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Is Ibuprofen As Deadly As Vioxx?

Is Ibuprofen As Deadly As Vioxx?

Our medicalized approach to pain may be putting us in harms way.   However, there are safe, natural approaches that can ease painful conditions.

How Coxibs Killed Tens of Thousands

Non-steroidal anti-inflammatory drugs (NSAIDs), which include over-the-counter pharmaceuticals such as ibuprofen, naproxen, and aspirin, rank among the most widely used pharmaceuticals worldwide. Their chief mechanism of action is inhibition of two forms of cyclo-oxygenase (COX), namely COX-1 and COX-2 (1). Also known as prostaglandin-endoperoxide synthase (PTGS), COX is responsible for the production of downstream mediators of pain and inflammation, such as thromboxane and prostaglandins. Due to their suppression of prostaglandins, which exert protective roles in the gastrointestinal tract, one of the most frequent adverse effects of NSAIDs is irritation of the gastric mucosa. 

Thus, newer generation selective COX-2 drugs, known as the coxibs, were introduced in the 1990s to mitigate the risk of peptic ulceration that results from COX-1 suppression. By 2004, coxibs had dominated the prescription drug market for NSAIDs, with worldwide sales of approximately $10 billion (2). Their development was based on the premise that COX-1 was the source of the cytoprotective prostaglandins in the gastric epithelium, whereas COX-2 was the source of the inflammatory mediators, prostaglandins E2 and I2 (2). However, as early as 1999, scientists had reported that coxibs inhibit generation of prostaglandin I2, the primary product of COX in the endothelium, responsible for reducing platelet aggregation and proliferation of vascular smooth muscle cells and for inducing vascular vasodilation (2). 

Traditional NSAIDs inhibit both prostaglandin I2 and the major COX-1 product of platelets, thromboxane A2. Thromboxane A2 opposes the actions of prostaglandin I2, causing vasoconstriction, coagulation, and vascular proliferation (2). Thus, unlike traditional NSAIDs, coxibs leave thromboxane A2 production unopposed, such that,

“Suppression of the COX-2-dependent formation of prostaglandin I2 by coxibs might predispose patients to myocardial infarction or thrombotic stroke…depression of prostaglandin I2 formation might be expected to elevate blood pressure, accelerate atherogenesis, and predispose patients receiving coxibs to an exaggerated thrombotic response or to the rupture of an atherosclerotic plaque” (2, p. 1709).

Other researchers echoed these warnings, stating, “By decreasing vasodilatory and antiaggregatory prostacyclin production, COX-2 antagonists may lead to increased prothrombotic activity” and consequently raise risk for thrombotic cardiovascular events (4). This mechanism of action panned out in placebo-controlled trials, which unequivocally revealed that despite their lower gastrointestinal toxicity, coxibs were correlated with an increased risk of atherothrombotic vascular events (3).

In fact, the multi-center, randomized, placebo-controlled, double-blind trial that led Merck to withdraw Vioxx from the market demonstrated that thromboembolitic event rates were double for the coxib rofecoxib, also known as Vioxx, compared to placebo (5). However, the incidence of myocardial infarction observed in those receiving Vioxx was increased by a factor of five (2). The safety of Vioxx was had been called into question ever since data from the Vioxx gastrointestinal outcomes research (VIGOR) study, submitted by Merck to the US Food and Drug Administration (FDA) in 2000, was re-analyzed. Mukherjee et al. (2001) found that Vioxx increased the risk of developing a myocardial infarction, cardiac thrombus, unstable angina, resuscitated cardiac arrest, ischemic stroke, transient ischemic attack, or sudden and unexplained death, by 2.38 times compared to a non-selective NSAID, Naproxen (4). Rather than attributing enhanced cardiac risk to Vioxx, Merck maintained that Naproxen was cardioprotective to explain the disparity in cardiac events, a claim which remained to be proven.

