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Driving Ability Under Long-Term Treatment with Transdermal Fentanyl

      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.

      Keywords

      Introduction

      The management of chronic pain is often difficult. The aim of therapy is not only to reduce pain intensity but also to improve various aspects of the patient's quality of life. Opioids are a cornerstone for pain management and are used not only for the treatment of cancer pain, but also for the management of continuous non-cancer pain.
      • Portenoy R.K
      Current pharmacotherapy of chronic pain.
      • Savage S.R
      Opioid use in the management of chronic pain.
      The side effects of opioids are well documented and must be taken into consideration when determining the potential risks and benefits of treatment. The use of opioids for the treatment of acute pain is often associated with varying degrees of cognitive impairment. This observation has raised concern that long-term opioid treatment might have a negative impact on cognition and psychomotor function. However, there is some evidence that tolerance to opioid-related side effects, such as sedation, develops during long-term treatment.
      • Portenoy R.K
      Tolerance to opioid analgesics clinical aspects.
      • Bruera E
      • Macmillan K
      • Hanson J
      • MacDonald R.N
      The cognitive effects of the administration of narcotic analgesics in patients with cancer pain.
      Additionally, opioid-induced cognitive failure in palliative care patients can often be minimized by opioid switching.
      • de Stoutz N.D
      • Bruera E
      • Suarez-Almazor M
      Opioid rotation for toxicity reduction in terminal cancer patients.
      The influence of opioids on cognitive function and psychomotor performance has been examined in laboratory studies. Studies with patients receiving long-term opioid therapy, as well as single or repeated bolus doses, have demonstrated a range from no impairment to significantly impaired psychomotor function and/or cognition.
      • Banning A
      • Sjogren P
      Cerebral effects of long-term oral opioids in cancer patients measured by continuous reaction time.
      • Sjogren P
      • Thomsen A.B
      • Olsen A.K
      Impaired neuropsychological performance in chronic nonmalignant pain patients receiving long-term oral opioid therapy.
      • Vainio A
      • Ollila J
      • Matikainen E
      • et al.
      Driving ability in cancer patients receiving long-term morphine analgesia.

      Larsen B, Otto H, Dorscheid E, Larsen R. [Effects of long-term opioid therapy on psychomotor function in patients with cancer pain or non-malignant pain]. Anaesthesist 1999;48:613–624.

      • Hanks G.W
      • O'Neill W.M
      • Simpson P
      • Wesnes K
      The cognitive and psychomotor effects of opioid analgesics. II. A randomized controlled trial of single doses of morphine, lorazepam and placebo in healthy subjects.
      However, most studies examined the effects of opioids on cancer patients and only a minority focused on non-cancer pain populations.
      • Sjogren P
      • Thomsen A.B
      • Olsen A.K
      Impaired neuropsychological performance in chronic nonmalignant pain patients receiving long-term oral opioid therapy.
      • Galski T
      • Williams J.B
      • Ehle H.T
      Effects of opioids on driving ability.
      Most of these studies have investigated the impact of long-term administration of morphine. To date, there have been no studies of populations receiving long-term fentanyl therapy. In healthy volunteers, parenteral bolus administration of fentanyl has been shown to produce pronounced cognitive impairment compared to placebo, diazepam, or alcohol.
      • Schneider U
      • Bevilacqua C
      • Jacobs R
      • et al.
      Effects of fentanyl and low doses of alcohol on neuropsychological performance in healthy subjects.
      • Stevenson G.W
      • Pathria M.N
      • Lamping D.L
      • et al.
      Driving ability after intravenous fentanyl or diazepam. A controlled double-blind study.
      • Zacny J.P
      • Lichtor J.L
      • Zaragoza J.G
      • de Wit H
      Subjective and behavioral responses to intravenous fentanyl in healthy volunteers.
      • Thapar P
      • Zacny J.P
      • Thompson W
      • Apfelbaum J.L
      Using alcohol as a standard to assess the degree of impairment induced by sedative and analgesic drugs used in ambulatory surgery.
      The effects of intravenous fentanyl were demonstrated to be dose dependent.
      • Veselis R.A
      • Reinsel R.A
      • Feshchenko V.A
      • et al.
      Impaired memory and behavioral performance with fentanyl at low plasma concentrations.
      Opioids, such as transdermal fentanyl, have been shown to be effective in the treatment of moderate to severe continuous pain associated with both cancer and other chronic conditions.
      • Dellemijn P.L
      • van Duijn H
      • Vanneste J.A
      Prolonged treatment with transdermal fentanyl in neuropathic pain.
      • Donner B
      • Zenz M
      • Strumpf M
      • Raber M
      Long-term treatment of cancer pain with transdermal fentanyl.
      • Nugent M
      • Davis C
      • Brooks D
      • Ahmedzai S
      Long-term observations of patients receiving transdermal fentanyl after a randomized trial.
      • Radbruch L
      • Sabatowski R
      • Petzke F
      • et al.
      Transdermal fentanyl for the management of cancer pain—a survey of 1005 patients.
      There is little knowledge about relevant impairments of cognitive functions, such as interference with driving ability, during long-term treatment with transdermal fentanyl, especially in noncancer patients. Driving is an important feature of modern living and contributes considerably to an independent lifestyle. Even when opioids are used successfully to reduce pain, patients' ability to live a normal life may be constrained if they are disqualified from driving.
      Driving under the influence of alcohol (defined as a blood concentration of >0.05%) or various illicit drugs is prohibited in Germany, as in other European countries. However, there is an exception for patients taking drugs such as opioids prescribed by their physician as part of the therapeutic regimen. Though driving with prescribed opioid medications is not illegal, there is an ongoing discussion about the driving ability of pain patients in Germany. We, therefore, studied patients receiving a stable dose of transdermal fentanyl for continuous noncancer pain to provide more data on the impact of fentanyl on complex psychomotor and cognitive performance that is thought to be related to driving ability.

