The PINE study: rationale and design of a randomised comparison of epidural injection of local anaesthetics and steroids versus care-as-usual to prevent postherpetic neuralgia in the elderly [ISRCTN32866390]

Herpes zoster (HZ) or shingles is a common disease, with a reported incidence varying from 2.2 to 3.4/1000 persons/year [1‐4]. This incidence increases with age, rising from 2.4/1000 persons/year in younger subjects to 6.9/1000 persons/year in individuals older than 55 years of age [2, 4, 5]. The symptoms of HZ include a painful, vesicular rash with erythema.

It is a self-limiting disease for most patients, with healing of the skin and resolution of the pain generally occurring within three to four weeks. The most frequent complication of HZ is persistent pain that may last for several months or years, also called postherpetic neuralgia (PHN). PHN is commonly defined as the presence of HZ-related pain one month or more after the onset of the rash [5‐7], whereas some use the threshold of three months [8, 9]. This chronic pain has a potentially high impact on the quality of life. Many patients develop severe physical, occupational, and social disabilities as a consequence of their unceasing pain [8].

Depending on the applied definition, 9–34% of all HZ patients develop PHN. The risk of developing PHN is also age-dependent: the cumulative incidence of PHN is only 2% in HZ patients younger than 50 years of age, rising to about 20% in those older than 50 years and to 35% in those over 80 years [3, 10‐12]. Therefore, the number of patients with this disorder is expected to increase in our ageing society. Other important risk indicators for PHN include the severity of acute pain and inflammation during HZ.

Treatment of existing PHN has been rather disappointing. In fact, most treatment strategies such as tricyclic antidepressants [13, 14], topical capsaicin [15, 16], gabapentin [17], and controlled-release oxycodone [18], have demonstrated limited effects [19]. Intrathecal steroid injections appeared to be effective in one study [20]. Further evidence, however, of this invasive and potentially riskful intervention is lacking.

Much attention has therefore been given to strategies to prevent PHN [21]. Meta-analyses showed that antiviral medicines have no or limited effect on the incidence of PHN, although the duration of the HZ-related pain may be reduced [21, 22]. One small randomised controlled trial showed that early medical treatment with amitriptyline caused a 50% reduction in the occurrence of PHN [23]. At present, there is no more evidence available.

Another preventive strategy proposed is epidural administration of steroids with or without local anaesthetics. These drugs can be administered either repeatedly by means of an epidural catheter for a certain number of days [24] or through a single epidural injection [25, 26]. The latter is less burdensome for the patient and can be performed in an outpatient setting. Two retrospective, though uncontrolled, studies on this single epidural injection demonstrated a cumulative incidence of 2% of PHN when the injection was given during the acute phase of HZ, i.e. within one week from the onset of the rash [25, 26]. This suggests that it is a promising strategy for preventing PHN. However, referring all patients with HZ to an anaesthesiologist for a preventive epidural injection will increase short-term medical costs. Part of these costs may be offset by savings due to a decrease in the costs related to the treatment of PHN. Whether these savings will outweigh the increased initial costs is subject of research.

Since randomised trials on the effectiveness and the cost-effectiveness of a single epidural injection of steroids and local anaesthetics are lacking, the PINE (Prevention by epidural Injection of postherpetic Neuralgia in the Elderly) study was set up. This paper describes the rationale and design of the study, preceded by a brief outline of the current hypotheses of PHN pathophysiology and the possible modes of action of the intervention. In the discussion we will elaborate on dilemmas encountered when designing the study.

Some aspects of the design of the PINE study, however, must be addressed in order to appreciate its importance for primary care.

First, we specifically opted for a pragmatic trial instead of a placebo-controlled trial. An epidural injection is quite burdensome and not without risks. An epidural haematoma, for example, although rare, can occur and we feel that the risk of such severe complication makes it unethical to perform a sham injection. Besides, the addition of local anaesthetics offers immediate pain relief, which can not be realised by a placebo. The most important reason for a pragmatic approach, however, is that we aim to quantify the effect of an epidural injection as might be expected in future practice. Hence, we chose to evaluate the addition of the epidural injection to care-as-usual. Consequently, the placebo effects in this trial must be considered as part of the overall treatment effect that would also be encountered during care-as-usual in future HZ patients.

Second, the treatment in the control group was not standardised. Meta-analyses have shown that antiviral drugs, when given within 72 hours after the onset of the rash, have some effect on the duration of HZ-associated pain [21]. Hence, all patients participating in the PINE study who consult their GP within this time limit will be prescribed antiviral medicines. Since there is no clear proof of a difference in efficacy between the three antiviral drugs (aciclovir, famciclovir, and valaciclovir) on the development or duration of PHN, the choice of drug is left to the GP. However, the prescribed antiviral drug of each patient will be registered on the data forms. One consequence of not standardising the treatment protocol is that GPs may prescribe therapies in addition to the antiviral medication more often to those patients randomised to the care-as-usual (control) group. An additional therapy, for example, includes amitriptyline, which has been reported to potentially prevent the development of PHN [23]. Such therapies could reduce the observed difference in outcome between the two groups. Although the pre-emptive prescription of amitriptyline is unusual in The Netherlands, the careful registration of all prescribed drugs in relation to HZ will enable us to correct for the possible effect of any additional drug.

Third, epidural administration of steroids and local anaesthetics can be performed either repeatedly by means of an epidural catheter for a certain number of days [24] or through a single epidural injection [25, 26]. As the latter is less burdensome for the patients, can be performed in an outpatient setting, and is advocated by the Dutch Society of Anaesthesiology, we decided to evaluate the single rather than the multiple injection therapy.

Finally, we chose for the presence of HZ-related pain four weeks after enrolment in the trial as the primary outcome of the PINE study, because it is the most widely advocated definition of PHN [5, 6]. There is some controversy, however, about the definition of PHN with respect to the severity and the duration of pain after the onset of the rash [5‐7, 36‐38]. Some researchers define PHN as HZ-related pain that occurs after the rash has healed, while others describe it as HZ-related pain one [5, 6] or three months [13] after the onset of the rash. Hence, we chose as secondary outcomes the severity of pain at one month, the presence of HZ-related pain after three and six months since rash onset, and the duration of pain. To minimise bias that is inherent to a subjective endpoint in an open-label trial, we will systematically document endpoints using structured written questionnaires.

In summary, the PINE study is the first randomised trial to quantify the effectiveness and cost-effectiveness of an epidural injection of local anaesthetics and steroids on the prevention of postherpetic neuralgia in elderly patients with acute-phase herpes zoster. The results of this study may also facilitate the selection of HZ patients who are at risk of developing PHN.