Systematic review

Identifying and treating codeine dependence:

a systematic review
Suzanne Nielsen1, Tim MacDonald2,3, Jacinta L Johnson4,5

odeine is globally the most frequently used opiate,1 and its

C
Abstract
consumption is increasing. In Australia, 27 780 234 packs
Objectives: Codeine dependence is a significant public health
of codeine-containing analgesics were supplied by problem, motivating the recent rescheduling of codeine in
community pharmacies during 2013, a rate of 1.24 packs per Australia (1 February 2018). To provide information for informing
person.2 In New Zealand, most of Canada, South Africa, clinical responses, we undertook a systematic review of what is
Ireland, and the United Kingdom, codeine is available over the known about identifying and treating codeine dependence.
counter, usually combined with simple analgesics such as Study design: Articles published in English that described
paracetamol or ibuprofen;3 until recently, it was also available people who were codeine-dependent or a clinical approach to
without prescription in Australia and France. Products con- treating people who were codeine-dependent, without
taining greater amounts of codeine are generally only available restriction on year of publication, were reviewed. Articles not
on prescription.3 including empirical data were excluded. One researcher
screened each abstract; two researchers independently
Codeine has low affinity for and intrinsic activity at m-opioid reviewed full text articles. Study quality was assessed, and data
receptors, and is considered a prodrug; its analgesic effects were extracted with standardised tools.
depend largely on its being converted to morphine by the Data sources: MEDLINE and EMBASE were searched for
polymorphic cytochrome P450 isoenzyme (CYP) 2D6.4,5 Genetic relevant publications on 22 November 2016. The reference lists
variability in the activity of CYP2D6 underlie interperson of eligible studies were searched to identify further relevant
differences in the analgesia achieved and the risk of opioid publications. 2150 articles were initially identified, of which
toxicity.6 Tolerance can develop after a relatively short period of 41 were eligible for inclusion in our analysis.
regular use.7-9 Data synthesis: Studies consistently reported specific
characteristics associated with codeine dependence, including
In view of the limited evidence that adding low dose codeine
mental health comorbidity and escalation of codeine use
(< 30 mg) to simple analgesics increases pain relief,10-15 the attributed to psychiatric problems. Case reports and series
variability in its metabolism, and the availability of opioids described codeine dependence masked by complications
with more predictable effects, the role of codeine in pain manage- associated with overusing simple analgesics and delayed
ment is contentious.16,17 detection. Ten studies described the treatment of codeine
dependence. Three reports identified a role for behavioural
The liability of codeine to be misused has been shown in a therapy; the efficacy of CYP inhibitors in a small open label trial
randomised, double blind, placebo-controlled drug adminis- was not confirmed in a randomised controlled trial; four case
tration study,18 and has been documented in several case series/chart reviews described opioid agonist therapy and
series.19,20 Although the prevalence of codeine dependence medicated inpatient withdrawal; two qualitative studies
is unknown, the harms associated with overuse are well identified barriers related to perceptions of codeine-dependent
established, including serious morbidity causing great cost to people and treatment providers, and confirmed positive
the health care system.21 perceptions and treatment outcomes achieved with opioid
agonist treatments.
Some harms associated with codeine overuse are directly Conclusion: Strategies for identifying problematic codeine use
related to prolonged intake, but many serious consequences are needed. Identifying codeine dependence in clinical settings is
stem from concomitant overconsumption of ibuprofen often delayed, contributing to serious morbidity. Commonly
or paracetamol in combination products.19 Sequelae of described approaches for managing codeine dependence
supratherapeutic ibuprofen ingestion secondary to codeine include opioid taper, opioid agonist treatment, and psychological
dependence that require intensive care have been described, therapies. These approaches are consistent with published
including several codeine-related deaths.22 As a result, access to evidence for pharmaceutical opioid dependence treatment and
over-the-counter codeine has been restricted or removed in with broader frameworks for treating opioid dependence.
Manitoba (February 2016), France (July 2017), and Australia PROSPERO registration: CRD42016052129.
(February 2018).23-25
In order to respond appropriately, we need to identify
MJA 208 (10)

people who are codeine-dependent. There has been greater Methods

awareness of dependence with the imminent rescheduling
of codeine in Australia. Both in Australia and internationally,
presentations to addiction treatment services have Search strategy
increased,26-28 but treatment approaches for codeine depen- We searched MEDLINE and EMBASE on 22 November 2016 for
j
4 June 2018

dence are poorly defined. The purpose of our systematic review the following terms: “codeine”, “dependence”, “substance-related
was to identify the characteristics of people who are codeine- disorders”, “opioid-related disorders”, “behaviour, addictive”,
dependent, and to define approaches for identifying codeine and “substance withdrawal syndrome” (online Appendix, table 1).
dependence. We restricted our search to human studies published in English;