Even after Dr. Eric Topol, chairman of the Cleveland Clinic’s department of cardiovascular medicine and co-author of the aforementioned study, called for trials to ascertain whether Vioxx and other coxibs increased cardiovascular risk, Merck and Pfizer, the latter of which manufacturers Celebrex, rejected their requests (6). In an interview, Dr. Topol asserts that industry scientists even paid him a visit in attempts to persuade him not to publish his findings (6). Thousands of internal industry documents revealed that Merck “misrepresented study results and used ghostwriters to prepare manuscripts for journal publication,” and that they shelved unfavorable company-funded studies that revealed cardiac risk (7, 8). Most damning was a study at Kaiser Permanente underwritten by the FDA, which revealed that high doses of Vioxx increased the risk of heart disease by 3.7 times (6).

As a result of criminal malfeasance, in 2011, the pharmaceutical company Merck was ordered to pay $950 million over Vioxx, including $202 million to state Medicaid agencies and $426 million to the federal government to settle civil suits contending that its illegal marketing tactics convinced physicians to prescribe Vioxx and bill the government (9). Also part of that figure was the $321 million in criminal fines that Merck was ordered to pay resulting from their guilty plea to illegally introducing the drug into interstate commerce (9). These figures were in addition to the $2.85 billion Merck paid in 2007 to settle 27,000 lawsuits by patients, survivors, and their relatives who suffered injury or mortality after taking Vioxx (9). Further, Merck was also held culpable in a class-action securities lawsuit by investors who claimed they were defrauded by the drug maker and lost tens of billions of dollars in shareholder value when the drug was withdrawn (10). Altogether, over 20 million Americans took Vioxx, and conservative estimates by the FDA attest that the drug caused more than 27,000 deaths and heart attacks between 1999 and 2003 (6, 11).

Are Traditional NSAIDs Any Safer?

As a consequence, traditional non-selective NSAIDs (tNSAIDs) came to be perceived as safer in terms of cardiovascular effects than coxibs. However, this superior safety is an illusion, since meta-analyses of observational studies and randomized trials have underscored that both coxibs and tNSAIDs are associated with enhanced cardiovascular risk as well as gastrointestinal problems (12, 13, 14). 

A previous meta-analysis of placebo-controlled trials illuminated that tNSAIDs might predispose individuals to atherothrombotic events, depending on the extent and duration of suppression of platelet COX-1 inhibition (12). Other than Naproxen, high-dose tNSAID regimens that elicited transient effects on platelet COX-1 have been associated with statistically significant increases in vascular hazard (12). In addition, in a meta-analysis of 31 trials including 116,429 subjects, Trelle et al. (2011) found that both selective and non-selective NSAIDs significantly increased risk of heart attack, stroke, and cardiovascular death (14). As a result of these findings, the FDA required that all NSAIDs carry a black box warning of cardiovascular disease risk (3). 

Although the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) declared that coxibs are contraindicated for patients with pre-existing stroke, coronary heart disease, or risk factors for these conditions, they have not made the same decree regarding tNSAIDs (3). Because of biases inherent in some of the correlational studies, “There has been uncertainty about the nature and magnitude of these risks, and the relative safety of different NSAID regimens, especially in those at increased risk of coronary heart disease” (3, p. 775). Therefore, in order to quantify the cardiovascular and gastrointestinal risks of NSAID regimens, a recent meta-analysis examined individual participant and tabular data from randomized trials of NSAIDs (3). 

Researchers undertook a meta-analysis of 280 trials of tNSAIDs use versus placebo, consisting of 124,513 subjects and 68,342 person-years, and 474 trials comparing one NSAID regimen to another, comprised of 229,296 participants and a total of 165,456 person-years (3). The end-points analyzed were major coronary events, including non-fatal myocardial infarction or coronary death, and major vascular events, including non-fatal myocardial infarctions, non-fatal strokes, or vascular deaths (3). Researchers also examined other cardiovascular outcomes, including stroke, congestive heart failure, and mortality, as well as upper gastrointestinal complications including bleeds, obstructions, and perforations (3). The authors mention that the vast majority primary outcomes occurred in trials that used either a coxib or a high-dose NSAID, such as 1000 mg a day of naproxen, 150 mg a day of diclofenac, or 2400 mg a day of ibuprofen (3).

