Abstract
Postherpetic neuralgia is defined as neuropathic pain persisting for greater than 3 months along dermatomes affected by herpes zoster infection or shingles, despite resolution of the herpes zoster rash. It is the most common complication of shingles caused by the varicella-zoster virus, and occurs in 20% to 35% of patients. Positive predictors of this complication include older age, greater acute pain severity, higher percentage of dermatome affected by the herpes zoster rash, and higher pain interference with physical or social functioning. Prevention with the zoster vaccine is the most effective treatment and is recommended for people over the age of 60. Administration of antivirals within 72 hours of symptoms’ onset from varicella-zoster reactivation is also effective for preventing shingles complications. First-line pharmaceutical treatments for postherpetic neuralgia include oral anticonvulsants, antidepressants, and opioid analgesics. Second-line treatments include topical lidocaine and capsaicin. Third-line treatments include subcutaneous botulinum toxin, nerve blocks, and epidural steroids. Rehabilitation including desensitization, electrical stimulation, and physical exercise can help reduce pain and maintain function. Combination therapy provides superior pain management.
Definition
Postherpetic neuralgia is the most common complication of herpes zoster infection or shingles caused by the varicella- zoster virus. The varicella-zoster virus is a lipid-enveloped, double-stranded DNA alphaherpesvirus that expresses its genes sequentially, leading to expression of nonstructural proteins, nonstructural protein enzymes, and late structural proteins. Late structural proteins encapsulate the DNA core, infect host cells, and replicate in host cell nuclei.
Acute varicella-zoster, or chicken pox, occurs with the primary infection by the virus and is very common in children. The classical rash may be preceded by fever and malaise. Evolution of the rash begins as morbilliform erythema that progresses into widespread vesicles or pustules that crust within 2 to 4 days. The virus is highly contagious and is transmitted through droplets or direct contact with the vesicle fluid, which contain large amounts of virus. In children, chicken pox is usually self-limiting.
Herpes zoster, or shingles, is the reactivation of latent varicella-zoster virus. After acute herpes zoster infection, the virus remains dormant in the spinal dorsal root ganglia and cranial sensory ganglia. Reactivation often follows a decline in cell-mediated immunity due to stress, illness, medications, aging, or other idiopathic causes. With reactivation, the virus replicates within the ganglia and subsequently spreads along the peripheral nerves to the skin. This results in a painful erythematous rash along the affected dermatomes. On rare occasions, the spread of the inflammation into the anterior horn may result in paresis. Multiple dermatomal involvement may occur in immunocompromised patients, indicating potentially life-threatening dissemination of the infection. It is a painful condition with a highly age-related incidence, with the rate of herpes zoster more than tripling in individuals over the age of 50. It affects men and women equally, and generally resolves within a few weeks.
Postherpetic neuralgia is conventionally described as neuropathic pain persisting for 3 months in the affected dermatomes despite resolution of the herpes zoster rash. Postherpetic neuralgia occurs in approximately 20% to 35% of patients following acute herpes zoster. The likelihood for development of postherpetic neuralgia increases with older age, greater acute pain severity, higher percentage of dermatome affected by the herpes zoster rash, and higher pain interference with physical or social functioning. The mechanism of postherpetic neuralgias likely stems from underlying nerve damage from the varicella-zoster virus, which has been found to induce neuroinflammation and damage to the ganglia and spinal cord. Postherpetic neuralgia has been associated with greater nerve damage with reduction of superficial sensory nerve action potentials and lower subepidermal nerve densities following herpes zoster. One study found elevated levels of inflammatory factors with corresponding decreased levels of nerve growth factor and brain-derived neurotrophic factors within the cerebrospinal fluid of patients with postherpetic neuralgia. These findings were independent of age and medical history. Proposed mechanisms for the neuropathic pain associated with postherpetic neuralgia include: increased ectopic firing of nociceptors resulting from damaged nerve endings; loss of inhibitory neurons to interrupt central signaling; pain amplification from central sensitization; and persistent peripheral stimulation due to elevated inflammatory factors altering chemistry within the cutaneous environment. In one study, significant pain of greater than 6 on the visual analog scale at 6 months following acute herpes zoster infection was a poor prognostic indicator, with high probability of persistent chronic postherpetic neuralgia with pain continuing for months to years.
Symptoms
Prodromal symptoms may precede varicella-zoster reactivation by a few days up to 1 week. These include low-grade fever and malaise with hyperesthesia, dysesthesia, paresthesia, or pruritus along the distribution of affected dermatomes.
