PCT 3.en - Id

27
pasca operasi Analgesia

Ronald B. George, MD, FRCPC, Brendan Carvalho, MBBCh, FRCA, MDCH,
Alexander Butwick, MBBS, FRCA, MS, Pamela Banjir, MD
GARIS BESAR BAB

Rasa sakit setelah caesar Pengiriman, 627 Intratekal Opioid, 641
Sistemik Analgesia, 627 Efek Samping dari neuraksial Opioid, 644
Opioid Analgesia, 627 Neuraksial nonopioid Analgesik Adjuvants, 649
Multimodal Analgesia, 630 Teknik non-neuraksial Regional Analgesik, 652
Neuraksial Analgesia, 633 Perut fasia Sheath Blok, 652
Khasiat dan Manfaat neuraksial Analgesia, 633 Luka Infusion Kateter, 655
Neuraksial Opioid, 634 Ilioinguinal-Iliohypogastric Block, 655
Epidural Opioid, 635 Subkutan Infiltrasi lokal Anestesi, 655
Tingkat sesar di Amerika Serikat dan di seluruh dunia telah terus Setelah sesar, konsentrasi luka sitokin berkorelasi positif dengan
meningkat sebagai akibat dari perubahan pola dalam praktek kebidanan. 1 Data konsumsi obat analgesik. 13 Kisaran nyeri dilaporkan setelah sesar lebih
terbaru menunjukkan bahwa lebih dari 1 juta kelahiran sesar sekarang besar daripada setelah melahirkan vagina, tetapi beban rasa sakit dan
dilakukan setiap tahun di Amerika Serikat. 2 Dengan sesar akuntansi untuk durasi yang sangat mirip ( Gambar. 27,1 ). 4,14 Sebuah sampel ibu hamil
32% dari semua kelahiran di Amerika Serikat, strategi untuk mengurangi menghadiri kelas melahirkan diidentifikasi nyeri selama dan setelah
hasil ibu postcesarean merugikan, termasuk nyeri pasca operasi, memiliki sesar sebagai kepedulian mereka yang paling penting ( Meja
klinis dan publik implikasi kesehatan yang penting. 2
27.1 ). 15 Mengukur intensitas dan kepuasan dengan alat-alat sederhana sakit belum
memenuhi tujuan mencegah dan mengobati nyeri sedang dan berat. 4,8,14-18
Nyeri merupakan bahaya potensial yang dapat terjadi selama dan setelah
prosedur bedah. Tidak cukup sakit diobati dapat menyebabkan banyak fisiologis Parah nyeri akut pasca operasi merupakan salah satu faktor penting yang paling
yang tidak diinginkan dan konsekuensi psikologis pada wanita yang menjalani berhubungan dengan nyeri pasca operasi kronis. 3,5,19-21
sesar, termasuk gangguan pemulihan, rasa sakit terus-menerus dan kronis, dan Beberapa studi menunjukkan bahwa penggunaan blokade neuraksial
peningkatan biaya. 3-5 perioperatif dapat mencegah sensitisasi sentral dan nyeri kronis. 22,23 Penelitian
mekanistik dan klinis tambahan diperlukan untuk meningkatkan pemahaman
kita tentang nyeri persisten setelah sesar (lihat Bab 42). farmakologis
multimodal dan pengobatan nonfarmakologis untuk rasa sakit adalah
PAIN SETELAH PENGIRIMAN SESAREA
pendekatan yang optimal dan harus ditawarkan setiap kali layak dan indikasi
Manajemen nyeri pasca operasi sering lancar, dengan 30% sampai 80% dari medis.
pasien yang mengalami nyeri sedang hingga pasca operasi parah. 6-8 Nyeri
setelah sesar mungkin setara dengan yang dilaporkan setelah histerektomi. 9 Hasil
nyeri pasca operasi dari trauma jaringan langsung dan peradangan berikutnya.
SISTEMIK ANALGESIA Opioid
sitokin inflamasi lokal dan sistemik bertindak untuk menyadarkan saraf perifer
dan meningkatkan persepsi nyeri. 10 Peradangan mungkin memainkan peran Analgesia
yang sangat signifikan dalam nyeri setelah melahirkan karena sitokin inflamasi Di Amerika Serikat, kebanyakan wanita yang menjalani sesar dengan anestesi
meningkat sebagai bagian dari proses persalinan dan melahirkan normal. 11,12 neuraksial menerima opioid neuraksial untuk analgesia pasca operasi. Namun,
banyak wanita membutuhkan analgesik sistemik untuk meningkatkan terapi
neuraksial, dan beberapa
627
Download untuk FK UMI Makassar ( mahasiswafkumi05@gmail.com ) di Universitas Muslim Indonesia dari ClinicalKey.com oleh Elsevier pada 31 Maret 2020.
Untuk penggunaan pribadi saja. Tidak ada kegunaan lain tanpa izin. Copyright © 2020. Elsevier Inc All rights reserved.
628 BAGIAN VII Pengiriman sesar
vagina Pengiriman Pengiriman sesar
10 8
10 8
Pain (NRS)
6420
Pain (NRS)
6420
0 20 40 60 80
0 20 40 60 80
Post-partum Day
Post-partum Day
Gambar. 27,1 Nyeri lintasan setelah melahirkan vagina dan sesar. garis putus-putus mewakili laporan sakit dari subyek individu, dan garis
putih padat adalah rata-rata bergerak. daerah yang diarsir mencakup rentang dari 5 ke 95 persentil dari data. NRS, verbal numerik Rating
Scale dari 0 sampai 10, dengan 0 = tidak ada rasa sakit dan 10 dibayangkan nyeri = terburuk. (Dari Komatsu R, Carvalho B, Banjir PD
Pemulihan setelah lahir nulipara:. Analisis rinci analgesia nyeri dan pemulihan fungsi. Anestesiologi. 2017; 127: 684-694).
TABEL 27.1 Nilai Ranking dan relatif perempuan TABEL 27.2 Opioid equianalgesic Dosis
Potensi Anestesi Hasil Dinilai sebelum Sesar
Subkutan / intravena
Obat Oral (mg) (mg)
Morfin 30 10
Hasil Pangkat Sebuah Nilai relatif b oksikodon 20 NA
Nyeri saat sesar 8.4 ± 2.2 27 ± 18 hydrocodone 20 NA
Rasa sakit setelah sesar 8.3 ± 1.8 18 ± 10 hidromorfon 7,5 1,5
muntah 7.8 ± 1,5 12 ± 7 fentanyl NA A 25- μ g / h transdermal 0.1 (100 μ g)
Mual 6.8 ± 1,7 11 ± 7 patch equianalgesic untuk
kram 6.0 ± 1,9 10 ± 8

gatal 5.6 ± 2.1 9±8
Gemetaran 4.6 ± 1,7 6±6 ≈ 50 mg morfin oral per
Kegelisahan 4.1 ± 1,9 5±4 hari
Sifat tidur 2,9 ± 1.4 3±3 oxymorphone 10 1
Normal 1 0 NA, Tak dapat diterapkan.

Courtesy dari Dana Farber Cancer Institute Nyeri dan Program Perawatan
Data yang berarti ± standar deviasi.
Sebuah Rank = 1 sampai 10 dari yang paling diinginkan (1) ke diinginkan (10) hasil sedikit. Paliatif dan Brigham dan Komite Nyeri Rumah Sakit Wanita. Dimodifikasi
dengan izin dari Bridget C. Fowler, Pharm. D., Farmasi Klinis Manager, Dana
b nilai relatif = pasien nilai dolar akan membayar untuk menghindari hasil (misalnya, Farber Cancer Institute.
mereka akan membayar $ 27 dari teoritis $ 100 untuk nyeri menghindari selama sesar).
Dari Carvalho B, Cohen SE, Lipman SS, et al. preferensi pasien untuk anestesi hasil
terkait dengan kelahiran sesar. Anestesi analg. 2005; 101: 1182-1187. College of Obstetricians dan Gynecologists (ACOG) 26 dan American Pain
Society 27 telah putus asa penggunaan meperidine pada pasien kebidanan
karena akumulasi normeperidine pada neonatus dan efek selanjutnya
wanita tidak dapat menerima anestesi neuraksial. Di Amerika Serikat itu pada skor neurobehavioral. tabel 27.2 menunjukkan umum digunakan
adalah praktek umum untuk meresepkan opioid oral pulang dari rumah alternatif untuk meperidine dengan dosis equianalgesic.
sakit, meskipun hal ini tidak praktek yang umum di bagian lain dunia. 24
Intravena Pasien-Controlled Analgesia

Pilihan Opioid Intramuskular dan subkutan opioid yang murah, mudah untuk mengelola, dan
Faktor-faktor yang mempengaruhi pilihan opioid adalah kecepatan onset, durasi kerja, terkait dengan sejarah panjang keamanan tetapi tidak umum digunakan di
keberhasilan secara keseluruhan, dan jenis dan frekuensi efek samping. Jika efek Amerika Serikat karena kebutuhan untuk suntikan yang menyakitkan berulang,
samping mencegah analgesia yang memadai, opioid lain atau adjuvant nonopioid harus tertunda (dan kadang-kadang tidak menentu) penyerapan obat, dan tidak
digunakan. preferensi pasien berdasarkan pengalaman masa lalu dan analgesia yang konsisten respon analgesik yang disebabkan oleh variasi konsentrasi opioid
diinginkan juga harus dipertimbangkan. 25
plasma.
Intravena analgesia pasien-dikendalikan
Secara historis, meperidine (petidin) telah menjadi opioid populer (PCA) memungkinkan pasien untuk mengontrol manajemen rasa sakit mereka sendiri
untuk analgesia pasca operasi. Namun, Amerika dengan diri pemberian dosis kecil opioid intravena. SEBUAH
BAB 27 pasca operasi Analgesia 629
2015 meta-analisis menyimpulkan bahwa PCA sering disukai oleh pasien perlu perubahan khusus untuk manajemen nyeri, terutama penggunaan analgesia
dibandingkan dengan analgesia perawat-dikelola berdasarkan permintaan, multimodal (lihat pembahasan selanjutnya).
dan PCA ditunjukkan untuk memberikan kontrol nyeri yang lebih baik dan profesional perawatan kesehatan yang meresepkan PCA harus (1) dapat
meningkatkan kepuasan pasien dibandingkan dengan metode mengevaluasi calon PCA (misalnya, keadaan mental, tingkat kesadaran,
non-pasien-dikendalikan. 28 American Society of Anesthesiologists (ASA) Task pemahaman pasien); (2) Kriteria know pemilihan obat, dosis jadwal, periode
Force untuk Akut Sakit di Pengaturan perioperatif dianjurkan bahwa “modalitas lockout, dan perangkat infus; (3) mampu memberikan pendidikan pasien pada
ini [epidural atau intratekal opioid, PCA opioid sistemik, dan teknik daerah manajemen nyeri dan penggunaan PCA; (4) memahami kapan harus
perifer] harus digunakan dalam preferensi untuk opioid intramuskular mengubah pengaturan PCA dan kapan untuk memberikan atau tidak
memerintahkan 'yang diperlukan .' ” 29 memberikan tambahan (rescue) dosis obat; dan (5) dapat menanggapi efek
samping dan efek samping. studi observasional kohort nonobstetric telah
The American Pain Society telah merekomendasikan penggunaan melaporkan kejadian depresi pernapasan dengan PCA intravena 0% menjadi
intravena opioid PCA saat pemberian parenteral analgesik diperlukan 11,5%, yang setara atau lebih tinggi dari yang dilaporkan untuk opioid
dan rute oral tidak tersedia. 30 neuraksial. 36-41
PCA telah digunakan melalui rute intravena dan epidural setelah sesar.
Sebuah studi yang membandingkan PCA intravena dan epidural
menggunakan fentanyl melaporkan skor nyeri yang lebih tinggi dan konsumsi Pada bulan Desember 2004, Komisi Bersama 42 mengeluarkan Sentinel acara
fentanil lebih besar dengan rute intravena, meskipun kepuasan pasien adalah Alert pada PCA “oleh proxy” (yaitu, ketika orang lain, termasuk anggota
serupa pada kedua kelompok. 31 Dalam studi lain yang dibandingkan intravena keluarga, menjadi terlibat dalam pemberian obat oleh PCA). Komisi Bersama
dibandingkan PCA epidural menggunakan hidromorfon, kebutuhan obat mengakui bahwa PCA adalah metode yang aman dan efektif untuk mengontrol
adalah 3 sampai 4 kali lipat lebih tinggi pada kelompok intravena; kedua nyeri bila digunakan seperti yang ditentukan; Namun, efek samping yang serius,
kelompok memiliki skor nyeri dan sedasi serupa, tetapi pasien dalam termasuk oversedation, depresi pernafasan, dan kematian, dapat terjadi ketika
kelompok intravena dilaporkan lebih sering mengantuk dan kurang pruritus. 32 Studi analgesia disampaikan “oleh proxy.” Komisi Bersama 42 membuat rekomendasi
yang membandingkan intravena morfin PCA untuk single-shot administrasi berikut: (1) mengembangkan kriteria untuk memilih calon yang tepat untuk PCA,
morfin epidural analgesia postcesarean menunjukkan bahwa analgesia dan (2) hati-hati memantau pasien, (3) pasien mengajar dan anggota keluarga
kepuasan pasien lebih baik dan sedasi kurang dengan morfin epidural, tentang penggunaan yang tepat dari PCA dan bahaya lain menekan tombol
meskipun kejadian pruritus lebih tinggi. 33-35 untuk pasien, (4) staf waspada terhadap bahaya pemberian dosis di luar protokol
yang ditentukan, dan (5) mempertimbangkan menempatkan tag peringatan pada
semua liontin pengiriman PCA menyatakan “hanya pasien harus menekan
tombol ini.” Pengaturan PCA (obat, dosis permintaan, lockout selang, batas 4
jam, dan tingkat infus kontinu, jika digunakan) didokumentasikan pada lembar
Efek Samping dan Pertimbangan Keamanan aliran, dan setiap perubahan dalam pengaturan PCA jelas didokumentasikan.
Tujuan dari pemberian opioid adalah untuk mencapai analgesia maksimal
dengan efek samping yang minimal. Hal ini penting untuk memantau
pernapasan tingkat dan sedasi tingkat sebelum memberikan dosis tambahan
atau menyesuaikan dosis PCA bolus. Pasien dengan penyakit penyerta
seperti disfungsi hati atau ginjal (misalnya, terjadi dengan preeklamsia berat),
obesitas morbid, dan / atau apnea tidur obstruktif sangat rentan terhadap efek Infusion Pump Pengaturan
depresan pernafasan opioid; pasien ini mungkin parameter PCA diprogram termasuk pilihan obat, bolus dosis, dosis
maksimum, dan interval lockout ( tabel 27.3 ).
TABEL 27.3 Umum Pasien-Controlled Analgesia Pengaturan di Opioid-Naïve Pasien
Obat Morfin hidromorfon fentanyl
Konsentrasi 1 mg / mL 1 mg / mL 10 μ g / mL
PCA Bolus Dosis 1-1,5 mg 0,2 mg 20 μ g
Lockout Interval (min) 5-10 5-10 5
4-Hour Dosis Batas Dihitung dengan pengaturan Dihitung dengan pengaturan Dihitung dengan pengaturan
Khas PCA Dosis Ganti 0,5 mg 0,1 mg 5μg

penyelamatan Dosis 2 mg IV q 5 menit (hingga tiga dosis) 0,3 mg IV q 5 menit (hingga tiga 25 μ g IV q 5 menit (hingga tiga dosis)
dosis)
Catatan Kontraindikasi relatif pada pasien dengan fungsi Lebih kuat dari morfin efek klinis lebih pendek dari morfin
ginjal terganggu
Tercatat sebagai: PCA bolus dosis / lockout Interval / limit 4 jam / laju infus kontinu. Sebuah infus latar belakang terus menerus biasanya dihindari kecuali dalam kasus-kasus yang dipilih (misalnya,
toleransi opioid).
IV, intravena; PCA, pasien yang dikendalikan analgesia.
Courtesy dari Dana Farber Cancer Institute Nyeri dan Program Perawatan Paliatif dan Brigham dan Komite Nyeri Rumah Sakit Wanita. Dimodifikasi dengan izin dari
Bridget C. Fowler, PharmD, Farmasi Klinis Manager, Dana Farber Cancer Institute.
Owen et al. 43-45 dilakukan beberapa penyelidikan PCA pada pasien yang Oral Opioid Analgesia
menjalani operasi perut. Dalam penilaian PCA permintaan morfin dosis bolus Beberapa peneliti telah menganjurkan penggunaan analgesik lisan
(0,5, 1, atau 2 mg dengan interval lockout 5 menit), lebih banyak pasien pada bukan PCA intravena sebagai jarang ada persyaratan untuk jangka
waktu puasa berkepanjangan setelah sesar. 48-51
kelompok 0,5 mg memiliki nyeri yang tidak memadai, sedangkan pada
kelompok 2-mg memiliki lebih banyak sisi efek, termasuk depresi pernafasan Sebagian besar bukti menunjukkan intravena opioid tidak unggul opioid
(respiratory rate kurang dari 10 napas / menit). 45 hasil ini berkorelasi dengan oral untuk analgesia pasca operasi. 30 Bahkan, pasien diacak untuk
total dosis morfin dikelola sendiri. Meskipun peran interval lockout tidak dibahas oksikodon lisan mengalami sedikit rasa sakit, mual, dan mengantuk 6
dalam penelitian ini, para peneliti menyarankan bahwa analgesia memadai jam setelah sesar dibandingkan dengan mereka yang menerima infus
dapat diproduksi oleh interval lockout yang terlalu panjang atau dosis PCA morfin. 51 Dieterich et al. 52 ditemukan PCA intravena dan opioid oral
permintaan yang terlalu kecil. Sebaliknya, dosis yang lebih besar atau interval disediakan derajat kepuasan yang sama dan nyeri skor setelah sesar.
lockout pendek mungkin menyebabkan lebih banyak efek samping terkait Karena itu, ketika ditoleransi, pemberian oral opioid mungkin rute yang
opioid-. disukai administrasi. Keuntungan dari pendekatan ini adalah
penghematan biaya, fasilitasi mobilitas awal, dan, mungkin, kepuasan
pasien lebih besar. Long-acting opioid oral tidak dianjurkan pada
Meskipun pasien yang mengalami analgesia yang tidak memadai akan diharapkan
periode pasca operasi segera. 30
untuk membuat tuntutan PCA lebih, hal ini sering tidak terjadi. 45 Pasien mungkin takut
untuk mengelola terlalu banyak opioid atau mengantisipasi efek samping yang lebih
berat. Selain itu, telah menyarankan bahwa pasien tidak dianjurkan oleh efek analgesik
yang tidak memadai atau mereka mungkin mengharapkan respon tertunda. 45 multimodal Analgesia
analgesia multimodal menyeimbangkan efektivitas analgesik individu,
Terus menerus basal (background) infus tidak diperlukan pada wanita memaksimalkan keberhasilan mereka ketika mencoba untuk
opioid-naif. 45 The American Pain Society tidak merekomendasikan meminimalkan efek samping. Alasan analgesia multimodal adalah
penggunaan rutin infus basal dari opioid pada pasien opioid-naif; optimalisasi efek aditif atau sinergis dari berbagai modus analgesia atau
sebagian bukti tidak menunjukkan peningkatan analgesia dibandingkan obat kelas, sambil mengurangi dosis dan meminimalkan efek samping
dengan pasien yang tidak menerima infus basal. 30 infus basal opioid obat individu dengan mekanisme yang berbeda dari tindakan. 53 Meskipun
berhubungan dengan peningkatan insiden mual dan muntah, dan khasiat analgesik adalah tujuan utama, tujuan sekunder penting
beberapa studi telah menunjukkan peningkatan risiko untuk depresi termasuk meminimalkan transfer obat untuk ASI dan mengurangi efek
pernafasan. 30 Parker et al. 46 dibandingkan kelompok menerima intravena samping ibu yang dapat mengganggu menyusui atau perawatan bayi.
PCA morfin rejimen (bolus dosis 2 mg) dengan kelompok yang menerima Berbagai kombinasi opioid, obat anti inflamasi (NSAID), acetaminophen
rejimen PCA intravena yang sama dan malam hari infus kontinu (1 mg / (parasetamol), dan anestesi lokal adalah salah obat yang telah
jam). Tidak ada perbedaan antara kelompok sakit pasca operasi, pola digunakan dengan berbagai tingkat keberhasilan. 54-56
tidur, permintaan atau disampaikan bolus dosis per jam, konsumsi opioid,
atau pemulihan dari operasi. Penggunaan infus kontinyu mengakibatkan
enam kesalahan selama pemrograman perangkat. Tiga pasien Beberapa studi telah menunjukkan analgesia unggul bila analgesik oral
diperlukan penghentian infus terus menerus karena oksihemoglobin diberikan pada interval tetap yang telah ditentukan bukan pada
desaturation signifikan. 46 ASA Task Force pada Akut Sakit menyimpulkan permintaan. 48,57
bahwa perhatian khusus harus diambil ketika infus kontinyu digunakan
karena potensi efek samping dari akumulasi opioid. 29 acetaminophen
Acetaminophen digunakan secara luas untuk analgesia pasca operasi dan
memberikan efek opioid-sparing sekitar 10% sampai 20%. 58-60 Sebuah 2012
meta-analisis mengidentifikasi empat uji coba terkontrol secara acak
mengevaluasi acetaminophen dan efeknya pada konsumsi opioid setelah
Selama PCA, rasio tuntutan pasien untuk dosis bolus disampaikan tampaknya operasi besar; hanya satu penelitian termasuk pasien kebidanan. 61 Meta-analisis
menjadi ukuran yang baik analgesia dan sangat berkorelasi dengan skor nyeri. 47 Rasio menunjukkan bahwa acetaminophen kurang efektif daripada NSAID untuk
yang tinggi mungkin mencerminkan kesalahpahaman pasien atau analgesia tidak mengurangi konsumsi opioid dan mual pasca operasi dan muntah (PONV). 61 Perbandingan
memadai; rasio dekat dengan 1 menandakan rasa sakit yang memadai. Analgesia acetaminophen intravena dengan ibuprofen oral pada pasien postcesarean
dapat ditingkatkan dengan peningkatan dosis bolus, interval lockout pendek, atau ditemukan skor yang sama nyeri, konsumsi opioid, dan kepuasan pasien. 62 Kombinasi
perubahan dari opioid. NSAID dan acetaminophen telah terbukti sinergis dalam studi nyeri
eksperimental manusia. 63-65
Karena morbiditas signifikan yang terkait dengan dosis tinggi opioid,

penggunaan obat ini harus memanggil penerapan algoritma untuk
penilaian nyeri, manajemen, dan pemantauan. nyeri pasca operasi akut Pada tahun 2009, Amerika Serikat Food and Drug Administration (FDA)
terbatas dalam durasi; Oleh karena itu, rencana harus dirancang untuk menurunkan dosis harian maksimum direkomendasikan acetaminophen dari 4000
transisi dari opioid intravena ke agen analgesik lisan ketika rasa sakit mg untuk 3250 mg karena kepedulian terhadap toksisitas. 66 Menghindari opioid /
pasien dikendalikan dan dia mampu mengambil obat melalui mulut. acetaminophen obat kombinasi dianjurkan untuk mengurangi penggunaan opioid
yang tidak perlu dan tidak melampaui direkomendasikan dosis maksimum
acetaminophen. Perubahan ini memaksa penggantian kombinasi lisan analgesik sedasi setelah sesar. 72 Fixed-interval pemberian dosis NSAID memberikan
opioid-acetaminophen dengan dijadwalkan acetaminophen dan sebagai analgesia yang lebih efektif dan menghasilkan kepuasan pasien lebih baik
dibutuhkan opioid analgesia postcesarean. Valentine et al. 67 dilakukan rekor dari on-demand dosis. 48
tinjauan medis retrospektif perempuan yang menjalani sesar sebelum dan ibuprofen adalah salah satu NSAID yang paling banyak digunakan
setelah perubahan dalam praktek klinis di institusi mereka. Semua pasien dalam yang tersedia tanpa resep. Karena nonselektif menghambat COX-1 dan
penelitian mereka menerima anestesi spinal yang mengandung intratekal morfin COX-2 isoenzim, selain anti-inflamasi, analgesik, dan antipiretik
0,2 mg dan NSAID dijadwalkan selama 48 jam pasca operasi. Setelah sifat-sifatnya, ibuprofen juga menghambat platelet adhesi dan
perubahan, para wanita menerima lisan asetaminofen 650 mg setiap 6 jam menyebabkan vasokonstriksi arteri ginjal dan gastrointestinal
selama 48 jam pasca operasi dengan oxycodone lisan diberikan sesuai gangguan.
kebutuhan untuk nyeri terobosan. 67 dijadwalkan acetaminophen kohort Oleh karena itu, penggunaan NSAID pada pasien yang berisiko untuk
digunakan opioid kurang dari sejarah kohort yang dibutuhkan dalam 48 jam perdarahan dan gagal ginjal waran hati-hati. Meskipun demikian, di sebagian
pertama ( Gambar. 27.2 ). 67 besar ibu melahirkan tanpa faktor risiko perdarahan atau gagal ginjal,
penggunaan NSAID dianggap aman. Karena transfer terbatas ASI, NSAID
sangat bermanfaat untuk ibu menyusui. Dalam sebuah penelitian kecil (lisan
acetaminophen intravena telah mendapatkan popularitas, dengan plasma ibuprofen 400 mg setiap 6 jam selama 24 jam), kurang dari 1 mg ibuprofen
sebelumnya dan lebih tinggi dan tingkat cairan serebrospinal dibandingkan dengan itu diekskresikan dalam ASI dalam waktu 36 jam. 73 Banyak pusat mengelola
acetaminophen lisan lebih lambat diserap. 68,69 600-800 mg setiap 6 sampai 8 jam sebagai dosis standar. Ibuprofen disetujui
Namun, pada pasien dengan sistem pencernaan berfungsi, tidak ada sebagai obat terapi untuk anak-anak dan karena itu dianggap kompatibel
didokumentasikan keuntungan analgesik intravena dibandingkan dengan menyusui. 71
pemberian oral.
Nonsteroid anti peradangan Obat Lisan naproxen 500 mg setiap 12 jam telah terbukti mengurangi nyeri insisi
NSAID menekan peradangan dengan menghambat siklooksigenase (COX) enzim dibandingkan dengan plasebo dan menurunkan konsumsi opioid ( Gambar. 27,3 ).
74
dan merupakan komponen kunci dari analgesia multimodal. Mereka adalah efektif
untuk nyeri perineum setelah melahirkan vagina dan nyeri perut postcesarean; diklofenak memiliki juga telah dipelajari secara ekstensif; supositoria rektal
ketika diberikan bersama opioid, mereka menghasilkan efek opioid-sparing 30% (100 mg dua kali sehari) penurunan konsumsi morfin (14 mg dibandingkan 22
sampai 50% 60,70 yang dapat mengurangi opioid-terkait efek samping. 71 Sebuah 2016 mg dalam 32 jam) dibandingkan dengan plasebo setelah sesar. 75 Dosis dubur
review sistematis dan meta-analisis menunjukkan bahwa penggunaan NSAID tunggal diklofenak 100 mg berkepanjangan waktu yang berarti untuk
mengakibatkan skor nyeri yang lebih rendah hingga 24 jam pasca operasi, kurang administrasi analgesik pertama dengan lebih dari 5 jam pada pasien yang
konsumsi opioid, dan kurang menerima morfin intratekal. 76 Pasien yang menerima dosis morfin intratekal
sekecil 0,025 mg tidak membutuhkan analgesik penyelamatan ketika
intramuskular diklofenak 75 mg diberikan setiap 8 jam. 77 Munishankar et al. 78 pasien
secara acak yang menerima anestesi spinal dengan bupivacaine dan fentanyl
25 untuk menerima salah satu dari tiga modalitas analgesik:
20
(mg intraveous morphine equivalents)
15
Opioid use
* *
10
100
Oral Codeine (mg)
5
80
60
P < . 01
0
< 24 ≥ 24 - < 48 40 0-12 120 140
Placebo
Pasca operasi interval waktu (h) 20
Naproxen
Gambar. 27.2 penggunaan opioid dalam miligram intravena morfin setara setelah sesar 0
di 24 jam bertahap pada pasien yang menerima dijadwalkan acetaminophen dengan 13-24 25-36 37-48 49-60 61-72
yang dibutuhkan opioid ( bar gelap) Waktu (h)

dibandingkan pasien yang menerima sebagai dibutuhkan kombinasi opioid-acetaminophen ( bar
cahaya). Data yang berarti ( batang) dan standar deviasi Gambar. 27,3 Pengaruh naproxen pada kebutuhan untuk kodein oral setelah sesar:
(Kumis). * perbedaan yang signifikan antara kelompok ( P < . 001). (Digambar ulang dari Valentine penggunaan kodein lisan dalam miligram setara (dinyatakan sebagai mean) dari waktu
AR, Carvalho B, Lazo TA, Riley ET. Dijadwalkan acetaminophen dengan yang dibutuhkan opioid ke waktu oleh kelompok. (Dari Sudut PJ, Halpern SH, Leighton BL, et al. Sebuah uji
dibandingkan dengan yang dibutuhkan acetaminophen ditambah opioid untuk manajemen nyeri terkontrol acak memeriksa efek naproxen pada analgesia selama hari kedua setelah
pasca bedah caesar. Int J Obstet Anesth. 2015; 24: 210-216). sesar. Anestesi analg. 2002; 95: 741-745).
normal, setelah dosis intravena 40 mg tunggal setelah sesar. 84

25
Parasetamol
20
Alfa 2- Adrenergik Reseptor Agonis
Alfa 2- agonis reseptor adrenergik telah digunakan untuk pengobatan akut
Morphine (mg)
15 dan nyeri kronis pada pasien nonobstetric. 85
melalui pembuluh darah dexmedetomidine telah digunakan sebagai

10 Parasetamol / diklofenak Diklofenak tambahan untuk opioid sebagai komponen anestesi umum untuk sesar. 86 Dexmedetomidine
diekskresikan dalam ASI dalam konsentrasi yang sangat kecil; dosis bayi
5 relatif adalah
0.034%. 87 neuraksial clonidine memiliki telah digunakan untuk analgesia
persalinan tetapi tidak umum digunakan untuk analgesia postcesarean.
0 0-3,9
4-7,9 8-11,9 12-15,9 16-19,9 20-23,9 Perumusan epidural clonidine membawa “kotak hitam” peringatan dari FDA
Waktu (h) karena insiden hipotensi pada dosis intratekal yang lebih tinggi. 88
Gambar. 27,4 konsumsi morfin dalam miligram di berturut-turut 4 jam periode setelah
melahirkan sesar pada wanita secara acak untuk menerima acetaminophen (parasetamol),
diklofenak, atau keduanya. Data dianalisis dengan menggunakan analisis tindakan Magnesium sulfat
berulang varians; pasien dalam kelompok acetaminophen / diklofenak digunakan kurang Peripartum magnesium sulfat terapi digunakan untuk tokolisis untuk persalinan
morfin per 4 jam dibandingkan pasien di acetaminophen tapi bukan kelompok diklofenak.
prematur, profilaksis kejang pada wanita dengan preeklamsia, dan pelindung
(Digambar ulang dari Munishankar B, Fettes P, Moore C, McLeod GA. Sebuah
saraf janin pada wanita yang berisiko kelahiran prematur. 89 Sebuah 2013
double-blind acak terkontrol parasetamol, diklofenak atau kombinasi untuk menghilangkan
rasa sakit setelah operasi caesar. Int J Obstet Anesth. 2008; 17: 9-14). meta-analisis dari uji coba melalui pembuluh darah magnesium untuk
pengobatan akut nyeri pasca operasi setelah operasi nonobstetric dilakukan
dengan anestesi umum menyimpulkan bahwa pemberian magnesium sulfat
menghasilkan pengurangan kecil dalam skor nyeri pasca operasi dan
pengurangan substansial dalam penggunaan opioid, meskipun insiden mual dan
acetaminophen, diklofenak, atau diklofenak dan acetaminophen. Wanita yang muntah tidak berkurang. 90 Penggunaan magnesium intravena sebagai tambahan
menerima baik diklofenak dan acetaminophen diperlukan kurang morfin untuk analgesia postcesarean belum ketat dipelajari.
daripada mereka yang menerima acetaminophen saja ( Gambar. 27,4 ). 78
Lowder et al. 79 menunjukkan bahwa ketorolac penurunan skor nyeri pada 2,

