Placebos, sham surgeries and CCSVI

Recently GPs took part in a survey which showed that 97% of them had used placebos at some point in their careers. The truth is inevitably more nuanced than that headline figure: 97% had used what the researchers called "impure" placebos such as antibiotics for viruses, and the figure for "pure" placebos, treatments containing no active ingredients at all, was in fact 10%.

"Pure", inactive placebos such as sugar pills may seem the more dangerous, but "impure" placebos may be actively dangerous to health. For instance, antibiotics can have side-effects and may promote antibiotic resistance.

Most of the doctors questioned thought that any risk of damaging the trust between doctor and patient was unacceptable, but that it was possible to prescribe a placebo to a patient without actively lying to them. For instance, half of the doctors told the patient that the intervention had helped others.

Is this ethical, particularly if it's possible that the patient would have got better anyway? If something is at the extreme ends of a range of measurements, the likelihood is that it will move towards the average. This is the statistical phenomenon called regression to the mean. The medical application of this is that if someone is ill, on the whole they're likely to get better whether there's any intervention or not.

There may be a psychological effect from receiving a placebo, even if the patient knows that's what it is. One study found that even when the patient was fully aware that their treatment had no active ingredients, the placebo effect was still seen. However there were methodological flaws in that study. More research is needed, to see if the results can be replicated.

Placebos are commonly used in trials to assess whether a new medication is better than no treatment at all. How can a surgical intervention be tested? Sometimes sham surgery is used. Sham surgery forms an important control, as anaesthesia, the incision, post-operative care, and the patient's perception of having had an operation are the same.

However again there are ethical issues, as all surgery has the potential to harm the patient. As a result, sham surgical procedures are rare in human subjects.

In a classic study in 2002, patients with osteoarthritis in the knee either had standard surgery, had their knee joint washed out, or had an incision made in the skin and sewn up again. All the patients in the trial therefore experienced "surgery" of some sort, but didn't know which type. All three groups reported similar levels of pain reduction and improvement in mobility, suggesting that the standard surgery produced no advantage over placebo.

A sham surgery trial has recently reported relating to the controversial CCSVI theory of the causation of MS, which hypothesises that MS is caused by compromised drainage of blood from the central nervous system. The proposed treatment is balloon venoplasty, whereby a small balloon is threaded into the vein and then inflated to clear the blockage. Since 2009, around 30,000 MS patients worldwide have had this treatment, almost always privately rather than as part of a trial.

In this small trial, 30 patients received either the balloon venoplasty treatment or a sham surgery. The treatment did not provide sustained improvement in patients. In fact in some cases, there was a deterioration.

Clearly this was a small study, and more research is needed. But in the meantime, the researchers, who studied under Paolo Zamboni, the developer of the CCSVI theory, have urged patients to enroll for trials rather than pay for the treatment privately.

Overall I believe placebos certainly have a valuable place in research, assuming of course that patients know they may receive the placebo rather than the active treatment. In the GP surgery, I'm not so sure. We should be using evidence-based medicine: that means the best available treatment for the condition, not sugar pills or inappropriate antibiotics. I suspect placebos will always be with us though, one way or the other.

Big Pharma and price hikes: not NICE

Having a long-term illness affects your life, and your concerns, in lots of ways. For once, I'm not talking about the symptoms, about pain, fatigue, or whatever characterises your particular flavour of poorliness. I want to write about the medications many of us need, and how we, and our doctors, are held to ransom by the pharmaceutical companies - "Big Pharma" - that manufacture them.

Epanutin is one brand name of a drug called phenytoin, which reduces the risk of seizures for people with epilepsy. It's used less than it used to be, but it's still taken by around 100,000 people in the UK. The cost of this was around £2 million a year.

The rights to manufacture Epanutin have recently been sold by Pfizer, to UK firm Flynn Pharma. They've repackaged it and increased the bill by a staggering 2330% to £46.6 million. All that has changed is the packaging: the capsules themselves are identical.

Because phenytoin is a relatively old drug, it's out of patent and any drug company can make it. So the NHS can just switch to another supplier, right? Sadly, wrong. Pfizer, and now Flynn, are virtually the only manufacturers of the capsules. Phenytoin is also available as a syrup and as tablets, but there's a problem. People with epilepsy tend to be extremely sensitive to levels of their medication in their blood, so they and their doctors are reluctant to switch from the Epanutin capsules. As a result, there's virtually no competition to make another version of phenytoin, and Flynn pretty much have a monopoly.

Result: Flynn basically have the NHS over a barrel. Because Epanutin is a standard treatment for epilepsy, it's more or less 100% sure that the NHS will go on funding it.

That's a standard treatment. What's the situation with newer medications?

Alemtuzumab, or Campath, is currently licensed for use in leukaemia. Neurologists have also been prescribing it off label for aggressive multiple sclerosis since a large, encouraging trial in 1998 and subsequent published trials showing it as superior to other MS treatments.

It's also considerably cheaper than other MS treatments, at around £2,500 a year per person. Or it was. The manufacturers, Genzyme, have applied for a license for Campath for the treatment of MS, and are expected to relaunch it at up to 20 times its current price. They have also withdrawn it from off-label use for MS pending approval, on the grounds that "any adverse event outside a clinical trial … may complicate the regulatory process".

