Painkillers: the 14-day time bomb

Although these over-the-counter and prescription pills are the modern standby for every ache and pain, what Big Pharma hasn’t told you about the risks of non-steroidal anti-inflammatory drugs could just kill you, as Celeste McGovern discovers

When Aaron Marino opened his own gym for business, he thought the stress of running it was giving him tension headaches. Each morning on the way to work at about 5:00 am, and as the dull throb began at the base of his skull, he would reach for one of the world’s most popular over-the-counter (OTC) painkillers for arthritis, headaches, menstrual cramps and more, and wash down two ibuprofen pills with black coffee—and the pain soon melted away.

Popping a couple of Advil—or Motrin or Aleve or other, generic versions of non-steroidal anti-inflammatory drugs (NSAIDs)—was so effective that it became a habit for Marino, a simple reflex to pain and he did it three to five days a week without a thought for years.

“I knew there was a risk to taking them,” says Marino, who had scanned the label and thought the warning applied to people who were gobbling far more than two pills a day. As a ‘superfit’ gym owner in the prime of his mid-30s, he had little reason to worry about a painkiller he could purchase in bulk at Costco—and, besides that, it worked.

Three years into this routine, though, one Tuesday in 2010, Marino rose from the toilet and noticed that his stool was liquorice black. By Friday, he was feeling dizzy when he stood and friends commented on his pallor. A Google search told him his black ‘tarry’ stools were indications of an upper gastrointestinal (GI) bleed, and when he went to the doctor, he was sent for an emergency blood transfusion and surgery to close a perforation in his duodenum.

“I was about two days from actually kicking the bucket,” says Marino, owner of Alpha M men’s image consulting business in Atlanta, Georgia. He wasn’t exaggerating: every year in the US alone, more than 100,000 people are hospitalized for NSAID painkiller-related stomach ulcers and injuries, and thousands die from NSAID-induced GI bleeding.

Silent epidemic of GI bleeds

Way back in 1999, this NSAID-induced GI problem was described in the New England Journal of Medicine as a “silent epidemic” claiming at least 16,500 lives each year in the US alone—and those only among arthritis patients and those taking prescription NSAIDs—not the OTC pills. The report also said that almost 75 per cent of those surveyed who ingested NSAIDs regularly were “either unaware of or unconcerned about possible gastrointestinal complications”.

And while nearly two-thirds of regular users indicated that they expected warning signs before the development of serious NSAID-induced complications, in reality, more than 80 per cent of patients with serious GI complications experience no prior gut discomfort as
a warning.

Current estimates have lowered the NSAID-induced GI-bleed mortality figure to somewhere between 7,000 and 10,000 each year in the US, according to the American College of Gastroenterology. German researchers have calculated the risk too: just two months of using an NSAID puts your odds of dying from a GI bleed at one in 1,220, which may sound small but is actually, they say, more dangerous than bungee-jumping a few hundred times.1 Use them longer and the odds multiply.

NSAID heart attacks and strokes

GI ulcers and bleeding are only one part of the NSAIDs’ toll. The unwanted side-effect of inducing heart attacks and strokes is now relatively well known to doctors, but these potential dangers and and the drug’s maker Merck’s attempts to deliberately obscure the risk only came to light in courtrooms when the drug Vioxx (rofecoxib) was withdrawn from the market in 2004 after an estimated 120,000 people died taking it.

But the NSAID carnage has still not ended as, recently, the US Food and Drug Administration (FDA) upgraded its warning on these drugs yet again. After reviewing new data on the drugs using compounds like ibuprofen, naproxen, diclofenac, ketorolac, celecoxib and more, the US oversight agency required new drug labelling for both the OTC and prescription non-aspirin NSAIDs stating that they increase the risk of heart failure and stroke even within the first week of use, and that the risk may increase further with longer use and higher doses.

It had previously been thought that only people at higher risk of cardiovascular events could possibly suffer vascular injury induced by NSAIDs. But the recent FDA warning makes it clear that the risk is also increased in those with no known heart issues and that injury can happen “without warning”. NSAIDs pose the greatest risk to patients following a first heart attack, with those treated with the drugs being, according to the FDA, “more likely to die in the first year after the heart attack” compared with patients who aren’t taking the drugs.

