Postherpetic neuralgia

INTRODUCTION — Varicella-zoster virus (VZV) is the causative agent of varicella, or "chickenpox," and herpes zoster, or "shingles." Acute herpes zoster typically presents with a rash that is painful but self-limited. Some patients may continue to experience pain for months to years after the resolution of the rash, a condition known as postherpetic neuralgia (PHN).

The pathogenesis, epidemiology, clinical features, diagnosis, and treatment of PHN are reviewed here. Other aspects of VZV and the acute therapy of herpes zoster infection are discussed separately. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster" and "Treatment of herpes zoster".)

PATHOGENESIS — Inflammation associated with acute herpes zoster may induce fibrosis and other structural changes in nerves that result in spontaneous activity capable of maintaining pain in the absence of ongoing tissue damage [1-5]. Changes that may contribute to the persistent pain of PHN include spinal or ganglionic hyperexcitability and post-infectious alterations in neuronal gene expression [6,7].

Acute herpes zoster that precedes PHN is caused by reactivation of the varicella-zoster virus (VZV). Herpes zoster is characterized by hemorrhagic inflammation of the peripheral nerve, dorsal root, and dorsal root ganglion. As cellular immunity wanes with age or immunocompromise, the virus may be transported along peripheral nerves, producing an acute neuritis [8,9]. Extension centrally into the spinal cord and leptomeninges has also been described [10]. Subsequent fibrosis has been reported in the dorsal root ganglion, nerve root, and peripheral nerve following resolution of the acute process [11,12].

There are three phases of pain associated with herpes zoster [13-15]:

●Acute herpetic neuralgia refers to pain preceding or accompanying the eruption of rash that may persist for up to 30 days.

●Subacute herpetic neuralgia refers to pain that persists beyond healing of the rash but that resolves within three months of onset.

●PHN refers to pain persisting beyond three months from the initial onset of the rash.

Autopsy data for cases of well-established PHN are limited. One study reported five cases, three with severe PHN and two with no persistent pain [16]. Findings in patients with persistent pain included dorsal horn atrophy as well as cellular, axonal, and myelin loss with fibrosis in the sensory ganglion. Marked axonal and myelin loss in the nerve and/or sensory root were found in patients both with and without persistent pain.

A search for responsible neurotransmitters in PHN has been difficult. Substance P is a peptide implicated in the transmission of pain signals, while serotonin and norepinephrine are neurotransmitters thought to play a role in the inhibition of pain signals. However, studies of the affected dorsal horn and dermatomes from patients with PHN have failed to demonstrate differences in cytokine profiles, levels of neurotransmitters, or opiate receptors compared with the unaffected side [1,17,18].

Some have speculated that ongoing VZV viral replication after an acute infection might be responsible for PHN [19]. However, in a randomized trial of 10 patients with severe PHN, intravenous and oral acyclovir given for 56 days failed to influence the course of PHN [20].

EPIDEMIOLOGY AND RISK FACTORS — The probability of developing PHN increases with age. The best incidence data in older patients come from the placebo arm of a large randomized trial that evaluated vaccination against the varicella-zoster virus (VZV) [21]. In 334 patients 60 to 69 years of age who developed herpes zoster and were followed for a median of 3.1 years, PHN occurred in 6.9 percent. By contrast, among 308 patients age 70 years or older who developed herpes zoster, PHN occurred in 18.5 percent.

For adults younger than 60 years of age with herpes zoster, the risk of PHN is estimated to be less than 2 percent [22]. PHN is rare in children.

The major risk factors for PHN are [23-27]:

●Age >60 years

●Severe or incapacitating pain with acute herpes zoster

●More severe rash with acute herpes zoster

Older age is also associated with increasing severity and persistence of PHN symptoms [28]. The risk of PHN may increase with immunosuppression, although the evidence is not entirely consistent [27,29,30].

CLINICAL MANIFESTATIONS — In most cases, PHN is a continuation of the pain that developed during an acute episode of herpes zoster and never resolved. However, in some cases, PHN pain may develop months to years after resolution of the initial acute event [31]. These episodes occur in the same distribution as the initial rash and are typically precipitated by a specific trigger (eg, a surgical procedure, tooth abscess).

The pain associated with PHN can be burning, pruritic, sharp, or stabbing and constant or intermittent [13,32]. More than 90 percent of patients with PHN also report allodynia (sensation of pain evoked by normally nonpainful stimuli such as light touch) [33].

