Risk of overdose and death following codeine prescription among immigrants
Joel G. Ray, MD, MSc1,2,3
Simon Hollands, MSc1,3
Tara Gomes, MHSc1
Marcelo Urquia, PhD1,2,3
Erin M. Macdonald, MSc1
Ping Li, PhD1
Muhammad M Mamdani, PharmD, MA, MPH1,2,3
David Juurlink, MD PhD1,2
for The Canadian Drug Safety and Effectiveness Research Network
1
Institute for Clinical Evaluative Sciences,
University of Toronto, Toronto, Ontario
2
Department of Medicine,
University of Toronto, Toronto, Ontario
3
Keenan Research Centre, Li Ka Shing Knowledge Institute,
St. Michael’s Hospital, Toronto, Ontario
Contact:
Joel G Ray
Department of Medicine, St. Michael’s Hospital
30 Bond Street
Toronto, Ontario
M5B 1W8
Tel: (416) 864-6060, Ext 77442
Fax : (416) 864-5485
e-mail: rayj@smh.ca
ABSTRACT COUNT: 285
MAIN WORD COUNT: 3234
1
Abstract
Background: Immigrants may be at higher risk of adverse drug reactions, in that poor language
proficiency reduces one’s understanding of drug label instructions. Additionally, there are
reports of severe or fatal toxicity due to CYP2D6 ultrarapid hepatic metabolism of codeine to
morphine among some ethnic groups, especially those from Eastern Africa.
Methods: Between 2002 and 2012 we conducted a population-based cohort study among
residents of Ontario, Canada. We used administrative health databases that linked both
immigrants and Canadian-born individuals to both prescription medication use and emergency
department visits and hospital admissions. The primary composite outcome was the risk of drug
overdose or all-cause mortality within 30 days of codeine prescription, comparing patients from
various world regions to Canadian-born individuals. A secondary analysis stratified by codeine
dose and ability to speak English and/or French.
Results: There were 553,504 individuals exclusively prescribed codeine. Relative to an
incidence rate of 57.1 per 100,000 persons-days among Canadian-born codeine recipients, those
who migrated from various World regions were at lower risk of drug overdose or death. For
example, Eastern Africans had an adjusted hazard ratio (HR) of 0.60 (95% confidence interval
[CI] 0.31 to 1.17) upon controlling for potential confounders such as age, sex, income and
physician visits. Patients unable to speak English or French who were prescribed codeine were at
lower risk of the composite outcome relative to those proficient in either language (adjusted HR
0.63, 95% CI 0.54 to 0.74).
Interpretation: Overdose and death following the institution of codeine therapy is not more
commonly observed among immigrants from world regions with a high prevalence of ultrarapid
CYP2D6 status relative to those born in Canada. Lower proficiency in English or French also did
not appear to heighten that risk.
Keywords: Codeine, opioids, immigration, ethnicity, overdose, toxicity, cytochrome P4502D6,
CYP2D6 polymorphism, language ability, literacy.
2
Introduction
The avoidance of medication-related errors, including opioid overdose, is an ongoing
international priority <1,2 >. Adverse drug events are common among all age groups, even
among those who are appropriately dosed <3,4>. Patients with low literacy are more likely to
misunderstand prescription medication label instructions than those with adequate literacy <5,6>.
Some new immigrants to countries like Canada, the US and the UK may have less health literacy
because of a different mother tongue, with difficulty following verbal or written information
<7,8>. This may increase the risk of adverse drug events.
For many drugs, susceptibility to adverse drug events also has a biological basis, arising from
differences in hepatic drug metabolism. For example, several reports suggest an increased risk of
severe or fatal opioid toxicity due to enhanced conversion of codeine to morphine among some
non-white ethnic groups, resulting up to a 45-fold increase in the O-demethylated codeine
metabolites, namely, morphine, morphine-3-glucuronide and morphine-6-glucuronide <9,10>.
The enzyme responsible for the O-demethylation to morphine has been identified as cytochrome
P450 isoform 2D6 (CYP2D6) <11>. This polymorphism has a prevalence of 1 per 100 Chinese,
Japanese and Hispanic individuals, 3 per 100 African Americans, and 16 to 28 per 100 persons
of North African, Arab or Eastern African descent <12>. Since codeine is frequently
recommended as a first-choice agent for the treatment of acute or chronic pain, it is of
importance to know whether it has a differing safety profile among various ethnic groups.
