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The risk of motor vehicle accidents involving drivers with prescriptions for codeine or tramadol
nature publishing group
The Risk of Motor Vehicle Accidents Involving
Drivers With Prescriptions for Codeine or TramadolLC Bachs1, A Engeland2,3, JG Mørland1,4 and S Skurtveit2,5
Previous studies have only partially characterized the road-
accident risks linked to driving while taking opioid analgesics
We studied the impact of nonregular use by examining data
used for moderate pain.
1–4 A prospective cohort design
from accidents resulting in injury and involving users who fil ed
with data from national population–based registries—the
their first prescription for codeine after a washout period of 180
Norwegian Prescription Database and the Norwegian Road
days. The SIR for nonregular users of codeine was not increased,
Accident Registry—and observation of >8 million person-
years were used in order to examine whether a driver who has
filled a prescription for codeine or tramadol is at increased low vs. high drug consumption
risk of being involved in a road accident resulting in injury hows the SIR data relating to traffic accidents involv
ing exposure to codeine in drivers who had filled prescriptions
for fewer than 60 defined daily doses (DDDs) of codeine (low
consuming group) and those who had fil ed prescriptions for 60
or more DDDs (highconsuming group) in the 6month period
During the study period (33 months), 181 accidents that resulted prior to the cohort observation time, which was 27 months. The
in injury and involved drivers with codeine exposure (defined as SIR was markedly increased in the highconsuming group and
within 7 days after the date of dispensation) were registered; 20 not increased in the lowconsuming group. When data from
involved drivers exposed to tramadol. The risk of being involved those who had been exposed to other impairing drugs during
in an accident was significant for drivers using codeine (stan
the relevant time period were excluded from consideration, the
dardized incidence ratio (SIR) for both sexes and all age groups SIR for accidents among the highcodeineconsuming group no
combined: 1.9; 95% confidence interval: 1.6−2.2). The SIR for longer showed any increase.
tramadol (1.5; 95% confidence interval: 0.9–2.3) was not signifi
left column, shows the SIR for accidents involving Codeine/acetaminophen combinations (30 mg codeine and
injury to persons, for male and female drivers of different age 400 or 500 mg acetaminophen) and, to a much lesser extent,
groups after exposure to codeine. The relatively few accidents tramadol are the preferred analgesics with opioid effects used
in the tramadol group did not allow further stratification into in Norway for moderate pain. In Norway, prescriptions are
required for all compounds containing codeine or tramadol.
Like other central nervous depressants, opioids may reduce
psychomotor performance or other functions that are poten
A further study of the codeine group showed that, when data tially relevant to the ability to drive safely. Existing studies have
from those who were simultaneously exposed to other impairing only partially characterized the roadaccident risks linked to
drugs (other opioids, benzodiazepines, hypnotics, carisoprodol, opioid analgesics prescribed for moderate pain. Some control ed
and sodium oxybate) were excluded, the SIR for accidents in the studies have indicated that codeine and tramadol, especially in
codeineexposed drivers no longer showed an increase high doses, might impair driver performance.1,5,6 Other studies
have failed to demonstrate such effects.7–10 We have previously
1Division of Forensic Toxicology and Drug Abuse, Department of Pharmacological and Toxicological Assessment, Norwegian Institute of Public Health, Oslo, Norway;
2Division of Epidemiology, Department of Pharmacoepidemiology, Norwegian Institute of Public Health, Oslo, Norway; 3Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway; 4Institute of Pharmacology, University of Oslo, Oslo, Norway; 5Department of Pharmacy, University of Tromsø, Tromsø, Norway. Correspondence: LC
Received 24 November 2008; accepted 23 January 2009; advance online publication 11 March 2009.
VOLUME 85 NUMBER 6 | JUNE 2009 | www.nature.com/cpt
table 1 exposure to codeine
(B) Codeine, person–time with coprescription excluded
(A) Standardized incidence ratios (SIRs) for traffic accidents after exposure to codeine. The table shows the number of observed accidents, the number of expected accidents, and the SIR for 7 days starting on the day after dispensation of the drugs, stratified by gender and age group. (B) SIR for traffic accidents after exposure to codeine excluding person–time exposure to other impairing drugs (other opioids, benzodiazepines, hypnotics, carisoprodol, and sodium oxybate) and stratified by gender and age. Individuals who filled a prescription for other impairing drugs the same day as they were dispensed the opioid studied, or on any of the 6 prior days, were excluded. The observation duration was 33 months for both groups A and B.
