PAINFUL CHOICES
NSAIDs--selective or nonselective, prescription or nonprescription--are under close scrutiny after the COXib fiasco. Is the pain relief they offer worth the risk? What options are there for patients in chronic pain?
C. Russell Y. Cruz, MD
Correspondent
The recognition of pain as a herald of disease is as old as the art of medicine itself. A deceptively simple problem, antedating all known descriptions of medical conditions, it still lacks definitive solutions. Pain remains a leading cause of morbidity. It is the most universal symptom; yet it is also the most disparate among patients.
Healers of antiquity concocted a variety of tonics and mortar-and-pestle powders, all seeking to soothe different aches. Although it has been centuries since, the search for medicines to alleviate pain goes on. Its protean manifestations spurred the development of a multibillion-dollar industry: over-the-counter and prescription analgesics generate huge profits for drug companies.
One of the most ubiquitous is aspirin, whose chemical structure traces its roots to the willow tree-a pain reliever prescribed by Hippocrates no less. Considered the original analgesic, aspirin has since 1897 been widely used for different pain syndromes--with generally favorable results. By 1971, scientists have known that its actions depended on its irreversible inhibition of prostaglandin synthesis.
In the 1980s, nonsteroidal antiinflammatory drugs (NSAIDs) led by ibuprofen and naproxen largely supplanted aspirin for the management of pain and inflammation, owing in large part to their higher therapeutic-to-side-effect ratios. (Aspirin, however, is far from obsolete; it is being used in low doses by millions of patients worldwide for the prevention of cardiovascular disease.)
Unfortunately, both aspirin and NSAIDs limit an important mucoprotective substance in the stomach--prostaglandin E. "Although they are effective," wrote Dr. Garrett Fitz- Gerald in a review for the New England Journal of Medicine (NEJM) in 2001, "their long-term use is limited by gastrointestinal effects such as dyspepsia and abdominal pain, and less often, gastric or duodenal perforation or bleeding."
Coaxing a better effect
Before the turn of the century, two isoforms of the cyclooxygenase enzyme-the enzyme blocked by NSAIDs--have been recognized: a constitutive form, COX-1, responsible for, among other things, the production of gastroprotective prostaglandins, and an inducible form, COX-2, activated during inflammatory states.
Dr. Robert Levine (Medical Progress, July 2004) described COX-2 as the "enzyme responsible for prostaglandins associated with fever, pain, inflammation, and some renal functions." He wrote: "Peripherally, COX-2 prostaglandins sensitize nociceptors causing hyperalgesia. Centrally, COX-2 prostaglandins sensitize neurons and cause increased excitability of neurons, resulting in hyperalgesia and allodynia."
These pathomechanisms, however, provide only a general schema. As FitzGerald noted, "distinguishing cyclooxygenase-1 as a constitutive enzyme and cyclooxygenase-2 as an inducible enzyme that accounts for the formation of prostanoid in disease is an oversimplification of the biologic reality."
The earlier NSAIDs inhibited both COX-1 and COX-2, accounting for their gastro-intestinal toxicity. This bothersome side effect was enough impetus for the drug industry. Pharmaceutical companies raced to develop selective COX-2 inhibitors, whose superiority over earlier NSAIDs in terms of fewer GI side effects was immediately demonstrated in numerous studies. They are mainly indicated for the treatment of osteoarthritis and rheumatoid arthritis.
Rofecoxib (Vioxx, Merck) and celecoxib (Celebrex, Pfizer), and the newer valdecoxib (Bextra, Pfizer) and etoricoxib (Arcoxia, Merck), hit pharmacies worldwide, backed by campaigns emphasizing their relative GI safety. In 2003, these drugs sold approximately US$5.6 billion, US$2.5 billion for Vioxx and US$1.8 billion for Celebrex.
A cascade of events
In hindsight, a seemingly innocuous finding in the immediate postmarketing report for rofecoxib was the unassuming catalyst in the COX-2 downfall.
