REVIEW

Resolving Issues About Efficacy and Safety of Low-Dose Codeine in Combination Analgesic Drugs:A Systematic Review

Ivan Celic . Lidija Bach-Rojecky . Iveta Mercep . Ana Soldo .

Anja Kos Petrak . Ana Bucan

Received: February 2, 2020 / Published online: March 14, 2020� The Author(s) 2020

ABSTRACT

Introduction: The objective of this systematicreview is to reflect on assumptions in relation tocodeine use in combination with otheranalgesics.Methods: MEDLINE was searched according tothe predetermined keywords and criteria. OnlyEnglish language studies were taken into con-sideration and the outcome data of the finalstudies were extracted by two reviewers inde-pendently from each other and were checked by

the third reviewer. Additionally, the availablecodeine-related Individual Case Safety Reports(ICSRs) retrieved from EudraVigilance werereviewed.Results: Sixteen placebo-controlled studies thatinvolved 3378 subjects suffering from acutepain were analyzed for the efficacy of low-dosecodeine (B 30 mg) combination products.Twelve of them found low-dose codeine com-binations more efficient in relieving pain thanthe assigned comparator. According to 20 ran-domized clinical trials which included at leastone dose of codeine (from 30 to 240 mg daily),the vast majority of reported side-effects weremild or moderate in severity. A total of 20 ICSRsfor dependence were identified in theEudraVigilance database with codeine as a sus-pect drug for the 10-year time period for theEuropean region.

Enhanced Digital Features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.11925480.

Electronic Supplementary Material The onlineversion of this article (https://doi.org/10.1007/s40122-020-00162-8) contains supplementary material, which isavailable to authorized users.

I. CelicDepartment of Dual Diagnosis, UniversityPsychiatric Hospital Vrapce, Bolnicka Cesta 32,10000 Zagreb, Croatia

L. Bach-Rojecky (&)Department of Pharmacology, University of ZagrebFaculty of Pharmacy and Biochemistry, Domagojeva2, 10000 Zagreb, Croatiae-mail: lbach@pharma.hr

I. MercepDepartment of Internal Medicine, Zagreb UniversityHospital Center, 10000 Zagreb, Croatia

I. MercepUniversity of Zagreb School of Medicine, Kispaticeva12, 10000 Zagreb, Croatia

A. SoldoCroatian Chamber of Pharmacists, Marticeva 27/II,10000 Zagreb, Croatia

A. K. Petrak � A. BucanRegulatory Department, Marti Farm Ltd, 10000Zagreb, Croatia

Pain Ther (2020) 9:171–194

https://doi.org/10.1007/s40122-020-00162-8

Conclusions: Low-dose codeine combinationsare effective after a single application in treatingacute pain. Codeine in doses B 30 mg andhigher was considered safe since only mild tomoderate side-effects were observed. There is noindication in the available sources which clearlylinks low doses of codeine to substance usedisorder in non-dependent subjects.

Keywords: Acute pain; Clinical studies;Combination analgesic drugs; Efficacy; Low-dose codeine; Review; Safety; Substance-usedisorder

Key Summary Points

Sixteen placebo-controlled studies thatinvolved 3378 subjects suffering fromacute pain were analyzed for the efficacyof low-dose codeine (B 30 mg)combination products.

Twenty randomized clinical trials whichincluded at least one dose of codeine(from 30 to 240 mg daily), were analyzedfor the safety and adverse-effects profile.

In EudraVigilance database for the 10-yeartime period, a total of 20 individual casesafety reports for dependence wereidentified with codeine as a suspect drug.

Low-dose codeine in fixed combinationswith other drugs is effective and safe whenused as recommended.

There is no exact proof in the availableliterature that clearly links low doses ofcodeine to substance use disorder issues innon-dependent subjects.

INTRODUCTION

Codeine or 3-methylmorphine is a mild opioidwith analgesic and antitussive effect [1]. Itsanalgesic activity is mostly due to the conver-sion to morphine by the cytochrome P450

enzyme CYP2D6, although codeine also hassome (low) affinity for the l-opioid receptordisplayed in the central nervous system (CNS)and at peripheral tissues, like the gastrointesti-nal tract [2]. In the context of analgesic action,codeine can be considered as a prodrug. Onlyaround 10% of codeine is converted to mor-phine. Other metabolic enzymes (CYP3A4,UDP-glucuronyltransferase) catalyse the con-version of codeine to other mostly inactivemetabolites norcodeine (10–15%) and codeine-6-glucuronide (50–70%). Different rates ofmetabolism correlate with genotypes of theCYP2D6 [3]. Poor metabolizers, with one or twonon-functional alleles are presented in 7–10%of the white population and may havedecreased metabolism of codeine to morphine,and lower possibility for the analgesic effect incomparison to normal (extensive metabolizers).On the contrary, ultrarapid metabolism is con-sidered to occur in 1–7% of the white popula-tion, whereas the incidence is 5–10% and 3%for Southern and Northern Europeans, respec-tively. As a result, in patients with more thantwo copies of the CYP2D6 functional allele,there is increased formation of morphine and ahigher potential for experiencing adverse effects(AEs), such as sleepiness, confusion, and shal-low breathing, even at recommended doses ofcodeine. Because of the unpre-dictable metabolism rate, codeine use as ananalgesic drug is often replaced by other opi-oids, although its combination with non-opioidanalgesic drugs is still largely available and usedfor pain treatment [4–8].

It has been found repeatedly that a combi-nation of different analgesic drugs at fixeddoses, rather than their single use, leads to afaster and better acute pain relief. The mainpurpose of such combination is the synergisticanalgesic effect due to the multimodalapproach to pain processing, alongside thebetter safety profile with no increase of theadverse effect incidence due to the initial lowerdoses of individual analgesics [9]. For example,the combination of non-opioid analgesic/an-tipyretic drugs, like paracetamol, ibuprofen, oracetylsalicylic acid with codeine was found tobe rational since these substances have differentmechanisms of action on pain with greater

172 Pain Ther (2020) 9:171–194

analgesic potential being possibly achieved,without reaching drugs individual toxic limits[10–12].

It is worth mentioning that doses of codeinein combinations with other drugs vary signifi-cantly, from 8 up to 60 mg, where a vastmajority of studies investigated the effects ofhigher dose codeine combinations (codeinedoses C 30 mg).

A recent systematic review and meta-analysisby Abdel Shaheed et al. of ten randomizedclinical trials investigated efficacy and safety ofcombination analgesic products with codeine indoses up to 30 mg and found low to moderatelevel of evidence for relief of acute pain. Theauthors found limited data about adverse effectsoutcomes [13].

At adult standard daily dose (30–60 mg every4 h orally up to a maximum of 240 mg daily)codeine was found to cause no euphoria orrespiratory depression. Also, despite the manyspeculations, existing proofs from clinicalpractice show it to be rarely addictive if appliedas recommended [10, 14].

In this systematic review, using a compre-hensive literature search strategy, we evaluatedefficacy and safety of the low-dose codeine incombinations with other analgesics, to elabo-rate their efficacy and safety in treating acutepain. In contrast to a recent systematic reviewand meta-analysis [13] which evaluated thesame ten studies for efficacy and safety andincluded single but also the multiple combina-tion dosing regimens, here we evaluated justsingle-dose studies when assessing the efficacyof low-codeine combination medicinal prod-ucts. Furthermore, here we focused on codeinesafety in general and have included both,codeine in doses B 30 mg and above, alone orin combination with other analgesics after sin-gle and multiple dosing regimens. Moreover, inaddition to the scientific literature, the availableindividual safety reports data as retrieved fromthe European Medicines Agency’s (EMA) ser-vice—EudraVigilance were reviewed and thetopic of substance use disorder is speciallyaddressed.

METHODS

General Search Strategy

A bibliographic database MEDLINE was sear-ched according to the predetermined keywords(codeine, analgesia, pain, efficacy, safety,adverse event, side effect, addiction, depen-dence, overdose, misuse, abuse) and criteria(randomized clinical trial/study and range frominception to end of January 2019).

