Prescription opioids are the opium of the people

The 2016 World Congress on Pain (WCP), meeting in Yokohama in late September, held a packed Special Session on Opioids. The theme was their role in pain medicine. This might seem fairly settled since the analgesic properties of opium have been known for at least 3000 years. Not so!

The scene was set by eminent pain specialist Jane Ballantyne, president of Physicians for Responsible Opioid Prescribing and adviser to the US Centers for Disease Control and Prevention (CDC). She described how over the last 25 years sales of prescription opioids have soared, as have emergency admissions and deaths. In the US, some 1 in 5 patients with chronic non-cancer pain (CNCP) are prescribed opioids; since 1999, sales of prescription opioids have quadrupled; between 1999 and 2014, over 165,000 people died from overdose related to prescription opioids; more than 14,000 died this way in 2014, at least half of all opioid overdose deaths; nearly 2 million Americans abused or were dependent on prescription opioids in 2014, a quarter of those taking prescription opioids; over 1,000 people are treated in emergency departments for misusing prescription opioids every day.1

Eighty per cent of opioid prescriptions world wide are in the US, with just 5% of the population.2 This is not because Americans are suffering more pain: it is the product of drug companies “educating” physicians and patients, together with a production line model of health care. How has it come to this and will the problem spread? Drug companies would no doubt like to increase their opioid sales. This is a gigantic problem without an obvious solution. The new CDC Guidelines on Prescription Opioids1 may prevent the worsening of the situation but rolling back such a tide of addiction to legal drugs will not be easy.

The history of medical opioid use

The opium poppy, Papaver somniferum, has been known at least since Neolithic times (and perhaps even by Neanderthal people) and was widely cultivated and used in ancient Egypt, Sumer, Greece and so on. Morphine was isolated from opium in the 19th Century and this allowed safer dosing, since the amount being dispensed could be accurately measured. Later, derivatives of morphine or compounds with similar actions, such as heroin, methadone, pethidine, oxycodone, hydrocodone and fentanyl, were developed. These, the opioids, are mainly used for anaesthesia in operations (pethidine, fentanyl), for pain relief during childbirth (pethidine), and post-operative pain (often morphine). Morphine is supplied to US and British soldiers for use if injured on the field of battle. Opioids were also used as a cough suppressant (e.g. Codeine Linctus) and to treat diarrhoea (e.g. Collis Browne’s or Kaolin & Morphine).

Since the opioids efficiently suppress the acute pain of injury or operation, a wholly desirable outcome, one might wonder why they are so tightly controlled or even banned around the world. One reason is that the therapeutic dose is fairly close to the toxic dose: they suppress the breathing reflex and an overdose stops the victim breathing. As Paracelsus said, “The dose makes the poison,” and for heroin the Therapeutic Index (TI: the ratio of the toxic dose to the effective dose) is 25:1. This is a problem for recreational heroin users who don’t know the purity of the drug they are taking.

Another reason is that, if the patient takes opioids over a long period, they develop a tolerance to the drugs: the amount needed to achieve the desired effect slowly increases and can reach levels that would be instantly fatal to a new patient.

The main reason for controlling or banning opioids is that they are very addictive. This is less of a problem for those taking them, as they should, for short periods to deal with acute pain or to deal with pain associated with some terminal cancers. But, for those taking them for chronic pain or to experience the euphoric effect found with larger non-therapeutic doses, dependence or addiction can result, as well as side effects such as constipation, breathing problems in sleep, heart problems, suppressed immune systems, more bone fractures (perhaps because of dizziness and slower reactions), and disruption of hormone systems (including sex hormones). There is also, paradoxically, increased sensitivity to pain in a significant proportion of chronic opioid users.

For most of the time that opium has been known, it has been legal in most of the world, if rather frowned upon when used recreationally. Indeed, the British authorities allowed opium sale in India and imposed it by force in China in the Opium Wars. Sales of laudanum (tincture of opium and alcohol) in Britain were legal though regulated from 1868. Gradually, particularly in the first half of the 20th Century, opium and its derivatives became illegal unless prescribed by a doctor. Following the International Opium Convention in 1912, drug control was incorporated into the Treaty of Versailles in 1919, and the League of Nations signatories agreed to prohibit trade in narcotics except for medical uses. Laws have become stricter and the “war on drugs” has escalated so that many countries now impose stiff penalties, up to execution, for possession and sale of opioids. Except in terms of job creation, this war has not succeeded.

The problem of not enough and of too much opioids

Like other wars, this one has caused collateral damage with the legitimate medical use of opiates, especially in palliative care of cancer patients, being restricted unnecessarily. The WCP Special Session on Opioids3 heard from an Indian pain specialist that in half of the world opioids were not available to alleviate unbearable suffering. In her own country, opioids were theoretically available but legal restrictions made doctors afraid to prescribe them for fear of falling foul of the criminal law.

It was in the USA, however, that the situation was the most bizarre. Alongside serious jail terms for mere possession of opioids, the drug companies had successfully argued from about 1980 that opioid prescriptions should be allowed for patients with chronic (long-term) non-cancer pain. It was argued that this would not result in dependence problems since only a small percentage of patients had hitherto become addicted to prescription opioids. This went against medical advice that they be used only for acute pain or for cancer pain, especially in those with a terminal diagnosis.

The epidemic started in 1995 when the US Food and Drug Administration (FDA) approved the opioid painkiller OxyContin (oxycodone). Its manufacturer Purdue Pharma sold $45 million’s worth of OxyContin in 1996, $1.1 billion in 2000, $3.1 billion in 2010, some 30% of the painkiller market. It achieved this by aggressive advertising and targeting doctors already prescribing a lot of painkillers. The result has been a large number of people addicted to OxyContin and as many deaths as occur with illegal use of opioids. The opioid-paracetamol mixture Vicodin (containing hydrocodone) is involved in opioid dependence but also in deaths from paracetamol overdose.

This is at present almost entirely a US problem, with 80% of the world’s opioid consumption, legal and illegal, taking place in the USA. Most of the users are poor whites in areas like the Appalachians: hence its nickname “hillbilly heroin.” The historic pattern of under-treatment of pain in Afro-Americans due to racist assumptions has ironically largely spared them from the opioid epidemic.

A related problem is deaths from heroin overdose which have nearly tripled in 12 years, exceeding 10,500 in 2014. The number of addicts has doubled in that time, with the vast majority of new users being people who had previously misused prescription opioids. What to do? In a “shutting the stable door” move, the CDC have issued a new guideline for prescribing opioids for chronic pain, emphasising non-opioid treatments, low dosages, and following up patients to check that opioids are having the desired effect or to help them taper off the drugs. This sounds a very labour-intensive policy and one wonders how this would work in the US health system.

Other private health systems will be prone to the problems of prescription opioids but so too may public health systems: already it is reported that prescription opioid use has increased four-fold in 10 years in Australia while Canada, Germany, Austria, Switzerland, Belgium, Netherlands and Denmark are starting to catch up the USA. Other European countries and New Zealand also seem to be increasing prescription opioid use. With the USA, these countries account for 96% of prescription opioids used world-wide with just 15% of the population. We should remember, however, that this is also a problem for the 85% who may need access to prescription opioids but can’t get them. ………………………………………………………………………………………………………………

Information: How opioids work

Endogenous opioids (e.g. endorphin and enkephalins) have been found in all animals where they have been looked for, such as the very simple flatworms, as well as nematode worms, annelids, molluscs, crustaceans and insects, and all vertebrates. One major purpose may be to suppress pain when the priority is escape but endogenous opioids are involved in many other systems, such as the gut, and in social behaviours and in reward systems in the brain. They work by binding to opioid receptors,* of which there are at least four types, found in different tissues and causing different effects.

Morphine (and to a lesser extent codeine) is produced by the opium poppy as part of its defence mechanism against damage. Entirely fortuitously, morphine binds strongly to opioid receptors and activates them, resulting in relief of pain, euphoria (in the reward systems), inhibition of gut movement (resulting in constipation), suppression of the cough reflex, and depression of the breathing reflex (risking cessation of breathing). Codeine has no effect but is broken down by liver enzymes to produce morphine and other metabolites. People lacking these enzymes get no benefit from codeine.

Repeated use of morphine, or its derivatives such as heroin, reduces the body’s natural production of endogenous opioids, encouraging increased doses and resulting in withdrawal (abstinence) syndrome, an exaggeration of the opposite effects to those caused by morphine. This makes the original problem worse which is why opioids should only be used for short periods. Interestingly, there are some compounds, such as naloxone, which bind to opioid receptors even more strongly than morphine but do not activate them. These are opioid antagonists and can be used to reverse opioid poisoning since they rapidly displace opioids from the receptors and deactivate them.

