Treating herpes zoster and postherpetic neuralgia: An evidence-based approach

Postherpetic neuralgia (PHN) is a management challenge—because of its severity, long duration, and potential for debilitation, often in the highly vulnerable elderly population. And, as the most common complication of an acute episode of herpes zoster (shingles) in an immunocompetent person, PHN is likely no stranger to your practice.

Herpes zoster is one of the most common neurological problems, with an incidence of up to 1 million new cases per year in the United States.¹ Although the precise number for the prevalence of PHN in the United States is unknown, investigators estimate it at 500,000 to 1 million.²

Major risk factors for development of PHN after an episode of herpes zoster include:

• older age

• greater acute pain during herpes zoster

• greater severity of rash.^3,4

PHN is commonly defined as “dermatomal pain that persists 120 days or more after the onset of rash.”⁵ The pain of PHN has been characterized as a stimulus-dependent continuous burning, throbbing, or episodic sharp electric shock-like sensation⁶ and as a stimulus-dependent tactile allodynia (ie, pain after normally nonpainful stimulus) and hyperalgesia (exaggerated response to a painful stimulus). In addition, some patients experience myofascial pain secondary to excessive muscle guarding. Chronic pruritus can be present.

More than 90% of patients who have PHN have allodynia,⁷ which tends to occur in areas where sensation is relatively preserved. Patients also feel spontaneous pain in areas where sensation is lost or impaired.

In this article, we review the evidence for the range of treatments for acute herpes zoster and PHN, as well offer preventive strategies for herpes zoster.

Acute herpes zoster: Start antivirals early

Evidence-based treatment of acute herpes zoster includes antiviral drugs and analgesics.

Antiviral agents suppress viral replication and have a beneficial effect on acute and chronic pain. Acyclovir (800 mg, 5 times a day), valacyclovir (1000 mg, every 8 hours), and famciclovir (500 mg, every 8 hours) are antivirals commonly used to treat herpes zoster. All 3 drugs have comparable efficacy and safety profiles.

In a meta-analysis of patients older than 50 years who were treated with acyclovir or placebo, pain persisted in 15% of the acyclovir-treated group, compared with 35% of the placebo group.⁸ In terms of duration, a study comparing famciclovir treatment with placebo showed that subjects in the placebo group had persistent pain for 163 days, whereas famciclovir-treated patients had pain for 63 days.⁹

Based on this evidence, antiviral medications are strongly recommended for treating herpes zoster, especially for patients at increased risk of developing PHN. Antiviral treatment should be started within 72 hours of the onset of the rash.

No good evidence supports the efficacy of antiviral treatment administered 72 hours after the onset of rash. One uncontrolled trial, however, examined the effectiveness of acyclovir started before vs after 72 hours; the difference in pain persistence was not significant between the groups, suggesting acyclovir has benefit even when given after 72 hours.¹⁰

In clinical practice, the diagnosis of herpes zoster is often not made within 72 hours of symptom onset; nevertheless, it is important to identify patients who could still benefit from antiviral medication even when treatment is started relatively late in the disease course. This is especially true in ocular zoster, because viral shedding may continue beyond 72 hours.¹¹

Analgesics are part of a practical approach for managing herpes zoster–associated pain that begins with a short-acting opioid in combination with acetaminophen or a nonsteroidal anti-inflammatory (NSAID) agent. Gabapentin or pregabalin, followed by a tricyclic antidepressant, can be added if conventional analgesics are not entirely effective. The analgesic regimen should be tailored to the patient’s needs and tolerance of adverse effects. If pain control is inadequate or adverse effects are intolerable, consider referring the patient to a pain management center for possible interventional modalities.

Corticosteroids are not recommended routinely for treatment of herpes zoster; you can try them in otherwise healthy older adults, however, if antiviral therapy and analgesics do not relieve pain. In 2 double-blind controlled trials, a combination of acyclovir and corticosteroids for 21 days did not decrease the incidence of PHN—although some benefit was seen in terms of patients’ return to normal activities, cessation of analgesic therapy, and improved sleep.^12,13

Evidence-based treatment options for PHN

Pharmacotherapy for PHN includes anticonvulsants, tricyclic antidepressants, opioids, and topical agents. Invasive interventions have a limited but important role in the management of PHN pain in clinical practice.

Calcium channel-blocking anticonvulsants gabapentin and pregabalin are safe and relatively well tolerated. They can be used as first-line agents for PHN, starting with a low dosage and titrating up, based on effectiveness and tolerability.

Gabapentin is FDA approved for the treatment of PHN. The starting dosage is 100 to 300 mg taken at night, titrated as needed by 100 to 300 mg every 3 to 5 days, to as high a dosage as 1800 to 3600 mg/d in 3 or 4 divided doses. In 2 large, randomized controlled trials, gabapentin produced a statistically significant reduction in pain ratings and improved sleep and quality of life.^14,15 Adverse effects include somnolence, dizziness, peripheral edema, visual adverse effects, and gait and balance problems.

Because gabapentin is excreted by the kidneys, take care when using it in patients with renal insufficiency. Gabapentin clearance is linearly related to creatinine clearance and is decreased in the elderly and in individuals with impaired renal function. Hence, the gabapentin dose and the frequency of dosing must be adjusted in these patients.

In patients on hemodialysis, plasma gabapentin levels can be maintained by giving a dose of 200 to 300 mg 4 hours after hemodialysis.¹⁶

Extended-release gabapentin. The FDA recently approved an extended-release gabapentin formulation for PHN. Approval was based on a 12-week pivotal study and 2 adjunct studies. In a multicenter, randomized, double-blind, parallel-group, placebo-controlled, 12-week study evaluating the efficacy, safety, and dose response of 3 doses, extended-release gabapentin was effective at 1200 mg/d dosing. The initial recommended dose is 600 mg, once daily for 3 days, followed by 600 mg, twice daily, beginning on Day 4.¹⁷ The premise is that the extended-release preparation improves bioavailability of the active drug and, therefore, reduces the incidence of adverse effects, compared with regular gabapentin.

Overall, evidence is mixed. Two randomized controlled trials of extended-release gabapentin showed benefit (ie, reduced pain score on a numerical rating scale) with twice-a-day dosing (600 mg in the morning and 1200 mg at night), compared with a once-daily 1800-mg dose as well as placebo, for reduction in intensity of pain¹⁸ and specific pain quality.¹⁹ In another trial, however, extended-release gabapentin, 1800 mg once daily, did not show any benefit compared with placebo.²⁰

Pregabalin is also FDA approved for PHN. The effective dosage range is 150 to 600 mg/d. Pregabalin provided significantly superior pain relief and improved sleep scores compared with placebo in 776 patients with PHN.²¹ Adverse effects include weight gain, dizziness, and somnolence. Titrate the dosage slowly in the elderly.

Sodium channel-blocking anticonvulsants topiramate, lamotrigine, carbamazepine, oxcarbazepine, levetriacetam, and valproic acid are not FDA approved for PHN. These agents may be a treatment option, however, for patients with PHN who do not respond to conventional therapy. In an 8-week randomized controlled trial, patients treated with divalproex sodium (valproic acid and sodium valproate), 1000 mg/d, experienced significant pain relief compared with placebo-treated patients.²² Adverse effects included vertigo, hair loss, headache, nausea, and diarrhea.

Tricyclic antidepressants, including amitriptyline, desipramine, and nortriptyline, might work by (1) inhibiting norepinephrine and serotonin uptake, (2) sodium-channel blockade, or (3) another mechanism that is unclear. Although amitriptyline is the most studied tricyclic antidepressant for PHN, available evidence and clinical experience suggest that nortriptyline and desipramine have comparable efficacy and are better tolerated.^23,24

Nortriptyline and desipramine are preferred in frail and elderly patients. Start therapy with 10 to 25 mg nightly, titrating as tolerated every 2 weeks to 75 to 150 mg as a single daily dose. Adverse effects include dry mouth, fatigue, dizziness, sedation, urinary retention, orthostatic hypotension, weight gain, blurred vision, QT interval prolongation, constipation, and sexual dysfunction.

Serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants. Use of such agents as duloxetine and venlafaxine in PHN patients is extrapolated from their proven efficacy in treating diabetic neuropathy and other neuropathic pain conditions. Try duloxetine if your patient does not respond to or tolerate a tricyclic. The recommended dosage is 60 to 120 mg/d in 2 divided doses.²⁴

Two randomized, 12-week, double-blind, placebo-controlled trials using duloxetine 60 mg once a day and 60 mg twice a day for diabetic peripheral neuropathy concluded that 120 mg was safe and effective in treating diabetic peripheral neuropathy, but 120 mg was not as well tolerated as 60 mg once a day.²⁵

Monitor liver function periodically in patients taking duloxetine. Alternatively, you can give venlafaxine; the recommended dosage is 75 to 225 mg/d.²⁶

Opioid analgesics are recommended as second- and third-line agents for PHN. Adverse effects include nausea, pruritus, sedation, confusion, constipation, hypogonadism, and risk of developing tolerance and abuse.

