Features of this month's Journal

In his Republic, Plato tells how Socrates asks his friend Cephalus how old age affects love. Cephalus quotes Sophocles on the subject ‘Most gladly have I escaped the thing of which you speak; I feel as if I had escaped from a mad and furious master’, to which Cephalus adds, ‘Certainly old age has a great sense of calm and freedom; when the passions relax their hold, then … we are freed from the grasp not of one mad master only, but of many.’ Now that more of us are living longer, we may hope to experience eventually the inner peace that comes with release from such tyrannical passions. But old age brings other problems with it, as papers in this month's Journal highlight.

Old-age medicine

In the first two articles in a new series we highlight some of the problems of ageing, starting with the effects of ageing on pharmacological responses in the cardiovascular system (pp. 254–260) and the clinical pharmacology of delirium, incontinence, and falls (pp. 261–272), the Tisiphone, Alecto, and Megaera of old age. Cameron Swift sets the scene in his editorial (pp. 249–253), emphasizing the importance of a basic understanding of clinical science, clinical pharmacology, and therapeutic evidence when prescribing for elderly people.

New Age medicine

The increased average age of the population brings other, more general health care problems with it. Elderly people are about 30% more likely to need admission to hospital when they fall ill than younger patients, partly because there is likely to be nobody at home to take care of them, partly because of their failing physiology, making them less able to cope, and partly because of the increased complexity of their problems, including multiple pathologies and polypharmacy. This is one of the reasons for increased demands on health services. And when conventional medicine fails as a result, people will seek alternatives, as they are doing increasingly. For example, in the recent BBC survey of the use of complementary and alternative medicine among 1204 adults in the UK, 20% had used complementary medicine in the previous year. Herbalism, aromatherapy, homoeopathy, acupuncture or acupressure, massage, and reflexology were the most popular forms used. On average, users spent £13.62 per month on complementary and alternative medicine, which multiplies to an annual national expenditure of about £1.6 billion. And the use of complementary medicine is particularly prevalent among elderly people, especially women [2].

There may be other reasons for the increased uptake of complementary and alternative medicine. There is, for example, increasing interest in the West in cultural aspects of developing countries – witness, for example, the burgeoning interest in what is called ‘world music’; and with this comes an interest in exotic systems of medicine. There is also increasing distrust in conventional science, which is sometimes seen as having failed, as in the case of BSE and the emergence of variant Creutzfeld–Jakob disease. However, Sam Vožeh (pp. 292–296) suggests another reason. He points out that complementary methods (excepting herbal medicines with proven effects) substitute well for placebo therapies, particularly in conditions in which the placebo effect is high and conventional treatments either are ineffective, despite having well-described pharmacological actions, or are associated with a high rate of adverse effects, or, as is commonly so, both.

Take the case of irritable bowel syndrome. You might just use a placebo and tell the patient that you are using a formulation that has no real active ingredient but that sometimes works. No, argues Vožeh – not in these days of increasing involvement of patients in their own care and demands for evidence-based practice. After all, as Dylan Evans has pointed out in his recent masterly survey of placebos, the true size of the placebo effect is rarely known, because placebos are almost never compared with no treatment at all [3]. So a true placebo will not do. Some practitioners therefore have recourse to a drug that might be expected to bring therapeutic benefit, because it has a well-defined pharmacological effect (e.g. the anticholinergic effect of a tricyclic antidepressant), but which is not in fact effective. This allows the allopathic doctor to say with confidence that the drug has a well-known action that is or may be relevant to the condition, but it does not get round the problem that evidence of real efficacy may be poor. Furthermore, it brings with it adverse effects. So, because evidence-based practice has cast doubt upon the value of medicines that are not unequivocally better than placebo, patients have recourse to complementary and alternative medicine. But if Vožeh's thesis is true, an explanation is needed about why people do not demand the same high evidential standards of complementary and alternative medicine, the various forms of which, as a thorough review has shown, are often ineffective – by evidence-based medicine standards [4].

Age and testosterone

Age-related differences in the pharmacokinetics of the hypnotic benzodiazepine receptor agonist zolpidem are not fully understood. When Olubodun et al. (pp. 297–304) studied the pharmacokinetics of a single dose of zolpidem in 16 men of different ages (eight young and eight old) they found a good relation between the serum concentration of unbound testosterone and the clearance of zolpidem – the lower the testosterone concentration the lower the clearance. Some steroids induce CYP3A4, as Hesselink et al. (pp. 327–330) showed in 65 patients with kidney transplants taking the immunosuppressants tacrolimus and mycophenolate mofetil plus either daclizumab or prednisone. The patients who were taking prednisone required higher doses of tacrolimus to achieve the same plasma concentrations, an effect that was attributed to induction of CYP3A4 by prednisone. In contrast, testosterone does not induce CYP3A4, but it does activate it, and since CYP3A4 is the main isozyme responsible for the metabolism of zolpidem, testosterone concentrations might explain age-related differences in the pharmacokinetics of zolpidem. Testosterone can't be the whole story, however – although zolpidem clearance was much lower in 16 young women than in the young men, it was still higher than in the old men and there was a further fall in eight old women, unrelated to testosterone concentrations.

Now then, perhaps the pacifying effects of male ageing that Plato reported are to do with reduced clearance of endogenous benzodiazepine-like substances, freed from the metabolic influence of testosterone?