There's the rub
Published on 01 July 2008
Expert Howard Bird guides readers through the contentious world of pain-relieving skin creams with a personal view in the light of recent NICE guidelines on the treatment of osteoarthritis.
It used to be said, partly in jest, that the nationality of a European could be predicted by knowledge of the way in which they consumed their non-steroidal anti-inflammatory drugs (NSAIDs).
Scandinavians, the Dutch and the British invariably swallowed a tablet because that was what their licensing authority recommended. Germanic races were not averse to injection and the French were not averse to suppositories. Mediterranean races, including the Italians and Greek, favoured rubbing it into the skin, the more fragrant the better.
Pharmaceutical companies producing a new drug to be marketed worldwide gave serious consideration to local and national preferences, ever keen to make a profit by satisfying the consumer.
Against that background, several recent studies, and, in turn, the guidelines recently produced by the National Institute for Health and Clinical Excellence (NICE) for the treatment of osteoarthritis, have resuscitated and even encouraged the use of creams rubbed into the skin, known as topical applications, in the UK.
Do they work? Do they have a placebo effect? What drugs can be given by pasting on the skin? What are the advantages, if any, over taking the same amount of drug by mouth?
The different routes of administration
Unless a tablet is specifically dissolved in the mouth by placing under the tongue, it will be swallowed into the stomach, from which most of it will be absorbed. If the drug is formulated as a ‘delayed release’ preparation, a drug in a protective covering will sit in the stomach until that covering is dissolved and released more gradually.
If the same amount of the same drug is given by injection, absorption of the full amount is instantaneous, the drug is available to act within minutes rather than hours. Absorption of the same amount of drug from a suppository is similar to absorption from the mouth though slower.
The skin represents the body’s protective barrier. Quite a few drugs are absorbed through the skin but much more slowly and usually less efficiently and reliably than when taken by mouth. However, the evidence for absorption for many painkillers is poor. NSAIDs are better and most are absorbed to some extent, though absorption is less reliable and slower than by the oral route.
Formulating the active drug with a vehicle that enhances absorption can speed up the process; normally by opening up blood vessels in the skin (rather than closing them down) or by enhancing sweat production.
Is this not where the drug is needed?
This is a more complex question. If the evidence is reliable for transcutaneous absorption, especially when the skin is inflamed, the evidence that pasting a drug over the affected joint gives efficacy exactly where it is needed is more controversial. Once in the body, the drug will be subject to the flow of the bloodstream and body fluids. Although this may be into an inflamed joint, the mere presence of this inflammation means the drug will also leave the joint quickly. It seems unlikely that once a drug is in the body it has the ability to turn left and then to turn left again to reach the knee joint by the back door.
Surely there is a placebo effect?
This is probably true. Cosmetics have been applied to the skin since prehistoric times. Colour may be important. There is some evidence that the same drug given in a red capsule is more effective than when it is given as a white capsule. Few topical applications are coloured, mainly because this has tended to stain clothing. Fragrance probably counts for even more and very few of the more expensive proprietary NSAIDs are without odour.
For some preparations a ‘placebo’ effect is specifically sought. It has long been known that pain, whether superficial or deep seated, is relieved by any method that itself produced irritation of the skin. ‘Rubefacients’, designed to be massaged into the skin and usually containing pure analgesics, work on this principle of counter-irritation, which can be comforting. This perhaps reaches its zenith with capsaicin, a cream that is derived from hot chilli peppers. Intriguingly, the instructions for application emphasise that this pain needs to be experienced and proves that it is working! The downside is that if the cream is accidentally applied to the lips or eyes (as can happen with elderly people), the pain becomes excruciating.
NSAID applications available
Just as with NSAIDs in tablet form, some of the longest established are available as non-proprietary creams that are inexpensive (as well as being of minimal fragrance!). Examples at the time of writing are ketoprofen cream with a recommendation to apply 3–4 times a day and piroxicam cream with a similar recommendation even though, when given by tablet formulation, the frequency of dosing with piroxicam is much less than with ketoprofen because piroxicam stays longer in the body.
In addition, ibuprofen and diclofenac are available in (normally) more expensive proprietary formulation, as well as proprietary ketoprofen and piroxicam. A fifth such drug is felbinac. Although the majority of formulations are as gels, one preparation is a solution dispensed from a pencil, another a foam and another a gel patch.
NICE guidelines for osteoarthritis
Published in February 2008, these emphasise a wide variety of non-pharmaceutical treatments including rest and physiotherapy that should be tried before resorting to drugs. Oral paracetamol is still given as the drug of first choice but in the list that follows, should paracetamol alone be ineffective, topical NSAIDs are recommended for the knee and hand osteoarthritis before oral NSAIDs and certainly before opioids. Even topical capsaicin gets a prominent mention though rubefacients are not recommended for osteoarthritis on the current evidence base.
Osteoarthrits remains a large and expanding market and it seems likely that this advice will act as a stimulus to the development of even more drugs formulated as topical applications in the near future.
What else will ‘rub it better’?
Old-fashioned liniments, ointments and balms have been used for centuries. Tiger balm once had its advocates and even preparations such as glucosamine have recently been formulated for topical administration as well as tablets for the oral route. Local anaesthetics have their advocates though are often short acting and sometimes cause allergic reactions. Opioids, for example buprenorphine (BuTrans) or fentanyl (Durogesic), both available in patch formulation have been much in vogue on theContinent and have recently been introduced here. Detailed discussion is beyond the scope of this article but suffice to say that none of these have figured prominently in the NICE guidelines.
What about arthritis other than osteoarthritis?
The NICE guidelines are specific for osteoarthritis, a condition often encountered in the elderly (a group particularly susceptible to drug toxicity) and for whom, arguably, no adequate ‘disease-modifying drugs’ are yet available. The situation is quite different for, for example, rheumatoid arthritis, for which an increasing number of disease-modifying drugs, many ‘biologic’, are now available. NSAIDs, which merely mask symptoms, play a lesser role in such conditions and would normally only be prescribed as an adjunct to disease modification. Nor would it seem appropriate to treat polymyalgia rheumatica, also a disease of the elderly, with topical rather than systemic steroids, however effective topical steroids might be in the management of eczema and other skin conditions where their absorption through the skin is rapid.
Howard Bird is Professor of Pharmacological Rheumatology at the University of Leeds.