Post-Herpetic Neuralgia

Number: 0725

Table Of Contents

Policy

Scope of Policy

This Clinical Policy Bulletin addresses post-herpetic neuralgia.

1. Medical Necessity

   Aetna considers the use of intrathecal, interlaminar, or transforaminal epidural corticosteroids medically necessary for post-herpetic neuralgia (PHN). 

2. Experimental, Investigational, or Unproven

   Aetna considers any the following diagnostic/therapeutic modalities for PHN experimental, investigational, or unproven because their effectiveness for these indications have not been established (not an all-inclusive list):

   1. Acupoint herbal patching
   2. Acupuncture
   3. Blood-letting puncture and cupping
   4. Combined pulsed radiofrequency and transforaminal epidural steroid injection
   5. Combined therapy of nerve block and pulsed radiofrequency
   6. Combination of trigeminal ganglion and retrobulbar nerve block
   7. Cryocautery
   8. Dorsal root entry zone lesions/dorsal root ganglion destruction
   9. Epidural morphine
   10. Extracorporeal shockwave therapy
   11. Ganglioside GM1
   12. Injectable biperiden
   13. Injectable chlorprothixene
   14. Intercostal nerve block
   15. Intralesional corticosteroid
   16. Intravenous antiviral therapy
   17. Intravenous ketamine
   18. Intravenous lidocaine
   19. Intravenous nicardipine
   20. Intravenous vitamin C
   21. Intravenous zinc sulfate
   22. Iontophoresis of vincristine
   23. Laser irradiation
   24. Low-level laser therapy (LLLT)
   25. Narrow-band ultraviolet light B
   26. Ozone injection into the intervertebral foramen
   27. Peripheral nerve stimulation
   28. Pulsed radiofrequency of the dorsal root ganglion
   29. Serum level of miR-34c-5p for diagnosis of postherpetic neuralgia, and evaluation of rehabilitation effect
   30. Stellate ganglion blockade
   31. Sympathectomy
   32. Thermotherapy (including fire needle and moxibustion)
   33. Transcranial magnetic stimulation
   34. Transcutaneous electrical nerve stimulation (TENS)
   35. Trigeminal nerve block
   36. Vitamin B-12 injection (see CPB 0536 - Vitamin B-12 Therapy);

3. Related Policies

   Refer to applicable pharmacy benefit plan for capsaicin topical (Qutenza).

   See also:

   • CPB 0011 - Peripheral Electrical Nerve Stimulation for Pain
   • CPB 0113 - Botulinum Toxin
   • CPB 0115 - Varicella and Herpes Zoster Vaccines
   • CPB 0135 - Acupuncture and Dry Needling
   • CPB 0194 - Spinal Cord Stimulation
   • CPB 0297 - Cryoanalgesia and Therapeutic Cold
   • CPB 0536 - Vitamin B-12 Therapy
   • CPB 0735 - Pulsed Radiofrequency.

Background

Herpes zoster (HZ) results from the reactivation of the varicella zoster virus, which remains latent after the primary infection (varicella). Once a person is infected with herpes zoster, the virus sequesters itself in the nerve roots and can reappear, traveling down the dermatome where it resides. This flare-up is typically characterized by local and radiating pain throughout the dermatome. Patients are often treated with antivirals such as acyclovir or valacyclovir. In some cases, the virus causes noticeable nerve damage, leading to moderate to severe pain that radiates, similar to most neuropathies. This condition is known as post-herpetic neuralgia (PHN).

The overall incidence of HZ is approximately 3 per 1,000 of the population per year, increasing to 10 per 1,000 per year by age 80. About half of individuals reaching age 90 will have experienced HZ. A second episode of HZ may occur in approximately 6% of cases, typically several decades after the first attack. The most common complication of HZ is PHN, defined as significant pain or dysesthesia persisting for 3 months or more following HZ. More than 5% of the elderly experience PHN one year after acute HZ. Reduced cell-mediated immunity to HZ occurs with aging, which may explain the increased incidence in the elderly, as well as in individuals with tumors, human immunodeficiency virus infection, or those receiving immunosuppressant drugs. Diagnosis of PHN is usually clinical, based on typical unilateral dermatomal pain and rash, with common prodromal symptoms including pain, itching, and malaise (Johnson and Whitton, 2004).

The observation that patients with PHN experience different types of pain (e.g., continuous burning or intense paroxysmal pain, often accompanied by tactile allodynia) suggests that multiple pathophysiological mechanisms are involved, potentially affecting both the peripheral and central nervous systems. Traditional treatments for PHN typically include tricyclic antidepressants (TCA) such as amitriptyline, nortriptyline, desipramine, and maprotiline; antiepileptic drugs like gabapentin and pregabalin; topical 5% lidocaine patches (Lidoderm), which often reduce allodynia; as well as long-acting oral opioid preparations and tramadol (Ultram). Oral antiviral agents (acyclovir, famciclovir, valaciclovir) are used during an acute herpes zoster attack to prevent the development of PHN (Wareham, 2006). There is evidence that intrathecal corticosteroids may be effective in patients who do not respond to conservative measures (Wu and Raja, 2008; Hempenstall et al., 2005), but caution is advised due to the potential for neurological sequelae (Christo et al., 2007). Epidural corticosteroids have not been shown to provide effective analgesia for PHN (Christo et al., 2007). Many alternative treatments for PHN, such as cryocautery, dorsal column (spinal cord) stimulation, iontophoresis of vincristine, intravenous administration of ketamine (an N-methyl-D-aspartate [NMDA] antagonist), laser therapy, peripheral nerve stimulation, and transcutaneous electrical nerve stimulation (TENS), have not been adequately studied.

Iontophoresis has been suggested as a potentially effective treatment for PHN (Ozawa et al., 1999). However, a randomized controlled trial by Dowd et al. (1999) reported that iontophoresed vincristine was no more effective than iontophoresed saline in treating this condition. Although TENS has been reported to benefit some patients with PHN (Milligan and Nash, 1985; Robertson and George, 1990), these findings have not been validated by randomized controlled studies. Furthermore, on behalf of the Canadian Coordinating Office for Health Technology Assessment (CCOHTA), Reeve and Corabian (1995) evaluated the scientific evidence regarding the clinical effectiveness of TENS for treating acute, chronic, and labor-related pain, concluding that there is little evidence supporting TENS as an effective treatment for chronic pain.

In a review on sympathectomy for neuropathic pain, Mailis and Furlan (2003) stated that the practice of surgical and chemical sympathectomy is based on poor-quality evidence, uncontrolled studies, and anecdotal experience. Additionally, complications from the procedure may be significant, potentially worsening pain or producing new pain syndromes, as well as causing abnormal sweating (e.g., compensatory hyperhidrosis and pathological gustatory sweating). The authors concluded that more clinical studies are needed to establish the potential risks and overall effectiveness of sympathectomy.

In a pilot study involving 10 patients, Johnson and Burchiel (2004) found that peripheral nerve stimulation of the supra-orbital or infra-orbital branches of the trigeminal nerve effectively relieved trigeminal neuropathic pain following facial trauma or herpetic infection. The investigators suggested that a prospective clinical trial using this novel approach to treat these disorders is warranted. A recent Cochrane review (Mailis-Gagnon et al., 2004) on spinal cord stimulation (SCS) concluded that, although there is limited evidence supporting SCS for failed back surgery syndrome and complex regional pain syndrome (also known as reflex sympathetic dystrophy), more research is needed to confirm whether SCS is an effective treatment for other types of chronic pain. Gilden et al. (2005) noted that because only a few studies have utilized antiviral therapy to manage PHN, with conflicting results, larger, double-blind studies administering intravenous antiviral drugs are needed. Thus, well-designed, multi-center, controlled clinical trials are necessary to ascertain the effectiveness of various alternative treatments for PHN.

An earlier systematic review of randomized controlled trials on treatments for PHN (Volmink et al., 1996) reported that pooled analysis of the effects of TCA demonstrated statistically significant pain relief. However, pooling the results of three studies comparing the effects of capsaicin and placebo could not be performed due to heterogeneity, primarily attributable to an unpublished trial that differed in dosage and duration of treatment. When this study was excluded, no heterogeneity was found, and the pooled analysis revealed a statistically significant benefit. Nonetheless, issues with blinding in patients using capsaicin may have influenced the positive effect. One small study comparing iontophoresis of vincristine to placebo yielded favorable results. Other therapies evaluated included lorazepam, acyclovir, topical benzydamine, and acupuncture, but there was no evidence that these treatments effectively relieved pain associated with PHN. The investigators concluded that, based on evidence from randomized trials, TCAs appear to be the only agents with proven benefit for established PHN.

“An evidence-based report on the treatment of PNH, developed by the Quality Standards Subcommittee of the American Academy of Neurology (Dubinsky et al., 2004), consider the effectiveness of nicardipine, biperiden, and chlorprothixene as unproven in the treatment for PNH.”

Christo et al. (2007) stated that epidural corticosteroids have not been shown to provide effective analgesia for post-herpetic neuralgia (PHN). Furthermore, Wu and Raja (2008) noted that the majority of interventional therapies demonstrate equivocal analgesic efficacy, although some data suggest that intrathecal methylprednisolone may be effective. The authors emphasized that further randomized controlled trials are necessary to confirm the analgesic efficacy of various analgesic and interventional therapies, including sympathetic nerve blocks, other nerve blocks, intrathecal methylprednisolone, and spinal cord stimulation, to determine their role in the overall treatment of patients with PHN.

In a Cochrane review, He et al. (2008) examined the effectiveness of corticosteroids in preventing PHN. The review included individuals of all ages with herpes zoster of varying severity, provided they were treated within 7 days after the onset of the rash. The interventions assessed included corticosteroids administered orally, intramuscularly, or intravenously during the acute stage (starting within one week of rash onset) compared to no treatment or placebo, but not compared with other treatments. The primary outcome measure was the presence of PHN 6 months after the onset of the acute herpetic rash. Secondary outcome measures included pain severity assessed by a validated visual analog scale (VAS) or numerical descriptive scale at 3, 6, and 12 months; quality of life measured with the Short Form 36 questionnaire after 6 months; and adverse events occurring during or within 2 weeks after stopping treatment. Five trials were included, encompassing a total of 787 participants, all of which were randomized, double-blind, placebo-controlled parallel group studies. The results showed no significant difference between the corticosteroid and control groups for the primary outcome (risk ratio [RR] 1.27, 95% confidence interval [CI]: 0.20 to 7.97). Additionally, there was no significant difference between the corticosteroid plus antiviral agents and placebo plus antiviral agents groups for the primary outcome (RR 0.90, 95% CI: 0.40 to 2.03). None of the included trials evaluated pain severity using a validated VAS or numerical descriptive scale, nor did any measure quality of life with the Short Form 36 questionnaire. Adverse events during or within 2 weeks after stopping treatment were reported by all five included trials; however, after meta-analysis, there was no significant difference in any serious adverse events (e.g., death, acute cardiac insufficiency, rash dissemination, bacterial pneumonia, or hematemesis) or non-serious adverse events (e.g., dizziness, nausea, vomiting, hypertension, or hyperglycemia). The authors concluded that there is insufficient evidence to support the safety or effectiveness of corticosteroids in preventing PHN. They stated that more randomized controlled trials with larger participant numbers are needed to reliably determine whether corticosteroid therapy provides real benefits or harms in preventing PHN, and that future trials should also measure functional outcomes and quality of life.

