Ibuprofen safety: A look back on 50 years

Purpose Ibuprofen is nearing its golden anniversary (50 years) and remains among the most widely prescribed and frequently taken over-the-counter analgesic in the world. First developed in the United Kingdom by Boots Pure Drug Company, Limited,1 the drug evolved when scientist Stewart Adams sought to elucidate the anti-inflammatory effects of aspirin which seemed to him to be a clear advantage over acetaminophen.2 Adams and his colleague John Nicholson developed over 200 compounds and brought four to clinical trials with disappointing results. It was the fifth drug they tried that succeeded and came to market in 1969 in the United Kingdom and in 1974 in the United States.3 An anecdote told by Adams himself said that he took the first dose of the new drug himself to treat a hangover.1 Despite lengthy clinical experience with ibuprofen, new safety concerns had been raised about its role in infections4 and its safety for COVID-19 patients.5 Ibuprofen is unique in the NSAID family in that it appears to block both cyclooxygenase (COX) 1 and COX 2 enzymes. The COX enzymes synthesize prostaglandins which are associated with the inflammatory cascade. Safety concerns related to COX-1 inhibition mainly involved gastrointestinal adverse events;the introduction of selective COX-2 inhibitors or coxibs likewise raised safety concerns, in particular relating to cardiovascular events. Almost all NSAIDS may be associated with elevating blood pressure but the safety profiles of various NSAIDs are unique. Ibuprofen's position of balance 'middle of the road' position as being neither strongly selective for COX-1 or COX-2 has afforded it a strong safety and tolerability profile. The authors sought to review safety data on ibuprofen at the half-century mark and to consider the advantages and disadvantages of this versatile and popular analgesic. Methods Articles were obtained via PubMed search in June of 2019 through the searching various keywords. 'Ibuprofen safety gastrointestinal' resulted 223, 'ibuprofen safety cardiovascular' resulted 122, 'ibuprofen safety renal' resulted 111, 'ibuprofen safety infection' resulted 35, and 'ibuprofen Streptococcus' resulted 35. Bibliographies of certain articles were also searched. Cost-effectiveness studies, and non-safety aspect of analgesia studies were excluded along with studies exclusively on pediatric, geriatric, or special populations like patent ductus arteriosus patients were excluded. Non-English studies without full text translation were also excluded. Articles focusing on major safety concerns of ibuprofen were kept including meta-analyses, safety, and safety and efficacy studies. Studies published in the last ten years were emphasized. In addition, among the authors are several physicians with relevant clinical experience with analgesics whose expertise contributed to the project. Results Ibuprofen is an analgesic and antipyretic. Its Tmax is 1.9 ± 1.4 hours in healthy subjects with a half-life of about 2.2 ± 0.4 hours. (1.4 hours).6 In safety studies, ibuprofen was found in the Paracetamol, Aspirin, and Ibuprofen New Tolerability (PAIN) study to have similar rates of adverse events as acetaminophen (paracetamol) at doses of ≤ 1200 mg/day and significantly fewer adverse events compared to ≤ 3000 mg/day of aspirin.7,8 The PRECISION trials of osteoarthritis and rheumatoid arthritis patients found that in long-term follow-up NSAID toxicity occurred in 5.3% of ibuprofen patients compared to 4.1% of celecoxib and 4.8% of naproxen patients.9 A meta-analysis (n = 2187 patients) found that ibuprofen was associated with a numerical frequency of adverse events similar or lower than placebo patients.10 In the Ibuprofen Paracetamol Study in Osteoarthritis (IPSO), 222 patients were randomized to receive 400 mg ibuprofen three times a day or acetaminophen (paracetamol) 1000 mg three times a day;ibuprofen was the more effective pain reliever with a similar risk of gastrointestinal adverse events as paracetamol over the 14-day study.11 The association of ibuprofen to infections is complex bec use in some cases, it confers a benefit (cystic fibrosis) but in others, it appears to exacerbate the infection. Ibuprofen was not found to be associated with increased bleeding risk following surgery.12 Hypersensitivity reactions in various NSAIDs have been reported but are so rare there are insufficient data to compare individual agents. Conclusions After 50 years, new evidence continues to emerge regarding the safety profile of ibuprofen. Taken as directed in the therapeutic dose range, ibuprofen is associated with significant anti-inflammatory action, effective analgesia, and a comparatively low risk of GI, CV, renal, hepatic, or infectious side effects. Ibuprofen, with its favorable safety profile, may be considered the safest of all NSAIDs pain relievers. Risks for GI, CV, renal, and hepatic side effects are lower than other NSAIDS. Prescribers must always balance benefit against risk with any medication and NSAIDs should only be taken at the lowest effective dose for the shortest amount of time. Ibuprofen may not be appropriate for all patients, but its safety profile makes it an attractive first line for many acute and chronic pain conditions., Clinicians should evaluate the evidence and safety when making prescribing choices or recommending OTC products to their patients.

