Intravenous Oxycodone Versus Other Intravenous Strong Opioids … · 2019. 5. 13. · Jeong-Hwa Seo. Aida Rosita Tantri. Hongwei Wang. Tianlong Wang. Kristal Cielo Buemio. Consuelo

REVIEW

Intravenous Oxycodone Versus Other IntravenousStrong Opioids for Acute Postoperative Pain Control:A Systematic Review of Randomized Controlled Trials

Milton Raff . Anissa Belbachir . Salah El-Tallawy . Kok Yuen Ho .

Eric Nagtalon . Amar Salti . Jeong-Hwa Seo . Aida Rosita Tantri .

Hongwei Wang . Tianlong Wang . Kristal Cielo Buemio .

Consuelo Gutierrez . Yacine Hadjiat

Received: January 3, 2019 / Published online: April 19, 2019� The Author(s) 2019

ABSTRACT

Introduction: Optimal pain management iscrucial to the postoperative recovery process.We aimed to evaluate the efficacy and safety ofintravenous oxycodone with intravenous fen-tanyl, morphine, sufentanil, pethidine, andhydromorphone for acute postoperative pain.Methods: A systematic literature search ofPubMed, Cochrane Library, and EMBASE data-bases was performed for randomized controlledtrials published from 2008 through 2017

(inclusive) that evaluated the acute postopera-tive analgesic efficacy of intravenous oxy-codone against fentanyl, morphine, sufentanil,pethidine, and hydromorphone in adultpatients (age C 18 years). Outcomes examinedincluded analgesic consumption, pain intensitylevels, side effects, and patient satisfaction.Results: Eleven studies were included in thereview; six compared oxycodone with fentanyl,two compared oxycodone with morphine, andthree compared oxycodone with sufentanil.There were no eligible studies comparing oxy-codone with pethidine or hydromorphone.Overall, analgesic consumption was lower withoxycodone than with fentanyl or sufentanil.Oxycodone exhibited better analgesic efficacythan fentanyl and sufentanil, and comparableanalgesic efficacy to morphine. In terms ofsafety, there was a tendency towards more sideeffects with oxycodone than with fentanyl, but

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Electronic supplementary material The onlineversion of this article (https://doi.org/10.1007/s40122-019-0122-4) contains supplementary material, which isavailable to authorized users.

M. Raff (&)Pain Clinic, Christiaan Barnard Memorial Hospital,Cape Town, South Africae-mail: [email protected]

A. BelbachirFaculté de médecine, Université Paris-Descartes,Pôle d’anesthésie-réanimation, Hôpital Cochin,Paris, France

S. El-TallawyDepartment of Anesthesia and Pain Management,College of Medicine, King Khalid UniversityHospital, King Saud University, Riyadh, Saudi Arabia

K. Y. HoThe Pain Clinic, Mount Alvernia Medical Centre,Singapore, Singapore

E. NagtalonDepartment of Anesthesia, University of the EastRamon Magsaysay Memorial Medical Center,Quezon City, Philippines

A. SaltiAnesthesiology Institute, Sheikh Khalifa MedicalCity, Abu Dhabi, United Arab Emirates

Pain Ther (2019) 8:19–39

https://doi.org/10.1007/s40122-019-0122-4

http://orcid.org/0000-0002-1194-2656https://doi.org/10.6084/m9.figshare.7931558https://doi.org/10.6084/m9.figshare.7931558https://doi.org/10.6084/m9.figshare.7931558https://doi.org/10.6084/m9.figshare.7931558https://doi.org/10.1007/s40122-019-0122-4https://doi.org/10.1007/s40122-019-0122-4https://doi.org/10.1007/s40122-019-0122-4https://doi.org/10.1007/s40122-019-0122-4http://crossmark.crossref.org/dialog/?doi=10.1007/s40122-019-0122-4&domain=pdfhttps://doi.org/10.1007/s40122-019-0122-4

the incidence of side effects with oxycodonewas comparable to morphine and sufentanil.Where patient satisfaction was evaluated,higher satisfaction levels were observed withoxycodone than with sufentanil and compara-ble satisfaction was noted when comparingoxycodone with fentanyl. Patient satisfactionwas not evaluated in the studies comparingoxycodone with morphine.Conclusions: Our findings suggest that intra-venous oxycodone provides better analgesic effi-cacy than fentanyl and sufentanil, andcomparable efficacy tomorphinewith less adverseevents such as sedation. No studies comparingintravenous oxycodone with pethidine or hydro-morphone were identified in this review. Betteralignment of study methodologies for futureresearch in this area is recommended to providethe best evidence base for a meta-analysis.Funding: Mundipharma Singapore Holding PteLtd, Singapore.

Keywords: Acute postoperative pain; Fentanyl;Hydromorphone; Morphine; Oxycodone;Pethidine; Sufentanil

INTRODUCTION

The majority of patients who undergo surgicalprocedures experience acute postoperative pain,with over 80% reporting moderate-to-severe

pain [1]. Acute postoperative pain is multi-mechanistic and may consist of both nocicep-tive and neuropathic pain [2]. Inadequatepostoperative pain control may impede recov-ery and delay rehabilitation, leading to pooroutcomes [3]. Effective pain management isthus central to the postoperative recovery pro-cess and can help improve patient comfort,enhance tissue healing, and promote early dis-charge [4, 5].

Analgesia administered by the intravenousroute is typically used in the early postoperativeperiod when administration by the oral route isless feasible [6]. In the case of moderately sev-ere-to-severe acute postoperative pain, clinicalpractice guidelines recommend the use ofstrong opioids such as oxycodone, morphine,fentanyl, or hydromorphone as part of themultimodal analgesic approach [7–12]. Thestrong opioids, sufentanil and pethidine, areless widely recommended—sufentanil due to itsshort duration of action and pethidine due tosafety concerns. The unfavorable risk–benefitprofile of pethidine has led to a gradual declineof its use for peri-operative analgesia in devel-oped countries [13, 14]. Many government,professional, and accreditation agencies viewthe use of pethidine as an indicator of poorquality of care [14]; however, pethidine is stillextensively used in regions composed largely oflow- and middle-income countries (such asAfrica, Eastern Mediterranean, and South-EastAsia) [13].

Pharmacological properties vary amongststrong opioids (Table 1). Choosing betweenthese opioids is challenging when used for post-operative analgesia as there is little evidence tosupport the use of one opioid analgesic overanother. Intravenous morphine is traditionallythe opioid of choice, but oxycodone is beingincreasingly utilized [15–17]. Unlike moststrong opioids that act primarily through the l-opioid receptor to induce analgesia [18, 19],oxycodone has additional agonistic effects onthe j- and d-opioid receptors [20–22]; its addi-tional action on the j-receptor has been sug-gested to be of particular significance for anti-nociception in the visceral pain system [23–26].Some studies also suggest that oxycodone hasan enhanced analgesic effect on neuropathic

J.-H. SeoDepartment of Anesthesiology and Pain Medicine,Seoul National University Hospital, Seoul NationalUniversity College of Medicine, Seoul, Korea

A. R. TantriDepartment of Anesthesiology and Intensive Care,Universitas Indonesia, Dr. CiptomangunkusumoNational General Hospital, Jakarta, Indonesia

H. WangDepartment of Anesthesiology, Tongde Hospital ofZhejiang Province, Hangzhou, Zhejiang, China

T. WangDepartment of Anesthesiology, Xuanwu Hospital ofCapital Medical University, Beijing, China

K. C. Buemio � C. Gutierrez � Y. HadjiatMundipharma Singapore Holding Pte. Ltd.,Singapore, Singapore

20 Pain Ther (2019) 8:19–39

pain [27, 28]. Furthermore, oxycodone has beenreported to be faster-acting than morphine [29],and to provide longer-lasting analgesic effectwhen compared with fentanyl [30, 31] andmorphine [32].

Given the increasing clinical use of oxy-codone for the management of acute postoper-ative pain, further understanding is neededregarding the efficacy and safety of oxycodoneversus other strong opioids. This systematicreview aims to summarize and synthesize thefindings of recent head-to-head randomizedcontrolled trials (RCTs) comparing the efficacyand safety of oxycodone with other strongopioids (in particular, morphine, fentanyl,

sufentanil, hydromorphone, and pethidine) inthe management of acute postoperative pain.

