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Acute Opioid Administration Improves Work-Related Exercise Performance in Patients With Chronic Back Pain
The Journal of Pain, Vol 9, No 9 (September), 2008: pp 856-862 Available online at www.sciencedirect.com
Acute Opioid Administration Improves Work-Related Exercise Performance in Patients With Chronic Back Pain Douglas P. Gross,* Yagesh Bhambhani,‡ Mark J. Haykowsky,* and Saifudin Rashiq§ *Department of Physical Therapy, ‡ Department of Occupational Therapy, and § Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, Canada.
Abstract: We studied the impact of acute opioid administration on work-related exercise performance in patients with chronic back pain. A double-blinded, random-order, placebo-controlled, crossover trial was conducted. Subjects were predominately men (63%), with a mean age of 49 years. Subjects performed a continuous lifting and lowering test to voluntary fatigue at a load equivalent to 33% of their predetermined maximal lifting load twice: Once after receiving a single intravenous dose of 1 g/kg fentanyl (a narcotic analgesic) and once after saline placebo. Of the 30 subjects undergoing testing, 3 subjects were unable to complete testing due to medication-induced nausea. Subjects lifted on average 29.4 ⴞ 17.9 kg under the influence of fentanyl versus 25.6 ⴞ 3.1 kg with placebo (effect size ⴝ 0.23). Time to fatigue was higher in the fentanyl group (312 ⴞ 251.4 vs 231 ⴞ 199.9 seconds, effect size ⴝ 0.40), and these subjects also performed more total work (7004 ⴞ 5144 vs 4748 ⴞ 3147 J, effect size ⴝ 0.72). Opioid analgesia improves lifting performance in the short term in individuals with chronic back pain. Longer trials of the effectiveness of opioid analgesia as an adjunct to functional restoration programs are recommended. Perspective: This article presents the results of a clinical trial showing that acute opioid administration improves work-related exercise performance in individuals with chronic back pain. Longer trials of the effectiveness of opioid analgesia as an adjunct to functional restoration programs are recommended. © 2008 by the American Pain Society Key words: Narcotic analgesia, functional capacity evaluation, work-related function, lumbar spine, work ability.
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hronic low back pain is a common reason for work loss and decreased productivity in the workplace.4,31 Currently, few interventions are effective in managing chronic back pain or its associated disability.1,34 One option for physicians is to prescribe opioid analgesia with the goals of reducing pain and increasing function.15 Opioid analgesia appears to be effective for short-term pain reduction in patients with chronic low back pain, but few clinical trials have been reported that examine their influence on functional performance.5,15,21 The lack of controlled clinical trials is disturbing, given the potential side effects of opioids Received February 15, 2008; Revised April 21, 2008; Accepted April 28, 2008. Supported by the University of Alberta. Address reprint requests to Dr. Douglas P. Gross, 2-50 Corbett Hall, University of Alberta, Edmonton, Alberta, Canada T6G 2G4. E-mail: [email protected] 1526-5900/$34.00 © 2008 by the American Pain Society doi:10.1016/j.jpain.2008.04.006
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including physiological dependency or addiction when used over the long term.25 An expert panel has recently recommended that opioids be prescribed for patients with chronic back pain as part of a multimodal treatment plan including exercise therapy, behavioral therapy, or maintenance of normal activity.15 Whether opioids effectively augment such rehabilitation programs or actually have an impact on functional performance has not been well investigated.16 Most randomized, controlled trials conducted have subjectively investigated function through the use of self-report outcome measures such as the Roland Disability Questionnaire.5 To date, only 1 study has investigated the effect of opioid analgesia on performance-based exercise testing in patients with chronic back pain.26 Results indicated that subjects receiving intravenous administration of opioids had reduced pain and performed to higher levels during an isometric trunk extension exercise test. These findings may imply that diminishing pain levels could
Gross et al lead to improved ability to undertake functional tasks. A limitation of the study cited was the reliance on a single exercise test, the Biering-Sorenson low back muscle endurance test.3 In this test, subjects lie prone with the lower limbs strapped onto an adjustable plinth, then elevate and support their upper torso and arms in the horizontal plane to the point of fatigue. The test was initially described as a trunk endurance test; however, recent findings indicate that the test may be terminated more frequently by pain than reduced trunk endurance.30 Thus, it is not surprising that decreasing pain levels with analgesia resulted in improved test performance. Additionally, the Sorenson test is not truly a functional test in that the maneuver does not simulate any activity commonly performed during real life or work activity. Therefore, further evaluation of the impact of opioid analgesics on more realistic functional activities is needed. In an attempt to more realistically evaluate the ability for work activity, many performance-based functional measures have been developed that attempt to simulate true functional activities.7,20 A variety of functional protocols have been described, with most containing some form of dynamic or incremental lifting task. Lifting represents a task commonly performed during work and other activities of daily living and is often reported as difficult by patients with back pain.23 It is also a commonly prescribed exercise during functional restoration programs. Whether opioids alter performance potential for lifting in patients with chronic back pain is unknown. We examined the impact of acute opioid administration on repetitive lifting and lowering exercise performance in patients with chronic back pain. Our null hypothesis was that administration of opioids would not alter the lifting load and the time to voluntary fatigue in these patients.
857
Figure 1. Flow diagram of subject recruitment.
