid receptor [3]. So the current
practice is based on a hypnotic for induction and on an
inhaled ether or hypnotic for maintenance of uncon-
sciousness. Muscle relaxants are administered to pro-
duce immobility and opioids are the most commonly
used drug to manage nociception intraoperatively and
pain postoperatively [2,3]. Opioids used to be the ideal
drug to block autonomic nervous system reactions and
allow hemodynamic stability [2,5].
Nociception is intimately related to control of the
au- tonomic nervous system since nociceptive
disorders are a primary source of hemodynamic
instability, as well as, postoperative chronic pain
syndromes [6].
A sufficient level of antinociception has been
reached when applied surgical stimuli, clinical re-
sponses as heart rate and blood pressure elevations no
longer occur [2,3,5]. Nevertheless, according to a
recent clinical trial, despite absent clinical responses,
nociceptive activation persists during deep general
anaesthesia. Therefore, lack of clinical responses is not
indicative of the absent nociception specific ac- tivation
[7].
Undoubtedly, opioids are effective antinociceptive
agents and one of the three pillars of balanced anaes-
thesia is the administration of opioids in the periopera-
tive period [3,8].
The approach of opioid administration before sur-
gery has been used as a strategy to reduce postoper-
ative pain. However, a recent meta-analysis of 20 ran-
domised controlled trials concluded that there is no
clear evidence that preventive opioids result in reduc-
tion in pain scores [9]. It is also known that perioper-
ative opioid administration predisposes to persistent
opioid use [10].
A 2014 meta-analysis that evaluated the clinical
con- sequences of intraoperative doses of opioid,
revealed that high doses of opioids during surgery are
associat- ed with an increased perception of pain and
increased postoperative opioids requirements [11].
This can be explained by two related phenome-
na: Opioid tolerance and opioid-induced hyperalgesia
[12,13]. Tolerance is a pharmacological effect that
leads to a progressive lack of response to opioid
adminis- tration that can be overcome by increasing
the dose. Opioid-induced hyperalgesia is a sensitization
process whereby opioids, paradoxically, cause
increased pain sensitivity (Opioid Paradox) [8,12].
These neuroadapta- tion processes cause a highlighting
of existing pain and enablement of chronic pain
development [12,13]. Any opioid is capable of
potentially inducing hyperalgesia, particularly short-
Basto and Machado. Int J Anesthetic Anesthesiol 2020, 7:104  Page 2 of 11 
DOI: 10.23937/2377-4630/1410104 ISSN: 2377-4630
[8,14,15]. OFA can also be performed with locore-
Although opioids are the most effective antinocice-
ptive drug, they have undesirable side effects, such as
respiratory depression, pharyngeal muscle weakness,
postoperative nausea and vomiting, urinary retention,
constipation, ileum, pruritus, tolerance and hyperalgesia
that may progress into chronic pain syndrome
[8,13,15]. Nausea and vomiting are particularly
responsible for de- layed patients recovery, prolonged
patient stay in the re- covery area and, therefore,
delayed hospital discharge. It is also known that
opioids disorganize sleep pattern and may lead to
postoperative delirium [16]. Also, pa- tients receiving
opioids as part of general anaesthesia and leaving the
hospital with opioid prescriptions, ap- pear to have an
increased risk of opioid dependence [17]. Therefore, it
is debatable whether perioperative opioid
administration is appropriate or necessary in cur- rent
clinical practice [18].
Due to concerns arising from the excessive use of
opioids and their side effects, new strategies have
emerged to achieve balanced general anaesthesia.
The concept of balanced anaesthesia has been
extended in order to include more drugs that target
different neu- rophysiologic mechanisms [2,3]. It is
known that when anaesthetic drugs with different
mechanisms are com- bined, they produce a synergic
interaction, meaning that using different drugs at
smaller doses maximizes desired effects while
minimizing side effects. This phe- nomenon is known
as Multimodal general anaesthesia and has allowed