METHODS

Literature Search Strategy

A search of PubMed, Cochrane Library, andEMBASE databases was conducted for studiespublished from 2008 through 2017 that evalu-ated the acute postoperative analgesic efficacy ofthe parenteral oxycodone compared with mor-phine, fentanyl, sufentanil, pethidine, orhydromorphone. The search terminology inclu-ded a variety of terms and medical subject

Table 1 Pharmacological properties of oxycodone, morphine, fentanyl, sufentanil, pethidine, and hydromorphone

Oxycodone[21, 22, 53–58]

Morphine[59–61]

Fentanyl[59, 61–63]

Sufentanil[64–67]

Pethidine[61, 68–70]

Hydromorphone[71, 72]

Absorption

Tmax 6–25 min 19 min 4 min 6 min 1.2 min 20 min

Distribution

Plasma

protein

binding

45% 35–36% 84% * 90% * 58% 8–19%

VD 2–3 l/kg 1–4.7 l/kg 4 l/kg 1.7–5.2 l/kg 3–5 l/kg 302.9 l

Metabolism

Major

metabolites

Noroxycodone,

oxymorphone

Morphine-3-

glucuronide

Norfentanyl Norfentanyl Norpethidine Hydromorphone-

3-glucuronide

Excretion

Cl 1.10 l/min 0.9–1.2 l/kg/h 0.8–1.0 ml/

min/kg

57.6 l/h 20.5 l/h 1.96 l/min

T1/2 2–3.5 h 1.5–4.5 h 3.7 h 2.7 h 2–5 h 2.3 h

Opioid receptor action

l ??? ??? ??? ??? ??? ???

j ?? ? ? ? ? Nil

d ?? ? Nil ? ? ?

Cl, clearance; Tmax, time to maximum plasma concentration; T1/2, half-life; VD, volume of distribution; l, mu-opioidreceptor; j, kappa-opioid receptor; d, delta-opioid receptor

Pain Ther (2019) 8:19–39 21

headings for post-operative, analgesia, injection,oxycodone, morphine, fentanyl, sufentanil,pethidine, hydromorphone, and RCTs. Searchstrategies were developed specifically for eachdatabase. The full list of database-specific searchqueries is presented in Supplementary Table 1.The bibliographies of included articles were alsoscreened for potentially relevant publications.

Selection of Studies

All articles identified in the search werescreened by title and abstract for relevance.Following the initial screening, the full-textarticles of potentially relevant publications wereevaluated for inclusion in the review. Articleswere included if they fulfilled all of the inclu-sion criteria and contained none of the exclu-sion criteria. Inclusion criteria were as follows:RCTs; adult patients (C 18 years of age) withpostoperative pain; administration of analgesicsafter operation; treatment with intravenousoxycodone and either intravenous morphine,fentanyl, sufentanil, pethidine, or hydromor-phone; and published between 2008 and 2017(inclusive). Exclusion criteria were as follows:non-human studies; treatment with modifiedrelease formulations (e.g., controlled-releasemorphine, transdermal fentanyl); interventionsused to treat pre-existing pain other than theacute postoperative pain; interventions used aspre-emptive analgesia or rescue therapy; non-English articles; and pediatric patients.

Assessment of Study Quality

The quality of included studies was assessedusing the Jadad scale, which assesses each studyaccording to three main categories: randomiza-tion (2 points), blinding (2 points), and attrition(1 point). Each included study was scored from0 (lowest quality) to 5 (highest quality),depending on method of randomization,blinding, and description for attrition. Studieswhich scored four or more points were consid-ered to be of high-quality. This article is basedon previously conducted studies and does notcontain any studies with human participants oranimals performed by any of the authors.

RESULTS

Study Inclusion

Figure 1 shows the flow of the screening andevaluation process. The systematic literaturesearch identified 450 publications. Ten studiesmet the eligibility criteria. One additional studyrecently published was included based onexperts’ recommendation after the search wasconducted. No additional studies were identi-fied from the bibliographic search of relevantarticles.

Of the 11 included studies, six comparedoxycodone with fentanyl, two compared oxy-codone with morphine, and three comparedoxycodone with sufentanil. No studies com-paring oxycodone with pethidine or hydro-morphone were identified from the literaturesearch.

Study Characteristics and Findings

Characteristics of all the included studies suchas reference (year), country, type of surgery,study duration, route of administration, treat-ment groups, dose conversion ratio, and repor-ted outcomes are presented in Table 2. Specificstudy characteristics are detailed in the follow-ing sections accordingly. Key findings of theincluded studies are summarized in Table 3.

Oxycodone vs. Fentanyl

Six studies involving a total of 466 patientsfrom the Republic of Korea, China, and Den-mark, compared oxycodone with fentanyl foracute postoperative pain (Table 2). Surgicalprocedures included laparoscopic hysterectomy[33–35], laparoscopic myomectomy [35],laparoscopic cholecystectomy [30, 31], andgastrointestinal laparotomy [36]. The follow-upduration in all studies was 48 h after surgery,except for the study by Koch et al. [30], whichmonitored patients until discharge from thepost-anesthesia care unit. Opioids were admin-istered via intravenous patient-controlled anal-gesia (IV-PCA) [31, 33–36], and IV bolus [30].The dose conversion ratios used for oxycodone

22 Pain Ther (2019) 8:19–39

Fig. 1 Flow diagram of the literature screening and evaluation process

Pain Ther (2019) 8:19–39 23

Table2

Characteristics

ofincluded

studies

References

(year)

Cou

ntry

Typeof

surgery

No.

ofpatients

inthe

main

analysis

set

Stud

ydu

ration

Rou

teof

administration

PCA

program

parameters

Drugs

administered

Doseconversion

ratioa

(oxycodo

ne:

fentanyl

ormorph

ineor

sufentanil)

Reportedou

tcom

es

Oxycodone

vs.fentanyl

Kim

etal.

(2017)

[34]

Republic

of Korea

Laparoscopic

hysterectomy

127

48h

IV-PCA

Oxycodone

Bolus

dose:0.5ml

Rateof

infusion:continuous;

1050

mcg/h

Lockout

interval:15

min

Fentanyl

Bolus

dose:0.5ml

Rateof


14mg/h

Lockout

interval:15

min

100mlmixture

of52.5

mgoxycodoneor

700mcg

fentanyl,

150mgketorolac,and

0.6mgramosetron

withNSsolution

75:1

Efficacy:pain

intensity—

atrest,o

ncoughing;analgesicconsum

ption;

useof

additionalanalgesics

Safety:nausea,vom

iting,sedation,

dizziness,drow

siness,h

eadache,

pruritus,respiratory

depression

Patientsatisfaction

Dingetal.

(2016)

[36]

China

Gastrointestinal

laparotomy

5648

hIV-PCA

Oxycodone

Bolus

dose:1ml

Rateof


1-2ml/h

Lockout

interval:15

min

Fentanyl

Bolus

dose:0.5ml

Rateof


1-2ml/h

Lockout

interval:15

min

100mlmixture

of0.7mg/kg

oxycodone

or12

mcg/kg

fentanyl,1

80mg

ketorolac,0.125mg

palonosetron

withNS

solution

60:1

Efficacy:p

ainintensity—

atrest,upon

movem

ent;analgesicconsum

ption;

useof


Safety:nausea,vom

iting,sedation,

dizziness,respiratoryrate,

respiratorydepression

Patientsatisfaction

Kim

etal.

(2015)

[33]

Republic

of Korea

Laparoscopic

hysterectomy

6048

hIV-PCA

Oxycodone

Bolus

dose:0.5ml

Rateof


1.4mg/h

Lockout

interval:15

min

Fentanyl

Bolus

dose:0.5ml

Rateof


14mcg/h

Lockout

interval:15

min

100-mlmixture

of70

mgoxycodoneor

700mcg

fentanyl,

150mgketorolac,and

0.6mgramosetron

withNSsolution

100:1

Efficacy:painintensity—

atrest,w

hile

coughing;analgesicconsum

ption;

useof


Safety:nausea,vom

iting,headache,

sedation,d

izziness,p

ruritus,


Patientsatisfaction

24 Pain Ther (2019) 8:19–39

Table2

continued

References

(year)

Cou

ntry

Typeof

surgery

No.

ofpatients

inthe

main

analysis

set

Stud

ydu

ration

Rou

teof

administration

PCA

program

parameters

Drugs

administered

Doseconversion

ratioa

(oxycodo

ne:

fentanyl

ormorph

ineor

sufentanil)

Reportedou

tcom

es

Park

etal.

(2015)

[35]

Republic

of Korea

Laparoscopic

hysterectomyor

laparoscopic

myomectomy

6948

hIV-PCA

Oxycodone

Bolus

dose:0.9mg

Rateof


0.9mg/h

Lockout

interval:15

min

Fentanyl

Bolus

dose:15

mcg

Rateof


15mcg/h

Lockout

interval:15

min

Oxycodone

(bolus

dose

0.9mg)

orfentanyl

(bolus

dose

15mcg),

and0.075mg

palonosetron

60:1

Efficacy:pain

intensity—

atrest,o

nmoving;analgesicconsum

ption

Safety:nausea,vom

iting,headache,

sedation,d

izziness

Patientsatisfaction

Hwang

etal.