Some opioids do not activate all receptor types. These partial agonists, such as Tramadol and buprenorphine, have been suggested as safer alternatives, with the latter being used to treat opioid dependence. When I was on a placement with Reckitt’s in the late 1970s, we were told that healthy volunteers taking buprenorphine for long periods had withdrawal symptoms when the drug was stopped but that they preferred these to the side effects from taking the drug.** Nevertheless, buprenorphine is abused by some people, as is Tramadol. ……………………………………………………………………………………………………………..


*Hans Kosterlitz developed the first bioassay for the opioids (allegedly after a dream!). This consisted of a length of guinea-pig intestine whose electrically-stimulated contractions were inhibited by certain concentrations of morphine. Other potential opioids could be checked against this to assess their potency. Kosterlitz and his colleagues predicted the existence of a naturally-occurring opioid in mammals and this was confirmed when some mashed-up pig brain was added to the saline solution bathing the intestine and its contractions were duly inhibited. Kosterlitz was a refugee from Nazi Germany who settled in Aberdeen; his son Michael, now based in USA, has just jointly won the 2016 Nobel Prize in Physics: both are marvellous advertisements for the benefits of migration. Michael has said that he is considering renouncing British citizenship if Brexit goes ahead.

**We were also told by a senior scientist that there were no serious health effects from long-term use of (prescription) opioids, apart from addiction. We now know that there are health effects and that long-term use of opioids does not solve the problem for which they are prescribed. It is still better to legally supply addicts than to criminalise them but the task of weaning them from their drugs is a difficult one.

References  (click after number to see)




Pain in dinosaurs: what’s the evidence?

I recently presented this poster at the International Association for the Study of Pain’s World Congress in Yokohama, 26-30 Sep 2016.

I am pleased to say that it generated a lot of interest. I believe that it helps push home the message that pain behaviour has evolved as animal life has evolved and many pain behaviours are conserved. This realisation may help to understand such seemingly inexplicable and harmful phenomena as chronic pain.

My poster partner, Amanda Williams, is developing a theoretical understanding of chronic pain: see her topical review What can evolutionary theory tell us about chronic pain? in the IASP journal, Pain, recently.
(April 2016:157(4);788–90 doi: 10.1097/j.pain.0000000000000464)


“Against stupidity, the gods themselves struggle in vain” (Goethe): The story of banning “legal highs”

Towards the end of January, “mostly supine” MPs passed a bill after a “clueless debate.” The Psychoactive Substances Act which is intended to ban “legal highs” (novel psychoactive substances – NPSs) is “one of the stupidest, most dangerous and unscientific pieces of drugs legislation ever conceived.” “Watching MPs debate…it was clear most didn’t have a clue. They misunderstood medical evidence, mispronounced drug names, and generally floundered. It would have been funny except lives and liberty were on the line.”

Not my words but those of an editorial in New Scientist (30 Jan 2016) and a report by Clare Wilson. The act came into force on 26 May, meaning that previously legal “head shops” must cease selling NPSs. The banned drugs will only be available from illegal drug dealers.

The story starts with the panic about “legal highs,” chemicals with similar effects on mood to banned drugs such as ecstasy, cocaine or speed, hence the term “psychoactive.” Legal highs were not covered by drug laws that banned named compounds but not new ones with similar effects.

If history tells us anything, it is that humans take drugs. Sometimes, these drugs cause harm to those who take them or to society in general. Banning specific drugs makes their use more dangerous. A logical approach would be to reduce the harm by controlling purity, taxing their sale, and educating users instead of criminalising them. Drug users would prefer not to break the law, providing a considerable incentive to synthesise new drugs that mimic banned drugs but aren’t on the banned list. But these new drugs will have unknown side effects and there is no control on dose and purity. In contrast, the effects of many “traditional” drugs are known.

The rationale for banning NPSs was that they were dangerous. Legal highs were mentioned in coroners’ reports for only 76 deaths from 2004 to 2013 (Office for National Statistics). Despite the government’s banning of NPSs as fast as it could, the number of mentions was increasing (23 in 2013). Reliable data are extremely difficult to obtain and mere mention of a drug in a coroner’s report is not evidence that the drug caused the death.

As each NPS was banned, more were synthesised. There were 24 NPSs in 2009 and 81 in 2013, making the government’s actions futile, so some bright spark came up with the idea of banning the production and supply of all substances which produce “a psychoactive effect in a person … by stimulating or depressing the person’s central nervous system [thus affecting] the person’s mental functioning or emotional state.” A bill was proposed by the new Conservative government and specified that anyone producing or supplying (but not merely possessing for personal use) the previously legal NPSs could be sent to prison for up to seven years.

The proposal soon ran into problems. Firstly, what is meant by stimulating or depressing the central nervous system? Secondly, what constitutes an effect on a person’s mental function or emotional state? Thirdly, how could it be proved that any suspected substance was psychoactive? After all, placebos can be psychoactive. Fourthly, what about alcohol, nicotine, caffeine, many medicines, and foodstuffs such as nutmeg and betel nut (or, in my case, cake)? Finally, would bona fide scientific research on psychoactive substances be outlawed?

Criticism poured in from scientists. Respected medical researchers said the bill was “poorly drafted, unethical in principle, unenforceable in practice, and likely to constitute a real danger to the freedom and well-being of the nation” (letter to The Times). The Royal Society, the Academy of Medical Sciences, the Wellcome Trust, and others wrote to Home Secretary Theresa May that “Many types of important research could potentially be affected by the Bill, particularly in the field of neuroscience, where substances with psychoactive properties are important tools in helping scientists to understand a variety of phenomena, including consciousness, memory, addiction and mental illness.”

Even the government’s Advisory Council of the Misuse of Drugs (ACMD), more in line with politicians’ wishes since the shameful “firing” of Professor David Nutt (see box), produced a list of objections. The government’s omission of the word “novel” made the bill apply to a vast number of other substances in addition to legal highs. It would be impossible to list all exemptions so benign substances, such as some herbal remedies, might be inadvertently included. Also, proving that a substance was psychoactive would require unethical human testing, since laboratory tests might not stand up in court.

The government changed the bill to exempt scientific research but otherwise remained obdurate. An example of the inevitable confusion concerns alkyl nitrites (poppers). Known since 1844 and used to treat heart problems, they have a short-acting psychoactive effect and are generally safe. However, the government referred to several non-specific risks and claimed that poppers had been “mentioned” in 20 death certificates since 1993 (far fewer than for lightning). After a Conservative MP appealed for poppers, which he used, not to be included, the government said they would consider the arguments later.

Another example concerns nitrous oxide (laughing gas), included in the ban despite its long history of use in medicine and recreationally. Discovered in 1772, laughing gas was greatly enjoyed by Sir Humphry Davy and friends, including the poet Shelley. It has an impressive safety record and has been used in dental and childbirth anaesthesia and sedation since 1844.* Nevertheless, the government referred to “the harms” of recreational laughing gas and included it in the bill. In fact, the deaths “caused” by nitrous oxide result from incorrect methods of inhalation which could be eliminated by education.

The Act was finally implemented on 26 May. Independent expert David Nutt described the government’s policy as “pathologically negative and thoughtless.” He predicts that deaths from drugs will increase as people turn to illegal drug dealers in the absence of legal “head shops.” Einstein defined insanity as “doing the same thing over and over again and expecting different results.” This just about sums up successive governments’ policies towards drugs.**


**But not all drugs. Nicotine and alcohol are legal, despite their addiction potential, toxicity, and role in causing accidents. See, for example, …………………………………………………………………………………………………………………..Labour’s problems with scientific evidence

Tories don’t have a monopoly on cluelessness. Expert neuroscientist Professor David Nutt was “sacked” from his position as chair of the Advisory Council on the Misuse of Drugs by the right-wing press’s favourite Labour politician, former Home Secretary Alan Johnson. This was after Nutt showed that cannabis, then being upgraded to Category B (the same as codeine, ketamine, mephedrone or speed) was less harmful than alcohol or tobacco. This wasn’t an ordinary sacking since Prof Nutt gave his time and expertise freely, believing that it was important to present the evidence to improve the quality of the debate. Three members of the ACMD resigned in protest.

Nutt stated in a lecture to fellow academics that the evidence showed that cannabis was less harmful than alcohol and tobacco. Johnson called this “campaigning against government policy” and “starting a debate in the national media without prior notification to my department.” Johnson was then accused of misleading MPs since Prof Nutt had given prior notice of the content of his lecture and no journalists were invited. Further, as an unpaid advisor, Nutt was not subject to the same rules as civil servants. Other ACMD members who resigned said that they “did not have trust” in the way the government would use the ACMD’s advice and that Johnson’s decision was “unduly based on media and political pressure.”