A double-blind crossover trial evaluated the analgesic efficacy of oral oxycodone; treatment resulted in significant reduction of allodynia, steady pain, and spontaneous paroxysmal pain. Oxycodone treatment resulted in superior scores of global effectiveness, disability reduction, and patient preference, compared with placebo.²⁷

In a randomized crossover trial, the combination of gabapentin and morphine was superior to either of these medications alone in relieving pain in PHN.²⁸

Tramadol, an atypical opioid, has a weak μ-opioid receptor agonist effect and inhibits reuptake of serotonin and norepinephrine. Avoid using it in patients with a history of seizures. The maximum recommended dosage is 400 mg/d. An extended-release formulation of tramadol is also available.

Tramadol provided superior pain relief and improved quality of life in PHN patients in a randomized placebo-controlled trial.²⁹

Tapentadol has weak μ-opioid receptor agonist activity; norepinephrine reuptake inhibition is more predominant than serotonin reuptake inhibition. This drug is also available as an extended-release formulation. The maximum recommended dosage is 600 mg/d.

Avoid using tapentadol in patients with a history of seizures. Note: Although there is no scientific evidence regarding the use of tapentadol in neuropathic pain, we use it often in our practice. 

Topical therapies

Treating PHN with a topical agent is associated with relatively fewer adverse effects than what has been seen with oral therapy because systemic absorption is minimal.

Lidocaine is available as a transdermal patch and as a topical gel ointment. The 5% lidocaine patch is FDA approved for treating PHN. Lidocaine, a sodium-channel blocker, is useful for treating patients with clinical evidence of allodynia. You can cut a patch to fit the affected area; a maximum of 3 patches can be used simultaneously for 12 hours on, 12 hours off. If helpful, the patch can be left in place for 18 hours.³⁰

In 2 open-labeled, nonrandomized prospective studies, patients treated with the lidocaine patch had reduced intensity of pain and improved quality of life.^31,32

If lidocaine patches are not available, or affordable, or if a patient has difficulty applying them, use 5% lidocaine gel instead.

Capsaicin topical cream is sold in 2 concentrations: 0.025% and 0.075%. An extract of hot chili peppers, capsaicin acts as an agonist at the vanilloid receptors. The recommended dosage is 3 or 4 times a day. Initial application causes burning to become worse, but repeated use results in diminished pain and hyperalgesia.

A 6-week, blinded parallel study, followed by a 2-year open label follow-up, showed that the 0.075% dose of topical capsaicin cream relieved pain in 64% of patients; pain was relieved in 25% of placebo-treated patients.³³

An 8% capsaicin patch is FDA approved for treating PHN. The patch must be applied by a health care professional in a monitored setting. Prepare the affected area by pretreating it with a local anesthetic cream; then apply the patch and leave it in place for 1 hour. As many as 4 patches can be used at once. A single application can provide pain relief for as long as 12 weeks. Adverse effects are mostly mild and transient.

In a double-blind, randomized, placebo-controlled trial with an open-label extension, the score on a numeric pain-rating scale declined from baseline in both the high-concentration capsaicin group and the placebo group during Week 1; however, the capsaicin-treated group experienced long-term improvement through Week 12.³⁴

(See TABLE 1^{14-21, 23, 24, 27-34} for a summary of pharmacotherapeutic options.)

TABLE 1

Pharmacotherapeutic options for managing postherpetic neuralgia^{14-21, 23, 24, 27-34}

Alternative modalities to reduce pain

Acupuncture and transcutaneous electrical nerve stimulation (TENS) have been tried for the relief of PHN without consistent evidence of efficacy. There are no significant adverse effects associated with these therapies; however, the cost of treatment may be an issue. Acupuncture is not covered by many insurance carriers. Mental-health interventions, including cognitive and behavioral therapy, might help with overall physical and emotional functioning and quality of life.

Invasive interventions

Researchers have examined several interventional modalities for treating PHN that is refractory to medication.

Sympathetic nerve blocks. Retrospective studies have shown that sympathetic nerve block provides short-term improvement in pain in 40% to 50% of patients with PHN.³⁵

Intercostal nerve block has been reported to provide long-lasting pain relief in patients with thoracic PHN.³⁶

Neuraxial use of intrathecal methylprednisone is supported by moderately good evidence of benefit in patients with intractable PHN.³⁷ Because this intervention poses significant risk of neurologic sequelae, we do not recommend that it be used in clinical practice.

Spinal cord stimulation was studied prospectively in a case series of 28 patients.³⁸ Long-term pain relief was obtained in 82%. Patients serve as their own controls by switching off the spinal cord stimulator and monitoring pain. Consider spinal cord stimulation for patients with well-established PHN that is refractory to conventional management.

Cryotherapy was used for facial neuralgia pain, without significant benefit.³⁹ Another trial showed short-term benefit in 11 of 14 patients who underwent cryotherapy of the intercostal nerves for thoracic PHN.⁴⁰

Botulinium toxin A injection. An abstract presented at the February 2010 meeting of the American Academy of Pain Medicine described how subcutaneous injection of botulinium toxin A reduced pain in patients with PHN, compared with lidocaine and placebo injections. The pain relief was noted in 1 week and persisted for 90 days.⁴¹

Surgery. Many surgical interventions have been described and used to treat PHN, but none has a role in clinical practice.

When should you refer to a pain management center?

Dermatomal pain that lasts for longer than 180 days after a herpes zoster rash can be considered “well-established PHN” to denote its refractory nature. As a primary care clinician, you can refer a patient with PHN to a pain management center at any stage of disease but especially when the:

• patient has a significant medical comorbidity and you think that he or she requires the services of a specialist to manage multimodal pharmacotherapy

• PHN pain is refractory to conventional treatment modalities

• patient needs an invasive intervention  
• patient needs treatment with a high-dose capsaicin patch and you have not been trained to apply it. 

Preventing herpes zoster and PHN

Obviously, preventing PHN is closely tied to preventing herpes zoster. To help prevent herpes zoster:

• vaccinate children with varicella vaccine to prevent primary varicella infection⁴²

• use varicella-zoster immunoglobulin, as recommended by the CDC’s Advisory Committee on Immunization Practices (ACIP), in immunocompromised, seronegative patients who were exposed recently to a person with chickenpox or herpes zoster⁴²

• administer the herpes zoster vaccine to patients 60 years and older, as recommended by ACIP.⁴³ The FDA recently approved use of this vaccine for people 50 through 59 years, but ACIP has not changed its recommendations.⁴⁴

As we’ve discussed, herpes zoster vaccination, antiviral therapy, and aggressive pain control can reduce the incidence, severity, and duration of acute herpes zoster and PHN.

A large multicenter, randomized, placebo-controlled trial demonstrated that herpes zoster vaccine decreases the likelihood of developing herpes zoster in immunocompetent individuals 60 years and older.⁴⁵ The vaccine reduced the incidence of herpes zoster by 51.3%; reduced the burden of illness by 61.1%; and reduced the incidence of PHN by 66.5%.⁴⁵ The live, attenuated vaccine is contraindicated in children, pregnant women, and immunocompromised individuals.

The number needed to treat for herpes zoster vaccine is 175; that is, 1 case of herpes zoster is avoided for every 175 people vaccinated.¹

Newer tools mean a better outcome

We have improved our ability to diminish the incidence of herpes zoster and PHN and to manage postherpetic pain more effectively. These advances include the development of a herpes zoster vaccine; consensus that antiviral therapy and aggressive pain management can reduce the burden of PHN; identification of efficacious treatments for PHN; and recognition of PHN as a study model for neuropathic pain research.

Disclosure

The authors reported no potential conflict of interest relevant to this article.

References

1. Oxman MN, Levin MJ, Johnson GR, et al; Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271–2284.
    
2. Bennett GJ. Neuropathic pain: An overview.  In: Borsook D, ed. Molecular Neurobiology of Pain. Seattle, WA: IASP Press; 1997:109-113.
    
3. Jung BF, Johnson RW, Griffin DR, Dworkin RH. Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurology. 2004;62:1545–1551.
    
4. Dworkin RH, Boon RJ, Griffin DR, Phung D. Postherpetic neuralgia: impact of famciclovir, age, rash severity, and acute pain in herpes zoster patients. J Infect Dis. 1998;178(suppl 1):S76–S80.
    
5. Volpi A, Gross G, Hercogova J, Johnson RW. Current management of herpes zoster: the European view. Am J Clin Dermatol. 2005;6:317–325.
    
6. Dworkin RH, Portenoy RK. Pain and its persistence in herpes zoster. Pain. 1996;67:241–251.
    
7. Bowsher D. Pathophysiology of postherpetic neuralgia: towards a rational treatment. Neurology. 1995;45(12 suppl 8):S56–S57.
    