The patient with PHN typically involves a specific nerve and localizes to a dermatome (figure 1). Thoracic (typically T4 to T6), cervical, and trigeminal nerves are most commonly affected with PHN [34]. Patients with PHN often report sensory deficits within the affected dermatomes including areas of anesthesia or other specified deficits of thermal, tactile, pinprick, or vibratory sensation [33]. Sensory deficits may extend beyond dermatomal margins, but the contralateral dermatomes are unimpaired. Spontaneous pain may predominate in cutaneous regions with lost or impaired sensation while allodynia may be triggered in other regions with relatively preserved sensation.

On examination, the areas affected by PHN may show scarring related to the vesicular eruption of the preceding acute herpes zoster infection or by areas of excoriation caused by scratching.

The pain associated with acute herpes zoster and PHN can be severe and associated with profound psychosocial dysfunction including impaired sleep, decreased appetite, and diminished libido [32,35].

EVALUATION

Diagnosis — The diagnosis of PHN is made when localized neuropathic pain persists beyond three months in the same distribution as a preceding documented episode of acute herpes zoster. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster", section on 'Approach to diagnosis'.)

In atypical cases of PHN, the characteristic, localized, and persisting pain consistent with PHN supports the diagnosis. Additional factors supporting the diagnosis are [36]:

●Age >60 years

●Distribution in trigeminal or brachial plexus dermatomes

●The presence of localized allodynia

●Severe pain or rash with acute herpes zoster episode

We obtain neuroimaging, typically magnetic resonance imaging (MRI) with contrast, for patients with atypical clinical presentations including those with dermatomal pain not preceded by an episode of acute herpes zoster and those with neurologic signs or symptoms suggestive of alternative pathologies, such as radiculopathy. Imaging should include the spinal level corresponding to the dermatome of the pain; MRI of the brain is performed for patients with pain in trigeminal or other cranial distributions. (See 'Differential diagnosis' below.)

Testing for varicella-zoster virus (VZV) antibodies in the blood or cerebrospinal fluid is available and may be useful in atypical cases to confirm past exposure to the virus; however, positive tests do not specify PHN as the source of pain. (See "Diagnosis of varicella-zoster virus infection".)

Differential diagnosis — The diagnosis is based on the clinical presentation and is straightforward in most cases. However, the diagnosis of PHN can be more challenging when a patient was not diagnosed with (or does not recall) a preceding acute herpes zoster episode [36]. In addition, the identification of a preceding acute herpes zoster episode may be challenging in some patients with PHN whose symptoms began as dermatomally restricted neuropathic pain without rash, a condition called "zoster sine herpete" [37].

Other causes of focal, persistent neuropathic pain include:

●Trigeminal neuropathy – Patients with trigeminal neuropathy (ie, anesthesia dolorosa) report pain and reduced sensation in the distribution of the trigeminal nerve. Trigeminal neuropathy may be attributed to PHN, but patients without a history of a preceding rash typical for acute herpes zoster warrant neuroimaging to evaluate for secondary causes such as neoplasm. (See "Overview of craniofacial pain", section on 'Painful trigeminal neuropathy'.)

●Other forms of craniofacial pain – Craniofacial pain syndromes involving nerve distributions other than the trigeminal nerve are described by their distinct characteristics such as headache or cranial neuropathies that may distinguish them from PHN. These syndromes are described separately. (See "Overview of craniofacial pain".)

●Acute radiculopathy – Patients with spinal radiculopathies, often from nerve root compression, may report dermatomal pain but typically also have weakness in the muscles innervated by the affected nerve. Radiculopathies are more common in lumbosacral and cervical regions, unlike PHN, which is more common in thoracic regions. Nerve conduction studies and electromyography as well as spinal imaging may help identify patients with radiculopathies. (See "Clinical features and diagnosis of cervical radiculopathy" and "Acute lumbosacral radiculopathy: Etiology, clinical features, and diagnosis".)

●Diabetic amyotrophy and idiopathic lumbosacral radiculoplexus neuropathy – The onset of pain with diabetic or idiopathic amyotrophy may be acute and focal but typically extends beyond a dermatome. Patients may also report weakness, autonomic symptoms such as orthostatic hypotension or urinary dysfunction, and weight loss. While the pain with PHN is typically lateralized and dermatomally restricted, diabetic and idiopathic amyotrophy frequently progresses to become more widespread and involve the contralateral side. (See "Diabetic amyotrophy and idiopathic lumbosacral radiculoplexus neuropathy".)