the dose reduction of opioids used [3,19]. Moreover, a
multimodal approach can poten- tially reduce central
neuroadaptation to opioids [17].
Concerned about the significant opioid side effects,
strategies for balanced general anaesthesia are now
us- ing different antinociceptive agents that target the
cen- tral nervous system, like dexmedetomidine [20],
and less specific targets, like lidocaine [21], to manage
the nociceptive component of anaesthesia [2].
Nonopioid adjuvants such as NSAIDs, beta-block-
ers, NMDA antagonists (ketamine), alpha2-agonists,
lidocaine, gabapentin, etc. can decrease the need for
opioids to achieve adequate intraoperative antinocice-
ption or post-operative analgesia [8,13]. Nevertheless,
we should keep in mind that they must be chosen
based on the patient and procedure for which their
pharma- cologic profile suits best [22]. Most of these
drugs are able to decrease intraoperative opioid use at
the cost of longer sedation [8].
Due to the new reasons that are added every year
for the reduction of opioid use associated with the
broadening of the concept of general multimodal an-
aesthesia, a new concept has emerged: Opioid-free
anaesthesia. Opioid-free anaesthesia (OFA) can be
defined as the combination of various opioids-spar-
ing techniques leading to no administration of intra-
operative systemic, neuraxial or intracavitary opioids
Basto and Machado. Int J Anesthetic Anesthesiol 2020, 7:104  Page 3 of 11 
 Opioid
addiction
Chronic
pain
syndrome
s
OFA
Colorectal
ERAS
Cancer
surger
y
Figure 1: Specific populations that benefit from the use of OFA technique.
gional analgesia for better pain control, but it is not
compulsory [14]. This strategy helps to reduce the in-
cidence of opioid-induced adverse effects and spares
opioids as analgesics for the postoperative period [16].
There are specific populations that benefit from the
use of OFA, namely in opioid addiction, chronic pain
syndromes, obesity, obstructive sleep apnoea, cancer
surgery and colorectal ERAS (Figure 1) [8,13-15].
Even though perioperative opioid administration is
a common and long-standing practice, it is
questionable whether it is still necessary in current
practice. There- fore, the aim of this review is to
understand to which extend is opioid free beneficial in
the perioperative peri- od, more specifically the
analgesic impact of opioid-free anaesthesia.
Methods
The search for this review was performed on Pu-
bMed and Medline until 30 November 2019 using the
query: (“opioid-free”[All Fields] AND ((((“anaesthe-
sia”[All Fields] OR “anesthesia”[MeSH Terms]) OR “an-
esthesia”[All Fields]) OR “anaesthesias”[All Fields]) OR
“anesthesias”[All Fields])) OR (((“opioid-free”[All Fields]
OR “non-opioid”[All Fields]) OR (“intra-operative”[All
Obesity
Obstructiv
e
sleep
apnoea
Fields] AND ((((((“analgesics opioid”[Pharmacological
Action] OR “analgesics, opioid”[MeSH Terms]) OR (“an-
algesics”[All Fields] AND “opioid”[All Fields])) OR
“opioid analgesics”[All Fields]) OR “opioid”[All Fields])
OR “opi- oids”[All Fields]) OR “opioid’s”[All Fields])))
AND ((((“an- aesthesia”[All Fields] OR
“anesthesia”[MeSH Terms]) OR “anesthesia”[All
Fields]) OR “anaesthesias”[All Fields]) OR
“anesthesias”[All Fields])). Finally, Google Scholar was
also used to identify any relevant study not already
identified using the strategy described above.
The results of this search strategy were limited to
meta-analyses, randomized controlled trials, prospec-
tive studies and humans, written in English or Portu-
guese. The analysis focus only on articles published in
the last 5 years (from 30.11.2014 to 30.11.2019). Arti-
cles in other languages, systematic or literature
reviews, retrospective studies, case reports, personal
opinion ar- ticles and letters to the editor were
excluded.
Titles and abstracts were screened in the first stage
based on inclusion and exclusion criteria. Only trials
that included patients under general anaesthesia and
inves- tigated pain outcomes comparing any type of
intra-op- erative opioid administration with absence of
opioids were included in the present review. Eligibility
criteria was only applied to primary studies.