1
National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW. 2 Currumbin Clinic, Gold Coast, QLD. 3 Griffith University, Gold Coast, QLD. 4 University of
South Australia, Adelaide, SA. 5 Southern Adelaide Local Health Network, Adelaide, SA. suzanne.nielsen@unsw.edu.au j doi: 10.5694/mja17.00749 j Published online 12/02/2018 451
Podcast with Suzanne Nielsen available at https://www.mja.com.au/podcasts
 Systematic review
there was no restriction on year of publication. The reference lists reported in a manner that enabled this approach. Meta-analysis
of eligible studies were searched to identify further relevant of treatment studies was not possible because of the heterogene-
publications. ity of study designs. When individual patient data were reported,
details were extracted at the patient level to enable synthesis of
One reviewer (SN, JJ or TM) independently examined the titles
patient characteristics.
and abstracts of identified articles. The full text of relevant articles
was independently assessed for inclusion by two authors, and
reasons for exclusion documented as appropriate. Inter-reviewer Results
disagreement about inclusion was resolved by consensus among
all three authors. Of the 2150 articles initially identified, 41 were eligible for inclusion
in our analysis (Box 1). The mean study quality score of the
Study inclusion criteria included articles was 3.0 (standard deviation [SD], 1.1).
We included studies that described people who were codeine-
dependent (identification studies) or any clinical approach for Identifying codeine dependence
treating people who were codeine-dependent (treatment studies). Fourteen reports described samples of patients who were
codeine-dependent (Box 2; online Appendix, table 4A); 22
Data extracted from identification studies included study charac- described presentations by individual patients (Box 3, Box 4; online
teristics (author, location, design, quality rating) and population Appendix, tables 4B and C). No studies reported developing an
characteristics (participant age, sex, employment, mental health, approach for identifying people with codeine dependence as an
pain and substance use history, adverse effects related to codeine aim, but two reported applying the Severity of Dependence Scale
use, and management of adverse effects). (SDS)32 for defining codeine dependence (cut-off score, 5).33,34
Treatment studies included randomised and non-randomised
controlled trials, quasi-experimental, before-and-after studies, Analyses of administrative data
prospective and retrospective cohort studies, caseecontrol studies, Three studies examined data from administrative sources on the
analytic cross-sectional studies, qualitative studies, and case treatment of people for opioid dependence.28,35,36 An Australian
reports and series. Treatment outcome measures included change study compared codeine-related treatment episodes with those for
in codeine use (days of use or amount used), retention in treatment, patients for whom another prescribed opioid or heroin was the
adverse events and other outcomes related to codeine use, opioid chief drug of concern. The proportion of women among those
dependence, and pain. treated for codeine dependence declined from 70% in 2002 to
47% in 2011; people for whom codeine was the drug of concern
Exclusion criteria were on average older and less likely to have a history of intrave-
Reports limited to describing the clinical applications or nous and illicit substance use than those treated for misuse of
pharmacology of codeine or other opioids, reports that did stronger prescription opioids or heroin.28 A study of codeine pre-
not separately report codeine-related data, and articles without scriptions in Norway found that 0.5% of all codeine recipients in
empirical data (eg, letters, commentaries, reviews) were excluded 2005 were likely to be using codeine problematically (annual pre-
(online Appendix, table 2). scription level exceeding twice the maximum daily dose for

Assessment of methodological quality

(identification studies)
1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses
The quality of descriptive studies was assessed with
(PRISMA) diagram of study selection
a modified version of the Joanna Briggs Institute
(JBI) Critical Appraisal Checklist for Analytical
Cross Sectional Studies.29 To enable application of
a single tool to all study methodologies, the JBI tool
was reduced from eight to five items, and an
item from the Evidence-Based Librarianship (EBL)
Critical Appraisal Tool for assessing sample bias
was added30 (online Appendix, table 3). The range
for total scores was 0e6, higher scores reflecting
higher quality.

Grading of evidence (treatment studies)

4 June 2018

Studies examining treatment approaches were

scored for quality according to GRADE criteria.31

Data collection
j
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Data were extracted with a standardised data

extraction tool into an Excel (Microsoft) spreadsheet.
The tool was piloted and reviewed before being
finalised.

Data synthesis
452 Findings were qualitatively and quantitatively
synthesised when population characteristics were
 Systematic review