      Methods

      This was a prospective comparison of patients receiving transdermal fentanyl for chronic non-cancer pain and a group of untreated, healthy controls. Subjects and controls were matched for age and sex, with three controls selected for every fentanyl patient.

      Patients

      Male and female outpatients aged between 18 and 65 years suffering from noncancer pain responsive to opioids could be enrolled if they had been treated with transdermal fentanyl for at least four weeks, without a dose change in the previous 12 days. Participants also required a valid driver's license and the ability to speak and write German. Patients were excluded from the study if they were receiving benzodiazepines or barbiturates >3 times per week, high dose antidepressant treatment (e.g., ⩾75 mg amitriptyline per day), or regular antihistamines. Patients with physical disabilities, severe psychiatric or neurological diseases, or visual disorders that would prevent them from performing the tests were also excluded. All patients gave written, informed consent to participate. The study protocol and the consent form were approved by the ethics committee of the University of Cologne.

      Control Group

      Controls were randomly selected from a pool of volunteers who had been tested between March 1996 and March 1998 (between 2 and 5 pm) at the Institute for Traffic Safety of the Technischer Überwachungsverein GmbH in Cologne, Germany. This pool was part of a larger sample composed of healthy volunteers, with five men and five women for each year of age from 18–80 years. For this study, volunteers over the age of 65 were excluded, resulting in a sample of 484 persons, from which the matched pairs were drawn. The control sample has been described as representative of the normal German population with regard to activity, autonomy and driving experience.
      • Herberg K
      • Herberg K.W
      Entwicklung der sicherheitsrelevanten Leistungsfähigkeit mit dem Lebensalter.

      Course of the Study

      After patients had been informed about the study and had given their consent to take part, their personal details (age, sex, etc.) and medical history were recorded, including full details of their pain disease and the treatments they were receiving. Participants were also asked about their driving experience. Testing was performed between 1 and 5 pm within one week after screening. Prior to testing, a blood sample was taken to determine the plasma fentanyl concentration, and a urine sample was taken to screen for the use of drugs not reported by the patients in the pain clinic. Data from patients using unreported drugs were included in the intent-to-treat (ITT) analysis while the remaining patients were analyzed as the per-protocol (PP) group. Pain intensity was rated immediately before testing using an 11-point numerical rating scale ranging from 0 (no pain) to 10 (worst pain that can be imagined).

      Test Battery

      The test battery followed the German national recommendations on tests to determine driving ability.
      • Bundesregierung D
      Verordnung über die Zulassung von Personen zum Strassenverkehr und zur Änderung strassenverkehrsrechtlicher Vorschriften.
      These require assessment of: performance under pressure, orientation, concentration, attention, and reaction time. Three of the tests performed in the present study (DT, COG, TAVT—described subsequently) cover these five areas.

      International Council on Alcohol Drugs and Traffic Safety. Guidelines on experimental studies undertaken to determine a medicinal drug's effect on driving or skills related to driving. 1999, Available at: www.agnp.de.

