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Accepted Article
Article type
: Original Manuscript
Interpreting the Effectiveness of Opioids and Pregabalin for Pain Severity, Pain
Interference, and Fatigue in Fibromyalgia Patients
1
Fred Davis, Mark Gostine,2 Bradley A. Roberts,1 Rebecca Risko,1 Joseph C. Cappelleri,3
Alesia Sadosky4
1
ProCare Systems, Inc; 2Michigan Pain Consultants; 3Pfizer Inc. Groton, CT; 4Pfizer Inc.,
New York, NY
Target journal: Pain Practice
Corresponding author:
Rebecca Risko, RN, BSN
ProCare Pain Solutions
61 Commerce Ave SW
Grand Rapids, MI 49503
Tel: 616-940-3504
Email: rrisko@procarepain.com
Keywords: Fibromyalgia, Pain, Fatigue , Opioids, Patient-reported outcomes
widespread pain , Sensitization
, Outcome Assessment
, chronic
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/papr.12651
This article is protected by copyright. All rights reserved.
Disclosure
Accepted Article
This study was sponsored by Pfizer. Joseph C. Cappelleri, and Alesia Sadosky are
employees of Pfizer, the sponsor of this study. Fred Davis, Bradley Roberts, and Rebecca
Risko are employees of ProCare Systems, Inc., which received funding from Pfizer for
conducting the analyses. Mark Gostine collaborated with Pfizer on this project; he was not
financially compensated for his participation or the development of this manuscript. Editorial
support was provided by E. Jay Bienen and was funded by Pfizer.
Abstract
Objective: To evaluate the effectiveness of opioids and/or pregabalin on patient-reported
outcomes among fibromyalgia (FM) patients based on levels of improvement.
Methods: A total of 1,421 FM patients were identified with 3,082 observational periods of
opioids with or without pregabalin use between April 2008 and February 2015. Patients were
categorized by opioids, and pregabalin with and without opioids; opioids were designated by
morphine equivalent dose (MED) of ≤20 (low MED), >20 to <100 (moderate MED), ≥100
(high MED), and pregabalin dosages ≤150mg, 151- 300mg, and 301-450mg. Proportions of
patients meeting clinically relevant thresholds of ≥30% and ≥50% improvement for pain
interference (Ability to enjoy life; Activity; Mood; Relationships; Sleep), pain severity, and
fatigue were compared among treatments, and area-under-the-curve (AUC) for improvement
and worsening of effects was determined, enabling ranking of treatments. Further analysis
compared pregabalin dosages.
Results: Pregabalin without opioids resulted in the highest proportions of patients with ≥30%
improvement on all pain items and pain interference with “Ability to enjoy life,” “Activity”
“Mood,” and “Sleep.” For the ≥50% threshold, pregabalin alone was highest for all pain
interference items and for “Average pain” and “Worst pain.” Pregabalin was consistently
This article is protected by copyright. All rights reserved.
lowest across thresholds for fatigue, but showed better results combined with moderate MED
Accepted Article
opioids. Pregabalin dosages recommended for treatment of FM (151-450mg) generally
resulted in the highest proportion of patients achieving thresholds relative to opioids. The
AUC results were consistent with thresholds; pregabalin without opioids resulted in the
greatest benefits with regard to improvement, with the highest ranking for overall
improvement and overall effects.
Conclusion: Pregabalin without opioids provided the most favorable outcomes overall based
on ≥30% and ≥50% improvement thresholds and AUC, with support for moderate MED
opioids+pregabalin in patients suffering from fatigue. While most patients took less than
recommended pregabalin doses, higher doses may lead to improved outcomes.
INTRODUCTION
Fibromyalgia (FM) is a chronic disorder that is thought to result from a dysfunction of central
pain processing pathways,1, 2 which results in the hallmark symptoms of widespread
musculoskeletal pain, joint stiffness, and fatigue. In addition to these symptoms, FM is
characterized by sleep disturbances, depression, and cognitive difficulties.3, 4 As FM severity
increases from mild to incapacitating, the disease inflicts a greater burden on patients as
shown by its associations with reductions in daily function and quality-of-life, lost
productivity, and higher healthcare resource use.5-7
Recommendations for the management of FM include use of pharmacologic agents from a
variety of therapeutic classes including antidepressants and anticonvulsants, but specifically
recommend against the use of opioids except for weak opioids such as tramadol.8-11 In the
United States, the Food and Drug Administration has approved three drugs for the treatment
of FM, two antidepressants (duloxetine and milnacipran), and an anticonvulsant (pregabalin).
This article is protected by copyright. All rights reserved.
