It’s a scene that’s played out every day in doctors’ surgeries. You’ve been suffering from a nagging pain in your knee for some days, and the stiffness just won’t go away. At your first visit, the doctor arranged for you to visit your local hospital for X-rays and a simple blood test. Now the results are back.
‘You’ve got early-stage osteoarthritis,’ says your doctor. ‘I’m afraid it’s all part of growing older, just the wear and tear of life.’
He might suggest some exercise before reaching for his pad to write out a prescription. This is the only response that medicine has to arthritis: a drug, usually an NSAID (non-steroidal anti-inflammatory drug) to alleviate pain.
The drugs used to control the symptoms are known as ‘first-line’ drugs, and include NSAIDs, which are claimed to reduce swelling in the joints, and the simple painkillers known as analgesics.
The most common and popular over-the-counter (OTC) analgesic (pain relief) medication for chronic pain is the old standby, aspirin (acetylsalicylic acid). The oldest and most popular analgesic on the market, aspirin is a classic NSAID (non-steroidal anti-inflammatory drug).
Paracetamol, sold as Calpol or Panadol in the UK (acetaminophen in the USA, sold as Tylenol and Excedrin), came onto the market in 1955. Although often used for arthritis pain, it’s assumed to have slightly less effect on pain from inflammation than aspirin and other, newer NSAIDs such as ibuprofen (with tradenames like Anadin, Arthrofen, Nurofen, Brufen, Calprofen, Galprofen, Ibuleve, Motrin, Orbifen and Advil). And, in fact, a study of 184 patients found that large (2,400mg) and small (1,200mg) daily doses of the NSAID ibuprofen worked about the same as high daily doses (4,000mg) of paracetamol in controlling pain and inflammation.1
Aspirin, ibuprofen and all the ibuprofen ‘clones’ are non-selective NSAIDs that supposedly work by inhibiting two enzymes that are involved with inflammation: cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2). The body produces COX enzymes wherever they are needed (in almost every organ of the body) to control the production of chemicals called prostaglandins, which, among other things, reduce pain by interrupting or suppressing pain signals carried along the nerves. Unfortunately, prostaglandins carry out a number of other complex functions in the body as well, and interfering with them causes a number of different side effects, including indigestion and stomach ulcers.
As the ‘anti-inflammatory’ element in their generic name suggests, these are painkillers that are also supposed to reduce swelling. However, as osteoarthritis doesn’t always involve swelling around the joints, it could be argued that, of the 24 million prescriptions for NSAIDs handed out in Britain alone, most could be replaced by a simple painkiller. Furthermore, there’s a question mark over their efficacy as anti-inflammatories: Dr Peter Gøtzsche, head of the Cochrane Collaboration in Denmark, who was a researcher on the early NSAID drug trials, admitted that some of the initial studies on NSAIDs were manipulated because they showed no benefit in reducing inflammation over simple painkillers.2
While NSAIDs have undoubtedly brought pain relief to some arthritis sufferers, they may also be accelerating the condition, especially in the case of osteoarthritis. Studies have shown that NSAIDs speed the progress of the disease, largely because they inhibit cartilage repair and promote cartilage destruction.3
If you’re less than happy with the drugs you take for osteoarthritis, Dr Peter Gøtzsche, head of the Scandinavian arm of the Cochrane Collaboration and one of its founders, believes he knows why. He’s made the extraordinary charge that non-steroidal anti-inflammatory drugs (NSAIDs) don’t, in fact, reduce inflammation.
In his book Deadly Medicines and Organised Crime: How Big Pharma has Corrupted Healthcare, he states: ‘The idea of an anti-inflammatory effect of NSAIDs is a hoax, like so many other myths about drugs that the drug companies have invented and marketed.’4
Gøtzsche has conducted extensive studies into non-steroidal anti-inflammatories, beginning from the time he was medical director at Astra-Syntex in 1977. Astra had produced naproxen, an early NSAID. When Gøtzsche investigated the actions of various NSAIDs, he discovered that drug companies were manipulating information about this entire class of drugs, giving doctors the impression, through inference and with no supporting data, that NSAIDs were better than paracetamol (acetaminophen) because they didn’t just reduce pain, but also reduced inflammation.
When Gøtzsche and a group of orthopaedic surgeons carried out their own independent study of naproxen, they found that the drug had no effect on reducing inflammation in patients with twisted ankles: patients recovered faster simply by keeping the affected limb moving.
After studying some 244 NSAIDs in trials, Gøtzsche uncovered an overwhelming amount of bias favouring any given sponsoring company’s drug over the control drug.5 Then, in his own studies, the drugs failed to work as anti-inflammatories: compared with placebos, they had no effect on swollen finger joints in patients with rheumatoid arthritis.