Compared to controls, risk of major vascular event was increased by approximately one-third in subjects randomized to receive a coxib or the tNSAID diclofenac, owing mainly to a three-quarters increased risk in major coronary events (3). More surprising, however, was that Ibuprofen, which is still perceived as relatively benign by most health care providers, significantly increased incidence of major coronary events (3). Moreover, although tNSAIDs did not significantly increase risk of stroke, “The risk of hospitalization due to heart failure was roughly doubled by all tNSAID regimens studied,” with Ibuprofen posing the highest risk (3, p. 773).

Further, both coxibs and diclofenac significantly increased risk of vascular death, whereas the increased risk of vascular death due to Ibuprofen did not reach statistical significance (3). Risk of overall mortality was increased by 25% for those administered a coxib; however, “Despite a clear excess of vascular deaths the corresponding excess was not significant for diclofenac,” or for ibuprofen or naproxen (3). In addition, although coxibs are advertised as posing less gastrointestinal risk, the meta-analysis showed that they increased risk of gastrointestinal complications, primarily bleeds, with higher doses yielding larger proportional excesses in risk of ulceration (3). As expected, the tNSAIDs diclofenac, ibuprofen, and naproxen exhibited the highest risk of gastrointestinal tract complications, doubling to quadrupling risk of upper gastrointestinal complications (3). Unambiguous evidence appeared that tNSAID use leads to higher rates of early risk of upper gastrointestinal complications as well (3).

The study authors conclude that tNSAIDs such as high-dose diclofenac, and possibly ibuprofen, exert vascular risks comparable to coxibs such as celecoxib, or Celebrex, and rofecoxib, or Vioxx, etoricoxib, or Arcoxia, and lumiracoxib, or Prexige (3). Importantly, researchers state that, although limited data existed for subjects with a history of atherosclerosis, “The proportional effects of coxibs and tNSAIDs seemed similar irrespective of baseline characteristics, and in particular were similar at all levels of risk of major vascular events” (3, p. 777).

Naproxen was the only tNSAID that did not increase risk of major vascular or coronary events, although it did almost double risk of hospitalization due to heart failure along with every other NSAID regimen (3). The authors attribute this possible advantage to the prolonged and intense COX-1 inhibition by naproxen, which is sufficient in magnitude to restrict platelet thromboxane biosynthesis, thus resulting in platelet inhibition, which mitigates vascular risks of COX-2 inhibition in some individuals (47). However, they still caution that this supposed advantage of naproxen may not persist with long-term use, and note that naproxen dramatically increases incidence of upper gastrointestinal complications (3, p. 777).

Detriment to the Gut Barrier: Another Reason to Avoid NSAIDs

If the cardiac risks were not enough to put the NSAIDs-are-safe myth to bed for good, even low-dose, short-term administration of NSAIDs adversely affects the small intestine, culminating in enhanced gut inflammation, intestinal permeability, ulcerations, and mucosal erosions (15). Endoscopic examinations have revealed that NSAIDs produce mucosal lesions along every segment of the gastrointestinal tract, especially the stomach and small intestine (16). After just two week courses of slow-release diclofenac or naproxen, small-bowel mucosal injuries were present in 68% to 75% of patients and in 55% of patients, respectively (17, 18). Similarly, large lesions and erosions appeared in 60% of healthy young individuals taking enteric-coated aspirin for only 7 days (19). Worse yet, small intestinal lesions often remain after NSAID discontinuation (20).

Although the effects of NSAID-inflicted small intestinal damage remains to be determined, possible implications include dyspepsia or irritable bowel syndrome, inflammatory bowel diseases including Crohn’s disease or ulcerative colitis, diverticulitis, exacerbation of pre-existing chronic liver and kidney diseases, and occult gastrointestinal bleeding and resultant microcytic anemia (16).

