Post-herpetic neuralgia (PHN) is a neuropathic pain (NP) syndrome defined as pain persisting for weeks to months or years after resolution of the vesicular dermatomal rash caused by acute herpes zoster. The pain associated with herpes zoster has three phases:

• Acute herpetic neuralgia that accompanies the rash and lasts for up to 30 days after the onset of the rash
• Subacute herpetic neuralgia that persists beyond healing of the rash but resolves within four months of onset
• PHN, defined as pain persisting beyond four months from the initial onset of the rash.^1,2

Varicella zoster virus (VZV) is the causative agent of varicella (chickenpox) and acute herpes zoster (shingles). Acute herpes zoster is caused by reactivation of VZV, which lies dormant for a period of years in the dorsal root ganglia of cranial or spinal nerves after resolution of the original infection. As cellular immunity wanes with age or immunocompromise, the virus is transported along peripheral nerves, producing an acute neuritis.³ Most cases of acute herpes zoster are self-limited, but a variable percentage of patients may continue to have PHN that can be quite difficult to treat. 

The incidence of acute herpes zoster infection increases with impairment of the immune system due to age, disease or chemotherapy. The individual lifetime risk of developing herpes zoster is between 23.8% and 30%. Two-thirds of herpes zoster cases occur in individuals aged 50 years or over. The risk of zoster in those aged 85 and over is 50%.⁴

Older adults are more likely to have PHN and to have longer lasting and more severe pain. Following acute herpes zoster approximately 13% (and possibly more) of people 60 years of age and older will get PHN.^4,6 The major risk factors for developing PHN are older age, greater acute pain and greater rash severity.⁷

Clinical manifestation

Thoracic (T4-T6), cervical and trigeminal nerves are most commonly affected. The typical symptoms of PHN are those of neuropathic pain. The quality of pain is usually described as ‘burning’ by the patients. Patients with PHN often demonstrate areas of hyperalgesia (abnormally increased pain after a painful stimulus) and allodynia (pain in response to a non-painful stimulus) within the affected dermatomes. 

The contralateral side is without symptoms.⁶ PHN most often follows the pain of an acute episode of herpes zoster (sharp or stabbing sensation), but has been reported on rare occasions to occur months to years after resolution of the acute episode.^1,8,9

Prevention

Greater acute pain and greater rash severity during an episode of acute herpes zoster have been identified as major risk factors for PHN. It is therefore important to reduce the severity of the acute herpes zoster infection in order to prevent PHN. The severity of acute zoster and the extent of neural damage caused can be reduced by early treatment with antiviral agents like acyclovir,⁵ famciclovir or valacyclovir as soon as there is a suspicion of acute herpes zoster.  Combining antiviral therapy with effective acute herpetic neuralgia pain relief (including opioids, tricyclic antidepressants and anticonvulsants) will further lessen the risk of developing PHN.²

Vaccines are available for the prevention of both varicella and herpes zoster. Numerous clinical trials are showing a reduction in the incidence of herpes zoster and PHN in immunocompetent patients receiving the herpes zoster vaccine.^{10,11,12,13,14}

The zoster vaccine is a live attenuated viral vaccine from the Oka/Merck strain of varicella zoster virus indicated for prevention of acute herpes zoster and zoster-related PHN in individuals 50 years and older. This vaccine is now available in Ireland.⁵ It has been reported to be well tolerated and is administered as a one-time subcutaneous injection (0.65ml), preferably in the deltoid region.^4,5 Side-effects include local pain, erythema and induration. Headache is common. Zoster vaccine is not advised in pregnant mothers, highly immunocompromised patients (due to disease or treatment) or patients with a history of anaphylaxis to gelatin or neomycin.^4,5

In Ireland, zoster vaccination is not included in the routine immunisation schedule. However, anyone aged 50 or older may choose to be immunised. Immunisation guidelines for Ireland 2013 for general practice are available online at www.hse.ie/eng/health/immunisation/hcpinfo/guidelines/⁴

An up-to-date list of licensed vaccines can be accessed on the Health Products Regulatory Authority (HPRA) website, formerly known as the Irish Medicines Board (www.hpra.ie). In the UK, immunisation against herpes zoster is part of the routine immunisation schedule for individuals 70 years of age up until the 80th birthday. The Green Book from Public Health England has the latest information on vaccines and vaccination.¹²

Management

General advice

Various treatment modalities exist for PHN.^15,18,19 The mainstay of treatment available in a primary care setting is pharmacological management that includes topical treatments, antidepressants, anticonvulsants and opioids, usually in combination, to reduce dose related side-effects.  Care should be taken, especially in the elderly, as side-effects can lead to acute confusion, sedation and mobility problems.  This can impair driving skills and cause falls and hip fractures, especially in the group of patients who are often frail and may live alone. 

Treatment usually starts with simple analgesics such as paracetemol and non-steroidal anti-inflammatory drugs in combination with topical treatment. If there is severe pain at the outset or if the above measures are not sufficient, adding in either an antidepressant or anticonvulsant (only one drug at a time in small increments) has been shown to be effective in the treatment of PHN. Do not forget the beneficial effect of opioids in PHN. The ultimate goal is to achieve pain control without sedation.