A double-blinded, random-order, placebo-controlled, crossover trial was conducted. Subjects performed a lifting test twice, once after receiving a single intravenous dose of 1 g/kg fentanyl (a narcotic analgesic) and once after saline placebo. The University of Alberta’s Health Research Ethics Board approved this study, and informed consent was obtained from each subject.
testing. A subject recruitment flow diagram is shown in Fig 1. Recruitment took place between August and October 2007. Specific criteria for inclusion in the clinical trial were (1) chronic back pain of ⬎6 months’ duration with or without leg pain; (2) back pain intensity rated as ⱖ3 of 10; (3) age ⬎18 years; (4) absence of specific pathology (eg, fracture, cancer, infection, or inflammatory arthritis); (5) no other comorbidity that would have affected maximal performance testing (eg, significant cardiovascular, pulmonary, endocrine, or neurologic disease); (6) absence of factors posing increased risk of harm from administration of intravenous opioid analgesic (eg, severe pulmonary disease); (7) no reported history of substance abuse; (8) willingness to stop taking opioid analgesics for at least 24 hours before the test session; (9) no known sensitivity to fentanyl or naloxone; and (10) ability to comprehend written and spoken English.
Subjects
Study Protocols
Written informed consent was obtained from 30 individuals with chronic back pain of at least 6 months’ duration. This sample size was chosen to detect a 10-kg difference in maximum floor-to-waist lift at a 0.05 ␣ level with 80% power. Subjects were recruited from the University Hospital Multidisciplinary Pain Centre and the local community via newspaper and television advertisements. Subjects completed the Physical Activity Readiness Questionnaire32 before entry and were screened by a physician for suitability to participate in functional
A schematic of the study procedures is shown in Fig 2. After screening by telephone and before recruitment and testing, all subjects completed a 24-hour, narcoticsfree washout period. Subjects took all of their other scheduled medications normally. Testing took place in the Work Physiology Research Laboratory at the University of Alberta. On arrival at the testing facility, basic demographic data were collected, a medical history and examination for fitness to participate was performed, and self-report measures were completed including a 10-
Materials and Methods Design
858
Opioids Improve Exercise Performance in Chronic Pain from the physical exertion of the first test session and to minimize carryover effects from the fentanyl to placebo phase before undergoing repeat testing under the alternate treatment condition. After 30 minutes, subjects continued to the next study phase and either fentanyl or saline placebo was administered (per the randomization). The same lifting capacity test was repeated. After completion of all testing, subjects were asked to guess the order of drug administration, and subjects were reimbursed $60 CDN for their time. Subjects were allowed to rest in a supervised waiting area until they were capable of independently driving home. The investigators arranged transportation via taxi for 1 subject who had nausea associated with medication administration.
Exercise Performance Measures
Figure 2. Schematic of study procedures.
point Numeric Pain Rating scale and the Roland Disability Questionnaire. Subjects were asked about whether they had abstained from narcotic medication for the required 24-hour period; however, urine toxicology tests were not conducted. Thereafter, a 22-gauge intravenous cannula was positioned in the hand or forearm and saline-locked. Random assignment was performed by using a Webbased random number generator (www.random.org). On the day of testing, the physician investigator opened an opaque, sealed envelope containing treatment order allocation (fentanyl then placebo or vice versa), prepared identical syringes containing either fentanyl (1 g/kg) or saline placebo, administered the medications, and monitored the participants’ vital signs but did not participate in the conduct of functional testing. This investigator was responsible for the subject’s safety and welfare throughout all stages of the procedure. All medications were given intravenously, and subjects were not told whether they were receiving medication or placebo. Subjects were instructed to speak only if they required help in some way and specifically were asked not to describe any changes in the way they felt after each injection unless it formed part of a request for assistance or termination of the study. All investigators who measured and recorded outcome data were blinded to treatment assignment until all subjects completed the protocol. The functional test protocol took less than 30 minutes. After the completion of functional testing, subjects in the fentanyl phase were given naloxone (3 g/kg iv) and those in the placebo group were given saline. Thereafter, a 30-minute rest was taken to permit recovery
An experienced rater who had been trained in the clinical administration of functional capacity evaluation performed all functional testing. Floor-to-waist lifting was the primary outcome of interest and was measured in 2 ways: 1-repetition maximal lift and repetitive lifting to fatigue. Floor-to-waist lifting as performed in a variety of functional capacity evaluation protocols has been reported to be a valid indicator of work-related function and modestly predicts future return to work.9-12,22,24
Maximum Floor-to-Waist Lifting Before initiating this test, each subject was shown a safe lifting technique. One-repetition maximum psychophysical methods were then used to test maximal lift ability.2,33 The subject was asked to lift a 5-kg crate (33 ⫻ 33 ⫻ 29 cm) fitted with circular handlebars from a table 76 cm high, to the floor, and then back to the table. Testing began at a light level (5 kg) to allow subjects to warm up and become familiar with the test; the weight was increased by 1 to 3 kg until the subjects thought that they had attained a maximum safe lift. Subjects were asked to identify the maximal weight that they would be able to dependably reproduce approximately 8 to 10 times per day. They were allowed 30 seconds between successive lifts to minimize the effects of fatigue. The reliability of psychophysical floor-to-waist lifting has been examined and found to be adequate for clinical use.2,14 Subjects were blinded to the amount of weight in the lifting unit during testing. The outcome from this test was maximum weight lifted in kilograms.
Repetitive Floor-to-Waist Lifting to Fatigue The repetitive lifting and lowering (RILL) protocol was next administered by using a modified procedure that has been used in subjects with back pain.17,18 Subjects were asked to repetitively complete dynamic floor-towaist lifting from the table to the floor, then back to the table. The weight level for the test was set at 33% of the load lifted during the maximal floor-to-waist lift, in accordance with the National Institute for Occupational Safety recommendations.29 Subjects were blinded to the amount of weight in the lifting unit. They were asked to
Gross et al lift at a predetermined cadence (10 lifts per minute), in rhythm with an electronic metronome. Heart rate and ratings of perceived exertion (RPE) using the Borg scale were monitored every minute. The following criteria were used to terminate the test: (1) Attainment of an RPE of 18 implying that the work was “very hard” and (2) inability to continue at the prescribed lifting cadence, that is, attainment of fatigue. Outcomes from this test included time to fatigue in seconds and total work done in kilogram meters (kgm). The latter was calculated as follows: weight lifted (kg) ⫻ number of repetitions completed during the time to fatigue ⫻ the distance between the floor and table top (76 cm). This value was converted into Joules, using a factor of 1 kgm ⫽ 9.80 Joules. Pain intensity was measured using an 11-point numeric rating scale (NRS, anchored at 0, meaning no pain at all, and 10 meaning the worst imaginable pain) at the beginning and end of testing procedures and at 120 seconds after each study injection. The ratings 120 seconds after injection served as the postintervention outcome for comparison to baseline measures. The NRS has been shown to be a reliable and valid measure of pain severity in the population with back pain.6