CI, confidence interval.
table 2 Nonregular use of codeine
end of the scale, the 1% of codeine users who were prescribed
Codeine, nonregular use
the greatest amount of codeine accounted for 16% of the total
codeine prescribed.18 This prescription pattern is also seen for
other drugs with potential for abuse.19 The fact that most of the
subjects consume small amounts of the drug while relatively
few have very high consumption is a determining factor in our
interpretation of the results. Furthermore, we showed that copre
Standardized incidence ratios (SIRs) for traffic accidents after exposure to codeine alone.
scription of benzodiazepines is highly prevalent and increases
Exposure times only for individuals who received their first prescription for codeine after
in parallel with the amount of codeine prescribed.18 This is an
a washout period of 180 days. Stratified by gender. Observation duration 27 months.
important confounding factor for evaluating accident risk. Of the
181 codeineexposed patients involved in accidents, 98 had been
reported that there is a relationship between blood codeine lev
prescribed other impairing drugs within 7 days prior to filling
els and drivingrelated impairment in those suspected of driving the prescription for codeine.
The SIR relating to nonregular use of codeine did not show
Analytical epidemiological studies of the risks of being an increase. The finding that the SIR was not increased in non
involved in traffic accidents while using drugs with limited regular codeine use may seem the very opposite of what would
opioid effects, or all opioids as a group, have shown low rela
be expected for an opioid. Tolerance is a prominent feature of
tive risks, often not statistical y significant.12–15 An earlier study, opioids as a group, although the development of tolerance for the
using the same methodology as in this one, has shown that effects of codeine in the context of driving is not well character
drivers using natural opium alkaloids face an increased risk of ized. The fact that nonregular codeine users did not have elevated
being involved in an accident, the SIR being 2.0 (95% confidence SIRs may reflect the fact that the roadaccident risk associated
with lowdose, sporadic consumption of the drug is low.
In this study, we found an increased SIR of motor vehicle acci
In order to find out more about the subgroup of high
dents that resulted in injury and involved drivers exposed to consumers, we analyzed our material according to the dose
codeine. The SIR was not increased when data involving simulta
of codeine prescribed. The population’s use of codeine com
neous exposure to other impairing drugs were excluded from the pounds was observed over a period of 6 months prior to the
relevant codeineexposure period or when codeine nonregular start of the cohort observation. We knew from a previous
use was analyzed alone. The SIR was markedly increased in the work that the amount of codeine used over a period of time
codeine “highconsuming group” but not in the “low consuming is a strong predictor of future patterns of use.20 The defini
group.” Again, the SIR dropped when data involving exposure to tion of “high consumers”—prescribed 60 or more DDDs in
other impairing drugs were excluded from the codeine exposure 6 months—had been set on the basis of previous work and
time in the highconsuming group. The SIR showed an upward applies to approximately 10% of all codeine users.18 In the same
trend, not statistically significant, for tramadol exposure. Data study, we showed that 50% of high consumers of codeine are
from 2005 show that ~60% of codeine users in Norway were also prescribed high amounts of benzodiazepines. One DDD
given only one prescription of codeine that year.17 At the other of the codeine combinations represents 120 and 90 mg codeine,
CliniCal pharmaCology & TherapeuTiCs | VOLUME 85 NUMBER 6 | JUNE 2009
table 3 low vs. high consumers of codeine
(C) Codeine high consumers,
(a) Codeine low consumers
(B) Codeine high consumers
person–time with coprescription excluded
(A) Standardized incidence ratios (SIRs) for traffic accidents after exposure to codeine for subjects filling prescriptions for fewer than 60 defined daily doses (DDDs) of codeine in the 6-month period prior to the cohort observation period. The table shows the number of observed accidents, the number of expected accidents, and the SIR for 7 days starting the day after dispensation of the drug, stratified by gender of the driver. (B) SIR for traffic accidents after exposure to codeine for subjects filling prescriptions for 60 or more DDDs of codeine in the 6-month period prior to the cohort observation period. (C) SIR for high-consuming group excluding person–time exposure to other impairing drugs (other opioids, benzodiazepines, hypnotics, carisoprodol, and sodium oxybate). Individuals who filled a prescription for other impairing drugs on the same day that they were dispensed the opioid being studied, or on any of the 6 previous days, were excluded. The observation duration was 27 months for groups A, B, and C.