There are no epidemiological analyses of the risk of fatal or severe adverse events following
codeine prescription among immigrants, or in relation to their language facility <13>.
Accordingly, we completed a large cohort study of fatal or near-fatal events in opioid-naïve
children and adults newly prescribed codeine, in relation to their world region of origin as well
as their spoken language ability.
Methods
We completed a population-based cohort study in the province of Ontario, Canada. These
individuals had universal access to physician services, hospital care and prescription drug
coverage. The study was approved by the Research Ethics Board of Sunnybrook Health Sciences
Centre, Toronto, Canada.
3
Data sources
We used administrative health databases housed at the Institute for Clinical Evaluative
Sciences (ICES) to identify all study variables. Patient level records in these data sources are
deterministically linked using a unique anonymized identifier. We used the Registered Persons
Database (RPDB) to determine date of birth, sex, postal code and death date (where applicable),
and the Canadian Institutes of Health Information Discharge Abstract Database (CIHI-DAD) to
identify all hospital admissions and discharges using the Canadian International Classification of
Diseases Version 9 (ICD-9) and Version 10 (ICD-10-CA) coding. The Ontario Health Insurance
Plan (OHIP) Database was used to capture all claims for physicians’ services, including the
claim date and diagnosis. Emergency department visits were identified using the CIHI National
Ambulatory Care Reporting System (NACRS) database from July 1, 2000 onward. The Ontario
Drug Benefit Database captures all medication prescriptions for Ontarians aged 65 years and
older, along with younger people deemed eligible for social assistance because of
unemployment, disability, high prescription drug costs relative to net household income and/or
receipt of long-term care or home care services.
The Citizenship and Immigration Canada (CIC) Database contains landing records for every
permanent legal immigrant to Canada who arrived from 1985 onward, including landing date,
country of origin, entry class (Family Class, Refugee Class, Economic Class and Other),
occupational skill level, language ability and educational level at the time of landing. The
MOMBABY dataset uses all DAD inpatient admission records of delivering mothers and their
newborns from fiscal year 2002/03 onward and links mothers and their newborns
deterministically based on the maternal/newborn chart number. The linked MOMBABY dataset
captures all live births in Ontario, such that a child’s ethnicity can be identified according to its
mother’s World region of origin. Income quintile and rurality were defined according to postal
code using Statistics Canada census data.
Participants
Between April 1, 2002 and February 28, 2012, we included individuals aged 6 months to 100
years who had OHIP eligibility for 6 months or longer and were enrolled in the Ontario Drug
Benefit Program at least 6 months preceding the index event. We excluded anyone with any prior
diagnosis (inpatient or otherwise) of drug overdose or drug dependence within 24 months of the
4
index prescription date (see Supplemental File 1 for related diagnostic codes based on the
International Classification of Diseases, 9th [ICD-9] and Tenth [ICD-10] Revisions). To create
an inception cohort of new users, we also excluded those prescribed codeine, another opioid, or
an NSAID within the 6 months preceding the index prescription date.
Exposure
Among eligible participants, we evaluated those newly prescribed oral codeine, in the form of
codeine with or without acetaminophen. Among this cohort, we assessed their World region of
birth, as follows: 1) Canada (including those who may have immigrated prior to 1985), 2)
Southeast Asia, 3) Other Western nations, 4) Caribbean, 5) Eastern Africa, 6) Western, Middle &
Southern Africa, 7) North Africa & Middle East, 8) Latin America and 9) South Asia
(Supplemental File 2). Western, Middle & Southern Africa were grouped together a priori. A
child born in Ontario was defined by the country of origin of his/her mother, since she would be
expected to fill the prescription, follow the instructions and administer the medication.