However, treatment of FM remains challenging, and studies have shown low or ineffective
Accepted Article
use of approved or recommended therapies, with opioids consistently reported as the most
frequently prescribed pharmacologic agent despite little evidence for their efficacy.2, 12-15
Indeed, studies have suggested that opioid use may be associated with higher healthcare
resource utilization and costs among patients with FM.15, 16 Nevertheless, an older survey
among patients with FM found that these patients perceived opioids to be among the most
effective therapies.17 Thus, since there remains a need for evaluating the effectiveness of
opioids, the objective of this study is to characterize and compare the effectiveness of opioids
with pregabalin both in the absence and presence of concomitant opioids use across a range
of patient-reported outcomes relevant to pain, daily function, and fatigue using two
complementary methods that can enrich the interpretation of effects.
METHODS
Data source and population
The data source for this retrospective analysis was clinic-level data from the ProCare Systems
network of chronic pain clinics in Michigan between April 2008 and February 2015. All
patient data were de-identified and fully compliant with the Health Insurance Portability and
Accountability Act (HIPAA).
Patients with FM were identified using traditional selection criteria and predictive modeling
as previously described.18 All patients were required to have Class 1 FM, i.e., regional FM
with classic symptoms, according to the four identified classes that reflect symptom severity
and comorbidities, pain regions, and treatment intensity.19 Patients were also required to
have been prescribed opioids and/or pregabalin and have completed baseline and follow-up
PRISM™ Pain Health Assessment (PHA). The PHA is a self-report measure that contains
This article is protected by copyright. All rights reserved.
core outcome domains for evaluating efficacy and effectiveness of treatments on disease
Accepted Article
presence, pain characteristics, physical function, and psychosocial function.
Patients were assigned to groups stratified by their average morphine equivalent dose (MED:
low, MED ≤20; moderate, MED >20 to <100; and high, MED ≥100), and subgroups to
investigate outcomes at varying levels of pregabalin dosage including ≤ 150 mg, 151- 300
mg, and 301-450 mg; the recommended dosages of pregabalin for the treatment of FM are
300-450 mg.20 Calculations of MED were performed using common guidelines.21
Observational time (i.e., days between baseline and follow-up PHAs) was limited to 56-365
days.
Outcomes
Outcomes consisted of questions from the PHA, including five items relating to pain
interference (Ability to enjoy life, Activity in general, Mood, Relationships with others, and
Sleep), three for measuring pain severity (Average pain in the last four weeks, Pain right now
while completing your PHA, and Worst pain in the last four weeks), and two for fatigue (Do
you feel tired? Do you feel worn out?). The questions on pain severity and interference in the
PHA are closely aligned with the Brief Pain Inventory, a validated measure of pain severity
and interference using a 0-10 numerical rating scale (NRS; 0 = no pain or interference, 10 =
worst possible pain or complete interference).22 Questions that address fatigue are similar to
those that comprise the “Vitality” scale of the validated 36-item Short Form Health Survey
SF-36.23
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These outcomes are consistent with general recommendations of the Initiative on Methods,
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Measurement, and Pain Assessment in Clinical Trials (IMMPACT)24 as well as more specific
recommendations for FM by the Outcome Measures in Rheumatology (OMERACT) group.25,
26
Analysis
A response was considered any improvement from baseline (change from baseline ≥ 0) on the
assessed outcome. The proportions of responders who reported improvement of at least 30%
and 50% from baseline were compared between treatment arms. These thresholds are
consistent with IMMPACT recommendations for clinically relevant improvements in pain,
with the 30% and 50% thresholds reflecting moderate and substantial improvements,
respectively.27 Statistical significance for all comparisons were based on 95% confidence
intervals calculated (bias corrected and accelerated method) using bootstrapping with 10,000
iterations.
Additionally, efficacy was evaluated using an area-under-the-curve (AUC) adaptation of a
cumulative proportion of responder’s analysis (CPRA). The CPRA is a method that
represents the cumulative proportion of patients who reach a specific response, calculated
across the range of possible responses for improvement from baseline.28 As has been
previously proposed,29, 30 the application of AUC to a responder analysis enriches the
interpretation of improvement in selected outcomes and encompass all relevant responder
information. Graphically, the change in the outcome of interest is depicted on the x-axis with
the proportion of patients on the y-axis. All possible cutoff points of improvement can be
incrementally represented, allowing for a visual representation of change scores. Extending
this concept, multiple groups can be included within the same graph and subsequently
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compared for patient responses to treatment. For each outcome, the AUC was estimated
Accepted Article
based on percent improvement on the outcome. In the current analysis, the AUC for each
item was derived using Simpson’s rule.31 Differences in the derived AUCs were compared
between treatments, with statistical significance based on calculated 95% confidence
intervals (95% CI) according to a bias corrected and accelerated method using bootstrapping
with 10,000 iterations.
