Prevention of postherpetic neuralgia

phlebotomy, both directed at oxidative stress, and with troglitazone, directed at insulin resistance. These therapies will now be subject to large randomised clinical trials. In the future, therapy directed at cytokine-triggered mechanisms, including Cox-2 inhibitors, and measures to reduce accumulation of visceral fat seem worthy of assessment in this intriguing and, until recently, largely ignored disorder. *Oliver James, Christopher Day Centre for Liver Research, Medical School, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK 1 2

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Byron D, Minuk GY. Profile of an urban hospital-based practice. Hepatology 1996; 24: 813–15. Ludwig J, Viggiano TR, McGill DB, Ott B. Nonalcoholic steatohepatitis:Mayo clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980; 55: 434–38. James OFW, Day CP. Non-alcoholic steatohepatitis (NASH): a disease of emerging identity and importance. J Hepatol 1998; 29: 495–501. Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994; 107: 1103–09. Younossi ZM, Matteoni CI, Gramlisch T, et al. Patient characteristics predicting cirrhosis and death in non-alcoholic steatohepatitis. Hepatology 1998; 28: 303A. Caldwell SH, Oelsner DH, Lezzoni JC, Hessenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 1999; 29: 664–69. Teli MR, James OFW, Burt AD, Bennett MK, Day CP. The natural history of non-alcoholic fatty liver: a follow up study. Hepatology 1995; 22: 1714–19. Kim WR, Poterucha JJ, Porayko MK, Dickson ER, Steers JL, Wiesner RH. Recurrence of non-alcoholic steatohepatitis following liver transplantation. Transplantation 1996; 62: 1802–05. Day CP, James OFW. Steatohepatitis: a tale of two “hits”? Gastroenterology 1998; 114: 842–45. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 1990; 12: 1106–10. Weltman MD, Farrell GC, Hall P, Ingelman-Sundberg M, Liddle C. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology 1998; 27: 128–33. Yang Sq, Lin HZ, Lane MD, Clemens M, Diehl AM. Obesity increases sensitivity to endotoxin liver injury:implications for the pathogenesis of steatohepatitis. Proc Natl Acad Sci 1997; 94: 2557–62. Day CP, James OFW. Hepatic steatosis—innocent bystander or guilty party? Hepatology 1998; 27: 1463–66. Bass NM. Three for the price of one knockout—a mouse model of congenital peroxisomal disorder, steatohepatitis and hepatocarcinogenesis. Hepatology 1999; 29: 606–07. Arner P. Not all fat is alike. Lancet 1998; 351: 13.

Prevention of postherpetic neuralgia Although there are many approaches to the treatment of postherpetic neuralgia (PHN),1–4 many patients do not respond or derive only partial benefit. The development of more effective and better tolerated treatments for PHN is therefore an important goal for future research. A method for preventing PHN would not only make the development of such treatments unnecessary but also eliminate the disability, psychological distress, and use of health-care resources due to PHN. At present, antiviral drugs provide the greatest opportunity for reducing the likelihood of PHN. Although the results of randomised controlled trials and metaanalyses showing that aciclovir, famciclovir, and valaciclovir reduce the duration of zoster pain and the risk of developing PHN7-9 can be challenged, overall the findings are consistent. Antiviral therapy is recommended10,11 for herpes-zoster patients at high risk of PHN and other complications—those who are old, have moderate or severe rash, have moderate or severe pain, or have ophthalmic involvement. 1636

