original article Wien Klin Wochenschr DOI 10.1007/s00508-014-0669-3
Prevention of post-herpetic neuralgia using transcutaneous electrical nerve stimulation Aleksander Stepanovic · ´ Marko Kolšek · Janko Kersnik · Vanja Er culj ˇ
Received: 26 April 2014 / Accepted: 26 October 2014 © Springer-Verlag Wien 2014
Summary Background Post-herpetic neuralgia (PHN) is the most common complication of herpes zoster (HZ) and is difficult to treat. The role of antiviral agents and nonpharmacologic procedures in preventing PHN is not entirely clear. Recent retrospective study showed that transcutaneous electrical nerve stimulation (TENS) may completely prevent PHN. The aim of our study was to identify predictors for PHN and evaluate the treatment with antiviral agents and TENS. Methods We conducted a multicenter prospective, randomized intervention study in patients with a new onset of HZ. Immunocompromised patients were excluded. Patients were randomly assigned to four groups (TENS, Antiviral agents, TENS and Antiviral agents, and Control Group). At the inclusion, the following criteria were recorded: age, gender, duration of pain before the onset of the rash, the number of efflorescence, the intensity of pain, and the analgesic prescribed. During the follow-up, we recorded a spontaneous pain sensation, pain intensity, and presence of allodynia, hyperalgesia, or paraesthesia.
A. Stepanovi´c, MD () Zdravstveni dom Kranj, Gosposvetska ulica 10, 4000 Kranj, Slovenia e-mail: [email protected] Prof. M. Kolšek, PhD, MD Medical Faculty, University of Ljubljana, Poljanski nasip 58, 1000 Ljubljana, Slovenia Prof. J. Kersnik, PhD, MD Osnovno zdravstvo Gorenjske, Gosposvetska ulica 9, 4000 Kranj, Slovenia V. Erˇculj Ro sigma, Topniška 45, 1000 Ljubljana, Slovenia
13
Results With each additional year of age, the odds for the presence of PHN with unchanged values of other predictors increase (odds ratio (OR) = 1.03 [1.01; 1.05], p = 0.001). The same is true for the initial intensity of the pain (OR = 1.25 [1.09; 1.43], p = 0.002). The odds for acute and subacute herpetic neuralgia are greater than for PHN. The odds for subacute herpetic neuralgia are the lowest in the group treated with TENS (OR = 0.15 [0.05; 0.47], p = 0.001). Conclusions PHN cannot be completely prevented. TENS as a single therapy was found the most successful among the tested treatments in reducing the incidence of subacute herpetic neuralgia. Keywords Herpes zoster · Post-herpetic neuralgia · Transcutaneous electrical nerve stimulation
Prävention von Post-Zoster-Neuralgie durch transkutane elektrische Nervenstimulation Zusammenfassung Grundlagen Post-Zoster-Neuralgie (PZN) ist die häufigste Komplikation des Herpes Zoster (HZ) und ist schwer zu behandeln. Die Rolle von antiviralen Mitteln und nicht- pharmakologischen Verfahren bei der Verhinderung von PZN ist nicht umfassend geklärt. Eine aktuelle retrospektive Studie hat gezeigt, dass Transkutane Elektrische Nervenstimulation (TENS) PZN vollständig verhindern kann. Das Ziel unserer Studie war es, Prädiktoren für PZN zu identifizieren und die Behandlung mit antiviralen Mitteln und TENS zu bewerten. Methodik Wir haben eine multizentrische, prospektive randomisierte Interventionsstudie bei Patienten mit neuem Auftreten eines HZ durchgeführt. Immunsupprimierte Patienten wurden ausgeschlossen. Die Patienten wurden randomisiert vier Gruppen (TENS, antivirale Mittel, TENS und antivirale Mittel, Kontrollgruppe)
Prevention of post-herpetic neuralgia using transcutaneous electrical nerve stimulation
1
original article