A Clinical Evidence systematic evidence review concluded that corticosteroids for post-herpetic neuralgia are likely to be ineffective or harmful in preventing post-herpetic neuralgia (Wareham, 2006). The evidence review noted that, not only have corticosteroids not been proven to be effective for this indication, but they may cause dissemination of herpes zoster.

Schencking and associates (2010) reported the findings of intravenous administration of vitamin C in the treatment of 2 patients with PHN. These 2 subjects (females aged 67 and 53 years) were from an average and unselected patient group of a general practice with confirmed acute herpetic neuralgia who were observed in the course of their illness. They received the basic analgesic (according to the WHO step scheme) and viral-static therapy. Furthermore, 15-g of vitamin C was administered intravenously every second day over a period of 2 weeks. Sudden and total remission of the neuropathic pain (measured on the basis of VAS) could be observed. Remission of the cutaneous lesions was noted within 10 days. The use of the vitamin C appears to be an interesting component of alternative therapeutic strategies in the treatment of HZ. Especially for therapy-resistant cases of PHN, vitamin C administration should be examined as an additional option. The authors concluded that to test and confirm these clinical findings, randomized clinical trials regarding the use of vitamin C in the concomitant treatment of zoster-associated neuralgia should be performed.

In a randomized, double-blind study, Backonja et al. (2008) examined the safety and effectiveness of one application of NGX-4010, a high-concentration (8%) capsaicin dermal patch, in the treatment of patients with PHN. A total of 402 patients were randomly assigned to one 60-min application of NGX-4010 (640 microg/cm(2) or a low-concentration capsaicin control patch (3.2 microg/cm(2) [0.04% capsaicin]). Patients were aged 18 to 90 years, had had PHN for at least 6 months, and had an average baseline numeric pain rating scale (NPRS) score of 3 to 9. The primary efficacy end point was percentage change in NPRS score from baseline to weeks 2 to 8. Analysis was by intention-to-treat. Patients who were randomly assigned to NGX-4010 (n = 206) had a significantly greater reduction in pain during weeks 2 to 8 than did patients who had the control patch (n = 196). The mean changes in NPRS score were -29.6% versus -19.9% (difference -9.7%, 95% CI: -15.47 to -3.95; p = 0.001). A total of 87 (42%) patients who received NGX-4010 and 63 (32%) controls had a 30% or greater reduction in mean NPRS score (odds ratio [OR] 1.56, 95% CI: 1.03 to 2.37; p = 0.03). Patients who had NGX-4010 had significant improvements in pain during weeks 2 to 12 (mean change in NPRS score -29.9% versus -20.4%, difference -9.5, -15.39 to -3.61; p = 0.002). Transient blood pressure changes associated with changes in pain level were recorded on the day of treatment, and short-lasting erythema and pain at the site of application were common, self-limited, and generally mild-to-moderate in the NGX-4010 group and less frequent and severe in the controls. The authors concluded that one 60-min application of NGX-4010 provided rapid and sustained pain relief in patients with PHN. No adverse events were associated with treatment except for local reactions at the site of application and those related to treatment-associated pain.

In a Cochrane review, Derry et al. (2009) reviewed the evidence from controlled trials on the efficacy and tolerability of topically applied capsaicin in chronic neuropathic pain in adults. Randomized, double-blind, placebo-controlled studies of at least 6 weeks' duration, using topical capsaicin to treat neuropathic pain were included in this analysis. A total of 6 studies (389 participants in total) compared regular application of low dose (0.075%) capsaicin cream with placebo cream; the numbers needed to treat to benefit (NNT) for any pain relief over 6 to 8 weeks was 6.6 (4.1 to 17). Two studies (709 participants in total) compared a single application of high dose (8%) capsaicin patch with placebo patch; the NNT for greater than or equal to 30% pain relief over 12 weeks was 12 (6.4 to 70). Local skin reactions were more common with capsaicin, usually tolerable, and attenuated with time; the numbers needed to treat to harm (NNH) for repeated low dose application was 2.5 (2.1 to 3.1). There were insufficient data to analyze either data set by condition or outcome definition. All studies satisfied minimum criteria for quality and validity, but maintenance of blinding remains a potential problem. The authors concluded that capsaicin, either as repeated application of a low dose (0.075%) cream, or a single application of a high dose (8%) patch may provide a degree of pain relief to some patients with painful neuropathic conditions. Local skin irritation, which is often mild and transient but may lead to withdrawal, is common. Systemic adverse effects are rare. Estimates of benefit and harm are not robust due to limited amounts of data for different neuropathic conditions and inconsistent outcome definition.

In a randomized, double-blind, controlled study with an open-label extension, Backonja et al. (2010) evaluated the safety, effectiveness and tolerability of NGX-4010 in patients with PHN. Patients were randomized to receive NGX-4010 or control patch in a 4-week, double-blind study. This was followed by an open-label extension phase (up to 48 weeks total) where patients could receive up to 3 additional treatments no sooner than 12 weeks after initial treatment. The primary efficacy variable was mean change from baseline in mean morning and evening NPRS scores. During days 8 to 28 after the double-blind treatment, NGX-4010 patients had a mean change in NPRS scores from baseline of -32.7% compared with -4.4% for control patients (p = 0.003). Mean NPRS scores decreased from baseline during week 1 in both treatment groups, remained relatively stable through week 12 in NXG-4010 patients, but returned to near baseline during weeks 2 to 4 in controls. Mean change in NPRS scores from baseline during weeks 2 to 12 was -33.8% for NGX-4010 and +4.9% for control recipients. A similar decrease in NPRS scores from baseline was maintained with subsequent NGX-4010 treatments, regardless of the number of treatments received. Transient increases in application site pain were adequately managed with analgesics. No increases in application site reactions or adverse events were observed with repeated treatments. No patients discontinued the study due to an adverse event. The authors concluded that NGX-4010 is a promising topical treatment for PHN patients, which appears to be tolerable, generally safe, and effective.

In an open-label study, Simpson and associates (2010) assessed the safety of repeated applications of NGX-4010 over 1 year in patients with moderate to severe PHN or human immunodeficiency virus-associated distal sensory polyneuropathy (HIV-DSP). Patients had successfully completed a previous NGX-4010 study and had a pain level appropriate for further treatment. Eligible patients had not been treated with NGX-4010 within 12 weeks of study initiation. Patients received pre-treatment with a topical local anesthetic (lidocaine 4%) for 60 minutes followed by either a 60-minute (PHN and HIV-DSP patients) or a 90-minute (HIV-DSP patients) treatment with NGX-4010. Patients could receive up to 3 additional treatments at intervals of greater than or equal to 12 weeks. Regardless of the number of treatments received, all patients were followed-up for 48 weeks except for those withdrawing early. A total of 106 patients were enrolled and received a total of 293 NGX-4010 treatments. The most frequently reported treatment-emergent adverse events were transient, mild-to-moderate application site erythema, pain, edema, and papules. Small, transient pain-related increases in blood pressure during and immediately after NGX-4010 application were observed. There was no evidence of an increased incidence of adverse events, dermal irritation, intolerability, or impaired neurological function with repeated treatments. The authors concluded that repeated treatments with NGX-4010 administered over a 1-year period are generally safe and well-tolerated.

McCormack (2010) stated that capsaicin dermal patch is an adhesive patch containing a high concentration (8% w/w) of synthetic capsaicin. It is indicated in the European Union for the treatment of peripheral neuropathic pain in non-diabetic adults using a single 30- or 60-minute application repeated every 90 days, as required, and in the United States for the treatment of neuropathic pain associated with PHN. In pivotal, randomized, double-blind, multi-center trials in adults with PHN, a single 60-minute application of capsaicin dermal patch reduced the mean NPRS scores from baseline to a significantly greater extent than a low-concentration (0.04% w/w capsaicin) control patch during weeks 2 to 8. In randomized, double-blind, multi-center trials in patients with HIV-associated neuropathy, capsaicin dermal patch reduced the mean NPRS scores from baseline significantly more than control in 1 study for the 30- and 90-minute, but not the 60-minute, application during weeks 2 to 12. In another study, the differences between capsaicin (30- and 60-minute applications) and control did not reach statistical significance. An integrated analysis of both studies showed that the 30-minute application of capsaicin dermal patch was significantly better than control for the reduction from baseline in mean NPRS scores during weeks 2 to 12. The efficacy of capsaicin dermal patch was maintained for up to 1 year in extension studies in which patients could receive up to 3 or 3 repeat treatments. Capsaicin dermal patch was generally well-tolerated in clinical trials. The most common adverse events were transient, mostly mild-to-moderate, application-site reactions.

On November 16, 2009, the Food and Drug Administration approved Qutenza (capsaicin, 8% patch) for the treatment of neuropathic pain associated with PHN. The capsaicin in Qutenza (capsaicin) 8% patch is a synthetic equivalent of the naturally occurring compound found in chili peppers. Capsaicin is an agonist for the transient receptor potential vanilloid 1 receptor (TRPV1), which is an ion channel‐receptor complex expressed on nociceptive nerve fibers in the skin. Topical administration of capsaicin causes an initial enhanced stimulation of the TRPV1‐expressing cutaneous nociceptors that may be associated with painful sensations. This is followed by pain relief thought to be mediated by a reduction in TRPV1‐expressing nociceptive nerve endings. Over the course of several months, there may be a gradual re‐emergence of painful neuropathy thought to be due to TRPV1 nerve fiber reinnervation of the treated area.

Qutenza must be applied to the skin by a health care professional since placement of the patch can be quite painful, requiring use of a local topical anesthetic, as well as additional pain relief such as ice or use of opioid pain relievers. The patient must also be monitored for at least 1 hour since there is a risk of a significant rise in blood pressure following patch placement. The product insert of Qutenza states that the patches should be applied to the most painful skin areas, using up to 4 patches. Furthermore, the patches should be applied for 60 minutes and repeat every 3 months or as warranted by the return of pain (not more frequently than every 3 months).

