Postherpetic neuralgia

Postherpetic neuralgia
Classification and external resources
Specialty	neurology
ICD-10	B02.2, G53.0, G44.847 Mm
ICD-9-CM	053.19
MedlinePlus	007423
eMedicine	neuro/317
Patient UK	Postherpetic neuralgia

Postherpetic neuralgia is a nerve pain due to damage caused by the varicella zoster virus. Typically, the neuralgia is confined to a dermatomic area of the skin, and follows an outbreak of herpes zoster (commonly known as shingles) in that same dermatomic area. The neuralgia typically begins when the herpes zoster vesicles have crusted over and begun to heal, but can begin in the absence of herpes zoster—a condition called zoster sine herpete (see Herpes zoster).

Treatment options for postherpetic neuralgia include antidepressants, anticonvulsants (such as gabapentin, pregabalin, or topiramate), gabapentin enacarbil (a prodrug of gabapentin) and topical agents such as lidocaine patches or capsaicin lotion. Opioid analgesics may also be appropriate in many situations. There are some sporadically successful experimental treatments, such as rhizotomy (severing or damaging the affected nerve to relieve pain) and TENS (a type of electrical pulse therapy).

Signs and symptoms

Symptoms:

• With resolution of the herpes zoster eruption, pain that continues for three months or more is defined as postherpetic neuralgia.
• Pain is variable, from discomfort to very severe, and may be described as burning, stabbing, or gnawing.

Signs:

• Area of previous herpes zoster may show evidence of cutaneous scarring.
• Sensation may be altered over the areas involved, in the form of either hypersensitivity or decreased sensation.
• In rare cases, the patient might also experience muscle weakness, tremor, or paralysis if the nerves involved also control muscle movement.

Pathophysiology

Postherpetic neuralgia is thought to be due to nerve damage caused by herpes zoster. The damage causes nerves in the affected dermatomic area of the skin to send abnormal electrical signals to the brain. These signals may convey excruciating pain, and may persist or recur for months, years, or for life.^[1]

A key factor in the neural plasticity underlying neuropathic pain is altered gene expression in sensory dorsal root ganglia neurons. Injury to sensory nerves induces neurochemical, physiological and anatomical modifications to afferent and central neurons, such as afferent terminal sprouting and inhibitory interneuron loss.^[1] Following nerve damage, NaCl channel accumulation causes hyperexcitability, and downregulation of the TTX-resistant Nav1.8 (sensory neuron specific, SNS1) channel and upregulation of TTX-sensitive Nav1.3 (brain type III) and TRPV1 channels. These changes contribute to increased NMDA glutamate receptor-dependent excitability of spinal dorsal horn neurons and are restricted to the ipsilateral (injured) side. A combination of these factors could contribute to the neuropathic pain state of postherpetic neuralgia.

Frequency

In the United States each year approximately 1,000,000 individuals develop herpes zoster.^[2] Of those individuals approximately 10-18% develop postherpetic neuralgia.^[3]

Less than 10 percent of people younger than 60 develop postherpetic neuralgia after a bout of herpes zoster, while about 40 percent of people older than 60 do.

Predisposing factors

• Race: It may influence susceptibility to herpes zoster. African Americans are one fourth as likely as Caucasians to develop this condition.
• Often an older, debilitated or immune compromised population.

Diagnosis

Lab Studies:

• No laboratory work is usually necessary.
• Results of cerebrospinal fluid evaluation are abnormal in 61%.
  • Pleocytosis is observed in 46%, elevated protein in 26%, and VZV DNA in 22%.
• These findings are not predictive of the clinical course of postherpetic neuralgia.
• Viral culture or immunofluorescence staining may be used to differentiate herpes simplex from herpes zoster in cases that are difficult to distinguish clinically.
• Antibodies to herpes zoster can be measured. A 4-fold increase has been used to support the diagnosis of subclinical herpes zoster (zoster sine herpete). However, a rising titer secondary to viral exposure rather than reactivation cannot be ruled out.

Imaging studies:

• Magnetic resonance imaging lesions attributable to herpes zoster were seen in the brain stem and cervical cord in 56% (9/16) of patients.
• At three months after onset of herpes zoster, 56% (5/9) of patients with an abnormal magnetic resonance image had developed postherpetic neuralgia.
• Of the seven patients who had no herpes-zoster-related lesions on the magnetic resonance image, none had residual pain.