Search strategy was made concise enough tomake sure that the exact data on efficacy andsafety, along with potential for codeine usedisorders is found, while remaining wideenough to include and extract the potentialvaluable data which could remain hidden ifsearching just for the codeine combination.Nevertheless, for the efficacy part, only placebo-controlled and combination studies wereincluded in the final review.

This article is based on previously conductedstudies and does not contain any studies withhuman participants or animals performed byany of the authors.

Study Selection

Only English language studies were included inthis review. Additional filters combininghuman species and studies published up toJanuary 31, 2019 were taken into considerationfor obtaining relevant literature findings. Fol-lowing initial screening of the titles andabstracts found for codeine, two reviewers setthe keywords and criteria in place for efficacyand safety studies on codeine. One of theexclusion criteria was paediatric population dueto recommended restrictions on the use ofcodeine for cough and cold in children. Basedon the abstracts, initial judgment call was madeon the potentially valuable studies. Afterretrieving the full texts, final decision was madeon to which studies shall be included in thereview. Efficacy and safety differed in finaldecision on importance of the found studies.

Pain Ther (2020) 9:171–194 173

Efficacy Study Search and Selection

Since codeine’s efficacy in combination wasproven time and again, especially for higherdoses ([30 mg), the main focus was to find therandomized, placebo-controlled studies whichincluded codeine in lower doses (B 30 mg) incombination with another non-opioid analgesicsubstance. Only single dose studies weredeemed acceptable. Despite the wider spectrumof codeine use, only studies focusing on anal-gesia were searched for (regardless of the exactindication). The selection was not limited to theduration of treatment or to the analgesic effectduration. Also, different doses of the substancesin the codeine combinations were not arestriction factor.

Safety Study Search and Selection

For the purpose of safety evaluation, random-ized controlled clinical studies involvingmedicines containing codeine either alone or incombinations, irrespective of doses, were takeninto consideration. Both single and multipledose studies, where codeine-treated subjectsreceived at least one dose of codeine (rangingfrom 15 to 240 mg daily dose), for any paincondition were reviewed in order to meet theeligibility criteria. The safety profile of codeinewas additionally determined involving key-words such as dependence, addiction, misuse,abuse and overdose throughout MEDLINE andEudraVigilance.

The summary on search strategy can be seenon Fig. 1.

Fig. 1 Search strategy summary for efficacy and safety as per the predetermined inclusion and exclusion criteria

174 Pain Ther (2020) 9:171–194

Data Extraction and Quality Assessment

Outcome data of the final studies were extractedby two reviewers independently from eachother, and were checked by the third reviewer.Recommendations from the Cochrane Hand-book were applied when and where applicable.

The quality of reports of randomised con-trolled trials was measured using a scale indexedon PEDro (provided as supplementary material),the Physiotherapy Evidence Database (https://www.pedro.org.au/).

RESULTS

Overview of Efficacy

Efficacy of low-dose codeine combinationmedicinal products was analysed throughreview of 16 placebo-controlled studies whichinvolved 3378 subjects. Most of the studies werefocused on codeine combination efficacyregarding surgery pain with most of themrelating to the dental surgery pain (9 out of thetotal 16 studies) [15–23]; two were focused ontension headache [20, 24]; one on acutemigraine attack [25]; one on post-episiotomypain [26]; one on post-orthopaedic surgery pain[27]; one on post-photorefractive keratectomypain [28]; and one on post-operative pain [29].

Medicinal products as found in the afore-mentioned studies contained the following 9substances alongside codeine: paracetamol—nine studies [10, 16–18, 20, 25, 27–29]; acetyl-salicylic acid—seven studies [15, 17–19, 22–25];and ibuprofen—six studies [16, 19, 22, 23 26,27]; followed by butalbital—three studies[16, 17, 24]; caffeine—three studies [16, 17, 24];zomepirac—one study [24]; meclofenam—onestudy [21]; pentazocine—one study [29]; andpropoxyphene napsylate—one study [29].

The lowest and highest doses of the mostcommonly used substances mentioned abovewere as follows: for paracetamol—300 mg and650 mg; for acetylsalicylic acid—325 mg and1000 mg; and for ibuprofen—400 mg and800 mg.

None of the studies were focused on thelong-term effects of codeine combination use,

with the analgesic efficacy period being evalu-ated for all of them: 2 h was the shortest timenoted [25], while 72 h being the longest timeobserved following single doses of combinationproducts [28].

Twelve studies based on statistically signifi-cant results provided the final conclusion thatlow-dose codeine combinations are more effi-cient in relieving pain compared to placebo[10, 15, 17–21, 24–26, 28, 29]. Complete oralmost complete pain relief was noted after:0.5 h [24]; 1 h [15, 26, 28, 29], 2 h [25], 5 h [19],6 h [17, 18, 20, 21], and 12-24 h [10]. Cooperand Beaver [15] discussed the minor role ofcodeine in analgesia, while concluding that thestatistically significant efficacy of the combina-tion is due to acetylsalicylic acid.

In contrast, two studies found codeine incombinations to be effective, but less than thecomparator [16, 27]. Daniels et al. [16] com-pared the efficacy of paracetamol and ibuprofencombinations (ibuprofen 200 mg ? paraceta-mol 500 mg; ibuprofen 200 mg ? codeine12.8 mg; paracetamol 500 mg ? codeine 15 mg)with placebo. They found that even thoughlow-dose codeine combinations were statisti-cally significantly superior to placebo, ibupro-fen-paracetamol combinations were moreeffective in pain management. Heidrich et al.[27] compared the single dose ibuprofen 400 mgwith a combination of paracetamol 300 mg andcodeine 30 mg. They found the single dose ofibuprofen to be more effective in pain reductionthan the combination containing codeine interms of sensory descriptors of pain. However,combination with codeine was more effectivewhen regarding the affective descriptors of pain.

Two studies found low-dose codeine incombination to be ineffective, or modestlyeffective in pain treatment [22, 23]. Giles et al.[22] argued in their study the efficacy of low-dose codeine, concluding that 15 mg codeine,alone or in combination, has little to noneanalgesic efficacy. A dose of 15 mg was dis-cussed to be a subtherapeutic dose with ques-tionable possibility to show the additive effectin combination. Squires et al. [23] found nostatistically significant difference between30 mg codeine (in combination with 375 mg

Pain Ther (2020) 9:171–194 175

Table1

Characteristicandconclusion

sof

theincluded

efficacystudies

Autho

rs

(reference)

Stud

ydesign

Num

berof

participants

Pop

ulationcharacteristics/Meanageof

the

participants

(years)

Indication

Intervention

(com

paredto

placebo)

Outcomemeasures

Analgesic

efficacy

period

measurement

(h)

Stud

yconclusion

on

codeine/codeine

combination

scomparedto

comparator/placebo

Cooper

and

Beaver

[15]

Arand

omized,

double-

blind,

single-

dose

study

128

64Femaleand64

malepatients/agedbetween

16and35

Oralsurgerypain

1.Ibuprofen

400mg?

codeine

phosphate30

mg

2.zomepirac

100mg

3.codeine30

mg

4.acetylsalicylicacid

650mg

5.codeine

30mg?

acetylsalicylic

acid

650mg

Pain

relief

Pain

intensitydifference

3Low

-dosecodeine

combination

ismore

efficient

inrelieving

pain

comparedto

placebo,

acetylsalicylicacid

650mg

andcodeine30

mgalone

Cater

etal.

[26]

Adouble-blin

d,

single-dose

study

127

Allfemalepatients/22.8

Moderateor

severe

postepisiotomy

pain

1.ibuprofen

400mg?

codeine

phosphate30

mg

2.zomepirac

100mg

3.codeine30

mg

4.acetylsalicylicacid

650mg

5.codeine

30mg?

acetylsalicylic

acid

650mg

Degreeof

pain

Pain

relief

Pain

halfgone

8Low

-dosecodeine

combination

ismore

efficient

inrelieving

pain

comparedto

placeboand

zomepirac

100mg

Heidrich

etal.

