Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a multisystemic and heterogeneous involvement and is most common in women of childbearing age.^1,2 SLE can cause tissue inflammation, injury, and damage that may manifest as pain, but pain can also be present in the absence of inflammation and be multifactorial in origin.³

Pain management in SLE can be complex. Among certain subsets of SLE patients, treatment options are limited. For example, SLE patients with renal involvement, on high doses of steroids, or anticoagulant therapy are at increased risk of complications related to the use of non-steroidal anti-inflammatory drugs (e.g., gastric ulcers, gastrointestinal bleed, and kidney injury).⁴ Although patients with SLE could use opioid therapy without increasing the risk of these complications, the associated long-term effects of opioid therapy, such as opioid use disorder and the ongoing opioid overdose epidemic have prompted efforts to optimize its use and achieve safer chronic pain treatment while reducing side effects and misuse of these drugs.⁵ As with any treatment, opioids should only be considered for chronic pain management if the expected benefits for pain and function outweigh the risks to the patient.⁵ There is little information about how opioid therapy is used in the pain management of SLE. A previous study of an SLE registry showed that 31% of SLE patients self-reported opioid therapy, and up to 21% of them were on therapy for more than one year, compared to 7.8% and 6.3% of the persons without SLE, respectively.⁶ A claims-based study reported that 52.6% of SLE patients used opioids and 18.2% received this therapy for 90 days or more over 12 months.⁷ However, the prior studies were limited by lack of access to prescription data or misclassification bias due to the use of administrative data. In addition, these studies did not report which factors were associated with higher use of opioid therapy in SLE.

Based on the considerations mentioned before, we hypothesize that the prevalence of long-term opioid therapy (LTOT) will be greater among patients with SLE compared to controls and painful clinical manifestations of the disease (e.g., serositis, inflammatory arthritis), lupus nephritis, and non-SLE-associated painful comorbid conditions would be associated with LTOT among patients with SLE. In this cross-sectional study, we aimed to determine the prevalence of LTOT among patients with SLE compared to subjects without SLE and investigate the clinical characteristics associated with LTOT among patients with SLE.

465 SLE patients and 465 non-SLE controls were identified on January 1, 2015. The mean age of the patients and matched non-SLE controls was 53.1 years (SD 16.2), while 82% were female and 85–86% were non-Hispanic White. The length of medical history in the REP was similar in both groups, with a mean length of 25.3 years (SD 17.8) and 25.3 years (SD 18.0) among SLE patients and controls, respectively. The mean SLE duration was 13.8 years (SD 11.6) (Table 1).

The most common clinical manifestations in this cohort were inflammatory arthritis (60%), leukopenia (41%), and acute cutaneous lupus (23%). 21% of patients had proteinuria, and the most common lupus nephritis classes were III and IV. All patients were ANA positive, and >70% were positive for anti-dsDNA (Table 2).

In this study, 13% of SLE patients received opioid therapy compared to 3% of the non-SLE population. One out of ten (11%) SLE patients were on LTOT with a median duration of more than 1.5 years (614.5 days). The use of LTOT among SLE patients was significantly associated with a history of acute pericarditis, fibromyalgia, hip or spine fragility fractures, CLBP, and mood disorders. We did not find an association between area-based measures of social determinants of health measured by ADI scores and opioid therapy or LTOT. These findings suggest that SLE patients are more likely to receive opioid therapy because of the pain that SLE could cause directly and because of their comorbid conditions.