Shamefully, PM Gordon Brown backed Nutt’s removal, saying that the government could not afford to send “mixed messages” on drugs. Both Brown and Johnson (some people’s favourite to replace Jeremy Corbyn) were quite happy to send the wrong message.

Supported by other scientists, Nutt was awarded the John Maddox Prize for standing up for science by the pro-evidence charity Sense About Science. The government subsequently accepted a new ministerial code allowing for academic freedom and independence for advisers, with proper consideration of their advice. Under this, Nutt would not have been dismissed.

Nutt now works with DrugScience.

Body by Darwin

How evolution shapes our health and transforms medicine*

Book review

What has the theory of evolution to offer to modern medicine? Evolutionary insights are rarely used by medical practitioners when treating our cancers, fertility problems, allergies, dementias and so on. Jeremy Taylor’s book gives many examples of where evolution helps explain our modern patterns of disease and suggests new strategies for treatment.

Taylor starts with some encouraging facts. Since our gatherer-hunter past, mortality has decreased enormously so that life expectancy in several countries exceeds 80 years. Painless and sterile surgery, effective drugs, public health measures, vaccines, and organ transplants, among others, have transformed medicine from a fairly futile and even harmful practice into something approaching a science. So why, asks Taylor, do so many people suffer from autoimmune diseases (rheumatoid arthritis, multiple sclerosis, Type 1 diabetes, inflammatory bowel disease etc.), allergies (like eczema and asthma), heart disease, eye problems, bad backs, appendicitis, reproductive problems, cancers, mental illness, and dementia?

How can evolution have allowed this to happen? The problems are obvious to us but evolution is “blind and witless.” Like a politician, it focuses on the immediate problem – how are genes to be passed on. The problem for evolution to solve is not health but reproduction. Evolution selects for traits that in principle can lead to immortality – for genes! To genes, bodies are vehicles to get them safely into the next generation. It’s no surprise then that evolution has not eradicated disease from our bodies, particularly after reproductive age, but evolution also has something to do with the types of disease we get.

Taylor looks first, in “Absent friends”, at allergies and autoimmune diseases, becoming more common in richer countries. For instance, childhood diabetes is 200 times more common in the UK than in China. For most of our evolutionary history, humans have lived with parasites and micro-organisms (ticks, worms, protozoa, bacteria and viruses), in close proximity to domestic animals, with polluted water supplies, and in dirty dusty dwellings. This caused much poor health but our immune systems evolved with this background. In advanced societies, these parasites are no longer present and our immune systems are not challenged at an early age. According to this hygiene (or “old friends”) hypothesis , the immune system is “damped down” by early and frequent exposure to antigens: in these more hygienic times, it responds with inappropriate strength to harmless stimuli such as peanut proteins, grass pollen, or gluten. Autoimmune diseases, like Type 1 diabetes, coeliac disease and multiple sclerosis, seem linked to reduced exposure to bacteria in childhood.

There is evidence that deliberately infecting MS sufferers with parasitic worms alleviates their symptoms. Intriguingly, a case of severe autism seems to have been ameliorated by infection with parasitic worms or attacks by biting mites. Taylor quotes the example of an American boy, Lawrence, with a severe form of autism which led him to become very agitated and violently harm himself. His parents noticed that his symptoms seemed to go away when he had a fever. When Lawrence was older, his parents reluctantly agreed to put him into permanent care but, when he was attending a specialised summer camp, they were called by the staff to say that he was behaving … normally! It seemed that he had been severely bitten by chiggers, a type of mite found in grasslands and forests, and the powerful immune response this provoked had led to a total remission of his symptoms, returning when the reaction had subsided. To cut a long story short, Lawrence was eventually deliberately infected with an intestinal parasite, the pig whipworm and his symptoms completely vanished. This type of treatment has also been used on some sufferers from Crohn’s disease, an autoimmune disease of the bowel.

The make-up of one’s gut bacteria (microbiota) seems to be an important factor in some autoimmune conditions. Babies delivered by Caesarean section or not breast-fed do not acquire normal gut microbiota, while treatment with antibiotics can upset this. One answer lies in administering the correct bacteria after birth or via a “faecal transplant” later in life. Infection with parasites seems to work for several conditions but doesn’t seem a very nice idea so perhaps people could be treated with a extract of parasite antigens. It has also been found that early exposure to peanut proteins drastically cuts the chance of peanut allergy in children.

In “A fine romance,” Taylor attacks infertility and diseases of pregnancy from the standpoint of evolution. Why do some women have many miscarriages and some pregnant women get life-threatening pre-eclampsia, often leading to premature birth. Reproduction is rather inefficient in humans, with only about a fifth of ovulations with unprotected intercourse resulting in successful pregnancy. Some 30% of fertilised eggs fail to implant and another 30% are lost during the first six weeks. About 10% miscarry before 12 weeks. Of pregnant women, some 10% develop diabetes and another 10% very high blood pressure. This can lead to kidney and liver damage (pre-eclampsia), leading to seizures and convulsions (eclampsia). In 2013, 29,000 women died worldwide from pre-eclampsia. The treatment is induction of birth or Caesarean section.

The evolutionary setting for all this is that the foetus carries not only the mother’s genes but those of the father. The investment of the mother’s resources in one baby is set off against the investment necessary in all the future babies she can have during her reproductive life. On the other hand, the foetus, carrying the genes of the father as well, is vitally interested in getting the maximum investment of resources from the mother, even if that detracts from the interests of the mother’s future offspring. The mother’s body will tend to weed out any but the most viable embryos (hence the massive loss of embryos in the first twelve weeks).

The occurrence of pre-eclampsia is increased when pregnancy occurs quickly in a new relationship and this relates to another puzzle, that of how and why the mother’s body tolerates the presence of a foetus with a substantial proportion of “foreign” antigens that would normally lead to rejection. It seems that, in the course of a longer relationship, the mother’s immune system becomes habituated to and tolerant of the father’s antigens. This points towards a version of the “old friends” hypothesis in which pre-eclampsia is a sort of inappropriately strong immune response to the father’s antigens.

It is a commonplace that our upright bipedal stance, while freeing our hands for a variety of tasks, puts strain on our backs resulting in an increasing prevalence of back pain as we age. In fact, the Global Burden of Disease 2010, looking at 291 conditions, ranked low back pain worst for years lived with disability (approaching 10% of the world’s population). We also suffer from bunions, varicose veins, haemorrhoids, hernias, hip and knee problems.

Our bipedality, unique among mammals (including our closest relatives), has allowed our brains to expand but, since evolution doesn’t have a plan, this could not have been the reason for its evolution. Taylor points out, in “The downside of upright,” that there must have been an overriding reason for bipedality which outweighs the down side. Early fossils of hominids close to the split with chimpanzees’ ancestors are adapted for bipedalism and climbing trees, with opposable big toes. True bipedalism allows for a more energy-efficient two-legged gait and would have enabled our ancestors to expand their foraging territory from forests to savanna. Their hands would have been free to make and use tools and carry food. We are also adapted for running long distances, unlike our closest relatives, allowing our ancestors to run down prey by simply exhausting it. Taylor’s explanation for the biped’s health involves our different lifestyles – standing for long periods, sitting on chairs (rather than squatting or sitting on the ground), less physical activity, even our use of footwear when we do run, protecting our feet but jarring our joints.

The eye is often cited by creationists as so complex that it could only have been created by a supernatural being. In fact, all variations between light-sensitive patches and the primate eye with colour vision are found in nature, Taylor shows in “DIY eye.” Even some bacteria can focus light and use this to direct their movements. Calculations show that eyes can evolve in a virtual “blink of the eye” in the time since life evolved. Genetics shows that the eye only evolved once and that all subsequent eyes are modifications of this. It has been claimed that its layout, with the nerve cells in front of the retina, is a fault that evolution was unable to avoid, given the way the eye evolved. Taylor cites evidence that this layout is actually more advantageous to smaller animals since it maximises the distance from the lens to the retina, allowing more precise vision.

Our acute eyesight requires a high concentration of photoreceptor cells in the fovea, the centre of the retina where light is focused. Taylor thinks that this puts a lot of pressure on the blood supply and that this results in some people losing vision through macular degeneration in later life. This is an evolutionary trade-off for the benefit of having acute eyesight when young.

Next, in “Hopeful monsters,” Taylor explains to us “why cancer is almost impossible to cure.” Part of the problem is that, having mutated to become cancerous, the cells keep mutating. They form clones that compete with each other (and with normal cells) for food and oxygen. Unlike normal cells, cancer cells are “immortal,” achieving this through six steps, ending up as spreading or metastasising cancers. This is evolution in miniature, the first mutating to produce their own growth signals and last developing the ability to break away from a tumour and travel around the body. The other aspect of evolution and cancer cells is the development of drug-resistant cancer cells (as with antibiotic-resistant bacteria).