Blinding of participants and personnel (performance bias)

The primary outcome to be evaluated will be first
reporting was judged based on the outcomes described
measure of pain score at rest and at 24 postoperative
in the Methods section but not reported in the Results
hours. The secondary outcome elated to acute pain in-

Random Sequence Generation (selection bias)

section.
cluded need for rescue analgesia and intravenous (i.v.)
morphine consumption equivalents at 24h postopera- If in any study the data was found to be incomplete,

Allocation Concealment (selection bias)

tively. Other secondary outcomes sought were rates of attempts were made to contact the corresponding au-
postoperative nausea and vomiting (PONV) within the thor via email for the relevant data. In one study, pain
first 24 postoperative hours, rates of antiemetic drugs, scores were presented in a graphical format [24].
and hospital resource-related outcomes including length There- fore, an online software
of stay in post-anaesthesia care unit (PACU) and the to- (https://apps.automeris.io/ wpd/) was used to extract
tal hospital length of stay. data points.
Extracted trial characteristics included: Surgical pro- Outcomes are reported as tables and relevant out-
cedure, intra-operative opioid regimen, medication used comes for each study are summarized. All opioids were
for anaesthetic maintenance and type of postoperative converted into equianalgesic doses of i.v. morphine for
analgesia. analysis (i.v. morphine 10 mg = oral morphine 30 mg =
i.v. pethidine 75 mg = i.v. piritramide 7.5 mg) [25,26].
Briefly, the Cochrane Collaboration’s Risk of Bias
Pain scores reported as visual, verbal or numeric rating
Tool for randomized controlled trials was used to as-
scales were converted to a standardised 0-10 analogue
sess the methodological quality of each randomised
scale for quantitative evaluations. Comparative effec-
trial [23]. No attempt was made to contact authors for
tiveness is reported either as proportion of patients
clarification on the Risk of Bias items. Selective
with the outcome or as mean score. The p value < 0.05
outcome
was considered significant.
Records identified through: Additional records identified
database searching through:
MEDLINE (n = 506) - Google Scholar (n = 996)
Identification

PUBMED (n = 635)

Records after duplicates removed (n =

1415)
Screening

Articles selected by title and

abstract
(n = 647)

Records excluded:
- Not meeting inclusion
criteria (n = 630)
Eligibility

Full- text articles assessed for

eligibility
(n = 17)

Full - text articles

excluded:
- Not meeting inclusion
Included

criteria (n = 6)

Studies included in
qualitative synthesis (n =
11)
 Three trials investigated remifentanil as an intra-op-
erative opioid regimen [28,31,32], two explored fentanyl
[24,35], one sufentanil [33]; two trials compared fentanyl

Blinding of Outcome Assessment (detection bias)

and remifentanil to a control group [27,34]. All included
trials administered volatile anaesthetics to maintain

Incomplete Outcome Data (attrition bias)

anaesthesia except two that administered propofol
[27,34].

Selective Reporting (reporting bias)

Bakan (2015)
Pain Scores
Choi (2017) Table 2 shows primary and secondary outcomes of
interest in all included studies. In three studies,
Elsaye (2019)
patients reported pain using a visual analog scale (VAS)
Hontoir (2016) score [24,28,33], two studies used the numerical rating
score (NRS) to quantify pain [27,31]. Both scoring
Karabayirli (2017) systems ranged from 0 to 10. The three meta-analysis
used a standardised 0-10 analogue scale [29,30,36].
Mulier (2018)
In two studies the first measure of pain score at rest
Salem (2019) were not reported [34,35]. Five studies also did not re-
port pain scores at 24h postoperatively [27,32,34-36].
Shalaby (2018)
Furthermore, Elsaye, et al. [24] showed pain scores in
Sriganesh (2019) the form of a graph only. Thus, numbers were extrapo-
Results lated for this study as the authors did not respond.
Figure 3: Cochrane Collaboration risk of bias summary of
included
Of theclinical
1415trials. Green circle,
studies low risk
identified byofour
bias;literature
red circle, Mean pain scores at rest in the first measure were
high risk of bias; yellow circle, unclear risk of bias.
search, 11 met the inclusion criteria, representing a to- statistically lower (p < 0.05) in opioid free anaesthe-
tal of 3483 patients (2975 from meta-analysis and 508 sia (OFA) than in opioid based anaesthesia (OBA) in
from trials) [24,27-36]. The flowchart following PRISMA six studies [24,27,30,31,33,36] and mean pain scores
guidelines shows the search and selection process of at 24 postoperative hours were also statistically low-
the literature (Figure 2). er in five studies [24,27,30,31,33].