859 Table 1.
Subject Characteristics (n ⴝ 30) VARIABLE
Age in years Pain intensity at baseline (of 10) Roland Disability Questionnaire (of 24) Number of previous treatments for LBP Male sex Currently working Currently receiving disability benefits for LBP Marital status Single Married Divorced Educational status No high school diploma High school diploma University Nonspecific diagnosis Surgery for LBP Previous narcotic use for LBP Treatment allocation Fentanyl first Unable to complete testing (all due to nausea)
MEAN (SD) OR PERCENTAGE 49.4 (16.4) 6.0 (2.1) 12.0 (4.7) 2.9 (1.7) 63% 60% 13% 50% 40% 10% 23% 20% 57% 80% 10% 63% 40% 10%
Abbreviation: LBP, lower back pain.
Analysis Descriptive statistics including means and standard deviations were calculated for continuous variables and percentages for categorical variables. Differences in performance between the fentanyl and placebo phases were examined by using a paired-sample t test for crossover designs. All analyses were completed as intention to treat. Standardized effect sizes were calculated by dividing the mean difference by the standard deviation of the control group. The paired-sample t test was also used to determine differences between the first and second testing occasions to judge if a testing effect was present in subjects undergoing testing. We also performed stratified analysis to test for a carryover effect in those subjects receiving fentanyl first, for the effect of inadequate blinding to treatment allocation, and for the effect of prior narcotic use. An ␣ level of .05 was used. Statistical analyses were performed using SPSS 14.0 for Windows (SPSS, Inc., Chicago, IL).
Results Demographics Subjects were predominately employed (60%) men (63%), with a mean age of 49 years (Table 1). The majority of subjects had nonspecific back pain (80%) and 63% had previously used narcotic analgesia to manage their pain.
Treatment Allocation Of the 30 subjects who underwent testing, 12 were randomly assigned to receive fentanyl first, whereas 18 received placebo first. Three subjects were unable to complete testing due to nausea or vomiting induced by
fentanyl administration. Of 27 subjects who completed testing, 18 (67%) correctly guessed their order of treatment. 1 week after testing, 13 subjects reported no adverse effects at all, 4 subjects reported lasting improvements in their pain, 12 reported increased pain for up to 72 hours after the test session, and 5 reported a persistent sensation of nausea for up to 24 hours. Eleven subjects did not return calls enquiring about their postexperimental experience, but it is unlikely these subjects had major difficulty because all subjects had been instructed to contact the investigators if they had pain exacerbation or other adverse effects after testing.
Pain Intensity Subjects reported a lower pain level after administration of opioid compared with placebo (3 ⫾ 2.1 vs 4 ⫾ 2.4 of 10, P ⬍ .001). Total pain intensity reduction was clinically important (2.9 ⫾ 2.3/10) after administration of fentanyl, and this reduction was statistically significantly lower than that seen with placebo (1.7 ⫾ 1.7/10 reduction). The effect size for pain reduction was 0.60 (95% CI, 0.01–1.17).
Maximum Floor-to-Waist Lift The mean weight lifted was 15% greater under the influence of opioid (29.4 ⫾ 17.9 kg) compared with placebo (25.6 ⫾ 3.1 kg, P ⫽ .02). This change corresponds to an effect size of 0.23 (95% CI, ⫺0.33 to 0.78).
Repetitive Floor-to-Waist Lifting to Fatigue Time to fatigue was 35% higher in the intervention group (312 ⫾ 251.4 vs 231 ⫾ 199.9 seconds, P ⫽ 0.03) and corresponds to an effect size of 0.40 (95% CI, ⫺0.21 to
860
Opioids Improve Exercise Performance in Chronic Pain
0.98). Subjects also performed more total work (7004 ⫾ 5144.4 vs 4748 ⫾ 3147.0 J, P ⫽ .000), representing a 48% improvement in functional ability (effect size of 0.72; 95% CI, ⫺0.03 to 1.44).
Table 3. Results Stratified According to Whether Subjects Initially Received Fentanyl or Placebo
Effect of Inadequate Blinding
Fentanyl first (n ⫽ 11) Maximum floor-to-waist lift (kg) Time to fatigue (seconds) Total work performed (Joules) Placebo first (n ⫽ 16) Maximum floor-to-waist lift (kg) Time to fatigue (seconds) Total work performed (Joules)
As mentioned, 18 of 27 subjects (67%) correctly guessed the order of treatment allocation. Analysis stratified according to whether they guessed correctly indicated that performance improvements were seen in both groups (Table 2). Subjects who did not guess correctly performed to lower work levels generally and reported smaller improvements in pain intensity; however, they had higher relative improvements in functional ability with fentanyl (21% to 87% vs 12% to 37% improvement).
Learning or Carryover Effects No statistically significant difference was observed for maximum floor-to-waist lift or total work done between the first and second testing occasions, indicating that a testing effect was unlikely to have occurred. Subjects receiving fentanyl first (n ⫽ 11) had smaller improvements in pain intensity (2.2 vs 3.3 reduction of 10), time to fatigue (0.1% vs 66% improvement), and total work performed (30% vs 59% improvement) compared with those receiving placebo first (n ⫽ 16), indicating that a potential carryover effect may have decreased observed effect sizes on these outcomes (Table 3). However, maximum floor-to-waist lift performance was improved to a greater extent in subjects receiving fentanyl first (36% vs
VALUE
FENTANYL
PLACEBO
P
28.3 (17.3)
20.8 (13.4)
.003
270.7 (184.7)
268.0 (269.5)
.98
6167 (4169)
4733 (3147)
.004
30.1 (18.9)
29.0 (17.5)
.56
339.8 (291.0)
205.2 (138.4)
.02
7572 (5773)
4758 (2771)
.006
NOTE. Values are mean (SD).