      Test batteries similar to the one used in this study are used for traffic delinquents in Germany. Permission to drive for traffic delinquents is usually denied if one or more of these tests is failed, that is, if the test result is below the 16th-percentile of the age-independent reference range.
      • Kroj G
      In addition, tests for motor coordination and for vigilance were also used in this study. These tests have been previously validated.
      All tests were performed under standardized conditions with standardized instructions and in the same sequence by means of the computerized test system (“Wiener Test System”). The entire test battery normally takes about 75 minutes to perform, with the vigilance test at the end taking 25 minutes.

      Attention test (COG)

      Four pictures (numbers, letters, figures, etc.) were presented in a row with another picture below. Subjects had to decide whether the lower picture matched any of the four pictures above. A new set of pictures was presented either after a response or automatically after 1.8 seconds. Up to 200 sets of pictures were used in this test. The number of correct and incorrect responses, and the mean time to a correct response (MRT) were recorded. The score was calculated as the sum of MRT and the square root of the product of MRT and mistakes. The number of mistakes was calculated as the number of wrong responses plus 80 minus the number of correct responses.

      Schuhfried GmbH, ed. Cognitrone - Handbuch. 1994, Dr. Schuhfried GmbH: Mödling.

      Test for reaction time under pressure, determination test (DT)

      Subjects were given a series of different audiovisual signals. Color symbols presented on the screen and acoustic signals had to be answered by corresponding buttons on the panel, symbols on the right or left side of the screen by corresponding pedals. The frequency of the stimuli was automatically adapted to the subject's response. A fixed time (480 seconds) was used in this study and the mean time to a correct response (mean reaction time, MRT) was used as the score.

      Schuhfried GmbH, ed. Wiener Determinationstest, Version 2.00. 1996, Dr. Schuhfried GmbH: Mödling.

      Test for visual orientation, tachistoscopic perception (TAVT)

      A complex picture of a situation commonly encountered in traffic was presented for 0.8 seconds. Subjects had to decide whether the picture showed: pedestrians, cars, bicycles, traffic signs, and/or traffic lights (corrections were possible). A total of 33 situations were presented. The number of missed or wrongly identified elements was used as the score.
      • Herberg K

      Test for motor co-ordination (2-Hand)

      Subjects had to keep a signal on a track by turning two steering wheels: one controlling horizontal movements, the other vertical movements. The track consisted of three different sections (circle, V-shape, and L-shape) and had to be negotiated 19 times. The mean time taken to negotiate the track (T, in seconds) and the mean percentage of total time during which the signal was off the track (Off%) were recorded. The score was calculated as (T × Off%)/100 + 0.1 × T.

      Schuhfried GmbH, ed. Zweihand-Koordination, Version 4.00. 1995, Dr. Schuhfried GmbH: Mödling.

      Vigilance test (VIG)

      Subjects were presented with a circle consisting of separate small spots on a monitor. A bright spot moved stepwise around this circle, like the hand of a watch. At long, but irregular intervals, the spot sometimes missed one of the positions (i.e., jumped over the marker spots). When this occurred, the subjects had to press a button as fast as possible. The number of mistakes (incorrect responses or undetected jumps) and the mean time to a correct response (MRT) were recorded. The score was calculated as the sum of MRT and the square root of the product of MRT and mistakes.

      Schuhfried GmbH, ed. Vigilanz, Version 5.00. 1995, Dr. Schuhfried GmbH: Mödling.

      Passed tests

      Another method of evaluating driving ability from the cognitive tests used here (DT, COG, TAVT) is to assume unimpaired driving ability if all test results are above the 16th-percentile of the age-independent test score distribution of the norm population.
      • Kroj G

      Statistical Methods

      The study was designed as a non-inferiority trial, that is, the object was to demonstrate that patients treated with transdermal fentanyl did not perform significantly worse in the tests than the untreated controls. In such trials, a clinically significant difference (delta, δ) has to be defined. Alcohol has been used as a standard to assess the degree of impairment induced by several drugs.
      • Thapar P
      • Zacny J.P
      • Thompson W
      • Apfelbaum J.L
      Using alcohol as a standard to assess the degree of impairment induced by sedative and analgesic drugs used in ambulatory surgery.
      A blood alcohol level of > 0.05% has been shown to cause a marked impairment of driving ability and is the threshold for being unfit to drive under German law.

      Richter R, Hobi V. [The impairment of the ability to drive with blood alcohol concentrations of 0.5 per mille. A review of the literature]. Schweiz Med Wochenschr 1975;105:884–890.

      Bartl G, Lager F, Domesle L. [Test performance with minimal alcoholic intoxication]. Blutalkohol 1996;33:1–16.

      Herberg KW. [Antidepressives and traffic safety]. Fortschr Neurol Psychiatr 1994;1:24–28.

