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2 t <p><font class="font-s">Q</font></p> Uploading Image...	t <p><font class="font-xs">Postherpetic neuralgia Postherpetic neuralgiaAuthors:Zahid H Bajwa, MDErik Ortega, MDSection Editor:Jeremy M Shefner, MD, PhDDeputy Editor:April F Eichler, MD, MPHContributor DisclosuresAll topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Feb 2018. \| This topic last updated: Feb 13, 2017.INTRODUCTION — Varicella-zoster virus (VZV) is the causative agent of varicella, or "chickenpox," and herpes zoster, or "shingles." Most cases of acute herpes zoster are self-limited, although the pain can cause significant suffering, particularly in older adults. Symptoms may be severe enough to interfere with sleep, appetite, or sexual function. In addition, a variable percentage of patients may continue to experience pain for months to years after the resolution of the rash, a condition known as postherpetic neuralgia (PHN). PHN can be quite difficult to treat.The pathogenesis, epidemiology, clinical features, diagnosis, and treatment of PHN are reviewed here. Other aspects of the varicella-zoster virus and the acute therapy of herpes zoster infection are discussed separately. (See "Epidemiology and pathogenesis of varicella-zoster virus infection: Herpes zoster" and "Treatment of herpes zoster in the immunocompetent host".)PATHOGENESIS — Acute herpes zoster is caused by reactivation of the varicella-zoster virus (VZV). The virus persists for a period of years in the dorsal root ganglia of cranial or spinal nerves after resolution of the original infection. As cellular immunity wanes with age or immunocompromise, the virus is transported along peripheral nerves, producing an acute neuritis [1,2].At the cellular level, infection with acute herpes zoster is characterized by hemorrhagic inflammation of the peripheral nerve, dorsal root, and dorsal root ganglion. Extension centrally into the spinal cord and leptomeninges also has been described [3]. Fibrosis is noted in the dorsal root ganglion, nerve root, and peripheral nerve upon resolution of the acute process [4,5].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 [6]. The findings included dorsal horn atrophy as well as cellular, axonal, and myelin loss with fibrosis in the sensory ganglion in patients with persistent pain. However, marked axonal and myelin loss in the nerve and/or sensory root were found in cases with and without 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. Studies of the affected dorsal horn from one patient with PHN failed to demonstrate differences in the levels of these neurotransmitters when compared with the unaffected side [7]. The same investigators were unable to demonstrate a deficiency of opiate receptors in the affected dorsal horn. Another study evaluated cytokine profiles extracted from skin punch biopsies of dermatomes affected by PHN and found no significant differences when compared with skin biopsies from the normal contralateral side [8].There are three phases of pain associated with herpes zoster [9-11]:●Acute herpetic neuralgia refers to pain preceding or accompanying the eruption of rash that persists up to 30 days from its onset●Subacute herpetic neuralgia refers to pain that persists beyond healing of the rash but which resolves within four months of onset●PHN refers to pain persisting beyond four months from the initial onset of the rashThe pain of acute herpetic neuralgia probably is produced both by the inflammation associated with the movement of viral particles from sensory nerves to skin and subcutaneous tissues, and by the damage to nerve structures detailed above. In addition, activity of primary afferent neurons that respond to tissue damage causes changes in the dorsal horn neurons, sensitizing them to further input and resulting in spontaneous activity capable of maintaining pain in the absence of ongoing tissue damage [7,12-15]. The persistence of this response may explain the continuing pain of PHN [16].Some have speculated that ongoing VZV viral replication might be responsible for PHN. However, a randomized, double-blind, placebo-controlled trial of intravenous and oral acyclovir for 56 days in 10 patients with severe PHN of at least six months duration failed to influence the course of PHN [17].EPIDEMIOLOGY — The incidence of acute herpes zoster infection increases with impairment of the immune system due to age, disease, or chemotherapy. The annual incidence among healthy people under the age of 20 years is approximately 1 per 1000; the incidence is 5 to 10 times greater for those older than 80 years [18]. Herpes zoster also is several times more common in patients with cancer or HIV infection [19]. (See "Epidemiology and pathogenesis of varicella-zoster virus infection: Herpes zoster", section on 'Epidemiology'.)Similarly, the probability of developing PHN increases with advanced age. Most studies agree that PHN is rare in children. In adults younger than 60 years of age with herpes zoster, the risk of PHN is estimated to be less than 2 percent [20].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. In contrast, among 308 patients age 70 years or older who developed herpes zoster, PHN occurred in 18.5 percent.Risk factors — The major risk factors for PHN are older age, greater acute pain, and greater rash severity [22-26]. The risk of PHN is probably increased as well with immunosuppression, although the evidence is not entirely consistent [26-28]. In patients who develop PHN, advanced age is associated with increasing severity and persistence of symptoms [29].CLINICAL MANIFESTATIONS — With PHN, thoracic (especially T4 to T6), cervical, and trigeminal nerves are most commonly affected [30]. The pain associated with acute zoster infection and PHN can be burning, sharp, or stabbing and constant or intermittent [9,31]. More than 90 percent of patients with PHN also have allodynia, defined as pain evoked by normally nonpainful stimuli such as light touch [32].Patients with PHN often demonstrate areas of anesthesia, as well as deficits of thermal, tactile, pinprick, and vibration sensation within the affected dermatomes [32]. The contralateral, uninvolved side tests normally. Sensory deficits may extend beyond dermatomal margins. It has been suggested that allodynia is most prominent in areas of relatively preserved sensation, while spontaneous pain is felt predominately within the area of lost or impaired sensation.PHN most often represents a continuum of pain that never resolved following an acute episode of herpes zoster. However, PHN rarely has been reported to occur months to years after resolution of the initial event [33]. These episodes occurred in the same distribution as the initial rash and were precipitated by a specific event (eg, a surgical procedure, tooth abscess).Both acute zoster and PHN can be severe conditions associated with profound psychosocial dysfunction including impaired sleep, decreased appetite, and diminished libido [31,34].DIAGNOSIS — In most cases, the diagnosis of PHN is straightforward and is made when pain persists beyond four months in the same distribution as a preceding documented episode of acute herpes zoster (see "Clinical manifestations of varicella-zoster virus infection: Herpes zoster", section on 'Diagnosis'). Thus, the diagnosis of PHN is based solely upon the clinical