The opioid epidemic highlights risks associated with opioid analgesics, including overdose and death [1,22,26,27,30]. Nonetheless, opioids remain a mainstay of postoperative analgesia, sometimes with prolonged outpatient use (e.g., knee arthroplasty), and they continue to be used in some chronic pain patients. Precision medicine research reveals meaningful variability in opioid responses and adverse effects [5,6,8,12,15–17,33,36,37]. Opioids are therefore likely being initiated in some patients with an unfavorable a priori risk-benefit profile, that is, who will obtain poor analgesia while being exposed to opioid-related risks [e.g.,10,37].
Cross-sectional studies indicate that differences in endogenous opioid (EO) function are one driver of opioid analgesic response variability [5,6,8,9], and possibly, misuse risk [8]. EO function and magnitude of opioid analgesia appear to be inversely related, and one interpretation of these inverse associations is that clinically-desired pain relief can be achieved by optimizing opioid receptor occupancy via low EO levels supplemented with significant opioid analgesics, or alternatively, by higher levels of EOs supplemented with minimal opioid analgesics (Figure 1; referred to hereafter as the opioid supplement model).
Figure 1.
The opioid supplemental model.
It is currently unknown whether manipulating EOs might alter opioid analgesic responses or permit adequate pain relief at lower doses. While directly manipulating EO levels is not straightforward, we hypothesized that aerobic exercise might enhance EO function, and potentially alter opioid analgesic responses. This was based on a small literature in pain-free athletes revealing acutely increased EO analgesia based on opioid antagonist responses after intense aerobic exercise [20,25], and PET studies indicating elevated brain EO levels after aerobic exercise [19,31,32]. Results from the larger randomized trial on which the current work is based indicated that an 18 session (6 week) aerobic exercise training program (compared to usual activity control): 1) significantly improved chronic back pain intensity and interference, and 2) enhanced EO analgesia (specifically in women) up to 3 weeks following the intervention [7]. Among exercisers, larger EO increases were associated with greater analgesia, supporting their clinical relevance [7].
The primary aim of the current study was to build on this recent work, and test whether the aerobic exercise intervention described above directly altered analgesic responses to intravenous morphine, and whether it resulted in desired pain relief pain being achieved with little or no morphine. Based on the opioid supplement model described above, we hypothesized that aerobic exercise would reduce morphine analgesia (by reducing morphine binding via increased EO receptor occupancy), but would nonetheless lead to analgesia comparable to that achieved only with morphine pre-intervention. Given known sex differences in pain responses [2,28] and morphine analgesia (women display greater analgesia with morphine than men) [24], we tested for possible moderation of intervention effects by sex. As a secondary aim, we also tested for the first time whether EO increases over time (regardless of source) were prospectively associated with contemporaneous decreases in morphine analgesia, as would be expected if inverse associations noted previously between EO function and opioid analgesic responses were causal.
Method
Design
This study was part of a randomized controlled trial [7] to evaluate the effects of a structured aerobic exercise training program on chronic low back pain, the role of EO mechanisms in those effects, and the impact of the intervention on opioid analgesic responsiveness (NCT02469077). The study used a parallel groups, mixed design, with placebo, morphine, and naloxone administered in double-blinded crossover fashion in randomized, counterbalanced order across 3 separate identical laboratory sessions (conducted over a 10-day period), with this lab protocol carried out both before and after either an 18-session (6 week) aerobic exercise training program or a usual activity control condition. The study was conducted at two separate study locations using identical procedures in a closely coordinated fashion. All procedures were approved by the Institutional Review Boards at the respective institutions.
Participants
Participants included 83 individuals with chronic low back pain (CLBP) who were not using opioid analgesics on a daily basis. Participants using as-needed opioid analgesics were asked to abstain from any opioid use within the 3 days prior to each laboratory session (confirmed via urine opioid screen), and all participants were instructed not to use any non-steroidal anti-inflammatory drugs or over-the-counter analgesics for at least 12 hours prior to each laboratory session. Participants were recruited through an informatics-based targeted recruiting system mining electronic medical records to identify potentially eligible patients previously indicating a willingness to participate in research studies (“My Research at Vanderbilt”), on-line advertisements on the Vanderbilt employee e-mail recruitment system, the Rush Pain Clinic, advertisements in local print media and Facebook, and posted flyers. General criteria for participation included age between 18–55; no self-reported history of liver or kidney disorders, posttraumatic stress disorder, bipolar disorder, psychotic disorder, diabetes, seizure disorder, or alcohol or drug dependence; and no daily use of opioid analgesics. To maximize potential exercise intervention effects, participants were additionally required to be low active, i.e., engaged in moderate or vigorous exercise < 2 days/week and < 60 min/week (based on responses to 6 questions assessing moderate to vigorous activity on the CDC Behavioral Risk Factor Surveillance Survey [39]). CLBP was defined as daily low back pain of at least 3 months’ duration, with an average past month severity of at least 3/10 on a 0–10 verbal numeric pain intensity scale. All participants were required to be able to provide documentation of a previous medical provider diagnosis consistent with CLBP. Individuals self-reporting CP related to malignancy or autoimmune disorders were excluded, as were individuals who were pregnant (determined by urine pregnancy screens). All participants were compensated for their time ($75 for initial screening, $100 for each lab visit, and $30 for each completed exercise session). A CONSORT flow chart is provided in Supplemental Figure 1, with n=44 participants randomized to the exercise intervention and n=49 randomized to the control condition. Based on an assumed effect size of d = .60 for effects of aerobic exercise training on enhancing EO analgesia (the primary outcome of the parent study), a targeted sample size of n=58 per group was originally chosen based on an a priori power analysis to permit >80% power to detect group differences in exercise-related changes in EO function, assuming a two-tailed p<.05 criterion for significance. Of the randomized participants, n=38 in the Exercise group and n=45 controls completed the intervention with full pre-post intervention lab data for morphine response assessment available for analysis in the current study. All participants were recruited by the research coordinator at each site, with all study procedures carried out between 9/28/15 and 9/17/19. The trial ended when grant support ended.