COVID-19 and NSAIDs: Knowns and unknowns

Purpose Concern about the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in COVID-19 have been raised. The viral point of entry is the angiotensin-converting enzyme (ACE)2 receptor and it has been speculated that some NSAIDs, in particular ibuprofen, may upregulate ACE2 receptors and that NSAIDs may also have certain immunosuppressive effects. Two specific questions have been raised: do NSAIDs increase the risk of contracting COVID-19 and, in infected persons, do NSAIDs worsen outcomes? While NSAIDs represent a well-known drug class, there are considerable variations among NSAIDs, such as selective and nonselective NSAIDs. It is unknown if such differences are clinically important in COVID-19 patients. The purpose of this research is to provide an overview of what is currently known-and what is not known-about the use of NSAIDs in the setting of COVID-19. Methods The body of literature is large and new reports, case studies, clinical studies, and commentaries appear daily. The authors used the PubMed database of the National Institutes of Medicine to search for keywords 'COVID' plus 'NSAID,' 'ibuprofen,' and 'naproxen.' Some of our authors are frontline clinicians in and outside of the United States who brought their expertise to the discussion. Selected articles were obtained and their bibliographies searched for other relevant material. Content was synthesized but it must be noted that there are no large randomized clinical trials investigating the question of NSAIDs but there are emerging reports. Information about COVID-19 is changing rapidly, even daily. This was a qualitative narrative review. The content was reviewed, discussed among the authors, and synthesized. Results The inflammatory cascade or cytokine storm, known to play a role in worse outcomes in influenza,1 is associated in COVID-19 with tissue injury, morbidity, and mortality.2 In diseases associated with coronaviruses, such as Middle Eastern Respiratory Syndrome (MERS) or Severe Acute Respiratory Syndrome (SARS), the marked increase in inflammatory cytokines parallels a rapid replication of the virus resulting in lung injury and potentially life-threatening acute respiratory distress syndrome.3 Early evaluations of COVID-19 patients suggest similarly high levels of pro-inflammatory cytokines along the lines of MERS and SARS.3 As cytokine storm likely plays a major role in adverse outcomes of severely ill COVID-19 patients, the role of anti-inflammatories ranging from NSAIDs to glucocorticoids to hydroxychloroquine and others would seem beneficial in an effort to reduce inflammation before it overwhelms the body's systems. The role of NSAIDs in viral infections of other kinds has been controversial.4 Anti-inflammatory therapy for influenza may be associated with certain drawbacks. The use of an antiinflammatory might potentially slow viral elimination and elevate the risk of a secondary infection. While an antiinflammatory can reduce inflammation, it may have limited or poorly understood effect on cytokine storm, which involves multiple cytokines and complex interactions. One argument against the use of NSAIDs and also acetaminophen is that these are antipyretic drugs that may mask a rising fever associated with COVID-19 and thus delay diagnosis and rapid management of the infection.5 There is no evidence that the occasional use of an oral, over-the-counter NSAID for a few days by a person with suspected or diagnosed mild COVID-19 infection will exacerbate the infection. Second, there is no reason to think that patients taking prescribed NSAIDs for a chronic painful condition should stop taking this drug for fear it might increase their risk of contracting COVID-19 or exacerbate it if they get it.6 The confusion about NSAIDs arises mainly because prostaglandin production is complex and can both promote and inhibit inflammatory processes. As with other analgesics, there are considerations with NSAIDs which should be taken at the lowest effective doses for the shortest periods of time. The Expert Working Group of the Commission on Human Medici es in the United Kingdom has issued a statement that there is 'currently insufficient evidence to establisha link between the use of ibuprofen and susceptible to contracting COVID-19 or the worsening of its symptoms.'7 Conclusions To date there is no evidence in favor or disputing the use of NSAIDs in COVID-19. Indeed, any blanket 'for' or 'against' statement on this topic would not be clinically realistic or prudent.

