The Effect of Alcohol Abuse on the Risk of NSAID-Related

Gastrointestinal Events
C. INEKE NEUTEL, PhD, FACE, AND W. CURT APPEL, PhD

PURPOSE: Non-steroidal anti-inflammatory drugs (NSAIDs) are known to increase the risk of gastroin-
testinal (GI) complications. Excessive alcohol consumption may further increase this risk and the FDA
is requiring warnings on over-the-counter (OTC) NSAIDs. Our objective is to evaluate the risk of
NSAID-related GI events for persons with a history of alcohol abuse.
METHODS: This case control study used data from Saskatchewan Health. Cases consisted of 1083
patients hospitalized for severe GI events, whereas the control group consisted of 14,754 persons without
such hospitalizations.
RESULTS: Five percent of cases (n ⫽ 54) and 1.9% of controls (n ⫽ 273) had a history of treatment
for alcohol abuse. The presence of either NSAID use or a history of alcohol abuse led to an odds ratio
(OR) of 2.9* for severe GI events, whereas the presence of both risk factors simultaneously led to an
OR of 10.2* (additive would be 5.8). Similarly, the presence of ibuprofen and naproxen use, which are
OTC in the USA, without alcohol abuse led to an OR of 1.9*, whereas alcohol abuse by itself led to
an OR of 2.4*. The presence of both OTC NSAIDs and alcohol abuse simultaneously, led to an OR
of 6.5 (additive would be 4.3). Thus with both risk factors present, the resulting risk ratio is greater
than the additive risk of the separate risk factors.
CONCLUSIONS: The Food and Drug Administration (FDA) warning concerns concurrent use of
alcohol with NSAIDs, whereas the present study presents the effect of long term alcohol abuse. Further
research is needed to separate these two issues to allow physicians to provide the best advice to their
patients. *Statistically significant at p ⬍ 0.05.
Ann Epidemiol 2000;10:246–250.  2000 Elsevier Science Inc. All rights reserved.
KEY WORDS: Alcohol Abuse, NSAIDs, Gastrointestinal Complications, Adverse Drug Reaction,
Pharmacoepidemiology.

INTRODUCTION Committee and the Arthritis Drugs Advisory Committee)

On October 23, 1998, the USA Food and Drug Agency
(FDA) issued a notice in the Federal Register requiring an
alcohol warning on the packages of all over-the-counter
(OTC) drug products containing analgesic/antipyretic ac-
tive ingredients (1). For the USA, this includes the nonste-
roidal anti-inflammatory drugs (NSAIDs) ibuprofen, keto-
profen, and naproxen. The warning would caution consumers
who consume three or more drinks per day to consult a
physician for advice before taking these NSAIDs. The FDA
advisory committees (the Non-prescription Drugs Advisory
From the Bureau of Drug Surveillance, Therapeutic Products Programme,
Health Canada, Ottawa, Ontario, Canada (C.I.N.); and Kusuri Canada
Corporation, Ottawa, Ontario, Canada (W.C.A.)
Address reprint requests to: Dr. C.I. Neutel, Research Department,
SCO Health Service, 43 Bruyere Street, Ottawa, Ontario, Canada.
Disclaimer: This study is based in part on data provided by the Saskatch-
ewan Department of Health. The interpretation and conclusions contained
herein do not necessarily represent those of the Government of Saskatche-
wan or the Saskatchewan Department of Health.
Received December 9, 1998; revised July 7, 1999; accepted October
8, 1999.
had concluded that the adverse effect of alcohol and ibupro-
fen or naproxen was at least additive and that heavy/chronic
drinkers (as stated in the FDA document) were at increased
risk of serious gastrointestinal (GI) problems. Other regula-
tory agencies, so far, are not requiring warning labels of this
nature for OTC NSAIDs.
A great deal of evidence has accumulated over the years
demonstrating that use of NSAIDs leads to an increased
risk of GI bleeds. Both case-control and cohort studies,
conducted over the past decade, have clearly established
NSAID use as an independent risk factor for serious GI
events (2–6). The three NSAIDs mentioned above as OTC
in the US are no exception, although the increase in risk
is lower than for other NSAIDs (6–9). Further, the same
studies indicated that the risk of GI complications, such as
haemorrhage and perforation, increased substantially with
NSAID frequency, dose, and period of exposure and varied
according to the type of NSAID used.
