Treatment of Postherpetic Neuralgia

Although postherpetic neuralgia is generally a self-limited condition, it can last indefinitely. Treatment is directed at pain control while waiting for the condition to resolve. Pain therapy may include multiple interventions, such as topical medications, over-the-counter analgesics, tricyclic antidepressants, anticonvulsants and a number of nonmedical modalities. Occasionally, narcotics may be required. Dosage recommendations are provided in Table 2. TABLE 2 Treatment Options for Postherpetic Neuralgia* Medication Dosage Topical agents Capsaicin cream Apply to affected area three to five times daily. (Zostrix) Lidocaine Apply to affected area every 4 to 12 hours as needed. (Xylocaine) patch

Tricyclic antidepressants Amitriptyline 10 to 25 mg orally at bedtime; increase dosage by 25 mg every 2 to 4 weeks (Elavil) until response is adequate, or to maximum dosage of 150 mg per day.

Nortriptyline (Pamelor)

10 to 25 mg orally at bedtime; increase dosage by 25 mg every 2 to 4 weeks until response is adequate, or to maximum dosage of 125 mg per day.

Imipramine (Tofranil)

25 mg orally at bedtime; increase dosage by 25 mg every 2 to 4 weeks until response is adequate, or to maximum dosage of 150 mg per day.

Desipramine (Norpramin)

25 mg orally at bedtime; increase dosage by 25 mg every 2 to 4 weeks until response is adequate, or to maximum dosage of 150 mg per day.

Anticonvulsants Phenytoin (Dilantin)

100 to 300 mg orally at bedtime; increase dosage until response is adequate or blood drug level is 10 to 20 g per mL (40 to 80 mol per L).

Carbamazepine (Tegretol)

100 mg orally at bedtime; increase dosage by 100 mg every 3 days until dosage is 200 mg three times daily, response is adequate or blood drug level is 6 to12 g per mL (25.4 to 50.8 mol per L).

Medication Gabapentin (Neurontin)

Dosage 100 to 300 mg orally at bedtime; increase dosage by 100 to 300 mg every 3 days until dosage is 300 to 900 mg three times daily or response is adequate. (Drug levels for clinical use are not available.)

*Additional modalities include transcutaneous electric nerve stimulation (TENS), biofeedback and nerve blocks. ANALGESICS Capsaicin, an extract from hot chili peppers, is currently the only drug labeled by the U.S. Food and Drug Administration for the treatment of postherpetic neuralgia.19 Trials have shown this drug to be more efficacious than placebo but not necessarily more so than other conventional treatments.20 Substance P, a neuropeptide released from pain fibers in response to trauma, is also released when capsaicin is applied to the skin, producing a burning sensation. Analgesia occurs when substance P is depleted from the nerve fibers. To achieve this response, capsaicin cream must be applied to the affected area three to five times daily. Patients must be counseled about the need to apply capsaicin regularly for continued benefit. They also need to be counseled that their pain will likely increase during the first few days to a week after capsaicin therapy is initiated. Patients should wash their hands thoroughly after applying capsaicin cream in order to prevent inadvertent contact with other areas. Patches containing lidocaine have also been used to treat postherpetic neuralgia. One study found that compared with no treatment, lidocaine patches reduced pain intensity, with minimal systemic absorption. Although lidocaine was efficacious in relieving pain, the effect was temporary, lasting only four to 12 hours with each application.21 Over-the-counter analgesics such as acetaminophen (e.g., Tylenol) and nonsteroidal antiinflammatory drugs have not been shown to be highly effective in the treatment of post-herpetic neuralgia. However, these agents are often useful for potentiating the pain-relieving effects of narcotics in patients with severe pain. Because of the addictive properties of narcotics, their chronic use is discouraged except in the rare patient who does not adequately respond to other modalities. TRICYCLIC ANTIDEPRESSANTS Tricyclic antidepressants can be effective adjuncts in reducing the neuropathic pain of postherpetic neuralgia. These agents most likely lessen pain by inhibiting the reuptake of serotonin and norepinephrine neurotransmitters.22 Tricyclic antidepressants commonly used in the treatment of postherpetic neuralgia include amitriptyline (Elavil), nortriptyline (Pamelor), imipramine (Tofranil) and desipramine (Norpramin). These drugs are best tolerated when they are started in a low dosage and given at bedtime. The dosage is increased every two to four weeks to achieve an effective dose.