3, 4, 6, 12, dan 24 jam setelah persalinan sesar dan juga penurunan konsumsi gabapentin
opioid. Ketorolac sebelumnya memiliki “kotak hitam” peringatan bahwa itu Gabapentin adalah antikonvulsan yang memiliki sifat analgesik, terutama dalam
“kontraindikasi pada ibu menyusui,” tapi rekomendasi saat ini untuk pengaturan nyeri neuropatik. Ini telah dipelajari secara ekstensif dalam
menggunakannya dengan hati-hati. American Academic of Pediatrics (AAP) pengelolaan nyeri kronis dan untuk analgesia pasca operasi di mana hal ini
menganggap NSAID yang aman untuk ibu menyusui. 80 Penggunaan NSAID pada terkait dengan penghentian opioid lebih cepat. 91 Namun, perannya pada pasien
wanita hamil dan menyusui dibahas secara rinci dalam Bab 14. opioid-naif setelah melahirkan sesar kurang jelas. Sebagai bagian dari rejimen
analgesik multimodal pada pasien yang menjalani sesar, dosis preoperatif
gabapentin lisan 600 mg dikaitkan dengan skor nyeri yang lebih rendah dengan
gerakan dan saat istirahat; Namun, kejadian sedasi lebih besar pada kelompok
Cyclooxygenase-2-selektif Inhibitors gabapentin dibandingkan pada kelompok plasebo (19% vs 0%). 92 Dalam sebuah
inhibitor COX-2-selektif memiliki potensi manfaat dibandingkan dengan NSAID studi tindak lanjut, dua dosis gabapentin (300 mg dan 600 mg) dibandingkan
nonselektif tradisional dalam bahwa mereka memiliki efek minimal pada adhesi dengan plasebo dalam harapan menemukan dosis efektif yang berhubungan
platelet dan dengan demikian cenderung mengganggu pembentukan gumpalan dengan kurang sedasi. Sayangnya, percobaan gagal untuk menunjukkan
darah dan berkontribusi terhadap perdarahan. Kategori ini NSAID memiliki keberhasilan dalam kedua kelompok gabapentin. 93 Hasil ini dikonfirmasi oleh
efektivitas analgesik yang sama dan opioid dosis-sparing untuk NSAID Monks et al. 94 di uji coba secara acak membandingkan gabapentin perioperatif
tradisional dalam pengaturan nonobstetric. 81 Namun, dalam pengaturan (600 mg sebelum operasi diikuti oleh 200 mg setiap 8 jam selama 2 hari) dengan
kelahiran sesar, mereka tidak muncul untuk menjadi seefektif NSAID. 82,83 Selain plasebo ketika ditambahkan ke multimodal postcesarean analgesik rejimen.
itu, kekhawatiran tentang potensi untuk meningkatkan risiko kejadian Gabapentin menghasilkan perbaikan klinis tidak signifikan dalam analgesia
kardiovaskular dan trombotik, dikombinasikan dengan baseline ditinggikan risiko (perbedaan 100-mm skor nyeri skala analog visual pada gerakan -7 mm, 95%
untuk kejadian ini selama kehamilan dan setelah melahirkan, mencegah COX-2 confidence interval [CI]
inhibitor dari memainkan peran utama dalam analgesia postpartum. celecoxib adalah
satu-satunya tersedia secara luas inhibitor COX-2-selektif di Amerika Serikat.
Kandungan ASI dari
- 13-0; P = . 047) setelah melahirkan sesar tetapi dikaitkan dengan insiden yang
lebih tinggi dari sedasi.
parecoxib dan metabolit aktif utama valdecoxib sangat rendah, dan Gabapentin mungkin memainkan peran dalam analgesia postcesarean pada pasien
neurologis dan adaptif skor neonatal yang dengan nyeri kronis dan orang-orang dengan toleransi opioid.
Ketamine dan Dekstrometorfan dikombinasikan tulang belakang-epidural [CSE] teknik). 100-102 Hal ini
Ketamine, sebuah N- metil d- aspartat (NMDA) antagonis, memiliki sifat memungkinkan pemberian obat neuraksial untuk analgesia pasca operasi.
analgesik dan mungkin memainkan peran dalam pengobatan nyeri pasca
operasi akut dan pencegahan atau pembalikan sensitisasi sentral. 95 Evaluasi administrasi opioid neuraksial saat ini merupakan “standar emas” untuk
ketamin dosis rendah untuk analgesia postcesarean dibandingkan intravena menyediakan analgesia postcesarean efektif. Sebuah 2010 tinjauan sistematis
ketamine 0,15 mg / kg, intratekal fentanyl 10 μ g, Sebuah dan plasebo. 96 Penelitian menemukan bahwa dosis tunggal morfin epidural analgesia menyediakan lebih
menunjukkan durasi berkepanjangan analgesia baik di fentanil dan ketamin baik dari opioid parenteral setelah sesar. 103 Sebuah meta-analisis dari penelitian
kelompok dibandingkan dengan kelompok plasebo (waktu untuk permintaan yang melibatkan populasi luas pasien yang menjalani berbagai prosedur bedah
analgesik pertama 145 menit pada kelompok plasebo, 165 menit pada menegaskan bahwa opioid disampaikan oleh salah satu pasien yang
kelompok fentanil, 199 menit pada kelompok ketamin). Ketamine adalah dikendalikan analgesia epidural (PCEA) atau terus-menerus epidural infus (CEI)
unggul fentanyl dan plasebo untuk mengurangi skor nyeri pada 90 dan 180 memberikan bantuan nyeri pasca operasi yang lebih unggul yang disediakan
menit, dan mengurangi kebutuhan analgesik dalam 24 jam pertama, tapi oleh PCA intravena. 104 Hasil serupa telah dilaporkan dalam studi
tidak dalam kedua 24 jam, setelah sesar. 96 Dalam pengaturan di mana opioid membandingkan intratekal dan epidural administrasi opioid dengan PCA opioid
intratekal tidak tersedia, administrasi ketamin intravena 0,15 mg / kg segera intravena atau administrasi opioid intramuskular setelah sesar ( Gambar. 27,5 ). 33,34,105,106
setelah bupivacaine anestesi spinal menghasilkan analgesia pasca operasi

yang lebih baik dan mengurangi kebutuhan analgesik dibandingkan dengan
garam-plasebo. 97 Sebaliknya, dalam studi lain di mana wanita yang menjalani
sesar secara acak menerima intravena ketamin 10 mg atau plasebo tak lama opioid neuraksial juga menyediakan analgesia postcesarean unggul
setelah melahirkan sebagai bagian dari rejimen multimodal morfin intratekal dibandingkan dengan teknik non-neuraksial daerah (misalnya, transversus
dan administrasi NSAID biasa, penulis tidak dapat menunjukkan perbedaan abdominis pesawat block), infiltrasi luka lokal, dan lisan analgesik (misalnya,
NSAIDs dan opioid). 54,107-109
sakit terobosan , waktu untuk permintaan analgesik pertama, atau
persyaratan penyelamatan analgesik kumulatif. 98 Namun, skor nyeri yang Meskipun penawaran analgesia neuraksial manfaat penting dalam
lebih rendah pada kelompok ketamin 2 minggu setelah operasi. mengoptimalkan analgesia pasca operasi, strategi analgesik multimodal
menambah efek analgesik opioid neuraksial. 109
Paling umum, neuraksial analgesia opioid berfungsi sebagai komponen

utama dari analgesia multimodal.
Meskipun analgesia lebih unggul, beberapa efek samping terkait
opioid-(misalnya, pruritus) lebih umum setelah pemberian opioid neuraksial. 105.110.111
Sebuah 2015 tinjauan literatur sistematis dan meta-analisis termasuk tujuh kedua tinggi 111.112 dan menurunkan 106.113 skor kepuasan ibu telah dilaporkan
studi penggunaan ketamin selama anestesi spinal dan lima selama anestesi dengan neuraksial dibandingkan dengan analgesia opioid sistemik. variabilitas
umum. 99 ketamin intravena dalam pengaturan anestesi spinal menunda waktu dalam skor kepuasan ibu melaporkan hal ini mungkin dipengaruhi oleh
untuk permintaan opioid pertama dan mengurangi rasa sakit setelah sesar bagaimana pasien menilai kualitas analgesik terhadap keberadaan dan tingkat
dengan tidak ada perbedaan dalam kejadian mual, muntah, pruritus, dan efek keparahan efek samping (misalnya, pruritus, mual dan muntah). Tergantung
psychomimetic. 99 pada prioritas individu, wanita diberi pilihan akan memilih morfin intratekal lebih
rendah jika mereka ingin
neuraksial ANALGESIA
Khasiat dan Manfaat neuraksial Analgesia
100
Kebanyakan sesar di negara maju dilakukan dengan anestesi
85% *
neuraksial (spinal, epidural, atau
80
60% †
Percentage of patients
60
Sebuah The Institute of Medicine Safe Praktek (ISMP) telah merekomendasikan bahwa berat (8-10)
45%
penyedia layanan kesehatan tidak pernah menggunakan μ g sebagai singkatan untuk
40 33% Moderate (4-7)
mikrogram, melainkan mereka harus menggunakan mcg ( http://www.ismp.org/tools/
errorproneabbreviations.pdf , Diakses Juni 2018). Penggunaan simbol μ g sering 49% Mild (0-3)
20
disalahartikan dan terlibat dalam kesalahan pengobatan berbahaya. singkatan mungkin 11% 4%
7% 6%
keliru untuk mg (miligram), yang akan menghasilkan overdosis 1000 kali lipat. Simbol μ g
0
tidak boleh digunakan ketika berkomunikasi informasi medis, termasuk farmasi dan epidural PCA AKU
resep layar agar komputer masuk, label yang dihasilkan komputer, label untuk tempat
penyimpanan obat, dan catatan administrasi pengobatan. Namun, sebagian besar Gambar. 27,5 uji coba secara acak dari analgesia postcesarean dengan analgesia
epidural, intravena analgesia pasien yang dikontrol ( PCA), atau intramuskular ( AKU) pemberian
publikasi ilmiah terus menggunakan singkatan μ g. Para editor memilih untuk
morfin. Persentase pasien melaporkan ketidaknyamanan ringan, sedang, atau berat
mempertahankan penggunaan singkatan μ g seluruh teks ini. Namun, para editor
selama periode penelitian 24 jam. * P < . 05, epidural dibandingkan PCA dan IM; † P = NS,
merekomendasikan penggunaan mcg singkatan dalam praktek klinis.
PCA dibandingkan IM. (Dari Harrison DM, Sinatra RS, Morgese L, Chung JH. Epidural
narkotika dan pasien yang dikendalikan analgesia pasca-caesar lega bagian nyeri. Anestesiologi.
1988; 68: 454-457).
efek samping menghindari atau memilih dosis yang lebih tinggi jika mereka ingin mempengaruhi fungsi motorik, nada simpatik, atau proprioception. 133 Pada
mengoptimalkan analgesia pengiriman postcesarean. 25
tahun 1979, Wang et al. 134 menerbitkan laporan pertama dari administrasi
teknik neuraksial bisa memberikan manfaat lain selain analgesia pasca morfin intratekal pada manusia yang diikuti lama kemudian oleh laporan dari
operasi yang lebih baik, termasuk peningkatan kemampuan fungsional, meperidine intratekal. morfin intratekal (0,5-1 mg) yang dihasilkan nyeri
ambulasi sebelumnya, dan kembali lebih awal dari fungsi usus. 114-118 Manfaat lengkap selama 12 sampai 24 jam di enam dari delapan pasien yang
potensial lainnya termasuk insiden lebih rendah dari infeksi paru dan menderita nyeri kanker keras, dengan tidak ada bukti sedasi, depresi
emboli paru, lebih sedikit gangguan kardiovaskular dan koagulasi, dan pernafasan, atau penurunan fungsi motorik. 134
pengurangan respon inflamasi dan stres-diinduksi untuk operasi. 114-116 Meskipun
kekayaan data dari studi klinis dan meta-analisis menunjukkan penurunan Selanjutnya, peneliti dan dokter telah divalidasi khasiat analgesik
nyeri pasca operasi, ada bukti kurang konsisten menghubungkan anestesi opioid neuraksial.
neuraksial dengan penurunan morbiditas pasca operasi dan kematian. 114.119
Sistem Saraf Pusat Penetrasi
Opioid diberikan epidural harus menembus dura, pia, dan membran arachnoid
untuk mencapai tanduk dorsal dan mengaktifkan reseptor opioid tulang
trauma bedah dan imobilitas pasca operasi berhubungan dengan belakang. Lapisan arachnoid adalah penghalang utama untuk mentransfer
peningkatan risiko pasca operasi trombosis vena dalam dan emboli obat ke dalam sumsum tulang belakang. 135 Gerakan narkoba melalui lapisan ini
paru. Insiden tromboemboli kebidanan telah meningkat 72% selama adalah pasif dan tergantung pada sifat fisikokimia opioid (lihat Bab 13). Obat
dirawat di rumah sakit untuk melahirkan antara 1998 dan 2009. 120 Faktor menembus lapisan arachnoid ini pertama harus pindah ke membran lipid
risiko tromboemboli, termasuk obesitas, usia ibu lanjut, dan bilayer, kemudian melintasi sel hidrofilik, dan akhirnya partisi ke dalam
komorbiditas medis utama, semakin umum dalam populasi obstetri. 121-123 membran sel lain sebelum memasuki cairan cerebrospinal (CSF). Opioid yang
Secara teori, ambulasi dini dan menghindari imobilitas berkepanjangan sangat larut dalam lemak (misalnya, sufentanil, fentanyl) dapat dengan mudah
dapat mengurangi risiko postpartum deep vein thrombosis dan emboli melewati membran sel hidrofobik. Namun, obat ini mengalami kesulitan
paru. analgesia pasca operasi yang efektif dapat mengurangi rasa menyeberang melalui cairan seluler hidrofilik. Sebaliknya, obat yang kurang
sakit pada gerakan, sehingga memfasilitasi pernapasan dalam, batuk, larut lemak (misalnya, morfin) memiliki tantangan yang lebih besar melintasi
dan ambulasi dini. Efek menguntungkan dapat menyebabkan membran sel, tetapi dapat dengan mudah melintasi interior sel. Dengan
penurunan kejadian komplikasi paru (yaitu, atelektasis, pneumonia) demikian, penetrasi opioid dari mater arachnoid tergantung pada kelarutan
setelah sesar. lipid obat. 136 Sangat obat larut lemak memiliki CSF bioavailabilitas miskin
karena (1) penetrasi miskin melalui lapisan arachnoid, (2) penyerapan cepat
dan penyerapan oleh lemak epidural, dan (3) penyerapan cepat oleh vena
teknik analgesik neuraksial mungkin sangat berguna untuk epidural.
mengurangi morbiditas perioperatif pada pasien kebidanan berisiko tinggi.
Wanita dengan preeklamsia berat, penyakit jantung, dan obesitas morbid
dapat mengambil manfaat dari pengurangan stres kardiovaskular dan
fungsi paru membaik terkait dengan analgesia postcesarean efektif. 124.125 Beberapa peneliti telah mempertanyakan spesifisitas neuraksial opioid
lipofilik diberikan epidural dan telah menyarankan bahwa efek analgesik utama
Peneliti telah menemukan bahwa CEI dari larutan opioid dan encer terjadi melalui penyerapan pembuluh darah, penyerapan sistemik, dan
attenuates anestesi kelainan koagulasi lokal, fluktuasi hemodinamik, dan redistribusi obat ke situs supraspinal. 137-142 Penelitian sebelumnya menyarankan
respon hormon stres pada pasien tidak hamil. 126-128 Beberapa studi bahwa fentanyl parenteral memberikan analgesia setara dengan yang
menunjukkan bahwa PCEA berbasis opioid dapat meningkatkan hasil disediakan oleh fentanyl epidural, 142.143 tetapi lebih banyak bukti baru
pascaoperasi. 129-131 Pasien yang diobati dengan PCEA meperidin setelah menunjukkan bahwa fentanyl epidural analgesia menyediakan melalui
sesar ambulated lebih cepat dan mengalami kembali awal fungsi mekanisme tulang belakang. 144-146 Cohen et al., 147 membandingkan infus kontinyu
gastrointestinal dibandingkan dengan pasien yang sama yang menerima dari fentanyl intravena dengan fentanyl epidural setelah sesar, melaporkan
infus meperidine PCA. 129 Namun, teknik analgesia neuraksial pasca peningkatan analgesia dan konsumsi analgesik kurang tambahan meskipun
operasi terus menerus juga memiliki kelemahan, termasuk mengurangi tingkat fentanyl plasma yang lebih rendah dengan pemberian epidural.
mobilitas karena infus pompa, manajemen yang lebih rumit dari Perbedaannya mungkin berhubungan dengan kecepatan administrasi. Ada
thromboprophylaxis pasca operasi, dan peningkatan beban kerja bukti bahwa pemberian bolus opioid lipofilik memiliki kedua tulang belakang dan
keperawatan. 132 efek supraspinal. 144-146,148 Sadurni et al. 148
acak 30 pasien yang menjalani operasi perut untuk menerima analgesia

neuraksial Opioid intraoperatif dengan bolus fentanyl dikelola baik oleh toraks epidural atau
Penemuan bahwa reseptor opioid dilokalisasi dalam wilayah diskrit intravena rute; pasien yang menerima fentanyl epidural diperlukan dosis
dari sumsum tulang belakang (lamina I, II, dan V dari tanduk dorsal) fentanil intraoperatif lebih rendah dibandingkan dengan mereka yang
menyarankan bahwa opioid eksogen dapat diberikan ke neuraxis menerimanya dengan rute intravena, menunjukkan bahwa fentanyl
untuk menghasilkan antinociception. Opioid diberikan untuk lapisan epidural memiliki tulang belakang serta efek supraspinal. Selain itu,
permukaan dorsal horn hasil selektif analgesia durasi lama tanpa setelah pemberian bolus epidural dari sufentanil
50 μ g dalam model anjing, konsentrasi CSF dari sufentanil adalah 140 kali lebih opioid lipid-larut menembus sumsum tulang belakang lebih cepat dan
besar daripada yang ditemukan dalam plasma, dan jumlah terdeteksi dalam CSF memiliki lebih cepat onset aksi dari agen yang larut dalam air lagi. Durasi
cisternal hanya 5% dari yang diukur dalam lumbal CSF. 149 aktivitas dipengaruhi oleh tingkat clearance obat dari situs aktivitas. opioid
lipid-larut dengan cepat diserap dari ruang epidural, sedangkan agen
morfin hidrofilik memiliki CSF bioavailabilitas yang lebih besar, hidrofilik tetap dalam CSF dan jaringan tulang belakang untuk waktu yang
dengan penetrasi yang lebih baik dalam CSF dan penyerapan kurang lama. 138.157
sistemik dari opioid lipid-larut. 150 Dosis bolus dari epidural morfin 6 hasil
mg dalam konsentrasi plasma puncak 34 ng / mL pada 15 menit setelah Intratekal dan epidural opioid sering menghasilkan analgesia intensitas lebih
pemberian dan konsentrasi CSF puncak sekitar 1000 ng / mL pada 1 besar dari dosis yang sama diberikan secara parenteral. Keuntungan dalam
jam. 151 Sebuah korelasi miskin antara efek analgesik dan kadar plasma potensi berbanding terbalik dengan kelarutan lipid dari agen yang digunakan.
morfin telah diamati setelah pemberian epidural, menunjukkan lokasi opioid hidrofilik menunjukkan keuntungan terbesar dalam potensi; rasio potensi
didominasi tulang belakang aksi. 152.153 administrasi intratekal untuk intratekal dengan morfin sistemik adalah sekitar 1: 100. 157.158
memungkinkan untuk injeksi obat langsung ke CSF. Ini adalah metode
yang lebih efisien memberikan opioid reseptor saraf tulang belakang dari
administrasi epidural atau parenteral. Dosis bolus dari intratekal morfin epidural Opioid
0,5 mg menghasilkan lebih tinggi konsentrasi CSF dari 10.000 ng / mL, Penyediaan sesar anestesi menggunakan kateter epidural (ditempatkan
dengan konsentrasi plasma hampir tidak terdeteksi. 154 selama persalinan atau sebagai bagian dari teknik CSE) telah mendorong
evaluasi yang luas dari opioid epidural untuk memfasilitasi analgesia pasca
operasi ( tabel 27.5 ).
Morfin
Distribusi dan Gerakan Opioid dalam sistem saraf pusat Bebas pengawet morfin menerima persetujuan FDA untuk administrasi
neuraksial pada tahun 1984, dan kemudian pemberian morfin epidural
Gerakan dan distribusi opioid dalam sistem saraf pusat (SSP) berikut telah banyak diteliti dan banyak digunakan. 159 administrasi epidural morfin
pola tertentu. Gerakan di sumsum tulang belakang adalah seperti yang memberikan analgesia postcesarean unggul yang disediakan oleh morfin
agen lipofilik (misalnya, fentanyl) yang diambil oleh materi putih dengan intravena atau intramuskular. 33,34,105,106 Sebuah meta-analisis
jauh lebih besar afinitas dari agen hidrofilik (misalnya, morfin), dan obat menyimpulkan bahwa Memperpanjang pemberian morfin epidural waktu
kurang akan mencapai materi abu-abu dari tanduk dorsal. 135.136.155 Dalam untuk permintaan analgesik pertama, menurun skor nyeri, dan
ruang epidural (dan lemak kemudian epidural atau vena), agen lipofilik mengurangi permintaan analgesik pasca operasi selama 24 jam pertama
lebih mungkin untuk diserap dan diangkut dari ruang epidural untuk setelah sesar dibandingkan dengan pemberian opioid sistemik. 103 Namun,
sirkulasi sistemik. Penyebaran rostral di CSF ditentukan oleh CSF pemberian morfin epidural dikaitkan dengan peningkatan risiko untuk
bioavailabilitas obat dan gradien konsentrasi obat; opioid hidrofilik pruritus (risiko relatif [RR], 2,7; 95% CI, 2,1-3,6) dan mual (RR, 2,0; 95%
(misalnya, morfin) berhubungan dengan spread yang lebih rostral. 149.156 CI, 1,2-3,3) dibandingkan dengan pemberian opioid sistemik . 103
Meskipun dosis opioid, volume injectate, dan derajat ionisasi adalah

variabel penting, kelarutan lemak memainkan peran kunci dalam Onset dan durasi. Setelah pemberian epidural, konsentrasi morfin
menentukan timbulnya analgesia, yang dermatomal menyebar, dan durasi plasma adalah serupa dengan yang diamati setelah injeksi intramuskular.
aktivitas ( tabel 27.4 ). 138.157 Sangat morfin epidural memiliki relatif
TABEL 27.4 Spinal Opioid Physiochemistry dan farmakodinamik
Potensi Gain
(Epidural vs
μ- Opioid IV atau SC)
Berat molekul lipid larut Sebuah parenteral Receptor disosiasi Timbulnya Durasi
opioid Potensi pKa Affinity Kinetics Analgesia Analgesia
Morfin 285 0,7 1 7,9 Moderat Lambat 10 Terlambat berkepanjangan
meperidine 247 39 0,1 8,5 Moderat Moderat 2-3 Cepat Menengah

metadon 309 116 2 9.3 Tinggi Lambat 2-3 Cepat Menengah
hidromorfon 285 1,28 10 Tinggi Lambat 5 Cepat berkepanjangan
alfentanil 417 129 25 6,5 Tinggi sangat cepat 1-2 Yang sangat cepat pendek
fentanyl 336 717 80 8.4 Tinggi Cepat 1-2 Yang sangat cepat pendek
sufentanil 386 2842 800 8,0 Sangat tinggi Moderat 1-1,5 Yang sangat cepat pendek
IV, intravena; SC, subkutan.

Sebuah koefisien partisi oktanol-air pada pH 7,4.
TABLE 27.5 Epidural Opioids for Cesarean Delivery
Onset Puncak Effect Durasi (h)

Narkoba) Dosis (min) (min) Keuntungan kekurangan
Morfin 2-4 mg 30-60 60-90 12-24 Durasi panjang Delayed onset Side-effect profile Potential
for delayed respiratory depression
Fentanyl 50–100 µ g 5 20 2–3 Rapid onset Short duration

Sufentanil 10–25 µ g 5 15–20 2–4 Rapid onset Short duration
Meperidine 25–50 mg 15 30 4–6 Rapid onset Nausea and vomiting
Hydromorphone 0.4–1 mg 15 45–60 10–20 Intermediate onset and duration Side-effect profile similar to that of
morphine
Morphine/fentanyl 3 mg/50 µ g 10 15 12–24 Rapid onset Long duration
Fewer side effects than
morphine 5-mg dose
Morphine/sufentanil 3 mg/10 µ g 5 15 12–24 Rapid onset Long duration

Fewer side effects than
morphine 5-mg dose
onset lambat tindakan sebagai akibat dari yang kelarutan lemak rendah dan
*
penetrasi lebih lambat dalam jaringan tulang belakang. 138-140,157 Efek analgesik
puncak diamati 60 sampai 90 menit setelah pemberian. 151 Banyak dokter lebih
90
memilih untuk menunda pemberian morfin epidural sampai segera setelah 100
110
melahirkan bayi. 70 **
Morfin memiliki durasi berkepanjangan analgesia, dan kemanjuran 80
PCA morphine use (mg)
40
analgesik biasanya berlanjut lama setelah konsentrasi plasma telah 50
menurun ke tingkat subterapeutik. 138.151.157 morfin epidural memberikan 60
10
rasa sakit selama kurang lebih 24 jam setelah sesar 160-163 ; Namun, ada 20
variasi yang luas dalam durasi analgesik dan kemanjuran antara 30
pasien. Dalam rentang sempit dosis dipelajari, peneliti belum

menunjukkan korelasi antara dosis morfin dan durasi analgesia. 161.163.164
0
0.0 1.25 2.50 3.75 5.0
Epidural morphine dose (mg)

Volume pengencer tidak muncul untuk mempengaruhi
farmakokinetik atau kegiatan klinis morfin epidural. Kualitas dan Fig. 27.6 Random allocation dose-response trial of epidural morphine
0, 1.25, 2.5, 3.75, and 5.0 mg for postcesarean delivery analgesia. Breakthrough pain
durasi analgesia, kebutuhan analgesik tambahan, dan kejadian efek
as assessed by total 24-hour patient-controlled analgesia ( PCA) morphine use. Data
samping adalah serupa ketika epidural morfin 4 mg diberikan dengan are mean ± 95% confidence interval. Groups were significantly different ( P < . 001).
*Group 0.0 mg was significantly different from groups 2.5, 3.75, and 5.0 mg.
2, 10, dan 20 mL saline steril. 165
Dosis tunggal epidural rejimen untuk mengoptimalkan postcesarean * * Group 1.25 mg was significantly different from groups 3.75 and
5.0 mg. (From Palmer CM, Nogami WM, Van Maren G, Alves DM. Postcesarean
analgesia dan meminimalkan efek samping opioid-terkait. Dalam sebuah studi
epidural morphine: a dose-response study. Anesth Analg. 2000;90:887–891.)
dosis-respons calon, Palmer et al. 164 mengamati bahwa analgesia postcesarean
(dinilai dengan kebutuhan morfin intravena tambahan oleh PCA) ditingkatkan
sebagai dosis morfin epidural meningkat 0-3,75 mg. Sebuah peningkatan lebih
lanjut dalam dosis (sampai 5 mg) tidak secara signifikan meningkatkan analgesia direkomendasikan epidural morfin 3 mg setelah penelitian retrospektif besar
atau mengurangi jumlah morfin intravena tambahan yang digunakan dalam 24 jam morfin epidural dalam dosis berkisar antara 2 sampai 5 mg untuk analgesia
pertama pasca operasi ( Ara. postcesarean.
Dalam praktek klinis kontemporer, dosis morfin epidural 2 sampai 4 mg yang
27,6 ). 164 Chumpathong et al. 161 tidak mengamati perbedaan dalam menghilangkan paling sering digunakan. Lebih rendah dosis mungkin tidak memberikan analgesia
rasa sakit, kepuasan pasien, atau efek samping pada wanita yang menerima yang efektif, dan wanita mungkin memerlukan tambahan analgesia tambahan, 162.164 sedangkan
epidural morfin 2,5 mg, 3 mg, atau 4 mg untuk analgesia postcesarean. Rosen et al. 162 dosis yang lebih tinggi dapat meningkatkan opioid terkait efek samping tanpa
menemukan bahwa epidural morfin 5 mg dan 7,5 mg disediakan khasiat analgesik meningkatkan analgesia. Singh et al. 166 melakukan secara acak, noninferiority sidang
serupa, tetapi dosis 2 mg disediakan analgesia tidak efektif. Fuller et al. 163 di mana semua wanita yang diterima dijadwalkan
Downloaded for FK UMI Makassar (mahasiswafkumi05@gmail.com) at University of Muslim Indonesia from ClinicalKey.com by Elsevier on March 31, 2020.
For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved.
CHAPTER 27 Postoperative Analgesia 637
ketorolac and acetaminophen as well as epidural morphine. Morphine 1.5 found that the duration of analgesia ranged from 1 to 2 hours. 171
mg was noninferior to 3 mg for postcesarean delivery analgesia. They
found no difference in 24-hour opioid consumption between the 1.5-mg Local anesthetics may have a synergistic effect with epidurally
and 3-mg epidural morphine groups. 166 Thus, lower epidural morphine administered opioids. The concurrent administration of local anesthetic
doses may be appropriate when multimodal analgesia is used and reduces epidural fentanyl dose requirements after cesarean delivery. 177 Epidural
minimizing side effects is a priority. fentanyl, administered either as a single dose or as a continuous or
patient-controlled infusion, generally has fewer side effects than epidural
Epidural versus intrathecal administration. A number of studies morphine. 141,175,176 Some investigators have suggested that the
have compared the analgesic efficacy of epidural and intrathecal administration of epidural fentanyl before incision may provide preemptive
administration of opioids. Sarvela et al. 167 compared epidural morphine 3 analgesia that improves postoperative analgesia. 172
mg with intrathecal morphine