From the eligible participants not prescribed codeine, we considered, as a tracer exposure
group, those newly prescribed an oral NSAID, as a non-opioid analgesia. Among this cohort we
again assessed their World region of birth. The NSAID group was created because, like codeine,
they are prescribed as an oral analgesia, but NSAIDs are otherwise not associated with
respiratory depression, and they do not undergo CYP2D6 ultrarapid metabolism that might result
in overdose. Hence, the NSAID tracer approach allows one to explore whether the risk
associated with codeine prescription is distinct, and not shared by another commonly prescribed
non-opioid analgesic agent.
New codeine users, and separately, new NSAID users, were further grouped by their selfdescribed ability to speak English and/or French (Canada’s official languages) at the time arrival
of immigration to Canada. Canadian-born participants were assumed to be either English or
French speaking.
Outcomes
The main study outcome was a composite of any drug overdose or death from any cause within
30 days of index analgesic prescription. Death was determined using the RPDB, and drug
overdose was identified by an Emergency Department diagnosis or an admitting diagnosis at
5
hospitalization (see Supplemental File 1). In secondary analyses, each outcome was examined
individually.
Data analysis
Each participant was followed for 30 days from the index prescription of either codeine or an
NSAID. Individuals who changed from one drug class to the other were censored on that date to
maintain exclusive exposure to one of two drug groups. Baseline participant characteristics were
compared using standardized differences, which are more meaningful than P values for large
samples.
For the main analysis, we calculated the incidence rate of overdose or death within 30 days of
an index prescription of codeine, per 100,000 person-days. We used multivariable Cox
proportional hazards regression to derive a hazard ratio (HR) and 95% confidence interval (CI)
comparing each drug exposure-World region of origin exposure to the Canadian-born-NSAID
group (the referent). The HRs were adjusted for age at cohort entry (continuous, in years), sex,
income quintile, rural vs. urban location of residence, number of distinct medications prescribed
and physician visits within 12 months preceding cohort entry, being a child of an immigrant
mother, and prescription of a CYP2D6 inhibitor (fluoxetine, paroxetine, bupropion, quinidine,
cinacalcet, ritonavir or amiodarone) within 120 before and up to 30 days after the index
prescription of codeine or an NSAID. We repeated this same analysis for the NSAID tracer exposure
group.
We also separately analyzed the 30-day risk of overdose as well as all-cause mortality, again,
for the codeine- and NSAID-exposed cohorts.
For new codeine recipients, we stratified the main analysis by sex, age (< 50 years vs. ≥ 50
years), and codeine dose (< 30 mg or ≥ 30 mg per tablet). The 30-mg threshold was chosen
because it is the standard amount in Tylenol #3
Finally, we assessed the composite outcome among the codeine and NSAID cohorts,
respectively, comparing those who did not speak French and/or English to those who did (the
referent). The same covariates were used as in the main multivariable Cox proportional hazard
model.
All analyses were performed using SAS Version 9.3 (SAS Institute Inc. Cary, NC) and used an
alpha of 0.05 as the threshold for statistical significance. Data suppression was necessary when
6
there were five or fewer individuals per group, in compliance with institutional privacy
regulations.
Results
General cohort
We identified 553,504 persons newly prescribed codeine and 673,740 persons newly
prescribed an NSAID (Table 1). The mean age was 63.6 and 65.5 years, respectively, and 48%
of codeine users and 42% of NSAID users were male. In the preceding 12 months, there was an
appreciably higher mean (SD) number of physician visits among codeine (16.2 [15.1]) than
NSAID recipients (12.8 [11.7]) (Table 1). Among codeine recipients, 32% received a per-tablet
dose under 30 mg and 68% a per-tablet dose of 30 mg or higher, while nearly 30% of NSAID
recipients were prescribed a COX-2 inhibitor.
Overall, 50,247 of codeine (9.1%) and 77,248 of NSAID (11.5%) recipients were immigrants
from another world region or were born to a mother from that world region (Table 1). Among all
immigrants, their average duration of residence in Canada was about approximately 10 years,
and about half declared that they spoke neither English nor French at the time of immigration.