presentation. Additional factors supporting the diagnosis are [35]:●Advanced age●Severe prodromal pain with acute herpes zoster●Severe preceding rash●Distribution in trigeminal or brachial plexus dermatomes●The presence of allodyniaHowever, the diagnosis of PHN can be missed if the rash has resolved and the patient no longer remembers it or does not ascribe the pain to it [35]. Uncommonly, the nerve pain in acute herpes zoster may emerge in the absence of any skin eruption, as occurs in a condition called "zoster sine herpete" or in intercostal neuralgia. The presence of pain in trigeminal or radicular distribution combined with the detection of varicella-zoster virus by polymerase chain reaction (PCR) in the cerebrospinal fluid supports the diagnosis of zoster sine herpete [36]. (See "Diagnosis of varicella-zoster virus infection", section on 'Polymerase chain reaction'.)On examination, the areas affected by PHN may be remarkable for scarring related to the vesicular eruption of the preceding acute herpes zoster infection, or by areas of excoriation caused by scratching. The affected skin may display decreased sensation to mechanical and thermal stimuli, hyperalgesia (increased sensitivity to painful stimuli), or allodynia (pain produced by normally non-noxious stimulation).TREATMENT — Tricyclic antidepressants, gabapentin, and pregabalin are generally the drugs of first choice for the treatment of PHN. In systematic reviews, treatments more effective than placebo for PHN include tricyclic antidepressants, gabapentin, pregabalin, and opioids [37-40]. The long-term benefits of most therapies are uncertain, and side effects are common.Because the pain of PHN may be chronic, long-term therapy is often required [41].We recommend initial treatment with one of the nonopioid agents effective in controlled trials, ie, tricyclic antidepressants, gabapentin, and pregabalin. The choice among treatments for PHN should be individualized according to patient-specific characteristics, comorbid conditions, medication side effect profile, and patient values and preferences. Based upon the available data and our experience, we typically use the following approach:●We suggest initial treatment with a tricyclic drug for most patients with moderate to severe pain from PHN. Exceptions include patients with heart disease, epilepsy, or glaucoma. Because of their anticholinergic effects, tricyclic drugs should be used cautiously in older patients, particularly those with cognitive impairment or dementia. (See 'Tricyclic antidepressants' below.)●We suggest gabapentin or pregabalin for patients with moderate to severe PHN who have contraindications to or intolerance of tricyclic antidepressants. Gabapentin and pregabalin should be avoided in patients with renal insufficiency. (See 'Anticonvulsants' below.)●We suggest topical capsaicin for patients with mild to moderate localized pain from PHN who do not desire systemic therapy with tricyclic drugs, gabapentin, and pregabalin. However, topical capsaicin is often poorly tolerated. Topical lidocaine is an alternative that may provide short-term relief. (See 'Capsaicin' below.)●Opioids are associated with the potential for abuse and addiction, and thus many experts consider them as second- or third-line treatment options for PHN. However, opioids can be used cautiously if the preventive agents (tricyclic drugs, gabapentin, and pregabalin) are unsuccessful. Opioids also can also be administered simultaneously with the nonopioid preventive agents, since the nonopioid drugs may not be immediately effective. Opioids should be initiated at low doses, if used, and titrated to provide relief while awaiting benefit from preventive treatments, at which point opioids should be tapered off. (See 'Opioids' below.)●Intrathecal glucocorticoid injections are an option for patients who continue to have intractable pain despite the above measures. These injections do not work for pain in the distribution of the trigeminal nerve. (See 'Intrathecal glucocorticoids' below.)The evidence supporting these recommendations is reviewed in the sections that follow. Mild analgesics such as aspirin and other nonsteroidal anti-inflammatory drugs are of limited value in patients with either acute herpetic neuralgia or PHN [41,42].Tricyclic antidepressants — Tricyclic antidepressant (TCA) medications are effective for PHN [43], and they are often thought of as the mainstay of therapy. These drugs 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 [44,45].The efficacy of TCAs was originally demonstrated in a small study of 24 patients with PHN [46]. In a subsequent prospective, randomized, double-blind, crossover comparison, 58 older adult patients with PHN were randomly assigned to six weeks of therapy with amitriptyline (12.5 to 150 mg per day), lorazepam (0.5 to 6 mg per day, an "active" placebo), or an inactive placebo [47]. A mean amitriptyline dose of 65 mg per day was achieved. Amitriptyline was significantly more effective than lorazepam or inactive placebo in providing moderate relief of pain (47, 15, and 16 percent, respectively). Equal numbers of patients withdrew from each group due to side effects. There was a significant correlation between the degree of symptom relief and serum amitriptyline levels. The authors concluded that serum levels of amitriptyline and active metabolites must be maintained at concentrations of 100 ng/mL for at least three weeks before a patient is considered to have failed TCA therapy.Anticholinergic side effects (principally sedation and dry mouth) limit patient acceptance of TCAs (table 1). A head-to-head trial concluded that nortriptyline was better tolerated than amitriptyline [48]. Desipramine has the fewest side effects of the first generation TCAs [49], and it was also effective in relieving PHN in one small trial (mean dose 165 mg per day) [50], though methodologic problems limit the strength of this trial [51]. There may be a lag of up to three weeks before TCAs begin to reduce pain.Our preferred tricyclic drug for PHN is amitriptyline, starting at 10 mg each night and titrating slowly to effect as tolerated, with a maximum dose of 150 mg daily.Anticonvulsants — Anticonvulsant medications are useful in the treatment of neuropathic pain, most notably in reducing the lancinating component of painful syndromes such as PHN. Drugs that have been evaluated in randomized trials include gabapentin [38,52], pregabalin [53], and valproic acid [54].Gabapentin — Immediate release gabapentin is probably effective for PHN, but there are inconsistent data regarding the efficacy of the once-daily (extended release) formulation of gabapentin.●A 2014 systematic review [55] identified four placebo-controlled randomized trials, with two trials evaluating immediate release gabapentin [56,57] and two trials evaluating extended release gabapentin [58,59]. In the pooled analysis, gabapentin at doses between 1800 and 3600 mg daily was beneficial for PHN compared with placebo for the outcome of "much or very much improved" (38 versus 20 percent, risk ratio 1.9, 95% CI 1.5-2.3, number needed to treat 5.5) [52].