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Am J Kidney Dis. 2020 Apr 18. pii: S0272-6386(20)30042-1. doi: 10.1053/j.ajkd.2019.12.010. [Epub ahead of print]
Association of Opioids and Nonsteroidal Anti-inflammatory Drugs With Outcomes in CKD: Findings From the CRIC (Chronic Renal Insufficiency Cohort) Study.
Zhan M, Doerfler RM, Xie D, Chen J, Chen HY, Diamantidis CJ, Rahman M, Ricardo AC, Sondheimer J, Strauss L, Wagner LA, Weir MR, Fink JC; CRIC Study Investigators
PMID: 32317121 Free full text at AJKD
Introduction
Non steroidal anti-inflammatory drugs (NSAIDs) are on the top of the list of drugs we warn patients not to take. They can cause AKI and CKD and hypertension and electrolyte problems. They are poison, stay away from them. You have pain? Here’s some tramadol, or oxycodone, or hydromorphone even. Anything but NSAIDs for pain, we would tell.
Were we wrong?
Classic analgesic nephropathy was described almost seven decades ago (Spuhler and Zollinger, Z Klin Med, 1953). However, this was mostly phenacetin, and often in combination with one more NSAID - as well as a barbiturate, codeine or caffeine. It was accompanied with classic pathologic features including papillary necrosis, and at its peak, contributed to 15-20% of the incidence of kidney failure (Nanra et al, Kidney Int 1978). NSAID usage in those volumes (many pills a day, for a lifetime) is uncommon now, but epidemiological data still points towards NSAIDs being bad for kidneys.
A study in the 1990s (Perneger et al, NEJM 1994) showed that NSAID users with a cumulative exposure to more than 5000 pills had an odds ratio for ESKD of 8.8 compared to non-users. Another early study (Sandler et al, Annals Int Med 1991) showed higher risk of a creatinine of 1.5 plus a diagnosis of chronic renal insufficiency up to 2-8 times higher than non users. A study from this century in patients over 66 years of age with glomerular filtration rate (GFR) of 63ml/min/1.73m^2 (Gooch et al, Am J Med, 2007) followed for 3 years reported a linear relationship between cumulative NSAID dose and mean GFR. Higher dose (Ibuprofen 700mg or naproxen 300mg daily) had a 26% increased risk of GFR loss >15ml/min/1.73m^2. But if GFR was already <60ml/min/1.73m^2, NSAID use was not associated with rapid progression. An issue with all these epidemiological studies is the underlying confounding by indication, discussed in a recent review (Sriperumbuduri and Hiremath, Curr Op Nephrol HT, 2018). NSAID use is for a reason: people are in pain from arthritis, inflammatory conditions, and these may associate with kidney outcomes that one may not be able to adjust away. We discussed the PRECISION trial on #NephJC 3 years ago, which reported a low rate of kidney events after almost 3 years of daily NSAID use. Another study we discussed last year reported a higher risk of GFR fall with heavy NSAID use. But all patients in that trial and the more recent study received an NSAID, what can one surmise without a correct control group?
Enter the opioid crisis. Avoiding NSAIDs has come at the cost of higher opioid use. During 1999–2018, opioids were involved in 446,032 deaths in the United States (Wilson et al, MMWR weekly, 2020). The WHO pain ladder for cancer escalates to opioids very quickly, at step 2 (WHO pain ladder). Is it appropriate to avoid the nephrotoxicity of NSAIDs, and be exposed to the addiction and overdose potential of opioids? Despite some pushback, pain management for C KD has followed the conservative path of NSAID avoidance (Koncicki et al, Am J Kidney Dis 2017). Why should we not compare the effects of opioids versus NSAIDs?
The Chronic Renal Insufficiency Cohort (CRIC) Study is a prospective observational cohort of CKD which started enrolling patients with GFRs of 20 to 70 ml/min/1.73m^2 in 2003. Data from CRIC was used to report 24% NSAID use in CKD, moreover that NSAID discontinuation was accompanied by opioid initiation (Zhan et al, CJASN 2017). This sets up the current study perfectly: lets compare the outcomes of Opioids and NSAIDs in patients with CKD.
The Study
Methods
Prospective cohort study of 3,939 patients with CKD in the Chronic Renal Insufficiency Cohort Study (CRIC). CRIC enrolled participants between 2003 to 2006 from 13 clinical sites in the U.S. Participants underwent annual in-center visits providing clinical, demographic, and biochemical information.