Main analysis
The 30-day rate of overdose or death was 57.1 per 100,000 persons-days among Canadian-born
persons prescribed codeine (Figure 1, squares). Relative to this group, the adjusted HR for the
30-day composite outcome was significantly lower among most immigrant groups compared to
Canadian-born persons. Exceptions to this were Eastern Africa (0.60, 95% CI 0.31 to 1.17), other
Western nations (HR 0.84, 95% CI 0.69 to 1.02) or Western, Middle and Southern Africa (HR
0.76, 95% CI 0.34 to 1.70), where no significant difference in study outcomes between groups
was observed (Figure 1). Similar effects were seen for the secondary outcomes of 30-day
overdose and all-cause mortality in the codeine group (Figure 1, squares).
Among the NSAID tracer cohort the incidence rate of the composite outcome was less frequent
than that observed in the codeine groups (Figure 1, circles). Among NSAID recipients, only the
Southeast Asian and South Asian immigrant groups were at significantly lower risk than the
Canadian-born group.
7
Sub-group analyses
The observed lower relative risk of the composite outcome among most immigrant groups
prescribed codeine was evident across all sub-group analyses (Figure 2). The lower HR was
slightly more pronounced among males (Figure 2, upper), those aged 50 years and older (Figure
2, middle), and those prescribed lower doses of codeine (Figure 2, lower).
Analysis by language
Codeine recipients who did not report speaking English or French at the time of immigration
were significantly less likely to experience the primary outcome of overdose or death (adjusted
HR 0.63, 95% CI 0.54 to 0.74) (Table 2). Among NSAID users, we also observed a lower risk of
the primary outcome among those without English or French as a spoken language compared to
those who spoke English or French (adjusted HR 0.44, 95% CI 0.42 to 0.58) (Table 2)
Discussion
In this study of 1.27 million individuals, immigrants were at lower short-term risk of overdose
or death following codeine prescription relative to Canadian-born individuals. In addition,
immigrants not proficient in English or French had a lower relative risk of adverse outcomes. In
the NSAID tracer cohort, only Southeast Asian and South Asian immigrant groups were at
significantly lower compared to their Canadian-born counterparts.
Some limitations of our work merit emphasis. Despite including 127,495 immigrants or their
offspring, there were instances in the stratified analyses in which data suppression was necessary
due to few events, or there was imprecision around the risk estimates. We only included persons
within the Ontario Drug Benefit Database. For Ontarians aged 65 years and older, this reflects
the entire eligible population. We also note that 7% of all codeine users age 50+ years were
immigrants, while the proportion of immigrants among those under age 50 years was 17.5%. As
seen in Figure 2, the number of Canadian-born persons aged 50+ years prescribed codeine was
about 4.5 times greater than that of Canadian-born persons under 50 years (N = 413,798 vs.
89,459), and for Southeast Asians it was about 5 times higher (N = 10,222 vs. 2003); yet, among
those from South Asia the corresponding ratio was only 1.4, Latin American 1.3, North Africa
and the Middle East 0.7, Eastern Africa 0.3, and the Caribbean 0.9. These differences certainly
reflect the fact that those born in Canada are older than many new immigrant groups. While the
8
majority of participants were over age 65 years, and we adjusted for age, income quintile and
rurality, we acknowledge that our data may not apply to non-seniors who purchase their
medications through self-pay or privately insured means. In addition, there may remain
unaccounted for differences between immigrant and non-immigrant individuals eligible for the
Ontario Drug Benefit Programme, related to unemployment or disability, for example. Together,
these limitations lend caution about drawing conclusions about the risk of codeine-related
overdose or death in the general adult population under age 65 years.
We excluded those prescribed an NSAID or any opioid in the preceding 6 months, or those
diagnosed with drug overdose or drug dependence within the prior 2 years. Within the 30-day
follow-up period, we also censored a participant if they were prescribed a medication from the
other exposure group, or were prescribed any non-codeine opioid. Thus, we maintained
exclusivity between the codeine and the NSAID tracer group.
We did not have data about the indication for initiation of codeine or NSAID. Thus, we cannot
exclude the possibility of confounding by indication, in which codeine or NSAID recipients from
one World region were generally more ill than those from another region. Even adjusting for the
number of physician visits does not directly deal with this issue. Since codeine is often combined
with acetaminophen (paracetamol), it is possible that some adverse outcome events herein were
related to the latter drug. A potentially toxic dose of acetaminophen in a 65 kg person -- 150
mg/kg -- would require ingestion of forty 250-mg tablets (about 10,000 mg), yet, in combination
with 15 mg of codeine per tablet would produce a 600 mg ingestion of the latter, certain to lead
to life-threatening respiratory depression.