Fulminant shingles is marked by the emergence of erythematous macules accompanied by severe burning, stinging pain in a single sensory or cranial nerve distribution. This is followed by the eruption of fluid-filled papules, clusters, and vesicles. New skin eruptions generally continue to appear for 3 to 5 days. Thoracic dermatomes are most frequently affected. During this period, prodromal low-grade fever and malaise may continue to persist, and lymphadenopathy may also be present.
Zoster affecting exposed areas may result in sun or wind sensitivity. Sensitivity to light touch, intolerance to wearing of clothes over the erupted area, and brief jolts of shooting pain are also common.
Of the cranial nerves, the ophthalmic branch of the trigeminal nerve is the most often affected. If there is ophthalmic involvement, photophobia may be present. This is known as herpes zoster ophthalmicus and can result in monocular blindness. It has an incidence of 1% in the general population.
In very rare cases, zoster of the geniculate ganglion occurs, affecting the seventh and eighth cranial nerves. Symptoms include otalgia, vertigo, tinnitus, ataxia, loss of hearing, loss of taste, and even ipsilateral facial paralysis. This is known as Ramsay Hunt syndrome (herpes zoster oticus).
In most cases, symptoms tend to resolve shortly after healing of the rash. However, neuralgia may persist after resolution of the rash in around 20% of patients at 3 months and 15% at 2 years. Pain sensation associated with postherpetic neuralgia may be variable, including: constant deep, aching, or burning pain; paroxysmal, lancinating pain; hyperalgesia; and allodynia.
Physical Examination
In shingles, typical skin eruptions follow a dermatomal distribution, appearing as raised, fluid-filled vesicles. Once the vesicles burst and release fluid that contains live virus, they crust. Once the vesicles have crusted, the patient is no longer infectious. Lesions are often exquisitely tender to light touch. If deeper dermal involvement is present, scarring and discoloration may be seen.
Ophthalmic zoster is usually accompanied by a rash in the dermatomal distribution of the nasociliary nerve, along the side of the nose (Hutchinson sign). Periorbital edema, petechial hemorrhages, conjunctivitis, scleritis, and corneal sensitivity are also commonly associated with ophthalmic zoster. Hutchinson sign and an unexplained red eye are indications for ophthalmologic consultation.
Ramsay Hunt syndrome is manifested as a rash on the auricle and external ear accompanied by exquisite otalgia, vestibulocochlear dysfunction, and facial nerve palsy. Any suspicion for Ramsay Hunt syndrome should lead to an urgent otolaryngology consultation.
With postherpetic neuralgia, there are no visible skin abnormalities on inspection. However, the patient may describe allodynia or hyperalgesia.
The Zoster Brief Pain Inventory is a validated and convenient tool for the assessment of acute herpes zoster and postherpetic neuralgia.
Functional Limitations
Postherpetic neuralgia significantly reduces overall quality of life. Functional limitations due to herpes zoster include difficulty with activities involving pressure or heat exposure to the affected area. If the facial divisions of the trigeminal nerve or areas by the ear are affected, individuals may not tolerate wearing of protective headgear or facemasks and facial exposure to sun or wind. If the thoracic dermatomes are affected, clothing or even touching of the back against an office chair may increase pain. Both sexual activities and contact sports may be intolerable. Difficulty in sleeping may arise from discomfort from sheets touching the skin. Bathing and toweling often exacerbate pain along the affected dermatome.
If the optic nerve or the ophthalmic branch to the trigeminal nerve is affected by shingles, monocular low vision may result in impaired depth perception and decreased field of view. If the patient has herpes zoster oticus, hearing, balance, tasting, and facial muscle movements are impaired. Thus, driving may be affected by zoster involvement of the trigeminal nerve or the geniculate ganglion.
Diagnostic Studies
Postherpetic neuralgia is usually easy to diagnose on the basis of a recent history of herpes zoster infection and physical examination. In general, laboratory tests for diagnosis of reactivation of herpes zoster virus are not clinically useful. For atypical cases, the Centers for Disease Control and Prevention guidelines suggest direct fluorescent antibody testing for rapid diagnosis. To obtain a specimen, apply a sterile cotton swab to the base of an open lesion or, less preferably, a lesion crust.
