Postherpetic neuralgia (PHN) continues to be a significant clinical problem, with an average of 25% of patients developing persistent neuropathic pain after acute herpes zoster (HZ).1–8 The risk of PHN increases with age. Few children have PHN, whereas 49%, 65%, and 74% of adults older than 50, 60, and 70 yr of age, respectively, have PHN after acute HZ.9 PHN can become a severe and debilitating condition affecting all aspects of a patient’s life.10 The development of more effective treatments for preventing PHN has therefore become an important focus of current research.
It is believed that repetitive painful stimuli that reach the central nervous system might lead to central sensitization of the nociceptive system, the most important mechanism underlying long-lasting chronic pain.11 Interventions that decrease the repetitive painful stimuli and inflammation during the acute phase of HZ may attenuate central sensitization and substantially reduce the incidence of chronic pain.12,13 In support of this idea, epidemiological studies have shown that the prevalence of PHN is proportional to the degree of acute pain and inflammation in HZ.14 Because HZ mainly affects the sensory ganglia and adjacent neuronal tissues, interventions can be aimed at blocking the painful stimuli that reach the central nervous system and reducing the inflammation in this area. In this respect, epidural, intrathecal, and sympathetic nerve blocks have been used in the treatment of pain caused by HZ and PHN.15,16
Paravertebral block (PVB) is one of the easiest and most time-efficient techniques for providing analgesia by injecting local anesthetic in a space immediately lateral to where the spinal nerves emerge from the intervertebral foramina. PVB and epidural analgesia provide comparable pain relief, but PVB has a better side effect profile.17 In fact, PVB not only has a favorable effect on resolving the acute phase of HZ but also seems to be capable of preventing the onset of PHN.13,18–21 This randomized, controlled trial was designed to test the hypothesis that repetitive PVB with bupivacaine and methylprednisolone during the acute phase of HZ reduces the incidence of PHN.
This study was a prospective, randomized, clinical trial with a 1-yr follow-up period. The protocol of the study was approved by the Human Ethics Committee of the Fourth Military Medical University and was conducted in accordance with the Declaration of Helsinki and subsequent amendments. Written informed consent was obtained from all patients before inclusion.
From July 1, 2006, to June 30, 2007, 132 consecutive patients with HZ-associated pain diagnosed 1–7 days after the onset of the rash at the Pain Clinic of Xijing Hospital (one of the state’s largest hospitals in northwest China) were enrolled in this clinical trial. We defined acute HZ as a painful skin rash with blisters in a limited area on one side of the body, often in a stripe. Inclusion criteria were HZ within 7 days after onset of the rash, dermatome below C6, age older than 50 yr, and willingness to comply with the allocated treatment and follow-up measurements. We excluded patients with one or more of the following conditions: coagulation abnormalities, infection of the skin overlying the vertebra of the affected dermatome, psychiatric diseases, allergy to methylprednisolone or bupivacaine, and known serious immune disorders.
Baseline measurements of the clinical characteristics of the patients included pain severity and duration, localization of the rash, and quality of life. The patients were asked to quantify their averaged pain severity and changes in quality of life in the last 24 h. The severity of burning pain and lancinating pain was evaluated with the use of a 10-cm visual analog scale (VAS) (on which 0 cm represented no pain and 10 cm the worst imaginable pain). The severity of allodynia was also evaluated with the use of a 10-cm VAS. Quality of life was assessed by means of the Nottingham scale. After this, an administrative assistant immediately randomized the patient using a computer program with block randomization. The severity of pain and quality of life were evaluated just before randomization, at the end of 1 mo, and then 3 mo, 6 mo, and 1 yr after the end of treatment. Physicians who were unaware of the patients’ treatment assignments conducted the evaluations of pain severity.
The patients were randomized to one of the following treatment groups.
- Standard group: Patients randomized to the control group received the current standard treatment for herpes (oral administration of 800 mg acyclovir, 5 times daily for 7 days, and analgesics as needed). Patients were permitted to take the nonsteroidal antiinflammatory drug diclofenac (50-mg tablets, up to 4 times daily) at any time during the study. The use of oral narcotic or nonnarcotic analgesics other than diclofenac was prohibited, and no intrathecal, epidural, or neurolytic nerve blocks were administered during the entire follow-up period.
- Paravertebral group: Patients allocated to this group also received the above-mentioned standard treatment. Additionally, they were given repetitive paravertebral injections with a mixture of 10 mL 0.25% bupivacaine and 40 mg methylprednisolone acetate every 48 h for a week (total 4 injections at each desired level).