NSAID enteropathy is mediated by changes in the microbiota and pathophysiological mechanisms involving innate inflammatory cascades, as illustrated by studies that show 100% protection from indomethacin-induced ulcerations in germ-free animals or animals pretreated with antibiotics (21, 22). As elucidated by Marlicz and colleagues (2014), “It is possible that NSAID-induced mucosal damage allows for deeper microbial penetration and subsequent interaction with components of the innate immune system through activation of the Toll-like receptor 4 intestinal pathways” (16). These pathophysiological changes lead to mast cell degranuation, neutrophil recruitment, and release of pro-inflammatory cytokines such as tumor-necrosis factor-alpha (TNF-α ) and monocyte chemoattractant protein-1 (MCP-1) (23).

Notably, NSAIDs have been observed to induce pathologic paracellular intestinal permeability, or leaky gut syndrome (16). According to the work of Dr. Alessio Fasano, intestinal permeability is prerequisite for the development of autoimmune disease, along with genetic predisposition and an environmental trigger (24). Breach of the mucosal barrier enables undigested food proteins, bacterial byproducts, and toxicants to traverse the gut lining and incite an inflammatory response that can result in the immune system becoming misdirected against self (24).

When combined with proton pump inhibitors (PPIs) such as Prilosec or Prevacid, even low-dose NSAIDs can cause gut mucosal injury as well as bleeding and anemia (16). Marlicz and colleagues (2014) state that the use of PPIs should be conceived as an independent risk factor for NSAID-associated enteropathy, and discuss that, “The frequent use of PPIs can exacerbate NSAID-induced small intestinal injury by altering intestinal microbiota” (16, p. 1699). This is alarming in light of the recommendations by professional societies of gastroenterology, rheumatology, and cardiology, all of which promote the co-administration of NSAIDs with PPIs to minimize NSAID-related gastrointestinal complications (25, 26, 27). By altering the small intestinal microbiome, PPIs may accelerate the injurious effects of NSAIDs on the intestinal mucosa and lead to complications such as anemia (28, 29).

NSAIDs likewise have been observed to decrease concentrations of beneficial commensal flora in our gut, including bifidobacteria and lactobacilli populations (30, 31). In addition, NSAIDs increase concentrations of gram-negative bacteria, which generate an endotoxin known as lipopolysaccharide (LPS) that can translocate across the gut barrier and generate a pro-inflammatory metabolic milieu (16). According to Marlicz and colleagues, “There is mounting evidence that disturbances in the interplay between bacteria and host at the mucosal level in the gut affect the gut-liver axis and contribute to the development of low-grade inflammation, metabolic endotoxemia, obesity, metabolic liver disorders (nonalcoholic fatty liver disease [NAFLD] and nonalcoholic steatohepatitis), and some cancers” (16, p. 1700). Metabolic endotoxemia is likewise associated with coronary heart disease, carotid atherosclerosis, fibrogenesis, adverse neurocognitive changes, increased mortality in chronic kidney disease, enhanced vulnerability to infection, and altered pain perception (16).

Natural Alternatives to Dangerous NSAIDs

As extensively catalogued in GreenMedInfo’s databases, there are a plethora of nontoxic substances with analgesic properties that can be used in place of NSAIDs for natural pain management.

Dysmenorrhea

For menstrual pain, 250 mg capsules of ginger rhizome powder taken four times a day was found to be as effective as 250 mg mefenamic acid or 400 mg ibuprofen capsules, in relieving menstrual pain (32). Another study demonstrated that 25 drops of thyme vulgaris essential oil given every six hours was as effective as 200 mg of ibuprofen administered at the same dosing frequency (33). Thyme contains active constituents such as thymol and carvacrol which have anti-spasmodic properties that improve menstrual cramping (33).

Osteoarthritis

A combination of two flavonoids, baicalin from Chinese skullcap and catechin from green tea, was found to be as effective as naproxen for osteoarthritis of the knee in a randomized, double-blind pilot study, without the edema and non-specific musculoskeletal discomfort that accompanied naproxen administration (34). In another multi-center, prospective, open-label study, osteoarthritis patients were given 1300 mg capsules of bromelain, a proteolytic enzyme from pineapple stems, combined with devil’s claw and turmeric, two to three times a day depending on pain severity (35). Both acute and chronic pain patients experienced statistically significant improvements in pain after fifteen or sixty days of follow-up, respectively (35). In fact, the researchers suggest this formula of plant extracts as a safe alternative to NSAIDs for patients suffering from degenerative joint diseases (35).