●Recurrent acute herpes zoster – Neuropathic pain may be prolonged in patients who develop a recurrent episode of acute herpes zoster. The recurrent acute attack may be identified by a recurring rash along with the neuritis. Recurrent acute herpes zoster is likelier to occur in immunocompromised patients. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster", section on 'Recurrent herpes zoster'.)

TREATMENT — Multiple medications have shown benefit in reducing PHN symptoms. However, PHN can be difficult to treat, and some patients require multimodal therapy to manage symptoms. The choice among treatments for PHN should be individualized according to the severity and location of pain, comorbid conditions, medication side effect profile, treatment cost and availability, and patient values and preferences (algorithm 1). Because the pain of PHN may be chronic, long-term therapy is often required [38]. However, the long-term benefits of most therapies are uncertain, and side effects are common [39].

Initial therapies — Both gabapentinoids (ie, gabapentin and pregabalin) and tricyclic antidepressants (TCAs) have been found to be effective and generally well tolerated for PHN in clinical trials and meta-analyses [40-44]. Gabapentinoids may have a lower risk of discontinuation due to adverse effects than TCAs, but these agents have not been compared directly for PHN. We use patient variables including medication side effect profile, comorbid conditions, and symptom severity to help select initial therapy. As examples, gabapentin or pregabalin may be preferred for patients to help co-treat a seizure disorder or to avoid the risk of cognitive impairment associated with TCAs. Amitriptyline or other TCAs may be preferred for patients to help co-treat depression.

Gabapentinoids for most patients with moderate or severe pain — For most patients with moderate to severe pain, we suggest a gabapentinoid (gabapentin or pregabalin) as initial therapy [45]. Gabapentin and pregabalin are structural analogs of gamma-aminobutyric acid (GABA) and have been approved by the US Food and Drug Administration (FDA) for PHN. Both are generally well tolerated and neither alters the pharmacokinetics of other medications because neither binds to plasma proteins [46,47]. We typically start with gabapentin because of lower cost and more favorable tolerability [43]. However, pregabalin is also a reasonable initial choice for PHN based on efficacy because there are no direct comparisons with gabapentin.

●Gabapentin − Gabapentin is typically started at a low dose to minimize the risk of discontinuation from adverse effects. The daily dose is titrated to effect, for most patients typically from 1800 up to 3600 mg. Our suggested initial titration of the immediate release formulation of gabapentin for PHN is:

•300 mg on day 1

•300 mg twice daily on day 2

•300 mg three times daily on day 3

•Thereafter, increase as needed by 300 mg every three days up to 600 mg three times daily

Lower doses may be used or the titration may be slowed for patients who report relief or adverse effects at intermediate doses during the initial titration.

For patients who report minimal or no relief after one month at a total daily dose of 1800 mg, we switch to a TCA. (See 'Tricyclic antidepressants if gabapentinoids ineffective or not tolerated' below.)

For patients who report partial but inadequate pain relief at a total daily dose of 1800 mg, gabapentin may be further increased as needed and tolerated by up to 600 mg each week to a maximum of 3600 mg given in three divided doses.

The extended-release formulation of gabapentin is titrated according to the same schedule using the total daily dosage to determine the once-daily dosing. Adjustment for kidney impairment is required for both immediate- and extended-release formulations, and use of the extended-release formulation is not recommended in patients with severe kidney impairment (eg, creatinine clearance <30 mL/minute).

There is moderate-quality evidence supporting the efficacy of gabapentin for PHN, but some trials have failed to show a benefit with the extended-release formulation of gabapentin, and benefits beyond 12 weeks are uncertain [43,48]. In a meta-analysis including eight trials of more than 2200 patients with moderate to severe pain due to PHN, patients receiving gabapentin at a daily dose of 1200 mg or higher daily were more likely to report benefit (at least 50 percent reduction in pain intensity or "very much improved" pain) than those receiving placebo (32 versus 17 percent) [49].

Gabapentin is generally well tolerated. In a pooled analysis of adverse effects including 37 trials for multiple types of neuropathic pain, patients were more likely to discontinue gabapentin than placebo due to adverse effects (11 versus 8 percent) [49]. The most common adverse effects reported were somnolence or drowsiness (14 versus 5 percent), dizziness (19 versus 7 percent), peripheral edema (7 versus 2 percent), and ataxia or gait disturbance (14 versus 3 percent). The rate of serious adverse effects was 3 percent for both groups.