RESULTS
Population characteristics
A total of 1,421 unique FM patients taking opioids and/or pregabalin were identified, with
3,082 pre-/post-observational periods. Of these observations, 2,396 (77.7%) were female with
a mean (SD) age of 50.5 (12.7) years (Table 1). The time under assessment was
approximately 180 days and was similar among the treatments. Because there were some
gaps in opioid and pregabalin prescriptions during patients’ assessment periods, the mean
percent time on opioids and pregabalin represent the fraction of time in days that patient
prescriptions could be accounted for over the entire assessment period, and ranged from 50%
to 99%. The number of opioid prescriptions tended to be higher across increasing levels of
MED (Table 1). The mean MED for all patients taking opioids was 60.6  111.4, and the
mean pregabalin dosage was 159.7  140.8 mg. On average, pregabalin dosage was higher in
patients taking a combination opioids + pregabalin relative to pregabalin without opioids and
increased across the MED levels (Table 1).
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When pregabalin dosages were stratified across all patients by strata of ≤150 mg, 151-300
Accepted Article
mg, 301-450 mg, and 451-600 mg (Table 1), the largest proportions of patients were taking
≤150 mg, ranging from approximately 52% (high MED opioids, pregabalin) to 77%
(pregabalin without opioids). Few patients (n = 14; 3.4%) were in the 300-450 mg FDA
recommended dosage group. Generally, the proportions of patients taking opioids +
pregabalin were higher for all dosage groups than patients taking pregabalin alone.
Analysis by response thresholds
Pregabalin without opioid use resulted in the highest proportions of patients achieving ≥ 30%
improvement across all pain items (Table 2), and was statistically significant relative to low
MED opioids + pregabalin for “Pain right now while completing your PHA” (13.2%, 95% CI
0.8%, 27.2%; P < 0.05). While pregabalin without opioids had a low ranking for both of the
fatigue items, there were no significant differences for any of the treatment comparisons.
On pain interference (Table 2), pregabalin without opioids also resulted in the highest
proportions of patients who achieved ≥ 30% improvement except for “Relationships with
others,” which was highest with moderate MED opioids + pregabalin. Pairwise comparisons
showed that differences between treatments were significant with pregabalin for “Activity in
general” relative to low MED opioids (15.0%, 95% CI 0.9%, 30.5%), moderate MED opioids
(15.4%, 95% CI 1.1%, 31.1%), and high MED opioids (16.7%, 95% CI 2.3%, 32.4%) (all P
< 0.05). The difference was also significant for high MED opioids + pregabalin relative to
low MED opioids + pregabalin (16.2%, 95% CI 2.5%, 30.9%; P < 0.04). For “Relationships
with others,” pairwise comparisons showed that the differences were significant, with higher
proportions reporting ≥ 30% improvement (Table 2), with moderate MED opioids +
pregabalin relative to high MED opioids (9.4%, 95% CI 0.7%, 18.7%), low MED opioids
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(9.7%, 95% CI 1.5%, 18.2%), and low MED opioids + pregabalin (13.1%, 95% CI 1.9%,
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23.9%) (all P < 0.05).
Pregabalin in the absence of opioids resulted in the highest proportions of patients with ≥
50% improvement in “Average pain” and “Worst pain,” although none of the differences
with other groups was significant (Table 2). While pregabalin without opioids was
significant versus high MED opioids + pregabalin for “Ability to enjoy life” (14.2%, 95% CI
28.5%, 4.5%; P < 0.05), it had the lowest ranking for ≥ 50% improvement in fatigue items,
with differences in “Worn out” that were significant relative to low MED opioids (-9.8%,
95% CI -15.3%, -2.1%) and moderate MED opioids + pregabalin (-10.2%, 95% CI -1.0%, 18.1%) (both P < 0.05).
While pregabalin, with or without opioids, at a dosage of 301-450 mg resulted in the highest
proportions of patients achieving ≥ 30% improvement on the two psychosocial items
(“Mood” and “Relationships with others”), the 151-300 mg dose showed the best results on
the other pain interference items (Table 3). Opioids resulted in the lowest proportions except
for “Sleep,” for which it ranked next to lowest, with the highest pregabalin dose ranked last.
On pain severity (Table 3), the highest pregabalin dose had the best effects on “Average
pain” and “Pain right now,” but very low proportions of patients reported ≥ 30%
improvement on “Worst pain.” For patients reporting an improvement of at least 50% from
baseline, the pregabalin dosages of 151-300 mg and 301-450 mg were found to have the
greatest proportion in all ten items, split amongst the three domains, pain interference, pain
severity, and fatigue (Table 3).
