Opioid Use in Patients with Rheumatoid Arthritis 2005–2014: A
Population-Based Comparative Study
Jorge A. Zamora-Legoff, M.D.
1
, Sara J. Achenbach, M.S.
2
, Cynthia S. Crowson, M.S.
1,2
,
Megan L. Krause, M.D.
1
, John M. Davis III, M.D. M.S.
1
, and Eric L. Matteson, M.D. M.P.H.
1,3
1
Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN, USA
2
Division of Biomedical Statistics and Informatics, Department of Health Sciences Research,
Mayo Clinic College of Medicine, Rochester, MN, USA
3
Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic College of
Medicine, Rochester, MN, USA
Abstract
Objective—Opioid prescriptions have seen an increase across the United States (US), Canada,
Europe and the United Kingdom (UK). In the US they have quadrupled from 1999 to 2010. Opioid
use among patients with rheumatoid arthritis (RA) over time is not well described. This study
examined trends of opioid use in patients with RA.
Methods—Retrospective prescription data was examined from 2005–2014 in a population-based
incidence cohort of patients with RA by 1987 ACR criteria and comparable non-RA subjects.
Differences in opioid use were examined with Poisson models.
Results—A total of 501 patients with RA (71% female) and 532 non-RA subjects (70% female)
were included in the study. Total and chronic opioid use in 2014 was substantial in both cohorts
40% RA vs 24% non-RA and 12% RA vs. 4% non-RA, respectively. Opioid use increased by 19%
per year in both cohorts during the study period (95% confidence interval [CI]: 1.15, 1.25).
Relative risk (RR) of chronic opiate use for RA patients compared to non-RA subjects was highest
in adults aged 50–64 years (RR: 2.82; 95%CI: 1.43–6.23). RA disease characteristics, biologic use
at index, treated depression/fibromyalgia, education, smoking status were not significantly
associated with chronic opiate use.
Conclusions—Over a third of patients with RA use opioids in some form, and in more than a
tenth use is chronic. Use has increased in recent years. Patients aged 50–64 with RA use
substantially more opioids than their non-RA counterparts.
Keywords
Rheumatoid arthritis; Opioid trends; Chronic pain management
Corresponding Author/Request for Reprints: Eric L. Matteson, 200 First Street SW, Rochester, MN 55905, Phone: 507-284-8450, Fax:
507-284-0564, Matteson.Eric@mayo.edu.
The authors disclose that they have no relevant conflicts of interest to disclose.
HHS Public Access
Author manuscript
Clin Rheumatol
. Author manuscript; available in PMC 2017 May 01.
Published in final edited form as:
Clin Rheumatol
. 2016 May ; 35(5): 1137–1144. doi:10.1007/s10067-016-3239-4.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
The use of opioid analgesics is on the rise in the western world with increasing rates
reported through most of Europe, Canada, United Kingdom (UK), and the United States
(US) [1, 2]. The rise of the opioid analgesic use has been especially dramatic in the US as
individual prescription sales quadrupled from 1999 to 2010 [3]. Along with the boom in
sales, age-adjusted opioid drug poisoning death rates (81% of which are unintentional) have
more than doubled from 2000 to 2013, from 6.2 to 13.8 per 100,000 [4, 5]. There are now
more opioid-based analgesic users in the general patient population than ever before, but to
what extent specific subpopulations are affected by this rise is in need of clarification.
Traditionally, opioid therapy has been divided into two pain groups, cancer related and non-
cancer related pain, as well as into two therapy duration groups, acute and chronic, of which
non-cancer chronic opioid use is the fastest growing [3].
Although the efficacy and relative safety of short-term opioid use has been established, there
is limited evidence regarding long-term opioid analgesic use for pain management [6]. Rates
of diagnosis of chronic non-cancer pain have increased in recent years in the US population.
Prevalence studies by random sampling in general adult communities have revealed rates as
high as 64.4% [7], while others have estimated that as many as 25.3 million adults are
suffering from chronic pain [8].
Patients with non-cancer related pain may be at a particularly high risk for opioid use.
Rheumatoid arthritis (RA) is a chronic disease associated with chronic pain. Patients who
suffer from RA repeatedly report that pain is the primary driver in seeking medical
consultation [9]. Patients suffer from multiple inflammatory and noninflammatory chronic
pain syndromes throughout their disease course [10].
From a public health perspective, RA is also a particularly important disease to be studied
for opioid use since the Centers for Disease Control and Prevention (CDC) estimate that RA
affected 1.5 million Americans in 2007 and that by the year 2030, 67 million persons in the
US will have been diagnosed with some form of arthritis [11]. The aim of this study was to
identify trends in opioid use among patients with RA compared to similar subjects without
RA and to describe the characteristics of patients with RA at greatest risk for chronic opioid
use.