When a medication is licensed for use in the UK, it then has to be reviewed by the National Institute of Health and Clinical Excellence (NICE). NICE has the difficult task of deciding which treatments should be funded by the NHS, to share out the limited amount of cash available. Should it approve the use of an operation that costs, say, £20,000 per person, or a medication for a completely different condition that can treat 50 people for the same amount? What if the operation saves lives, while the medication is for something far less serious?

So, assuming Campath is licensed for use with MS, NICE will have to decide whether the NHS should fund it. If it was still cheaper than existing treatments, with better results, it would be a no-brainer (though of course the risk of side-effects also comes into the equation). But it looks like it's going to cost far more than that.

We've all seen stories in the newspapers about people denied treatments by NICE, often for cancer. Is Campath going to be another such? MS is progressive: people denied Campath would be at risk of severe disability as a result. And if Campath is approved, what else will be denied?

These are two examples of big hikes in price. I have no doubt there are others. What these pharmaceutical companies are doing is certainly not illegal, but is it moral? These are existing drugs. There are no additional research and development costs to recoup.

Big Pharma. Getting bigger every day, and at the expense of sick and disabled people.

Taking the piss

So what would make you want to have a tube shoved up your bahookie and have someone give injections to your bladder from the inside? There's some people would pay good money for that I know, but it's not really to my taste.

Well, it was the latest treatment for my bladder problems.For a long time now, I've had frequency (needing to go all the time) and urgency (once I need to go, I need to go NOW.) I've also had regular UTIs. Last year this reached ridiculous levels. When I stopped antibiotics for one infection, I would have about one blissful bacterium-free week, before succumbing again.

All this was down to my detrusor muscle, the muscle that contracts when you're weeing to squeeze the wee out. I have overactive bladder as a symptom of MS, where the muscle reacts on a hair-trigger: it sends the "I'm full" signal to the brain well before that's actually the case; it responds to external stimuli like running water or opening the front door; and its contractions cause stress and urge incontinence.

So what could be done? Well, obviously, antibiotics for the infections: I worked my way through a wide range, collecting allergies and interesting side-effects along the way (mostly hallucinations - the gazelle giving me a jar of hand cream was my favourite).

I took part in a drug trial, self-injecting twice a week. I knew when I was on the drug rather than the placebo because I got skin reactions. It really, really helped. But then the trial ended, and I was back to the standard medication.

The standard medication is anticholinergic drugs, which help to stop the detrusor muscle from over-reacting. They help, a little, but not much. I still have a lot of problems.

So it was proposed that I should have botox. No, not up there. Down there. The idea is to partially paralyse the detrusor muscle so that it's not so twitchy. And the way they access it is through what's normally the exit.

In due course, therefore, I found myself on an operating table with my legs up in stirrups, with a charming consultant in there at the business end shoving a tube with a camera attached up where only one man has been before (the urologist who did my previous cystoscopy). The equipment that let him see what was going on also had a small screen that I could see (if I wanted, which being me of course I did), and he was good enough to give me a guided tour of my own bladder - this is the top, this is where the left kidney opens into the bladder etc etc.

The actual injections...weren't nice. But hey, I've got MS, I've experienced a lot worse. If you can imagine someone pinching a bit of your insides, FROM the inside, really hard, that's kind of what each one is like.

But it was soon over, and there was no pain afterwards. And the very next morning, I woke up, needing the loo, yes, but not desperate - I'd forgotten what that felt like! Generally the effects have been wonderful. I can hold on for absolute hours, as opposed to my previous average of about 40 seconds!

Predictably enough, with my history, I got an infection, but that was soon sorted out with antibiotics. I'm still on a low dose, to protect me against any more. The ongoing side-effect is that I've kind of gone the opposite way to where I was before. I now can't wee when I want to! Well, I can, but it's hard work, y'know? Seems the injections have worked a little too well. Hopefully that'll settle down in time. In the meantime it's still preferable to my previous problems.

So all in all a positive experience, and I'd definitely recommend botox if you have overactive bladder and the standard meds aren't helping you. I'll have to have it repeated every 6-9 months, but that's small price to pay for the benefits.

And, of course, for having the smoother, more youthful bladder I've always dreamed of...

Life's a trial

When I'm doing research roundups, I quite often talk about clinical trials being "Phase 2" or "Phase 3". But what do these terms mean? The development of a new drug or other intervention is a long-term process. commonly taking 12 or more years before being available to patients. The regulatory process adds another hefty chunk of time.What's happening for it all to take so long?

Research begins in the laboratory, where potential treatments are tested on animals: for instance, there is a strain of mice which have a condition very like MS. Testing drugs on them gives a reasonable idea of whether they're likely to help people with MS. Around 1000 potential drugs are tested for each one that makes it to clinical trials.

The use of animals in drug trials is a whole other question, one I might discuss in a future blog post. If the drug is helpful for the animals (and how that's worked out is again a subject for a future blog post), the researchers will look for more funding to test it out on people, in clinical trials. The clinical trial process has four phases.