zugeordnet. Die Auswertung erfolgte anhand folgender Kriterien: Alter, Geschlecht, Dauer der Schmerzen vor dem Einsetzen des Hautausschlags, die Anzahl von Ausblühungen, die Intensität von Schmerzen und die Anzahl verschriebener schmerzstillender Mittel. Während des Follow-up verzeichneten wir spontane Schmerzempfindungen, Schmerzintensität und das Vorhandensein von Allodynia, Hyperalgesie oder Parästhesie. Ergebnisse Mit jedem Lebensjahr steigen die Chancen für das Vorhandensein von PZN mit unveränderten Werten anderer Prädiktoren (OR = 1,03 [1,01; 1,05], p = 0,001). Das gleiche gilt für die anfängliche Intensität des Schmerzes (OR = 1,25 [1,09; 1,43], p = 0,002). Die Chancen für eine akute und subakute Zoster-Neuralgie sind größer als für PZN. Die Chancen für eine subakute Zoster-Neuralgie sind am niedrigsten in der Gruppe, die mit TENS (OR = 0,15 [0,05; 0,47], p = 0,001) behandelt wurde. Schlussfolgerungen PZN kann nicht vollständig verhindert werden. TENS als Einzeltherapie ist die erfolgreichste unter den getesteten Behandlungen bei der Verringerung der Häufigkeit von subakuter Neuralgie. Schlüsselwörter Herpes Zoster · Post-Zoster-Neuralgie · Transkutane Elektrische Nervenstimulation
Introduction Primary infection with varicella-zoster virus (VZV) is clinically manifested as chickenpox, which usually appear in childhood or early adolescence [1]. After infection, the VZV settles in the dorsal and cranial ganglia. Herpes zoster (HZ), also known as “shingles”, results from reactivation of VZV and its spread from a single ganglion to the neural tissue of the affected segment and the corresponding cutaneous dermatome [2]. A total of 60 % of cases occur in individuals aged 50 years or older [3]. Post-herpetic neuralgia (PHN) is the most common complication of HZ and is difficult to treat. PHN is defined as pain that occurs 3 months after the rash healing [4]. Some authors identify three distinct phases of pain: pain present within 30 days from the onset of HZ is defined as acute herpetic neuralgia, pain present between 30 and 120 days is defined as subacute herpetic neuralgia, and pain presenting after 120 days is defined as chronic pain or PHN [5, 6]. It is estimated that the prevalence of PHN is present in 2 % of patients younger than 50 years after HZ, approximately 20 % for those aged between 50 and 80 years, and up to 35 % for those aged more than 80 years [7–11]. Besides the patient age, the intensity of pain at the time of active HZ, the size of rash area, prodromal pain, and various psychological factors such as anxiety, depression, and life dissatisfaction are often mentioned as risk factors for PHN [12–16]. Gender has been suggested as another factor predisposing to PHN, with women suffering more than men, but this may be a result of the greater longevity of women [16]. Antiviral agents inhibit the replication of the virus in the acute phase of HZ and may reduce damage to nerve fibers and subse-
quent onset of PHN. This hypothesis was confirmed in a study with famcyclovir [12], whereas some other authors have found that antiviral agents appear to be effective in reducing PHN severity and its duration, but not its incidence [17]. A recent Cochrane review of six clinical studies indicate that acyclovir did not significantly reduce the incidence of PHN and that evidence for famcyclovir and other antiviral drugs are insufficient [18]. As the intensity of pain in the acute phase of HZ is an important risk factor for PHN, several authors tried to prove that pain relief in HZ might reduce the incidence of PHN. However, steroids and antidepressants proved to be ineffective in preventing PHN [19, 20]. The role of nonpharmacologic procedures in preventing PHN is not entirely clear [21]. Electro acupuncture is effective in relieving pain in patients with PHN [22, 23]. Transcutaneous electrical nerve stimulation (TENS) in combination with pregabalin was more effective in reducing PHN than placebo in combination with pregabalin [24]. TENS in combination with local cobalamin injection has been proved to have a significant analgesic effect in patients with PHN [25]. The results of recent retrospective study showed that TENS—used as a single treatment of HZ (without antiviral agents)—may completely prevent PHN [26]. This stimulated us to analyze the effectiveness of TENS for the treatment of HZ and prevention of PHN in a prospective study.
