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Non-steroidal anti-inflammatory drugs: To use or not to use? That is the question

21 Aug 2017
Analgesic selection needs to be individualized for patients with chronic pain. Nonselective NSAIDs (ns-NSAIDs) have been available in the market for decades and have a well-known safety profile.However, there are concerns surrounding the risk of GI adverse events, such as bleeding and ulcers in the gastric mucosa. In addition, healthcare professionals are also increasingly conscious of potential CV and renal adverse events with ns-NSAIDs.

Pain specialists commonly prescribe NSAIDs as a first-line analgesic for chronic pain conditions, muscular pain, and for pain management following surgery.[Pharmacotherapy 2008;28:788-805] In recent years, NSAIDs have also been studied for their role in neuropathic pain.[Pharmacotherapy 2008;28:788-805; Pain 2009;143:169-171] As such, assessing the efficacy and safety profiles of NSAIDs, and their suitability for individual patients, is integral to treatment selection.

Is paracetamol a suitable alternative to traditional NSAIDs?

Some guideline-issuing organizations recommend paracetamol for pain management, but paracetamol may not be suitably efficacious for patients with chronic pain as it is ineffective in managing lower back pain and provides minimal short-term relief in patients with osteoarthritis.[BMJ 2015;350:h1225]

As reflected in a survey of patients’ preferences, over 60% of respondents preferred NSAIDs and considered them more efficacious than paracetamol.[Arthritis Rheum 2000;43:378-385] Furthermore, recent data suggest that the GI, CV and renal safety profiles of paracetamol are not as favourable as previously believed and is, in fact, comparable with that of traditional NSAIDs.[Arthritis Rheum 2000;43:378-385; Ann Rheum Dis 2016;75:552-559]

Selective cyclo-oxygenase-2 (COX-2) inhibitors for chronic pain management

Selective COX-2 inhibitors were developed in an attempt to avoid GI adverse events related to COX-1 inhibition observed in patients given ns-NSAIDs. However, following reports of an increased risk of CV events in patients administered rofecoxib,[N Engl J Med 2005;352:1092-1102] only two selective COX-2 inhibitors are available locally to fill this need – celecoxib and etoricoxib.[Celebrex® (celecoxib). Singapore prescribing information. Accessed 29 March 201; Arcoxia® (etoricoxib). Singapore prescribing information. Accessed 29 March 201]

Celecoxib offers pain relief for patients with osteoarthritis that has been assessed as comparable with or greater than that offered by naproxen, while also improving physical function and stiffness.[Mayo Clin Proc 1999;74:1095-1105; Pharmacotherapy 1999;19:1269-1278] No significant increase in CV risk has been reported for celecoxib compared with controls, and indirect comparisons also suggest that celecoxib has a CV risk that is comparable with naproxen.[JAMA 2006;296:1633-1644; Lancet 2013;382:769-779] Celecoxib is also not associated with an increased risk of hospitalization for heart failure. When comparing celecoxib with all NSAIDs, thehospitalization risk is amongst thelowest recorded.[BMJ 2016;354:i4857]

The PRECISION study: Assessing the safety of celecoxib in patients with a high CV risk

The first randomized trial data about CV adverse effects of NSAIDs in patients at high CV risk came from the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION) trial. The PRECISION trial prospectively evaluated the CV safety of celecoxib with the two most commonly prescribed nonselective NSAIDs, ibuprofen and naproxen, in patients with osteoarthritis or rheumatoid arthritis and established or be at high risk of developing CV disease.[N Engl J Med 2016;375:2519-2529] This study also investigated the GI and renal outcomes, and all-cause mortality of celecoxib, ibuprofen and naproxen, as secondary and tertiary endpoints, respectively.[N Engl J Med 2016;375:2519-2529]

Notably, celecoxib was found to be non-inferior to ibuprofen and naproxen in terms of CV risk  (Figure 1), despite patients enrolled in the PRECISION trial having a higher prevalence of CV risk factors.[N Engl J Med 2016;375:2519-2529; Rheumatology 2009;48:425-432]

Figure 1. Primary composite outcome of CV death (including haemorrhagic death),
non-fatal MI or non-fatal stroke in the PRECISION study
Figure 1. Primary composite outcome of CV death (including haemorrhagic death), non-fatal MI or non-fatal stroke in the PRECISION study

GI safety of NSAIDs

While GI adverse events in patients administered NSAIDs are most commonly associated with the stomach, NSAIDs have also been implicated in cases of stricture, bleeding and inflammation in the lower GI tract. Lower GI events also tend to be more severe, with higher mortality, longer hospitalization times, and are  associated with a greater number of diagnostic tests.[Am J Gastroenterol 2009;104:1633-1641]