(2014)

[31]

Republic

of Korea

Laparoscopic

cholecystectom

y81

48h

IV-PCA

Oxycodone

Bolus

dose:1

ml(4hlim

itof

40ml)

Rateof

infusion:nil

Lockout

interval:6min

Fentanyl

Bolus

dose:1ml(fourhour

limitof

40ml)

Rateof

infusion:nil

Lockout

interval:6min

3mgoxycodoneor

30mcg

fentanyl,and

4.5mgketorolac

100:1

Efficacy:pain

intensity—

atrest,

during

coughing;analgesic

consum

ption

Safety:nausea,vom

iting,headache,

shivering,pruritus,respiratory

depression,sedation

Patientsatisfaction

Koch

etal.

(2008)

[30]

Denmark

Laparoscopic

cholecystectom

y73

30min

todischarge

IVbolus

–10

mgoxycodoneor

100

mcg

fentanyl

100:1

Efficacy:pain

intensity—

overall,on

coughing,abdom

inal;analgesic

consum

ption;

pressure

tolerance

thresholds

Safety:nausea,vom

iting,sedation

Oxycodone

vs.m

orphine

Pedersen

(2013)

[37]

Denmark

Percutaneous

nephrolithotomy

surgery

444h

IV–

IVoxycodoneor

morphine0.1mg/kg

1:1

Efficacy:pain

intensity—

overall;

analgesicconsum

ption—

timeto

firstdose,d

ose

Safety:nausea,vom

iting,dizziness,

sedation,itching,respiratory

effects,

useof

anti-emetics

Pain Ther (2019) 8:19–39 25

Table2

continued

References

(year)

Cou

ntry

Typeof

surgery

No.

ofpatients

inthe

main

analysis

set

Stud

ydu

ration

Rou

teof

administration

PCA

program

parameters

Drugs

administered

Doseconversion

ratioa

(oxycodo

ne:

fentanyl

ormorph

ineor

sufentanil)

Reportedou

tcom

es

Lenzetal.

(2009)

[32]

Norway

Laparoscopic

supracervical

hysterectomyor

laparoscopictotal

hysterectomy

9124

hIV-PCA

Oxycodone

Bolus

dose:0.015mg/kg

Rateof

infusion:nil

Lockout

interval:5min

Morphine

Bolus

dose:0.015mg/kg

Rateof

infusion:nil

Lockout

interval:5min

IVoxycodoneor

morphine0.015mg/

kg

1:1

Efficacy:pain

intensity—

atrest,

during

coughing;analgesic

consum

ption—

timeto

firstdose

Safety:post-operative

nausea

and

vomiting,sedation,itching

Oxycodone

vs.sufentanil

Han

etal.

(2018)

[40]

China

Electiveabdominal

surgery

(laparotom

yor

endoscopy)

48h

120

IV-PCA

Oxycodone

Bolus

dose:2mg

Rateof

infusion:nil

Lockout

interval:5min

Sufentanil

Bolus

dose:2mcg

Rateof

infusion:0.02

mcg/

kg/h

Lockout

interval:5min

Oxycodone

0.1mg/kg

(end

oscopy)or

0.15

mg/kg

(laparotom

y)or

sufentanil0.1mcg/kg

(end

oscopy)or

0.15

mcg/kg(laparotom

y)

1000:1

Efficacy:pain

intensity;analgesic

consum

ption—

numberof

PCA

boluses,nu

mberof

bolustimes

pressedby

patients,tim

eto

first

dose;rescue

analgesicdose;

functionalactivity

score

Safety:nausea,vom

iting,pruritus,


Patientsatisfaction

26 Pain Ther (2019) 8:19–39

Table2

continued

References

(year)

Cou

ntry

Typeof

surgery

No.

ofpatients

inthe

main

analysis

set

Stud

ydu

ration

Rou

teof

administration

PCA

program

parameters

Drugs

administered

Doseconversion

ratioa

(oxycodo

ne:

fentanyl

ormorph

ineor

sufentanil)

Reportedou

tcom

es

Nieet

al.

(2017)

[38]

China

Cesareansection

24h

117

IV-PCA

Oxycodone

Bolus

dose:2ml

Rateof


1ml/h

Lockout

interval:15

min

Sufentanil70

mcg/oxycodone

30mg

Bolus

dose:2ml

Rateof


1ml/h

Lockout

interval:15

min

Sufentanil50

mcg/oxycodone

50mg

Bolus

dose:2ml

Rateof


1ml/h

Lockout

interval:15

min

Sufentanil

Bolus

dose:2ml

Rateof


1ml/h

Lockout

interval:15

min

100mlmixture

ofoxycodone100mg,

sufentanil70

mcg/

oxycodone30

mg,

sufentanil50

mcg/

oxycodone50

mg,or

sufentanil100mcg,

and0.3mg

ramosetron

1000:1

Efficacy:pain

intensity—

uterine

cram

ping

pain,atrest,m

ovinginto

sittingposition;analgesic

consum

ption

Safety:nausea,vom

iting,dizziness,

pruritus,respiratory

depression,

hypotension,

hypoxemia,sedation

Patientsatisfaction

Wang

etal.

(2016)

[39]

China

Laparoscopicradical

gastrectom

y48

h50

IV-PCA

Oxycodone

Bolus

dose:0.02

mg/kg

Rateof

infusion:nil

Lockout

interval:10

min

Sufentanil

Bolus

dose:0.04

mcg/kg

Rateof

infusion:nil

Lockout

interval:10

min

Oxycodone

0.02

mg/kg

orsufentanil0.04

mcg/kg

500:1

Efficacy:pain

intensity—

oncoughing,atrest

Safety:nausea,vom

iting,dizziness,

sedation,itching

Patientsatisfaction

IV,intravenous;IV-PCA,intravenous

patient-controlledanalgesia;mcg,m

icrogram

;NS,norm

alsalin

eaCalculatedbasedon

relative

dosesused

Pain Ther (2019) 8:19–39 27

to fentanyl were 100:1 [30, 31, 33], 60:1 [35, 36],and 75:1 [34]. Outcomes collected for efficacyincluded pain intensity at rest and duringmovement or coughing; while those for safetyincluded side effects such as nausea, vomiting,sedation, and dizziness; and patientsatisfaction.

Efficacy: Pain Intensity

Oxycodone exhibited greater analgesic efficacythan fentanyl, especially at earlier time points.In three studies, pain relief was significantlybetter with oxycodone than with fentanyl fromas early as 30 min after surgery [30, 33, 36]. Painrelief remained significantly better with oxy-codone for 24 h [33] to 48 h after surgery [36],or until discharge from the post-anesthesia care

Table 3 Comparison of key findings of oxycodone with fentanyl, morphine, and sufentanil in included studies

Studies First author(year)

Efficacy Safety Patientpreference

Painintensity

Analgesicconsumption

Side effects Satisfaction

Oxycodone vs.

fentanyl

Kim et al. (2017)

[34]

O O F (nausea, dizziness) Comparable/

F

Ding et al. (2016)

[36]

O F Comparable/O (sedation) Comparable

Kim et al. (2015)

[33]

Comparable/

O

Comparable/O Comparable/F (nausea) Comparable

Park et al. (2015)

[35]

O O Comparable/F (dizziness) O

Hwang et al.

(2014) [31]

Comparable O Comparable/F (nausea) Comparable

Koch et al. (2008)

[30]

O O Comparable –

Oxycodone vs.

morphine

Pedersen et al.

(2013) [37]

Comparable Comparable Comparable –

Lenz et al. (2009)

[32]

Comparable/

O

O Comparable/O (sedation) –

Oxycodone vs.

sufentanil

Han et al. (2018)

[40]

Comparable O O (nausea, vomiting) O

Nie et al. (2017)

[38]

O O Comparable/O (nausea,

vomiting, pruritus)

O

Wang et al. (2016)

[39]

Comparable O Comparable O

Table illustrates opioid that fared better in terms of the outcomes listed; specific side effects are listed in parentheses‘‘Comparable’’ was listed if a set of comparator drugs in a particular study fared similarly for an outcome‘‘–’’ Was listed if the outcome was not evaluatedF, fentanyl; M, morphine; O, oxycodone

28 Pain Ther (2019) 8:19–39

unit [30]. Two studies reported significantlybetter postoperative pain relief with oxycodonecompared with fentanyl between 4 and 8 h aftersurgery [34, 35], however, no significant anal-gesic difference between groups was observedthereafter. The remaining study by Hwang et al.found comparable pain scores between oxy-codone and fentanyl at rest and during cough-ing from 4 h to 48 h during the postoperativeperiod [31].