According to our assessment following the Analgesia Requirements

Cochrane Collaboration Risk of Bias tool (Figure 3), the Use of supplemental postoperative analgesia was
majority of trials had an unclear risk of bias. Attempts reported inferior in the OFA group in five articles, but
were made to contact three authors [24,34,35], but only two of them reported statistically significant dif-
none provided the additional data requested. ference in the number of patients that required res-
The characteristics of studies included in this study cue analgesia [24,27].
are shown in Table 1. All primary studies in- cluded a Four trials found a significantly lower requirement
total of patients ranging from 40 to 80. Regarding the of intravenous (i.v.) morphine consumption equiva-
types of surgery, three trials in- cluded patients lents at 24h postoperatively in the opioid free group
scheduled for laparoscopic chol- ecystectomy [30,31,33,36].
[24,27,35], two for bariatric surgery [33,36] and four
for different types of elective sur- geries [28,31,32,34]. Postoperative Nausea and Vomiting (PONV)
Two studies included all types of surgical operations The incidence of PONV was reported in all but one
[29,30]. study [31]. Eight of the ten studies that compared the
incidence of PONV in opioid versus non-opioid groups
observed a statistically significant trend toward a de-
crease in PONV among patients who did not receive
opioids [24,28-30,33-36]. The use of antiemetic drugs
was significantly lower in the opioid free group in
four of five studies [27,28,34,35].
Length of Stay
In all studies length of stay in the post-anaesthesia
care unit (PACU) was longer in the opioid free group,
but only three of six trials reported a statistically signif-
icant difference [27,28,30]. Finally, total length of stay
in the hospital was investigated by two trials and was
similar between groups [33,35].
Ba Table 1: Trial characteristics. D
st OI
o :
an Opioid regimen 10
d Control Anaesthetic Postoperative Primary Out- .2
M Reference Study design Group (n) Surgery 39
Group Maintenance analgesia come
ac 37
ha OBA OFA /2
do 37
. Fentanyl induc- 7-
Int tion dose (2 μg/ Fentanyl con- 46
J kg) + Remifentanil Dexmedetomidine [loading dose sumption used 30
An Bakan M, Randomized Opioid-free (40) Laparoscopic chol- Normal infusion (0.25 μg/ (0.6 μg/kg) + infusion (0.3 μg/ PCA of Fentanyl for pain relief /1
es et al. [27] Controlled Trial Opioid-based (40) ecystectomy saline kg/min) kg/h)] + Lidocaine (2 mg/kg/h) Propofol i.v. in the first 6h. 41
th
eti Dexmedetomidine [loading dose
c Choi E, et Randomized Opioid-free (40) Remifentanil 2-4 (1 μg/kg) + infusion (0.3-0.5 μg/
An al. [28] Controlled Trial Opioid-based (40) Thyroidectomy None ng/ml (TCI) kg/h)] Sevoflurane Ketorolac i.v. Not specified
es
th Dexmedetomidine [loading dose
es (0.5 μg/kg) + infusion (0.25 μg/
iol kg/h)] + Lidocaine [bolus dose (1
20 mg/kg) + infusion (1 mg/kg/h)] +
Fentanyl induc- Compare OBA
20
tion dose (1-2 μg/ Magnesium sulfate [loading dose with OFA on
Elsaye R, Randomized Opioid-free (20) Laparoscopic chol- kg) + intermittent (30 mg/kg) + infusion (10 mg/ postoperative
et al. [24] Controlled Trial Opioid-based (20) ecystectomy None boluses (50 mic) kg/h)] Desflurane Pethidinei.m. pain relief
Pain score
Frauenkne- at rest at 2
cht J, et al. Any surgical oper- postoperative
[29] Meta-analysis Total (1304) ation NA NA NA NA NA hours
Pain score
at rest at 2
Grape S, et Any surgical oper- postoperative
al. [30] Meta-analysis Total (1309) ation NA NA NA NA NA hours
Postoperative
Paracetamoli.v.+ patient comfort
Clonidine [loading dose (0.2 μg/ Diclofenaci.v. assessed by
Hontoir S, Randomized Opioid-free (31) Breast cancer sur- Remifentanil DNM kg)] + Ketamine bolus dose (0.2 + PCA of piritr- QoR-40 ques-
et al. [31] Controlled Trial Opioid-based (33) gery None (TCI) mg/kg) if necessary Sevoflurane amidei.v. tionnaire
Remifentanil
[loading dose (1
Karabayirli Functional en- μg/kg) + infusion
S, et al. Randomized Opioid-free (23) doscopic sinus (0.25-0.50 μg/kg/ Dexmedetomidine [loading dose
 P
[32] Controlled Trial Opioid-based (24) surgery None min)] (1 μg/kg) + infusion (0.7 μg/kg/h)] Sevoflurane Paracetamoli.v. Not specified IS
a
S
g
N:
e
23
77
6 -
46
tamine bolus dose (0.25mg/kg) (0.5 μg/kg) + infusion (0.25 - 1 μg Dexmedetomidine [loading dose Sevoflurane + PCA of mor- phine i.v. Paracetamoli.v. Not specified

