Postherpetic neuralgia

INTRODUCTION — 

Postherpetic neuralgia (PHN) is a condition characterized by focal nerve pain that occurs or persists ≥90 days after the onset of an episode of acute herpes zoster virus reactivation (shingles). In most cases of acute herpes zoster reactivation, the characteristic rash and pain resolve within 90 days of onset. In PHN, the pain persists. PHN pain localizes to the territory of the affected cranial or spinal nerve associated with the preceding acute zoster rash. PHN symptoms may be persistent and severe, leading to impairments in quality of life.

This topic will review the pathophysiology, clinical presentation, diagnosis, and management of PHN. The clinical manifestations, diagnosis, prevention, and treatment of acute herpes zoster reactivation (shingles) are discussed separately. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster" and "Treatment of herpes zoster".)

PATHOPHYSIOLOGY

●Preceding episode of acute herpes zoster – PHN develops after an episode of acute herpes zoster, a condition caused by reactivation of varicella-zoster virus (VZV). Following primary viremia, VZV particles enter sensory nerve endings and travel in a retrograde fashion to the dorsal root ganglia where they may evade immune response and remain dormant. Acute herpes zoster reflects a reactivation of latent VZV, with viral replication and subsequent inflammation and rash along the dermatome of the affected peripheral nerve. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster", section on 'Pathogenesis'.)

In most cases, the acute pain of herpes zoster occurs during initial viral reactivation and resolves concordantly with the rash, typically within 30 days of rash onset [1]. However, pain persists in some patients, despite the resolution of the rash and initial inflammatory response.

●Pathogenesis – The exact cause of the persisting pain in PHN is uncertain. Contributing hypotheses include:

•Postinflammatory nerve degeneration – In acute herpes zoster, the acute pain and rash are related to neuronal injury and inflammation after reactivation of latent VZV in the sensory ganglion of the affected cranial nerve or spinal nerve (eg, dorsal root ganglion [DRG]). PHN may represent chronic nerve damage following the acute event.

Autopsy reports of patients with PHN have shown resolution of typical inflammatory changes within the sensory ganglia associated with acute herpes zoster and the presence of marked loss of myelin and axonal loss in the impacted peripheral nerves consistent with neuronal (Wallerian) degeneration [2]. Studies that have followed patients with herpes zoster longitudinally have also identified evidence of Wallerian degeneration in areas of the affected skin, even in instances where initial pain resolved and sensory function recovered [3].

•Persisting viremia – The persistence of pain in PHN has also been attributed to the possible persistence of active VZV leading to further inflammation and/or nerve damage. VZV has been detected in blood and mononuclear cells in some patients with PHN [4,5]. In addition, hyperintensities in the dorsal root ganglia have been reported on magnetic resonance imaging (MRI) of patients with PHN, but it is unclear if the observed changes are related to persistent inflammation or expected changes from prior injury [6,7]. By contrast, the viral load in the blood can persist up to six months following acute herpes zoster episodes despite the resolution of pain which would indicate that blood viral load is not an accurate surrogate for persistent symptoms of PHN [4,5,8].

•Spinal (central) changes – In some patients with acute herpes zoster, interstitial inflammation, hemorrhage, and necrosis typically seen in the DRG can extend to the dorsal horn of the spinal cord [2,9]. These central changes may lead to peripheral nerve sensitization and aberrant nociception.

Hyperintensities on brain and spinal MRI have been reported in some patients with acute herpes zoster who subsequently developed PHN, and autopsy data have likewise identified corresponding macrophage and lymphocytic infiltration of the spinal cord and atrophy of dorsal horn [2,10,11].

•Genetic changes – Acute herpes zoster may lead to changes in gene expression that contribute to the development of PHN. Experimental data have identified changes in the expression of sodium and calcium channel genes related to nociception in PHN and other forms of neuropathic pain [12-15].

●Mechanisms of PHN pain – The character of PHN pain may be related to the nature and extent of damage to the affected nerve fibers. Paroxysmal pain may be related to Ab-fiber demyelination or peripheral sensitization (eg, neuralgic or irritable nociceptor type), and constant pain may be related to a marked loss of nociceptive afferents (eg, neuropathic, nonirritable nociceptor type, or deafferentation type) [16,17]. (See 'Clinical features' below.)

EPIDEMIOLOGY

Incidence and prevalence — The prevalence of PHN ranges from 5 to 20 percent of patients who develop acute herpes zoster in large population studies including adults of all ages [18]. Among older patients, one epidemiologic study assessing herpes zoster complications found one-third of patients ≥79 years old subsequently developed PHN [19].

In a claims-based study, the incidence rate of PHN was 57.5 cases per 100,000 person-years [20]. PHN developed in 13 percent of patients with herpes zoster, occurring at a median age of 66 years old (interquartile range: 54 to 75 years). The incidence of PHN increases with age and the presence of risk factors [20-22]. (See 'Risk factors' below.)

The incidence of acute herpes zoster and the proportion of patients developing PHN appears to be increasing over time, despite vaccination and antiviral treatments [20,21,23].

Risk factors — The likelihood of developing PHN after an episode of herpes zoster depends on patient factors such as age and immunocompetence which may affect the return to viral latency as well as the reparative processes following neuronal injury [19].

●Age — Older age has consistently been shown to be associated with the development of PHN [21]. In a meta-analysis of 19 studies assessing the risk of PHN, each 10-year increase in age was associated with an estimated increase in the relative risk of PHN from 1.22 to 3.11 [22]. In a large claims-based study in the United States, the incidence of PHN increased with age from 1.6 cases per 100,000 person-years for individuals younger than 10 years old up to 228.5 cases per 100,000 person-years for individuals ≥71 years old [20].