2 Studies describing characteristics of people who were codeine-dependent

Sex Age Quality
Study Design, location Sample size, type (women) (years) rating
Sproule 199920 Survey, Canada 339 people who had used codeine 51% mean, 43.5 5
3 days/week for at least 6 months (range, 18e82)
Fredhein 200935 National prescription database, 385 190 people prescribed codeine 56% mean, 52.3 5
Norway during 2005 (SD, 18.8)
Frei 201019 Case series of patients who 27 treatment admissions for serious harms 48%
20 3
presented or were referred to from over-the-counter ibuprofenecodeine
hospital addiction medicine, products
Australia
Thekiso 201042 Retrospective chart review, 20 inpatients admitted with over-the- 65% mean, 49 4
Ireland* counter codeine abuse or dependence (SD, 23)
McAvoy 201140 Case series, New Zealand* 15 patients presenting for over-the-counter 46% mean, 44 3
codeine detoxification (range, 30e60)
McDonough 201141 Retrospective chart review, 32 people referred to hospital drug and 72% median, 38 2
Victoria alcohol services for excessive over-the-
counter codeine use (Sept 2005 e
Sept 2010)
Nielsen 201133 Online survey, Australia 137 people who met criteria for codeine 66% mean, 37 3
dependence (subset of 800 people (SD, 13)
reporting over-the-counter codeine use)
Cooper 201338 Qualitative interviews, United 25 participants recruited from internet 52% 20e60s 3
Kingdom* support groups
Nielsen 201339 Survey (qualitative research 20 codeine-dependent people 60% mean, 39 2
methodology), Australia (SD, 11)
Dada 201536 National administrative treatment 425 codeine-related admissions to 25% 11e70 2
dataset, South Africa alcohol and other drug treatment (20e39 years: 59%)
centres, 137 with codeine as drug
of primary concern
Nielsen 201528 Cross-sectional study of national 4424 codeine treatment episodes 70% (2002) mean, 36 2
administrative datasets, Australia 47% (2011)
Nielsen 201527 Retrospective chart review, 135 (53 codeine-dependent) 66% mean, 38 4
Australia* (SD, 8)
Qiu 201537 Caseecontrol study mapping 60 (30 codeine-dependent people, 30 7% mean, 25 2
brain differences, China controls)
Van Hout 201534 Qualitative interviews, Ireland* 21 participants recruited through drug 57% mean, 39 2
treatment centres (in treatment or in (range, 26e62)
recovery for over-the-counter codeine use)
SD ¼ standard deviation. * Study also included in Box 5 (treatment approaches). For further details, see online Appendix, table 4A. u

12 months); further, high dose prescribing of benzodiazepines was Caseecontrol study

more prevalent in this group.35 A South African study of national A prospective caseecontrol study described patients attending an
data on treatment for substance misuse (alcohol, pharmaceutical addiction medicine clinic in China who were dependent on a
and illicit drugs) found that 2.5% of admissions involved codeine, codeine-containing cough syrup.37 This imaging study found that
and that codeine was recorded as the primary substance of concern the patients, who exhibited increased impulsivity, had cortical
for 0.8% of patients.36 white matter microstructural abnormalities.37
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Quantitative convenience samples

Qualitative studies
Two studies included convenience samples of people who
Three qualitative studies have examined the perceptions of
reported using codeine. In an Australian web-based survey, 137
pharmacists and codeine-dependent people.34,38,39 A British
codeine-dependent participants were compared with 633 non-
author38 described the perception that dependence is not identified
dependent participants; characteristics associated with depen-
j

early, the challenges posed by the stigma attached to dependence,

4 June 2018

dence (assessed with the SDS) included taking higher than

the fact that codeine-dependent people saw themselves as different
recommended doses, experiencing psychological distress, previ-
to users of illicit opioids, and medical reasons for initiating codeine
ous drug treatment, and chronic pain.33 A 1999 Canadian postal
use.38 A recent Irish study similarly described social stigma as a
survey on prescribed and over-the-counter codeine (participants
treatment barrier, and reported emotional distress as a driver for
recruited via newspaper advertisements) found that 37% of
codeine use.34
respondents met DSM-IV criteria for codeine dependence, most
of whom reported chronic pain and family histories of substance Two typologies of codeine dependence have been 453
use problems.20 proposed:38,39 users who do not exceed therapeutic doses, and
 Systematic review

3 Individual patient reports: acute description or management of codeine-related harms

Location of patient
Study (age, sex) Harms from codeine use Details of codeine dependence Treatment
Faierman USA Hepatic injury with extensive fibrosis 16e20 ounces codeine cough Not reported
197350 (male, 30) attributed to terpin hydrate syrup daily
component of cough syrup, as
opposed to codeine
Wylie Scotland Elevated liver enzyme levels Up to 30  500 mg paracetamol/ Treated for potential hepatotoxicity
199464 (female, 37) 30 mg codeine phosphate per day with acetylcysteine; discharged
after 2 days
Dyer 200447 United Kingdom Perforated duodenal ulcer 3 years 30  200 mg Serum potassium corrected with
(male, 49) previously (inappropriate ibuprofen ibuprofen/12.8 mg intravenous potassium therapy;
use), hypokalaemia codeine in the 3 days before advised that Nurofen Plus misuse
admission. GP reported their taking caused his recurrent hypokalaemic
24 tablets at once previously episodes; offered assistance
Dutch Australia Anterior gastric antrum ulcer and 16e24  200 mg ibuprofen/12.8 mg Transferred to intensive care in
200846 (female, 39) 2.6 L of green turbid fluid in the codeine per day for 3 weeks another hospital
peritoneal cavity
Australia Gastric antrum ulcer with gross “A packet” of 200 mg ibuprofen/ Postoperatively, patient offered
(male, 41) abdominal contamination 12.8 mg codeine per day for one year inpatient drug treatment, absconded
before transfer arranged
Karamatic Australia Multiple jejunal ulcers with early 10  200 mg ibuprofen/12.8 mg 40 mg omeprazole, 15 mg
201153 (male, 42) structuring consistent with NSAID codeine phosphate per day mirtazapine daily; 5 mg oxycodone
enteropathy every 4e6 h as needed
Australia Multiple web-like strictures with 20  200 mg ibuprofen/12.8 mg Iron supplement
(female, 41) circumferential ulceration throughout codeine phosphate per day, 5 years
small bowel consistent with NSAID
enteropathy
Australia Multiple jejunal ulcers 10e12  200 mg ibuprofen/12.8 mg Omeprazole and amitriptyline daily;
(male, 41) codeine phosphate per day, hyoscine butylbromide, paracetamol
> 5 years and codeine and tramadol as
needed
Ng 201158 Australia Oesophageal erosions, benign gastric 20  200 mg ibuprofen/12.8 mg Electrolyte replacement
(female, 32) ulcer, enlarged, oedematous kidneys codeine phosphate per day
without nephrocalcinosis
Australia Progressive muscle weakness, low 24  200 mg ibuprofen/12.8 mg Electrolyte replacement,
(male, 37) serum potassium level, biochemical codeine per day buprenorphine maintenance therapy
features consistent with distal renal
tubular acidosis
Australia Microcytic anaemia, gastric antral 50  200 mg ibuprofen/12.8 mg Electrolyte replacement
(female, 45) ulceration with a peptic oesophageal codeine phosphate per day
stricture
Australia Generalised weakness associated 1.4e2.0 g ibuprofen in codeine Electrolyte replacement
(male, 40) with hypokalaemia, with distal renal combination product per day for
tubular acidosis 3 months
Page 201159 Australia Renal tubular acidosis, normal anion Longstanding misuse of ibuprofen Biochemical recovery of all patients;
(females, 35, 39; gap metabolic acidosis (5e18 g/day) and codeine two patients required intensive care
males, 41, 55) (320e1152 mg/day) in over-the- admission for central venous access
counter medications and potassium replacement
Lake 201356 Australia Small bowel stricture secondary to Up to 90  200 mg ibuprofen/ Exploratory laparotomy and small
(male, 35) NSAID, loss of partner and 12.8 mg codeine phosphate per day, bowel resection; patient controlled
employment clear salience and neuroadaptation concomitant ketamine use;
community drug treatment on
discharge
Roussin France Included depressive mood, and 120e200 mg codeine phosphate Not reported
4 June 2018