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Analysis by area-under-the-curve
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Figure 1 presents sample profiles for the responder and non-responder using the top four
treatments for “Activity in general.” This figure visualizes the comparison across the full
range of responses and assists in the simultaneous assessment of improvement and
worsening, with higher curves for improvement and lower curves for worsening the preferred
outcomes. The area under each line represents the AUC, and the area between the two lines
expresses the differences in AUC response between treatments. As shown, pregabalin results
in consistently better responses across the range of improvement levels, and results in
worsening similar to or less than with the comparator opioid groups. Similar results were
generally observed for the other outcomes (data not shown).
The derived AUCs for percent improvement in pain and fatigue items are shown in Figure 2.
While the highest AUCs for pain were observed for pregabalin, the greatest effects on fatigue
were observed with moderate MED opioids + pregabalin. These AUCs can be interpreted as
if all responders were improved by the same percentage. For example, the AUC of 20.4%
with pregabalin for “Pain right now” suggests that pregabalin responders had on average a
20.4% reduction in current pain. Similarly, Figure 2 also presents the AUCs for pain
interference, and shows that pregabalin results in the highest AUC for all interference
outcomes except for “Relationships,” which was highest with moderate MED opioids +
pregabalin.
Figure 3 provides a holistic perspective among the treatments by summarizing patient
responses along the entire range of responders and non-responders by rank of improvement
(Figure 3A),
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rank of worsening (Figure 3B) and the total effect (Figure 3C) as represented by summation
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of improvement and worsening; the higher the rank, the better the effect (greater
improvement and less worsening). The top three treatments as determined by their total
effect are pregabalin, high MED opioids + pregabalin, and high MED opioids.
Statistical comparison of pairwise differences in percent improvement for the treatment
having the greatest response are shown in Figure 4 for pain severity and fatigue, and Figure 5
for pain interference. Treatment groups that included pregabalin, either in the absence of or
combined with opioids, showed the greatest differences in effects. Generally, where the
differences are statistically significant, patients taking pregabalin without opioids exhibited
an improvement of 5%-15% greater than the other treatments (i.e., high MED opioids +
pregabalin, high MED opioids, moderate MED opioids, and moderate MED opioids +
pregabalin); patients taking high MED opioids + pregabalin reported an improvement of 4%10% greater than the other treatments; patients taking moderate MED opioids + pregabalin
improved 1%-5% more than patients taking moderate or high MED opioids alone.
Placing the AUC results in a similar context as the main treatment comparisons, Figure 6
shows that pregabalin dosages of 301-450 mg and 151-300 mg were the top two ranked
subgroups for overall total effect, improvement, and worsening. Opioids were third ranked
based on patients reporting less worsening than pregabalin dosages of ≤150 mg.
DISCUSSION
The few studies on opioids for the treatment of FM have suggested that while responders to
the weak opioid tramadol may have a reduction in pain but not in health-related quality of
life,32 opioids may have contributed to increased resource use and costs, or less favorable
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outcomes.15, 16, 33 The current study expands on the evaluated effectiveness of opioids for FM
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by showing that although opioids may provide benefits in pain and pain interference
outcomes, treatment with pregabalin, which is approved for the treatment of FM, appeared to
provide more favorable outcomes relative to opioids. Notably, this responder analysis not
only used improvement thresholds to show that the benefits represent clinically relevant
outcomes that affect patients’ daily lives, but also included an approach that takes into
account the entire response profile for patients who reported improvement as well as for those
who worsened.
Assessment of worsening is an infrequently evaluated concept that provides broader
comparative characterization of treatment effects and enables ranking of treatment modalities
based on their overall appropriateness. For example, while responders in the moderate MED
opioids + pregabalin group exhibited favorable outcomes for improvement, non-responders in
this treatment group seemed to worsen to a greater extent than with other treatments,
resulting in moderate MED opioids + pregabalin having the lowest ranking for overall
worsening relative to other treatments. In contrast, pregabalin in the absence of opioids had
the highest ranking for overall improvement as well as for overall effects, with responders not
only achieving, on average, improvements in pain that ranged from 11% for “Worst pain” to
20% for “Pain right now,” but average improvements of 18%-26% for pain interference
items.
