1. health and fitness
2. addiction

Codeine Misuse
and Dependence
Factsheet for Healthcare Professionals
CODEMISUSED is a European Union funded project looking into Use, Misuse and
Abuse of Codeine. Research has been undertaking in the Republic of Ireland, the
United Kingdom and the Republic of South Africa.
The misuse of opioid containing pharmaceuticals is of
growing global concern. It is driven by a host of factors,
including marketing strategies, inappropriate
prescribing, public perceptions of safety, access to other
illicit sources, self-medication of pain and recreational
popularity. [1-6]Opioid use is commonly associated with
lower educational attainment, unemployment, disability,
comorbidity, history of problematic substance use and
suicide. [7]
Codeine is a widely used opioid worldwide, with
different countries regulating its supply to different
extents. Some governments only permit its supply on
prescription, whereas it is common to allow purchase
from pharmacies in limited doses and quantities. The
legislation has been tightened more recently in some
areas as a response to the growing diversion of codeine
containing pharmaceuticals for illicit purposes.
There is growing concern about risk/ benefit ratio with
questions whether it has any place remaining in
therapy. [8] Codeine is a pro-drug that is metabolized by
the enzyme CYP 2D6 in the liver to morphine. Codeine
itself has very little intrinsic pain relieving activity. The
metabolism rate varies in people according to their race
or geographical location (see table 1). There is
considerable concern about unltra-rapid metabolizers
as it leads to sudden high levels of morphine in their
blood, which can lead to respiratory depression and
other adverse effects. Conversely slow metabolizers
often do not obtain adequate pain relief as they only
achieve sub therapeutic
blood concentrations of
morphine.
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Risk Factors for
Misuse
History of
Substance and
Alcohol Abuse
History of
Chronic Pain
Request for
replacement
prescriptions
Multiple
appointments
with different GPs
Purchasing of
medicines from
pharmacies to
supplement
prescription
medication
Using other
peoples
medication
Table 1 [9]
Ethnicity
African
Asian
Ultra-rapid
metabolisers
5-30%
1.2% to 2%
Caucasian
3.6% to 6.5%
Slow
Metabolisers
0-20%
No data
found
7-10%
There is no consensus in the literature about the definitions of misuse and abuse. We
think the following will be helpful:
Misuse
‘The problematic consumption of codeine where risks and adverse consequences outweigh
the benefits, and which includes use of codeine with or without prescription, outside of
acceptable medical practice or guidelines, for recreational reasons, when self-medicating,
with higher doses and for longer than advisable’. [10]
Abuse
‘A pattern of maladaptive substance use that is associated with recurrent and significant
adverse consequences’. (American Psychiatric Association 2000)
Pharmaceutical forms of Codeine are increasingly being diverted for illicit use. There are
different ways of obtaining Codeine such as:
 family sharing, when the drug is passed onto family members or friends
 doctor and pharmacy shopping, where different healthcare professionals are
accessed to obtain excessive amounts
 and the black market.
‘Tampering’ with pharmaceutical forms of Codeine is increasingly common in order to
extract Codeine or to produce other related substances of abuse, for example:
 Cold Water Extraction
- Easy home-based method utilizing the different solubility of paracetamol
and codeine in cold water. This allows the extraction of nearly pure
codeine from co-codamol preparations.
 Krokodil
- Home-made substance derived as a replacement for herion in Russia
from readily available chemicals and pharmaceutical forms of codeine. A
highly addictive substance containing Desomorphine and impurities
which causes devastating health outcomes. [11] [12]
 Purple Drank
- There are different home-made mixtures containing codeine cough
syrups, alcohol, soft drink or energy drink and possibly other substances
such as promethazine. [13]
 Home bake
- Home-made form of heroin produced from pharmaceutical forms of
codeine. Particularly seen in New Zealand. [14] [12]
Consequences of Misuse
Adverse Effects
Chronic use can cause dependency which leads to patients
taking higher doses to achieve the same effects and avoid
withdrawal symptoms such sweats, runny nose, anxiety,
muscle cramps, nervous tremor, diarrhoea.
Our search of the literature has revealed a number of further
consequences of codeine use and misuse.
Normal Side
Effects
In common with
other opioids
Codeine can
cause range of
side effects with
normal use. The
most common
are: drowsiness
and cyclomotor
impairment,
nausea and
vomiting,
constipation,
itching and
rarely, breathing
difficulties.