mg/ kg) + infusion (DNM)] (0.6 μg/kg) + infusion (1 μg /kg/h)] Dexmedetomidine [loading dose Propofol Parecoxib Frequency of IO deviated
MAP meas- ures and
necessity of interference.
DOI: 10.23937/2377-4630/1410104

(1 μg/kg) + infusion (0.5 μg/kg/h)] Dexmedetomidine [loading dose Isoflurane NM Not specified

NA NA NA 24 postoper- ative hours

morphine con- sumption

Basto and Machado. Int J Anesthetic Anesthesiol 2020, 7:104

ot applicable; DNM: Dose not mentioned; NM: Not mentioned; OBA: Opioid-based anaesthesia; OFA: Opioid-free anaesthesia; DNM: Dose not mentioned; QoR: Quality of recovery; IO: Intraoperative;
MAP: Mean arterial pressure.
Discussion

Page 7 of 11 
ISSN: 2377-4630

during

reduce
This

trauma
One

control.
analysis

adverse
attempt

nervous
nervous
remains

as anal-
ing of ex
agents [
pain, ra

in- traop
hyperalg

by short
opioid-fr

pain dev

should b
First, opi
vomiting

whereby

techniqu
is a mo

depende
by the n

This t

[8,14,5,3
Opioid P
length of

drugs th
drugs wi
evidence

Howe

potential
postoper

analgesic
apparent
anaesthe

prevent s

oid-induc
that bloc

that als
Furtherm
Opioid
opioid-ba

the perio

neuroada
conseque

increased
increased

reduction
reduction

opioid re

Opioid
[5,8,14,38].
A relevant meta-analysis by
Frauenknecht, et al. evaluated
the use of intra-operative
opioids with the control being
no opioids (normal saline) [
Al- though a control group with
no opioid may be
Ba Table 2: Summary of findings. D
st OI
o Pain Score Rescue Analgesia Use Nausea and Vomiting Length of stay :
an 10
d i.v. morphine .2
PONV 24h Post- Antiemetic drugs Total length of
M Reference Measure of First measure 24h postoper- Rescue Analge- equivalents (mg) Length of stay 39
ac op (% of pa- stay in hospital 37
(year) pain postoperative ative sia Need (%) for Rescue Analge- (% of patients) in PACU (min)
ha tients) (days) /2
sia in 24h
do 37
. OBA OFA OBA OFA OBA OFA OBA OFA OBA OFA OBA OFA OBA OFA OBA OFA 7-
Int 46
J Bakan M, et al. 15 10 30
NRS (0 - 10) 4 3 48 23 33* 13* 0 15
An [27] /1
es 41
th VAS (0 - 10) 4.2* 3.8* 1.7 1.0 62.5* 40* 65 17.5 37.5 7.5 18.7 26.6
eti Choi E, et al. [28]
c Elsaye R, et al.
An VAS (0 - 10) 4.5b 1.4b 1.9 b 1.3 b 85 30 9.4* 6.7* 60 0
[24]
es
th Mean Difference: Mean difference: Mean differ-
es Frauenknecht J, 0 - 10 scale 3.6* 3.4* 24 19
et al. [29] 0.0 *
0.9* ence: 0.6*
iol
20 Mean Difference: Mean difference:
20 Grape S, et al. 2x more frequent Mean differ-
0 - 10 scale 4.0 3.3
[30] -0.9 -4.6 with OBAa ence: 8.9
Hontoir S, et al.
NRS (0 - 10) 3 1 2 0 17.5 10.8 95.0* 96.6*
[31]
Karabayirli S, et No significant
20.8* 13* 25* 21.7* 4.2* 4.3*
al. [32] difference*a
Mulier J, et al. 3.68*
VAS (0 - 10) 4.9 1.7 3.3 2.0 18.2 14.7 63.6 13.0 3.30*
[33]
Salem A, et al.
100* 100* 86.1 61.1 36.1 11.1 27.9* 25.1*
[34]
Shalaby M, et al. No significant
32.5 12.5 15 0
[35] difference*a
Mean Difference:
Singh P, et al. 0 - 10 scale 54.4 18.1 48.5 23.1
[36] -2.27

NA: Not applicable; NM: Not mentioned; PACU: Post-anaesthesia care unit; NRS: Numerical Rating Score; VAS: Visual Analog Scale; PCA: Patient Controlled Analgesia; PONV:
Postoperative nausea and vomiting
*
Not significante (p > 0.05)
 P a
Values not mentioned
IS
a b
Numbers extrapolated from graph. S
g
N:
e
23
77
8 -
46
DOI: 10.23937/2377-4630/1410104 ISSN: 2377-4630

OFA, it is important to clarify that the OFA technique [29,30,36].