Study Population:
Inclusion criteria
Age 21 to 74
Age-specific eGFR of 20 to 70mL/min/1.73m2
Exclusion criteria
None mentioned
Classification of analgesics
NSAIDs included oral NSAIDs and cyclooxygenase 2 inhibitors. Aspirin was defined as an NSAID if the daily dosage was over 325mg, dose frequency was more than once daily, or the drug was part of a combination analgesic
Opioids included all orally administered opioids (as designated in First Databank) such as hydrocodone, codeine, and oxycodone. Of note, methadone represented <1% of opioid entries and no one reported use of buprenorphine or naloxone
Tramadol was considered its own separate category unless taken in combination with an NSAID or opioid, in which the medication was classified in the latter’s category
Other included others, predominantly acetaminophen
Excluded: Cold/cough remedies, intravenous or topic analgesics
The analgesic use was noted at baseline (as reported in table 1) but the analysis does not compare the groups as described here. Patients may change their analgesic use with time - it is difficult to blame kidney failure or death occurring 4 years after you stopped an NSAID on the baseline use. Hence the authors used a time updated exposure. If someone was on an NSAID (or an opioid etc) at their annual visit, that was counted for any outcomes that occurred in the following year. At their next visit, if the NSAID use had stopped, they would switch groups for the analysis for that year. Ascertainment of drug use for made on the basis of use in the 30 days preceding the study visit, which were annual. To reduce recall bias, participants were asked to maintain a list or bring medications to visits.
Outcomes
Kidney failure requiring kidney replacement therapy
Composite of kidney failure requiring kidney replacement therapy and 50% reduction in eGFR from baseline
Pre-kidney failure death
Annual number of pre-kidney failure hospitalizations
Statistical analysis
Firstly, the authors performed a crude (non-adjusted) comparison, for the outcomes mentioned above in the year following each visit, using the time-updated exposure as mentioned above.
In addition, an adjusted analysis was also performed, to examine the association between time-updated opioid and NSAID use and the study outcomes while controlling for time-dependent covariates. They applied joint marginal structural models because several time-dependent covariates including eGFR could be both a consequence and a predictor for analgesic use. The CRIC workgroup has experience performing such analysis for causal inference (for further reading, see Howe et al, Epidemiology, 2012).
The authors looked a comprehensive list of covariates including baseline factors (e.g. sex, race, education, income), age, alcohol use, comorbid conditions (diabetes, cardiovascular disease, HTN, asthma, non-skin cancer, hyperkalemia, and arthritis), GFR, urinary protein-creatinine ratio, response on Beck Depression Inventory, symptom severity, and Kidney Disease Quality of Life 36 questionnaire, 12-item short form Health Survey, SF-12 mental composite, nephrologist visit, and other analgesic use (non-opioid/non-NSAID analgesic and tramadol).
Stratified analyses were also completed using demographic variables and key predictors of kidney outcomes such as baseline age, sex, race (nonblack and black), diabetes status, eGFR, and UPCR.
To demonstrate that results are not due to confounding, the researchers also examined the association of opioids and NSAIDs with risk for incident diabetes as a negative control outcome among CRIC participants without diabetes at enrolment.
Funding
NIDDK R01 - 3 authors
CRIC - several grants from NIDDK
Internal funds from the Perelman School of Medicine at the University of Pennsylvania CTSA
Others: NCATS component of the NIH and NIH Roadmap for Medical Research, Michigan Institute for Clinical and Health Research, University of Illinois at Chicago CTSA, Tulane COBRE for Clinical and Translational Research in Cardiometabolic Diseases, Kaiser Permanente NIH/National Center for Research Resources.
Results
Study Population
3,939 participants were included & followed for a median of 6.84 years.
24,838 visits for time to kidney failure with kidney replacement therapy or pre-kidney failure death. 24,552 visits for the composite outcome of kidney failure with kidney replacement therapy and 50% reduction in eGFR.
Table 1 and Table 2 show participant characteristics by baseline use of the drugs
Important differences:
Compared to participants that reported no opioid use, the group that reported baseline opioid use was more likely to be: female, black, have an annual income of <50K, and have a history of rheumatoid arthritis, cardiovascular disease, asthma, non-skin cancer, and drink alcohol.
Compared to participants that reported no NSAID use, the group that reported baseline NSAID use was more like to be aged 45 to 64 years, female, non-black, a college graduate or higher, have an income > 50K, and report drinking alcohol.
Compared to nonusers, opioid users were more likely to have depressive symptoms and lower scores for the KDQOL SF-36 and its component domains.
Compared to nonusers, NSAID users had higher KDQOL-36 scores compared to nonusers.
Crude (unadjusted) Results
Table 3 shows crude rates of outcomes, using time-updated exposure
Death: Crude incidence of death was highest in the opioid use alone and opioid and NSAID group with crude rates (per 100 person-years) of 3.5 (95% CI, 2.8-4.3) and 3.5 (95% CI, 2.2-5.5), respectively.