But the most scandalous aspect of the NSAID trials, according to Gøtzsche, was that certain dangers associated with the drugs, many of which cause gastrointestinal bleeding and heart attacks, were minimized.
Furthermore, he discovered that doubling the dose, as patients have often been encouraged to do with all NSAIDs, produced negligible benefits, yet twice the amount of harm, including an increased risk of bleeding ulcers and even death.6
For all their commonness and assumed benevolence, aspirin and other common non-selective NSAIDs may be major killers – ones that few of us ever suspect.
For decades aspirin has been promoted as a relatively benign drug. The American Association of Poison Control Centers receives reports of just 59 aspirin deaths in the USA each year, while researchers put the rate for all painkilling NSAIDs at around 7,600 deaths a year.7 Either way, doctors have argued that these figures represent an acceptable risk in relation to the benefits – including the many additional thousands who might otherwise have died from heart disease if not for taking these magic white pills.
But scientists are now discovering that we’ve been shockingly misled by the medical community. Far from being benign, aspirin, ibuprofen and other NSAIDs cause serious – and, in some cases, fatal – gastrointestinal (GI) bleeding. According to C.J. Hawkey, a researcher at Queen’s Medical Centre, University Hospital in Nottingham, ‘NSAIDs account for more reports of drug-related toxicity than any other class of drugs.’8 Their most widespread adverse effects are on the gastrointestinal tract, where they are responsible for more than a staggering 50 per cent of all cases of ulcer bleeding and perforation, says Hawkey – cases so severe that the arthritis patient may be hospitalized or even die. It’s been estimated that NSAID side effects on the gut cause more than 16,000 deaths per year in the USA alone.9
And researchers have discovered another worrying side effect of aspirin, ibuprofen and other NSAIDs: they may be a major cause of stroke among the elderly. However, it isn’t just the elderly who are affected. Recent studies show that ibuprofen and similar NSAIDs could treble the risk of strokes and double the chance of heart attack in those taking heavy doses over the long term in the general population.10
The US Food and Drug Administration’s own best estimate is that 200,000 cases of gastric bleeding occur with NSAIDs each year, including 10,000–20,000 deaths. In the UK, some 4,000 people die each year from these drugs – twice the number of deaths from asthma. Besides ulcers, even the ‘safest’ of NSAIDs, ibuprofen, can cause colitis. The NSAIDS indomethacin, naproxen and a sustained-release preparation of ketoprofen all can cause perforations of the colon.
Most of these deaths are slipping under the radar and not being associated with NSAIDs at all. Researchers at the Eastern Virginia Medical School were among the first to make an alarming discovery when they interviewed patients at a clinic that specializes in GI problems. Nearly one in five patients were taking aspirin or some other painkilling NSAID, but not reporting the fact to the medical staff because it wasn’t regarded as significant.11
‘This reflects a common misperception,’ said Dr David Johnson, one of the researchers, ‘that these medications are insignificant or benign when actually their chronic use, particularly among the elderly and those with conditions such as arthritis, is linked to serious and potentially fatal GI injury and bleeding.’
If the researchers’ estimates are correct, the worldwide NSAID death toll could be as high as 100,000 individuals every year – with another 500,000 needing hospital care to treat a serious reaction to the drugs.12
Equally worrying is the effect of this class of drugs on people over 75 years of age. Far from protecting them against stroke, it appears these NSAIDs are causing just such an attack, often with fatal or disabling results. Researchers at Oxford University have discovered that NSAIDs have caused a sevenfold increase in intracerebral haemorrhagic stroke – bleeding within the brain – during the past 25 years among groups of elderly patients who participated in their trial.13
Research team leader Professor Peter Rothwell says that NSAIDs may soon replace high blood pressure as the leading cause of intracerebral haemorrhagic stroke, especially among those aged over 75. ‘There are elderly people who take aspirin as a lifestyle choice and, in that situation, the trials have shown there’s no benefit. And what our study suggests is that, particularly in the very elderly, the risks of aspirin outweigh the benefits.’
In Rothwell’s study, researchers assessed the records of stroke victims between 1981 and 1985, and again between 2002 and 2006. While the overall rate of stroke caused by high blood pressure had dropped by 65 per cent between those two periods, the rate among the over-75s remained the same, mainly because there’d been an increase in the number of strokes among patients taking blood-thinners such as aspirin.
The team discovered that the use of these drugs had increased dramatically, especially among healthy people who were taking them as a preventative.14 Between 1981 and 1985, only 4 per cent of patients were taking a blood-thinner, a figure that rose to 40 per cent in the more recent time period.