According to the lesion area of the skin and nerve segments of the pain, the injured nerves were determined and the levels for PVB selected. At each level, a 4-in., 21-gauge insulated needle (Stimuplex, B. Braun, Melsungen, Germany), attached to a nerve stimulator (initial stimulating current: 5 mA, 1 Hz, 9 V; Stimuplex, B. Braun), was introduced perpendicularly to the skin. After piercing the costotransverse ligament, a proper muscular response of the intercostal muscles of the corresponding level was obtained, and the needle’s tip was manipulated into a position allowing a muscular response while reducing the stimulating current to 0.4–0.6 mA. After aspiration of the syringe, the treatment solution was injected. The injection was always followed by verification of the disappearance of pain in the relevant dermatome. If disappearance of pain was not complete 30 min after injection, the procedure was repeated until this objective was achieved; this action was necessary in 2 patients. All injections were administered by the same physician.
We defined PHN as burning and lancinating pain that was accompanied by allodynia and that was restricted to the dermatomes involved in the original eruption of HZ. Follow-up examinations were performed at 1, 3, 6, and 12 mo after the end of the treatments by physicians who were unaware of the patients’ treatment assignments. During each follow-up examination, the patients were asked to categorize and assess the intensity of their pain using the following: 1) Presence of “pain” and its intensity, as measured on a 10-cm VAS. These patients demonstrated spontaneous, continuous, or intermittent pain and/or allodynia. 2) “Complete recovery” (patients without pain and/or allodynia: VAS = 0).
The patients enrolled in the study were given instructions on how to use the VAS scales. Provoked pain assessment was performed with the patient’s eyes closed and consisted of both the involved skin area and the healthy contralateral dermatome being rubbed lightly with a cotton ball or pinched lightly with tweezers.
The use of diclofenac was not permitted during the 24 h before each evaluation. The primary end point was the presence of zoster-associated pain 1 mo after inclusion. Presence and severity of pain at other time points were secondary end points. If a patient was not able to present at the pain clinic for examination, one of the physicians tried to complete the follow-up interview by telephone, which was necessary in 3 patients. All adverse events correlated with the paravertebral injection were recorded throughout the study.
Earlier studies showed an incidence of PHN of 49%–74% among those 50 yr or older.9 Based on an α of 5% and 80% power, we calculated that 56 patients were needed in each group to detect a clinically relevant reduction in the incidence of PHN from 52% to 25% 1 mo after the onset of the zoster rash. Allowing for 10% loss of follow-up, the required number of study patients was 124.
Statistical analyses were performed based on intent-to-treat. Two-tailed Z tests and χ2 tests were used to verify that the 2 groups were balanced in terms of demographic and clinical variables (sex, age, severity of pain, localization of HZ, and duration of rash). The Mann–Whitney test was used to analyze VAS scores between groups, and the χ2 test and Fisher’s exact test (for variables that had a low frequency in at least one cell) were used to compare the frequency of the presence or absence of pain. VAS scores are expressed as the median and range.
Of the132 enrolled patients, 68 (51%) were allocated to the standard treatment group and 64 (49%) assigned to the paravertebral injection group. Nineteen of these patients did not complete the study because of loss of follow-up. One hundred thirteen patients completed the 1-yr follow-up (58 in the standard group and 55 in the paravertebral group) (Fig. 1). The demographic and clinical characteristics of the patients before the start of the study did not differ significantly between the 2 groups (Table 1).
The incidence of reported pain and/or allodynia (VAS ≥1) was significantly reduced in the paravertebral group compared with standard group at each follow-up time point (Fig. 2, Table 2). At 1 mo posttherapy, 8 of 60 patients (13%) in the paravertebral group reported zoster-related pain and/or allodynia, compared with 29 of 64 (45%) in the standard group (P < 0.001, Fig. 2). At 3 and 6 mo posttherapy, significantly fewer patients in the paravertebral group had PHN than in the standard group (P = 0.001 and 0.003, respectively, Fig. 2, Table 2). After 1 yr, the incidence of PHN was still significantly lower in the paravertebral group (2%) than in the standard group (16%; P = 0.017, Fig. 2, Table 2). For those patients who did report pain and/or allodynia, the severity of pain and/or allodynia (VAS score) was similar in the 2 groups at all time points (Table 3).
The quality of life improved in both groups at each follow-up time point. At 1, 3, 6, and 12 mo posttherapy, the mean (sd) scores on the Nottingham scale decreased in the paravertebral group from 15.6 (8.2) to 9.8 (8.6), 6.3 (6.1), 5.8 (4.9), and 5.6 (5.0), respectively; the mean (sd) scores decreased in the standard group from 14.4 (7.2) to 10.8 (8.2), 8.3 (7.2), 6.8 (5.6), and 6.7 (5.4), respectively. There was no significant difference between the groups (P = 0.921).