●Sex – While acute herpes zoster is more common among females, the influence of sex on rates of PHN is less certain, perhaps due to heterogeneity in study populations [22-24]. Female sex appears to be a risk factor for PHN among individuals <60 years old but protective among those ≥60 years old [22].

●Race – The incidence of PHN is higher in White Americans when compared with Black, Asian, and Hispanic Americans [20].

●Immunocompromised state and other patient-level factors — Patient comorbidities contribute to the risk of PHN. Conditions that cause an immunocompromised state and are associated with the risk of PHN include [22,25]:

•High-dose glucocorticoids

•Immunosuppressive medications

•Active lymphoproliferative disease

•History of hematopoietic stem cell or organ transplantation

•Acquired immune deficiency syndrome (AIDS)

The risk of PHN in patients with treated human immunodeficiency virus (HIV) or solid tumor malignancies is conflicted [22].

Other conditions associated with an increased risk of PHN include autoimmune conditions such as systemic lupus erythematosus and physical trauma at the site of the preceding acute herpes zoster rash [22,26]. Better overall physical health has been associated with a reduced risk of developing PHN, whereas diabetes mellitus and tobacco use history are associated with an increased risk [22].

Genetic factors may play a role in susceptibility, and a strong reaction to a varicella-zoster virus (VZV) skin test may be a marker of cell-mediated immunity to VZV and a reduced risk of developing PHN [27-31].

●Clinical features of preceding acute herpes zoster — The severity and other specific features of the preceding acute herpes zoster have been associated with the risk of PHN [10,22]. These include:

•Prodromal pain prior to the onset of acute zoster rash

•Severity of pain during acute herpes zoster

•Associated sensory abnormalities (eg, sensory loss or allodynia)

•Extent of acute zoster rash within the affected dermatome

•Trigeminal nerve involvement (herpes zoster ophthalmicus)

•Presence of abnormal brain or spinal imaging findings (eg, dorsal horn hyperintensities on MRI)

Interestingly, the extent of the acute rash within the affected dermatome has been associated with an increased PHN risk, while a longer duration of acute rash has been associated with a reduced risk of PHN [22]. This finding suggests that the duration of the rash may reflect a robust immune response to VZV reactivation.

Patients with an episode of acute herpes zoster without rash (zoster sine herpete) who frequently report severe pain and sensory abnormalities are also at elevated risk of PHN [5].

●Vaccination to prevent herpes zoster – Herpes zoster vaccination reduces the risks of developing acute herpes zoster attacks as well as PHN. (See "Vaccination for the prevention of shingles (herpes zoster) in adults".)

CLINICAL FEATURES — 

PHN produces focal nerve pain in the same dermatomal distribution of the preceding episode of herpes zoster.

Distribution of pain — The location of pain in PHN reflects the distribution observed in acute herpes zoster in individual cases. PHN is most common among patients with trigeminal herpes zoster followed by those with episodes involving thoracic dermatomes and then appendicular (eg, cervical or lumbar) dermatomes (figure 1) [32,33].

Character of pain — PHN is classified as a neuralgia, but patients may report a spectrum of chronic, often severe, nerve injury-related pain. Pain may be predominantly neuralgic (ie, brief, recurrent, electric) or predominantly neuropathic (ie, constant, burning). In many instances, patients can report a mixed pain phenotype consisting of both neuralgic and neuropathic features.

●Neuralgic-type pain – The neuralgic phenotype consists of brief, recurrent, and paroxysmal pain that is electric, shock-like, shooting, or sharp in character [31,34]. These paroxysms of pain can be spontaneous or evoked by surface triggers in the distribution of pain (eg, brush-evoked pain) [12,31,34,35]. Both mechanical and thermal stimuli may elicit allodynia (pain triggered by nonpainful stimuli). Thermal allodynia is more frequently elicited from cold stimuli than warm stimuli [36].

Sensation in the affected dermatome is typically preserved in neuralgic PHN pain [12].

Neuralgic-type PHN pain may be due to aberrant nerve transmission from demyelination (irritable nociceptor) after an episode of herpes zoster [31]. (See 'Pathophysiology' above.)

●Neuropathic-type pain – The neuropathic phenotype consists of constant and burning spontaneous pain, but the patient may also describe the pain as sharp with fluctuations in severity [31,34].

Sensory loss in the affected dermatome is common in neuropathic PHN pain [12].

Neuropathic-type PHN pain may be due to aberrant nerve transmission from loss of afferent sensory neurons (deafferentation) after an episode of herpes zoster [31]. (See 'Pathophysiology' above.)

●Mixed-type – Patients with a mixed phenotype report frequent features of both neuralgic and neuropathic PHN pain [31]. Many patients with PHN may report some features suggestive of both phenotypes, but one type is often predominant. However, patients with mixed-type PHN report frequent features of both neuralgic and neuropathic types.

Pressure-evoked allodynia, hyperalgesia, and paresthesia can be observed in all phenotypes [12,37].

Patients with PHN have significant impairments in activities of daily living and disrupted quality of life along with increased health care costs [38,39].

DIAGNOSIS AND EVALUATION — 

PHN should be considered in patients with pain in the distribution of a cranial or peripheral nerve. The diagnosis of PHN is made when focal neuropathic or neuralgic pain persists for ≥3 months in the same dermatomal distribution as a preceding episode of acute herpes zoster [32].

Diagnostic testing — For most patients, no additional testing is required; the diagnosis of PHN is made based on the presence of dermatomally restricted pain in the same location of the rash from a preceding episode of acute herpes zoster.