Pharmacological

Topical treatments

Lidocaine 5% medicated patches belong to the amide local anaesthetic group. Each adhesive patch contains 700mg of lidocaine with very little systemic absorption (after application mean peak blood concentration reaches about one tenth of the therapeutic concentration required to treat cardiac arrhythmias). It is effective in reducing sharp/burning and aching pain as well as allodynia that accompanies PHN and is easy to use, with minimal and rare side-effects.¹⁶

Up to three patches can be applied simultaneously to the most painful area, once a day for up to 12 hours, followed by a 12 hour patch-free period. This can be repeated daily. The patches should only be applied to intact skin and should be removed if local irritation occurs.⁵

Capsaicin is an active component of chilli peppers and elicits an analgesic effect by mimicking a burning/stinging sensation followed by erythema that leads to a calcium influx, rendering the nerves unable to report pain for an extended period of time. Capsaicin cream must be applied three to four times daily at the standard concentration (0.025-0.075%). 

In a pain clinic setting, high-concentration capsaicin (8%) patch can be used topically if other treatments have not worked, are not appropriate or at a patient’s request. It is a single 60 minute application and patients are monitored for up to two hours after treatment. In practice, application of capsaicin is intolerable in up to one-third of patients, but referral to a local pain clinic for a trial is advisable.^5,17

Transcutaneous electrical nerve stimulation (TENS) is an option if the individual patient finds it beneficial.

Tricyclic antidepressants (TCA)

TCA are generally a popular choice because of efficacy and improvement in sleep. They are thought to increase the inhibition of nociceptive signals from the periphery.^18,19

Amitriptyline is most widely used.⁵ Side-effects are mainly anticholinergic: sedation, tachycardia, constipation, urinary retention (caution in elderly males) and dry mouth. 

Side-effects generally experienced at higher doses (above 50mg daily). Initial dose is usually 10mg at night. Increase by weekly increments of 10-25mg until pain is controlled or side-effects occur.

Anticonvulsants

Gabapentin or pregabalin, alone or combined with other pharmacological agents, has become a popular choice for PHN in recent years.^18,19 Gabapentin and pregabalin interact with voltage-sensitive calcium channels in the central nervous system and reduce the release of specific neurotransmitters. The common side-effects of these drugs include somnolence, dizziness, ataxia, weight gain, dry mouth and peripheral oedema.⁵

Written instructions regarding sedative effects and impact on driving should be given to all patients on initiation of treatment.

• Pregabalin: Usually initiated at a dose of 25-50mg twice daily.⁵ Total daily dose can be titrated up in small increments as tolerated. Maximum daily dose of 600mg. Faster tolerable titration than gabapentin. A dose reduction is required in patients with renal insufficiency.
• Gabapentin: Usually initiated at a dose of 300mg once daily on day one, 300mg twice daily on day two, and 300mg three times daily on day three.⁵ Total daily dose can be titrated up by 100-300mg daily every three to seven days as tolerated. Maximum daily dose of 3,600mg. This dose should be achieved over a minimum period of three weeks. Slower titration may be needed for patients such as the elderly or frail. Because of the slow dose titration, adequate trial may take more than two months.²⁰ A dose reduction is required in patients with renal insufficiency.

Opioids

Opioids are effective for pain relief in acute herpes zoster and PHN. The usual risk of physical dependence and addiction is less common in the elderly compared to the younger population. The most common side-effects are constipation, sedation, and nausea. In the elderly, cognitive impairment and mobility problems can arise that may lead to falls and hip fractures.

There are numerous short-and long-acting opioid analgesics available. Opioids should be initiated at low doses and should be prescribed with a laxative. Careful titration and monitoring is necessary and evaluation by a pain specialist may be considered when higher doses are contemplated.  Hospitalisation may be required.²¹ Low-dose opioid patches are popular in the elderly. The addition of naloxone to oxycodone hydrochloride in a prolonged-release tablet format reduces the incidence of constipation and makes this drug a popular choice.⁵

Patient referral to pain specialist  

It is advisable to refer to a specialist pain clinic when the above treatments do not control pain after four to six weeks, if the pain is severe or when there are adverse effects of medication that are affecting/limiting treatment. The pain clinic can help with difficulty in titration of medication.

Trial of the following may help pain but these treatment options have been shown to have variable results: 

• Intercostal lytic nerve block
• Stellate ganglion block
• Botulinum toxin injection²²
• NMDA receptor antagonists like ketamine and intravenous lidocaine²³
• Intrathecal or epidural glucocorticoid injection (triamcinolone)²⁴
• Spinal cord stimulation (SCS)⁶
• Cryotherapy involving freezing of peripheral nerves has been attempted without long-term success.²⁵

Summary

PHN can be a severe condition associated with significant psychosocial dysfunction, including impaired sleep, loss of appetite, depression and suicide.^8,9

The prevention of PHN is a very important goal and can be approached by a combination of vaccination against herpes zoster and the aggressive treatment of acute herpes zoster infection with antiviral agents and analgesia. 

If PHN develops despite prevention strategies, based on available data and our own experience, we recommend the following approach:

• Lidocaine 5% medicated patch
• Amitriptyline 10mg nocte titrating up to 50mg as required to help sleep
• Pregabalin 25mg twice daily titrating up as required and tolerated
• Opioids, combined with naloxone in tablet form, or prescribed with a laxative.

Sedative side-effects are common in the oral treatment options and careful titration in the elderly is important to prevent further morbidity. In difficult cases, we recommend to contact the local pain clinic for advice, additional input or referral. 

References

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