driving ability under long-term treatment with transdermal fentanyl

© 2003 U.S. Cancer Pain Relief Committee 0885-3924/03/$–see front matterPublished by Elsevier. All rights reserved. PII S0885-3924(02)00539-0

38 Journal of Pain and Symptom Management Vol. 25 No. 1 January 2003

Original Article

Driving Ability Under Long-Term Treatment with Transdermal Fentanyl

Rainer Sabatowski, MD, Susanne Schwalen, MD, Klaus Rettig, MS,Klaus W. Herberg, MD, Stephan M. Kasper, MD, and Lukas Radbruch, MD

Department of Anesthesiology (R.S., S.M.K., L.R.), University of Cologne, Cologne; Medical Affairs Department (S.S.), Janssen-Cilag GmbH, Neuss; Bureau of Evaluation and Quality Assurance in Medicine (K.R.), Meerbusch; and Technischer Überwachungsverein GmbH (K.W.H.),Cologne, Germany

Abstract

Clinical experience shows that neuropsychological side effects due to opioid therapy usually decrease during the first weeks of therapy. However, the effect of long-term treatment with transdermal fentanyl on complex activities, such as driving, is not yet clear. In a prospective trial, patients with continuous noncancer pain, who had received stable doses of transdermal fentanyl for at least 2 weeks, completed a series of computerized tests to measure attention, reaction, visual orientation, motor coordination and vigilance. Data from 90 healthy volunteers were matched to 30 patients; 9 patients were excluded from the per-protocol analysis because they took additional drugs in violation of the protocol. None of the performance measures for the 21 remaining fentanyl patients was significantly inferior to the controls. We conclude that stable doses of transdermal fentanyl for the treatment of chronic non-cancer pain are not associated with significant impairments in psychomotor and cognitive performance. The threshold for fitness to drive as defined by German law did not differ significantly between

the groups.

J Pain Symptom Manage 2003;25:38–47.

© 2003 U.S. Cancer Pain Relief Committee. Published by Elsevier. All rights reserved.

Key Words

Psychomotor performance, cognition, transdermal fentanyl, driving ability, non-cancer pain

Introduction

The management of chronic pain is often dif-ficult. The aim of therapy is not only to reducepain intensity but also to improve various as-pects of the patient’s quality of life. Opioids area cornerstone for pain management and areused not only for the treatment of cancer pain,

but also for the management of continuous

non-cancer pain.

1,2

The side effects of opioidsare well documented and must be taken intoconsideration when determining the potentialrisks and benefits of treatment. The use of opio-ids for the treatment of acute pain is often asso-ciated with varying degrees of cognitive impair-ment. This observation has raised concern thatlong-term opioid treatment might have a nega-tive impact on cognition and psychomotorfunction. However, there is some evidence thattolerance to opioid-related side effects, such assedation, develops during long-term treat-ment.

3,4

Additionally, opioid-induced cognitive

Address reprint requests to:

Rainer Sabatowski, MD, PainClinic, Department of Anesthesiology, University ofCologne, 50924 Cologne, Germany.

Accepted for publication: February 25, 2002.

Vol. 25 No. 1 January 2003 Long-Term Transdermal Fentanyl and Driving Ability 39

failure in palliative care patients can often beminimized by opioid switching.

5

The influence of opioids on cognitive func-tion and psychomotor performance has beenexamined in laboratory studies. Studies withpatients receiving long-term opioid therapy, aswell as single or repeated bolus doses, havedemonstrated a range from no impairment tosignificantly impaired psychomotor function

and/or cognition.

6–10

However, most studiesexamined the effects of opioids on cancer pa-tients and only a minority focused on non-can-cer pain populations.

7,11

Most of these studieshave investigated the impact of long-term ad-ministration of morphine. To date, there havebeen no studies of populations receiving long-term fentanyl therapy. In healthy volunteers,parenteral bolus administration of fentanyl hasbeen shown to produce pronounced cognitiveimpairment compared to placebo, diazepam,or alcohol.

12–15

The effects of intravenous fent-

anyl were demonstrated to be dose dependent.

16

Opioids, such as transdermal fentanyl, havebeen shown to be effective in the treatment ofmoderate to severe continuous pain associatedwith both cancer and other chronic condi-tions.