We obtain neuroimaging for patients with atypical features including:

●Uncertain history of preceding acute herpes zoster (including zoster sine herpete)

●Associated motor or multifocal sensory deficits

●Nondermatomal (figure 1) pain or sensory loss

MRI with contrast is the preferred imaging technique to assess nerves and adjacent soft tissue. Computed tomography with contrast may be performed as a less sensitive alternative for patients unable to undergo MRI. Imaging should include the spinal level corresponding to the affected dermatome (eg, thoracic spine imaging for back/chest symptoms, cervical spine imaging for arm symptoms). Brain imaging is performed for patients with trigeminal or other cranial pain.

Imaging may help to identify alternative causes of symptoms, such as acute radiculopathy or a mass lesion. If interventional options are pursued, imaging can also be helpful for preprocedural planning in refractory severe pain.

Laboratory and cerebrospinal fluid testing for varicella zoster antibodies is typically reserved for atypical cases to confirm prior exposure to the virus, such as patients with an uncertain prior history of herpes zoster. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster", section on 'Diagnostic tests'.)

Differential diagnosis — The differential diagnosis of PHN includes other conditions that cause focal nerve pain. They may be categorized by the affected body region and distinguished from PHN by specific clinical features (including lack of preceding episode of acute herpes zoster) and/or results of diagnostic testing.

Other causes of neuropathic facial pain

●Trigeminal neuralgia – Trigeminal neuralgia is characterized by brief, recurrent paroxysms of electric or shock-like pain in the territory of one or more branches of the trigeminal nerve, similar to neuralgic symptoms of PHN occurring after herpes zoster ophthalmicus (see 'Character of pain' above). Paroxysms of pain may be spontaneous or provoked by tactile stimuli in both conditions. However, trigeminal neuralgia is not preceded by an acute zoster rash and more commonly affects the lower (V2 and V3) divisions of the trigeminal nerve. Brain imaging may show a vascular or other compressive lesion in classical trigeminal neuralgia. (See "Trigeminal neuralgia".)

●Other causes of trigeminal neuropathy – Painful trigeminal neuropathy is characterized by persistent burning or aching pain in the territory of the trigeminal nerve, similar to neuropathic symptoms of PHN occurring after herpes zoster ophthalmicus (see 'Character of pain' above). Neuropathic pain that follows traumatic trigeminal nerve injury may be diagnosed as painful trigeminal neuropathy. Trigeminal neuropathy may also occur spontaneously due to a structural lesion such as a perineural neoplasm. (See "Overview of craniofacial pain", section on 'Painful post-traumatic trigeminal neuropathy'.)

●Other cranial neuralgias – Several other cranial neuralgic conditions can produce neuralgic pain similar to PHN symptoms, including nervus intermedius neuralgia, auricular neuralgia, and occipital neuralgia. However, limited data suggest nontrigeminal cranial nerve involvement in PHN is uncommon [40]. These cranial neuralgias can be differentiated from PHN by the presence of a rash during a preceding episode of herpes zoster.

Other causes of neuropathic pain in the trunk and extremities

●Radiculopathy – Spinal nerve root impingement commonly causes focal nerve pain with sensory abnormalities, similar to patients with PHN. Both conditions are common in older patients. However, patients with radiculopathy may also have motor symptoms or deficits on examination. Imaging may identify degenerative spondylosis, disc herniation, or other structural causes of radiculopathy. Electrodiagnostic studies can help confirm the presence of motor dysfunction associated with radiculopathy. (See "Clinical features and diagnosis of cervical radiculopathy" and "Acute lumbosacral radiculopathy: Etiology, clinical features, and diagnosis" and "Polyradiculopathy: Spinal stenosis, infectious, carcinomatous, and inflammatory nerve root syndromes", section on 'Diabetic thoracic radiculopathy'.)

●Traumatic mononeuropathy – Trauma that results in peripheral nerve injury may produce chronic neuropathic pain similar to PHN pain. Patients with traumatic mononeuropathies may also have motor symptoms or weakness on examination. (See "Traumatic peripheral neuropathies".)

Of note, patients with a history of prior traumatic mononeuropathy and acute herpes zoster may be a risk for the persistence of pain and PHN [26]. (See 'Risk factors' above.)

●Radiculoplexus neuropathy – Radiculoplexus neuropathies such as diabetic amyotrophy may mimic PHN especially when initial symptoms are focal and involve the thoracic regions. However, radiculoplexus neuropathy most commonly involves the lumbosacral regions in a multiradicular distribution and produces weakness along with pain and sensory deficits. (See "Diabetic amyotrophy and idiopathic lumbosacral radiculoplexus neuropathy".)

Recurrent herpes zoster — Acute herpes zoster is typically monophasic but may recur, especially in immunocompromised patients, females, and older adults. Zoster recurrence is uncommon, unlikely to occur more than three times in any individual, and recurrences often occur in a different region of the body than the index episode [41]. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster", section on 'Recurrent herpes zoster'.)

Recurrent herpes zoster is identified by a re-emergence of the characteristic rash in contrast to PHN in which the onset of pain occurs along with or following the healing of the herpes zoster rash. However, a minority of patients with a dermatomally restricted pattern of nerve pain do not develop (or recall) a rash and may be diagnosed with acute herpes zoster as “zoster sine herpete” when evidence of viremia (eg, skin, blood, cerebrospinal fluid [CSF]) along with pain in distribution and character compatible with herpes zoster are found [4]. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster", section on 'Acute neuritis'.)

MANAGEMENT — 

PHN is a painful and chronic condition that is treated in a step-wise fashion as needed to manage symptoms (algorithm 1). Treatment typically starts with oral therapy, but patients with persistent pain may require a multimodal strategy integrating oral pharmacotherapy with topical treatments and behavioral therapy. Interventional options may be required for those with severe refractory pain.