Heart disease is the major killer in the West: in “A problem with the plumbing,” Taylor explains how the evolution of the coronary arteries makes heart attacks more likely. Heart muscle needs oxygen but how is it to be supplied? Paradoxically, the oxygen-rich blood pumped by the heart passes through too quickly. Most vertebrates have coronary arteries to supply the heart with oxygen. These are very narrow and are prone to become narrowed even further by atherosclerosis, the formation of layers of plaque. When the muscle contracts, the branches of the coronary arteries are squeezed shut: they can only fill during relaxation. With increased exercise, the more rapid contractions reduce the time for the arteries to refill. If these are obstructed by plaque, the muscle is starved of oxygen causing pain (angina) and long-term damage. Pieces of plaque can break off, causing a blockage: the muscle supplied by that branch dies – a heart attack. Heart disease is usually attributed to lifestyle and diet but Taylor draws attention to another factor, the immune system. People who have had tonsils or appendixes removed in childhood are much more prone to heart attacks. This is due to disrupted development of the immune system (and shows that the appendix has some purpose). Also, people with autoimmune diseases are more prone to atherosclerosis (the “old friends” hypothesis).

Finally, in “Three score years – and then?” Taylor tackles Alzheimer’s disease. He convincingly argues that the focus on amyloid protein tangles in the brain cells of sufferers is misplaced. These are actually a symptom, rather than the cause, the underlying problem being inflammation. The genetic component of Alzheimer’s involves genes connected with the immune system. It seems that regularly taking anti-inflammatory drugs like aspirin or ibuprofen can delay onset. It may also be that a viral brain infection can cause the problematic inflammation. One candidate is Herpes simplex (cold sore) virus (HSV), found in 90% of people. Infecting the lips, it enters the trigeminal nerve and shelters from the immune system in the nerve ganglion, inside the skull next to the brain. Triggered by immune decline or by another infection, reactivated HSV can migrate back to the lips to cause more cold sores…or perhaps into the brain to start causing the changes in Alzheimer’s disease. Though not proven, this may indicate that Alzheimer’s is a consequence late in life, after genes have been passed on to offspring, of the early development of the nervous system which enables our success.

Jeremy Taylor has produced a meticulously detailed account of part of the growing field of evolutionary medicine which is going to affect treatments more and more.

Note: Taylor has produced science programmes for television, including The Blind Watchmaker and Nice Guys Finish First with Richard Dawkins for the BBC. His first book was Not a Chimp: the hunt to find the genes that make us human.

*University of Chicago Press, London (2015). £21.00 Hbk. ISBN 978-0-226-05988-4 (also e-book).

Headstrong – 52 Women Who Changed Science and the World*


Women are notoriously under-represented in science but the situation seems worse because such women scientists as there are tend to be misunderstood, misinterpreted, under-rated or ignored. Out of the 52 in Rachel Swaby’s book, the general reader might only have heard of Mary Anning (fossil hunter), Rachel Carson (author of Silent Spring), Rosalind Franklin (the “dark lady of DNA,” played by Nicole Kidman in the West End play, Photograph 51), Ada Lovelace (Byron’s daughter and pioneer of computing), Florence Nightingale (famed for nursing in the Crimean war), and Hedy Lamarr (celebrated actress, less known as an inventor). Swaby deliberately omits Marie Curie who has received substantial coverage (though there can never be enough about this double Nobel prizewinner, in my opinion).

In the past, it was difficult for women to gain an education or to carry on with their studies or work when they married. I will just mention a few of the 52, choosing those of earlier times or who are known for other activities.

Maria Sibylla Merian (1647-1717) became interested in insects as a child in Frankfurt. At thirteen, she was bringing up a colony of silkworms, taking notes and painting the stages in their life cycle. At a time when the metamorphosis from caterpillar to moth was not understood, Merian observed and painted insects throughout their lives, showing them in their habitats. These illustrations were published in her groundbreaking book Der Raupen wunderbarer Verwandlung (The Wondrous Transformation of Caterpillars) in 1679.

At 52, she set off for Surinam with her children on a very early example of a purely scientific expedition to collect and study the insects of plantations and jungle alike. The result was Metamorphosis insectorum Surinamensium, with 60 exquisite copperplate engravings of insects and other animals on leaves and branches, crawling, flying, eating, unfurling proboscises, attacking each other…

Her work was admired by Goethe and used by Linnaeus in developing his classification of living things.

Mary Anning (1799-1847) was a child of a poor family which gained extra income by selling fossils from the cliffs of Lyme Regis to tourists. Mary learnt her father’s fossil-hunting trade at ten and, after his death, carried on with her brother Joseph. Usually finding fossil shellfish, her brother noticed part of a skull protruding from the rock. This was the head of an ichthyosaur and Mary unearthed the rest of it. This, the first example of its kind, was sold for £23, a considerable sum. In her early 20s, Mary took over the business, going out in winter (the best time for the cliff falls that exposed new fossils) with just her dog. She discovered the first plesiosaur skeleton and the first pterosaur found in Britain.

Her discoveries were evidence for extinction of species which contradicted the notion that God’s creation was perfect. Furthermore, there seemed to have been an age when the dominant animals were reptiles. Her knowledge of fossils and geology was extensive and yet, being a working-class woman, gentleman geologists tended to gain the credit from writing about her discoveries. She began to be treated as a fellow scientist, gaining the respect of geologists William Buckland, Charles Lyell and Roderick Murchison, and of the Swiss palaeontologist Louis Agassiz.

Never well off, she was helped by her scientific colleagues selling specimens and drawings on her behalf. Eventually she was awarded a civil list pension by the government. When she became ill with breast cancer, the Geological Society (which had earlier refused her membership as a woman) raised money for her and, after her death aged 47, paid for a stained glass window in her local church. Charles Dickens wrote of her life in 1865, ending his article with “The carpenter’s daughter has won a name for herself, and has deserved to win it.” In 2010, the Royal Society included Anning in a list of the ten British woman who have most influenced the history of science.

Émilie du Châtelet (1706-49) is largely known as a lover and intellectual companion of Voltaire but she was instrumental in introducing Newton’s ideas to France. Born rich (which always helps) but mainly self-taught, she followed a conventional path for the time until, aged 27 and expecting her second child, she became interested in mathematics, studying Descartes’s geometry and engaging talented tutors who introduced her to Newton’s work. At 32, she entered the French Royal Academy of Sciences essay competition on the nature of fire (i.e., heat), in which she predicted what we now know as infra-red radiation: her entry was highly praised and published by the academy.

She then published Institutions de Physique (Foundations of Physics), a state-of-the art textbook in which she not only put forward Newton’s theories but improved on them. When this was attacked by the secretary of the academy as being the unsound ideas of a fickle and weak-minded woman, she refuted each of his criticisms and sent her response to all members of the academy. The secretary resigned soon after.

Her experimental work confirmed that the kinetic energy of an object was proportional to its speed squared (Newton had not discussed this, focusing rather on momentum). Her greatest achievement was her translation (from Latin) of and commentary on Newton’s Principia. It remains the standard French translation. Days after completing it, she died, aged 42, after giving birth to her fourth child.

Florence Nightingale (1820-1910) is famous for her innovations in nursing but is arguably one of the founders of evidence-based medicine. Gathering data on causes of death among British soldiers in Scutari, she devised a method of displaying her statistics in a visual form, the polar-area diagram (essentially a circular bar-chart or histogram). The diagram is composed of wedges, one for each month, whose area is proportional to the total deaths. The wedges were subdivided in proportion to causes of death – wounds, infections, or other. She was able to show that death rates declined as sanitary methods improved. The government soon established a Statistical Branch of the Army Medical Department.

Later, she devised statistical forms for hospitals to gather data on their patients’ progress. She became the first woman member of the Royal Statistical Society in 1858.

Emmy Noether (1882-1935) was a mathematical genius who succeeded despite the active obstruction of the authorities, whether of universities, the Prussian state or the Nazis. For eight years, she worked at the University of Erlangen, unpaid, developing the theory of invariants, supervising PhD students, publishing several papers and lecturing on behalf of her professor father whose health was deteriorating. In 1915, she was invited by two of the world’s greatest mathematicians, David Hilbert and Felix Klein, to work on General Relativity at the University of Göttingen but she was refused employment after protests by those who thought it inappropriate to have men taught by a woman. With Hilbert’s support, she worked for several years, until 1923, unpaid. Here she proved her first theorem, Noether’s Theorem, which states that, for each law of symmetry, there is a conservation law. This solved a problem with General Relativity where it seemed to violate the Law of Conservation of Energy. It has been said that this theorem is on a par with Pythagoras’ Theorem in importance.