[27]

Adouble-blin

d,

single-dose,

parallel-

group

120

48Femaleand72

malepatients/31

Post-orthopaedic

surgerypain

1.ibuprofen400mg

2.paracetamol

300mg?

codeine30

mg

Pain

relief

Pain

intensity

Mood

6Codeine

incombination

is

effective,butlessthan

the

comparator

176 Pain Ther (2020) 9:171–194

Table1

continued

Autho

rs

(reference)

Stud

ydesign

Num

berof

participants

Pop

ulationcharacteristics/Meanageof

the

participants

(years)

Indication

Intervention

(com

paredto

placebo)

Outcomemeasures

Analgesic

efficacy

period

measurement

(h)

Stud

yconclusion

on

codeine/codeine

combination

scomparedto

comparator/placebo

Fram

e

etal.

[19]

Adouble-blin

d,

singledose

study

165

Bothgend

erswereincluded/24.4

Rem

ovalof

an

impacted

mandibular

thirdmolar

tooth

1.acetylsalicylicacid

600mg

2.ibuprofen200mg?

codeinephosphate15

mg

3.ibuprofen

400mg?

codeine

phosphate30

mg

4.ibuprofen

800mg?

codeine

phosphate60

mg

Pain

relief(degreeof

pain)

5Low

-dosecodeine

combinationsaremore

efficient

inrelieving

pain

comparedto

placeboand

acetylsalicylicacid

Desjardins

etal.

[17]

Adouble-blin

d,

rand

omized,

single-dose

study

123

77Femaleand46

malepatients/23.8

Oralsurgerypain

1.paracetamol

300mg?

codeine

30mg

2.acetylsalicylicacid

325mg?

butalbital

50mg?

caffeine

40mg?

codeine30

mg

Sum

ofpain

intensity

difference

(SPID)

Peak

pain

intensity

difference

Totalpain

relief

(TOTPA

R)

Peak

pain

relief

Sum

ofobservations

with

pain

halfgone

Totalanxiety

Peak

anxiety

Totalrelaxation

Peak

relaxation

Overallevaluation

Tim

eto

remedication

withan

alternate

analgesic

6Low

-dosecodeine

combinationsaremore

efficient

inrelieving

pain

than

placebo

Pain Ther (2020) 9:171–194 177

Table1

continued

Autho

rs

(reference)

Stud

ydesign

Num

berof

participants

Pop

ulationcharacteristics/Meanageof

the

participants

(years)

Indication

Intervention

(com

paredto

placebo)

Outcomemeasures

Analgesic

efficacy

period

measurement

(h)

Stud

yconclusion

on

codeine/codeine

combination

scomparedto

comparator/placebo

Forbes

etal.

[18]

Adouble-blin

d,

parallel

group,

rand

omized

study

122

77Femaleand45

malepatients/21.63

Moderateor

severe

pain

afterthe

surgicalremoval

ofim

pacted

thirdmolars

1.acetylsalicylicacid

325mg?

caffeine

40mg?

codeine

30mg?

butalbital

50mg

2.paracetamol

300mg?

codeine30

mg

Pain

intensitydifference

score(PIO

)

Sum

ofthepain

intensity

difference

scores(SPIO)

Peak

PIO

score

Pain

reliefscore

Totalpain

reliefscore

Peak

pain

reliefscore

Totalhoursof

50%

relief

Overallevaluation

Anxiety

difference

score

Sum

oftheanxiety

difference

scores

Peak

anxietydifference

score

Relaxationdifference

score

Sum

oftherelaxation

difference

scores

Peak

relaxation

difference

score

Tim

eun

tiltaking

the

backup

medication

6Low

-dosecodeine

combinationsaremore

efficient

inrelieving

pain

than

placebo

Gileset

al.

[22]

Adouble-blin

d,

singledose

study

202

Bothgend

erswereincluded/24.8

Surgicalremovalof

thirdmolars

pain

1.acetylsalicylicacid

600mg

2.ibuprofen200mg

3.codeine15

mg

4.ibuprofen

200mg?

codeine15

mg

Degreeof

pain

Pain

relief

Ifthepain

was

halfgone

5Codeine,alone

orin

combination,h

aslittle

to

none

analgesicefficacy

178 Pain Ther (2020) 9:171–194

Table1

continued

Autho

rs

(reference)

Stud

ydesign

Num

berof

participants

Pop

ulationcharacteristics/Meanageof

the

participants

(years)

Indication

Intervention

(com

paredto

placebo)

Outcomemeasures

Analgesic

efficacy

period

measurement

(h)

Stud

yconclusion

on

codeine/codeine

combination

scomparedto

comparator/placebo

Hwang

etal.

[24]

Arand

omized,

double-

blind,

placebo-

controlled,

multicenter

trial

208

Bothgend

erswereincluded/agedbetween18

and65

Tension

headache

1.butalbital

50mg?

caffeine

40mg?

acetylsalicylic

acid

200mg?

phenacetin

130mg

2.codeinephosphate30

mg

3.butalbital

50mg?

caffeine

40mg?

acetylsalicylic

acid

200mg?

phenacetin

130mg?

codeine30

mg

Patients’self-evaluation:

Pain

severity

Pain

relief

Tension

anduptight

feeling

Relaxationand

contentm

ent

Musclestiffness

Dailyactivities

Average

tensioncomposite

Average

pathology

Physician’sglobal

evaluation:

Headachepain

Psychictension

Musclecontraction

4Low

-dosecodeine

combinationsaremore

efficient

inrelieving

pain

comparedto

placebo,

butalbital

50mg?

caffeine

40mg?

acetylsalicylic

acid

200mg?

phenacetin

130mgandcodeine

phosphate30

mg

Pettiet

al.

[29]

Asingle-blin

d,

parallel-

groupstudy

129

Bothgend

erswereincluded/agedbetween18

and80

Moderate

postoperative

pain

1.paracetamol

650mg?

pentazocine

25mg

2.paracetamol

300mg?

codeine30

mg

3.paracetamol

650mg?

propoxyphene

napsylate100mg

Severity

ofpain

Degreeof

pain

relief

6Low

-dosecodeine

combination

ismore

efficient

inrelieving

pain

comparedto

placebo,

paracetamol

650mg?

pentazocine

25mgandparacetamol

650mg?

propoxyphene

napsylate100mg

Pain Ther (2020) 9:171–194 179

Table1

continued

Autho

rs

(reference)

Stud

ydesign

Num

berof

participants

Pop

ulationcharacteristics/Meanageof

the

participants

(years)

Indication

Intervention

(com

paredto

placebo)

Outcomemeasures

Analgesic

efficacy

period

measurement

(h)

Stud

yconclusion

on

codeine/codeine

combination

scomparedto

comparator/placebo

Giglio

and

Laskin

[21]

Asingle-dose,

rand

omized,

double-

blind,

parallel-

treatm

ent

study

200

165Femaleand35

malepatients/22.7

Surgicalremovalof

thirdmolars

pain

1.meclofenamate

100mg?

codeine

60mg

2.meclofenamate

50mg?

codeine30

mg

3.meclofenamate100mg

4.codeine60

mg

Pain

intensitydifference

(PID

)

Sum

ofpain

intensity

differences(SPID)

Sum

ofpain

reliefscores

(TOTPA

R)

Peak

pain

relief

Num

berof

observations

at

which

pain

was

half

relieved

Overallevaluation

of

studymedication

effectiveness

Tim

eto

remedication

withabackup

analgesic

6Low

-dosecodeine

combination

ismore

efficient

inrelieving

pain

comparedto

placeboand

codeine60

mg,butslightly

lessefficient

than

meclofenamate100mg

andmeclofenamate

100mg?

codeine60

mg

Boureau

etal.

[25]

Arand

omized,

multicentre,

double-blin

d

study

247

190Femaleand57

malepatients/40.1±

11.6

Acute

migraine

attack

1.paracetamol

400mg?

codeine

25mg

2.acetylsalicylicacid

1000

mg

Com

pleteor

near

completereliefof

pain

2Low

-dosecodeine

combination

ismore

efficient

inrelieving

pain

comparedto

placeboand

slightly

lessefficient

than

acetylsalicylicacid

1000

mg

Daniels

etal.