●Pregabalin − The immediate-release formulation of pregabalin is given two or three times daily. Our titration regimen based on effect and tolerability is:

•75 mg twice daily for one week, then

•150 mg twice daily for one to three weeks, then

•300 mg twice daily

An extended-release preparation is also available for once-daily dosing. The titration schedule is the same used for the immediate-release formulation; however, the starting dose is 165 mg daily and the maximum dose is 660 mg daily.

When stopping the drug, pregabalin should be tapered over a week to reduce the risk of withdrawal symptoms [50].

Adjustment for kidney impairment is required for both the immediate- and extended-release formulations; the extended-release formulation is not recommended for patients with severe kidney impairment (eg, creatinine clearance <30 mL/minute). Pregabalin is designated as a schedule V controlled substance in the United States because it has been reported to cause euphoria.

A systematic review of pregabalin for neuropathic pain identified eight trials including more than 2300 patients with PHN [51]. In the meta-analysis of 732 patients in four trials of patients with PHN, a dose response and significant reduction in pain (at least 50 percent) was more likely for patients receiving pregabalin than those receiving placebo: 150 mg (24 versus 13 percent), 300 mg (32 versus 13 percent), and 600 mg (41 versus 15 percent). Common side effects associated with pregabalin dosing included somnolence (300 mg, 16 percent; 600 mg, 25 percent) and dizziness (300 mg, 29 percent; 600 mg, 35 percent). Other side effects are dry mouth, peripheral edema, and weight gain.

Tricyclic antidepressants if gabapentinoids ineffective or not tolerated — For patients who do not tolerate or respond to a gabapentinoid, we suggest a TCA. They are frequently used for depression or other types of neuropathic pain and are also effective for PHN but have a lower tolerability than gabapentinoids [52,53]. For most patients using a TCA, we typically start with amitriptyline; however, nortriptyline or desipramine may be preferred for patients at risk for anticholinergic symptoms and those with adverse effects from amitriptyline.

●Amitriptyline is started at 10 mg each night. The dose may be uptitrated as needed and tolerated over four weeks up to a dose of 50 mg each night. For patients who report minimal or no relief after one month at 50 mg, we switch to an alternative agent (see 'Alternative therapies' below). For those who report partial but inadequate relief at a dose of 50 mg, the dose may be further uptitrated every four weeks up to a maximum daily dose of 150 mg, monitoring for adverse effects.

●Nortriptyline is typically started at 10 mg each night and increased by 10 to 20 mg each week to effect as tolerated, with a maximum daily dose of 150 mg.

●Desipramine is typically started at 25 mg each night and increased by 25 mg each week to effect as tolerated, with a maximum daily dose of 150 mg.

TCAs inhibit the reuptake of norepinephrine and serotonin in the central nervous system. They are thought to increase the inhibition of nociceptive signals from the periphery [54,55].

Anticholinergic side effects (principally sedation and dry mouth) limit the tolerability of TCAs (table 1) [56]. Because of their anticholinergic effects, TCAs should be used cautiously in older patients, particularly those with cognitive impairment or dementia. We also avoid TCAs in patients with heart disease, epilepsy, or glaucoma. Adverse effects may be reduced by using a slow titration; however, delayed onset of efficacy (up to three weeks) before TCAs begin to reduce pain may lead to premature discontinuation. A treatment trial of at least one month at a target dose may be needed to assess the efficacy of TCAs. In one study, symptom relief correlated with serum levels of amitriptyline and active metabolites [57]. Patients who reported no benefit despite serum levels of 100 ng/mL for at least three weeks were considered to have failed TCA therapy.

A 2015 systematic review found moderate-quality evidence supporting the efficacy of TCAs for PHN [43]. Efficacy among TCAs is best established for amitriptyline, which was found effective in producing at least moderate pain relief in multiple short-term studies, typically at doses of 65 to 75 mg daily [57,58]. Nortriptyline was better tolerated than amitriptyline in a small crossover trial of 33 patients with PHN [59]. Approximately two-thirds of patients reported a good response with either medication, but adverse effects leading to discontinuation were more common with amitriptyline than nortriptyline (48 versus 30 percent). The small study size limits generalizability of these results. Desipramine appears to have the fewest side effects of the first-generation TCAs and was effective for PHN in a small trial at mean dose 165 mg per day [60,61]. Almost half reported good response with desipramine. However, methodologic criticisms of this trial limit the certainty of these conclusions [62].

Topical therapy for patients with milder symptoms — For patients with mild to moderate and localized pain and for those who prefer a topical agent, we suggest capsaicin. We switch to lidocaine patches for those who do not tolerate capsaicin.