There are no controlled studies with pregnant or lactating mothers. The safety and efficacy of Qutenza in patients under the age of 18 has also not been studied. Studies did involve patients over 75 years of age with similar efficacy and safety profiles. Therefore no dose adjustments are required in the geriatric population.

According to the 2004 American Academy of Neurology treatment guidelines for post-herpetic neuralgia, the magnitude of benefit for topical capsaicin is below the level that is considered clinically important in the treatment of chronic pain related to post‐herpetic neuralgia. Since the guidelines have not been updated since 2004, the same AAN evidence rating tool was used to evaluate the two Qutenza trials cited in the package insert. Both studies were prospective, randomized, double‐blind controlled trials. Primary outcomes and drop‐out rationale were clearly defined. The endpoints were mean percent reductions in Numeric Pain Rating Scale (NPRS) score from baseline. Pain endpoints such as these, are subject to user bias. In addition possible confounders in these studies were the fact that half of the patients were allowed to continue taking their current pain regimen and the subjects were also allowed to take extra pain medications during the treatment period as well. Both endpoints did not reach statistically significance, only showed pain improvement. The patients who did not complete the trials were assigned to 0% improvement which is a conservative approach when evaluating outcomes. These trials would be classified as AAN Class II because of the potential bias and the lack of convincing evidence to support Qutenza’ use in PHN.

Young and colleagues (2017) noted that capsaicin has been traditionally used to manage pain; however, the safety and effectiveness of this practice is still elusive. These researchers examined the effect of topical capsaicin in pain management. All double-blinded, randomized placebo- or vehicle-controlled trials that were published in English addressing PHN were included.  Meta-analysis was performed using Revman version 5.3. Upon application of the inclusion and exclusion criteria, only 6 trials fulfilled all the criteria and were included in the review for qualitative analysis. The difference in mean percentage change in NPRS score ranged from -31 to -4.3. This demonstrated high efficacy of topical capsaicin application and implied that capsaicin could result in pain reduction. Furthermore, meta-analysis was performed on 5 of the included studies. All the results of studies were in favor of the treatment using capsaicin. The incidence of side effects from using topical capsaicin is consistently higher in all included studies, but the significance of safety data cannot be quantified due to a lack of p-values in the original studies. The authors concluded that topical capsaicin is a promising therapeutic option for specific patient groups or certain neuropathic pain conditions such as PHN.

In a pilot study, Nabarawy et al. (2011) evaluated the effect of narrow-band ultra-violet light B (nbUVB) in the treatment PHN. The study included 17 patients with distressing PHN. Patients were evaluated using the Verbal Rating Scale (VRS). They received nbUVB sessions, 3 times a week, for a total of 15 sessions or until the pain disappeared.  Patients were followed-up for a period of 3 months after the end of therapy.  Using intention-to-treat analysis, more than 50% improvement was achieved in 6 (35.29%) and 8 (47.06%) patients, at the end of therapy and after 3 months follow-up, respectively.  An improvement of less than 50% was achieved in 11 (64.71%) and 9 (52.94%) patients, at the end of therapy and after 3 months follow-up, respectively. The pain severity assessed by the VRS significantly improved both at the end of sessions (p = 0.005) and after 3 months follow-up (p = 0.005). The authors concluded that nbUVB may be of beneficial use in the treatment of PHN. The drawbacks of this pilot study were small number of patients and limited follow-up period. These preliminary findings need to be validated by well-designed studies.

Barros et al. (2012) stated that herpes zoster infection may cause PHN. This phenomenon may be reversed by (S)-ketamine (SKET), but its use results in intolerable side effects, while its topical administration seems to be safe. In a cross-over study, these researchers examined the effectiveness of topical (S)-ketamine for pain management of PHN. A total of 12 patients were randomly divided into 2 groups. There was a significant effect of time on pain intensity, but no statistical difference in pain scores for SKET or placebo use in this sample in this treatment regimen. Only few mild cutaneous reactions were observed with topical SKET use.

In a Cochrane review, Han and colleagues (2013) examined the effectiveness of corticosteroids in preventing PHN. These researchers updated the searches for randomized controlled trials (RCTs) of corticosteroids for preventing PHN in the Cochrane Neuromuscular Disease Group Specialized Register (April 16, 2012), CENTRAL (2012, Issue 3), MEDLINE (January 1966 to April 2012), EMBASE (January 1980 to April 2012), LILACS (January 1982 to April 2012), and the Chinese Biomedical Retrieval System (1978 to 2012). They also reviewed the bibliographies of identified trials, contacted authors and approached pharmaceutical companies to identify additional published or unpublished data. These investigators included all RCTs involving corticosteroids given by oral, intramuscular, or intravenous routes for people of all ages with HZ of all degrees of severity within 7 days after onset, compared with no treatment or placebo but not with other treatments. They did not include quasi-RCTs (trials in which a systematic method of randomization such as alternation or hospital number was used). Two authors identified potential articles, extracted data, and independently assessed the risk of bias of each trial. Disagreement was resolved by discussion among the co-authors. A total of 5 trials were included with 787 participants in total.  All were randomized, double-blind, placebo-controlled, parallel-group studies. They conducted a meta-analysis of 2 trials (114 participants) and the results gave moderate quality evidence that oral corticosteroids did not prevent PHN 6 months after the onset of herpes (RR 0.95, 95% CI: 0.45 to 1.99). One of these trials was at high-risk of bias because of incomplete outcome data, the other was at low-risk of bias overall. The 3 other trials that fulfilled inclusion criteria were not included in the meta-analysis because the outcomes were reported at less than 1 month or not in sufficient detail to add to the meta-analysis. These 3 trials were generally at low-risk of bias. Adverse events during or within 2 weeks after stopping treatment were reported in all 5 included trials. There were no significant differences in serious or non-serious adverse events between the corticosteroid and placebo groups. There was also no significant difference between the treatment groups and placebo groups in other secondary outcome analyses and subgroup analyses. The review was first published in 2008 and no new RCTs were identified for inclusion in subsequent updates in 2010 and 2012. The authors concluded that there is moderate quality evidence that corticosteroids given acutely during zoster infection are ineffective in preventing PHN. In people with acute HZ the risks of administration of corticosteroids do not appear to be greater than with placebo, based on moderate quality evidence. Corticosteroids have been recommended to relieve the zoster-associated pain in the acute phase of disease. These investigators stated that if further research is designed to evaluate the effectiveness of corticosteroids for HZ, long-term follow-up should be included to observe their effect on the transition from acute pain to PHN; and future trials should include measurements of function and quality of life.

Ing and colleagues (2015) stated that PHN remains a therapeutic challenge for the clinician. Many modalities have been utilized with limited success. In this pilot randomized study of patients who were refractory to previous medicinal treatment, the patients were treated with TENS with a biofeedback capability. After every 2 treatments with the sham and true device, the patients were required to fill out a standard neuropathic pain scale score. The patients were allowed to select the other device after 3 consecutive treatments if they felt an inadequate decrease in their pain. The true device was chosen over the sham device by all patients. The majority of these patients treated by the true device reported a statistically significant decrease in pain scores (p < 0.001). The authors concluded that further investigation of this Food and Drug Administration (FDA)-class 2 electronic device for relief of pain is needed for patients with a history of recalcitrant PHN.

Combination of Trigeminal Ganglion and Retrobulbar Nerve Block for the Treatment of Post-Herpetic Neuralgia

Huang and colleagues (2017) noted that varicella zoster virus reactivation can cause permanent histological changes in the central and peripheral nervous system. Neural inflammatory changes or damage to the dorsal root ganglia sensory nerve fibers during reactivation can lead to PHN. For PHN of the first division of the 5th cranial nerve (ophthalmic division of the trigeminal ganglion), there is evidence of inflammatory change in the ganglion and adjacent ocular neural structures. First division trigeminal nerve PHN can prove to be difficult and sometimes even impossible to manage despite the use of a wide range of conservative measures, including anti-convulsant and anti-depressant medication. Steroids have been shown to play an important role by suppressing neural inflammatory processes. Thus, these researchers chose the trigeminal ganglion as an interventional target for an 88-year old woman with severe ophthalmic division PHN after she failed to respond to conservative treatment. Under fluoroscopic guidance, a trigeminal ganglion nerve block was performed with lidocaine combined with dexamethasone; and a retrobulbar block with lidocaine and triamcinolone settled residual oculodynia. At 1-year follow-up, the patient remained pain-free and did not require analgesic medication. The authors concluded that to their knowledge, this was the first reported case of ophthalmic division PHN successfully treated with a combination of trigeminal ganglion and retrobulbar nerve block using a local anesthetic agent and steroid for central and peripheral neural inflammatory processes. This preliminary finding need to be validated by well-designed studies.

CT-Guided Pulsed Radiofrequency for the Treatment of Post-Herpetic Neuralgia

In a retrospective study, Han and colleagues (2020) compared the safety and effectiveness of computed tomography (CT)-guided PRF at 3 different voltages for the treatment of patients with PHN. This trial included 109 patients with PHN involving the thoracic dermatome who were treated from January 2017 to May 2019. They were divided into 3 groups based on the PRF voltage used: group A (45 V), group B (55 V), and group C (65 V). The PRF therapy (voltage 45, 55, and 65 V) was carried out in all patients by targeting the thoracic dorsal root ganglion. After surgery, patients were followed at 3 days, 1 month, 3 months, 6 months, and 12 months. Observation at each follow-up included basic patient characteristics, VAS, SF-36 scores, patient satisfaction, complications, and side effects. Visual analog scale scores decreased; and SF-36 scores increased for all patients in the 3 groups at each post-operative time-point (1, 3, 6, and 12 months; all p < 0.01). Pain relief, improvement in QOL, and overall satisfaction were more significant for patients in group C than for those in groups A and B at the 3-, 6-, and 12-month follow-ups (all p < 0.05). Patients in group B had lower VAS scores and higher overall satisfaction levels than those in group A (both p < 0.01). A small number of patients from each group (n less than or equal to 3) experienced mild intra-operative and post-operative complications, which bore no relationship with group assignment (all p > 0.05).  At post-operative day 3, patients in group C had skin numbness affecting a larger area than patients in the other 2 groups (both p < 0.05), but the differences were no longer statistically significant at day 30 after the operation. All patients experienced a drop in numbness area of more than 30% after surgery. The authors concluded that compared with PFR at 45 and 55 V, PFR at 65 V had superior efficacy in treating PNH, with a favorable safety profile. Moreover, these researchers stated that large, multi-center studies are needed to further verify these findings.

