Safe Use of Non-Steroidal Anti-Inflammatory Drugs (Nsaids)

Essentials

• Consider the different pain management options.
  • Non-pharmacological methods
  • Oral nonsteroidal antiinflammatory drugs (NSAIDs)
  • Topical NSAIDs
  • Paracetamol
  • Codeine, tramadol
• An NSAID is usually justified in the treatment of inflammatory rheumatic disease and acute pain (such as injury, back pain, migraine, menstrual pain).
• Check the need for long-term medication and the dose regularly.
  • Use the lowest effective dose.
• Consider the possibility of drug interactions and contraindications (use electronic tools if available).
• Assess the benefits and risks involving the gastrointestinal tract, cardiovascular system and kidneys, particularly in patients aged 65 or more.
  • Short-acting preparations may be safer.
  • Topical products are absorbed through the skin and have very few systemic effects.
  • For patients with heart disease or its risk factors (hypertension, diabetes, high cholesterol level or smoking) or renal failure, choose primarily a topical NSAID or paracetamol.
    • If, however, an oral NSAID is needed, use the lowest effective dose for the shortest possible time.
  • If gastrointestinal risks are significant, use prophylactic antiulcer medication or choose a COX-2-selective NSAID.

The most common adverse effects of NSAIDs

• Upper abdominal complaints, ulcer, upper gastrointestinal bleeding, intestinal mucosal injury and oozing of blood
• Cardiovascular adverse effects (hypertension, myocardial infarction, cerebral events, oedema)
• Exacerbation of asthma, allergic reactions
• Renal failure (particularly in association with acute disease and dehydration, for instance)

NSAID-induced peptic ulcer disease Gastrointestinal Safety Profile of Meloxicam, Celecoxib for Rheumatoid Arthritis, NSAID Drugs for Acute Gout

• Risk factors http://www.dynamed.com/prevention/prevention-of-nsaid-induced-gastrointestinal-toxicity#GUID-95B001FB-1E8C-4A81-9406-79D1FE6A2DCE include
  • age over 65 years
  • a history of ulcer
  • diseases that worsen the patient's general condition
  • concurrent glucocorticoid treatment
  • concurrent treatment with anticoagulants or other drugs that prevent blood coagulation (e.g. acetylsalicylic acid, clopidogrel, ticagrelor)
  • concurrent SSRI or SNRI treatment for depression
  • concurrent use of more than one NSAID
  • high daily dose of an NSAID
  • Helicobacter infection.
• Low risk: no above-mentioned risk factors
• Increased risk: one of the above-mentioned risk factors, but no earlier peptic ulcer haemorrhage
• High risk: earlier gastrointestinal haemorrhage associated with NSAID use or several risk factors
• Often asymptomatic, and may first present as bleeding ulcer or perforation
• The risk of ulcer associated with NSAIDs is increased even in short-term use.
• In patients on warfarin, COX-2-selective drugs are probably no safer than the rest.
• NSAIDs aggravate reflux oesophagitis.
• Perform Helicobacter eradication therapy Peptic Ulcer Disease, Helicobacter Pylori Infection and Chronic Gastritis before starting long-term use of NSAIDs http://www.dynamed.com/prevention/prevention-of-nsaid-induced-gastrointestinal-toxicity#HELICOBACTER_PYLORI_ERADICATION, at least in patients with a history of ulcer Eradication of Helicobacter Pylori in Patients Starting Long-Term Treatment with Nsaids.

Gastrointestinal adverse effects

• Intestinal lesions are in most cases mild but they may lead to bleeding, perforation or stricture and thereby to intestinal obstruction.
• NSAIDs may also cause colitis and exacerbate an earlier-diagnosed inflammatory bowel disease.
• Intestinal complications may possibly form a significant part of all NSAID-induced gastrointestinal adverse effects. Earlier intestinal damage and advanced age are risk factors.
• PPIs will not prevent and may even add to the adverse effects on the lower gastrointestinal tract.
• COX-2-selective NSAIDs are probably no safer than conventional NSAIDs.