[16]

Adouble-blin

d,

5-arm,

parallel-

group,

placebo-

controlled,

rand

omised,

single-dose

study

678

105Femaleand68

malepatients/20.2

Postoperative

dentalpain

1.ibuprofen

200mg?

paracetamol

500mg

Pain

relief

Pain

intensitydifference

12Codeine

incombinationsis

effective,butlessthan

the

comparator

ibuprofen?

paracetamol

combination

180 Pain Ther (2020) 9:171–194

Table1

continued

Autho

rs

(reference)

Stud

ydesign

Num

berof

participants

Pop

ulationcharacteristics/Meanageof

the

participants

(years)

Indication

Intervention

(com

paredto

placebo)

Outcomemeasures

Analgesic

efficacy

period

measurement

(h)

Stud

yconclusion

on

codeine/codeine

combination

scomparedto

comparator/placebo

Gatoulis

etal.

[20]

Arand

omized,

double-

blind,

placebo-

controlled,

single-dose

clinicaltrial

302

185Femaleand115malepatients/23.13

Dentalpain

1.acetylsalicylicacid

1000

mg

2.paracetamol

300mg?

codeine30

mg

Sum

ofpain

intensity

differencesfrom

baselin

e(SPID)

The

time-

interval–w

eightedsum

ofpain

reliefscores

(TOTPA

R)

Pain

intensitydifference

(PID

)

Peak

PID

Pain

reliefscore(PAR)

Peak

PAR

Tim

eto

onsetof

meaningfuland

completerelief

Tim

eto

useof

rescue

medication

6Low

-dosecodeine

combination

ismore

efficient

inrelieving

pain

comparedto

placeboand

comparablyefficient

comparedto

acetylsalicylic

acid

1000

mg

676

304Femaleand183malepatients/37.12

Tension-type

headache

4

Cristalli

etal.

[10]

Arand

omized,

placebo-

controlled,

double-blin

d

32Bothgend

erswereincluded/agedbetween20

and29

Mandibularthird

molar

surgery

pain

Paracetamol

500mg?

codeine

30mg

Postoperativepain

The

numberof

patients

usingrescue

therapy,

Tim

eto

thefirstuseof

rescue

analgesia

Totalnu

mberof

postoperative-

supplement

paracetamol

?codeine

tablets

48Low

-dosecodeine

combination

ismore

efficient

inrelieving

pain

than

placebo

Pain Ther (2020) 9:171–194 181

acetylsalicylic acid and 30 mg caffeine) andplacebo in their study.

There are four studies which found low-dosecodeine in combination to be effective, but lessthan the comparator [16, 21, 25, 27]. Thispotentially suggests that low-dose codeinecombinations are more efficient when com-pared to placebo, but not when compared toother non-opioid agents.

Most of the studies which were included arefrom more than 30 years ago, with the oldeststudy found dated 1976. Conclusions from fournewer studies (time period from 2011–2017) arein line with conclusions from the older ones—stating that low-dose codeine combination ismore efficient in pain management whencompared to placebo [10, 16, 20, 28]. Still, oneof those studies found that low-dose codeinecombination is as effective as the comparator[20], while one study found that such combi-nation is less efficient than the comparator [16].

The characteristics and conclusions of theincluded efficacy studies are available in theTable 1.

Overview of Safety

Analgesics containing codeine are in generalwell-tolerated and usually exhibit favourablesafety profile with most AEs classified as mild tomoderate in severity if used for short period oftime and in recommended doses. Based on theliterature data discussed further in the text, theincidence of treatment discontinuation due tosevere AEs is low and comparable to othertreatment options for pain management.

Most of the analysed studies for safety over-view included combination of non-steroidalantiinflammatory drugs (NSAIDs) with codeinein higher single dose ([ 30 mg).

The overall safety of codeine alone or incombinations was assessed through 20 ran-domized clinical trials where codeine-treatedsubjects received at least one dose of codeine(ranging from 30 to 240 mg daily dose). Themost represented dose within the studies was60 mg single dose and was used in 75% of allevaluated clinical trials. Safety profiles of studymedications were determined in adult patients

Table1

continued

Autho

rs

(reference)

Stud

ydesign

Num

berof

participants

Pop

ulationcharacteristics/Meanageof

the

participants

(years)

Indication

Intervention

(com

paredto

placebo)

Outcomemeasures

Analgesic

efficacy

period

measurement

(h)

Stud

yconclusion

on

codeine/codeine

combination

scomparedto

comparator/placebo

Pereira

etal.

[28]

Arand

omized,

double-

blind,

placebo-

controlled

add-on

trial

4027

Femaleand13

malepatients/30

Pain

after

photorefractive

keratectom

y

Codeine

30mg?

paracetamol

500mg

Difference

inpain

intensity

Meanpain

scores

72Low

-dosecodeine

combination

ismore

efficient

inrelieving

pain

comparedto

placebo

182 Pain Ther (2020) 9:171–194

Table2

Studiesincluded

inthesafety

analysiswithnu

mberof

patientsfrom

rand

omized

clinicaltrialsreportingadverseeffects

Stud

ies

Treatment

Com

parator

Stud

yconclusion

Num

berof

patients

repo

rtingadverse

drug

reaction

s(n/N

)

Treatment

(n/N

)Com

parator

(n/N

)Treatment

vs.

comparator

Cooper

etal.[33]

I.codeine60

mg,

II.acetylsalicylicacid

650mg?

codeine

60mg,

III.ibuprofen

400mg?

codeine

60mg

A.acetylsalicylicacid

650mg,

B.ibuprofen

400mg,

C.p

lacebo

There

wereno

significant

differences

regardingAEswithintreatm

ent

groups.N

owithdrawalfrom

thestudy

was

recorded

I.26.8%

(11/41)

II.2

6.7%

(12/45)

III.43.9%

(18/41)

A.2

3.7%

(9/

38)

B.2

8.9%

(11/38)

C.1

0.9%

(5/

46)

32.3%

vs.

20.5%

Forbes

etal.

[34]

Paracetamol

600mg?

codeine

60mg

A.d

iflun

isal500mg,

B.d

iflun

isal1000

mg,

C.p

aracetam

ol600mg,

D.p

lacebo

There

wereno

significant

differences

regardingAEswithintreatm

ent

groups

42.3%

(11/

26)

A.4

6.2%

(12/26)

B.4

6.4%

(13/28)

C.4

2.3%

(11/26)

D.1

5.4%

(4/

26)

42.3%

vs.

37.7%

Desjardins

etal.[17]

I.paracetamol

300mg?

codeine

30mg,

II.acetylsalicylicacid

325mg?

butalbital

50mg?

caffeine

40mg?

codeine

30mg

Placebo

There

wereno

significant

differences

regardingAEswithintreatm

ent

groups

I.5.1%

(2/

39)

II.1

1.6%

(5/43)

9.8%

(4/41)

8.5%

vs

9.8%

Pain Ther (2020) 9:171–194 183

Table2

continued

Stud

ies

Treatment

Com

parator

Stud

yconclusion

Num

berof

patients

repo

rtingadverse

drug

reaction

s(n/N

)

Treatment

(n/N

)Com

parator

(n/N

)Treatment

vs.

comparator

Forbes

etal.

[18]

I.codeinesulfate

60mg,

II.n

aproxensodium

550mg?

codeine

60mg

A.n

aproxensodium

550mg,

B.acetylsalicylicacid

650mg,

C.p

lacebo

Reportincludes

AEsoccurred

within

12hof

taking

studymedication.

Incidenceof

AEswas

higher

in

codeinetreatm

entgroups

I.25.5%

(12/47)

II.3

5.6%

(16/45)

A.1

6.3%

(7/

43)

B.7

.3%

(3/

41)

C.1

5.2%

(7/

46)

30.4%

vs.

13.1%

Sagneet

al.

[35]

Paracetamol

650mg?

codeine

60mg

Paracetamol

650mg?

dextropropoxyphene

65mg

Adverse

eventsweremorefrequent

in

wom

enfrom

paracetamol

?codeine

group

38.1%

(37/

97)

26.6%

(25/

94)

38.1%

vs.