●The gastroretentive extended release formulation of gabapentin was not significantly more effective than placebo for PHN when given once daily (1800 mg daily) in two trials included in the systematic review, which together included 723 patients [58,59], but was more effective than placebo at an alternative twice daily dosing schedule (600 mg AM and 1200 mg PM) in one of these trials [58]. In a third trial of 452 patients with PHN, the group assigned to extended release gabapentin (1800 mg) taken once daily had a statistically significant reduction in mean pain scores compared with placebo, leading to regulatory approval of the drug in the United States as once-daily treatment for PHN [60,61].In two small randomized controlled trials, gabapentin enacarbil (the prodrug of gabapentin), another extended release formulation, showed some evidence of benefit for reducing average pain intensity scores in PHN [62,63].Gabapentin is typically started at a low dose and titrated to effect. Our suggested gabapentin regimen for PHN is 300 mg on day 1, 300 mg twice daily on day 2, and 300 mg three times daily on day 3; the dose is then titrated as needed for pain relief to the range of 1800 to 3600 mg/day in three divided doses. For the extended release formulation of gabapentin, one regimen begins with 300 mg on day 1, 600 mg on day 2, 900 mg once daily on days 3 to 6, 1200 mg once daily on days 7 to 10, 1500 mg once daily on days 11 to 14, and 1800 mg once daily on day 15 and thereafter.Pregabalin — Pregabalin is a structural analog of gamma-aminobutyric acid (GABA) and is similar to gabapentin. Two randomized controlled trials involving over 400 patients with PHN have shown improvement in sleep and decrease in pain at doses of 150 to 600 mg daily [64,65]. Common side effects are dizziness, somnolence, dry mouth, peripheral edema, and weight gain. It is designated as a schedule V controlled substance in the United States because it has been reported to cause euphoria.The recommended starting dose for pregabalin is 150 mg, divided into two or three doses daily, and increased to a total daily dose of 300 mg based upon tolerability and effect. Further titration (to 600 mg daily) after two to four weeks may be considered in patients who do not experience sufficient relief of pain provided they are able to tolerate pregabalin. When stopping the drug it should be tapered over a week, as withdrawal symptoms may occur [66].Valproic acid — In an eight-week randomized controlled trial of 48 patients with PHN, treatment with divalproex sodium (1000 mg per day) led to significantly greater pain relief than placebo [54]. More patients treated with divalproex sodium had at least moderate improvement in pain (58 versus 15 percent).Capsaicin — Limited data suggest that topical application of standard concentration capsaicin is effective for PHN [38]. In one study, capsaicin cream appeared to produce moderate relief when applied four times per day: there was a 21 percent reduction in the pain score in those receiving capsaicin, versus a 6 percent reduction in those receiving placebo [67]. Capsaicin and placebo vehicle caused skin reactions in a similar proportion of patients.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.Another approach is the use of a single 60-minute application of a high-concentration capsaicin patch (8 percent), rather than the multiple daily applications needed for standard concentration capsaicin cream (0.025 to 0.075 percent). 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) [68]. High-concentration capsaicin must be administered by a healthcare professional and patients are monitored for up to two hours after treatment. To manage local pain from capsaicin application, the skin is pretreated with a local anesthetic such as topical lidocaine, and some studies used posttreatment oral analgesics such as oxycodone for up to five days [69]. Further study is needed to confirm long-term effectiveness and tolerance of the high-concentration capsaicin patch.Opioids — The use of opioids for chronic noncancer pain remains controversial. Opioid analgesics appear to be effective for pain relief in patients with PHN, but are associated with a risk of physical dependence, tolerance, addiction, and overdose. Because of these risks, many experts consider opioids as second or third-line treatment options for PHN [40,41,70]. Other experts consider low-dose opioids as a first-line treatment option for select patients with PHN, arguing that these patients may have a lower risk of opioid abuse and addiction because they are generally older and have lower levels of psychiatric comorbidity compared with patients affected by other types of chronic pain.Unfortunately, the available randomized controlled trials of opioids for neuropathic pain (including PHN) do not clearly address the issues of abuse and addiction [71]. Pharmacovigilance is essential to using opioids in any population (table 2). (See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis" and "Overview of the treatment of chronic non-cancer pain", section on 'Opioids'.)A number of small trials support the efficacy of opioid analgesics for PHN [72-75]. As an example, a randomized, double-blind, crossover study compared clonidine (0.2 mg), ibuprofen (800 mg), codeine (120 mg), and placebo in 40 patients with PHN (median duration of pain 17 months) [72]. Clonidine and codeine decreased pain relative to placebo, while ibuprofen was ineffective. Clonidine provided more pain relief than codeine, although the degree of relief with either agent was modest. It was suggested that the side effects associated with these drugs contributed to their associated analgesic effect by suggesting to patients that they had received a potent drug.In another randomized trial involving 76 patients, treatment with the opioids morphine (mean daily dose 91 mg) or methadone (mean daily dose 15 mg) or the tricyclic drugs nortriptyline (mean daily dose 89 mg) or desipramine (mean daily dose 63 mg) for eight weeks was significantly more effective than placebo [74]. There was a trend toward greater pain relief with opioids, but this was not statistically significant.Intrathecal glucocorticoids — In patients who have PHN affecting nerves other than the trigeminal nerve, intrathecal glucocorticoids may be a reasonable option, particularly if there has been no response to the above measures [37,53]. However, the evidence that intrathecal glucocorticoids are beneficial is not entirely consistent:●The largest trial evaluated 277 patients with intractable PHN for at least one year who were randomly assigned to one of three groups: treatment with intrathecal methylprednisolone plus lidocaine once per week for four weeks; treatment with intrathecal lidocaine alone once per week for four weeks; or no treatment [76]. More than 90 percent of patients in the methylprednisolone group reported excellent or good pain relief at four weeks and at one and two years compared with 6 and 4 percent in the lidocaine and no treatment groups, respectively. In addition, the areas of allodynia were reduced by more than 70 percent in the methylprednisolone group and only 25 percent in the lidocaine group. There were no serious adverse events associated with the injection.●Another trial of 25 patients with PHN that compared intrathecal with epidural methylprednisolone found significantly greater improvements with intrathecal administration [77].●A later trial of 10 patients with intractable PHN found no benefit of intrathecal methylprednisolone [78].