Cardiovascular adverse effects Selective and Traditional Non-Steroidal Anti-Inflammatory Drugs and the Risk of Atherothrombosis

• NSAIDs (including COX-2-selective drugs) increase the risk of myocardial infarction, cardiac failure, stroke and death.
• The risk depends on the patient's cardiovascular disease and risk factors, as well as on the dose of NSAID.
  • In the absence of an underlying cardiovascular disease, the risk is low (a lot lower than that associated with smoking, for instance).
  • Naproxen and low-dose ibuprofen are probably safer than the rest with regard to the risk of infarction.
• For patients with cardiovascular disease, either paracetamol or a topical NSAID should be used.
• NSAIDs (including COX-2-selective drugs) increase fluid accumulation and may aggravate cardiac failure. In patients with renal disease, they should not be used at all (they reduce the efficacy of ACE inhibitors, ARBs and diuretics).
• NSAIDs (including COX-2-selective drugs) may raise blood pressure and they may have a negative effect on blood pressure control in patients with hypertension http://www.dynamed.com/condition/renal-manifestations-of-nonsteroidal-anti-inflammatory-drugs-nsaids#TOPIC_DZL_RLJ_2GB. Etoricoxib must not be used in patients with blood pressure continuously exceeding 140/90 mmHg.

Renal adverse effects Nsaids and Blood Pressure, Nsaids and Postoperative Renal Function

• Under normal circumstances and at normal doses, renal adverse effects are very rare.
• Such effects may be varied, including acute kidney injury, disturbances of electrolyte or acid-base balance, and acute interstitial nephritis.
• Acute renal failure http://www.dynamed.com/condition/renal-manifestations-of-nonsteroidal-anti-inflammatory-drugs-nsaids#TOPIC_WMS_2ZS_R2B1 may develop rapidly in patients with risk factors, such as advanced age, diabetes, heart or kidney failure, dehydration, infection or use of other nephrotoxic drugs; see Acute Kidney Injury. The disorder is usually reversible upon discontinuation of the medication.
  • Combined use of ACE inhibitors, ARBs and NSAIDs clearly increases the risk of acute renal failure.
• Use of high doses for several years may lead to rare, irreversible analgesic nephropathy.
• In patients with renal failure, any use of NSAIDs and the dose used should be adjusted to the renal function; see locally available electronic tools and the article on the Treatment of chronic renal failure Treatment of Chronic Renal Failure.

Asthma and allergies

• In aspirin-sensitive asthma (present in a small share of all patients with asthma), NSAIDs cause bronchial constriction. In this case, all NSAIDs are contraindicated.
• NSAIDs may cause allergic or pseudoallergic reactions also in people with no asthma.
• They may cause different types of skin reactions.
• All NSAIDs are contraindicated in patients who have experienced a severe asthmatic or hypersensitivity reaction after taking a drug belonging to this group.

References

• Coxib and traditional NSAID Trialists' (CNT) Collaboration., Bhala N, Emberson J et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013;382(9894):769-79. [PubMed]
• Szeto CC, Sugano K, Wang JG et al. Non-steroidal anti-inflammatory drug (NSAID) therapy in patients with hypertension, cardiovascular, renal or gastrointestinal comorbidities: joint APAGE/APLAR/APSDE/APSH/APSN/PoA recommendations. Gut 2020;69(4):617-629. [PubMed]
• Solomon DH, Husni ME, Wolski KE et al. Differences in Safety of Nonsteroidal Antiinflammatory Drugs in Patients With Osteoarthritis and Patients With Rheumatoid Arthritis: A Randomized Clinical Trial. Arthritis Rheumatol 2018;70(4):537-546. [PubMed]
• Chan FKL, Ching JYL, Tse YK et al. Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial. Lancet 2017;389(10087):2375-2382. [PubMed]
• Guo CG, Leung WK. Potential Strategies in the Prevention of Nonsteroidal Anti-inflammatory Drugs-Associated Adverse Effects in the Lower Gastrointestinal Tract. Gut Liver 2020;14(2):179-189. [PubMed]
• Bally M, Dendukuri N, Rich B et al. Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data. BMJ 2017;357():j1909. [PubMed]
• Arfè A, Scotti L, Varas-Lorenzo C et al. Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study. BMJ 2016;354():i4857. [PubMed]
• Gunter BR, Butler KA, Wallace RL et al. Non-steroidal anti-inflammatory drug-induced cardiovascular adverse events: a meta-analysis. J Clin Pharm Ther 2017;42(1):27-38. [PubMed]
• Martín Arias LH, Martín González A, Sanz Fadrique R et al. Cardiovascular Risk of Nonsteroidal Anti-inflammatory Drugs and Classical and Selective Cyclooxygenase-2 Inhibitors: A Meta-analysis of Observational Studies. J Clin Pharmacol 2019;59(1):55-73. [PubMed]