A previous study described a prevalence of opioid use of 31% among a sample of SLE patients from the Michigan Lupus Epidemiology and Surveillance Program (MILES) and 7.8% among a matched cohort without SLE. They found that 21% of SLE patients fulfilled their definition of long-term opioid use (more than one year). The median duration of opioid use in SLE patients was three years, which was similar to matched persons.⁶ In two claims-based studies, between 46–52.6% of SLE patients received opioids during their 12-month period of observation, and 16–18.2% received opioids for 90 days or more.^7,19 Compared to these prior studies, we found a lower prevalence of opioid therapy in our SLE population and matched controls. Differences in study design and populations likely explain the differences between the studies. The MILES study was based on a sample of patients from the initial registry; possibly, the patients participating in the study may have had a more severe disease or comorbidities than those identified in the registry but did not participate, resulting in a greater prevalence of opioid use. We also need to consider the higher dispensing rates in Michigan at the time of the MILES study compared with the rates in Minnesota or Wisconsin at the time of our study,²⁰ which might account for some of these differences. The MILES study was based on interviews, which is subject to response bias, as the investigators acknowledged. We were able to avoid this by using prescription data. Finally, the study population from the MILES cohort was more diverse, with more representation of racial or ethnic minorities.⁶ Claims-based studies suffer from misclassification and are performed in populations of beneficiaries of a specific insurance type limiting their generalizability,⁷ while we included all patients in a well-defined geographic area, irrespective of their insurance status or access to care. In a study of SLE patients who frequently visited the emergency department (ED), the prevalence of LTOT (defined as having a prescription for daily or near-daily use of opioids for at least 90 days, or total days of opioid supply >120 days) was also higher (37.7%) than ours; they also found that ADI scores in SLE patients who were receiving LTOT were higher than the regional average, but they did not compare SLE patients to a sample matched on key demographic characteristics, limiting the usefulness of the comparison.²¹ Our study did not find a difference in ADI scores between SLE patients and the rest of the non-SLE population or between LTOT patients and the rest of SLE patients. The patient population and setting likely explain the differences in findings between our study and the ED study; our study included SLE patients in the community, while Lee et al. included SLE patients seen in the ED in a different geographic area.²¹ Recently, a study from Germany derived from an insurance database reported that 8.8% of patients had a long-term prescription for opioids (defined as a prescription in ≥3 consecutive quarters).²² This is lower than our estimates (10%), but in general, the German population has a lower use of opioids than the US population, and their cases were identified based on diagnosis codes, which may risk misclassification.^5,23

Among patients with SLE, we found that those who had serositis (pleural/pericardial effusion) and in particular acute pericarditis were more likely to be on LTOT. Other painful manifestations like inflammatory arthritis were as frequent among those on LTOT and the rest of the patients. One of our hypotheses was that renal involvement would be associated with LTOT, given the more limited options to treat pain (e.g., nephrotoxicity from non-steroidal anti-inflammatory drugs). However, those with and without kidney involvement were equally likely to receive LTOT. Lee et al. described in their group of SLE patients who frequently visited the ED that 44.2% had a history of renal involvement and 18.2% had a history of pericarditis, but they did not include a comparison group and did not analyze associations.²¹

We found that SLE patients receiving LTOT were more likely to have fibromyalgia and mood disorders than SLE patients who were not on LTOT. In contrast, the MILES study did not find associations between long-term opioid users and self-reported fibromyalgia, depression, or anxiety. They also did not find any association with damage index score (a proxy for comorbidities), the prescription of opioids, or the disease duration. It is important to note that their population was derived from a cohort diagnosed more than ten years before the interview.⁶ Differences in findings could be explained by the different methods used to detect the presence of fibromyalgia and depression and the limitations intrinsic to an interview study. While the MILES study relied on self-reported diagnoses, our study identified diagnoses through medical record reviews. We explored other conditions associated with pain. We identified that SLE patients with a history of CLBP and hip or spine fragility fractures were also considerably more likely to be on LTOT. Our results about higher LTOT in SLE patients with comorbid back pain are in agreement with reports about the general population, where a prevalence of 18.8% of back pain patients receiving LTOT has been reported.²⁴ Opioid therapy and fragility fractures have been associated both as cause and consequence in the general population, with a higher probability of receiving opioid therapy after a fracture and as a risk factor for fractures.²⁵ Fibromyalgia and depression have been previously associated with higher use of opioid therapy in the general population.^26,27 Although there is no evidence of efficacy of opioid therapy in fibromyalgia, it is frequently used in these patients, with rates of opioid use ranging from 11.3 to 69%.²⁷

Our study has some limitations. The cross-sectional design does not allow us to infer causality between LTOT and the factors associated with it, more studies are needed to better understand this association among patients with SLE. The principal ethnic composition of our cohort, derived from a limited geographic area in the upper midwest of the United States, where most of the population is non-Hispanic White, may restrict the generalizability of our findings to other populations. Nevertheless, the non-Hispanic White population had the highest opioid-involved overdose death rates during 2014–2015.²⁸ Opioid prescribing has decreased since its height in 2012;^29,30 it is possible that after the release of the 2016 CDC guideline for prescribing opioids, fewer patients might be on LTOT; however, associations identified in this study may still apply to current practice.

In conclusion, 13% of SLE patients in this population were receiving opioid therapy as of January 1, 2015. One of every ten patients was on LTOT. Patients with a history of acute pericarditis, pleural or pericardial effusion, fibromyalgia, depression, CLBP, and hip or spine fragility fractures were more likely to receive LTOT. These findings will help clinicians identify factors that are associated with opioid therapy in SLE patients and optimize their pain management. Given the lack of evidence of the efficacy of opioid therapy in SLE and its comorbid conditions, a multidisciplinary pain management approach, including maximizing non-pharmacological and non-opioid therapies, is needed to preserve or improve the quality of life and function.