In the original new-drug application for rofecoxib submitted by Merck to the US Food and Drug Administration (FDA), which included 60 studies involving 5,000 patients exposed to rofecoxib in varying doses, it said "no cardiovascular signal was observed." But a large postmarketing surveillance of 8,000 patients--the Vioxx Gastrointestinal Outcomes studies (VIGOR)--showed in June 2000 an increased risk of cardiovascular thrombotic events, like driven heart attacks, in patients taking rofecoxib compared with those taking naproxen.
 |
Merck initially attributed this finding to a cardioprotective effect previously unseen in naproxen. An FDA advisory committee convened in February 2001 to look into the VIGOR study concluded that the research possessed several limitations that hindered the formation of a generalization based on the observed cardiovascular findings. Among these were the study design (using only one comparator and no placebo), the use of a higher dose not recommended for chronic use, a population limited to rheumatoid arthritis patients, and the exclusion of patients on low-dose aspirin.
By July of the same year, safety profiles and data from the other ongoing studies were presented to the FDA. In September, the FDA asked Merck to put on Vioxx labels "balanced information" obtained from the VIGOR trial. Still, concerns over drug safety persisted. In early 2002, Merck proposed the analysis of cardiovascular thrombotic events using placebo-controlled studies. Three multicenter, randomized, double-blind, placebo-controlled studies were started. After 18 months, one of the protocols, the Adenomatous Polyp Prevention on Vioxx (APPROVE) trial showed increased risks of myocardial infarction and stroke for dosages of 12.5 and 25 mg compared with placebo.
In September 2004, Merck voluntarily withdrew Vioxx from the market. Raymond Gilmartin, Merck chief executive officer, said the company took the action to serve patient interest. "Although we believe it may have been possible to continue to market Vioxx with labeling that would incorporate these new data, given the availability of alternative therapies and the questions raised by these data, we concluded that a voluntary withdrawal is the responsible course to take," he said.
APPROVE involved 2,586 patients with a history of colorectal adenomas. The study showed that compared with placebo, rofecoxib brought a significantly increased relative risk for cardiovascualr event (1.92), which "became apparent after 18 months of treatment."
"The results primarily reflect a greater number of myocardial infarctions and ischemic cerebrovascular events in the rofecoxib group," said the authors led by Dr. Robert Bresalier.
The pains of public scrutiny
Following Vioxx's withdrawal, an internal memorandum by Dr. David Graham, associate director for science at the office of drug safety was made public. Graham, the priNCIpal FDA investigator in a study that looked into the cardiovascular risks of the COX-2 selective NSAIDs, found increased risks of serious coronary heart disease with rofeCOXib--3.7 times at high doses and 1.5 times at the standard dose.
He criticized Merck's handling of the early data from the VIGOR study. "The manufacturer attributed [the increased cardiovascular risks] to a never-before-recognized protective effect of naproxen," he said. "To explain a fivefold difference, naproxen would have had to be one of the most potent and effective cardioprotectants known." He also debunked studies that surfaced earlier to corroborate this claim. "The three case-control studies that reported a protective effect were misleading," he noted. "When analyzed in a manner comparable to the present study, no protective effect is shown."
Questions of a class effect quickly ensued, and doubts over the risk-to-benefit ratios of the COX-2 inhibitors began to rise.
Drs. Wayne Ray, Marie Griffin, and Michael Stein of the Vanderbilt University School of Medicine wrote the NEJM recommending that clinicians stop prescribing valdecoxib except in extraordinary circumstances. They cited four reasons: "the long delay between the initial evidence of the cardiotoxicity of rofecoxib and its withdrawal, recent studies demonstrating the cardiotoxicity of valdecoxib in high-risk patients, the availability of other therapies not currently known to have cardiovascular risks, and the lack of compelling evidence of countervailing benefits."
In an editorial for NEJM, Dr. Bruce Psaty suggested that the drugs might have inherent pharmacologic properties that make them raise cardiovascular risks. "COX-2 inhibitors not only lack the antiplatelet effects of aspirin," he opined. "By inhibiting the production of prostacyclin, they also disable one of the primary defenses of the endothelium against platelet aggregation, hypertension, and atherosclerosis. COX-2 inhibitors also promote an imbalance in favor of vasoconstriction. These biologic actions, known since 1998, suggest that COX-2 inhibitors may increase the risk of cardiovascular events, including myocardial infarction, stroke, hypertension, and heart failure."