201361 (females, 38, 38, 42, constipation and vertigo in combination product with
47; males, 42, 55) paracetamol per day for 1e10 years
Ammit Australia Gastric erosion and renal tubular 520 mg/day (over-the-counter Symptomatic medication
201644 (female, 39) acidosis ibuprofen combination) for past (diazepam, paracetamol, baclofen);
j
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year; increased with physical and balloon enteroscopy/dilation (small

psychological stress bowel obstruction); education about
harms of ibuprofen. Following
admission: opioid substitution
therapy, counselling and 12-step
program
NSAID ¼ non-steroidal anti-inflammatory drug. For further details, see online Appendix, table 4B. u

454
 Systematic review

4 Individual patient reports: treatment of codeine dependence, with or without management of acute harms
Location
Study (sex, age) Harms from codeine use Details of codeine dependence Treatment and outcome
Gruber 194851 USA Neuroadaptation and decline in Intravenous codeine up to 4.8 g Reducing doses of intravenous
(male, 57) functioning, loss of weight, likely daily in weeks before codeine over 12 days; 100 mg
maintenance of chronic pain hospitalisation; 660 mg per day pethidine iv 4e6 times per day (days 3
symptoms, suicide following in previous months e11), acetylsalicylic acid injections
withdrawal (days 12e15)
Withdrawal syndrome tolerated with
some discomfort; committed suicide
after discharge
Vaughan 196763 New Zealand Renal failure (fatal) 8e12 aspirin/phenacetin/codeine Supportive therapy
(male, 53) tablets daily, several years
New Zealand Renal failure (fatal) 50 aspirin/phenacetin/codeine Symptomatic treatment for renal
(female, 39) tablets per week failure

New Zealand Analgesic nephropathy 8 aspirin/phenacetin/codeine

(female, 70) tablets per day, 20 years

New Zealand Possible medication overuse 6e20 aspirin/phenacetin/codeine Education on link between symptoms
(male, 28) headache tablets per day, 20 years and analgesic use; patient ceased
analgesics
Senjo 198962 Japan Suspected codeine use 10-year history of codeine use Inpatient stay (2 months); withdrawal
(male, 34) contributed to symptoms after 5 days codeine-free
obsessiveecompulsive Obsessiveecompulsive disorder
disorder in both patients improved after withdrawal
Japan 10-year history of codeine use Patient was violent after 2 days,
(male, 35) transferred to another hospital
Returned 2 months later with
complete remission of symptoms
Bedi 199145 India Dependence and opioid Two bottles Phensedyl (total Loperamide, diazepam, nitrazepam;
(male, 42) withdrawal symptoms content: 450 mg codeine, 366 mg supportive psychotherapy and family
ephedrine, 180 mg promethazine) counselling advocated; drugs reduced
per day over 10 days
Eng 199648 USA Medication overuse headache 6e15  paracetamol/codeine Detoxification (methadone); referral
(male, 54) tablets to anxiety disorders program
(diagnosed with GAD), CBT, taught
relaxation
Self-managed analgesic use (reduced
analgesic use to paracetamol twice a
week or less), developed alternative
strategies for psychological symptoms
Lake 200855 USA Transformation of episodic to 10 butalbital with codeine and Withdrawn from butalbital, codeine;
(female, 39) daily headache acetaminophen tablets per day coached in relaxation techniques.
for pain control for past year After multiple admissions: weekly
psychotherapy, formal substance
abuse program, observed urine drug
screens). CBT, pain
management.12-step program
Ongoing relapse, eventually ceased
substance use, diagnosed with
fibromyalgia and prescribed opioids
Evans 201049 New Zealand Acute gastric ulcer, severe More than 100  200 mg Reducing codeine dose prescribed;
(male, 35) gastritis and post-bulbar ibuprofen/12.8 mg codeine counselling
duodenitis with active bleeding phosphate per day for back pain Gastrointestinal symptoms healed,
but balloon dilation of pyloric stenosis
required
Robinson 201060 New Zealand 60e80  200
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Gastric ulcer, gastric bleeding, Treatment not reported