8. Dworkin RH, Schmader KE. Epidemiology and natural history of herpes zoster and postherpetic neuralgia.  In Watson CPN, Gershon AA, eds. Herpes Zoster and Postherpetic Neuralgia. 2nd ed. New York, NY: Elsevier Press; 2001:39-64.
    
9. Tyring S, Barbarash RA, Nahlik JE, et al. Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1995;123:89–96.
    
10. Kurokawa I, Kumano K, Murkawa K. Clinical correlates of prolonged pain in Japanese patients with acute herpes zoster. J Int Med Res. 2002;30:56–65.
     
11. Zaal MJ, Volker-Dieben HJ, Wienesen M, et al. Longitudinal analysis of varicella-zoster virus DNA on the ocular surface associated with herpes zoster ophthalmicus. Am J Ophthalmol. 2001;131:25–29.
     
12. Wood MJ, Johnson RW, McKendrick MW, et al. A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med. 1994;330:896–900.
     
13. Whitley RJ, Weiss H, Gnann JW  Jr, et al. Acyclovir with and without prednisone for the treatment of herpes zoster: a randomized, placebo-controlled trial. Ann Intern Med. 1996;125:376–383.
     
14. Rice AS, Maton S. Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain. 2001;94:215–224.
     
15. Collins SL, Moore RA, McQuay HJ, Wiffen P. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage. 2000;20:449–458.
     
16. Wong MO, Eldon MA, Keane WF, et al. Disposition of gabapentin in anuric subjects on hemodialysis. J Clin Pharmacol. 1995;35:622–626.
     
17.  Horizant (gabapentin encarbil) extended-release tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2012.
     
18. Irving G, Jensen M, Cramer M, et al. Efficacy and tolerability of gastric-retentive gabapentin for the treatment of postherpetic neuralgia: results of a double-blind, randomized, placebo-controlled clinical trial. Clin J Pain. 2009;25:185–192.
     
19. Jensen MP, Chiang YK, Wu J. Assessment of pain quality in a clinical trial of gabapentin extended release for postherpetic neuralgia. Clin J Pain. 2009;25:286–292.
     
20. Wallace MS, Irving G, Cowles VE. Gabapentin extended-release tablets for the treatment of patients with postherpetic neuralgia: a randomized, double-blind, placebo-controlled, multicenter study. Clin Drug Investig. 2010;30:765–776.
     
21. Frampton JE, Foster RH. Pregabalin in the treatment of postherpetic neuralgia. Drugs. 2005;65:111–118.
     
22. Kochar D, Garg P, Bumb RA, et al. Divalproex sodium in the management of postherpetic neuralgia: a randomized double-blind placebo-controlled study. QJM. 2005;98:29–34.
     
23. Watson CP, Vernich L, Chipman M, Reed K. Nortriptyline vs amitriptyline in postherpetic neuralgia: a randomized trial. Neurology. 1998;51:1166–1171.
24. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007;132:237–251.
     
25.  Cymbalta (duloxetine hydrochloride) delayed-release capsules [package insert]. Indianapolis, IN: Lilly USA; 2011.
     
26. Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004;110:697–706.
     
27. Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology. 1998;50:1837–1841.
     
28. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352:1324–1334.
     
29. Boureau F, Legallicier P, Kabir-Ahmadi M. Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial. Pain. 2003;104:323–331.
     
30. Hermann DN, Barbano RL, Hart-Gouleau S, et al. An open-label study of the lidocaine patch 5% in painful idiopathic sensory polyneuropathy. Pain Med. 2005;379–384.
     
31. Davies PS, Galer BS. Review of lidocaine patch 5% studies in the treatment of postherpetic neuralgia. Drugs. 2004;64:937–947.
     
32. Gammaitoni AR, Alvarez NA, Galer BS. Safety and tolerability of the lidocaine patch 5%, a targeted peripheral analgesic: a review of literature. J Clin Pharmacol. 2003;43:111–117.
     
33. Watson CP, Tyler KL, Bickers DR, et al. A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia. Clin Ther. 1993;15:510–526.
     
34. Backonja MM, Malan TP, Vanhove GF, Tobias JK. C102/106 Study Group. NGX-4010, a high concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized, double-blind, controlled study with an open-label extension. Pain Med. 2010;11:600–608.
     
35. Kumar V, Krone K, Mathieu A. Neuraxial and sympathetic blocks in herpes zoster and postherpetic neuralgia: an appraisal of current evidence. Reg Anesth Pain Med. 2004;29:454–461.
     
36. Doi K, Nikai T, Sakura S, Saito Y. Intercostal nerve block with 5% tetracaine for chronic pain syndromes. J Clin Anesth. 2002;14:39–41.
     
37. Kotani N, Kushikata T, Hashimoto H, et al. Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med. 2000;343:1514–1519.
     
38. Harke H, Gretenkort P, Ladleif HU, et al. Spinal cord stimulation in postherpetic neuralgia and in acute herpes zoster pain. Anesth Anal. 2002;94:694–700.
     
39. Barnard D, Lloyd J, Evans J. Cryoanalgesia in the management of chronic facial pain. J Maxillofac Surg. 1981;9:101–102.
     
40. Jones MJ, Murrin KR. Intercostal block with cryotherapy. Ann R Coll Surg Engl. 1987;69:261–262.
     
41. Xiao L, Hui H. Therapeutic effect of botulinium toxin A in the treatment of postherpetic neuralgia by subcutaneous injection. Presented at: 26th Annual Meeting of the American Academy of Pain Medicine; February 3-6, 2010; San Antonio, TX.
     
42. Marin M, Güris D, Chaves SS, et al. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56(RR-4):1–40.
     
43. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1–30.
     
44. Centers for Disease Control and Prevention (CDC). Update on herpes zoster vaccine: licensure for persons aged 50 through 59 years. MMWR Morb Mortal Wkly Rep. 2011;60(44):1528.
     
45. Gnann JW  Jr. Vaccination to prevent herpes zoster in older adults. J Pain. 2008;9(1 suppl 1):S31–S36.

Postherpetic neuralgia (PHN) is a management challenge—because of its severity, long duration, and potential for debilitation, often in the highly vulnerable elderly population. And, as the most common complication of an acute episode of herpes zoster (shingles) in an immunocompetent person, PHN is likely no stranger to your practice.

Herpes zoster is one of the most common neurological problems, with an incidence of up to 1 million new cases per year in the United States.¹ Although the precise number for the prevalence of PHN in the United States is unknown, investigators estimate it at 500,000 to 1 million.²

Major risk factors for development of PHN after an episode of herpes zoster include:

• older age

• greater acute pain during herpes zoster

• greater severity of rash.^3,4

PHN is commonly defined as “dermatomal pain that persists 120 days or more after the onset of rash.”⁵ The pain of PHN has been characterized as a stimulus-dependent continuous burning, throbbing, or episodic sharp electric shock-like sensation⁶ and as a stimulus-dependent tactile allodynia (ie, pain after normally nonpainful stimulus) and hyperalgesia (exaggerated response to a painful stimulus). In addition, some patients experience myofascial pain secondary to excessive muscle guarding. Chronic pruritus can be present.

More than 90% of patients who have PHN have allodynia,⁷ which tends to occur in areas where sensation is relatively preserved. Patients also feel spontaneous pain in areas where sensation is lost or impaired.

In this article, we review the evidence for the range of treatments for acute herpes zoster and PHN, as well offer preventive strategies for herpes zoster.

Acute herpes zoster: Start antivirals early

Evidence-based treatment of acute herpes zoster includes antiviral drugs and analgesics.

Antiviral agents suppress viral replication and have a beneficial effect on acute and chronic pain. Acyclovir (800 mg, 5 times a day), valacyclovir (1000 mg, every 8 hours), and famciclovir (500 mg, every 8 hours) are antivirals commonly used to treat herpes zoster. All 3 drugs have comparable efficacy and safety profiles.

In a meta-analysis of patients older than 50 years who were treated with acyclovir or placebo, pain persisted in 15% of the acyclovir-treated group, compared with 35% of the placebo group.⁸ In terms of duration, a study comparing famciclovir treatment with placebo showed that subjects in the placebo group had persistent pain for 163 days, whereas famciclovir-treated patients had pain for 63 days.⁹

Based on this evidence, antiviral medications are strongly recommended for treating herpes zoster, especially for patients at increased risk of developing PHN. Antiviral treatment should be started within 72 hours of the onset of the rash.