Treatment

Treatment for postherpetic neuralgia depends on the type and characteristics of pain experienced by the patient. Pain control is essential to quality patient care; it ensures patient comfort. Possible options include:

• Antiviral agents, such as famciclovir, are given at the onset of attacks of herpes zoster to shorten the clinical course and to help prevent complications such as postherpetic neuralgia. However, they have no role to play following the acute attack once postherpetic neuralgia has become established.
• Analgesics
  • Locally applied topical agents
    • Aspirin mixed into an appropriate solvent such as diethyl ether may reduce pain.^[4]
    • Lidocaine skin patches. These are small, bandage-like patches that contain the topical, pain-relieving medication lidocaine. The patches, available by prescription, must be applied directly to painful skin and deliver relief for four to 12 hours. Patches containing lidocaine can also be used on the face, taking care to avoid mucus membranes e.g., the eyes, nose and mouth.
  • Systemically delivered
    • Non-opiates such as paracetamol or the non-steroidal anti-inflammatory drugs.
    • Opioids provide more potent pain control and the weaker members such as codeine may be available over the counter in combination with paracetamol (co-codamol). Other opioids are prescription-only and include higher dosages of codeine, tramadol, morphine or fentanyl. Most opioids have sedating properties, which are beneficial for patients who experience pain.
• Pain modification therapy
  • Antidepressants. These drugs affect key brain chemicals, including serotonin and norepinephrine, that play a role in both depression and how the body interprets pain. Doctors typically prescribe antidepressants for postherpetic neuralgia in smaller doses than they do for depression. Low dosages of tricyclic antidepressants, including amitriptyline, seem to work best for deep, aching pain. They do not eliminate the pain, but they may make it easier to tolerate. Other prescription antidepressants (e.g., venlafaxine, bupropion and selective serotonin reuptake inhibitors) may be off-label used in postherpetic neuralgia and generally prove less effective, although they may be better tolerated than the tricyclics.
  • Anticonvulsants. These agents are used to manage severe muscle spasms and provide sedation in neuralgia. They have central effects on pain modulation. Medications such as phenytoin (Dilantin, Phenytek), used to treat seizures, also can lessen the pain associated with postherpetic neuralgia. The medications stabilize abnormal electrical activity in the nervous system caused by injured nerves. Doctors often prescribe another anticonvulsant called carbamazepine (Carbatrol, Tegretol) for sharp, jabbing pain. Newer anticonvulsants, such as gabapentin (Neurontin) and lamotrigine (Lamictal), are generally tolerated better and can help control burning and pain.
  • gabapentin enacarbil (HORIZANT), an alpha-2-delta-1 ligand and a prodrug of gabapentin, was approved by the FDA in 2012 for the management of postherpetic neuralgia.
• Corticosteroids are commonly prescribed but a Cochrane Review found moderate evidence of no benefit.^[5]
• Other non-pharmacological treatments for postherpetic neuralgia include the following:
  • Acupuncture.
  • Moxibustion.
  • Relaxation techniques. These can include breathing exercises, visualization and distraction.
  • Heat therapy.
  • Cold therapy. Cold packs can be used.
  • Transcutaneous Electrical Nerve Stimulation. This involves the stimulation of peripheral nerve endings by the delivery of electrical energy through the surface of the skin.^[6]
  • Spinal cord stimulator. The electrical stimulation of the posterior spinal cord works by activating supraspinal and spinal inhibitory pain mechanisms.^[7]

In some cases, treatment of postherpetic neuralgia brings complete pain relief. But most people still experience some pain, and a few do not receive any relief. Although some people must live with postherpetic neuralgia the rest of their lives, most people can expect the condition to gradually disappear on its own within five years.

Prognosis

The natural history of postherpetic neuralgia involves slow resolution of the pain syndrome. Most people who develop postherpetic neuralgia respond to agents such as tricyclic antidepressants. A subgroup of affected individuals may develop severe, long-lasting pain that does not respond to medical therapy.

Prevention

Primary prevention

In 1995, the Food and Drug Administration (FDA) approved the Varicella vaccine to prevent chickenpox. Its effect on postherpetic neuralgia is still unknown. The vaccine—made from a weakened form of the varicella-zoster virus—may keep chickenpox from occurring in nonimmune children and adults, or at least lessen the risk of the chickenpox virus lying dormant in the body and reactivating later as shingles. If shingles could be prevented, postherpetic neuralgia could be completely avoided.

In May 2006 the Advisory Committee on Immunization Practices approved a new vaccine by Merck (Zostavax) against shingles. This vaccine is a more potent version of the chickenpox vaccine, and evidence shows that it reduces the incidence of postherpetic neuralgia.^[8] The CDC recommends use of this vaccine in all persons over 60 years old.^[9]