4% improvement), indicating that any carryover effect did not systematically affect all outcomes.
Effect of Previous Narcotic Use Ten of 27 subjects (37%) reported no prior use of narcotic analgesics. Analysis stratified according to whether or not subjects had used narcotics indicated consistent improvements with fentanyl in both groups. Subjects who reported no previous narcotic use had less improvement in maximum lift ability but comparable improvement in time to fatigue and total work performed.
Discussion Results Stratified According to Whether Subjects Correctly Guessed Treatment Allocation Order
Table 2.
VALUE Guessed incorrectly (n ⫽ 9) Maximum floor-towaist lift (kg) Time to fatigue (seconds) Total work performed (Joules) Total pain reduction (out of 10) Guessed correctly (n ⫽ 18) Maximum floor-towaist lift (kg) Time to fatigue (seconds) Total work performed (Joules) Total pain reduction (of 10) NOTE. Values are mean (SD).
FENTANYL
PLACEBO
P
28.2 (23.9)
23.3 (21.3)
.02
208.7 (148.3)
127.0 (75.7)
.03
5694.6 (6662.8)
3042.8 (3081.6)
.07
1.6 (1.7)
0.9 (2.0)
.05
30.0 (15.6)
26.8 (13.5)
.15
363.1 (279.1)
282.7 (223.4)
.14
7652.3 (4260.3)
5600.6 (2888.0)
.003
3.5 (2.3)
2.1 (2.0)
.004
In this double-blinded, randomized, controlled trial, we found that the acute administration of opioid analgesics improved lifting performance between 15% and 48%, depending on the specific outcome variable chosen. Opioids exerted a more pronounced effect on the ability to resist fatigue than on maximal lift capacity. Results are consistent with the only other study of the influence of opioid analgesia on exercise performance testing.26 The controlled laboratory setting of this study is quite different from routine clinical practice; however, our results support further controlled trials of the role of opioid analgesia in augmenting the rehabilitation of patients with chronic back pain.13,28 The improvements in exercise performance observed are most likely due to reduced pain intensity. The pain reduction observed indicates that we succeeded in delivering clinically relevant analgesia. Pain intensity fell by approximately 3 points on the Numeric Pain Scale when opioid was administered, indicative of a clinically meaningful decrease.19 Pain reduction seen in the placebo group was not clinically meaningful. Fentanyl is in clinical use (as a transdermal delivery system) for the treatment of chronic pain, and our objective was to simulate the plasma level of fentanyl that might be delivered in that scenario. We chose a dosing schedule to achieve this
Gross et al
861 26
in accordance with previous work in this area. In choosing this design, however, we ran the risk of a carryover effect in those who received fentanyl first. To protect against this, our testing schedule was designed to allow more time than the effective analgesic duration of fentanyl to expire between phases, and we administered a specific opioid antagonist between phases. Despite this, our analysis suggests that a carryover effect may indeed have occurred on the outcomes of time to fatigue, total work performed, and pain intensity. This suggests that the actual difference in performance between the 2 experimental conditions may be even larger than we recorded. However, this effect was not observed in the outcome of maximum floor-to-waist lift, indicating that either the effect did not operate systematically on all outcomes or that the improved performance in the placebo arm of subjects receiving fentanyl first was not due to a carryover effect. Some debate remains in the literature regarding the influence of pain on performance testing during functional capacity evaluation in patients with chronic painful conditions.8 Pain intensity has been inconsistently reported as either being an important determinant of lift performance or as having a weak or nonexistent association with performance during functional capacity evaluation.10,27 The current study implies that analgesia and pain reduction do result in improved lift ability, therefore implicating pain as an important influence on functional capacity evaluation. In this study, 67% of subjects correctly guessed their treatment allocation order. There is no medication available that simultaneously mimics the subjective effects of fentanyl injection that does not affect pain intensity and for which a specific antagonist is available. We were thus prevented from using an active placebo. However, given the improvements in lifting ability observed even in the 9 subjects who were unable to guess their allocation order, we do not believe that subjects voluntarily and consciously performed differently under the 2 treatment
conditions to satisfy their own a priori beliefs that opioids should indeed improve performance. Also of note is the improved performance with fentanyl even in subjects reporting no previous narcotic use for their pain. Our subjects were a heterogeneous group, comprising both genders, a wide range of ages, body mass, and fitness levels, and persons both currently taking and not taking opioids. We are therefore confident that our sample is broadly generalizable to the population with chronic low back pain at large. However, limitations of this study include its controlled setting, which is quite unlike clinical practice. The medication was administered intravenously; therefore, results may not be fully applicable to immediate or sustained-release oral opioids or transdermal fentanyl patches. Further trials of the role of opioid analgesia in augmenting rehabilitation are recommended. A small subset of our subjects was unable to tolerate the medication and terminated testing due to nausea. Another small subset had improvement lasting up to 1 week that cannot be explained physiologically. Potentially this improvement in self-reported outcomes was due to social desirability bias. Additionally, our sample size was not sufficient to perform multivariate statistics to account for potentially confounding variables such as age, gender, and occupational or workers compensation status.
Conclusions Acute opioid administration improves work-related exercise performance in the short term. Effect sizes were moderate to large for time to fatigue and total work performed during the repetitive floor-to-waist lift test (34% and 48% improvement, respectively) but modest for maximum psychophysical lift ability (15% improvement). Longer trials of the effectiveness of opioid analgesia as an adjunct to functional restoration programs for patients with chronic back pain are recommended.