Apparently, the true dangers of aspirin have been known for some time: it’s just that no one in the medical community has been prepared to do anything about it. Scientists from the West Midlands Regional Health Authority in Birmingham were among the first to raise the warning flag in the mid-1990s when they investigated the reasons why people were in hospital for treatment of bleeding peptic ulcer.
At that time, they discovered that 12.8 per cent of the 1,121 patients being investigated were ‘regular’ users of aspirin, which they defined as five days a week for at least a month. When they compared these patients against other patients with the same problem, but who were not regularly taking aspirin, it was evident that taking the NSAID had increased the risk of hospitalization for bleeding peptic ulcer by 2.3 times at a low dose of just 75mg, and by up to 3.9 times at the more standard dose of 300mg.15 The 300mg dose is the recommended level for ‘just in case’ prophylactic use against heart disease.
Not only can the use of NSAIDs lead to gastrointestinal problems, it can also cause blurred or diminished vision, Parkinson’s disease, and hair and fingernail loss. These drugs can also damage the liver and kidneys, and increase the risk of high blood pressure (hypertension), especially when taken in large doses. Instead of issuing warnings, one drug industry response to these side effects was to create topical NSAID lotions, which are supposed to take away the pain of arthritis while avoiding the drawbacks of their oral cousins.
However, when a group of scientists at Nottingham University studied the topical lotions in depth, they found they don’t really work. The group analysed 13 trials comparing topical NSAIDs with placebo treatments and NSAIDs given orally as tablets. Although the topical creams offered better pain relief at first, after two weeks they offered no more relief than the fake (placebo) treatments. They also caused a number of side effects of their own, such as itching, rash and burning. The researchers concluded that ‘No evidence supports the long-term use of topical NSAIDs in osteoarthritis.’16
The research indicates that approximately twice as many men as women end up in hospital with aspirin/NSAID-related gastric problems. And individuals who take several NSAIDs in combination increase their risk of having a serious GI reaction. In a separate study, researchers who examined patients’ records from databases in the UK and Spain found that 60 per cent of those who suffered a GI reaction from an NSAID were aged over 60. Thirteen per cent were using several NSAIDs in combination. Also worth noting is that 6 per cent had a recent history of peptic ulcers – even though patients with pre-existing GI problems are not supposed to be taking an NSAID in the first place.17
But perhaps the group of people most at risk are those taking the lethal drug combination of an NSAID with a SSRI (selective serotonin reuptake inhibitor) type of antidepressant such as Prozac, Zoloft or Paxil – a common drug cocktail among arthritis sufferers who are often prescribed an NSAID to ease joint pain and inflammation and an SSRI to ease their mild depression.
Researchers from the University of East Anglia made this discovery when they carried out a meta-analysis of four trials involving a total of 153,000 patients who were taking either an SSRI or an NSAID, or a combination of the two. Patients who took just the SSRI increased the risk of a GI reaction 2.4 times, and those taking just an NSAID had a 3.2 times greater risk.18 However, when the two drugs were combined, the risk of upper GI haemorrhage increased by 6.3 times. This means that potentially a patient only has to take the combination around 82 times before suffering a serious gastrointestinal reaction – in other words, less than three months into treatment if the combination of the two drugs is taken on a daily basis, which it usually is.
‘Before I did this study, I didn’t worry at all when I saw patients who were on combinations of SSRIs and NSAIDs,’ said lead researcher Dr Yoon K. Loke. ‘Now that I have seen the fairly substantial excess risk, physicians should review the patients’ charts – do they need to be on these drugs at all, or are there safer alternatives?’
Gastrointestinal problems linked with NSAIDs have been known for a long time – even if the severity and extent have only recently been revealed – and manufacturers have tried to reduce the risk by producing versions that are either enteric-coated – given a polymer coating to keep the pill intact in the stomach, allowing for easier absorption by the small intestine – or buffered, which coats the standard pill with a substance that neutralizes stomach acid.
But far from reducing the GI risk, these coatings appear actually to increase it. Researchers from the Boston University School of Medicine interviewed 550 hospital patients with major upper gastrointestinal bleeding about their aspirin use. To their surprise, they found that those who’d regularly taken buffered aspirin were at far greater risk of developing GI problems than were those taking regular aspirin tablets. At doses greater than 325mg, patients taking the buffered tablets were seven times more likely to develop GI problems compared with a fivefold increased risk among those taking the standard pills.19
Aspirin holds an unusual place in trademark law. As ‘Aspirin’ with a capital ‘A’, it’s a protected brand, owned by Bayer, the German pharmaceutical giant.