Impairment
Injury
There is weak evidence that suggest that
codeine can lead to psychomotor impairment.
[15] This has consequences for driving and
performing other complicated tasks. One
study compared the volume and weight of
bilateral corpus striatum in codeine cough
syrups addicts to healthy subjects and found
reduced values. [16] Scans suggested
alteration in a dopaminergic system
responsible for cognitive and motor action.
Another study found that driving test
parameters and a psychomotor-vigilance test
correlated with morphine and codeine blood
concentrations. [17]Further research is
required to confirm these findings.
Increase
risk of
injury as a result of using codeine medication
was found in two papers, one in an older
population and one in the normal population.
[18]It is possible that comorbidities such as
rheumatoid and osteoarthritis are confounding
factors in these studies. Further research is
required.
Adverse Health Effects
A number of case reports have reported
adverse health effects which were considered
to be chronic or life threatening. Two papers
reported adverse effects on neonate following
administration of prescribed co-codamol to
the mother post-partum. Both mother and
infant are found to be fast metabolizers of
codeine [19] This added to reports of death of
children in the USA post tonsillectomy. This
led to medicines control agencies around the
world issuing recent guidance on the use of
codeine such as Medicines and Healthcare
Product Regulatory Agency (MHRA) in the
UK, found on page 4.
Latest MHRA Guidance
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Those who use opiates often experience
psychiatric disturbances. One paper found
that a number of patients were admitted with
psychiatric disorders including psychosis and
affective episodes following abuse of codeine
containing cough syrups. [20]
Rare reports of acute pancreatitis are in the
literature following repeated high doses use
of codeine. All patients recovered after the
codeine was stopped. One case was
readmitted after resumption of codeine
taking.
There are reports of chronic headaches after
prolonged misuse. Cellular changes were
noted in one study. [21]
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Combined Preparations
Codeine is frequently taken as a combination
product with either paracetamol or ibuprofen.
Its addictive potential means that patients can
expose themselves to high doses and
prolonged use of these other substances.
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Hypokaleamia and gastro-intestinal problems
have been reported due to overuse of
codeine/ibuprofen preparations. [22] [23, 24]
Dependence
Overall the number of studies examining dependence on
codeine is small, the majority of the research identified looks
specifically at opioids as a group of medication and it is often
hard to ascertain the extent of the problem. Severe
dependence on opioids appears to be part of a multiple
substance misuse pattern and more research is required to
evaluate the role of codeine in development of dependency.
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Codeine should only be used to
relieve acute moderate pain in
children older than 12 years and only
if it cannot be relieved by other
painkillers such as paracetamol or
ibuprofen
Codeine is contraindicated in all
children (ie, younger than 18 years)
who undergo tonsillectomy or
adenoidectomy (or both) for
obstructive sleep apnoea
Codeine is not recommended for use
in children whose breathing might be
compromised, including those with:
neuromuscular disorders; severe
cardiac or respiratory conditions;
upper respiratory or lung infections;
multiple trauma; or extensive surgical
procedures. The symptoms of
morphine toxicity may be increased
in these settings
In children age 12–18 years, the
maximum daily dose should not
exceed 240 mg. This may be taken in
divided doses, up to four times a day
at intervals of no less than 6 hours. It
should be used at the lowest effective
dose for the shortest period. Duration
of treatment should be limited to 3
days and if no effective pain relief is
achieved, treatment should be
reviewed by a physician
Information should be given to
parents and caregivers on how to
recognise the signs of morphine
toxicity, and advice should be given
to stop giving the child codeine and to
seek medical attention immediately if
their child is showing these signs or
symptoms
Symptoms of codeine toxicity
include: reduced levels of
consciousness; lack of appetite;
somnolence; constipation; respiratory
depression; ‘pin-point’ pupils; or
nausea and vomiting
Codeine is contraindicated in all
patients of any age known to be
CYP2D6 ultra-rapid metabolisers
Codeine should not be used by
breastfeeding mothers because it can
pass to the baby through breast milk
and potentially cause harm
Funding Acknowledgement
The research leading to these results has received funding from the European Community's Seventh Framework Programme
FP7/2007-2013 under grant agreement no 611736.
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