      In a previous study, the effect of different antidepressants on cognitive and psychomotor function was compared using a computerized test battery similar to our study. During this study, patients received alcohol orally with a targeted blood concentration of 0.05%. The strongest impairment was seen in the testing of vigilance.

      Herberg KW. [Antidepressives and traffic safety]. Fortschr Neurol Psychiatr 1994;1:24–28.

      From the data of that study an effect size of δ = 0.57 for the alcohol-related impairment of vigilance was calculated. Using this effect size, the raw values of the control group in our study were transformed to obtain virtual values that would be equivalent to test performance under the influence of 0.05% blood alcohol.
      Using this assumption, non-inferiority in the test battery results of the opioid patients compared to controls can be interpreted as a performance significantly better than that of the control group with a blood alcohol concentration of 0.05%. The sample size needed to demonstrate non-inferiority using 1:1 randomization was calculated as 39 (one-sided t-test, α = 0.05, β = 0.20), assuming no difference between patients, and controls. In order to reduce the required number of patients, we decided to perform a 1:3 randomization, namely, three controls were matched to each patient. This gave a sample size of 26 patients and 78 controls. We therefore aimed to enroll 30 patients to allow for dropouts or protocol violators.
      Each of the five tests used involve the recording of several parameters. To reduce the problem of multiple testing, one ‘relevant score’ was defined prior to the study. The primary endpoint was defined as the sum of the scores of the DT, COG, and TAVT tests after z-transformation of the individual scores, using the mean and the standard deviation of the whole sample.
      • O'Brien P
      Procedures for comparing samples with multiple endpoints.
      Testing was performed using the Mann–Whitney U-test. A one-sided P-value < 0.05 was regarded as significant. Significance tests for parameters other than the primary endpoint are exploratory in nature and were performed without adjustment for alpha. Unless stated otherwise, results are presented as arithmetic mean ± standard deviation (SD) and P-values correspond to the test for non-inferiority as described above.

      Results

      Between October 1999 and January 2001, a total of 30 outpatients were enrolled and matched to 90 controls. As a result of matching, the study and control populations had similar demographic characteristics (Table 1). The most frequent diagnosis in the fentanyl group was lower back pain (n = 18), and 6 patients suffered from various types of neuropathic pain (e.g., postherpetic neuralgia, atypical facial pain) or from miscellaneous diseases (n = 6) such as osteoporosis (Table 1). Seventy-three percent of the patients suffered from mixed pain (neuropathic and nociceptive), whereas 10% had nociceptive and 17% pure neuropathic pain only. The median duration of pain was 36 months. Details of previous treatment with transdermal fentanyl are shown in Table 2. Only three patients had received doses higher than 100 μg/hour. Mean current pain intensity (measured on an 11-step numerical rating scale) was rated as 3.73 ± 2.59. All but one patient considered themselves fit to drive when the test was performed, the other patient answered “I do not know.”
      Table 1Demographic Characteristics
      Fentanyl Group (ITT, n = 30)Control Group (n = 90)
      Sex
      Male, 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 syndromes6
      Miscellaneous6
      Duration of pain (months): median (range)36 (2–216)
      Pain intensity (NRS): mean ± SD3 (0–8)
      Driving experience (km/year): median (range)10,000 (500–60,000)
      Driving license (years): median (range)27 (5–46)
      Table 2Previous Treatment with Transdermal Fentanyl
      Fentanyl Group (ITT, n = 30)
      Duration (days): median (range)44 (30–1530)
      Current dose (μg/hour): median (range)50 (25–400)
      Fentanyl level (ng/ml): median (range)1.35 (0.53–17.7)
      Urine screening detected use of unreported drugs such as cocaine, morphine, thebaine, benzodiazepines, or tricyclic antidepressants in 9 cases. Data from these patients were included in the intent-to-treat (ITT) analysis, while the remaining 21 patients without any violation of the study protocol were analyzed as the per-protocol (PP) group. Results of the tests are shown Table 3.
      Table 3Psychomotor and Cognitive Performance Measures Including the Calculated Score of the Different Tests
      Fentanyl GroupControl Group
      VariableITTPP(raw values)(raw values + δ)
      COG (n)30219090
      Wrong answers (n)34.23 ± 17.9229.81 ± 16.28
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      26.83 ± 14.2935.69 ± 14.29
      Correct answers (n)53.03 ± 11.09
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      53.62 ± 11.89
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      53.70 ± 10.2947.74 ± 10.29
      MRT (sec)1.08 ± 0.10
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      1.10 ± 0.09
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      1.01 ± 0.071.15 ± 0.07
      Score9.09 ± 1.018.86 ± 1.08
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      8.36 ± 1.369.36 ± 1.36
      DT (n)30219090
      Processed items (n)438.8 ± 73.79459.1 ± 72.67n.a.n.a.
      Wrong reactions (n)19.93 ± 12.9119.71 ± 14.23n.a.n.a.
      Correct reactions (n)418.87 ± 72.9439.38 ± 70.75
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      443.70 ± 72.07402.22 ± 72.07
      MRT (sec)/Score1.18 ± 0.211.12 ± 0.19
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      1.11 ± 0.201.23 ± 0.20
      TAVT (n)30219090
      Processing time (sec)267.70 ± 108.22252.81 ± 81.16n.a.n.a.
      Wrong answers (n)/Score30.53 ± 13.11
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      29.76 ± 15.31
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      29.08 ± 14.7437.23 ± 14.74
      2-Hand (n)30209090
      Mean time (sec)42.97 ± 14.7537.54 ± 11.82
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      36.35 ± 14.2944.68 ± 14.29
      Time off track (%)4.42 ± 3.85
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      5.09 ± 4.42
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      5.26 ± 4.327.66 ± 4.32
      Score6.12 ± 2.315.65 ± 2.26
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      5.38 ± 2.186.64 ± 2.18
      VIG (n)29209090
      Wrong answers (n)7.34 ± 10.01
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      5.85 ± 6.62
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      6.88 ± 6.7811.24 ± 6.78
      MRT (sec)0.52 ± 0.08
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      0.51 ± 0.09
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      0.52 ± 0.070.56 ± 0.07
      Score2.20 ± 1.24
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      2.01 ± 1.13
      Result shown to be significantly non-inferior compared to the control group (P > 0.05)
      2.23 ± 0.972.81 ± 0.97
      Results are presented as arithmetic mean ± SD.
      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 value transformed by δ and the variance of the item in the whole sample).
      a Result shown to be significantly non-inferior compared to the control group (P > 0.05)