17–20

There is little knowledge about rele-vant impairments of cognitive functions, such

as interference with driving ability, during long-term treatment with transdermal fentanyl, es-pecially in noncancer patients. Driving is animportant feature of modern living and con-tributes considerably to an independent life-style. Even when opioids are used successfullyto reduce pain, patients’ ability to live a normallife may be constrained if they are disqualifiedfrom driving.

Driving under the influence of alcohol (de-

fined as a blood concentration of

�

0.05%) orvarious illicit drugs is prohibited in Germany,as in other European countries. However,there is an exception for patients taking drugssuch as opioids prescribed by their physician aspart of the therapeutic regimen. Though driv-ing with prescribed opioid medications is notillegal, there is an ongoing discussion aboutthe driving ability of pain patients in Germany.We, therefore, studied patients receiving a sta-ble dose of transdermal fentanyl for continu-ous noncancer pain to provide more data onthe impact of fentanyl on complex psychomo-tor and cognitive performance that is thoughtto be related to driving ability.

Methods

This was a prospective comparison of patientsreceiving transdermal fentanyl for chronic non-cancer pain and a group of untreated, healthycontrols. Subjects and controls were matchedfor age and sex, with three controls selectedfor every fentanyl patient.

Patients

Male and female outpatients aged between18 and 65 years suffering from noncancer painresponsive to opioids could be enrolled if theyhad been treated with transdermal fentanyl forat least four weeks, without a dose change inthe previous 12 days. Participants also requireda valid driver’s license and the ability to speakand write German. Patients were excludedfrom the study if they were receiving benzodi-azepines or barbiturates

�

3 times per week,high dose antidepressant treatment (e.g.,

�

75mg amitriptyline per day), or regular antihista-mines. Patients with physical disabilities, severepsychiatric or neurological diseases, or visualdisorders that would prevent them from per-forming the tests were also excluded. All pa-tients gave written, informed consent to partic-ipate. The study protocol and the consentform were approved by the ethics committee ofthe University of Cologne.

Control Group

Controls were randomly selected from apool of volunteers who had been tested be-tween March 1996 and March 1998 (between 2and 5 pm) at the Institute for Traffic Safety ofthe Technischer Überwachungsverein GmbHin Cologne, Germany. This pool was part of alarger sample composed of healthy volunteers,with five men and five women for each year ofage from 18–80 years. For this study, volunteersover the age of 65 were excluded, resulting in asample of 484 persons, from which the matchedpairs were drawn. The control sample has beendescribed as representative of the normal Ger-man population with regard to activity, auton-omy and driving experience.

21,22

Course of the Study

After patients had been informed about thestudy and had given their consent to take part,their personal details (age, sex, etc.) and medi-cal history were recorded, including full details

40 Sabatowski et al. Vol. 25 No. 1 January 2003

of their pain disease and the treatments theywere receiving. Participants were also askedabout their driving experience. Testing wasperformed between 1 and 5 pm within oneweek after screening. Prior to testing, a bloodsample was taken to determine the plasma fen-tanyl concentration, and a urine sample wastaken to screen for the use of drugs not re-ported by the patients in the pain clinic. Datafrom patients using unreported drugs were in-

cluded in the intent-to-treat (ITT) analysis whilethe remaining patients were analyzed as the per-protocol (PP) group. Pain intensity was ratedimmediately before testing using an 11-pointnumerical rating scale ranging from 0 (nopain) to 10 (worst pain that can be imagined).

Test Battery

The test battery followed the German nationalrecommendations on tests to determine driv-ing ability.

23

These require assessment of: per-formance under pressure, orientation, concen-tration, attention, and reaction time. Three ofthe tests performed in the present study (DT,COG, TAVT—described subsequently) coverthese five areas.

24

Test batteries similar to theone used in this study are used for traffic delin-quents in Germany. Permission to drive fortraffic delinquents is usually denied if one ormore of these tests is failed, that is, if the testresult is below the 16th-percentile of the age-independent reference range.

25

In addition,tests for motor coordination and for vigilancewere also used in this study. These tests havebeen previously validated.

All tests were performed under standardizedconditions with standardized instructions andin the same sequence by means of the comput-erized test system (“Wiener Test System”). Theentire test battery normally takes about 75 min-utes to perform, with the vigilance test at theend taking 25 minutes.

Attention test (COG).