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Acute Opioid Administration Improves Work-Related Exercise Performance in Patients With Chronic Back Pain Douglas P. Gross,* Yagesh Bhambhani,‡ Mark J. Haykowsky,* and Saifudin Rashiq§ *Department of Physical Therapy, ‡ Department of Occupational Therapy, and § Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, Canada.
Abstract: We studied the impact of acute opioid administration on work-related exercise performance in patients with chronic back pain. A double-blinded, random-order, placebo-controlled, crossover trial was conducted. Subjects were predominately men (63%), with a mean age of 49 years. Subjects performed a continuous lifting and lowering test to voluntary fatigue at a load equivalent to 33% of their predetermined maximal lifting load twice: Once after receiving a single intravenous dose of 1 g/kg fentanyl (a narcotic analgesic) and once after saline placebo. Of the 30 subjects undergoing testing, 3 subjects were unable to complete testing due to medication-induced nausea. Subjects lifted on average 29.4 ⴞ 17.9 kg under the influence of fentanyl versus 25.6 ⴞ 3.1 kg with placebo (effect size ⴝ 0.23). Time to fatigue was higher in the fentanyl group (312 ⴞ 251.4 vs 231 ⴞ 199.9 seconds, effect size ⴝ 0.40), and these subjects also performed more total work (7004 ⴞ 5144 vs 4748 ⴞ 3147 J, effect size ⴝ 0.72). Opioid analgesia improves lifting performance in the short term in individuals with chronic back pain. Longer trials of the effectiveness of opioid analgesia as an adjunct to functional restoration programs are recommended. Perspective: This article presents the results of a clinical trial showing that acute opioid administration improves work-related exercise performance in individuals with chronic back pain. Longer trials of the effectiveness of opioid analgesia as an adjunct to functional restoration programs are recommended. © 2008 by the American Pain Society Key words: Narcotic analgesia, functional capacity evaluation, work-related function, lumbar spine, work ability.
C
hronic low back pain is a common reason for work loss and decreased productivity in the workplace.4,31 Currently, few interventions are effective in managing chronic back pain or its associated disability.1,34 One option for physicians is to prescribe opioid analgesia with the goals of reducing pain and increasing function.15 Opioid analgesia appears to be effective for short-term pain reduction in patients with chronic low back pain, but few clinical trials have been reported that examine their influence on functional performance.5,15,21 The lack of controlled clinical trials is disturbing, given the potential side effects of opioids Received February 15, 2008; Revised April 21, 2008; Accepted April 28, 2008. Supported by the University of Alberta. Address reprint requests to Dr. Douglas P. Gross, 2-50 Corbett Hall, University of Alberta, Edmonton, Alberta, Canada T6G 2G4. E-mail: [email protected] 1526-5900/$34.00 © 2008 by the American Pain Society doi:10.1016/j.jpain.2008.04.006
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including physiological dependency or addiction when used over the long term.25 An expert panel has recently recommended that opioids be prescribed for patients with chronic back pain as part of a multimodal treatment plan including exercise therapy, behavioral therapy, or maintenance of normal activity.15 Whether opioids effectively augment such rehabilitation programs or actually have an impact on functional performance has not been well investigated.16 Most randomized, controlled trials conducted have subjectively investigated function through the use of self-report outcome measures such as the Roland Disability Questionnaire.5 To date, only 1 study has investigated the effect of opioid analgesia on performance-based exercise testing in patients with chronic back pain.26 Results indicated that subjects receiving intravenous administration of opioids had reduced pain and performed to higher levels during an isometric trunk extension exercise test. These findings may imply that diminishing pain levels could
Gross et al lead to improved ability to undertake functional tasks. A limitation of the study cited was the reliance on a single exercise test, the Biering-Sorenson low back muscle endurance test.3 In this test, subjects lie prone with the lower limbs strapped onto an adjustable plinth, then elevate and support their upper torso and arms in the horizontal plane to the point of fatigue. The test was initially described as a trunk endurance test; however, recent findings indicate that the test may be terminated more frequently by pain than reduced trunk endurance.30 Thus, it is not surprising that decreasing pain levels with analgesia resulted in improved test performance. Additionally, the Sorenson test is not truly a functional test in that the maneuver does not simulate any activity commonly performed during real life or work activity. Therefore, further evaluation of the impact of opioid analgesics on more realistic functional activities is needed. In an attempt to more realistically evaluate the ability for work activity, many performance-based functional measures have been developed that attempt to simulate true functional activities.7,20 A variety of functional protocols have been described, with most containing some form of dynamic or incremental lifting task. Lifting represents a task commonly performed during work and other activities of daily living and is often reported as difficult by patients with back pain.23 It is also a commonly prescribed exercise during functional restoration programs. Whether opioids alter performance potential for lifting in patients with chronic back pain is unknown. We examined the impact of acute opioid administration on repetitive lifting and lowering exercise performance in patients with chronic back pain. Our null hypothesis was that administration of opioids would not alter the lifting load and the time to voluntary fatigue in these patients.
857
Figure 1. Flow diagram of subject recruitment.
A double-blinded, random-order, placebo-controlled, crossover trial was conducted. Subjects performed a lifting test twice, once after receiving a single intravenous dose of 1 g/kg fentanyl (a narcotic analgesic) and once after saline placebo. The University of Alberta’s Health Research Ethics Board approved this study, and informed consent was obtained from each subject.
testing. A subject recruitment flow diagram is shown in Fig 1. Recruitment took place between August and October 2007. Specific criteria for inclusion in the clinical trial were (1) chronic back pain of ⬎6 months’ duration with or without leg pain; (2) back pain intensity rated as ⱖ3 of 10; (3) age ⬎18 years; (4) absence of specific pathology (eg, fracture, cancer, infection, or inflammatory arthritis); (5) no other comorbidity that would have affected maximal performance testing (eg, significant cardiovascular, pulmonary, endocrine, or neurologic disease); (6) absence of factors posing increased risk of harm from administration of intravenous opioid analgesic (eg, severe pulmonary disease); (7) no reported history of substance abuse; (8) willingness to stop taking opioid analgesics for at least 24 hours before the test session; (9) no known sensitivity to fentanyl or naloxone; and (10) ability to comprehend written and spoken English.