Study Drugs
The opioid analgesic examined in this study was morphine sulfate, the prototypic mu opioid receptor agonist, which was administered in one laboratory session pre-intervention and one session post-intervention. Morphine was infused intravenously over a 2-minute period through a cannula placed in the non-dominant arm in four incremental doses: 0.03 mg/kg initially, followed by 0.02 mg/kg X 3. After each dose, there was a 10-minute seated rest to allow onset of drug effects, followed by assessment of back pain severity and evoked pain responsiveness (detailed below), with incremental drug doses provided at 25-minute intervals. The total morphine dosage used was the equivalent of approximately 7.0 mg for a 170 lb. individual.
The opioid antagonist naloxone was administered in one laboratory session pre-intervention and one session post-intervention. This naloxone condition was included to permit derivation of a quantitative index of EO system function, specifically, the difference in evoked pain responses between naloxone and placebo conditions [5,6]. Naloxone was infused incrementally, with an initial 8mg dose administered prior to the first heat pain trial, followed by saline placebo prior to the second heat pain trial, a 4mg maintenance dose prior to the third trial (to maintain full opioid blockade during the remaining trials), and then a final saline placebo dose before the fourth trial. Normal saline was infused in the same incremental manner across all four trials during the placebo condition. A drug order randomization schedule was prepared by an independent statistician using the Proc Plan procedure in SAS version 9.2 (SAS Institute, Cary, NC), with drug order randomized separately for pre-intervention and post-intervention lab sessions. Blinding of drug order was maintained and randomized drug assignment was carried out according to the randomization schedule by the investigational pharmacy at each site.
Measures
Chronic Pain Measures.
To assess the impact of the study drugs on specific qualitative features of chronic pain, current clinical back pain pre-drug administration and following each drug dose was assessed within each drug condition using the Short Form-McGill Pain Questionnaire-2 (MPQ-2) [13,14]. The MPQ-2 is a validated measure containing 22 items rated using an NRS format (0 = none and 10 = worst possible). It contains 4 subscales (Continuous, Intermittent, Neuropathic, and Affective). In addition, to more broadly capture overall differences in pain intensity, a 10cm visual analog scale (VAS) of overall back pain intensity was used, anchored with “no pain” and “worst possible pain.”
Evoked Pain Intensity Measure
Perceived intensity of the thermal pain stimulus described below was assessed using the original MPQ-Short Form (MPQ-SF; [23]). The MPQ-SF contains Sensory and Affective subscales that capture the sensory intensity and unpleasantness components of pain (all items on a 4-point scale rated from 0 = “none” to 3 = “severe”), and also produces a total score. Use of a different version of the MPQ to assess responses to the evoked pain stimuli versus clinical back pain was implemented to minimize potential participant confusion regarding the type of pain being rated (evoked vs. chronic). The MPQ-SF also includes a 10cm VAS of overall pain intensity (same anchors as above), and a 6-point Present Pain Intensity (PPI) numeric scale of overall intensity with verbal pain descriptors. Ratings on the latter were made on a 0 (“no pain”) to 5 (“excruciating”) scale.
Evoked Pain Stimulus
The evoked pain stimulus in the current study was a heat pain task using a computerized Medoc TSAII NeuroSensory Analyzer (Medoc US., Minneapolis, MN) as in our prior work [5]. After administration of each incremental drug dose and a 10 minute rest to permit onset of drug activity, three trials were conducted for both heat pain threshold and heat pain tolerance using a standard ascending method of limits protocol. Each trial was conducted sequentially at one of three different non-overlapping sites on the non-dominant ventral forearm to minimize local sensitization effects, with an interval of 30 sec between successive stimuli. For pain threshold trials, the probe started at an adaptation temperature of 32○C, with the temperature increasing at a ramp rate of 0.5○C/sec until the participant indicated that the stimulus had begun to feel “painful” by pressing a button on a computer mouse. For each tolerance trial, the probe started at an adaptation temperature of 40○C, with the temperature increasing at a ramp rate of 0.5○C/sec until the participant indicated maximum tolerance had been reached. The maximum possible tolerance temperature was 51○C due to an automatic hardware cutoff in the TSAII device to ensure participant safety. Immediately upon completion of the final heat pain tolerance trial at each drug dosage, participants were asked to rate the pain just experienced using the MPQ-SF described above. Prior to beginning the first laboratory session, all participants underwent standardized training to familiarize them with the thermal stimulus device and the concepts of pain threshold and tolerance. Mean value across trials were used for analyses of evoked pain threshold and tolerance, as well as pain ratings.