Four pictures (numbers, let-ters, figures, etc.) were presented in a row withanother picture below. Subjects had to decidewhether the lower picture matched any of thefour pictures above. A new set of pictures waspresented either after a response or automati-cally after 1.8 seconds. Up to 200 sets of pic-tures were used in this test. The number of cor-rect and incorrect responses, and the meantime to a correct response (MRT) were re-

corded. The score was calculated as the sum ofMRT and the square root of the product ofMRT and mistakes. The number of mistakeswas calculated as the number of wrong re-sponses plus 80 minus the number of correctresponses.

26

Test for reaction time under pressure, determinationtest (DT).

Subjects were given a series of dif-ferent audiovisual signals. Color symbols pre-sented on the screen and acoustic signals hadto be answered by corresponding buttons onthe panel, symbols on the right or left side ofthe screen by corresponding pedals. The fre-quency of the stimuli was automatically adaptedto the subject’s response. A fixed time (480 sec-onds) was used in this study and the mean timeto a correct response (mean reaction time,MRT) was used as the score.

27

Test for visual orientation, tachistoscopic perception

(TAVT).

A complex picture of a situation com-monly encountered in traffic was presented for0.8 seconds. Subjects had to decide whetherthe picture showed: pedestrians, cars, bicycles,traffic signs, and/or traffic lights (correctionswere possible). A total of 33 situations werepresented. The number of missed or wronglyidentified elements was used as the score.

21

Test for motor co-ordination (2-Hand).

Subjects hadto keep a signal on a track by turning two steer-ing wheels: one controlling horizontal move-ments, the other vertical movements. Thetrack consisted of three different sections (cir-cle, V-shape, and L-shape) and had to be nego-tiated 19 times. The mean time taken to nego-tiate the track (T, in seconds) and the meanpercentage of total time during which the sig-nal was off the track (Off%) were recorded.The score was calculated as (T

�

Off%)/100 +0.1

�

T.

28

Vigilance test (VIG).

Subjects were presented witha circle consisting of separate small spots on amonitor. A bright spot moved stepwise aroundthis circle, like the hand of a watch. At long,but irregular intervals, the spot sometimesmissed one of the positions (i.e., jumped overthe marker spots). When this occurred, thesubjects had to press a button as fast as possi-ble. The number of mistakes (incorrect re-sponses or undetected jumps) and the mean


time to a correct response (MRT) were re-corded. The score was calculated as the sum ofMRT and the square root of the product ofMRT and mistakes.

29

Passed tests.

Another method of evaluating driv-ing ability from the cognitive tests used here(DT, COG, TAVT) is to assume unimpaireddriving ability if all test results are above the16th-percentile of the age-independent testscore distribution of the norm population.

25

Statistical Methods

The study was designed as a non-inferioritytrial, that is, the object was to demonstrate thatpatients treated with transdermal fentanyl didnot perform significantly worse in the teststhan the untreated controls. In such trials, aclinically significant difference (delta,

�

) has tobe defined. Alcohol has been used as a stan-dard to assess the degree of impairment in-duced by several drugs.

15

A blood alcohol levelof

�

0.05% has been shown to cause a markedimpairment of driving ability and is the thresh-old for being unfit to drive under Germanlaw.

30–32

In a previous study, the effect of differ-ent antidepressants on cognitive and psycho-motor function was compared using a comput-erized test battery similar to our study. Duringthis study, patients received alcohol orally witha targeted blood concentration of 0.05%. Thestrongest impairment was seen in the testing ofvigilance.

32

From the data of that study an ef-fect size of

�

�

0.57 for the alcohol-related im-pairment of vigilance was calculated. Using thiseffect size, the raw values of the control groupin our study were transformed to obtain virtualvalues that would be equivalent to test perfor-mance under the influence of 0.05% blood al-cohol.

Using this assumption, non-inferiority in thetest battery results of the opioid patients com-pared to controls can be interpreted as a perfor-mance significantly better than that of the con-trol group with a blood alcohol concentrationof 0.05%. The sample size needed to demon-strate non-inferiority using 1:1 randomization

was calculated as 39 (one-sided

t

-test,

�

�

0.05,

�

�

0.20), assuming no difference between pa-tients, and controls. In order to reduce the re-quired number of patients, we decided to per-

form a 1:3 randomization, namely, three controlswere matched to each patient. This gave a sam-

ple size of 26 patients and 78 controls. Wetherefore aimed to enroll 30 patients to allowfor dropouts or protocol violators.

Each of the five tests used involve the record-ing of several parameters. To reduce the prob-lem of multiple testing, one ‘relevant score’was defined prior to the study. The primaryendpoint was defined as the sum of the scoresof the DT, COG, and TAVT tests after z-trans-formation of the individual scores, using themean and the standard deviation of the wholesample.