The tricyclic antidepressants share common side effects, such as sedation, dry mouth, postural hypotension, blurred vision and urinary retention. Nortriptyline and amitriptyline appear to have equal efficacy; however, nortriptyline tends to produce fewer anticholinergic effects and is therefore better tolerated. Treatment with tricyclic antidepressants can occasionally lead to cardiac conduction abnormalities or liver toxicity. The potential for these problems should be considered in elderly patients and patients with cardiac or liver disease. Because tricyclic antidepressants do not act quickly, a clinical trial of at least three months is required to judge a patient's response. The onset of pain relief using tricyclic antidepressants may be enhanced by beginning treatment early in the course of herpes zoster infection in conjunction with antiviral medications.20 ANTICONVULSANTS Phenytoin (Dilantin), carbamazepine (Tegretol) and gabapentin (Neurontin) are often used to control neuropathic pain. A recent double-blind, placebo-controlled study showed gabapentin to be effective in treating the pain of postherpetic neuralgia, as well as the often associated sleep disturbance.23 The anticonvulsants appear to be equally effective, and drug selection often involves trial and error. Lack of response to one of these medications does not necessarily portend a poor response to another. The dosages required for analgesia are often lower than those used in the treatment of epilepsy. Anticonvulsants are associated with a variety of side effects, including sedation, memory disturbances, electrolyte abnormalities, liver toxicity and thrombocytopenia. Side effects may be reduced or eliminated by initiating treatment in a low dosage, which can then be slowly titrated upward. There are no specific contraindications to using anticonvulsants in combination with antidepressants or analgesics. However, the risk of side effects increases when multiple medications are used. Effective treatment of postherpetic neuralgia often requires multiple treatment approaches. In addition to medications, modalities to consider include transcutaneous electric nerve stimulation (TENS), biofeedback and nerve blocks.

Final Comment
Herpes zoster and postherpetic neuralgia are relatively common conditions, primarily in elderly and immunocompromised patients. Although the diagnosis of the conditions is generally straightforward, treatment can be frustrating for the patient and physician. Approaches to management include treatment of the herpes zoster infection and associated pain, prevention of postherpetic neuralgia, and control of the neuropathic pain until the condition resolves. Primary treatment modalities include antiviral agents, corticosteroids, tricyclic antidepressants and anticonvulsants.

The Authors

Management of Herpes Zoster (Shingles) and Postherpetic Neuralgia

SETH JOHN STANKUS, MAJ, MC, USA, MICHAEL DLUGOPOLSKI, MAJ, MC, USA, and DEBORAH PACKER, MAJ, MC, USA, Eisenhower Army Medical Center, Fort Gordon, Georgia Am Fam Physician. 2000 Apr 15;61(8):2437-2444. REFERENCES 19. Lee PJ, Annunziato P. Current management of herpes zoster. Infect Med. 1998;15:709 20. MacFarlane BV, Wright A, O'Callaghan J, Benson HA. Chronic neuropathic pain and its control by drugs. Pharmacol Ther. 1997;75:119. 21. Rowbotham MC, Davies PS, Verkempinck C, Galer BS. Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain. 1996;65:3944. 22. Ardid D, Guilbaud G. Antinociceptive effects of acute and chronic injections of tricyclic antidepressant drugs in a new model of mononeuropathy in rats. Pain. 1992;49:27987. 23. Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia. JAMA. 1998;280:183742.

Zoster
o

Acyclovir, a purine nucleoside analog, has been proved effective in both localized and disseminated zoster. Administered intravenously for acute zoster, it decreases the duration of pain and the healing time. In the immunocompromised patient, it can also prevent or abort dissemination. Side effects are rare but include a transient recurrence of pain on discontinuing therapy and impaired renal function following rapid infusion. Topical acyclovir (5% in polyethylene glycol applied q4h for 10 days) promotes healing of localized zoster in immunocompromised patients. However, it is ineffective in reducing pain and preventing postherpetic neuralgia. Oral acyclovir (800 mg q4h, five times daily for 7 to 10 days), if started within the first 24 to 48 hours, is capable of shortening the time to lesion crusting, healing, and cessation of pain, and reducing new lesion formation. Treatment within 72 hours at onset may halve the incidence of residual neuropathic pain at 6 months in immunocompetent patients (11).