Initial pharmacotherapy

Medication selection and administration

●Character of pain – Initial pharmacotherapy for PHN is guided by whether the predominating character of pain is neuralgic (brief, recurrent, and paroxysmal pain that is electric, shock-like, shooting, or sharp) or neuropathic (constant and burning). PHN pain that is predominantly neuralgic may be treated with medications used for other neuralgic conditions such as trigeminal neuralgia, while PHN pain that is predominantly neuropathic may be treated with therapies used for neuropathies and other neuropathic conditions that produce chronic pain. The response to pharmacotherapy varies by PHN pain phenotype in some studies [37], studies on other conditions that produce nerve pain [42-44], and in the author’s clinical experience.

Patients with PHN pain that is both neuralgic and neuropathic may require combination therapy directed toward the respective components of pain. We typically start a single agent to assess clinical response and tolerability and subsequently add the second agent as needed.

●Formulations – Several oral therapies for PHN may be administered in three to four divided doses daily using immediate-release formulations or as extended-release formulations given once or twice daily.

More frequent daily dosing can minimize adverse effects and permit titration to improve efficacy, especially for patients with frequently recurring neuralgic PHN pain. In addition, immediate-release formulations may be absorbed more effectively for patients with conditions or concomitant therapy that lead to gastroparesis or malabsorption [45-47]. Compliance with this regimen may be facilitated by the presence of residual or recurrent baseline pain serving as a reminder for patients to take the medication.

By contrast, extended-release formulations are dosed less frequently and are easier to take. These formulations may be preferred for patients with constant neuropathic PHN pain because the limited peak-to-trough fluctuations produce more consistent benefits throughout the day.

●Alternative and adjunctive therapy – If the initial medication option is ineffective or not tolerated even at low doses, we switch to an alternative agent from a different class. For patients with a partial response to initial therapy, we typically add a second oral agent.

Many patients may require combination pharmacotherapy and/or adjunctive nonpharmacologic options for optimal benefit. Combination therapy may provide additional benefits if monotherapy is insufficient [48]. If initial therapy provides some benefit, we add a medication from a different class. Dose adjustments and additional clinical and laboratory monitoring may be required to minimize the risk of adverse effects from combination therapy.

Prior to starting combination therapy, the list of patient medications should be assessed for potential drug interactions. For specific interactions, use the drug interactions program included with UpToDate. Tricyclic antidepressants may need to be discontinued or the dose lowered before starting duloxetine, venlafaxine, or other serotonergic medications to reduce the risk of serotonin syndrome. (See "Serotonin syndrome (serotonin toxicity)".)

●Duration of therapy – We typically administer medications at an effective dose for at least one month to assess benefit. Maximal benefit of some medications such as tricyclic antidepressants may be delayed up to two to three months after reaching a target dose. For patients with pain resolution sustained for at least one month with treatment, we typically offer a slow weaning. Therapy can be resumed if pain recurs.

Neuropathic-predominant pain

Tricyclic antidepressants — For most patients with neuropathic-predominant PHN pain, we suggest a tricyclic antidepressant (amitriptyline or nortriptyline) over other options. The selection between these options should be individualized based on response to any prior treatment and individual risk of adverse effects.

●Amitriptyline – We start amitriptyline at 10 mg once at bedtime and increase by 10 to 25 mg each week up to a maximum of 150 mg or the highest tolerated dose once at bedtime.

●Nortriptyline – We start nortriptyline at 10 mg once at bedtime and increase by 10 to 25 mg each week up to a maximum of 150 mg or the highest tolerated dose once at bedtime.

Adverse effects of tricyclics include dry mouth, constipation, weight gain, and sedation. Tricyclics are contraindicated in patients with cardiac disease. The sedating effects may be used as a sleep aid but may result in morning grogginess leading the provider to recommend taking the medication two hours before bedtime or even earlier. Lower doses may be preferred in older patients and others at risk for delirium or orthostatic hypotension. Nortriptyline may be preferred over amitriptyline in this setting. Slow titration of these medications may reduce the likelihood of adverse effects but at the competing risk of delaying benefit.

In a systemic review of trials assessing pharmacotherapy for all forms of neuropathic pain including patients with PHN, tricyclic antidepressants appear modestly effective [48]. In one small crossover trial of 33 patients with PHN, approximately two-thirds of patients reported a good response to amitriptyline and to nortriptyline, but adverse effects were higher with amitriptyline [49].

Alternative oral options — For patients with neuropathic-predominant PHN with a contraindication or inadequate response to tricyclic antidepressants, we add or switch to a gabapentinoid or serotonin/norepinephrine reuptake inhibitor. Options and typical effective dose ranges include:

●Gabapentin – 900 to 3600 mg daily given in three divided doses

●Pregabalin – 300 to 600 mg daily given in two to three divided doses

●Duloxetine – 60 to 120 mg given once daily

●Venlafaxine – 150 to 225 mg given once daily

For patients with neuropathic-type PHN pain who have a suboptimal response to tricyclic antidepressants and/or alternative medications, other medications that may provide benefit include desipramine and imipramine [48].

All medications being taken by the patient should be reviewed before starting an additional agent to assess for the risk of interactions and guide selection among options to minimize the risk of adverse effects from combination therapy. Tricyclics may need to be discontinued or the dose lowered before starting duloxetine or venlafaxine to reduce the risk of adverse effects. (See 'Medication selection and administration' above.)

In a systematic review of trials assessing pharmacotherapy for all forms of neuropathic pain, evidence found that gabapentin, pregabalin, duloxetine, and venlafaxine were each modestly more effective than placebo [48]. Limited data support the use of desipramine or imipramine for PHN and other types of nerve-related pain [50].