The authors stated that this study had several drawbacks. First, the sample size in this study was small. Second, these investigators did not carry out subgroup analysis based on patients’ disease stage and age. They continued to collect cases and intend to refine the groupings and get more in-depth results in the future. Third, these researchers did not increase the PRF voltage beyond 65 V. If the voltage was further increased, the temperature could not be maintained below 50° C, which might cause protein degeneration and nerve damage; meanwhile, the objective of this trial was also to distinguish It from the CRF technology. In future studies, these researchers will further refine the PRF voltage parameters and expand parameter range as long as it can be tolerated by the patients.

Ganglioside GM1 for the Treatment of Post-Herpetic Neuralgia

Koju and Lei (2016) noted that PHN is a commonest and difficult-to-manage complication of Herpes zoster. This comparative study included 140 cases of PHN admitted in the department of dermatology in Renmin Hospital of Wuhan University, Wuhan, China, from March 2014 to February 2015, divided into a control and a study group.  In addition to the combination of anti-viral, analgesic, and neurotrophic agents given to the control group, additional ganglioside GM1 was given to patients in the study group. Pain assessment was performed at the time of admission, and then on the 3rd, 7th and 10th day of treatment, on both groups, using a 10 cm VAS. There was a significant statistical difference between the pain VAS score of the 2 groups, on the 7th day (3.73 ± 1.66 versus 3.03 ± 1.86, p = 0.024) and on the 10th day (3.25 ± 1.78 versus 2.20 ± 1.59, p = 0.006) of treatment. The number of patients who have good/and complete response (37.5%) were largely higher in the study group than those in the control group (15%, p < 0.05). The authors concluded that these findings demonstrated that the administration of ganglioside GM1 may potentially serve as a neoadjuvant therapy to reduce the severity and duration of pain in PHN patients.

Low-Level Laser for the Prevention of Post-Herpetic Neuralgia

Combined Therapy of Nerve Block and Pulsed Radiofrequency

In a prospective, randomized clinical trial, Li and co-workers (2018) examined the combined effects of nerve block therapy (NBT) and pulsed radiofrequency (PRF) in patients with PHN.  A total of 60 PHN patients were divided into 4 groups (n = 15 each): the conventional puncture group (group CP), the nerve block therapy group (group NB), the PRF group (group PRF), and the combined treatment group (PRF combined with nerve block therapy (group CT). To evaluate the extent of remission of hyperalgesia, these investigators recorded the VAS scores during cotton swab reaction before and after treatment and in the resting and active pain states. In addition, blood samples were collected and plasma cytokine and neuropeptides such as interleukin-6 (IL-6), substance P (SP), and β-endorphin (β-EP) were measured by enzyme-linked immunosorbent assay (ELISA) at the admission (basic state), before the operation, and at 12 hours post-operatively. The number of AEs (nausea, vomiting, constipation, puncture point hemorrhage, swelling and redness) within 12 hours of the treatment were also documented. The results showed that VAS scores during cotton swab reaction decreased after treatment in all patients (p < 0.05). Compared to group CP, plasma IL-6 and SP levels decreased (p < 0.05) and β-EP levels increased (p < 0.05) in groups NB, PRF, and CT. There were no significant differences in AEs among groups (p > 0.05). These researchers found that PRF in combination with NBT increased β-EP levels and decreased plasma IL-6 and SP, thereby alleviating pain and hyperalgesia in PHN patients. The authors concluded that these findings suggested that combined therapy of NBT and PRF was safe and effective for PHN patients.

The authors stated that the drawbacks of this study included its design as a single-center study and its small sample size (n = 15 in the combined NBT and PRF group). They did not evaluate the effects of liver or renal dysfunction on the treatment effects either. These researchers stated that their study might have limited statistical power to detect difference among the groups. They stated that future multi-center studies with larger sample sizes are needed to validate these findings.

Intravenous Zinc Sulfate

Lin and colleagues (2018) noted that gabapentinoids (gabapentin and pregabalin) are 1st-line drugs for PHN, but some PHN patients have inadequate therapeutic response. Zinc deficiency has been identified as a risk factor for PHN.  Zinc can alleviate pain through binding to Ca(v)3.2 T-channels and N-methyl-D-aspartate receptors. Mechanisms of gabapentinoids on neuropathic pain include inhibiting N-methyl-D-aspartate receptors and calcium channels. The afore-mentioned findings provided a molecular pain-relieving basis for zinc supplements as an add-on therapy to pregabalin. These investigators report 2 zinc-deficient PHN patients who received zinc sulfate intravenously as an add-on therapy to pregabalin and responded well.  These preliminary findings need to be validated by well-designed studies.

Dorsal Root Ganglion Pulsed Radiofrequency Lesioning

Huang and colleagues (2018) examined the clinical effects of selective dorsal root ganglion pulsed radiofrequency lesioning in combination with oral administration of gabapentin in the treatment PHN. A total of 116 consecutive cases of initially diagnosed patients with PHN were randomly divided into the control and the observation groups, with each group consisting of 58 patients. The control group was treated with oral gabapentin (2,400 mg/day, tid), while the observation group received gabapentin and pulsed radiofrequency lesioning of the dorsal root ganglion. The clinical efficacy of both the regimens was compared after a follow-up period of 6 months. The observation group had a significantly lower score on the VAS than the control group (p ≤ 0.05, with no significant complications occurring in both the groups) at a 1, 2, and 4 week post-treatment duration. The percentage of cluster of differentiation (CD) 4+ cells and the CD4+/CD8+ ratio increased gradually, while the percentage of CD8 + cells decreased in the observation group (p ≤ 0.05). No significant alterations were observed in the control group (p > 0.05).  The observation group had significantly lower serum IL-6, C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α) levels than the control group (p < 0.05) at 1, 2, and 4 weeks after the treatment was instituted. The observation group also demonstrated a superior total effective rate and efficiency than the control group (p ≤ 0.05). The authors concluded that the findings of this study demonstrated that radiofrequency combined with gabapentin in the treatment of PHN had a good safety and efficacy profile. The effects of this treatment may be related to an increased T-cell immunity and an inhibited inflammatory response.

In a commentary regarding the afore-mentioned study, Dauffenbach and Sharma (2018) stated that there are a number of clinically relevant questions that need to be addressed. The outcomes chosen for this observational study were not entirely well-defined, aside from the ubiquitous VAS and “no severe complications”. The total effective rate appeared to be either a novel or a rarely used assessment of the objective response rate.  It may be argued that this was a mere extrapolation of the VAS data as anything above a VAS change of 50% was classified as “effective”. Incorporating robustly validated and commonly reported pain indices such as the Brief Pain Inventory-Short Form, Neuropathic Pain Scale, and/or the McGill Pain Scale would have added greater clarity to the conclusions. On the contrary, the emphasis on immune and inflammatory indices shifted the focus away from reported clinical observations that the title of the article clearly highlighted. The commentators noted that additional data regarding the technique used for trigeminal nerve pulsed radiofrequency lesioning, which was carried out in 9 of 58 observational subjects, would have been useful. Although, the chosen parameters for pulsed radiofrequency fell within commonly reported and recommended ranges, the authors failed to clarify the rationale for repeating the 120-second therapy cycle and whether this could have impacted the clinical outcomes. The rationale behind using a dosing regimen of gabapentin at 2,400-mg, administered thrice-daily, was also not explained. Common clinical practice for dosing of neuromodulating medications is to reach a maximal daily dose (3,600 mg/day of gabapentin in this case) or a maximum tolerable dose (MTD), as limited by the side effects of the medication. Furthermore, the authors failed to report the presence or absence of adverse side effects in either the control or observational groups.  Although, the inclusion criteria outlined “good treatment compliance”, the article did not reveal medication tolerance or adherence. As regards, dorsal root ganglion pulsed radiofrequency lesioning improving the immune functioning of these patients, the authors felt that this reasoning may be a trifle over-arching. It was possible that the difference in the reported immune and inflammatory indices between the control and observational groups may reflect a natural response to procedural stress. It was also interesting to note that, in this group of largely healthy individuals with severe PHN, the mean age was essentially in the mid-40s. This was far younger than that reported in world literature. Finally, the reader was left without the ability to infer a dose-dependent effect of gabapentin and the unanswered question regarding whether or not the observed results of the use of selective dorsal root ganglion pulsed radiofrequency lesioning would vary in patients taking lower or higher doses of this neuromodulating agent.

In a retrospective study, Huang and associates (2021) examined the safety and efficacy of US-guided PRF modulation on thoracic DRG or intercostal nerve (ICN) for PHN in elderly patients and provided a theoretical basis for clinical treatment. These investigators classified elderly patients into 2 groups, DRG group and ICN group, based on the needle tip position; VAS and concise health status questionnaire (SF-36) were used to examine the pain intensity and the QOL of the patients before and 2, 4 and 12 weeks after the PRF treatments. These investigators also recorded the adverse reactions during the treatments. After the PRF treatment, the scores of VAS and SF-36 (assessing general health perception, social function, emotional role, mental health, and pain) improved significantly in both groups (p < 0.05).  The mean VAS score in the DRG group was significantly lower than that in the ICN group 2 weeks after treatment; and remained for 12 weeks. The SF-36 scores in the DRG group were significantly higher than those in the ICN group (p < 0.05). These researchers found a similar incidence of adverse reactions between the 2 groups (p > 0.05). The authors concluded that PRF therapy was safe and effective for elderly patients with PHN; however, PRF treatment in DRG was superior to that in ICN with improving VAS and SF-36 scores to a greater extent in elderly patients.

The authors stated that the findings of this study showed that the scores of VAS and SF-36 in the DRG group were better than those in the ICN group. DRG neurons have the primary receptors of pain and temperature perceptions. The electrical signals of pain in the trunk are first integrated at DRGs and then transmitted to the spinal cord, which finally arrive in the central nervous system. PRF can stimulate DRGs by intermittent pulse currents and block the pain signal transduction. Furthermore, PRF could form a high voltage field around DRGs, which further inhibits the activation of glial cells. However, the mechanism that PRF of DRG is better than that of ICN to treat PHN still needs further researches.  Besides, as a retrospective study, it was difficult to avoid selectivity bias. These researchers stated that prospective studies are still needed to confirm the findings of this retrospective study.