is based on the incorporation of different non-opioid
techniques as part of a multi-modal analgesia plan.
Nevertheless, Frauenknecht, et al. meta-analysis
demonstrates that there is no significant difference
between the postoperative pain scores and mor-
phine consumption of the opioid-inclusive anaesthe-
sia group compared to normal saline-treated group.
In other words, this study demonstrated that opi-
oid-based anaesthesia does not offer a significant ad-
vantage for postoperative pain outcomes [29].
The trials included in this review revealed that pain
scores at rest in the first postoperative measure as well
as at 24 postoperative hours were lower in the opioid
free anaesthesia group when compared to opioid
based group. Also, opioid-free anaesthesia when
compared with opioid-based anaesthesia is associated
with lower
i.v. morphine equivalents requirements in 24 postoper-
ative hours and lower request of rescue analgesia.
Grape, et al. meta-analysis demonstrated that dex-
medetomidine opioid-free anaesthesia was superior to
remifentanil opioid-based anaesthesia with improved
pain outcomes in the immediate postoperative period
and for up to 24h postoperatively, as well as, lower re-
quirement of i.v. morphine equivalents [30]. Clonidine,
also an alpha-2-agonists, was used in one trial that re-
ported statistically lower pain scores in immediate
post- operative period and 24 postoperative hours in
the OFA group [31].
Singh, et al. meta-analysis regarding patients under-
going bariatric surgery concluded that patients who re-
ceived dexmedetomidine required 33% less opioids in
the first 24h after surgery in comparison with the con-
trols [36].
Prolonged analgesic effect of dexmedetomidine
may explain these findings. Dexmedetomidine is a
highly se- lective alfa-2-agonist that has anxiolytic,
sympatholytic, and analgesic properties. It has been
used as an opioid substitute in various surgical
interventions because has been shown to lower
postoperative pain scores, opioid consumption, and
the risk of opioid-related adverse events [39,40].
The reduction of postoperative pain by dexmedeto-
midine may be explained by activation of alfa-2-adran-
oreceptores that inhibited release of substance P from
the dorsal horn, which leads to a reduction on the noci-
ceptive inputs [28,40].
In addition to our primary outcome, opioid-free an-
aesthesia was associated with reduction in postopera-
tive nausea and vomiting. Also, the use of rescue an-
tiemetic drugs was significantly lower in the opioid free
group [27,28,34,35]. Likewise, the three meta-analysis
included in this review also reported significantly lower
incidence of PONV in 24 postoperative hours
Basto and Machado. Int J Anesthetic Anesthesiol 2020, 7:104  Page 9 of 11 
DOI: 10.23937/2377-4630/1410104
Not only postoperative opioid use, but also intra- OFA, namely in opioid addiction,
op- erative administration are risk factors for chronic pain syndromes,
postoperative nausea and vomiting [29]. While PONV morbid obese patients,
is considered an unpleasant but inherent effect of ob- structive sleep
opioid-based general anaesthesia, patients ranked apnoea, cancer surgery
vomiting as the main out- come to be avoided in and abdominal surgery.
postoperative period, ahead to postoperative pain However,
[41]. PONV is responsible for system resource contraindications for the
consumption including prolonged length stay in both use of OFA are less clear.
recovery area and hospital and finally, increased costs
There is evidence that
of health service [29]. The risk factors that affect the