Despite her brilliant achievements in pure mathematics and physics, she was the first professor at Göttingen to be sacked under the Nazis’ anti-Jewish laws. She carried on tutoring illegally, even to Nazi students, but soon was found a job at Bryn Mawr College in the US. She died two years later after surgery for an ovarian cyst. Shortly before her death, Norbert Wiener described her as “the greatest woman mathematician who has ever lived; and the greatest woman scientist of any sort now living,” while Einstein said after her death “Fräulein Noether was the most significant creative mathematical genius thus far produced since the higher education of women began.”

Hedy Lamarr (1914-2000), better known as an Austrian-American film actor, was in the US when war broke out. Incensed by the torpedoing of ships carrying civilians by her erstwhile compatriots, she wanted to help the Allied effort. US torpedoes in 1942 had a 60% failure rate, largely due the inability to guide them. This could be improved by radio transmissions from ship to torpedo but these could be easily jammed by the enemy. Interested since childhood in machines and how they worked, Lamarr and a composer friend, George Antheil, worked on an idea of frequency changing programmed into the transmitter and receiver. This would be impossible to crack before the torpedo struck. They patented their idea and reported it to the US government, who immediately classified it as secret. Unfortunately, for various reasons, the idea was not used in war time. However, it had a wider applicability and is used in such areas as wireless cash registers, bar code readers, Wi-Fi, Bluetooth, and GPS. Hedy Lamarr was awarded the Electronic Frontier Foundation’s Pioneer Award in 1997.

This is a very readable book and all the women chosen are fascinating characters. Each is worthy of following. I include a few illustrations of the work of the women mentioned in this review. They are:

1 From Merian’s Metamorphosis insectorum Surinamensium (1705)

2 Drawing of plesiosaur found by Anning (from Transactions of the Geological Society of London).

3 A version of one of Nightingale’s polar-area diagrams.

4 Du Châtelet’s essay on the nature of fire.

5 Emmy Noether sometimes discussed abstract algebra by postcard. This is addressed to Ernst Fischer at her former university of Erlangen.

6 Hedy Lamarr’s secret communication system patent.

*By Rachel Swaby. Broadway Books, 2015: ISBN 9780553446791

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Where were you when gravitational waves were detected?

About a billion years ago, a billion light-years away, two black holes collided. Out of their total mass of some 60 times that of our Sun, about three solar masses were converted into energy. The amount of energy thus released can be calculated with Albert Einstein’s famous 1905 equation, E = mc*2 {energy = mass x (speed of light squared)}.1

The resulting disturbance in space-time was detected as gravitational waves on 14 September 2015, whose existence was predicted by Einstein 100 years previously, and announced (after rigorous checking) on 11 February 2016. This is yet another confirmation of Einstein’s General Theory of Relativity.

Following on from his 1905 Special Theory of Relativity, Einstein extended his theory to include gravity, publishing his findings in his General Theory in 1915. The Special Theory stated that: the speed of light in vacuum was a constant and could not be exceeded; space and time were aspects of each other and should be called space-time; for fast-moving objects, time passes more slowly, lengths are decreased, and mass is increased; and light from approaching or receding objects is blue-shifted or red-shifted respectively. All of these are contrary to “commonsense” and yet have all been verified.

In his General Theory, Einstein says that: mass distorts (curves) space-time; light heading towards or away from massive objects is blue-shifted or red-shifted respectively; time passes more slowly close to massive bodies; and moving masses produce ripples or waves in space-time. It also led to the prediction of black holes.

The first success of the theory was that it explained the anomalous orbit of Mercury, an ellipse whose major axis moves round gradually by a greater amount than predicted by Newton’s theory. This results from the curvature of space-time by the mass of the Sun, altering the geometry of the orbit from that in a perfectly flat space-time. This ‘precession’ of Mercury’s orbit had been a major defect in Newtonian physics. The theory also predicted the bending of light from distant stars passing close by the Sun: it was a major triumph for the theory and made Einstein famous when this was observed during the total solar eclipse in 1919.

The gravitational red- or blue-shift was demonstrated about 50 years ago; gravitational time dilation was shown over 40 years ago and is corrected for continually in GPS systems and other orbiting satellites to keep them synchronised with Earth-based clocks. Black holes have been adequately demonstrated more than once.

In 1916, Einstein realised that if a mass moves, the distortion in space-time should also move, spreading out like ripples on a pond: these ripples in space-time are gravitational waves. These should also be detectable because they would cause changes in length of objects in their path, a rhythmic squashing and stretching at right angles to the direction of the waves. The first gravitational wave detecting system was built nearly 50 years ago but was unsuccessful. This is because the effect of the waves is so small that the apparatus was nowhere near sensitive enough. Indirect evidence of gravitational waves was obtained some 40 years ago by observing binary pulsars. These were found to be spiralling in towards each other as predicted if they were radiating away energy in the form of gravitational waves.2

The recent detection of gravitational waves was by LIGO (Laser Interferometry Gravitational-wave Observatory) detectors in Hanford and Livingston, US. These consist of two 4-km-long vacuum tubes at right angles. Laser beams are split, sent down each branch, reflected back and forth 400 times, recombined, and detected. The beams interfere3 with each other and, if gravitational waves arrive and change the length of one arm more than the other, the interference pattern will change.

Unfortunately, the change in length is predicted to be less than a millionth of the width of an atom, even if the mass involved is large. The waves detected came from the movement of a very large amount of mass, the collision of two black holes of total mass about 60 times that of our Sun. In this, about three solar masses were converted to gravitational wave energy in about a fifth of a second.1 In the signals detected, this is seen as rapidly increasing oscillations which then cease as the black holes form one large one. This is the same “shape” as the waves of a ‘chirp’ sound.4 It was also proved that gravitational waves travel at the speed of light and that the graviton (the particle associated with gravitational waves) must be massless, like photons of light.

Now this has been achieved, more and better gravitational wave detectors will be designed. Some will be space-based, with much longer distances so that they will be more sensitive. Other LIGO detectors in different countries will enable us to pinpoint more accurately where the waves are coming from. It may be possible to use pulsars (very regularly pulsing stars) as gravitational wave detectors by observing slight delays in their signals caused by the passage of waves. Since gravitational waves can pass through everything, while light can’t, we will be able to “see” hitherto invisible regions of the universe (like the centre of our galaxy). Different types of gravitational waves are produced by different events, such as stars being swallowed by black holes, neutron stars spiralling into each other, or even relic waves from the ‘big bang,’ giving us a source of information about that in addition to the cosmic microwave background.

Government bean-counters (and not just them) constantly question the value of basic, curiosity-driven, ‘blue skies’ research. Why can’t the money be spent on more practical things or given back to taxpayers? This ignores the importance and interest of knowledge about us and our universe. Why should we only know what is of value to our employers? It also ignores the spin-offs of basic research, some of which have transformed our lives. These include transistors, lasers, LEDs, nuclear power, computers, microwave ovens, accurate GPS, X-ray machines, the structure of DNA, MRI scanners, proton beam cancer therapy, genetic engineering, DNA fingerprinting…and the internet! ………………………………………………………………………………………………………………….. 1 This sounds like a lot and it is (6 x 10*30 kg x (3 x 10*8)*2). But remember The Hitch-hiker’s Guide to the Galaxy: “Space is big. Really big. You just won’t believe how vastly, hugely, mindbogglingly big it is.” My back-of-an-envelope calculations show that, if this energy is spread out across a sphere of radius 1.3 billion light-years, the energy reaching us is about 1 milliwatt per metre squared. I don’t know how reliable this calculation is as the first time I did it I got a number 10 billion times smaller!

2 The Earth is spiralling in towards the Sun through gravitational wave radiation but will take 10 trillion times the current age of the universe to hit the Sun. Don’t panic!

3 The light waves meet and recombine. The apparatus is designed so that they arrive out of step and destructively interfere, leaving darkness! If a gravitational wave arrives, altering the length of the arms differently, the light beams will start to interfere constructively and some light will appear.


Excellent explanations of gravitational waves and their discovery:

Lies, Damned Lies, and Jeremy Hunt’s Statistics

The government’s argument in their attack on junior doctors’ pay and conditions has been that they had a manifesto commitment to introduce 7-day access to all aspects of health care and that this was necessary to reduce excess deaths among weekend hospital admissions. The government’s approach seems to amount to forcing junior doctors to work more at weekends for less pay. But, unless they also force them to work longer hours, this must reduce the number of doctors on weekdays. If the original problem of excess deaths was due to a lack of junior doctors at weekends, the result would be to equalise death rates by lowering death rates following weekend admissions and raising those following weekday admissions.

Health Secretary Jeremy Hunt was very keen to talk about the evidence of excess deaths to justify his actions and, of course, evidence is very important. He claimed “We now have seven independent studies showing mortality is higher for patients admitted at weekends.” Therefore, we will look at this evidence.