Neuralgic-predominant pain

Gabapentinoids — For most patients with neuralgic-predominant PHN pain, we suggest a gabapentinoid (gabapentin or pregabalin) over other options. The selection between these options should be individualized based on response to any prior treatment and insurance coverage.

●Gabapentin – We typically start at 300 mg once daily at night and increase by 300 mg each week up to 600 mg three times daily. Adverse effects typically include weight gain, sedation, dizziness, somnolence, and gait imbalance. Depending on response and adverse effects, the dose can be increased gradually on a weekly basis by 300 mg up to the highest tolerated dose or 3600 mg per day in divided doses. With doses above 600 mg three times daily, there are diminished therapeutic gains in part related to gastrointestinal absorption.

●Pregabalin – We start pregabalin at 75 mg once daily and increase by 75 mg each week up to 150 mg twice daily or highest tolerated dose.

For patients taking gabapentin who wish to transition to pregabalin, we do a 6:1 conversion to avoid symptom exacerbation with a cross-taper. For example, for a patient maintained on gabapentin 600 mg three times daily, we discontinue gabapentin without a taper and start pregabalin 100 mg three times daily. For total daily gabapentin doses above 1800 mg, a more conservative conversion may be warranted to minimize adverse events during the transition to pregabalin.

Adverse effects for pregabalin are similar to gabapentin, except in prior studies of pregabalin, in which a subset of patients reported euphoria which resulted in pregabalin being classified as a controlled substance and is a class V scheduled medication. Lower doses of gabapentinoids may be required if chronic kidney disease is present.

Gabapentin and pregabalin each appear to be effective in reducing pain in PHN. In a systematic review of trials assessing pharmacotherapy for all forms of neuropathic pain, both gabapentin (900 to 3600 mg daily) and pregabalin (150 to 600 mg daily) appeared modestly more effective than placebo [48]. A meta-analysis of patients with neuropathic pain (predominantly PHN and diabetic neuropathy) reported a higher rate of pain reduction of at least 50 percent among those treated with gabapentin at 1200 mg or higher than patients who received placebo (32 versus 17 percent) [51]. Another meta-analysis of 732 patients from four placebo-controlled PHN trials reported higher rates of pain reduction of at least 50 percent among those receiving pregabalin at each dose assessed: 150 mg (24 versus 13 percent), 300 mg (32 versus 13 percent), 600 mg (41 versus 15 percent) [52].

Alternative oral therapy — For patients with neuralgic-predominant PHN with a contraindication or inadequate response to gabapentinoids, we add or switch to a tricyclic antidepressant or sodium channel blocker. Options and typical effective dose ranges include:

●Amitriptyline – 50 to 150 mg given once daily or in two divided doses

●Nortriptyline – 50 to 150 mg given once daily

●Oxcarbazepine – 900 to 1800 mg given once daily or in up to three divided doses

●Carbamazepine – 600 to 1200 mg daily given in two to four divided doses

For patients with neuralgic-type PHN pain who have a suboptimal response or contraindication to gabapentinoids and/or alternative medications, other medications that may provide benefit include duloxetine, lamotrigine, and lacosamide [48].

All medications being taken by the patient should be reviewed before starting an additional agent to assess for the risk of interactions and guide selection among options to minimize the risk of adverse effects from combination therapy. Carbamazepine is a strong cytochrome P450 inducer that may interact with other medications. Tricyclics may need to be discontinued or the dose lowered before starting duloxetine or venlafaxine to reduce the risk of adverse effects. (See 'Medication selection and administration' above.)

We suggest testing for the HLA-B*15:02 allele in genetically at-risk populations (ie, those with East Asian or South Asian ancestry) before initiating treatment with oxcarbazepine or carbamazepine. The HLA-B*15:02 allele is a genetic susceptibility marker that is associated with an increased risk of developing Stevens-Johnson syndrome and/or toxic epidermal necrolysis. If genetic testing results are positive for the presence of at least one copy of the HLA-B*15:02 allele, oxcarbazepine or carbamazepine should be avoided.

Oxcarbazepine may be effective for patients with PHN, sometimes within the first week of treatment [53]. In a clinical trial of 83 patients with PHN, those who were assigned to oxcarbazepine 1800 to 2400 mg daily had greater pain relief (on a 0 to 10 numeric rating scale) at six-week follow-up than patients assigned to placebo (mean difference -0.7, 95% CI 0.4-1.4) [37]. The response to treatment was greater among those with neuralgic-type pain. In a systematic review of trials assessing pharmacotherapy for neuropathic pain, high-quality evidence found that tricyclic antidepressants were more effective than placebo [48]. The evidence for sodium channel blockers such as carbamazepine is uncertain.

Limited roles for opioids — We typically reserve opioid analgesics for selected patients with PHN for short-term relief of constant or neuropathic-type pain while effective oral medications are being titrated or while alternative therapies are being planned.

For patients with PHN using an opioid, we typically start with short-acting agents such as tramadol or tapentadol, at the lowest effective dose [48]. Concomitant dose reductions or monitoring for adverse effects may be warranted for patients taking tricyclics or other antidepressants because coadministration with tramadol and tapentadol may increase the risk of adverse effects, including serotonin syndrome.

Other more potent opioids could be used for patients unresponsive to tramadol and tapentadol (table 1 and table 2). In a meta-analysis of studies assessing treatment of neuropathic pain that included the use of opioids, no added benefit was observed above a dose of 180 mg oral morphine equivalents per day [48]. For the rare patient unresponsive to other therapies with adverse effects to oral opioids, intrathecal drug delivery systems have been used to minimize systemic adverse effects [54].