Methods We conducted a multicenter prospective, randomized intervention study at the primary health care level. Patients of both sexes with acute HZ who had signed the informed consent have been included in the study by their family doctors. Immunocompromised patients as well as the patients with HZ in the area of the eye or genitals, with any other acute infectious disease, patients who have had neuralgic pain prior to the current disease, patients with pacemakers, old scars on the site rashes, and those patients who due to compelling reasons would not be able to receive regular TENS or antivirotics were excluded from the study. Patients were randomized into four groups. 1. In the first two groups were patients younger than 50 years, which according to the recommendations do not necessary require treatment with antiviral agents [27], and those patients older than 50 years, who did not receive antiviral agents because of late diagnosis of the disease (more than 72 h after rash onset). In this first group, patients (n = 36, 16.2 %) received only TENS (and oral analgesics if needed). 2. In the second group, patients (n = 38; 17 %) were treated only symptomatically with analgesic, if needed; this group was used as the control group. 3. In the third group were patients (n = 71; 32 %) who received antiviral agents.
2 Prevention of post-herpetic neuralgia using transcutaneous electrical nerve stimulation
13
original article
4. In the fourth group were patients (n = 77; 34.7 %) who were treated with a combined treatment with antiviral agents and TENS as additional therapy. Among the patients who received antiviral agents, 141 patients received brivudine at a dose of 125 mg daily for 7 days and 7 patients received valacyclovir 1000 mg 3 × daily for 7 days. For TENS therapy, two electrodes of TENS device were used: one was attached near the root of affected nerve and the other in the course of that nerve. Stimulation frequency was 20–40 Hz, pulse duration 0.02 ms, and intensity 3–30 mA (until the patient felt a pleasant tingling). It took 10–15 sessions (depending on the period of rash healing), one session per day, lasting 30 min. At the beginning of the study, the following parameters were recorded: age, gender, duration of the pain before the onset of the rash, the number of efflorescence, the intensity of the pain as assessed by visual analog scale, and analgesic medication prescribed. Patients were followed up twice a week until the rash has disappeared. During this time, we recorded: the emergence of new efflorescence, the emergence of crusts, the intensity of pain, side effects of the treatment, and any complications of HZ. Patients were followed up three times more; 1, 3, and 6 months after the onset of the rash. At these three follow-ups, we recorded spontaneous feelings of pain, pain intensity, presence of allodynia, hyperalgesia and/ or paresthesia, and changes on the skin and prescribed therapy for pain relief. For statistical analysis of discrete data, we used the c2 test or likelihood ratio test when the expected frequency in any of the cells was lower than 5. The differences in the severity of pain by groups were tested by analysis of covariance, with time and type of treatment as independent variables. Control variables or covariates were: patient's age, duration of disease (efflorescence) before the first visit and intenisty of pain at the first visit. To determine the factors that influence the appearance of PHN, we carried out a repeated measures multivariate logistic regression, with the presence of PHN as the dependent variable. Independent variables were time, type of treatment, the initial intensity of pain, the patient’s age, number of efflorescence at the beginning of treatment, analgesics prescribed, and the correlation between time
and type of treatment. We assumed the same correlations between successive measurements. The study has been approved by the National Medical Ethics Committee on May 26th, 2009 No.246/05/09.