opioid-free anaesthesia,
incidence of nausea and vomiting are multifacto- rial
when compared with
and include type of anaesthesia, type of surgery and
opioid-based anaesthesia,
characteristics of the patient [42]. Therefore, an
does not pres- ent inferior
opioid-free regimen should be considered, especially
results regarding pain
in high-risk patients, among the strategies to prevent
PONV. scores or opioid con-
sumption in the
However, some trials provide no information on postoperative period. It is
routine prophylaxis against PONV or rescue antiemet- also associ- ated with
ic drugs [24,31,33,36]. It is not clear whether the in- reduced postoperative
creased incidence of PONV in the opioid based group nausea and vomiting.
can be wholly attributed to opioid administration
However, many drugs
versus lack of prophylaxis. used in this technique
The length of stay in the post-anaesthesia care unit such as ketamine and
(PACU) was longer in the opioid free group, but only gabapentin also have
three studies presented statistically significant results substantial addic- tive
potential and may also
[27,28,30]. Total length of stay in the hospital was
only investigated by two trials and was similar lead to long-term
between groups. difficulties [38].
Sultana, et al. claims that systemic alpha-2-agonists The opioid-free
do not prolong recovery times [15]. Nonetheless, anaesthesia presents as
many trials reported a statistically longer stay in post- future challenges an
anaes- thesia care unit in the opioid-free group objective documentation
[27,28,30]. This is related to the fact that of both its short-term
dexmedetomidine has a long half-life (2-2.5 h), thus and long-term benefits
associated with slow recovery [27,37,39,40]. and inconvenien- cies
using large sample sizes
There are notable limitations to this review. Firstly,
and development of ad-
our review was based on a limited number of studies,
most of which had inherent biases. Secondly, the stud- equate monitoring of
ies included present a large heterogeneity. intraoperative
Consequent- ly, it was not possible to form subgroups nociception. In order to
clarify some questions,
regarding the intraoperative opioid regimen,
maintenance medica- tion and type of surgery for the Postoperative and
Opioid-Free Anesthesia
further analysis. Finally, we were unable to draw any
robust conclusion regarding the impact of opioid-free (POFA) trial, a prospective
anaesthesia on total length of stay in the hospital. randomised, single-blind,
Therefore, the existing literature would benefit from multicentre study is now
ongoing (NCT03316339),
additional trials to better define the impact of each
anaesthetic strategy on health system resources. recruiting 400 patients
[43]. The results will give
Conclusion information regarding
Despite the current trend in favour of safety of opioid-free
individualised anaesthesia modalities and the growing anaesthesia technique.
number of pro- viders practicing opioid-free In conclusion, further
anaesthesia, there is aston- ishingly little data. There research with robust
are specific populations that benefit from the use of meth- odological trials
Basto and Machado. Int J Anesthetic Anesthesiol 2020, 7:104
ISSN: 2377-4630
with large sample sizes are
required to better
determine the efficacy
and safety of opioid-free
anaesthetic strategy.
Conflicts of Interest
The authors declare no
conflicts of interest.
Funding
The authors have no
sources of funding to
declare for this
manuscript.
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