Methods
Study Population
This historic cohort study was approved by the Mayo Clinic and Olmsted Medical Center
Institutional Review Boards. Study subjects were identified using resources from the
Rochester Epidemiology Project (REP), a special record-linkage system that records all
inpatient and outpatient encounters among the residents of Olmsted County, Minnesota [12]
[13], including prescription data. All Olmsted County, Minnesota residents aged 18 years or
older who first fulfilled 1987 American College of Rheumatology criteria for RA in 1980–
2004 were previously identified [14]. A comparison cohort of patients without RA with
similar age, sex, and calendar year was randomly selected from the same population. The
index date was defined to be January 1
st
2005 and included all patients from the RA and
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non-RA cohorts who were alive and followed on that date. All subjects in both cohorts were
followed longitudinally until death, migration, or December 31, 2014.
Data collection
All outpatient opioid prescriptions were identified by generic and trade names for 2004 to
2014. For each prescription, the frequency, dose, and refills were obtained and manually
converted to days of use. Data on RA therapies and disease severity indicators was
previously collected by manual record review. Biologic use at any time prior to index and
current glucocorticoid therapy at index date was recorded for all patients with RA. Data on
disease severity indicators included rheumatoid factor and/or anti-citrullinated protein
antibodies (RF/ACPA) positivity, rheumatoid nodules, erosions/destructive changes on
radiographs and erythrocyte sedimentation rate (ESR) values. The time from first joint
swelling to fulfillment of ACR criteria was abstracted to assess delay in diagnosis of RA.
Medical records of all subjects with an electronically coded diagnosis of depression and
fibromyalgia were identified then manually reviewed and data on the use of medical therapy
for these diagnoses at index were collected. Subsequently only those individuals receiving
current medical therapy for either depression and/or fibromyalgia after the index date were
labeled as such. Diagnoses of comorbidities prior to index were obtained electronically for
both cohorts and classified using the Deyo adaptation of the Charlson Comorbidity Index
[15]. These included myocardial infarction, peripheral vascular disease, cerebrovascular
disease, cancer, peptic ulcer and diabetes mellitus. Smoking status and educational
achievement were obtained from self-answered questionnaires routinely administered at
clinic visits.
Opioid use definitions
Any opioid use was defined as one or more opioid prescriptions in the study period. Chronic
use was defined as a prescription(s) for 60 or more days at usual dose and usual schedule
(table 1) within a 6 month period or those subjects using fentanyl, methadone and
controlled/extended release oxycodone. Opioid presentation, formulation, and strength
considered for the study are listed in table 1.
Statistical analysis
Descriptive statistics (means, percentages, etc.) were used to summarize the characteristics
of each cohort. Characteristics were compared between cohorts using Chi-square and rank
sum tests. Person-year methods were used to compute the overall rate of first chronic opioid
use in the time period of interest as the number of patients meeting the definition of chronic
opioid use divided by the number of person-years of follow-up. Patients who had any opioid
prescription in 2004 were excluded from analyses of first chronic use of opioids in an
attempt to estimate the rate of incident chronic use of opioids. Poisson regression models
were used to estimate the relative risk of first chronic opioid use among those with RA
compared to those without RA.
Yearly estimates of percentage of subjects with any opioid use were computed as the number
of patients with any opioid prescription in a particular calendar year divided by the person-
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years of follow up in that calendar year. Yearly estimates of the percentage of subjects with
chronic opioid use were computed similarly. To avoid overestimation of the rate of chronic
use of opioids, after having met our definition of chronic use, subjects were returned to non-
chronic use when there was a year without an opioid prescription.
Cox models adjusted for age, sex, and other characteristics were used to examine difference
in time to first opioid use during the time frame of interest between the cohorts. Cox models
were also used to examine characteristics associated with first chronic opioid use among the
patients with RA. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC,
USA) and R 3.1.1 (R Foundation for Statistical Computing, Vienna, Austria).
Results
A total of 501 patients with RA (71% female) and 532 non-RA subjects (70% female) were
included in the study. The patients with RA had a mean (±SD) age at index date of 61.3
± 14.5 years, with a mean follow-up from index of 8.5 ± 2.7 years. The non-RA subjects had
a mean age at index date of 62.6 ± 14.7 years, with a mean follow-up from index of 8.7
± 2.4 years. Any opioid prescription in the year prior to the index date was significantly
higher in the RA cohort, 31% RA vs 20% non-RA (p<0.001). Further characteristics found
to be significantly different between the RA and non-RA subjects at index were peripheral
vascular disease 19% RA vs. 13% non-RA (p=0.006), and a prior peptic ulcer 19% RA vs
13% non-RA (p=0.005). There were no apparent differences at index data between subjects
with and without RA regarding a previous diagnosis of diabetes mellitus, cancer, myocardial
infarction, congestion heart failure or cerebrovascular disease (table 2). The opioids
identified by prescription frequency were oxycodone (39%), hydrocodone (18%), tramadol
(22%), fentanyl (6%) morphine (3%), propoxyphene (4%) and codeine (5%).