Alcohol is also known to cause GI problems (10). Several
epidemiologic studies have shown that alcohol use is an
independent risk factor for GI complications (11–14) with

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AEP Vol. 10, No. 4
May 2000: 246–250
Selected Abbreviations and Acronyms
NSAIDs ⫽ non-steroidal anti-inflammatory drugs
OTC ⫽ over-the-counter
FDA ⫽ Food and Drug Administration
RR ⫽ relative risk
OR ⫽ odds ratio
a relative risk (RR) or odds ratio (OR) as high as 4.5,
although another study showed no effect (15). Epidemiolog-
ical studies investigating the relationship between NSAIDs
and GI events have dealt with the confounding effect of
alcohol use in several ways. Some studies were limited to
adjusting for alcohol use or alcoholism in the analysis of
their data (9, 16, 17). Other studies excluded all those who
used alcohol to excess (3, 18). Alcohol exposure measures
used in these studies varied from recording the presence of
alcoholic cirrhosis or other alcohol-associated diagnoses to
obtaining current drinking habits from a questionnaire com-
pleted by the patient.
Several studies have examined the combined effect of
alcohol and NSAID use in more depth. Carson and cowork-
ers found that NSAID-users with any diagnoses related to
alcoholism or to diseases known to be caused by alcoholism,
such as alcoholic cirrhosis, had a higher risk for GI bleeds
and suggested the presence of “synergism” (effect modifica-
tion) between alcoholism and NSAID use (2, 11). Henry
and coworkers found that NSAID use or aspirin use, or five
or more drinks daily as independent risk factors led to ORs
between 2.8 and 3.8, whereas the presence of all three led
to an OR of 9.1 (19). Kaufman and coworkers found an
increase in GI bleeding if NSAID use was concomitant with
three or more alcoholic drinks per day (20). However, they
did not show a clear dose-response relationship with increas-
ing amounts of alcohol consumed, either with or without
NSAID use.
From an epidemiological methodology standpoint, the
type of interaction between alcohol use or abuse and
NSAID-related GI events could be of different kinds. The
two substances could act independently, thus an additive
effect. There could also be effect modification, defined as
the variation in the magnitude of a measure of exposure
effect across levels of another variable (21). Thus, effect
modification would occur if the effect of NSAID exposure
on the risk of GI events was modified across the levels of
alcohol exposure.
This present study has two objectives. The first is to
evaluate whether alcohol abuse and NSAID exposure inter-
act by increasing the risk of serious GI events more than
an additive effect. The second is to determine whether two
of the NSAIDs which are OTC in the USA, i.e., ibuprofen
and naproxen, have a similar response as do other NSAIDs,
which still require a prescription.
Neutel and Appel 247
ALCOHOL ABUSE AND NSAID-RELATED GI EVENTS
METHODS
The Saskatchewan Health Databases, although intended
for the province’s health care delivery and payment claim
systems, also provide a valuable source of data for pharma-
coepidemiological research (22). More than 95% of the
Saskatchewan resident population are eligible for coverage
under the Saskatchewan Drug Plan. The remainder are resi-
dents with a federal government-funded drug benefit plan,
such as native populations, Royal Canadian Mounted Police
(RCMP), or armed forces. The study population included
persons who were born in 1940 or later, and who filled three
or more prescriptions for a study NSAID during the study
period, 1976 to 1986. The five NSAIDs included in the
present analysis (ibuprofen, indomethacin, naproxen, phe-
nylbutazone, and piroxicam) were the most commonly pre-
scribed NSAIDs in Saskatchewan during this time period.
The remaining NSAIDs were grouped in one category as
‘other NSAID’. During the years of data collection for this
study, all NSAIDs required a prescription, leading to a re-
cord in the Saskatchewan Health Drug Plan database for
each prescription filled. Since ibuprofen no longer requires
a prescription in Canada, its use would not be accessible to
a study of this nature. Only data up to the end of 1986
could be included because of changes in the administration
of the Saskatchewan Health Drug Plan which resulted in
the drug data being incomplete between July 1987 and
December 1988.
