Friday, 11 June 2010

Traditional Chinese Arsenic for Cancer

Arsenic is another favourite poison of crime writers and has a long history of medical use. As usual, it’s a bit difficult to imagine how it could ever have been considered a medicine, considering the effects of a toxic dose:

“Soon after taking it the suffer experiences faintness, nausea, sickness, epigastric pain and tenderness. The symptoms quickly increase. The vomit is brown, and often streaked with blood; the pain is very severe; there is profuse diarrhoea, with much tenesemus [painful straining]; and there are cramps in the calves and legs. The vomiting becomes violent and incessant; there is a burning sensation in the throat, with intense thirst. Soon collapse sets in; the skin is cold, the pulse small and feeble, and the patient dies collapsed.”

- W. Hale White, Material Medica (1892).

Understandably, Agatha Christie and her ilk tended to omit the more propulsive effects of arsenic on the upper and lower gastrointestinal tract, but they otherwise describe fatal arsenic poisoning pretty well. It’s violent, nasty and painful.

It’s difficult to keep an account of the use of arsenic in medicine short, but thought-provoking (generally the aim), so interesting is the long history of the use of this poison. Where ever you turn, another fascinating connection pops up. Composing a pithy post is further complicated by the number of arsenic-containing compounds (“arsenicals” rather than simple arsenic oxides and sulfides) which have also been used as therapeutics, and provide a springboard for an adventurous dive in a completely different direction.

Arsenic is a metal (technically, a metalloid) that occurs in nature, mainly in two sulphur-containing forms, red arsenic (realgar) and yellow arsenic (orpiment); if either is burned in air the trioxide form, white arsenic, is the result. It’s not hard to imagine that when the ancients found such a rare, colourful and mysterious material that they would have thought it was a gift from the gods. Hippocrates described how to find arsenic, and how it could be used as a medicine in his view (earlier uses are entirely feasible though). Various later Greek physicians that found it killed lice and caused skin growths to slough off. Around the same time arsenic entered recorded use in far eastern Asian folk remedies, usually in mixtures with other herbal or animal components. TCM remedies are rightly treated with caution by “western” clinicians, since they frequently contain arsenic and long term exposure to low doses of arsenic is known to lead to a variety of tumours. In contrast to the arsenic that may naturally occur in soil and our water supplies, arsenic in TCM isn't a contaminant but rather purposeful ingredients, and has been for hundreds of years.

Although the use of arsenic in medicine has a long history in Europe, it was during the 18th century that the use of arsenic flourished, as the self-administration of poisons as therapeutics became fashionable. Most famously, physician Thomas Fowler produced a solution of arsenic (in conjunction with Withering of digitalis fame) which although initially indicated for "periodic fevers" and "agues" (malaria) inevitably became a popular panacea. As with so many poisonous preparations of the age, Fowler's Solution soon became a popular nerve and stomach tonic, a treatment for hysteria, dropsy, ulcers, and cancer. It was used externally to kill parasites, to treat skin conditions (eg psoriasis) and as an antiseptic. Every well-to-do home would have had a bottle, and felt safer for it. Physicians' recommendations for dosage varied widely from a few drops to spoonfuls several times a day. This was the era of theatrical pharmacology: drugs that had a violent effect on the body were held to have equally potent effects on disease. Arsenic became known as "the mule", not only because it's effects on the body were unpredictable and dangerous, but also because of the perception that it could perform in all diseases, under all circumstances. Amongst its other actions on the body, arsenic produced generalised swelling of tissues, creating the illusion of weight gain and a general improvement in health; many diabetics’ lives were shortened as a result.

Towards the end of the 19th century, the use of heroic dosing in general had declined and Fowler's Solution was used more cautiously. However, it was still held to be efficacious in a variety of clinical settings. Slowly, the use of such tonics declined as more clearly efficacious drugs came into use. There was one notable exception: arsenic remained in use for the treatment of leukaemia well into the 1930s, until chemotherapeutics and radiotherapy came to the fore. The 1936 edition of W. Hale White's Materia Medica notes that arsenic had been replaced by diathermy for skin conditions, while preparations of liver had surpassed it in the treatment of anemia. In contrast to earlier editions, no other conditions rate a mention. Arsenic had finally had it's day.

Or had it?

Chinese physicians began investigating TCM preparations as cancer treatments in the 1970s and reported their results to the world. One such remedy - Ailing-1 - appeared to be beneficial in a subgroup of patients who all had acute promelocytic leukaemia (APL). Patients were followed for long periods, and survival rates were impressive. Ailing-1 is a typical TCM remedy composed of several ingredients, but the 1% arsenic stood out as a likely active ingredient (the next likely would probably be the mercury). This was indeed found to be the case, and arsenic has now been the subject of several trials worldwide for APL, the consensus being that it has efficacy in this cancer. In all cases, arsenic has been used in patients who have relapsed after successful treatment with, or have developed resistance to conventional treatments. There is now ongoing interest in using arsenic again as an adjunct to existing therapies in other malignancies.