Transforaminal Epidural Steroid Injection

Mehta and colleagues (2015) reported on the case of a 64-year old man with a history of herpes zoster exposure presented with severe, constant, burning pain in the left T10 dermatome consistent PHN. Previous treatment included oral and topical medications as well as an intercostal nerve block; however, these therapeutic options did not provide significant relief. The patient was treated with a single-level T10 thoracic transforaminal epidural steroid injection for refractory PHN. He reported complete resolution of his symptoms at 2- and 12-week follow-ups. The authors concluded that this case illustrated transforaminal epidural steroid injections may be a successful therapeutic option for PHN.

Fujiwara et al. (2018) stated the acute phase of shingles is characterized by severe pain, and one of the complications of shingles known as PHN is associated with prolonged pain. Although factors predicting the development of PHN, as well as its preventative measures, have been investigated, there is no single treatment effective for PHN. Some studies showed effectiveness of epidural injection to alleviate pain associated with acute-phase shingles. In these studies, epidural injection was performed by interlaminar (IL) approach. However, transforaminal (TF) approach may be more effective as it enables injection of steroids and local anesthetics closer to the dorsal root ganglion where inflammation primarily occurs. There have not been any studies comparing the analgesic effects of epidural injection approaches for pain associated with acute-phase shingles. This randomized prospective trial study compared the analgesic effects of IL and TF epidural injection approaches for pain associated with acute-phase shingles. Nara Medical University Hospital, Department of Anesthesiology. Forty patients with acute-phase shingles were randomly assigned to receive epidural steroid injections by TF or IL approaches. Patients were evaluated at the baseline, as well as at 1 month and 3 months after the treatment using the VAS and 36-Item Short-Form Health Survey (SF-36) scores. Patients with VAS score of over 40 at the 3-month follow-up were considered as having PHN, and the number of patients with PHN was compared between the IL and TF groups. Except the mental component of the SF-36 score and severity of skin rash, patient characteristics were not significantly different between the groups. VAS scores at 1 and 3-month follow-up were significantly lower than those at the baseline, and there was no difference between the groups. All SF-36 scores were not significantly different between groups at 1- and 3-month. There was no significant difference in the occurrence of PHN between the groups. Study limitations included a small sample size that did not reach the number of patients needed by the power analysis in the study. Also, the follow-up period of 3 months was relatively short. The authors concluded that VAS scores, the SF-36 RCS and MCS scores improved in both groups, however, there was no difference in the analgesic effects of the IL and TF epidural steroid injections at 1 and 3 months for acute-phase shingles patients.

Park and associates (2019) noted that despite the high frequency of nerve blocks in the acute phase of herpes zoster, factors associated with intervention, such as response to epidural block, have not been analyzed as predictive factors of PHN. These  researchers determined the predictive factors of progression to PHN in the presence of interventions; they analyzed the medical records of 145 patients who underwent transforaminal epidural injection (TFEI) in the acute phase of herpes zoster. A total volume of 5 ml (a mixture of 0.5% lidocaine and 5-mg dexamethasone) was injected during TFEI. Corticosteroid was used only for the first TFEI. Clinical data of age, sex, involved dermatome, presence of co-morbidity, time from zoster onset to first TFEI, numerical rating scale (NRS) before TFEI, NRS at 1 week and 1, 3, and 6 months after the first TFEI, and number of TFEI were collected and analyzed. Through multi-variate logistic regression analysis, pain improvement less than 50% at 1 week after the first TFEI was a strong predictive factor of progression of PHN at all time-points.  Response to TFEI appeared to be a stronger predictive factor of progression to PHN than patient factors of sex, age, degree of initial pain, and presence of co-morbidity.

Extracorporeal Shockwave Therapy

Chen and colleagues (2020) noted that PHN is one of the most common types of chronic neuropathic pain, which seriously affects QOL because of pain severity and poor response to the currently available treatments. The main strategies for PHN management are medication and invasive interventional therapies; however, these approaches have many adverse effects, so it is important to find another safe and effective treatment for PHN. These researchers presented the study protocol of a RCT that will examine the safety and effectiveness of extracorporeal shockwave therapy (ESWT) in patients with PHN. A single-blind, single-center RCT will evaluate 98 study participants randomized in a 1:1 ratio into control and experimental groups. The control group will receive conventional treatment including medication therapy and invasive interventional therapy. The experimental group will receive ESWT in addition to conventional therapy. The primary outcome is pain intensity assessed on a VAS; the secondary outcomes are QOL assessed by the SF-36, psychological state for anxiety and depression measured by the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS), and sleep quality (SQ) measured by the Pittsburgh Sleep Quality Index (PSQI). Assessors blinded to the randomization will collect data during the intervention period at baseline and weeks 1, 4, and 12. The plasma levels of TNF-α and IL-6 will be evaluated before and after ESWT to examine the biochemical mechanisms of ESWT in the treatment of PHN. The authors stated that this RCT will examine the safety and effectiveness of ESWT in patients with PHN, and will provide clinical evidence for its use in the management of PHN and examine the potential biochemical mechanisms of this treatment.

The authors stated that the proposed study has several limitations. First, it is a single-center clinical trial, which might influence participant recruitment. Second, this clinical trial is single-blind because a double-blind design would be difficult to ensure considering the therapeutic properties of ESWT, which might cause patient bias. In addition, the primary outcome measure is a subjective evaluation, which may be a potential risk for bias because participants will know in which arm of the trial they are enrolled. Another limitation is that although the trial follow-up is 3 months after the treatment, extended follow-up may be needed to demonstrate the benefits of ESWT in further studies.

Pulsed Radiofrequency of the Dorsal Root Ganglion

In a systematic review, Vuka and colleagues (2020) examined the evidence regarding the safety and efficacy of PRF applied to the dorsal root ganglion (DRG) for the treatment of neuropathic pain. These investigators searched Medline, CINAHL, Embase, and PsycINFO through January 8, 2019, as well as ClinicalTrials.gov and the clinical trial register of the World Health Organization (WHO); all study designs were eligible. They evaluated risk of bias using the Cochrane tool for RCTs and the Risk Of Bias In Non-Randomized Studies of Interventions (ROBINS-I). These researchers examined level of evidence using the Oxford tool and quality of evidence with GRADE. They included 28 studies with subjects suffering from lumbo-sacral, cervical, or thoracic radicular pain, PHN, neuropathic bone pain in cancer patients, or carpal tunnel syndrome. Only 5 studies were RCTs, while others were of non-randomized designs, predominantly before and after comparisons. A total of 991 subjects were included, with a median number (range) of 31 (1 to 101) subjects. Only 204 subjects were included in the RCTs, with a median number (range) of 38 (23 to 62) subjects. The overall quality of evidence was low, as the majority of the included studies were rated as evidence level IV or V; and the quality of evidence was very low. The authors concluded that evidence regarding the safety and efficacy of PRF of the DRG for the treatment of neuropathic pain is based mainly on results from very small studies with low evidence quality. Current research results regarding the benefits of PRF of the DRG for the treatment of neuropathic pain should be considered preliminary and confirmed in high-quality RCTs with sufficient numbers of subjects.

Transcranial Magnetic Stimulation

In a prospective RCT, Pei and colleagues (2020) examined the safety and efficacy of repetitive transcranial magnetic stimulation (rTMS) at different high frequencies (5-Hz and 10-Hz) for the treatment of PHN. A total of 60 patients with PHN who were treated at the Department of Pain Management at Xuanwu Hospital of Capital Medical University were recruited. Using a computer-created number list, the cases were equally divided into 3 groups (n = 20), namely, the sham rTMS group, 5-Hz rTMS group, and 10-Hz rTMS group. The sham rTMS group received sham stimulation, and the other 2 groups received high-frequency (5-Hz and 10-Hz) rTMS, respectively. The primary motor cortex (M1) on the healthy side was stimulated with an intensity of 80% transcranial magnetic stimulation (RMT). For the 5-Hz rTMS group, each stimulation session consisted of a series of 300 1-second pulses with a frequency of 5-Hz and an interval of 2.5 seconds between each train, giving a total of 1,500 pulses per session. For the 10-Hz rTMS group, each stimulation session consisted of a series of 300 0.5-second pulses with a frequency of 10-Hz and an interval of 3 seconds between each train, giving a total of 1,500 pulses per session; the total time of stimulations was 17.5 mins. rTMS was performed once-daily for 10 days. The 3 groups received conventional medication therapy. Baseline data (gender, age, course of disease, affected side) were recorded in the 3 groups.  At different time-points (before treatment, T0; during treatment, T1-T10; 1 month after treatment, T11; and 3 months after treatment, T12), the patients were evaluated on the following scales: VAS, short-form McGill Pain Questionnaire (SF-MPQ), QOL scale, SQ scale, SDS, Patient Global Impression of Change (PGIC), and incidence of AEs. Compared with the sham rTMS group, there was a significant reduction in VAS scores in the 5-Hz rTMS group and 10-Hz rTMS group at T2-T12 (p < 0.05).  VAS scores in the 10-Hz rTMS group at T7-T12 were significantly lower compared with the 5-Hz rTMS group (p < 0.05).  The average VAS reduction was significantly different between the 5-Hz and 10-Hz rTMS groups; 28.3% (95% CI: 19.48% to 49.35%), compared to 39.89% (95% CI: 22.47% to 58.64%), with (F = 5.289, p = 0.022). The 3 groups did not differ significantly in general SF-MPQ, QOL, SQ, SDS, and PGIC scores.  However, the QQL, SQ, and PGIC scores of the 5-Hz rTMS group and the 10-HZ rTMS group at T12 were significantly higher than that of the sham rTMS group. The authors concluded that rTMS at either frequency, 5-Hz or 10-Hz, relieved PHN and improved the patients' QOL; rTMS at 10-Hz was superior to rTMS at 5-Hz in terms of pain relief, QOL, and improvement in SQ, although the latter had higher safety. These investigators stated that rTMS at either 5-Hz or 10-Hz can be used as an adjuvant therapy for PHN.

The authors stated that the main drawback of this study was that the patients were only followed-up for 3 months. In future work, these researchers will follow patients for 6 months or even longer to observe the safety and effectiveness of rTMS at different high frequencies for PHN. Furthermore, this study had a small sample (n = 20 in each of the 3 groups) size due to time limitations, and these investigators could have refined the screening for rTMS evaluation indicators. In the future, these researchers will enlarge the sample size and confirm the current findings on the safety and effectiveness of rTMS for PHN.