“For people who have coronary artery disease and have suffered a heart attack, the risk starts with the very first pill, and the risk does not get any better if you wait for a year or even five years after a heart attack,” says pain specialist Gary Kaplan, of Georgetown University School of Medicine and author of Total Recovery: Solving the Mystery of Chronic Pain and Depression (Michael Joseph, 2014).

The new FDA heart and stroke warning is now added atop its GI warning, which states that NSAIDs like ibuprofen may cause ulcers, bleeding or holes in the stomach or intestines which “may develop at any time during treatment, may happen without warning symptoms, and may cause death”. It then adds that the risk may be higher the longer you’ve taken the NSAID, if you are elderly, in poor health or drink three or more alcoholic drinks per day while taking ibuprofen.

Ignorance of the GI risks of NSAIDs is apparently just as widespread as the New England Journal of Medicine described in 1999 because in 2010, the FDA conducted surveys to determine if illiteracy among the elderly was the underlying reason for their lack of awareness of the risks associated with NSAID consumption. It was not.

In the UK, the reason for such ignorance may well be down to the lack of awareness of the National Health Service itself: its current information page on NSAIDs describes the side-effects as “troublesome”, and lists ulcers and GI bleeds below stomach aches and diarrhoea, with heart attacks and strokes last of all as “rare” side-effects. The site offers no information on the suddenness with which symptoms can arise.

As for alcohol, while the increased risk of GI bleeding with its greater consumption has been documented in the medical literature since 1999, the NHS blithely states: “It’s usually safe to drink alcohol while taking NSAIDs, but drinking alcohol excessively during treatment may irritate your stomach.”

Other dangers

While heart and GI problems are well documented among NSAIDs’ unwanted effects, there’s more. In 2005, Pfizer pulled its NSAID valdecoxib (Bextra) from the US market because of its high heart risks, but also because it was linked to more than 150 cases of serious and sometimes fatal skin reactions.

Two years later, the UK and Australia abruptly pulled the NSAID lumiracoxib (Prexige) when they discovered that some patients taking it were suffering from severe liver damage as a result; indeed, some patients even required liver transplants. And last year, the drugs regulators reviewing diclofenac-based NSAIDs moved them from the OTC category to prescription-only.

NSAIDs’ risk to kidneys is also well known to regulators. A recent pooled analysis of five earlier studies confirmed that NSAID use significantly increases the risk of acute kidney injury.2 They’ve also been linked to hearing loss in both men and women.3 And while there are conflicting results for NSAID dangers in pregnancy, some researchers have concluded that several NSAIDs can induce “spontaneous abortion”.4 The painkillers can also induce or exacerbate sinusitis and hives, and studies have shown they can increase allergic responses by 10 to 30 per cent in asthma sufferers.

NSAIDs can make pain worse

Ironically, for those dealing with pain, NSAIDs may actually interfere with the body’s own painkilling machinery, the long-term effect of which is to sustain pain rather than eliminate it. This is exactly what happened to image-consultant Marino. When his gut problems forced him to stop taking NSAIDs, he noticed that, in less than a week, the headaches he’d been taking
the drugs for in the first place, for years, simply vanished.

“NSAIDs are not truly addictive, but can make you dependent,” explains pain-expert Kaplan. “Regular use, three times or more a week of NSAIDs and Tylenol [not an NSAID, but acetaminophen/paracetamol] can suppress the body’s own natural pain-relieving system. The result can be rebound pain when you stop the medication because your own pain-relieving system has been suppressed. Over time, when you stop the medications, your own system kicks back in and the pain goes away. The problem has been well documented in people with chronic headaches. In some people with chronic headaches, all we need to do to fix the headache is to get them to stop taking NSAIDs and Tylenol for a few weeks, and the body will fix itself.”