Pregabalin dosages of 301-450 mg generally provided the most benefit to patients compared
with other pregabalin dosages as well as with patients prescribed only opioids. Interestingly,
the mean dosage of pregabalin increased as the opioid MED increased, which may be
consistent with a greater need for pain control. These results are in concordance with a recent
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review that reported pregabalin ≥ 300 mg results in major reductions in pain accompanied by
Accepted Article
ancillary improvements in functional and quality-of-life outcomes.34 However, in the current
study, not only was the mean pregabalin dose, 159.7 mg, approximately half of the lowest
recommended dose for FM treatment,20 but the largest proportion of patients (60.5%) were
taking pregabalin ≤ 150 mg; the 150 mg dose also had the lowest ranking with regard to total
effects. While use of low pregabalin doses, i.e., less than the recommended dose, in the
clinical setting has consistently been reported,35-37 the reason for such suboptimal dosing is
unclear. It should also be noted that very few patients were taking 451-600 mg, which
exceeds the indicated dose range for FM.20
The differences in the AUC (Figures 4 and 5) can be interpreted as an indication of the
treatment groups that were favored for each comparison across the evaluated outcomes, and
the magnitude of the differences in response. Based on these differences, the domains that
showed the greatest responses with pregabalin alone as well as when combined with opioids,
i.e., pain interference on “Activity in general” and “Sleep”, were also those that are
considered of importance by patients.38, 39 The effects on sleep are not surprising given not
only the reciprocal relationship between pain and sleep,40-42 but that pregabalin has positive
effects on sleep across a range of conditions, with these effects appearing to occur directly on
sleep as well as through the reduction in pain including in patients with FM.43, 44 Such effects
are especially important in FM, since sleep disturbances are a primary complaint among these
patients even though there is little evidence supporting a role for sleep physiology in
maintaining FM.45 Pregabalin without opioids was also the treatment that resulted in the
greatest benefits in reducing pain interference on “Mood.” Despite the benefits of pregabalin
on sleep and activity, pregabalin in the absence of opioids had a lower impact on fatigue than
on other outcomes and also relative to the other treatment groups. This observation suggests
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that fatigue represents a multidimensional concept in FM that may not necessarily reflect the
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previously described mediation of fatigue through pain and sleep disturbance.46
Nevertheless, this lack of effect on fatigue by pregabalin is not surprising given previous
results suggesting that pregabalin does not reduce fatigue in FM.47
Strengths and limitations
A strength of this study is its use of data from clinical practice. However, its retrospective
design rather than a randomized controlled trial represents a limitation, as does the fact that
the population was from a limited geographic area, reducing generalizability. Another
limitation is that longitudinal assessment was not performed in individual patients, since
duration of treatment may affect the measured outcomes. Furthermore, it should also be
considered that polypharmacy is common in FM patients for the treatment of FM itself as
well as for comorbid conditions.2, 48, 49 Thus, since many patients are likely to be taking other
medications that are recommended or commonly used for treatment of FM (e.g.,
antidepressants) in addition to pregabalin and opioids, the positive outcomes may have been
impacted in part by medications other than pregabalin and/or opioids.
CONCLUSIONS
Pregabalin in the absence of opioids generally provided the most favorable outcomes in pain
severity and pain interference among responders regardless of whether the results were based
on clinically relevant thresholds of improvement from baseline (i.e., ≥ 30% and ≥ 50%) or the
entire response profile. However, while most patients took less than the recommended
pregabalin doses, the preferential pregabalin dosages for improvement and total effects
appears to most likely be between 151 and 450 mg, suggesting that higher doses than
currently used by patients in the clinical setting may lead to better outcomes. Some
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consideration for the use of opioids in combination with pregabalin was also suggested, in
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particular, high MED opioids + pregabalin demonstrated positive outcomes with a favorable
response profile.
Figure 1. Sample response profiles illustrating the analysis based on area-under-the-curve
(AUC). The gray area represents the difference in the AUC between the compared treatments
among non-responders (worsening) and responders (improvement); results are shown for
“Activity in general” for the top four ranked treatments, with all other variables analyzed in a
similar manner.
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Figure 2. Percent improvement in pain, fatigue, and pain interference among responders by
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treatment derived by area under the response curve.
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Figure 3. Area under the curve (AUC) rankings for pain interference, pain
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severity, and fatigue by treatment.
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Figure 4. Differences (95% confidence intervals [CI]) in area under the response curve
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among responders for pain interference improvement for the top five ranked treatments. *P <
0.05. Values to the left of the broken vertical line indicate the response favors the comparator
treatment listed in the column, while values to the right favor the comparator indicated in the
row.
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Figure 5. Differences (95% confidence intervals [CI]) in area under the response curve
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among responders for pain severity and fatigue improvement for the top five ranked
treatments. *P < 0.05. Values to the left of the broken vertical line indicate the response
favors the comparator treatment listed in the column, while values to the right favor the
comparator indicated in the row.
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Figure 6. Area under the curve (AUC) rankings for pain interference, pain
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severity, and fatigue by pregabalin dosage and patients prescribed any opioids.