Prior to starting opioids, the prescribing clinician should discuss with patients the risks and benefits of therapy, establish goals, and plan for monitoring of therapy (table 3). Patients should receive therapy from a single provider and sign an opioid agreement which should include periodic urine drug monitoring to ensure compliance (table 4). (See "Use of opioids in the management of chronic pain in adults", section on 'Initiating a trial of opioid therapy'.)

Adjunctive topical and nonpharmacologic options — We offer adjunctive topical and/or nonpharmacologic options for all patients with a suboptimal response to initial pharmacotherapy. These therapies should be given along with oral therapy as evidence of efficacy is limited to their use in combination with oral agents. Topical therapies may be preferred for those with dose-limiting systemic adverse effects of oral pharmacotherapy, while nonpharmacologic options may be preferred for those who wish to minimize the risk of adverse effects associated with medications.

●Lidocaine patches – Lidocaine patches can provide short-term adjunctive relief for patients with PHN. In a retrospective case series of 87 patients with neuropathic pain including PHN, pain relief with lidocaine patches was more common in those with allodynia than without (86 versus 39 percent) [55]. Lidocaine patches are available as an over-the-counter 4% formulation and as a 5% formulation by prescription. Patches are placed over the affected pain region for up to 12 hours daily [56,57].

Topical lidocaine is well tolerated with minimal adverse effects and has been shown to provide benefits in PHN [56-58]. However, benefit is typically reported in patients using lidocaine patches along with oral medications.

●Capsaicin – Topical capsaicin is available as an over-the-counter option that may provide some short-term adjunctive benefit for most patients with PHN [59]. These options may be formulated as a cream, lotion, or gel and may be applied to the affected area up to four times daily.

High-concentration capsaicin patches are also available by prescription and administered by a health care professional up to once every three months. (See 'Topical high-concentration capsaicin' below.)

●Behavioral therapy – Cognitive behavioral therapy and mindfulness strategies may be used as an adjunctive nonpharmacologic option for patients with PHN. They have been shown to improve outcomes in pain management in PHN with improvements in pain, depression, and anxiety [60,61]. (See "Approach to the management of chronic non-cancer pain in adults", section on 'Cognitive-behavioral therapy'.)

●Acupuncture – Limited data suggest acupuncture for PHN is well tolerated and has the potential to improve outcomes in pain, sleep, and depressive symptoms as well as augment outcomes with other treatments [62-66].

Patients with refractory pain — For patients with severe PHN pain who have an inadequate response to two or more oral therapies, we refer to pain management specialists for interventional and other treatments for refractory pain. Options for refractory pain vary by severity and duration, local availability, and patient preferences.

Topical high-concentration capsaicin — High-concentration capsaicin patches may be tried by patients with refractory PHN pain who prefer a topical option. Topical high-concentration (8%) capsaicin patches can provide pain relief for several weeks in PHN. Pain reduction was reported in nearly 45 percent of patients in an open-label 12-week study of patients with PHN [67]. Repeat application every three months may provide a more sustained response [68]. High-concentration capsaicin is administered as a 60-minute application performed by a medical professional. However, the application is painful, requiring pretreatment with topical lidocaine, and may also cause swelling or sensory loss. Burns have been reported in patients receiving incorrect dosing or administration of high-concentration capsaicin [69].

In a clinical trial of 402 patients with PHN, those who received high-concentration capsaicin patches had a greater reduction in baseline pain than those who received low-concentration (0.04%) control patches (30 versus 20 percent) by eight-week follow-up [70]. A similar benefit was reported in another trial that assessed change in baseline pain scores among patients randomized to high-concentration capsaicin or placebo patches [71]. By twelve-week follow-up, the mean reduction in baseline pain scores was greater for those assigned to capsaicin (33 versus 4 percent). High-concentration capsaicin patches are approved by the United States Food and Drug Administration for the treatment of PHN.

Interventional options — For patients with refractory PHN pain who do not respond to or who decline high-concentration capsaicin, we suggest interventional options based on the symptom duration. If PHN symptoms have been present for <12 months, we start with epidural glucocorticoid injections, paravertebral blocks, or nerve blocks. For patients with PHN symptoms >12 months, we use intradermal botulinum toxin or neuromodulation.

Epidural injections or nerve blocks — For patients with refractory PHN pain <12 months in duration and predominantly neuralgic in character, we refer for spinal epidural or peripheral nerve injections. The selection of specific therapy depends on the involved dermatome (nerve), local protocol/available expertise, and patient-level factors [33,72,73].

●Epidural glucocorticoid injections are used for patients with PHN pain in the cervical, thoracic, or lumbar spinal segments. For thoracic PHN with discrete regions of pain, intercostal nerve or paravertebral blocks with fluoroscopic or ultrasound guidance may also be pursued.

●Peripheral nerve blocks are typically used for patients with trigeminal PHN. Options include trigeminal gasserian ganglion blocks, as well as supraorbital, infraorbital, maxillary, or pterygopalatine fossa blocks.

Peripheral nerve blocks are also used for patients with PHN pain in the spinal segments who decline or are at elevated risk of morbidity with more invasive epidural injections (eg, challenging spinal anatomy or concurrent anticoagulation therapy).

Epidural glucocorticoid injections or nerve blocks may provide pain relief for some patients with subacute refractory PHN. In a series of 42 patients with PHN treated with epidural injection, good pain relief at 12-week follow-up was likelier in those who reported symptom duration <12 months compared with those with longer duration (55 versus 23 percent) [74].

Intradermal onabotulinumtoxinA injections — For patients with refractory PHN pain ≥12 months in duration and predominantly neuralgic in character, we refer for intradermal botulinum toxin injections.