o o

Acyclovir-resistant VZV infection has been reported in patients with AIDS; clinically, they have persistent, generalized hyperkeratotic papules. Two of the drugs listed below (Valtrex and Famvir) are more bioavailable prodrugs of Acyclovir and are therefore more effective. A comparison study between Valtrex and Famvir showed no difference in effectiveness (12). Valacyclovir (Valtrex) is the L-valyl ester and prodrug of acyclovir. It displays improved bioavailability and prolonged half-life compared with acyclovir (see Chap. 15, sec. V.A.1). The current recommended dose of valacyclovir is 1,000 mg by mouth three times a day for 7 days. Valacyclovir is superior in decreasing the duration or PHN and zoster-associated pain compared with acyclovir. Valacyclovir is as effective as famciclovir. The use of valacyclovir is contraindicated in immunocompromised patients. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome have occurred in patients with advanced HIV disease, renal transplant, or bone marrow transplant. Famciclovir (Famvir), another purine nucleoside analogue, was approved for use in herpes zoster in 1994. It displays improved availability compared with acyclovir and valacyclovir (see Chap 15, sec. V.A.2.). The dose is 500 mg three times a day for 7 days; the cost is similar to that of acyclovir. Famciclovir was effective in reducing PHN in individuals older than 50 years old when compared with placebo. Valacyclovir and famciclovir appear to be equally efficacious for the treatment of herpes zoster and both may be superior to acyclovir in decreasing the duration of acute pain as well as PHN. This suggests that both cost and prescription plan availability should be taken into consideration when selecting between the two newer antiviral agents. Foscarnet is a pyrophosphate antagonist that inhibits DNA polymerase. It is approved for use in the treatment of acyclovir-resistant herpes zoster infections. It is administered intravenously, 40 mg/kg every 8 to 12 hours within 7 to 10 days in patients suspected of having acyclovir-resistant herpes zoster infection. Foscarnet is administered for 10 days. The associated side effects include azotemia secondary to nephrotoxicity, hyperphosphatemia, hypocalcemia, anemia, nausea, vomiting, and genital ulceration. Analgesics should be given as necessary. Opiates may be needed. For the vesicular stages, one of the following may be effective: Application of cool compresses with 1:20 Burow's solution. Painting of lesions with equal parts of tincture of benzoin and flexible collodion or with flexible collodion q12h. Application of a drying lotion containing alcohol, menthol, and/or phenol. Splinting the area with an occlusive dressing is often very useful in relieving pain. Lesions should be covered with cotton and then wrapped with an elastic bandage as for a fractured rib. When lesions are crusted and/or secondarily infected, Burow's solution compresses should be applied (see Chap. 40, Wet Dressings, Baths, Astringents, sec. I.B.1) and systemic antibiotics used if appropriate. Ocular involvement should be evaluated by an ophthalmologist. Herpes zoster keratoconjunctivitis is treated with topical ophthalmic corticosteroids. The