26.6%

Stam

baugh

andDrew

[36]

Acetylsalicylicacid

650mg?

codeine

60mg

A.k

etoprofen100mg,

B.k

etoprofen300mg,

C.p

lacebo

There

wereno

significant

differencesin

relation

withsafety

data

within

treatm

entgroups

22.5%

(9/

40)

A.1

7.5%

(7/

40)

B.1

7.5%

(7/

40)

C.2

2.5%

(9/

40)

22.5%

vs.

19.2%

Sunshine

etal.[37]

Codeine

60mg

A.p

iroxicam

20mg,

B.p

lacebo

The

highestincidenceof

reported

AEs

was

observed

intheplacebogroup

19.6%

(10/

51)

A.1

4.0%

(7/

50)

B.5

0.0%

(25/50)

19.6%

vs

32.0%

184 Pain Ther (2020) 9:171–194

Table2

continued

Stud

ies

Treatment

Com

parator

Stud

yconclusion

Num

berof

patients

repo

rtingadverse

drug

reaction

s(n/N

)

Treatment

(n/N

)Com

parator

(n/N

)Treatment

vs.

comparator

Turek

etal.

[38]

Paracetamol

650mg?

codeine

60mg

A.ketoprofen50

mg,

B.k

etoprofen150mg,

C.p

lacebo

There

was

asignificantlygreater

incidenceof

centralnervoussystem

AEsin

theparacetamol

plus

codeine

group

28.2%

(11/

39)

A.3

4.1%

(14/41)

B.2

0.5%

(8/

39)

C.9

.8%

(4/

41)

28.2%

vs.

21.5%

Forbes

etal.

[39]

Paracetamol

600mg?

codeine

60mg

A.fl

urbiprofen

100mg,

B.p

aracetam

ol600mg,

C.p

lacebo

Reportincludes

AEsoccurred

within

12hof

taking

studymedication

5.9%

(1/17)

A.3

.4%

(1/

29)

B.1

1.5%

(3/

26)

C.7

.7%

(2/

26)

5.9%

vs.

7.4%

Minotti

etal.[31]

Acetylsalicylicacid

640mg?

codeine

40mg

A.n

efopam

60mg,

B.d

iclofenacsodium

50mg

AEswereslightly

morefrequent

within

acetylsalicylicacid

?codeineand

nefopam

treatm

entgroups

36.4%

(12/

33)

A.3

9.4%

(13/33)

B.6

.1%

(2/

33)

36.4%

vs.

27.3%

Carlso

n

etal.[30]

Paracetamol

600mg?

codeine

60mg

Ketorolac

10mg

AEswereacceptableforboth

treatm

ent

groups

47.5%

(19/

40)

61.8%

(21/

34)

47.5%

vs.

61.8%

Pain Ther (2020) 9:171–194 185

Table2

continued

Stud

ies

Treatment

Com

parator

Stud

yconclusion

Num

berof

patients

repo

rtingadverse

drug

reaction

s(n/N

)

Treatment

(n/N

)Com

parator

(n/N

)Treatment

vs.

comparator

Forbes

etal.

[40]

Paracetamol

600mg?

codeine

60mg

A.k

etorolac

10mg,

B.k

etorolac

20mg,

C.ibuprofen

400mg,

D.p

aracetam

ol600mg,

E.p

lacebo

AllAEsweretransient,andnone

of

them

required

additionaltreatm

ent

20.0%

(8/

40)

A.1

2.8%

(5/

39)

B.1

8.6%

(8/

43)

C.1

8.6%

(8/

43)

D.1

2.2%

(5/

41)

E.0

%

20.0%

vs.

15.7%

Hellman

etal.[41]

I.codeine30

mg,

II.ibuprofen

200mg?

codeine

30mg,

III.acetylsalicylicacid

500mg?

codeine

30mg

NA

Codeine

alonecaused

ahigher

rate

of

AEsthan

incombination

s(17%

vs.

11%)

I.16.7%(8/

48)

II.1

0.6%

(5/47)

III.10.3%

(4/39)

NA

12.7%

vs.

0%

Petersen

etal.[42]

Ibuprofen

400mg?

codeine

60mg

Ibuprofen400mg

Incidenceof

AEswerehigher

in

ibuprofen?

codeinegroup

48.3%

(14/

29)

19.4%

(6/31)

48.3%

vs.

19.4%

186 Pain Ther (2020) 9:171–194

Table2

continued

Stud

ies

Treatment

Com

parator

Stud

yconclusion

Num

berof

patients

repo

rtingadverse

drug

reaction

s(n/N

)

Treatment

(n/N

)Com

parator

(n/N

)Treatment

vs.

comparator

Stubhaug

etal.[43]

Paracetamol

1000

mg?

codeine

60mg

A.tramadol

50mg,

B.tramadol

100mg,

C.p

lacebo

AEsweremorecommon

fortram

adol

treatm

entgroups

27.0%

(10/

37)

A.5

4.3%

(19/35)

B.5

0.0%

(18/36)

C.4

1.7%

(15/36)

27.0%

vs.

49.1%

Soulieret

al.

[44]

Paracetamol

300mg?

codeine

phosphate30

mg

Flurbiprofen

50mg

Differencesbetween2groups

werenot

statistically

significant

57.5%

(23/

40)

46.3%

(19/

41)

57.4%

vs.

46.3%

Inneset

al.

[45]

Paracetamol

600mg?

60mg

codeine

Ketorolac

10mg

Patientsin

theparacetamol

?codeine

groupreported

significantlymoreAEs;

7outof

60patientswithdrewfrom

thestudybecauseof

AEsafter7-day

treatm

ent

64.4%

(38/

59)

33.9%

(21/

62)

64.4%

vs.

33.9%

Daniels

etal.[16]

Paracetamol

2400

mg?

codeine

240mg

A.ibuprofen

2400

mg,

B.etoricoxib90

mg,

C.etoricoxib120mg,

D.p

lacebo

Significantlymorediscontinu

ations

due

toAEswereobserved

in

paracetamol

?codeinegroup

48.4%

(30/

62)

A.9

.4%

(18/

192)

B.1

1.0%

(21/191)

C.1

2.4%

(12/97)

D.1

3.0%

(6/

46)

48%

vs.

10.8%

Pain Ther (2020) 9:171–194 187

Table2

continued

Stud

ies

Treatment

Com

parator

Stud

yconclusion

Num

berof

patients

repo

rtingadverse

drug

reaction

s(n/N

)

Treatment

(n/N

)Com

parator

(n/N

)Treatment

vs.

comparator

Gatoulis

etal.(2

studies

included;

1.and2.)

[20]

Paracetamol

600mg?

codeine

phosphate60

mg

A.acetylsalicylicacid

1000

mg,

B.p

lacebo

There

wereno

statistically

significant

differencesregardingAEsandno

seriousAEswerereported

1.31.4%

(38/121)

A.2

8.3%

(34/120)

B.3

9.3%

(24/61)

31.4%

vs.

32.0%

2.24.5%

(57/233)

A.1

7.0%

(38/223)

B.1

8.4%

(19/103)

24%

vs.

17.5%

Mitchell

etal.[32]

Paracetamol

600mg?

caffeine

30mg?

codeine

60mg

Paracetamol

650mg?

ibuprofen

400mg

There

wereno

significant

differences

regardingAEswithintreatm

ent

groups,h

owever,d

iscontinuation

sdue

toAEswerehigher

inthecodeine

group

41.4%

(29/

70)

42.3%

(30/

71)

41.4%

vs.

42.3%

Differentcomparatorsweredifferentiated

withcapitalalphabeticalletters(A.,B.,etc.).‘‘Treatment’’denotescombination

therapywithcodeineor

codeinealone

nnu

mberof

patientsexperiencing

anadverseeffect,N

totalnu

mberof

patientsin

therespective

treatm

entgroup,

AEsadverseeffects

188 Pain Ther (2020) 9:171–194

by self-reporting of undesirable effects, includ-ing suggestive questioning regarding adversesymptoms, dependently on a study design.