Kidney failure with KRT: Crude incidence of kidney failure with kidney replacement therapy in the opioid and other (nonopioid non-NSAID) groups were 4.2 (95% CI, 3.4-5.2) and 4.3 (95% CI, 4.0-4.6) per 100 person-years while the crude incidence of kidney failure with KRT in the NSAID-only group was 1.9 (CI, 1.4-2.5) and the opioid and NSAID group at 2.5 (95% CI, 01-1.5).
Composite kidney disease outcome: Crude incidence of composite kidney disease outcome in the opioid and other (nonopioid non-NSAID) groups were 5.9 (95% CI, 5.3-6.3) and 5.9 (95% CI, 5.5-6.3), respectively while the crude incidence of the composite kidney disease outcome in the NSAID-only group was 2.4 (95% CI 1.9-3.2) and 2.3 (95% CI, 1.2-4.2), respectively.
Hospitalizations: Crude rate of hospitalizations in the opioid only group was the highest while the NSAID-only group had the lowest crude rate: 108.6 (95% CI 99.1-118.9) versus 58 (95% CI, 51.5-65.3) per 100 person years.
Adjusted Results (after accounting for covariates)
Table 4 shows the Associations of Time-Updated cumulative NSAID and Opioid Exposure with Outcomes
Strength of association between opioid use and the outcomes was comparable to the full cohort.
The associations between NSAID use and hospitalization, kidney failure with KRT, the kidney disease composite, and death were no longer significant.
Table S1 shows the varying HRs for the association of each analgesic group and the outcomes w/in subgroups designated by age, sex, race, DM, GFR, and UPCR at baseline.
Strength of association between time-updated NSAID use and the composite kidney disease outcome was strong in blacks versus non-blacks with HR of 1.31 (95% CI, 1.01-1.69) and HR of 0.83 (95% CI, 0.64-1.09) respectively, P=0.02 for effect modification.
Strength of association of time-updated NSAID use and kidney failure with KRT also varied across sex and baseline eGFRs with a higher HR for males versus females with HR of 1.21 (95% CI 0.91-1.61) and 0.63 (95% CI, 0.45-0.88), respecively, P=0.004 for effect modification.
Strength of association of pre-kidney failure hospitalization with opioid use was higher in the lower versus higher baseline UPCR subgroups with RRs of 1.90 (95% CI, 1.66-2.17) and 1.54 (95% CI, 1.36-1.74), respectively, P=0.02 for effect modification.
When they investigators looked for an association with diabetes as a negative control neither opioid nor NSAID use were associated with incident diabetes.
Potential confounding of other drug groups that may be used as analgesics (such as anxiolytics and antiepileptics) was explored and only antiepileptics were associated with the outcome of death. Adding antiepileptics as a confounder did not change the results.
Discussion
In this cohort of adults with CKD, it was demonstrated that reported opioid use within 30 days of ascertainment and treated as a time-updated exposure was associated with a substantial risk for adverse kidney disease outcomes, death, and hospitalization. This was in contrast with the unexpected and modest relationship of NSAID use with adverse outcomes. The association between NSAID use and adverse kidney disease events was most prominent in blacks, with a potentially beneficial association with outcomes observed in subgroups including women and those with lower eGFRs.
Strengths:
First study to compare harm of NSAID versus opioid use in CKD.
One of the few reports to describe opioid use in non-dialysis requiring CKD.
Limitations:
Observational analysis.
Confounding by indication. Patients on NSAIDs followed by nephrologists may have been judged as low risk, and hence may have slower kidney function decline. Patients on NSAIDs with faster decline may have had their NSAIDs stopped (even prior to enrolment, or in between visits).
Modest sample size.
CRIC study did not have detailed pain assessment including measures of severity and type of pain.
Use was self reported, limited to 30 days preceding an annual visit and may not reflect actual use over more distant intervals.
Did not the effect of acetaminophen which was used as an analysis reference group.
Use of analgesic may have been different over the course of years when the opioid epidemic was less broadly recognised.
GFR was modeled as a categorical outcome, and not as a continuous outcome (eg as slope of GFR).
Conclusion:
In this study, opioids had more adverse effects in CKD compared to NSAIDs with a substantial increase in risk for death and poor kidney outcomes. The use of opioids as being safer in CKD patients for pain relief seems to be misleading and harmful. Judicious NSAID use, under careful supervision of a nephrologist, may not be harmful for kidney function, as previously thought.
Summary prepared by
Anju Yadav MD FASN, Thomas Jefferson University, Philadelphia, PA
Lilia Cervantes, MD, Denver Health and University of Colorado School of Medicine, Denver, CO