Sunday, June 04, 2006

The Wilder Shores of Arthritis - Fit the Fourth


Before leaping into the twentieth century, a word about painkillers in general, not just anti-arthritis drugs. (We'll get to the NSAIDs one day, I promise.) Pain is only a symptom that something has gone wrong. If you have acute pain from a single reversible cause, such as a fracture or an abscess, you can hope to relieve the pain by curing the cause. If, however, you have a chronic condition, such as arthritis, where the pain is due to multiple irreversible tissue changes and damage, you could, excluding surgery, relieve the pain only by (a) physically interrupting the sensory nerves which supply the information to the brain (b) distracting the patient physically (by counter-irritant) or psychologically (by analgesic, antidepressant, sedative or hypnotic) (c) continually damping down the inflammatory response which is causing the pain.

For most of history, option (b) has been the only one available. The daddies of all analgesics are, of course, opium, and alcohol. Opium goes back long before Hippocrates (fourth century BCE); it has been recorded by the ancient Assyrians, Sumerians and Egyptians, and appears in ancient Greek legends as well. Alcohol probably dates to when the first man ate a bit of rotting, fermented fruit and liked the sensation of getting high. The problem with them is that they are both potent CNS (central nervous system, ie the brain) depressants and they both cause habituation. A weaker ancient alternative to opium is lactuarium, extracted from the juice of wild lettuce.

Mandrake (Atropa mandragora) was used by the ancient Egyptians 1400 years BCE; it is one of the Solanaceae (potato family) as is henbane (Hyoscyamus niger). Cannabis (Cannabis sativa) was known to the ancient Chinese as an analgesic but seems to have been used recreationally by everyone else. Hemlock (Conium maculatum), the poison that killed Socrates, was used by the Romans and in medieval times in poultices and as "sleeping sponges" - a form of analgesic glue-sniffing.

Opium dissolved in alcohol became the basis of many analgesic/sedative tinctures, the most well-known of which is laudanum, the favourite tipple of Samuel Taylor Coleridge, Wilkie Collins, Branwell Brontë and many other unfortunates, who became insidiously addicted. In 1805 morphine was refined from raw opium. When its addictive properties were realised in turn, diamorphine was developed as a further, safer, refinement; ironically, although it is a much stronger painkiller, it is also many times more addictive. After the first world war, in the UK and many other countries, the opiates (except for codeine in the UK) were declared to be Dangerous Drugs and their use strictly forbidden without prescription; cannabis followed in the 1930s and the barbiturates in the 1950s.

Also in the 1950s came a Wonder Drug, the first of all the synthetic steroids - cortisone. Its discoverer, Tadeus Reichstein, and his co-scientists, got the Nobel Prize for its discovery. Corticosteroids are produced naturally in the body by the adrenal cortex; they are essential hormones involved in the stress response, immune response, and inflammatory response amongst other functions; the immune and the inflammatory are the ones that concern arthritics. They revolutionised the treatment of intractable disabling inflammatory and autoimmune conditions like Crohn's, ulcerative colitis, asthma, lupus, sarcoidosis, psoriasis. They also had horrendous and often irreversible side-effects, as may any drug, but this was not realized until quite some time later.

Meanwhile, over-prescribing ("Let's see what other conditions it will cure") and overdosage ("If one milligram works then two milligrams must work better") had done their damage: the loss of bone, the thinning of skin, damaged gastric mucosa, diabetes mellitus, behavioural changes, notably aggression and delusions.

When the side-effects of steroids became apparent, many alternative painkillers were developed: good old over-the-counter paracetamol, phenacetin (long-since banned); the NSAIDs: mefenamic acid, ibuprofen, indomethacin, naproxen, diclofenac sodium; the opioids: tramadol, pentazocine, buprenorphine....they all have their disadvantages to the continual user. Those that aren't gastric irritants or addictive tend to be hepatotoxic (paracetamol) or nephrotoxic (phenacetin).

But steroids were the first class of drug to tackle the problem of arthritis at a stage more sophisticated than just masking the symptoms. Everyone ever since has been hoping for the philosopher's stones: why does osteo-arthrosis occur in the first place, in some individuals and not in others (rheumatoid is certainly an autoimmune reaction); how exactly does it do its damage; and thus, what can be done to prevent, or if not that, reverse it?

These are still largely unanswerable questions in the 21st century.

Let's say there's going to be a genetic predisposition: even if (when) we can identify the gene(s) responsible, and if (large presupposition) it turns out that these genes don't also have a benevolent function as well which we can ill do without: what are we going to do about it? Is the arthritis gene to be added to the growing list of ills that flesh is no longer going to be heir to because they are going to be screened out at the pre-implanted embryo stage or by abortion?

It is now possible to detect the bony changes of arthritis much earlier and more easily. There is now a recently-developed technique called acoustic emission which can be used by any GP in his local surgery, to actually hear the noise made by the moving joint, before any symptoms of pain or stiffness have even become noticeable. Fine; but what do you do then, if you can neither limit the damage (because you don't know the why) or reverse it (because you don't know the what)?

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