Subjects
Study Protocols
Written informed consent was obtained from 30 individuals with chronic back pain of at least 6 months’ duration. This sample size was chosen to detect a 10-kg difference in maximum floor-to-waist lift at a 0.05 ␣ level with 80% power. Subjects were recruited from the University Hospital Multidisciplinary Pain Centre and the local community via newspaper and television advertisements. Subjects completed the Physical Activity Readiness Questionnaire32 before entry and were screened by a physician for suitability to participate in functional
A schematic of the study procedures is shown in Fig 2. After screening by telephone and before recruitment and testing, all subjects completed a 24-hour, narcoticsfree washout period. Subjects took all of their other scheduled medications normally. Testing took place in the Work Physiology Research Laboratory at the University of Alberta. On arrival at the testing facility, basic demographic data were collected, a medical history and examination for fitness to participate was performed, and self-report measures were completed including a 10-
Materials and Methods Design
858
Opioids Improve Exercise Performance in Chronic Pain from the physical exertion of the first test session and to minimize carryover effects from the fentanyl to placebo phase before undergoing repeat testing under the alternate treatment condition. After 30 minutes, subjects continued to the next study phase and either fentanyl or saline placebo was administered (per the randomization). The same lifting capacity test was repeated. After completion of all testing, subjects were asked to guess the order of drug administration, and subjects were reimbursed $60 CDN for their time. Subjects were allowed to rest in a supervised waiting area until they were capable of independently driving home. The investigators arranged transportation via taxi for 1 subject who had nausea associated with medication administration.
Exercise Performance Measures
Figure 2. Schematic of study procedures.
point Numeric Pain Rating scale and the Roland Disability Questionnaire. Subjects were asked about whether they had abstained from narcotic medication for the required 24-hour period; however, urine toxicology tests were not conducted. Thereafter, a 22-gauge intravenous cannula was positioned in the hand or forearm and saline-locked. Random assignment was performed by using a Webbased random number generator (www.random.org). On the day of testing, the physician investigator opened an opaque, sealed envelope containing treatment order allocation (fentanyl then placebo or vice versa), prepared identical syringes containing either fentanyl (1 g/kg) or saline placebo, administered the medications, and monitored the participants’ vital signs but did not participate in the conduct of functional testing. This investigator was responsible for the subject’s safety and welfare throughout all stages of the procedure. All medications were given intravenously, and subjects were not told whether they were receiving medication or placebo. Subjects were instructed to speak only if they required help in some way and specifically were asked not to describe any changes in the way they felt after each injection unless it formed part of a request for assistance or termination of the study. All investigators who measured and recorded outcome data were blinded to treatment assignment until all subjects completed the protocol. The functional test protocol took less than 30 minutes. After the completion of functional testing, subjects in the fentanyl phase were given naloxone (3 g/kg iv) and those in the placebo group were given saline. Thereafter, a 30-minute rest was taken to permit recovery
An experienced rater who had been trained in the clinical administration of functional capacity evaluation performed all functional testing. Floor-to-waist lifting was the primary outcome of interest and was measured in 2 ways: 1-repetition maximal lift and repetitive lifting to fatigue. Floor-to-waist lifting as performed in a variety of functional capacity evaluation protocols has been reported to be a valid indicator of work-related function and modestly predicts future return to work.9-12,22,24
Maximum Floor-to-Waist Lifting Before initiating this test, each subject was shown a safe lifting technique. One-repetition maximum psychophysical methods were then used to test maximal lift ability.2,33 The subject was asked to lift a 5-kg crate (33 ⫻ 33 ⫻ 29 cm) fitted with circular handlebars from a table 76 cm high, to the floor, and then back to the table. Testing began at a light level (5 kg) to allow subjects to warm up and become familiar with the test; the weight was increased by 1 to 3 kg until the subjects thought that they had attained a maximum safe lift. Subjects were asked to identify the maximal weight that they would be able to dependably reproduce approximately 8 to 10 times per day. They were allowed 30 seconds between successive lifts to minimize the effects of fatigue. The reliability of psychophysical floor-to-waist lifting has been examined and found to be adequate for clinical use.2,14 Subjects were blinded to the amount of weight in the lifting unit during testing. The outcome from this test was maximum weight lifted in kilograms.
Repetitive Floor-to-Waist Lifting to Fatigue The repetitive lifting and lowering (RILL) protocol was next administered by using a modified procedure that has been used in subjects with back pain.17,18 Subjects were asked to repetitively complete dynamic floor-towaist lifting from the table to the floor, then back to the table. The weight level for the test was set at 33% of the load lifted during the maximal floor-to-waist lift, in accordance with the National Institute for Occupational Safety recommendations.29 Subjects were blinded to the amount of weight in the lifting unit. They were asked to
Gross et al lift at a predetermined cadence (10 lifts per minute), in rhythm with an electronic metronome. Heart rate and ratings of perceived exertion (RPE) using the Borg scale were monitored every minute. The following criteria were used to terminate the test: (1) Attainment of an RPE of 18 implying that the work was “very hard” and (2) inability to continue at the prescribed lifting cadence, that is, attainment of fatigue. Outcomes from this test included time to fatigue in seconds and total work done in kilogram meters (kgm). The latter was calculated as follows: weight lifted (kg) ⫻ number of repetitions completed during the time to fatigue ⫻ the distance between the floor and table top (76 cm). This value was converted into Joules, using a factor of 1 kgm ⫽ 9.80 Joules. Pain intensity was measured using an 11-point numeric rating scale (NRS, anchored at 0, meaning no pain at all, and 10 meaning the worst imaginable pain) at the beginning and end of testing procedures and at 120 seconds after each study injection. The ratings 120 seconds after injection served as the postintervention outcome for comparison to baseline measures. The NRS has been shown to be a reliable and valid measure of pain severity in the population with back pain.6