The data for this study were analysed using a nested case-
control study design. From the study population mentioned
above, 1083 cases were identified as having required hospi-
talization for definite GI haemorrhage and/or perforation
during the study period. The cases were identified from
hospital discharge data with ICD-9 codes 531–534, i.e.,
gastric, duodenal, peptic, or gastrojejunal ulcers (23). The
present study was limited to cases with haemorrhage and/
or perforation which could be selected from the fourth digit
of the ICD-9 code. These are referred to as ‘severe GI events’
throughout this article. Several controls drawn from the
same population (see above), were randomly selected for
each case resulting in 14,754 controls. Members of the con-
trol group were assigned an index date, corresponding to
the dates of hospitalization for the GI events which were
the index dates for the cases. Subsequently, only cases with
a diagnosis of haemorrhage or perforation were kept but all
controls were retained. Index dates were used to determine
the end of a four-month exposure window during which
the number of NSAID prescriptions filled were totalled for
this study.
The presence of alcohol abuse was determined by search-
ing for any record of alcoholism-related treatment or through
filling prescriptions for disulfiram, a drug used in the treat-
ment of alcohol abuse. Such treatment could be recorded
248 Neutel and Appel AEP Vol. 10, No. 4
ALCOHOL ABUSE AND NSAID-RELATED GI EVENTS May 2000: 246–250

TABLE 1. Study population size and attributes for cases and increases with the number of prescriptions filled for study
controls NSAIDs, varying from a low OR of 1.8 with one prescription
Cases (n ⫽ 1083) Controls (n ⫽ 14754) to an OR of 4.4 for three or more. The ‘other NSAID’
Variable % (N) % (N) category shows a similar effect on risk for GI bleeds and
Age groups receiving any prescriptions for these resulted in a near tri-
36–60 22.0 (238) 35.3 (5203) pling of risk.
60–79 52.5 (569) 49.8 (7350) Table 3 shows two logistic regression models, both strati-
80⫹ 25.5 (276) 14.9 (2201) fied by history of alcohol abuse. Model 1 shows that a history
Sex of alcohol abuse consistently leads to a higher risk of NSAID-
Males 47.3 (512) 43.7 (6443)
Females 5.0 (54) 56.3 (8311) related severe GI events. Model 2 shows that this was true
History of alcohol abuse also for the two NSAIDs, ibuprofen and naproxen, at present
No 95.0 (1029) 98.1 (14481) OTC in the US, although the ORs are lower.
Yes 5.0 (54) 1.9 (273) Table 4 shows that persons who either have been exposed
NSAID treatment to NSAIDs, or have a history of alcohol abuse have an OR
Number of prescriptions
in exposure window of 2.9 for severe GI events, whereas people with both risk
0 51.8 (561) 75.1 (11087) factors have an OR of 10.2, when compared to those with
1 15.6 (169) 12.3 (1817) neither risk factor. It should be noted that the OR of 10.2
2 12.7 (137) 6.3 (933) for both risk factors is more than the additive OR of 5.8.
3⫹ 20.0 (216) 6.3 (917) Table 5 shows a similar analysis confined to the use of
Other (non-study) NSAID
Any prescriptions ibuprofen and/or naproxen. The presence of both alcohol
in exposure window abuse and NSAID use leads to an OR of 6.5, which is also
No 90.7 (982) 96.6 (14257) higher than the additive OR of 4.5.
Yes 9.3 (101) 3.4 (497)

DISCUSSION
at any time during the study period of 1976–1986 regardless The results of this study confirm that a history of alcohol
of the index date. abuse leads independently to an increased risk of severe GI
The following variables were used for the analysis for
this study: age, sex, the number of prescriptions filled for
the five study NSAIDs (ibuprofen, indomethacin, naproxen, TABLE 2. Logistic regression model: the outcome variable is
presence/absence of severe GI events. All variables listed are
phenylbutazone, and piroxicam), and other NSAIDs com- included in the model
bined. Logistic regression analysis was used to calculate ORs
and their 95% confidence intervals (CI). All analyses were Adjusted
Variable OR (95% CI)
performed using the SAS (version 6) software package (24).
