Pain relief gamble enough to cause a headache

Ann Price was a whisker away from a painkiller-induced heart attack. Early last year, the arthritis sufferer was happily popping Celebrex, one of a new breed of anti-inflammatories called cox-2 inhibitors, when a routine visit to the doctor revealed her blood pressure to be sky high.

"My blood pressure had always been slightly high but this was panic stations," she says.

The first thing was to get her blood pressure down. Ten days later her doctor phoned to say he owed her an apology. "He said he'd accepted what the salesman said and hadn't got around to reading the small print [about Celebrex]. I had to stop taking them straight away."

This was six months before a similar cox-2, Vioxx, was withdrawn by its manufacturer, Merck, after researchers in a cancer trial linked it to a doubling in the risk of heart attacks and strokes.

Another cancer prevention trial, using Celebrex, was halted last December over concerns of an increased heart risk for participants on higher than normal doses. A third brand, Bextra, was withdrawn by its manufacturer, Pfizer, in April after reports of severe skin reactions.

Merck now faces ruin after a Texan court awarded US$253 million ($358 million) to the widow of a man who died of a heart attack in 2001 after taking Vioxx. Worldwide, more than 4000 people have lodged negligence claims against Merck, either victims or relatives of those who suffered heart attacks after taking the drug.

But Celebrex and other cox-2s Mobic, Arcoxia and Dynastat remain on the market. The Ministry of Health, after reviewing cox-2s, bowed to strong arguments from patients and doctors against banning the drugs despite "unanswered questions" about their safety. Clearer warnings were placed on boxes and doctors encouraged to make them a drug of last resort for low risk patients on low doses. The ministry also extended a ban on advertising them.

In the late-1990s, cox-2s were hailed as a breakthrough painkiller and were heavily promoted in the United States and New Zealand, where direct-to-consumer advertising of prescription drugs is allowed. Television ads for Vioxx and Celebrex targeted older people with images of pain-free bowling, golf or a brisk walk along the beach.

They were good not only for arthritis but for lower back pain, painful periods and migraine. It's a lucrative market - between 10 and 20 per cent of New Zealanders are in chronic pain at any one time while studies suggest two-thirds of the over-60s suffer musculoskeletal pain.

Within a couple of years of their launch, 60,000 New Zealanders were taking cox-2 inhibitors, unsubsidised by Pharmac.

The pills took their name from an enzyme which plays a role in pain and inflammation, the cyclo-oxygenase (cox) enzyme, which comes in two forms, cox-1 and cox-2. Whereas traditional painkillers were non-selective, the "new Aspirin" worked by suppressing cox-2.

They were touted as easier on the stomach than older painkillers, long-implicated in fatalities from stomach ulcers and intestinal bleeding. What was not revealed, or not thought to be a concern, was their clotting effect on blood.

Price learned about them through her doctor. Osteoarthritis had developed in her left ankle five years ago, while her badly broken leg was in plaster.

"By the time my ankle came out of the moon boot I couldn't move it at all. Every time I put my foot to the floor was like treading on a knifeblade."

The 68-year-old now has arthritis in her upper spine, shoulders, hips, hands and both ankles. She says it waxes and wanes - but the flare ups are excruciating. "You can go out in the morning feeling fine and come back an absolute cot case."

Like many, Price could not tolerate traditional anti-inflammatories. "Voltaren and ibuprofen upset my tummy terribly. I was getting stomach pains and bleeding."

Yet it is these pills which many - especially older people and others at risk of heart problems - have reverted to after Vioxx. Arthritis educator Avro Graham starkly sums up the options: "It's as if you have a choice between a peptic ulcer or a dicky ticker - which do you want?"

Price now takes only paracetamol, which she says works nowhere near as well as Celebrex.

"I have to cope with a lot more pain and arthritis degeneration. It's not easy ... "

But the cox-2 debacle was only the beginning for those on chronic pain medication. A parade of studies has since raised doubts about the cardiovascular safety of established anti-inflammatories - brand names lurking in most household medicine cabinets. Naproxen, ibuprofen (sold in low doses over-the-counter as Nurofen and Brufen) and diclofenac (Voltaren) have all been linked to an increased heart attack risk.

In April, the US Food and Drug Administration asked all manufacturers of these non-steroidal anti-inflammatory drugs to include a boxed warning on packaging inserts about the potential for increased heart attack and stroke risk as well as life-threatening gastrointestinal bleeding.

Last month, a Spanish study suggested a death rate from gastrointestinal complications linked to anti-inflammatories of 15 for every 100,000 users.

IN the murky world of drug company-sponsored research, these studies are taken with a large grain of salt by doctors. The researchers themselves caution that their findings merely suggest the need for more studies. But until, or unless, randomised trials of sufficient size and duration take place, all people in chronic pain must live with the nagging doubt that their painkillers could kill them.

Even paracetamol is suffering bad press, with studies suggesting that small doses can double the risk of hypertension.

The latest pain reliever to come under the microscope is Coproxamol, a combination of paracetamol and the narcotic dextropropoxyphene, which is sold here as Capadex or Paradex. Taken for osteoarthritis and back pain, Copraxamol is being withdrawn in Britain because of a link to overdoses and suicides, prompting a review of its future by New Zealand authorities.