Intervention
Participants were randomly assigned to the exercise intervention or usual activity control group by the study coordinators using a 1:1 randomization schedule developed by an independent statistician prior to study initiation using the Proc Plan procedure in SAS version 9.2 (SAS Institute, Cary, NC). Experimenters were not blinded to intervention condition (but were blinded to the randomized drug order in the lab sessions). More detailed information on the 6 week, 18 session aerobic exercise intervention and its effects on chronic pain and EO outcomes are provided elsewhere [7]. Exercise intensity was based on target heart rate zones established using the Karvonen formula and heart rate reserve (HRR), with duration of exercise standardized at 30 minutes with a target exercise intensity between 70–85% HRR. To ensure that participants were exercising within their prescribed workload during each session, HR and RPE were assessed every 5 minutes during exercise using HR monitors and Borg’s 6–20 RPE scale [3].
Participants assigned to the usual activity Control condition (all of whom were low active per inclusion criteria) were asked to maintain their normal daily activity levels throughout the study.
Procedure
All procedures were conducted at the Vanderbilt General Clinical Research Center or a dedicated research room at the Rush University Pain Center. After providing informed consent, participants engaged in an assessment session during which they completed a packet of questionnaires, including chronic pain and functional measures and demographic information. Individuals then participated in identical experimental procedures across the drug conditions, with all sessions scheduled at the same time of day within individuals to control for variance due to circadian rhythms. The protocol for the lab sessions is summarized in Figure 2.
Figure 2.
Protocol for laboratory sessions pre- and post-intervention.
Participants remained seated upright in a chair throughout all lab procedures. The investigational pharmacy at each institution prepared and provided the study drugs in blinded fashion to the study nurses. In each session, after a 10-min seated rest, an indwelling venous cannula was inserted into the non-dominant arm by a trained research nurse under physician supervision. Ten minutes later, current low back pain was assessed using the MPQ-2 and VAS intensity measures. Participants then received (via the cannula) their first dose of the study drug as assigned per the randomization schedule. After a 10-min rest period to permit onset of drug activity, participants again rated their current low back pain using the MPQ-2 and VAS, and then completed the first evoked thermal pain tasks and ratings of evoked pain. Fifteen minutes later, the second assigned drug dose was given followed by a 10-min rest, assessment of current low back pain, and then the evoked thermal pain tasks and pain ratings, with the same procedure followed through the fourth and final drug dose. All participants remained in the lab under observation for 1 hour after the final drug dose to allow drug effects to remit, after which they were released to a responsible adult.
After completing the final pre-intervention lab session, participants then began their randomized intervention (exercise or control). The exercise group completed 18 supervised aerobic exercise sessions over the following 6 weeks (minimum per protocol was 13 sessions, but all completed at least 16 sessions). Within 10 days of the final exercise session, follow-up post-intervention lab assessment was begun, with participants again completing the lab protocol described above over a 10-day period.
Statistical Analysis
All analyses were conducted using IBM SPSS for Windows Version 26 (IBM Corp., Armonk, NY). In preparation for conducting analyses, changes in back pain intensity from pre-drug baseline to the assessment following each sequential drug administration were derived (as pre-drug minus post-drug value) separately within the morphine, naloxone, and placebo conditions. The four resulting change values within each drug condition were then separately averaged as an overall index of within-session changes in back pain, a strategy potentially increasing the accuracy of these change measures by averaging out random measurement error associated with the individual measures. Next, morphine effects (as a placebo-controlled index of opioid analgesia) were derived separately for pre-intervention and post-interventions lab sessions based on pre-post drug changes (as described above) in low back pain intensity on the MPQ-2 and VAS. These morphine effects were derived by subtracting pre- to post-drug changes under placebo from comparable changes after morphine had been administered, such that more positive morphine effect values indicated greater morphine-induced reductions in back pain intensity. For example, if VAS intensity decreased from 50 to 45 pre- to post-drug in the placebo condition (change of 5), but decreased from 50 to 35 after morphine administration (change of 15), the morphine effect value would be +10, indicating that morphine produced analgesia relative to the placebo condition. Similar average placebo-controlled morphine effect variables (across the four drug doses) were derived for evoked pain ratings, with positive morphine effect values indicating greater morphine analgesia. To index EO function for testing the secondary hypothesis, opioid blockade effects were calculated separately for pre- and post-intervention laboratory sessions, reflecting the differences between placebo and naloxone condition pain responses (for both low back pain and evoked pain). These blockade effects were calculated such that positive values indicated greater EO analgesia (i.e., naloxone produced hyperalgesia).
Preliminary analyses used between-subject t-tests (continuous measures) or chi-square analyses (categorical measures) to test for differences between groups on baseline characteristics, and Pearson correlations to evaluate possible confounds to tests of study hypotheses. Primary analyses of intervention effects used analysis of covariance (ANCOVA) procedures examining main and interacting effects of intervention status (Group) and sex on pre-post intervention changes in evoked and chronic pain morphine analgesic outcomes, with covariates including age and BMI (both significantly associated with blockade effects and morphine effects), as well as baseline values of the targeted outcome (i.e., to assess baseline-corrected change). Estimated marginal means (± SE) from ANCOVAs are presented graphically to portray the source of significant intervention effects, controlling for relevant covariates. Primary analyses were conducted on a per protocol basis given the focus on intervention-related changes in morphine effect outcomes (which were obtained at follow-up only in individuals who completed the exercise protocol). We note that inclusion in primary analyses of the only available measure capturing potential impact of as needed opioid use (dichotomized yes/no), although suboptimal, did not alter the pattern of results presented below.