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 [79,80]. Thus, their use has been controversial.Botulinum toxin — Botulinum toxin injection for PHN is not well-studied, but the available evidence suggests it is effective. One double-blind randomized controlled trial evaluated 30 adults with PHN who had persistent pain for at least three months [81]. Compared with placebo injections, botulinum toxin type A (onabotulinumtoxinA) injections were beneficial for pain reduction at two weeks; the number of responders (ie, patients achieving at least a 50 percent reduction in pain score) was significantly greater for the active treatment group (13 of 15 patients [87 percent] versus none of 15 in the placebo group) and the benefit persisted for a median of 16 weeks. Treatment was well-tolerated.Lidocaine — Data from a few small relatively low-quality placebo-controlled trials and open label studies suggest that topical lidocaine (5 percent) is beneficial for pain relief in patients with PHN [82]. However, given the paucity of evidence and shortcomings of the included trials, no firm conclusions can be made regarding the efficacy of topical lidocaine for the treatment of PHN [83].Intravenous lidocaine may provide benefit in patients who do not respond to other therapies [84]; however, small controlled trials have not convincingly demonstrated that this therapy is superior to placebo [37].NMDA receptor antagonists — Animal data suggest a role for excitatory amino acid neurotransmitters in the maintenance of chronic pain due to nerve injury [85,86]. Antagonists of the N-methyl-D-aspartate (NMDA) receptor relieve neuropathic pain in humans [87].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 [88]. In a randomized, double-blind, crossover trial that compared six weeks of treatment with dextromethorphan versus placebo, no significant relief was demonstrated [89].Cryotherapy — Cryotherapy involves freezing peripheral nerves. A small, unblinded study of cryotherapy for facial pain was unable to show a significant benefit in patients with PHN [90]. The authors did not provide inclusion criteria, concomitant therapies, or information on how the response was assessed. In contrast, a second trial reported "considerable" relief in 11 of 14 patients with cryotherapy to the intercostal nerves for PHN [91]. In most cases, however, the duration of relief was less than two weeks as assessed by questionnaire.Surgery — Surgical interventions including electrical stimulation of the thalamus, anterolateral cordotomy, and electrocoagulation of the dorsal root carry substantial risks of permanent neurologic deficits. No consistent benefit has been demonstrated in patients with PHN.Other — The effectiveness of therapies such as transcutaneous electrical nerve stimulation (TENS), transcranial magnetic stimulation (TMS), and acupuncture has not been proven. The experimental agent EMA401, a selective angiotensin II type 2 receptor antagonist, was more effective than placebo for relief of PHN pain in a preliminary randomized controlled trial [92]. However, the effect size was small, and additional trials are needed to determine whether this drug is clinically useful for PHN.PROGNOSIS — The pain of PHN may persist for months, years, or even life [41]. However, there are few data for follow-up beyond one year.●In a prospective study that enrolled 1358 patients (age ≥50 years) with acute herpes zoster, the prevalence of zoster-related pain on day 0 and months 3, 6, 9, and 12 was 80, 12, 9, 7, and 6 percent, respectively [93].●Another prospective study reported long-term outcomes for adults (age >60 years) enrolled with acute herpes zoster in a randomized trial; with a mean of nine years follow-up data available for 158 of 298 original subjects, the proportion experiencing pain from zoster within the previous 12 months was 21 percent [94].●A report of 85 immunocompetent patients (ages 47 to 92 years) with PHN who were followed from study enrollment (at least six months from the episode of acute herpes zoster) to one year after enrollment observed that neuropathic pain of moderate to severe intensity persisted in approximately 55 percent [95].●In a questionnaire study of 385 adults age ≥65 years with persistent, active PHN, the mean duration of PHN was 3.3 years [96].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 in the immunocompetent host" 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".)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 5th to 6th 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 10th to 12th 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 e-mail 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●The incidence of acute herpes zoster infection increases with impairment of the immune system due to age, disease, or chemotherapy. Among patients with acute herpes zoster infection, the major risk factors for postherpetic neuralgia (PHN) are older age, greater acute pain, and greater rash severity. (See 'Epidemiology' above.)●With PHN, thoracic, cervical, and trigeminal nerves are most commonly affected. The pain associated with acute zoster infection and PHN can be burning, sharp, or stabbing and constant or intermittent. More than 90 percent of patients with PHN also have allodynia, defined as pain evoked by normally nonpainful stimuli such as light touch. (See 'Clinical manifestations' above.)●In most cases, the diagnosis of PHN is straightforward and is made when pain persists beyond four months in the same distribution as a preceding documented episode of acute herpes zoster. (See 'Diagnosis' above.)●For patients with PHN, we recommend initial treatment with tricyclic antidepressants, gabapentin, or pregabalin (Grade 1B) (see 'Treatment' above):•For most patients with moderate to severe pain from PHN, we suggest initial treatment with one of the tricyclic antidepressants (Grade 2C). Exceptions include patients with heart disease, epilepsy, or glaucoma. Tricyclic drugs should be used cautiously in older patients. (See 'Tricyclic antidepressants' above.)•For patients with moderate to severe PHN who have contraindications to or intolerance of tricyclic antidepressants, we suggest gabapentin or pregabalin (Grade 2C). Gabapentin and pregabalin should be avoided in patients with renal insufficiency. (See 'Gabapentin' above and 'Pregabalin' above.)•For patients with mild to moderate localized pain from PHN and for patients with PHN who do not desire therapy with oral drugs, we suggest treatment with topical capsaicin (Grade 2C). (See 'Capsaicin' above.)•Opioids are associated with the potential for abuse and addiction, and thus many experts consider them as second- or third-line treatment options for PHN. However, opioids can be used at low doses and titrated to provide relief while awaiting benefit from preventive treatments (ie, tricyclic drugs, gabapentin, or pregabalin), at which point opioids should be tapered off. Opioids also can be used cautiously for intractable PHN that is refractory to treatment with preventive treatments. (See 'Opioids' above.)•Intrathecal glucocorticoid injections are another option for patients with intractable pain refractory to the above measures. However, intrathecal glucocorticoid injections are not useful for PHN involving the trigeminal nerve. (See 'Intrathecal glucocorticoids' above.)●The pain of PHN may persist for months, years, or even life. (See 'Prognosis' above.)</font></p> Uploading Image...	t Uploading Image...	t R
