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Postherpetic neuralgia—fi ghting pain with fi rePostherpetic neuralgia (PHN) is a neuropathic pain syndrome that is often insuffi ciently managed despite advances in our knowledge of the neurobiology and central processing of nociceptive signalling.1 Owing to this under management and because of its severity and chronic course, PHN is a substantial health-care problem.2

An important cause of chronic PHN is thought to be pathological hyperexcitability and abnormal sensitisation of primary aff erent nociceptors,3 which are the main site of expression of transient receptor potential vanilloid 1 receptor (TRPV1).4 Physiologically, TRPV1 respond to noxious heat and can be activated by capsaicin, a component of hot chilli peppers.5 Partial injury to the nerve triggers the downregulation of TRPV1 on many of the damaged aff erents and the novel expression of TRPV1 on uninjured nociceptors, which is probably involved in the development of the abnormal sensitisation.6

The application of small doses of capsaicin on the skin or mucosa induces the hot burning sensation that is well known to consumers of Asian cuisine. Exposure to high doses of capsaicin can result in a reduction in the function and reversible degeneration of TRPV1-containing, small-diameter aff erent nerves, leading to the inhibition of peripheral nociceptive transmission. Thus, the rationale for topical, high-dose capsaicin treatment is clear.

In this issue of The Lancet Neurology, Backonja and colleagues7 present the data from a randomised, double-blind clinical trial of one 60-min application of a high-concentration capsaicin patch (NGX-4010) for the treatment of PHN. Backonja and collegues report a signifi cantly greater reduction in pain in the patients who received NGX-4010 compared with the recipients of a low-dose capsaicin control patch during weeks two to 12 after treatment. Exacerbation of pain during and after the application of the capsaicin-containing patches was common but could be managed by pretreatment with topical lidocaine and the use of strong opioids for 5 days. The observed side-eff ects were localised and mild.

Although the 12-week results of this study are convincing, two caveats are relevant for the long-term use of capsaicin. First, for chronic-pain states, such

as PHN, the patch will have to be reapplied every few months because the capsaicin-aff ected cutaneous nociceptors recover within months and the pain will therefore probably recur after this period. Second, in addition to the functional eff ect of capsaicin on neurons, skin biopsies have shown that high-dose capsaicin leads to a reduction in the density of epidermal nerve fi bres (ie, the cutaneous nociceptor terminals degenerate).8 Experiments in animals have shown that nerve degeneration can trigger many profound molecular and cellular changes in the primary aff erent nociceptor, which can induce pain.9 With regard to both caveats, long-term trials are needed to determine the intervals between treatments and to assess the long-term effi cacy.

Do we have the strategies to minimise any potential risks? One possibility is to develop new methods to select prospectively the patients who are most likely to benefi t from treatment with capsaicin (ie, potential treatment responders). The peripheral sensitisation of cutaneous nociceptors is the target of treatment with topical capsaicin, but pathophysiological pain mechanisms cannot be investigated readily in human beings. Because the characteristic signs of hyposensitivity and hypersensitivity to mechanical and thermal stimuli that occur in various combinations probably translate into pain-generating mechanisms, the individual pattern of somatosensory abnormalities at the aff ected body area—the somatosensory phenotype—has promise as a biomarker for investigation of pathophysiological pain. The precise phenotypic characterisation of each patient’s pain can be obtained by systematic clinical examination with quantitative sensory testing (QST), and the German Research Network on Neuropathic Pain (DFNS) has developed a standardised and comprehensive QST protocol;10 for example, abnormal nociceptor sensitisation, which is the target for topical capsaicin, is related to signs of thermal hypersensitivity. The future benefi ts of such selection are likely to be twofold: in clinical proof-of-concept trials, the study population could be enriched with potential responders on the basis of predefi ned pathophysiologically clean and reasonable entry criteria; and in clinical practice, the patients who require a specifi c treatment could be identifi ed.