In a systematic review and meta-analysis, Dai et al. (2024) examined the effectiveness of rTMS in the treatment of PHN. Through an extensive search in four databases until October 2023, these investigators selected 5 RCTs adhering to their specific criteria, entailing 257 patients.  For continuous outcomes, the standardized mean difference (SMD) was calculated.  Heterogeneity among the studies was evaluated using Cochran's I2 and Q statistics, adopting a random-effects model for I2 values over 50%. For examining potential publication bias, these researchers employed both funnel plot and Egger's test. This analysis found that rTMS reduced the overall VAS (SMD: -1.52, 95% CI: -2.81 to -0.23, p = 0.02), VAS at 1 month post-treatment (SMD: -2.21, 95% CI: -4.31 to -0.10, p = 0.04), VAS at 3 months post-treatment (SMD: -1.51, 95% CI: -2.81 to -0.22, p = 0.02), as well as PGIC (SMD: -1.48, 95% CI: -2.87 to -0.09, p = 0.04), and short-form McGill pain questionnaire (SF-MPQ) (SMD: -1.25, 95% CI: -2.41 to -0.09, p = 0.03) compared to the sham-rTMS group.  The authors concluded that the findings of this study suggested that rTMS might have a potential alleviating effect on PHN symptoms. However, due to the limited number of studies and variations in rTMS parameters, larger sample studies involving more diverse populations, as well as further clarification of the most appropriate stimulation protocol, are still needed.

Trigeminal Nerve Block

Moon et al. (2016) stated that neuropathic pain includes PHN, painful diabetic neuropathy (PDN) and trigeminal neuralgia. Although various drugs have been tried to treat neuropathic pain, the effectiveness of the drugs sometimes may be limited for chronic intractable neuropathic pain, especially when they cannot be used at an adequate dose, due to undesirable severe side effects and the underlying disease itself. Botulinum toxin type A (BoNT-A) has been known for its analgesic effect in various pain conditions. Nevertheless, there are no data of nerve block in PHN and PDN. These investigators reported the findings of 2 patients who were successfully treated with ultrasound (US)-guided peripheral nerve block using BoNT-A for intractable PHN and PDN; 1 patient had PHN on the left upper extremity (UE) and the other patient had PDN on a lower extremity (LE). Due to side effects of drugs, escalation of the drug dose could not be made. The authors injected 50 Botox units (BOTOX) into brachial plexus and lumbar plexus, respectively, under US guidance. Pain was significantly decreased for approximately 4 to 5 months. These researchers concluded that US-guided nerve block with BoNT-A may be an effective analgesic modality in a chronic intractable neuropathic pain especially when conventional treatment failed to achieve adequate pain relief.

Huang et al. (2017) noted that varicella zoster virus re-activation can cause permanent histological changes in the central and peripheral nervous system. Neural inflammatory changes or damage to the dorsal root ganglia (DRG) sensory nerve fibers during re-activation can lead to PHN. For PHN of the 1st division of the 5th cranial nerve (ophthalmic division of the trigeminal ganglion), there is evidence of inflammatory change in the ganglion and adjacent ocular neural structures. First division trigeminal nerve PHN can prove to be difficult and sometimes even impossible to manage despite the use of a wide range of conservative measures, including anti-convulsant and anti-depressant medication.  Steroids have been shown to play an important role by suppressing neural inflammatory processes. Therefore, these researchers chose the trigeminal ganglion as an interventional target for an 88-year old woman with severe ophthalmic division PHN after she failed to respond to conservative treatment. Under fluoroscopic guidance, a trigeminal ganglion nerve block was carried out with lidocaine combined with dexamethasone. A retrobulbar block with lidocaine and triamcinolone settled residual oculodynia. At 1-year follow-up, the patient remained pain-free and did not require analgesic medication. The authors concluded that to their knowledge, this was the 1st reported case of ophthalmic division PHN successfully treated with a combination of trigeminal ganglion and retrobulbar nerve block using a local anesthetic agent and steroid for central and peripheral neural inflammatory processes. This was a single-case study and its findings were confounded by the combined use of trigeminal ganglion and retrobulbar nerve block.

Kodama-Takahashi et al. (2018) reported a case of persistent corneal epithelial defect that had occurred after a trigeminal nerve block. A 75-year old woman had suffered from PHN for 8 years. She underwent Gasserian ganglion block surgery and noticed declining visual acuity (VA) in the right eye on the following day. She presented with severe hyperemia and corneal epithelial defects in the right eye and experienced remarkable reduction of sensitivity in the right cornea. She was diagnosed with neurotrophic keratopathy.  Ofloxacin eye ointment and rebamipide ophthalmic suspension ameliorated the corneal epithelial defects but superficial punctate keratopathy, corneal superficial neovascularization, and Descemet's fold persisted. Although the epithelial defects occasionally recurred, the corneal sensation and epithelial defects, Descemet's fold, and corneal superficial neovascularization all improved around 5 months after trigeminal nerve block. The HRT II Rostock Cornea Module (RCM) could not detect any corneal sub-basal nerve fibers at post-operative 4 months; however, it could detect them at post-operative 6 months. The authors concluded that as the nerve block effect wore off, the corneal sub-basal nerve fibers slowly regenerated. As the corneal sensation improved, the corneal epithelial defects and superficial neovascularization also improved. The HRT II RCM appeared useful for observing loss and regeneration of the corneal sub-basal nerve fibers.

Thermotherapy (Including Fire Needle and Moxibustion)

Li et al. (2021) stated that PHN, as the most frequent sequela of HZ, can persist a long time. Both HZ and PHN may significantly impact the QOL and made great economical afford to affected patients. The optimal treatment on HZ and PHN is still an urgent problem. In China, thermotherapy (including fire needle and moxibustion) is widely used because they can quickly promote the recovery of shingles and reduce the occurrence of PHN. Thermotherapy can also reduce pain intensity, relieve anxiety, and improve QOL of PHN. Based on the current literatures, the safety and effectiveness of thermotherapy will be systematically evaluated to provide appropriate complementary therapies for HZ and PHN. Studies search for eligible RCTs that use thermotherapy including fire needle and moxibustion for HZ or PHN from the following databases: PubMed, Embase, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biology Medicine Database (CBM), Technology Periodical database (VIP), and Wanfang database. Language restrictions for retrieving literature are English and Chinese. Their data extraction will be performed by 2 researchers. Mean difference (MD) or RR with fixed or random effect model in terms of 95% CI will be adopted for the data synthesis. To evaluate the risk of bias, the Cochrane's risk of bias assessment tool will be employed. The sensitivity or subgroup analysis will also be carried out when meeting high heterogeneity (I2 > 50%). This meta-analysis will provide an authentic synthesis of the thermotherapy's effect on HZ and PHN, including incidence of PHN and AEs. The authors concluded that the findings of the review will offer updated evidence and identify whether thermotherapy can be an effective treatment for HZ and PHN for clinicians.

Wu et al. (2021) noted that PHN is one of the most common complications of HZ, and there is still a lack of effective therapies. An increasing number of studies have found that compared to traditional therapy, moxibustion treatment is beneficial for the treatment of PHN, although current evidence remains inconclusive. In a systematic review and meta-analysis, these investigators examined the safety and effectiveness of moxibustion for PHN.  They carried out a broad literature review of a range of databases from inception to December 2020, including the Cochrane Library, PubMed, Embase, Web of Science, Clinical Trails, China National Knowledge Infrastructure (CNKI), VIP Database for Chinese Technical Periodicals (VIP), China Biomedical Network Information, and Wanfang databases. These researchers included RCTs that compared moxibustion to pharmacological therapies, herbal medicine, or no treatment for in the treatment of PHN. The main outcome measure was efficacy rate and VAS; the secondary outcome measure was AEs. Data accumulation and synthesis included meta-analysis, publication bias, sensitivity analysis, risk-of-bias assessment, and AEs. These investigators included 13 RCTs entailing 798 patients. Compared with the controls (pharmacological therapies, herbal medicine, or no treatment), moxibustion achieved a significantly higher efficacy rate (OR: 3.65; 95% CI: 2.32 to 5.72; p < 0.00001). Subgroup analysis of the distinct moxibustion modalities showed that both Zhuang medicine medicated thread and thunder-fire moxibustions obtained higher clinical efficacy than the control group. Compared with the controls, moxibustion resulted in significantly lower scores on the VAS (weighted mean difference [WMD] = -1.79; 95% CI: -2.26 to -1.33; p < 0.00001). However, there was no significant difference in terms of safety between moxibustion and the controls (OR = 0.33; 95% CI: 0.06 to 1.77; p = 0.19). The authors concluded that due to the lack of methodological quality as well as the significant heterogeneity of the included studies, it was difficult to draw a firm conclusion regarding the safety and effectiveness of moxibustion for the treatment of PHN. These researchers stated that future high-quality studies are needed to compare moxibustion to pharmacological treatments; and more attention should be paid to the selection of medications with well-established efficacy for neuropathic pain and longer treatment duration. Furthermore, these investigators also noted that it is important to include a sufficiently large sample size to ensure statistical power is retained.

Capsaicin 8% Patch (Qutenza) for Neuropathic Pain not Associated with Post-Herpetic Neuralgia

Giaccari et al. (2021) noted that surgery is a frequent cause of persistent pain, defined chronic post-surgical pain (CPSP). The capsaicin 8% patch (Qutenza®) is approved for the treatment of post-herpetic neuralgia (PHN) and for diabetic peripheral neuropathy (DPN) of the feet.  These investigators examined a review of the literature on use of the capsaicin 8% patch to treat neuropathic pain associated with surgery. They identified studies by searching electronic databases using a combination of such terms as "capsaicin 8% patch", "Qutenza®", and "chronic postsurgical pain". They identified 14 selected studies reporting on a total of 632 CPSP cases treated with capsaicin 8% patch. Treatment with the capsaicin 8% patch significantly reduced the average pain intensity. Only 5 studies reported adverse events (AEs) after the patch application. The most common AEs were erythema, burning sensation and pain. The authors concluded that the findings of this review indicated that capsaicin 8% patch treatment for CPSP was effective, safe and well-tolerated; however, randomized controlled trials (RCTs) on efficacy, safety and tolerability should be conducted.