Adverse events in the GI tract can become a barrier that prevents patients from being physically active – physical activity is a useful approach for the management of chronic pain. The risk of GI bleeding with NSAIDs also dramatically increases in patients over the age of 60 years, but GI adverse events are often asymptomatic until a serious event occurs.[Gut 1987;28:527-532. 18; Arch Intern Med 1996;156:1530-1536; Epidemiology 1997;8:18-24]
 
Celecoxib, in comparison to other NSAIDs, is non-acidic (pKa 9.66), and is also associated with minimal endoscopy damage when used short-term.[Aliment Pharmacol Ther 2007;26:95-106; J Gastroenterol 2009;44:23-29. 22; Eur J Pharm Biopharm 2009;72:91-98]20-22 Therefore, even though proton pump inhibitors (PPIs) are generally co-administered as a gastroprotective agent with  traditional NSAIDs, PPIs do not lower the risk of lower GI tract mucosal damage in patients.[Clin Gastroenterol Hepatol 2005;3:133-141. 24; Aliment Pharmacol Ther 2007;25:1211-1222]

The risk of lower GI adverse events associated with use of celecoxib is less than that in patients treated with diclofenac plus a PPI,[Lancet 2010;376:173-179] and superior to ibuprofen and naproxen even when all patients receive PPI gastroprotection.[N Engl J Med 2016;375:2519-2529]

PPIs, which are most frequently  used as co-therapy with traditional NSAIDs, have been linked to an increased risk of infection and may interfere with absorption of vitamins and minerals, which can lead to an increase in the risk of bone fractures.[Arch Intern Med 2010;170:747-748. 27; Clin Gastroenterol Hepatol 2013;11:458-464]

Renal safety of NSAIDs

In patients with advanced baseline renal impairment [estimated glomerular filtration rate (eGFR) <30 mL/min], NSAIDs were associated with an increased risk of decline in renal function.[Ann Rheum Dis 2015;74:718-723]  In contrast, in individuals with eGFR values above  60 mL/min, NSAIDs or selective COX-2 inhibitors might be prescribed.[Ann Rheum Dis 2015;74:718-723] 

Compared with ibuprofen and naproxen, celecoxib was comparable to naproxen and superior to ibuprofen with regard to the risk of dialysis initiation, and hospitalization for acute renal failure or increased serum creatinine.[Rheumatology 2009;48:425-432]

Apart from renal outcomes, hospitalization for hypertension was also significantly lower among patients administered celecoxib versus ibuprofen in the PRECISION trial.[Rheumatology 2009;48:425-432]

Conclusion

When managing chronic pain, GI, CV and renal adverse events are key safety considerations for healthcare professionals. Selective COX-2 inhibitors were developed with the aim of avoiding GI adverse events, but excessive selectivity has been linked to an increased risk of CV events.Overall, celecoxib provides effective pain relief with lower GI risk profile, and CV risk profile comparable to naproxen and possibly lower renal risk compared with ibuprofen.

Open Forum Q&A

Q: Is there a role for ns-NSAIDs in pain management if COX-2 selective inhibitors offer similar pain relief with a more favourable safety profile?
A: In certain situations, some ns-NSAID are still useful as they seem to be more efficacious than COX-2s (eg, indomethacin in gouty arthritis). However, from a safety point of view, COX-2 selective inhibitors are  preferable, due to similar CV risk and lower GI risk.

Q: Is efficacy or safety more important when choosing a selective COX-2 inhibitor?
A: This depends on the risk profile (GI, CV and renal) of the patient. Safety always takes priority in patients with more risk factors. The favourable safety profile of celecoxib makes it preferable to other selective  COX-2 inhibitors, especially in high-risk patients. If celecoxib 200 mg twice daily provides adequate pain  relief, the dose of celecoxib may be reduced to 200 mg once daily.

Q: Should patients with a high CV risk always be treated with celecoxib 200 mg daily, in accordance with the dose used in the PRECISION study?
A: Dosing should be individualized for each patient. CV risk is one of several factors that should be considered when choosing the most appropriate dose of celecoxib.
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Most Read Articles
Yesterday
Older individuals experiencing persistent pain have a twofold increased risk of developing frailty, a study has found.
Elvira Manzano, 6 days ago
A new study reinforces the gut-brain connection in Alzheimer’s disease (AD), untangling the complex interplay between gut and brain health that could potentially lead to new therapies targeted at manipulating the gut microbiome to treat AD.
5 days ago
Supplementation with conjugated linoleic acid appears to increase inflammatory markers such as C-reactive protein and tumour necrosis factor-α, according to a recent meta-analysis.
Yesterday
Diet quality is an independent risk factor for stroke mortality, such that recommendations based on the 2010 Healthy Eating Index (HEI-2010) may help prevent stroke deaths, a recent study has found.