How Safe Are My Pills?

A series of withdrawals of major drugs have caused widespread concern for patients and pharmaceutical companies alike.

Merck, the US manufacturer of Cox-2 inhibitor Vioxx, withdrew the drug after they noticed an increase in nonfatal heart attacks amongst patients undergoing a 3-year international trial on the drug. The trial was testing a promising new indication for Vioxx (also known as rofecoxib) in the prevention of the recurrence of colon polyps in patients that have been treated for these tumours. Warnings to patients already predisposed to heart attacks and strokes have been contained in the patient information for Vioxx since its release over 5 years ago, but the results from the recent trial were such that the company decided to voluntarily withdraw the drug. However, there are questions about how much the company and the regulatory authorities knew or should have known about the heart risks and whether the drug should have been withdrawn earlier, especially as there are safer alternatives. Indeed, Pfizer, another US drug firm, were quick to promote their Cox-2 inhibitor, Celebrex (celecoxib) as a safe alternative, in the aftermath of Merck’s withdrawal of Vioxx, but it too is under investigation for possible heart problems and sales are falling.

The main losers in all of this are arthritis pain sufferers who have lost medicines that improved their life and are now left wondering if the very pills that brought that relief have harmed them. Mo Atachia of Arthritis Care, quoted on the BBC website, said that “It’s essential that the European safety regulators deliver a swift a verdict as possible on the whole class of Cox-2 treatments”.

How can this happen?

So how can our medicines cause such serious side effects when they are supposed to be tested for safety? The problem is that it is always easier to prove that a drug is unsafe than to prove the opposite. Let’s say a potential new pain treatment causes heart disease in 10% of patients at normal doses. That would most likely show up in early animal tests and no human patient would ever be given the drug – it’s been proven unsafe. What about if the risk is 1% or 0.1%? This might still be an unacceptable risk, but because it is rare there is a good chance that safety tests in animals will not pick it up and even widespread patient trials could miss it.

Only when the number of patients receiving the drug is up in the hundreds of thousands might some rare, but unacceptable risk emerge. “Sometimes then you may pick up side effects that we hadn’t been able to see during clinical trials” (European drug regulator quoted on the BBC website). The US Food and Drug Administration (FDA) looked at the risk of heart attack for Vioxx. 1.4 million Californians who had used painkillers were analysed. In round figures 1 million patients used ibuprofen, 400 000 used naproxen, 40 000 used celecoxib and 27 000 used Vioxx. Amongst the 1.4 million patients the total number with coronary heart disease was 8100 (0.6%), but when the incidence of coronary heart disease was compared with individual drugs they found a 1.6x higher risk, i.e. 1% in patients using Vioxx.

So if you are a doctor in California and you have 1000 patients on painkillers other than Vioxx, you might find that 6 of them have coronary heart disease. And if you have 1000 patients on Vioxx you might find that 10 have heart disease. That’s the problem. How do you decide if such a small increase is chance or genuinely due to the drug? Are some of the other painkillers protecting against heart disease (like aspirin does) or are some of the ibuprofen users taking it for sprains caused by jogging – these people would be unlikely to get heart disease compared with some one with rheumatoid arthritis. Merck’s spokesman points out that heart disease is multifactorial and must be assessed case by case. Only as pieces of evidence like that accumulate with time can some sort of certainty emerge which enables a balance to be struck between putting patients at unacceptable risk of dangerous side effects and depriving patients of beneficial life enhancing medicines. It’s never going to be easy and the only certainty is that mistakes can be made in both directions.

Co-proxamol

In another development, the UK drug authority (the Medicines and Healthcare Regulatory Agency) has ordered the withdrawal of co-proxamol following a report from the Committee on Safety of Medicines (CSM). The reason is that four hundred people commit suicide every year using co-proxamol. Patient groups are really finding it hard to understand why this should lead to their being deprived of an effective treatment. The chairman of the CSM, Professor Gordon Duff, said that there was no need for panic or concern. Arthritis Research Campaign are concerned: It’s incredibly bad news, they said.

The problem is not just suicide. There are a number of accidental deaths with co-proximal especially when used with alcohol and there is no denying its toxicity. The problem for regulators is that while there is “great brand loyalty” according to one GP writing to the BBC website, there is little objective evidence that co-proximal is any better than other pain killers such as paracetamol (itself not exactly the safest substance people pop into their mouths). Nonetheless pain is a symptom, an internal perception, and if a patient states that Drug A gives them better relief than Drug B it is hard to do anything other than believe them.

Individual patients are adding their own stories to web sites and letters pages all saying the same – that for them co-proximal gives relief like no other medicine. The rights and wrongs of this are hard to determine, but it all adds up to very bad news for pain sufferers as medicines are withdrawn and symptoms return.

But What About Opioids?

The opioids have suffered a bad press because of addiction but as the cox-2 saga developed perhaps its time to look again at older drugs such as morphine. Addiction is in fact over stated as a risk and few people suffer more than constipation, yet their efficacy as painkillers is very high. Will governments overcome their fears on recreational use and make these highly safe and efficacious drugs more widely available? People wanting more information should start with the British Pain Society’s leaflet “Opioid Medicines for Persistent Pain” (see below).

And Cannabis??

If opioids are finding it hard to overcome political prejudice then multiply it several times for cannabis. At the moment many people whose only crime is to be incurably ill are risking a criminal prosecution for acquiring and using cannabis. All eyes are on Health Canada, that country’s regulator of drugs who will shortly decide whether to licence an oral spray of cannabis (Sativex). Spain, too, is about to start a trial. Marijuana affects behaviour by imitating the effects of natural brain chemicals called endocannabinoids. These natural chemicals help in the regulation of pain, nausea, anxiety and hunger. Hopefully drugs based on the endocannabinoids will give better pain relief than actual cannabis and will not meet the political resistance that use of the real weed does

OK, There’s Always Complementary Medicine

Imperfect though the safety evaluation of drugs might be, at least there is a system. In contrast many “natural” or “alternatives” are subject to no testing whatsoever. In a recent landmark ruling two doctors working outside the NHS were convicted of serious professional misconduct for prescribing complementary therapies to patients with breast cancer. None of the prescribed treatments had any evidence that they were effective and the information handed out to patients was not evidence-based. The judgement said that “Providing information about a treatment for which there was no scientific evidence was irresponsible and not in the best interests of patients”. This does not mean that complementary medicine is not effective, but that any treatment, whether herbal or produced by a major drug company must have evidence behind it that it works and is safe and is the best treatment for that particular patient

Useful Publications:

Focus on your medicines, Medicines Partnership and the Department of Health (copies available from Pain Concern; please enclose an SAE with your request).
Health and Medicine Information, Guide and Directory, ABPI at www.askaboutmedicines.org
Opioid Medicines for Persistent Pain, British Pain Society, 21 Portland Place, London, W1B 1PY, www.britishpainsociety.org.
The Brain’s Own Marijuana by Roger Nicoll and Bradley Alger in Scientific American, December 2004.