Postherpetic neuralgia

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Postherpetic neuralgia
Specialty Neurology   OOjs UI icon edit-ltr-progressive.svg
Symptoms burning or stabbing pain, pain doesn't end after the shingles subsides.
Durationlifelong

Postherpetic neuralgia (PHN) is neuropathic pain that occurs due to damage to a peripheral nerve caused by the reactivation of the varicella zoster virus (herpes zoster, also known as shingles). PHN is defined as pain in a dermatomal distribution that lasts for at least 90 days after an outbreak of herpes zoster. [1] Several types of pain may occur with PHN including continuous burning pain, episodes of severe shooting or electric-like pain, and a heightened sensitivity to gentle touch which would not otherwise cause pain or to painful stimuli. [2] Abnormal sensations and itching may also occur. [2]

Contents

Postherpetic neuralgia is the most common long-term complication of herpes zoster, and occurs in approximately 20% of patients with shingles. [2] Risk factors for PHN include older age, severe prodrome or rash, severe acute zoster pain, ophthalmic involvement, immunosuppression, and chronic conditions such as diabetes mellitus and lupus. [1] The pain from postherpetic neuralgia can be very severe and debilitating. There is no treatment which modifies the course of the disease and management primarily aims to control symptoms. [2] Affected individuals often experience a decrease in their quality of life. [2]

Shingles vaccination is the only way for adults to be protected against both shingles and postherpetic neuralgia, with the vaccine Shingrix providing 90% protection from postherpetic neuralgia. [3] The chickenpox vaccine is approved for infants to prevent chickenpox, which also protects against PHN from a herpes zoster infection. [4]

Overview

Postherpetic neuralgia (PHN) is neuropathic pain that occurs due to damage to a peripheral nerve caused by the reactivation of the varicella zoster virus (herpes zoster, also known as shingles). Typically, the nerve pain (neuralgia) is confined to an area of skin innervated by a single sensory nerve, which is known as a dermatome. PHN is defined as dermatomal nerve pain that persists for more than 90 days after an outbreak of herpes zoster affecting the same dermatome. [2] [1] Several types of pain may occur with PHN including continuous burning pain, episodes of severe shooting or electric-like pain, and a heightened sensitivity to gentle touch which would not otherwise cause pain (mechanical allodynia) or to painful stimuli (hyperalgesia). [2] Abnormal sensations and itching may also occur. [2]

The nerve pain of PHN is thought to result from damage in a peripheral nerve that was affected by the reactivation of the varicella zoster virus or troubles after chemotherapy. PHN 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.

There is no treatment that modifies the disease course of PHN; therefore, controlling the affected person's symptoms is the main goal of treatment. Medications applied to the skin such as capsaicin or topical anesthetics (e.g., lidocaine) are used for mild pain and can be used in combination with oral medications for moderate to severe pain. [2] Oral anticonvulsant medications such as gabapentin and pregabalin are also approved for treatment of PHN. [2] Tricyclic antidepressants reduce PHN pain, but their use is limited by side effects. [2] Opioid medications are not generally recommended for treatment except in specific circumstances. Such cases should involve a pain specialist in patient care due to mixed evidence of efficacy and concerns about potential for abuse and addiction. [2]

Shingles vaccination is the only way for adults to be protected against both shingles and postherpetic neuralgia, with the vaccine Shingrix providing 90% protection from postherpetic neuralgia. [3] The chickenpox vaccine is approved for infants to prevent chickenpox, which also protects against PHN from a herpes zoster infection. [4]

PHN is the most common long-term complication of herpes zoster. [2] The incidence and prevalence of PHN are uncertain due to varying definitions. Approximately 20% of people affected by herpes zoster report pain in the affected area three months after the initial episode of herpes zoster, and 15% of people similarly report this pain two years after the herpes zoster rash. [2] Since herpes zoster occurs due to reactivation of the varicella zoster virus, which is more likely to occur with a weakened immune system, both herpes zoster and PHN occur more often in the elderly. [2] Risk factors for PHN include older age, severe prodrome or rash, severe acute zoster pain, ophthalmic involvement, immunosuppression, and chronic conditions such as diabetes mellitus and lupus. [1] PHN is often very painful and can be quite debilitating. Affected individuals often experience a decrease in their quality of life. [2]