859 Table 1.
Subject Characteristics (n ⴝ 30) VARIABLE
Age in years Pain intensity at baseline (of 10) Roland Disability Questionnaire (of 24) Number of previous treatments for LBP Male sex Currently working Currently receiving disability benefits for LBP Marital status Single Married Divorced Educational status No high school diploma High school diploma University Nonspecific diagnosis Surgery for LBP Previous narcotic use for LBP Treatment allocation Fentanyl first Unable to complete testing (all due to nausea)
MEAN (SD) OR PERCENTAGE 49.4 (16.4) 6.0 (2.1) 12.0 (4.7) 2.9 (1.7) 63% 60% 13% 50% 40% 10% 23% 20% 57% 80% 10% 63% 40% 10%
Abbreviation: LBP, lower back pain.
Analysis Descriptive statistics including means and standard deviations were calculated for continuous variables and percentages for categorical variables. Differences in performance between the fentanyl and placebo phases were examined by using a paired-sample t test for crossover designs. All analyses were completed as intention to treat. Standardized effect sizes were calculated by dividing the mean difference by the standard deviation of the control group. The paired-sample t test was also used to determine differences between the first and second testing occasions to judge if a testing effect was present in subjects undergoing testing. We also performed stratified analysis to test for a carryover effect in those subjects receiving fentanyl first, for the effect of inadequate blinding to treatment allocation, and for the effect of prior narcotic use. An ␣ level of .05 was used. Statistical analyses were performed using SPSS 14.0 for Windows (SPSS, Inc., Chicago, IL).
Results Demographics Subjects were predominately employed (60%) men (63%), with a mean age of 49 years (Table 1). The majority of subjects had nonspecific back pain (80%) and 63% had previously used narcotic analgesia to manage their pain.
Treatment Allocation Of the 30 subjects who underwent testing, 12 were randomly assigned to receive fentanyl first, whereas 18 received placebo first. Three subjects were unable to complete testing due to nausea or vomiting induced by
fentanyl administration. Of 27 subjects who completed testing, 18 (67%) correctly guessed their order of treatment. 1 week after testing, 13 subjects reported no adverse effects at all, 4 subjects reported lasting improvements in their pain, 12 reported increased pain for up to 72 hours after the test session, and 5 reported a persistent sensation of nausea for up to 24 hours. Eleven subjects did not return calls enquiring about their postexperimental experience, but it is unlikely these subjects had major difficulty because all subjects had been instructed to contact the investigators if they had pain exacerbation or other adverse effects after testing.
Pain Intensity Subjects reported a lower pain level after administration of opioid compared with placebo (3 ⫾ 2.1 vs 4 ⫾ 2.4 of 10, P ⬍ .001). Total pain intensity reduction was clinically important (2.9 ⫾ 2.3/10) after administration of fentanyl, and this reduction was statistically significantly lower than that seen with placebo (1.7 ⫾ 1.7/10 reduction). The effect size for pain reduction was 0.60 (95% CI, 0.01–1.17).
Maximum Floor-to-Waist Lift The mean weight lifted was 15% greater under the influence of opioid (29.4 ⫾ 17.9 kg) compared with placebo (25.6 ⫾ 3.1 kg, P ⫽ .02). This change corresponds to an effect size of 0.23 (95% CI, ⫺0.33 to 0.78).
Repetitive Floor-to-Waist Lifting to Fatigue Time to fatigue was 35% higher in the intervention group (312 ⫾ 251.4 vs 231 ⫾ 199.9 seconds, P ⫽ 0.03) and corresponds to an effect size of 0.40 (95% CI, ⫺0.21 to
860
Opioids Improve Exercise Performance in Chronic Pain
0.98). Subjects also performed more total work (7004 ⫾ 5144.4 vs 4748 ⫾ 3147.0 J, P ⫽ .000), representing a 48% improvement in functional ability (effect size of 0.72; 95% CI, ⫺0.03 to 1.44).
Table 3. Results Stratified According to Whether Subjects Initially Received Fentanyl or Placebo
Effect of Inadequate Blinding
Fentanyl first (n ⫽ 11) Maximum floor-to-waist lift (kg) Time to fatigue (seconds) Total work performed (Joules) Placebo first (n ⫽ 16) Maximum floor-to-waist lift (kg) Time to fatigue (seconds) Total work performed (Joules)
As mentioned, 18 of 27 subjects (67%) correctly guessed the order of treatment allocation. Analysis stratified according to whether they guessed correctly indicated that performance improvements were seen in both groups (Table 2). Subjects who did not guess correctly performed to lower work levels generally and reported smaller improvements in pain intensity; however, they had higher relative improvements in functional ability with fentanyl (21% to 87% vs 12% to 37% improvement).
Learning or Carryover Effects No statistically significant difference was observed for maximum floor-to-waist lift or total work done between the first and second testing occasions, indicating that a testing effect was unlikely to have occurred. Subjects receiving fentanyl first (n ⫽ 11) had smaller improvements in pain intensity (2.2 vs 3.3 reduction of 10), time to fatigue (0.1% vs 66% improvement), and total work performed (30% vs 59% improvement) compared with those receiving placebo first (n ⫽ 16), indicating that a potential carryover effect may have decreased observed effect sizes on these outcomes (Table 3). However, maximum floor-to-waist lift performance was improved to a greater extent in subjects receiving fentanyl first (36% vs
VALUE
FENTANYL
PLACEBO
P
28.3 (17.3)
20.8 (13.4)
.003
270.7 (184.7)
268.0 (269.5)
.98
6167 (4169)
4733 (3147)
.004
30.1 (18.9)
29.0 (17.5)
.56
339.8 (291.0)
205.2 (138.4)
.02
7572 (5773)
4758 (2771)
.006
NOTE. Values are mean (SD).
