Agony: Dr Paul Debenham suffers from an enzyme deficiency that can't metabolise the painkiller codeine to break it down into morphine
Dr Paul Debenham suffered tremendous pain while recovering from surgery for skin cancer. ‘I was given lots of codeine-based medicines but they seemed to do nothing for me,’ recalls Paul, 60, a biotech entrepreneur.
He followed his doctors’ instructions carefully, believing that if he took the painkillers for long enough they would start working. But they didn’t.
‘The pain was particularly intense in my neck where I’d had lymph nodes removed — I assumed it was because they’d sliced through nerves. It was some of the worst pain I’d ever experienced and it was constant for many weeks.’
But he felt there was little to be done. ‘It didn’t occur to me to complain to my doctors as I was on the maximum dose and I just thought it reflected how ill I was, not that the drugs weren’t working.
‘At the time I was more concerned with staying alive, as the cancer was quite advanced and had spread to lymph nodes under my arms and in my neck,’ says Paul, who lives in Newbury, Berkshire, with his wife Kathy, 60, and daughter Lara, 21.
Several weeks after the surgery Paul’s pain finally disappeared. But it was only six years later, while developing new genetic tests as part of his job, that he suddenly realised why the medication had not touched his pain.
Paul, who has a PhD in molecular biology, was working with Professor Bob Smith, an expert in drug metabolism at Imperial College, London, who had identified differences in the way our bodies respond to drugs. Professor Smith had worked out that these differences may be linked to variations in genes controlling enzyme production.
Enzymes are proteins, made in the liver, which control the speed of chemical reactions in our bodies. They help to break down drugs so the body can use them. Professor Smith found that gene variations can affect certain enzymes so that too much or too little of a chemical is produced. For example, an enzyme called CYP2D6 breaks down codeine into morphine to provide pain relief.
Codeine, which is given for mild to moderate pain, is a cheap drug for GPs to prescribe and is widely used — in 2012 there were nearly 19 million NHS prescriptions for painkillers containing codeine, including co-codamol (codeine and paracetamol), the tenth most prescribed drug in the UK. Codeine is also an effective cough suppressant, used in many non-prescription cough medicines and cold remedies.
The problem is that an estimated 7 to 10 per cent of the population have a gene variation which means they don’t make enough CYP2D6 to obtain pain relief from codeine. Up to six million Britons may be affected in this way, although most are unaware of it.
Tests confirmed that Paul’s body can’t make enough of the enzyme. He explains: ‘If you don’t make enough CYP2D6 you can take as much codeine as you like but it won’t make a blind bit of difference. It’s as simple as that.’
Codeine is given for mild to moderate pain and is the tenth most prescribed drug in the UK
But that is not the only issue with this particular enzyme. There is another group of people who produce too much CYP2D6, so codeine is broken down too quickly in their bodies. This creates a fast ‘hit’ which then rapidly wears off, explains Dr Martin Johnson, a GP and pain specialist for the Royal College of General Practitioners.
‘These so-called rapid metabolisers experience a quick morphine hit when the drug is broken down. The effects of the dose then wear off too quickly, so they start clock-watching until their next dose. In some rare cases this fast-acting effect has caused respiratory depression (when breathing stops), particularly in children, and even deaths.’
This is why children recovering from surgery are now no longer given codeine-based pain relief, and why children’s cough medicines no longer contain the drug.
Dr Johnson suggests that there may be even more fast metabolisers than non-metabolisers — and that put together they could amount to about 30 per cent of the population.
‘Patients often keep taking codeine in the vain hope that it will work eventually — but all they experience are the side-effects, such as constipation (it slows down gut movement in the intestine) and none of the pain-relieving benefits,’ says Dr Johnson.
‘They might return to their GP for a higher dose and still not get any relief.
‘Then there are all the people who buy over-the-counter codeine products, who also get no pain relief.
‘There could be huge numbers of people on medication that doesn’t work for them, or works too quickly to control pain effectively.’
Yet there are alternatives, including paracetamol, ibuprofen, diclofenac and other anti-inflammatories. Exercise can help with pain too — particularly for people with arthritis.
Common issue: It is estimated that between seven and ten per cent of the population cannot break down codeine
Codeine is not the only drug metabolised by CYP2D6.
There are some 25 others including the opioid painkiller tramadol, certain antidepressants known as selective serotonin re-uptake inhibitors, or SSRIs, which include Prozac and Zoloft, and antipsychotic drugs used to treat mental illness.
Beta-blockers prescribed for high blood pressure and the breast cancer drug tamoxifen, taken by 13,000 women, also fall into this category.
Dr Debenham says it’s a big issue. ‘If a woman is taking tamoxifen, as a side-effect she may experience hot flushes, and sometimes SSRIs are prescribed for these.
Certain types of SSRI are also metabolised by the CYP2D6 enzyme, so the two drugs compete for the small amount of enzyme in the liver — this could mean that the cancer-suppressing action of tamoxifen doesn’t work as there is not enough CYP2D6 to metabolise the drugs.’
Jo Cumming, of the charity Arthritis Care, says patients frequently ring its helpline in tears because codeine is not working for them. ‘Many have simply not been told that it doesn’t work for everyone, so they soldier on, believing that if they keep taking it or just up their dose it will work eventually. Or they stop taking it and don’t tell their doctor.
‘We encourage them to go back to their GP so they can be switched to something else.’
Dr Roger Knaggs, associate professor of pharmacy at Nottingham University and a spokesman for the Royal Pharmaceutical Society, says pharmacists are usually aware of the CYP2D6 problem but it is less well known among GPs.
‘We need greater awareness of the condition among patients as well as GPs,’ he says.
Could the answer be to screen people for the genetic variation? Dr Johnson says more research is needed to investigate how widespread the problem is, but he believes genetic screening could potentially be beneficial.
‘It may be money well spent in cases where patients have a pain condition,’ he says.
‘Screening could determine how well other drugs work, too. It’s common sense to find out whether a drug is going to work for you at the beginning.’
In fact Dr Debenham is developing a gene test for CYP2D6 using both saliva and blood tests which can give results within 45 minutes — it could cost less than £50 and may be available within a year (currently CYP2D6 tests are only available privately from the U.S.).
However, Dr Cathy Stannard, consultant in pain medicine at Frenchay Hospital, Bristol, is less convinced about the benefits of routine screening.
‘People are shocked drugs don’t work for everyone but all drugs are metabolised differently. If you gave ten people the same drug you’d get a different response in each. The reasons are not just down to CYP2D6,’ she says.
‘If codeine was the only painkiller available, there would be more interest in screening people routinely for this enzyme problem.’
Indeed as Dr Knaggs points out, ‘even if you don’t have a problem with production of the CYP2D6 enzyme, codeine still might not work for you, as drug response in pain is such a complex process’.
In the meantime, if codeine isn’t working for you, tell your doctor so he can prescribe another type of painkiller, advises Dr Johnson.
www.arthritiscare.org.uk
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Read more: http://www.dailymail.co.uk/health/article-2531361/Why-codeine-painkillers-dont-work-millions-harm-health.html#ixzz2p17GJ4EC
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