To further evaluate the opioid supplement model, focused a priori analyses compared placebo condition pain responses post-intervention to morphine condition pain responses pre-intervention. Difference scores reflecting the comparisons above were derived for both evoked pain and clinical back pain ratings, with negative values indicating that pain responses post-intervention in the absence of any analgesic drug (placebo condition) were lower than pre-intervention pain responses following administration of approximately 7mg of morphine. These differences scores were compared across intervention groups using between-subject t-tests (one-tailed to minimize Type II error and optimize power given the directional nature of the a priori opioid supplement hypothesis). Specifically, we hypothesized that participants assigned to the aerobic exercise intervention would show post-exercise placebo condition pain ratings more similar to their pre-exercise morphine condition values than would control subjects.
Secondary analyses of changes in EO function as a predictor of changes in morphine analgesic effects for evoked and chronic pain outcomes were carried out using a series of hierarchical multiple regressions, given the continuous nature of these variables. These regressions entered control variables in the first step (age, BMI, sex, and pre-intervention morphine effects for the targeted measure [i.e., baseline corrected change]), main effects of intervention group and pre-post intervention changes in opioid blockade effects for the targeted measure (the EO index) in the second step, and the Group X EO interaction in the third step. This latter interaction was included to determine whether associations between EO function changes and morphine response changes differed between intervention groups. All analyses used the maximum number of available cases and a two-tailed probability value of p<.05 as the criterion for significance.
Results
Preliminary Analyses
None of the sample characteristics at baseline were significantly different between the aerobic exercise and control groups (all p’s >.14; Table 1). The majority of participants in both groups were female, white, and non-Hispanic. Chronic pain was characterized as moderate in intensity and of long duration. Less than 16% of the sample was using as-needed opioids in either group, and none had used opioids in the 3 days prior to each laboratory session (confirmed by urine screen). In terms of exercise protocol engagement, 94.7% of the exercise group participants completed the full 18 sessions of exercise, with one participant (2.6%) completing 17 sessions and one (2.6%) completing 16 sessions. For exercise participants, the mean amount of time per session during which achieved heart rate was within the specified target HR training zone was 21.1 minutes (SD = 4.65; range = 6.7 – 27.8 minutes) over the full exercise protocol. Pre- and post-intervention values for all morphine effect outcomes are summarized by intervention group in Table 2, with pain outcome values detailed by drug condition in Supplementary Tables 1A and 1B.
Table 1.
Baseline sample characteristics by intervention group.
| Group | ||
|---|---|---|
| Characteristic | Exercise (n=38) | Control (n=45) |
| Sex (% Female) | 55.3 | 66.7 |
| Race: | ||
| White | 60.5 | 59.1 |
| African-American | 26.3 | 34.1 |
| Ethnicity (% Non-Hispanic) | 94.7 | 95.2 |
| Age (years) | 40.0 ± 10.00 | 41.6 ± 9.54 |
| Body Mass Index | 29.9 ± 5.74 | 31.8 ± 7.13 |
| Pain Duration (Median ± IQR) | 75.6 ± 112.81 | 84.2 ± 159.06 |
| Post-Menopausal | 19.0 | 25.0 |
| Birth Control or Hormone Replacement Therapy | 19.0 | 30.0 |
| As Needed Opioid Use | 15.8 | 13.3 |
| Neuroleptic Use | 7.9 | 8.9 |
| Antidepressant Use | 23.7 | 20.0 |
| Pre-Intervention Past 24 Hour: | ||
| Average NRS Pain Intensity | 4.6 ± 2.20 | 5.3 ± 2.21 |
| Worst NRS Pain Intensity | 6.3 ± 2.15 | 6.5 ± 2.00 |
Note: All group comparisons are nonsignificant (p’s > .10). Unless otherwise noted, all values are percentages or Mean ± SD.
Table 2.
Unadjusted morphine effect outcomes (Mean ± SD) pre- and post-intervention by intervention group. Larger positive morphine effect values indicate greater morphine analgesia relative to placebo.