(male, 53) hepatotoxicity mg ibuprofen/12.8 mg codeine Many patients reported significant
phosphate per day, 2 years opioid withdrawal symptoms despite
treatment with ancillary medications
New Zealand Peptic ulcer and anaemia 48  200 mg ibuprofen/12.8 mg
j

(female, 31) codeine phosphate per day, 2 years

4 June 2018

New Zealand Gastric ulcer 20  200 mg ibuprofen/12.8 mg

(female, 63) codeine phosphate (and
prescription codeine) per day,
3 years
New Zealand “Inflammatory bowel disease” Up to 72  200 mg ibuprofen/
(female, 47) 12.8 mg codeine phosphate per
day, one year
(continued)
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 Systematic review

4 Individual patient reports: treatment of codeine dependence, with or without management of acute harms (continued)
Location
Study (sex, age) Harms from codeine use Details of codeine dependence Treatment and outcome
New Zealand Ileal resection Up to 80  200 mg ibuprofen/
(male, 52) 12.8 mg codeine phosphate per
day, one year
New Zealand Gastric ulcer and bleeding Up to 120  200 mg
(female, 31) (previous gastrectomy) ibuprofen/12.8 mg codeine
phosphate per day, 2 years
New Zealand Up to 48  200 mg
(male, 35) ibuprofen/12.8 mg codeine
phosphate per day, 2 years
Hard 201452 United Kingdom Neuroadaptation, exclusion of 10-year history of codeine GP changed from codeine to
(female, mid-20s) other activities, financial dependence (initially prescribed) dihydrocodeine as a harm
minimisation strategy
(approximately 2940 mg
dihydrocodeine daily). Buprenorphine/
naloxone (maintenance:
10 mg buprenorphine/2.5 mg
naloxone); engaged with recovery
support services and psychosocial
counselling; 12-step program
Initially mild precipitated withdrawal;
stabilised and returned to work
Marr 201557 Scotland Dependence Initially self-medication for dental Stabilised on 16 mg buprenorphine/
(female, 24) pain, escalated to prescribed and 4 mg naloxone, transferred to mono-
over-the-counter opioids product for pregnancy
Transferred to community
prescriber, reported stigma and
discomfort with drug treatment
clinic environment
Kean 201654 United Kingdom Neuroadaptation, relationship Codeine prescribed by GP for back Buprenorphine/naloxone induction
(male, mid-30s) disharmony, rebound headaches, pain, later supplemented with illicit (up to 8 mg/2 mg daily), tapered over
hypoalbuminaemia, ALT levels codeine, escalating over years to 4 months. Anxiety/depression at end
elevated 250 mg/day of taper responded to fluoxetine,
counselling
Abstinent, functioning and intact
relationships
Van Hout 201665 Ireland Estranged from family, unable to Use escalated from 12 to 24e48 Stabilised on 4 mg buprenorphine/1 mg
(female, 57) work, episode of haematemesis tablets per day over 3 years after naloxone, counselling every 2 weeks
fracture Continues treatment in pharmacy
setting; plan after 2 years to begin taper
Ireland Identified because of high volume Escalated use of over-the-counter Commenced buprenorphineenaloxone,
(female, 44) of sick notes (impact on codeine (about 36 tablets per day) venlafaxine for depression, propranolol
employment) at time of traumatic event for migraine and omeprazole for a
peptic ulcer
Stabilised on a 14 mg buprenorphine/
3.5 mg naloxone, migraines largely
resolved; soon after treatment,
antidepressant treatment ended.
Returned to work, planned reduction of
buprenorphine
Ireland Perforated ulcer requiring surgical Long history of over-the-counter Several failed detoxifications; attempts
(male, 45) repair, three later ulcers, multiple codeine misuse causing life- to stabilise on maintenance dose of
surgical admissions for epigastric threatening morbidity codeine failed. Prescribed
pain and gastrointestinal bleeding buprenorphine/naloxone
Overdosed on benzodiazepines,
4 June 2018

hospitalised, buprenorphine withdrawn.