Efficacy: Analgesic Consumption

Amongst the five studies that used IV-PCA, fourreported on the quantity of opioid consumed[31, 33–35]. All four studies that used doseconversion ratios (oxycodone:fentanyl)between 60:1 and 100:1 observed significantlyless analgesic consumption with oxycodonethan with fentanyl during the first 48 h aftersurgery [31, 33–35]. Of three studies whichevaluated analgesic consumption at varioustime points during the 48-h postoperative per-iod [31, 33, 34], two reported significantly lowercumulative IV-PCA volumes with oxycodonethan with fentanyl from 8 to 48 h [31, 33],however, no significant difference was reportedbetween groups during the first 4 h after surgery[31, 33, 34].

Three studies reported data on the use ofadditional/rescue analgesics during the postop-erative period. Of these, two found that the useof rescue analgesics was significantly more fre-quent with fentanyl than with oxycodone[33, 34], whereas one found no significant dif-ference between these agents [36].

Safety: Side Effects

Six studies compared the common opioid-re-lated side effects of oxycodone with those offentanyl in acute postoperative pain manage-ment. Overall, there was a tendency towards alower occurrence of some side effects with fen-tanyl than with oxycodone (Table 3). It shouldbe noted, however, that none of the studieswere specifically designed to assess differencesin side effects between opioid groups and are

thus likely underpowered (i.e., inadequatesample size) to do so.

Nausea

All except one study [21] administeredantiemetics before the end of surgery as pro-phylaxis against postoperative nausea andvomiting. Antiemetics were also provided in thepostoperative care unit in all but one study [23].Although most of the patients in these studieswould have received antiemetic treatment atthe end of surgery, at least 10% of patients inboth treatment groups still experienced post-operative nausea and vomiting.

The overall incidence of postoperative nau-sea with oxycodone ranged from 14.8 to 53.7%,while that with fentanyl ranged from 10.3 to35% across four studies [30, 31, 35, 36]. Three ofthese studies reported higher incidences ofnausea with oxycodone than with fentanyl, butthese differences were not statistically signifi-cant [30, 35, 36]. Three other studies that eval-uated the incidence of nausea at various timepoints showed a significantly higher incidenceof nausea with oxycodone than with fentanylstarting from as early as 2 h [33] and 4 h [34]after surgery, and between 6 and 24 h aftersurgery [23].

Vomiting

The incidence of postoperative vomiting withoxycodone ranged from 3.7 to 14%, while thatwith fentanyl ranged from 3 to 5% across threestudies [30, 35, 36]. Vomiting associated withoxycodone occurred significantly more fre-quently than with fentanyl at 8 h postopera-tively [34]. The incidence of vomiting withoxycodone and fentanyl was found to be com-parable by Ding et al. (3.7 vs. 3.4%) [36], and byKim et al. at all-time points [33]. Hwang et al.noted no reports of vomiting with either treat-ment [31].

Pruritus

The incidence of pruritus with oxycodone ran-ged from 2.4 to 14.0%, while that with fentanyl

Pain Ther (2019) 8:19–39 29

ranged from 4.8 to 10.0% across three studies[31, 33, 34]. Hwang et al. reported a lowerincidence of pruritus with oxycodone than withfentanyl (2.4 vs. 7.5%), but this result was notstatistically significant [31]. A higher incidenceof pruritus was observed with oxycodone thanwith fentanyl by Kim et al. (14.0 vs. 4.8% [34])and Kim et al. (13.3 vs. 10.0% [33]), but thesedifferences were not statistically significant.

Sedation

Sedation was assessed in all studies, but Hwanget al. did not report incidence rates of sedationin their study [31]. The incidence of sedationwith oxycodone ranged from 11 to 38%, whilethat with fentanyl ranged from 3.2 to 69.0%across five studies [30, 33–36]. Only Ding et al.found the incidence of sedation with fentanylto be significantly higher than that with oxy-codone (69 vs. 11%) [36]. The other five studiesfound sedation levels to be comparable betweenoxycodone and fentanyl [30, 31, 33–35].

Dizziness

Four studies assessed the incidence of dizziness[33–36]. The incidence of dizziness with oxy-codone ranged from 22.2 to 67.1%, while thatwith fentanyl ranged from 10 to 25.3% acrossfour studies [33–36]. Two studies found dizzi-ness with oxycodone to be significantly higherthan with fentanyl [34, 35], while two otherstudies found comparable incidences of dizzi-ness between groups [33, 36].

Respiratory Effects

There were no reports of respiratory depressionwith either treatment in all four studies thatevaluated respiratory effects [31, 33, 34, 36].Additionally, respiration rate over 48 h wasfound to be comparable between treatmentgroups [36].

Other Side Effects

Three studies assessed the incidence of head-ache. The incidence of headache with oxy-codone ranged from 13.3 to 19.0%, while thatwith fentanyl ranged from 3.0 to 14.3% acrossthree studies. Park et al. reported a higher inci-dence of headaches with oxycodone than withfentanyl (19 vs. 3%), but this difference was notstatistically significant [35]. The other twostudies reported comparable incidences ofheadache with oxycodone and fentanyl[33, 34].

Hwang et al. [31] also assessed the incidenceof shivering. In the oxycodone group, only onepatient (2.4%) experienced shivering whilenone in the fentanyl group experienced shiv-ering [31]. This difference between treatmentgroups was not statistically significant.

Patient Satisfaction

Five of six studies that compared oxycodonewith fentanyl evaluated patient satisfaction.The proportion of patients who were satisfiedwith oxycodone ranged from 53.0 to 82.9%,while that for patients who were satisfied withfentanyl ranged from 55.2 to 85.7% across fourstudies [31, 33, 34, 36]. Park et al. found thatsatisfaction with pain control at 6 h after thesurgery was significantly higher with oxy-codone than with fentanyl [mean (SD) 3.9 (1.0)vs. 3.2 (1.1); P\ 0.05], although satisfaction atother time points was comparable [35]. On theother hand, Kim et al. reported higher patientsatisfaction with fentanyl than with oxycodoneat 48 h (85.7 vs. 53.0%) [34]. The remainingthree studies did not find any significant dif-ferences in patient satisfaction between treat-ment groups [31, 33, 36].

Oxycodone vs. Morphine

Two studies involving a total of 135 patientsfrom Denmark and Norway compared oxy-codone with morphine for acute postoperativepain (Table 2). Surgical procedures includedpercutaneous nephrolithotomy [37] andlaparoscopic supracervical hysterectomy or

30 Pain Ther (2019) 8:19–39

laparoscopic total hysterectomy [32]. Studydurations were 4 h [37] and 24 h [32]. Opioidswere administered via IV [37] and IV-PCA [32]routes. The dose conversion ratio used for oxy-codone to morphine was 1:1 in both studies[32, 37]. Outcomes collected for efficacy inclu-ded pain intensity at rest and during movementor coughing; those for safety included sideeffects such as nausea, vomiting, sedation, anddizziness; and patient satisfaction.


Both studies compared the analgesic effect ofoxycodone with morphine for the managementof acute postoperative pain. One of these stud-ies found comparable analgesic effect betweentreatment groups [37]. Another study reportedless pain on coughing with oxycodone thanwith morphine during the first postoperativehour [32].


Both studies compared the analgesic consump-tion of oxycodone with morphine for managingpostoperative pain. One of these studies foundcomparable opioid consumption betweentreatment groups [37]; although the mean timeto first opioid dosing with oxycodone tended tobe shorter than with morphine, the differencewas not statistically significant [37]. Theremaining study found significantly less cumu-lative oxycodone consumption compared withmorphine consumption [mean (SD)13.3 ± 10.4 mg vs. 22.0 ± 13.1 mg; P = 0.001)and significantly longer mean time from emer-gence to first use of PCA with oxycodone thanwith morphine (20 min vs. 16 min; P = 0.038)[32].


Both studies compared the incidence of com-mon opioid-related side effects of oxycodonewith morphine for the management of acutepostoperative pain. Overall, the tolerabilityprofile was comparable (Table 3). It should benoted, however, that none of the studies were

specifically designed to assess differences in sideeffects between opioid groups and are thuslikely underpowered (i.e., inadequate samplesize) to do so.

Nausea

Antiemetics were administered as prophylaxisfor postoperative nausea and vomiting in thetwo studies [32, 37]. Despite antiemetic pro-phylaxis, at least 15% of patients in both treat-ment groups still experienced postoperativenausea and vomiting. Pedersen et al. reported asignificantly higher incidence of nausea withoxycodone than with morphine (55 vs. 23%)[37], whereas Lenz et al. reported no significantdifferences between treatment groups [32].

Vomiting

In the study by Pedersen et al., the incidence ofvomiting between treatment groups was com-parable at 9% [37]. The study by Lenz et al. alsoreported no significant differences betweentreatment groups [32].

Pruritus

Pedersen et al. reported no incidence of pruritusin either treatment group [37]. Although nodata for the incidence of postoperative prurituswas provided, Lenz et al. noted comparableincidences of pruritus between both treatmentgroups [32].