| Exercise | Control | |||
|---|---|---|---|---|
| Morphine Effect Measures | Pre-Intervention | Post-Intervention | Pre-Intervention | Post-Intervention |
| Thermal Pain Threshold | −0.27 ± 1.82 | −0.02 ± 1.48 | 0.24 ± 2.31 | 0.11 ± 1.45 |
| Thermal Pain Tolerance | −0.02 ± 0.90 | 0.09 ± 0.52 | 0.20 ± 0.80 | 0.02 ± 1.02 |
| Thermal MPQ-Sensory | 0.73 ± 4.03 | −0.03 ± 2.58 | 0.74 ± 3.90 | 0.95 ± 2.22 |
| Thermal MPQ-Affective | 0.29 ± 1.17 | 0.12 ± 0.87 | 0.06 ± 1.14 | 0.28 ± 0.93 |
| Thermal MPQ-Total | 1.03 ± 4.87 | 0.09 ± 3.13 | 0.80 ± 4.85 | 1.23 ± 2.75 |
| Thermal MPQ-PPI | 0.15 ± 0.71 | 0.14 ± 0.58 | 0.16 ± 0.92 | 0.02 ± 0.67 |
| Thermal VAS Intensity | 2.38 ± 11.73 | 6.20 ± 10.26 | 7.92 ± 22.60 | 3.29 ± 11.31 |
| CLBP MPQ2-Continuous | 0.26 ± 1.41 | 0.37 ± 1.18 | 0.39 ± 1.49 | 0.15 ± 1.51 |
| CLBP MPQ2-Intermittent | 0.35 ± 1.30 | 0.13 ± 0.81 | 0.09 ± 1.22 | 0.14 ± 1.32 |
| CLBP MPQ2-Neuropathic | −0.02 ± 0.57 | 0.17 ± 0.58 | 0.23 ± 1.05 | −0.06 ± 0.71 |
| CLBP MPQ2-Affective | −0.13 ± 1.27 | −0.01 ± 0.80 | 0.22 ± 1.23 | 0.22 ± 1.35 |
| CLBP MPQ2-Total | 0.12 ± 0.97 | 0.16 ± 0.59 | 0.23 ± 1.05 | 0.11 ± 1.01 |
| CLBP VAS Intensity | 6.67 ± 17.55 | 3.78 ± 12.25 | 5.98 ± 16.53 | 5.46 ± 14.21 |
Note: All baseline (pre-intervention) differences between groups are nonsignificant. Primary analyses examined intervention effects on changes in morphine effects within participants from pre- to post-intervention, with no significant main effects of intervention noted. MPQ = McGill Pain Questionnaire-Short Form; MPQ-PPI = McGill Pain Questionnaire-Short Form - Present Pain Intensity; CLBP = Chronic Low Back Pain; MPQ-2 = McGill Pain Questionnaire-2.
Intervention Effects on Morphine Analgesic Outcomes
Morphine effect values for all evoked pain and chronic back pain measures did not differ significantly at pre-intervention baseline across groups (all p’s > .16). For MPQ-2 ratings of back pain, there were no significant main effects of Group or Group X Sex interactions on any subscale or the total MPQ-2 measure (all p’s > .06). However, for pre-post intervention changes in morphine analgesic effects on the VAS measure of overall back pain intensity, a significant Group X Sex interaction was observed [F(1,68) = 4.15, p = .046, η2 = .058]. The source of this interaction is portrayed graphically in Figure 3. Simple effects analyses indicated that this interaction was due to male exercise participants reporting decreases in morphine analgesia over the intervention period that were significantly different from the increases in morphine analgesia noted in controls [F(1,26) = 5.46, p = .027]. In contrast, for females, there were no significant intervention effects on morphine responses [F(1,39) = 0.41, p = .527].
Figure 3.
Source of Group X Sex interaction for the VAS low back pain intensity morphine effect outcome.
For the evoked pain measures, a marginally significant Group X Sex interaction was observed for heat pain threshold [F(1,72) = 2.90, p = .093, η2 = .039]. Simple effects analyses indicated that this interaction was due to male exercise participants reporting small directional decreases in morphine analgesia over the intervention period, whereas controls exhibited somewhat larger increases in morphine analgesia over the same time period, although these differences were not statistically significant [F(1,27) = 1.67, p = .21; Exercise: M = −0.29, SE = 0.36; Control: M = 0.51, SE = 0.38]. This effect is similar in nature to the Group X Sex interaction noted above for VAS overall intensity ratings of back pain. In contrast, for females, differences between the exercise and control groups were notably smaller [F(1,42) = 0.72, p = .40; Exercise: M = 0.25, SE = 0.36; Control: M = −.125, SE = 0.28]. ANCOVAs did not reveal any other significant main effects of Group or Group X Sex interactions on any evoked pain morphine effect outcome (all p’s > .09).
Overall, these results indicate that the exercise intervention had limited direct effects on changes in morphine analgesic responses over the course of the trial. When effects were present, the strongest findings indicated that exercise was associated with diminished morphine analgesic responses over time relative to controls, with these effects being specific to male participants. This pattern observed in males is what would be expected if exercise increased EO function and opioid receptor occupancy, leaving it more difficult for morphine to bind to opioid receptors to produce additional analgesia.
Might Exercise Reduce Analgesic Requirements?
The opioid supplement hypothesis proposes in part that aerobic exercise training, by enhancing EO function, can reduce pain endogenously to levels achieved only with morphine administration pre-exercise, but with little or no supplementation with opioid analgesics required. For context regarding the nature and extent of intervention effects on pain outcomes in this study, we refer the reader to the full description of primary intervention outcomes detailed in Bruehl et al. [7]. To provide a test of the opioid supplement hypothesis in the current study, we compared the differences between pre-intervention morphine condition and post-intervention placebo condition pain ratings across groups (Table 3). Results indicated that for evoked pain measures including pain threshold [t(81) = −1.77, p = .04]; MPQ-Sensory [t(75) = −1.84, p = .035], MPQ-Total [t(81) = −1.83, p = .035], and VAS intensity ratings [t(77) = −1.72, p = .045]; and MPQ-2 Affective ratings of back pain intensity [t(81) = −2.01, p = .024], placebo condition pain responses in the exercise group post-intervention were significantly closer to (and in some cases lower than) pre-intervention pain responses after receiving approximately 7mg of intravenous morphine, relative to the control group. In other words, aerobic exercise training resulted in participants’ pain levels being similar to those observed in the same individual following morphine administration prior to undergoing exercise training, as the opioid supplement hypothesis would predict.