Aspirin’s principal ingredient is salicylic acid, derived from the bark of the willow tree (recognized by Hippocrates as a pain-reliever and antipyretic, or fever-reducer, as long ago as the 5th century bc) and from the herb meadowsweet. Chemists at Bayer successfully synthesized salicylic acid with the common chemical acetic anhydride, giving Aspirin its generic name. As ‘aspirin’, it’s a generic drug that can be used in countries where Aspirin is not trademark-protected. Around 50 other over-the-counter preparations contain aspirin, labelled as ‘Aspirin’ or ASA, Aspirin’s ‘official’ generic name, acetylsalicylic acid.
Bayer began marketing this drug in 1899, along with another of the company’s therapeutic discoveries: heroin. Despite its widespread use and popularity, no one understood how aspirin worked until 1971, when the British pharmacologist John Vane found that it suppresses the production of prostaglandins and thromboxanes, hormones that regulate many physiological functions, including the transmission of pain signals to the brain.
Current global consumption is 35,000 tons of aspirin every year – amounting to around 100 billion tablets – a figure that’s increasing annually by 15 per cent.
Aspirin is no longer recommended for children under the age of 12 because of the very real danger of children taking aspirin developing Reye’s syndrome, a rare, often fatal disorder primarily seen in children recovering from a viral illness but also linked with aspirin use.20
Despite this setback, ever since NSAIDs were given over-the-counter status in the 1990s, drug companies have pursued the lucrative kiddy market for painkillers. Currently ibuprofen has replaced paracetamol as the first port of call for treating juvenile pain. However, recent lawsuits in the USA on behalf of children who developed the rare and potentially fatal skin condition Stevens-Johnson syndrome (SJS) after taking children’s ibuprofen could send ibuprofen into the same market tailspin as kiddy aspirin.
The cases include a nine-year-old California girl who died 20 months after taking children’s Motrin, a seven-year-old who went blind two months after taking the same drug and a three-year-old who died a week after taking just a few doses of kiddy Advil.
SJS causes painful blistering of the skin. The biggest concern is that it will progress to the more serious form of the illness, toxic epidermal necrolysis, or TEN, where the outermost layer of skin peels off. TEN is fatal in about a third of cases. The syndrome can also cause blisters, and even erosion and perforation of the cornea of the eye. Most cases of SJS are drug reactions: it should be added that virtually any drug can cause SJS.
Cases of SJS from NSAIDs are not confined to children. Currently, though, the US Food and Drug Administration is not requiring drug-makers – including those manufacturing NSAIDs – to put a warning on their products, largely because SJS is so rare. Stevens-Johnson syndrome supposedly affects one to six people per million in the USA. The official position is that labels should only mention the more common side effects such as gastrointestinal bleeding. At the moment, the FDA does not even require cases of SJS to be reported.
The FDA claims it has received, thus far, some 150 reports of SJS in patients who’d taken ibuprofen. The Stevens-Johnson Syndrome Foundation in Westminster, Colorado, has warned parents to stop giving their children ibuprofen or any other drugs if they develop a rash (an early sign of SJS) or blisters on the ears, nose and genitals, or develop sores inside their mouth.
Other potential side effects from ibuprofen include heartburn, abdominal pain, nausea, ulcers and gastrointestinal bleeding, increased problems in patients with ulcers, mental depression, ringing in the ears (tinnitus), weight gain, swelling in the lower extremities, vomiting, changes in eyesight or hearing, nosebleeds, drowsiness, confusion and constipation.
Besides all the gut problems, researchers at the Johns Hopkins University School of Medicine say that common NSAID painkillers can cause a wide range of other unsuspected problems because, as new research has found, the drugs attack enzymes within cell membranes and cause unpredictable side effects in different parts of the body.
Researchers tested the effects of three prescription NSAIDs – flurbiprofen, indomethacin and sulindac – on human cells. The effect was greatest if the drug was administered for lengthy periods or in large doses. Over-the-counter painkillers didn’t have the same damaging effects on enzymes.21
In the heady world of the pharmaceutical industry, the most profitable industry in the world, the pressure is always intense to develop new products that will revolutionize treatment in a particular area and redefine the marketplace.
No area offers more potential for major commercial success than something that will take away the pain of arthritis. Pharmaceutical corporations have been so desperate to find a breakthrough for arthritis pain that they’ve even experimented with a chemotherapy cocktail originally developed to combat non-Hodgkin’s lymphoma – a drug so toxic it can cause acute respiratory failure within an hour of taking it.22
Enter the COX-2 inhibitors, the fair-haired boys of arthritis treatment, the ‘super-aspirin’ drugs that were marketed as the ultimate pain-reliever with no side effects attached. Indeed, the first two to be launched, celecoxib (Celebrex) and rofecoxib (Vioxx) (virtually all of these drugs have an ‘x’ in their names), became the most successful drugs in medical history almost overnight, snatching the mantle from Viagra.