Migraines

Patients with migraine disorders have been shown to be magnesium deficient. A meta-analysis of 21 randomized controlled trials concluded that intravenous magnesium infusion reduces migraine attacks, whereas oral magnesium alleviates the frequency and intensity of migraines (36). Further, feverfew extract, which contains compounds called parthenolides which exert anti-migraine effects, has been shown to significantly reduce migraine frequency from 4.76 to 1.9 migraine attacks per month (37). Another herb effective in migraine prophylaxis is butterbur, which elicited a 48% decrease in migraine frequency when subjects received 75 mg twice a day for four months, compared to an only 26% decrease in the control group (38).

Back Pain

White willow bark, the botanical from which aspirin was originally derived, has anti-inflammatory, anti-pyretic, and analgesic qualities, owing to active constituents such as salicin, polyphenols, and flavonoids (39). In particular, the anti-inflammatory mechanism of willow bark extract occurs via down-regulation of inflammatory mediators TNF-α and nuclear factor-kappa B (NFkB) (39). A systematic review demonstrated that white willow bark exerts a dose-dependent analgesic effect that is not inferior to rofecoxib for low back pain (40).

Functional Foods

Wild lettuce of the Lactuca virosa and Cichorium intybus species, as well as other members of the family Asteraceae such as chicory root, can be incorporated into a food-as-medicine approach to pain management. These wild lettuce varieties contain guaiane-type sesquiterpene lactones including lactucin and its ester derivative, lactucopicrin (41). According to Wesolowska et al. (2006), “The latex released from damaged lactifers of leaves or stems of the flowering plants, when left in the open, dries into a brown gummy product, known as lactucarium or lettuce opium,” which exhibits antitussive, sedative, and analgesic properties (41, p. 254). These compounds, which have an extensive history of use in traditional Ayurvedic and Unani medical systems, induce pain-relieving effects comparable to ibuprofen in animal models (41, 42). Probable mechanisms include inhibition of NFkB, prostaglandin E2, and COX-2 expression (41).

Lastly, tart cherry anthocyanins, administered at 400 mg/kg, suppressed inflammation as effectively as the NSAID indomethacin in an animal model (43). Moreover, an in vitro study found that anthocyanins from sweet cherries and raspberries were as effective as naproxen and ibuprofen at inhibiting COX-1 and COX-2 enzymes (44). Another randomized, double-blind, placebo-controlled trial of healthy runners found that ingesting 355 mL bottles of tart cherry juice twice daily for seven days preceding a strenuous running event and on the day of the event minimized post-race muscle pain (45). According to researchers, “These data suggest that tart cherry anthocyanins may have a beneficial role in the treatment of inflammatory pain” (43, p. 181).

Practice Root Cause Resolution Medicine

According to philosopher Ivan Illich, we have become divorced from the metaphysical meaning of pain as an inevitable component of the subjective human experience and instead seek to artificially anesthetize ourselves against its presence (46). Pain has become medicalized within our cultural landscape, such that pain is perceived as an emergent contingency requiring heroic measures to be annihilated (46). The social determinants of pain, as well as the value of pain as an intrinsic and intimate facet of human life, go unrecognized, as “medical civilization focuses primarily on pain as a systemic reaction that can be verified, measured, and regulated” (46). 

Instead of seeking to extinguish pain whenever it manifests, we should search for the meaning in the pain, and the message that our physical, psychic and social body is attempting to communicate (46). We would be better served by unearthing the root causes of our physical pain—whether they be micronutrient deficiencies, toxicant burden, or deviance from the ancestral lifestyles to which we are evolutionary accustomed—and by adopting the ancient wisdom of traditional cultures (46). According to Illich, pain is made tolerable by its integration into a meaningful context: “Traditional cultures confront pain, impairment, and death by interpreting them as challenges soliciting a response from the individual under stress” (46).

References

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Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of GreenMedInfo or its staff.
Sayer Ji
Founder of GreenMedInfo.com

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