Results More women (n = 133; 60 %) than men (n = 89; 40 %) were included in the study. Difference in gender between the groups was not statistically significant (c2 = 1.63, p = 0.653). The mean age (median, standard deviation) in the control group was 59.9 (62, 18.94) years, in the “TENS” group was 57.3 (55.5, 21.7) years, in the “antivirals” group was 70.6 (73, 14.2) years, and the “TENS + antivirals group” was 65.6 (69, 71.3) years. In the latter two groups, patients were statistically significantly older than patients in the control and “TENS” group (Kruskall–Wallis c2 = 13. 98, p = 0.003) (Table 1). Patients in the control group came to the first visit later compared with the other groups. For one day disparity in pain odds for each of the groups compared with the control group were significantly lower (TENS: 0.89 [0.79, 0.99], p = 0.049; antivirals: 0.76 [0.67; 0.86], p 35)
0.49 (0.22; 1.09)
0.080
16–35 (> 35)
1 (0.48; 2.08)
0.999
Initial intensity of pain
1.25 (1.09; 1.43)
0.002
Analgesic (Yes)
0.03 (0.01; 0.09)
Prevention of post-herpetic neuralgia using transcutaneous electrical nerve stimulation Aleksander Stepanovic · ´ Marko Kolšek · Janko Kersnik · Vanja Er culj ˇ
Received: 26 April 2014 / Accepted: 26 October 2014 © Springer-Verlag Wien 2014
Summary Background Post-herpetic neuralgia (PHN) is the most common complication of herpes zoster (HZ) and is difficult to treat. The role of antiviral agents and nonpharmacologic procedures in preventing PHN is not entirely clear. Recent retrospective study showed that transcutaneous electrical nerve stimulation (TENS) may completely prevent PHN. The aim of our study was to identify predictors for PHN and evaluate the treatment with antiviral agents and TENS. Methods We conducted a multicenter prospective, randomized intervention study in patients with a new onset of HZ. Immunocompromised patients were excluded. Patients were randomly assigned to four groups (TENS, Antiviral agents, TENS and Antiviral agents, and Control Group). At the inclusion, the following criteria were recorded: age, gender, duration of pain before the onset of the rash, the number of efflorescence, the intensity of pain, and the analgesic prescribed. During the follow-up, we recorded a spontaneous pain sensation, pain intensity, and presence of allodynia, hyperalgesia, or paraesthesia.
A. Stepanovi´c, MD () Zdravstveni dom Kranj, Gosposvetska ulica 10, 4000 Kranj, Slovenia e-mail: [email protected] Prof. M. Kolšek, PhD, MD Medical Faculty, University of Ljubljana, Poljanski nasip 58, 1000 Ljubljana, Slovenia Prof. J. Kersnik, PhD, MD Osnovno zdravstvo Gorenjske, Gosposvetska ulica 9, 4000 Kranj, Slovenia V. Erˇculj Ro sigma, Topniška 45, 1000 Ljubljana, Slovenia
13
Results With each additional year of age, the odds for the presence of PHN with unchanged values of other predictors increase (odds ratio (OR) = 1.03 [1.01; 1.05], p = 0.001). The same is true for the initial intensity of the pain (OR = 1.25 [1.09; 1.43], p = 0.002). The odds for acute and subacute herpetic neuralgia are greater than for PHN. The odds for subacute herpetic neuralgia are the lowest in the group treated with TENS (OR = 0.15 [0.05; 0.47], p = 0.001). Conclusions PHN cannot be completely prevented. TENS as a single therapy was found the most successful among the tested treatments in reducing the incidence of subacute herpetic neuralgia. Keywords Herpes zoster · Post-herpetic neuralgia · Transcutaneous electrical nerve stimulation
Prävention von Post-Zoster-Neuralgie durch transkutane elektrische Nervenstimulation Zusammenfassung Grundlagen Post-Zoster-Neuralgie (PZN) ist die häufigste Komplikation des Herpes Zoster (HZ) und ist schwer zu behandeln. Die Rolle von antiviralen Mitteln und nicht- pharmakologischen Verfahren bei der Verhinderung von PZN ist nicht umfassend geklärt. Eine aktuelle retrospektive Studie hat gezeigt, dass Transkutane Elektrische Nervenstimulation (TENS) PZN vollständig verhindern kann. Das Ziel unserer Studie war es, Prädiktoren für PZN zu identifizieren und die Behandlung mit antiviralen Mitteln und TENS zu bewerten. Methodik Wir haben eine multizentrische, prospektive randomisierte Interventionsstudie bei Patienten mit neuem Auftreten eines HZ durchgeführt. Immunsupprimierte Patienten wurden ausgeschlossen. Die Patienten wurden randomisiert vier Gruppen (TENS, antivirale Mittel, TENS und antivirale Mittel, Kontrollgruppe)
Prevention of post-herpetic neuralgia using transcutaneous electrical nerve stimulation