Sedation

Lenz et al. reported that the overall incidence ofpostoperative sedation was significantly lowerwith oxycodone than with morphine (P\ 0.05)[32]. Pedersen et al. noted comparable inci-dence of sedation between treatment groups(oxycodone: 86% vs. morphine: 73% [37]).

Dizziness

Dizziness was only assessed in the study byPedersen et al. and the incidence was found to

Pain Ther (2019) 8:19–39 31

be comparable between treatment groups (oxy-codone: 59%; morphine: 50%) [37].

Respiratory Effects

Respiratory effects were only assessed in thestudy by Pedersen et al. and the incidence wasfound to be comparable between treatmentgroups (oxycodone: 41.0%; morphine: 23.0%)[37].


None of the included studies evaluated patientsatisfaction.

Oxycodone vs. Sufentanil

Three studies involving a total of 287 patientsfrom China compared oxycodone with sufen-tanil for acute postoperative pain (Table 2).Surgical procedures included Cesarean section[38], laparoscopic radical gastrectomy [39], andlaparotomic or endoscopic elective abdominalsurgery [40]. Study durations were 24 h [30] and48 h [38, 40]. Opioids were administered via IV-PCA in all three studies. The dose conversionratios used for oxycodone to sufentanil were1000:1 [38, 40] and 500:1 [39]. Outcomes col-lected for efficacy included pain intensity (atrest and during movement or coughing) andanalgesic consumption [38, 40]; those for safetyincluded side effects such as nausea, vomiting,sedation, dizziness, and patient satisfaction.


All three studies compared the analgesic effectof oxycodone with sufentanil for managingacute postoperative pain (Table 3). Wang et al.[39] and Han et al. [40] found that oxycodoneand sufentanil provided comparable postopera-tive analgesia. However, in Nie et al., uterinecramping pain scores and pain during move-ment were significantly lower with oxycodonethan with sufentanil at all time points afterCesarean delivery [38].


All three studies compared the analgesic con-sumption of oxycodone with sufentanil formanaging acute postoperative pain. All studiesdemonstrated significantly higher consumptionof sufentanil PCA doses than of oxycodone PCAdoses [38–40].


All three studies compared the common opioid-related side effects of oxycodone with those ofsufentanil for managing acute postoperativepain. In two studies, safety outcomes werecomparable between oxycodone and sufentanil[38, 39], whereas in the study by Han et al.,there was a tendency towards a lower occur-rence of side effects with oxycodone than withsufentanil [40] (Table 3). It should be noted,however, that none of the studies were specifi-cally designed to assess differences in sideeffects between opioid groups and are thuslikely underpowered (i.e., inadequate samplesize) to do so.

Nausea

Antiemetics were administered as prophylaxisagainst postoperative nausea and vomiting inthe studies by Nie et al. [38] and Wang et al.[39], but not in the study by Han et al. [40].Despite antiemetic prophylaxis, some patientsstill experienced postoperative nausea andvomiting.

All three studies assessed the incidence ofnausea for oxycodone and sufentanil. In thestudy by Han et al., the incidence of nausea wasassessed at three time points: 3, 24, and 48 h[40]. At all time points, the incidence of nauseawas significantly lower with oxycodone thanwith sufentanil [40]. By contrast, Nie et al. andWang et al. showed that there was no statisti-cally significant difference in the incidence ofnausea between oxycodone and sufentanil (0.0vs. 16.7% [38]; and 12 vs. 16% [39],respectively).

32 Pain Ther (2019) 8:19–39

Vomiting

In the studies by Nie et al. [38] and Wang et al.[39], no patients on oxycodone reported vom-iting. There were no reports of vomiting withsufentanil by Nie et al. [38]; however, 4% ofpatients who received sufentanil in the study byWang et al. experienced vomiting [39]. In thestudy by Han et al., the incidence of vomitingwas assessed at three time points: 3, 24, and48 h [40]. At 3 and 24 h, the incidence ofvomiting was significantly lower with oxy-codone than with sufentanil.

Pruritus

There were no reports of pruritus with eitheroxycodone or sufentanil in the study by Nieet al. [38]. Wang et al. noted no reports of pru-ritus with oxycodone; however, one of 25patients (4%) who received sufentanil experi-enced pruritus [39]. In the study by Han et al.,the incidence of pruritus was assessed at threetime points: 3, 24, and 48 h [40]. At all timepoints, fewer patients on oxycodone experi-enced pruritus than those on sufentanil; how-ever, this difference was not significant.

Sedation

Wang et al. noted no reports of sedation withoxycodone; however, one of 25 patients (4%)who received sufentanil experienced sedation[39]. All patients in the Nie et al. study experi-enced light sedation (Ramsay sedation score of2), regardless of treatment with oxycodone orsufentanil [38]. None of these results were sta-tistically significant. The incidence of sedationwas not assessed by Han et al. [40].

Dizziness

Reports on the incidence of dizziness in twostudies were conflicting. Nie et al. noted thatthree patients (10.3%) experienced dizzinesswith oxycodone, whereas no patients onsufentanil experienced this side effect [38]. Incontrast, the other study reported 12% of

patients on sufentanil experienced dizzinesscompared with 8% of those on oxycodone [39].None of these results were statisticallysignificant.

Respiratory Effects

Respiratory depression was assessed in twostudies. Nie et al. reported that no patients ineither treatment group experienced respiratorydepression [38]. Han et al. reported thatthroughout the study, only one patient treatedwith sufentanil experienced respiratory depres-sion at 3 h, whereas no patients treated withoxycodone experienced respiratory depressionat any time points (3, 24, and 48 h) [40].

Other Side Effects

Hypotension and hypoxemia were assessed byNie et al.; no patients in either treatment groupexperienced hypotension or hypoxemia [38].


All three studies compared patient satisfactionbetween oxycodone and sufentanil for manag-ing acute postoperative pain. All studiesdemonstrated greater patient satisfaction withoxycodone than with sufentanil [38–40](Table 3).

Quality of Included Studies

The quality of included studies is summarizedin Supplementary Table 2. Overall, ten of the 11included studies were considered to be of highquality.

Of the six studies comparing oxycodonewith fentanyl, five scored at least four points.All six studies mentioned randomization[30, 31, 33–36], and five mentioned blinding[30, 31, 34–36], although two studies and onestudy had not described the methods used forrandomization [31, 33] and blinding [33],respectively. Attrition was described in five ofsix studies [30, 31, 34–36].

Pain Ther (2019) 8:19–39 33

All studies comparing oxycodone with mor-phine and sufentanil scored at least four points,which was considered to be of high quality.Attrition was not described by Wang et al. [39].

DISCUSSION

The aim of this review was to assess the efficacyand safety of intravenous oxycodone comparedwith fentanyl, morphine, sufentanil, pethidine,and hydromorphone for the management ofacute postoperative pain. While a number ofhead-to-head RCTs were retrieved for oxy-codone vs. fentanyl, oxycodone vs. morphine,and oxycodone vs. sufentanil, none were foundfor oxycodone vs. hydromorphone and oxy-codone vs. pethidine. Despite the heterogeneityof the included studies (in terms of types ofsurgical procedures, study procedures, addi-tional analgesia, and assessment methods),there were some consistencies in the resultsreported by the majority of the studies regard-ing the efficacy and safety of oxycodone com-pared with the other strong opioids.

Oxycodone appears to provide better anal-gesia than fentanyl, especially in the earlypostoperative period. The lower oxycodoneconsumption reported is important given theemphasis on opioid-sparing regimens inEnhanced Recovery After Surgery programs [41].Safety reports, however, suggest a tendencytowards more side effects with oxycodone, par-ticularly central nervous system side effectssuch as nausea and dizziness. These findingsindicate that the doses of oxycodone and fen-tanyl used were unlikely to be equi-analgesic.The dose conversion ratios between oxycodoneand fentanyl used in the included studies variedfrom 60:1 to 100:1, likely due to the lack ofstandard guidelines for equi-analgesic conver-sion doses of the two opioids [42, 43]. Closerexamination of studies that used dose ratios atthe lower end of spectrum (i.e., 60–75:1) stillshow better analgesia and a tendency towardsmore side effects with oxycodone, indicatingthat the appropriate equi-analgesic dose ratio islikely to be less than 60:1. Further studies arewarranted to fine-tune and determine the equi-

analgesic doses of intravenous oxycodone andintravenous fentanyl.