0.1 mg and 0.2 mg; the two routes of administration provided
postcesarean analgesia with similar efficacy and equal duration. Duale et
al. 168 observed modest improvements in pain scores and lower morphine Sufentanil
consumption with epidural morphine 2 mg than with intrathecal morphine Epidural sufentanil is a lipid-soluble opioid that provides a rapid onset of
0.075 mg. In both studies, the incidence of side effects (e.g., sedation, effective postcesarean analgesia. The potency ratio of epidural sufentanil
pruritus, nausea and vomiting) was not different between the epidural and to epidural fentanyl is approximately 5 : 1. 171 No differences in onset,
intrathecal routes. 167,168 A meta-analysis concluded that both epidural and quality, or duration of analgesia were found after epidural administration of
intrathecal techniques provide effective postcesarean analgesia; neither equianalgesic doses of sufentanil and fentanyl. 171 Like fentanyl, epidural
technique is superior in terms of analgesic efficacy. 169 However, intrathecal sufentanil does not provide postoperative analgesia of significant duration.
administration results in less systemic drug exposure and less potential Rosen et al. 178 compared epidural morphine 5 mg with epidural sufentanil
fetal drug exposure and has a faster onset of action than epidural 30, 45, or 60 µ g. Although most patients who received sufentanil reported
administration of morphine. Profound sedation and respiratory depression pain relief within 15 minutes, the duration of analgesia was 4 to 5 hours, in
requiring opioid reversal and intensive care monitoring has been reported contrast to 26 hours of analgesia with epidural morphine. 178 The duration of
after unintentional subdural or intrathecal administration of a dose analgesia is dose-dependent; an epidural bolus of sufentanil 25 µ g
intended for epidural administration. 170 If a CSE anesthetic is planned, produced less than 2 hours of analgesia, whereas 60 µ g provided 5 hours
intrathecal administration of the opioid may be preferable. of pain relief. 171,178
Meperidine
Fentanyl Epidural meperidine has local anesthetic properties, and it has been used
Fentanyl is not approved by the FDA for neuraxial administration, but it is for postcesarean analgesia. Two clinical trials compared the safety and
very commonly administered for short-term analgesia. Commercial efficacy of epidural meperidine 50 mg and intramuscular meperidine 100
preparations of fentanyl contain no preservative, are suitable for epidural mg administered to patients after cesarean delivery. 179,180 Epidural
or intrathecal administration, and have an excellent safety record. Grass meperidine provided a faster onset of analgesia with a duration (2 to 4
et al. 171 hours) similar to that provided by intramuscular meperidine. Paech 181 evaluated
reported that the 50% and 95% effective doses (ED 50 and ED 95, respectively) the quality of analgesia and side effects produced by a single epidural bolus
of epidural fentanyl to reduce postcesarean pain scores to less than 10 mm of meperidine 50 mg or fentanyl 100 µ g. The onset of pain relief was slightly
(using a 100-mm visual analog scale) were 33 µ g and 92 µ g, respectively. faster with fentanyl; however, the duration of analgesia was longer with
An epidural fentanyl dose of 1 µ g/kg has also been suggested to optimize meperidine. Ngan Kee et al. 182,183 compared different doses of epidural
meperidine (12.5, 25, 50, 75, and 100 mg) as well as varying volumes of
intra operative analgesia. 172 In clinical practice, doses of 50 to 100 µ g are diluent. They concluded that meperidine 25 mg diluted in 5 mL of saline
given alone or in combination with epidural morphine. was superior to 12.5 mg and that doses greater than 50 mg offered no
improvement in the quality or duration of analgesia. Studies that have
The slow onset of action of morphine limits its ability to provide optimal compared a single bolus dose of epidural or intrathecal morphine with
intraoperative analgesia, and more lipophilic opioids (e.g., fentanyl) with a PCEA meperidine have reported superior analgesia with morphine, but with
faster onset of analgesia are more appropriate for supplementation of a higher incidence of opioid-related side effects such as nausea, pruritus,
intraoperative anesthesia (see Table 27.4 ). 157,173 Although single-dose and sedation. 184,185
epidural fentanyl improves intraoperative anesthesia, no meaningful

postoperative pain relief occurs beyond 4 hours. 174 Duration is variable and
dose dependent. 175,176 A dose-response study of epidural fentanyl 25, 50,
100, and 200 µ g, administered at the time of first complaint of
postoperative pain following epidural anesthesia (lidocaine with Other Epidural Opioids
epinephrine), Hydromorphone is a hydroxylated derivative of morphine with a lipid
solubility intermediate between that of morphine
638 PART VII Cesarean Delivery
and meperidine. 186 The quality of epidural hydromorphone analgesia after 50 µ g, or morphine 2 mg with sufentanil 25 µ g. The addition of sufentanil
cesarean delivery appears to be similar to that observed with epidural to epidural morphine provided a more rapid onset and similar duration of
morphine; however, its onset is faster and its duration shorter. 187–189 Evidence postcesarean analgesia than morphine alone. 201 In another study,
suggests a potency ratio of 3 : 1 to 5 : 1 between epidural morphine and morphine alone or in combination with sufentanil provided analgesia of
epidural hydromorphone. 186 Chestnut et al. 189 evaluated postcesarean longer duration than sufentanil alone. Sinatra et al. 202 were unable to show
analgesia with epidural hydromorphone 1 mg. Most patients reported good any potentiation when epidural sufentanil 30 µ g was added to morphine 3
or excellent pain relief, and the mean time to first request for supplemental mg, and the duration of this combination was shorter than that of epidural
analgesia was 13 hours. Dougherty et al. 187 reported that epidural morphine 5 mg alone.
hydromorphone 1.5 mg provided 18 hours of postcesarean analgesia and
that the duration was prolonged to 24 hours with the addition of
epinephrine. Henderson et al. 188 observed 19 hours of postcesarean Patient-Controlled Epidural Analgesia (PCEA)
analgesia with epidural hydromorphone 1 mg. The incidence of pruritus The use of continuous epidural analgesia is a popular means of providing
was high in the two latter studies. 187,188 postoperative analgesia in patients undergoing thoracic or upper abdominal
surgery. Better analgesia at rest and with movement has been reported in
reviews of studies that compared epidural analgesia with intravenous PCA
Halpern et al. 190 found no overall differences in quality of postcesarean after nonobstetric surgery. 7,104 A systematic review of studies comparing
analgesia or severity of side effects between patients who received PCEA, CEI, and intravenous PCA suggested that CEI provides better
epidural hydromorphone 0.6 mg or epidural morphine 3 mg. A analgesia than PCA and PCEA in nonobstetric patients. 104 However, marked
meta-analysis suggested that epidural morphine and hydromorphone heterogeneity among studies prevented definitive conclusions.
provide analgesia with similar efficacy and side effects when given for the
treatment of acute or chronic pain. 191
PCEA is less frequently used for analgesia after cesarean delivery

Diamorphine ( heroin) is a lipid-soluble diacetylated derivative of compared with single-dose epidural morphine. Fanshawe 203 compared
morphine that is commonly administered neuraxially in the United PCEA meperidine with single-dose epidural morphine. Postoperative pain
Kingdom. 192 The lipid solubility of diamorphine provides rapid-onset scores were better with epidural morphine at 6, 8, and 24 hours. 203 However,
analgesia, and its principal metabolite (morphine) facilitates prolonged lipophilic opioids have been widely evaluated for PCEA after cesarean
duration of analgesia, although less than that of morphine. Roulson et al. 193 delivery ( Table 27.6 ) and can be used when requirement for long-lasting
found that epidural diamorphine 2.5 mg provided postcesarean analgesia analgesia is anticipated. 204,205 Epidural morphine’s prolonged latency and
for 16 hours. Other investigators have found a duration of postcesarean risk for delayed respiratory depression make it a less safe option for
analgesia of 6 to 12 hours after epidural diamorphine 5 mg. 194–196 In the continuous epidural infusion. Previous investigations have compared
United Kingdom, the National Institute for Health and Care Excellence meperidine PCEA with other routes of parenteral administration (PCA,
(NICE) suggests a dose of epidural diamorphine of 2.5 to 5 mg for intramuscular). Paech et al. 206 performed a crossover study comparing
postcesarean analgesia. 197 PCEA with intravenous PCA meperidine after cesarean delivery; patients
were randomly assigned to either PCEA or intravenous PCA for 12 hours
before crossing over to the other route of drug administration for the next
12 hours. The PCEA and PCA meperidine protocols in this study were
Epidural Opioid Combinations identical (20-mg bolus, 5-minute lockout). Patients receiving meperidine
Theoretically, the epidural administration of a lipophilic opioid combined PCEA had lower pain scores at rest and with coughing than patients
with morphine should provide analgesia of rapid onset and prolonged receiving intravenous PCA. Ngan Kee et al. 31 observed that PCEA (fentanyl
duration. The use of lipophilic opioids administered intrathecally (e.g., or meperidine) regimens were associated with lower pain scores compared
fentanyl 15 µ g) or epidurally (e.g., fentanyl 100 µ g) in combination with with the respective PCA regimens. Goh et al. 207 observed similar analgesic
epidural morphine 3.5 mg improves intraoperative anesthesia and profiles among patients receiving fentanyl and meperidine PCEA, but noted
reduces nausea and vomiting during cesarean delivery. 198,199 Some more favorable side-effect profiles and better patient satisfaction among
investigators have expressed concern that opioid interactions might patients receiving meperidine PCEA.
reduce analgesic efficacy after epidural administration and that neuraxial
fentanyl might initiate acute tolerance or affect the pharmacokinetic and
receptor-binding characteristics of morphine. However, these concerns
have not been confirmed in subsequent studies. 199,200
Cooper et al. 130 postulated that the combination of epidural fentanyl with
Epidural fentanyl, administered immediately after delivery of the infant, local anesthetic (fentanyl 2 µ g/mL with
improved the quality of intraoperative analgesia without worsening epidural 0.05% bupivacaine) would provide better analgesia than that provided by a
morphine analgesia after cesarean delivery. 199 single-drug PCEA regimen (fentanyl 4 µ g/mL or 0.1% bupivacaine). The
combination drug regimen was associated with lower pain scores at rest
Studies of combined epidural morphine and sufentanil have and significantly lower total drug requirements. However, no significant
produced mixed results. Dottrens et al. 201 compared a single epidural differences in pain scores during coughing were reported among
dose of either morphine 4 mg, sufentanil
TABLE 27.6 Comparative Studies Investigating Opioid-Containing, Patient-Controlled Epidural Analgesia

Regimens for Postcesarean Analgesia
Mean Total 24-h
Comparison(s) a PCEA Dosing Regimen Pain Scores Opioid Use
PCEA versus Intramuscular Opioids

Meperidine PCEA versus meperidine IM (100 mg, B = 10 mg LO = PCEA group lower VAS score 625 mg versus 485 mg
q3–4 h) 129
20 min BI = 10 (3–24 h) (PCEA versus IM; P < . 05)
mg/h
PCEA versus Epidural Opioid

Meperidine PCEA versus epidural morphine (B = 4 mg) 203 B = 15 mg LO = VAS score lower at 2 h; higher at PCEA = 192 mg (NA for
10 min No BI 8, 10, 24 h in PCEA group epidural morphine)
Fentanyl PCEA versus epidural morphine (B B = 50 µ g LO = 5 min (max 100 µ g/h) No differences in pain PCEA = 680 µ g
= 3 mg) 204 outcome measurements
PCEA versus PCA

Meperidine PCEA versus meperidine PCA (B = 20 mg; B = 20 mg LO PCEA lower VAS score (2–24 NA
LO = 5 min) 206
= 5 min No BI h)
Meperidine PCEA versus PCA; fentanyl PCEA versus Meperidine PCEA/PCA: B = 20 Meperidine PCEA versus PCA: NA
PCA (4 groups: cross-over study) 31 mg LO = 6 min No BI Fentanyl lower VAS score Meperidine
PCEA/PCA: B = 40 µ g LO = 6 versus fentanyl: no difference in
min No BI VAS score (PCEA and PCA)
Hydromorphone PCEA versus PCA (B = 0.15 Hydromorphone PCEA: Loading dose = No differences in pain VAS PCEA 1.8–2.1 mg versus
mg, LO = 10 min) 32
0.225–0.9 mg B = 0.15 mg LO = 30 min score PCA 7.6 mg
PCEA versus PCEA

Meperidine PCEA versus fentanyl PCEA 207 Meperidine PCEA: B = No differences in pain VAS NA
25 mg LO = 20 min No score
BI Fentanyl PCEA: B =
50 µ g LO = 20 min
Three groups 130 : All PCEA regimens: B = 5 No differences in pain VAS score NA
Bupivacaine 0.1% PCEA mL LO = 10 min on coughing
Fentanyl PCEA 4 µ g/mL
Bupivacaine 0.1% + fentanyl PCEA 4 µ g/mL
Four groups 131 : All PCEA regimens: B = 2 No differences in pain VAS NA

Hydromorphone PCEA Hydromorphone PCEA + BI mL LO = 30 min score
Hydromorphone + 0.08% bupivacaine PCEA Hydromorphone BI =
0.0375 mg/h
Hydromorphone + 0.08% bupivacaine PCEA + Combination BI =
combination BI hydromorphone
0.0375 mg/h + bupivacaine
0.04 mg/h
Continued
TABLE 27.6 Comparative Studies Investigating Opioid-Containing, Patient-Controlled Epidural Analgesia

Regimens for Postcesarean Analgesia—cont’d
Mean Total 24-h
Comparison(s) a PCEA Dosing Regimen Pain Scores Opioid Use
Four groups 205 : All PCEA regimens: BI = Ropivacaine 0.025% group NA

Ropivacaine 0.025% PCEA 10 mL/h B = 4 mL LO = 10 reported lower VAS score
Ropivacaine 0.05% PCEA min
Ropivacaine 0.1% PCEA
Ropivacaine 0.2% PCEA
(All PCEA solutions contained fentanyl
3.0 µ g/mL + epinephrine 0.5 µ g/mL)
Sufentanil PCEA 0.8 µ g/mL versus fentanyl PCEA 2 µ g/mL All PCEA regimens: B = 3 No differences in pain VAS NA
b , 208
mL LO = 15 min BI = 16 score
mL/h
B, Bolus; BI, background infusion; IM, intramuscular injection; LO, lockout interval; NA, data not available; PCA, intravenous patient-controlled analgesia; PCEA, patient-controlled
epidural analgesia; VAS, visual analog scale.
a Superscript numbers indicate chapter references.
b Both groups received 0.01% bupivacaine + epinephrine 0.5 µ g/mL.
found between the two treatment groups. In a follow-up study, these

100
investigators assessed hydromorphone PCEA, with and without a
90
background infusion, and hydromorphone combined with 0.08%
80 bupivacaine, with and without a background infusion. 131 No differences in
Visual analog scale on coughing (mm)
pain scores, PCEA usage, or 24-hour PCEA requirements were noted,

70
and the combination of hydromorphone-bupivacaine PCEA with a
60
background infusion was associated with a greater degree of lower
50 extremity numbness and weakness.
40
Cohen et al. 208 compared fentanyl 2 µ g/mL and sufentanil
30
0.8 µ g/mL PCEA with 0.01% bupivacaine and epinephrine
20 0.5 µ g/mL after cesarean delivery. Pain scores and side effects (nausea,
10
pruritus, and sedation) were similar in the two groups; however, vomiting
occurred more commonly in the sufentanil group. Vercauteren et al. 209 compared
0
0.5 4 8 12 24
sufentanil PCEA (bolus 5 µ g, lockout 10 minutes) with an identical PCEA
Time after operation (h) regimen accompanied by a background infusion of sufentanil 4 µ g/h. 209 Pain
was lower at 6 hours in the group receiving PCEA with a background
Fig. 27.7 Randomized trial of postcesarean delivery patientcontrolled epidural infusion, but no other differences in analgesia were reported between 6
analgesia ( PCEA) with fentanyl 4 µ g/mL, 0.1% bupivacaine, or both fentanyl 2 µ g/mL
and 24 hours. It is not surprising that the overall incidence and severity of
and 0.05% bupivacaine. Pain scores during coughing on a 100-mm visual analog
scale. Median score ( bars) and interquartile range ( whiskers) for groups who received
sedation were higher in the background infusion group that received
epidural bupivacaine ( dark blue bars), fentanyl ( medium blue bars), and bupivacaine considerably more sufentanil.
plus fentanyl ( light blue bars). There were no differences in scores among the three
groups. (From Cooper DW, Ryall DM, McHardy FE, et al. Patient-controlled extradural
analgesia with bupivacaine, fentanyl, or a mixture of both, after caesarean section. Br
Although CEI or PCEA can provide satisfactory postoperative
J Anaesth. 1996;76:611–615.)
analgesia, these techniques may diminish maternal satisfaction as a
result of local anesthetic–induced motor block in lower limbs and the lack
of physical independence from infusion devices in the postpartum period.
the three groups ( Fig. 27.7 ). Cohen et al. 205 compared four different They increase cost and potentially increase the risk for catheter-related
concentrations of ropivacaine (0.025%, 0.05%, complications (e.g., hematoma, infection) in comparison with single-dose
0.1%, 0.2%) with fentanyl 3 µ g/mL and epinephrine 0.5 µ g/ administration of neuraxial morphine. 101,210
mL. The lowest-dose group (0.025%) received the largest volume in the
epidural space, and had the lowest 24-hour pain scores and highest Neuraxial morphine may facilitate early discharge after elective cesarean
satisfaction scores with no immobility or urinary retention. deliveries, a strategy suggested by the NICE guidelines, which state that
“women who are recovering well, are apyrexial and do not have
Parker and White 32 compared hydromorphone PCEA with intravenous complications following cesarean should be offered early discharge.” 197
PCA; no differences in pain scores were
Extended-Release Epidural Morphine weighed against the potential risk for serious side effects associated with
Extended-release epidural morphine (EREM) is an FDAapproved drug EREM administration. The role of EREM for postcesarean analgesia
that delivers standard morphine sulfate via DepoFoam (Pacira remains unclear.
Pharmaceuticals, Inc., San Diego, CA). DepoFoam is a drug-delivery
system composed of multivesicular lipid particles containing nonconcentric Intrathecal Opioids
aqueous chambers that encapsulate the active drug. 211,212 These naturally Spinal anesthesia has become the preferred anesthetic technique for
occurring lipids are broken down by erosion and reorganization, resulting patients undergoing elective cesarean delivery in the United States and the
in a sustained release of morphine for up to 48 hours after epidural United Kingdom. 100–102 Intrathecal opioids are commonly administered with a
administration of a single dose. 212–214 local anesthetic to improve intraoperative anesthesia and postoperative
analgesia ( Table 27.7 ).
After treatment with EREM, lower pain scores and lower requirement
for supplemental analgesia over 48 hours were reported compared with
standard epidural morphine. 160,215 Morphine
Supplemental analgesia consumption was reduced by 60% in women who The potency differences between intrathecal and epidural opioids
received a single dose of EREM 10 mg compared with standard epidural account for the smaller doses of intrathecal opioid used for cesarean
morphine 4 mg after cesarean delivery. 160 However, caution is required as delivery. Intrathecal morphine 0.075 to
pooled data from EREM studies for nonobstetric surgery suggest that 0.2 mg is equivalent to epidural morphine 2 to 3 mg. 167,168 The analgesic
EREM is associated with more opioid-related side effects, especially with efficacy, duration of action, and side-effect profile of intrathecal morphine are
higher doses, including a significantly higher risk for respiratory depression similar to that of epidural morphine (see earlier discussion). 167,168,222
compared with intravenous opioid PCA (odds ratio [OR], 5.8; 95% CI, 1.1 to
31.9; P = . 04). 212,216,217 Onset and duration. Intrathecal morphine administration may result
in a faster onset of analgesia than epidural morphine, but 60 to 90
Use of EREM requires extended monitoring for respiratory depression minutes are still required for the drug to achieve a peak effect. The
duration of analgesia is similar to the duration after epidural administration
(48 hours compared with 24 hours with standard epidural morphine). 218 Unintentional
intrathecal EREM administration has the potential to result in profound (14 to 36 hours). a A systematic review and meta-analysis found that the
and prolonged opioid-related side effects, although a case report of median time to first analgesic request after cesarean delivery was 27
unintentional intrathecal administration of a standard dose of EREM did hours (range, 11 to 29 hours) after intrathecal morphine administration. 113 The
not result in significant side effects or respiratory depression. 219 duration of analgesia is dose-dependent. 113,223,226 A 2016 meta-analysis
comparing low-dose (0.05 to 0.1 mg) and high-dose (>0.1 to 0.25 mg)
intrathecal morphine found mean time to first analgesic request was
Caution should be exercised when the administration of EREM longer (mean difference, 4.5 hours; 95% CI, 1.8 to 7.1; P = . 0008) for the
follows the use of any epidural local anesthetic. A 2011 study found that high-dose group compared with the low-dose group. 226
epidural lidocaine administration (20 to 35 mL) for cesarean delivery,
administered 1 hour before EREM administration, increased peak
venous blood morphine levels and increased the incidence of vomiting,
use of supplemental oxygen, and hypotension, compared with a control Dose. Several studies have attempted to determine the optimal dose
group that did not receive epidural lidocaine. 220 of intrathecal morphine for postcesarean analgesia. Palmer et al. 227 compared
postcesarean intravenous PCA morphine use after doses of intrathecal
However, Gambling et al. 221 demonstrated no differences in the morphine ranging from 0.025 to 0.5 mg. The investigators found no
pharmacokinetic and pharmacodynamic profiles of EREM when
administered 15, 30, and 60 minutes after epidural bupivacaine 0.25%.
Any analgesic advantage must be a 29,112,113,138–140,157,167,168,222–225
TABLE 27.7 Intrathecal Opioids for Cesarean Delivery
Drug Dose Onset (min) Peak Effect (min) Duration (h) Advantages Disadvantages
Morphine 0.05–0.2 mg 30–60 60–90 14–36 Long duration Side-effect profile

(50–200 µ g) Potential for delayed respiratory depression
Fentanyl 10–25 µ g 5 10 2–3 Rapid onset Minimal postoperative analgesia Short

duration Pruritus
Sufentanil 2.5–5 µ g 5 10 2–4 Rapid onset Minimal postoperative analgesia Short

duration Pruritus
Meperidine 10 mg 10–15 15–20 4–5 Rapid onset Minimal postoperative analgesia Nausea
and vomiting
significant difference in PCA morphine use with morphine doses greater but are associated with increasing side effects and limited improvement
than 0.075 mg. 227 They concluded that there was little justification for using in analgesic quality in the average patient. Because of the variability in
a dose of intrathecal morphine higher than 0.1 mg. Milner et al. 228 noted that patient response to intrathecal morphine, some patients treated with low
intrathecal morphine 0.1 mg and 0.2 mg produced comparable analgesia doses may experience inadequate postoperative analgesia and/or
but that the lower dose led to less nausea and vomiting. Yang et al. 229 found opioidrelated side effects. Thus, the use of low-dose intrathecal morphine
that intrathecal morphine 0.1 mg provided similar postcesarean analgesia as a component of multimodal analgesia may provide optimal analgesia
with fewer side effects in comparison with 0.25 mg. Uchiyama et al. 230 performed with a low risk for side effects.
a doseresponse study with intrathecal morphine 0, 0.05, 0.1, and
The relationship between patients’ expectations for pain after a
cesarean delivery and their analgesic needs requires more study.
0.2 mg. They observed that 0.1 mg and 0.2 mg provided comparable and Carvalho et al. 25 investigated the relationship between patients’ choice for
effective postcesarean analgesia for 28 hours. The 0.05-mg dose was less their dose of intrathecal morphine and postcesarean pain scores and
effective, and the incidence of side effects was greater with the 0.2-mg opioid use. Patients were randomly assigned to a choice of 0.1 or 0.2 mg
dose; therefore, the investigators concluded that intrathecal morphine 0.1 of intrathecal morphine or no choice. Women assigned a choice were
mg is the optimal dose for postcesarean analgesia. 230 Berger et al. 231 read a standardized script that discussed the trade-off of pain relief with
increased risk for the most common intrathecal morphine side effects
compared 0.05, 0.1, and 0.15 mg of intrathecal morphine in women who (nausea, vomiting, and pruritus). 25 Participants who requested the larger
received multimodal analgesia with intravenous ketorolac; all doses dose of intrathecal morphine required more supplemental opioids and
provided similar analgesia after cesarean delivery. There were no reported more pain with movement regardless of the intrathecal morphine
differences in 24-hour morphine consumption or reported pain or nausea dose they actually received. 25 Thus, patients may correctly anticipate a
scores, but pruritus scores were lower at 6 and 12 hours in the 0.05-mg greater postoperative opioid need. Using a higher dose of intrathecal
group. A retrospective study reported that intrathecal morphine morphine in patients predicted to be at risk for high acute postpartum pain
after cesarean delivery may result in less acute postoperative pain. 25,235 Shared
0.2 mg provided better analgesia than 0.1 mg but with the “trade-off” of decision-making, involvement of both the patient and her anesthesia
increased nausea. 232 Girgin et al. 233 reported no differences in analgesia provider in a sharing of information to build a consensus about preferred
with intrathecal morphine doses ranging from 0.1 to 0.4 mg; however, dose, and reaching an agreement about which dose to use may result in
pruritus was increased with higher morphine doses. improved analgesia. 236
Sultan et al. 226 completed a meta-analysis to determine whether

low-dose (0.05 to 0.1 mg) intrathecal morphine provides comparable
duration and quality of analgesia with fewer side effects than a
high-dose (greater than 0.1 to
0.25 mg). Pain scores at 12 hours and morphine consumption at 24 hours Fentanyl
were not significantly different, but duration of analgesia was longer with the Intrathecal fentanyl improves intraoperative anesthesia
higher doses. The incidence of opioid-related side effects, including nausea (especially during uterine exteriorization), reduces intraoperative nausea
or vomiting (OR and vomiting, decreases local anesthetic dose requirement, and provides a
0.4; 95% CI, 0.3 to 0.7]) and pruritus (OR 0.3; 95% CI, 0.2 to better postoperative transition to other pain medications during recovery
0.6) were lower in the low-dose group. 226 Thus, there is a trade-off with from spinal anesthesia for cesarean delivery. 237–240 However, intrathecal
incidence of side effects and duration of analgesia. fentanyl provides a limited duration of postoperative analgesia, with a
median time to first request for additional analgesia of 4 hours (range, 2 to
Studies have compared the analgesic efficacy and sideeffect profile of 13 hours). 113 A study that compared intrathecal morphine 0.1 mg with
intrathecal morphine with those of PCEA after cesarean delivery. fentanyl 25 µ g found that morphine provided better and longer
Intrathecal morphine 0.15 mg compared with PCEA with 0.06% postoperative analgesia after cesarean delivery. 241
bupivacaine and sufentanil 1 µ g/mL provided superior analgesia and
fewer side effects. 210
Paech et al. 185 compared intrathecal morphine 0.2 mg with PCEA The analgesic effects, duration of analgesia, and side effects after
meperidine for postcesarean analgesia. Patients in the morphine group intrathecal fentanyl are dose-related. 113,237,238 Belzarena 237
reported lower pain scores offset by a higher incidence of pruritus, nausea, found that intrathecal fentanyl provided analgesia for a duration of 305 to
and drowsiness. In another study in which intrathecal morphine (0, 0.05, 787 minutes (with 0.25 µ g/kg and 0.75 µ g/kg, respectively). However,
and 0.1 mg) was combined with CEI (0.2% ropivacaine at 6 mL/h), patients who received the higher dose experienced decreased respiratory
inclusion of intrathecal morphine improved postcesarean analgesia rate and a high incidence of side effects (e.g., pruritus, nausea). Dahlgren
compared with placebo. 234 et al. 238
reported that intrathecal fentanyl 10 µ g added to bupivacaine increased

In summary, the intrathecal administration of a small dose of morphine the mean time of effective analgesia from 121 minutes to 181 minutes.
(0.05 to 0.2 mg) provides effective analgesia for 14 to 36 hours after Similarly, Wilwerth et al. 242 added intrathecal fentanyl 25 µ g to
cesarean delivery. Higher doses (greater than 0.1 mg) may slightly increase bupivacaine and intrathecal morphine with a resultant median duration of
the duration of analgesia analgesia of
Other Intrathecal Opioids

187 minutes (interquartile range [IQR], 151 to 230 minutes). Hunt et al. 243 compared
a range of intrathecal fentanyl doses (2.5 to 50 µ g) in combination with Intrathecal meperidine reduces the intensity of pain associated with the
intrathecal bupivacaine for cesarean delivery. Intrathecal fentanyl doses regression of spinal anesthesia and provides postoperative analgesia of
larger than intermediate duration (4 to 5 hours). 250,251 Yu et al. 252 found that the addition
6.25 µ g were associated with better intraoperative anesthesia and a longer of meperidine 10 mg to hyperbaric bupivacaine 10 mg prolonged the mean
time to first request for additional analgesia than administration of duration of postcesarean analgesia (234 minutes in the meperidine group
bupivacaine alone (72 minutes versus 192 minutes, respectively). 243 Chu et versus 125 minutes in the placebo group). However, the incidence of
al. 244 found that fentanyl doses of 12.5 to 15 µ g were required to increase the intraoperative nausea and vomiting was greater in the meperidine group.
duration of effective analgesia. A dose of 7.5 mg added to bupivacaine 10 mg also prolonged
postoperative analgesia for 257 ± 112 minutes (mean ± SD) compared with
In summary, intrathecal fentanyl optimizes intraoperative anesthesia and a saline group (161 ± 65 min). 253
provides immediate postoperative analgesia. However, intrathecal fentanyl

(10 to 25 µ g) provides a limited duration of postcesarean analgesia (2 to 4
hours) and does not decrease subsequent postoperative analgesic Unlike other opioids, meperidine possesses local anesthetic qualities in
requirements. addition to µ- opioid receptor agonism. Some anesthesia providers have
administered a higher intrathecal meperidine dose (1 mg/kg) as the sole
Sufentanil anesthetic agent for cesarean delivery under spinal anesthesia. However,
Sufentanil has a fast onset of action, which may improve intraoperative surgical anesthesia was unreliable, with a short mean ( ± SD) anesthetic
anesthesia and reduce the dose of local anesthetic required for duration of 41 ± 15 minutes. 250,251
cesarean anesthesia. 245 However, its pharmacokinetic properties limit the
duration of effective postoperative analgesia after intrathecal Diamorphine has physicochemical properties that are of value in
administration. 113
providing intrathecal analgesia as well as epidural analgesia. A high
Courtney et al. 246 found that intrathecal sufentanil 10, 15, or 20 µ g resulted lipophilicity (octanol-water coefficient, 280) results in a rapid onset of
in a mean duration of postcesarean analgesia of approximately 3 hours. analgesia, and diamorphine’s active metabolite (morphine) provides
More than 90% of patients reported pruritus, but only one patient required prolonged duration of analgesia. The more rapid onset of diamorphine is an
treatment. Dahlgren et al. 238 compared the safety and efficacy of the advantage in the provision of intraoperative as well as postoperative
coadministration of sufentanil 2.5 or 5 µ g, fentanyl 10 µ g, or placebo with analgesia. 254,255 Saravanan et al. 256 concluded that the ED 95 for intrathecal
hyperbaric bupivacaine 12.5 mg for cesarean delivery. The duration of diamorphine to prevent intraoperative discomfort was 0.4 mg when
effective analgesia was longer with inclusion of the opioids, particularly in combined with hyperbaric bupivacaine
the sufentanil groups; sufentanil 5 µ g provided the longest duration of
analgesia but also had the highest incidence of pruritus. Patients receiving 12.5 mg. Kelly et al. 257 compared intrathecal diamorphine 0.125,
intrathecal sufentanil had lower requirements for intraoperative antiemetics
and postoperative intravenous morphine rescue. 238 Intrathecal sufentanil 0.25, and 0.375 mg for postcesarean analgesia. The 0.25-mg and
7.5 µ g did not provide more effective postoperative analgesia than that 0.375-mg doses provided effective analgesia; the incidence of both
observed in the 5- µ g group, and the incidence of pruritus was higher. 247 vomiting and pruritus was dose related. Stacey et al. 258 reported that the
duration of analgesia was dosedependent and found that intrathecal
diamorphine 1 mg provided 10 hours of postcesarean analgesia,
compared with 7 hours for 0.5 mg. A dose-response study using
Karaman et al. 248 found that intrathecal sufentanil 5 µ g delayed the time intrathecal diamorphine 0.1, 0.2, or 0.3 mg reported a dose-dependent
to first analgesic request to 6 hours, compared with 20 hours for enhancement of analgesia and an increase in pruritus. 18
intrathecal morphine 0.2 mg. A study that compared intrathecal fentanyl