All of which leaves patients with a headache. Price, who chairs an arthritis support group on the North Shore, says it's hard enough for chronic pain sufferers to come to terms with their restricted lifestyle - most experience depression. The Vioxx withdrawal and subsequent Ministry of Health review of cox-2s caused panic.

"Most were quite upset and anxious. If you get to rely on a drug that you know eases your pain and somebody suddenly says you can't have it, you wonder how you're going to cope.

"A lot of the people who come to our support group are elderly, most live alone - it's quite frightening for them."

Many insisted they remain on cox-2s. Others, particularly those at increased risk of heart attack, switched to non-selective anti-inflammatories, despite the emerging doubts about them.

Should consumers feel like ticking timebombs? Not in most cases, say the experts. Dr Stewart Jessamine, principal medical adviser for Medsafe, says the risks for most of us are small. "Most people who take Aspirin and anti-inflammatories don't get peptic ulcers and similarly most people will not get heart attacks.

"We are talking about an increase in the background risk of two or three times and that is still a very small increase."

But the heart attack risk increases with age, says Jessamine.

"The background risk for a 40-year-old non-smoker who doesn't have high blood pressure is extremely small. But if you're 80 and not a hypertensive and you don't smoke and your blood pressure's normal, there's still a 30 to 40 per cent chance you'll have a heart attack in the next five years. So a doubling of the risk [as with Vioxx] is quite a substantial increase."

Yet some experts still query the clampdown on cox-2s when people are in severe pain waiting for hip and knee surgery. Rheumatologist Andrew Harrison and pain specialist Ted Hughes suggest regulators over-reacted to the heart attack risk.

"What's happened is that a very useful drug has been ripped out of circulation because of a small number of patients who suffer an adverse effect from it," says Hughes.

"For some people the heart risk is negligible compared to the risk of stomach ulcers and other side effects."

Harrison says doctors and specialists can reliably assess heart risks over time. Most patients are willing to take a small risk if it means they can function.

"There are a lot of patients who would prefer to make the decision themselves rather than have their options narrowed. You'd get the odd disaster occurring but, as long as the patient was fully informed and took the risk on themselves, that's the risk you take in return for making available drugs which make a huge difference to people's lives."

He concedes it's a difficult call.

"It's really hard to know which way to go as a prescriber. People steered away from cox-2s, now there's evidence that anti-inflammatories in general have an increased risk.

"When the patient is at risk you get very nervous keeping them on an anti-inflammatory."

Hughes says new drugs are subjected to much more scrutiny than established remedies.

"If you tried to legalise Aspirin or penicillin nowadays you probably wouldn't get them through the regulatory authorities - they'd be regarded as too bloody dangerous.

"There are probably as many things that cause trouble with some of the older drugs that just aren't being recognised because nobody's looking."

Certainly, doubts are growing. In December, naproxen, taken for gout and painful periods as well as arthritis, was linked to an increased risk of heart attack during a US study into its use in preventing Alzheimer's disease.

A study suggesting an increased risk for ibuprofen and diclofenac was published in the British Medical Journal in June. There are even studies questioning whether anti-inflammatories do much for pain at all.

Norwegian researchers found they reduced pain in the short term only slightly better than a placebo and recommended prescribing more critically. Last month, Australian researchers reported that Celebrex worked no better than paracetamol in most patients.

Professor Les Toop, an early whistleblower against Vioxx, says the rash of reports has the look of a smokescreen by drug companies keen to disperse blame. Previous studies have found naproxen protective against heart attack compared to Vioxx, he says. "If it's true naproxen is bad then that makes Vioxx even worse.

"The side effects of conventional anti-inflammatories were always known about. But they weren't being sold as if they were safe and being hyper-promoted to the public."

Toop says the cox-2 experience sounds warnings not only about direct-to-consumer advertising but the way drug companies use half-truths. Much of the demand for cox-2s was patient-generated but doctors were also "suckered in".

"They were promoted as cleaner and safer but there's mounting evidence that drug companies knew they were worse than the old ones.

"Cox-2s are going to be a classic example for doctors for years to come. People were screaming from the rooftops about cardiovascular problems for four or five years [but were ignored]."

Toop says the root of the problem is that regulators approve new drugs on the basis of efficacy, which is "entirely different from showing whether something is safe or not".

"As long as we have a drug licensing system which allows a company to produce one or two trials showing it's better than a placebo, and ignore trials which don't show [a positive] effect, then we've got a problem."

Efficacy studies for new drugs were neither large enough nor long enough to reveal long term adverse effects. "What tripped up Vioxx was research for a completely different use against colonic cancer."

Where does this leave patients?

"The bottom line," says Hughes, "is the fewer tablets you are on the better off you are, but if you're forced to take something you have to look at the risks."

When Price's arthritis flares up, the risk is calculated.

"Either put up with the pain or take something which you know will push your blood pressure up for a couple of days and hope you don't have a stroke. Quite honestly, I would rather get rid of the pain."