Complex regional pain syndrome
Contact dermatitis
Drug-related allergic infection
Eczema
Other herpetic neuralgias
Nonherpetic viral infection
Radiculitis
Tertiary syphilis
Treatment
Initial
Prevention is important in this condition. Varicella vaccination in childhood is primary prevention for chickenpox. The Centers for Disease Control and Prevention and the Advisory Committee on Immunization Practices recommends administration of the zoster vaccine for people 60 years of age or older to prevent herpes zoster reactivation as shingles. A randomized controlled phase-3 trial of a herpes zoster subunit vaccine found 90% effectiveness in reducing the incidence of herpes zoster in adults over the age of 70. Reduction in herpes zoster carries over to a reduction in incidence of postherpetic neuralgia in the vaccinated population; however, the rate of postherpetic neuralgia among those who develop herpes zoster has not been shown to be reduced by the vaccine. Contraindications of the zoster vaccine include: previous hypersensitivity to components of the vaccine; primary or secondary immunodeficiency; immunosuppression in human immunodeficiency virus/acquired immunodeficiency syndrome; cellular immunity deficiency; use of immunosuppressive therapies; active untreated tuberculosis; and pregnancy.
If given within 72 hours of symptom onset, antiviral medication with oral acyclovir, valacyclovir, or famciclovir has been shown to reduce acute zoster pain and shorten rash duration, with subsequently lower risk of developing postherpetic neuralgia.
Nerve blocks, including paravertebral injection of bupivacaine and methylprednisolone and continuous or repeated epidural blocks, may help reduce the duration of herpes zoster-related pain and the incidence of postherpetic neuralgia. A randomized study of 132 herpes zoster patients compared standard therapy of oral antivirals and analgesics or standard therapy with adjuvant paravertebral injections. The incidence of postherpetic neuralgia was 2% in the intervention group compared with 16% with standard treatment.
Topical therapies that are approved by the US Food and Drug Administration (FDA) for postherpetic neuralgia include lidocaine and capsaicin. Lidocaine is available both as a 5% patch and in a gel cream form. Studies have shown significant improvements in pain, allodynia, quality of life, and sleep measures with lidocaine patch compared with placebo, with good safely profile even in elderly patients.
Topical capsaicin in the form of patches or gels are safe and efficacious for pain reduction in postherpetic neuralgia patients. Capsaicin is an extract of hot chili peppers that works as an agonist of the vanilloid receptor TRPV1, which is upregulated in the nociceptive nerve terminals in the skin of these patients. The agonist effect may result in a transient increase in pain; however, prolonged exposure results in desensitization of the sensory neurons and subsequent inhibition of pain transmission. Low-dose capsaicin (0.025% to 0.075%) patches require continuous application multiple times throughout the day. This frequency may affect compliance. High-dose capsaicin (8%) patches require application by trained personnel. They are applied for a single 60- to 90-minute application on the most painful area with intact skin and may be re-administered every 90 days if pain returns or persists. Topical capsaicin treatment may be a preferred initial treatment due to the low systemic toxicity and lack of drug interactions. However, it is typically considered a second-line treatment in clinical practice. Adverse effects of topical capsaicin include: self-limiting application-site burning, pain, erythema, pruritus, papules, swelling, dryness, and hypertension.
Other topical treatments that have been studied include topical aspirin, indomethacin, and diclofenac. These have not been well studied and are not widely used in clinical practice.
Oral medications effective in treating postherpetic neuralgia include antiepileptic drugs, antidepressants, and opioid analgesics. The anticonvulsants gabapentin and pregabalin are approved by the FDA for treatment of postherpetic neuralgia. Both gabapentin and pregabalin are calcium channel ligands. Gabapentin can provide statistically significant improvement in daily pain rating, sleep, mood, and quality of life for patients with postherpetic neuralgia. Pregabalin acts like gabapentin and is similarly useful in postherpetic neuralgia. Gabapentin extended-release formulations produced significant pain relief but were associated with increased adverse events with increasing dosages, including dizziness, somnolence, and peripheral edema. Gabapentin enacarbil was found to be more effective and safe for postherpetic neuralgia without significant side effects.
Whereas amitriptyline has been most studied, secondary amine tricyclics such as nortriptyline are usually preferred because of the side effect profile. However, they are not recommended as first-line treatment, as there is greater evidence to support the use of duloxetine and pregabalin for neuropathic pain.
Use of opioids and opioid-like analgesics including tramadol, oxycodone, morphine, and methadone can also reduce severe pain in postherpetic neuralgia. Use of opioids and opioid-like analgesics requires caution and close monitoring for side effects and medication abuse.
Melatonin has been proposed for analgesic effects for postherpetic neuralgia with effects mediated by increased expression of delta-opiod and melatonin receptors in the central nervous system. A rat study demonstrated dose-dependent increase in heat pain latency following administration.
Plerixafor, a bone marrow stimulant currently used in non-Hodgkin lymphoma and multiple myeloma, has also been proposed for the treatment of intractable postherpetic neuralgia, as stem cell therapy has been shown to aid neuronal repair in animal models.