33

Testing was performed using the Mann–Whitney U-test. A one-sided

P

-value

0.05 wasregarded as significant. Significance tests forparameters other than the primary endpointare exploratory in nature and were performedwithout adjustment for alpha. Unless statedotherwise, results are presented as arithmeticmean

standard deviation (SD) and

P

-valuescorrespond to the test for non-inferiority as de-scribed above.

Results

Between October 1999 and January 2001, atotal of 30 outpatients were enrolled and matchedto 90 controls. As a result of matching, thestudy and control populations had similar de-mographic characteristics (Table 1). The mostfrequent diagnosis in the fentanyl group waslower back pain (

n

�

18), and 6 patients suf-fered from various types of neuropathic pain(e.g., postherpetic neuralgia, atypical facialpain) or from miscellaneous diseases (

n

�

6)such as osteoporosis (Table 1). Seventy-threepercent of the patients suffered from mixedpain (neuropathic and nociceptive), whereas10% had nociceptive and 17% pure neuro-pathic pain only. The median duration of painwas 36 months. Details of previous treatmentwith transdermal fentanyl are shown in Table2. Only three patients had received doseshigher than 100

�

g/hour. Mean current painintensity (measured on an 11-step numericalrating scale) was rated as 3.73

2.59. All butone patient considered themselves fit to drivewhen the test was performed, the other patientanswered “I do not know.”

Urine screening detected use of unreporteddrugs such as cocaine, morphine, thebaine,benzodiazepines, or tricyclic antidepressants in9 cases. Data from these patients were includedin the intent-to-treat (ITT) analysis, while the


remaining 21 patients without any violation ofthe study protocol were analyzed as the per-protocol (PP) group. Results of the tests areshown Table 3.

DT

The number of processed items and thenumber of wrong answers were not availablefor the control group. The number of correctanswers was the lowest in the ITT-group andsignificant non-inferiority could only be shownfor the PP-group (

P

�

0.034). Mean reactiontime was marginally longer in the ITT-groupthan in the PP-group and in the control group.Significant non-inferiority could only be shownfor the PP-group (

P

�

0.015) but not for theITT-group (

P

�

0.3).

COG

The ‘number of correct answers’ and ‘meanreaction time’ were similar in the fentanyl andcontrol groups. Both of the fentanyl groups(ITT, PP) were statistically non-inferior to thecontrol +

�

group (

P

0.05) in this respect.However the ITT-group gave more wrong re-sponses. Therefore, although the calculatedscore of the PP-group proved to be signifi-

cantly non-inferior (

P

�

0.037) to the control +

�

group, the ITT-group did not.

TAVT

The mean number of mistakes was almostthe same in all three groups and significantnon-inferiority could be shown in both analy-ses (ITT:

P

�

0.004; PP:

P

�

0.003) (Figure 1).

2-Hand

The mean time for passing the track waslongest (i.e., worst) in the ITT-group, followedby the PP-group and the control group. For thePP-group, significant non-inferiority to thecontrol group could be shown (

P

�

0.029).The percentage of ‘time off the track’ was low-est (i.e., best) in the ITT-group, followed bythe PP-group and the control group. Thus, sig-nificant non-inferiority could be shown in bothanalyses (

P

0.001 for ITT and PP). For thecalculated score, significant non-inferioritycould be demonstrated for the PP-group (

P

�

0.019) but not for the ITT-group (

P

�

0.1).

VIG

The mean number of mistakes was lowest inthe PP-group, followed by the control group and

Table 1

Demographic Characteristics

Fentanyl Group(ITT,

n

�

30)Control Group

(

n

�

90)

SexMale,

n

(%) 18 (60%) 57 (63%)Female,

n

(%) 12 (40%) 33 (37%)Age (years)

mean

SD (range) 50

9 (34–65) 50

9 (34–65)Diagnosis

Lower back pain (including failed back surgery) 18 –Neuropathic pain syndromes 6 –Miscellaneous 6 –

Duration of pain (months): median (range) 36 (2–216) –Pain intensity (NRS): mean

SD 3 (0–8) –Driving experience (km/year): median (range) 10,000

(500–60,000)–

Driving license (years): median (range) 27 (5–46) –

Table 2

Previous Treatment with Transdermal Fentanyl

Fentanyl Group(ITT,

n

�

30)

Duration (days): median (range) 44 (30–1530)Current dose (

�

g/hour): median (range) 50 (25–400)Fentanyl level (ng/ml): median (range) 1.35 (0.53–17.7)


the ITT-group. Almost no difference was ob-served for the MRT between the three groups.Significant non-inferiority in comparison tothe control group was shown in both analyses(ITT, PP) for both parameters, as well as forthe calculated scores (all

P

-values

0.005).