Age
⬍60 years old 1.00
60–79 1.6* (1.3–1.8)
RESULTS 80⫹ 2.3* (1.9–2.7)
Table 1 shows descriptive information on the study popula- Sex
Females 1.0
tion by presenting the distribution of cases and controls Males 1.3* (1.2–1.5)
according to selected characteristics. A larger proportion of History of alcohol abuse
males and of the oldest age group (⬎80 years old) were No 1.00
found among cases than among controls. Cases filled more Yes 3.1* (2.3–4.2)
prescriptions for NSAIDs during the exposure window than NSAID treatment
Number of prescriptions
did controls. Five percent of cases and just under 2% of in exposure window
controls had a history of alcohol abuse. 0 1.00
Table 2 shows a logistic regression model relating the 1 1.8* (1.5–2.1)
risk of severe GI events to the risk factors as shown with 2 2.7* (2.2–3.3)
statistical significance indicated for each risk factor. The 3⫹ 4.4* (3.6–5.2)
Other (non-study) NSAID
variable for age shows an increase in risk of severe GI events Any prescriptions
with every 20 years of increase in age. The variable for sex in exposure window
shows that males have a greater risk than females. A history No 1.00
of alcohol abuse independently triples the risk of severe GI Yes 2.9* (2.3–3.7)
events (OR ⫽ 3.1). In addition, the risk of severe GI events * Statistically significant at p ⬍ 0.05.
AEP Vol. 10, No. 4 Neutel and Appel 249
May 2000: 246–250 ALCOHOL ABUSE AND NSAID-RELATED GI EVENTS

TABLE 3. Logistic regression models: the outcome variable is TABLE 5. Logistic regression model: the outcome variable is
presence/absence of severe GI events. The models are stratified presence/absence of severe GI events. The model is stratified
for history of alcohol use by history of alcohol abuse and ibuprofen and/or naproxen use
during the exposure window
No alcohol abuse Alcohol abuse
NSAID treatment OR (95% CI) OR (95% CI) History of treatment for alcohol abuse
Model 1 Ibuprofen,
Number of NSAID prescription naproxen No Yes
in exposure window treatmenta OR (95% CI) OR (95% CI)
0 1.0 1.0
1 1.8* (1.5–2.1) 2.4* (1.0–5.5) None 1.0 (reference) 2.6* (1.9–3.7)
Any 1.9* (1.6–2.3) 6.5* (2.8–15.0)
2 2.6* (2.1–3.2) 5.0* (1.9–13.4)
3⫹ 3.6* (2.9–4.5) 5.7* (1.7–19.0) * Statistically significant at p ⬍ 0.05.
Model 2 The model was also adjusted for age, sex, and all other NSAID use.
a
Number of ibuprofen/naproxen Any ibuprofen and/or naproxen prescriptions during the exposure window.
prescriptions in exposure window
0 1.0 1.0
1 1.6* (1.2–2.0) 1.7 (0.5–5.5)
2⫹ 2.0* (1.6–2.5) 4.3* (1.1–17.6) OTC show lower OR than the other NSAIDs studies , but
* Statistically significant at p ⬍ 0.05. the effect-modification is still present.