For the comparisons between oxycodoneand morphine, analgesic efficacy and tolerabil-ity profile appear to be comparable. Given thatthe dose conversion ratios of oxycodone tomorphine used were 1:1 in all the includedstudies, the findings suggest that oxycodoneand morphine are equipotent, contrary to whatother reports indicate [44]. Findings from olderstudies of oxycodone vs. morphine for postop-erative pain management also demonstratedequipotency between the two opioids [45, 46].One of the two included studies did howevernotice significantly less analgesic consumptionand sedation with oxycodone than with mor-phine. These findings were consistent with thatby Kalso et al., where oxycodone was found tobe faster-acting and to cause less sedation thanmorphine [45]. The lower oxycodone con-sumption may be due to faster blood–brain-barrier transport and thus more rapid onset ofanalgesic action compared with morphine[47, 48]. The active metabolite of morphine,morphine-6-glucuronide, is thought to beresponsible for increased sedation, drowsiness,nausea, vomiting, and respiratory depression[49]. The studies included in this review did notassess patient satisfaction; however, findingsfrom a study of epidural oxycodone (off-labeluse) vs. morphine suggest similarity in patientsatisfaction between these opioids [50].

The findings of all three studies, whichcompared oxycodone with sufentanil for acutepostoperative pain, suggest that oxycodoneprovides better analgesia with higher patientsatisfaction. Analgesic consumption of oxy-codone was lower than sufentanil when thedose conversion ratio used was 500–1000:1. Thedifferences in analgesic consumption are likelydue to the pharmacological properties of theopioids, where the longer duration of action ofoxycodone compared to sufentanil reduced theneed to re-dose IV-PCA as frequently [51, 52].The lower rate of re-dosing IV-PCA may alsohave resulted in greater overall patient satisfac-tion with oxycodone.

The mechanistic actions of the opioidsshould be considered when interpreting thefindings on postoperative pain and side effects.

34 Pain Ther (2019) 8:19–39

Oxycodone is a l-receptor agonist; activity onthe j-opioid receptor has been demonstrated inanimal studies [20, 21]. Oxycodone has weakerl-receptor affinity than morphine, fentanyl,and sufentanil, which may mitigate gastroin-testinal side effects caused by l-receptor ago-nism [19, 51]. Nonetheless, common opioid-related side effects such as nausea and vomitingare known to be dose-dependent and are rever-sible with dose tapering and/or effectivelymanaged with standard symptomatic treatment(e.g., antiemetics). Available literature suggestthat oxycodone has a different pharmacologicalprofile compared to that of morphine and thatit is more effective in attenuating visceral pain[24, 25]. This property (i.e., better antinocicep-tion in visceral pain) could give oxycodone anadvantage over other opioids after surgeries inwhich a large component of the patient’s over-all postoperative pain is visceral pain. In fact,this was the basis for investigating oxycodonein many of the included studies [30, 32, 36–39].Some studies also suggested that oxycodone hasan enhanced analgesic effect on neuropathicpain [27, 28]. Nonetheless, acute postoperativepain often involves multiple mechanisms; bet-ter designed studies are needed to confirm theclinical superiority of oxycodone over otherstrong opioids in treating the visceral and neu-ropathic components of acute postoperativepain.

Our systematic review revealed significantvariability in the incidence of side effects for therespective opioids across studies. Efficacy find-ings were also not always consistent. Severalfactors may be responsible for this inconsis-tency. First, the studies were heterogeneous interms of surgery types, which includes mini-mally invasive laparoscopic procedures, to openprocedures (e.g., Cesarean section), and to evenmore invasive surgeries such as total hipreplacement. The efficacy and need of opioidsto relieve pain after minimally invasive surgeryare clearly different from that after more inva-sive procedures. The postoperative pain inten-sity after laparoscopic surgeries (as were moststudies) may be too low to detect significantdifferences in pain scores or opioid consump-tion. Doses of opioids used would also be lower,thus side effects may not appear as frequent or

severe. Secondly, in a few studies, nursesadministered opioids in pre-determined vol-umes rather than via IV-PCA as is used in themajority of the studies. In studies that used IV-PCA, PCA program settings were not uniform interms of bolus doses, background infusion doses(or the lack thereof), and lockout intervals.These discrepancies may have an effect on effi-cacy and safety outcomes and patient satisfac-tion. Thirdly, pain assessment scales used variedamong studies (e.g., VAS, NRS 0–10, NRS 0–100)and are likely to differ in sensitivity. Somestudies did not specify the method of painassessment. Finally, side effects may be under-estimated in studies that collected safety databased on patient self-reports and observationsby investigators rather than via specific queriesby trained healthcare professionals. All thesefactors precluded pooling of the data acrossstudies in a meta-analysis. Additionally, itshould be noted that all the included studieswere not specifically designed to assess differ-ences in side effects between opioid groups.Future studies with sufficient power to comparesafety endpoints may thus be important.

Our systematic review of literature publishedover the last 10 years found only a handful ofhead-to-head studies comparing oxycodonewith morphine, fentanyl, and sufentanil formanaging acute postoperative pain. Notably,there were no head-to-head studies of oxy-codone vs. pethidine or hydromorphone for thesame indication during the same search period.More evidence from high-quality RCTs wouldbe welcomed. If greater alignment in opioidadministration and efficacy/safety assessmentmethods can be achieved in future studies, ameta-analysis may be possible to further clarifythe role of oxycodone compared with the otheropioids in managing acute postoperative pain.

CONCLUSIONS

Prompt and adequate postoperative pain man-agement is crucial to a patient’s postoperativerecovery process. Oxycodone is known to beeffective in the treatment of nociceptive, vis-ceral, and neuropathic pain and is increasinglybeing used as a postoperative analgesic. The

Pain Ther (2019) 8:19–39 35

intravenous route is typically used in theimmediate postoperative period, and conver-sion to oral oxycodone is initiated once oralintake of analgesia is possible. Our findingssuggest that intravenous oxycodone providessuperior efficacy to both fentanyl and sufen-tanil, and comparable efficacy to morphinewith less cumulative dose consumption and lessadverse events such as sedation. In some caseswhere oxycodone was more effective, a ten-dency towards more side effects was noted. Pre-emptive treatment of side effects and/or fine-tuning of doses where necessary could help tomanage side effects and maximize clinical ben-efits. No studies comparing intravenous oxy-codone with pethidine or hydromorphone wereidentified in this review.

The findings of this systematic review ofhead-to-head trials add to current evidence ofthe use of intravenous oxycodone for postop-erative pain management, and support its inte-gration into a multimodal analgesic approachfor optimal pain management.

ACKNOWLEDGEMENTS

Funding. This study was sponsored byMundipharma Singapore Holding Pte Ltd, Sin-gapore. Article processing charges were fundedby Mundipharma Singapore Holding Pte Ltd,Singapore. All authors had full access to thearticles reviewed in this manuscript and takecomplete responsibility for the integrity andaccuracy of this manuscript.

Medical Writing and Editorial Assis-tance. Medical writing and editorial supportwere funded by Mundipharma SingaporeHolding Pte Ltd, Singapore, and provided byBao Hui Lee and Wei Yi Kwok from TechObserver Asia Pacific Pte Ltd.

Authorship. All authors meet the Interna-tional Committee of Medical Journal Editors(ICMJE) criteria for authorship for this articleand gave final approval for the version to bepublished.

Disclosures. Milton Raff has receivedspeaker honorarium from and participated inadvisory boards by Mundipharma. Eric Nag-talon has received speaker honorarium fromand participated in advisory boards by Mundi-pharma. Kok Yuen Ho has received speakerhonorarium and participated in advisory boardsfrom Pfizer, Menarini, and Mundipharma. AmarSalti has served as a consultant and lecturer forMundipharma, GE Healthcare, Pfizer, MSD, andAbbott. Jeong-Hwa Seo has participated inadvisory board meetings organized by Mundi-pharma. Hongwei Wang has participated inadvisory board meetings by Mundipharma andBaxter. Kristal Buemio is an employee of Mun-dipharma Pte Ltd, Singapore. Consuelo Gutier-rez is an employee of Mundipharma Pte Ltd,Singapore. Yacine Hadjiat is an employee ofMundipharma Pte Ltd, Singapore. Anissa Bel-bachir, Aida Rosita Tantri, Tianlong Wang andSalah El-Tallawy have nothing to disclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the current study.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any non-commercial use, distribution, and reproductionin any medium, provided you give appropriatecredit to the original author(s) and the source,provide a link to the Creative Commons license,and indicate if changes were made.

REFERENCES

1. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postop-erative pain experience: results from a nationalsurvey suggest postoperative pain continues to be

36 Pain Ther (2019) 8:19–39

http://creativecommons.org/licenses/by-nc/4.0/http://creativecommons.org/licenses/by-nc/4.0/

undermanaged. Anesth Analg. 2003;97(2):534–40(table of contents).

2. Gupta A, Kaur K, Sharma S, Goyal S, Arora S, Mur-thy RS. Clinical aspects of acute post-operative painmanagement & its assessment. J Adv Pharm Tech-nol Res. 2010;1(2):97–108.