Sum Score (Primary Endpoint)For the sum score of the z-transformed DT-,

COG-, and TAVT- scores, representing the cog-

nitive items of the test battery, significant non-inferiority could be shown for the PP-group incomparison to the control group (0.22 2.30versus �0.05 2.57, P � 0.036), but not forthe ITT-group (0.60 2.21 versus �0.20 2.58, P � 0.38) (Figure 2).

Table 3Psychomotor and Cognitive Performance Measures Including the Calculated Score of the Different Tests

Fentanyl Group Control Group

Variable ITT PP (raw values) (raw values �)

COG (n) 30 21 90 90Wrong answers (n) 34.23 17.92 29.81 16.28a 26.83 14.29 35.69 14.29Correct answers (n) 53.03 11.09a 53.62 11.89a 53.70 10.29 47.74 10.29MRT (sec) 1.08 0.10a 1.10 0.09a 1.01 0.07 1.15 0.07Score 9.09 1.01 8.86 1.08a 8.36 1.36 9.36 1.36

DT (n) 30 21 90 90Processed items (n) 438.8 73.79 459.1 72.67 n.a. n.a.Wrong reactions (n) 19.93 12.91 19.71 14.23 n.a. n.a.Correct reactions (n) 418.87 72.9 439.38 70.75a 443.70 72.07 402.22 72.07MRT (sec)/Score 1.18 0.21 1.12 0.19a 1.11 0.20 1.23 0.20

TAVT (n) 30 21 90 90Processing time (sec) 267.70 108.22 252.81 81.16 n.a. n.a.Wrong answers (n)/Score 30.53 13.11a 29.76 15.31a 29.08 14.74 37.23 14.74

2-Hand (n) 30 20 90 90Mean time (sec) 42.97 14.75 37.54 11.82a 36.35 14.29 44.68 14.29Time off track (%) 4.42 3.85a 5.09 4.42a 5.26 4.32 7.66 4.32Score 6.12 2.31 5.65 2.26a 5.38 2.18 6.64 2.18

VIG (n) 29 20 90 90Wrong answers (n) 7.34 10.01a 5.85 6.62a 6.88 6.78 11.24 6.78MRT (sec) 0.52 0.08a 0.51 0.09a 0.52 0.07 0.56 0.07Score 2.20 1.24a 2.01 1.13a 2.23 0.97 2.81 0.97

Results are presented as arithmetic mean SD.aResult shown to be significantly non-inferior compared to the control group (P � 0.05)n.a. � data not available; MRT � mean reaction time.The results of the control group are presented as raw values as well as the calculated result of the effect of impairment due to alcohol (raw valuetransformed by � and the variance of the item in the whole sample).

Fig. 1. TAVT score. The number of mistakes in thetesting of tachistoscopic perception showing signifi-cant non-inferiority in the intent-to-treat (ITT) groupas well as in the per-protocol-group (PP) compared tothe control group (ITT: P � 0.004; PP: P � 0.003).Results of the control group are shown as raw values.

Fig. 2. Sum score. Sum score of the z-transformedDT, COG, and TAVT, representing the cognitiveitems of the test battery. The PP-group was shown tobe significantly non-inferior to the control group(P � 0.036); the ITT group did not differ signifi-cantly from the control group (P � 0.188). The fullcircles represent the mean score plus the calculateddelta as described in the method section. The valuesof the control group of the ITT- and the PP-groupdiffer due to the different samples used in the z-transformation.


Passed TestsThe percentages of patients who passed the

single tests, that is, whose relevant test scorewas above the 16th percentile, are displayed inFigure 3. The results of the PP-group, as well asof the ITT-group, demonstrated no statisticallysignificant difference from the control groupin any of the five tests. If one considers allthree primary target tests (DT, COG, TAVT) si-multaneously, it was found that all 3 tests werepassed by 60% of patients in the ITT-groupand by 67% of patients in the PP-group, ascompared to 74% of patients in the controlgroup. Thus, 12 of 30 ITT- patients treatedwith fentanyl-TTS (40%) failed at least one ofthe three tests (1: 30%; 2: 7%; 3: 3%). However26% of the control group failed one or moretests as well (1: 13.5%; 2: 9%; 3: 3.5%). Five outof nine patients with a positive urine screeningfor unreported drug intake failed at least inone of the three tests (56%). There was no sta-tistically significant difference in the numberof tests failed between the fentanyl groups andthe control (P � 0.224).

