ORIGINAL ARTICLE Effects of an Opioid (Oxycodone/Paracetamol) and an NSAID (Bromfenac) on Driving Ability, Memory Functioning, Psychomotor Performance, Pupil Size, and Mood Joris C. Verster, PhD, Dieuwke S. Veldhuijzen, PhD, and Edmund R. Volkerts, PhD Key Words: analgesics, driving, memory, mood, oxycodone Objective: It has been suggested that driving a car is relatively safe when the driver is treated with nonsteroid anti-inflamma- (Clin J Pain 2006;22:499–504) tory drugs than when he or she is treated with opioid analgesics. However, the evidence for this statement is scarce. The objective he majority of patients treated with analgesics are of this study was to determine the effects of a nonsteroid anti- ambulatory outpatients. Because driving is critical to inflammatory drug (bromfenac 25 mg and 50 mg) and an opioid T maintaining independence in today’s society, it is reason- (oxycodone/paracetamol 5/325 mg and 10/650 mg), and placebo able to assume that these patients are also involved in on driving ability, memory functioning, psychomotor perfor- potentially dangerous daily activities such as driving a mance, pupil size, and mood. car. Pain is usually managed by pharmacological treat- Methods: Out of 30 healthy volunteers, 18 completed this ment with opioids or nonsteroid anti-inflammatory drugs randomized, double-blind, placebo-controlled crossover study, (NSAIDs). Unfortunately, the effects of these analgesics before the study had to be stopped due to bromfenac being on driving ability and consequent safety are not well pulled out from the market. One hour after administration of understood. the drugs, the participants performed a standardized driving test This becomes evident from the conflicting results during normal traffic. Thereafter, driving quality, mental effort from epidemiological studies. In these studies, the risk of and mental activation during driving were assessed. A labora- becoming involved in a traffic accident when treated with tory test battery was performed 2.5 hours after administration of analgesics is expressed as an odds ratio (OR) with an the drug. Visual analog scales assessing mood and pupil accompanying 95% confidence interval (CI) that must be measurements were performed on several occasions during each above 1.0 to produce a statistically significant value. Ray test day. and colleagues1 examined the traffic accident risk in elderly drivers treated with psychoactive drugs. The use of Results: Both analgesics did not significantly affect performance opioid analgesics did not significantly increase in any test. However, volunteers reported that significantly more traffic accident risk (OR = 1.1; 95%CI = 0.5–2.4). In effort was needed to perform the driving test when treated with contrast, Leveille and colleagues,2 who also examined oxycodone/paracetamol, and that they experienced increased traffic accident risk in the elderly treated with psycho- sedation and reduced alertness. Also, the pupil size was tropic drugs, did report an increased traffic accident significantly decreased. In contrast, subjective assessments after risk for patients using opioid analgesics (OR = 1.8; both doses of bromfenac matched that of placebo. 95%CI = 1.0–3.4), including codeine-containing opioids, Discussion: No significant impairment in behavior was found in propoxyphene, and oxycodone. McGwin and colleagues3 the volunteers for both bromfenac and oxycodone/paracetamol. reported an increased traffic accident risk in the elderly The lack of impairment from oxycodone/paracetamol may have using NSAIDs (OR = 1.7; 95%CI = 1.0–2.6). In these been related to the participants reporting increased effort during cohort studies in the elderly it remains unclear whether driving while under the influence of this drug. analgesics, pain, the underlying disease process, or a combination of these factors caused the accidents. Thus, although the use of both opioids and NSAIDs has been associated with increased traffic accident risk in the Received for publication May 22, 2004; accepted December 6, 2005. elderly, current evidence is limited and further epidemio- From the Utrecht Institute for Pharmaceutical Sciences, Utrecht logical research is necessary. University, 3508 TB, Utrecht, The Netherlands. Opioid labeling often warns of drowsiness and Reprints: Dr Joris C. Verster, Utrecht Institute for Pharmaceutical sedation in the users , and danger in their operating heavy Sciences, Department of Psychopharmacology, University of Utrecht, PO Box 80082, 3508 TB Utrecht, The Netherlands (e-mail: machinery. However, reviews of experimental research on [email protected]). behavioral effects of opioids conclude that these analge- Copyright r 2006 by Lippincott Williams & Wilkins sics have little to no effect on driving related skills Clin J Pain