Unfortunately, a substantial number of zoster patients still have chronic pain despite adequate antiviral therapy. Although more effective antiviral agents may be developed, a different strategy for preventing PHN is to supplement antiviral treatment. Two recent double-blind trials have suggested that the addition of a corticosteroid does not shorten the overall duration of herpes zoster pain, although it may hasten return to premorbid quality of life.12,13 The well-established efficacy of tricyclic antidepressants in PHN and other neuropathic pain syndromes14 prompted Bowsher15 to test the hypothesis that very early treatment with an antidepressant would greatly shorten the duration of pain in herpes zoster and thereby reduce the likelihood of PHN. Patients were given amitriptyline 25 mg or matching placebo daily, starting within 48 h of onset of the rash and continuing for 90 days. There were many commendable aspects of this trial; not only was it randomised, double-blind, and placebocontrolled, but also treatment was begun very soon after onset of the rash and enrolment was limited to patients aged over 60 years, the group at greatest risk of PHN. In addition, pain was assessed 6 months after onset of the rash, a follow-up duration that satisfies all major criteria that have been used to diagnose PHN.1,16 Unfortunately, however, patients’ general practitioners were allowed to decide whether or not an antiviral agent should be administered. Hence, there were four treatment groups— amitriptyline plus aciclovir,amitriptyline only, placebo plus aciclovir, and placebo only. The major analysis was a comparison of the percentage of patients free of pain at 6 months after onset of the rash among all amitriptylinetreated patients (84·2%) with that among all placebotreated patients (64·7%),irrespective of aciclovir treatment (p<0·05). Bowsher concluded that the results strongly suggest that early treatment of older patients with acute herpes zoster with low-dose amitriptyline reduces the longterm prevalence of PHN.15 This conclusion could have a major impact on the treatment of patients with acute herpes zoster. However, because it is based on pooled data from patients who were and were not treated with aciclovir, Bowsher’s conclusion does not reflect current clinical practice guidelines.10,11 Furthermore, it has the potential to mislead readers into believing that antiviral treatment is unnecessary if patients are treated with amitriptyline. A trial on preventive therapy for PHN should compare an antiviral agent plus the agent under investigation with an antiviral agent plus a placebo matching the investigational treatment. Bowsher’s report enables this comparison to be examined. As can be seen from the figure, only 11% (one of nine) of patients treated with both aciclovir and amitriptyline had PHN 6 months after onset of the rash, whereas 47% (eight of 17) of those treated with aciclovir and placebo had PHN. This difference is significant (p=0·0455, one-sided likelihood ratio test with continuity correction). However, this analysis is post hoc, based on a small sample of patients, and does not reflect random assignment of patients to treatment with aciclovir. Nevertheless, the data suggest that antidepressants may have an important role in the treatment of acute herpes zoster when combined with antiviral therapy. The results also provide justification for additional studies of preemptive antidepressant treatment, for PHN as well as for other neuropathic pain syndromes. Other drugs with demonstrated efficacy in PHN and/or painful diabetic

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14 McQuay HJ, Tramèr M, Nye BA, et al. A systematic review of antidepressants in neuropathic pain. Pain 1996; 68: 217-27. 15 Bowsher D. The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: a randomized, double-blind,placebocontrolled trial. J Pain Symptom Manage 1997; 13: 327-31. 16 Dworkin RH, Portenoy RK. Proposed classification of herpes zoster pain. Lancet 1994; 343: 1648. 17 Harati, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 1998; 50: 1842–46. 18 Byas-Smith MG, Max MB, Muir J, Kingman A. Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two-stage “enriched enrollment” design. Pain 1995; 60: 267–74.