All patients who had complete pain relief (VAS = 0) in the 2 groups stopped their analgesics immediately after the treatments. Those patients with pain continued to take analgesics, but no one was given paravertebral or epidural injections during the follow-up period. In the PVB group, the use of diclofenac decreased by more than 70% during treatment and the follow-up period. In the standard group, diclofenac use decreased by <20% during treatment. The decrease in diclofenac use was therefore significantly greater in the PVB group than in the standard group (P < 0.001). Of the 64 patients who received paravertebral injections, no adverse events were reported during the course of the study.
The findings of this randomized study show that repetitive paravertebral injections with bupivacaine and methylprednisolone in acute HZ within 7 days of rash onset reduced the incidence of PHN more effectively than standard treatment (oral administration of acyclovir and analgesics). The difference between treatments was observed as early as 1 mo and it lasted for up to 1 yr.
Historically, epidural, intrathecal, and sympathetic nerve blocks have all been used in the treatment of pain caused by HZ and PHN. However, there are a few well-controlled randomized trials of nerve blocks in the prevention of PHN, and their effects are still controversial. For example, Yanagida et al.22 reported no prophylactic effect of early sympathetic blockade on PHN. Two randomized clinical trials have been performed for the prevention of PHN by single or repetitive epidural injections of local anesthetics and corticosteroids in the acute phase of HZ. The study by van Wijck et al.23 showed that a single epidural injection of bupivacaine and methylprednisolone induced a moderate pain reduction within the first month after injection, but no long-lasting effect, and no effect on the incidence of PHN after 6 mo. Pasqualucci et al.24 reported that repetitive epidural administration of bupivacaine and methylprednisolone was significantly more effective in preventing PHN at 12 mo compared with IV acyclovir and prednisolone. These studies suggest that repetitive administration of anesthetic in combination with steroids is significantly more effective than treatment with a single injection in preventing PHN. In this study, we used a more convenient and safe approach; paravertebral injection, when promptly applied, can effectively prevent the occurrence of PHN.
It was accepted by some investigators that nerve blocks do not provide lasting relief in established PHN, but injection of corticosteroids has been suggested to be of some benefit. Kotani et al.16 published remarkable results after the intrathecal injection of methylprednisolone in patients with intractable PHN for at least 1 yr, which showed a 50% decrease in interleukin-8 concentrations, and this decrease correlated with the duration of neuralgia and with the extent of global pain relief. Therefore, we incorporated steroids in this study, the results of which are satisfactory without enhancing the risk of herpes dissemination or systemic dissemination, although such an effect has been observed by early investigators.25
In this study, we chose the first 1–7 days of the onset of acute HZ as the time for intervention. Our rationale is that interventions that decrease the repetitive painful stimuli and inflammation during the acute phase of HZ may attenuate central sensitization and substantially reduce the incidence of development of chronic pain.12,13 This rationale is supported by the observation that although sympathetic blocks terminated the pain of acute HZ and prevented or relieved PHN in patients treated within 2 mo of the onset of the acute phase of the disease, the success rate decreased drastically thereafter.26 We therefore presume that faster resolution of inflammation and less painful stimuli as a result of timely intervention treatment would account for the prevention of PHN.
It is suggested that intrathecal administration of local anesthetics and steroids was more effective than the epidural approach for relieving the pain and allodynia associated with PHN.27 Meanwhile, adding intrathecal steroids to local anesthetics has been shown to be more effective than local anesthetics alone.16 However, the risks of adhesive arachnoiditis imposed by intrathecal steroid administration continues to be a controversial issue.28 The repetitive PVB technique we used in this study achieved long-lasting pain relief without any adverse effect, thus establishing its distinctive efficacy and safety profile when properly administered and monitored.
There is a limitation in this study. The study was not designed to be double blind. Although a placebo-controlled trial would have been more appropriate in a study to measure the effectiveness that can be expected in a daily-care setting, we did not consider using the injection of placebo as a control. We judged such a trial to be unethical. Moreover, blinding would be difficult to maintain because the absence of immediate local analgesia after injection with placebo (for instance, steroid alone) or sham puncture reveals the assigned therapy.
In conclusion, this single-center trial suggests that repetitive anesthetic PVB in combination with steroids plus standard treatment with acyclovir and analgesics is significantly more effective than the standard treatment alone in preventing PHN. A large-scale multicenter clinical trial is needed to reliably determine whether there is a real benefit from this simple alternative treatment to prevent PHN.
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