In December last year, the US National Cancer Institute (NCI) halted the Adenoma Prevention with Celecoxib (APC) trial after patients taking 400 mg of Celebrex twice daily had 3.4 times greater risk of CV events compared with those taking placebo. The FDA said that while it had not seen all available data, the findings were "similar to recent results from a study of Vioxx."
The trial was refocused to assess data on cardiovascular safety after reports following the APPROVe findings. Preliminary data showed dose-dependent increased risks for death from cardiovascular causes, myocardial infarction, stroke, and heart failure. The hazard ratio was 2.3 percent for those given 200 mg and 3.4 percent for those given 400 mg.
However, preliminary reports from a study using 400 mg celecoxib once daily--the Prevention of Spontaenous Adenomatous Polyps (PreSAP) trial--did not show any increase in cardiovascular risks. So did the Celecoxib in Long-term Arthritis Safety Study (CLASS), which compared 400 mg twice daily of celecoxib with two nonselective NSAIDs. A metaanalysis of celecoxib trials by William White et al. in the American Journal of Cardiology showed "no evidence of increased risk of cardiovascular thrombotic events events associated with celecoxib compared with either conventional NSAIDs or placebo." Also, a postmarketing surveillance in the Philippines involving over 10,000 patients reported only 1.7 percent adverse clinical events.
But in another randomized study involving 1,671 patients who underwent coronary- artery bypass surgery, more frequent cardiovascular events were noted among patients using parecoxib and valdecoxib (two percent) vis-à-vis those given placebo (0.5 percent). This study looked at short-term use of a coxib among patients who are arguably already more predisposed to these risks.
Pfizer maintains that there is more than ample difference between Celebrex and Vioxx. In a statement given to MEDICAL OBSERVER, it said: "[We] did not withdraw celecoxib from the market because these new results...[were] unexpected and not consistent with the existing body of data. The study used high doses of celecoxib (400 mg and 800 mg per day). These are two to four times the actual recommended dose for osteoarthritis. [This is different from] the APPROVE trial of Merck, where the dose of Vioxx used (25 mg) is the recommended dose for osteoarthritis."
Hazard explained
FitzGerald elucidated on the prevailing theory implicating the coxibs: "Prostaglandin I2 had previously been shown to be the predominant cyclooxygenase product in the endothelium inhibiting platelet aggregation, causing vasodilatation, and preventing the proliferation of vascular-smooth-muscle cells in vitro."
It was later found that the predominant isoform of cyclooxygenase responsible for the production of this prostanoid was COX-2. FitzGerald noted that the individual cardiovascular effects of prostaglandin I2 in vitro contrast with those of thromboxane A2, the major COX-1 product of platelets, which causes platelet aggregation, vasoconstriction, and vascular proliferation.
While both aspirin and traditional NSAIDs block both thromboxane A2 and prostacyclin (another name for prostaglandin I2, essentially negating both their effects), COX-2 inhibitors preferentially limit the production of prostacyclin while inadvertently allowing the continued expression of thromboxane A2.
"Thus, a single mechanism--depression of prostaglandin I2 formation--might be expected to elevate blood pressure, accelerate atherogenesis, and predispose patients receiving coxibs to an exaggerated thrombotic response to the rupture of an atherosclerotic plaque," FitzGerald added. "The higher a patient's intrinsic risk of cardiovascular disease, the more likely it would be that such a hazard would manifest itself rapidly in the form of a clinical event."
Recommendations and decisions
On February 16 to 18, the FDA convened an advisory panel to look into existing data on concerning COX-2 inhibitors. An important point raised during the discussion was the paucity of data on the safety profiles of nonselective NSAIDs, whose use is likely to increase in the aftermath of the coxib controversy. There are, for instance, no major studies that specifically determined the cardiovascular safety of long-term NSAID use. Dr. Steven Nissen of the Cleveland Clinic Cardiovascular Coordinating Center said that the shift in the use of NSAIDs carries some risks, and part of it is that the shift to other agents "may actually turn out, in the final analysis, to be less safe."