Injections are performed along the affected dermatome in a grid pattern (1 to 1.5 cm apart) using total doses ranging from 50 to 200 units depending on number of injections and the size of the affected surface area [48,75,76]. To target the dermal-subcutaneous junction for PHN treatment, the needle is typically inserted at a 45-degree angle to a depth of two to three millimeters [42,76-78]. Adverse effects are minimal in thoracic dermatomes other than injection site pain with proper technique, but in the trigeminal dermatomes, the risk of temporary facial weakness is considerable and can occur in up to 20 percent [75,79].

The benefit of cutaneous injection of onabotulinumtoxinA for neuropathic pain has been shown in multiple meta-analyses with up to half of patients reporting pain relief [48,75]. Predictors of response were paroxysmal pain, limited sensory loss (specifically thermal sensation), and allodynia [42]. However, data are somewhat limited by the heterogeneity of outcome, possibly attributable to technical factors (eg, injection technique) and patient selection (eg, neuralgic versus neuropathic pain) that impact clinical outcomes.

OnabotulinumtoxinA is an off-label agent for PHN, and availability may be limited by cost and insurance coverage.

Neuromodulation — For patients with refractory PHN pain ≥12 months in duration that is predominantly neuropathic or burning and constant in character, we refer for neuromodulation. We also refer patients who do not respond to other refractory options for neuromodulation. Selection among options depends on the site of pain (cranial versus spinal) and local expertise. Options include:

●PHN involving trunk or limbs:

•Spinal cord stimulation

•Dorsal root ganglion (DRG) stimulation

•Peripheral nerve stimulation (eg, intercostal)

Spinal cord stimulation may be preferred for patients with cervical and thoracic level pain. DRG stimulation may be preferred for patients with distal and focal pain such as those with PHN pain involving the foot. Peripheral nerve stimulation may be used for patients with prior spinal surgery or those with medical contraindications to more invasive neuromodulation procedures (eg, DRG or spinal cord stimulation).

●PHN involving the face:

•Peripheral nerve stimulation (eg, supraorbital or infraorbital)

•Transcranial magnetic stimulation

•Motor cortex stimulation

•High cervical spinal cord stimulation

Modalities used depend largely on local availability and insurance coverage. High cervical cord stimulation for PHN involving the face may be used if peripheral nerve and motor cortex stimulation are unavailable.

Evidence of efficacy for neuromodulation is limited to observational studies [80-83]. Long-term pain relief is reported in approximately 65 to 82 percent of patients [82,83]. Some comparative efficacy studies have reported spinal cord stimulation demonstrated better short-term analgesic effect and safety than pulsed radiofrequency [80,81,84-87]. Both DRG and intercostal nerve stimulation have been reported in case series to be beneficial and may be options for patients not responsive to spinal cord stimulation [83,88,89]. Supraorbital nerve stimulation was found to be more effective than supraorbital nerve block for patients with refractory trigeminal PHN in one trial response rates (≥50 percent pain relief) of 72 and 44 percent, respectively [90]. Repetitive transcranial magnetic stimulation was reported to provide short-term pain relief and even to be predictive of a response to motor cortex stimulation [81].

Additional data are needed to better identify the role of specific neuromodulation techniques for the pain phenotypes of PHN (neuralgic versus neuropathic).

Treatments of uncertain benefit or not recommended — Several treatments used for neuropathic and other types of pain are generally avoided for PHN because benefit for this condition has not been established or because risks outweigh benefits.

●Medications — Several oral medications used for other painful conditions and agents used for other neurologic conditions that have not shown consistent benefit for PHN include [48,91]:

•Acetaminophen

•Nonsteroidal anti-inflammatory drugs

•Mexiletine

•Levetiracetam

•Valproate

•Topiramate

Ketamine infusions have been assessed as a refractory option for PHN. A small prospective study reported response rates with ketamine or magnesium sulfate infusions were similar [92]. In addition, ketamine is associated with a risk of hepatoxic and cardiogenic adverse effects [93].

●Cannabis and cannabinoids – Some systematic reviews have reported evidence to support the use of cannabis-based medicines for the treatment of chronic neuropathic pain, but guidelines for the management of neuropathic pain have recommended against the use of medical cannabis or cannabinoids in the treatment of neuropathic pain due to very low-quality evidence suggesting modest or uncertain benefit outweighed by the risk of adverse effects [48,94]. In addition, the concurrent use of opioids and cannabis-based medicines should be avoided due to the risk of abuse and uncertainty of benefits in this setting [95]. Cannabis-based medicines should only be used in compliance with local laws and regulations. (See "Medical use of cannabis and cannabinoids in adults".)

●Interventions — The available evidence does not support the use of sympathetic blocks such as stellate ganglion blocks or lumbar sympathetic blocks for the treatment of PHN [80].

Intrathecal glucocorticoids were found to be beneficial in one randomized controlled trial, but these results were not reproduced in subsequent studies where a number of patients had worsening pain [80,96]. The procedure also carries a risk of arachnoiditis that may outweigh the potential benefits [80].

Evidence of efficacy has not been established for deep brain stimulation to treat neuropathic pain including PHN [81].

Destructive lesioning procedures (eg, chemical neurolysis or ablation of the DRG) have been shown to provide short-term relief, but longer-term benefits have not been established, and the procedure may cause painful posttraumatic chronic neuropathy (anesthesia dolorosa) [84].

PREVENTION — 

Herpes zoster vaccination can reduce the risk of developing acute herpes zoster (shingles) and PHN. Vaccination is indicated for immunocompromised adults and immunocompetent adults ≥50 years old. The indications and administration of herpes zoster vaccination are discussed in greater detail separately. (See "Vaccination for the prevention of shingles (herpes zoster) in adults".)