Four pandemics: Lessons learned, lessons lost

Purpose In the past hundred years, the world has faced four distinctly different pandemics: the Spanish flu of 1918-1919, the SARS pandemic of 2003, the H1N1 or 'swine flu' pandemic of 2012, and the ongoing COVID-19 pandemic. Each public health crisis exposed specific systemic shortfalls and provided public health lessons for future events. The Spanish flu revealed a nursing shortage and led to a great appreciation of nursing as a profession. SARS showed the importance of having frontline clinicians be able to work with regulators and those producing guidelines. H1N1 raised questions about the nature of a global organization such as the World Health Organization (WHO) in terms of the benefits and potential disadvantages of leading the fight against a long-term global public health threat. In the era of COVID-19, it seems apparent that we are learning about both the blessing and curse of social media. The authors did not include the Middle Eastern Respiratory Syndrome (MERS) among the pandemics although it is sometimes described as a pandemic. It began in 2014 and cases have been reported every year since then, but usually in a geographically limited area and never more than 500 per year. Methods This was a commentary. The authors used the PubMed database to search for keywords relating to Spanish flu, SARS, H1N1, and COVID-19 and reviewed primarily articles that discussed the management and public health ramifications of these pandemics. The information was synthesized and presented in light of what was learned in each pandemic that carried forward or failed to carry forward to aid us in future crises. Results Each pandemic brought to light deficiencies and shortfalls in the healthcare system and the opportunity to create better systems to manage these emerging illnesses. Following the Spanish flu pandemic, educational pathways in the United States were set up to allow people to become licensed as a practical nurse and the clinical role of nurses was better defined. One lesson learned in SARS was the life-saving role of extracorporeal membrane oxygenation (ECMO) for patients with severe respiratory illness. In 2007, the International Health Regulations had gone into effect, which was an official attempt to codify lessons learned from SARS in terms of connecting front-line clinicians with politicians, regulators, and other public health authorities. The H1N1 pandemic highlighted limitations with the capabilities and authority of the WHO. While WHO has demonstrated great ability and dexterity in managing short-term health crises, the long-term management of a severe pandemic may exceed the competence and financial strength of any global organization. COVID-19 occurred in the post-television era where most people obtain news from online platforms. On one hand, social media allowed rapid dissemination of basic strategies to prevent COVID-19, however, misleading and false information also emerged. WHO labeled it an 'infodemic' that paralleled the pandemic. Conclusions Each of these four pandemics has had a devastating effect but has also left us with lessons to learn that may blunt or even prevent future disasters. The Spanish flu exposed a shortage of trained nurses that has since been largely remedied. The SARS epidemic drove home the fact that ECMO could be lifesaving in selected cases. Guidance is often urgently needed not just from experts but from front-line clinicians. In the H1N1 pandemic, the role of WHO in pandemic care was highlighted and certain key questions emerged about how well one global organization can manage a long-term pandemic. Today, in COVID-19 the role of 'viral' media in the context of a viral pandemic will no doubt fuel many later studies.