The Department of Health’s “evidence”

The DH says there is significant evidence of a “weekend effect” where patients admitted over the weekend have higher rates of mortality (or “morality,” in one amusing typo).1 The DH lists eight pieces of what they call research in support.

1 The major study cited by DH is from the British Medical Journal (Freemantle et al., 2015):2 one of its co-authors is Bruce Keogh, National Medical Director of NHS England. It found that death rates were higher for patients admitted on Fridays (2%), Saturdays (10%), Sundays (15%) and Mondays (5%) than on other days. Since the overall death rate within 30 days for all admissions is 1.8%, this means that the Sunday rate is 2.1% or 3 in 1000 “extra” deaths.

Of course, we need to understand why, and this is where it is important to look at how ill patients are on the day of admission. The study informs us that, while 29% of weekday admissions are emergencies, on Saturdays the figure is 50% and on Sunday 65%. Using another criterion, mortality risk from all factors except day of admission, while 20% of weekday admissions were in the highest category, 25% on Saturdays and 29% on Sundays were in this highest risk of dying group. On these bases, we would expect an increased death rate for weekend admissions of anywhere between 25% and 125%. The observed ‘excess’ of 15% on Sundays should be a cause for congratulation.

This paper is an update of the previous study by Freemantle et al. (2012)3 (see 5 below), also including Keogh. The findings were broadly similar except that the death rate on Saturdays and Sundays were very significantly lower than the average for weekdays. In the update this curious fact, which certainly needs discussion and explanation, is barely mentioned.

To summarise, death rates for admissions on Saturdays and Sundays are increased by 10 to 15% but death rates for those already in hospital are reduced by 5 to 8%. Thus, the main source of support for the government’s Seven Day NHS plans does not provide any evidence for it. The weekend death rates for all patients are in fact far lower than one would predict from the seriousness of their illness. Nevertheless, the authors try to explain what they persist in describing as an overly increased rate.

They cite: reduced or altered staffing and mix of skills at weekends; impact of shift system; fewer senior staff available; more staff who are unfamiliar with policies; and need for more prompt treatment than available. They give the example of treatment for hip fractures which should be very prompt but they admit that their figures showed no significant difference for this condition. Nothing about the need for more junior doctors at weekends, still less that Saturdays should be counted as part of the normal week and that junior doctors should have this part of their pay cut.

Freemantle et al. (2012)3 tentatively say that “It may be that…7-day access to all aspects of care could improve outcomes for higher risk patients…admitted at the weekend.” They then say that the economics need looking at to see if this is “an efficient use of scarce resources.” The update, Freemantle et al. (2015),2 states that “It is not possible to ascertain the extent to which these excess deaths may be preventable; to assume that they are avoidable would be rash and misleading.” They draw attention to the reduced level of support services at weekends and state that “There is evidence that junior hospital doctors feel clinically exposed during the weekend.” This does not mean there are too few junior doctors on duty but that the support services and senior staff are not sufficient. Nothing about cutting juniors’ pay and forcing them to do more weekend shifts! They signally fail, in fact, to address the question in their paper’s title: “a case for expanded seven day services?

2 Ruiz et al.4 shows that there is a “weekend effect” in other countries where “The participating hospitals represent varied models of service delivery.” Nothing special about the NHS, then!

3 The East Midlands 7 Day Services Project merely quotes the results of Freemantle et al. (2012).3 It provides no further evidence but discusses how services might be expanded. It talks of increasing access to diagnostic services but, apart from calling for a more speedy examination by consultants, makes no specific mention of doctors. It does identify a substantial need for more funding, not so far addressed by DH.

4 NHS Services, Seven Days a Week Forum also quotes Freemantle et al. (2012).3 It then discusses 7-day services wholly in terms of increases in the availability of consultants. Juniors are mentioned in the context of benefiting from the advice and supervision of more consultants, which would reduce the need for such a large number at weekends, while improving their medical education and training.

5 This is Freemantle et al. (2012)3 and is essentially the same as the first paper (above).

6 Seven Day Consultant Present Care5 calls for daily reviews of patients by consultants and consultant-recommended treatments to be available seven days a week. Support services should also be available seven days a week both in hospitals and in primary care (general practice etc.). No mention of juniors except that their training would benefit from the wider availability of consultants. No support for Hunt’s attack on junior doctors.

7 This (Aylin et al.)6 is research on death rates among emergency admissions. It predates the Freemantle papers and the latter incorporate its findings. It found a 10% higher death rate at weekends. It wasn’t able to rule out that emergency admissions at weekends (of which there were fewer than during the week) were different in some way. Freemantle et al. (2012; 2015)3,2 showed that they were different, with more in the highest risk category. In particular, they suggest that cancer patients in a terminal condition were more likely to be admitted to hospital at weekends because of a lack of community and primary care options then. This would skew the death rates of cancer patients in hospitals. Aylin et al. say that this “may be a whole health system problem.” Interestingly, they quote studies showing that there is no “weekend effect” in intensive care units, attributing this to the high level of consultant input. Nothing about junior doctors but more about lack of senior staff and services.

8 The final paper (Temple, 2010) refers to trainees (i.e., junior doctors) being unsupported and unsupervised (according to DH website – the paper itself seems no longer available – “404 page not found”). Nothing justifying pay cuts and increased weekend working for juniors.

Jeremy Hunt’s new clothes

The DH’s evidence is aimed at supporting the idea of a 7-day NHS but they themselves, in their introduction, only mention urgent and emergency care and consultant cover. There is nothing about junior doctors. Of the eight papers, only three provided data and these were updated samples of the same type of data; one showed that the NHS “weekend effect” was international; the other four called for more consultant support and hospital services at weekends and increased funding; none mentioned junior doctors apart from their need for more senior support. There is one very simple possible explanation for this – people are admitted at weekends because they have to be – they are much more ill. A recently-leaked DH report7 admits that changing to a 7-day NHS may have no effect on the supposed excess deaths; it “cannot evidence the mechanism by which increased consultant presence and diagnostic tests at weekends will translate into lower mortality and reduced length of stay.” Jeremy Hunt’s attack on junior doctors’ pay and conditions (like his support for homoeopathy) completely lacks evidence.


2 Increased mortality associated with weekend hospital admission: a case for expanded seven day services? Freemantle et al. 2015

3 Weekend hospitalization and additional risk of death: An analysis of inpatient data. Freemantle et al. 2012

4 The Global Comparators project: international comparison of 30-day in-hospital mortality by day of the week

5 from Academy of Medical Royal Colleges

6 Weekend mortality for emergency admissions. A large, multicentre study


Aubrey Sheiham (1936-2015)

My friend Aubrey Sheiham, emeritus professor of Dental Public Health at UCL, has died at 79 of the asbestos-related disease mesothelioma.

A dental epidemiologist, he was a pioneer of evidence-based medicine. In 1977, his research showed that six-monthly dental check-ups might do more harm than good by leading to overtreatment. This was not popular with his colleagues but was eventually accepted by NICE. Other examples of routine check-ups leading to the danger of overtreatment have emerged since.

He was also a pioneer in emphasising the importance of diet in dental health and drawing attention to how inequalities in society lead to inequalities in dental health.

He was an early collaborator with Archie Cochrane who inspired the foundation of the Cochrane Collaboration; he was dedicated to improving health in underdeveloped countries, including his native South Africa. He and his wife, Helena Cronin (philosopher and Darwinian theorist),* generously supported evidence-based medicine researchers mainly in Africa.

He was fit and healthy, maintaining his interest in his work despite being technically retired, as well as developing an interest in ceramics and sculpture. It seems that he was exposed to asbestos early in his career, probably in dental dressings containing asbestos.

I will remember him as an immensely kind person who was always interested in the well-being of others.

The following links are to an on-line obituary in The Guardian by Michael Marmot, tributes from UCL and the Cochrane Collaboration, and a description of the Aubrey Sheiham Award:

*author of The Ant and the Peacock.

The one NHS cut we should support

Homoeopathic medicines do nothing that a placebo does not do. This is because they contain no active ingredient…like a placebo. But the NHS spends our money on them.

The “rationale” behind homoeopathy is that “like cures like”. This idea had been around at least since the time of Hippocrates (about 400 BC) but was formulated as the basis of a “natural” system of medicine by Samuel Hahnemann, a doctor in Germany in the 1780s. He rightly objected to medical practices of the time, such as bloodletting, which did more harm than good, and soon gave up his practice, fearing being “a murderer or malefactor towards…[his] fellow human beings.”

Hahnemann continued to ponder medicine’s mistakes. He observed the actions of several drugs, such as quinine, on himself and got the impression that they caused symptoms similar to those of the diseases they cured. He developed the notion, to him a law, that whatever causes symptoms of a disease in a healthy person can cure that disease in a sick one.