After restabilisation, maintained on
12 mg buprenorphine/3 mg naloxone
Ireland Not specifically reported Escalating amounts of over-the- Buprenorphineenaloxone,
(male, 44) counter codeineeibuprofen (up to psychosocial interventions. Initial
j
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72 tablets per day) over several relapse (attempt to self-detoxify),

years recommenced on higher dose
Initially stabilised on maintenance dose
of 8 mg buprenorphine/2 mg naloxone
daily; recommenced and stabilised on
12 mg buprenorphine/3 mg naloxone
daily, ongoing counselling
ALT ¼ alanine transaminase; CBT ¼ cognitive behavioural therapy; iv ¼ intravenous. For further details, see online Appendix, table 4C. u
456
 Systematic review
codeine-dependent people who consume high doses of the described.19,27,34,38,40,43,69 The role of internet support groups38 and
drug. The second group is characterised by severe dependence psychosocial treatments, including cognitive behavioural therapy,
and harms. Additional typologies include recreational users39 were highlighted in some studies.42,67,69
and people who slightly exceed recommended doses.38
Two studies tested the hypothesis that preventing the
O-demethylation of codeine to morphine with CYP inhibitors
Retrospective chart reviews and case series would reduce codeine use.66,68 Initial promising results from
Five case series or retrospective chart reviews19,40-43 identified an open label pilot study of fluoxetine (14 subjects)66 were not
common features of people with codeine dependence, including replicated in a small randomised controlled trial that compared
higher proportions of women than among those treated for the effectiveness of fluoxetine or quinidine (two potent CYP2D6
misuse of other opioids, histories of problematic alcohol use, inhibitors) with placebo.68
mental health comorbidity, and serious side effects resulting from
using combination medicines containing codeine, including one A retrospective review of inpatient admissions described taper
death.41 Prior heroin dependence was rare. with clonidine and benzodiazepines, combined with an intensive
4-week mental health treatment program.42 Patients had a mean
stay of 42 days (SD, 23 days), with withdrawal symptoms requiring
Reports on individual patients treatment for a mean 16 days (SD, 10 days). Taper with bupre-
Twenty-two reports described 49 individuals who were codeine- norphine was described by an Australian study which noted that
dependent44-65 (Box 3, Box 4; online Appendix, tables 4B and 4C). codeine dependence was more likely to be treated with taper rather
Twenty-three were women (mean age, 42 years [SD, 9 years]). Of than maintenance.27 Relapse after taper was not uncommon.34,42
the 15 people for whom data on employment status were reported,
nine were employed. Acute harms and information on treatment A single arm study (11 patients) found that cognitive behavioural
approaches were described. Inherent to cases of acute harm were therapy could significantly reduce codeine use — six patients
complications attributable to the co-medications paracetamol and ceased using codeine altogether — and neuropsychological func-
ibuprofen, including distal renal tubular acidosis, hypokalaemia, tioning was improved by codeine reduction or cessation without
gastritis and other enteropathies, medication overuse headache, deterioration in pain or quality of life.67 A mixed methods study
hepatic necrosis, hypoalbuminaemia, microcytic anaemia, and also highlighted the role of psychological therapies.69
weight loss. In a case series of 27 patients,19 most had initiated Seven studies described treatment with opioid
codeine to treat pain but later escalated their intake for other agonists,19,27,34,38,40,43,69 four of which did not report
reasons; this was also reported in many case reports. outcomes.19,34,40,69 One small retrospective cohort study described
Acute management of harms was characterised by inpatient high retention rates for patients treated with buprenorphine over
hospital management of serious problems (often requiring inten- 28 days (median daily dose, 12e16 mg); one patient described
sive care) to restore electrolyte balance,47,58,59 manage gastroin- initial sedation that necessitated reducing the dose.43
testinal symptoms44,53 (including bowel resection),56 and to assess Two qualitative studies described positive experiences and
or treat hepatotoxicity.50,64 Opioid withdrawal was managed outcomes for treatment with methadone and buprenorphine,
with symptomatic medications and buprenorphine; potential despite patient concerns about the treatment experience and the
hepatotoxicity was managed with acetylcysteine.64 clinic environment.34,38
Psychiatric comorbidity in people with codeine dependence was According to GRADE criteria, the quality of evidence from
dominated by high prevalence conditions (depression and anxiety treatment studies was very low to low; most studies were
disorders).20,27,44,48,53,58,60,61 Some reports described prior or retrospective and descriptive, and all had small sample sizes.
comorbid addictions (benzodiazepines, opioids, alcohol),34,35,40,42,60
and mental health conditions.20,40-42,60 Bipolar disorder,27,42 Discussion
obsessiveecompulsive disorder,62 relationship breakdown,47
suicide behaviour,51,56 and bereavement or loss47 were also described. Our review of codeine-dependent people indicates that approxi-
mately equal proportions of men and women are involved; their
Individual patient reports described treatment approaches,
mean age is greater than for patients treated for problematic use of
including attempted self-management,45,65 use of symptomatic
other opioids, the prevalence of mental health comorbidity is high,
medications,60 prescribed codeine or dihydrocodeine49,52 or
identification of dependence is often delayed, and patients
buprenorphine and naloxone,52,54,65 and detoxification with
experience serious complications associated with excessive
methadone.48 Management of mental health symptoms with
consumption of combination products that include codeine.
antidepressants and behavioural therapies was described.48,54,55,65
Problematic codeine use was associated with mental health prob-
One notable case combined methadone taper, cognitive behav-
lems. The quality and methodology of the studies we assessed
ioural therapy, and relaxation strategies, enabling codeine cessa-
MJA 208 (10)

varied considerably, but their depictions of the features associated

tion and self-management of pain.48 Resolution of presenting
with codeine dependence were consistent, describing a clinically
complaints (obsessiveecompulsive disorder, medication overuse
challenging area in which under-reporting is highly likely. The
headache) after codeine cessation was described.62,63
reports highlight the importance of asking about the use of non-
prescribed analgesics in a range of health care situations, particu-
j
4 June 2018