Most of the performed single and multipledose studies included codeine in combinationswith paracetamol (65%), acetylsalicylic acid(25%) and ibuprofen (15%) usually for acutepain management including pre- and post-op-erative analgesia, headache and low-back pain.Only 3 from total of 20 evaluated studies (15%)were dealing with codeine containing anal-gesics being administered for up to 10 days, andthese were the studies regarding chronic cancerpain [30, 31], along with outpatient breast sur-gery study [32]. Comparators that were usedthroughout the studies were standard pain kill-ers such as paracetamol, nefopam, NSAIDs(ibuprofen, acetylsalicylic acid, ketorolac, flur-biprofen, etoricoxib, ketoprofen, piroxicam,and naproxen), opioids (tramadol) and placebo.

The list of all of the studies included in thesafety analysis is provided in Table 2.

The most commonly reported AEs, regardlessof study drug-relatedness, were: nausea, gas-trointestinal pain, constipation, dyspepsia,vomiting, dizziness, tiredness, headache, pho-tophobia, somnolence, dry mouth, euphoria,and faintness. The vast majority of them weremild or moderate in severity. There was noobserved difference regarding the incidence ofundesirable effects within the treatment groups,irrespective of acute vs. chronic pain treatment.Incidence of AEs reporting was shown to beconsistent, regardless of the patient’s age, raceand gender. However, study from Sagne et al.[35] indicates that AEs are more frequentlyexperienced by women taking codeine con-taining pain killers and that the frequency ofunwanted effects is probably weight-dependent.

Discontinuation due to AEs in both treat-ment and comparator group was observed in 10from total of 20 clinical trials (50%) and wasmore attributed to the treatment group whencomparing with the comparator group (10% vs.3%). It is worth mentioning that majority of theserious AEs were due to toxicity of the otherdrug in combination product, not to codeine(ibuprofen, acetylsalicylic acid, paracetamol).

In general, the safety profile of codeinecontaining analgesics in doses of 30 mg and

higher has been well characterised combiningthe results from clinical studies and extensivepost-marketing surveillance. Most of the repor-ted AEs were transient and mild to moderate inseverity. There were no deaths nor serious, drug-related AEs observed following treatment withcodeine.

Codeine Use Disorders

Codeine, acting as opioid receptor agonist, is asubstance with a well-known risk for substanceuse disorder (mild, moderate or severe) due toits conversion to morphine, usually when usedat higher than recommended doses for chronicpain treatment. Besides dose and duration ofcodeine use, a patient psychosocial characteris-tics (substance use disorder, previous experiencewith drugs, mental illnesses, etc.) are relevantfor the risk of codeine use disorder. Althoughthe liability for substance use disorder is lowerthan with stronger opioids, neuro-adaption andthe development of such disorder may appearfollowing inappropriate use of codeine. Themisuse of codeine is considered in case of takinghigher doses and/or for longer period thanadvisable. The potential for codeine use disordercannot be excluded when used for recreationalpurposes and in excessive doses [1, 46].

Due to the fact that codeine is the very oftenused either alone or in combo-preparation forpain relief, there is a growing concern regardingboth intentional and unintentional misuse ofcodeine-containing products. There are avail-able reports claiming both, low potential forsubstance use disorder and common issues inrelation with addictive-related disorders linkedto codeine use. Following search strategy withinthis systematic review, there were no ran-domised controlled clinical studies related tocodeine use disorder found. The prevalence ofcodeine use disorder is not likely to be deter-mined as most of the available evidence isaddressed within case study reports. Moreover,there is limitation regarding data fordoses\ 30 mg [1, 7, 46, 47].

Consumption of higher doses was evident inCanadian survey which involved 339 subjectswho had used codeine for 3 days/week for at

Pain Ther (2020) 9:171–194 189

least 6 months and where was found that 37%of subjects who have used approximately180 mg per day have met DSM-IV criteria fordependence [48]. Another big survey involvingtotal of 800 subjects compared characteristics ofdependent vs. non-dependent codeine users.Similar to findings from the study from Sprouleet al. [49], most of the dependent patientsreported family history of substance use disor-ders and long-term treatment for chronic pain.

Following review of EudraVigilance database,a total of 20 ICSRs (Individual Case SafetyReports) reporting dependence as a reactionwere identified with codeine as a suspect drug(as a single substance, not in combination) forthe time period since the January 2009 up untilJanuary 2019, for the European region. Addi-tionally, there were 3 cases reporting medica-tion overuse headache, while withdrawalsyndrome was recorded in 25 ICSRs wherecodeine was defined as a suspect drug [50].

For medicinal product containing codeinephosphate sesquihydrate or hemihydrate indose of 10 mg and in combination with parac-etamol, propyphenazone and caffeine for acutepain treatment, a total of 66 ICSRs were repor-ted for the Republic of Croatia (as found inEudraVigilance). A substance use disorder wasrecorded in 4 ICSRs and in most of the casesthere were missing information related to otherpossible suspect drugs [50]. It is worth men-tioning that during this 10 year period, in total,29,520,348 packages of such combined prod-ucts with low-dose codeine phosphate were soldin the territory of Croatia [51].

DISCUSSION

Acute pain is a common condition which needsadequate therapy. Non-steroidal anti-inflam-matory drugs, along with paracetamol andacetylsalicylic acid are the first line in combat-ing the pain of low to moderate severity. Addi-tionally, concomitant use of drugs fromdifferent classes has proved to be rational.Codeine, as a weak opioid agonist is a commoningredient of combination analgesic drugs.However, due to its opioid-like features, thecodeine-containing products are often tagged

with an increased risk of AEs, and with a risk ofsubstance use disorder development. It shouldbe noted that a vast majority of publishedstudies regarding codeine combinations arerelated to the higher doses of codeine (mostlyfor doses C 30 mg) with non-opiate analgesic,leaving a very large gap of evidence for thecodeine doses below 30 mg, which are oftenavailable as over-the-counter products.

Therefore, with this systematic review, wewanted to evaluate available data related to low-dose codeine efficacy and safety along with thepotential for codeine substance use disorderusing a comprehensive search strategy. Efficacyand safety differed in final decision on impor-tance of the founded studies, however withlimitations of only English studies and adultpopulation that were taken into consideration.In this systematic review, efficacy of low-dosecodeine (B 30 mg) combination medicinalproducts was analysed by reviewing the 16 pla-cebo-controlled, single-dose studies whichinvolved 3378 subjects suffering from differenttypes of acute pain. Out of 16 studies, 12 ofthem were based on statistically significantresults leading to the final conclusion that low-dose codeine combinations are more efficient inrelieving pain than the assigned comparator (asshown and referenced in Table 1). Four studiesout of 16 found codeine in combinations to beeither less effective than the comparator (twostudies) or to be ineffective altogether in paintreatment (also two studies).

Similar findings in terms of efficacy for low-dose codeine combinations (15–30 mg) havebeen presented in recently published systematicreview and meta-analysis which included 10randomized placebo controlled clinical trials.For the purpose of codeine safety analysis, andin contrast to Shaheed et al. [13], we haveextended our research and included respectivedata from EudraVigilance database along withavailable data from RTC, regardless of thecodeine doses.

This review assessed the overall safety ofcodeine, alone or in combinations, by reviewingthe 20 randomized clinical trials (as shown andreferenced in Table 2). These trials includedcodeine-treated subjects that received at leastone dose of codeine, ranging from 30 to 240 mg

190 Pain Ther (2020) 9:171–194

daily dose (with 60 mg single dose being themost represented one). Codeine containinganalgesics have shown good tolerability with nostatistically significant differences in adversereactions reporting among the treatment andthe comparator group (Table 2) It was alsodemonstrated that the most AEs are in rela-tionship with higher dose combinations (30 or60 mg of codeine per tablet).

In general, the safety profile of codeinecontaining analgesics in doses of 30 mg andhigher has been well characterised combiningthe results from clinical studies and extensivepost-marketing surveillance. When used asprescribed, for short periods of time and inrecommended doses (up to 240 mg daily), mostof the AEs are classified as mild to moderate inseverity.