Volume 22, Number 5, June 2006 499 Verster et al Clin J Pain Volume 22, Number 5, June 2006 measured in a number of psychomotor tests in the show any improvement in particular tests on at least 3 laboratory.4–6 Also, a driving simulator study showed consecutive trials (ie, baseline performance). no significant impairment in people on stable dosages of oral opioids.7 Up to now, effects of commonly used Procedure analgesics on driving ability have not been determined by In a double-blind crossover design, bromfenac 25 mg, means of standardized driving tests during normal traffic. bromfenac 50 mg, oxycodone/paracetamol 5/325 mg, oxy- Because opioids predominantly act centrally (on the codone/paracetamol 10/650 mg, and placebo were admini- central nervous system), whereas NSAIDs reduce pain strated in identically appearing capsules with 200-mL tap predominantly by peripheral mechanisms (at the site of water, exactly 30 minutes before a standardized breakfast. injury), it can be expected that compounds from these Treatment sequences were randomized across the partici- drug classes may differentially affect driving ability. pants. One hour after treatment administration, a standar- The present study compares the effects on the dized driving test was administered. Approximately driving ability and cognitive functioning of people who 2.5 hours after intake a laboratory test battery was are on NSAID (bromfenac) and an opioid analgesic performed including a Sternberg memory scanning test, (oxycodone/paracetamol). Oxycodone is a full m-opioid tracking test, and divided attention test. Test days were agonist that is frequently prescribed in combination with separated by a washout period of 7 days (range from 4 to paracetamol. This combination is used to reduce the 14 days). opioid dosage while retaining the analgesic efficacy, to The Driving Test reduce opioid-related adverse effects. In this context, it is 10 important to note that paracetamol itself has been shown The standardized 100-km driving test was per- to produce neither significant subjective effects,8 nor formed during normal traffic over a 50-km segment of the significant performance impairments on a variety of primary highway running between 2 Dutch cities, Utrecht cognitive and psychomotor tests.9 The recommended (start and end point) and Arnhem (turning point). The dose is 5 mg oxycodone with 325 mg paracetamol. highway consists of 2 traffic lanes in both directions. Bromfenac, with a recommended dose of 25 mg, is an Participants were instructed to drive with a steady lateral NSAID indicated for the short-term management (<10 position within the right (slower) traffic lane, while days) of acute pain. Taking the differences between both maintaining a constant speed of 90 km/h (56 miles/h). types of analgesics into account, it is hypothesized that Participants were allowed to deviate from the instructions oxycodone/paracetamol will significantly impair driving to overtake a slower-moving vehicle in the same traffic performance, whereas driving is not expected to be lane. A licensed driving instructor who had access to dual significantly affected after bromfenac. To gain supportive controls sat in the right front seat, guarding the evidence, laboratory tests measuring driving related skills, participants safety during the driving test. Driving tests subjective assessments, and pupil measurements were could be terminated before completion if the driving conducted. instructor or the participants felt it was unsafe to continue. The amount of weaving of the car, measured by the standard deviation of the lateral position (SDLP, METHODS cm), is an index of driving safety, and the primary Participants outcome parameter of the driving test. SDLP expresses Thirty healthy volunteers were enrolled to partici- vehicle control in terms of how well participants are able pate in the study. The Medical Ethical Committee of the to maintain their chosen lateral position within the right University Medical Center, Utrecht, approved the study traffic lane. The standard deviation of speed (km/h) is a and participants were treated according to ICH guidelines secondary parameter, showing how well participants are for Good Clinical Practice and the Declaration of capable of maintaining a constant speed. Mean lateral Helsinki and its amendments. Written informed consent position and speed are control variables, determined to was obtained before their inclusion in the study. ensure that participants performed the tests according to Participants underwent a detailed medical examination the instructions. Data were recorded continuously during and their medical history was screened. Before the start the test, and edited off-line to remove data that were and at the end of the study, blood chemistry, hematology disturbed