On February 28 the panel decided to advise the FDA to keep rofecoxib (even if it had been voluntarily withdrawn), celecoxib, and valdecoxib on the market, even as it found that indeed, long-term use of these drugs could result in serious cardiovascular problems. The panel recommended the drugs' manufacturers to do three things--provide a black-box warning on the drugs' cardiovascular risk in the packaging; stop advertising of said drugs in consumer venues; and make each prescription come with a guide that outlines the risks involved in taking the drugs.
The Philippine Bureau of Food and Drugs (BFAD), for its part, issued a circular on April 4. All COX-2 inhibitors registered with the BFAD-Celebrex, Bextra, Arcoxia, and Dynastat (parecoxib)--were required to carry a black-box warning on cardiovascular risk. Their manufacturers were also asked to detail "absolute contraindications," such as stroke patients and those with "uncontrolled" blood pressure. Also, Bextra's indication for arthritis was withdrawn; precribers were reminded of the possible skin reactions that could result from Bextra and Dynastat use. NSAIDs--whether over-the-counter or prescription, including the oxicams, were also asked to put warnings "regarding potential class effect, however not necessarily in a black box."
"Respectfully disagrees"
But this is not where the issue ended--the decision made by the US FDA on all NSAIDs and coxibs on April 7 also led to the BFAD coming up with a new advisory on April 12.
Despite the advisory panel's recommendation to keep Bextra on the market, the US FDA decided to ask Pfizer to withdraw the drug, because its "overall risk-versus-benefit profile…is unfavorable." Pfizer, meanwhile, said it "respectfully disagrees" with the decision on Bextra, but decided to suspend the sale and marketing of the drug in the US.
The FDA also required Pfizer to provide a boxed warning on Celebrex's label. All other prescription NSAIDs, whether selective or nonselective, were also required to carry the same boxed warning on the potential for cardiovascular adverse events. OTC NSAIDs were required to carry more specific information on the risk for CV and GI adverse events, as well as potential skin reactions.
The BFAD advisory on April 12 made public the agency's decision to require all prescription NSAIDs to carry a black-box warning regarding possible CV and GI side effects, and all OTC NSAIDs except aspirin to carry additional information about CV and GI side effects, as well as possible skin reactions.
The BFAD also asked Pfizer Philippines to withdraw both Bextra and Dynastat (which is not marketed in the US) from the market, since these drugs pose "a risk of rare but life-threatening skin reactions like erythema multiforme, Stevens Johnson's syndrome, and toxic epidermal necrolysis." On the same day that the advisory came out, Pfizer Philippines issued an official statement, saying it "respectfully disagrees with the BFAD decision, but in deference to the agency's views, agreed to voluntarily suspend" the sale of the said drugs.
Dr. Anthony Leachon, Pfizer Philippines' medical director, told MEDICAL OBSERVER that the company's deference to the BFAD's recommendation on Bextra has to do with the indications that the drug had been approved for--the management of both acute and chronic pain. He said: "We are requesting BFAD to retain the acute-pain indication--five days in patients without cardiovascular problems, based on the TGA (Therapeutic Goods Authority) Australia's recommendations, and the local approval last August 2004."
As for the warning on possible skin reactions--specifically Steven Johnson's syndrome-he said: "In our preliminary local postmarketing surveillance study (2004 - 5), none of the 2,200 patients using Bextra had SJ syndrome." He added that this risk is "present in other NSAIDs [and] other existing drugs in the market [like] allopurinol, antibiotics, sulfas, anticonvulsants, etc."
How Filipino doctors view it
MEDICAL OBSERVER sought the views of several Filipino physicians to see the local impact of the coxib controversy.
Rheumatologist Michael Tee knows this class of drugs well. "I give coxibs to relieve the pain in my patients with osteoarthritis and rheumatoid arthritis," said the assistant to the director of the University of the Philippines-Philippine General Hospital (UP-PGH). "These are especially useful in patients at risk for gastrointestinal bleeding, in whom traditional NSAIDs are contraindicated."
Tee said the recent developments would have minimal impact on his prescribing practice. "The recent advisory on coxibs reaffirms the role of this group of drugs in the treatment of rheumatologic conditions," he added, noting that the cardiovascular risks of traditional NSAIDs have not been thoroughly studied.