Secondary prevention

An April 2013 Cochrane Collaboration meta-analysis of 6 randomized controlled trials (RCTs) investigating oral antiviral medications given within 72 hours after the onset of herpes zoster rash in immunocompetent people for preventing postherpetic neuralgia (PHN) found no significant difference between placebo and acyclovir. Combining four RCTs, 44.1% of the acyclovir treatment group developed herpetic neuralgia whereas 53.3% of the placebo group developed herpetic neuralgia. Heterogeneity between the four RCTs was moderate: Chi² =3.36, df = 2 (P=0.19); I² = 40%. Additionally, there was no significant difference in preventing the incidence of PHN found in the one RCT included in the meta-analysis that compared placebo to PO famciclovir treatment within 72 hours of HZ rash onset. Studies using valaciclovir treatment were not included in the meta-analysis. PHN was defined as pain at the site of the dermatomic rash at 120 days after the onset of rash, and incidence was evaluated at 1, 4, and 6 months after rash onset. There was a slight reduction in the incidence of pain at 4 weeks after the onset of rash in the aciclovir group (153 study participants with pain out of 347 study participants in the aciclovir group) versus the placebo group (184 study participants with pain out of 345 study participants in the placebo group). Patients who are prescribed PO antiviral agents after the onset of rash should be informed that their chances of developing PHN are no different than those not taking PO antiviral agents.^[10]

A randomized controlled trial found that amitriptyline 25 mg per night for 90 days starting within two days of onset of rash can reduce the incidence of postherpetic neuralgia from 35% to 16% (number needed to treat is 6).^[11]

Research directions

• Gallium maltolate in a cream or ointment base has been studied in a case report as a treatment of refractory postherpetic trigeminal neuralgia.^[12]

References

1. Gharibo, Christopher; Kim, Carolyn (December 2011). "Neuropathic Pain of Postherpetic Neuralgia" (PDF). Pain Medicine News. McMahon Publishing. Retrieved 6 October 2014.
2. Brian J. Hall, John C. Hall. "Infectious diseases in the skin". Sauer's Manual of Skin Diseases. Lippincott Williams & Wilkins, 2010. p. 232.
3. Weaver, B A (2009). "Herpes zoster overview: natural history and incidence." (PDF). J Am Osteopath Assoc 109 (6 (Suppl 2)): S2–6. PMID 19553632. Retrieved 6 October 2014.
4. De Benedittis G, Besana F, Lorenzetti A (1992). "A new topical treatment for acute herpetic neuralgia and post-herpetic neuralgia: the aspirin/diethyl ether mixture. An open-label study plus a double-blind controlled clinical trial". Pain 48 (3): 383–90. doi:10.1016/0304-3959(92)90088-S. PMID 1594261.
5. Han, Y; Zhang, J; Chen, N; He, L; Zhou, M; Zhu, C (28 March 2013). "Corticosteroids for preventing postherpetic neuralgia.". The Cochrane database of systematic reviews 3: CD005582. doi:10.1002/14651858.CD005582.pub4. PMID 23543541.
6. Doble S (2008). "Spinal Management of patients with post-herpetic neuralgia". Nursing Standard 22 (39): 49–56. doi:10.7748/ns2008.06.22.39.49.c6569. PMID 18578133.
7. Harke H, Gretenkort P, Ladleif HU, Koester P, Rahman S (2002). "Spinal cord stimulation in postherpetic neuralgia and in acute herpes zoster pain". Anesthesia & Analgesia 94 (3): 694–700. doi:10.1097/00000539-200203000-00040. PMID 11867400.
8. Chen N, Li Q, Zhang Y, Zhou M, Zhou D, He L (2011). He, Li, ed. "Vaccination for preventing postherpetic neuralgia". Cochrane Database Syst Rev (3): CD007795. doi:10.1002/14651858.CD007795.pub2. PMID 21412911.
9. http://www.cdc.gov/vaccines/vpd-vac/shingles/default.htm
10. Chen N, Li Q, Yang J, et al. (2014). He L, ed. "Antiviral treatment for preventing postherpetic neuralgia". Cochrane Database Syst Rev 2 (2): CD006866. doi:10.1002/14651858.CD006866.pub3. PMID 24500927.
11. Bowsher D (1997). "The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: a randomized, double-blind, placebo-controlled trial". Journal of pain and symptom management 13 (6): 327–31. doi:10.1016/S0885-3924(97)00077-8. PMID 9204652.
12. Bernstein, L.R. (2013). "Gallium, therapeutic effects" (PDF). In Kretsinger, R.H.; Uversky, V.N.; Permyakov, E.A. Encyclopedia of Metalloproteins. New York: Springer. pp. 823–835. ISBN 978-1-4614-1532-9.

External links

• Management of Herpes Zoster (Shingles) and Postherpetic Neuralgia
• Clinical Trials for Shingles Pain
• Herpes Zoster and Postherpetic Neuralgia: Prevention and Management
• The Center for Shingles and Postherpetic Neuralgia
• Postherpetic Neuralgia. Mayo Clinic
• Hempenstall K, Nurmikko TJ, Johnson RW, A'Hern RP, Rice AS (2005). "Analgesic therapy in postherpetic neuralgia: a quantitative systematic review". PLoS Med. 2 (7): e164. doi:10.1371/journal.pmed.0020164. PMC 1181872. PMID 16013891.
• Post Herpetic Neuralgia