Phase 0 Very low doses of the drug are given to 10-15 people to see whether the drug does what was expected in humans. Tests are carried out to check what the drug does to the body, and what the body does to the drug.

Phase I The drug is tested on usually 20-100 healthy volunteers, to check that it is safe. These volunteers are normally paid, as they won't get any health benefit from participating, and are taking the risk of being given an untested drug. Some of you may remember news coverage of a Phase 1 trial in 2006 where 6 healthy volunteers became violently ill after taking a new drug.

Phase II Designed to assess how well the drug works, and what is the best dosage. Between 100 and 300 volunteer patients take either the drug or something else - the existing treatment if there is one, or a placebo.

Phase III The drug is tested on a large number of patients over a number of sites. This phase aims to be the definitive assessment of how effective the drug is, compared with any current treatments. Sometimes a manufacturer wants to prove that their drug works for other patients or other conditions than those originally established. In that case the Phase 2 or 3 trial would be the first stage.

Phase IV This is the period of surveillance once the drug is on the market. Safety continues to be checked, and technical support is available.

Clinical trials can take a long time to run. It can be difficult to recruit the number of people needed, particularly in Phase III. For many long-term conditions, it can take several months to see any effect from the drug. I recently participated in a Phase II trial for a full year.

Most Phase III trials (and some Phase II) are randomised, double-blind and controlled.

• Randomised means that participants are randomly assigned to the treatment or placebo groups
• Double-blind means that neither the participant nor the researchers know whether they're receiving the treatment or the placebo. It's important that the researchers don't know, as they might subconsciously behave differently to people in the two groups.
• Controlled means that one group receives a placebo (or the existing treatment, if there is one).This means that the effect of the new drug can be isolated. Is it better than the existing treatment? If so, how much better?
• Some trials are designed to cross-over, This means that halfway through the trial period, the participants swap over to receiving the other treatment. Those who were gettng the active drug will change onto the placebo, and vice versa.

After the trial process, the manufacturer will apply for the drug to be licensed, which has to be done separately in different parts of the globe.Here in the UK, once it's been licensed, the action then moves to an agency called NICE, who decide whether the NHS should fund treatments.

Their decisions are based on cost-effectiveness, potentially leading to some controversial outcomes. Recently they've refused funding to the new MS drug Gilenya, and there have been several decisions where funding has been refused for expensive cancer drugs which were likely to give only a few more months of life.

In some cases, local Primary Care Trusts still have to agree to fund the treatment. There have been problems recently with Sativex, which is licensed for use in MS spasticity if other treatments don't help. Many PCTs are refusing to fund it. The MS Society is campaigning on this: if you have funding for Sativex refused, they provide advice on what steps to take.

You're most likely to find out about trials through your consultant. If you'd be interested in participating in a research project (without commiting yourself to anything!) let them know.

It can't be denied that there are some risks involved, as there are with any treatment. But I found trial participation interesting, and if the drug concerned goes on to be approved I'll feel quite proud: I was part of that!

Walking back to happiness?

Walking. It's such a significant ability, isn't it? Being able to walk is one of the markers of development from babyhood to childhood.

And to many of the general population in our culture, it's whether someone can walk or not that determines whether or not they're disabled. Many of us with MS quite rightly complain that our invisible symptoms disable us just as much, if not more, than mobility problems. Even so, we often resist using mobility aids such as sticks, crutches or wheelchairs for as long as possible: visible symbols of our disabilities.

The worst symptoms of my MS are fatigue and pain. Even so, any improvement in my mobility would make my life far easier! I'm currently able to walk very short distances, and use a power wheelchair outside the house.

That's why I've been so excited watching the trials of the new drug Fampridine (Fampyra), which was finally released in the UK this week.

Fampridine is a tablet taken twice daily. It's not like Beta Interferon, Copaxone or Tysabri - it has no effect on disease progression. It's effective for roughly 33-40% of people with MS with walking problems: when it does work, it gives an average 25% improvement in walking speed.

Back when it was in trials, I discussed Fampridine with my neurologist. She said that she would want to put me on it as soon as it was approved.

So far, so excellent. But like every medication, Fampridine has potential side effects. Some of these are relatively minor, and pass as you get accustomed to the drug. But some are potentially very dangerous.

Among these is a slight risk of seizures (fits). Now in general, for most people, that very small chance would be a risk worth taking. But I already have epilepsy. So although it's well controlled, anything that increases my seizure risk is not really very good news.

It's all about swings and roundabouts: balancing risks and benefits. At the moment I don't know if my neurologist will consider me suitable for Fampridine, given the seizure risk. I'm seeing her in 6 weeks, and will be asking about it.

But if she leaves the decision up to me, will a possible improvement in my walking be worth risking losing control of my epilepsy? If I have a seizure, I'll lose my driving licence for a year, and I really don't want that to happen. But easier walking would make my life so much simpler.

At the moment, I really don't know what my decision would/will be. I suppose I'm going to have to do some hard thinking over the next few weeks. And who knows? Pretty soon, like Helen Shapiro, I might be Walking Back to Happiness!