COX-2 selective inhibitors primarily block the COX-2 enzyme. Selective non-steroidal anti-inflammatory drugs like these were designed to improve upon the usual NSAIDs, because of the latter’s gastrointestinal (GI) side effects such as dyspepsia, peptic (oesophagus, stomach or duodenum) and intestinal ulcers, and a sometimes fatal haemorrhage.23
COX-2s were so popular in the arthritis market that doctors worldwide wrote more than 100 million prescriptions for Celebrex and Vioxx in the year 2000 alone. Vioxx had sales of $2.5 billion in 2003 and at one point an estimated 80 million people worldwide were taking the drug before it was pulled off the market by Merck in 2004 after disclosures that the company had withheld information from doctors and the public about the almost doubled risk of heart attack and stroke associated with high-dosage long-term use of the drug.
Celebrex, the only COX-2 selective NSAID drug still marketed in the UK and the USA, raked in more than $4 billion for Pfizer in the first six years of its launch.24
Not only have the COX-2 drugs had a nasty track record for heart attack and stroke, most haven’t even lived up to their original promise of providing a clean gastrointestinal bill of health for users. Researchers at Nottingham University have revealed that the COX-2s are just as bad as the original NSAIDs they were meant to replace. In a study of more than 9,400 patients diagnosed with a stomach ulcer or GI bleeding, the researchers found an increased risk of GI problems that was associated not only with the conventional NSAIDs but with the COX-2s as well.25
The safety risk was deemed slightly less for celecoxib (Celebrex), the only COX-2 selective NSAID left on the market after valdecoxib (Bextra), like rofecoxib (Vioxx), was recalled owing to concerns over cardiovascular problems. However, one study found that the patients taking celecoxib developed even more dyspepsia than those taking the conventional NSAID naproxen.26
One study, known as CLASS (Celecoxib Long-Term Arthritis Safety Study), claimed that it caused fewer GI side effects compared with the traditional NSAIDs. However, among patients taking aspirin as a just-in-case medicine to prevent heart disease, those given celecoxib as well had similar GI problems (such as ulcers) as those given diclofenac or ibuprofen.27
Numerous trials show that many of these drugs can cause ulcers.28 And a Norwegian study concluded that COX-2s were actually more dangerous than NSAIDs and caused more side effects.29 Valdecoxib (Bextra) was quickly linked to many life-threatening skin conditions, as well as potentially fatal anaphylactic (allergic) shock.
Drugs such as Celebrex have been linked to deaths from gastrointestinal ulcers and to heart problems. The Adenoma Prevention with Celecoxib (APC) study, co-sponsored by the US National Cancer Institute and Pfizer, which makes the drug, revealed that patients taking 200 mg of Celebrex twice daily were nearly two and a half times more likely to suffer a heart attack or stroke. This risk rose to 3.4 times with 400mg twice daily. Needless to say, the authors recommended that the study be discontinued before it ran its intended course.30
In terms of thromboembolic events (blood clots leading to stroke), Celebrex was no better than its banned sister Vioxx.31
As if all this weren’t enough, taking COX-2 inhibitors has also been linked with kidney problems – frequently reported as footnotes to studies. According to one report, celecoxib resulted in hypertension, peripheral oedema and kidney failure in a quarter of all patients receiving the COX-2 drug.32
This should come as no surprise, because sodium excretion by the kidneys is at least partially assisted by COX-2 enzymes, and thus the use of COX-2 inhibitors can slow the elimination of sodium from the body. According to another study comparing the effects of rofecoxib with the conventional NSAID indomethacin during regular long-term use, both drugs hampered the kidney’s ability to filter waste.
Consequently, patients on sodium-restricted diets and diuretic therapy, and individuals suffering from impaired kidney function, hypertension, congestive heart failure or liver disease, should avoid NSAID therapy, including COX-2 inhibitors.
Given the evidence linking COX-2s with an increased incidence of heart attack and stroke, some reconsideration of the cardiovascular safety profile of all NSAIDs – whether selective or non-selective – seems warranted. The FDA recommended back in 2005 that all such drugs carry a ‘black box’ warning for GI and cardiovascular risks,33 and finally, in July 2015, it has strengthened those warnings in the light of evidence that not only can these drugs ‘increase the chance of a heart attack or stroke, either of which can lead to death’, but they aggravate the danger even in people ‘without an underlying risk for cardiovascular disease’.34