1
original article
zugeordnet. Die Auswertung erfolgte anhand folgender Kriterien: Alter, Geschlecht, Dauer der Schmerzen vor dem Einsetzen des Hautausschlags, die Anzahl von Ausblühungen, die Intensität von Schmerzen und die Anzahl verschriebener schmerzstillender Mittel. Während des Follow-up verzeichneten wir spontane Schmerzempfindungen, Schmerzintensität und das Vorhandensein von Allodynia, Hyperalgesie oder Parästhesie. Ergebnisse Mit jedem Lebensjahr steigen die Chancen für das Vorhandensein von PZN mit unveränderten Werten anderer Prädiktoren (OR = 1,03 [1,01; 1,05], p = 0,001). Das gleiche gilt für die anfängliche Intensität des Schmerzes (OR = 1,25 [1,09; 1,43], p = 0,002). Die Chancen für eine akute und subakute Zoster-Neuralgie sind größer als für PZN. Die Chancen für eine subakute Zoster-Neuralgie sind am niedrigsten in der Gruppe, die mit TENS (OR = 0,15 [0,05; 0,47], p = 0,001) behandelt wurde. Schlussfolgerungen PZN kann nicht vollständig verhindert werden. TENS als Einzeltherapie ist die erfolgreichste unter den getesteten Behandlungen bei der Verringerung der Häufigkeit von subakuter Neuralgie. Schlüsselwörter Herpes Zoster · Post-Zoster-Neuralgie · Transkutane Elektrische Nervenstimulation
Introduction Primary infection with varicella-zoster virus (VZV) is clinically manifested as chickenpox, which usually appear in childhood or early adolescence [1]. After infection, the VZV settles in the dorsal and cranial ganglia. Herpes zoster (HZ), also known as “shingles”, results from reactivation of VZV and its spread from a single ganglion to the neural tissue of the affected segment and the corresponding cutaneous dermatome [2]. A total of 60 % of cases occur in individuals aged 50 years or older [3]. Post-herpetic neuralgia (PHN) is the most common complication of HZ and is difficult to treat. PHN is defined as pain that occurs 3 months after the rash healing [4]. Some authors identify three distinct phases of pain: pain present within 30 days from the onset of HZ is defined as acute herpetic neuralgia, pain present between 30 and 120 days is defined as subacute herpetic neuralgia, and pain presenting after 120 days is defined as chronic pain or PHN [5, 6]. It is estimated that the prevalence of PHN is present in 2 % of patients younger than 50 years after HZ, approximately 20 % for those aged between 50 and 80 years, and up to 35 % for those aged more than 80 years [7–11]. Besides the patient age, the intensity of pain at the time of active HZ, the size of rash area, prodromal pain, and various psychological factors such as anxiety, depression, and life dissatisfaction are often mentioned as risk factors for PHN [12–16]. Gender has been suggested as another factor predisposing to PHN, with women suffering more than men, but this may be a result of the greater longevity of women [16]. Antiviral agents inhibit the replication of the virus in the acute phase of HZ and may reduce damage to nerve fibers and subse-
quent onset of PHN. This hypothesis was confirmed in a study with famcyclovir [12], whereas some other authors have found that antiviral agents appear to be effective in reducing PHN severity and its duration, but not its incidence [17]. A recent Cochrane review of six clinical studies indicate that acyclovir did not significantly reduce the incidence of PHN and that evidence for famcyclovir and other antiviral drugs are insufficient [18]. As the intensity of pain in the acute phase of HZ is an important risk factor for PHN, several authors tried to prove that pain relief in HZ might reduce the incidence of PHN. However, steroids and antidepressants proved to be ineffective in preventing PHN [19, 20]. The role of nonpharmacologic procedures in preventing PHN is not entirely clear [21]. Electro acupuncture is effective in relieving pain in patients with PHN [22, 23]. Transcutaneous electrical nerve stimulation (TENS) in combination with pregabalin was more effective in reducing PHN than placebo in combination with pregabalin [24]. TENS in combination with local cobalamin injection has been proved to have a significant analgesic effect in patients with PHN [25]. The results of recent retrospective study showed that TENS—used as a single treatment of HZ (without antiviral agents)—may completely prevent PHN [26]. This stimulated us to analyze the effectiveness of TENS for the treatment of HZ and prevention of PHN in a prospective study.