20 µ g and sufentanil Husaini and Russell 259 observed that intrathecal diamorphine
2.5 µ g added to bupivacaine for cesarean delivery found no difference in 0.2 mg and intrathecal morphine 0.2 mg provided similar postcesarean
the quality of intraoperative and postoperative analgesia, as well as no analgesia as assessed by rescue postoperative intravenous PCA
difference in the frequency of nausea and pruritus between the two opioid morphine requirements. However, the patients who received intrathecal
groups. 249 Wilwerth et al. 242 added intrathecal fentanyl 25 µ g, sufentanil 2.5 µ morphine had a higher incidence of pruritus and drowsiness. Hallworth
g, or sufentanil 5 µ g to hyperbaric bupivacaine 10 mg. Effective analgesia et al. 260
was defined as time from spinal injection to first intravenous morphine reported that intrathecal diamorphine 0.25 mg produced the same duration
administered. Duration of analgesia was longer with sufentanil 2.5 µ g (214 and quality of postcesarean analgesia as epidural diamorphine 5 mg, with
minutes) and 5 µ g (236 minutes) compared with fentanyl 25 µ g (187 less nausea and vomiting.
minutes). 242 Diamorphine is commonly used in the United Kingdom, but it is not
available for clinical use in the United States and Canada. In the United
The incidence of pruritus and PONV was similar among groups. In Kingdom, the NICE suggests an intrathecal diamorphine dose of 0.3 to 0.4
summary, intrathecal sufentanil, similar to fentanyl, enhances mg for postcesarean analgesia. 197
intraoperative anesthesia but has limited postoperative analgesia. It has a

ceiling dose of 5 µ g, and the likelihood of pruritus increases with higher Intrathecal hydromorphone has been used to provide analgesia
doses. following cesarean delivery as an alternative to
morphine. The use of intrathecal hydromorphone has increased with postoperative analgesia to that provided by intrathecal morphine alone.
shortages of intrathecal morphine in the United States. Two Carvalho et al. 268 found no difference in postoperative analgesia
retrospective studies found an analgesic advantage in favor of requirements but small increases in
intrathecal morphine. Marroquin et al. 261 retrospectively compared postoperative pain scores with the addition of increasing doses of
intrathecal morphine intrathecal fentanyl (5, 10, or 25 µ g) to intrathecal morphine 0.2 mg for
0.2 mg or epidural morphine 3 mg with intrathecal hydromorphone 60 µ g cesarean delivery. The authors suggested that intrathecal fentanyl may
or epidural hydromorphone 0.6 mg. Time to first opioid request was 17 to induce subtle acute tolerance to intrathecal morphine. The clinical
21 hours with neuraxial morphine compared with 13 to 15 hours for significance of this finding is unclear, however, especially because of
neuraxial hydromorphone. 261 Beatty et al. 262 compared intrathecal widespread evidence that intrathecal lipid-soluble opioids decrease the
morphine incidence of intraoperative visceral pain and nausea. Many anesthesia
0.1 mg with intrathecal hydromorphone 40 µ g and found 24-hour providers currently administer both intrathecal morphine and fentanyl with a
supplemental opioid use favored intrathecal morphine (8 mg versus 33 local anesthetic for spinal anesthesia for cesarean delivery (see Chapter
mg). The side effects of intrathecal morphine and hydromorphone are 26). 101 The co-administration of intrathecal fentanyl does not appear to
similar. 261,262
significantly compromise the postoperative analgesia provided by
The optimal intrathecal hydromorphone dose has not been fully intrathecal morphine.
elucidated. Using an up-down sequential allocation method, Lynde 263 estimated
that the ED 50 of intrathecal hydromorphone was 4.6 µ g. In a dose-response
study, Sviggum et al. 264 randomized 80 participants to intrathecal morphine Despite the administration of neuraxial opioid analgesia, the quality and
or intrathecal hydromorphone using a biased-coin, up-down sequential duration of analgesia after cesarean delivery is often incomplete. Thus,
allocation method to assign dose. The effective dose (ED 90) for achieving a neuraxial opioid analgesia is rarely the sole analgesic technique used for
numeric pain score (0 to 10 scale) less than or equal to 3 for a duration of postcesarean analgesia. Rather, neuraxial opioids should be considered as
12 hours was 75 µ g for intrathecal hydromorphone compared with 150 µ g part of a multimodal analgesic approach for the treatment of postcesarean
for intrathecal morphine. 264 Further research will need to help refine the pain. 54,109,118
optimal dose of intrathecal hydromorphone for postcesarean analgesia.
Side Effects of Neuraxial Opioids

Careful evaluation of the potential adverse effects of neuraxial pharmacologic
agents is important before making the decision to administer these drugs. In
Intrathecal Opioid Combinations obstetric patients, adverse maternal effects as well as potential neonatal
Intrathecal administration of morphine in combination with a lipophilic effects should be considered.
opioid (e.g., fentanyl, sufentanil) may offer some advantages, similar to
their combination in the epidural space. Intrathecal morphine has a
delayed onset; therefore, the co-administration of lipophilic opioids may Maternal Safety
serve to improve intraoperative anesthesia and reduce the intensity of Neurotoxicity (safety) studies suggest that morphine, fentanyl, sufentanil,
pain associated with the regression of spinal anesthesia in the hydromorphone, meperidine, clonidine, and neostigmine are safe for
neuraxial administration. 269–272
postanesthesia care unit. Chung et al. 265 found that the combination of
intrathecal meperidine 10 mg and morphine Morphine and clonidine are approved by the FDA for neuraxial
administration. Although unlicensed for neuraxial administration, fentanyl
0.15 mg provided better intraoperative analgesia, less need for and sufentanil have been used for many years without evidence of
supplemental analgesia, and greater satisfaction than intrathecal neurotoxicity. Studies in sheep have reported potential neurotoxicity with
morphine alone following cesarean delivery. Intrathecal sufentanil 5 µ g intrathecal butorphanol. 273 Culebras et al. 274 reported potential toxic
co-administrated with morphine interactions with the co-administration of nalbuphine and local anesthetic.
0.15 mg provided better and longer pain relief than intrathecal sufentanil However, Rawal et al. 273 evaluated the behavioral and histopathologic
plus a single injection of subcutaneous morphine; however, a higher effects of butorphanol, sufentanil, and nalbuphine after intrathecal
incidence of side effects, such as nausea and vomiting, was observed administration in sheep and found that nalbuphine caused the least
with intrathecal morphine. 266 evidence of neural tissue damage.
Some investigators have suggested that intrathecal morphine may be

less effective when concurrently administered with intrathecal fentanyl, Clinicians should avoid neuraxial administration of any agent before
suggesting acute spinal opioid tolerance. 267 This claim is controversial, adequate evaluation for potential neurotoxicity has been completed. 275–277 Drugs
and study results are inconsistent. Cooper et al. 267 reported that patients and diluents that are proven safe for parenteral use may have adverse
who received intrathecal fentanyl 25 µ g with bupivacaine had higher effects when administered intrathecally. Despite these valid concerns, a
postoperative intravenous morphine PCA requirements than patients who number of opioid analgesics, including fentanyl and sufentanil, have been
received bupivacaine alone. By contrast, Sibilla et al. 225 found that the administered intrathecally to healthy obstetric patients without prior
intrathecal combination of fentanyl 25 µ g and morphine 0.1 mg provided adequate investigation of their safety profile in animal and clinical volunteer
similar studies. 277
Preservatives added to many commercial preparations may be No studies in the obstetric setting have reported serious morbidity,
hazardous if administered to the neuraxis. Examples are sodium although some patients have required naloxone administration for
treatment of respiratory depression. 163
(meta)bisulfite and disodium ethylenediaminetetraacetic acid (EDTA),
which are known to incite inflammatory and fibrotic changes in Early reports suggested that intrathecal morphine was more likely to cause
pia-arachnoid and spinal tissue after intrathecal administration. Dezocine delayed respiratory depression than epidural morphine. 157 However, this
has been shown to cause neuropathologic changes in the dog spinal likely reflected the relatively high intrathecal morphine doses (1 to 10 mg)
cord. 278 Similarly, glycine, a neurotransmitter, is added as a preservative to used in early clinical studies. 292 Subsequently, lower doses of intrathecal
remifentanil preparations and is specifically contraindicated for neuraxial morphine have been found to provide effective analgesia with a low risk for
injection. clinically significant respiratory depression. No maternal deaths attributable
to maternal neuraxial opioid administration were reported in the 2013–2015
Confidential Enquiries report from the United Kingdom. 293 In a retrospective
Neonatal Effects study of 5036 postpartum women who received low-dose neuraxial
All opioids have the potential for placental transfer and neonatal effects. morphine for cesarean delivery, no instances of respiratory depression were
Minimal neonatal effects have been found after the administration of identified (defined as clinically relevant episodes of respiratory depression
epidural morphine 2 to 7.5 mg for cesarean delivery. 279 This is not surprising requiring naloxone administration or a rapid-response team call). 294 Thus,
given the slow increase in plasma concentration after epidural clinicians have concluded that the analgesic benefits derived from neuraxial
administration and active transport of morphine out of the blood brain opioids outweigh the risks associated with respiratory depression in most
barrier 280 and placenta 281 by P-glycoproteins. Some clinicians prefer to patients. The incidence of respiratory depression associated with systemic
administer neuraxial opioids after umbilical cord clamping to avoid placental (intravenous or intramuscular) opioids is likely to be equivalent or higher
transfer, although it is minimal. Lipophilic opioids are associated with faster than that observed with neuraxial opioids. 38,223,295
systemic uptake; if indicated (e.g., for treatment of intraoperative pain
before delivery), the smallest necessary dose should be administered.
Courtney et al. 246 found that intrathecal sufentanil (10, 15, or 20 µ g) did not
affect neonatal outcome as assessed by umbilical cord blood gas
measurements and Apgar and neurobehavioral scores. Smaller doses of There are very few case reports of respiratory depression after
intrathecal opioids are associated with less neonatal drug transfer than neuraxial administration of a lipophilic agent in the obstetric setting. In
epidural or intravenous opioid administration. 282 one report, respiratory depression occurred 25 minutes after spinal
anesthesia with intrathecal fentanyl 15 µ g and required reversal with
naloxone. 296 Respiratory depression has been described after
administration of epidural fentanyl 90 to 100 µ g for cesarean delivery. 297,298
Respiratory Depression Cohen et al. 284 reported that epidural sufentanil 30 to 50 µ g depressed the
Neuraxial opioids can depress the respiratory center in the brainstem via ventilatory response to CO 2 after cesarean delivery. Although overt
direct and/or indirect mechanisms. 138,140,156,157,283–285 Respiratory depression respiratory depression did not occur, the highest sedation scores and
after neuraxial morphine administration is biphasic. 286 Early respiratory depression of CO 2 response occurred 45 minutes after administration.
depression can occur 30 to 90 minutes after epidural morphine Another group reported that epidural fentanyl 100 µ g or sufentanil 10 to 50 µ
administration owing to systemic vascular absorption from the epidural g added to lidocaine for cesarean delivery caused significant changes in
space, 157 whereas delayed respiratory depression can occur 6 to 18 hours respiratory rate and end-tidal CO 2 but no adverse clinical events. 299
after epidural or intrathecal morphine administration owing to rostral
spread in CSF and slow penetration into the brainstem. 173,287 In contrast,
lipophilic opioids do not cause delayed respiratory depression but may Historically, respiratory depression was more common because
cause early respiratory depression, typically within 30 minutes, because patients received greater doses of neuraxial opioid than those currently
of vascular uptake and rostral spread in CSF and, potentially, direct used in modern practice. For cesarean delivery, neuraxial morphine
transit in epidural veins. 283,284 appears to have a limit or “ceiling” in analgesic efficacy. More specifically,
effective doses of intrathecal and epidural morphine are 0.075 to 0.2 mg
and 2 to 4 mg, respectively, in opioid-naïve patients. 113,164,227,300
Although rare, perioperative opioid–induced respiratory depression can

lead to death or permanent brain damage. 288,289
Sultan et al. 226 performed a systematic review of studies of low-dose
The incidence of respiratory depression after neuraxial morphine compared with high-dose intrathecal morphine administered for
administration in obstetric patients is very low, with reported ranges from postoperative analgesia following elective cesarean delivery; there were no
0% to 0.9%. 290 The Serious Complication Repository (SCORE) project of reported episodes of respiratory depression. Thus, avoiding high doses of
the Society for Obstetric Anesthesia and Perinatology (SOAP) neuraxial morphine may improve safety without compromising analgesia. 300
systematically tracked complications related to obstetric anesthesia

between 2004 and 2009. 291 Among 90,795 reported cases of neuraxial
anesthesia for cesarean delivery, no cases of respiratory arrest secondary Monitoring and Detection of Respiratory Depression
to neuraxial opioid administration were reported. Guidelines for the prevention, detection, and management of respiratory
depression associated with neuraxial opioid
administration have been published by the American Society of Palmer et al. 227 found no difference in PONV between intrathecal morphine
Anesthesiologists (ASA) and the American Society of Regional Anesthesia (0.025 to 0.5 mg) and placebo, nor a relationship between PONV and
and Pain Medicine (ASRA). 218 These guidelines do not specifically address morphine dose. A similar study by the same group found no difference in
obstetric patients and are likely overly prescriptive given the low risk for the severity of PONV in patients receiving increasing doses of epidural
clinically significant neuraxial opioid–induced respiratory depression with morphine (1.25 to 5 mg). 164 However, neither study was adequately
conventional dosing in this patient population. 290 The SOAP has powered to investigate absence of PONV as a primary outcome measure.
commissioned a consensus statement (planned publication in 2019) to Many studies have investigated different regimens to reduce PONV in
provide recommendations specifically for the obstetric population following patients receiving neuraxial opioids for cesarean delivery, but these studies
cesarean delivery. did not standardize PONV outcome measures and did not stratify patients
according to risk for PONV. In a blinded study assessing PONV as a
All patients who receive neuraxial opioids should be monitored for secondary outcome after intrathecal morphine 0.1 and 0.2 mg, an
adequacy of ventilation, oxygenation, and level of consciousness. Opioid increased incidence and severity of nausea was identified in the high-dose
effects on respiration include reduced minute ventilation (decrease in group. 25
respiratory rate, tidal volume, or both) and decreased response to
hypoxemia and changes in PaCO 2. 292,301 Nearly two-thirds of cases of
respiratory depression following general anesthesia in the Anesthesia Single antiemetic agents. Older antiemetics, such as
Closed Claims Project database reported somnolence was present, but not metoclopramide and droperidol, have been used to prevent or treat
addressed, before the respiratory depression event. 302 neuraxial opioid–induced emesis in the obstetric setting. Metoclopramide
antagonizes dopamine receptors in the chemoreceptor trigger zone. It is
often administered preoperatively owing to its favorable gut prokinetic
Vigilant nursing care and hourly assessments of respiratory effort, properties, and it is associated with a reduction in rates of intraoperative
respiratory rate, and somnolence are probably adequate for low-risk nausea and vomiting (IONV) and PONV in patients receiving spinal
patients who receive neuraxial opioid analgesia. 163,290,303,304 Continuous anesthesia. 308 In a meta-analysis of studies that assessed efficacy of
pulse oximetry, although appropriate for obstetric patients with risk factors antiemetic prophylaxis, metoclopramide was associated with a reduced
for respiratory depression such as obesity, may be unnecessary in healthy incidence of IONV and early PONV compared with placebo. 309
patients receiving low doses of neuraxial opioid (e.g., intrathecal morphine ≤
0.2 mg, epidural morphine ≤ 4 mg). 290
The use of a transdermal scopolamine patch may also lower the

Greater surveillance and ventilation monitoring (e.g., capnography) incidence of PONV after cesarean delivery. A transdermal scopolamine
may be warranted in patients at high risk for respiratory depression who patch (1.5 mg) provided efficacy similar to that provided by ondansetron 4
are receiving supplemental oxygen; the monitoring of patients at mg in reducing emesis among parturients receiving spinal anesthesia
high-risk for respiratory depression merits further study. 305 (incidence of 40% and 42%, respectively, versus 59% in the control group). 310
However, transdermal scopolamine has a latency period of 3 to 4 hours,
The duration of respiratory monitoring corresponds to the expected and side effects, including dry mouth, visual disturbances, dizziness, and
duration of action of the administered opioid. The onset of respiratory agitation, are common.
depression after neuraxial opioids is variable and has been reported to
range from 2 to 12 hours. 295
Serotonin (5-HT 3) receptor antagonists have been used for both
CO 2 responsiveness is depressed for up to 24 hours after the administration prophylaxis and treatment of PONV. These drugs bind to 5-HT 3 receptors in
of epidural morphine 5 mg. 306 The ASA recommends that respiratory the chemoreceptor trigger zone and at vagal afferents in the
monitoring after neuraxial administration of morphine should occur at least gastrointestinal tract. Prophylactic administration of ondansetron 4 to 8 mg
every hour for the first 12 hours and then every 2 hours for the next 12 has been shown to have a better antiemetic profile in the first 24 hours
hours. 218 after intrathecal and epidural opioid administration compared with placebo
Early-onset respiratory depression associated with lipophilic opioids ( Fig. 27.8 ). 311 A meta-analysis of six trials found that the use of 5-HT 3 receptor
usually occurs within 30 minutes of administration and is likely to occur antagonists reduced the incidence of PONV and the need for rescue
in a high-visibility, controlled setting (e.g., operating or labor room). The antiemetic treatment in women who received intrathecal opioids for
ASA and ASRA recommend that respiratory monitoring after cesarean delivery. 312
administration of neuraxial fentanyl should continue for a minimum of 2
hours. 218
Corticosteroid receptors have been identified in areas important to
the signal processing of nausea and vomiting, including the nucleus of
Nausea and Vomiting the solitary tract, the nucleus of raphe, and the area postrema. Tzeng et
Nausea and vomiting are common complaints after cesarean delivery, and al. 313 reported that intravenous dexamethasone 8 mg and droperidol 1.25
the causes are likely multifactorial. Neuraxial opioids increase the risk for mg provided similar efficacy in the prevention of PONV. Wang et al. 314 suggested
PONV after cesarean delivery in a non–dose-dependent manner via rostral that dexamethasone 5 mg is the minimum effective dose for preventing
spread of opioid in the CSF to the brainstem or from vascular uptake and PONV. In both studies, patients received epidural morphine 3 mg. 313,314 In
delivery to the vomiting center and chemoreceptor trigger zone. 307 a 2012
bands with a plastic bead placed bilaterally on the P6 [HG-6] acupoint) for
100 ‡ reducing PONV after neuraxial anesthesia for cesarean delivery. A
‡ ‡ meta-analysis of six studies (649 patients) that assessed the effect of P6
80
‡
stimulation versus placebo to reduce IONV and PONV revealed
Distribution of number
† inconsistent results, thereby limiting any definitive conclusions regarding

of emesis and nausea
60 the efficacy of this intervention. 320 Based on very limited evidence in

patients having cesarean delivery, supplemental oxygen and generous
episodes (%)
40
intravenous fluid administration do not appear to reduce IONV or PONV. 321
20
0
Pruritus
1 or less 0 1 or less 0
Pruritus is a common side effect of neuraxial opioid administration in
episode of (emesis- episode of (nausea-
emesis free) nausea free)
obstetric patients. In a retrospective review of 4880 patients undergoing
cesarean delivery who received epidural morphine 2 to 5 mg, pruritus was
Placebo Ondanestron Metoclopramide reported by 58% of patients. 163 However, a sample of patients who received
spinal anesthesia for cesarean delivery ranked pain, nausea, and vomiting
Fig. 27.8 Randomized trial of postoperative nausea and emesis in patients undergoing as more undesirable than pruritus (see Table 27.1 ). 15
cesarean delivery with epidural anesthesia (2% lidocaine with epinephrine and
fentanyl) who received prophylactic ondansetron, metoclopramide, or placebo.
The incidence and severity of pruritus are likely influenced by the opioid
Distribution of nausea and emesis episodes (0 [nausea or emesis free] or 1 or less) in
dose, route of administration (more common after intrathecal administration),
the first 24 hours. Values are given as percentages of each patient group. #Group
and method of assessment. 226,322
metoclopramide versus ondansetron; P < . 05. *Group metoclopramide versus placebo; P
< . 05. †Group metoclopramide versus placebo; P < . 005. ‡Group ondansetron versus The incidence of pruritus after intrathecal morphine is as high as 70% to
placebo; P < . 005. (Data from Pan PH, Moore CM. Comparing the efficacy of 90%, with approximately 25% to 40% of patients requesting treatment. 163,167,323–326
prophylactic metoclopramide, ondansetron, and placebo in cesarean section patients
given epidural anesthesia. J Clin Anesth. 2001;13:430–435.)
Pruritus may manifest in the dermatomal distribution of neuraxial
opioid spread as well as nonspecific areas of the head and neck; specific
symptoms and severity vary among patients. 327 Opioid-induced histamine
release from mast cells does not appear to be the causative mechanism
meta-analysis of studies of obstetric and gynecologic patients who for pruritus after neuraxial opioid administration. Plasma opioid and
received neuraxial morphine, prophylactic dexamethasone (2.5 to 10 mg) histamine levels are clinically insignificant at the time of symptom
was associated with a reduced risk for PONV and need for antiemetic presentation (3 to 6 hours after intraspinal morphine administration). 157,173,328
rescue therapy compared with placebo. 315 Administration of cyclizine 50 At present, the mechanisms of spinal and epidural opioid–induced pruritus
mg has been reported to be associated with fewer episodes of PONV (0 to remain unclear. Postulated theories include (1) direct or indirect excitatory
12 hours after cesarean delivery) than administration of dexamethasone 8 effects on central µ- opioid receptors; (2) cephalad migration of the opioid
mg after intrathecal opioid (fentanyl and morphine) administration. 316 within the CSF to the trigeminal nucleus (which contains the subnucleus
caudalis, integrates facial sensory input, and exhibits high opioid receptor
density); (3) excitatory effects on dorsal or ventral horn neurons; and (4)
Combination antiemetic regimens. Administration of drugs acting at other mechanisms (e.g., effects on dopamine-2 [D 2] receptors,
two different receptor sites may improve antiemetic efficacy through prostaglandin system, serotonin 5-HT 3 receptors, and CNS
additivity or synergism. 317 Drug combinations may also facilitate a gamma-aminobutyric acid [GABA] and glycine receptors). 328
concomitant reduction in drug doses limiting individual side effects. Wu et
al. 318 reported lower rates of PONV after intrathecal morphine
administration with use of a combination of dexamethasone 8 mg and
droperidol 0.625 mg than with use of dexamethasone 8 mg or droperidol Pregnant patients may be more susceptible as a result of estrogen
1.25 mg alone. In a multicenter study, Habib et al. 319 randomized women to interaction with opioid receptors. 329 The incidence of moderate-to-severe
one of three groups: placebo, metoclopramide 10 mg plus placebo, or a pruritus with epidural morphine administered for postcesarean analgesia
combination of metoclopramide 10 mg plus ondansetron 4 mg. Spinal has been reported to be lower in patients homozygous for the G118G
anesthesia–induced hypotension was managed prophylactically with a polymorphism in the µ- opioid receptor gene ( OPRM1) than in patients with
phenylephrine infusion to maintain the systolic blood pressure within 20% the A118G or A118A genotype (incidence 5%, 42%, and 53%,
of baseline or greater than 90 mm Hg. The combination of respectively). 330 In a study of 63 women undergoing elective cesarean
metoclopramide and ondansetron reduced IONV and PONV compared delivery with spinal anesthesia with morphine 0.1 mg, Pettini et al. 331 reported
with placebo. 319 an incidence of pruritus of 50% in patients homozygous for the G118G
polymorphism and 82% in patients with the A118G or A118A genotype.
Nonpharmacologic techniques. Several studies have investigated the

prophylactic use of acupressure ( using wrist
There is little consensus regarding the prevention and treatment of over 48 hours) than in patients in a control group. Similarly, Culebras et al. 274
neuraxial opioid–induced pruritus after cesarean delivery. 332 Further, investigated the effects of three different doses of intrathecal nalbuphine
there are currently no validated or consistent methods for assessing (0.2, 0.8, and 1.6 mg) and found a significantly lower incidence of pruritus
pruritus, which limits the analysis of data from studies investigating the in all of the nalbuphine groups compared with a control group that
efficacy of antipruritic regimens. received intrathecal morphine without nalbuphine. However, the duration
of analgesia was shorter among patients in the nalbuphine groups. 274 It is
Studies comparing opioid antagonists for the treatment of pruritus not clear whether an optimal dose of µ- opioid receptor antagonists can be
have demonstrated mixed results. Nalbuphine found that prevents pruritus without reducing analgesia. These drugs are
(5 mg) significantly reduced the severity of pruritus after epidural not approved for administration into the neuraxial canal.
morphine, and fewer patients required additional treatment of persistent
pruritus. 325 Smaller doses of nalbuphine (2 to 3 mg) adequately treat
moderate-to-severe pruritus after intrathecal morphine administration. 333 Wu Propofol has been reported to relieve pruritus caused by neuraxial
et al. 334 found that butorphanol 1 mg followed by an infusion of 0.2 mg/h opioids in nonobstetric patients after a single 10-mg bolus dose 344 and after
was associated with reduced pruritus compared with a saline-control a 10-mg bolus dose followed by a 30 mg/24 h infusion. 345 The mechanism
group in patients who received intrathecal morphine. of the antipruritic effect of propofol is unknown, and these results have not
been replicated in obstetric patients who received subhypnotic doses of
propofol (10 to 20 mg) for treatment of intrathecal morphine–induced
Prophylactic treatment with opioid antagonists has also been pruritus. 346,347 A comparative study demonstrated that intravenous
investigated as a method of reducing the incidence of opioid-induced nalbuphine 3 mg is superior to propofol 20 mg for treating pruritus after
pruritus. Morgan et al. 335 reported that pretreatment with intravenous administration of intrathecal morphine. 348
nalbuphine (20 mg at skin closure) with subsequent postoperative
administration (20 mg in divided doses) was ineffective in reducing
pruritus in patients receiving epidural morphine. Similarly, pretreatment Stimulation of 5-HT 3 receptors found in the dorsal horn of the spinal
with subcutaneous naloxone ( 0.4 mg) did not reduce the incidence of cord and in the nucleus of the spinal tract of the trigeminal nerve in the
pruritus in patients receiving intrathecal fentanyl and morphine for elective medulla may occur after subarachnoid opioid administration. A
cesarean delivery. 336 This is not surprising given the short half-life of meta-analysis of studies of surgical patients receiving neuraxial opioids
naloxone. However, naloxone and nalbuphine administered via concluded that prophylaxis with a 5-HT 3 antagonist results in a reduced
patient-controlled bolus doses with a continuous background infusion risk for postoperative pruritus compared with placebo (OR, 0.44; 95% CI,
have been found to reduce the incidence of pruritus after cesarean 0.29 to 0.68). 349 Intravenous ondansetron 4 to 8 mg has been shown to be
delivery in patients who received epidural morphine 5 mg. 324 more effective than placebo for reducing the incidence of postcesarean
pruritus after intrathecal administration of morphine 0.15 to 0.2 mg. 350,351 However,
other studies that compared ondansetron 8 mg with placebo found no
The long-acting oral opioid antagonist naltrexone reduced pruritus significant reduction in pruritus after intrathecal administration of morphine
compared with placebo after cesarean delivery in patients who received (0.1 to 0.2 mg) alone 352 or in combination with a lipophilic opioid (sufentanil
epidural or intrathecal morphine. 337,338
or fentanyl). 353,354 The lack of antipruritic effect in these studies may be
Paech et al. 323 compared methylnaltrexone, a peripherally acting µ- opioid caused by the peak effect of ondansetron occurring sooner (15 minutes
receptor antagonist developed to antagonize the peripheral side effects of after intravenous administration) than that of intrathecal morphine. The
opioids while preserving centrally mediated analgesia, with placebo. antipruritic effects associated with ondansetron may depend on the dose,
Women undergoing elective cesarean delivery under spinal anesthesia lipophilicity, and duration of action of the intrathecal opioid. 355 Siddik-Sayyid
with intrathecal morphine 0.1 mg were randomized to receive et al. 352 found no significant differences in the incidence or severity of
subcutaneous methylnaltrexone 12 mg or placebo after delivery. The pruritus among patients who received granisetron
incidence and severity of pruritus were not statistically different between
groups, although the study may have been underpowered to identify a
small effect. Pentazocine, a
κ- opioid receptor agonist and partial µ- opioid receptor agonist, may be a 3 mg or ondansetron 8 mg or saline. In contrast, Tan et al. 356
useful drug for treating opioid-induced pruritus. 339–341 Hirabayashi et al. 342 randomized
observed that the severity of pruritus was reduced at 8 and 24 hours after
women scheduled for cesarean delivery with spinal anesthesia cesarean delivery in patients who received granisetron 3 mg compared with
containing fentanyl 10 µ g and morphine 0.1 mg to receive pentazocine those who received ondansetron 8 mg.
15 mg or saline-placebo. Pentazocine reduced the overall incidence of
pruritus within the first 24 hours compared with saline. 342 George et al. 312 reported a meta-analysis of studies of women who
received spinal anesthesia with morphine for cesarean delivery; prophylactic
administration of a 5-HT 3
The effects of neuraxially administered opioid antagonists have also antagonist did not reduce the risk for pruritus compared with the
been investigated. Jeon et al. 343 reported less pruritus in patients who placebo control group. However, administration of a 5-HT 3 antagonist
received epidural naloxone (1.2 mg over 48 hours) with epidural 0.1% reduced the severity of pruritus and the need for rescue treatment
bupivacaine and morphine (6 mg compared with placebo.
Heterogeneity and small sample sizes in the studies included in this To avoid impairment of bladder/detrusor function, urinary
systematic review limited detailed analysis of the efficacy of prophylactic catheterization should be considered if voiding has not occurred within 6
administration of a 5-HT 3 antagonist. hours. 365 Risk factors for postcesarean urinary retention include low body
Few studies have assessed the therapeutic effect of 5-HT 3 mass index, multiparity, emergency cesarean delivery, prolonged
antagonists for managing postcesarean pruritus induced by neuraxial operation time, perineal injury, and postoperative analgesia. 366–368 Transient
opioids. In one study, ondansetron 4 mg had a high rate of success for the postpartum voiding difficulty is not detrimental to urinary function and
treatment of moderate-to-severe pruritus compared with placebo (80% and does not subsequently lead to voiding difficulties. 367 Reversal with
36%, respectively). 357
systemic naloxone may be considered in problematic cases.
Historically, antihistamines have been a popular first choice for
treatment of pruritus. However, the efficacy of these agents has been
questioned in patients receiving neuraxial opioids, as histamine release is
not the mechanism of pruritus. Alhashemi et al. 358 demonstrated that Neuraxial Nonopioid Analgesic Adjuvants
diphenhydramine was less effective than nalbuphine (higher itching scores The addition of neuraxial nonopioid adjuvants to local anesthetic agents
and more treatment failures) after administration of intrathecal morphine 0.2 may improve the quality of both intraoperative anesthesia and
mg. Yeh et al. 351 found that the incidence of pruritus was comparable among postcesarean analgesia. Nonopioid neuraxial adjuvants have different
patients receiving diphenhydramine 30 mg and placebo (80% and 85%, sites and mechanisms of actions, and interactions between neuraxial
respectively); however, both groups had a higher incidence of pruritus than opioids and nonopioid adjuvants may be additive or synergistic. Potential
did a group that received ondansetron 0.1 mg/kg (25%). In contrast, advantages of neuraxial drug combinations include a reduction in dose of
Siddik-Sayyid et al. 359 found that the therapeutic success rates for individual drugs (with subsequent reductions in dosedependent side
ondansetron 4 mg and diphenhydramine 25 mg were identical (70% for effects), in particular a reduction in postoperative opioid requirements and
each drug), with similar recurrence rates in successfully treated patients opioid-related side effects. 369
(28% versus 35%, respectively). Differences in study methodology and

antihistamineinduced sedation may explain the inconsistent antipruritic
effect of diphenhydramine observed in these studies.
Alpha 2- Adrenergic Receptor Agonists
Alpha 2- adrenergic receptor agonists bind to presynaptic and postsynaptic
alpha 2- adrenergic receptors at peripheral, spinal (dorsal horn), and
brainstem sites. Epidural and intrathecal alpha 2- adrenergic receptor agonists
Urinary Retention provide analgesia by activating the descending noradrenergic system. 370,371 This
The mechanisms by which neuraxial opioids affect specific components of process subsequently leads to norepinephrine release, which in turn
micturition (urge sensation, detrusor and sphincter function) are also not modulates pain processing in the dorsal horn by inhibiting the release of
fully understood, although spinal and supraspinal sites of action are likely substance P and increasing acetylcholine levels to produce analgesia. 372,373 Clonidine,
to be involved. Kuipers et al. 360 performed urodynamic studies in healthy an alpha 2- adrenergic receptor agonist, provides a more potent analgesic
male volunteers who received intrathecal sufentanil and morphine. Both response with fewer side effects when administered neuraxially than
opioids caused dose-dependent decreases in detrusor contractility and the systemically. Clonidine also potentiates sensory and motor block when
urgency to void. Volunteers receiving intrathecal sufentanil had earlier administered with epidural local anesthetics and acts additively or
recovery of lower urinary tract function than those receiving intrathecal synergistically with intraspinal opioids. 369,373
morphine. 360
Intrathecal local anesthetics (bupivacaine and lidocaine) have also been In combination with an intrathecal local anesthetic, intrathecal clonidine may
shown to ablate detrusor contractility and urge sensation until the also prolong the regression of sensory block, improve postoperative
dermatomal block regresses to S2 to S3, with no partial recovery until this analgesia, and decrease intraoperative pain. 374 However, a combination of
regression has occurred. 361 intrathecal clonidine and local anesthetic may also increase the risk for
Evron et al. 362 performed an observational study investigating the hypotension in a non–dose-dependent manner. 374 Pregnancy may enhance
urinary effects of epidural morphine and methadone in 120 women the analgesic effects of alpha 2- adrenergic receptor agonists, thus making
undergoing cesarean delivery. Not surprisingly given the longer duration them particularly valuable in this setting. 375
of action, difficulty in micturition and need for bladder catheterization