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<p><font class="font-xs">Postherpetic neuralgia     Postherpetic neuralgiaAuthors:Zahid H Bajwa, MDErik Ortega, MDSection Editor:Jeremy M Shefner, MD, PhDDeputy Editor:April F Eichler, MD, MPHContributor DisclosuresAll topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Feb 2018. | This topic last updated: Feb 13, 2017.INTRODUCTION — Varicella-zoster virus (VZV) is the causative agent of varicella, or "chickenpox," and herpes zoster, or "shingles." Most cases of acute herpes zoster are self-limited, although the pain can cause significant suffering, particularly in older adults. Symptoms may be severe enough to interfere with sleep, appetite, or sexual function. In addition, a variable percentage of patients may continue to experience pain for months to years after the resolution of the rash, a condition known as postherpetic neuralgia (PHN). PHN can be quite difficult to treat.The pathogenesis, epidemiology, clinical features, diagnosis, and treatment of PHN are reviewed here. Other aspects of the varicella-zoster virus and the acute therapy of herpes zoster infection are discussed separately. (See "Epidemiology and pathogenesis of varicella-zoster virus infection: Herpes zoster" and "Treatment of herpes zoster in the immunocompetent host".)PATHOGENESIS — Acute herpes zoster is caused by reactivation of the varicella-zoster virus (VZV). The virus persists for a period of years in the dorsal root ganglia of cranial or spinal nerves after resolution of the original infection. As cellular immunity wanes with age or immunocompromise, the virus is transported along peripheral nerves, producing an acute neuritis [1,2].At the cellular level, infection with acute herpes zoster is characterized by hemorrhagic inflammation of the peripheral nerve, dorsal root, and dorsal root ganglion. Extension centrally into the spinal cord and leptomeninges also has been described [3]. Fibrosis is noted in the dorsal root ganglion, nerve root, and peripheral nerve upon resolution of the acute process [4,5].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 [6]. The findings included dorsal horn atrophy as well as cellular, axonal, and myelin loss with fibrosis in the sensory ganglion in patients with persistent pain. However, marked axonal and myelin loss in the nerve and/or sensory root were found in cases with and without 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. Studies of the affected dorsal horn from one patient with PHN failed to demonstrate differences in the levels of these neurotransmitters when compared with the unaffected side [7]. The same investigators were unable to demonstrate a deficiency of opiate receptors in the affected dorsal horn. Another study evaluated cytokine profiles extracted from skin punch biopsies of dermatomes affected by PHN and found no significant differences when compared with skin biopsies from the normal contralateral side [8].There are three phases of pain associated with herpes zoster [9-11]:●Acute herpetic neuralgia refers to pain preceding or accompanying the eruption of rash that persists up to 30 days from its onset●Subacute herpetic neuralgia refers to pain that persists beyond healing of the rash but which resolves within four months of onset●PHN refers to pain persisting beyond four months from the initial onset of the rashThe pain of acute herpetic neuralgia probably is produced both by the inflammation associated with the movement of viral particles from sensory nerves to skin and subcutaneous tissues, and by the damage to nerve structures detailed above. In addition, activity of primary afferent neurons that respond to tissue damage causes changes in the dorsal horn neurons, sensitizing them to further input and resulting in spontaneous activity capable of maintaining pain in the absence of ongoing tissue damage [7,12-15]. The persistence of this response may explain the continuing pain of PHN [16].Some have speculated that ongoing VZV viral replication might be responsible for PHN. However, a randomized, double-blind, placebo-controlled trial of intravenous and oral acyclovir for 56 days in 10 patients with severe PHN of at least six months duration failed to influence the course of PHN [17].EPIDEMIOLOGY — The incidence of acute herpes zoster infection increases with impairment of the immune system due to age, disease, or chemotherapy. The annual incidence among healthy people under the age of 20 years is approximately 1 per 1000; the incidence is 5 to 10 times greater for those older than 80 years [18]. Herpes zoster also is several times more common in patients with cancer or HIV infection [19]. (See "Epidemiology and pathogenesis of varicella-zoster virus infection: Herpes zoster", section on 'Epidemiology'.)Similarly, the probability of developing PHN increases with advanced age. Most studies agree that PHN is rare in children. In adults younger than 60 years of age with herpes zoster, the risk of PHN is estimated to be less than 2 percent [20].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. In contrast, among 308 patients age 70 years or older who developed herpes zoster, PHN occurred in 18.5 percent.Risk factors — The major risk factors for PHN are older age, greater acute pain, and greater rash severity [22-26]. The risk of PHN is probably increased as well with immunosuppression, although the evidence is not entirely consistent [26-28]. In patients who develop PHN, advanced age is associated with increasing severity and persistence of symptoms [29].CLINICAL MANIFESTATIONS — With PHN, thoracic (especially T4 to T6), cervical, and trigeminal nerves are most commonly affected [30]. The pain associated with acute zoster infection and PHN can be burning, sharp, or stabbing and constant or intermittent [9,31]. More than 90 percent of patients with PHN also have allodynia, defined as pain evoked by normally nonpainful stimuli such as light touch [32].Patients with PHN often demonstrate areas of anesthesia, as well as deficits of thermal, tactile, pinprick, and vibration sensation within the affected dermatomes [32]. The contralateral, uninvolved side tests normally. Sensory deficits may extend beyond dermatomal margins. It has been suggested that allodynia is most prominent in areas of relatively preserved sensation, while spontaneous pain is felt predominately within the area of lost or impaired sensation.PHN most often represents a continuum of pain that never resolved following an acute episode of herpes zoster. However, PHN rarely has been reported to occur months to years after resolution of the initial event [33]. These episodes occurred in the same distribution as the initial rash and were precipitated by a specific event (eg, a surgical procedure, tooth abscess).Both acute zoster and PHN can be severe conditions associated with profound psychosocial dysfunction including impaired sleep, decreased appetite, and diminished libido [31,34].DIAGNOSIS — In most cases, the diagnosis of PHN is straightforward and is made when pain persists beyond four months in the same distribution as a preceding documented episode of acute herpes zoster (see "Clinical manifestations of varicella-zoster virus infection: Herpes zoster", section on 'Diagnosis'). Thus, the diagnosis of PHN is based solely upon the clinical presentation. Additional factors