Antiviral therapy for acute herpes zoster is indicated to reduce the duration and severity of the rash and acute pain. However, the effect of antiviral therapy on the prevention of PHN is unclear. (See "Treatment of herpes zoster", section on 'Antiviral therapy'.)

PROGNOSIS — 

PHN is frequently a chronic condition that may require long-term treatment to manage symptoms in many patients; however, some patients achieve symptom resolution and are able to wean from therapy.

In one study that included 158 patients with acute zoster who were contacted after a mean of nine years, symptoms of PHN in the preceding year were reported by 21 percent [97]. In another cohort of 94 patients with herpes zoster, the percentage of patients who met criteria for PHN decreased from 50 percent at three months to 32 percent at six months [98]. In addition, clinical recovery of sensory function was reported by six months, and only 2 patients had “clinically meaningful” pain. Among patients with resolution of PHN symptoms with a follow-up at a median of 7.7 years, PHN recurrence was reported in only 1 of 10 patients, and severity was mild [3].

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 – PHN is a condition characterized by focal nerve pain that occurs or persists ≥90 days after the onset of an episode of acute herpes zoster virus reactivation (shingles). Pain localizes to the territory of the affected cranial or spinal nerve associated with the preceding acute zoster rash. (See 'Introduction' above and 'Pathophysiology' above.)

●Risk factors – Risk factors for PHN include older age, female sex among individuals <60 years old, conditions that cause an immunocompromised state, autoimmune conditions, diabetes mellitus, tobacco use, and physical trauma at the site of the preceding acute herpes zoster rash. (See 'Risk factors' above.)

●Clinical features – PHN produces focal nerve injury-related pain in the same dermatomal distribution of the preceding episode of herpes zoster. Patients may present with pain that is predominantly neuralgic (brief, recurrent, electric), predominantly neuropathic (constant, burning), or a mixed phenotype. (See 'Clinical features' above.)

PHN is most common among patients with trigeminal herpes zoster followed by those with episodes involving thoracic dermatomes and then appendicular (eg, cervical or lumbar) dermatomes (figure 1).

●Diagnosis – The diagnosis of PHN is made when focal neuropathic or neuralgic pain persists for ≥3 months in the same dermatomal distribution as a preceding episode of acute herpes zoster. (See 'Diagnosis and evaluation' above.)

We obtain diagnostic testing using MRI with contrast for patients with atypical features including (see 'Diagnostic testing' above):

•Uncertain history of preceding acute herpes zoster (including zoster sine herpete)

•Associated motor or multifocal sensory deficits

•Nondermatomal (figure 1) pain or sensory loss

Imaging should include the spinal level corresponding to the affected dermatome (eg, thoracic spine imaging for back/chest symptoms, cervical spine imaging for arm symptoms). Brain imaging is performed for patients with trigeminal or other cranial pain.

●Differential diagnosis – The differential diagnosis of PHN includes other conditions that cause focal nerve pain. These include facial pain syndromes such as trigeminal neuralgia, painful trigeminal neuropathy, and other cranial neuralgias as well as trunk/limb pain syndromes such as radiculopathies, mononeuropathies, and radiculoplexus neuropathy. (See 'Differential diagnosis' above.)

●Treatment – PHN treatment typically starts with oral therapy, but patients with persistent pain may require a multimodal strategy integrating oral pharmacotherapy with topical treatments and behavioral therapy. Interventional options may be required for those with severe refractory pain (algorithm 1). (See 'Medication selection and administration' above.)

•Initial pharmacotherapy

-For most patients with neuropathic-predominant (constant, burning) PHN pain, we suggest initial therapy with a tricyclic antidepressant (amitriptyline or nortriptyline) (Grade 2C). These agents have established efficacy in the treatment of other forms of neuropathic pain as well as observational evidence of benefit in PHN. (See 'Neuropathic-predominant pain' above.)

For such patients with a contraindication or inadequate response to tricyclic antidepressants, we switch to alternative medication from a different class such as a gabapentinoid or serotonin/norepinephrine reuptake inhibitor. Tricyclics may need to be discontinued or the dose lowered before starting an alternative agent to reduce the risk of adverse effects.

-For most patients with neuralgic-predominant (brief, recurrent, electric) PHN pain, we suggest initial therapy with a gabapentinoid (gabapentin or pregabalin) based on efficacy in several placebo-controlled trials (Grade 2C). For such patients with a contraindication or inadequate response to gabapentinoids, we add or switch to a tricyclic antidepressant or sodium channel blocker. (See 'Neuralgic-predominant pain' above.)

•Adjunctive options – We offer adjunctive topical and/or nonpharmacologic modalities for all patients with a suboptimal response to initial pharmacotherapy. Options include lidocaine patches, capsaicin, behavioral therapy, and acupuncture. (See 'Adjunctive topical and nonpharmacologic options' above.)

•Refractory cases – For patients with severe PHN pain who have an inadequate response to two or more oral therapies, we refer to pain management specialists for interventional and other treatments for refractory pain. (See 'Patients with refractory pain' above.)

Options for refractory pain vary by severity and duration, local availability, and patient preferences and include:

-High-concentration capsaicin patches

-Spinal epidural glucocorticoid injections or nerve blocks if symptom duration <12 months

-Intradermal botulinum toxin or neuromodulation (eg, spinal cord or peripheral nerve stimulation) if symptom duration ≥12 months

●Prognosis – PHN is frequently a chronic condition that may require long-term treatment to manage symptoms in many patients, but some patients achieve symptom resolution and are able to wean from therapy. (See 'Prognosis' above.)