Postherpetic Neuralgia

Postherpetic neuralgia (PHN) is pain and often some distortion of sensation that follows an episode of herpes zoster, also called shingles. To be defined as postherpetic neuralgia, the pain has to persist for at least 3 months after the resolution of the episode of shingles.
There may be abnormal function of unmyelinated nocioceptors along with minimal sensory loss. Pain and temperature sensation as well as light touch, is hypersensitive and this can cause severe pain. This aberration of sensation is called allodynia. Allodynia may be caused by new connections involving central pain transmission neurons. Some patients with PHN have severe, spontaneous pain without allodynia. This may be due to increased spontaneous activity in deafferented central neurons or reorganization of central connections. An imbalance involving loss of large inhibitory fibres and an intact or increased number of small excitatory fibres is a suggested hypothesis.
There is evidence that both central and peripheral areas are involved in the production of pain.

The incidence of neuralgia following an episode of shingles increases with age. It is almost unreported below the age of 50 but becomes more frequent with advancing age. The total number of cases shows a female preponderance but this probably represents the female preponderance amongst the very old rather than a predisposition for it to attack women. The incidence of shingles also rises with advancing age.
Figures of the numbers of patients who have had shingles and now have PHN have to be interpreted with care in the light of the management of the shingles. It would seem that early implementation of antiviral therapy reduces the risk but too often this treatment is not given or given at too late a stage.¹

Factor that predispose to PHN include:²

• Older age
• Female sex but this may represent the distribution in the very old age group
• A prodrome before the shingles
• A more extensive and severe rash
• More severe acute pain.
• It is possible that some psychosocial factors predispose to risk.³

The risk also varies according to the site of the herpes lesion.

• Risk of PHN is low in the jaw, neck, sacral, and lumbar regions.
• It is moderate in the thoracic area.
• The highest risk is in the trigeminal area, especially the ophthalmic division, and also the brachial plexus.

People with immune compromise are known to be at high risk of herpes zoster infection and this can be very disseminated and dangerous. For this reason, antiviral therapy must be used early and energetically. However, there does not seem to be any evidence of increased risk of PHN. The risk after transplantation seems to be variable. In one paper,⁴ a third of patients who had received liver transplants developed PHN and they tended to be young. Heart transplantation does not appear to carry such a risk.⁵ There may be a slightly increased risk after bone marrow transplantation.⁶

• The herpes zoster presents initially with a painful vesicular eruption in a single dermatome.
• The eruption resolves but pain continues for at least 3 months to fulfill the definition of PHN.
• Pain is intense and may be described as burning, stabbing, or gnawing.
• Herpes zoster can reactivate with pain in a dermatome but without a rash. This is called zoster sine herpete and may be more complicated, affecting multiple levels of the nervous system and causing multiple cranial neuropathies, polyneuritis, myelitis, or aseptic meningitis.

Examination

• The area that had shown shingles may show scarring.
• Sensation may be altered over the affected areas, with either hypersensitivity or reduced sensation.

The differential diagnosis is largely with other causes of neurogenic pain such as trigeminal neuralgia. The continuation of the pain or allodynia after the resolution of the rash of shingles is the diagnostic feature.

The diagnosis is usually entirely clinical and no specific investigations are indicated.

There are a number of different types of drugs that may be of benefit. Some may be of benefit in the acute attack of herpes zoster to reduce the severity of the attack and possibly to reduce the risk of PHN. Others may be of value in the treatment of established PHN. It is regarded as a condition that is notoriously difficult to manage.

• Tricyclic antidepressants such as amitryptylline may be useful. They inhibit reuptake of serotonin and/or noradrenaline by the presynaptic neuronal membrane and may increase synaptic concentration in the CNS. They are useful as an analgesic for certain types of chronic and neuropathic pain. Early in the shingles, a dose of amitryptylline at 25mg nocte may help to reduce the risk of PHN developing. If pain does develop, a higher dose, up to 100mg daily is required. This may require divided doses. This is actually an unlicensed indication for this drug.
• If tricyclics fail, another approach is the anticonvulsant gabapentin. This is a licenced indication. It is usual to start the dose at 100mg tds and to titrate up to between 900 and 1800mg daily.
• Capsaicin cream 0.75% is an interesting approach. The substance is derived from chilli peppers and acts by depleting and preventing reaccumulation of substance P in peripheral sensory neurons. It may render skin and joints insensitive to pain. Substance P is thought to be a chemomediator of pain transmission from peripheral nerves to the CNS. Capsaicin is licenced for this indication.
• Local anaesthetic creams may provide some relief but they can also cause hypersensitivity.
• Corticosteroids may provide some benefit in the acute disease although they must always be used with caution in viral infections. They do not appear to reduce the risk of PHN.⁷ A review echoed these sentiments and added that intrathecal corticosteroids may provide a benefit for intractable postherpetic neuralgia, but because of risks of serious complications, this is a last-line option and should only be administered by experienced personnel.⁸
• Antiviral therapy does seem to be of value in the acute condition⁹ in terms of preventing progress to PHN but it is not used as readily as it should be¹ especially in the elderly. Once PHN is established it is unlikely to be of further benefit.
• Clinical Evidence reviewed postherpetic neuralgia¹⁰ and made the following recommendations:
  • To prevent PHN, in the acute shingles, antivirals are of value, amitryptylline¹¹ and topical idoxuridine are unproven and steroids are ineffective and may have adverse effects. This refers to the use of amitryptylline in the acute condition, not the neuralgia.
  • In terms of treating the PHN, gabapentin and tricyclic antidepressants are effective. Oral opiates, capsaicin and topical anaesthetics are of dubious value.
• An American systematic review was more positive.¹² It concluded that no single best treatment for PHN is known. Tricyclic antidepressants, topical capsaicin, gabapentin, and oxycodone are effective for alleviating pain. Long-term, clinically meaningful benefits are uncertain and side effects are common. Patients with PHN refractory to these therapies may benefit from intrathecal methylprednisolone. Little evidence is available regarding treatment of PHN of less than 6 months' duration.
• Transcutaneous Electrical Nerve Stimulation (TENS) may be effective in some cases.¹³

As always, the literature must be interpreted with care. Bodies such as Cochrane and Clinical Evidence tend to have very vigorous criteria for acceptance of evidence and it is important to distinguish between lack of adequate evidence that an intervention is effective and evidence that an intervention is ineffective or harmful. In controlled trials, it is essential to compare like with like. Age is a very important parameter that affects outcome. Other variables include the extent of the lesions and the early use of antiviral agents. Many trials have had fairly small numbers, have not had adequate blinding procedures and have permitted variable additional interventions. Although PHN is a very common condition, poor methodology has marred much research.
PHN can produce severe pain and opiate analgesics may be required to control it. Some people are very wary about the use of such drugs in conditions that are neither acute not terminal, fearing that addiction may occur. This should be discussed with the patient. If such drugs are used purely as analgesics and not for any psychological side-effects, then as the pain subsides they can be weaned off with far less difficulty than is experienced when treating a drug abuser.

The prognosis is that most patients with PHN will experience a slow improvement over a long period of time. There is a small group who fail to show any improvement.

It is thought that the introduction of a chicken pox vaccine in the future will reduce the risk of herpes zoster and postherpetic neuralgia when this cohort of children become elderly. The vaccine may also be given to older people.¹⁴