supporting the diagnosis are [35]:●Advanced age●Severe prodromal pain with acute herpes zoster●Severe preceding rash●Distribution in trigeminal or brachial plexus dermatomes●The presence of allodyniaHowever, the diagnosis of PHN can be missed if the rash has resolved and the patient no longer remembers it or does not ascribe the pain to it [35]. Uncommonly, the nerve pain in acute herpes zoster may emerge in the absence of any skin eruption, as occurs in a condition called "zoster sine herpete" or in intercostal neuralgia. The presence of pain in trigeminal or radicular distribution combined with the detection of varicella-zoster virus by polymerase chain reaction (PCR) in the cerebrospinal fluid supports the diagnosis of zoster sine herpete [36]. (See "Diagnosis of varicella-zoster virus infection", section on 'Polymerase chain reaction'.)On examination, the areas affected by PHN may be remarkable for scarring related to the vesicular eruption of the preceding acute herpes zoster infection, or by areas of excoriation caused by scratching. The affected skin may display decreased sensation to mechanical and thermal stimuli, hyperalgesia (increased sensitivity to painful stimuli), or allodynia (pain produced by normally non-noxious stimulation).TREATMENT — Tricyclic antidepressants, gabapentin, and pregabalin are generally the drugs of first choice for the treatment of PHN. In systematic reviews, treatments more effective than placebo for PHN include tricyclic antidepressants, gabapentin, pregabalin, and opioids [37-40]. The long-term benefits of most therapies are uncertain, and side effects are common.Because the pain of PHN may be chronic, long-term therapy is often required [41].We recommend initial treatment with one of the nonopioid agents effective in controlled trials, ie, tricyclic antidepressants, gabapentin, and pregabalin. The choice among treatments for PHN should be individualized according to patient-specific characteristics, comorbid conditions, medication side effect profile, and patient values and preferences. Based upon the available data and our experience, we typically use the following approach:●We suggest initial treatment with a tricyclic drug for most patients with moderate to severe pain from PHN. Exceptions include patients with heart disease, epilepsy, or glaucoma. Because of their anticholinergic effects, tricyclic drugs should be used cautiously in older patients, particularly those with cognitive impairment or dementia. (See 'Tricyclic antidepressants' below.)●We suggest gabapentin or pregabalin for patients with moderate to severe PHN who have contraindications to or intolerance of tricyclic antidepressants. Gabapentin and pregabalin should be avoided in patients with renal insufficiency. (See 'Anticonvulsants' below.)●We suggest topical capsaicin for patients with mild to moderate localized pain from PHN who do not desire systemic therapy with tricyclic drugs, gabapentin, and pregabalin. However, topical capsaicin is often poorly tolerated. Topical lidocaine is an alternative that may provide short-term relief. (See 'Capsaicin' below.)●Opioids are associated with the potential for abuse and addiction, and thus many experts consider them as second- or third-line treatment options for PHN. However, opioids can be used cautiously if the preventive agents (tricyclic drugs, gabapentin, and pregabalin) are unsuccessful. Opioids also can also be administered simultaneously with the nonopioid preventive agents, since the nonopioid drugs may not be immediately effective. Opioids should be initiated at low doses, if used, and titrated to provide relief while awaiting benefit from preventive treatments, at which point opioids should be tapered off. (See 'Opioids' below.)●Intrathecal glucocorticoid injections are an option for patients who continue to have intractable pain despite the above measures. These injections do not work for pain in the distribution of the trigeminal nerve. (See 'Intrathecal glucocorticoids' below.)The evidence supporting these recommendations is reviewed in the sections that follow. Mild analgesics such as aspirin and other nonsteroidal anti-inflammatory drugs are of limited value in patients with either acute herpetic neuralgia or PHN [41,42].Tricyclic antidepressants — Tricyclic antidepressant (TCA) medications are effective for PHN [43], and they are often thought of as the mainstay of therapy. These drugs 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 [44,45].The efficacy of TCAs was originally demonstrated in a small study of 24 patients with PHN [46]. In a subsequent prospective, randomized, double-blind, crossover comparison, 58 older adult patients with PHN were randomly assigned to six weeks of therapy with amitriptyline (12.5 to 150 mg per day), lorazepam (0.5 to 6 mg per day, an "active" placebo), or an inactive placebo [47]. A mean amitriptyline dose of 65 mg per day was achieved. Amitriptyline was significantly more effective than lorazepam or inactive placebo in providing moderate relief of pain (47, 15, and 16 percent, respectively). Equal numbers of patients withdrew from each group due to side effects. There was a significant correlation between the degree of symptom relief and serum amitriptyline levels. The authors concluded that serum levels of amitriptyline and active metabolites must be maintained at concentrations of 100 ng/mL for at least three weeks before a patient is considered to have failed TCA therapy.Anticholinergic side effects (principally sedation and dry mouth) limit patient acceptance of TCAs (table 1). A head-to-head trial concluded that nortriptyline was better tolerated than amitriptyline [48]. Desipramine has the fewest side effects of the first generation TCAs [49], and it was also effective in relieving PHN in one small trial (mean dose 165 mg per day) [50], though methodologic problems limit the strength of this trial [51]. There may be a lag of up to three weeks before TCAs begin to reduce pain.Our preferred tricyclic drug for PHN is amitriptyline, starting at 10 mg each night and titrating slowly to effect as tolerated, with a maximum dose of 150 mg daily.Anticonvulsants — Anticonvulsant medications are useful in the treatment of neuropathic pain, most notably in reducing the lancinating component of painful syndromes such as PHN. Drugs that have been evaluated in randomized trials include gabapentin [38,52], pregabalin [53], and valproic acid [54].Gabapentin — Immediate release gabapentin is probably effective for PHN, but there are inconsistent data regarding the efficacy of the once-daily (extended release) formulation of gabapentin.●A 2014 systematic review [55] identified four placebo-controlled randomized trials, with two trials evaluating immediate release gabapentin [56,57] and two trials evaluating extended release gabapentin [58,59]. In the pooled analysis, gabapentin at doses between 1800 and 3600 mg daily was beneficial for PHN compared with placebo for the outcome of "much or very much improved" (38 versus 20 percent, risk ratio 1.9, 95% CI 1.5-2.3, number needed to treat 5.5) [52].