No good evidence supports the efficacy of antiviral treatment administered 72 hours after the onset of rash. One uncontrolled trial, however, examined the effectiveness of acyclovir started before vs after 72 hours; the difference in pain persistence was not significant between the groups, suggesting acyclovir has benefit even when given after 72 hours.¹⁰

In clinical practice, the diagnosis of herpes zoster is often not made within 72 hours of symptom onset; nevertheless, it is important to identify patients who could still benefit from antiviral medication even when treatment is started relatively late in the disease course. This is especially true in ocular zoster, because viral shedding may continue beyond 72 hours.¹¹

Analgesics are part of a practical approach for managing herpes zoster–associated pain that begins with a short-acting opioid in combination with acetaminophen or a nonsteroidal anti-inflammatory (NSAID) agent. Gabapentin or pregabalin, followed by a tricyclic antidepressant, can be added if conventional analgesics are not entirely effective. The analgesic regimen should be tailored to the patient’s needs and tolerance of adverse effects. If pain control is inadequate or adverse effects are intolerable, consider referring the patient to a pain management center for possible interventional modalities.

Corticosteroids are not recommended routinely for treatment of herpes zoster; you can try them in otherwise healthy older adults, however, if antiviral therapy and analgesics do not relieve pain. In 2 double-blind controlled trials, a combination of acyclovir and corticosteroids for 21 days did not decrease the incidence of PHN—although some benefit was seen in terms of patients’ return to normal activities, cessation of analgesic therapy, and improved sleep.^12,13

Evidence-based treatment options for PHN

Pharmacotherapy for PHN includes anticonvulsants, tricyclic antidepressants, opioids, and topical agents. Invasive interventions have a limited but important role in the management of PHN pain in clinical practice.

Calcium channel-blocking anticonvulsants gabapentin and pregabalin are safe and relatively well tolerated. They can be used as first-line agents for PHN, starting with a low dosage and titrating up, based on effectiveness and tolerability.

Gabapentin is FDA approved for the treatment of PHN. The starting dosage is 100 to 300 mg taken at night, titrated as needed by 100 to 300 mg every 3 to 5 days, to as high a dosage as 1800 to 3600 mg/d in 3 or 4 divided doses. In 2 large, randomized controlled trials, gabapentin produced a statistically significant reduction in pain ratings and improved sleep and quality of life.^14,15 Adverse effects include somnolence, dizziness, peripheral edema, visual adverse effects, and gait and balance problems.

Because gabapentin is excreted by the kidneys, take care when using it in patients with renal insufficiency. Gabapentin clearance is linearly related to creatinine clearance and is decreased in the elderly and in individuals with impaired renal function. Hence, the gabapentin dose and the frequency of dosing must be adjusted in these patients.

In patients on hemodialysis, plasma gabapentin levels can be maintained by giving a dose of 200 to 300 mg 4 hours after hemodialysis.¹⁶

Extended-release gabapentin. The FDA recently approved an extended-release gabapentin formulation for PHN. Approval was based on a 12-week pivotal study and 2 adjunct studies. In a multicenter, randomized, double-blind, parallel-group, placebo-controlled, 12-week study evaluating the efficacy, safety, and dose response of 3 doses, extended-release gabapentin was effective at 1200 mg/d dosing. The initial recommended dose is 600 mg, once daily for 3 days, followed by 600 mg, twice daily, beginning on Day 4.¹⁷ The premise is that the extended-release preparation improves bioavailability of the active drug and, therefore, reduces the incidence of adverse effects, compared with regular gabapentin.

Overall, evidence is mixed. Two randomized controlled trials of extended-release gabapentin showed benefit (ie, reduced pain score on a numerical rating scale) with twice-a-day dosing (600 mg in the morning and 1200 mg at night), compared with a once-daily 1800-mg dose as well as placebo, for reduction in intensity of pain¹⁸ and specific pain quality.¹⁹ In another trial, however, extended-release gabapentin, 1800 mg once daily, did not show any benefit compared with placebo.²⁰

Pregabalin is also FDA approved for PHN. The effective dosage range is 150 to 600 mg/d. Pregabalin provided significantly superior pain relief and improved sleep scores compared with placebo in 776 patients with PHN.²¹ Adverse effects include weight gain, dizziness, and somnolence. Titrate the dosage slowly in the elderly.

Sodium channel-blocking anticonvulsants topiramate, lamotrigine, carbamazepine, oxcarbazepine, levetriacetam, and valproic acid are not FDA approved for PHN. These agents may be a treatment option, however, for patients with PHN who do not respond to conventional therapy. In an 8-week randomized controlled trial, patients treated with divalproex sodium (valproic acid and sodium valproate), 1000 mg/d, experienced significant pain relief compared with placebo-treated patients.²² Adverse effects included vertigo, hair loss, headache, nausea, and diarrhea.

Tricyclic antidepressants, including amitriptyline, desipramine, and nortriptyline, might work by (1) inhibiting norepinephrine and serotonin uptake, (2) sodium-channel blockade, or (3) another mechanism that is unclear. Although amitriptyline is the most studied tricyclic antidepressant for PHN, available evidence and clinical experience suggest that nortriptyline and desipramine have comparable efficacy and are better tolerated.^23,24

Nortriptyline and desipramine are preferred in frail and elderly patients. Start therapy with 10 to 25 mg nightly, titrating as tolerated every 2 weeks to 75 to 150 mg as a single daily dose. Adverse effects include dry mouth, fatigue, dizziness, sedation, urinary retention, orthostatic hypotension, weight gain, blurred vision, QT interval prolongation, constipation, and sexual dysfunction.

Serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants. Use of such agents as duloxetine and venlafaxine in PHN patients is extrapolated from their proven efficacy in treating diabetic neuropathy and other neuropathic pain conditions. Try duloxetine if your patient does not respond to or tolerate a tricyclic. The recommended dosage is 60 to 120 mg/d in 2 divided doses.²⁴

Two randomized, 12-week, double-blind, placebo-controlled trials using duloxetine 60 mg once a day and 60 mg twice a day for diabetic peripheral neuropathy concluded that 120 mg was safe and effective in treating diabetic peripheral neuropathy, but 120 mg was not as well tolerated as 60 mg once a day.²⁵

Monitor liver function periodically in patients taking duloxetine. Alternatively, you can give venlafaxine; the recommended dosage is 75 to 225 mg/d.²⁶

Opioid analgesics are recommended as second- and third-line agents for PHN. Adverse effects include nausea, pruritus, sedation, confusion, constipation, hypogonadism, and risk of developing tolerance and abuse.

A double-blind crossover trial evaluated the analgesic efficacy of oral oxycodone; treatment resulted in significant reduction of allodynia, steady pain, and spontaneous paroxysmal pain. Oxycodone treatment resulted in superior scores of global effectiveness, disability reduction, and patient preference, compared with placebo.²⁷

In a randomized crossover trial, the combination of gabapentin and morphine was superior to either of these medications alone in relieving pain in PHN.²⁸

Tramadol, an atypical opioid, has a weak μ-opioid receptor agonist effect and inhibits reuptake of serotonin and norepinephrine. Avoid using it in patients with a history of seizures. The maximum recommended dosage is 400 mg/d. An extended-release formulation of tramadol is also available.

Tramadol provided superior pain relief and improved quality of life in PHN patients in a randomized placebo-controlled trial.²⁹

Tapentadol has weak μ-opioid receptor agonist activity; norepinephrine reuptake inhibition is more predominant than serotonin reuptake inhibition. This drug is also available as an extended-release formulation. The maximum recommended dosage is 600 mg/d.

Avoid using tapentadol in patients with a history of seizures. Note: Although there is no scientific evidence regarding the use of tapentadol in neuropathic pain, we use it often in our practice. 

Topical therapies

Treating PHN with a topical agent is associated with relatively fewer adverse effects than what has been seen with oral therapy because systemic absorption is minimal.

Lidocaine is available as a transdermal patch and as a topical gel ointment. The 5% lidocaine patch is FDA approved for treating PHN. Lidocaine, a sodium-channel blocker, is useful for treating patients with clinical evidence of allodynia. You can cut a patch to fit the affected area; a maximum of 3 patches can be used simultaneously for 12 hours on, 12 hours off. If helpful, the patch can be left in place for 18 hours.³⁰

In 2 open-labeled, nonrandomized prospective studies, patients treated with the lidocaine patch had reduced intensity of pain and improved quality of life.^31,32

If lidocaine patches are not available, or affordable, or if a patient has difficulty applying them, use 5% lidocaine gel instead.

Capsaicin topical cream is sold in 2 concentrations: 0.025% and 0.075%. An extract of hot chili peppers, capsaicin acts as an agonist at the vanilloid receptors. The recommended dosage is 3 or 4 times a day. Initial application causes burning to become worse, but repeated use results in diminished pain and hyperalgesia.

A 6-week, blinded parallel study, followed by a 2-year open label follow-up, showed that the 0.075% dose of topical capsaicin cream relieved pain in 64% of patients; pain was relieved in 25% of placebo-treated patients.³³

An 8% capsaicin patch is FDA approved for treating PHN. The patch must be applied by a health care professional in a monitored setting. Prepare the affected area by pretreating it with a local anesthetic cream; then apply the patch and leave it in place for 1 hour. As many as 4 patches can be used at once. A single application can provide pain relief for as long as 12 weeks. Adverse effects are mostly mild and transient.