Table 3.
Difference between morphine condition pain responses pre-intervention and placebo condition pain responses post-intervention across intervention groups. Negative values indicate that placebo condition pain responses post-intervention were lower than pre-intervention pain responses after receiving approximately 7mg of intravenous morphine.
| Group | ||
|---|---|---|
| Pain Measure | Exercise (n=38) | Control (n=45) |
| Thermal Pain Threshold | −0.73 ± 2.49* | 0.16 ± 2.09 |
| Thermal Pain Tolerance | −0.07 ± 0.94 | 0.01 ± 0.62 |
| Thermal MPQ-Sensory | 0.54 ± 3.22* | 2.26 ± 5.21 |
| Thermal MPQ-Affective | 0.05 ± 1.59 | 0.51 ± 1.40 |
| Thermal MPQ-Total | 0.60 ± 4.32* | 2.77 ± 6.14 |
| Thermal MPQ-PPI | −0.01 ± 0.72 | −0.01 ± 1.05 |
| Thermal VAS Intensity | −1.49 ± 15.34* | 5.81 ± 23.01 |
| CLBP MPQ2-Continuous | 0.06 ± 1.10 | 0.40 ± 1.29 |
| CLBP MPQ2-Intermittent | 0.00 ± 1.03 | 0.30 ± 0.92 |
| CLBP MPQ2-Neuropathic | 0.02 ± 0.47 | 0.03 ± 0.44 |
| CLBP MPQ2-Affective | −0.17 ± 0.65* | 0.21 ± 1.00 |
| CLBP MPQ2-Total | −0.02 ± 0.66 | 0.23 ± 0.79 |
| CLBP VAS Intensity | 3.35 ± 15.48 | 2.79 ± 17.10 |
p < .05
Note: MPQ = McGill Pain Questionnaire-Short Form; MPQ-PPI = McGill Pain Questionnaire-Short Form - Present Pain Intensity; CLBP = Chronic Low Back Pain; MPQ-2 = McGill Pain Questionnaire-2.
Impact of EO Changes Over Time on Variability in Morphine Responses
Beyond specific intervention effects on changes in morphine analgesia over time, the data available permitted us to examine for the first time whether increases in EO function over time (from any source) were associated with decreases in opioid analgesic responses over the same time period. In other words, this was a prospective test (i.e., supporting a causal mechanistic association) of prior cross-sectional inverse associations noted between EO function and morphine analgesia [5,6,8]. Table 4 presents zero-order correlations between endogenous opioid changes over the trial period and changes in morphine analgesic responses on the corresponding measure over the same period. All correlations were inverse and significant, and reflected moderate to large effect sizes.
Table 4.
Zero-order correlations in the overall sample between changes in blockade effects (EO function) over the 6 week intervention period and changes in morphine analgesic effects for the respective measure.
| Measure | Correlation (r) |
|---|---|
| Thermal Pain Threshold | −0.53*** |
| Thermal Pain Tolerance | −0.44*** |
| Thermal MPQ-Sensory | −0.60*** |
| Thermal MPQ-Affective | −0.53*** |
| Thermal MPQ-Total | −0.61*** |
| Thermal MPQ-PPI | −0.34** |
| Thermal VAS Intensity | −0.43*** |
| CLBP MPQ2-Continuous | −0.64*** |
| CLBP MPQ2-Intermittent | −0.54*** |
| CLBP MPQ2-Neuropathic | −0.43*** |
| CLBP MPQ2-Affective | −0.77*** |
| CLBP MPQ2-Total | −0.71*** |
| CLBP VAS Intensity | −0.47*** |
p < .01
p < .001
Note: Inverse correlations indicate that greater increases in EO function over time were associated with larger decreases in morphine analgesia. MPQ = McGill Pain Questionnaire-Short Form; MPQ-PPI = McGill Pain Questionnaire-Short Form - Present Pain Intensity; CLBP = Chronic Low Back Pain; MPQ-2 = McGill Pain Questionnaire-2.
A series of hierarchical multiple regressions confirmed that larger EO function increases from pre- to post-intervention were associated with larger pre-post intervention reductions in morphine analgesic responses, independent of any influence of intervention assignment and confounds (sex, age, BMI). On the evoked heat pain task, this pattern was observed for pain threshold [t = −2.03, p = .046; beta = −0.154], VAS intensity ratings [t = −2.54, p = .013; beta = −0.174], and MPQ-Sensory [t = −4.11, p < .001; beta = −0.284] and MPQ-Total ratings [t = −3.94, p < .001; beta = −0.281], with a similar nonsignificant trend noted for MPQ-Affective ratings [t = −1.88, p = .064; beta = −0.169]. For the MPQ-PPI measure only, there was a significant Group X EO interaction [t = −2.51, p = .014], resulting from a significant association between increased EO function over the trial and reduced morphine analgesia in controls [t = −2.88, p < .01; beta = −0.272], that was absent in exercise participants [t = 0.86, p = .395; beta = 0.129]. There were no other significant effects noted for evoked pain measures (all p’s > .06).