4% improvement), indicating that any carryover effect did not systematically affect all outcomes.
Effect of Previous Narcotic Use Ten of 27 subjects (37%) reported no prior use of narcotic analgesics. Analysis stratified according to whether or not subjects had used narcotics indicated consistent improvements with fentanyl in both groups. Subjects who reported no previous narcotic use had less improvement in maximum lift ability but comparable improvement in time to fatigue and total work performed.
Discussion Results Stratified According to Whether Subjects Correctly Guessed Treatment Allocation Order
Table 2.
VALUE Guessed incorrectly (n ⫽ 9) Maximum floor-towaist lift (kg) Time to fatigue (seconds) Total work performed (Joules) Total pain reduction (out of 10) Guessed correctly (n ⫽ 18) Maximum floor-towaist lift (kg) Time to fatigue (seconds) Total work performed (Joules) Total pain reduction (of 10) NOTE. Values are mean (SD).
FENTANYL
PLACEBO
P
28.2 (23.9)
23.3 (21.3)
.02
208.7 (148.3)
127.0 (75.7)
.03
5694.6 (6662.8)
3042.8 (3081.6)
.07
1.6 (1.7)
0.9 (2.0)
.05
30.0 (15.6)
26.8 (13.5)
.15
363.1 (279.1)
282.7 (223.4)
.14
7652.3 (4260.3)
5600.6 (2888.0)
.003
3.5 (2.3)
2.1 (2.0)
.004
In this double-blinded, randomized, controlled trial, we found that the acute administration of opioid analgesics improved lifting performance between 15% and 48%, depending on the specific outcome variable chosen. Opioids exerted a more pronounced effect on the ability to resist fatigue than on maximal lift capacity. Results are consistent with the only other study of the influence of opioid analgesia on exercise performance testing.26 The controlled laboratory setting of this study is quite different from routine clinical practice; however, our results support further controlled trials of the role of opioid analgesia in augmenting the rehabilitation of patients with chronic back pain.13,28 The improvements in exercise performance observed are most likely due to reduced pain intensity. The pain reduction observed indicates that we succeeded in delivering clinically relevant analgesia. Pain intensity fell by approximately 3 points on the Numeric Pain Scale when opioid was administered, indicative of a clinically meaningful decrease.19 Pain reduction seen in the placebo group was not clinically meaningful. Fentanyl is in clinical use (as a transdermal delivery system) for the treatment of chronic pain, and our objective was to simulate the plasma level of fentanyl that might be delivered in that scenario. We chose a dosing schedule to achieve this
Gross et al
861 26
in accordance with previous work in this area. In choosing this design, however, we ran the risk of a carryover effect in those who received fentanyl first. To protect against this, our testing schedule was designed to allow more time than the effective analgesic duration of fentanyl to expire between phases, and we administered a specific opioid antagonist between phases. Despite this, our analysis suggests that a carryover effect may indeed have occurred on the outcomes of time to fatigue, total work performed, and pain intensity. This suggests that the actual difference in performance between the 2 experimental conditions may be even larger than we recorded. However, this effect was not observed in the outcome of maximum floor-to-waist lift, indicating that either the effect did not operate systematically on all outcomes or that the improved performance in the placebo arm of subjects receiving fentanyl first was not due to a carryover effect. Some debate remains in the literature regarding the influence of pain on performance testing during functional capacity evaluation in patients with chronic painful conditions.8 Pain intensity has been inconsistently reported as either being an important determinant of lift performance or as having a weak or nonexistent association with performance during functional capacity evaluation.10,27 The current study implies that analgesia and pain reduction do result in improved lift ability, therefore implicating pain as an important influence on functional capacity evaluation. In this study, 67% of subjects correctly guessed their treatment allocation order. There is no medication available that simultaneously mimics the subjective effects of fentanyl injection that does not affect pain intensity and for which a specific antagonist is available. We were thus prevented from using an active placebo. However, given the improvements in lifting ability observed even in the 9 subjects who were unable to guess their allocation order, we do not believe that subjects voluntarily and consciously performed differently under the 2 treatment
conditions to satisfy their own a priori beliefs that opioids should indeed improve performance. Also of note is the improved performance with fentanyl even in subjects reporting no previous narcotic use for their pain. Our subjects were a heterogeneous group, comprising both genders, a wide range of ages, body mass, and fitness levels, and persons both currently taking and not taking opioids. We are therefore confident that our sample is broadly generalizable to the population with chronic low back pain at large. However, limitations of this study include its controlled setting, which is quite unlike clinical practice. The medication was administered intravenously; therefore, results may not be fully applicable to immediate or sustained-release oral opioids or transdermal fentanyl patches. Further trials of the role of opioid analgesia in augmenting rehabilitation are recommended. A small subset of our subjects was unable to tolerate the medication and terminated testing due to nausea. Another small subset had improvement lasting up to 1 week that cannot be explained physiologically. Potentially this improvement in self-reported outcomes was due to social desirability bias. Additionally, our sample size was not sufficient to perform multivariate statistics to account for potentially confounding variables such as age, gender, and occupational or workers compensation status.
Conclusions Acute opioid administration improves work-related exercise performance in the short term. Effect sizes were moderate to large for time to fatigue and total work performed during the repetitive floor-to-waist lift test (34% and 48% improvement, respectively) but modest for maximum psychophysical lift ability (15% improvement). Longer trials of the effectiveness of opioid analgesia as an adjunct to functional restoration programs for patients with chronic back pain are recommended.
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