The most common challenge faced withcodeine use is its well-known potential forsubstance use disorder. This is attributed to itsconversion to morphine, usually when used athigher doses than advised and for longer peri-ods of time (e.g. for chronic pain treatment).Although observed substance use disorder islower than with stronger opioids, the develop-ment of such disorder may appear following theinappropriate use, usually higher than recom-mended daily doses either recreationally orcontinuously for chronic pain treatment invulnerable patient population [1, 46].

Currently available reports can be foundwhich claim both, low potential for substanceuse disorder (mild, moderate, severe) and com-mon issues in relation with addictive-relateddisorders linked to codeine use. Followingsearch strategy within this systematic review,no randomised controlled clinical studies rela-ted to codeine use disorders were found. Theprevalence of codeine use disorder is not likelyto be determined as most of the available evi-dence is addressed within case study reports.Moreover, there is limitation regarding data fordoses\ 30 mg. Only findings that were foundfor codeine use disorder pertained to the higherdoses, with no exact and statistically significantdata. Most of the patients with codeine usedisorder have reported family history of sub-stance use disorders and long-term treatmentfor chronic pain.

CONCLUSION

This comprehensive systematic review hasfound low-dose codeine combinations to beeffective and safe when applied in recom-mended daily doses and for short periods oftime. There is no indication in the availableliterature which clearly links low doses ofcodeine (alone or in combination) to substanceuse disorder (low, moderate, severe) issues innon-dependent subjects. In fact, we have foundlow-dose codeine combinations to be safe, withmost of the adverse reactions reported as mildto moderate in severity. Publicly accessible datafrom European Medicines Agency also show avery small number of codeine use disorderadverse reactions as reported. However, tofinally eliminate issues related to low-dosecodeine in combination analgesic products,further well-designed clinical studies are war-ranted to provide more data relevant for effi-cacy, safety profile, and risk for substance usedisorder.

ACKNOWLEDGEMENTS

We thank Croatian Chamber of Pharmacists forall of their support.

Funding. This project and the journal’sRapid Service Fee was funded by a project by theCroatian Chamber of Pharmacists funded byPLIVA Hrvatska and Alkaloid AD Skopje.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Lidija Bach-Rojecky is a mem-ber of the Advisory Board at Alkaloid AD Skopje.Lidija Bach-Rojecky reports personal fees fromAlkaloid AD Skopje, PLIVA Hrvatska, SandozHrvatska, and Medis Adria for giving lectures,outside the submitted work. Ivan Celic reportsspeaking fees for the following companies:

Pain Ther (2020) 9:171–194 191

Alkaloid AD Skopje and Sandoz. Iveta Mercep,Anja Kos Petrak, Ana Soldo and Ana Bucan havenothing to disclose. Anja Kos Petrak is nowaffiliated with Makpharm Ltd., Pharmacovigi-lance Department, Zagreb, Croatia.

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 licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

REFERENCES

1. Nielsen S, Van Hout MC. Over-the-counter codeine-from therapeutic use to dependence, and the greyareas in between. Curr Top Behav Neurosci.2017;34:59–75. https://doi.org/10.1007/7854_2015_422.

2. Yaksh TL, Wallace MS. Opiods, analgesia, and painmanagement. In: Brunton LL, Hilal-Dundan R,Knollmann BC, editors. Goodman & Gilman’s: thepharmacological basis of therapeutics. New York:McGraw Hill Education; 2018. p. 355–85.

3. Crews KR, Gaedigk A, Dunnenberger HM, Leeder JS,Klein TE, Caudle KE, Haidar CE, Shen DD, Cal-laghan JT, Sadhasivam S, Prows CA, Kharasch ED,Skaar TC, Clinical Pharmacogenetics Implementa-tion Consortium. Clinical PharmacogeneticsImplementation Consortium guidelines for cyto-chrome P450 2D6 genotype and codeine therapy:2014 update. Clin Pharmacol Ther. 2014;95(4):376–82. https://doi.org/10.1038/clpt.2013.254.

4. Sekhri NK, Cooney MF. Opioid metabolism andpharmacogenetics: clinical implications. J Peri-anesth Nurs. 2017;32(5):497–505. https://doi.org/10.1016/j.jopan.2017.07.005.

5. Dean L. Codeine therapy and CYP2D6 genotype. In:Pratt V, McLeod H, Dean L, Malheiro A, RubinsteinW (eds) Medical genetics summaries. Bethesda:National Center for Biotechnology Information;2012. http://www.ncbi.nlm.nih.gov/books/NBK100662/. Acessed 31 May 2019.

6. He YJ, Brockmoller J, Schmidt H, Roots I, Kirch-heiner J. CYP2D6 ultrarapid metabolism and mor-phine/codeine ratios in blood: was it codeine orheroin? J Anal Toxicol. 2008;32(2):178–82.

7. Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S,Dayer P, Desmeules J. Codeine intoxication associ-ated with ultrarapid CYP2D6 metabolism. N Engl JMed. 2004;351(27):2827–31.

8. Bradley CM, Nicholson AN. Effects of a mu-opioidreceptor agonist (codeine phosphate) on visuo-motor coordination and dynamic visual acuity inman. Br J Clin Pharmacol. 1986;22(5):507–12.

9. Wardhan R, Chelly J. Recent advances in acute painmanagement: understanding the mechanisms ofacute pain, the prescription of opioids, and the roleof multimodal pain therapy. F1000Res. 2017;6:2065. https://doi.org/10.12688/f1000research.12286.1.

10. Cristalli MP, La Monaca G, De Angelis C, Pranno N,Annibali S. Efficacy of preoperative administrationof paracetamol-codeine on pain following impactedmandibular third molar surgery: a randomized,split-mouth, placebo-controlled, double-blind clin-ical trial. Pain Res Manag. 2017;2017:9246352.https://doi.org/10.1155/2017/9246352.

11. de Craen AJ, Di Giulio G, Lampe-SchoenmaeckersJE, Kessels AG, Kleijnen J. Analgesic efficacy andsafety of paracetamol-codeine combinations versusparacetamol alone: a systematic review. BMJ.1996;313(7053):321–5.

12. Mehlisch DR. The efficacy of combination analgesictherapy in relieving dental pain. J Am Dent Assoc.2002;133(7):861–71.

192 Pain Ther (2020) 9:171–194

13. Abdel Shaheed C, Maher CG, McLachlan AJ. Effi-cacy and safety of low-dose codeine-containingcombination analgesics for pain: systematic reviewand meta-analysis. Clin J Pain. 2019;35(10):836–43.https://doi.org/10.1097/AJP.0000000000000746.

14. Kim I, Barnes AJ, Oyler JM, Schepers R, Joseph RE Jr,Cone EJ, Lafko D, Moolchan ET, Huestis MA.Plasma and oral fluid pharmacokinetics and phar-macodynamics after oral codeine administration.Clin Chem. 2002;48(9):1486–96.

15. Cooper SA, Beaver WT. A model to evaluate mildanalgesics in oral surgery outpatients. Clin Phar-macol Ther. 1976;20(2):241–50.

16. Daniels SE, Bandy DP, Christensen SE, Boice J,Losada MC, Liu H, Mehta A, Peloso PM. Evaluationof the dose range of etoricoxib in an acute painsetting using the postoperative dental pain model.Clin J Pain. 2011;27(1):1–8.

17. Desjardins PJ, Cooper SA, Finizio T. Efficacy of lowdose combination analgesics: acet-aminophen/codeine, aspirin/butalbital/caf-feine/codeine, and placebo in oral surgery pain.Anesth Prog. 1986;33(3):143–6.

18. Forbes JA, Keller CK, Smith JW, Zeleznock JR,Sevelius H, Beaver WT. Analgesic effect of naproxensodium, codeine, a naproxen-codeine combinationand aspirin on the postoperative pain of oral sur-gery. Pharmacotherapy. 1986;6(5):211–8.

19. Frame JW, Fisher SE, Pickvance NJ, Skene AM. Adouble-blind placebo-controlled comparison ofthree ibuprofen/codeine combinations and aspirin.Br J Oral Maxillofac Surg. 1986;24(2):122–9.