Main effects similar in nature to those described above were observed for the impact of increases in EO function over the intervention period on reductions in morphine analgesia over the same period for several low back pain intensity measures. This pattern was observed for VAS overall back pain intensity [t = −4.00, p < .001; beta = −0.279], and ratings on the MPQ-2 Continuous [t = −5.10, p < .001; beta = −0.382] and Affective subscales [t = −6.58, p < .001; beta = −0.507]. To highlight the nature of these inverse relationships, a scatterplot portraying associations between pre-post intervention changes in EO function and changes in morphine responses for the VAS back pain intensity measure is provided in Figure 4. Interactions similar in nature to that noted above for the MPQ-PPI evoked pain outcome were also observed. For the MPQ-2 Intermittent subscale, there was a significant Group X EO interaction [t = −5.75, p < .001; beta = −1.144], resulting from a significant inverse association between EO changes and changes in morphine analgesia in controls [t = −7.06, p < .001; beta = −0.542], that was absent in exercise participants [t = 1.70, p = .101, beta = 0.190]. There was also a significant Group X EO interaction for MPQ-2 Total ratings of low back pain [t = −4.16, p < .001; beta = −0.847], deriving from a significant inverse association between EO changes and changes in morphine analgesia in controls [t = −8.66, p < .001; beta = −0.594], that was again absent in exercise participants [t = 0.18, p = .856; beta = 0.025]. One unique finding was noted for the MPQ-2 Neuropathic subscale only. On this measure, there was not only a main effect of EO function increases on reductions in morphine analgesia like those observed for the measures above [t = −3.30, p = .002; beta = −0.244], but there was also a main effect of intervention [t = −2.36, p = .021; beta = −0.168]. This intervention main effect was the result of individuals in the exercise group (relative to controls) showing significantly greater increases in morphine analgesia over time, independent of any EO changes, when compared to control group participants. Overall, the most consistent finding across evoked pain and clinical back pain measures were prospective associations between increased EO function over time and decreased morphine analgesia over the same time period. Several significant interactions on both evoked pain and chronic pain outcomes suggested that the inverse association between changes in EO function and morphine analgesic responses over time was prominent in control participants, but obscured in exercise participants.
Figure 4.
Scatterplot portraying associations between pre-post intervention changes in endogenous opioid function (opioid blockade effects) and changes in morphine responses for the VAS low back pain intensity measure.
Discussion
In this study, we hypothesized that aerobic exercise training would reduce analgesic responses to a weight-adjusted dose of morphine and permit desired pain relief levels to be achieved with little or no opioid analgesics required to supplement the EO analgesia. This opioid supplement hypothesis was driven by prior work suggesting cross-sectional inverse associations between EO function and degree of morphine analgesia [5,6,8], and the idea that optimal opioid receptor occupancy might be achieved equally either by maximizing EO analgesic function or supplementing low EO levels with exogenous opioid analgesics [5].
Results of primary analyses provided very limited evidence of a synergistic effect [e.g., 38] of exercise on magnitude of morphine analgesia, a potential alternative to the opioid supplement hypothesis. For MPQ-2 Neuropathic subscale ratings of back pain only, the exercise intervention was associated with increased morphine analgesia, but this effect was observed only when intervention-related changes in EO function were statistically-controlled. Thus, this single finding of apparent synergism between exercise and morphine analgesia was independent of any EO-related effects of exercise. Mechanisms that may contribute to this isolated effect, if it represents real synergism, are unknown. We can only speculate that exercise-related changes in other neurochemicals (e.g., endocannabinoids, serotonin, norepinephrine) [4,11,18,34] that are known to act synergistically with opioids could have contributed.
There were two findings suggesting that aerobic exercise reduced morphine analgesic responsiveness, at least for male participants, as hypothesized in the opioid supplement model. For the VAS back pain intensity outcome, a significant Group X Sex interaction was noted, resulting from male exercisers exhibiting decreased morphine analgesia over the treatment period whereas male controls exhibited an increase in morphine analgesia over the same time period (with no such intervention effects in females). An interaction approaching significance similar in nature to that described above was also noted for the evoked thermal pain threshold outcome. This pattern would be consistent with exercise-related EO increases resulting in diminished morphine analgesia as suggested by cross-sectional inverse associations between EO levels and morphine analgesia reported previously [5,6,8]. However, our recently reported primary intervention outcomes from the same dataset on which the current work is based [7] indicated that significant exercise-related increases in EO function were observed only in females. This might argue against EO changes contributing substantively to the reduced morphine analgesia following the exercise intervention noted exclusively in males in the current work. Overall, the direct effects of aerobic exercise training on opioid analgesic responses appeared to be relatively limited in scope, and provided only modest support for a key aspect of the opioid supplement hypothesis proposing that exercise would reduce morphine analgesia.