Ausín-Crespo et al. (2022) stated that pain units manage approximately 20% of the patients with neuropathic pain, usually presenting with severe uncontrolled pain associated with substantial impairment of quality-of-life (QOL) and disability. In a retrospective, observational study, these researchers analyzed the experience with the capsaicin 8% dermal patch for managing patients with neuropathic pain in a pain unit. This trial was carried out at a single pain unit on patients with peripheral neuropathic pain under routine clinical care. Diagnosis of neuropathic pain was based on the Douleur Neuropathique 4 (DN4) questionnaire. Evaluations included pain intensity according to a visual analog scale (VAS) and the QOL as evaluated with the European Quality of Life-5 Dimensions (EQ-5D). These researchers included 66 patients with neuropathic pain lasting for a median of 24 months. The most frequent diagnosis was iatrogenic neuropathic pain (47%) and 2/3 of patients exhibited extreme pain or discomfort. Pain intensity was reduced significantly from a mean (standard deviation [SD]) of 7.20 (1.95) at baseline to 6.02 (2.77) at month 3, leading to a mean change from baseline of 1.19 (95% confidence interval [CI]: 0.59 to 1.78; p < 0.001; Cohen's d 0.49). The extent of the pain area was also significantly reduced from a median (inter-quartile range [IQR]) of 169.5 cm2 (69.3 to 299.9) at baseline to 121.2 cm2 (35.4 to 183.9) at month 3 (p < 0.001). There was an improvement in most dimensions of QOL, especially regarding "usual activities", "pain/discomfort" and "anxiety/depression". Tolerability was consistent with the known profile. The authors concluded that the findings of this study suggested that the capsaicin 8% dermal patch was a useful and well-tolerated therapeutic option for managing peripheral neuropathic pain in pain units.

Dupoiron et al. (2022) noted that data supporting the use of high-concentration capsaicin patches (HCCPs) in breast cancer (BC) patients and BC survivors (BCSs) with peripheral neuropathic pain (PNP) are limited. In an observational study, these researchers examined the safety and effectiveness of HCCP applications in BCSs/BC patients with PNP. Data from all patients treated with HCCP in the pain department of a French comprehensive cancer center were collected from January 1, 2014 to October 14, 2020. Independent pain specialists completed the Clinical Global Impression of Change (CGIC) for each included patient based on data extracted from patient's electronic medical record compiled by the treating pain specialist after each HCCP application. Patients (n = 279; mean age of 59.2 years; previous history of PNP medication: 54.5%) received on average 4.1 repeated HCCP applications (1,141 HCCP applications); 68.8% received HCCP as an add-on to systemic therapy and 27.9% as 1st-line therapy. PNP was most frequently caused by surgery (62.4%) followed by chemotherapy (11.8%) and radiotherapy (6.5%).  A complete or important analgesic effect was reported at least once by 82.3% of patients. A 6.0% reported no effect at all. For post-surgical PNP existing for less than 12 months and greater than 10 years an important or complete effect was observed for 70.7% and 56.0% of applications. For chemotherapy- or radiotherapy-induced PNP, this important or complete effect was observed for 52.7% and 52.3% of applications, respectively. The authors concluded that HCCP application was associated with site reactions in 54.4% of patients (mainly burning sensation or pain, 45.9%, or erythema, 30.8%) and high blood pressure [BP] in 7.2%. The authors concluded that this real-world chart review provided important safety and effectiveness information to clinicians when considering topical options to treat PNP in BCSs/BC patients.

Vieira et al. (2022) stated that chronic neuropathic pain is a disabling condition that affects QOL. Despite recommendations and guidelines, treatment remains suboptimal as it often does not result in significant symptom relief. Capsaicin 8% patch has been used for the treatment of several peripheral neuropathic pain etiologies with encouraging results. In a retrospective, observational study, these researchers examined the results of capsaicin 8% patch on neuropathic pain by evaluating pain intensity and the painful treatment area.  Participants included all patients submitted to capsaicin treatment at the Chronic Pain Unit of the Hospital Center of Tondela Viseu, from 2011 through 2019. Records of capsaicin treatments were reviewed, and the data collected. The primary outcome was pain intensity and painful treatment area reduction between the 1st and last treatment.  Furthermore, the number of treatments performed, neuropathic pain duration, anatomic location, pain etiology, and concomitant oral pain medication at baseline and upon treatment conclusion was also listed. Post-surgical neuropathic pain was the most common etiology (49%), followed by PHN (28%). The median (inter-quartile range [IQR]) baseline pain intensity assessed by the Numeric Rating Scale (NRS-11) was 6 (5 to 8) and the median (IQR) final NRS-11 was 3 (1 to 5), with a median (IQR) relative difference of -0.5 (-0.85 to 0.17) with statistically significant differences (p < 0.001) between baseline and last pain intensity, regarding all groups. In addition, there was a reduction in the painful treatment area between baseline and the last evaluation, with a median (IQR) relative difference of -0.4 (-0.625 to 0.167). The authors concluded that capsaicin 8% patch was a valuable option for the treatment of peripheral neuropathic pain, providing a significant reduction in pain intensity and painful area. It was well-tolerated and has a high treatment compliance. These investigators stated that the limitations of this trial included relatively small sample (100 patients included, 66% were women), the co-existence of oral pain medication, the size asymmetry between groups as well as occasional different timing for pain intensity and pain treatment area assessment due to logistical difficulties.

Laude-Pagniez et al. (2022) reported the findings of 13 patients with neuropathic CPSP after excision of a skin melanoma treated with capsaicin 8% patch (CP8) at a single academic institution over a 40-month period. Response to treatment and adverse effects were presented. The authors concluded that CP8 may be an additional effective and well-tolerated treatment for high neuropathic CPSP with a very impaired QOL after melanoma surgery. Moreover, these researchers stated that this treatment could be included in the therapeutic arsenal if prospective RCTs confirms its effectiveness. These investigators stated that limitations of this trial included a small sample size (n = 13) and the lack of a control group. Furthermore, this cohort represented a selected group of patients compared to general melanoma patients because of hospital-based recruitment in a specialized institution.

Boden et al. (2022) stated that neuropathic pain is common in cancer survivorship and is one of the most distressing symptoms for patients previously treated for head and neck cancer (HNNC). Persistent neuropathic pain, when it is ongoing and uncontrolled, has a detrimental effect and erodes patients' QOL. Patients treated for HNNC are chronic opioid users to manage their post-treatment pain, which may entail an increased risk of addiction and over-dose. These researchers proposed to examine the analgesic activity of high-concentration capsaicin patches for the treatment of HNNC survivors presenting with neuropathic pain sequelae. TEC-ORL is a comparative, parallel, randomized, multi-center, phase-II clinical trial examining if Capsaicin patches (Qutenza) would reduce neuropathic pain when compared to Amitriptyline (Laroxyl) in HNNC survivors presenting with neuropathic pain sequelae. The primary efficacy outcome is the rate of patients with a pain reduction of at least 2 points at 9 months compared to baseline.  Assuming that 5% of patients become lost to follow-up, a total of 130 patients will need to be randomized to detect a 25% improvement (i.e., standard: 25%, experimental: 50%) using a 1-sided Chi-square test with an alpha of 0.05%. According to the recommendations for comparative phase-II clinical trials, the target differences and type I error rates are relaxed. Randomized patients will either be treated with a capsaicin 8% (Qutenza) patch applied at 3 time-intervals in the experimental arm or with Amitriptyline (Laroxyl) (oral solution 40 mg/ml) taken for 9 months at the recommended daily dose of 25 mg to 75 mg in the control arm. The authors concluded that TEC-ORL is a randomized, comparative phase-II clinical trial designed to comprehensively examine the analgesic activity of capsaicin compared to Laroxyl in HNNC survivors presenting with neuropathic pain sequelae.

Olusanya et al. (2023) stated that neuropathic pain (NP) after spinal cord injury (SCI) exacerbates disability, decreases QOL, and is often refractory to available therapies. Patients report willingness to trade potential recovery of strength, bowel, bladder, or sexual function for pain relief. One proposed mechanism causing NP is up-regulation of transient receptor potential vanilloid 1 (TRPV 1) protein in uninjured C fibers and dorsal root ganglia causing neuronal excitability. Recent studies have found up-regulation of TRPV 1 proteins after SCI. In a randomized, single-blind, cross-over study, these researchers hypothesized that the application of capsaicin 8% patch (C8P) would improve pain, function and QOL in persons with SCI. This study included 11 patients with SCI and NP refractory to 2 oral pain medications who received C8P or a control low-dose capsaicin 0.025% patch (CON) over 2 12-week periods. Pain (VAS, MPI-SCI), QOL (WHO-QOL), and functional status (SCIM) were measured at 2 to 4-week intervals. There was a main treatment effect of C8P over CON on VAS and MPI-SCI outcomes with pain reduction of 35% and 29% at weeks 2 and 4, respectively. C8P also demonstrated a main treatment effect over CON on the SCIM mobility subscale. WHO-QOL scores did not improve with C8P. The authors concluded that C8P improved pain and mobility for patients with SCI and refractory NP.  Moreover, these researchers stated that larger studies are needed to examine the impact of repeat applications and QOL outcomes.

Acupoint Herbal Patching

In a systematic review and meta-analysis, Pu et al. (2024) examined safety and effectiveness of acupoint herbal patching (AHP; the use of uses a processed herbal medicine patch that is strategically placed on specific acupoints) in the treatment of PHN. These investigators searched 8 databases including PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wan-Fang Database, China Biomedical Literature Service System, and Chongqing VIP Chinese Science. The search time was set to October 2023. Two independent investigators screened the literature according to the inclusion and exclusion criteria; extracted the basic information, acupoints, Chinese herbal medicine, pain score, sleep score, depression score, and other information of the subjects, and independently examined the risk of bias by 2 researchers. Meta-analysis of the included studies was carried out using the StataMP 16 software.  A total of 15 studies with 1,362 subjects were included in this meta-analysis. Ashi is the acupoint frequency at the fore-front, and Borneol is the Chinese herbal medicine frequency at the fore-front. The acupoint herbal patching group showed significant improvements in VAS (SMD: -2.09; 95% Cl: -2.77 to -1.42; Pp < 0.001), sleep score (SMD: -1.58; 95% Cl: -2.11 to -1.05; p < 0.001), depression score (SMD: -1.61; 95% Cl: -2.22 to -0.99; p < 0.001), Chinese medicine syndrome score (SMD: -2.32; 95% Cl: -2.84 to -1.80; p = 0.06), dermatology life quality index (WMD: -4.11; 95% Cl: -4.58 to -3.63; p = 0.98), and related laboratory indicators compared to the control group, and the total effective rate was significantly higher (relative risk: 1.20; 95% CI: 1.15 to 1.26; p = 0.99) than the control group. Two studies reported adverse reactions, but the 2 groups were not statistically significant. The authors concluded that AHP intervention in PHN was effective in improving pain, sleep, anxiety, depression, and the QOL of patients. However, the heterogeneity of the results was high, and it was affected by factors such as the quality of the literature, which resulted in the need for more high-quality evidence in this study. The manner in which it plays a role may be related to nerves, immunity, and inflammation, and more in-depth mechanistic research is still needed to verify this. Furthermore, AHP has many ideas for acupoint selection and medication, and standardized operation is especially important in clinical practice.  In the future, AHP clinical research should continue to optimize the clinical research design, select appropriate clinical research design methods, and examine the effectiveness of AHP in the treatment of PHN.