The median plasma fentanyl concentrationwas 1.35 ng/ml (range 0.53–17.7) at the timeof the testing. Two patients had to be excludeddue to missing blood samples and incompleteperformance of the test battery. There was astatistical correlation between plasma fentanyllevels and the items: ‘number of errors’ (r �0.673; P � 0.002), MRT (r � 0.48; P � 0.04)and the score (r � 0.573; P � 0.01) of the vigi-lance testing of the PP-group (n � 19), but fen-

tanyl concentration was not correlated withany of the other items measured. There was nocorrelation between driving experience (kilo-meters per year) or current pain intensity andthe different items of the test battery. However,the age of the patients correlated with thenumber of ‘processed items’ of the DT (r ��0.686; P � 0.001), the number of ‘correct an-swers’ of the DT (r � �0.72; P 0.001), as wellas to the sum score of the DT (r � 0.782; P 0.001), of the TAVT (r � 0.644; P � 0.002) andthe relevant scores after z-transformation (r �0.766; P 0.001).

DiscussionWith increasing skills in pain management

and increasing use of opioids, the focus of at-tention has shifted from simple pain reductionto the different issues of pain-related impair-ment and quality of life. More and more pa-tients with noncancer pain are receiving long-term opioid treatment.2 Neuropsychologicalsymptoms, such as sedation and dizziness, arefrequent side effects of opioids, and may be-come a major problem with long-term treat-ment.32,34,35

Pain also may impair cognitive and motorfunction,36,37 and opioids might therefore re-duce pain-related impairment of psychomotorand cognitive performance. In our study, cur-rent pain intensity was found not to be signifi-cantly correlated to any items of the test bat-tery. However, this may have been due to thefact that the pain experienced by patients inour study was generally mild (mean: NRS 3.73 2.59), similar to the findings of Galski et al.who also studied patients with mild current pain.11

Numerous trials of bolus dosing of opioidson healthy volunteers have been performed toassess the impact on cognition and psychomo-tor performance.38–43 There have been a fewstudies using fentanyl, which showed impair-ment of cognitive and motor function, thoughnot all elements were impaired to the same de-gree.12–14,16 However, these studies do not re-flect the situation of patients on long-term opi-oid treatment.

Increasing use of long-term opioid therapyin noncancer pain necessitates further studiesof these patients. Haythornthwaite et al. dem-onstrated that treatment with long-acting oralopioids for noncancer pain did not result in a

Fig. 3. Percentage of passed tests. The percentageof patients who passed the five tests (i.e., scoredabove the 16th percentile) showed no difference be-tween the ITT-, PP- and control groups (ITT-group:n � 30 in DT, COG and TAVT; n � 29 in 2-Handand VIG; PP-group: n � 21 in DT, COG and TAVT;n � 20 in 2-Hand and VIG; Control-group: n � 90 inall tests).


decline in cognitive function compared with pa-tients receiving unstable treatment with short-acting opioids.44 Sjögren et al. compared 40non-cancer pain patients on a long-term stableopioid dose to matched healthy volunteers. Thepatients had a significantly impaired perfor-mance in a test of continuous reaction time(CRT), finger tapping test, and a test for atten-tion (PASAT).7 However, the clinical relevanceof the results remains unclear, since a mean-ingful cut-off point had not been defined.

Strumpf et al. compared 20 patients (17non-cancer, 3 cancer) receiving stable doses oforal opioids with healthy volunteers, patientsreceiving benzodiazepines prior to an electiveoperation, and with volunteers under the influ-ence of alcohol (blood alcohol level 0.08%).Patients treated with opioids showed a signifi-cantly impaired reaction time compared to thehealthy volunteers, but there was no statisti-cally significant difference in attention. How-ever, patients taking benzodiazepines had sig-nificantly impaired reaction time compared toall other subgroups. Compared to the opioidgroup, patients under the influence of alcoholhad inferior reaction time, and made moremistakes in attention tests.45 Even though a cut-off point had not been defined, this study sug-gests that patients receiving stable dose of opi-oids have better psychomotor and cognitiveperformance than patients under the influ-ence of benzodiazepines or alcohol.