were greater in the morphine group (58%) compared with the methadone Mendez et al. 376 compared the analgesic efficacy of lowdose epidural
group (3%). 362 A similar study by Liang et al. 363 reported a higher incidence clonidine (400- µ g bolus) versus high-dose clonidine (800- µ g bolus),
of postcesarean urinary retention and urinary catheterization (22%) followed by epidural infusion at 10 or 20 µ g/h after cesarean delivery.
among patients receiving epidural morphine compared with other They observed shortlived, dose-dependent analgesia and sedation, and
analgesia modalities (PCEA with ropivacaine-fentanyl [7%] and prolonged motor block, which might lead to delays in the discharge of
intramuscular meperidine [3%]). In a study of male volunteers, naloxone patients from the postanesthesia care unit. Huntoon et al. 377
reversed the impact of neuraxial morphine on urodynamic function. 364
reported similar postcesarean analgesia in patients receiving epidural
clonidine 400 or 800 µ g after epidural bupivacaine anesthesia.
Several studies have investigated epidural clonidine in combination observed in postoperative morphine consumption or in pain scores before
with epidural opioids for optimizing postcesarean analgesia. An and after discharge. Carvalho et al. 385 randomized 195 women to receive
isobolographic evaluation of epidural clonidine (in doses ranging from 50 intrathecal hyperbaric bupivacaine with morphine 0.05 mg, morphine 0.1
to 400 µ g) with fentanyl (15 to 135 µ g) demonstrated additivity but not mg, or morphine
synergism between clonidine and fentanyl in patients recovering from 0.05 mg combined with clonidine 75 µ g for surgical anesthesia. Pain
cesarean delivery. 378 However, marked variability in drug response and intensity at rest or while coughing did not differ among groups. 385 During
failure of high doses to produce complete analgesia limited the validity of recovery, the incidences of hypotension, bradycardia, and sedation were
dose-response and ED 50 analyses. Capogna et al. 379 observed that the similar among groups.
addition of clonidine 75 to 150 µ g to epidural morphine 2 mg lengthened Crespo et al. 386 performed a systematic review of trials comparing
the duration of postcesarean analgesia without increasing the incidence of intrathecal clonidine as an adjuvant to local anesthetics with or without
side effects. additional opioids in women undergoing cesarean delivery. They
evaluated outcomes related to efficacy of clonidine as an intrathecal
adjuvant, including duration of analgesia and motor block. Clonidine
A number of studies have evaluated the potential role of intrathecal prolonged the duration of sensory block by 128 minutes and motor block
clonidine for postcesarean analgesia. Ginosar et al. 380 administered by 45 minutes while also increasing sedation compared with intrathecal
intrathecal clonidine (0 to 100 µ g) to healthy volunteers to assess the blocks without clonidine. 386 Allen et al. 387
analgesic effect of doses below 100 µ g; analgesia to experimental heat

pain was detected for doses greater than 25 µ g. 380 Van Tuijl et al. 381 assessed performed a systematic review and meta-analysis evaluating the effect of
postcesarean analgesia in patients who received intrathecal clonidine 75 µ g neuraxial clonidine on 24-hour morphine consumption and time to first
combined with bupivacaine compared with intrathecal bupivacaine alone. analgesic request in women undergoing elective cesarean delivery.
Early postoperative analgesia (for 1 to 2 hours) was improved in patients Eighteen studies were included in the analysis (12 intrathecal
who received clonidine; however, no difference was found in 24-hour administration, 6 epidural administration). Neuraxial clonidine reduced
morphine consumption between the groups, likely reflecting the short 24-hour morphine consumption by 7.2 mg and prolonged time to first
duration of action of a bolus dose of clonidine. analgesic request by 135 minutes compared with the control group. 387 Intraoperative
hypotension and intraoperative sedation were more frequent with
neuraxial clonidine.
Interaction studies of intrathecal opioids combined with clonidine have
investigated the contribution of each drug to analgesia and side effects. In summary, neuraxial clonidine may offer a small improvement in
Benhamou et al. 382 evaluated postcesarean analgesic outcomes in patients postcesarean analgesia in addition to that provided by neuraxial
who received hyperbaric bupivacaine alone, or bupivacaine and clonidine morphine. Epidural clonidine (150 to 800 µ g) may prolong postcesarean
75 µ g, or bupivacaine with clonidine and fentanyl 12.5 µ g. Patients who analgesia when given in combination with epidural opioids. Intrathecal
received the bupivacaine-clonidine-fentanyl combination reported less clonidine (75 to 450 µ g) has modest efficacy and a relatively short
intraoperative pain and more prolonged postcesarean analgesia (time to duration of action. Ongoing concern about the adverse side-effect profile
first analgesia request 215 minutes) than those receiving of epidural and intrathecal clonidine—notably sedation and
bupivacaine-clonidine and bupivacaine alone (183 and 137 minutes, hypotension—limit the neuraxial administration of this agent in most
respectively). However, higher rates of pruritus and sedation were reported patients undergoing cesarean delivery. Additionally, in the United States,
for the bupivacaine-clonidine-fentanyl group. Paech et al. 383 epidural clonidine has a “black box” warning stating that it is not
recommended for obstetric, postpartum, or perioperative pain
management because of the risk for hypotension and bradycardia that
performed a six-arm study assessing postcesarean analgesia after were identified after high doses. In selected cases, the anesthesia
intrathecal bupivacaine 12.5 mg with fentanyl 15 µ g and one of the following provider may conclude that the potential benefits outweigh the risks.
regimens: clonidine 150 µ g; morphine
0.1 mg; and morphine 0.1 mg with clonidine 30, 60, 90, or 150 µ g. They
concluded that the morphine-clonidine regimens provided optimal
analgesia with lower pain scores at rest and with coughing in the first 4 Dexmedetomidine is a highly selective alpha 2- adrenergic receptor
hours. The minimum effective intrathecal dose of clonidine was 30 to 60 agonist that provides some analgesic effects mediated at the spinal level.
µ g combined with bupivacaine, fentanyl 15 µ g, and morphine Its systemic administration is widespread in anesthesia and critical care;
however, its use in peripheral nerve blocks and neuraxial anesthesia is
0.1 mg. However, an increase in intraoperative sedation was observed in all off-label. 388 In one of the few studies evaluating neuraxial dexmedetomidine,
groups receiving clonidine. 80 healthy women were randomly assigned to a control group (intrathecal
Lavand’homme et al. 384 compared antihyperalgesic effects in patients hyperbaric bupivacaine 5 mg and an epidural mixture of 10-mL plain
receiving intrathecal clonidine 150 µ g with bupivacaine, clonidine 75 µ g bupivacaine 0.25% and fentanyl 50 µ g) or a study group who received the
with bupivacaine-sufentanil, or bupivacaine-sufentanil. The same drugs with the addition of epidural dexmedetomidine (0.5 µ g/kg). 389 The
bupivacaine-clonidine 150- µ g group had a smaller area of peri-incisional dexmedetomidine group required less intraoperative and postoperative
hyperalgesia and a lower incidence of hyperalgesia compared with the fentanyl than the control group (4/40 and 18/40,
other study groups. However, no between-group differences were
respectively). There was no difference between the groups in block receptors and the release of nitric oxide. As both nicotinic and muscarinic
characteristics or sedation. 389 In the only study of intrathecal dexmedetomidine receptors are important to central and peripheral pain transmission, the
for cesarean anesthesia, Qi et al. 390
resulting analgesia may be caused by central and/or peripheral alterations
compared bupivacaine 10 mg, bupivacaine 10 mg combined with in pain modulation and transmission. Initial studies of intrathecal neostigmine
dexmedetomidine 5 µ g, and bupivacaine 10 mg combined with morphine in animals and human volunteers have demonstrated analgesic effects
0.1 mg. Sensory blockade was longer in the dexmedetomidine groups than without neurotoxic effects. 398–400 However, despite producing
in other groups. Intrathecal dexmedetomidine provided similar analgesia dose-dependent analgesia, intrathecal neostigmine results in nausea that is
and less pruritus and shivering compared with morphine. 390 particularly resistant to traditional antiemetic treatment, and therefore the
use of intrathecal neostigmine is generally not recommended.
Epinephrine has a direct analgesic effect by activating alpha 2- adrenergic
receptors and may potentiate local anesthetics by inducing local
vasoconstriction through alpha 1- Kaya et al. 401 assessed the analgesic efficacy of epidural
adrenergic activation, resulting in slower drug clearance. A number of neostigmine administration after cesarean delivery. A CSE technique was
clinical studies have investigated epinephrine as a spinal or epidural employed with intrathecal bupivacaine 8 mg and fentanyl 10 µ g, and
adjunct. Robertson et al. 141 reported that patients subsequently received epidural neostigmine doses of 75, 150, or
epidural epinephrine 25 µ g prolonged the duration of analgesia with 300 µ g after delivery. The investigators reported modest, short-lived, and
epidural fentanyl 100 µ g but increased the incidence of pruritus. Similar doseindependent reductions in postoperative pain in the neostigmine
prolongation of analgesia has been observed when epinephrine (5 to 30 µ g/mL)groups. 401 No differences among groups in 24-hour morphine consumption
was combined with epidural diamorphine or sufentanil; however, the after surgery were observed.
incidence of side effects (including vomiting that required treatment) was
also increased. 195,391 In contrast, McMorland et al. 392 did not replicate this The use of epidural neostigmine is not currently recommended for
finding, although their study was not powered to demonstrate routine use until additional studies substantiate clinically significant
noninferiority. Importantly, studies of the addition of epidural epinephrine postcesarean analgesic benefits with fewer side effects compared with
(5 µ g/mL) to 2% lidocaine or 0.5% bupivacaine have not demonstrated alternatives. Data regarding the maternal and fetal safety profile of epidural
any detrimental effects of epinephrine on umbilical artery blood-flow neostigmine are reassuring. 402
velocity waveforms, uteroplacental or fetal vascular resistance, fetal
myocardial function, or fetal heart rate or neonatal outcomes. 393,394
N- Methyl- D- Aspartate Receptor Antagonists
Ketamine. Limited data exist regarding the role of neuraxial ketamine
in the provision of postcesarean analgesia. Anesthetic and subanesthetic
The use of intrathecal epinephrine as an adjuvant to local anesthetics, doses of ketamine have analgesic properties via noncompetitive
with or without opioids, has been evaluated in several studies. The antagonism of NMDA receptors. In patients undergoing cesarean delivery
addition of epinephrine 200 µ g to hyperbaric spinal bupivacaine improved randomly assigned to receive intrathecal bupivacaine alone or in
perioperative analgesia but was associated with a longer duration of combination with S(+) ketamine 0.05 mg/kg or fentanyl 25 µ g, significantly
residual sensory and motor block. 395 In a separate study, a combined prolonged and better quality analgesia was observed in the fentanyl group. 403
intrathecal regimen of epinephrine 200 µ g with morphine 0.2 mg improved It is unclear whether the S(+) or R(–) isomers of ketamine have analgesic
intra- and postoperative analgesia compared with intrathecal morphine 0.2 advantages over the racemate. No published studies have evaluated
mg alone. 396 Zakowski et al. 397 found earlier and higher peak plasma perioperative epidural ketamine administration in patients undergoing
bupivacaine concentrations with the addition of spinal epinephrine 200 µ g cesarean delivery. At this time neuraxial use cannot be recommended for
to spinal bupivacaine in patients undergoing cesarean delivery. In contrast, patients undergoing cesarean delivery because there is a lack of data
plasma levels of morphine were approximately 66% regarding the safety of neuraxial administration.
lower in the epinephrine group than in the control group. 397

The investigators concluded that the enhanced efficacy of intrathecal Magnesium. Magnesium is a noncompetitive antagonist of the
bupivacaine combined with morphine and epinephrine was not caused by NMDA receptor and may alter pain signaling by preventing central
vasoconstriction alone. sensitization after nociceptive
In summary, the use of epidural epinephrine (2.5 to 30 µ g/ stimulation. 404 Magnesium blocks NMDA ion channels in a
mL) seems to prolong the duration of analgesia with epidural opioids but voltage-dependent manner. Studies investigating intrathecal or epidural
may increase side effects. The use of intrathecal epinephrine 200 µ g does magnesium have shown variable analgesic effects after cesarean delivery.
seem to enhance neuraxial opioid analgesia but is associated with prolonged Sun et al. 405 compared the postcesarean analgesic profile of four different epidural
sensory and motor block. solutions administered in the perioperative period. All patients received
0.1% bupivacaine 10 mL with one of the following: morphine 1.5 mg,
magnesium 500 mg, morphine 1.5 mg and
Neostigmine
By interfering with the breakdown of acetylcholine, neostigmine indirectly magnesium 500 mg, or placebo. Patients who received magnesium and
stimulates spinal nicotinic and muscarinic morphine had lower postoperative pain scores at
rest and with movement, an increased time to first analgesic request, and patients who received either intrathecal midazolam 1 mg or no midazolam. 417
increased satisfaction at 24 hours after surgery compared with women who Dodawad et al. 418 randomly assigned 60 women with pregnancy-induced
received only one drug or placebo. Albrecht et al. 406 reviewed 18 trials hypertension undergoing cesarean delivery to receive intrathecal
(including some trials in women undergoing cesarean delivery) of the bupivacaine 10 mg (control group) or bupivacaine combined with
efficacy and safety of neuraxial magnesium sulfate for postoperative midazolam 2 mg (study group). Postoperative analgesia was longer in the
analgesia. They observed an overall increase in the interval to first midazolam group than in the control group (202 minutes and 358 minutes,
analgesic request (mean difference of 40 minutes after intrathecal respectively). It is unknown whether intrathecal midazolam has any benefit
administration and 110 minutes after epidural administration). However, compared with intrathecal morphine or in addition to morphine.
only four trials assessed neurologic complications, and the authors
concluded that there were not enough patients ( n = 140) to evaluate the risk
for neurologic complications. Several neuraxially administered drugs have been shown to produce
antinociceptive effects by altering calcium channel conductance in the
spinal cord. Intrathecal gabapentin
Intrathecal magnesium sulfate 50 mg prolonged the duration of spinal reduced incision-induced allodynia in rats, 419,420 and epidural
anesthesia and improved postoperative analgesia in patients undergoing verapamil lowered postoperative opioid consumption after lower abdominal
nonobstetric surgery with bupivacaine and fentanyl spinal anesthesia. 407,408 In surgery. 421 Ziconotide, a neuronal N-typeselective voltage-sensitive calcium
women undergoing cesarean delivery, no difference in the first request for entry–blocking agent, has been shown to have analgesic effects after
postcesarean analgesia was found among patients who were randomized intrathecal administration in chronic pain patients. 422
to receive intrathecal magnesium sulfate 50 mg compared with placebo
(median time, 100 minutes versus 105 minutes, respectively), and patients Before recommendations can be made about the potential use of new
who received intrathecal fentanyl 25 µ g had a longer time to first request adjunct agents, neurotoxicity studies are necessary to ensure these
for analgesia (132 minutes) compared with the magnesium group. 409 agents’ safety for neuraxial administration. In addition, studies assessing
analgesic efficacy, side effects, and toxicity must demonstrate that these
agents result in significant improvement over the neuraxial local
anesthetic and opioid regimens currently used in clinical practice.
In summary, neuraxial administration of magnesium may have a
favorable analgesic effect in patients after cesarean delivery. However,
more research, including dose-response studies and comparison with
systemic administration, are needed to more formally assess the analgesic NON-NEURAXIAL REGIONAL
efficacy of epidural and intrathecal magnesium.
ANALGESIC TECHNIQUES Abdominal
Fascial Sheath Blocks
Experimental Agents The transversus abdominis plane (TAP) block and quadratus lumborum
In the future, newer agents and adjuvants may enhance postoperative pain block (QLB) are regional anesthetic techniques in which local anesthetic is
management strategies in patients receiving neuraxial anesthesia for injected between fascial sheaths of the abdominal musculature. In clinical
cesarean delivery. Adenosine ( and adenosine analogues) have been practice, the blocks are usually performed using ultrasonography to verify
proposed to have antinociceptive activity related to activation of spinal correct needle position and site of injection. In the TAP block, infiltration is
adenosine A 1 between the internal oblique and the transversus abdominis muscle layers
receptors. 410 However, studies have not demonstrated improved ( Fig. 27.9 ), and in the QLB ( Fig.
analgesia with intrathecal adenosine administration in patients
undergoing hysterectomy 411,412 or for labor analgesia. 413 27.10 ), infiltration is adjacent to the anterolateral aspect of the quadratus
lumborum muscle. Both techniques block the plexus of nerves supplying
A direct relationship may exist between central potassium channel the anterior abdominal wall. Some have suggested the possibility that the
activity and antinociception. Several animal studies have investigated potassium QLB may have greater efficacy than the TAP block because of spread of
channel activators (nicorandil, sildenafil) administered by the intrathecal 414 the local anesthetic solution beyond the muscle fascia into an interfascial
or epidural 415 plane close to the paravertebral space. 423 Chin et al. 424
route. Neuraxial administration of these drugs has not been studied in

humans. provide a detailed review of the anatomy of abdominal wall blocks.
A meta-analysis of studies that assessed the clinical benefit and side
effects of intrathecal midazolam in obstetric and nonobstetric patients Three systematic reviews and meta-analyses of TAP blocks for
suggested a favorable pharmacologic profile. 416 Intrathecal midazolam was postcesarean analgesia have been completed. Mishriky et al. 107 reviewed
associated with improved analgesia and a reduced risk for PONV. After the efficacy of TAP blocks after cesarean delivery with primary outcomes of
cesarean delivery, patients who received intrathecal midazolam 2 mg pain intensity scores and opioid consumption at 24 hours. Nine studies
(without neuraxial opioids) had prolonged postoperative analgesia, compared TAP blocks with inactive controls, seven of them done in
reduced requirement for rescue analgesic, and lower pain scores for 6 combination with spinal anesthesia for cesarean delivery. In women who
hours after surgery compared with did not receive intrathecal morphine, TAP blocks
A B
Fig. 27.9 Mid-axillary transversus abdominis plane (TAP) block. (A) With the patient in the supine position, the transducer is placed near
the mid-axillary line between the costal margin and pelvic brim for a transverse imaging plane. (B) Line drawing of a transverse section
through the abdominal wall with local anesthetic injected in the transversus abdominis plane. EO, Exernal oblique; IO, internal oblique; RA,
rectus abdominis;
TA, transversus abdominis. The transversus abdominis plane lies between the internal oblique and transversus abdominis muscles.
Visualization of an elliptical distribution of the local anesthetic with well-defined margins provides evidence for the proper injection of the
solution into the plane between the internal oblique and transversus abdominis muscles. ( A, From Gray AT. Atlas of Ultrasound-Guided
Regional Anesthesia. 2nd ed. Philadelphia, PA: Elsevier; 2013.)
reduced opioid consumption (mean difference, –20.2 mg morphine administration relative to the quadratum lumborum muscle; consensus on
equivalents [95% CI, –33.7 to –6.8]) and opioidrelated side effects. 107 In the best approach is lacking. 424 Local anesthetic is infiltrated into the space
patients who received intrathecal morphine, there was no difference between the quadratus lumborum muscle and the medial layer of the
between TAP blocks and inactive controls in pain scores at 24 hours, and thoracolumbar fascia 429;
the impact on opioid consumption was inconclusive. Three studies directly the solution may spread to the paravertebral space. Blanco et al. 430 reported
compared TAP blocks with intrathecal morphine, two with a randomized placebo-controlled trial of QLB after cesarean delivery; 25
women who did not receive neuraxial morphine received a QLB with
0.1 mg 425,426 and one with 0.2 mg. 427 Intrathecal morphine provided lower 0.125% bupivacaine
pain scores on movement (mean difference, 0.2 mL/kg, and outcomes were compared with 25 women who received a
0.98 [95% CI, 0.06 to 1.91]) and reduced 24-hour opioid consumption placebo block with saline. Patients in the QLB group used less morphine at
(mean difference, − 8.4 mg morphine equivalents [95% CI, 1.7 to 15.1]). A 6 and 12 hours postoperatively; the difference was not significant at 24
limitation of the meta-analysis was the significant heterogeneity among hours (median dose, 11 mg [IQR 5 to 18] and 19 mg [IQR 11 to 36],
studies. Champaneria et al. 428 completed a subsequent meta-analysis respectively; P
with additional studies; they confirmed the conclusion that TAP blocks = . 11). 430 Similarly, Blanco et al. 423 compared the QLB and the TAP block in
are effective but do not confer additional analgesia when intrathecal women scheduled for elective cesarean delivery under spinal anesthesia
morphine is included as part of a multimodal analgesia regimen. with bupivacaine and fentanyl. Women in the QLB group used less
morphine than those in the TAP block group with no difference in pain
scores between groups. Future research will likely shed light on whether the
The QLB is an abdominal fascial block similar to the TAP block, but QLB adds benefit to current multimodal analgesia practices and whether the
with potential for more diffuse analgesia because the point of injection is analgesia it provides is superior to that of intrathecal morphine after
more posterior. QLB 1, 2, and 3 are all described based on location of cesarean delivery.
local anesthetic
Anterolateral Lateral Posterolateral
EOM LDM
RAM IOM
TAM
QLM
Fig. 27.10 Ultrasonographic image of the quadratus lumborum block-1 (QLB-1). (A) With the patient in the supine position, the three
muscle layers of the abdomen and the quadratus lumborum muscle are visualized with a high-frequency linear probe. (B) The outlines
the abdominal fascial planes and the infiltration site for the QLB-1 between the quadratus lumborum muscle and the medial layer of the
thoracolumbar fascia are clearly outlined. The broken arrow shows the needle path and point of injection. EOM, External oblique muscle; IOM,
internal oblique muscle; LDM, latissimus dorsi muscle; QLM, quadratus lumborum muscle; RAM, rectus abdominus muscle; TAM, transversus
abdominus muscle. (Modified from Murouchi T, Iwasaki S, Yamakage
M. Quadratus lumborum block: analgesic effects and chronological ropivacaine concentrations after laparoscopic surgery. Reg Anesth
Pain Med. 2016;41:146–150.)
Current data support the conclusion that abdominal fascial sheath who had spinal anesthesia for elective cesarean delivery (this dose
blocks may represent a reasonable alternative for patients who are unable corresponds to 20 mL of 0.5% ropivacaine on each side for an 80-kg
to receive neuraxial morphine, and they may serve as a rescue technique patient). The mean ( ± SD) peak plasma ropivacaine concentration 30
in special cases. 107,428,431 However, they are not superior to neuraxial opioid minutes after injection was
analgesia–based multimodal techniques, which remain the gold standard 1.82 ± 0.69 µ g/mL. Although this concentration is below the reported
for postcesarean analgesia. Additionally, because analgesia from TAP threshold for LAST (2.2 µ g/mL), 12 of 30 patients had peak concentration
blocks may be comparable to that provided by simple wound infiltration or measurements above this threshold (maximum, 3.76 µ g/mL), and 3
a continuous wound infiltration catheter (see later discussion), the value of patients had symptoms of mild LAST (perioral tingling, metallic taste). 433 Similarly,
TAP blocks in postcesarean analgesia remains unclear. Trabelsi et al. 434 demonstrated that bilateral TAP blocks with bupivacaine
100 mg (total dose) led to plasma concentrations above the reported toxic
threshold in 3 of 17 women; plasma bupivacaine concentration above the
Complications of the blocks are infrequent and include local threshold value persisted for as long as 90 minutes. The addition of
anesthetic systemic toxicity (LAST) from systemic absorption of local epinephrine to the local anesthetic solution decreases local anesthetic
anesthetic or intravascular injection, and bowel perforation. The peak plasma concentration. 435 Clinically significant LAST (seizures) has
described potential benefit of the QLB, spread to the paravertebral been reported following TAP block in obstetric patients. 436–438
space, may also result in unintended motor blockade. Wikner 432 described
a patient with hip flexion and knee extension weakness leading to
unplanned overnight admission following QLB with 20 mL of
The concentration of local anesthetic (ropivacaine, bupivacaine,
0.25% levobupivacaine for a laparoscopic gynecologic procedure. levobupivacaine) has ranged from 0.125% to 0.5% for QLB and TAP blocks.
Presumably, paravertebral spread to the lumbar spinal nerves led to A 2018 meta-analysis comparing high (greater than 50 mg) versus low
weakness of the psoas and quadriceps muscles. doses (less than or equal to 50-mg bupivacaine equivalents per side) for
The relationships between local anesthetic dose, volume, TAP block in women undergoing cesarean delivery found no difference in
concentration, and response have not been well studied, and consensus opioid consumption, time to first analgesia, pain scores, or satisfaction
on the optimal volume and concentration of local anesthetic for between doses. 439 Given current reports, we suggest that a local anesthetic
dose less than 2.5 mg/kg should be used and that patients should be
single-shot abdominal fascial plane blocks is lacking. Griffiths et al. 433 performed
bilateral TAP blocks with a total ropivacaine dose of 2.5 mg/kg (diluted observed for LAST for at least 30 minutes after these blocks are performed. 440
with 0.9% saline to a total volume of 40 mL) in women
Continuous wound infusion below the fascia has been shown to be

Wound Infusion Catheters more effective in reducing postcesarean morphine consumption
Wound infusion of local anesthetic provides effective analgesia after compared with infusion above the fascia. 445 Klasen et al. 446 evaluated a
cesarean delivery. However, whether wound infusion provides additional multimodal analgesic regimen for cesarean delivery and found no
analgesia beyond that provided by neuraxial morphine is not clear. In a difference between a TAP block and continuous subfascial wound
study comparing pain control provided by wound infusion or epidural infiltration. Although some centers use wound-infusion catheters, the
levobupivacaine, the epidural group had less pain in the first 4 hours, but additional cost of the pump and some minor inconveniences, such as
pain control did not differ between groups thereafter. 441 There was no wound leakage, may have discouraged widespread use.
difference between groups in opioid consumption. 441 In another study
comparing intrathecal morphine analgesia and wound infusion with
ropivacaine or saline, more oxycodone was required in the ropivacaine
wound infusion group than in the intrathecal morphine group during the Ilioinguinal-Iliohypogastric Block
first 24 hours (48 mg versus 26 mg; P = . 004); there was no difference in Ilioinguinal-iliohypogastric nerve block is useful for postoperative
oxycodone use between the ropivacaine wound infusion and saline-control analgesia after lower abdominal surgery. Similar to a TAP block, the block
groups. 442 Carvalho et al. 443 compared wound infusion with bupivacaine can be performed with ultrasonographic guidance. Evidence is
alone to bupivacaine combined with ketorolac in patients who had inconsistent as to whether ilioinguinaliliohypogastric blocks improve
received intrathecal morphine. The addition of ketorolac was associated analgesia provided by neuraxial morphine. 447,448 In a study in women who
with a decrease in pain scores and opioid consumption, and lower did not receive neuraxial morphine, women who received multilevel
concentrations of inflammatory mediators were collected from the wound. 443 ilioinguinal-iliohypogastric blocks used less systemic opioid, although no
Lalmand et al. 444 randomly allocated patients undergoing elective cesarean difference in opioid-related side effects was observed. 449
delivery into three groups: control, intrathecal morphine, and wound
catheter infusion. All patients received spinal anesthesia with bupivacaine
and sufentanil, and a multiorifice catheter was inserted into the wound.
The control group received saline intrathecally and through the catheter, Subcutaneous Infiltration of Local Anesthetics
the morphine group received intrathecal morphine 0.1 mg and saline Subcutaneous local wound infiltration is a relatively simple component of
infusion through the wound catheter, and the catheter group received multimodal postoperative analgesia. In a study of patients who did not
intrathecal saline and 0.2% ropivacaine infused through the catheter receive neuraxial morphine for postcesarean analgesia, infiltration of
(15-mL bolus followed by a 10-mL/h infusion). Intrathecal morphine and 0.25% bupivacaine with epinephrine (40 mL) before wound closure was
0.2% ropivacaine wound infusion increased the time to the first oral associated with decreased opioid requirements in the first 12 hours
morphine request and reduced morphine consumption compared with compared with saline placebo. 450 In the absence of intrathecal morphine,
placebo. The wound infusion was not superior to intrathecal morphine 0.1 wound infiltration may confer similar analgesia to bilateral TAP blocks
mg for analgesia and had a similar side-effect profile. 444 following cesarean delivery with spinal anesthesia. 451,452 Simavli et al. 453 randomized
patients who had general anesthesia for cesarean delivery to receive
bupivacaine-soaked absorbable gelatin sponges or placebo, placed in the
wound. Pain scores were lower in the sponge group compared with the
control group, and fewer patients required rescue opioid. Adesope et al. 454 conducted
a systematic review of randomized trials to assess the efficacy of local
anesthetic wound infiltration in women undergoing cesarean delivery.
Some of the differences in outcomes among these studies may be Wound infiltration reduced opioid consumption at 24 hours (morphine
because of differences in catheter-insertion technique, local anesthetic equivalent − 9.7 mg) but had no clinical effect on pain scores and did not
concentration, and rate of infusion. Taken together, current evidence does reduce opioid-related side effects. 454
not support the superiority of local anesthetic wound infusion over

neuraxial opioid administration, although there may be additive benefit in
some circumstances.
K E Y PO I NT S
• Cesarean•deliveries•account•for•nearly•one-third•of•all•deliveries in the • Optimal•postcesarean•analgesia•consists•of•a•multidisciplinary
United States; therefore, strategies for reducing adverse postcesarean approach that should involve physicians, nurses, pharmacists, and other
maternal outcomes, including postoperative pain, have important health care providers.
clinical and public health implications. • Multimodal•techniques•provide•efficient•postcesarean•analgesia by
acting on different pain pathways to maximize analgesia while limiting
• Effective•postoperative•analgesia•confers•many•physiologic•and side effects.
psychological benefits and may improve maternal and neonatal outcomes • Neuraxial•morphine•administration•currently•represents•the “gold
after cesarean delivery. standard” for providing effective postcesarean
analgesia and is the most important component of multimodal • Opioids•are•the•most•common•systemic•medications•administered for

