Postherpetic neuralgia

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Postherpetic neuralgia
Classification and external resources
ICD-10	B02.2, G53.0, G44.847
ICD-9	053.19
eMedicine	neuro/317

Postherpetic neuralgia (PHN) is a neuralgia 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 (HZ, commonly known as shingles) in that same dermatomic area. The neuralgia typically begins when the HZ vesicles have crusted over and begun to heal, but it can begin in the absence of HZ, in which case zoster sine herpete is presumed (see Herpes zoster).

Treatment options for PHN include antidepressants, anticonvulsants (such as gabapentin or pregabalin) 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).

GlobalData’s analysis suggests that the global Postherpetic Neuralgia (PHN) market was worth $648.5m in 2010. It is forecast to decline at a Compound Annual Growth Rate(CAGR) of 2% for the next seven years, to reach $563.3m by 2017.^[1]

Pathophysiology

Postherpetic neuralgia is thought to be 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 until death.

A key factor in the neural plasticity underlying neuropathic pain is altered gene expression in sensory dorsal root ganglia (DRG) 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 . Following nerve damage, NaC channel accumulation causes hyperexcitability, downregulation of the TTX-resistant Nav1.8 (sensory neuron specific, SNS1) channel and upregulation of TTX-sensitive Nav1.3 (brain type III) 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 PHN.

Frequency

In the United States each year approximately 1,000,000 individuals develop herpes zoster. Of those individuals approximately 20%, or 200,000 individuals, develop postherpetic neuralgia.

Less than 10 percent of people younger than 60 develop postherpetic neuralgia after a bout of HZ, 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.

Signs and symptoms

Symptoms:

• With resolution of the HZ eruption, pain that continues for 3 months or more is defined as PHN.
• Pain is variable from discomfort to very severe and may be described as burning, stabbing, or gnawing.

Signs:

• Area of previous HZ may show evidence of cutaneous scarring.
• Sensation may be altered over involved areas, 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.

When to seek medical advice

It is strongly recommended by professionals that patients see a doctor at the first sign of shingles. Treating shingles early — within three days of developing the rash — and aggressively with oral antiviral drugs may reduce the length and severity of postherpetic neuralgia. In addition, amitriptyline may reduce the risk of developing PHN.^[2]

If patients do develop postherpetic neuralgia, they are also advised to see their doctor immediately. They may have to work with their doctor and sometimes other specialists such as neurologists to try a variety of treatments before they find something that helps.

Lab and imaging studies

Lab Studies:

• No laboratory work is usually necessary.
• Results of cerebrospinal fluid (CSF) 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 PHN clinical course.
• 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 (MRI) lesions attributable to HZ were seen in the brain stem and cervical cord in 56% (9/16) of patients.
• At 3 months after onset of HZ, 56% (5/9) of patients with an abnormal MRI had developed PHN.
• Of the 7 patients who had no HZ-related lesions on MRI, 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 if postherpetic neuralgia has become established.
• Analgesics
  • Locally applied topical agents
    • Aspirin mixed into an appropriate solvent such as diethyl ether may reduce pain.^[3]
    • 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 to 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. 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 your 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 don't 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.
• Corticosteroids are commonly prescribed but a Cochrane Review found limited evidence and no benefit.^[4]

• Other non-pharmacological treatments for postherpetic neuralgia include the following:
  • Relaxation techniques. These can include breathing exercises, visualization and distraction.
  • Heat therapy.
  • Cold therapy. Cold packs can be used.
  • Transcutaneous Electrical Nerve Stimulation (TENS). This involves the stimulation of peripheral nerve endings by the delivery of electrical energy through the surface of the skin.^[5]
  • Spinal cord stimulator. The electrical stimulation of the posterior spinal cord works by activating supraspinal and spinal inhibitory pain mechanisms.^[6]

In some cases, treatment of postherpetic neuralgia brings complete pain relief. But most people still experience some pain, and a few don't 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.

High-Concentration Capsaicin Patch Granted Orphan Drug Designation for PHN from:http://www.medscape.com/viewarticle/704117?sssdmh=dm1.489879&src=ddd On June 9, 2009, The FDA approved orphan drug designation for a high-concentration capsaicin dermal patch (Qutenza [formerly NGX-4010], NeurogesX, Inc) for the treatment of pain associated with postherpetic neuralgia (PHN). Relief of pain is possible up to three months with no to minimal^{[clarification needed]} side effects. Qutenza has been recently^[when?] approved by the FDA for general use in PHN. Distribution is planned for the first half of 2010.^{[dated info]} See NeutrogesX for distribution plans.

