Date:
April 25, 2006
Promotors:
Prof. C.J. Kalkman, MD, PhD
Prof. Th.J.M. Verheij, MD, PhD
Prof. K.G.M. Moons, PhD
Postherpetic neuralgia (PHN) is a pain syndrome that afflicts mostly the elderly. It starts with a common viral disease, herpes zoster (HZ, shingles). Herpes zoster is caused by a reactivation of the varicella zoster virus. Almost everyone contracts the virus during childhood and infection results in chickenpox. After recovery the virus remains in the nervous system indefinitely. Cellular immunity normally keeps the virus under control, but after many years this immunity gradually subsides. At a certain moment the virus, which until then had been silently residing in a sensory ganglion, may become active again and will be transported through the axons to the skin. This leads to the typical dermatomal spread of vesicles. In most patients, the rash and the pain last only a few weeks, but in some patients the pain persists and may progress to a chronic pain syndrome: postherpetic neuralgia.
Mechanisms secondary to the inflammation of the affected sensory ganglion play an important role in the development of postherpetic neuralgia. Therefore, early treatment of herpes zoster might decrease postherpetic neuralgia. Options are analgesics, antivirals, antidepressants and neural blockade. However, strong evidence for the effectiveness of these preventive strategies is lacking. Once PHN has been established, the syndrome is difficult to treat. By “trial and error” the best drug or combination of drugs for the individual patient has to be sought. Drugs of use are tricyclic antidepressants, anti-epileptics, opiates, capsaicin, lidocain and intrathecal methylprednisolone.
To evaluate the current practice in primary and secondary care, a questionnaire was sent to 350 randomly chosen general practitioners (GPs). Forty-two percent of the responding GPs prescribed antiviral medication if HZ exists for 2 days. Analgesics were prescribed by a vast majority (80%) of the GPs. Approximately 2500-3000 HZ patients per year (10% of the number at risk for developing PHN) are referred to an anaesthesiologist for a preventive epidural steroid injection. If PHN occurs, 73% of the GPs refer to a specialist, in general, a pain clinic. Most anaesthesiologists used a dorsal approach for the epidural space, without the aid of fluoroscopy; the medication mostly used was a combination of a local anaesthetic and a corticosteroid. We conclude that the use of antiviral medication is not common practice in the Netherlands. Patients with HZ are seldom referred to a pain clinic, but referral occurs more often once PHN has been established.
Epidural injection of local anaesthetics and steroids in the acute phase of HZ is a promising therapy for the prevention of PHN. Since randomised trials on the effectiveness of this intervention are lacking, the PINE (Prevention by epidural Injection of postherpetic Neuralgia in the Elderly) study was set up. The PINE study was an open, multicenter clinical trial. We randomly assigned 598 patients older than 50 years, with acute herpes zoster (rash <7 days) below dermatome C6, to receive either standard therapy (oral antivirals and analgesics) or standard therapy with one additional epidural injection of 80 mg methylprednisolone acetate and 10 mg bupivacaine. The primary endpoint was the proportion of patients with zoster-associated pain 1 month after inclusion. Secondary endpoints include duration and severity of pain, re-interventions aiming to treat the existing pain, side effects, quality of life, and cost-effectiveness. Analyses were by intention-to-treat. At 1 month, 137 (48%) patients in the epidural group reported pain compared with 164 (58%) in the control group (relative risk [RR] 0.83, 95% CI 0.71–0.97, p=0.02). After 3 months these values were 58 (21%) and 63 (24%) respectively (0.89, 0.65–1.21, p=0.47) and, at 6 months, 39 (15%) and 44 (17%; 0.85, 0.57–1.13, p=0.43). We detected no subgroups in which the relative risk for pain 1 month after inclusion substantially differed from the overall estimate. No patient had major adverse events related to epidural injection. We concluded that a single epidural injection of steroids and local anaesthetics in the acute phase of herpes zoster has a modest effect in reducing zoster-associated pain for 1 month. This treatment is not effective for prevention of long-term postherpetic neuralgia. The cost effectiveness of this treatment seems acceptable from a societal perspective, but may not be from a payers perspective.
In the participants of the PINE study we measured prospectively the natural history of zoster associated pain, up to 24-48 months after the occurrence of herpes zoster. At three months, 22% (95% confidence interval (CI) 19-26) reported pain; 8% (95% CI 6-10) significant pain (Visual Analogue Scale (VAS) >30) and 2% (95% CI 1-3) severe pain (VAS>70). The proportion of patients reporting any pain gradually decreased to 17% at one year, 16% at two years and to 10% at three and four years. From 3 months onwards, about 8% of the patients reported significant pain and about 2% severe pain. We discovered a phenomenon that has not been described yet. In 13% of the patients, pain recurred after a pain free interval. The intensity of this recurrent pain is mostly mild, but in a minority recurrent pain was severe.
One of the most widely used instruments to measure health status is EQ-5D. EQ-5D requires respondents to provide information about their health by recording the level of their problems (no problems, moderate problems, severe problems) on five dimensions (mobility, self-care, usual activities, pain or discomfort and anxiety or depression). These responses are classified into one of 243 unique EQ-5D health states, which are valuated based on responses to time trade off exercises collected from a sample of the general public. Therefore, the opinion of the general (mostly healthy) public is an important factor in calculating QALYs. However, a common observation is that patients often attribute a value to their own health state that differs from the societal value for the same health state. In general, individuals who are in a given health state tend to value that state more favourably than healthy individuals who are asked to consider that state hypothetically. There is reason to believe that this does not apply to the appreciation of chronic pain. We tested the hypothesis that patients with chronic pain will value their own health state lower than the general public, when asked to value the same health state hypothetically. This hypothesis is tested in two ways: First by comparing the EQ-5Dvas score of patients with the VAS score that society gives to that patient’s health state. This is done in several patient groups with diseases that represent pain and disability in varying degrees. Secondly, by comparing the values given to a number of hypothetical pain states in a sample of patients with and without chronic pain. The findings did not support the hypothesis. In contrast to our expectations, patients with coxarthrosis and Complex Regional Pain Syndrome valued their health state significantly higher than the values given to these health states by the general public. Patients with herpes zoster (acute pain) actually gave a lower value to their health state than the general public does to that health state. The discrepancy between patients with chronic pain and the general public was similar to the one found between patients with other diseases and the general public. This implies that the use of societal values in cost-effectiveness analyses does not result in an underestimation of the potential of chronic pain treatments.
In the analysis of the results of many trials a problem may rise: a treatment significantly reduces the incidence of a certain disease, that disease significantly reduces quality of life (QOL), but no significant effect of the treatment is found on quality of life as a secondary outcome measure of the trial. The power to detect a difference between the active group and the control group is too low. We present a method to improve the power of the QOL analysis. If the treatment has no long term side effects, it can be assumed that QOL is equal for all persons that do not suffer the disease, irrespective whether they are in the active or in the control group (first assumption). Similarly it may be true that QOL is equal for all patients that do have the disease, irrespective of the assigned treatment group (second assumption). These two assumptions can be used in a frequentist and in a Bayesian approach for analysis of QOL. Both were explored in a quantitative way by means of simulated trials. The results showed that both approaches increase the power to an acceptable level. For the frequentist approach, a stepwise analysis builds in a safeguard for making the wrong assumptions. The Bayesian approach has the major advantage of the possibility to use prior knowledge on certainty of the assumptions.