This is a type of magical thinking (“sympathetic magic”) with not a shred of evidence to support it and would have actually been quite dangerous if applied without modification. Sensibly, he decided to dilute these harmful drugs but developed the even more magical notion that the drugs would be more effective if diluted in a special way. This “potentisation” involved dilution and succussion (vigorous shaking to you and me) by which, somehow, the water maintained a “memory” of the active ingredient. There was unlikely to be any molecule of the drug present: the commonly-used dilution of 30C (30 times a 1 in 100 dilution) contains 1 part in 10*60 of the original drug. This is equivalent to one molecule in a volume of water 20 times the size of the Sun!

But perhaps homoeopathy does work, despite its apparent implausibility. What’s the evidence? This is a job for systematic reviewers of randomised controlled trials (RCTs). An RCT matches a treatment against a placebo (that is, nothing, but supplied in an identical form) in such a way that participants do not know which they are getting and, crucially, neither do the health care staff. Other people analyse the results and use statistics to see whether the treatment is better than nothing to a high degree of certainty, meaning that the result is very unlikely to have been caused by chance. A systematic review1 is an unbiased synthesis of all RCTs of a particular treatment. Such reviews are fundamental to evidence-based medicine. What do such reviews tell us about homoeopathy?

The Cochrane Collaboration2 lists nine systematic reviews of homoeopathic treatments for various conditions, all but two of which showed no evidence of a positive effect. One review showed evidence of benefit in irritable bowel syndrome from just two rather inadequate trials. Another showed benefit in treating adverse effects of cancer therapy: it examined eight trials of which four showed no benefit and four showed benefit (only two of these were good quality, with little risk of bias). This was out of a total of 33 RCTs analysed in the nine reviews – rather underwhelming!

You get a different picture from the website of the Faculty of Homeopathy (FoH).3 It refers to 42 systematic reviews of RCTs, of which only 15 (36%) are said to indicate benefits. Six of these reviews are of homeopathic treatments in general. Since two of these analyse the same data, there are really only five reviews of this kind. A closer look at one of these five (Cucherat et al., 2000)4 gives a more nuanced picture: the authors say that the 16 RCTs analysed indicated a highly significant benefit of homoeopathy but, excluding RCTs of poor quality, the benefit disappeared. They conclude that there is weak evidence of benefit, with better designed RCTs more likely to be negative. The other five systematic reviews of this type5 listed on the FoH website give similarly lukewarm conclusions – and these are the ones they are proud of!

The nine other reviews are of homoeopathy for single conditions, some of which offer some evidence of vague positive effects (see footnote for details).5 It admits that the other 27 studies of the 42 initially referred to were inconclusive or negative.

The British Homeopathic Association proudly cites the most recent systematic review (one of the six mentioned previously),6 partly carried out by its own researchers, which shows a benefit of homoeopathic treatments. But this review includes 32 RCTs with either a high (20) or uncertain (12) risk of bias (three of these were said to have minor uncertainties and their data was classed as “reliable” by the study authors). Only 22 could be analysed, with an overall finding of a benefit from homoeopathic treatments. However, the authors warn that caution is needed in interpreting this finding because of the low or unclear quality of the evidence. This caution was wholly lacking when prominent homoeopath (and Physician to HM The Queen) Dr Peter Fisher was interviewed on BBC Radio 4’s Today Programme on 13 November. He triumphantly cited this study but failed to mention the low quality of the trials.7

So even the evidence quoted by homoeopathic organisations gives only weak support to their claims, while there is a wealth of evidence showing that homoeopathic treatments are indistinguishable from placebos. But does homoeopathy do any harm? In earlier times, bloodletting made patients weaker and can hardly have improved their chances. It is frequently quoted (by homoeopaths) that cholera patients in the Royal Homoeopathic Hospital in the 1840s survived better than those in the nearby Middlesex Hospital. This is because the latter were “treated” with bloodletting and opium, not because the former could cure cholera. When the alternative is a harmful treatment, simply looking after the patient and giving them pills or potions with no active ingredient is better. Nowadays, there are many minor illnesses which conventional medicine cannot treat, such as colds and ‘flu. Patients tend to get better without treatment so homoeopathic remedies will do no harm.

But there are serious diseases, such as malaria, yellow fever, dysentery, typhoid,8 and even cancer,9 as well as vaccinations, where some overseas homoeopaths claim efficacy for their treatments. Despite celebrity endorsements, these claims lack evidence and it would be extremely dangerous to reject conventional medicine for homoeopathy in these cases. It is reassuring to learn that the FoH “denounces the use of homeopathy as an alternative in the management of the Ebola outbreak,” though they see a place for it in conjunction with conventional medicine. However, you can buy homoeopathic medicines on the internet for such conditions as: diabetes (reduces your need for insulin); tumours (stops them returning after surgery); heart conditions (including valve disease, irregular heartbeat and heart attack); kidney disease (protein in the urine); anti-viral drops (prevents swine flu; epilepsy; brain haemorrhage; and dwarfism!10

Paradoxically, official homoeopathy in the UK (BHA, FoH, Dr Peter Fisher) advises following conventional medical advice on malaria and vaccination – there is no hint of “like cures like.” But some practitioners offer their own homoeopathic “vaccines.” You can get these for your pets in Britain. In North America, Health Canada has licensed homoeopathic “vaccines” for influenza, poliomyelitis, measles and whooping cough though it states that these are not alternatives to vaccination (one wonders what they are, then). However, the US Food and Drug Agency comes down quite hard on unfounded claims for treatments. The BHA proposes working with conventional medicine for treating prostate and breast cancers but claims that its methods can prolong life in the latter “by months or even years.”

Homoeopathy gets very positive ratings from its patients (71% reported positive health changes in a survey at the Bristol Homeopathic Hospital) and here the words of another alternative medicine practitioner are relevant: “The fact that patients swear by us does not mean we are actually helping them. Satisfaction is not the same thing as effectiveness.”11 Homoeopathy costs the NHS in Britain a bit over £5 million per year. It’s only a small proportion of the total budget but…£5 million is £5 million and it could be used for something worthwhile.

Notes and references:


2 The Cochrane Collaboration is the most respected organisation carrying out such reviews: its findings are used to inform health service policies world-wide. Here is a summary of its nine homoeopathy reviews: Asthma, Dementia, ADHD, Menopausal symptoms in breast cancer patients, Induction of labour, Molluscum infection (skin virus), Influenza prevention or treatment: little or no evidence of effectiveness; Irritable Bowel Syndrome: possible benefit shown in two small old low quality trials; Adverse effects of cancer treatments: four of eight studies showed benefit (two poor quality).


4 Cucherat et al. Evidence of clinical efficacy of homeopathy – A meta-analysis of clinical trials. Eur J Clin Pharmacol 2000; 56: 27–33.

5 All from FoH website (see reference 3).

Kleijnen (1991) 105 RCTs: “the evidence… is positive but not sufficient to draw definitive conclusions because most trials are of low methodological quality.”

Linde (1997) 89 RCTs: “clinical effects … [not] completely due to placebo. However, …insufficient evidence…that homeopathy is clearly efficacious for any single clinical condition.”

Linde (1999) Same data as 1997 but excluding low quality RCTs. “…studies with better methodological quality tended to yield less positive results.”

Linde and Melchart (1998) Individualised treatments (the “gold standard” for homoeopathy): 19 RCTs: “overall …superior to placebo” but better quality trials have less positive results. “The evidence… is, therefore, not fully convincing.” [my emphasis]

Mathie (2014) See discussion in text.

Barnes (1997) Recovery from gut surgery: “apparently positive overall result” but drawbacks in studies “preclude a firm conclusion.”

Taylor (2000) Hayfever: 4 RCTs: air flow through the nose is improved. Curiously, the participants don’t feel different from those taking placebo. Review queried since placebo response of 3% is surprisingly low.

Jacobs (2003) Childhood diarrhoea: 3 RCTs: duration reduced from 4.1 to 3.3 days. Homoeopathy recommended in addition to conventional treatment.

Linde (2003) Data from 6 RCTs already analysed in Linde (1997) for three painful conditions. Was this an example of ‘cherry-picking’? This small number of different studies gave a positive result, though two were not significant (i.e. inconclusive).

Several of the other 5 studies have been criticised for poor methods. See Bewley BMJ 2011; 343 doi: “If evidence of efficacy as poor as this was offered for registration of a new drug, it would not succeed.”

6 Mathie et al. Randomised placebo-controlled trials of individualised homeopathic treatment: systematic review and meta-analysis. Systematic Reviews 2014, 3:142.