There are several guidelines for treatment of postherpetic neuralgia, with slight variations in recommended protocols. Most would consider topical lidocaine, tricyclic antidepressants, and gabapentin or pregabalin first-line agents. Topical capsaicin, tramadol, and opioid analgesics are second- or third-line therapies. Combination therapy may provide superior pain management while minimizing medication side effects.
Rehabilitation
Physical therapy is important as part of a multimodal therapy approach for the management of postherpetic neuralgia. Chronic neuropathic pain can lead to persistent guarding and fear-avoidance behaviors, resulting in a decline of physical and social functioning. Active exercise training can help improve perceived physical function.
Desensitizing treatments, such as alternating exposure to heat and cold, vibration, and repeated light tapping of the affected area, may be helpful but are not well studied.
In cases of ophthalmic involvement, occupational therapists can instruct in scanning techniques for low vision and decreased peripheral vision. If the geniculate ganglion is affected, occupational therapists may work on techniques for hearing impairment or vestibulocochlear dysfunction. Occupational therapists can also assist with fall risk reduction, such as by removal of loose rugs, improvement in lighting, and decrease of clutter in the home and work environment.
Other practical measures to improve function include rearrangement of workstations to reduce contact of sensitive areas with seat backs and armrests, use of low-friction fabrics such as silk, use of a hand-held showerhead to direct water flow away from painful dermatomes, and modification of sexual positions.
Transcutaneous electrical nerve stimulation (TENS) is a widely used nonpharmacologic treatment thought to reduce nociception from small delta fibers and nonmyelinated fibers by stimulating larger, myelinated afferent nerve fibers, although its exact mechanism of action is still not well understood. A randomized clinical trial found the combination of TENS with cobalamin injections to have significant improvements in pain reduction, similar to the combination of cobalamin and lidocaine injections. Although there is theoretical support for TENS as a treatment for neuropathic pain and it has been recently studied in combination with other drugs, there is a need for studies comparing TENS alone against placebo in patients with postherpetic neuralgia. Although there is no consensus about voltage, pulse duration, or pulse frequency, TENS is thought to be most effective when applied at the maximum setting that is not uncomfortable.
Procedures
Subcutaneous botulinum toxin A injection has been successful in relieving pain, improving sleep, and reducing opioid use in trigeminal neuralgia and postherpetic neuralgia that is minimally responsive or refractory to conventional medical management.
Sympathetic nerve blocks may be considered in the management of postherpetic neuralgia as part of a multimodal treatment approach. A retrospective study showed pain reduction rates similar to the use of 5% lidocaine plasters. However, there were significantly more pain-free patients in the sympathetic nerve block group.
Epidural injection of steroids may provide modest, short-term pain relief in postherpetic neuralgia. In a randomized, controlled trial of 598 patients receiving standard oral antiviral and analgesic therapy with and without epidural steroid injection, the injection of bupivacaine and methylprednisolone was found to have a modest effect in reducing the pain of postherpetic neuralgia for 1 month but did not prevent long-term postherpetic neuralgia.
Intrathecal administration of methylprednisolone and lidocaine has led to a significant decrease in pain intensity and area in a randomized trial of 277 patients with intractable postherpetic neuralgia. Patients in the intrathecal steroid group also had decreased nonsteroidal anti-inflammatory drug use.
Other interventions, such as greater occipital nerve block, deep cervical nerve blocks, stellate ganglion blocks, and Jaipur block with subcutaneous lidocaine, bupivacaine, and methylprednisolone, have occasionally improved symptoms in case reports and observational studies. The effects of cryotherapy, percutaneous nerve stimulation, and radiofrequency have not been well established. Spinal cord stimulation may be of benefit in medically complicated patients with multiple drug sensitivities, polypharmacy, and serious comorbid conditions. Although these interventions have not been adequately studied, they may have some efficacy in treatment of recalcitrant postherpetic neuralgia symptoms. One randomized controlled trial demonstrated elevation of brain-derived neurotrophic factor following pulsed radiofrequency combined with pregabalin compared with pregabalin alone. This was associated with early pain reduction.
Technology
There is no specific technology for the treatment or rehabilitation of this condition.
Surgery
Surgery is generally not indicated for postherpetic neuralgia.
Peripheral field stimulation for truncal and ophthalmic postherpetic neuralgia has been used with varying degrees of success. This procedure requires the surgical implantation of percutaneous electrodes in the subcutaneous plane, attached to a pulse generator. The exact mechanism is unknown, with proposed theories including: alteration of local blood flow; inhibition of cellular depolarization and nerve conduction; and stimulation of endogenous endorphin release. A small retrospective review reported an average of 75% persistent reduction in pain scores with long-term follow-up in patients who were refractory to other treatments.
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