Methods We conducted a multicenter prospective, randomized intervention study at the primary health care level. Patients of both sexes with acute HZ who had signed the informed consent have been included in the study by their family doctors. Immunocompromised patients as well as the patients with HZ in the area of the eye or genitals, with any other acute infectious disease, patients who have had neuralgic pain prior to the current disease, patients with pacemakers, old scars on the site rashes, and those patients who due to compelling reasons would not be able to receive regular TENS or antivirotics were excluded from the study. Patients were randomized into four groups. 1. In the first two groups were patients younger than 50 years, which according to the recommendations do not necessary require treatment with antiviral agents [27], and those patients older than 50 years, who did not receive antiviral agents because of late diagnosis of the disease (more than 72 h after rash onset). In this first group, patients (n = 36, 16.2 %) received only TENS (and oral analgesics if needed). 2. In the second group, patients (n = 38; 17 %) were treated only symptomatically with analgesic, if needed; this group was used as the control group. 3. In the third group were patients (n = 71; 32 %) who received antiviral agents.
2 Prevention of post-herpetic neuralgia using transcutaneous electrical nerve stimulation
13
original article
4. In the fourth group were patients (n = 77; 34.7 %) who were treated with a combined treatment with antiviral agents and TENS as additional therapy. Among the patients who received antiviral agents, 141 patients received brivudine at a dose of 125 mg daily for 7 days and 7 patients received valacyclovir 1000 mg 3 × daily for 7 days. For TENS therapy, two electrodes of TENS device were used: one was attached near the root of affected nerve and the other in the course of that nerve. Stimulation frequency was 20–40 Hz, pulse duration 0.02 ms, and intensity 3–30 mA (until the patient felt a pleasant tingling). It took 10–15 sessions (depending on the period of rash healing), one session per day, lasting 30 min. At the beginning of the study, the following parameters were recorded: age, gender, duration of the pain before the onset of the rash, the number of efflorescence, the intensity of the pain as assessed by visual analog scale, and analgesic medication prescribed. Patients were followed up twice a week until the rash has disappeared. During this time, we recorded: the emergence of new efflorescence, the emergence of crusts, the intensity of pain, side effects of the treatment, and any complications of HZ. Patients were followed up three times more; 1, 3, and 6 months after the onset of the rash. At these three follow-ups, we recorded spontaneous feelings of pain, pain intensity, presence of allodynia, hyperalgesia and/ or paresthesia, and changes on the skin and prescribed therapy for pain relief. For statistical analysis of discrete data, we used the c2 test or likelihood ratio test when the expected frequency in any of the cells was lower than 5. The differences in the severity of pain by groups were tested by analysis of covariance, with time and type of treatment as independent variables. Control variables or covariates were: patient's age, duration of disease (efflorescence) before the first visit and intenisty of pain at the first visit. To determine the factors that influence the appearance of PHN, we carried out a repeated measures multivariate logistic regression, with the presence of PHN as the dependent variable. Independent variables were time, type of treatment, the initial intensity of pain, the patient’s age, number of efflorescence at the beginning of treatment, analgesics prescribed, and the correlation between time
and type of treatment. We assumed the same correlations between successive measurements. The study has been approved by the National Medical Ethics Committee on May 26th, 2009 No.246/05/09.
Results More women (n = 133; 60 %) than men (n = 89; 40 %) were included in the study. Difference in gender between the groups was not statistically significant (c2 = 1.63, p = 0.653). The mean age (median, standard deviation) in the control group was 59.9 (62, 18.94) years, in the “TENS” group was 57.3 (55.5, 21.7) years, in the “antivirals” group was 70.6 (73, 14.2) years, and the “TENS + antivirals group” was 65.6 (69, 71.3) years. In the latter two groups, patients were statistically significantly older than patients in the control and “TENS” group (Kruskall–Wallis c2 = 13. 98, p = 0.003) (Table 1). Patients in the control group came to the first visit later compared with the other groups. For one day disparity in pain odds for each of the groups compared with the control group were significantly lower (TENS: 0.89 [0.79, 0.99], p = 0.049; antivirals: 0.76 [0.67; 0.86], p 35)
0.49 (0.22; 1.09)
0.080
16–35 (> 35)
1 (0.48; 2.08)
0.999
Initial intensity of pain
1.25 (1.09; 1.43)
0.002
Analgesic (Yes)
0.03 (0.01; 0.09)