CI, confidence interval.
respectively, for the two compounds that are currently on the Statistics Norway, provides information about accidents on Norwegian
market in Norway. When we divided the available data into roads resulting in injuries.21 There is a legal obligation to report such
“low” and “high” consumer categories, it became apparent that accidents to the police.
it was the highconsuming group that was at increased risk for NorPD. The NorPD16,22 is a research database that captures all prescrip
tions at pharmacies dispensed to individual patients treated in ambula
Of the 83 codeineexposed subjects in the high consuming tory care in Norway since 1 January 2004. All pharmacies are obliged to
group who had been involved in accidents, 65 had been pre
report data on all prescribed drugs to NorPD.
scribed other impairing drugs in the days prior to filling a pre
exposure period. We studied those who used codeine and tramadol dur
scription for codeine compounds. When the other 18 patients ing the study period and compared them with nonusers of the same age
in the highconsuming group, who had not been exposed to range.
other impairing drugs in the accident period, were analyzed
In the analysis of accident incidence rates in the low and high
separately, the SIR was no longer elevated. The low number consumption cohorts, the observation time was 6 months less,
of accidents in this group is not sufficient to reliably exclude
The NorPD includes no information on when or whether the dis
the possibility that a high dose of codeine alone can increase pensed medicines were actually used. We therefore used an assumed
accident risk, even without other factors. On the other hand, period of usage of 7 days, starting the day after the date of dispensing. In
this study does not provide evidence that codeine use by itself this study, the date of dispensation is the date of delivery to the patient
statistical methods. The incidence of accidents in the group comprising
exposed persons–time was compared with the incidence of accidents
Materials and methods are described in detail elsewhere16 and are further
among the group comprising unexposed persons–time, by calculating
described in the Supplementary Data online. Data were retrieved from
the SIR. Individuals who were not exposed to any of the study opioids
three Norwegian population–based registries: the Norwegian Prescrip
but fil ed a prescription for other impairing drugs were excluded from
tion Database (NorPD), the Norwegian Road Accident Registry, and the
the unexposed persons–time group at 7 days starting the day after they
Norwegian Central Population Registry.
fil ed the prescription. These “exclusion drugs” included all other opioids,
benzodiazepines, and other hypnotics registered in Norway, as well as
study cohort. All inhabitants of Norway born from January 1934
through September 1988, and living in Norway in 2004–2006, were
The study period was divided into 1month periods so as to adjust for
possible seasonal variations. Findings were calculated for both sexes and
The individuals were fol owed up from the age of 18 or from 7 January
in 10 age groups (18–24, 25–29,…, and 65–69 years). The age grouping
2004 until the date of their involvement (as a driver) in an accident result
was based on age as of 1 May 2005. SIRs above unity indicate an increased
ing in injury, or their emigration, or their reaching the age of 70 years, or
risk of being involved as a driver in an accident that results in injury.
their death, or until 30 September 2006, whichever occurred first (i.e., the
Results are presented for three broader age groups (18–34, 35–54, and
study period was from 7 January 2004 until 30 September 2006).
55–69 years). SIRs and confidence intervals were calculated in accordance
To analyze the role of the consumption levels of codeine (low vs. high),
with the method described by Andersen et al.23
we observed the amount of prescribed codeine compounds in the whole
Supplementary Table S1 online shows the total observation time and
population from 1 January 2004 to 30 June 2004. After this 6month
the exposed persons–time data for each drug.
observation period, data from individuals who were prescribed 60 or
more DDDs of codeine during the observation period were analyzed
1. Exposure: “Exposed” and “unexposed” were taken as relating only
separately from data from those who were prescribed fewer than 60
DDDs (as two different cohorts). The observation time for these two
2. Coprescription: Individuals exposed to study opioids were
groups was from 1 July 2004 to 30 September 2006.
excluded if they filled a prescription for other impairing drugs
the same day as the opiate, or on any of the 6 previous days. These
“exclusion drugs” included all other opioids, benzodiazepines,
Norwegian Road Accident Registry. The Norwegian Road Accident
and hypnotics registered in Norway, as well as carisoprodol and
Registry, based on the police’s database of accidents and maintained by
VOLUME 85 NUMBER 6 | JUNE 2009 | www.nature.com/cpt
3. Nonregular use: Exposure time related only to individuals who
experimentally induced pain. Eur. J. Clin. Pharmacol. 21, 485–490
received their first prescription for weak opiates after a washout
10. Walker, D.J. & Zacny, J.P. Subjective, psychomotor, and analgesic effects of oral
4. High consumption: Individuals who filled prescriptions for 60 or
codeine and morphine in healthy volunteers. Psychopharmacology (Berl). 140,
more DDDs in the observation period of 6 months were analyzed
11. Bachs, L., Skurtveit, S. & Morland, J. Codeine and clinical impairment in
samples in which morphine is not detected. Eur. J. Clin. Pharmacol. 58,
The strengths and shortcomings of our study as well as materials
and methods are discussed in more detail in the Supplementary Data
12. Drummer, O. Drugs in drivers killed in Australian road traffic accidents. Report
of the Victorian Institute of Forensic Pathology. Report no. 0594 (The Victorian Institute of Forensic Pathology, Melbourne, Australia, 1994).