Better coronary risk assessment in women

neuropathy—another common peripheral neuropathic pain syndrome—that could be evaluated in this way include gabapentin,4 oxycodone,5 ketamine,1 tramadol,17 dextromethorphan,1 and clonidine.18 Robert H Dworkin Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA 1 Dworkin RH, Johnson RW. A belt of roses from hell: pain in herpes zoster and postherpetic neuralgi a .I n :B l o c k ,A R , Kremer EF, Fernandez E, eds. Handbook of pain syndromes: biopsychosocial perspectives. Hillsdale,NJ:Erlbaum,1998. 2 Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998; 280: 1837-42. 3 Watson CPN, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 1998; 50: 1837-41. 4 Watson CPN, Vernich L, Chipman M, Reed K. Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial. Neurology 1998; 51: 1166-71. 5 Beutner KR, Friedman DJ, Forszpaniak C, Andersen PL, Wood MJ. Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 1995; 39: 1546-53. 6 Tyring S, Barbarash RA, Nahlik JE, et al. Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995; 123: 89-96. 7 Wood MJ, Kay R, Dworkin RH, Soong SJ, Whitley RJ. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo-controlled trials. Clin Infect Dis 1996; 22: 34147. 8 Jackson JL, Gibbons R, Meyer G, Inouye L. The effect of treating herpes zoster with oral acyclovir in preventing postherpetic neuralgia: a meta-analysis. Arch Intern Med 1997; 157: 909-12. 9 Dworkin RH, Boon RJ, Griffin DRG, Phung D. Postherpetic neuralgia: impact of famciclovir,age, rash severity, and acute pain in herpes zoster patients. J Infect Dis 1998; 178 (suppl 1): S76-80. 10 Guidelines for the management of shingles. Report of a working group of the British Society for the Study of Infection. J Infect 1995; 30: 193-200. 11 Wood MJ, Kroon S, eds. Management strategies in herpes: reducing the burden of zoster-associated pain—update. Worthing: PPS Europe, 1995. 12 Wood MJ, Johnson RW, McKendrick MW, et al. A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med 1994; 330: 896-900. 13 Whitley RJ, Weiss H, Gnann JW Jr, et al. Acyclovir with and without prednisone for the treatment of herpes zoster: a randomized, placebocontrolled trial. Ann Intern Med 1996; 125: 376-83.

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A vast body of information on causal factors (“risk factors”) guides treatment of established coronary disease (CHD) in men, whereas a dearth of like information in women has somehow implied that their treatment should be different. With a small number of women, the Scandinavian Simvastatin Survival Study in 1994 did not show benefits of treatment in women with established CHD.1 Recent trials with pravastatin2,3 have at last shown that the benefits of intervention are the same in women as in men, as one would have expected all along. Perhaps this effect is also true in the prevention of first coronary events, causal factors in women being the same. The same, that is, in relative terms. At any age, the absolute risk of a coronary event in women is about a fifth that of men. Women are affected, on average, some 10–15 years later in life.4 For women in western nations, the risk of dying from CHD by age 70 is of the order of 1·5 per 100, but lifetime risk approaches 30 per 100. Unfortunately, focus on relative risk may distort the true benefits of intervention. One way of thinking of risk is to consider “age equivalence”—how much earlier does disease develop in the presence of a particular risk factor? In these terms, being a woman is worth some 10–15 years, about the same as being a non-smoker, or not having diabetes or a strong family history of CHD. For most women, this delay serves as a period of grace, enabling intensive preventive efforts to be deferred until a later age. Who among young and middle-aged women need to take preventive efforts more seriously? Better late than never, more data on CHD risk factors in women are to hand. Guy deBacker and colleagues5 have reported 10-year follow-up of symptom-free men and women in Belgium with endpoints of total and cardiovascular mortality. Major electrocardiographic (ECG) abnormalities (ST depression, T inversion, bundle-branch block) indicated a higher risk of cardiovascular death in both sexes; relative risks ranged from 2·5 to 6·0 and were higher than those for usual risk factors. In some people, these ECG changes are likely to reflect ventricular hypertrophy associated with hypertension or valvular disease; in others, they probably reflect unrecognised coronary disease. Beyond aspirin, one would expect preventive efforts in women to be worthwhile: a post-hoc analysis of the Multiple Risk Factor Intervention Trial6 indicated unexpected benefits of treatment in men with resting ECG abnormalities. The finding that an abnormal ECG indicates high risk is not new. Why has it not assumed more importance in risk assessment? Like diabetes, an abnormal ECG has low prevalence (3·0% in the Belgian population aged 25 to 74 years, and 2·5% in men and 1·1% in women aged 45–74 years in Framingham7) and does not aid risk assessment in the majority. This is the “preventive paradox” described by Geoffrey Rose;8 the vast majority of CHD patients display 1637