Over the observed ten-year period any opioid use was found to be common in both cohorts
with 40% of patients with RA and 24% non-RA subjects having used an opioid in 2014
(figure 1, upper panel). Patients with RA were 1.5 times more likely to have experienced any
opioid use than non-RA subjects (age and sex adjusted hazard ratio [HR]: 1.58; 95%
confidence interval [CI]: 1.37, 1.82).
To estimate incidence of chronic opioid use, the 156 patients with RA and 105 non-RA
subjects who had an opioid prescription in 2004 were excluded from analysis of chronic
opioid use. Chronic opioid use was also substantial in both cohorts, 12% RA vs 4% non-RA
in 2014, and this rate increased over time (relative risk [RR]: 1.19 per year; 95% CI: 1.15,
1.25; figure 1, lower panel). Patients with RA were nearly twice as likely to require chronic
opioid therapy as comparator subjects (age and sex adjusted HR 1.90; 95% CI: 1.32, 2.72).
The higher rate of chronic use in RA subjects remained unchanged after adjusting for known
general population risk factors for opioid use including smoking status, educational level,
treatment for depression or fibromyalgia, and Charlson comorbidity index (HR 1.92; 95%
CI: 1.33, 2.78).
Additional analysis of the opioid use trend by sex and age group showed that chronic opioid
use was considerably higher in patients with RA aged 50–64 years, 2.3% vs. 0.8% in non-
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RA adults (relative risk [RR]: 2.82; 95% CI: 1.43, 6.23; table 3). There was no identified
difference in risk of chronic opioid use in younger adults age 18 to 49 or in adults 65 years
or older. Adult women with RA at any age were more likely to use chronic opioid therapy
than comparator non-RA women (RR 1.80; 95% CI: 1.19, 2.75). The greatest (threefold)
increased risk for chronic opioid use was noted in females with RA age 50–64 compared to
non-RA (RR 3.35; 95% CI: 1.47, 9.37).
Among patients with RA, those on systemic glucocorticoid therapy at index were at
markedly higher risk for chronic opioid use (HR 2.48; 95% CI: 1.51, 4.06). Disease severity
factors for RA were not significantly associated with an increased risk of chronic opioid use,
including RF/ACPA positivity, rheumatoid nodules, and ESR at diagnosis (table 4). Delay in
diagnosis, as measured by time from first joint swelling to fulfillment of criteria for RA, was
not associated with chronic opioid use (p=0.98). The presence of erosions/destructive
changes approached significance (HR: 1.50; 95% CI: 0.93, 2.41). Biologic therapy use
before index was also not associated with either a decreased or increased risk (HR 1.18; 95%
CI: 0.55, 2.50).
Discussion
In this study, opioid use was common and has increased in recent years in patients with RA
and non-RA populations. Over one third of patients with RA are prescribed an opioid and
disturbingly, one in ten use opioids chronically during their disease course. This is a
significantly greater opioid usage than that seen in an already opioid-burdened general
population, and the data suggest this will increase in the coming years [4][5]. While the
current study could not specifically interrogate the indications for opioid use in individual
patients, these high use rates are particularly concerning as available evidence does not
support the efficacy of chronic opioid use for chronic non-cancer pain management [6] [16]
[17].
The decision to use a sixty day or two-month definition for chronic opioid use is largely
derived from data gathered and released by the CDC on the safety of opioid use. Persons at
highest risk to suffer serious harm from opioids are all those aged 65 years or less who are
prescribed therapy for 6 weeks (or longer) and all persons, regardless of age, using extended
use formulations such as fentanyl patches, OxyContin®, and methadone [16]. In this
context, there are currently no reported randomized placebo-controlled trials on the
effectiveness of opioid therapy in RA. As well, there is no evidence that the analgesic
effectiveness of opioids can be maintained past eight weeks of continuous use in any form of
chronic non-cancer pain [6]. Therefore, the suggested definition for chronic opioid use is
both purposeful and representative of known data and it does not necessarily reflect
previously suggested definitions, such as a three-month period of use. This time frame of 90
days has been broadly borrowed from other studies of chronic pain, that is, pain persisting
past acute tissue injury [18]. A 60 day definition encompasses both the longest period of
demonstrated effectiveness for opioid based analgesics and those who at two months are
already at high risk to suffer harm from continuing therapy with opioids.
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