Prognosis

• The natural history of PHN involves slow resolution of the pain syndrome.
• In those patients who develop PHN, most will respond to agents such as the tricyclic antidepressants.
• A subgroup of patients may develop severe, long-lasting pain that does not respond to medical therapy. Continued research for new agents is necessary.

Prevention

Primary prevention

In 1995, the Food and Drug Administration (FDA) approved the vaccine to prevent chickenpox. Its effect on PHN 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.

Recently, Merck has tested a new vaccine (Zostavax) against shingles.^[7] This vaccine is a more potent version of the chickenpox vaccine. Evidence indicates that the vaccine reduced the incidence of shingles by 51 percent. Additionally, the vaccine reduced the incidence of PHN by two-thirds compared to placebo. However, the vaccine's protective effects diminished over the three years that most patients were followed.^[8] In December 2005, an FDA advisory committee unanimously agreed that the vaccine is safe and effective for persons over 60 years old.^[9] This was followed on 26 May 2006 by the FDA formally approving the use of the vaccine for that same age group.^[10] Further studies may demonstrate if there is benefit in patients 50–59 years old and if a booster dose is recommended.

Secondary prevention

• A meta-analysis reported that treating zoster at the time of rash with antiviral agents such as acyclovir can reduce the chance of postherpetic neuralgia.^[11]
• A randomized controlled trial found that amitryptyline 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).^[12]

References

1. ^ "CPostherpetic Neuralgia (PHN) Therapeutics - Pipeline Assessment and Market Forecasts to 2017". http://www.globaldata.com/reportstore/Report.aspx?ID=Postherpetic-Neuralgia-PHN-Therapeutics-Pipeline-Assessment-and-Market-Forecasts-to-2017&ReportType=Industry_Report&coreindustry=Industry_Report&Title=Pharmaceuticals_and_Healthcare. 
2. ^ Bowsher, David, MD, ScD, PhD. "Treating shingles with tricyclic antidepressants to lessen the risk of PHN". The Center for Shingles and Postherpetic Neuralgia. http://shingles.mgh.harvard.edu/tricyclics.htm. Retrieved 2006-05-11. 
3. ^ 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. 
4. ^ He L, Zhang D, Zhou M, Zhu C (2008). He, Li. ed. "Corticosteroids for preventing postherpetic neuralgia". Cochrane Database Syst Rev (1): CD005582. doi:10.1002/14651858.CD005582.pub2. PMID 18254083. 
5. ^ Doble S (2008). "Spinal Management of patients with post-herpetic neuralgia". Nursing Standard 22 (39): 49–56. PMID 18578133. 
6. ^ 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. 
7. ^ Oxman MN, Levin MJ, Johnson GR, et al. (2005). "A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults". N. Engl. J. Med. 352 (22): 2271–84. doi:10.1056/NEJMoa051016. PMID 15930418. 
8. ^ "Merck Zostavax Shingles Vaccine Decreases In Efficacy Over Three-Year Period, FDA Says". FDA Advisory Committee. 2005-12-15. http://www.fdaadvisorycommittee.com/FDC/AdvisoryCommittee/Committees/Vaccines+and+Related+Biological+Products/121505_Zostavax/121505_ZostavaxP.htm. Retrieved 2006-06-15. ^{[dead link]}
9. ^ "Merck Zostavax Shingles Vaccine Safe and Effective For Adults Over 60, Committee Says". FDA Advisory Committee. 2005-12-16. Archived from the original on 2006-05-06. http://web.archive.org/web/20060506202436/http://www.fdaadvisorycommittee.com/FDC/AdvisoryCommittee/Committees/Vaccines+and+Related+Biological+Products/121505_Zostavax/121505_ZostavaxR.htm. Retrieved 2006-06-15. 
10. ^ "FDA Licenses New Vaccine to Reduce Older Americans’ Risk of Shingles". United States Food and Drug Administration. 2005-05-26. http://www.fda.gov/bbs/topics/NEWS/2006/NEW01378.html. Retrieved 2006-06-15. 
11. ^ Alper BS, Lewis PR (2000). "Does treatment of acute herpes zoster prevent or shorten postherpetic neuralgia?". The Journal of family practice 49 (3): 255–64. PMID 10735485.  - Commentary at ACPJC
12. ^ 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. 

External links

• Management of Herpes Zoster (Shingles) and Postherpetic Neuralgia
• Clinical Trial 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1181872.