Signs and symptoms

Symptoms:[ citation needed ]

Signs:[ citation needed ]

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. [5]

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. [5] 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.[ citation needed ]

Diagnosis

Lab Studies:[ citation needed ]

Imaging studies:[ citation needed ]

Prevention

Primary prevention

Shingles vaccination is the only way for adults to be protected against both shingles and postherpetic neuralgia, with two vaccines approved for use in people over age 50. [3] The zoster vaccine Shingrix provides around 90% protection from postherpetic neuralgia, and has been used in many countries since 2017. The earlier vaccine Zostavax provides lesser protection against shingles, and PHN. [6]

The varicella vaccine is approved for infants to prevent chickenpox, which also protects against PHN from a herpes zoster infection. Vaccination decreases the overall incidence of virus reactivation, and also decreases the severity of disease development and incidence of PHN if reactivation does occur. [4]

Secondary prevention

A 2013 Cochrane 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 aciclovir. 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 oral 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. Patients who are prescribed oral antiviral agents after the onset of rash should be informed that their chances of developing PHN are no different than those not taking oral antiviral agents. [7]

Treatment

The pain from postherpetic neuralgia can be very severe and requires immediate treatment. There is no treatment which modifies the course of the disease and management primarily aims to control symptoms. [2]

Medications

Topical medications

Medications applied to the skin can be used alone if the pain from PHN is mild or in combination with oral medications if the pain is moderate to severe. [2] Topical medications for PHN include low-dose (0.075%) and high-dose (8%) capsaicin and anesthetics such as lidocaine patches. [2] Lidocaine patches (5% concentration) are approved in the United States and Europe to treat PHN though evidence supporting their use is limited. [2] A meta-analysis of multiple small placebo-controlled randomized controlled trials found that for every two people treated with topical lidocaine, one person experienced at least a 50% reduction in their PHN-associated pain (number needed to treat (NNT)=2). [8]

Low-dose capsaicin may be useful for reducing PHN-associated pain but is limited by side effects (redness and a burning or stinging sensation with application) and the need to apply it four times daily. [2] Approximately three people must be treated with low-dose capsaicin cream for one person to experience significant pain relief (number needed to treat =3.3). [2] [8] A single topical application of a high-dose capsaicin patch over the affected area after numbing the area with a topical anesthetic has also been found to relieve PHN-associated pain. [2] For every eleven people treated with a high-dose capsaicin patch for up to 12 weeks, one person experienced a significant improvement in their pain. (number needed to treat=11). [9] Due to the need for topical anesthesia before application of the high-dose capsaicin patch, referral to a pain specialist is generally recommended if this approach is being considered. [2]

Oral medications

Multiple oral medications have demonstrated efficacy in relieving postherpetic neuralgia pain. Tricyclic antidepressants (TCAs), such as nortriptyline or desipramine, are effective in reducing postherpetic neuralgia pain but are limited by their numerous side effects. For every three people treated with a tricyclic antidepressant, one person is expected to have a clinically significant reduction in their pain (NNT=3). [2] Additionally, of every sixteen people treated with a TCA, one person is expected to stop the medication due to a bothersome side effect, such as dry mouth, constipation, or urinary retention (number needed to harm=16). [2] The anticonvulsant medications pregabalin and gabapentin also effectively relieve postherpetic neuralgia pain. Treatment with pregabalin leads to a reduction in pain intensity of 50% or more in one person out of every 4–5 people treated (NNT=4–5). [10] Similarly, treatment with gabapentin also leads to a 50% reduction in pain intensity in one person out of every 7-8 people treated (NNT=7.5). [10]

Opioids such as tramadol, methadone, oxycodone, and morphine have not been well-studied for postherpetic neuralgia treatment. [11] [12] [13] [14] Acetaminophen and nonsteroidal anti-inflammatory drugs are thought to be ineffective and have not undergone rigorous study for PHN. [2] [15]