In a double-blind, randomized, placebo-controlled trial with an open-label extension, the score on a numeric pain-rating scale declined from baseline in both the high-concentration capsaicin group and the placebo group during Week 1; however, the capsaicin-treated group experienced long-term improvement through Week 12.³⁴

(See TABLE 1^{14-21, 23, 24, 27-34} for a summary of pharmacotherapeutic options.)

TABLE 1

Pharmacotherapeutic options for managing postherpetic neuralgia^{14-21, 23, 24, 27-34}

Alternative modalities to reduce pain

Acupuncture and transcutaneous electrical nerve stimulation (TENS) have been tried for the relief of PHN without consistent evidence of efficacy. There are no significant adverse effects associated with these therapies; however, the cost of treatment may be an issue. Acupuncture is not covered by many insurance carriers. Mental-health interventions, including cognitive and behavioral therapy, might help with overall physical and emotional functioning and quality of life.

Invasive interventions

Researchers have examined several interventional modalities for treating PHN that is refractory to medication.

Sympathetic nerve blocks. Retrospective studies have shown that sympathetic nerve block provides short-term improvement in pain in 40% to 50% of patients with PHN.³⁵

Intercostal nerve block has been reported to provide long-lasting pain relief in patients with thoracic PHN.³⁶

Neuraxial use of intrathecal methylprednisone is supported by moderately good evidence of benefit in patients with intractable PHN.³⁷ Because this intervention poses significant risk of neurologic sequelae, we do not recommend that it be used in clinical practice.

Spinal cord stimulation was studied prospectively in a case series of 28 patients.³⁸ Long-term pain relief was obtained in 82%. Patients serve as their own controls by switching off the spinal cord stimulator and monitoring pain. Consider spinal cord stimulation for patients with well-established PHN that is refractory to conventional management.

Cryotherapy was used for facial neuralgia pain, without significant benefit.³⁹ Another trial showed short-term benefit in 11 of 14 patients who underwent cryotherapy of the intercostal nerves for thoracic PHN.⁴⁰

Botulinium toxin A injection. An abstract presented at the February 2010 meeting of the American Academy of Pain Medicine described how subcutaneous injection of botulinium toxin A reduced pain in patients with PHN, compared with lidocaine and placebo injections. The pain relief was noted in 1 week and persisted for 90 days.⁴¹

Surgery. Many surgical interventions have been described and used to treat PHN, but none has a role in clinical practice.

When should you refer to a pain management center?

Dermatomal pain that lasts for longer than 180 days after a herpes zoster rash can be considered “well-established PHN” to denote its refractory nature. As a primary care clinician, you can refer a patient with PHN to a pain management center at any stage of disease but especially when the:

• patient has a significant medical comorbidity and you think that he or she requires the services of a specialist to manage multimodal pharmacotherapy

• PHN pain is refractory to conventional treatment modalities

• patient needs an invasive intervention  
• patient needs treatment with a high-dose capsaicin patch and you have not been trained to apply it. 

Preventing herpes zoster and PHN

Obviously, preventing PHN is closely tied to preventing herpes zoster. To help prevent herpes zoster:

• vaccinate children with varicella vaccine to prevent primary varicella infection⁴²

• use varicella-zoster immunoglobulin, as recommended by the CDC’s Advisory Committee on Immunization Practices (ACIP), in immunocompromised, seronegative patients who were exposed recently to a person with chickenpox or herpes zoster⁴²

• administer the herpes zoster vaccine to patients 60 years and older, as recommended by ACIP.⁴³ The FDA recently approved use of this vaccine for people 50 through 59 years, but ACIP has not changed its recommendations.⁴⁴

As we’ve discussed, herpes zoster vaccination, antiviral therapy, and aggressive pain control can reduce the incidence, severity, and duration of acute herpes zoster and PHN.

A large multicenter, randomized, placebo-controlled trial demonstrated that herpes zoster vaccine decreases the likelihood of developing herpes zoster in immunocompetent individuals 60 years and older.⁴⁵ The vaccine reduced the incidence of herpes zoster by 51.3%; reduced the burden of illness by 61.1%; and reduced the incidence of PHN by 66.5%.⁴⁵ The live, attenuated vaccine is contraindicated in children, pregnant women, and immunocompromised individuals.

The number needed to treat for herpes zoster vaccine is 175; that is, 1 case of herpes zoster is avoided for every 175 people vaccinated.¹

Newer tools mean a better outcome

We have improved our ability to diminish the incidence of herpes zoster and PHN and to manage postherpetic pain more effectively. These advances include the development of a herpes zoster vaccine; consensus that antiviral therapy and aggressive pain management can reduce the burden of PHN; identification of efficacious treatments for PHN; and recognition of PHN as a study model for neuropathic pain research.

Disclosure

The authors reported no potential conflict of interest relevant to this article.

References

1. Oxman MN, Levin MJ, Johnson GR, et al; Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271–2284.
    
2. Bennett GJ. Neuropathic pain: An overview.  In: Borsook D, ed. Molecular Neurobiology of Pain. Seattle, WA: IASP Press; 1997:109-113.
    
3. Jung BF, Johnson RW, Griffin DR, Dworkin RH. Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurology. 2004;62:1545–1551.
    
4. Dworkin RH, Boon RJ, Griffin DR, Phung D. Postherpetic neuralgia: impact of famciclovir, age, rash severity, and acute pain in herpes zoster patients. J Infect Dis. 1998;178(suppl 1):S76–S80.
    
5. Volpi A, Gross G, Hercogova J, Johnson RW. Current management of herpes zoster: the European view. Am J Clin Dermatol. 2005;6:317–325.
    
6. Dworkin RH, Portenoy RK. Pain and its persistence in herpes zoster. Pain. 1996;67:241–251.
    
7. Bowsher D. Pathophysiology of postherpetic neuralgia: towards a rational treatment. Neurology. 1995;45(12 suppl 8):S56–S57.
    
8. Dworkin RH, Schmader KE. Epidemiology and natural history of herpes zoster and postherpetic neuralgia.  In Watson CPN, Gershon AA, eds. Herpes Zoster and Postherpetic Neuralgia. 2nd ed. New York, NY: Elsevier Press; 2001:39-64.
    
9. Tyring S, Barbarash RA, Nahlik JE, et al. Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1995;123:89–96.
    
10. Kurokawa I, Kumano K, Murkawa K. Clinical correlates of prolonged pain in Japanese patients with acute herpes zoster. J Int Med Res. 2002;30:56–65.
     
11. Zaal MJ, Volker-Dieben HJ, Wienesen M, et al. Longitudinal analysis of varicella-zoster virus DNA on the ocular surface associated with herpes zoster ophthalmicus. Am J Ophthalmol. 2001;131:25–29.
     
12. Wood MJ, Johnson RW, McKendrick MW, et al. A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med. 1994;330:896–900.
     
13. Whitley RJ, Weiss H, Gnann JW  Jr, et al. Acyclovir with and without prednisone for the treatment of herpes zoster: a randomized, placebo-controlled trial. Ann Intern Med. 1996;125:376–383.
     
14. Rice AS, Maton S. Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain. 2001;94:215–224.
     
15. Collins SL, Moore RA, McQuay HJ, Wiffen P. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage. 2000;20:449–458.
     
16. Wong MO, Eldon MA, Keane WF, et al. Disposition of gabapentin in anuric subjects on hemodialysis. J Clin Pharmacol. 1995;35:622–626.
     
17.  Horizant (gabapentin encarbil) extended-release tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2012.
     
18. Irving G, Jensen M, Cramer M, et al. Efficacy and tolerability of gastric-retentive gabapentin for the treatment of postherpetic neuralgia: results of a double-blind, randomized, placebo-controlled clinical trial. Clin J Pain. 2009;25:185–192.
     
19. Jensen MP, Chiang YK, Wu J. Assessment of pain quality in a clinical trial of gabapentin extended release for postherpetic neuralgia. Clin J Pain. 2009;25:286–292.
     
20. Wallace MS, Irving G, Cowles VE. Gabapentin extended-release tablets for the treatment of patients with postherpetic neuralgia: a randomized, double-blind, placebo-controlled, multicenter study. Clin Drug Investig. 2010;30:765–776.
     
21. Frampton JE, Foster RH. Pregabalin in the treatment of postherpetic neuralgia. Drugs. 2005;65:111–118.
     
22. Kochar D, Garg P, Bumb RA, et al. Divalproex sodium in the management of postherpetic neuralgia: a randomized double-blind placebo-controlled study. QJM. 2005;98:29–34.
     
23. Watson CP, Vernich L, Chipman M, Reed K. Nortriptyline vs amitriptyline in postherpetic neuralgia: a randomized trial. Neurology. 1998;51:1166–1171.
24. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007;132:237–251.
     
25.  Cymbalta (duloxetine hydrochloride) delayed-release capsules [package insert]. Indianapolis, IN: Lilly USA; 2011.
     
26. Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004;110:697–706.
     
27. Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology. 1998;50:1837–1841.
     
28. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352:1324–1334.
     
29. Boureau F, Legallicier P, Kabir-Ahmadi M. Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial. Pain. 2003;104:323–331.
     
30. Hermann DN, Barbano RL, Hart-Gouleau S, et al. An open-label study of the lidocaine patch 5% in painful idiopathic sensory polyneuropathy. Pain Med. 2005;379–384.
     
31. Davies PS, Galer BS. Review of lidocaine patch 5% studies in the treatment of postherpetic neuralgia. Drugs. 2004;64:937–947.
     
32. Gammaitoni AR, Alvarez NA, Galer BS. Safety and tolerability of the lidocaine patch 5%, a targeted peripheral analgesic: a review of literature. J Clin Pharmacol. 2003;43:111–117.
     
33. Watson CP, Tyler KL, Bickers DR, et al. A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia. Clin Ther. 1993;15:510–526.
     
34. Backonja MM, Malan TP, Vanhove GF, Tobias JK. C102/106 Study Group. NGX-4010, a high concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized, double-blind, controlled study with an open-label extension. Pain Med. 2010;11:600–608.
     
35. Kumar V, Krone K, Mathieu A. Neuraxial and sympathetic blocks in herpes zoster and postherpetic neuralgia: an appraisal of current evidence. Reg Anesth Pain Med. 2004;29:454–461.
     
36. Doi K, Nikai T, Sakura S, Saito Y. Intercostal nerve block with 5% tetracaine for chronic pain syndromes. J Clin Anesth. 2002;14:39–41.
     
37. Kotani N, Kushikata T, Hashimoto H, et al. Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med. 2000;343:1514–1519.
     
38. Harke H, Gretenkort P, Ladleif HU, et al. Spinal cord stimulation in postherpetic neuralgia and in acute herpes zoster pain. Anesth Anal. 2002;94:694–700.
     
39. Barnard D, Lloyd J, Evans J. Cryoanalgesia in the management of chronic facial pain. J Maxillofac Surg. 1981;9:101–102.
     
40. Jones MJ, Murrin KR. Intercostal block with cryotherapy. Ann R Coll Surg Engl. 1987;69:261–262.
     
41. Xiao L, Hui H. Therapeutic effect of botulinium toxin A in the treatment of postherpetic neuralgia by subcutaneous injection. Presented at: 26th Annual Meeting of the American Academy of Pain Medicine; February 3-6, 2010; San Antonio, TX.
     
42. Marin M, Güris D, Chaves SS, et al. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56(RR-4):1–40.
     
43. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1–30.
     
44. Centers for Disease Control and Prevention (CDC). Update on herpes zoster vaccine: licensure for persons aged 50 through 59 years. MMWR Morb Mortal Wkly Rep. 2011;60(44):1528.
     
45. Gnann JW  Jr. Vaccination to prevent herpes zoster in older adults. J Pain. 2008;9(1 suppl 1):S31–S36.

Postherpetic neuralgia (PHN) is a management challenge—because of its severity, long duration, and potential for debilitation, often in the highly vulnerable elderly population. And, as the most common complication of an acute episode of herpes zoster (shingles) in an immunocompetent person, PHN is likely no stranger to your practice.

Herpes zoster is one of the most common neurological problems, with an incidence of up to 1 million new cases per year in the United States.¹ Although the precise number for the prevalence of PHN in the United States is unknown, investigators estimate it at 500,000 to 1 million.²

Major risk factors for development of PHN after an episode of herpes zoster include:

• older age

• greater acute pain during herpes zoster

• greater severity of rash.^3,4

PHN is commonly defined as “dermatomal pain that persists 120 days or more after the onset of rash.”⁵ The pain of PHN has been characterized as a stimulus-dependent continuous burning, throbbing, or episodic sharp electric shock-like sensation⁶ and as a stimulus-dependent tactile allodynia (ie, pain after normally nonpainful stimulus) and hyperalgesia (exaggerated response to a painful stimulus). In addition, some patients experience myofascial pain secondary to excessive muscle guarding. Chronic pruritus can be present.

More than 90% of patients who have PHN have allodynia,⁷ which tends to occur in areas where sensation is relatively preserved. Patients also feel spontaneous pain in areas where sensation is lost or impaired.

In this article, we review the evidence for the range of treatments for acute herpes zoster and PHN, as well offer preventive strategies for herpes zoster.

Acute herpes zoster: Start antivirals early

Evidence-based treatment of acute herpes zoster includes antiviral drugs and analgesics.

Antiviral agents suppress viral replication and have a beneficial effect on acute and chronic pain. Acyclovir (800 mg, 5 times a day), valacyclovir (1000 mg, every 8 hours), and famciclovir (500 mg, every 8 hours) are antivirals commonly used to treat herpes zoster. All 3 drugs have comparable efficacy and safety profiles.

In a meta-analysis of patients older than 50 years who were treated with acyclovir or placebo, pain persisted in 15% of the acyclovir-treated group, compared with 35% of the placebo group.⁸ In terms of duration, a study comparing famciclovir treatment with placebo showed that subjects in the placebo group had persistent pain for 163 days, whereas famciclovir-treated patients had pain for 63 days.⁹

Based on this evidence, antiviral medications are strongly recommended for treating herpes zoster, especially for patients at increased risk of developing PHN. Antiviral treatment should be started within 72 hours of the onset of the rash.

No good evidence supports the efficacy of antiviral treatment administered 72 hours after the onset of rash. One uncontrolled trial, however, examined the effectiveness of acyclovir started before vs after 72 hours; the difference in pain persistence was not significant between the groups, suggesting acyclovir has benefit even when given after 72 hours.¹⁰

In clinical practice, the diagnosis of herpes zoster is often not made within 72 hours of symptom onset; nevertheless, it is important to identify patients who could still benefit from antiviral medication even when treatment is started relatively late in the disease course. This is especially true in ocular zoster, because viral shedding may continue beyond 72 hours.¹¹

Analgesics are part of a practical approach for managing herpes zoster–associated pain that begins with a short-acting opioid in combination with acetaminophen or a nonsteroidal anti-inflammatory (NSAID) agent. Gabapentin or pregabalin, followed by a tricyclic antidepressant, can be added if conventional analgesics are not entirely effective. The analgesic regimen should be tailored to the patient’s needs and tolerance of adverse effects. If pain control is inadequate or adverse effects are intolerable, consider referring the patient to a pain management center for possible interventional modalities.

Corticosteroids are not recommended routinely for treatment of herpes zoster; you can try them in otherwise healthy older adults, however, if antiviral therapy and analgesics do not relieve pain. In 2 double-blind controlled trials, a combination of acyclovir and corticosteroids for 21 days did not decrease the incidence of PHN—although some benefit was seen in terms of patients’ return to normal activities, cessation of analgesic therapy, and improved sleep.^12,13

Evidence-based treatment options for PHN

Pharmacotherapy for PHN includes anticonvulsants, tricyclic antidepressants, opioids, and topical agents. Invasive interventions have a limited but important role in the management of PHN pain in clinical practice.

Calcium channel-blocking anticonvulsants gabapentin and pregabalin are safe and relatively well tolerated. They can be used as first-line agents for PHN, starting with a low dosage and titrating up, based on effectiveness and tolerability.

Gabapentin is FDA approved for the treatment of PHN. The starting dosage is 100 to 300 mg taken at night, titrated as needed by 100 to 300 mg every 3 to 5 days, to as high a dosage as 1800 to 3600 mg/d in 3 or 4 divided doses. In 2 large, randomized controlled trials, gabapentin produced a statistically significant reduction in pain ratings and improved sleep and quality of life.^14,15 Adverse effects include somnolence, dizziness, peripheral edema, visual adverse effects, and gait and balance problems.

Because gabapentin is excreted by the kidneys, take care when using it in patients with renal insufficiency. Gabapentin clearance is linearly related to creatinine clearance and is decreased in the elderly and in individuals with impaired renal function. Hence, the gabapentin dose and the frequency of dosing must be adjusted in these patients.

In patients on hemodialysis, plasma gabapentin levels can be maintained by giving a dose of 200 to 300 mg 4 hours after hemodialysis.¹⁶

Extended-release gabapentin. The FDA recently approved an extended-release gabapentin formulation for PHN. Approval was based on a 12-week pivotal study and 2 adjunct studies. In a multicenter, randomized, double-blind, parallel-group, placebo-controlled, 12-week study evaluating the efficacy, safety, and dose response of 3 doses, extended-release gabapentin was effective at 1200 mg/d dosing. The initial recommended dose is 600 mg, once daily for 3 days, followed by 600 mg, twice daily, beginning on Day 4.¹⁷ The premise is that the extended-release preparation improves bioavailability of the active drug and, therefore, reduces the incidence of adverse effects, compared with regular gabapentin.