We assumed that Canadian-born persons were fluent in English or French, and we knew
nothing about the ethnic composition of the Canadian-born persons. Among the immigrants in
our study, we only knew their declared fluency in one of these two official Canadian languages
at the time of their arrival, and not thereafter, nor did we possess information about their reading
literacy. Given that the median duration residence of the immigrants in our study was 10 years, it
can be assumed that a fair proportion gained enough language fluency to understand basic
medication instructions. Misclassification of the latter would have underestimated the true
observed association between language fluency and the risk of codeine-related overdose or
death.
9
We provide novel information about the risk of codeine-related overdose, including in relation
to race/ethnicity. A Medline search up to November 2013, limited to the title words "codeine"
and "overdose," generated just seven hits, none of which were controlled studies. In a recent
opinion piece, it was concluded "the risk of opioids stems primarily from these drugs, not from
patients." Certainly, our findings support the view that codeine too is associated with a higher
short-term risk of overdose than seen with NSAID use (Figure 1, top panel). A separate
unlimited search on Medline up to November 2013 with the terms ("codeine" and "overdose")
and ("ethnicity" or "immigration" or "immigrant" or "race") produced just one study, which
focused prescription patterns for hydrocodone and oxycodone, but not on adverse events <14>.
A limited number of studies have examined opioid prescribing patterns among racial groups in
the US, but they classified groups as White, Black, Hispanic, or Asian/Other, they did not assess
for adverse events, and codeine accounted for only 11% (n = 5600) of all opioids prescribed
<15>.
Our current findings also suggest that, compared to Canadian-born participants, the risk of
overdose or death is significantly lower among most immigrant groups identified by world
region of origin. This may conceivably be due to the healthy immigrant effect, in which
immigrants are more highly educated than the general population, and/or they maintain healthier
practices that places them at lower risk of disease. Another explanation may be that Canadianborn individuals partake in riskier behaviors, such as codeine misuse (even without a history of
drug dependence); that they combining of codeine with other prescribed or non-prescribed drugs,
including alcohol; that they have a greater tendency to overdose on other unmeasured drugs; or
they exhibit greater suicidal behavior using prescribed medications. In the 2005 cycle of the
Ontario Student Drug Use Survey of 7th to 12th graders, both illicit drug use and hazardous
drinking was lowest among first-generation youth, which increased with second and then third
generation Canadians <16>. This is reflective of the so-called “immigrant paradox”, in which
acculturation to one’s host country is predictive of increased health risks, such as substance use,
especially among young adults <17>. As we did not have specific information about the context
of the deaths or drug overdoses documented herein, including whether they were related to
codeine (or NSAID) use, or the generational status of the Canadian-born participants, we cannot
fully explain our findings with the current dataset.
10
We did not detect a higher risk of codeine-related adverse events among those originating from
North African, Middle Eastern or Eastern African regions, and who are thought to have the
highest prevalence of the ultrarapid CYP2D6 polymorphism <12,18>. About 29% of Ethiopians,
who originate from Eastern Africa, are believed to have the ultrarapid CYP2D6 polymorphism
<16>. Yet, there are more than 75 allelic variants of the CYP2D6 polymorphism, resulting in an
increase, reduction, or complete loss of activity <19> (See Table 3 in reference 12
[http://theoncologist.alphamedpress.org/content/11/2/126.full.pdf+html]). Systematic, population-based studies of the prevalence of
the ultrarapid CYP2D6 polymorphism, and its impact on drug handling, are lacking. Since
CYP2D6 is responsible for the metabolism of many commonly prescribed drugs, including
codeine <20>, there is a basis for future research in this area, using unbiased and representational
sampling methods. If ethnicity can aid in predicting who is at highest risk of a critical adverse
event following codeine prescription, then altered prescribing of codeine and substitution with
another analgesic agent could be done efficiently and avoid costly and impractical screening for
the CYP2D6 polymorphism. Until then, no recommendations should be made about “safer” drug
prescribing among specific immigrant or native-born ethnic groups, and we refer readers to a
recent clinical practice guideline about CYP2D6 genotyping and safe codeine therapy <21>.