New medications

Pharmacological treatment of PHN is unsatisfactory for many patients and there is a clinical need for new treatments. Between 2016 and 2023, 18 clinical trials have been carried out evaluating 15 molecules with pharmacological actions on nine different molecular targets: antagonism of the angiotensin type 2 receptor (AT2R) (olodanrigan), inhibition of the α2δ subunit of the voltage-gated calcium channel (VGCC)(crisugabalin, mirogabalin and pregabalin), activated sodium channel (VGSC) blockade (funapide and lidocaine), cyclooxygenase-1 (COX-1) inhibition (TRK-700), adapter-associated kinase 1 inhibition ( AAK1) (LX9211), lanthionine synthase C-like protein (LANCL) activation (LAT8881), N-methyl-D-aspartate (NMDA) receptor antagonism (esketamine), mu opioid receptor agonism (tramadol, oxycodone e hydromorphone) and nerve growth factor (NGF) inhibition (fulranumab). Of them, some of them report promising results while others did not work. [16] Hopefully, these experimental treatments will result in better clinical management of PHN.

Prognosis

The natural history of postherpetic neuralgia involves slow resolution of the pain syndrome. A subgroup of affected individuals may develop severe, long-lasting pain that does not respond to medical therapy.[ citation needed ]

Epidemiology

In the United States each year approximately 1,000,000 individuals develop herpes zoster, with nearly 1 in 3 people in the United States developing it in their lifetime. [17] [18] Of those individuals, approximately 10–18% develop postherpetic neuralgia. [19]

The incidence of herpes zoster, and also developing postherpetic neuralgia, both increase with age. [17] The frequency and severity of postherpetic neuralgia increase with advancing age, occurring in 20% of people age 60–65 years old who have had herpes zoster, and in more than 30% of people over 80 years old. [20]

Related Research Articles

<span class="mw-page-title-main">Ramsay Hunt syndrome type 2</span> Presentation of shingles in the geniculate ganglion

Ramsay Hunt syndrome type 2, commonly referred to simply as Ramsay Hunt syndrome (RHS) and also known as herpes zoster oticus, is inflammation of the geniculate ganglion of the facial nerve as a late consequence of varicella zoster virus (VZV). In regard to the frequency, less than 1% of varicella zoster infections involve the facial nerve and result in RHS. It is traditionally defined as a triad of ipsilateral facial paralysis, otalgia, and vesicles close to the ear and auditory canal. Due to its proximity to the vestibulocochlear nerve, the virus can spread and cause hearing loss, tinnitus, and vertigo. It is common for diagnoses to be overlooked or delayed, which can raise the likelihood of long-term consequences. It is more complicated than Bell's palsy. Therapy aims to shorten its overall length, while also providing pain relief and averting any consequences.

<span class="mw-page-title-main">Bell's palsy</span> Facial paralysis resulting from dysfunction in the cranial nerve VII (facial nerve)

Bell's palsy is a type of facial paralysis that results in a temporary inability to control the facial muscles on the affected side of the face. In most cases, the weakness is temporary and significantly improves over weeks. Symptoms can vary from mild to severe. They may include muscle twitching, weakness, or total loss of the ability to move one or, in rare cases, both sides of the face. Other symptoms include drooping of the eyebrow, a change in taste, and pain around the ear. Typically symptoms come on over 48 hours. Bell's palsy can trigger an increased sensitivity to sound known as hyperacusis.

<span class="mw-page-title-main">Varicella zoster virus</span> Herpes virus that causes chickenpox and shingles

Varicella zoster virus (VZV), also known as human herpesvirus 3 or Human alphaherpesvirus 3 (taxonomically), is one of nine known herpes viruses that can infect humans. It causes chickenpox (varicella) commonly affecting children and young adults, and shingles in adults but rarely in children. VZV infections are species-specific to humans. The virus can survive in external environments for a few hours.