Overall, evidence is mixed. Two randomized controlled trials of extended-release gabapentin showed benefit (ie, reduced pain score on a numerical rating scale) with twice-a-day dosing (600 mg in the morning and 1200 mg at night), compared with a once-daily 1800-mg dose as well as placebo, for reduction in intensity of pain¹⁸ and specific pain quality.¹⁹ In another trial, however, extended-release gabapentin, 1800 mg once daily, did not show any benefit compared with placebo.²⁰

Pregabalin is also FDA approved for PHN. The effective dosage range is 150 to 600 mg/d. Pregabalin provided significantly superior pain relief and improved sleep scores compared with placebo in 776 patients with PHN.²¹ Adverse effects include weight gain, dizziness, and somnolence. Titrate the dosage slowly in the elderly.

Sodium channel-blocking anticonvulsants topiramate, lamotrigine, carbamazepine, oxcarbazepine, levetriacetam, and valproic acid are not FDA approved for PHN. These agents may be a treatment option, however, for patients with PHN who do not respond to conventional therapy. In an 8-week randomized controlled trial, patients treated with divalproex sodium (valproic acid and sodium valproate), 1000 mg/d, experienced significant pain relief compared with placebo-treated patients.²² Adverse effects included vertigo, hair loss, headache, nausea, and diarrhea.

Tricyclic antidepressants, including amitriptyline, desipramine, and nortriptyline, might work by (1) inhibiting norepinephrine and serotonin uptake, (2) sodium-channel blockade, or (3) another mechanism that is unclear. Although amitriptyline is the most studied tricyclic antidepressant for PHN, available evidence and clinical experience suggest that nortriptyline and desipramine have comparable efficacy and are better tolerated.^23,24

Nortriptyline and desipramine are preferred in frail and elderly patients. Start therapy with 10 to 25 mg nightly, titrating as tolerated every 2 weeks to 75 to 150 mg as a single daily dose. Adverse effects include dry mouth, fatigue, dizziness, sedation, urinary retention, orthostatic hypotension, weight gain, blurred vision, QT interval prolongation, constipation, and sexual dysfunction.

Serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants. Use of such agents as duloxetine and venlafaxine in PHN patients is extrapolated from their proven efficacy in treating diabetic neuropathy and other neuropathic pain conditions. Try duloxetine if your patient does not respond to or tolerate a tricyclic. The recommended dosage is 60 to 120 mg/d in 2 divided doses.²⁴

Two randomized, 12-week, double-blind, placebo-controlled trials using duloxetine 60 mg once a day and 60 mg twice a day for diabetic peripheral neuropathy concluded that 120 mg was safe and effective in treating diabetic peripheral neuropathy, but 120 mg was not as well tolerated as 60 mg once a day.²⁵

Monitor liver function periodically in patients taking duloxetine. Alternatively, you can give venlafaxine; the recommended dosage is 75 to 225 mg/d.²⁶

Opioid analgesics are recommended as second- and third-line agents for PHN. Adverse effects include nausea, pruritus, sedation, confusion, constipation, hypogonadism, and risk of developing tolerance and abuse.

A double-blind crossover trial evaluated the analgesic efficacy of oral oxycodone; treatment resulted in significant reduction of allodynia, steady pain, and spontaneous paroxysmal pain. Oxycodone treatment resulted in superior scores of global effectiveness, disability reduction, and patient preference, compared with placebo.²⁷

In a randomized crossover trial, the combination of gabapentin and morphine was superior to either of these medications alone in relieving pain in PHN.²⁸

Tramadol, an atypical opioid, has a weak μ-opioid receptor agonist effect and inhibits reuptake of serotonin and norepinephrine. Avoid using it in patients with a history of seizures. The maximum recommended dosage is 400 mg/d. An extended-release formulation of tramadol is also available.

Tramadol provided superior pain relief and improved quality of life in PHN patients in a randomized placebo-controlled trial.²⁹

Tapentadol has weak μ-opioid receptor agonist activity; norepinephrine reuptake inhibition is more predominant than serotonin reuptake inhibition. This drug is also available as an extended-release formulation. The maximum recommended dosage is 600 mg/d.

Avoid using tapentadol in patients with a history of seizures. Note: Although there is no scientific evidence regarding the use of tapentadol in neuropathic pain, we use it often in our practice. 

Topical therapies

Treating PHN with a topical agent is associated with relatively fewer adverse effects than what has been seen with oral therapy because systemic absorption is minimal.

Lidocaine is available as a transdermal patch and as a topical gel ointment. The 5% lidocaine patch is FDA approved for treating PHN. Lidocaine, a sodium-channel blocker, is useful for treating patients with clinical evidence of allodynia. You can cut a patch to fit the affected area; a maximum of 3 patches can be used simultaneously for 12 hours on, 12 hours off. If helpful, the patch can be left in place for 18 hours.³⁰

In 2 open-labeled, nonrandomized prospective studies, patients treated with the lidocaine patch had reduced intensity of pain and improved quality of life.^31,32

If lidocaine patches are not available, or affordable, or if a patient has difficulty applying them, use 5% lidocaine gel instead.

Capsaicin topical cream is sold in 2 concentrations: 0.025% and 0.075%. An extract of hot chili peppers, capsaicin acts as an agonist at the vanilloid receptors. The recommended dosage is 3 or 4 times a day. Initial application causes burning to become worse, but repeated use results in diminished pain and hyperalgesia.

A 6-week, blinded parallel study, followed by a 2-year open label follow-up, showed that the 0.075% dose of topical capsaicin cream relieved pain in 64% of patients; pain was relieved in 25% of placebo-treated patients.³³

An 8% capsaicin patch is FDA approved for treating PHN. The patch must be applied by a health care professional in a monitored setting. Prepare the affected area by pretreating it with a local anesthetic cream; then apply the patch and leave it in place for 1 hour. As many as 4 patches can be used at once. A single application can provide pain relief for as long as 12 weeks. Adverse effects are mostly mild and transient.

In a double-blind, randomized, placebo-controlled trial with an open-label extension, the score on a numeric pain-rating scale declined from baseline in both the high-concentration capsaicin group and the placebo group during Week 1; however, the capsaicin-treated group experienced long-term improvement through Week 12.³⁴

(See TABLE 1^{14-21, 23, 24, 27-34} for a summary of pharmacotherapeutic options.)

TABLE 1

Pharmacotherapeutic options for managing postherpetic neuralgia^{14-21, 23, 24, 27-34}

Alternative modalities to reduce pain

Acupuncture and transcutaneous electrical nerve stimulation (TENS) have been tried for the relief of PHN without consistent evidence of efficacy. There are no significant adverse effects associated with these therapies; however, the cost of treatment may be an issue. Acupuncture is not covered by many insurance carriers. Mental-health interventions, including cognitive and behavioral therapy, might help with overall physical and emotional functioning and quality of life.

Invasive interventions

Researchers have examined several interventional modalities for treating PHN that is refractory to medication.

Sympathetic nerve blocks. Retrospective studies have shown that sympathetic nerve block provides short-term improvement in pain in 40% to 50% of patients with PHN.³⁵

Intercostal nerve block has been reported to provide long-lasting pain relief in patients with thoracic PHN.³⁶

Neuraxial use of intrathecal methylprednisone is supported by moderately good evidence of benefit in patients with intractable PHN.³⁷ Because this intervention poses significant risk of neurologic sequelae, we do not recommend that it be used in clinical practice.

Spinal cord stimulation was studied prospectively in a case series of 28 patients.³⁸ Long-term pain relief was obtained in 82%. Patients serve as their own controls by switching off the spinal cord stimulator and monitoring pain. Consider spinal cord stimulation for patients with well-established PHN that is refractory to conventional management.

Cryotherapy was used for facial neuralgia pain, without significant benefit.³⁹ Another trial showed short-term benefit in 11 of 14 patients who underwent cryotherapy of the intercostal nerves for thoracic PHN.⁴⁰

Botulinium toxin A injection. An abstract presented at the February 2010 meeting of the American Academy of Pain Medicine described how subcutaneous injection of botulinium toxin A reduced pain in patients with PHN, compared with lidocaine and placebo injections. The pain relief was noted in 1 week and persisted for 90 days.⁴¹

Surgery. Many surgical interventions have been described and used to treat PHN, but none has a role in clinical practice.

When should you refer to a pain management center?

Dermatomal pain that lasts for longer than 180 days after a herpes zoster rash can be considered “well-established PHN” to denote its refractory nature. As a primary care clinician, you can refer a patient with PHN to a pain management center at any stage of disease but especially when the:

• patient has a significant medical comorbidity and you think that he or she requires the services of a specialist to manage multimodal pharmacotherapy

• PHN pain is refractory to conventional treatment modalities

• patient needs an invasive intervention  
• patient needs treatment with a high-dose capsaicin patch and you have not been trained to apply it. 