      Dt

      The number of processed items and the number of wrong answers were not available for the control group. The number of correct answers was the lowest in the ITT-group and significant non-inferiority could only be shown for the PP-group (P = 0.034). Mean reaction time was marginally longer in the ITT-group than in the PP-group and in the control group. Significant non-inferiority could only be shown for the PP-group (P = 0.015) but not for the ITT-group (P = 0.3).

      Cog

      The ‘number of correct answers’ and ‘mean reaction time’ were similar in the fentanyl and control groups. Both of the fentanyl groups (ITT, PP) were statistically non-inferior to the control + δ group (P < 0.05) in this respect. However the ITT-group gave more wrong responses. Therefore, although the calculated score of the PP-group proved to be significantly non-inferior (P = 0.037) to the control + δ group, the ITT-group did not.

      Tavt

      The mean number of mistakes was almost the same in all three groups and significant non-inferiority could be shown in both analyses (ITT: P = 0.004; PP: P = 0.003) (Figure 1).
      Figure thumbnail gr1
      Fig. 1TAVT score. The number of mistakes in the testing of tachistoscopic perception showing significant non-inferiority in the intent-to-treat (ITT) group as well as in the per-protocol-group (PP) compared to the control group (ITT: P = 0.004; PP: P = 0.003). Results of the control group are shown as raw values.

      2-Hand

      The mean time for passing the track was longest (i.e., worst) in the ITT-group, followed by the PP-group and the control group. For the PP-group, significant non-inferiority to the control group could be shown (P = 0.029). The percentage of ‘time off the track’ was lowest (i.e., best) in the ITT-group, followed by the PP-group and the control group. Thus, significant non-inferiority could be shown in both analyses (P < 0.001 for ITT and PP). For the calculated score, significant non-inferiority could 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 in the PP-group, followed by the control group and the ITT-group. Almost no difference was observed for the MRT between the three groups. Significant non-inferiority in comparison to the control group was shown in both analyses (ITT, PP) for both parameters, as well as for the 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 cognitive items of the test battery, significant non-inferiority could be shown for the PP-group in comparison to the control group (0.22 ± 2.30 versus −0.05 ± 2.57, P = 0.036), but not for the ITT-group (0.60 ± 2.21 versus −0.20 ± 2.58, P = 0.38) (Figure 2).
      Figure thumbnail gr2
      Fig. 2Sum score. Sum score of the z-transformed DT, COG, and TAVT, representing the cognitive items of the test battery. The PP-group was shown to be significantly non-inferior to the control group (P = 0.036); the ITT group did not differ significantly from the control group (P = 0.188). The full circles represent the mean score plus the calculated delta as described in the method section. The values of the control group of the ITT- and the PP-group differ due to the different samples used in the z-transformation.