<span class="mw-page-title-main">Trigeminal neuralgia</span> Neurological pain disorder

Trigeminal neuralgia, also called Fothergill disease, tic douloureux, trifacial neuralgia, or suicide disease is a long-term pain disorder that affects the trigeminal nerve, the nerve responsible for sensation in the face and motor functions such as biting and chewing. It is a form of neuropathic pain. There are two main types: typical and atypical trigeminal neuralgia. The typical form results in episodes of severe, sudden, shock-like pain in one side of the face that lasts for seconds to a few minutes. Groups of these episodes can occur over a few hours. The atypical form results in a constant burning pain that is less severe. Episodes may be triggered by any touch to the face. Both forms may occur in the same person. It is regarded as one of the most painful disorders known to medicine, and often results in depression and suicide.

<span class="mw-page-title-main">Shingles</span> Viral disease caused by the varicella zoster virus

Shingles, also known as herpes zoster, is a viral disease characterized by a painful skin rash with blisters in a localized area. Typically the rash occurs in a single, wide mark either on the left or right side of the body or face. Two to four days before the rash occurs there may be tingling or local pain in the area. Other common symptoms are fever, headache, and tiredness. The rash usually heals within two to four weeks; however, some people develop ongoing nerve pain which can last for months or years, a condition called postherpetic neuralgia (PHN). In those with poor immune function the rash may occur widely. If the rash involves the eye, vision loss may occur.

<span class="mw-page-title-main">Keratitis</span> Medical condition

Keratitis is a condition in which the eye's cornea, the clear dome on the front surface of the eye, becomes inflamed. The condition is often marked by moderate to intense pain and usually involves any of the following symptoms: pain, impaired eyesight, photophobia, red eye and a 'gritty' sensation. Diagnosis of infectious keratitis is usually made clinically based on the signs and symptoms as well as eye examination, but corneal scrapings may be obtained and evaluated using microbiological culture or other testing to identify the causative pathogen.

Diabetic neuropathy is various types of nerve damage associated with diabetes mellitus. Symptoms depend on the site of nerve damage and can include motor changes such as weakness; sensory symptoms such as numbness, tingling, or pain; or autonomic changes such as urinary symptoms. These changes are thought to result from a microvascular injury involving small blood vessels that supply nerves. Relatively common conditions which may be associated with diabetic neuropathy include distal symmetric polyneuropathy; third, fourth, or sixth cranial nerve palsy; mononeuropathy; mononeuropathy multiplex; diabetic amyotrophy; and autonomic neuropathy.

<span class="mw-page-title-main">Peripheral neuropathy</span> Nervous system disease affecting nerves beyond the brain and spinal cord

Peripheral neuropathy, often shortened to neuropathy, is a general term describing damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerves are affected. Neuropathy affecting motor, sensory, or autonomic nerves result in different symptoms. More than one type of nerve may be affected simultaneously. Peripheral neuropathy may be acute or chronic, and may be reversible or permanent.

<span class="mw-page-title-main">Aciclovir</span> Antiviral medication used against herpes, chickenpox and shingles

Aciclovir (ACV), also known as acyclovir, is an antiviral medication. It is primarily used for the treatment of herpes simplex virus infections, chickenpox, and shingles. Other uses include prevention of cytomegalovirus infections following transplant and severe complications of Epstein–Barr virus infection. It can be taken by mouth, applied as a cream, or injected.

Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous and/or episodic (paroxysmal) components. The latter resemble stabbings or electric shocks. Common qualities include burning or coldness, "pins and needles" sensations, numbness and itching.

<span class="mw-page-title-main">Valaciclovir</span> Antiviral medication

Valaciclovir, also spelled valacyclovir, is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster (shingles). It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases. It is taken by mouth.

Neuralgia is pain in the distribution of a nerve or nerves, as in intercostal neuralgia, trigeminal neuralgia, and glossopharyngeal neuralgia.