analgesia. postcesarean analgesia. Adverse effects associated with opioids, which
• Morphine•has•the•longest•duration•of•action•among•available often limit their use, include respiratory depression, sedation,
neuraxial opioids, and neuraxial administration of opioids provides constipation, nausea and vomiting, urinary retention, and pruritus.
better postoperative pain relief than systemic administration.
• Oral•analgesic•adjuvants•(acetaminophen,•NSAIDs)•should be
• In•clinical•practice,•single-dose•epidural•(2•to•4•mg)•or•intrathecal prescribed at a fixed interval, rather than on patient request.
(0.075 to 0.2 mg) morphine administration is most commonly
administered for postcesarean analgesia. Higher doses may increase • Abdominal•fascial•sheath•blocks•may•represent•a•reasonable
opioid-related side effects without improving analgesia. alternative for patients who are unable to receive neuraxial morphine, or
they may be used as a rescue technique in selected cases.
• Nonopioid•neuraxial•adjuncts•(e.g.,•alpha 2- adrenergic receptor
agonists, anticholinesterases) may be considered as alternatives to, or • Local•wound•instillation•may•be•considered•in•addition•to•neuraxial
combined with, neuraxial opioids. However, these adjuncts are morphine, acetaminophen, and NSAIDs to provide further multimodal
associated with modest analgesic benefits, and the risk for spinal analgesia.
neurotoxicity associated with many of these drugs remains to be
determined.
14. Komatsu R, Carvalho B, Flood PD. Recovery after nulliparous birth: a detailed
REFERENCES
analysis of pain analgesia and recovery of function. Anesthesiology. 2017;127:684–694.
1. Betrán AP, Ye J, Moller AB, et al. The increasing trend in caesarean
section rates: global, regional and national estimates: 1990-2014. PLoS 15. Carvalho B, Cohen SE, Lipman SS, et al. Patient preferences for anesthesia
One. 2016;11:e0148343. outcomes associated with cesarean delivery.
2. Martin J, Hamilton B, Osterman M, et al. Births: final data for Anesth Analg. 2005;101:1182–1187.
2015. Natl Vital Stat Rep. 2017;66:1–69. 16. Scher C, Meador L, Van Cleave JH, Reid MC. Moving beyond pain as the fifth
3. Nikolajsen L, Sorensen HC, Jensen TS, Kehlet H. Chronic pain following vital sign and patient satisfaction scores to improve pain care in the 21st
caesarean section. Acta Anaesthesiol Scand. century. Pain Manag Nurs.
2004;48:111–116. 2018;19:125–129.
4. Eisenach JC, Pan PH, Smiley R, et al. Severity of acute pain after childbirth, 17. Gordon DB. Acute pain assessment tools: let us move beyond simple pain
but not type of delivery, predicts persistent pain and postpartum ratings. Curr Opin Anaesthesiol. 2015;28: 565–569.
depression. Pain. 2008;140:87–94.
5. Kainu JP, Sarvela J, Tiippana E, et al. Persistent pain after caesarean 18. Wrench IJ, Sanghera S, Pinder A, et al. Dose response to intrathecal
section and vaginal birth: a cohort study. Int J Obstet Anesth. 2010;19:4–9. diamorphine for elective caesarean section and compliance with a national
audit standard. Int J Obstet Anesth. 2007;16:17–21.
6. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience:
results from a national survey suggest postoperative pain continues to be 19. Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of
undermanaged. Anesth Analg. 2003;97:534–540. predictive factors. Anesthesiology.
2000;93:1123–1133.
7. Dolin SJ, Cashman JN, Bland JM. Effectiveness of acute postoperative pain 20. Lavand’homme P. Chronic pain after vaginal and cesarean delivery: a reality
management: I. Evidence from published data. Br J Anaesth. 2002;89:409–423. questioning our daily practice of obstetric anesthesia. Int J Obstet Anesth. 2010;19:1–2.
8. Houle TT, Miller S, Lang JE, et al. Day-to-day experience in resolution of 21. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors
pain after surgery. Pain. 2017;158:2147–2154. and prevention. Lancet. 2006;367:1618–
9. Fassoulaki A, Gatzou V, Petropoulos G, Siafaka I. Spread of subarachnoid 1625.
block, intraoperative local anaesthetic requirements and postoperative 22. De Kock M, Lavand’homme P, Waterloos H. The short-lasting analgesia and
analgesic requirements in caesarean section and total abdominal long-term antihyperalgesic effect of intrathecal clonidine in patients
hysterectomy. Br J Anaesth. 2004;93:678–682. undergoing colonic surgery. Anesth Analg. 2005;101:566–572.
10. Woolf CJ. Pain: moving from symptom control toward mechanism-specific 23. Lavand’homme P, De Kock M, Waterloos H. Intraoperative epidural analgesia
pharmacologic management. Ann Intern Med. 2004;140:441–451. combined with ketamine provides effective preventive analgesia in patients
undergoing major digestive surgery. Anesthesiology. 2005;103:813–820.
11. Smith R. Parturition. N Engl J Med. 2007;356:271–283.
12. Unal ER, Cierny JT, Roedner C, et al. Maternal inflammation in spontaneous 24. Wong CA, Girard T. Under- or overtreated? Opioids for postdelivery
term labor. Am J Obstet Gynecol. analgesia. Br J Anaesth. 2018;121: 339–342.
2011;204:223.e1–223.e5.
13. Carvalho B, Clark DJ, Angst MS. Local and systemic release of cytokines, nerve 25. Carvalho B, Mirza F, Flood P. Patient choice compared with no choice of
growth factor, prostaglandin e2, and substance P in incisional wounds and intrathecal morphine dose for caesarean analgesia: a randomized clinical
serum following cesarean delivery. J Pain. 2008;9:650–657. trial. Br J Anaesth.
2017;118:762–771.
26. American College of Obstetricians and Gynecologists. Practice Bulletin No. 43. Owen H, Brose WG, Plummer JL, Mather LE. Variables of patient-controlled
177: Obstetric analgesia and anesthesia. analgesia. 3: test of an infusion-demand system using alfentanil. Anaesthesia.
Obstet Gynecol. 2017;129:e73–e89. 1990;45:452–455.
27. American Pain Society. Principles of Analgesic Use in the 44. Owen H, Kluger MT, Plummer JL. Variables of patient-controlled analgesia 4: the
Treatment of Acute Pain or Chronic Cancer Pain. American Pain Society. 4th ed. relevance of bolus dose size to supplement a background infusion. Anaesthesia.
Glenview, IL: American Pain Society; 1999.
28. McNicol ED, Ferguson MC, Hudcova J. Patient controlled opioid analgesia 1990;45:619–622.
versus non-patient controlled opioid analgesia for postoperative pain. Cochrane 45. Owen H, Plummer JL, Armstrong I, et al. Variables of
Database Syst Rev. patient-controlled analgesia. 1. Bolus size. Anaesthesia.
2015;(6):CD003348. 1989;44:7–10.
29. American Society of Anesthesiologists. Practice guidelines for acute pain 46. Parker RK, Holtmann B, White PF. Effects of a nighttime opioid infusion
management in the perioperative setting. An updated report by the American with PCA therapy on patient comfort and analgesic requirements after
Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. abdominal hysterectomy.
Anesthesiology. 1992;76:362–367.
2012;116:248–273. 47. McCoy EP, Furness G, Wright PM. Patient-controlled analgesia with and
30. Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of without background infusion. Analgesia assessed using the demand:
postoperative pain: a clinical practice guideline from the American Pain delivery ratio. Anaesthesia.
Society, the American Society of Regional Anesthesia and Pain Medicine, 1993;48:256–260.
and the American Society of Anesthesiologists’ Committee on Regional 48. Jakobi P, Solt I, Tamir A, Zimmer EZ. Over-the-counter oral analgesia for
Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17:131–157. postcesarean pain. Am J Obstet Gynecol.
2002;187:1066–1069.
49. Bloomfield SS, Cissell GB, Mitchell J, et al. Analgesic efficacy and potency of
31. Ngan Kee WD, Lam KK, Chen PP, Gin T. Comparison of patient-controlled two oral controlled-release morphine preparations. Clin Pharmacol Ther. 1993;53:469–478.
epidural analgesia with patient-controlled intravenous analgesia using
pethidine or fentanyl. Anaesth Intensive Care. 1997;25:126–132. 50. Jakobi P, Weiner Z, Solt I, et al. Oral analgesia in the treatment of post-cesarean
pain. Eur J Obstet Gynecol Reprod Biol.
32. Parker RK, White PF. Epidural patient-controlled analgesia: an alternative to 2000;93:61–64.
intravenous patient-controlled analgesia for pain relief after cesarean 51. Davis KM, Esposito MA, Meyer BA. Oral analgesia compared with intravenous
delivery. Anesth Analg. patient-controlled analgesia for pain after cesarean delivery: a randomized
1992;75:245–251. controlled trial. Am J Obstet Gynecol. 2006;194:967–971.
33. Lim Y, Jha S, Sia AT, Rawal N. Morphine for post-caesarean section
analgesia: intrathecal, epidural or intravenous? 52. Dieterich M, Muller-Jordan K, Stubert J, et al. Pain management after
Singapore Med J. 2005;46:392–396. cesarean: a randomized controlled trial of oxycodone versus intravenous
34. Harrison DM, Sinatra R, Morgese L, Chung JH. Epidural narcotic and piritramide. Arch Gynecol Obstet. 2012;286:859–865.
patient-controlled analgesia for post-cesarean section pain relief. Anesthesiology.
1988;68:454–457. 53. Kehlet H, Dahl JB. The value of “multimodal” or “balanced analgesia” in
35. Rapp-Zingraff N, Bayoumeu F, Baka N, et al. Analgesia after caesarean postoperative pain treatment. Anesth Analg.
section: patient-controlled intravenous morphine vs epidural morphine. Int J 1993;77:1048–1056.
Obstet Anesth. 1997;6:87–92. 54. Pan PH. Post cesarean delivery pain management: multimodal approach. Int J
36. Kopka A, Wallace E, Reilly G, Binning A. Observational study of perioperative Obstet Anesth. 2006;15:185–188.
PtcCO 2 and SpO 2 in non-ventilated patients receiving epidural infusion or 55. Sutton CD, Carvalho B. Optimal pain management after cesarean
patient-controlled analgesia using a single earlobe monitor (TOSCA). Br J delivery. Anesthesiol Clin. 2017;35:107–124.
Anaesth. 56. Lavoie A, Toledo P. Multimodal postcesarean delivery analgesia. Clin
2007;99:567–571. Perinatol. 2013;40:443–455.
37. McCormack JG, Kelly KP, Wedgwood J, Lyon R. The effects of different 57. Yefet E, Taha H, Salim R, et al. Fixed time interval compared with on-demand
analgesic regimens on transcutaneous CO 2 after major surgery. Anaesthesia. 2008;63:814–821.
oral analgesia protocols for post-caesarean pain: a randomised controlled
trial. BJOG.
38. Cashman JN, Dolin SJ. Respiratory and haemodynamic effects of acute 2017;124:1063–1070.
postoperative pain management: evidence from published data. Br J 58. Remy C, Marret E, Bonnet F. Effects of acetaminophen on morphine
Anaesth. 2004;93:212–223. side-effects and consumption after major surgery: meta-analysis of
39. Hagle ME, Lehr VT, Brubakken K, Shippee A. Respiratory depression in randomized controlled trials. Br J Anaesth.
adult patients with intravenous patient-controlled analgesia. Orthop Nurs. 2004;23:18–27. 2005;94:505–513.
59. Maund E, McDaid C, Rice S, et al. Paracetamol and selective and
40. Gwirtz KH, Young JV, Byers RS, et al. The safety and efficacy of intrathecal non-selective non-steroidal anti-inflammatory drugs for the reduction in
opioid analgesia for acute postoperative pain: seven years’ experience with morphine-related side-effects after major surgery: a systematic review. Br J
5969 surgical patients at Indiana University Hospital. Anesth Analg. 1999;88:599–604. Anaesth. 2011;106:292–297.
60. Elia N, Lysakowski C, Tramer MR, Phil D. Does multimodal analgesia with
41. Pattinson KT. Opioids and the control of respiration. Br J acetaminophen, nonsteroidal antiinflammatory drugs, or selective
Anaesth. 2008;100:747–758. cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer
42. Joint Commission on the Accreditation of Healthcare Organizations. JCAHO advantages over morphine alone? Anesthesiology.
alert gives new recommendations for PCA. Hosp Peer Rev. 2005;30:24–25.
2005;103:1296–1304.
61. Rawlinson A, Kitchingham N, Hart C, et al. Mechanisms of reducing 77. Cardoso MM, Carvalho JC, Amaro AR, et al. Small doses of intrathecal
postoperative pain, nausea and vomiting: a systematic review of current morphine combined with systemic diclofenac for postoperative pain control
techniques. Evid Based Med. after cesarean delivery. Anesth Analg. 1998;86:538–541.
2012;17:75–80.
62. Alhashemi JA, Alotaibi QA, Mashaat MS, et al. Intravenous acetaminophen 78. Munishankar B, Fettes P, Moore C, McLeod GA. A double-blind randomised
vs oral ibuprofen in combination with morphine PCIA after cesarean controlled trial of paracetamol, diclofenac or the combination for pain relief
delivery. Can J Anaesth. after caesarean section. Int J Obstet Anesth. 2008;17:9–14.
2006;53:1200–1206.
63. Ing Lorenzini K, Besson M, Daali Y, et al. A randomized, controlled trial 79. Lowder JL, Shackelford DP, Holbert D, Beste TM. A randomized, controlled trial
validates a peripheral supra-additive antihyperalgesic effect of a to compare ketorolac tromethamine versus placebo after cesarean section to
paracetamol-ketorolac combination. Basic Clin Pharmacol Toxicol. 2011;109: reduce pain and narcotic usage. Am J Obstet Gynecol.
357–364.
2003;189:1559–1562.
64. Ong CK, Seymour RA, Lirk P, Merry AF. Combining paracetamol 80. American Academy of Pediatrics Committee on Drugs. Transfer of
(acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative drugs and other chemicals into human milk.
systematic review of analgesic efficacy for acute postoperative pain. Anesth Pediatrics. 2001;108:776–789.
Analg. 81. Romsing J, Moiniche S. A systematic review of COX-2 inhibitors compared
2010;110:1170–1179. with traditional NSAIDS, or different COX-2 inhibitors for post-operative
65. Chandrasekharan NV, Dai H, Roos KL, et al. COX-3, a cyclooxygenase-1 pain. Acta Anaesthesiol Scand. 2004;48:525–546.
variant inhibited by acetaminophen and other analgesic/antipyretic drugs:
cloning, structure, and expression. Proc Natl Acad Sci USA. 2002;99:13926–13931. 82. Paech MJ, McDonnell NJ, Sinha A, et al. A randomised controlled trial of
parecoxib, celecoxib and paracetamol as adjuncts to patient-controlled
66. Krenzelok EP. The FDA Acetaminophen Advisory Committee meeting - what is epidural analgesia after caesarean delivery. Anaesth Intensive Care. 2014;42:
the future of acetaminophen in the United States? The perspective of a 15–22.
committee member. Clin Toxicol (Phila). 2009;47:784–789.
83. Lee LH, Irwin MG, Lim J, Wong CK. The effect of celecoxib on intrathecal
67. Valentine AR, Carvalho B, Lazo TA, Riley ET. Scheduled acetaminophen with morphine-induced pruritus in patients undergoing caesarean section. Anaesthesia.
as-needed opioids compared to as-needed acetaminophen plus opioids for 2004;59: 876–880.
post-cesarean pain management. Int J Obstet Anesth. 2015;24:210–216.
84. Paech MJ, Salman S, Ilett KF, et al. Transfer of parecoxib and its primary active
68. Petring OU, Dawson PJ, Blake DW, et al. Normal postoperative gastric emptying metabolite valdecoxib via transitional breastmilk following intravenous
after orthopaedic surgery with spinal anaesthesia and i.m. ketorolac as the first parecoxib use after cesarean delivery: a comparison of naive pooled data
postoperative analgesic. Br J Anaesth. 1995;74:257–260. analysis and nonlinear mixed-effects modeling. Anesth Analg.
69. Singla NK, Parulan C, Samson R, et al. Plasma and cerebrospinal fluid 2012;114:837–844.
pharmacokinetic parameters after single-dose administration of 85. Blaudszun G, Lysakowski C, Elia N, Tramer MR. Effect of perioperative
intravenous, oral, or rectal acetaminophen. Pain Pract. 2012;12:523–532. systemic alpha-2 agonists on postoperative morphine consumption and pain
intensity: systematic review and meta-analysis of randomized controlled
70. Kim JH, Lee YS, Shin HW, et al. Effect of administration of ketorolac and local trials.
anaesthetic infiltration for pain relief after laparoscopic-assisted vaginal Anesthesiology. 2012;116:1312–1322.
hysterectomy. J Int Med Res. 86. Palanisamy A, Klickovich RJ, Ramsay M, et al. Intravenous
2005;33:372–378. dexmedetomidine as an adjunct for labor analgesia and cesarean delivery
71. Bloor M, Paech M. Nonsteroidal anti-inflammatory drugs during anesthesia in a parturient with a tethered spinal cord. Int J Obstet Anesth. 2009;18:258–261.
pregnancy and the initiation of lactation. Anesth Analg. 2013;116:1063–1075.
87. Yoshimura M, Kunisawa T, Suno M, et al. Intravenous dexmedetomidine for
72. Zeng AM, Nami NF, Wu CL, Murphy JD. The analgesic efficacy of cesarean delivery and its concentration in colostrum. Int J Obstet Anesth. 2017;32:28–32.
nonsteroidal anti-inflammatory agents (NSAIDs) in patients undergoing
cesarean deliveries: a meta-analysis. 88. Package insert: Duraclon (clonidine hydrochloride) injection, solution. Available
Reg Anesth Pain Med. 2016;41:763–772. at: https://www.accessdata.fda.gov/
73. Townsend RJ, Benedetti TJ, Erickson SH, et al. Excretion of ibuprofen into drugsatfda_docs/label/2010/020615s003lbl.pdf . Accessed June
breast milk. Am J Obstet Gynecol. 23, 2018.
1984;149:184–186. 89. Pryde PG, Mittendorf R. Contemporary usage of obstetric magnesium
74. Angle PJ, Halpern SH, Leighton BL, et al. A randomized controlled trial sulfate: indication, contraindication, and relevance of dose. Obstet
examining the effect of naproxen on analgesia during the second day after Gynecol. 2009;114:669–673.
cesarean delivery. Anesth Analg. 90. De Oliveira G, Castro-Alves L, Khan J, McCarthy R. Perioperative systemic
2002;95:741–745. magnesium to minimize postoperative pain: a meta-analysis of randomized
75. Dahl V, Hagen IE, Sveen AM, et al. High-dose diclofenac for postoperative controlled trials.
analgesia after elective caesarean section in regional anaesthesia. Int J Anesthesiology. 2013;119:178–190.
Obstet Anesth. 2002;11:91–94. 91. Hah J, Mackey SC, Schmidt P, et al. Effect of perioperative gabapentin on
76. Dennis AR, Leeson-Payne CG, Hobbs GJ. Analgesia after caesarean section. postoperative pain resolution and opioid cessation in a mixed surgical
The use of rectal diclofenac as an adjunct to spinal morphine. Anaesthesia. 1995;50:297–299. cohort: a randomized clinical trial. JAMA Surg. 2018;153:303–311.
92. Moore A, Costello J, Wieczorek P, et al. Gabapentin improves postcesarean systematic review and meta-analysis. Br J Anaesth.
delivery pain management: a randomized, placebo-controlled trial. Anesth 2012;109:679–687.
Analg. 2011;112:167–173. 109. Lavand’homme P. Postcesarean analgesia: effective strategies and association
93. Short J, Downey K, Bernstein P, et al. A single preoperative dose of with chronic pain. Curr Opin Anaesthesiol.
gabapentin does not improve postcesarean delivery pain management: a 2006;19:244–248.
randomized, double-blind, placebo-controlled dose-finding trial. Anesth 110. Cade L, Ashley J, Ross AW. Comparison of epidural and intravenous opioid
Analg. analgesia after elective caesarean section.
2012;115:1336–1342. Anaesth Intensive Care. 1992;20:41–45.
94. Monks DT, Hoppe DW, Downey K, et al. A perioperative course of gabapentin 111. Terajima K, Onodera H, Kobayashi M, et al. Efficacy of intrathecal morphine for
does not produce a clinically meaningful improvement in analgesia after analgesia following elective cesarean section: comparison with previous
cesarean delivery. delivery. J Nippon Med Sch. 2003;70:327–333.
95. Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the 112. Swart M, Sewell J, Thomas D. Intrathecal morphine for caesarean section: an
management of acute postoperative pain: a review of current techniques and assessment of pain relief, satisfaction and side-effects. Anaesthesia. 1997;52:373–377.
outcomes. Pain.
1999;82:111–125. 113. Dahl JB, Jeppesen IS, Jorgensen H, et al. Intraoperative and postoperative
96. Sen S, Ozmert G, Aydin ON, et al. The persisting analgesic effect of analgesic efficacy and adverse effects of intrathecal opioids in patients
low-dose intravenous ketamine after spinal anaesthesia for caesarean undergoing cesarean section with spinal anesthesia: a qualitative and
section. Eur J Anaesthesiol. quantitative systematic review of randomized controlled trials.
2005;22:518–523.
97. Menkiti ID, Desalu I, Kushimo OT. Low-dose intravenous ketamine improves Anesthesiology. 1999;91:1919–1927.
postoperative analgesia after caesarean delivery with spinal bupivacaine in 114. Tziavrangos E, Schug SA. Regional anaesthesia and perioperative
African parturients. Int J Obstet Anesth. 2012;21:217–221. outcome. Curr Opin Anaesthesiol.
2006;19:521–525.
98. Bauchat JR, Higgins N, Wojciechowski KG, et al. Low-dose ketamine with 115. Guay J. The benefits of adding epidural analgesia to general
multimodal postcesarean delivery analgesia: a randomized controlled trial. Int anesthesia: a metaanalysis. J Anesth. 2006;20: 335–340.
J Obstet Anesth. 2011;20:3–9.
99. Heesen M, Bohmer J, Brinck EC, et al. Intravenous ketamine during spinal and 116. Richman JM, Wu CL. Epidural analgesia for postoperative pain. Anesthesiol
general anaesthesia for caesarean section: systematic review and Clin North America. 2005;23:125–140.
meta-analysis. Acta Anaesthesiol Scand. 117. Cohen SE, Woods WA. The role of epidural morphine in the postcesarean
2015;59:414–426. patient: efficacy and effects on bonding.
100. Jenkins JG, Khan MM. Anaesthesia for caesarean section: a survey in a UK Anesthesiology. 1983;58:500–504.
region from 1992 to 2002. Anaesthesia. 118. Rosaeg OP, Lui AC, Cicutti NJ, et al. Peri-operative multimodal pain therapy for
2003;58:1114–1118. caesarean section: analgesia and fitness for discharge. Can J Anaesth. 1997;44:803–809.
101. Aiono-Le Tagaloa L, Butwick AJ, Carvalho B. A survey of perioperative and
postoperative anesthetic practices for cesarean delivery. Anesthesiol Res 119. Kettner SC, Willschke H, Marhofer P. Does regional anaesthesia
Pract. 2009;2009:510642. really improve outcome? Br J Anaesth.
102. Traynor AJ, Aragon M, Ghosh D, et al. Obstetric Anesthesia Workforce 2011;107(suppl 1):i90–i95.
Survey: a 30-year update. Anesth Analg. 120. Ghaji N, Boulet SL, Tepper N, Hooper WC. Trends in venous thromboembolism
2016;122:1939–1946. among pregnancy-related hospitalizations, United States, 1994-2009. Am J
103. Bonnet MP, Mignon A, Mazoit JX, et al. Analgesic efficacy and adverse effects of Obstet Gynecol.
epidural morphine compared to parenteral opioids after elective caesarean 2013;209(433):e1–e8.
section: a systematic review. 121. Callaghan WM, Creanga AA, Kuklina EV. Severe maternal morbidity among
Eur J Pain. 2010;14:894.e1–894.e9. delivery and postpartum hospitalization in the United States. Obstet Gynecol. 2012;120:1029–1
104. Wu CL, Cohen SR, Richman JM, et al. Efficacy of postoperative
patient-controlled and continuous infusion epidural analgesia versus 122. Jacobsen AF, Skjeldestad FE, Sandset PM. Incidence and risk patterns of venous
intravenous patient-controlled analgesia with opioids: a meta-analysis. Anesthesiology. thromboembolism in pregnancy and puerperium—a register-based case-control
study. Am J Obstet Gynecol. 2008;198(2):233.e1–233.e7.
2005;103:1079–1088.
105. Cohen SE, Subak LL, Brose WG, Halpern J. Analgesia after cesarean delivery: 123. Sultan AA, Tata LJ, West J, et al. Risk factors for first venous
patient evaluations and costs of five opioid techniques. Reg Anesth. 1991;16:141–149. thromboembolism around pregnancy: a population-based cohort study
from the United Kingdom. Blood.
106. Eisenach JC, Grice SC, Dewan DM. Patient-controlled analgesia 2013;121:3953–3962.
following cesarean section: a comparison with epidural and 124. Ramanathan J, Coleman P, Sibai B. Anesthetic modification of hemodynamic and
intramuscular narcotics. Anesthesiology. neuroendocrine stress responses to cesarean delivery in women with severe
1988;68:444–448. preeclampsia. Anesth Analg. 1991;73:772–779.
107. Mishriky BM, George RB, Habib AS. Transversus abdominis plane block for
analgesia after cesarean delivery: a systematic review and meta-analysis. Can 125. Rawal N, Sjostrand U, Christoffersson E, et al. Comparison of intramuscular
J Anaesth. 2012;59:766–778. and epidural morphine for postoperative analgesia in the grossly obese:
108. Abdallah FW, Halpern SH, Margarido CB. Transversus abdominis plane influence on postoperative ambulation and pulmonary function. Anesth Analg.
block for postoperative analgesia after caesarean delivery performed
under spinal anaesthesia? A 1984;63:583–592.
126. Tuman KJ, McCarthy RJ, March RJ, et al. Effects of epidural anesthesia and and pain in human volunteers: epidural versus intravenous administration
analgesia on coagulation and outcome after major vascular surgery. Anesth of fentanyl. Anesth Analg. 1996;82:98–102.
Analg. 1991;73:696–704. 146. Ginosar Y, Riley ET, Angst MS. The site of action of epidural fentanyl in
127. Yeager MP, Glass DD, Neff RK, Brinck-Johnsen T. Epidural anesthesia and humans: the difference between infusion and bolus administration. Anesth
analgesia in high-risk surgical patients. Analg. 2003;97:1428–1438.
Anesthesiology. 1987;66:729–736. 147. Cohen S, Pantuck CB, Amar D, et al. The primary action of epidural fentanyl
128. Armitage EN. Postoperative pain—prevention or relief? Br J after cesarean delivery is via a spinal mechanism. Anesth Analg. 2002;94:674–679.
Anaesth. 1989;63:136–138.
129. Yarnell RW, Polis T, Reid GN, et al. Patient-controlled analgesia with 148. Sadurni M, DE Heredia BS, Dursteler C, et al. Epidural vs. intravenous
epidural meperidine after elective cesarean section. Reg Anesth. 1992;17:329–333. fentanyl during colorectal surgery using a double-blind, double-dummy
design. Acta Anesthesiol Scand.
130. Cooper DW, Ryall DM, McHardy FE, et al. Patient-controlled extradural 2013;57:1103–1110.
analgesia with bupivacaine, fentanyl, or a mixture of both, after caesarean 149. Stevens RA, Petty RH, Hill HF, et al. Redistribution of sufentanil to
section. Br J Anaesth. cerebrospinal fluid and systemic circulation after epidural administration in
1996;76:611–615. dogs. Anesth Analg.
131. Parker RK, Sawaki Y, White PF. Epidural patient-controlled analgesia: influence 1993;76:323–327.
of bupivacaine and hydromorphone basal infusion on pain control after 150. Bujedo BM. Spinal opioid bioavailability in postoperative pain. Pain Pract. 2014;14:350–364.
cesarean delivery. Anesth Analg.
1992;75:740–746. 151. Nordberg G, Hedner T, Mellstrand T, Dahlstrom B. Pharmacokinetic
132. Carvalho B, Butwick AJ. Postcesarean delivery analgesia. Best aspects of epidural morphine analgesia.
Pract Res Clin Anaesthesiol. 2017;31:69–79. Anesthesiology. 1983;58:545–551.
133. Yaksh TL, Rudy TA. Analgesia mediated by a direct spinal action of 152. Youngstrom PC, Cowan RI, Sutheimer C, et al. Pain relief and plasma
narcotics. Science. 1976;192:1357–1358. concentrations from epidural and intramuscular morphine in post-cesarean
134. Wang JK, Nauss LA, Thomas JE. Pain relief by intrathecally applied morphine patients. Anesthesiology.
in man. Anesthesiology. 1979;50:149–151. 1982;57:404–409.
135. Bernards CM, Hill HF. Morphine and alfentanil permeability through the spinal 153. Weddel SJ, Ritter RR. Serum levels following epidural administration of
dura, arachnoid, and pia mater of dogs and monkeys. Anesthesiology. 1990;73:1214–1219. morphine and correlation with relief of postsurgical pain. Anesthesiology. 1981;54:210–214.
136. Bernards CM, Hill HF. Physical and chemical properties of drug molecules 154. Nordberg G, Hedner T, Mellstrand T, Dahlstrom B. Pharmacokinetic aspects
governing their diffusion through the spinal meninges. Anesthesiology. 1992;77:750–756. of intrathecal morphine analgesia.
137. George MJ. The site of action of epidurally administered opioids and its 155. Ummenhofer WC, Arends RH, Shen DD, Bernards CM. Comparative spinal
relevance to postoperative pain management. distribution and clearance kinetics of intrathecally administered morphine,
Anaesthesia. 2006;61:659–664. fentanyl, alfentanil, and sufentanil. Anesthesiology. 2000;92:739–753.
138. Gourlay GK, Cherry DA, Plummer JL, et al. The influence of drug polarity on
the absorption of opioid drugs into CSF and subsequent cephalad migration 156. Gourlay GK, Murphy TM, Plummer JL, et al. Pharmacokinetics of fentanyl
following lumbar epidural administration: application to morphine and in lumbar and cervical CSF following lumbar epidural and intravenous
pethidine. Pain. administration.
1987;31:297–305. Pain. 1989;38:253–259.
139. Bernards CM, Shen DD, Sterling ES, et al. Epidural, cerebrospinal fluid, and 157. Cousins MJ, Mather LE. Intrathecal and epidural administration of opioids. Anesthesiology.
plasma pharmacokinetics of epidural opioids (part 2): effect of epinephrine. Anesthesiology. 1984;61:276–310.
158. van den Hoogen RH, Colpaert FC. Epidural and subcutaneous morphine,
2003;99:466–475. meperidine (pethidine), fentanyl and sufentanil in the rat: analgesia and
140. Bernards CM, Shen DD, Sterling ES, et al. Epidural, cerebrospinal fluid, and other in vivo pharmacologic effects. Anesthesiology. 1987;66:186–194.
plasma pharmacokinetics of epidural opioids (part 1): differences among
opioids. Anesthesiology. 159. Brill S, Gurman GM, Fisher A. A history of neuraxial administration of
2003;99:455–465. local analgesics and opioids. Eur J Anaesthesiol. 2003;20:682–689.
141. Robertson K, Douglas MJ, McMorland GH. Epidural fentanyl, with and without
epinephrine for post-caesarean section analgesia. Can Anaesth Soc J. 1985;32:502–505.
160. Carvalho B, Roland LM, Chu LF, et al. Single-dose, extended-release epidural
morphine (DepoDur) compared to conventional epidural morphine for
142. Glass PS, Estok P, Ginsberg B, et al. Use of patient-controlled analgesia to post-cesarean pain.
compare the efficacy of epidural to intravenous fentanyl administration. Anesth Anesth Analg. 2007;105:176–183.
Analg. 1992;74:345–351. 161. Chumpathong S, Santawat U, Saunya P, et al. Comparison of different doses of
143. Ellis DJ, Millar WL, Reisner LS. A randomized double-blind comparison of epidural morphine for pain relief following cesarean section. J Med Assoc
epidural versus intravenous fentanyl infusion for analgesia after cesarean Thai. 2002;85(suppl
section. Anesthesiology. 3):S956–S962.
1990;72:981–986. 162. Rosen MA, Hughes SC, Shnider SM, et al. Epidural morphine for the relief of
144. D’Angelo R, Gerancher JC, Eisenach JC, Raphael BL. Epidural fentanyl produces postoperative pain after cesarean delivery.
labor analgesia by a spinal mechanism. Anesth Analg. 1983;62:666–672.
Anesthesiology. 1998;88:1519–1523. 163. Fuller JG, McMorland GH, Douglas MJ, Palmer L. Epidural morphine for
145. Liu SS, Gerancher JC, Bainton BG, et al. The effects of electrical stimulation analgesia after caesarean section: a report of 4880 patients. Can J
at different frequencies on perception Anaesth. 1990;37:636–640.
164. Palmer CM, Nogami WM, Van Maren G, Alves DM. Postcesarean 182. Ngan Kee WD, Lam KK, Chen PP, Gin T. Epidural meperidine after cesarean
epidural morphine: a dose-response study. section: the effect of diluent volume. Anesth Analg. 1997;85:380–384.
Anesth Analg. 2000;90:887–891.
165. Asantila R, Eklund P, Rosenberg PH. Epidural analgesia with 4 mg of 183. Ngan Kee WD, Lam KK, Chen PP, Gin T. Epidural meperidine after cesarean
morphine following caesarean section: effect of injected volume. Acta section. A dose-response study. Anesthesiology.
Anaesthesiol Scand. 1993;37: 764–767. 1996;85:289–294.
184. Rosaeg OP, Lindsay MP. Epidural opioid analgesia after caesarean
166. Singh SI, Rehou S, Marmai KL, Jones PM. The efficacy of 2 doses of section: a comparison of patient-controlled analgesia with meperidine
epidural morphine for postcesarean delivery analgesia: a randomized and single bolus injection of morphine. Can J Anaesth. 1994;41:1063–1068.
noninferiority trial. Anesth Analg.
2013;117:677–685. 185. Paech MJ, Pavy TJ, Orlikowski CE, et al. Postoperative intraspinal opioid
167. Sarvela J, Halonen P, Soikkeli A, Korttila K. A double-blinded, randomized analgesia after caesarean section; a randomised comparison of
comparison of intrathecal and epidural morphine for elective cesarean subarachnoid morphine and epidural pethidine. Int J Obstet Anesth. 2000;9:238–245.
delivery. Anesth Analg.
2002;95:436–440. 186. de Leon-Casasola OA, Lema MJ. Postoperative epidural opioid analgesia:
168. Duale C, Frey C, Bolandard F, et al. Epidural versus intrathecal what are the choices? Anesth Analg.
morphine for postoperative analgesia after caesarean section. Br J 1996;83:867–875.
Anaesth. 2003;91:690–694. 187. Dougherty TB, Baysinger CL, Henenberger JC, Gooding DJ. Epidural
169. Ng K, Parsons J, Cyna AM, Middleton P. Spinal versus epidural anaesthesia for hydromorphone with and without epinephrine for post-operative analgesia
caesarean section. Cochrane Database Syst Rev. 2004;(2):CD003765. after cesarean delivery. Anesth Analg.
1989;68:318–322.
170. Chadwick HS, Bernards CM, Kovarik DW, Tomlin JJ. Subdural injection 188. Henderson SK, Matthew EB, Cohen H, Avram MJ. Epidural hydromorphone:
of morphine for analgesia following cesarean section: a report of three a double-blind comparison with intramuscular hydromorphone for
cases. Anesthesiology. postcesarean section analgesia. Anesthesiology. 1987;66:825–830.
1992;77:590–594.
171. Grass JA, Sakima NT, Schmidt R, et al. A randomized, double-blind, 189. Chestnut DH, Choi WW, Isbell TJ. Epidural hydromorphone for postcesarean
dose-response comparison of epidural fentanyl versus sufentanil analgesia analgesia. Obstet Gynecol. 1986;68:65–69.
after cesarean section. Anesth Analg. 1997;85:365–371. 190. Halpern SH, Arellano R, Preston R, et al. Epidural morphine vs hydromorphone
in post-caesarean section patients. Can J Anaesth. 1996;43:595–598.
172. Preston PG, Rosen MA, Hughes SC, et al. Epidural anesthesia with fentanyl and
lidocaine for cesarean section: maternal effects and neonatal outcome. Anesthesiology.191. Quigley C. Hydromorphone for acute and chronic pain.
Cochrane Database Syst Rev. 2002;(1):CD003447.
1988;68:938–943. 192. Rawal N, Allvin R. Acute pain services in Europe: a 17-nation survey of 105
173. Bromage PR, Camporesi EM, Durant PA, Nielsen CH. Rostral spread of epidural hospitals. The EuroPain Acute Pain Working Party. Eur J Anaesthesiol. 1998;15:354–363.
morphine. Anesthesiology.
1982;56:431–436. 193. Roulson CJ, Bennett J, Shaw M, Carli F. Effect of extradural diamorphine on
174. King MJ, Bowden MI, Cooper GM. Epidural fentanyl and analgesia after caesarean section under subarachnoid block. Br J Anaesth. 1993;71:810–813.
0.5% bupivacaine for elective caesarean section. Anaesthesia.
1990;45:285–288. 194. Haynes SR, Davidson I, Allsop JR, Dutton DA. Comparison of epidural
175. Naulty JS, Datta S, Ostheimer GW, et al. Epidural fentanyl for postcesarean methadone with epidural diamorphine for analgesia following caesarean
delivery pain management. Anesthesiology. section. Acta Anaesthesiol Scand.
1985;63:694–698. 1993;37:375–380.
176. Sevarino FB, McFarlane C, Sinatra RS. Epidural fentanyl does not influence 195. Semple AJ, Macrae DJ, Munishankarappa S, et al. Effect of the addition of
intravenous PCA requirements in the post-caesarean patient. Can J Anaesth. 1991;38:450–453.
adrenaline to extradural diamorphine analgesia after caesarean section. Br J
Anaesth. 1988;60:632–638.
177. Cohen S, Lowenwirt I, Pantuck CB, et al. Bupivacaine 0.01% and/or 196. Macrae DJ, Munishankrappa S, Burrow LM, et al. Double-blind
epinephrine 0.5 µ g/mL improve epidural fentanyl analgesia after cesarean comparison of the efficacy of extradural diamorphine, extradural
section. Anesthesiology. phenoperidine and i.m. diamorphine following caesarean section. Br
1998;89:1354–1361. J Anaesth.
178. Rosen MA, Dailey PA, Hughes SC, et al. Epidural sufentanil for postoperative 1987;59:354–359.
analgesia after cesarean section. 197. National Institute for Health and Care Excellence. Caesarean section, 2012.
Anesthesiology. 1988;68:448–454. Available at https://www.nice.org.uk/guidance/ cg132 . Accessed June 3, 2018.
179. Perriss BW, Latham BV, Wilson IH. Analgesia following extradural and
i.m. pethidine in post-caesarean section patients. Br J Anaesth. 1990;64:355–357. 198. Palmer CM, Voulgaropoulos D, Alves D. Subarachnoid fentanyl augments
lidocaine spinal anesthesia for cesarean delivery. Reg Anesth. 1995;20:389–394.
180. Brownridge P, Frewin DB. A comparative study of techniques of postoperative
analgesia following caesarean section and lower abdominal surgery. Anaesth 199. Vincent RD Jr, Chestnut DH, Choi WW, et al. Does epidural fentanyl decrease
Intensive Care. the efficacy of epidural morphine after cesarean delivery? Anesth Analg. 1992;74:658–663.
1985;13:123–130.
181. Paech MJ. Epidural pethidine or fentanyl during caesarean section: a 200. Cooper DW, Garcia E, Mowbray P, Millar MA. Patient-controlled epidural
double-blind comparison. Anaesth Intensive Care. fentanyl following spinal fentanyl at caesarean section. Anaesthesia. 2002;57:266–270.
1989;17:157–165.
201. Dottrens M, Rifat K, Morel DR. Comparison of extradural administration of 217. Sumida S, Lesley MR, Hanna MN, et al. Meta-analysis of the effect of
sufentanil, morphine and sufentanil-morphine combination after caesarean extended-release epidural morphine versus intravenous patient-controlled
section. Br J Anaesth. 1992;69:9–12. analgesia on respiratory depression. J Opioid Manag. 2009;5:301–305.
202. Sinatra RS, Sevarino FB, Chung JH, et al. Comparison of epidurally 218. American Society of Anesthesiologists Task Force on Neuraxial Opioids,
administered sufentanil, morphine, and sufentanil-morphine American Society of Regional Anesthesia and Pain Medicine. Practice
combination for postoperative analgesia. Anesth Analg. 1991;72:522–527. guidelines for the prevention, detection, and management of respiratory
depression associated with neuraxial opioid administration. An updated
203. Fanshawe MP. A comparison of patient controlled epidural pethidine versus report by the American Society of Anesthesiologists Task Force on Neuraxial
single dose epidural morphine for analgesia after caesarean section. Anaesth Opioids and the American Society of Regional Anesthesia and Pain
Intensive Care. Medicine. Anesthesiology.
1999;27:610–614.
204. Yu PY, Gambling DR. A comparative study of patient-controlled epidural 2016;124:535–552.
fentanyl and single dose epidural morphine for post-caesarean analgesia. Can 219. Gerancher JC, Nagle PC. Management of accidental spinal administration
J Anaesth. of extended-release epidural morphine.
1993;40:416–420. Anesthesiology. 2008;108:1147–1149.
205. Cohen S, Chhokra R, Stein MH, et al. Ropivacaine 0.025% mixed with 220. Atkinson Ralls L, Drover DR, Clavijo CF, Carvalho B. Prior epidural lidocaine
fentanyl 3.0 µ g/ml and epinephrine 0.5 µ g/ml is effective for epidural alters the pharmacokinetics and drug effects of extended-release epidural
patient-controlled analgesia after cesarean section. J Anaesthesiol Clin morphine (DepoDur(R)) after cesarean delivery. Anesth Analg. 2011;113:251–258.
Pharmacol.
2015;31:471–477. 221. Gambling DR, Hughes TL, Manvelian GZ. Extended-release epidural morphine
206. Paech MJ, Moore JS, Evans SF. Meperidine for patient-controlled analgesia (DepoDur) following epidural bupivacaine in patients undergoing lower
after cesarean section. Intravenous versus epidural administration. Anesthesiology. abdominal surgery: a randomized controlled pharmacokinetic study. Reg
Anesth Pain Med. 2009;34:316–325.
1994;80:1268–1276.
207. Goh JL, Evans SF, Pavy TJ. Patient-controlled epidural analgesia 222. Chadwick HS, Ready LB. Intrathecal and epidural morphine sulfate for
following caesarean delivery: a comparison of pethidine and fentanyl. Anaesth post-cesarean analgesia—a clinical comparison.
Intensive Care. 1996;24: 45–50. Anesthesiology. 1988;68:925–929.
223. Abboud TK, Dror A, Mosaad P, et al. Mini-dose intrathecal morphine for the
208. Cohen S, Amar D, Pantuck CB, et al. Postcesarean delivery epidural relief of post-cesarean section pain: safety, efficacy, and ventilatory
patient-controlled analgesia. Fentanyl or sufentanil? responses to carbon dioxide. Anesth Analg. 1988;67:137–143.
209. Vercauteren MP, Coppejans HC, ten Broecke PW, et al. Epidural 224. Abouleish E, Rawal N, Rashad MN. The addition of 0.2 mg subarachnoid
sufentanil for postoperative patient-controlled analgesia (PCA) with or morphine to hyperbaric bupivacaine for cesarean delivery: a prospective study
without background infusion: a double-blind comparison. Anesth Analg. 1995;80:76–80. of 856 cases. Reg Anesth.
1991;16:137–140.
210. Vercauteren M, Vereecken K, La Malfa M, et al. Cost-effectiveness of analgesia 225. Sibilla C, Albertazz P, Zatelli R, Martinello R. Perioperative analgesia for
after caesarean section. A comparison of intrathecal morphine and epidural caesarean section: comparison of intrathecal morphine and fentanyl alone or
PCA. Acta Anaesthesiol Scand. 2002;46:85–89. in combination. Int J Obstet Anesth. 1997;6:43–48.
211. Howell SB. Clinical applications of a novel sustained-release injectable drug 226. Sultan P, Halpern SH, Pushpanathan E, et al. The effect of intrathecal
delivery system: DepoFoam technology. morphine dose on outcomes after elective cesarean delivery: a
Cancer J. 2001;7:219–227. meta-analysis. Anesth Analg.
212. Angst MS, Drover DR. Pharmacology of drugs formulated with DepoFoam: a 2016;123:154–164.
sustained release drug delivery system for parenteral administration using 227. Palmer CM, Emerson S, Volgoropolous D, Alves D. Dose-response
multivesicular liposome technology. Clin Pharmacokinet. 2006;45:1153–1176. relationship of intrathecal morphine for postcesarean analgesia. Anesthesiology.
1999;90:437–444.
213. Mantripragada S. A lipid based depot (DepoFoam technology) for sustained 228. Milner AR, Bogod DG, Harwood RJ. Intrathecal administration of morphine for
release drug delivery. Prog Lipid Res. elective caesarean section. A comparison between 0.1 mg and 0.2 mg. Anaesthesia.
2002;41:392–406.
214. Viscusi ER, Gambling DR, Hughes TL, Manvelian GZ. Pharmacokinetics of 1996;51:871–873.
extended-release epidural morphine sulfate: pooled analysis of six clinical 229. Yang T, Breen TW, Archer D, Fick G. Comparison of 0.25 mg and 0.1 mg
studies. Am J Health Syst Pharm. 2009;66:1020–1030. intrathecal morphine for analgesia after cesarean section. Can J Anaesth. 1999;46:856–860.
215. Carvalho B, Riley E, Cohen SE, et al. Single-dose, sustained-release epidural 230. Uchiyama A, Nakano S, Ueyama H, et al. Low dose intrathecal morphine and
morphine in the management of postoperative pain after elective cesarean pain relief following caesarean section. Int J Obstet Anesth. 1994;3:87–91.