Given these mixed findings regarding direct influences of aerobic training on responses to analgesic medications, a critical clinical question is whether the exercise intervention impacted on pain responses in a manner that might permit reduction or elimination of reliance on opioids. Specifically, might the exercise intervention alone reduce pain in a manner comparable to that achieved with opioid analgesic administration prior to undergoing the aerobic training intervention? Evidence regarding this aspect of the opioid supplement model was more consistent. As noted in the primary intervention outcomes of this project, the aerobic exercise intervention significantly reduced both chronic back pain intensity and interference [7]. Findings in the current work indicated that for multiple evoked pain measures and MPQ-2 Affective ratings of back pain intensity, exercise participant pain ratings obtained after completion of the aerobic exercise intervention in the absence of morphine (i.e., placebo condition) were more similar to their pre-exercise morphine condition pain ratings than was the case for control participants. For some outcomes (evoked heat pain threshold and VAS intensity, MPQ-2 Affective ratings of back pain), post-exercise placebo-condition pain ratings were actually lower than pre-exercise ratings after receiving approximately 7mg of intravenous morphine. These results imply that the degree of chronic back pain relief achievable with a systematic aerobic exercise training program alone may not be dissimilar to the relief attained with moderate dose opioid analgesic medications in the absence of an exercise program. Given the better risk/benefit ratio of exercise training relative to chronic administration of opioid analgesics, these findings could represent a practical clinical implication of the present results. Although additional work in this area needs to be done, our results hint that progressive, supervised aerobic exercise training might to some extent be able to replace reliance on daily opioids in some patients without sacrificing quality of life. Recent animal work indicates that exercise also reduces desire to use opioids in addicted animals, suggesting potential benefits of exercise in the chronic pain setting in terms of reduced misuse risk as well [35]. Obviously, success of an exercise-focused approach requires that patients be willing to adopt a self-management orientation to chronic pain management, an orientation that is also a central tenet of multidisciplinary pain programs [21,40]. Given the design of the current study, one issue that cannot be addressed is whether placebo effects may have played a role in the findings described above. There was no assessment of evoked and chronic back pain in the absence of any drug or placebo manipulation. If aerobic exercise enhanced mechanisms contributing to placebo effects [29], this could potentially have exaggerated the degree of post-exercise placebo-condition pain relief relative to pre-exercise morphine conditions pain responses. The extent to which this may have impacted the current findings cannot be addressed due to the study’s design.
A secondary aim of this study was testing for the first time whether prospective changes in EO function over time are associated with contemporaneous changes in morphine responsiveness. Prior work on this issue was entirely cross-sectional, indicating strong inverse associations between EO function and degree of morphine analgesia [5,6,8]. Results of the current study provide some support for these associations being causal, given that prospective increases over time in EO function (whether intervention-related or from other sources) were associated with reductions in morphine responsiveness over the same approximately 8 week period. This effect was consistent across numerous evoked pain and clinical back pain outcomes. Group X EO interaction effects noted all suggested that inverse associations between EO function and morphine analgesia were stronger in non-exercising controls than in exercise participants. These latter findings might suggest that non-opioid mediated changes in pain or morphine responses elicited by the exercise intervention may have obscured these associations to some degree in the exercise group.
There are several limitations of this study. The fact that all participants were low active individuals at the study outset and that they were motivated sufficiently to volunteer to participate in 18 sessions of aerobic exercise training may diminish generalizability of the results to many pain clinic patients. The requirement that there be no daily opioid analgesic use (for safety reasons with naloxone) also may limit generalizability of the results to chronic pain patients using opioids daily. Limited statistical power related to the challenges of recruiting for a study involving 6 extended laboratory sessions and 18 sessions of aerobic exercise may also have adversely affected ability to detect effects that were present. In addition, we note that the lone significant finding in primary analyses (a Group X Sex interaction) would not be significant if analyses were adjusted for multiple comparisons, although findings regarding associations between changes in EO function and changes in morphine responses would, with one exception, remain significant. Results of this study require replication, ideally using a larger sample to enhance power. Finally, to the extent that EO changes related to aerobic training would be expected to account for any impact on morphine responsiveness, we note that while the primary clinical outcomes of the trial [7] showed clear benefits of the intervention, evidence for associated changes in EO function was somewhat weaker. Moreover, the degree of exercise-related changes in EO function and their benefits regarding chronic pain outcomes appeared dependent on exercise intensity (indexed by heart rate changes) [7]. It is possible that the degree of EO enhancement observed in the exercise group was simply too weak to exhibit consistent group level changes in the magnitude of morphine analgesia.
In conclusion, the current findings showed limited direct effects of aerobic exercise training on morphine analgesic responses, most often with reduced morphine responses being observed. Nonetheless, aerobic exercise training did appear to provide analgesia of a magnitude similar to that observed with approximately 7 mg of morphine pre-exercise. Overall findings provide at least partial support for the hypothesized opioid supplement model. Our results suggest the possibility that non-drug exercise therapies could potentially provide back pain relief in the same general range as moderate opioid analgesic dosages in individuals motivated to engage in this type of behavioral intervention. If replicated, we believe this is an important potential clinical implication of the study. Finally, this work prospectively demonstrates for the first time that factors that reduce EO capacity over time (e.g., increased depression as suggested by prior work [9]) are likely to increase responsiveness to opioid analgesics. Possible applications of such findings to precision pain medicine protocols remain to be determined.
Supplementary Material
Supplementary Figure 1. CONSORT flow diagram.
Supplementary Tables 1A and 1B. Pain values (Mean ± SD) by drug condition across intervention groups pre-intervention (A) and post-intervention (B).
Acknowledgements
This research was supported by NIH Grant R01DA037891, training grant T32GM108554, and CTSA award UL1TR002243 from the National Center for Advancing Translational Sciences. Contents of this work are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. The authors report no conflicts of interest.
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Associated Data
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Supplementary Materials
Supplementary Figure 1. CONSORT flow diagram.
Supplementary Tables 1A and 1B. Pain values (Mean ± SD) by drug condition across intervention groups pre-intervention (A) and post-intervention (B).