Galski et al. performed a pilot study in 16 pa-tients with chronic non-malignant pain on long-term opioid therapy. Results were compared toa historical control group of cerebrally com-promised patients. Even though patients treatedwith opioids demonstrated a slight weakness insome tests compared to the control group, theoverall performance was significantly betterthan the performance of the controls. Com-pared to those historical control patients whodid not pass an on-road, behind-the wheel eval-uation, patients receiving opioids showed a sig-nificantly superior performance, which wasmore similar to those control group patientswho did pass the on-road evaluation.11 This isin line with the results of our study, demon-strating the non-inferiority to healthy volun-teers and giving evidence that patients receiv-ing stable doses of transdermal fentanylperform better than the estimated results ofthe effects of alcohol. In the study of Galski

and colleagues, as well as in our study, no sys-tematic pattern of scores that reflected do-main-specific deficits could be detected.

In the present study, scores for 3 out of 5tests were slightly worse in the fentanyl groupthan in the matched controls. However, afterexcluding patients who were using unreporteddrugs, the performance of the remaining per-protocol-group was shown to be significantlynon-inferior to the control group in all tests, aswell as in the overall performance score (sumscore). The observed tendency towards slightlyimpaired function in the larger intent-to-treatgroup, therefore, is probably related to the useof unreported drugs such as benzodiazepines.The habit of taking additional medications notspecified to the pain specialist is a commonphenomenon in pain patients.46 Thirty percentof the patients in our study did take additionalunreported drugs. However, drugs with nega-tive impact on cognitive and psychomotor per-formance were not strictly excluded in ourstudy and this may have deteriorated the re-sults in the per-protocol-group as well. Chronicpain syndromes may lead to reduced physicalperformance status, mood disorders and de-pression, and this may also be related to im-paired function.47 However, this was not evalu-ated in our study.

In agreement with previous studies, otherfactors such as the age of the participants anduse of concomitant medication, seem to havean impact on psychomotor performance andcognition.7,9,48 In the present study, age corre-lated with 3 of 13 sub-items of the test battery aswell as with the sum score of the relevant tests.

It has been recommended that psychoactivedrugs under investigation for behavioral toxic-ity should be compared to alcohol.15,49 Com-paring oral alcohol, intravenous fentanyl, mi-dazolam, and propofol, a similar degree ofimpairment of psychomotor and cognitivefunction was found.15 We did not compare al-cohol and fentanyl directly in our study, butused calculated values from a historical controlgroup. Assumptions used for the calculation ofthe effect size of the blood alcohol level and inthe transformation of the raw values of thecontrol group may have influenced the results.

Comparisons between studies on cognitive andpsychomotor function should be made with cau-tion. Differences in opioid dosage, test systems,patient groups and duration of opioid treatment


as well as other factors such as motivation, per-sonality traits, and fatigue might also affect testresults. It is also unclear in some studies whethera statistically significant finding is related to aclinically relevant result. Only few studies haveused positive controls such as benzodiazepines,alcohol or cerebrally compromised patients as abenchmark for the degree of impairment in painpatients treated with opioids.11,45

ConclusionsIn the present study, patients receiving long-

term treatment with transdermal fentanyl forcontinuous noncancer pain were compared toa historical control group of healthy volun-teers. The results demonstrated that their per-formance was significantly non-inferior to thatof the control group. This study used a test bat-tery covering the relevant aspects of trafficsafety, as recommended by a working group ofthe International Council on Alcohol, Drugsand Traffic Safety and the German legisla-tion.23,24 Our findings also suggested that addi-tional intake of illicit drugs can compromisetest results. However, generalizations from thesefindings should be made with care. Severalvariables that might have an impact on perfor-mance such as the etiology of the pain and theuse of a historical control group for compari-son have not been evaluated. Nevertheless, re-sults from this study demonstrate that patientssuffering from chronic noncancer pain whoare treated with a stable dose of transdermalfentanyl do not have a clinically significant im-pairment of psychomotor or cognitive functionwhich would prevent them from performingcomplex daily activities, such as driving a car.

AcknowledgmentsThis study was supported by a grant of the

Deutsche Krebshilfe e.V. and by Janssen-CilagGmbH, Germany.

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