Neurologist Jose Paciano Reyes, on the other hand, only uses COX-2 inhibitors when his patients have comorbidities like joint pains. And even in this subgroup of patients, he only gives the drug short-term. "I often use other analgesics," he said. Reyes admits he is more cautious now prescribing the coxibs. "I will be very careful when giving them to patients with ischemic heart disease or hypertension, even on a shorter duration."
Cardiologist Petrarch Bravo, who recently attended an American College of Cardiology symposium in Florida, said most physicians are really saying "use coxibs" sparingly.
Added the consultant at the UP-PGH and San Juan de Dios Hospital: "Given the option, I will not prescribe the coxibs anymore. There are other alternatives--parace-tamol, ibuprofen. For patients at risk for gastrointestinal bleeding, I will probably add proton-pump inhibitors to the regimen…. You would rather have an ulcer than a heart attack….There are also other nonpharmacologic methods of addressing pain that clinicians seldom use, like massage and transcutaneous electrical nerve stimulation…. But if the patient insists on using coxibs, or if a referring physician who seeks my opinion thinks coxib use is necessary, I will probably allow it...granting the patient experiences great benefits from using coxibs and possesses very low cardiovascular risks."
While noting that clinical evidence is still limited and equivocal, Dr. Ernesto Valdez, UP professor emeritus, nevertheless said physicians should exercise caution when prescribing COX-2 inhibitors for patients with risk factors for heart disease. Said he: "This development does not make much of an impact on pain management. However, caution is always indicated [in the prescription of drugs]….The lowest effective dose of COX-2 inhibitors should be used for the shortest necessary period."
He said doctors should be informed that COX-2 agents are not recommended for routine use. "These drugs should only be prescribed when other drugs cannot be tolerated or have caused severe adverse effects. Alternative therapies could be evaluated, taking into account individual needs and risk factors. For all patients, the balance between GI and cardiovascular risk should be considered before prescribing a COX-2 inhibitor, particularly for those with risk factors for heart disease and those taking low-dose aspirin."
The coxib debate and the growing number of focused trials ultimately make a substantial contribution to the existing body of knowledge available to physicians. Said Tee: "Now we understand these issues better. We have identified those at increased risk, not just for gastrointestinal events, but for cardiovascular events as well."
Beyond safety, the controversy spills over into some fundamental issues in the world of health care. "This debate is very complicated, because it is not just a medical issue," said Reyes. "It takes added dimensions especially in a litiginous society like the United States."
Physicians should also start thinking about their clinical decision making, advised Bravo. "We should change this culture of merely listening to what the medreps tell us, and stop basing our prescribing practices on the pharmaceutical companies' statements."
No adverse reactions to the coxibs, cardiovascular or otherwise, have been noted by all four physicians in their practice.
Paracetamol as effective v. arthritis as newer drugs
SYDNEY
The inexpensive analgesic paracetamol eases the chronic pain of osteoarthritis as effectively and more safely than newer and more expensive antiinflammatory drugs, says an Australian study in the American Journal of Therapeutics.
The three-year University of Queensland study showed that two-thirds of the 188 patients found paracetamol was better than ibuprofen, aspirin, or the newer nonsteroidal antiinflammatory drugs (NSAIDs) such as Celebrex.
Michael Yelland, a senior lecturer at the university's Center for General Practice, said around 90 percent of the patients who suffered from osteoarthritis were unaware which medication they were receiving in the study. "We found that in two-thirds of patients, the paracetamol was just as effective or more effective than antiinflam-matories for pain and stiffness generally," he said. "The aim of the test was to work out what was the best medication for them."
Drugs such as aspirin or old-generation NSAIDs containing ibuprofen had long been available over the counter.
But Yelland said they may cause or exacerbate serious stomach problems such as ulcers or milder symptoms including nausea. He said the best option may be to go for a check-up with a health professional, improve diet, and take an alternative medicine such as glucosamine, which helps preserve joint cartilage.
"It's as effective as antiinflammatories and has [fewer] side effects but it's slower to work and it can take up to six weeks," he said. "But if they are thinking of changing, they should consult their health-care professional because there may be other reasons for taking antiinflammatories."
AFP
|