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ccepted Articl
Table 1. Demographic characteristics the fibromyalgia patients prescribed opioids and/or pregabalin
Variable
No. of observations (n)
Sex, n (%)
Female
Male
Age, years, mean (SD)
No. of assessment days,
mean (SD)
Opioids
Percent time on opioid,
mean (SD)*
No. of prescriptions,
mean (SD)
MED, mean (SD)†
Pregabalin
Percent time on
prescription, mean
(SD)*
No. of prescriptions,
mean (SD)
Dosage, mg, mean
(SD)†
Total
Pregabalin
without
opioids
Opioids + pregabalin
Low MED
opioids
(≤20)
Only opioids
Moderate
MED
opioids
(>20, <100)
150 (83)
High MED
opioids
(≥100)
Low MED
opioids
(≤20)
Moderate
MED opioids
(>20, <100)
High MED
opioids
(≥100)
60 (28)
1194 (593)
1057 (491)
459 (195)
3082
(1,421)
52 (40)
110 (78)
2396 (77.7)
686 (22.3)
50.5 (12.7)
179.5
(63.3)
41 (78.8)
11 (21.2)
49.8 (12.4)
180.9
(75.1)
91 (82.7)
19 (17.3)
49.5 (12.3)
185.0
(58.5)
112 (74.7)
38 (33.3)
49.9 (12.0)
179.8 (63.4)
59 (98.3)
1 (1.7)
51.0 (11.1)
170.2 (44.1)
921 (77.1)
273 (22.9)
51.1 (13.7)
179.1 (65.9)
789 (74.6)
268 (25.4)
50.3 (11.9)
177.6 (64.0)
383 (83.4)
76 (16.6)
49.9 (12.3)
184.4 (55.3)
77.9 (31.3)
—
58.1 (33.5)
90.5 (17.6)
98.5 (3.5)
56.1 (34.6)
92.9 (15.8)
97.6 (7.7)
6.5 (5.1)
—
3.3 (2.4)
7.6 (4.4)
12.7 (5.0)
3.1 (2.3)
7.6 (4.1)
12.3 (5.5)
8.3 (5.4)
47.6 (20.4)
227.6 (140.4)
8.0 (5.7)
47.1 (20.9)
223.3 (199.5)
60.6
(111.4)
65.4 (35.1)
52.9 (37.3)
58.6 (37.0)
71.9 (31.5)
72.4 (33.7)
—
—
—
3.7 (2.4)
2.7 (1.7)
3.5 (2.3)
4.0 (2.8)
4.0 (2.2)
—
—
—
159.7
(140.8)
110.8
(124.3)
141.1
(138.2)
176.2
(131.1)
194.6 (165.6)
—
—
—
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ccepted Articl
Variable
Total
Pregabalin
without
opioids
Opioids + pregabalin
Low MED
opioids
(≤20)
Pregabalin dosage, %
≤ 150 mg
60.5
76.9
68.2
151-300 mg
23.1
17.3
15.5
301-450 mg
12.6
1.9
12.7
451-600 mg
3.4
3.9
3.6
MED, morphine equivalent dose; SD, standard deviation
Moderate
MED
opioids
(>20, <100)
High MED
opioids
(≥100)
Low MED
opioids
(≤20)
Moderate
MED opioids
(>20, <100)
High MED
opioids
(≥100)
52.7
30.7
14.7
2.0
51.7
23.2
16.7
8.3
—
—
—
—
—
—
—
—
—
—
—
—
*Mean percent time on prescription (days of prescription/days of assessment)
†Doses adjusted for time (percent time on prescription x daily dosage)
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Only opioids
ccepted Articl
Table 2. Proportion of fibromyalgia patients who reported improvement ≥ 30% and ≥ 50% from baseline. Pairs of similar superscripts indicate
significant differences (P < 0.05) between the indicated treatments. Values reflect total number of patients in the treatment group with nonmissing data for the item evaluated.
