First do no harm
People at high risk for all adverse effects, whether cardiovascular, gastrointestinal, or renal, should avoid using a Non-steroidal anti-inflammatory drug (NSAID) if possible. Any NSAID use in these people should be at the lowest effective dose for the shortest possible duration, to minimise such risk.
Diclofenac (Voltaren, Glaxo-Smith Kline in Australia), for instance, is associated with a lower risk of gastrointestinal complications than other NSAIDs, so a switch from it to an alternative NSAID could inadvertently place the patient at increased risk to gastrointestinal complications. That said, although nominally an NSAID, diclofenac acts more like a COX-2 inhibitor and its anti-inflammatory efficacy may also be commensurately less than that of other anti-inflammatories. Although anecdotal evidence to back this claim seems inconsistent.
On average 7 in 1,000 (0.7 %) people with osteoarthritis, and 13 in 1,000 (1.3 %) with rheumatoid arthritis, who take an NSAID for 1 year will experience a serious gastrointestinal adverse effect, such as perforation, obstruction, or bleeding. The incidence of complications is higher in people with risk factors:
- age > 65 years
- history of gastroduodenal ulcer
- concomitant corticosteroids or anticoagulants
- choice and dose of NSAID
Along with Diclofenac, celecoxib, ibuprofen (≤ 1,200 mg), and lumiracoxib, are associated with a low risk of gastrointestinal adverse effects. In clinical trials, approximately 12 in 1,000 people taking a COX-2 selective NSAID for a year experienced serious vascular events, however, 3 per 1,000 more than those receiving placebo, and higher in those with higher baseline cardiovascular risk.
Evidence to distinguish between NSAIDs in terms of cardiovascular risk is still emerging.
NSAIDs can also cause acute renal failure and exacerbate heart failure symptoms, or cause them to develop in susceptible people. To date, there is little evidence that NSAIDs differ greatly in their propensity to cause these adverse effects, although COX-2 (including diclofenac) cardiac risk is likely greater than that from conventional NSAIDs.
| Drug | Relative Risk of serious vascular event |
| celecoxib | 1.06 (0.91-1.23) |
| diclofenac | 1.40 (1.16-1.70) |
| ibuprofen | 1.07 (0.97-1.18) |
| meloxicam | 1.25 (1.00-1.55) |
| naproxen | 0.97 (0.87-1.07) |
| piroxicam | 1.06 (0.70-1.59) |
| rofecoxib (≤ 25 mg/day) | 1.33 (1.00-1.79) |
| rofecoxib (> 25 mg/day) | 2.19 (1.64-2.91) |
Alleviate suffering
Although the evidence is inconclusive, weigh those risks against respective NSAID efficacy outlined in The Oxford Pain Group’s league table (See Reference list for more complete table):
Low-dose ibuprofen may be the safest but the NSAID with the best balance of efficacy and safety may be naproxen, although at a higher dose than the regular 250 mg. Of course, inter-individual efficacy and adverse event variation with NSAID use is strong.
Naproxen has the lowest relative risk for serious vascular event, according to the table above: 0.97 (0.87 – 1.07); with efficacy varying between NNT: 3.1 for the 220 or 250 mg strength, NNT 3.0 for a 550 mg strength and, paradoxically, NNT 2.3 for a 440 mg strength.
Any advice to take NSAIDs with food and/or combined with a gastroprotective Proton Pump Inhibitor seems appropriate. To reduce particularly gastrointestinal risk, patients should take their NSAID in the middle of a substantial meal. Ideally, ask them to eat half the meal, take the tablet with a glass of water, and then finish the meal.
For what it’s worth, my NSAID preference essentially follows the lines of lowest risk for vascular events (table above): naproxen is my preferred drug. (In other words, avoid COX-2s in those with cardiac disease.) But that does not mean that it works in everyone and that reduced vascular risk comes at a price, likely a greater gastrointestinal risk.
Use the NSAID judiciously: short course, lowest dose necessary. Consider adding PPI cover in elderly or those with GI risks: be extremely cautious prescribing NSAIDs in those who drink, even modest drinkers.
GI Risk vs NSAID use:
High-Risk
- h/o complicated ulcer
- multiple risk factors
Moderate risk
-
- 1 – 2 risk factors
Low risk
-
- no risk factors
The Risk factors are:
- > 65 years old
- high-dose
- h/o (uncomplicated) ulcer
- concurrent ASA / steroids / anticoagulants
- (multiple NSAID use)
Preference (“Best”)
- CVS risk: naproxen
- Asthma: celecoxib
- Topical: Voltaren
- Bleeding: COX-2
- GI ulcer: COX-2 (e.g. Mobic, Celecoxib) + PPI
H. pylori is an independent and additive risk factor; however, eradication alone is not sufficient to prevent Upper GI bleeding in chronic NSAID-induced ulcer. ∴ Rx with PPI as superior to eradication therapy (and by all means, in due course, treat with H. pylori eradication therapy also).
Reversible (aspirin is irreversible), non specific cyclooxygenase inhibition of both COX-1 (constitutive, as in gastric mucosa, platelets, and kidneys) and COX-2 (inducible at sites of injury/inflammation):
- Ceiling effect exists for NSAIDs (increasing dose may not increase efficacy)
- Disproportionate use and complication rate among the elderly
- Renal insufficiency or severe hepatic disease may require dose reduction or preclude use
- Ibuprofen can be given up to 24 hours preoperatively, other NSAIDs should be discontinued 3 days preoperatively (full dose aspirin 7 days if not contraindicated), to reduce the possibility of bleeding complications
- Association with asthma, rhinitis/nasal polyps, and aspirin allergy [6]
References
- NPS, Fact Sheet: Diclofenac and cardiovascular risk -15 September 2006. Reviewed 30 November 2012.
- Diclofenac use and cardiovascular risks: series of nationwide cohort studies (Schmidt, 2018)
- TGA, Australian Government Department of Health. Safety review of diclofenac. Version 2.1, October 2014. Available at https://www.tga.gov.au/sites/default/files/medicines-review-safety-diclofenac.pdf. Accessed 23 June 2020.
- Wongrakpanich, Supakanya, Wongrakpanich Amaraporn, Melhadol, Katie and
Rangaswami, Janani. A Comprehensive Review of Non-Steroidal Anti-Inflammatory Drug Use in The Elderly. Aging Dis. 2018 Feb; 9(1): 143–150. doi: 10.14336/AD.2017.0306. - Oxford League Table of Analgesic efficacy. Available at www.nature.com/ebd.
- Singh, Nina. 5-Minute Anesthesia Consult, Wolters Kluwer, 2012.