While immigrants in our study were not at higher risk of overdose or death following codeine
prescription, it is surprising that those without proficiency in spoken English or French were also
at lower risk. Hence, more research is needed about the value of medication instructions among
specific immigrants or groups who speak or read another primary language <22>.
Licence for Publication.
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behalf of all authors, an exclusive licence (or non exclusive for government employees) on a
worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be
published in JECH and any other BMJPGL products and sublicences such use and exploit all
subsidiary rights, as set out in our licence (http://group.bmj.com/products/journals/instructionsfor-authors/licence-forms).
Competing Interest.
None declared.
Funding.
This project was supported by research funds from Canadian Drug Safety and Effectiveness
Research Network (CDSERN) and by the Institute for Clinical Evaluative Sciences (ICES),
which is funded by a grant from the Ontario Ministry of Health and Long-Term
11
Care (MOHLTC). The funders had no role in designing the study; collecting, analyzing, or
interpreting the data; writing the report; or in the decision to submit the article for publication.
Disclaimer.
This study was supported by the Institute for Clinical Evaluative Sciences (ICES), which is
funded by an annual grant from the Ontario Ministry of Health and Long-Term Care
(MOHLTC). The opinions, results and conclusions reported in this paper are those of the authors
and are independent from the funding sources. No endorsement by ICES or the Ontario
MOHLTC is intended or should be inferred.
Authors contributions:
 Ray: study concept, analysis and interpretation of the data, drafting of manuscript,
manuscript revision, approval of final version
 Hollands: analysis and interpretation of the data, drafting of manuscript, manuscript
revision, approval of final version
 Gomes: study design, analysis and interpretation of the data, approval of final version
 Urquia: study design, analysis and interpretation of the data, approval of final version
 Macdonald: study design, interpretation of the data, approval of final version
 Li: study design, analysis of the data, approval of final version
 Mamdani: study design, analysis of the data, approval of final version
 Juurlink: study concept, analysis and interpretation of the data, manuscript revision,
approval of final version
What is already known on this subject?
Immigrants may be at higher risk of adverse drug reactions due to poor language proficiency or
from severe or fatal toxicity due to CYP2D6 ultrarapid hepatic metabolism of codeine to
morphine.
What this study adds?
Immigrants were observed to be at lower short-term risk of overdose or death following
codeine prescription, relative to Canadian-born individuals. Immigrants not proficient in English
or French at the time of migration were at lower relative risk of overdose or death following
codeine prescription. Hence, no recommendations should be made about “safer” drug prescribing
among specific immigrant groups.
Figure legends
Figure 1. Risk of the composite outcome of drug overdose or all-cause mortality (top), overdose (middle) or
all-cause mortality (lower) within 30 days being newly prescribed an NSAID (circles) or oral codeine
(squares) according to World region of origin. Data are suppressed with 5 or fewer outcome events.
Figure 2. Risk of the composite outcome of drug overdose or all-cause mortality within 30 days being newly
prescribed oral codeine, according to World region of origin, stratified by sub-groups. Data are suppressed
with 5 or fewer outcome events.