delivery: results of a multicenter randomized controlled study. Anesth Analg.
231. Berger JS, Gonzalez A, Hopkins A, et al. Dose-response of intrathecal
2005;100:1150–1158. morphine when administered with intravenous ketorolac for post-cesarean
216. Nagle PC, Gerancher JC. DepoDur®: Extended-release epidural morphine: a analgesia: a two-center, prospective, randomized, blinded trial. Int J Obstet
review of an old drug in a new vehicle. Anesth.
Tech Reg Anesth Pain Manag. 2007;11:9–18. 2016;28:3–11.
232. Wong JY, Carvalho B, Riley ET. Intrathecal morphine 100 and 200 µ g for anesthesia in patients undergoing cesarean section. Korean J Anesthesiol. 2011;60:103–108.
post-cesarean delivery analgesia: a trade-off between analgesic efficacy and
side effects. Int J Obstet Anesth. 250. Kafle SK. Intrathecal meperidine for elective caesarean section: a
2013;22:36–41. comparison with lidocaine. Can J Anaesth.
233. Girgin NK, Gurbet A, Turker G, et al. Intrathecal morphine in anesthesia for 1993;40:718–721.
cesarean delivery: dose-response relationship for combinations of low-dose 251. Nguyen Thi TV, Orliaguet G, Ngu TH, Bonnet F. Spinal anesthesia with
intrathecal morphine and spinal bupivacaine. J Clin Anesth. 2008;20:180–185. meperidine as the sole agent for cesarean delivery. Reg Anesth. 1994;19:386–389.
234. Mikuni I, Hirai H, Toyama Y, et al. Efficacy of intrathecal morphine with epidural 252. Yu SC, Ngan Kee WD, Kwan AS. Addition of meperidine to bupivacaine for
ropivacaine infusion for postcesarean analgesia. J Clin Anesth. 2010;22:268–273. spinal anaesthesia for caesarean section. Br J Anaesth. 2002;88:379–383.
235. Booth JL, Harris LC, Eisenach JC, Pan PH. A randomized controlled trial 253. Imarengiaye CO, Asudo FD, Akpoguado DD, et al. Subarachnoid bupivacaine
comparing two multimodal analgesic techniques in patients predicted to and pethidine for caesarean section: assessment of quality of perioperative
have severe pain after cesarean delivery. Anesth Analg. 2016;122:1114–1119. analgesia and side effects. Niger Postgrad Med J. 2011;18:200–204.
236. Charles C, Gafni A, Whelan T. Shared decision-making in the medical encounter: 254. Cowan CM, Kendall JB, Barclay PM, Wilkes RG. Comparison of intrathecal
what does it mean? (or it takes at least two to tango). Soc Sci Med. 1997;44:681–692. fentanyl and diamorphine in addition to bupivacaine for caesarean section
under spinal anaesthesia. Br J Anaesth. 2002;89:452–458.
237. Belzarena SD. Clinical effects of intrathecally administered fentanyl in
patients undergoing cesarean section. Anesth Analg. 1992;74:653–657. 255. Lane S, Evans P, Arfeen Z, Misra U. A comparison of intrathecal fentanyl and
diamorphine as adjuncts in spinal anaesthesia for caesarean section. Anaesthesia.
238. Dahlgren G, Hultstrand C, Jakobsson J, et al. Intrathecal sufentanil,
fentanyl, or placebo added to bupivacaine for cesarean section. Anesth 2005;60:453–457.
Analg. 1997;85:1288–1293. 256. Saravanan S, Robinson AP, Qayoum Dar A, et al. Minimum dose of
239. Siddik-Sayyid SM, Aouad MT, Jalbout MI, et al. Intrathecal versus intrathecal diamorphine required to prevent intraoperative supplementation
intravenous fentanyl for supplementation of subarachnoid block during of spinal anaesthesia for caesarean section. Br J Anaesth. 2003;91:368–372.
cesarean delivery. Anesth Analg.
2002;95:209–213. 257. Kelly MC, Carabine UA, Mirakhur RK. Intrathecal diamorphine for analgesia
240. Meyer RA, Macarthur AJ, Downey K. Study of equivalence: spinal after caesarean section. A dose finding study and assessment of
bupivacaine 15 mg versus bupivacaine 12 mg with fentanyl 15 µ g for side-effects. Anaesthesia.
cesarean delivery. Int J Obstet Anesth. 1998;53:231–237.
2012;21:17–23. 258. Stacey R, Jones R, Kar G, Poon A. High-dose intrathecal diamorphine for
241. Siti Salmah G, Choy YC. Comparison of morphine with fentanyl added to analgesia after caesarean section.
intrathecal 0.5% hyperbaric bupivacaine for analgesia after caesarean Anaesthesia. 2001;56:54–60.
section. Med J Malaysia. 259. Husaini SW, Russell IF. Intrathecal diamorphine compared with morphine for
2009;64:71–74. postoperative analgesia after caesarean section under spinal anaesthesia. Br
242. Wilwerth M, Majcher JL, Van der Linden P. Spinal fentanyl vs. sufentanil for J Anaesth.
post-operative analgesia after c-section: a double-blinded randomised trial. Acta 1998;81:135–139.
Anaesthesiol Scand. 260. Hallworth SP, Fernando R, Bell R, et al. Comparison of intrathecal and
2016;60:1306–1313. epidural diamorphine for elective caesarean section using a combined
243. Hunt CO, Naulty JS, Bader AM, et al. Perioperative analgesia with subarachnoid spinal-epidural technique. Br J Anaesth. 1999;82:228–232.
fentanyl-bupivacaine for cesarean delivery.
Anesthesiology. 1989;71:535–540. 261. Marroquin B, Feng C, Balofsky A, et al. Neuraxial opioids for post-cesarean
244. Chu CC, Shu SS, Lin SM, et al. The effect of intrathecal bupivacaine with delivery analgesia: can hydromorphone replace morphine? A retrospective
combined fentanyl in cesarean section. Acta Anaesthesiol Sin. 1995;33:149–154. study. Int J Obstet Anesth.
2017;30:16–22.
245. Chen X, Qian X, Fu F, et al. Intrathecal sufentanil decreases the median 262. Beatty NC, Arendt KW, Niesen AD, et al. Analgesia after cesarean delivery: a
effective dose (ED50) of intrathecal hyperbaric ropivacaine for caesarean retrospective comparison of intrathecal hydromorphone and morphine. J
delivery. Acta Anaesthesiol Scand. Clin Anesth.
2010;54:284–290. 2013;25:379–383.
246. Courtney MA, Bader AM, Hartwell B, et al. Perioperative analgesia with 263. Lynde GC. Determination of ED50 of hydromorphone for postoperative
subarachnoid sufentanil administration. Reg Anesth. 1992;17:274–278. analgesia following cesarean delivery. Int J Obstet Anesth. 2016;28:17–21.
247. Braga Ade F, Braga FS, Poterio GM, et al. Sufentanil added to hyperbaric 264. Sviggum HP, Arendt KW, Jacob AK, et al. Intrathecal hydromorphone and
bupivacaine for subarachnoid block in caesarean section. Eur J Anaesthesiol. 2003;20:631–635.
morphine for postcesarean delivery analgesia: determination of the
ED90 using a sequential allocation biased-coin method. Anesth Analg.
248. Karaman S, Kocabas S, Uyar M, et al. The effects of sufentanil or morphine
added to hyperbaric bupivacaine in spinal anaesthesia for caesarean section. Eur 2016;123:690–697.
J Anaesthesiol. 265. Chung JH, Sinatra RS, Sevarino FB, Fermo L. Subarachnoid
2006;23:285–291. meperidine-morphine combination. An effective perioperative analgesic
249. Lee JH, Chung KH, Lee JY, et al. Comparison of fentanyl and sufentanil added adjunct for cesarean delivery. Reg Anesth. 1997;22:119–124.
to 0.5% hyperbaric bupivacaine for spinal
266. Draisci G, Frassanito L, Pinto R, et al. Safety and effectiveness of 284. Cohen SE, Labaille T, Benhamou D, Levron JC. Respiratory effects of epidural
coadministration of intrathecal sufentanil and morphine in hyperbaric sufentanil after cesarean section. Anesth Analg. 1992;74:677–682.
bupivacaine-based spinal anesthesia for cesarean section. J Opioid Manag. 2009;5:197–202.
285. Bernards CM. Recent insights into the pharmacokinetics of spinal opioids and
267. Cooper DW, Lindsay SL, Ryall DM, et al. Does intrathecal fentanyl produce the relevance to opioid selection. Curr Opin Anaesthesiol. 2004;17:441–447.
acute cross-tolerance to i.v. morphine? Br J Anaesth. 1997;78:311–313.
286. Kafer ER, Brown JT, Scott D, et al. Biphasic depression of ventilatory
268. Carvalho B, Drover DR, Ginosar Y, et al. Intrathecal fentanyl added to responses to CO 2 following epidural morphine.
bupivacaine and morphine for cesarean delivery may induce a subtle acute Anesthesiology. 1983;58:418–427.
opioid tolerance. Int J Obstet Anesth. 2012;21:29–34. 287. Bailey PL, Lu JK, Pace NL, et al. Effects of intrathecal morphine on the
ventilatory response to hypoxia. New Engl J Med. 2000;1228–1234.
269. Yaksh TL, Grafe MR, Malkmus S, et al. Studies on the safety of chronically
administered intrathecal neostigmine methylsulfate in rats and dogs. Anesthesiology. 288. Koo CY, Eikermann M. Respiratory effects of opioids in perioperative
medicine. Open Anesthesiol J. 2011;5: 23–34.
1995;82:412–427.
270. Yaksh TL, Rathbun M, Jage J, et al. Pharmacology and toxicology of 289. Weinger MB. Dangers of postoperative opioids. Anesthesia
chronically infused epidural clonidine.HCl in dogs. Fundam Appl Toxicol. 1994;23:319–335. Patient Safety Foundation Newsletter. 2006;21:61.
290. Carvalho B. Respiratory depression after neuraxial opioids in the obstetric
271. Sabbe MB, Grafe MR, Mjanger E, et al. Spinal delivery of sufentanil, alfentanil, setting. Anesth Analg. 2008;107:956–961.
and morphine in dogs. Physiologic and toxicologic investigations. Anesthesiology. 291. D’Angelo R, Smiley RM, Riley ET, Segal S. The Serious Complication
1994;81:899–920. Respository Project of the Society for Obstetric Anesthesia and Perinatology. Anesthesiology.
272. Abouleish E, Barmada MA, Nemoto EM, et al. Acute and chronic effects 2014;120: 1505–1512.
of intrathecal morphine in monkeys. Br J Anaesth. 1981;53:1027–1032.
292. Etches RC, Sandler AN, Daley MD. Respiratory depression and spinal
273. Rawal N, Nuutinen L, Raj PP, et al. Behavioral and histopathologic effects opioids. Can J Anaesth. 1989;36:165–185.
following intrathecal administration of butorphanol, sufentanil, and 293. Knight M, Nair M, Tuffnell D, et al. Saving Lives, Improving Mothers’ Care:
nalbuphine in sheep. Lessons learned to inform maternity care from the UK and Ireland
Anesthesiology. 1991;75:1025–1034. Confidential Enquiries into Maternal Deaths and Morbidity 2013–15, 2017.
274. Culebras X, Gaggero G, Zatloukal J, et al. Advantages of intrathecal nalbuphine, Available at https:// www.npeu.ox.ac.uk/downloads/files/mbrrace-uk/reports/
compared with intrathecal morphine, after cesarean delivery: an evaluation of MBRRACE-UK%20Maternal%20Report%202017%20-%20 Web.pdf .
postoperative analgesia and adverse effects. Anesth Analg. 2000;91:601–605. Accessed March 3, 2018.
275. Hodgson PS, Neal JM, Pollock JE, Liu SS. The neurotoxicity of drugs given 294. Crowgey TR, Dominguez JE, Peterson-Layne C, et al. A retrospective
intrathecally (spinal). Anesth Analg. assessment of the incidence of respiratory depression after neuraxial
1999;88:797–809. morphine administration for postcesarean delivery analgesia. Anesth
276. Eisenach JC, Yaksh TL. Safety in numbers: how do we study toxicity of spinal Analg.
analgesics? Anesthesiology. 2013;117:1368–1370.
2002;97:1047–1049. 295. Shapiro A, Zohar E, Zaslansky R, et al. The frequency and timing of
277. Yaksh TL, Collins JG. Studies in animals should precede human use of respiratory depression in 1524 postoperative patients treated with systemic
spinally administered drugs. Anesthesiology. or neuraxial morphine. J Clin Anesth. 2005;17:537–542.
1989;70:4–6.
278. Coombs DW, Colburn RW, Allen CD, et al. Toxicity of chronic spinal analgesia 296. Palmer CM. Early respiratory depression following intrathecal
in a canine model: neuropathologic observations with dezocine lactate. Reg fentanyl-morphine combination. Anesthesiology.
Anesth. 1991;74:1153–1155.
1990;15:94–102. 297. Brockway MS, Noble DW, Sharwood-Smith GH, McClure JH. Profound
279. Hughes SC, Rosen MA, Shnider SM, et al. Maternal and neonatal effects of respiratory depression after extradural fentanyl. Br J Anaesth. 1990;64:243–245.
epidural morphine for labor and delivery.
Anesth Analg. 1984;63:319–324. 298. Noble DW, Morrison LM, Brockway MS, McClure JH. Adrenaline, fentanyl or
280. Xie R, Hammarlund-Udenaes M, de Boer AG, de Lange EC. The role of adrenaline and fentanyl as adjuncts to bupivacaine for extradural anaesthesia
P-glycoprotein in blood-brain barrier transport of morphine: transcortical in elective caesarean section. Br J Anaesth. 1991;66:645–650.
microdialysis studies in mdr1a (-/-) and mdr1a (+/+) mice. Br J Pharmacol. 1999;128:563–568.
299. Madej TH, Strunin L. Comparison of epidural fentanyl with sufentanil. Analgesia
281. Hemauer SJ, Patrikeeva SL, Nanovskaya TN, et al. Opiates inhibit paclitaxel and side effects after a single bolus dose during elective caesarean section. Anaesthesia.
uptake by P-glycoprotein in preparations of human placental inside-out
vesicles. Biochem Pharmacol. 1987;42:1156–1161.
2009;78:1272–1278. 300. Sultan P, Gutierrez MC, Carvalho B. Neuraxial morphine and respiratory
282. Baraka A, Noueihid R, Hajj S. Intrathecal injection of morphine for depression: finding the right balance. Drugs.
obstetric analgesia. Anesthesiology. 2011;71:1807–1819.
1981;54:136–140. 301. Bauchat JR, McCarthy R, Fitzgerald P, et al. Transcutaneous carbon dioxide
283. Negre I, Gueneron JP, Ecoffey C, et al. Ventilatory response to carbon dioxide measurements in women receiving intrathecal morphine for cesarean delivery:
after intramuscular and epidural fentanyl. a prospective observational study. Anesth Analg. 2017;124:872–878.
Anesth Analg. 1987;66:707–710.
302. Lee LA, Caplan RA, Stephens LS, et al. Postoperative opioid-induced 319. Habib AS, George RB, McKeen DM, et al. Antiemetics added to phenylephrine
respiratory depression: a closed claims analysis. Anesthesiology. 2015;122:659–665. infusion during cesarean delivery: a randomized controlled trial. Obstet
Gynecol.
303. Celleno D, Capogna G, Sebastiani M, et al. Epidural analgesia during and after 2013;121:615–623.
cesarean delivery. Comparison of five opioids. Reg Anesth. 1991;16:79–83. 320. Allen TK, Habib AS. P6 stimulation for the prevention of nausea and vomiting
associated with cesarean delivery under neuraxial anesthesia: a systematic
304. Ready LB, Loper KA, Nessly M, Wild L. Postoperative epidural morphine is safe review of randomized controlled trials. Anesth Analg. 2008;107:1308–1312.
on surgical wards. Anesthesiology.
1991;75:452–456. 321. Griffiths JD, Gyte GM, Paranjothy S, et al. Interventions for preventing nausea
305. Weinger MB. No patient shall be harmed by opioid-induced respiratory and vomiting in women undergoing regional anaesthesia for caesarean
depression. Anesthesia Patient Safety Foundation Newsletter. 2011;26:21. section. Cochrane Database Syst Rev. 2012;(9):CD007579.
306. Abboud TK, Moore M, Zhu J, et al. Epidural butorphanol or morphine for the 322. Slappendel R, Weber EW, Benraad B, et al. Itching after intrathecal
relief of post-cesarean section pain: ventilatory responses to carbon morphine. Incidence and treatment. Eur J Anaesthesiol. 2000;17:616–621.
dioxide. Anesth Analg.
1987;66:887–893. 323. Paech M, Sng B, Ng L, et al. Methylnaltrexone to prevent intrathecal
307. Chaney MA. Side effects of intrathecal and epidural opioids. morphine-induced pruritus after caesarean delivery: a multicentre,
Can J Anaesth. 1995;42:891–903. randomized clinical trial. Br J Anaesth.
308. Lussos SA, Bader AM, Thornhill ML, Datta S. The antiemetic efficacy and safety 2015;114:469–476.
of prophylactic metoclopramide for elective cesarean delivery during spinal 324. Kendrick WD, Woods AM, Daly MY, et al. Naloxone versus nalbuphine
anesthesia. Reg Anesth. infusion for prophylaxis of epidural morphine-induced pruritus. Anesth
1992;17:126–130. Analg. 1996;82:641–647.
309. Mishriky BM, Habib AS. Impact of data by Fujii and colleagues on the 325. Cohen SE, Ratner EF, Kreitzman TR, et al. Nalbuphine is better than
meta-analysis of metoclopramide for antiemetic prophylaxis in women naloxone for treatment of side effects after epidural morphine. Anesth
undergoing caesarean delivery under neuraxial anaesthesia. Br J Analg. 1992;75:747–752.
Anaesth. 326. Kung AT, Yang X, Li Y, et al. Prevention versus treatment of intrathecal
2012;109:826. morphine-induced pruritus with ondansetron. Int J Obstet Anesth. 2014;23:222–226.
310. Harnett MJ, O’Rourke N, Walsh M, et al. Transdermal scopolamine for
prevention of intrathecal morphine-induced nausea and vomiting after 327. Morgan M. The rational use of intrathecal and extradural opioids. Br J
cesarean delivery. Anesth Analg. Anaesth. 1989;63:165–188.
2007;105:764–769. 328. Ganesh A, Maxwell LG. Pathophysiology and management of opioid-induced
311. Pan PH, Moore CH. Comparing the efficacy of prophylactic metoclopramide, pruritus. Drugs. 2007;67:2323–2333.
ondansetron, and placebo in cesarean section patients given epidural 329. LaBella FS, Kim RS, Templeton J. Opiate receptor binding activity of
anesthesia. J Clin Anesth. 17-alpha estrogenic steroids. Life Sci.
2001;13:430–435. 1978;23:1797–1804.
312. George RB, Allen TK, Habib AS. Serotonin receptor antagonists for the 330. Tsai FF, Fan SZ, Yang YM, et al. Human opioid µ- receptor
prevention and treatment of pruritus, nausea, and vomiting in women A118G polymorphism may protect against central pruritus by epidural morphine
undergoing cesarean delivery with intrathecal morphine: a systematic review for post-cesarean analgesia. Acta Anaesthesiol Scand. 2010;54:1265–1269.
and meta-analysis. Anesth Analg. 2009;109:174–182.
331. Pettini E, Micaglio M, Bitossi U, et al. Influence of OPRM1 polymorphism on
313. Tzeng JI, Wang JJ, Ho ST, et al. Dexamethasone for prophylaxis of nausea and postoperative pain after intrathecal morphine administration in Italian
vomiting after epidural morphine for post-caesarean section analgesia: patients undergoing elective cesarean section. Clin J Pain. 2018;34:178–181.
comparison of droperidol and saline. Br J Anaesth. 2000;85:865–868.
332. Kjellberg F, Tramer MR. Pharmacological control of opioid-induced pruritus: a
314. Wang JJ, Ho ST, Wong CS, et al. Dexamethasone prophylaxis of nausea and quantitative systematic review of randomized trials. Eur J Anaesthesiol. 2001;18:346–357.
vomiting after epidural morphine for post-cesarean analgesia. Can J Anaesth. 2001;48:185–190.
333. Somrat C, Oranuch K, Ketchada U, et al. Optimal dose of nalbuphine for
315. Allen TK, Jones CA, Habib AS. Dexamethasone for the prophylaxis of treatment of intrathecal-morphine induced pruritus after caesarean section.
postoperative nausea and vomiting associated with neuraxial morphine J Obstet Gynaecol Res.
administration: a systematic review and meta-analysis. Anesth Analg. 2012;114:813–822. 1999;25:209–213.
334. Wu Z, Kong M, Wang N, et al. Intravenous butorphanol administration reduces
316. Nortcliffe SA, Shah J, Buggy DJ. Prevention of postoperative nausea and intrathecal morphine-induced pruritus after cesarean delivery: a randomized,
vomiting after spinal morphine for caesarean section: comparison of cyclizine, double-blind, placebo-controlled study. J Anesth. 2012;26:752–757.
dexamethasone and placebo.
Br J Anaesth. 2003;90:665–670. 335. Morgan PJ, Mehta S, Kapala DM. Nalbuphine pretreatment in cesarean section
317. Heffernan AM, Rowbotham DJ. Postoperative nausea and vomiting—time patients receiving epidural morphine. Reg Anesth. 1991;16:84–88.
for balanced antiemesis? Br J Anaesth.
2000;85:675–677. 336. Lockington PF, Fa’aea P. Subcutaneous naloxone for the prevention of
318. Wu JI, Lo Y, Chia YY, et al. Prevention of postoperative nausea and vomiting intrathecal morphine induced pruritus in elective caesarean delivery. Anaesthesia.
after intrathecal morphine for cesarean section: a randomized comparison of 2007;62:672–676.
dexamethasone, droperidol, and a combination. Int J Obstet Anesth. 2007;16:122–127.337. Abboud TK, Afrasiabi A, Davidson J, et al. Prophylactic oral naltrexone with
epidural morphine: effect on adverse
reactions and ventilatory responses to carbon dioxide. vomiting but not on pruritus after cesarean delivery with intrathecal
Anesthesiology. 1990;72:233–237. sufentanil-morphine. J Clin Anesth.
338. Abboud TK, Lee K, Zhu J, et al. Prophylactic oral naltrexone with intrathecal 2002;14:183–186.
morphine for cesarean section: effects on adverse reactions and analgesia. Anesth 354. Sarvela PJ, Halonen PM, Soikkeli AI, et al. Ondansetron and tropisetron do
Analg. not prevent intraspinal morphine- and fentanyl-induced pruritus in elective
1990;71:367–370. cesarean delivery. Acta Anaesthesiol Scand. 2006;50:239–244.
339. Ko MC, Lee H, Song MS, et al. Activation of kappa-opioid receptors inhibits
pruritus evoked by subcutaneous or intrathecal administration of 355. Yazigi A, Chalhoub V, Madi-Jebara S, Haddad F. Ondansetron for prevention of
morphine in monkeys. J Pharmacol Exp Ther. 2003;305:173–179. intrathecal opioids-induced pruritus, nausea and vomiting after cesarean
delivery. Anesth Analg.
340. Shu H, Hayashida M, Arita H, et al. Pentazocine-induced antinociception is 2004;98:264.
mediated mainly by mu-opioid receptors and compromised by kappa-opioid 356. Tan T, Ojo R, Immani S, et al. Reduction of severity of pruritus after elective
receptors in mice. J Pharmacol Exp Ther. 2011;338:579–587. caesarean section under spinal anaesthesia with subarachnoid morphine: a
randomised comparison of prophylactic granisetron and ondansetron. Int J
341. Tamdee D, Charuluxananan S, Punjasawadwong Y, et al. A randomized Obstet Anesth. 2010;19:56–60.
controlled trial of pentazocine versus ondansetron for the treatment of
intrathecal morphine-induced pruritus in patients undergoing cesarean 357. Charuluxananan S, Somboonviboon W, Kyokong O, Nimcharoendee K.
delivery. Anesth Analg. 2009;109:1606–1611. Ondansetron for treatment of intrathecal morphine-induced pruritus after
cesarean delivery. Reg Anesth Pain Med. 2000;25:535–539.
342. Hirabayashi M, Doi K, Imamachi N, et al. Prophylactic pentazocine reduces
the incidence of pruritus after cesarean delivery under spinal anesthesia 358. Alhashemi JA, Crosby ET, Grodecki W, et al. Treatment of intrathecal
with opioids: a prospective randomized clinical trial. Anesth Analg. 2017;124:1930–1934. morphine-induced pruritus following caesarean section. Can J Anaesth. 1997;44:1060–1065.
343. Jeon Y, Hwang J, Kang J, et al. Effects of epidural naloxone on pruritus induced 359. Siddik-Sayyid SM, Yazbeck-Karam VG, Zahreddine BW, et al. Ondansetron is as
by epidural morphine: a randomized controlled trial. Int J Obstet Anesth. 2005;14:22–25. effective as diphenhydramine for treatment of morphine-induced pruritus after
cesarean delivery. Acta Anaesthesiol Scand. 2010;54:764–769.
344. Borgeat A, Wilder-Smith OH, Saiah M, Rifat K. Subhypnotic doses of propofol
relieve pruritus induced by epidural and intrathecal morphine. Anesthesiology. 360. Kuipers PW, Kamphuis ET, van Venrooij GE, et al. Intrathecal opioids and lower
1992;76:510–512. urinary tract function: a urodynamic evaluation. Anesthesiology. 2004;100:1497–1503.
345. Torn K, Tuominen M, Tarkkila P, Lindgren L. Effects of sub-hypnotic
doses of propofol on the side effects of intrathecal morphine. Br J 361. Kamphuis ET, Ionescu TI, Kuipers PW, et al. Recovery of storage and emptying
Anaesth. 1994;73:411–412. functions of the urinary bladder after spinal anesthesia with lidocaine and with
346. Beilin Y, Bernstein HH, Zucker-Pinchoff B, et al. Subhypnotic doses of propofol bupivacaine in men.
do not relieve pruritus induced by intrathecal morphine after cesarean Anesthesiology. 1998;88:310–316.
section. Anesth Analg. 362. Evron S, Samueloff A, Simon A, et al. Urinary function during epidural
1998;86:310–313. analgesia with methadone and morphine in post-cesarean section
347. Warwick JP, Kearns CF, Scott WE. The effect of subhypnotic doses of patients. Pain. 1985;23:135–
propofol on the incidence of pruritus after intrathecal morphine for 144.
caesarean section. Anaesthesia. 363. Liang CC, Chang SD, Wong SY, et al. Effects of postoperative analgesia on
1997;52:270–275. postpartum urinary retention in women undergoing cesarean delivery. J
348. Charuluxananan S, Kyokong O, Somboonviboon W, et al. Nalbuphine Obstet Gynaecol Res.
versus propofol for treatment of intrathecal morphine-induced pruritus 2010;36:991–995.
after cesarean delivery. Anesth Analg. 2001;93:162–165. 364. Rawal N, Mollefors K, Axelsson K, et al. An experimental study of
urodynamic effects of epidural morphine and of naloxone reversal. Anesth
349. Bonnet MP, Marret E, Josserand J, Mercier FJ. Effect of prophylactic 5-HT3 Analg. 1983;62:641–647.
receptor antagonists on pruritus induced by neuraxial opioids: a quantitative 365. Rathmell JP, Lair TR, Nauman B. The role of intrathecal drugs in the
systematic review. Br J Anaesth. 2008;101:311–319. treatment of acute pain. Anesth Analg.
2005;101:S30–S43.
350. Charuluxananan S, Kyokong O, Somboonviboon W, et al. Nalbuphine versus 366. Liang CC, Chang SD, Chang YL, et al. Postpartum urinary retention after
ondansetron for prevention of intrathecal morphine-induced pruritus after cesarean delivery. Int J Gynaecol Obstet.
cesarean delivery. Anesth Analg. 2003;96:1789–1793. 2007;99:229–232.
367. Liang CC, Wu MP, Chang YL, et al. Voiding dysfunction in women following
351. Yeh HM, Chen LK, Lin CJ, et al. Prophylactic intravenous ondansetron cesarean delivery. Taiwan J Obstet Gynecol.
reduces the incidence of intrathecal morphine-induced pruritus in patients 2015;54:678–681.
undergoing cesarean delivery. Anesth Analg. 2000;91:172–175. 368. Buchanan J, Beckmann M. Postpartum voiding dysfunction: identifying the risk
factors. Aust N Z J Obstet Gynaecol.
352. Siddik-Sayyid SM, Aouad MT, Taha SK, et al. Does ondansetron or 2014;54:41–45.
granisetron prevent subarachnoid morphine-induced pruritus after 369. Walker SM, Goudas LC, Cousins MJ, Carr DB. Combination spinal analgesic
cesarean delivery? Anesth Analg. 2007;104:421–424. chemotherapy: a systematic review. Anesth Analg. 2002;95:674–715.
353. Yazigi A, Chalhoub V, Madi-Jebara S, et al. Prophylactic ondansetron is 370. Kitahata LM. Spinal analgesia with morphine and clonidine.
effective in the treatment of nausea and Anesth Analg. 1989;68:191–193.
371. Taiwo YO, Fabian A, Pazoles CJ, Fields HL. Potentiation of morphine 388. Marhofer P, Brummett CM. Safety and efficiency of dexmedetomidine as
antinociception by monoamine reuptake inhibitors in the rat spinal cord. Pain. 1985;21:329–337.
adjuvant to local anesthetics. Curr Opin Anaesthesiol. 2016;29:632–637.
372. Kuraishi Y, Hirota N, Sato Y, et al. Noradrenergic inhibition of the release of 389. Yousef AA, Salem HA, Moustafa MZ. Effect of mini-dose epidural
substance P from the primary afferents in the rabbit spinal dorsal horn. Brain dexmedetomidine in elective cesarean section using combined
Res. 1985;359:177–182. spinal-epidural anesthesia: a randomized double-blinded controlled study. J
373. Eisenach JC, De Kock M, Klimscha W. Alpha(2)-adrenergic agonists for regional Anesth. 2015;29:708–714.
anesthesia. A clinical review of clonidine (1984-1995). Anesthesiology. 1996;85:655–674.
390. Qi X, Chen D, Li G, et al. Comparison of intrathecal dexmedetomidine with
morphine as adjuvants in cesarean sections. Bio Pharm Bull. 2016;39:1455–1460.
374. Elia N, Culebras X, Mazza C, et al. Clonidine as an adjuvant to intrathecal local
anesthetics for surgery: systematic review of randomized trials. Reg Anesth 391. Leicht CH, Kelleher AJ, Robinson DE, Dickerson SE. Prolongation of
Pain Med. 2008;33: 159–167. postoperative epidural sufentanil analgesia with epinephrine. Anesth Analg. 1990;70:323–325.
375. Iwasaki H, Collins JG, Saito Y, et al. Low-dose clonidine enhances 392. McMorland GH, Douglas MJ, Kim JH, et al. Epidural sufentanil for
pregnancy-induced analgesia to visceral but not somatic stimuli in rats. Anesth post-caesarean section analgesia: lack of benefit of epinephrine. Can J
Analg. 1991;72:325–329. Anaesth. 1990;37:432–437.
376. Mendez R, Eisenach JC, Kashtan K. Epidural clonidine analgesia after 393. McLintic AJ, Danskin FH, Reid JA, Thorburn J. Effect of adrenaline on
cesarean section. Anesthesiology. extradural anaesthesia, plasma lignocaine concentrations and the
1990;73:848–852. feto-placental unit during elective caesarean section. Br J Anaesth. 1991;67:683–689.
377. Huntoon M, Eisenach JC, Boese P. Epidural clonidine after cesarean section.
Appropriate dose and effect of prior local anesthetic. Anesthesiology. 1992;76:187–193.394. Alahuhta S, Rasanen J, Jouppila R, et al. Effects of extradural bupivacaine with
adrenaline for caesarean section on uteroplacental and fetal circulation. Br J
378. Eisenach JC, D’Angelo R, Taylor C, Hood DD. An isobolographic study of Anaesth.
epidural clonidine and fentanyl after cesarean section. Anesth Analg. 1994;79:285–290. 1991;67:678–682.
395. Abouleish EI. Epinephrine improves the quality of spinal hyperbaric
379. Capogna G, Celleno D, Zangrillo A, et al. Addition of clonidine to epidural bupivacaine for cesarean section. Anesth Analg.
morphine enhances postoperative analgesia after cesarean delivery. Reg 1987;66:395–400.
Anesth. 1995;20: 57–61. 396. Abouleish E, Rawal N, Tobon-Randall B, et al. A clinical and laboratory study
to compare the addition of 0.2 mg of morphine, 0.2 mg of epinephrine, or
380. Ginosar Y, Riley ET, Angst MS. Analgesic and sympatholytic effects of low-dose their combination to hyperbaric bupivacaine for spinal anesthesia in
intrathecal clonidine compared with bupivacaine: a dose-response study in cesarean section. Anesth Analg. 1993;77:457–462.
female volunteers. Br J Anaesth. 2013;111:256–263.
397. Zakowski MI, Ramanathan S, Sharnick S, Turndorf H. Uptake and distribution
381. van Tuijl I, van Klei WA, van der Werff DB, Kalkman CJ. The effect of addition of bupivacaine and morphine after intrathecal administration in parturients:
of intrathecal clonidine to hyperbaric bupivacaine on postoperative pain and effects of epinephrine. Anesth Analg. 1992;74:664–669.
morphine requirements after caesarean section: a randomized controlled
trial. Br J Anaesth. 2006;97:365–370. 398. Bouaziz H, Tong C, Eisenach JC. Postoperative analgesia from intrathecal
neostigmine in sheep. Anesth Analg.
382. Benhamou D, Thorin D, Brichant JF, et al. Intrathecal clonidine and fentanyl 1995;80:1140–1144.
with hyperbaric bupivacaine improves analgesia during cesarean section. Anesth 399. Hood DD, Eisenach JC, Tuttle R. Phase I safety assessment of intrathecal
Analg. neostigmine methylsulfate in humans.
1998;87:609–613. Anesthesiology. 1995;82:331–343.
383. Paech MJ, Pavy TJ, Orlikowski CE, et al. Postcesarean analgesia 400. Hood DD, Eisenach JC, Tong C, et al. Cardiorespiratory and spinal cord
with spinal morphine, clonidine, or their combination. Anesth Analg. 2004;98:1460–1466. blood flow effects of intrathecal neostigmine methylsulfate, clonidine, and
their combination in sheep.
384. Lavand’homme PM, Roelants F, Waterloos H, et al. An evaluation of the Anesthesiology. 1995;82:428–435.
postoperative antihyperalgesic and analgesic effects of intrathecal clonidine 401. Kaya FN, Sahin S, Owen MD, Eisenach JC. Epidural neostigmine produces
administered during elective cesarean delivery. Anesth Analg. 2008;107:948–955. analgesia but also sedation in women after cesarean delivery. Anesthesiology.
2004;100:381–385.
385. Carvalho FA, Tenorio SB, Shiohara FT, et al. Randomized study of 402. Ross VH, Pan PH, Owen MD, et al. Neostigmine decreases bupivacaine use
postcesarean analgesia with intrathecal morphine alone or combined with by patient-controlled epidural analgesia during labor: a randomized
clonidine. J Clin Anesth. controlled study. Anesth Analg.
2016;33:395–402. 2009;109:524–531.
386. Crespo S, Dangelser G, Haller G. Intrathecal clonidine as an adjuvant for 403. Unlugenc H, Ozalevli M, Gunes Y, et al. A double-blind comparison of
neuraxial anaesthesia during caesarean delivery: a systematic review and intrathecal S(+) ketamine and fentanyl combined with bupivacaine 0.5% for
meta-analysis of randomised trials. caesarean delivery. Eur J Anaesthesiol. 2006;23:1018–1024.
Int J Obstet Anesth. 2017;32:64–76.
387. Allen TK, Mishriky BM, Klinger RY, Habib AS. The impact of neuraxial clonidine 404. Tramer MR, Schneider J, Marti RA, Rifat K. Role of magnesium sulfate in
on postoperative analgesia and perioperative adverse effects in women postoperative analgesia. Anesthesiology.
having elective caesarean section-a systematic review and meta-analysis. Br 1996;84:340–347.
J Anaesth. 2018;120:228–240. 405. Sun J, Wu X, Xu X, et al. A comparison of epidural magnesium
and/or morphine with bupivacaine for
postoperative analgesia after cesarean section. Int J Obstet Anesth. 2012;21:310–316. 422. Schug SA, Saunders D, Kurowski I, Paech MJ. Neuraxial drug administration: a
review of treatment options for anaesthesia and analgesia. CNS Drugs. 2006;20:917–933.
406. Albrecht E, Kirkham KR, Liu SS, Brull R. The analgesic efficacy and
safety of neuraxial magnesium sulphate: a quantitative review. Anaesthesia. 423. Blanco R, Ansari T, Riad W, Shetty N. Quadratus lumborum block versus
2013;68:190–202. transversus abdominis plane block for postoperative pain after cesarean
407. Ozalevli M, Cetin TO, Unlugenc H, et al. The effect of adding intrathecal delivery: a randomized controlled trial. Reg Anesth Pain Med. 2016;41:757–762.
magnesium sulphate to bupivacaine-fentanyl spinal anaesthesia. Acta
Anaesthesiol Scand. 424. Chin KJ, McDonnell JG, Carvalho B, et al. Essentials of our current
2005;49:1514–1519. understanding: abdominal wall blocks. Reg Anesth Pain Med. 2017;42:133–183.
408. Arcioni R, Palmisani S, Tigano S, et al. Combined intrathecal and epidural
magnesium sulfate supplementation of spinal anesthesia to reduce 425. McMorrow RC, Ni Mhuircheartaigh RJ, Ahmed KA, et al. Comparison of
post-operative analgesic requirements: a prospective, randomized, transversus abdominis plane block vs spinal morphine for pain relief after
double-blind, controlled trial in patients undergoing major orthopedic surgery. Acta caesarean section. Br J Anaesth.
Anaesthesiol Scand. 2007;51:482–489. 2011;106:706–712.
426. Eslamian L, Jalili Z, Jamal A, et al. Transversus abdominis plane block reduces
409. Unlugenc H, Ozalevli M, Gunduz M, et al. Comparison of intrathecal postoperative pain intensity and analgesic consumption in elective cesarean
magnesium, fentanyl, or placebo combined with bupivacaine 0.5% for delivery under general anesthesia. J Anesth. 2012;26:334–338.
parturients undergoing elective cesarean delivery. Acta Anaesthesiol
Scand. 2009;53: 346–353. 427. Kanazi GE, Aouad MT, Abdallah FW, et al. The analgesic efficacy of
subarachnoid morphine in comparison with ultrasound-guided transversus
410. Gan TJ, Habib AS. Adenosine as a non-opioid analgesic in the perioperative abdominis plane block after cesarean delivery: a randomized controlled trial. Anesth
setting. Anesth Analg. 2007;105:487–494. Analg.
411. Rane K, Sollevi A, Segerdahl M. Intrathecal adenosine administration in 2010;111:475–481.
abdominal hysterectomy lacks analgesic effect. Acta Anaesthesiol Scand. 2000;44:868–872.
428. Champaneria R, Shah L, Wilson MJ, Daniels JP. Clinical effectiveness of
transversus abdominis plane (TAP) blocks for pain relief after caesarean
412. Sharma M, Mohta M, Chawla R. Efficacy of intrathecal adenosine for section: a meta-analysis. Int J Obstet Anesth. 2016;28:45–60.
postoperative pain relief. Eur J Anaesthesiol.
2006;23:449–453. 429. Murouchi T, Iwasaki S, Yamakage M. Quadratus lumborum block: analgesic
413. Rane K, Sollevi A, Segerdahl M. A randomised double-blind evaluation of effects and chronological ropivacaine concentrations after laparoscopic
adenosine as adjunct to sufentanil in spinal labour analgesia. Acta surgery. Reg Anesth Pain Med. 2016;41:146–150.
Anaesthesiol Scand. 2003;47:601–603.
414. Araiza-Saldana CI, Reyes-Garcia G, Bermudez-Ocana DY, et al. Effect of 430. Blanco R, Ansari T, Girgis E. Quadratus lumborum block for postoperative pain
diabetes on the mechanisms of intrathecal antinociception of sildenafil in after caesarean section: A randomised controlled trial. Eur J Anaesthesiol. 2015;32:812–818.
rats. Eur J Pharmacol.
2005;527:60–70. 431. Mirza F, Carvalho B. Transversus abdominis plane blocks for rescue analgesia
415. Asano T, Dohi S, Iida H. Antinociceptive action of epidural k+(ATP) channel following cesarean delivery: a case series. Can J Anaesth. 2013;60:299–303.
openers via interaction with morphine and an alpha(2)-adrenergic agonist in
rats. Anesth Analg. 432. Wikner M. Unexpected motor weakness following quadratus lumborum block
2000;90:1146–1151. for gynaecological laparoscopy. Anaesthesia.
416. Ho KM, Ismail H. Use of intrathecal midazolam to improve perioperative 2017;72:230–232.
analgesia: a meta-analysis. Anaesth Intensive Care. 2008;36:365–373. 433. Griffiths JD, Le NV, Grant S, et al. Symptomatic local anaesthetic toxicity and
plasma ropivacaine concentrations after transversus abdominis plane block for
417. Prakash S, Joshi N, Gogia AR, et al. Analgesic efficacy of two doses of caesarean section.
intrathecal midazolam with bupivacaine in patients undergoing cesarean Br J Anaesth. 2013;110:996–1000.
delivery. Reg Anesth Pain Med. 434. Trabelsi B, Charfi R, Bennasr L, et al. Pharmacokinetics of bupivacaine
2006;31:221–226. after bilateral ultrasound-guided transversus abdominis plane block
418. Dodawad R, Sumalatha GB, Pandarpurkar S, Jajee P. Intrathecal midazolam as following cesarean delivery under spinal anesthesia. Int J Obstet Anesth. 2017;32:17–20.
an adjuvant in pregnancy-induced hypertensive patients undergoing an
elective caesarean section: a clinical comparative study. Anesth Pain Med. 435. Kitayama M, Wada M, Hashimoto H, et al. Effects of adding epinephrine on the
early systemic absorption kinetics of local anesthetics in abdominal truncal
2016;6:e38550. blocks. J Anesth.
419. Cheng JK, Chen CC, Yang JR, Chiou LC. The antiallodynic action target of 2014;28:631–634.
intrathecal gabapentin: Ca 2+ channels, KATP channels or N-methyl- D- aspartic 436. Chandon M, Bonnet A, Burg Y, et al. Ultrasound-guided transversus abdominis
acid receptors? Anesth Analg. 2006;102:182–187. plane block versus continuous wound infusion for post-caesarean analgesia:
a randomized trial.
420. Cheng JK, Lai YJ, Chen CC, et al. Magnesium chloride and ruthenium red PLoS ONE. 2014;9:e103971.
attenuate the antiallodynic effect of intrathecal gabapentin in a rat model of 437. Weiss E, Jolly C, Dumoulin JL, et al. Convulsions in 2 patients after bilateral
postoperative pain. ultrasound-guided transversus abdominis plane blocks for cesarean analgesia. Reg
Anesthesiology. 2003;98:1472–1479. Anesth Pain Med.
421. Choe H, Kim JS, Ko SH, et al. Epidural verapamil reduces analgesic 2014;39:248–251.
consumption after lower abdominal surgery. Anesth Analg. 1998;86:786–790. 438. Scherrer V, Compere V, Loisel C, Dureuil B. Cardiac arrest from local
anesthetic toxicity after a field block and
transversus abdominis plane block: a consequence of plane block or continuous infiltration wound catheter: a randomized clinical
miscommunication between the anesthesiologist and surgeon. A A trial. TAP vs. infiltration after caesarean section. Anaesth Crit Care Pain
Case Rep. 2013;1:75–76. Med. 2016;35:401–406.
439. Ng SC, Habib AS, Sodha S, et al. High-dose versus low-dose local anaesthetic 447. Vallejo MC, Steen TL, Cobb BT, et al. Efficacy of the bilateral
for transversus abdominis plane block post-caesarean delivery analgesia: a ilioinguinal-iliohypogastric block with intrathecal morphine for postoperative
meta-analysis. Br J Anaesth. 2018;120:252–263. cesarean delivery analgesia.
ScientificWorldJournal. 2012;2012:107316.
440. Wong CA. Editorial comment: Cardiac arrest from local anesthetic toxicity after 448. Wolfson A, Lee AJ, Wong RP, et al. Bilateral multi-injection
a field block and transversus abdominis plane block: a consequence of iliohypogastric-ilioinguinal nerve block in conjunction with neuraxial
miscommunication between the anesthesiologist and surgeon and probable morphine is superior to neuraxial morphine alone for postcesarean
local anesthetic systemic toxicity in a postpartum patient with acute fatty liver analgesia. J Clin Anesth. 2012;24: 298–303.
of pregnancy after a transversus abdominis plane block. A A Case Rep. 2013;1:77–78.
449. Bell EA, Jones BP, Olufolabi AJ, et al. Iliohypogastricilioinguinal peripheral
nerve block for post-cesarean delivery analgesia decreases morphine use but
441. Ranta PO, Ala-Kokko TI, Kukkonen JE, et al. Incisional and epidural analgesia not opioid-related side effects. Can J Anaesth. 2002;49:694–700.
after caesarean delivery: a prospective, placebo-controlled, randomised
clinical study. Int J Obstet Anesth. 2006;15:189–194. 450. Niklasson B, Borjesson A, Carmnes UB, et al. Intraoperative injection of
bupivacaine-adrenaline close to the fascia reduces morphine requirements
442. Kainu JP, Sarvela J, Halonen P, et al. Continuous wound infusion with after cesarean section: a randomized controlled trial. Acta Obstet Gynecol
ropivacaine fails to provide adequate analgesia after caesarean section. Int J Scand.
Obstet Anesth. 2012;21:119–124. 2012;91:1433–1439.
443. Carvalho B, Lemmens HJ, Ting V, Angst MS. Postoperative subcutaneous 451. Tawfik MM, Mohamed YM, Elbadrawi RE, et al. Transversus abdominis plane
instillation of low-dose ketorolac but not hydromorphone reduces wound block versus wound infiltration for analgesia after cesarean delivery: a
exudate concentrations of interleukin-6 and interleukin-10 and improves randomized controlled trial. Anesth Analg. 2017;124:1291–1297.
analgesia following cesarean delivery. J Pain. 2013;14:48–56.
452. Telnes A, Skogvoll E, Lonnee H. Transversus abdominis plane block vs. wound
444. Lalmand M, Wilwerth M, Fils JF, Van der Linden P. Continuous ropivacaine infiltration in caesarean section: a randomised controlled trial. Acta
subfascial wound infusion compared with intrathecal morphine for Anaesthesiol Scand.
postcesarean analgesia: a prospective, randomized controlled, double-blind 2015;59:496–504.
study. 453. Simavli S, Kaygusuz I, Kinay T, et al. Bupivacaine-soaked absorbable gelatin
Anesth Analg. 2017;125:907–912. sponges in caesarean section wounds: effect on postoperative pain,
445. Rackelboom T, Le Strat S, Silvera S, et al. Improving continuous wound analgesic requirement and haemodynamic profile. Int J Obstet Anesth. 2014;23:302–308.
infusion effectiveness for postoperative analgesia after cesarean delivery:
a randomized controlled trial. Obstet Gynecol. 2010;116:893–900. 454. Adesope O, Ituk U, Habib AS. Local anaesthetic wound infiltration for
postcaesarean section analgesia: a systematic review and meta-analysis. Eur
446. Klasen F, Bourgoin A, Antonini F, et al. Postoperative analgesia after J Anaesthesiol.
caesarean section with transversus abdominis 2016;33:731–742.