How does it work? As with any chemotherapy, selective toxicity is probably the simplest explanation. Different cells respond to poisons at different doses; APL cells are sensitive to low doses of arsenic. The molecular jiggery-pokery is a little to complex to describe here (there’s a link at the end for those who think they can stomach it.)

While it easy to retort that TCM simply reignited interest in a known use for arsenic in this case, it’s not the first time that elements of a TCM remedy have been purified and employed by medicine. That said, there aren’t many such examples and most of TCM is probably dangerous nonsense.

More on the mechanism of action of arsenic in APL

Thursday, 3 June 2010

Chillies for arthritis

If you’ve ever been complacent in the kitchen when chopping chillies, you’ll know just how irritating they can be to the more sensitive parts of the body. In centuries past, herbs with such obvious effects on the body were frequently experimented with as therapeutics, and various healing powers were imposed upon them. The 17th century herbalist Culpepper attributed many virtues to these pungent fruit, such as supposed effects on digestion and the kidneys. However, the crude extracts of chillies that appear in the British Pharmacopoeia of the late 19th century were intended mainly for external use. Modern medicine is still exploring the potential uses of the fiery chemical that chillies contain.

Many are probably familiar with capsaicin as the principle active constituent of chilli peppers, since it is employed by the police as an irritant to incapacitate violent offenders. Once concentrated capsaicin contacts the mucosal surfaces of the eyes, nose and throat, the pain is absolutely excruciating (I inadvertently got some up my nose once in the lab, and it was an amazing experience that I choose not to repeat). If you sprayed a similar solution of capsaicin on your hands and rub it in, the pain would be much less severe, possibly just a mild tingling sensation (since skin is an effective barrier), depending on the strength of the preparation. This tingling, burning sensation is still exploited in some over-the-counter pharmacy preparations (which come with warnings about avoiding getting it in your nose and eyes.) These are hangers on from the days when such preparations would have been used as counter-irritants. Capsaicin isn’t unique, though, and many similarly burning or irritating materials were similarly employed.

A popular and long-lasting counter-irritant concoction appears in the Parke, Davis & Co. catalogues from early last century (mine is the 1921 edition). Their “Capsolin” ointment contained not only crude capsaicin but a mixture of similarly irritating herbal extracts:

Oleoresin of capsicum
Oil of turpentine
Oil of cajuput
Oil of croton

All of these can be classed roughly as rubefacients: chemicals that cause reddening of the skin. Contemporary accounts of this potion suggest that it was very painful to apply, although this would depend, of course, on how much was applied to a given surface area of skin. Capsolin was initially indicated for use where ever a counter-irritant was required, i.e. in any disease in which an inflammatory reaction was held to be responsible for the symptoms (many diseases of the day). It probably had little actual therapeutic effect in diseases beyond being a distracting placebo. It would have felt invigorating on arthritic knees on a cold morning, and our modern experiences in this setting can tell us something about how effective it might have been (see below). Somewhere along the way Capsolin (and other rubefacients) fell into use by sporty types, who used it as a means to “warm” muscles. Capsolin was not alone – the less irritating oil of wintergreen is still used for this counter-irritant purpose by athletes.

A quick Google search reveals that Capsolin was popular with American baseball players, acquiring the moniker 'atomic balm'. Some players seem to have used heroic amounts of it – entire tubes during the course of a single game. Much as one becomes accustomed to the heat of chillies as a culinary additive, these players must have deadened their nerves to some extent. It is this additional effect of regular, heavy use of potent preparations that brings us to the modern interest in capsaicin.

We classify the different sensory nerves in the body according to the modalities they respond to (eg. heat, cold, pressure, stretch), how fast they conduct nervous impulses to the central nervous system, and what neurotransmitters they release. When you stub your toe, the first impulses to reach the brain are conducted by nerves that carry impulses very quickly. This initial sharp pain triggers the gut feeling of “Oh, this is going to hurt”, and a second or so later, impulses carried by slower nerve fibres reach the brain; these nerves are responsible for the longer-lasting, dull and throbbing pain. Anyone with children will recognise the slight lag in the arrival of these impulses via different nerve fibres, since the wrong parental reaction (distraction) between them is the difference between “oops” and several minutes of screaming. Capsaicin acts on these slower sensory nerves. When applied for hours at low concentrations, capsaicin will deplete these sensory nerves of their neurotransmitters so that any impulses carried by them cannot be communicated to the central nervous system. At the same time, the pain induced elicits endorphin production in the brain. This combination of deadening peripheral nerves, as well as the release of endogenous pain-killers in the central nervous system produces effects much like true analgesia. Prolonged use (weeks), or short term use of very high concentrations (much higher than those in Capsolin) may eventually lead to damage to sensory nerves, producing a longer term relief from pain at the site of application. This is probably the effect that baseballers achieved: they became insensitive to the dull, throbbing pain from their worn out pitching shoulders. Few doctors would have recommended it over a proper rest, but professional athletes at the time could rarely afford to miss a game.