      Passed Tests

      The percentages of patients who passed the single tests, that is, whose relevant test score was above the 16th percentile, are displayed in Figure 3. The results of the PP-group, as well as of the ITT-group, demonstrated no statistically significant difference from the control group in any of the five tests. If one considers all three primary target tests (DT, COG, TAVT) simultaneously, it was found that all 3 tests were passed by 60% of patients in the ITT-group and by 67% of patients in the PP-group, as compared to 74% of patients in the control group. Thus, 12 of 30 ITT- patients treated with fentanyl-TTS (40%) failed at least one of the three tests (1: 30%; 2: 7%; 3: 3%). However 26% of the control group failed one or more tests as well (1: 13.5%; 2: 9%; 3: 3.5%). Five out of nine patients with a positive urine screening for unreported drug intake failed at least in one of the three tests (56%). There was no statistically significant difference in the number of tests failed between the fentanyl groups and the control (P = 0.224).
      Figure thumbnail gr3
      Fig. 3Percentage of passed tests. The percentage of patients who passed the five tests (i.e., scored above the 16th percentile) showed no difference between the ITT-, PP- and control groups (ITT-group: n = 30 in DT, COG and TAVT; n = 29 in 2-Hand and VIG; PP-group: n = 21 in DT, COG and TAVT; n = 20 in 2-Hand and VIG; Control-group: n = 90 in all tests).
      The median plasma fentanyl concentration was 1.35 ng/ml (range 0.53–17.7) at the time of the testing. Two patients had to be excluded due to missing blood samples and incomplete performance of the test battery. There was a statistical correlation between plasma fentanyl levels 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 vigilance testing of the PP-group (n = 19), but fentanyl concentration was not correlated with any of the other items measured. There was no correlation between driving experience (kilometers per year) or current pain intensity and the different items of the test battery. However, the age of the patients correlated with the number of ‘processed items’ of the DT (r = −0.686; P = 0.001), the number of ‘correct answers’ of the DT (r = −0.72; P < 0.001), as well as to the sum score of the DT (r = 0.782; P < 0.001), of the TAVT (r = 0.644; P = 0.002) and the relevant scores after z-transformation (r = 0.766; P < 0.001).

      Discussion

      With increasing skills in pain management and increasing use of opioids, the focus of attention has shifted from simple pain reduction to the different issues of pain-related impairment and quality of life. More and more patients with noncancer pain are receiving long-term opioid treatment.
      • Savage S.R
      Opioid use in the management of chronic pain.
      Neuropsychological symptoms, such as sedation and dizziness, are frequent side effects of opioids, and may become a major problem with long-term treatment.

      Herberg KW. [Antidepressives and traffic safety]. Fortschr Neurol Psychiatr 1994;1:24–28.

      • Hemmelgarn B
      • Suissa S
      • Huang A
      • et al.
      Benzodiazepine use and the risk of motor vehicle crash in the elderly.

      Soyka M, Dittert S, Gartenmeier A, Schafer M. [Driving fitness in therapy with antidepressive drugs]. Versicherungsmedizin 1998;50:59–66.