The authors stated that this study had several drawbacks. First, the number of high-quality studies included was small, and all of them were Chinese literature, which has certain limitations. Second, the inclusion and exclusion criteria could also cause bias. Third, the intervention methods of the experimental group and the control group were not the same. Fourth, there were some differences in the criteria of the outcome indicators, which resulted in the high heterogeneity of the studies. Fifth, the publication bias of VAS had a certain impact on the findings of this trial.

Blood-Letting Puncture and Cupping

In a systematic review and meta‑analysis, Kui et al. (2023) examined the safety and effectiveness of blood-letting puncture and cupping (BLP-C) in the treatment of PHN and provided guidance for clinical treatment; RCTs of BLP-C therapy in PHN were systematically searched in 8 databases from inception to September 2022. Literature screening, data extraction and quality assessment were carried out by 2 independent researchers. Dichotomous and continuous variables were pooled using the RR and WMD, respectively.  A total of 13 studies involving 1,129 patients with PHN (571 in the experimental group and 558 in the control group) were included in the present meta-analysis. Overall effectiveness (RR = 1.21, 95% CI: 1.15 to 1.28, p < 0.00001), VAS score (WMD = -1.10, 95% CI: -1.31 to -0.90, p < 0.00001) and PSQI score (WMD = -2.42, 95% CI: -2.87 to -1.96, p < 0.0001) were significantly different between the BLP-C group and Western medicine group. In addition, subgroup analysis showed that BLP-C alone or combined with other traditional Chinese medicines was more effective than Western medicine in PHN. A total of 4 RCTs mentioned adverse reactions, most of which were in the Western medicine group and were relieved following treatment discontinuation.  The authors concluded that BLP-C was superior to Western medicine in relieving pain and improving the sleep quality of patients with PHN with a lower incidence of adverse effects. Moreover, these researchers stated that due to the limited quantity and quality of the included studies, more high-quality studies are needed to validate these findings.

The authors stated that this study had several drawbacks. First, the studies included in this meta-analysis were of medium quality and there may be biases in the results due to language restriction. Second, the subjectivity of assessors may have introduced bias. Third, the duration of treatment varied among studies, which in turn may have affected the accuracy of the results.

Yang et al. (2024) noted that acupuncture therapy has shown effectiveness in the treatment of PHN, alleviating pain intensity and enhancing patients' QOL. However, the effectiveness of collateral-pricking and blood-letting cupping combined with electro-acupuncture in the treatment of PHN remains a subject of controversy. In a meta-analysis, these investigators examined the safety and effectiveness of collateral-pricking and blood-letting cupping combined with electro-acupuncture for the treatment of patients with PHN. They identified relevant RCTs by performing a comprehensive search in multiple databases: China National Knowledge Infrastructure, China Biomedical Literature, Wanfang Data, PubMed, Cochrane Central Register of Controlled Trials, Embase, and Web of Science. The outcome included effectiveness rate, VAS scores, and PSQI scores. These researchers examined the risk of bias in the included trials and carried out a meta-analysis; they analyzed 9 RCTs entailing 639 patients.  Collateral-pricking and blood-letting cupping combined with electro-acupuncture resulted in a significantly higher effectiveness rate (RR, 1.22 [95% CI: 1.13 to 1.31]; p < 0.001), reduced the VAS scores (standardized MD [SMD], -1.52 [95% CI: -2.26 to -0.79]; p < 0.001), and improved the PSQI scores (SMD, -2.31 [95% CI: -3.97 to -0.64]; p = 0.007) compared with the control groups. The subgroup analysis showed that the combined treatment of collateral-pricking and blood-letting cupping and electro-acupuncture had a significantly higher total effective rate compared with the carbamazepine, electro-acupuncture, and pregabalin groups (p < 0.05). The total effective rate of the collateral-pricking and blood-letting cupping combined with electro-acupuncture group was superior to that of the control group, irrespective of whether 2 or 3 courses were administered (p < 0.05). The authors concluded that existing evidence suggested that the combination of collateral-pricking and blood-letting cupping and electro-acupuncture showed effectiveness in pain relief, improvement of sleep quality, and enhanced therapeutic outcomes for patients with PHN. Moreover, these researchers stated that further validation via large, multi-center RCTs is needed due to the limited quantity and quality of the included literature in this study.

Serum miR-34c-5p for Diagnosis of Postherpetic Neuralgia and Evaluation of Rehabilitation Effect

Zhou et al. (2025) stated that PHN represents the most prevalent and distressing complication of shingles.These researchers examined the diagnostic significance of miR-34c-5p in PHN patients and evaluated its correlation with rehabilitation effect. This trial included 154 PHN patients and 108 healthy participants. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was employed to detect serum miR-34c-5p levels in the participants. Receiver operating characteristic (ROC) curve analysis was used to estimate the diagnostic significance of miR-34c-5p in PHN patients. Logistic regression analysis was carried out to analyze the risk factors related to the occurrence of PHN.  Visual analog score (VAS), Treatment Expectation Questionnaire (TEX-Q), and Hospital Anxiety and Depression Scale (HADS) scales were filled in by questionnaires to analyze the rehabilitation effect of PHN patients following treatment. Spearman correlation analysis was applied to examine the relationship of miR-34c-5p levels with rehabilitation effect in treated PHN patients. miR-34c-5p levels were notably elevated in PHN patients compared to healthy participants. miR-34c-5 had a high sensitivity (79.2%) and specificity (84.3%) to distinguish between healthy individuals and PHN patients. Logistic regression analysis showed that miR-34c-5p emerged as an independent risk factor for the development of PHN. miR-34c-5p levels, VAS, TEX-Q, HADS-A and HADS-D scores were reduced in prednisone-treated PHN patients compared to the basic treatment group. Furthermore, Spearman correlation suggested that miR-34c-5p levels were positively correlated with VAS, TEX-Q, for HADS for anxiety (HADS-A) and HADS for depression (HADS-D) scores. The authors concluded that miR-34c-5p demonstrated the ability to diagnose PHN and may be a biomarker for diagnosis of this disease. Moreover, reduced miR-34c-5p expression in PHN patients correlated with enhanced outcomes in rehabilitation. These preliminary findings need to be validated by well-designed studies.

Ozone Injection into the Intervertebral Foramen for the Treatment of Postherpetic Neuralgia

Wang et al. (2025) noted that chronic intractable PHN is a significant sequel of HZ and significantly impacts patients' QOL. Although some pharmacotherapies, interventional approaches, and neural modulation have been recommended as clinical options, their effectiveness is limited. These investigators reported the safety and effectiveness of a standardized therapeutic approach with CT-guided intervertebral foramen injection of ozone (IVFO) in PHN patients with chronic intractable thoracic and lumbar (n = 56) who had been intolerant or insensitive to 1st-line drugs, such as gabapentin (GBP) or pregabalin. VAS, quantitative sensory testing (von Frey filaments only), and infra-red (IR) thermography were used to identify and quantify the pain intensity, area of mechanical hyperalgesia, and skin temperature in the included patients with PHN before and after IVFO treatment. Moreover, the dosage of and the time to discontinue GBP and complications were also documented following discharge from hospitals. In this 1-year follow-up study, the primary end-point outcomes measured by VAS showed that IVFO treatment resulted in significant relief of spontaneous pain by 59.19% (2.67 ± 0.66) for immediate, 68.18% (2.08 ± 0.89) for half year, and 70.79% (1.91 ± 1.19) for 1 year after discharge versus admission; dramatic decrease in spatial area of mechanical hyperalgesia by 52.35% (3.11 ± 0.70) for immediate, and 87.41% (0.82 ± 0.50) for half year after discharge versus admission; and skin temperatures by 63.01% (0.85 ± 0.35) for immediate after discharge versus admission. Moreover, 50% of the patients stopped taking GBP 3 months after discharge. No serious complications were reported during the 1-year follow-up after IVFO treatment. The authors concluded that the findings of this study suggested that CT-guided IVFO treatment was a safe and effective interventional approach for the relief of chronic, drug-resistant, thoracic and lumbar PHN.

The authors stated that this trial had several drawbacks. First, this study was not a double-blind RCT. Second, this study only included patients with chest and waist PHN. Third, repeated medical ozone interventions may be needed for some patients with a long course of disease. Fourth, the sample size of this study was small (n = 56); thus, RCTs with larger sample sizes are needed to examine its risks and benefits of ozone injection therapy.

Combined Pulsed Radiofrequency and Transforaminal Epidural Steroid Injection for the Treatment of Postherpetic Neuralgia

In a retrospective study, Ertilav et al. (2025) examined the effectiveness of PRF and transforaminal anterior epidural steroid injection (TFAESI) applied to the dorsal root ganglion (DRG) in the treatment of HZ-related pain. Demographic and clinical examination findings (gender, age, involved dermatome, side, neurologic examination, and medications), VAS scores, and complications were recorded at 1, 6, and 12 months following the procedure.  Data of 93 patients were evaluated: 63 patients were in the acute/subacute pain phase, and 27 patients PHN at presentation.  A total of 11 patients (C2-C4: n = 1, C3-C5: n = 2, C4-C6: n = 2, C5-C7: n = 2, C6-C8: n = 2, C7-T1: n = 2) underwent cervical DRG PRF and TFAESI. A total of 75 patients underwent thoracic DRG PRF and TFAESI (T1-T3: n = 2, T2-T4: n = 6, T3-T5: n = 4, T4-T6: n = 11, T5-T7: n = 9, T6-T8:n = 9, T7-T9: n = 6, T8-T10: n = 5, T9-T11: n = 9, T10-T12: n = 7, T11-L1: n = 3, T12-L2: n = 4). A total of 7 patients underwent lumbar DRG PRF and TFAESI (L1-L3: n = 3, L2-L4: n = 1, L5-S2: n = 3).  VAS scores for all 3 regions were significantly lower than pre-procedure scores at 1, 6, and 12 months after the procedure (p < 0.001, p < 0.001, p = 0.008, respectively). While 2 patients developed nausea and dizziness due to subdural and intravenous leakage after the procedure, no fatal complications were recorded in any patient.  The authors concluded that in HZ-related refractory neuropathic pain, fluoroscopy-guided combined DRG and TFAESI provided long-term effective pain control and were safe both in the acute/subacute phase and in patients who developed PHN. Moreover, these researchers stated that the principal drawback of this trial was its retrospective design and not a comparative study. They stated that prospective, controlled studies would shed light on these preliminary findings.

References