<span class="mw-page-title-main">Neuritis</span> Inflammation of a nerve or generally any part of the nervous system

Neuritis, from the Greek νεῦρον), is inflammation of a nerve or the general inflammation of the peripheral nervous system. Inflammation, and frequently concomitant demyelination, cause impaired transmission of neural signals and leads to aberrant nerve function. Neuritis is often conflated with neuropathy, a broad term describing any disease process which affects the peripheral nervous system. However, neuropathies may be due to either inflammatory or non-inflammatory causes, and the term encompasses any form of damage, degeneration, or dysfunction, while neuritis refers specifically to the inflammatory process.

<span class="mw-page-title-main">Brivudine</span> Chemical compound

Brivudine is an antiviral drug used in the treatment of herpes zoster ("shingles"). Like other antivirals, it acts by inhibiting replication of the target virus.

<span class="mw-page-title-main">Zoster vaccine</span> Vaccine to prevent shingles

A zoster vaccine is a vaccine that reduces the incidence of herpes zoster (shingles), a disease caused by reactivation of the varicella zoster virus, which is also responsible for chickenpox. Shingles provokes a painful rash with blisters, and can be followed by chronic pain, as well as other complications. Older people are more often affected, as are people with weakened immune systems (immunosuppression). Both shingles and postherpetic neuralgia can be prevented by vaccination.

<span class="mw-page-title-main">Varicella vaccine</span> Vaccine to prevent chickenpox

Varicella vaccine, also known as chickenpox vaccine, is a vaccine that protects against chickenpox. One dose of vaccine prevents 95% of moderate disease and 100% of severe disease. Two doses of vaccine are more effective than one. If given to those who are not immune within five days of exposure to chickenpox it prevents most cases of disease. Vaccinating a large portion of the population also protects those who are not vaccinated. It is given by injection just under the skin. Another vaccine, known as zoster vaccine, is used to prevent diseases caused by the same virus – the varicella zoster virus.

<span class="mw-page-title-main">Chickenpox</span> Human viral disease

Chickenpox, or chicken pox, also known as varicella, is a highly contagious, vaccine-preventable disease caused by the initial infection with varicella zoster virus (VZV), a member of the herpesvirus family. The disease results in a characteristic skin rash that forms small, itchy blisters, which eventually scab over. It usually starts on the chest, back, and face. It then spreads to the rest of the body. The rash and other symptoms, such as fever, tiredness, and headaches, usually last five to seven days. Complications may occasionally include pneumonia, inflammation of the brain, and bacterial skin infections. The disease is usually more severe in adults than in children.

VZV globulin or VZV antibodies is an immune system medication that is used mostly for immunosuppressed patients who have been or may be exposed to the varicella zoster virus. It shortens the course of cutaneous disease and may protect against its dissemination. Varicella zoster virus is a human herpes virus that causes chickenpox, shingles, Ramsay Hunt syndrome type II, and postherpetic neuralgia. Unlike a Zoster vaccine which provides durable immunity, the protection is passive and short term; it may need to be readministered every 2-4 weeks as necessary. This medication is not recommended for administration to immune-competent persons for the treatment of active disease.

<span class="mw-page-title-main">Herpes zoster ophthalmicus</span> Shingles in the human eye

Herpes zoster ophthalmicus (HZO), also known as ophthalmic zoster, is shingles involving the eye or the surrounding area. Common signs include a rash of the forehead with swelling of the eyelid. There may also be eye pain and redness, inflammation of the conjunctiva, cornea or uvea, and sensitivity to light. Fever and tingling of the skin and allodynia near the eye may precede the rash. Complications may include visual impairment, increased pressure within the eye, chronic pain, and stroke.

Preherpetic neuralgia is a form of nerve pain (neuralgia) specifically associated with a Shingles viral infection. This nerve pain often precedes visible indications of a Shingles infection and consequently can be a key early indicator of a need to begin preventative anti-viral drug therapy. Pain associated with Shingles can be extremely difficult to treat whereas the source is related to the virus attacking the nervous system itself. Pain symptoms can last months or years beyond any outward sign of viral infection and can be quite severe. The combination of extreme pain severity and longevity can contribute to chronic depression and even suicide.

References

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