●The gastroretentive extended release formulation of gabapentin was not significantly more effective than placebo for PHN when given once daily (1800 mg daily) in two trials included in the systematic review, which together included 723 patients [58,59], but was more effective than placebo at an alternative twice daily dosing schedule (600 mg AM and 1200 mg PM) in one of these trials [58]. In a third trial of 452 patients with PHN, the group assigned to extended release gabapentin (1800 mg) taken once daily had a statistically significant reduction in mean pain scores compared with placebo, leading to regulatory approval of the drug in the United States as once-daily treatment for PHN [60,61].In two small randomized controlled trials, gabapentin enacarbil (the prodrug of gabapentin), another extended release formulation, showed some evidence of benefit for reducing average pain intensity scores in PHN [62,63].Gabapentin is typically started at a low dose and titrated to effect. Our suggested gabapentin regimen for PHN is 300 mg on day 1, 300 mg twice daily on day 2, and 300 mg three times daily on day 3; the dose is then titrated as needed for pain relief to the range of 1800 to 3600 mg/day in three divided doses. For the extended release formulation of gabapentin, one regimen begins with 300 mg on day 1, 600 mg on day 2, 900 mg once daily on days 3 to 6, 1200 mg once daily on days 7 to 10, 1500 mg once daily on days 11 to 14, and 1800 mg once daily on day 15 and thereafter.Pregabalin — Pregabalin is a structural analog of gamma-aminobutyric acid (GABA) and is similar to gabapentin. Two randomized controlled trials involving over 400 patients with PHN have shown improvement in sleep and decrease in pain at doses of 150 to 600 mg daily [64,65]. Common side effects are dizziness, somnolence, dry mouth, peripheral edema, and weight gain. It is designated as a schedule V controlled substance in the United States because it has been reported to cause euphoria.The recommended starting dose for pregabalin is 150 mg, divided into two or three doses daily, and increased to a total daily dose of 300 mg based upon tolerability and effect. Further titration (to 600 mg daily) after two to four weeks may be considered in patients who do not experience sufficient relief of pain provided they are able to tolerate pregabalin. When stopping the drug it should be tapered over a week, as withdrawal symptoms may occur [66].Valproic acid — In an eight-week randomized controlled trial of 48 patients with PHN, treatment with divalproex sodium (1000 mg per day) led to significantly greater pain relief than placebo [54]. More patients treated with divalproex sodium had at least moderate improvement in pain (58 versus 15 percent).Capsaicin — Limited data suggest that topical application of standard concentration capsaicin is effective for PHN [38]. In one study, capsaicin cream appeared to produce moderate relief when applied four times per day: there was a 21 percent reduction in the pain score in those receiving capsaicin, versus a 6 percent reduction in those receiving placebo [67]. Capsaicin and placebo vehicle caused skin reactions in a similar proportion of patients.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.Another approach is the use of a single 60-minute application of a high-concentration capsaicin patch (8 percent), rather than the multiple daily applications needed for standard concentration capsaicin cream (0.025 to 0.075 percent). 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) [68]. High-concentration capsaicin must be administered by a healthcare professional and patients are monitored for up to two hours after treatment. To manage local pain from capsaicin application, the skin is pretreated with a local anesthetic such as topical lidocaine, and some studies used posttreatment oral analgesics such as oxycodone for up to five days [69]. Further study is needed to confirm long-term effectiveness and tolerance of the high-concentration capsaicin patch.Opioids — The use of opioids for chronic noncancer pain remains controversial. Opioid analgesics appear to be effective for pain relief in patients with PHN, but are associated with a risk of physical dependence, tolerance, addiction, and overdose. Because of these risks, many experts consider opioids as second or third-line treatment options for PHN [40,41,70]. Other experts consider low-dose opioids as a first-line treatment option for select patients with PHN, arguing that these patients may have a lower risk of opioid abuse and addiction because they are generally older and have lower levels of psychiatric comorbidity compared with patients affected by other types of chronic pain.Unfortunately, the available randomized controlled trials of opioids for neuropathic pain (including PHN) do not clearly address the issues of abuse and addiction [71]. Pharmacovigilance is essential to using opioids in any population (table 2). (See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis" and "Overview of the treatment of chronic non-cancer pain", section on 'Opioids'.)A number of small trials support the efficacy of opioid analgesics for PHN [72-75]. As an example, a randomized, double-blind, crossover study compared clonidine (0.2 mg), ibuprofen (800 mg), codeine (120 mg), and placebo in 40 patients with PHN (median duration of pain 17 months) [72]. Clonidine and codeine decreased pain relative to placebo, while ibuprofen was ineffective. Clonidine provided more pain relief than codeine, although the degree of relief with either agent was modest. It was suggested that the side effects associated with these drugs contributed to their associated analgesic effect by suggesting to patients that they had received a potent drug.In another randomized trial involving 76 patients, treatment with the opioids morphine (mean daily dose 91 mg) or methadone (mean daily dose 15 mg) or the tricyclic drugs nortriptyline (mean daily dose 89 mg) or desipramine (mean daily dose 63 mg) for eight weeks was significantly more effective than placebo [74]. There was a trend toward greater pain relief with opioids, but this was not statistically significant.Intrathecal glucocorticoids — In patients who have PHN affecting nerves other than the trigeminal nerve, intrathecal glucocorticoids may be a reasonable option, particularly if there has been no response to the above measures [37,53]. However, the evidence that intrathecal glucocorticoids are beneficial is not entirely consistent:●The largest trial evaluated 277 patients with intractable PHN for at least one year who were randomly assigned to one of three groups: treatment with intrathecal methylprednisolone plus lidocaine once per week for four weeks; treatment with intrathecal lidocaine alone once per week for four weeks; or no treatment [76]. More than 90 percent of patients in the methylprednisolone group reported excellent or good pain relief at four weeks and at one and two years compared with 6 and 4 percent in the lidocaine and no treatment groups, respectively. In addition, the areas of allodynia were reduced by more than 70 percent in the methylprednisolone group and only 25 percent in the lidocaine group. There were no serious adverse events associated with the injection.●Another trial of 25 patients with PHN that compared intrathecal with epidural methylprednisolone found significantly greater improvements with intrathecal administration [77].●A later trial of 10 patients with intractable PHN found no benefit of intrathecal methylprednisolone [78].