suPPleMeNtARY MAteRiAl is linked to the online version of the paper at
13. Leveille, S.G., Buchner, D.M., Koepsell, T.D., McCloskey, L.W., Wolf, M.E. &
Wagner, E.H. Psychoactive medications and injurious motor vehicle collisions
involving older drivers. Epidemiology 5, 591–598 (1994).
14. Movig, K.L. et al. Psychoactive substance use and the risk of motor vehicle
This work has been funded by the Norwegian Institute of Health.
accidents. Accid. Anal. Prev. 36, 631–636 (2004).
15. Ray, W.A., Thapa, P.B. & Shorr, R.I. Medications and the older driver. Clin. Geriatr.
CoNfliCt of iNteRest
Med. 9, 413–438 (1993).
The authors declared no conflict of interest.
16. Engeland, A., Skurtveit, S. & Mørland, J. Risk of road traffic accidents associated
with the prescription of drugs: a registry-based cohort study. Ann. Epidemiol.
2009 American Society for Clinical Pharmacology and Therapeutics
17, 597–602 (2007).
17. Fredheim, O.M., Skurtveit, S., Moroz, A., Breivik, H. & Borchgrevink, P.
1. Baselt, R.C. Drug Effects on Psychomotor Performance (Biomedical Publications,
Prescription pattern of codeine for non-malignant pain in Norway—a
pharmacoepidemiological study from the Norwegian Prescription Database.
2. Chesher, G.B. The influence of analgesic drugs in road crashes. Accid. Anal.
Acta Anaesthesiol. Scand. (in press).
Prev. 17, 303–309 (1985).
18. Bachs, L., Bramness, J.G., Engeland, A. & Skurtveit, S. Repeated dispensing
3. Drummer, O., Chu, M. & Gerostamoulos, J. Involvement of drugs in accident
of codeine is associated with high consumption of benzodiazepines.
causation. Report of AustRoad Working Group (Victorian Institute of Forensic
Norwegian J. Epidemiol. 18, 185–190 (2008).
Medicine and Department of Forensic Medicine, Southbank, Australia, 1999).
19. Bramness, J.G., Furu, K., Engeland, A. & Skurtveit, S. Carisoprodol use and
4. Mørland, J. Driving under the influence of non-alcohol drugs. Forensic Sci. Rev.
abuse in Norway: a pharmacoepidemiological study. Br. J. Clin. Pharmacol. 64,
12, 79–105 (2000).
5. Bradley, C.M. & Nicholson, A.N. Effects of a mu-opioid receptor agonist
20. Skurtveit, S., Furu, K., Bramness, J.G. & Tverdal, A. Benzodiazepine use in all
(codeine phosphate) on visuo-motor coordination and dynamic visual acuity
alcohol consumers predicts use of opioids in patients 20 years later—a follow-
in man. Br. J. Clin. Pharmacol. 22, 507–512 (1986).
up study of 13,390 men and women aged 40–42 years. Pharmacoepidemiol.
6. Linnoila, M. & Häkkinen, S. Effects of diazepam and codeine, alone and in
Drug Saf. 17, 926–933 (2008).
combination with alcohol, on simulated driving. Clin. Pharmacol. Ther. 15,
21. Statistics Norway. Statistics Norway. <http://www.ssb.no/english/
7. Liljequist, R. Codeine-induced memory changes: nature and relationship to
22. Norwegian Prescription database. Norwegian Institute of Public Health.
opiate system. Eur. J. Clin. Pharmacol. 20, 99–107 (1981).
8. Saarialho-Kere, U., Mattila, M.J. & Seppälä, T. Pentazocine and codeine: effects
on human performance and mood and interactions with diazepam. Med. Biol.
64, 293–299 (1986).
23. Andersen, A., Barlow, L., Engeland, A., Kjaerheim, K., Lynge, E. & Pukkala, E.
9. Stacher, G., Bauer, P., Schneider, C., Winklehner, S. & Schmierer, G.
Work-related cancer in the Nordic countries. Scand. J. Work Environ. Health
Effects of a combination of oral naproxen sodium and codeine on
25 (suppl. 2), 1–116 (1999).
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