20. Gatoulis SC, Voelker M, Fisher M. Assessment of theefficacy and safety profiles of aspirin and acet-aminophen with codeine: results from 2 random-ized, controlled trials in individuals with tension-type headache and postoperative dental pain. ClinTher. 2012;34(1):138–48. https://doi.org/10.1016/j.clinthera.2011.11.018.

21. Giglio JA, Laskin DM. Double-blind comparison ofmeclofenamate sodium plus codeine, meclofena-mate sodium, codeine, and placebo for relief of painfollowing surgical removal of third molars. J OralMaxillofac Surg. 1990;48(8):785–90.

22. Giles AD, Hill CM, Shepherd JP, Stewart DJ, Pick-vance NJ. A single dose assessment of an ibupro-fen/codeine combination in postoperative dentalpain. Int J Oral Maxillofac Surg. 1986;15(6):727–32.

23. Squires DJ, Masson EL. A double-blind comparisonof ibuprofen, ASA-codeine-caffeine compound andplacebo in the treatment of dental surgery pain.J Int Med Res. 1981;9(4):257–60.

24. Hwang DS, Mietlowski MJ, Friedman AP. Fiorinalwith Codeine in the management of tensionheadache: impact of placebo response. Clin Ther.1987;9(2):201–22.

25. Boureau F, Joubert JM, Lasserre V, Prum B, Dele-coeuillerie G. Double-blind comparison of an acet-aminophen 400 mg-codeine 25 mg combinationversus aspirin 1000 mg and placebo in acutemigraine attack. Cephalalgia. 1994;14(2):156–61.

26. Cater M, O’Brien PM, Pickvance NJ. A double-blindcomparison of the new ibuprofen-codeine phos-phate combination, zomepirac, and placebo in therelief of postepisiotomy pain. Clin Ther. 1985;7(4):442–7.

27. Heidrich G, Slavic-Svircev V, Kaiko RF. Efficacy andquality of ibuprofen and acetaminophen pluscodeine analgesia. Pain. 1985;22(4):385–97.

28. Pereira VBP, Garcia R, Torricelli AAM, Mukai A,Bechara SJ. Codeine plus acetaminophen for painafter photorefractive keratectomy: a randomized,double-blind, placebo-controlled add-on trial. Cor-nea. 2017;36(10):1206–12. https://doi.org/10.1097/ICO.0000000000001328.

29. Petti A. Postoperative pain relief with pentazocineand acetaminophen: comparison with other anal-gesic combinations and placebo. Clin Ther.1985;8(1):126–33.

30. Carlson RW, Borrison RA, Sher HB, Eisenberg PD,Mowry PA, Wolin EM. A multiinstitutional evalua-tion of the analgesic efficacy and safety of ketorolactromethamine, acetaminophen plus codeine, andplacebo in cancer pain. Pharmacotherapy.1990;10(3):211–6.

31. Minotti V, Patoia L, Roila F, Basurto C, Tonato M,Pasqualucci V, Maresca V, Del Favero A. Double-blind evaluation of analgesic efficacy of orallyadministered diclofenac, nefopam, and acetylsali-cylic acid (ASA) plus codeine in chronic cancerpain. Pain. 1989;36(2):177–83.

32. Mitchell A, McCrea P, Inglis K, Porter G. A ran-domized, controlled trial comparing acet-aminophen plus ibuprofen versus acetaminophenplus codeine plus caffeine (Tylenol 3) after outpa-tient breast surgery. Ann Surg Oncol. 2012;19(12):3792–800. https://doi.org/10.1245/s10434-012-2447-7.

33. Cooper SA, Engel J, Ladov M, Precheur H, Rosen-heck A, Rauch D. Analgesic efficacy of an ibuprofen-codeine combination. Pharmacotherapy. 1982;2(3):162–7.

34. Forbes JA, Kolodny AL, Beaver WT, Shackleford RW,Scarlett VR. A 12-hour evaluation of the analgesic

Pain Ther (2020) 9:171–194 193

efficacy of diflunisal, acetaminophen, and acet-aminophen-codeine combination, and placebo inpostoperative pain. Pharmacotherapy. 1983;3(2 Pt2):47S–54S.

35. Sagne S, Henrikson PA, Kahnberg KE, Thilander H,Bertilson SO. Analgesic efficacy and side-effectprofile of paracetamol/codeine and paracetamol/dextropropoxyphene after surgical removal of alower wisdom tooth. J Int Med Res. 1987;15(2):83–8.

36. Stambaugh J, Drew J. A double-blind parallel eval-uation of the efficacy and safety of a single dose ofketoprofen in cancer pain. J Clin Pharmacol.1988;28(s1):S34–9.

37. Sunshine A, Roure C, Colon A, Olson NZ, GonzalezL, Siegel C, Laska E. Analgesic efficacy of piroxicamin the treatment of postoperative pain. Am J Med.1988;84(5A):16–22.

38. Turek MD, Baird WM. Double-blind parallel com-parison of ketoprofen (Orudis), acetaminophenplus codeine, and placebo in postoperative pain.J Clin Pharmacol. 1988;28(s1):S23–8.

39. Forbes JA, Butterworth GA, Burchfield WH, YorioCC, Selinger LR, Rosenmertz SK, Beaver WT. Eval-uation of flurbiprofen, acetaminophen, an acet-aminophen-codeine combination, and placebo inpostoperative oral surgery pain. Pharmacotherapy.1989;9(5):322–30.

40. Forbes JA, Kehm CJ, Grodin CD, Beaver WT. Eval-uation of ketorolac, ibuprofen, acetaminophen,and an acetaminophen-codeine combination inpostoperative oral surgery pain. Pharmacotherapy.1990;10(6):94S–105S.

41. Hellman M, Ahlstrom U, Andersson L, Strid S.Analgesic efficacy of an ibuprofen-codeine combi-nation in patients with pain after removal of lowerthird molars. Eur J Clin Pharmacol. 1992;43(4):347–50.

42. Petersen JK, Hansson F, Strid S. The effect of anibuprofen-codeine combination for the treatment

of patients with pain after removal of lower thirdmolars. J Oral Maxillofac Surg. 1993;51(6):637–40.

43. Stubhaug A, Grimstad J, Breivik H. Lack of analgesiceffect of 50 and 100 mg oral tramadol after ortho-paedic surgery: a randomized, double-blind, pla-cebo and standard active drug comparison. Pain.1995;62(1):111–8.

44. Soulier SM, Page JC, Larsen LC, Grose BC. Theefficacy of ANSAID (flurbiprofen) as an analgesic infoot surgery. J Foot Ankle Surg. 1997;36(6):414–7(discussion 466).

45. Innes GD, Croskerry P, Worthington J, Beveridge R,Jones D. Ketorolac versus acetaminophen-codeinein the emergency department treatment of acutelow back pain. J Emerg Med. 1998;16(4):549–56.

46. Nielsen S, MacDonald T, Johnson JL. Identifyingand treating codeine dependence: a systematicreview. Med J Aust. 2018;208(10):451–61.

47. Shaheed CA, Maher CG, McLachlan A. Investigat-ing the efficacy and safety of over-the-countercodeine containing combination analgesics forpain and codeine-based antitussives. Woden:Government of Australia, Department of Health,Therapeutic Goods Administration; 2016.

48. Sproule BA, Busto UE, Somer G, Romach MK, SellersEM. Characteristics of dependent and nondepen-dent regular users of codeine. J Clin Psychophar-macol. 1999;19(4):367–72.

49. Nielsen S, Cameron J, Lee N. Characteristics of anontreatment-seeking sample of over-the-countercodeine users: implications for intervention andprevention. J Opioid Manag. 2011;7(5):363–70.

50. EudraVigilance (2019) Online access to suspectedside-effect reports https://bi.ema.europa.eu/analyticsSOAP/saw.dll?PortalPages. Accessed 24Sept 2019.

51. MIDAS� (IQVIA) (2019). Sales of codeine phosphatefor the territory of Croatia. Accessed Aug 2019.

194 Pain Ther (2020) 9:171–194