distinction from herpes simplex keratitis is crucial, because the treatment is quite different (see Chap. 15, sec. V.C). When herpes zoster occurs along the facial nerve and involves the geniculate ganglionit may be accompanied by symptoms such as hearing loss and a rapid onset of facial painone must consider the diagnosis of herpes zoster oticus, also called Ramsay Hunt Syndrome. On physical examination, there may be a unilateral herpetic rash of the pinna and peripheral facial paralysis. Patients may also experience a loss of taste and vertigo. Systemic corticosteroids are thought to decrease the incidence of PHN presumably by inhibiting perineural inflammation and fibrosis in patients older than 50 years of age. The effectiveness of this treatment remains unclear. Several regimens have been proposed, all advocating that treatment is started early (within 5 to 7 days of the eruption), adequate doses are used (40- to 60-mg prednisone PO daily or its equivalent), and treatment be continued for 3 to 4 weeks in a tapering fashion. Acyclovir with prednisone has been shown to be at least as effective as acyclovir alone in reducing the time to healing of the acute eruption (13). While the additional benefit of adding systemic corticosteroids is not significant, the doses used do not increase the risk of dissemination. Corticosteroids decrease the severity of edema and pain and are very useful in patients with severe facial swelling either with or without ocular involvement. The riskbenefit ratio must be determined for each patient. Two larger studies reported that the addition of oral steroids to an antiviral course showed no protective effect against PHN (13,14). Intralesional injections of corticosteroids and/or anesthetics into the affected dermatome may be useful in decreasing the pain of acute zoster. Intralesional corticosteroids also might reduce the incidence of PHN in a fashion similar to their systemic usage. Use of the treatment techniques for injecting the involved skin is an innovative and useful approach (15). Therapy with levodopa and benserazide (a peripheral decarboxylase inhibitor) has been reported to ameliorate the pain of acute zoster and, in elderly patients or those with ophthalmic zoster, to promote healing. Its effect on PHN is unclear. Emetine or its derivative, dehydroemetine, with or without systemic corticosteroids, has also been reported to decrease the pain of acute zoster. Given their cardiotoxic side effects, these agents should be used with caution. The use of a live attenuated vaccine (Oka/Merck) in older adults to prevent herpes zoster and PHN was recently reported in the New England Journal of Medicine. Previous studies show that VZV vaccines can significantly increase a person's cell-mediated immunity to VZV in immunocompetent older adults (16). In the subpopulation of hematopoietic-cell transplant recipients, the VZV vaccine reduced the incidence and severity of herpes zoster (17). Oxman et al. showed that the burden of illness, defined as the incidence, severity, and duration of the associated pain and discomfort, was reduced by 61.1% (p <0.001) and the incidence of PHN was decreased by 66.5% (p <0.001). The incidence of herpes zoster was reduced by 51.3% (p <0.001). In conclusion, the zoster vaccine markedly reduced morbidity from herpes zoster and PHN among older adults (18).

PHN is defined as pain persisting longer than 1 month up to at least 120 days following resolution of the vesicles. When the pain starts within 120 days of the rash, it is defined as subacute herpetic neuralgia. With acute infection there is direct viral damage and inflammatory neuritis of the peripheral nerve fibers, dorsal route ganglia, and the spinal cord. When the inflammatory phase decreases, fibrosis and destruction on nerve tissue begins and affects all levels of the pain pathway (19). PHN occurs in 9% to 14% of patients. Its incidence and severity are directly related to age. The incidence in patients between ages 30 and 50 is 4%, in contrast to 50% in patients over the age of 80. The pain improves from severe to mild in two thirds of cases. Preexisting postherpetic pain is extremely difficult to alleviate, in testimony to which multiple approaches have been suggested. The most important strategy is prevention. Evidence supports the use of low doses of tricyclic antidepressants and phenothiazines. Local physical modalities can be helpful, and neurosurgical procedures remain an option in failed medical cases. Pain clinics can be very helpful in the long-term management of these patients. Researchers in the United Kingdom reported that after 3 months, 15% of patients still had pain and at 1 year roughly 5% to 10% still reported pain. Spontaneous resolution after 1 year is limited (20).
o

Application of capsaicin cream 0.025% or 0.075% (Zostrix) t.i.d. to q.i.d. may cause complete pain relief in 25% and reduction of pain in as many as 80% of patients with PHN. Capsaicin is a derivative of hot chilli peppers and depletes and prevents reaccumulation of the chemomediator substance P in peripheral sensory resources. The use of a combination of a tricyclic antidepressant and a substituted phenothiazine medication may lead to relief of pain within 1 to 2 weeks after institution of therapy. Amitriptyline (Elavil) 75 to 100 mg daily should be used in combination with either perphenazine (Trilafon) 4-mg t.i.d. to q.i.d., fluphenazine hydrochloride (Permitil) 1 mg t.i.d. to q.i.d., or thioridazine (Mellaril) 25 mg q.i.d. Nortriptyline (Aventyl, Pamelor) may be substituted for amitriptyline, with the former being as effective but associated with fewer unpleasant side effects (21). It may be necessary to continue medication for months. Chlorprothixene (Taractan) has been reported twice to be effective in the treatment of PHN. For severe pain, an initial 50 to 100 mg IM injection has been advocated. Otherwise, the dosage is 25 to 50 mg PO q6h. The recommended duration of therapy is 4 to 10 days. Higher doses are unwarranted and frequently result in side effects. Gabapentin (Neurontin) significantly decreases pain scores and sleep interference associated with PHN. An initial dose of 300 mg/day is increased over 4 weeks (900, 1,800, 2,400, 3,600 mg/day divided t.i.d.) until efficacy is obtained or side effects become intolerable. Dose-limiting adverse effects include somnolence, dizziness, ataxia, peripheral edema, and infection (22). Beneficial results have been reported with the combined use of either carbamazepine (Tegretol) 600 to 800 mg/day or phenytoin sodium (Dilantin) 300 to 400 mg/day with 50 to 100-mg nortriptyline (Aventyl, Pamelor) and with the combined use of carbamazepine (Tegretol) up to 1,000 mg/day and clomipramine up to 75 mg/day.