Treatment studies larly when gastrointestinal complications are identified. The di-
Ten studies described treatment approaches in detail (Box 5; online versity of those affected and the high level of morbidity suggest
Appendix, table 4D). Common medication-based approaches that population level interventions are required for screening and
included taper from codeine with symptomatic medications prevention wherever codeine is available over the counter. Careful
such as clonidine or benzodiazepines,42,67 buprenorphine main- questioning about recent patterns of use, the reasons for taking
tenance,19,27 CYP inhibitors,66,68 and gradual self-managed taper.38 codeine, and withdrawal symptoms upon cessation may help
Positive outcomes for opioid agonist treatment (methadone and identify when a patient should be comprehensively assessed for an 457
buprenorphine with or without naloxone) were opioid use disorder.
 Systematic review

5 Treatment approaches for codeine dependence

Evidence
quality
Study Design, location Sample size (sex), age Treatment approach and outcomes (GRADE)
Romach 200066 Open label pilot 14 (36% women); mean, 41 20 mg fluoxetine per day as CYP2D6 inhibitor Low
trial, Canada years (SD, 6.6 years) (began to taper opioids over 8 weeks of active
treatment)
All patients reduced opiate use (range, by 30
e100%). Depressive symptoms also reduced
Fernandes Double blind, 30 assessed, 17 started All patients received brief behavioural therapy. Two Low
200268 randomised treatment (65% female), weeks of baseline monitoring were followed by
controlled trial, mean, 40 years (SD, 12 8 weeks of daily treatment with fluoxetine or
Canada years) quinidine (two potent CYP2D6 inhibitors) or placebo
No significant difference among the three groups in
daily codeine intake or depression scores. By end of
treatment, large decrease from baseline in mean
daily codeine use in all groups: placebo by 57%,
quinidine by 56%, and fluoxetine by 51%
Frei 201019 Case series, Australia 27 (48% female); 20 years Opioid pharmacotherapy (16 patients), Very low
or more buprenorphine taper (3), buprenorphine
maintenance (10), methadone (3). Outcomes not
reported
Nilsen 201067 CBT-based clinical 11 (82% women); mean, Two specifically trained physicians delivered six CBT Very low
trial 43 years sessions (verbal reattribution, behavioural
with partial or experiments), tapering codeine gradually within
complete 8 weeks
codeine reduction, Codeine use significantly reduced from mean 237 mg
Norway to 45 mg; six ceased codeine
Thekiso 201042 Retrospective chart 20 (65% female): mean, Treated for substance withdrawal with standard Very low
review, Ireland 49.2 years (SD, 23.4 years) pharmacological protocol-driven regimes,
underwent up to 4 weeks’ comprehensive inpatient
treatment. Withdrawal regime included tapering
benzodiazepines and clonidine. Affective
comorbidities also treated (pharmacological,
“psycho-education”
Mean length of stay, 42 days; mean length of
treatment for withdrawal, 16 days
Cooper 201338 Qualitative 25 (52% female); range, One-quarter received drug treatment (methadone, Very low
interviews, 20e60 years buprenorphine) from treatment service or GP. Online
United Kingdom support important for attempts to self-treat
buprenorphine and methadone often achieved to
positive outcomes — either on maintenance doses or
opiate free — despite initial reservations
Nielsen 201527 Retrospective chart 135 (53 codeine-dependent, Codeine dependence more likely to be treated with Very low
review, Australia 66% women; buprenorphine than methadone, withdrawal
mean, 38.6 years) management more common than longer term
pharmacotherapy. Outcomes not reported
Nielsen 201543 Retrospective chart 19 (84% female); mean, 41 Buprenorphine maintenance treatment by drug Very low
review, Australia years (SD, 9 years) treatment services, five as inpatients,14 as
outpatients
Median dose, 12e16 mg buprenorphine, four patients
continued to use opioids. buprenorphine doses
higher than estimated based on codeine dose
Van Hout 201534 Qualitative 21 (57% female): mean, 39 Methadone (14 patients), buprenorphine (3). Very low
interviews, years (range 26e62 years) Supportive medical care and a slow tapering of
Ireland codeine products or substitution.
Buprenorphine viewed particularly positively in
4 June 2018

removing craving and withdrawal effects. Relapse

with codeine tapering was common; attributed to
lack of effect on cravings and use of over-the-
counter codeine
Norman 201669 Mixed methods 23 interviews with key Buprenorphine and methadone in substitution Very low
j
MJA 208 (10)

(systematic review, experts therapy. Notes efficacy of CBT for treating

qualitative opioid dependence
interviews), Outlined “best practices” in treatment reported by
Ireland, United stakeholders, suggested “innovations” for treatment.
Kingdom, Did not assess treatments
South Africa
CBT ¼ cognitive behavioural therapy; CYP ¼ cytochrome P450; SD ¼ standard deviation. For further details, see online Appendix, table 4D. u