Once it became clear just how capsaicin acts on the body, and how specifically it desensitises or destroys subtypes of sensory nerves, there was renewed interest in it as a therapeutic. Capsaicin was touted as a potential treatment for chronically painful conditions such as osteoarthritis and neuropathic pain (pain arising from disease-addled nerve fibres), with the aim of desensitising or damaging sensory nerves. We can gain an insight into how effective counter-irritation might have been by considering the results of modern, controlled trials of capsaicin in these conditions. Regularly applied low doses of capsaicin cream or patches does not appear to be consistently effective in relieving the pain of osteoarthritis, and these doses are high enough that some patients are put off by the burning heat. With continued application, some desensitisation occurs, but it is unclear whether this produces a clinically significant reduction in pain. Indeed, such low dose creams have been used as placebos in trials of stronger formulations. Where capsaicin appears to be useful is in neuropathic pain, where high dose applications have been shown to reduce pain indices. These doses probably approximate those used historically by baseball players, and are so painful that they can only be applied after the relevant area has been treated with a local anaesthetic. Such is the damage to sensory nerves after such an application that the degree of pain relief lasts for weeks. Whether patients with milder, arthritic pain will prefer such a treatment to conventional pain-killers remains to be seen. Nevertheless, lower dose formulations are still considered third-line agents for those that find it provides some relief, whether it is effective, or just an old-fashioned, counter-irritant placebo.


The ancient and somewhat vague concept of counter-irritation persists, in various guises, right through to the recent past. Through their history, counter-irritants have been either chemical (eg. extracts of chillies, mustards and the like) or physical (eg cupping, ‘medical electricity’, or even the brief flirtation of medicine with moxa) in nature and aimed to distract the body in one way or another from pain or irritation. Like many practices from medicines darker past, it could be deeply unpleasant: the desired effects of counter-irritants varied from mild itching through to severe inflammation and blistering.

Sometimes, a counter-irritant might be applied remote from the source of the problem. For example, during an attack of angina most patients experience shooting pains radiating away from the centre of the chest – typically down the left arm. Thus, one view held that a counter-irritant applied to the arm would distract (or “short-circuit”) the pain arising from the heart. In other cases, irritants were applied closer to the source of discomfort. Using angina as an example again, it was not uncommon for physicians to apply a mustard plaster to the chest to try to counter the pain within, or to try to somehow draw the inflammation out to the surface (it’s all a bit vague from our now more rigid perspective). These attempts to alleviate pain could be quite severe; it was not uncommon, and quite intentional, for painful blisters to develop. Counter-irritants would probably have been applied as frequently as (and as a adjunct to) copious blood letting. Although the practice of bleeding is now all but forgotten, the ghost of counter-irritation still walks. For example, clutching a hot water bottle to alleviate period pain is probably a hanger-on from this way of thinking. Whether this practice has any real therapeutic value would be difficult to determine with confidence; but few would deny it is soothing in some way. Similarly, acupuncture can be thought of as a counter-irritant, and many argue that this is how this largely unproven fad “works” (perhaps without realising it) to provide relief from pain. Many of us would bite a knuckle or part of the hand to counter pain elsewhere, especially as children. Counter-irritation makes tantalising sense at the lower end of the pain spectrum.

Until relatively recently, authors of medical texts tried to explain the mechanisms of counter-irritation by warping contemporary knowledge of neurophysiology around the supposed efficacy of the approach. For example, at one time it was thought that nerve impulses from pathologically painful sites could be short-circuited in the spinal cord or brain somehow by nerve impulses from the site of application of a counter-irritant. It’s not entirely absurd. We have probably all experienced vaguely similar phenomena when, for example, we are too preoccupied with a task to notice that we have cut ourselves in a way that would ordinarily be painful. Stories abound of soldiers enduring stressful combat experiences, only to notice a bullet wound that would have felled them if they had just been on guard. One current and popular explanation for such events would be that the brain produces endogenous analgesic substances such as endorphins in such situations. This is where the realms of actual efficacy and placebo effects intersect in the Venn diagram of pain: placebo effects of treatments have been consistently shown to depend on production of endorphins as well. Ironically, acupuncture is often touted on the basis that it induces endorphin release, as if this provides some scientific authority to this largely pointless practice, rather than evidence that it is nothing more than a placebo. And that is why the “ancient tradition” of acupuncture has been consistently found to be no better than just prodding someone randomly with a toothpick (placebo), but better than doing nothing at all.

The idea that sensory impulses can be short-circuited is still with us. There are a variety of devices that can be used to electrically stimulate the spinal cord in the vague hope of achieving pain relief. Some devices are surgically implanted, and patients can control when and how electrical stimulation is delivered. Despite the cost of equipment (and its implantation) there is very little evidence that this technique isn't just a placebo. At present it is indistinguishable from quackery: small, poorly-conducted clinical trials and anecdotes.