●Capsaicin – Capsaicin is formulated as a cream, gel, lotion, or a high-concentration patch.

We use capsaicin cream (0.025 to 0.075%) for most patients with PHN and reserve the high-concentration capsaicin (8%) patch for selected patients with partial response to capsaicin cream who prefer a longer acting formulation.

•Capsaicin cream may be applied to the affected area up to four times each day.

•High-concentration capsaicin patches are administered as a single 60-minute application. The application may be repeated after three months. It must be administered by a health care professional, and patients are monitored for up to two hours after treatment. To manage local pain from capsaicin application, the skin is usually pretreated with a local anesthetic such as topical lidocaine, and some studies also used post-treatment oral analgesics such as oxycodone for up to five days [63]. Further study is needed to confirm long-term effectiveness and tolerance of the high-concentration capsaicin patch.

Limited data suggest that topical application of standard-concentration capsaicin is effective for PHN [41]. In one small trial, 143 patients with PHN assigned to capsaicin cream (0.075%) four times per day for six weeks were likelier to report significant pain relief than those assigned to placebo (21 versus 6 percent) [64]. The rate of adverse skin reactions was similar in patients receiving capsaicin and placebo.

A 2013 systematic review identified four randomized controlled trials that evaluated 1272 subjects with PHN treated with one application of either high-concentration capsaicin patch or standard-concentration capsaicin. The only common endpoint reported by all four trials, a ≥30 percent pain intensity reduction at eight weeks compared with baseline, was significantly greater for high-concentration capsaicin patch (43 versus 34 percent; relative benefit 1.3, 95% CI 1.1-1.5) [65].

High-concentration capsaicin patches are approved by the FDA for the treatment of PHN. However, capsaicin can cause burning, stinging, and erythema, making it difficult to achieve true blinding in clinical studies. In practice, application of capsaicin is intolerable in up to one-third of patients.

●Lidocaine — Lidocaine patches (5%) may provide short term relief for PHN. Up to 3 patches may be applied over the affected area for up to 12 hours daily.

Data from small trials and open-label studies suggest that topical lidocaine (5 percent) may be beneficial for pain relief in patients with PHN [66]. Lidocaine patches have been approved by the FDA for PHN. However, a 2014 systematic review of topical lidocaine for neuropathic pain (including 280 patients with PHN) found only very low quality evidence of efficacy of topical lidocaine due to small numbers, incomplete outcome assessments, and modest outcome measures of efficacy [67].

Alternative therapies — For patients who do not tolerate or are unresponsive to initial therapy, we switch to an alternative agent (algorithm 1). For patients with a partial but suboptimal response with initial therapy, we use combination therapy by adding an alternative agent. We use patient preferences and medical comorbidities to help select among options.

Antiseizure medications — A trial of one of a (non-gabapentinoid) anticonvulsant agent may be useful for some patients who do not respond to or cannot tolerate initial medication options. Treatment decisions should be individualized based on patient characteristics, medical comorbidities, side effects, and drug interactions. The benefit of anticonvulsants is based in part on their efficacy in other neuropathic pain conditions such as trigeminal neuralgia and diabetic neuropathy and also on low-quality and anecdotal evidence for PHN. Options and typical target daily doses for PHN include:

●Valproic acid 500 to 1000 mg daily

●Carbamazepine 200 to 1200 mg daily

●Oxcarbazepine 600 to 1200 mg daily

●Lamotrigine 100 to 300 mg daily

The dosing, titration, and monitoring of these agents for PHN is similar to regimens used in trigeminal neuralgia and typically lower doses than those to achieve anticonvulsant effects. (See "Trigeminal neuralgia", section on 'Medical treatment'.)

In an eight-week trial of 48 patients with PHN, patients assigned to divalproex sodium (1000 mg per day) were likelier to report at least moderate improvement in pain than those assigned to placebo (58 versus 15 percent) [68]. Results of small trials of valproic acid in other neuropathic pain conditions were mixed [69]. In short-term trials in patients with trigeminal neuralgia, both carbamazepine and oxcarbazepine reduced pain more than placebo, but neither drug was tested in patients with PHN [70,71]. Lamotrigine may be better tolerated than carbamazepine but has not been studied extensively for neuropathic pain.

Serotonin-norepinephrine reuptake inhibitors — Serotonin-norepinephrine reuptake inhibitors (SNRIs) may be useful for some patients with PHN based on efficacy data for painful polyneuropathy [43]. These medications may be useful for patients with comorbid depression. We use duloxetine or venlafaxine for patients with PHN.