      Pain also may impair cognitive and motor function,
      • Lorenz J
      • Baumgärtner U
      • Zander A
      • Bromm B
      Differenzierung von schmerz- und morphinbedingter Beeinträchtigung kognitiver Leistungen und subjektiver Befindlichkeit bei Knochenmarktransplantationspatienten.
      • Lorenz J
      • Beck H
      • Bromm B
      Cognitive performance, mood and experimental pain before and during morphine-induced analgesia in patients with chronic non-malignant pain.
      and opioids might therefore reduce pain-related impairment of psychomotor and cognitive performance. In our study, current pain intensity was found not to be significantly correlated to any items of the test battery. However, this may have been due to the fact that the pain experienced by patients in our 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.
      • Galski T
      • Williams J.B
      • Ehle H.T
      Effects of opioids on driving ability.
      Numerous trials of bolus dosing of opioids on healthy volunteers have been performed to assess the impact on cognition and psychomotor performance.
      • Zacny J.P
      • Lichtor J.L
      • Thapar P
      • et al.
      Comparing the subjective, psychomotor and physiological effects of intravenous butorphanol and morphine in healthy volunteers.
      • Zacny J.P
      • Conley K
      • Galinkin J
      Comparing the subjective, psychomotor and physiological effects of intravenous buprenorphine and morphine in healthy volunteers.
      • Zacny J.P
      • Hill J.L
      • Black M.L
      • Sadeghi P
      Comparing the subjective, psychomotor and physiological effects of intravenous pentazocine and morphine in normal volunteers.
      • Hill J.L
      • Zacny J.P
      Comparing the subjective, psychomotor, and physiological effects of intravenous hydromorphone and morphine in healthy volunteers.
      • Walker D.J
      • Zacny J.P
      Subjective, psychomotor, and physiological effects of cumulative doses of opioid mu agonists in healthy volunteers.
      • Walker D.J
      • Zacny J.P
      Subjective, psychomotor, and analgesic effects of oral codeine and morphine in healthy volunteers.
      There have been a few studies using fentanyl, which showed impairment of cognitive and motor function, though not all elements were impaired to the same degree.
      • Schneider U
      • Bevilacqua C
      • Jacobs R
      • et al.
      Effects of fentanyl and low doses of alcohol on neuropsychological performance in healthy subjects.
      • Stevenson G.W
      • Pathria M.N
      • Lamping D.L
      • et al.
      Driving ability after intravenous fentanyl or diazepam. A controlled double-blind study.
      • Zacny J.P
      • Lichtor J.L
      • Zaragoza J.G
      • de Wit H
      Subjective and behavioral responses to intravenous fentanyl in healthy volunteers.
      • Veselis R.A
      • Reinsel R.A
      • Feshchenko V.A
      • et al.
      Impaired memory and behavioral performance with fentanyl at low plasma concentrations.
      However, these studies do not reflect the situation of patients on long-term opioid treatment.
      Increasing use of long-term opioid therapy in noncancer pain necessitates further studies of these patients. Haythornthwaite et al. demonstrated that treatment with long-acting oral opioids for noncancer pain did not result in a decline in cognitive function compared with patients receiving unstable treatment with short-acting opioids.
      • Haythornthwaite J.A
      • Menefee L.A
      • Quatrano-Piacentini A.L
      • Pappagallo M
      Outcome of chronic opioid therapy for non-cancer pain.
      Sjögren et al. compared 40 non-cancer pain patients on a long-term stable opioid dose to matched healthy volunteers. The patients had a significantly impaired performance in a test of continuous reaction time (CRT), finger tapping test, and a test for attention (PASAT).
      • Sjogren P
      • Thomsen A.B
      • Olsen A.K
      Impaired neuropsychological performance in chronic nonmalignant pain patients receiving long-term oral opioid therapy.
      However, the clinical relevance of the results remains unclear, since a meaningful cut-off point had not been defined.
      Strumpf et al. compared 20 patients (17 non-cancer, 3 cancer) receiving stable doses of oral opioids with healthy volunteers, patients receiving benzodiazepines prior to an elective operation, and with volunteers under the influence of alcohol (blood alcohol level 0.08%). Patients treated with opioids showed a significantly impaired reaction time compared to the healthy volunteers, but there was no statistically significant difference in attention. However, patients taking benzodiazepines had significantly impaired reaction time compared to all other subgroups. Compared to the opioid group, patients under the influence of alcohol had inferior reaction time, and made more mistakes in attention tests.
      • Strumpf M
      • Köhler A
      • Zenz M
      • et al.
      Opioide und Fahrtüchtigkeit.
      Even though a cut-off point had not been defined, this study suggests that patients receiving stable dose of opioids have better psychomotor and cognitive performance than patients under the influence of benzodiazepines or alcohol.
      Galski et al. performed a pilot study in 16 patients with chronic non-malignant pain on long-term opioid therapy. Results were compared to a historical control group of cerebrally compromised patients. Even though patients treated with opioids demonstrated a slight weakness in some tests compared to the control group, the overall performance was significantly better than the performance of the controls. Compared to those historical control patients who did not pass an on-road, behind-the wheel evaluation, patients receiving opioids showed a significantly superior performance, which was more similar to those control group patients who did pass the on-road evaluation.
      • Galski T
      • Williams J.B
      • Ehle H.T
      Effects of opioids on driving ability.
      This is in line with the results of our study, demonstrating the non-inferiority to healthy volunteers and giving evidence that patients receiving stable doses of transdermal fentanyl perform better than the estimated results of the effects of alcohol. In the study of Galski and colleagues, as well as in our study, no systematic pattern of scores that reflected domain-specific deficits could be detected.
      In the present study, scores for 3 out of 5 tests were slightly worse in the fentanyl group than in the matched controls. However, after excluding patients who were using unreported drugs, the performance of the remaining per-protocol-group was shown to be significantly non-inferior to the control group in all tests, as well as in the overall performance score (sum score). The observed tendency towards slightly impaired function in the larger intent-to-treat group, therefore, is probably related to the use of unreported drugs such as benzodiazepines. The habit of taking additional medications not specified to the pain specialist is a common phenomenon in pain patients.
      • Schulzeck S
      • Maier C
      • Rochholz G
      • Schütz H
      Stellenwert des “Medikamenten-Screenings” in der Therapie chronischer Schmerzen.
      Thirty percent of the patients in our study did take additional unreported drugs. However, drugs with negative impact on cognitive and psychomotor performance were not strictly excluded in our study and this may have deteriorated the results in the per-protocol-group as well. Chronic pain syndromes may lead to reduced physical performance status, mood disorders and depression, and this may also be related to impaired function.
      • Brown S.C
      • Glass J.M
      • Park D.C
      The relationship of pain and depression to cognitive function in rheumatoid arthritis patients.
      However, this was not evaluated in our study.
      In agreement with previous studies, other factors such as the age of the participants and use of concomitant medication, seem to have an impact on psychomotor performance and cognition.
      • Sjogren P
      • Thomsen A.B
      • Olsen A.K
      Impaired neuropsychological performance in chronic nonmalignant pain patients receiving long-term oral opioid therapy.