Preventing herpes zoster and PHN

Obviously, preventing PHN is closely tied to preventing herpes zoster. To help prevent herpes zoster:

• vaccinate children with varicella vaccine to prevent primary varicella infection⁴²

• use varicella-zoster immunoglobulin, as recommended by the CDC’s Advisory Committee on Immunization Practices (ACIP), in immunocompromised, seronegative patients who were exposed recently to a person with chickenpox or herpes zoster⁴²

• administer the herpes zoster vaccine to patients 60 years and older, as recommended by ACIP.⁴³ The FDA recently approved use of this vaccine for people 50 through 59 years, but ACIP has not changed its recommendations.⁴⁴

As we’ve discussed, herpes zoster vaccination, antiviral therapy, and aggressive pain control can reduce the incidence, severity, and duration of acute herpes zoster and PHN.

A large multicenter, randomized, placebo-controlled trial demonstrated that herpes zoster vaccine decreases the likelihood of developing herpes zoster in immunocompetent individuals 60 years and older.⁴⁵ The vaccine reduced the incidence of herpes zoster by 51.3%; reduced the burden of illness by 61.1%; and reduced the incidence of PHN by 66.5%.⁴⁵ The live, attenuated vaccine is contraindicated in children, pregnant women, and immunocompromised individuals.

The number needed to treat for herpes zoster vaccine is 175; that is, 1 case of herpes zoster is avoided for every 175 people vaccinated.¹

Newer tools mean a better outcome

We have improved our ability to diminish the incidence of herpes zoster and PHN and to manage postherpetic pain more effectively. These advances include the development of a herpes zoster vaccine; consensus that antiviral therapy and aggressive pain management can reduce the burden of PHN; identification of efficacious treatments for PHN; and recognition of PHN as a study model for neuropathic pain research.

Disclosure

The authors reported no potential conflict of interest relevant to this article.

References

1. Oxman MN, Levin MJ, Johnson GR, et al; Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271–2284.
    
2. Bennett GJ. Neuropathic pain: An overview.  In: Borsook D, ed. Molecular Neurobiology of Pain. Seattle, WA: IASP Press; 1997:109-113.
    
3. Jung BF, Johnson RW, Griffin DR, Dworkin RH. Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurology. 2004;62:1545–1551.
    
4. Dworkin RH, Boon RJ, Griffin DR, Phung D. Postherpetic neuralgia: impact of famciclovir, age, rash severity, and acute pain in herpes zoster patients. J Infect Dis. 1998;178(suppl 1):S76–S80.
    
5. Volpi A, Gross G, Hercogova J, Johnson RW. Current management of herpes zoster: the European view. Am J Clin Dermatol. 2005;6:317–325.
    
6. Dworkin RH, Portenoy RK. Pain and its persistence in herpes zoster. Pain. 1996;67:241–251.
    
7. Bowsher D. Pathophysiology of postherpetic neuralgia: towards a rational treatment. Neurology. 1995;45(12 suppl 8):S56–S57.
    
8. Dworkin RH, Schmader KE. Epidemiology and natural history of herpes zoster and postherpetic neuralgia.  In Watson CPN, Gershon AA, eds. Herpes Zoster and Postherpetic Neuralgia. 2nd ed. New York, NY: Elsevier Press; 2001:39-64.
    
9. Tyring S, Barbarash RA, Nahlik JE, et al. Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1995;123:89–96.
    
10. Kurokawa I, Kumano K, Murkawa K. Clinical correlates of prolonged pain in Japanese patients with acute herpes zoster. J Int Med Res. 2002;30:56–65.
     
11. Zaal MJ, Volker-Dieben HJ, Wienesen M, et al. Longitudinal analysis of varicella-zoster virus DNA on the ocular surface associated with herpes zoster ophthalmicus. Am J Ophthalmol. 2001;131:25–29.
     
12. Wood MJ, Johnson RW, McKendrick MW, et al. A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. N Engl J Med. 1994;330:896–900.
     
13. Whitley RJ, Weiss H, Gnann JW  Jr, et al. Acyclovir with and without prednisone for the treatment of herpes zoster: a randomized, placebo-controlled trial. Ann Intern Med. 1996;125:376–383.
     
14. Rice AS, Maton S. Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain. 2001;94:215–224.
     
15. Collins SL, Moore RA, McQuay HJ, Wiffen P. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage. 2000;20:449–458.
     
16. Wong MO, Eldon MA, Keane WF, et al. Disposition of gabapentin in anuric subjects on hemodialysis. J Clin Pharmacol. 1995;35:622–626.
     
17.  Horizant (gabapentin encarbil) extended-release tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2012.
     
18. Irving G, Jensen M, Cramer M, et al. Efficacy and tolerability of gastric-retentive gabapentin for the treatment of postherpetic neuralgia: results of a double-blind, randomized, placebo-controlled clinical trial. Clin J Pain. 2009;25:185–192.
     
19. Jensen MP, Chiang YK, Wu J. Assessment of pain quality in a clinical trial of gabapentin extended release for postherpetic neuralgia. Clin J Pain. 2009;25:286–292.
     
20. Wallace MS, Irving G, Cowles VE. Gabapentin extended-release tablets for the treatment of patients with postherpetic neuralgia: a randomized, double-blind, placebo-controlled, multicenter study. Clin Drug Investig. 2010;30:765–776.
     
21. Frampton JE, Foster RH. Pregabalin in the treatment of postherpetic neuralgia. Drugs. 2005;65:111–118.
     
22. Kochar D, Garg P, Bumb RA, et al. Divalproex sodium in the management of postherpetic neuralgia: a randomized double-blind placebo-controlled study. QJM. 2005;98:29–34.
     
23. Watson CP, Vernich L, Chipman M, Reed K. Nortriptyline vs amitriptyline in postherpetic neuralgia: a randomized trial. Neurology. 1998;51:1166–1171.
24. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007;132:237–251.
     
25.  Cymbalta (duloxetine hydrochloride) delayed-release capsules [package insert]. Indianapolis, IN: Lilly USA; 2011.
     
26. Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004;110:697–706.
     
27. Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology. 1998;50:1837–1841.
     
28. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352:1324–1334.
     
29. Boureau F, Legallicier P, Kabir-Ahmadi M. Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial. Pain. 2003;104:323–331.
     
30. Hermann DN, Barbano RL, Hart-Gouleau S, et al. An open-label study of the lidocaine patch 5% in painful idiopathic sensory polyneuropathy. Pain Med. 2005;379–384.
     
31. Davies PS, Galer BS. Review of lidocaine patch 5% studies in the treatment of postherpetic neuralgia. Drugs. 2004;64:937–947.
     
32. Gammaitoni AR, Alvarez NA, Galer BS. Safety and tolerability of the lidocaine patch 5%, a targeted peripheral analgesic: a review of literature. J Clin Pharmacol. 2003;43:111–117.
     
33. Watson CP, Tyler KL, Bickers DR, et al. A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia. Clin Ther. 1993;15:510–526.
     
34. Backonja MM, Malan TP, Vanhove GF, Tobias JK. C102/106 Study Group. NGX-4010, a high concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized, double-blind, controlled study with an open-label extension. Pain Med. 2010;11:600–608.
     
35. Kumar V, Krone K, Mathieu A. Neuraxial and sympathetic blocks in herpes zoster and postherpetic neuralgia: an appraisal of current evidence. Reg Anesth Pain Med. 2004;29:454–461.
     
36. Doi K, Nikai T, Sakura S, Saito Y. Intercostal nerve block with 5% tetracaine for chronic pain syndromes. J Clin Anesth. 2002;14:39–41.
     
37. Kotani N, Kushikata T, Hashimoto H, et al. Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med. 2000;343:1514–1519.
     
38. Harke H, Gretenkort P, Ladleif HU, et al. Spinal cord stimulation in postherpetic neuralgia and in acute herpes zoster pain. Anesth Anal. 2002;94:694–700.
     
39. Barnard D, Lloyd J, Evans J. Cryoanalgesia in the management of chronic facial pain. J Maxillofac Surg. 1981;9:101–102.
     
40. Jones MJ, Murrin KR. Intercostal block with cryotherapy. Ann R Coll Surg Engl. 1987;69:261–262.
     
41. Xiao L, Hui H. Therapeutic effect of botulinium toxin A in the treatment of postherpetic neuralgia by subcutaneous injection. Presented at: 26th Annual Meeting of the American Academy of Pain Medicine; February 3-6, 2010; San Antonio, TX.
     
42. Marin M, Güris D, Chaves SS, et al. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56(RR-4):1–40.
     
43. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-5):1–30.
     
44. Centers for Disease Control and Prevention (CDC). Update on herpes zoster vaccine: licensure for persons aged 50 through 59 years. MMWR Morb Mortal Wkly Rep. 2011;60(44):1528.
     
45. Gnann JW  Jr. Vaccination to prevent herpes zoster in older adults. J Pain. 2008;9(1 suppl 1):S31–S36.