Both models were also adjusted for other NSAID use, age, and sex. For the present study, a history of any type of recorded
treatment for alcohol abuse was used as an indicator for the
presence of alcohol abuse and whatever goes along with
events, as shown by the OR of 3.1 in Table 2. A history of that. By the time alcohol abuse is treated it has reached
alcohol abuse was also shown to increase the risk of NSAID- the point of a long term chronic condition with long term
related severe GI events more than the expected if these sequela even after drinking is stopped. Because of these long
two variables were independent. Tables 3, 4, and 5 illustrate term implications of alcoholism, any treatment in all of the
the presence of effect modification. For example, Table 3 study period was included rather than those before or after
demonstrates that filling three or more NSAID prescriptions the index GI event. Misclassification might results from not
without a history of alcohol abuse led to an OR of 3.6 for identifying those problem drinkers who have not had any
severe GI events but the same exposure with such a history treatment that would be recorded on the data bases, or from
led an OR of 5.7. This is confirmed in Table 4 by the OR including those who received such treatment at the end of
of 2.9 for GI events after exposure to any NSAID without the study period but had not started drinking until after
alcohol abuse, and an OR of 2.9 for alcohol abuse without their GI event. Any such misclassification would lead to a
NSAID exposure but an OR of 10.2 when both were present. decreased difference between the alcohol abusers and the
This OR of 10.2 is considerably higher than the additive non alcohol abusers, and thus the true effect of alcohol
5.8, indicating the presence of effect modification. Similarly, abuse on the relation between NSAID use and GI events
when the analysis was confined to ibuprofen/naproxen, the may be even larger than shown in this study. Individuals
OR for the presence of both alcohol abuse and ibuprofen/ being treated for alcohol abuse may also have some other
naproxen was 6.5, compared to the additive OR of 4.5. characteristics related to, or associated with, excessive alco-
Since the OTC NSAIDs are not as closely supervised by hol use such as malnutrition, health problems, and possibly
physicians, it is significant that these NSAIDs that are now a high rate of smoking. The alcohol abuser is thus considered
as an entity when using the measure used in this study, but
then it is as such they have been shown to be a high risk
TABLE 4. Logistic regression model: the outcome variable is group for GI events after NSAID use.
presence/absence of severe GI events. The model is stratified Besides measuring an indicator of chronic alcohol abuse,
by history of alcohol abuse and by NSAID use during the another approach to assessing the effect of alcohol would
exposure window be to measure daily alcohol exposure, e.g., in number of
History of treatment for alcohol abuse drinks consumed daily just prior to the time of the GI event.
NSAID No Yes
Although a person drinking more than three drinks a day
treatmenta OR (95% CI) OR (95% CI) could be a chronic alcohol abuser, he/she could also be
someone who has only started recently or is only drinking
None 1.0 (reference) 2.9* (1.9–4.5)
Any 2.9* (2.5–3.3) 10.2* (6.5–16.1) this amount temporarily and have neither current nor
chronic effects of their drinking. Both approaches include
* Statistically significant at p ⬍ 0.05.
Model also adjusted for sex, age. concurrent use and potential abuse. While the first empha-
a
NSAID includes any prescriptions for either study and/or non-study sizes long term alcohol abuse, the other stresses everyday
NSAID during the exposure window. use at the time of GI event. Concurrent alcohol use may
250 Neutel and Appel
ALCOHOL ABUSE AND NSAID-RELATED GI EVENTS
affect the metabolism of NSAID use in a different way than
the effect on the metabolism in someone with liver damage.
It is therefore important to sort out whether the two ap-
proaches are both of concern or whether one is more likely
to have detrimental effects than the other. The published
study showing results most similar to the present one also
determined alcohol abuse from the presence of recorded
treatment for alcohol abuse (2, 11). Two studies measuring
concurrent alcohol use did show the importance of alcohol
as a risk factor for GI events but did not show effect modifi-
cation with NSAIDs (19, 20). In these studies, alcohol ap-
peared to act as a risk factor independent from NSAID use.
The proposed FDA warning for packages of OTC NSAID
deals with concurrent use of three or more drinks per day
and not directly with long-term alcohol abuse. Although
concurrent alcohol use appears to increase the risk of GI
bleeds as an independent factor, it may not have the same
impact as alcohol abuse induced damage. Further research
is needed to study the nature of the interaction between
NSAID treatment and concurrent alcohol use and/or con-
tinuing or past alcohol abuse in more detail, including po-
tential confounders. In the end, it may be possible that a
warning on OTC NSAID labels needs to include a caution
about long term excessive alcohol use, as well as current
use. In any event, it is important that sufficient information
be available for health care professionals to allow them to
determine the risk for severe GI toxicity due NSAID use for
patients who are consuming, or in the past, have consumed
considerable amounts of alcohol.
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