PCT 3.en - Id

Diunggah oleh

Informasi Dokumen

Judul Asli

Hak Cipta

Format Tersedia

Bagikan dokumen Ini

Bagikan atau Tanam Dokumen

Opsi Berbagi

Apakah menurut Anda dokumen ini bermanfaat?

Apakah konten ini tidak pantas?

Hak Cipta:

Format Tersedia

PCT 3.en - Id

Diunggah oleh

Hak Cipta:

Format Tersedia

27

pasca operasi Analgesia

GARIS BESAR BAB

vagina Pengiriman Pengiriman sesar

Nyeri saat sesar 8.4 ± 2.2 27 ± 18 hydrocodone 20 NA

Rasa sakit setelah sesar 8.3 ± 1.8 18 ± 10 hidromorfon 7,5 1,5

muntah 7.8 ± 1,5 12 ± 7 fentanyl NA A 25- μ g / h transdermal 0.1 (100 μ g)

Mual 6.8 ± 1,7 11 ± 7 patch equianalgesic untuk

kram 6.0 ± 1,9 10 ± 8

Kegelisahan 4.1 ± 1,9 5±4 hari

Sifat tidur 2,9 ± 1.4 3±3 oxymorphone 10 1

Normal 1 0 NA, Tak dapat diterapkan.

Intravena Pasien-Controlled Analgesia

TABEL 27.3 Umum Pasien-Controlled Analgesia Pengaturan di Opioid-Naïve Pasien

Obat Morfin hidromorfon fentanyl

Khas PCA Dosis Ganti 0,5 mg 0,1 mg 5μg

Karena morbiditas signifikan yang terkait dengan dosis tinggi opioid,

didokumentasikan keuntungan analgesik intravena dibandingkan dengan menyusui. 71

25 untuk menerima salah satu dari tiga modalitas analgesik:

yang dibutuhkan opioid ( bar gelap) Waktu (h)

normal, setelah dosis intravena 40 mg tunggal setelah sesar. 84

15 dan nyeri kronis pada pasien nonobstetric. 85

melalui pembuluh darah dexmedetomidine telah digunakan sebagai

Lowder et al. 79 menunjukkan bahwa ketorolac penurunan skor nyeri pada 2,

setelah bupivacaine anestesi spinal menghasilkan analgesia pasca operasi

Paling umum, neuraksial analgesia opioid berfungsi sebagai komponen

acak 30 pasien yang menjalani operasi perut untuk menerima analgesia

Meskipun dosis opioid, volume injectate, dan derajat ionisasi adalah

TABEL 27.4 Spinal Opioid Physiochemistry dan farmakodinamik

Morfin 285 0,7 1 7,9 Moderat Lambat 10 Terlambat berkepanjangan

meperidine 247 39 0,1 8,5 Moderat Moderat 2-3 Cepat Menengah

IV, intravena; SC, subkutan.

TABLE 27.5 Epidural Opioids for Cesarean Delivery

Onset Puncak Effect Durasi (h)

Fentanyl 50–100 µ g 5 20 2–3 Rapid onset Short duration

Morphine/sufentanil 3 mg/10 µ g 5 15 12–24 Rapid onset Long duration

pasien. Dalam rentang sempit dosis dipelajari, peneliti belum

Epidural morphine dose (mg)

mg with intrathecal morphine

epidural fentanyl improves intraoperative anesthesia, no meaningful

PCEA is less frequently used for analgesia after cesarean delivery

TABLE 27.6 Comparative Studies Investigating Opioid-Containing, Patient-Controlled Epidural Analgesia

PCEA versus Intramuscular Opioids

PCEA versus Epidural Opioid

PCEA versus PCA

PCEA versus PCEA

Four groups 131 : All PCEA regimens: B = 2 No differences in pain VAS NA

TABLE 27.6 Comparative Studies Investigating Opioid-Containing, Patient-Controlled Epidural Analgesia

Four groups 205 : All PCEA regimens: BI = Ropivacaine 0.025% group NA

b Both groups received 0.01% bupivacaine + epinephrine 0.5 µ g/mL.

found between the two treatment groups. In a follow-up study, these

pain scores, PCEA usage, or 24-hour PCEA requirements were noted,

PCA; no differences in pain scores were

TABLE 27.7 Intrathecal Opioids for Cesarean Delivery

Morphine 0.05–0.2 mg 30–60 60–90 14–36 Long duration Side-effect profile

Fentanyl 10–25 µ g 5 10 2–3 Rapid onset Minimal postoperative analgesia Short

Sufentanil 2.5–5 µ g 5 10 2–4 Rapid onset Minimal postoperative analgesia Short

Sultan et al. 226 completed a meta-analysis to determine whether

reported that intrathecal fentanyl 10 µ g added to bupivacaine increased

Other Intrathecal Opioids

provides immediate postoperative analgesia. However, intrathecal fentanyl

intrathecal morphine 0.2 mg. A study that compared intrathecal fentanyl

intraoperative anesthesia but has limited postoperative analgesia. It has a