o o

o o o o o

Opioids are effective in controlling neuropathic pain; therefore, oxycodone may provide some relief from PHN. In one study, patients treated with oxycodone experienced greater pain relief (p <0.0001) and reduced allodynia (p <0.0004) as compared with the placebo group. The initial dose was oxycodone 10 mg every 12 hours and was increased over 4 weeks to a maximum of 30 mg every 12 hours. Across the oxycodone group, the average dose was 45 mg/day (23). Daily intralesional or subcutaneous injection of triamcinolone 0.2 mg/mL into the affected dermatome achieves pain relief in some patients with acute herpes zoster and in many patients with postzoster neuralgia. Up to 30 mL of the drug diluted in saline can be administered at each session. Injection by tumescent technique may be particularly helpful. Some authors report that when combined with local anesthetic and given over days or weeks the duration of pain is reduced (24). Topical EMLA cream applied for a 24-hour period of time significantly decreased pain scores in PHN. Lidocaine (5%) adhesive patch (Lidoderm) significantly reduces pain intensity. Several of the 10 14 cm patches can be used simultaneously to cover the affected area. Minimal systemic absorption of lidocaine occurs (25). Repeated cryosurgery to limited areas affected by PHN has been reported to reduce the sensitivity of trigger areas and produce long-term relief from pain. Transcutaneous electrical stimulation has brought pain relief to a high percentage of patients. Neurosurgical intervention is occasionally necessary in patients with intractable pain. Pain clinics at major medical centers can be helpful in evaluating and treating these patients. They often employ the use of nerve blocks (26). Intrathecal methylprednisolone has been reported to relieve pain and allodynia. Potential toxicities include arachnoiditis or other neurotoxic event. This treatment may be most appropriately administered by a pain clinic or neurologist (27).

19. Johnson RW. Herpes zoster in the immunocompetent patient: management of postherpetic neuralgia. Herpes 2003;10:3845. 20. Bowsher D. The lifetime occurrence of herpes zoster and prevalence of postherpetic neuralgia: a retrospective survey in an elderly population. Eur J Pain 1999;3:335342. 21. Watson CP. A new treatment for postherpetic neuralgia. N Engl J Med 2000;343:15631565. 22. Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998;280:18371842. 23. Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 1998;50:18371841. 24. Pasqualucci A, Pasqualucci V, Galla F, et al. Prevention of post-herpetic neuralgia: acyclovir and prednisolone versus epidural local anaesthetic and methylprednisolone. Acta Anaesthesiol Scand 2000;44:910918.

25. Rowbotham MC, Davies PS, Verkempinck C, et al. Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain 1996;65:3944. 26. Wu CL, Marsh A, Dworkin RH. The role of sympathetic nerve blocks in herpes zoster and postherpetic neuralgia. Pain 2000;87:121129. 27. Kotani N, Kushikata T, Hashimoto H, et al. Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med 2000;343:15141519.

ROOKs

Post-herpetic neuralgia [28]. The commonest and most intractable sequel of zoster is postherpetic neuralgia, generally defined as persistence or recurrence of pain more than a month after the onset of zoster, but better considered after 3 months. It is unusual in childhood and increases in incidence and severity with age. It occurs in about 30% of patients over 40 years of age and is most frequent when the trigeminal nerve is involved. It is more likely to develop if there was dermatomal pain prior to the eruption, if the acute pain of zoster was severe and if the zoster rash was prolonged. The pain has two main forms, a continuous burning pain with hyperaesthesia and a spasmodic shooting type, although a pruritic crawling paraesthesia may also occur. Allodynia, pain caused by normally innocuous stimuli, is often the most distressing symptom and occurs in 90% of people with post-herpetic neuralgia. The neuralgia varies in intensity from inconvenient to profoundly disabling.