      Larsen B, Otto H, Dorscheid E, Larsen R. [Effects of long-term opioid therapy on psychomotor function in patients with cancer pain or non-malignant pain]. Anaesthesist 1999;48:613–624.

      Emsbach M, Friedel B. [Traffic accidents of senior citizen car drivers]. Z Gerontol Geriatr 1999;32:318–325.

      In the present study, age correlated with 3 of 13 sub-items of the test battery as well as with the sum score of the relevant tests.
      It has been recommended that psychoactive drugs under investigation for behavioral toxicity should be compared to alcohol.
      • Thapar P
      • Zacny J.P
      • Thompson W
      • Apfelbaum J.L
      Using alcohol as a standard to assess the degree of impairment induced by sedative and analgesic drugs used in ambulatory surgery.
      • Willette R
      • Walsh J
      Comparing oral alcohol, intravenous fentanyl, midazolam, and propofol, a similar degree of impairment of psychomotor and cognitive function was found.
      • Thapar P
      • Zacny J.P
      • Thompson W
      • Apfelbaum J.L
      Using alcohol as a standard to assess the degree of impairment induced by sedative and analgesic drugs used in ambulatory surgery.
      We did not compare alcohol and fentanyl directly in our study, but used calculated values from a historical control group. Assumptions used for the calculation of the effect size of the blood alcohol level and in the transformation of the raw values of the control group may have influenced the results.
      Comparisons between studies on cognitive and psychomotor function should be made with caution. Differences in opioid dosage, test systems, patient groups and duration of opioid treatment as well as other factors such as motivation, personality traits, and fatigue might also affect test results. It is also unclear in some studies whether a statistically significant finding is related to a clinically relevant result. Only few studies have used positive controls such as benzodiazepines, alcohol or cerebrally compromised patients as a benchmark for the degree of impairment in pain patients treated with opioids.
      • Galski T
      • Williams J.B
      • Ehle H.T
      Effects of opioids on driving ability.
      • Strumpf M
      • Köhler A
      • Zenz M
      • et al.
      Opioide und Fahrtüchtigkeit.

      Conclusions

      In the present study, patients receiving long-term treatment with transdermal fentanyl for continuous noncancer pain were compared to a historical control group of healthy volunteers. The results demonstrated that their performance was significantly non-inferior to that of the control group. This study used a test battery covering the relevant aspects of traffic safety, as recommended by a working group of the International Council on Alcohol, Drugs and Traffic Safety and the German legislation.
      • Bundesregierung D
      Verordnung über die Zulassung von Personen zum Strassenverkehr und zur Änderung strassenverkehrsrechtlicher Vorschriften.

      International Council on Alcohol Drugs and Traffic Safety. Guidelines on experimental studies undertaken to determine a medicinal drug's effect on driving or skills related to driving. 1999, Available at: www.agnp.de.

      Our findings also suggested that additional intake of illicit drugs can compromise test results. However, generalizations from these findings should be made with care. Several variables that might have an impact on performance such as the etiology of the pain and the use of a historical control group for comparison have not been evaluated. Nevertheless, results from this study demonstrate that patients suffering from chronic noncancer pain who are treated with a stable dose of transdermal fentanyl do not have a clinically significant impairment of psychomotor or cognitive function which would prevent them from performing complex daily activities, such as driving a car.

      Acknowledgements

      This study was supported by a grant of the Deutsche Krebshilfe e.V. and by Janssen-Cilag GmbH, Germany.

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