●Duloxetine is typically started at 30 mg daily. Typical daily doses are 60 to 120 mg. The dose may be increased weekly to effect and as tolerated. Adverse effects including nausea, dry mouth, dizziness, and insomnia are more common at higher doses.

●Venlafaxine may be started at 75 mg daily and increased every two weeks to effect as tolerated. Typical daily doses are 150 to 225 mg. Venlafaxine should be used with caution in patients with glaucoma and in those taking anticoagulants. Common adverse effects include nausea, dizziness, and somnolence.

The initial titration and administration of SNRIs are presented in greater detail separately. (See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects".)

The effectiveness of SNRIs such as duloxetine and venlafaxine for patients with PHN is based on data for those with other types of neuropathic pain. A systematic review of eight trials and including 4084 patients found that duloxetine was beneficial for patients with painful diabetic neuropathy [72]. Venlafaxine was found to be effective in a short-term trial of 244 patients with painful diabetic polyneuropathy [73]. Patients assigned venlafaxine at 150 to 225 mg were likelier to report at least 50 percent pain reduction than those assigned placebo (50 versus 27 percent). However, a 2015 systematic review of six trials including 460 patients with neuropathic pain found only low-quality data of modest efficacy for venlafaxine [74]. The efficacy of SNRIs for diabetic neuropathy is presented in greater detail separately. (See "Management of diabetic neuropathy", section on 'Administration and efficacy'.)

Adjunctive options — For patients with symptoms refractory to prior therapies, adjunctive options and other interventional therapies such as botulinum toxin injections may be tried or added (algorithm 1). These include oral or transdermal opioid analgesics and intrathecal glucocorticoid injections. The selection of these agents depends on individual patient preferences and comorbidities.

Opioids — Opioids may be beneficial for selected patients with intractable pain during the titration of initial or alternative therapies. They can be administered simultaneously for short-term relief along with the nonopioid agents. They should be initiated at low doses if used and titrated to provide relief while awaiting benefit from nonopioid treatments, at which point opioids should be tapered off.

Opioids are available in short- or long-acting formulations (table 2 and table 3). We start with short-acting options for opioid-naïve patients and use the lowest effective dose. The strategies for initiation and chronic use of opioids for patients with PHN is similar to that of other patients with noncancer pain and is discussed in greater detail separately. (See "Use of opioids in the management of chronic non-cancer pain".)

Small trials support the efficacy of opioid analgesics for PHN [75-79]. In one crossover trial involving 76 patients with PHN, treatment with morphine (mean daily dose 91 mg) or methadone (mean daily dose 15 mg) or a TCA for eight weeks was more effective than placebo [77]. There was a trend toward greater pain relief with opioids, but certainty with these results is limited by small sample size.

The use of opioids for chronic PHN should be avoided. Opioids for chronic noncancer pain remains controversial due to the risk of physical dependence, tolerance, addiction, and overdose. Because of these risks, opioids are regarded as third-line treatment options and typically reserved for short-term, adjunctive use for PHN [38,43,80]. Available trials of opioids for neuropathic pain including PHN do not address the issues of abuse and addiction [81]. Pharmacovigilance is essential to using opioids in any population (table 4). (See "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment".)

Neuraxial glucocorticoid infusion — Intrathecal glucocorticoid injections may be beneficial for patients who continue to have intractable pain despite initial or alternative therapies. These injections are not useful for pain in the distribution of the trigeminal nerve.

Intrathecal glucocorticoids for PHN are typically given as a single course of weekly injections over four weeks [82]. Techniques for intrathecal glucocorticoid infusion are discussed in greater detail separately. (See "Spinal anesthesia: Technique".)

Intrathecal glucocorticoid injections are associated with an uncertain but probably low risk of serious adverse events, including aseptic meningitis, transverse myelitis, cauda equina syndrome, lumbar radiculitis, headache, urinary retention, and arachnoiditis [83,84].

Some [40,82,85] but not all [86] studies have found a benefit with intrathecal methylprednisolone infusions for patients with PHN. The largest trial evaluated 277 patients with intractable PHN who were assigned to one of three treatment groups: intrathecal methylprednisolone plus lidocaine once per week for four weeks, intrathecal lidocaine alone once per week for four weeks, or no treatment [82]. More than 90 percent of patients in the methylprednisolone group reported excellent or good pain relief both at four weeks compared with 6 and 4 percent in the lidocaine and no treatment groups, respectively. These results were sustained at two-year follow-up. There were no serious adverse events associated with the injection.