In the case of arthritis pain, doctors know NSAIDs do nothing to help the underlying condition, although they can alleviate pain in the short term. But a new study suggests that taking a painkiller like an NSAID can actually make arthritis worse in the long run. Researchers at Johns Hopkins University compared people taking painkillers (two-thirds were taking an NSAID) for knee arthritis with those who weren’t taking any drugs for a matching condition, and followed them all for three years, X-raying their knees at intervals. Those taking the painkillers were more likely to have knee arthritis that had visibly got worse on X-rays, and were also more likely to undergo knee replacement surgery compared with those not taking the drugs.5

The COX-2 scandals

COX-2-selective NSAIDs were developed as a way to target pain and inflammation while sparing COX-1 and the gut lining (see box, above). Merck’s Vioxx (rofecoxib) and Pfizer’s Celebrex (celecoxib) were the first of these
COX-2 inhibitors.

Launched in 1999, they quickly became blockbusters; doctors wrote more than 100 million prescriptions for them in the first year and the manufacturers of each raked in billions in dollars. But tens of thousands of patients began dying from heart attacks and strokes.

All of the sordid details of how Merck and Pfizer doctored the data and deliberately concealed the drugs’ dangers eventually trickled out in a myriad court cases years after Vioxx was first pulled from the market in 2004.

“The scandal of the COX-2 inhibitors is really monumental,” says former drug insider and co-founder of the Danish Cochrane Collaboration Peter Gøtzsche in his book, Deadly Medicines and Organised Crime (CRC Press, 2013). “The drugs were approved based on small, short-term trials that didn’t look for cardiovascular harms, in patients with low risk for such events, although nearly half of real-world patients with arthritis have coexisting cardiovascular disease.”

Gøtzsche recounts how Merck employees deliberately manipulated data too, not just by exaggerating the benefits of Vioxx, but also by actually producing a fake peer-reviewed journal just to market pro-Vioxx reports.6 They also did not publish data available in 1999—which clearly showed the increased rates of heart attacks and strokes—until 2006, two years after the drug was pulled from the market. When they did publish data, they distorted the findings: for example, they failed to report three heart attacks during a critical clinical trial, listing one cause of death as “unknown” when it was clearly a heart attack.

But to most of the American public, the true extent of Merck’s ruthless concealment was hidden by the media’s Pharma-friendly reporting. News of the Vioxx ban, for instance, was followed by a 10-minute interview with a Pfizer-funded representative of an American arthritis foundation lamenting the loss of the painkiller for patients. Yet, there was little national reporting in 2007 when the jury in a Vioxx case found that Merck’s conduct was “malicious, oppressive
and outrageous”.

And it wasn’t until 2009 in an Australian court that details emerged, such as Merck’s internal emails naming the influential doctors and researchers who were concerned about the drug’s risks. The emails described how company employees intended to “neutralize” and “discredit” these “problem” detractors. Neutralization was apparently achieved through the company’s lengthy list of “opportunities”, which included “Research,” “National Consultant Meetings,” “Program Faculty Training” and “Medical School Grants”. If these bribery tactics failed, schemes that were evidently not discussed via email were then employed to “discredit” the detractors.

Gøtzsche also describes how Celebrex (celecoxib) manufacturer Pfizer similarly contorted data to suit its drug-marketing strategy. Its biggest study, he says, was “fraudulent” and its authors were either employees or paid consultants to the company. When Vioxx was pulled from the market, Pfizer shamelessly seized the moment to promote its own drug.

The next day, the company wrote to Danish doctors that more than 50 million people worldwide used celecoxib and that the company had reviewed clinical trials of more than 400,000 patients. “That’s what they wrote; I suppose they meant 40,000,” says Gøtzsche, “and this had not yielded any sign that celecoxib increased the risk of cardiovascular events. The fine for this ruthless misinformation: $2,000.”

In reality, all COX-2-inhibiting NSAIDs increase the risk of heart attack and stroke. Celebrex, the only one left on the market, has similar cardiovascular risks to Vioxx. Pfizer has awarded millions of dollars in damages to patients who have suffered as a result, and has even paid out $164 million to its own shareholders, who claimed the company misrepresented the drug’s safety data.

As Gøtzsche says, “The NSAID story illustrates that drug regulators are consistently willing to award the benefit of scientific doubt to manufacturers rather than patients.

Know your painkillers

As with every other drug, there’s no such thing as ‘safe’. The top five categories of painkillers are rated here for their relative dangers.