Variable
≥ 30% improvement
Average pain
Pain right now
Worst pain
Tired
Worn out
Pain interference with
ability to enjoy life
Pain interference with
activity in general
Pain interference with
mood
Pain interference with
relationships
Pain interference with
sleep
Pregabalin
24.4 (11.1,
35.6)
25.0 (13.5,
36.5)a
9.6 (1.9,
17.3)
15.4 (5.8,
25.0)
21.2 (9.6,
32.7)
26.2 (11.9,
38.1)
32.5 (17.5,
45.0)abc
23.8 (9.5,
35.7)
25.6 (10.4,
38.5)
30.8 (15.4,
43.6)
Percent of patients (95% confidence interval)
Opioids + pregabalin
Only opioids
Low MED
Moderate
High MED
Low MED
Moderate MED
opioids
MED opioids
opioids
opioids
opioids
(≤20)
(>20, <100)
(≥100)
(≤20)
(>20, <100)
16.3 (9.2,
23.5)
11.8 (6.4,
18.2)ab
4.5 (0.9, 9.1)
16.5 (10.5,
22.6)
18.7 (12.0,
24.7)
4.7 (1.3, 8.0)
20.4 (9.3, 31.5)
13.6 (7.3,
20.0)
20.0 (12.7,
27.3)
20.5 (11.4,
28.4)
10.9 (4.3,
17.4)d
16.9 (9.0,
24.7)*
13.4 (6.1,
20.7)a
29.3 (19.6,
38.0)
22.0 (15.3,
28.0)
24.0 (17.3,
30.7)
17.9 (11.1,
24.8)
20.6 (13.5,
27.8)
20.5 (13.1,
27.0)
26.5 (18.8,
34.2)abc
24.4 (16.3,
31.7)
16.7 (6.7, 26.7)
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20.0 (10.0,
30.0)
5.0 (0, 10.0)
21.7 (11.7,
31.7)
14.6 (4.9, 24.4)
27.1 (14.6,
39.6)d
21.4 (9.5, 33.3)
17.5 (5.0, 27.5)
27.1 (14.6,
37.5)
High MED
opioids
(≥100)
17.2 (14.8,
19.5)
19.7 (17.4,
21.9)b
6.6 (5.2, 8.0)
16.6 (14.3, 19.0)
21.0 (17.2, 24.8)
16.8 (14.6, 19.0
17.6 (14.2, 21.1)
6.7 (5.2, 8.2)
6.3 (4.1, 8.5)
20.4 (18.0,
22.6)
24.5 (22.0,
27.0)
14.3 (12.0,
16.6)
17.5 (15.1,
19.8)a
17.3 (14.7,
19.7)
16.8 (14.1,
19.5)b
22.1 (19.4,
24.9)
19.6 (17.1, 21.9)
18.5 (15.0, 22.0)
21.5 (19.0, 23.9)
21.4 (17.4, 25.1)
17.0 (14.5, 19.5)
17.5 (13.8, 21.2)
17.1 (14.6, 19.7)b
15.8 (12.1,19.4)c
17.8 (15.1, 20.4)
16.7 (13.0< 20.2)
18.4 (15.6, 21.1)
17.1 (13.1, 20.8)c
22.5 (19.7, 25.3)
24.7 (20.5, 28.8)
ccepted Articl
Variable
≥ 50% improvement
Average pain
Pain right now
Worst pain
Tired
Worn out
Pregabalin
13.3 (4.4,
22.2)
11.5 (3.8,
21.2)
5.8 (0, 11.5)
5.8 (0, 11.5)
5.8 (0, 11.5)ab
Percent of patients (95% confidence interval)
Opioids + pregabalin
Only opioids
Low MED
Moderate
High MED
Low MED
Moderate MED
opioids
MED opioids
opioids
opioids
opioids
(≤20)
(>20, <100)
(≥100)
(≤20)
(>20, <100)
High MED
opioids
(≥100)
8.2 (3.1,
13.3)
7.3 (2.7,
11.8)
0.9 (0, 2.7)
6.4 (1.8,
10.9)
11.8 (5.5,
18.2)
9.0 (4.5,14.3)
5.6 (0, 11.1)
7.4 (5.7, 9.0)
7.0 (5.3, 8.7)
8.3 (5.7, 10.8)
10.0 (5.3,
14.7)
2.0 (0, 4.7)
13.3 (8.0,
18.7)
16.0 (10.0,
22.0)a
11.7 (3.3, 20.0)
11.1 (9.4,
12.9)a
1.9 (1.2, 2.8)
11.6 (9.9,
13.5)a
15.6 (13.6,
17.7)b
9.2 (7.5, 11.0)
7.0 (4.8, 9.4)a
2.4 (1.5, 3.3)
11.1 (9.2, 13.0)
2.2 (0.9, 3.7)
8.3 (5.9, 10.9)a
12.8 (10.8, 14.8)
12.6 (9.6, 15.7)
1.7 (0, 5.0)
6.7 (1.7, 13.3)
15.0 (6.7, 23.3)
Pain interference with
ability to enjoy life
16.7 (4.8,
28.6)a
11.4 (4.5,
18.2)
9.4 (4.3, 14.5)
2.4 (0, 7.3)a
8.8 (7.0,
10.7)
8.6 (6.7, 10.5)
8.1 (5.7, 10.8)
Pain interference with
activity in general
20.0 (7.5,
32.5)
8.7 (3.3,
15.2)
12.7 (7.1,
18.3)
10.4 (2.1, 18.8)
10.1 (8.1,
12.0)
9.6 (7.6, 11.6)
10.2 (7.3, 13.3)
Pain interference with
mood
16.7 (4.8,
28.6)
6.7 (2.2,
12.4)
11.5 (5.7,
17.2)
14.3 (4.8, 23.8)
9.8 (7.8,
11.8)
9.2 (7.2, 11.1)
9.7 (7.0, 12.7)
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ccepted Articl
Variable
Pregabalin
Pain interference with
relationships
17.9 (5.1,
28.2)
Pain interference with
sleep
23.1 (10.3,
35.9)
Percent of patients (95% confidence interval)
Opioids + pregabalin
Only opioids
Low MED
Moderate
High MED
Low MED
Moderate MED
opioids
MED opioids
opioids
opioids
opioids
(≤20)
(>20, <100)
(≥100)
(≤20)
(>20, <100)
7.3 (2.4,
13.7 (7.7,
7.5 (0, 15.0)
9.9(7.7, 12.0)
9.5 (7.3, 11.6)
13.4)
19.7)
13.0 (6.5,
19.6)
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18.7 (11.4,
25.2)
18.8 (8.3, 29.2)
13.8 (11.4,
16.1)
15.0 (12.5, 17.3)
High MED
opioids
(≥100)
9.1 (6.4, 12.3)
16.7 (13.1, 20.2)
ccepted Articl
Table 3. Proportion of fibromyalgia patients reporting improvement ≥ 30% and ≥ 50% from baseline by pregabalin dosages regardless of
concomitant opioid use relative to opioids only. Pairs of similar superscripts indicate significant differences (P < 0.05) between the indicated
treatments.