Intrathecal administration of methylprednisolone was found more effective than administration in the epidural space in a small trial of 25 patients with PHN [85].

Therapies for refractory symptoms — We reserve other interventional and surgical approaches such as botulinum toxin injections, cryotherapy, and neuromodulation for patients with refractory symptoms who do not respond to other therapies (algorithm 1). The benefit of such therapies has been shown in small trials and observational studies; larger studies are needed to better define their role for patients with PHN.

Botulinum toxin — Botulinum toxin injection for PHN is not extensively studied, but evidence from observational studies and small trials suggests it is effective [87-90]. One trial evaluated 30 adults with PHN who had persistent pain for at least three months [87]. Patients assigned to botulinum toxin type A (onabotulinumtoxinA) injections were likelier to achieve ≥50 percent pain reduction at two weeks compared with those who received placebo injections (13 of 15 patients [87 percent] versus none of 15). The benefit persisted for a median of 16 weeks. In a comparative study of 60 patients with PHN, patients who received onabotulinumtoxinA injection reported a greater pain reduction at seven days when rated on the visual analog scale compared with those who received lidocaine injections (4.5 versus 2.6 points) [88]. These findings were sustained at three months. Improvement in sleep and reduction in opiate use were also reported in the botulinum toxin group.

Botulinum toxin injections should be performed by a clinician experienced with this treatment [91-93]. No safety concerns were identified in small studies [87,88]. However, botulinum toxin may cause localized or systemic adverse effects including bruising, weakness, pain, or headache and may be contraindicated for some patients. Larger and longer-term studies would be helpful to further clarify the safety and efficacy on this treatment in PHN.

Neuromodulation and nerve stimulation — Invasive neuromodulatory strategies such as spinal cord stimulation and peripheral nerve stimulation are considered experimental. These techniques target peripheral nerves and are thought to modulate neuronal signaling or inflammatory processes [94]. Techniques that have shown some benefit for patients with PHN include:

●Transcutaneous electrical nerve stimulation (TENS) [95]

●Pulsed radiofrequency [96-100]

●Spinal cord stimulation [101,102]

These techniques been reported to be effective in approximately half of patients in case reports and case series [103]. They should be performed by experienced clinicians and in centers with expertise.

Cognitive and behavioral therapies — Some patients with PHN achieve only partial relief even with combination pharmacotherapy. For other patients, the efficacy of pharmacotherapy is limited by adverse effects. Nonpharmacologic approaches, including cognitive-behavioral therapy (CBT), may be useful for some patients with refractory PHN pain or associated impairment in mood, sleep, or other quality-of-life domains [104,105]. In a small trial of 40 patients with PHN treated with pregabalin, patients who were assigned to also receive CBT reported a greater improvement in pain intensity and mood symptoms than those assigned to pregabalin alone [106]. Cognitive and behavioral therapies for the treatment of chronic pain are discussed in detail separately. (See "Approach to the management of chronic non-cancer pain in adults", section on 'Psychological therapy'.)

Therapies of uncertain or limited benefit

●NMDA receptor antagonists – Animal data suggest a role for excitatory amino acid neurotransmitters in the maintenance of chronic pain due to nerve injury [107,108]. Antagonists of the N-methyl-D-aspartate (NMDA) receptor have been shown to relieve neuropathic pain in humans [109].

The most widely available NMDA receptor antagonists are ketamine and dextromethorphan. Intravenous ketamine induces modest pain relief in patients with PHN but at doses that cause sedation, dysphoria, and dissociative episodes [110]. In a crossover trial, pain relief after six weeks was similar in those taking dextromethorphan or placebo [111].

●Intravenous lidocaine – Small trials have failed to find sustained benefit of intravenous lidocaine compared with placebo in patients with PHN [40,112]. Any temporary changes in pain measured immediately after infusion do not appear to be sustained by four weeks [40,112-116].

The role of topical lidocaine for PHN is discussed separately. (See 'Topical therapy for patients with milder symptoms' above.)

●Surgical ablation and other interventional procedures – Cryotherapy is an ablation technique that involves freezing peripheral nerves. A small, unblinded study of cryotherapy for facial pain failed to show a significant benefit in patients with PHN [117]. The authors did not provide inclusion criteria, concomitant therapies, or information on how the response was assessed. By contrast, a second trial reported "considerable" relief in 11 of 14 patients with cryotherapy to the intercostal nerves for PHN [118]. In most cases, however, the duration of relief was less than two weeks as assessed by questionnaire.