3. Rawal N. Current issues in postoperative pain man-agement. Eur J Anaesthesiol. 2016;33(3):160–71.

4. Ibrahim MS, Alazzawi S, Nizam I, Haddad FS. Anevidence-based review of enhanced recovery inter-ventions in knee replacement surgery. Ann R CollSurg Engl. 2013;95(6):386–9.

5. Montgomery R, McNamara SA. Multimodal painmanagement for enhanced recovery: reinforcingthe shift from traditional pathways through nurse-led interventions. AORN J. 2016;104(6S):S9–16.

6. Charlton E. The management of postoperativepain. Update Anaesth. 1997;7:1–7.

7. American Society of Anesthesiologists Task Forceon Acute Pain M. Practice guidelines for acute painmanagement in the perioperative setting: anupdated report by the American Society of Anes-thesiologists Task Force on Acute Pain Manage-ment. Anesthesiology. 2012;116(2):248–73.

8. Celis-Rodriguez E, Birchenall C, de la Cal MA, et al.Clinical practice guidelines for evidence-basedmanagement of sedoanalgesia in critically ill adultpatients. Med Intensiva. 2013;37(8):519–74.

9. Misiolek H, Cettler M, Woron J, Wordliczek J,Dobrogowski J, Mayzner-Zawadzka E. The 2014guidelines for post-operative pain management.Anaesthesiol Intensive Ther. 2014;46(4):221–44.

10. Schug SA, Palmer GM, Scott DA, Halliwell R, TrincaJ. Acute pain management: scientific evidence,fourth edition, 2015. Med J Aust.2016;204(8):315–7.

11. The Management of Postoperative Pain WorkingGroup. VHA/DoD clinical practice guideline for themanagement of postoperative pain. https://www.healthquality.va.gov/guidelines/Pain/pop/pop_fulltext.pdf. Accessed 17 Oct 2018.

12. International Association for the Study of PainCancer Pain Special Interest Group Managing AcutePain in the Developing World. https://www.iasp-pain.org/PublicationsNews/NewsletterIssue.aspx?ItemNumber=2078. Accessed 17 Oct 2018.

13. Hastie BA, Gilson AM, Maurer MA, Cleary JF. Anexamination of global and regional opioid con-sumption trends 1980–2011. J Pain Palliat CarePharmacother. 2014;28(3):259–75.

14. Fisher JE, Zhang Y, Sketris I, JohnstonG, Burge F. Theeffect of an educational intervention on meperidineuse in Nova Scotia, Canada: a time series analysis.Pharmacoepidemiol Drug Saf. 2012;21(2):177–83.

15. Lassen CL, Link F, Lindenberg N, et al. Anesthesi-ological acute pain therapy in Germany: telephone-based survey. Anaesthesist. 2013;62(5):355–64.

16. Pergolizzi JV Jr, Seow-Choen F, Wexner SD, Zam-pogna G, Raffa RB, Taylor R Jr. Perspectives onintravenous oxycodone for control of postoperativepain. Pain Pract. 2016;16(7):924–34.

17. Poyhia R. Opioids in anaesthesia: a questionnairesurvey in Finland. Eur J Anaesthesiol.1994;11(3):221–30.

18. Schaefer CP, Tome ME, Davis TP. The opioid epi-demic: a central role for the blood brain barrier inopioid analgesia and abuse. Fluids Barriers CNS.2017;14(1):32.

19. Drewes AM, Jensen RD, Nielsen LM, et al. Differ-ences between opioids: pharmacological, experi-mental, clinical and economical perspectives. Br JClin Pharmacol. 2013;75(1):60–78.

20. NielsenCK, Ross FB, Lotfipour S, Saini KS, Edwards SR,Smith MT. Oxycodone and morphine have distinctlydifferent pharmacological profiles: radioligand bind-ing and behavioural studies in two rat models ofneuropathic pain. Pain. 2007;132(3):289–300.

21. Ross FB, Smith MT. The intrinsic antinociceptiveeffects of oxycodone appear to be kappa-opioidreceptor mediated. Pain. 1997;73(2):151–7.

22. Yang PP, Yeh GC, Yeh TK, et al. Activation of delta-opioid receptor contributes to the antinociceptiveeffect of oxycodone in mice. Pharmacol Res.2016;111:867–76.

23. Olesen AE, Staahl C, Arendt-Nielsen L, Drewes AM.Different effects of morphine and oxycodone inexperimentally evoked hyperalgesia: a humantranslational study. Br J Clin Pharmacol.2010;70(2):189–200.

24. Staahl C, Christrup LL, Andersen SD, Arendt-Niel-sen L, Drewes AM. A comparative study of oxy-codone and morphine in a multi-modal, tissue-differentiated experimental pain model. Pain.2006;123(1–2):28–36.

25. Staahl C, Dimcevski G, Andersen SD, et al. Differ-ential effect of opioids in patients with chronicpancreatitis: an experimental pain study. Scand JGastroenterol. 2007;42(3):383–90.

26. Staahl C, Upton R, Foster DJ, et al. Pharmacoki-netic-pharmacodynamic modeling of morphine

Pain Ther (2019) 8:19–39 37

https://www.healthquality.va.gov/guidelines/Pain/pop/pop_fulltext.pdfhttps://www.healthquality.va.gov/guidelines/Pain/pop/pop_fulltext.pdfhttps://www.healthquality.va.gov/guidelines/Pain/pop/pop_fulltext.pdfhttps://www.iasp-pain.org/PublicationsNews/NewsletterIssue.aspx?ItemNumber=2078https://www.iasp-pain.org/PublicationsNews/NewsletterIssue.aspx?ItemNumber=2078https://www.iasp-pain.org/PublicationsNews/NewsletterIssue.aspx?ItemNumber=2078

and oxycodone concentrations and analgesic effectin a multimodal experimental pain model. J ClinPharmacol. 2008;48(5):619–31.

27. Barrera-Chacon JM, Mendez-Suarez JL, Jauregui-Abrisqueta ML, Palazon R, Barbara-Bataller E, Gar-cia-Obrero I. Oxycodone improves pain control andquality of life in anticonvulsant-pretreated spinalcord-injured patients with neuropathic pain. SpinalCord. 2011;49(1):36–42.

28. Thibault K, Calvino B, Rivals I, et al. Molecularmechanisms underlying the enhanced analgesiceffect of oxycodone compared to morphine inchemotherapy-induced neuropathic pain. PLoSOne. 2014;9(3):e91297.

29. Lee KH, Kang JH, Oh HS, et al. Intravenous oxy-codone versus intravenous morphine in cancerpain: a randomized, open-label, parallel-group,active-control study. Pain Res Manag.2017;2017:9741729.

30. Koch S, Ahlburg P, Spangsberg N, Brock B, Ton-nesen E, Nikolajsen L. Oxycodone vs. fentanyl inthe treatment of early post-operative pain afterlaparoscopic cholecystectomy: a randomised dou-ble-blind study. Acta Anaesthesiol Scand.2008;52(6):845–50.

31. Hwang BY, Kwon JY, Kim E, Lee DW, Kim TK, KimHK. Oxycodone vs. fentanyl patient-controlledanalgesia after laparoscopic cholecystectomy. Int JMed Sci. 2014;11(7):658–62.

32. Lenz H, Sandvik L, Qvigstad E, Bjerkelund CE,Raeder J. A comparison of intravenous oxycodoneand intravenous morphine in patient-controlledpostoperative analgesia after laparoscopic hys-terectomy. Anesth Analg. 2009;109(4):1279–83.

33. Kim NS, Kang KS, Yoo SH, et al. A comparison ofoxycodone and fentanyl in intravenous patient-controlled analgesia after laparoscopic hysterec-tomy. Korean J Anesthesiol. 2015;68(3):261–6.

34. Kim NS, Lee JS, Park SY, et al. Oxycodone versusfentanyl for intravenous patient-controlled analge-sia after laparoscopic supracervical hysterectomy: aprospective, randomized, double-blind study.Medicine (Baltimore). 2017;96(10):e6286.

35. Park JH, Lee C, Shin Y, An JH, Ban JS, Lee JH.Comparison of oxycodone and fentanyl for post-operative patient-controlled analgesia after laparo-scopic gynecological surgery. Korean J Anesthesiol.2015;68(2):153–8.

36. Ding Z, Wang K, Wang B, Zhou N, Li H, Yan B.Efficacy and tolerability of oxycodone versus fen-tanyl for intravenous patient-controlled analgesiaafter gastrointestinal laparotomy: a prospective,

randomized, double-blind study. Medicine (Balti-more). 2016;95(39):e4943.

37. Pedersen KV, Olesen AE, Drewes AM, Osther PJ.Morphine versus oxycodone analgesia after percu-taneous kidney stone surgery: a randomised doubleblinded study. Urolithiasis. 2013;41(5):423–30.