Variable
≥ 30% improvement
Average pain
Pain right now
Worst pain
Tired
Worn out
Pain interference with ability to
enjoy life
Pain interference with activity in
general
Pain interference with mood
≤ 150 mg
(n = 225)
Percent of patients (95% confidence interval)
Pregabalin
151- 300 mg
301-450 mg
(n = 86)
(n = 47)
Opioids (n = 2710)
17.5 (12.5, 22.5)
17.3 (12.0, 22.2)
7.1 (4.0, 10.2)a
17.3 (12.4, 22.2)
20.9 (15.6, 26.2)
17.9 (12.1, 23.7)
19.2 (10.9, 27.4)
15.1 (8.1, 22.1)
2.3 (0, 5.8)a
18.6 (10.5, 26.7)
26.7 (17.4, 36.0)
25.0 (14.1, 34.4)
23.3 (11.6, 34.9)
25.5 (12.8, 36.2)
4.3 (0, 10.6)
14.9 (4.3, 25.5)
23.4 (10.6, 34.0)
21.1 (7.9, 34.2)
17.7 (16.1, 19.2)
18.2 (16.8, 19.7)
6.6 (5.7, 7.6)
19.7 (18.2, 21.2)
22.8 (21.3, 24.4)
16.0 (14.4, 17.5)
17.8 (12.2, 23.3)
22.2 (12.5, 30.6)
20.0 (7.5, 32.5)
17.0 (15.4, 18.6)
18.5 (12.9, 24.2)
19.4 (10.4, 28.4)
28.9 (13.2, 42.1)
17.4 (15.7, 19.0)
Pain interference with relationships
20.4 (14.4, 26.3)
22.4 (11.9, 32.8)
24.2 (9.1, 39.4)
17.5 (15.8, 19.2)
Pain interference with sleep
28.7 (21.9, 35.4)
29.0 (17.4, 39.1)
22.0 (9.8, 34.1)
22.8 (20.9, 24.5)
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ccepted Articl
≥ 50% improvement
Average pain
9.0 (5.5, 13.0)
11.0 (4.1, 17.8)
7.0 (0, 14.0)
7.4 (6.3, 8.5)
Pain right now
10.2 (6.2, 14.2)
7.0 (2.3, 12.8)
12.8 (*4.3, 23.4)
9.6 (8.5, 10.7)
Worst pain
2.7 (0.9, 4.9)
0 (0, 0)
4.3 (0, 10.6)
2.1 (1.6, 2.7)
Tired
7.6 (4.4, 11.1)
15.1 (8.1, 23.3)
6.4 (0, 12.8)
10.8 (9.7, 12.1)
Worn out
10.7 (6.7, 14.7)a
19.8 (11.6, 27.9)a
17.0 (6.4, 27.7)
14.0 (12.7, 15.3)
Pain interference with ability to
enjoy life
10.7 (6.7, 14.7)
12.5 (4.7, 20.3)
7.9 (0, 15.8)
8.6 (7.4, 9.8)
Pain interference with activity in
general
Pain interference with mood
12.2 (7.8, 17.2)
12.5 (5.6, 20.8)
7.5 (0, 15.0)
9.9 (8.6, 11.1)
11.2 (6.7, 15.7)
10.4 (3.0, 17.9)
13.2 (2.6, 23.7)
9.5 (8.3, 10.8)
Pain interference with relationships
10.2 (6.0, 15.0)
11.9 (4.5, 19.4)
18.2 (6.1, 30.3)
9.5 (8.3, 10.9)
18.0 (12.4, 23.6)
18.8 (10.1, 27.5)
14.6 (4.9, 24.4)
14.8 (13.2, 16.3)
Pain interference with sleep
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