7 To be fair, there are plenty of poor quality studies of medical drugs funded by drug companies which tend to show positive results where better designed studies don’t. (See Bad Pharma by Ben Goldacre).


9 Frenkel M et al.(2010). Cytotoxic effects of ultra-diluted remedies on breast cancer cells. Int J Oncol. 2010 Feb;36(2):395-403. This “study” took place in a dish, not in humans. It contained not one statistic on the significance of its findings so the best we can say is that we don’t know if homoeopathic treatment has any effect on cancer cells in culture, still less in actual people!


11 Chiropractor Preston Long in

You might also like: Xmas present suggestion! Trained as a homoeopathic doctor, Ernst realised that it was ineffective and has worked hard to ensure that groundless claims for complementary and alternative medicine are challenged. He was shamefully made to resign from his department at Exeter University after an unfounded accusation by the secretary of homoeopathy supporting Prince Charles. (

Homeopathic A&E (That MItchell and Webb Look):

The Health Gap

[book review]

Someone (possibly Stalin) once said “When one man dies, it’s a tragedy. When a million die, it’s a statistic.” But, to Professor Sir Michael Marmot, a million deaths is not just a statistic.

A million people have died prematurely in just the last five years in Britain, according to the renowned epidemiologist Michael Marmot, author of The Health Gap,1 who has spent a lifetime trying to counteract such cynicism. For him, the deaths of millions worldwide from the same cause, inequality, are millions of tragedies which could and should be prevented.

Marmot was a medical student in the ‘60s when he realised that illnesses were not just isolated problems for the doctor to solve but symptoms of something bigger. Sitting in with a psychiatrist in a Sydney hospital, he recounts seeing a woman enter, a “picture of misery”. She said “Oh doctor, my husband is drinking again and beating me, my son is back in prison, my teenage daughter is pregnant, and I cry most days, have no energy, difficulty sleeping. I feel life is not worth living.” It seems that she was depressed (Marmot describes his mood dipping also)! The psychiatrist told her to stop taking the blue pills and try some red ones, telling her to come back in a month’s time. Marmot felt that this seemed somewhat inadequate but the psychiatrist explained that there was very little else he could do.

But it wasn’t just mental illness that resulted from people’s living conditions: immigrant workers would come into his Sydney hospital with “a pain in the belly,” be prescribed antacids and sent home. What seemed obvious to Marmot, that conditions of life contributed to both mental and physical illness, was then not generally accepted and he lacked the evidence to prove it. He has devoted the rest of his career to gathering that evidence.

The young doctor Marmot felt that his profession were treating illnesses as fires that needed putting out, but the fires kept recurring. What about some fire prevention? The doctors didn’t seem to have the time or tools for that. When he expressed these views, his consultant suggested that Marmot go into epidemiology, the study of the connections between illness and the conditions of people’s lives.

Learning his trade as an epidemiologist in California, he looked at how the health of Japanese immigrants changed. He found that their rate of heart attacks went up but their rate of strokes went down, in both cases approaching that of the host American community. This was probably linked to their diet becoming more “American,” but they still maintained some health advantage from their previous lives in Japan, probably linked to their more supportive family and social networks.

Later, Marmot worked on two large studies of the British civil service, the Whitehall studies, following the health of some 27,000 government employees from the most senior down to unskilled manual workers. Contrary to received wisdom, it was not the top civil servants who had the highest rate of heart attacks but the lowest status ones. The lowest level workers had higher rates of nearly all diseases. In case you thought this was because they tended to drink and smoke more and have unhealthy diets, Marmot’s team corrected the data for this and found that two thirds of the health difference was due to the position or status of the workers in the hierarchy. Furthermore, the risk of ill health rose as you went down the levels – there was a social gradient to mortality for many diseases and everyone was somewhere on the gradient.

Briefly, it seemed that it was not poverty as such that disadvantaged people but low social status, and somehow this was making them ill. This brings us back to the million premature deaths every five years in Britain. The calculation comes from applying the death rate of university-educated people to the whole population. Once again, there is a gradient relating the amount of education to greater life expectancy. Marmot sees this as an aspect of the gradient of social status and refers to studies showing that stress hormones are generally higher in those with less control over their lives: “Inequalities in health arise from inequalities in society.”

These social gradients exist in all countries, superimposed on a gradient between countries. Thus, infant mortality in Mozambique is 12% compared with 0.2% in Colombia. But even in Mozambique there is a gradient, with the most educated mothers experiencing an infant mortality rate of less than half that of the least educated.

On the basis of average income (GDP per capita), Mozambique is one of the poorest countries while Colombia is in the middle. In general, average income is related to life expectancy but some countries buck the trend. The USA is the richest large country and yet average life expectancy is the same as for Cuba with about a fifth of the income. The difference is in the extent of inequality in these countries. We also find that within Europe, the Scandinavian countries have the least inequality and the greatest life expectancy.2

The gradients within countries can be staggering. In the UK, life expectancies can vary by nearly thirty years between neighbourhoods in the same city. In run-down Calton, Glasgow, male life expectancy, at 54, is less than the average for India (62) while in more affluent, higher status Lenzie, it is 82. It seems paradoxical that the income of a low status Glaswegian is much higher than that of the average Indian but Marmot quotes economist Amartya Sen saying it’s “not only how much money you have that matters for your health, but what you can do with what you have.”

Of course, you can find causes for ill health among the poor, smoking, poor nutrition, alcohol and drug abuse, respiratory disease from air pollution and so on but Marmot is more interested in the “causes of the causes.” These lie in lack of control over one’s life, high demand, isolated, low status work, lack of correspondence between effort and reward, as Marmot exemplifies with the case of a warehouse “picker” who works long shifts fulfilling orders for online shopping. The picker walks over 10 km per shift, lifting hundreds of heavy objects, not seeing a fellow worker, subject to discipline for trivial faults, and paid a pittance.

Communities, in Glasgow, Cuba, USA, are an important part of inequality – or equality. Marmot gives the example of Mary, a First Nations (native American) Canadian teenager, who killed herself. This individual tragedy had several contributory factors, home circumstances, community, welfare services, but it was not isolated. Many young First Nations Canadians also commit suicide, the rate being five times that for all young Canadians. But this is not just a sad statistic. First Nations people are organised into about 200 ‘bands’ of which half had hardly ever had a suicide while 90% of the suicides occurred in 12% of the bands. Poverty, low education, unemployment, poor health and low life expectancy are common in all bands – the difference was in the degree that bands were able to hold on to their cultural history and promote their collective future. Officials blamed the child welfare services but Marmot quotes a Canadian psychologist saying that, rather than target suicide, the aim should be to make communities healthier places for youth to live.

Marmot’s message is that to reduce health inequity we need fairer societies. This message comes from WHO’s Commission on Social Determinants of Health,3 chaired by Marmot, and from his review in England, Fair Society, Healthy Lives.4 The determinants of health are not so much the medical treatments people receive as they are the characteristics of their societies. Improving living conditions and working conditions, building supportive communities, reducing income inequality, reducing air pollution…are some of the factors that will help. This sounds like it would require a socialist society but a lot can be done right now. Many councils in Britain are trying to implement Marmot’s proposals (Coventry calls itself a “Marmot city,”5 while Lancashire, Chichester, Durham, Worcestershire, Barnsley and Walsall are introducing aspects of Marmot).

Crucially, working conditions, as well as wages, are better where trades unions are active. Not only that but workers themselves can have creative ideas to make their work more effective and fulfilling. Marmot gives the example of the Merseyside fire-fighters who started visiting people’s homes to encourage use of smoke detectors and found themselves sorting out housing problems, counselling people on how to give up smoking, inviting pensioners to use their gym and helping children take part in sport. There is also the West Midlands fire service who have explicitly responded to the Marmot review by trying to help the poor and needy in their community. One example was an octogenarian contacted about fire safety when he was found to be burning rubbish in his living room for warmth as his gas had been cut off. It took the fire officer three weeks to be allowed in: she asked the man what he did all day – nothing, apart from trips to local shops for food, since his electricity had been cut off 26 years earlier. He saw no one. “The fire officer brought him clothes, Christmas dinner, located his sister, and finally got him on needed medication and into sheltered accommodation.”

Marmot’s lesson is that the health of all of us is affected by inequality and we need to work together to reduce inequality and improve our health. Marmot doesn’t say it but this is best done through collective action of the sort discouraged by our present capitalist system.


1 The Health Gap: The Challenge of an Unequal World. Bloomsbury 2015. ISBN: 978-1-4088-5799-1

2 A wealth of animated graphs and other information about health, life expectancy, income etc. is available on this website:

3 WHO Commission on Social Determinants of Health report (2008):

4 Fair Society, Healthy Lives (UCL Institute of Health Equity, 2010):

5 Coventry: a Marmot City