38. Nie JJ, Sun S, Huang SQ. Effect of oxycodonepatient-controlled intravenous analgesia aftercesarean section: a randomized controlled study.J Pain Res. 2017;10:2649–55.

39. Wang N, Zhou H, Song X, Wang J. Comparison ofoxycodone and sufentanil for patient-controlledintravenous analgesia after laparoscopic radicalgastrectomy: a randomized double-blind clinicaltrial. Anesth Essays Res. 2016;10(3):557–60.

40. Han L, Su Y, Xiong H, et al. Oxycodone versussufentanil in adult patient-controlled intravenousanalgesia after abdominal surgery: a prospective,randomized, double-blinded, multiple-center clini-cal trial. Medicine (Baltimore). 2018;97(31):e11552.

41. Garimella V, Cellini C. Postoperative pain control.Clin Colon Rectal Surg. 2013;26(3):191–6.

42. Anderson R, Saiers JH, Abram S, Schlicht C. Accu-racy in equianalgesic dosing. Conversion dilemmas.J Pain Symptom Manag. 2001;21(5):397–406.

43. Rennick A, Atkinson T, Cimino NM, Strassels SA,McPherson ML, Fudin J. Variability in opioidequivalence calculations. Pain Med.2016;17(5):892–8.

44. Pereira J, Lawlor P, Vigano A, Dorgan M, Bruera E.Equianalgesic dose ratios for opioids. A criticalreview and proposals for long-term dosing. J PainSymptom Manag. 2001;22(2):672–87.

45. Kalso E, Poyhia R, Onnela P, Linko K, Tigerstedt I,Tammisto T. Intravenous morphine and oxycodonefor pain after abdominal surgery. Acta AnaesthesiolScand. 1991;35(7):642–6.

46. Silvasti M, Rosenberg P, Seppala T, Svartling N,Pitkanen M. Comparison of analgesic efficacy ofoxycodone and morphine in postoperative intra-venous patient-controlled analgesia. Acta Anaes-thesiol Scand. 1998;42(5):576–80.

47. Bostrom E, Hammarlund-Udenaes M, SimonssonUS. Blood–brain barrier transport helps to explaindiscrepancies in in vivo potency between oxy-codone and morphine. Anesthesiology.2008;108(3):495–505.

48. Bostrom E, Simonsson US, Hammarlund-UdenaesM. In vivo blood–brain barrier transport of oxy-codone in the rat: indications for active influx and

38 Pain Ther (2019) 8:19–39

implications for pharmacokinetics/pharmacody-namics. Drug Metab Dispos Biol Fate Chem.2006;34(9):1624–31.

49. Riley J, Ross JR, Rutter D, et al. No pain relief frommorphine? Individual variation in sensitivity tomorphine and the need to switch to an alternativeopioid in cancer patients. Support Care Cancer.2006;14(1):56–64.

50. Sng BL, Kwok SC, Mathur D, et al. Comparison ofepidural oxycodone and epiduralmorphine for post-caesarean section analgesia: a randomised con-trolled trial. Indian J Anaesth. 2016;60(3):187–93.

51. Deshpande CM, Mohite SN, Kamdi P. Sufentanil vsfentanyl for fast-track cardiac anaesthesia. Indian JAnaesth. 2009;53(4):455–62.

52. Leow KP, Cramond T, Smith MT. Pharmacokineticsand pharmacodynamics of oxycodone when givenintravenously and rectally to adult patients withcancer pain. Anesth Analg. 1995;80(2):296–302.

53. OxyNorm 50 mg/ml, solution for injection orinfusion: SmPC (UK). 2018.

54. Kalso E. Oxycodone. J Pain Symptom Manag.2005;29(5 Suppl):S47–56.

55. Kirvela M, Lindgren L, Seppala T, Olkkola KT. Thepharmacokinetics of oxycodone in uremic patientsundergoing renal transplantation. J Clin Anesth.1996;8(1):13–8.

56. Kokki M, Valitalo P, Kuusisto M, et al. Centralnervous system penetration of oxycodone afterintravenous and epidural administration. Br JAnaesth. 2014;112(1):133–40.

57. Arendt-Nielsen L, Olesen AE, Staahl C, et al. Anal-gesic efficacy of peripheral kappa-opioid receptoragonist CR665 compared to oxycodone in a multi-modal, multi-tissue experimental human painmodel: selective effect on visceral pain. Anesthesi-ology. 2009;111(3):616–24.

58. Product Monograph: OxyNorm� Injection (Oxy-codone hydrochloride solution for injection orinfusion). Napp Pharmaceuticals Limited, Cam-bridge, UK.

59. Aubrun F, Mazoit JX, Riou B. Postoperative intra-venous morphine titration. Br J Anaesth.2012;108(2):193–201.

60. United States FDA prescribing information: Mor-phine Sulfate injection, for intravenous or intra-muscular use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204223s006lbl.pdf.Accessed 16 Mar 2018.

61. Trivedi M, Shaikh S, Gwinnut C. Pharmacology ofopioids. Update Anaesth. 2008;24(2):118–24.

62. United States FDA prescribing information: Fen-tanyl Citrate Injection, for intravenous or intra-muscular use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/016619s038lbl.pdf.Accessed: 16 Mar 2018.

63. Fentanyl injection. Fentanyl solution for injection50 micrograms/ml: New Zealand data sheet. 2017.

64. United States FDA prescribing information: Sufen-tanil Citrate Injection, for intravenous and epiduraluse. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019050s034lbl.pdf. Accessed 16Mar 2018.

65. Willsie SK, Evashenk MA, Hamel LG, Hwang SS,Chiang YK, Palmer PP. Pharmacokinetic propertiesof single- and repeated-dose sufentanil sublingualtablets in healthy volunteers. Clin Ther.2015;37(1):145–55.

66. Freye E, Latasch L, Portoghese PS. The delta receptoris involved in sufentanil-induced respiratorydepression–opioid subreceptors mediate differenteffects. Eur J Anaesthesiol. 1992;9(6):457–62.

67. Monk JP, Beresford R, Ward A. Sufentanil. A reviewof its pharmacological properties and therapeuticuse. Drugs. 1988;36(3):286–313.

68. Chan K, Tse J, Jennings F, Orme ML. Pharmacoki-netics of low-dose intravenous pethidine inpatients with renal dysfunction. J Clin Pharmacol.1987;27(7):516–22.

69. United States FDA prescribing information:DEMEROL (meperidine hydrochloride injection),for subcutaneous, intramuscular, and intravenoususe. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021171s024s025lbl.pdf. Accessed16 Mar 2018.

70. Clark RF, Wei EM, Anderson PO. Meperidine:therapeutic use and toxicity. J Emerg Med.1995;13(6):797–802.

71. United States FDA prescribing information:DILAUDID� INJECTION (hydromorphonehydrochloride) and DILAUDID-HP� INJECTION(hydromorphone hydrochloride), for intravenous,intramuscular, or subcutaneous use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019034s029lbl.pdf. Accessed 16 Mar 2018.

72. Murray A, Hagen NA. Hydromorphone. J PainSymptom Manag. 2005;29(5 Suppl):S57–66.

Pain Ther (2019) 8:19–39 39

https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204223s006lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204223s006lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2016/016619s038lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2016/016619s038lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019050s034lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019050s034lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021171s024s025lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021171s024s025lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019034s029lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019034s029lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019034s029lbl.pdf

Intravenous Oxycodone Versus Other Intravenous Strong Opioids for Acute Postoperative Pain Control: A Systematic Review of Randomized Controlled TrialsAbstractIntroductionMethodsResultsConclusionsFunding

IntroductionMethodsLiterature Search StrategySelection of StudiesAssessment of Study Quality

ResultsStudy InclusionStudy Characteristics and FindingsOxycodone vs. FentanylEfficacy: Pain IntensityEfficacy: Analgesic ConsumptionSafety: Side EffectsNauseaVomitingPruritusSedationDizzinessRespiratory EffectsOther Side EffectsPatient SatisfactionOxycodone vs. MorphineEfficacy: Pain IntensityEfficacy: Analgesic ConsumptionSafety: Side EffectsNauseaVomitingPruritusSedationDizzinessRespiratory EffectsPatient SatisfactionOxycodone vs. SufentanilEfficacy: Pain IntensityEfficacy: Analgesic ConsumptionSafety: Side EffectsNauseaVomitingPruritusSedationDizzinessRespiratory EffectsOther Side EffectsPatient SatisfactionQuality of Included Studies

DiscussionConclusionsAcknowledgementsReferences

Intravenous Oxycodone Versus Other Intravenous Strong Opioids … · 2019. 5. 13. · Jeong-Hwa Seo. Aida Rosita Tantri. Hongwei Wang. Tianlong Wang. Kristal Cielo Buemio. Consuelo

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