458
 Systematic review
Treatment approaches include self-management with internet pre-existing headache disorder by excessive intake of codeine —
support, psychological treatments, symptomatic medications for is another potential complication of codeine dependence.48,55,63
opioid withdrawal, and opioid agonist treatments. In particular, Data that might guide the management of codeine overuse
buprenorphine treatment undertaken according to current guide- headache specifically have not been published. Management of
lines was commonly described. Studies of opioid taper found that opioid-related medication overuse headache usually consists of
relapse was common (consistent with taper for opioid dependence patient education, opioid withdrawal, and the initiation of pro-
in general). Taken together, the treatment studies and case reports phylactic agents,76-78 often in an inpatient setting.76 Medication
provide evidence that opioid agonist treatments, combined overuse headache that results from overusing analgesics,
with psychosocial adjuncts, may be suitable and acceptable to compared with overuse of triptans, is associated with a greater
patients. The evidence, albeit low in quality, indicates that positive withdrawal headache duration (about 10 days),79 with mean-
treatment outcomes could be achieved with these approaches. ingful improvement only after 12 weeks or more,80 and high
relapse rates (eg, 71% at 4 years81).
In the absence of specific high quality evidence, judgements about
approaches for treating people with codeine dependence must be Limitations of our analysis
based largely on studies of opioid dependence. The effectiveness of
Comparing codeine dependence in different groups of patients
treatment with methadone and buprenorphine has been reported,
was made difficult by changing usage patterns over time,
and maintenance is more effective than withdrawal and detoxifi-
subgroup heterogeneity, and probable under-reporting
cation for people who are dependent on pharmaceutical opioids70
of codeine use. Methodological constraints included low partici-
or opioids in general.71 Research on selecting patients for treat-
pant numbers, selection biases (admissions, help-seeking or
ment with opioid agonists is limited. According to the general
co-medication sequelae as a proxy for neuroadaptation to codeine),
principles of treatment, diagnosis of opioid dependence must first
and a lack of objective and standardised criteria for determining
be confirmed.72 A stepped care approach with less intensive
codeine dependence. Many studies employed internet-based
treatment (eg, taper, counselling) for low severity dependence is
recruitment or data collection,33,38 potentially limiting the
recommended by national guidelines.72 Patients who unsuc-
generalisability of findings to users without regular internet access,
cessfully attempt taper may be considered for maintenance opioid
but this might be offset by the ability to reach users who are other-
agonist treatment, which achieves better treatment outcomes
wise difficult to reach. Some studies did not specify whether codeine
than detoxification for pharmaceutical opioid dependence.71
was prescribed or obtained over the counter, but most reports were
Because of wide variations in codeine metabolism, predicting
concerned with over-the-counter codeine. Many studies that
opioid requirements with dose conversion tables is challenging;43
included codeine-dependent people were excluded from our
for this reason their use is discouraged.
analysis because they did not separately describe codeine depen-
Psychological adjunct therapies can be beneficial,73 but the role of dence; this particularly applied to studies of medication overuse
psychosocial interventions as accompaniments to opioid agonist headache. Nevertheless, our review is the most comprehensive
treatments requires further research.74 The high prevalence of mental synthesis of data on the phenomena of codeine dependence, and
health comorbidities and the preference of patients for online support we have described a range of potential treatment responses,
may indicate that online interventions for managing comorbidity including medication- and non-medication-based treatments.
may be useful. In general, the role of pharmacological treatments for
depression or anxiety at the start of treatment is unclear. It is Conclusion
recommended that comorbidities are assessed after a period of Codeine dependence can be identified by screening patients who
abstinence because of the potential for diagnostic uncertainty caused present with acute complications associated with taking combi-
by the acute effects of opioid toxicity and withdrawal.75 nation analgesics, and by routine questioning about over-the-
The treatment setting is also important. People consuming larger counter medication use. Common treatment approaches include
amounts of opioids together with sedatives (eg, benzodiazepines) detoxification and opioid agonist treatment. Clinical leadership in
are a population at greater risk, and referral to a specialist may be providing guidance about how to identify and treat individuals
required.72 Characteristics that may indicate that patients are with codeine dependence is required as a matter of public health.
appropriate for managing in primary care include being employed, Acknowledgements: Suzanne Nielsen holds a National Health and Medical Research Council Research
having social support, and not having another substance use Fellowship (1132433).

disorder or a history of illicit drug use. Competing interests: Suzanne Nielsen is a named investigator on untied educational grants from
ReckitteBenckiser and Indivior. Tim MacDonald has received honoraria, fees and professional
development resources from Servier, the Australian and New Zealand Mental Health Association, and
Medication overuse headache Healthe Care; he works in the private sector and receives income for clinical services.
Headache is a common reason for initiating codeine use
Provenance: Not commissioned; externally peer reviewed. -
by patients who develop dependence.19,61 Paradoxically, medi-
MJA 208 (10)

cation overuse headache — in this context, exacerbation of a ª 2018 AMPCo Pty Ltd. Produced with Elsevier B.V. All rights reserved.
j
4 June 2018

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