Published OnlineOctober 31, 2008DOI:10.1016/S1474-4422(08)70242-4

See Articles page 1106

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Where might topical capsaicin be in the treatment armamentarium for PHN? To date, the oral medical management of PHN consists of three main drug classes: antidepressants (eg, amitriptyline), anticonvulsants that probably act mainly on central calcium channels (eg, gabapentin and pregabalin), and opioids (eg, tramadol, oxycodone, and morphine);11 topical lidocaine is also eff ective. Because more than one mechanism of PHN is at work in most patients,

a combination of several drugs to cover many types of mechanism will generally give greater pain relief and fewer side-eff ects. Therefore, combinations of two or three compounds from diff erent classes early in the course of PHN might be more appropriate for some patients than a stepwise strategy of successive monotherapies.

Because topical high-concentration capsaicin does not increase plasma capsaicin concentrations, no drug–drug interactions and no impairment of the CNS are expected. Therefore, topical high-dose capsaicin might be an ideal candidate for combination treatment with

systemic drugs, particularly in elderly people, to reduce central side-eff ects. Whether the combination of two topical therapies, such as capsaicin and lidocaine, is eff ective needs to be shown. The burden of PHN is still a problem but novel options for better pain control are on the horizon.

Andreas Binder, Ralf BaronSektion Neurologische Schmerzforschung und Therapie, Klinik für Neurologie, Christian-Albrechts-Universität Kiel, Schittenhelmstrasse 10, 24105 Kiel, Germanyr.baron@neurologie.uni-kiel.de

RB has received honoraria from Pfizer, Grunenthal, Allergan, Genzyme, Sanofi, and Schwarz; and research grants from Pfizer, Grunenthal, and Genzyme. AB has received honoraria from Pfizer, Grunenthal, Allergan, and Genzyme.

1 Johnson RW, Wasner G, Saddier P, Baron R. Postherpetic neuralgia: epidemiology, pathophysiology and management. Exp Rev Neurother 2007; 7: 1581–95.

2 Schmader KE. Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clin J Pain 2002; 18: 350–54.

3 Baron R. Mechanisms of disease: neuropathic pain—a clinical perspective. Nat Clin Pract Neurol 2006; 2: 95–106.

4 Hudson LJ, Bevan S, Wotherspoon G, Gentry C, Fox A, Winter J. VR1 protein expression increases undamaged DRG neurons after partial nerve injury. Eur J Neurosci 2001; 13: 2150–14.

5 Tominaga M, Caterina MJ. Thermosensation and pain. J Neurobiol 2004; 61: 3–12.

6 Hong S, Wiley JW. Early painful diabetic neuropathy is associated with diff erential changes in the expression and function of the vanilloid receptor 1. J Biol Chem 2005; 280: 618–27.

7 Backonja M, Wallace MS, Blonsky ER, et al. NGX-4010, a high-concentration capsaicin patch for treatment of postherpetic neuralgia: a randomized, double-blind study. Lancet Neurol 2008; 7: 1106–12.

8 Polydefk is M, Hauer P, Sheth S, Sirdofsky M, Griffi n JW, McArthur JC. The time course of epidermal nerve fi bre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy. Brain 2004; 127: 1606–15.

9 Fields HL, Rowbotham M, Baron R. Postherpetic neuralgia: irritible nociceptors and deaff erentation. Neurobiol Dis 1998; 5: 209–27.

10 Rolke R, Baron R, Maier C, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 2006; 123: 231–43.

11 Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007; 132: 237–51.

Multiple sclerosis—a global disorder and still poorly managedThe launch of Atlas: Multiple Sclerosis Resources in the World 2008 (MS Atlas)1 during the World Congress on Treatment and Research in Multiple Sclerosis in September, 2008, was met with substantial global interest. This reaction is perhaps not surprising owing to the number of countries involved and the rather sobering and thought-provoking messages

the atlas contains. Together with WHO, the Multiple Sclerosis International Federation (MSIF) successfully acquired data from 112 countries, representing 88% of the world’s population. Furthermore, there was good representation from all six WHO regions and a broad spread of the four World Bank income categories (low, lower middle,

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