Surgical interventions including central electrical stimulation of the thalamus, ablation by anterolateral cordotomy, and electrocoagulation of the dorsal root carry substantial risks of permanent neurologic deficits. A systematic review of surgical procedures for patients with refractory PHN reported the pain reduction with surgical ablation procedures was frequently accompanied by serious complications including neuromuscular weakness [119].

●Simple analgesics – Analgesic medications such as aspirin or other nonsteroidal anti-inflammatory drugs are of limited value in patients with either acute herpetic neuralgia or PHN [38,120].

PROGNOSIS — The pain of PHN may persist for months, years, or even life [38]. However, there are few published data for follow-up beyond one year. Prognostic data on PHN is available from long-term outcome of observational studies in acute herpes zoster. In one study of 85 patients with PHN who were followed to one year, moderate to severe neuropathic pain persisted in approximately 55 percent [121]. In a long-term follow-up of a study that included 158 of 298 original patients from an acute herpes zoster trial, 21 percent of patients reported long-term pain (mean follow-up 9 years) [122].

In a questionnaire study of 385 adults age ≥65 years with persistent PHN, the mean duration of symptoms was 3.3 years [123].

PREVENTION — Prevention of PHN involves either treatment of acute zoster or the use of a vaccine to decrease the incidence of acute zoster and PHN. These issues are discussed separately. (See "Treatment of herpes zoster" and "Vaccination for the prevention of shingles (herpes zoster)" and "Prevention and control of varicella-zoster virus in hospitals".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Varicella-zoster virus" and "Society guideline links: Neuropathic pain".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Neuropathic pain (The Basics)")

●Beyond the Basics topic (see "Patient education: Shingles (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition and risk factors – Postherpetic neuralgia (PHN) refers to pain persisting beyond three months from the initial onset of the rash associated with a prior acute herpes zoster episode. The major risk factors for PHN are age >60 years and severe pain and rash with a preceding acute herpes zoster episode. (See 'Introduction' above and 'Epidemiology and risk factors' above.)

●Clinical features – PHN is most often a continuation of pain that failed to resolve following an acute episode of herpes zoster but may develop months to years after resolution of the initial acute event. (See 'Clinical manifestations' above.)

The pain is localized to a dermatome. Thoracic (especially T4 to T6), cervical, and trigeminal nerves are most commonly affected with PHN. The neuropathic pain associated with PHN can be burning, pruritic, sharp, or stabbing and constant or intermittent. Many patients also report allodynia.

●Diagnosis – The diagnosis of PHN is made when localized neuropathic pain persists beyond three months in the same distribution as a preceding documented episode of acute herpes zoster. (See 'Evaluation' above.)

●Treatments – PHN can be difficult to treat and some patients require multimodal therapy for symptomatic management. The choice among treatments for PHN should be individualized according to severity and location of pain, comorbid conditions, medication side effect profile, treatment cost and availability, and patient values and preferences (algorithm 1). (See 'Treatment' above.)

•Initial therapies – For most patients, we suggest a gabapentinoid (gabapentin or pregabalin) as initial therapy (Grade 2C). Tricyclic antidepressant medications are a reasonable alternative to gabapentinoids. Topical treatments (eg, capsaicin) are another reasonable alternative for patients with milder symptoms and for those who prefer a topical therapy. (See 'Gabapentinoids for most patients with moderate or severe pain' above and 'Tricyclic antidepressants if gabapentinoids ineffective or not tolerated' above and 'Topical therapy for patients with milder symptoms' above.)

•Alternative therapies – For patients who do not tolerate or are unresponsive to initial therapies, we add or switch to an alternative agent. Medications with evidence of efficacy for PHN or other types of neuropathic pain include other antiseizure medications (eg, valproic acid, carbamazepine) and serotonin-norepinephrine reuptake inhibitors (eg, duloxetine, venlafaxine). (See 'Alternative therapies' above.)

•Adjunctive options and therapies for refractory symptoms – For patients with partial response to initial or alternative therapies, adjunctive options may provide additional benefit. These include oral or transdermal opioid analgesics and intrathecal glucocorticoid injections. We reserve other interventional and surgical approaches such as botulinum toxin injections, cryotherapy, and neuromodulation for patients with refractory symptoms who do not respond to other therapies. (See 'Adjunctive options' above and 'Therapies for refractory symptoms' above.)

●Prognosis – The pain of PHN may persist for months, years, or even life. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Zahid H Bajwa, MD, who contributed to earlier versions of this topic review.