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 [79,80]. Thus, their use has been controversial.Botulinum toxin — Botulinum toxin injection for PHN is not well-studied, but the available evidence suggests it is effective. One double-blind randomized controlled trial evaluated 30 adults with PHN who had persistent pain for at least three months [81]. Compared with placebo injections, botulinum toxin type A (onabotulinumtoxinA) injections were beneficial for pain reduction at two weeks; the number of responders (ie, patients achieving at least a 50 percent reduction in pain score) was significantly greater for the active treatment group (13 of 15 patients [87 percent] versus none of 15 in the placebo group) and the benefit persisted for a median of 16 weeks. Treatment was well-tolerated.Lidocaine — Data from a few small relatively low-quality placebo-controlled trials and open label studies suggest that topical lidocaine (5 percent) is beneficial for pain relief in patients with PHN [82]. However, given the paucity of evidence and shortcomings of the included trials, no firm conclusions can be made regarding the efficacy of topical lidocaine for the treatment of PHN [83].Intravenous lidocaine may provide benefit in patients who do not respond to other therapies [84]; however, small controlled trials have not convincingly demonstrated that this therapy is superior to placebo [37].NMDA receptor antagonists — Animal data suggest a role for excitatory amino acid neurotransmitters in the maintenance of chronic pain due to nerve injury [85,86]. Antagonists of the N-methyl-D-aspartate (NMDA) receptor relieve neuropathic pain in humans [87].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 [88]. In a randomized, double-blind, crossover trial that compared six weeks of treatment with dextromethorphan versus placebo, no significant relief was demonstrated [89].Cryotherapy — Cryotherapy involves freezing peripheral nerves. A small, unblinded study of cryotherapy for facial pain was unable to show a significant benefit in patients with PHN [90]. The authors did not provide inclusion criteria, concomitant therapies, or information on how the response was assessed. In contrast, a second trial reported "considerable" relief in 11 of 14 patients with cryotherapy to the intercostal nerves for PHN [91]. In most cases, however, the duration of relief was less than two weeks as assessed by questionnaire.Surgery — Surgical interventions including electrical stimulation of the thalamus, anterolateral cordotomy, and electrocoagulation of the dorsal root carry substantial risks of permanent neurologic deficits. No consistent benefit has been demonstrated in patients with PHN.Other — The effectiveness of therapies such as transcutaneous electrical nerve stimulation (TENS), transcranial magnetic stimulation (TMS), and acupuncture has not been proven. The experimental agent EMA401, a selective angiotensin II type 2 receptor antagonist, was more effective than placebo for relief of PHN pain in a preliminary randomized controlled trial [92]. However, the effect size was small, and additional trials are needed to determine whether this drug is clinically useful for PHN.PROGNOSIS — The pain of PHN may persist for months, years, or even life [41]. However, there are few data for follow-up beyond one year.●In a prospective study that enrolled 1358 patients (age ≥50 years) with acute herpes zoster, the prevalence of zoster-related pain on day 0 and months 3, 6, 9, and 12 was 80, 12, 9, 7, and 6 percent, respectively [93].●Another prospective study reported long-term outcomes for adults (age >60 years) enrolled with acute herpes zoster in a randomized trial; with a mean of nine years follow-up data available for 158 of 298 original subjects, the proportion experiencing pain from zoster within the previous 12 months was 21 percent [94].●A report of 85 immunocompetent patients (ages 47 to 92 years) with PHN who were followed from study enrollment (at least six months from the episode of acute herpes zoster) to one year after enrollment observed that neuropathic pain of moderate to severe intensity persisted in approximately 55 percent [95].●In a questionnaire study of 385 adults age ≥65 years with persistent, active PHN, the mean duration of PHN was 3.3 years [96].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 in the immunocompetent host" 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".)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 5th to 6th 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 10th to 12th 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 e-mail 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●The incidence of acute herpes zoster infection increases with impairment of the immune system due to age, disease, or chemotherapy. Among patients with acute herpes zoster infection, the major risk factors for postherpetic neuralgia (PHN) are older age, greater acute pain, and greater rash severity. (See 'Epidemiology' above.)●With PHN, thoracic, cervical, and trigeminal nerves are most commonly affected. The pain associated with acute zoster infection and PHN can be burning, sharp, or stabbing and constant or intermittent. More than 90 percent of patients with PHN also have allodynia, defined as pain evoked by normally nonpainful stimuli such as light touch. (See 'Clinical manifestations' above.)●In most cases, the diagnosis of PHN is straightforward and is made when pain persists beyond four months in the same distribution as a preceding documented episode of acute herpes zoster. (See 'Diagnosis' above.)●For patients with PHN, we recommend initial treatment with tricyclic antidepressants, gabapentin, or pregabalin (Grade 1B) (see 'Treatment' above):•For most patients with moderate to severe pain from PHN, we suggest initial treatment with one of the tricyclic antidepressants (Grade 2C). Exceptions include patients with heart disease, epilepsy, or glaucoma. Tricyclic drugs should be used cautiously in older patients. (See 'Tricyclic antidepressants' above.)•For patients with moderate to severe PHN who have contraindications to or intolerance of tricyclic antidepressants, we suggest gabapentin or pregabalin (Grade 2C). Gabapentin and pregabalin should be avoided in patients with renal insufficiency. (See 'Gabapentin' above and 'Pregabalin' above.)•For patients with mild to moderate localized pain from PHN and for patients with PHN who do not desire therapy with oral drugs, we suggest treatment with topical capsaicin (Grade 2C). (See 'Capsaicin' above.)•Opioids are associated with the potential for abuse and addiction, and thus many experts consider them as second- or third-line treatment options for PHN. However, opioids can be used at low doses and titrated to provide relief while awaiting benefit from preventive treatments (ie, tricyclic drugs, gabapentin, or pregabalin), at which point opioids should be tapered off. Opioids also can be used cautiously for intractable PHN that is refractory to treatment with preventive treatments. (See 'Opioids' above.)•Intrathecal glucocorticoid injections are another option for patients with intractable pain refractory to the above measures. However, intrathecal glucocorticoid injections are not useful for PHN involving the trigeminal nerve. (See 'Intrathecal glucocorticoids' above.)●The pain of PHN may persist for months, years, or even life. (See 'Prognosis' above.)</font></p>

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