12
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14
Table 1. Baseline characteristics of participants in the codeine and NSAID exposure groups
Codeine
(N = 553,504)
NSAID
(N = 673,740)
Standardized
Difference
Mean (SD)
≥ 50
≥ 66
Male
Income quintile (Q)
63.6 (20.7)
445,067 (80.4)
379,378 (68.5)
264,332 (47.8)
65.5 (17.2)
569,248 (84.5)
482,238 (71.6)
285,111 (42.3)
0.1
0.11
0.07
Q1 (lowest)
Q2
Q3
Q4
Q5 (highest)
Rural location
No. physician visits, 1 year prior to cohort entry
136,315 (24.7)
116,720 (21.2)
102,253 (18.5)
97,585 (17.7)
98,541 (17.9)
72,891 (13.2)
163,244 (24.3)
143,082 (21.3)
127,219 (19.0)
120,579 (18.0)
117,087 (17.4)
95,318 (14.2)
0.01
0.0
0.01
0.01
0.01
0.03
Mean (SD)
≥ 1 Visit
World region of origin
Canada
Southeast Asia
Other Western nations
Caribbean
Eastern Africa
Western, Middle & Southern Africa
North Africa & Middle East
Latin America
South Asia
No. (%) of offspring born to an immigrant mother
16.2 (15.1)
546,085 (98.7)
12.8 (11.7)
664,131 (98.6)
0.26
0.01
503,257 (90.9)
12,225 (2.2)
9,342 (1.7)
3,547 (0.60)
2,962 (0.50)
1,047 (0.20)
6,011 (1.1)
3,716 (0.70)
11,397 (2.1)
3,810 (0.70)
596,492 (88.5)
17,771 (2.6)
11,514 (1.7)
4,612 (0.70)
3,829 (0.60)
1,375 (0.20)
9,627 (1.4)
5,674 (0.80)
22,846 (3.4)
2,028 (0.30)
0.08
0.03
0.0
0.01
0.0
0.0
0.03
0.02
0.08
No. medications prescribed within 1 year prior to
cohort entry
Mean (SD)
≥ 1 prescription
Prescription of a recognized CYP2D6 inhibitor 120
before and up to 30 days after cohort entry
NSAID type
4.9 (4.9)
393,102 (71.0)
28,269 (5.1)
4.4 (4.3)
498,667 (74.0)
28,315 (4.2)
0.1
0.07
0.04
COX-2
Non-COX-2
Mean (SD) estimated codeine dose per tablet (mg)
--25.7 (7.5)
198,282 (29.4)
475,458 (70.6)
--
Low Dose (< 30 mg)
176,029 (31.8)
--
High Dose (≥ 30 mg)
377,475 (68.2)
--
Characteristic*
Age, years
0.11
15
Characteristic*
Median (IQR) length of time since arrival to Canada
Median (IQR)
Language ability at the time of immigration***
English only
French only
Both French and English
Neither language
Level of education at the time of immigration
Secondary or Less
Any education above secondary school
Codeine
(N = 553,504)
NSAID
(N = 673,740)
Standardized
Difference
10 (4-15)
9 (4-14)
0.08
23,926 (48.5)
526 (1.1)
617 (1.3)
24,256 (49.2)
38,214 (47.7)
908 (1.1)
980 (1.2)
39,951 (49.9)
0.03
0.01
0
0.06
34,925 (70.8)
14,403 (29.2)
56,381 (70.4)
23,673 (29.6)
0.01
0.01
*All data are presented as a number (%) unless otherwise indicated
** Limited only to immigrants born outside of Canada
SD standard deviation; IQR interquartile range
16
Table 2. Risk of the composite outcome of all-cause mortality or diagnosed drug
overdose within 30 days of being newly prescribed oral codeine (red font) or an NSAID
(black font), according to language ability at the time of immigration
Exposure status†
Drug
NSAID
Spoken language*
English and/or French
No English or French
Codeine
English and/or French
No English or French
Composite outcome up to 30 days after prescription
Hazard ratio
(95% confidence interval)
No. (incidence
rate per 100,00
person-days)
Unadjusted
Adjusted**
2,584 (13.6)
1.00 (referent)
1.00 (referent)
46 (3.9)
0.29 (0.21 to 0.38) 0.44 (0.42 to 0.58)
8,691 (55.4)
174 (23.1)
1.00 (referent)
0.42 (0.36 to 0.49)
1.00 (referent)
0.63 (0.54 to 0.74)
*Language ability in one of Canada’s two official languages, namely, English and/or French.
The level of language ability is self-assessed. Canadian-born (non-immigrant) participants
were assumed to speak English and/or French, as were their children. Canadian-born children
of immigrant mothers were assigned the language of their mothers.
**Adjusted for age, sex, income quintile and rural location at the cohort entry date, number
of distinct drugs used in the past 1 year, number of physician visits in the past 1 year, and
prescription of a recognized CYP2D6 inhibitor 120 days before and up to 30 days after the
index prescription of codeine or an NSAID.
†The interaction term between medication group and language ability was statistically
significant (p=0.047) within the adjusted model.
17