Post Herpetic Neuralgia

Abstract

Background:

During the past decade, important advances have been made in understanding the epidemiology, pathogenesis, prevention and treatment of Post herpetic neuralgia pain as well as treatment of other neuropathic pain conditions. PHN is accepted as a model for management and clinical trials of neuropathic pain of less clear etiologies. In palliative medicine, where the etiology of pain may be nociceptive, neuropathic, or mixed, it is frequently to the research on PHN that we turn in order to extrapolate the data to the patients at hand.

Objective:

To review and summarize what is known about epidemiology, pathogenesis, clinical features and prevention strategies for Post herpetic Neuralgia. Discuss the available including the most recent therapeutic options as regards to their mechanism of action, efficacy, safety and tolerability in an attempt to explain the rationale for their use.

Conclusion:

A multidisciplinary and integrative approach has the best chance of success in the management of patients with PHN pain, a problem that can be often frustrating to the patient and challenging to the clinician. Prevention strategies for PHN include administration of zoster vaccine, treatment with antiviral therapy within 72 hours of rash onset and aggressive pain control. First and second line pharmacotherapy include anticonvulsants, antidepressants, topical lidocaine, high dose capsaicin, and opioids either used individually or in combination. Interventional techniques play a limited role in the management of PHN although some data indicate that Intrathecal methylprednisolone and spinal cord stimulation may be effective.

Introduction

Post herpetic neuralgia is a chronically painful sequel of acute herpes zoster that continues to pose a significant clinical challenge. One in four people will have an episode of acute herpes zoster infection in their lifetime.¹ The incidence is 5–10 times higher for those older than 80 years.² Herpes zoster is more common in patients who are immunocompromised due to chemotherapy, human immunodeficiency virus (HIV) infection, or other comorbidities.³

Post herpetic neuralgia (PHN) is the most common complication following an episode of acute herpes zoster. Investigators estimate that the prevalence of PHN ranges from 500,000 to 1 million. Herpes zoster is considered by many clinicians to be a mild and readily treatable disease. In fact, both acute zoster and PHN can be associated with severe psychosocial dysfunction, including impaired sleep, decreased appetite, and diminished libido that affects patient's quality of life,^4,5 normal daily, and social activities.⁶

PHN has been a model for management of neuropathic pain of less clear etiologies. In palliative medicine, where the etiology of pain may be nociceptive, neuropathic, or mixed, it is frequently to the research on PHN that we turn in order to extrapolate the data to the patients at hand. In addition, palliative medicine clinicians are frequently asked to consult for patients with intractable pain from conditions like PHN where there is severe impact in the psychosocial and spiritual domains and standard approaches have been unsuccessful. In fact, some might consider this pain worse than that in terminally ill patients because PHN is not life-threatening. There is the potential for endless years of agony. Yet, because patients are not considered “seriously ill,” they may not get the full attention of an interdisciplinary team that can help manage the suffering. Consequently, in this article we review the pathogenesis, clinical presentation, diagnosis, epidemiology, prevention, and available treatment options for PHN.

Pathogenesis of PHN

Pain can precede or accompany the onset of rash. Acute herpetic neuralgia is defined as pain that occurs within 30 days of rash onset.

Subacute herpetic neuralgia as pain that persists beyond 30 days from the rash onset and PHN as pain that persists for 120 days or more after the rash onset.⁷ PHN often represents a continuum of persistent pain or it can appear after a phase of initial resolution. PHN may be either due to the activity of the primary afferent neuron that responded to the tissue damage during the acute zoster phase or caused changes in the dorsal root ganglion, sensitizing them to further input and causing spontaneous activity capable of maintaining pain in the absence of ongoing tissue damage.^8,9

Varicella zoster viral reactivation followed by replication induces neural and inflammatory changes in the sensory ganglion and peripheral neurons. This may induce a cycle of sensitization resulting in persistent pain. Most of the research done in PHN is from autopsy studies that were performed in the eighteenth and nineteenth century. Modern anatomic study by Watson and coworkers,⁸ who compared autopsy tissue from patients with and without PHN, found marked degeneration of spinal cord dorsal horn in patients who developed PHN compared to those who did not. Thus, although shingles affect the peripheral sensory neurons, patients who develop PHN will show damage in the central nervous system (CNS) pain processing centers as well. Dorsal horn atrophy seen in PHN is thought to be either due to direct infection of the spinal cord or trans-synaptic degeneration. Punch skin biopsy has been developed as a tool and is used to study painful peripheral sensory neuropathy. A PHN biopsy of the affected skin showed loss of epidermal innervations.^11,12

In patients with PHN, epidermal innervation density was below 650 neurites/mm². Studies using quantitative sensory testing, which help identify sensory abnormalities in patients with PHN, demonstrated that there was greater variability of sensory loss in patients with PHN. These studies confirm that pain and sensory abnormalities in PHN often extend outside the dermatome originally affected by the zoster rash. Rowbotham et al.¹³ and Fields et al.¹⁴ have suggested that two different pathophysiologic mechanisms contribute to the development of PHN: sensitization and deafferentation. Both peripheral and central sensitization contribute to PHN. Peripheral sensitization occurs predominantly in small unmyelinated C fiber nociceptors. Sensitization of C nociceptors can be responsible for spontaneous burning pain and heat hyperalgesia in the presence of minimal sensory loss.

Allodynia in a subset of patients may be caused by ectopic discharges from damaged C nociceptors maintaining a state of central sensitization. Partial loss of C fiber input results in sprouting of A-beta fibers into the superficial layers of dorsal horn. This sprouting may lead to connection between regenerating beta fibers and fibers that previously received input from C fibers resulting in tactile allodynia.

In a subset of patients, there is loss of both large and small diameter sensory afferent fibers. This loss of peripheral input can result in the development of spontaneous discharge in deafferented central neurons. This may produce constant pain in area of sensory loss.¹³ These patients may suffer from severe mechanical allodynia. Assuming that the dorsal root ganglion and central connections are lost in some patients, the pain may be due to intrinsic CNS changes.

Clinical Manifestation of Herpes Zoster and PHN

Thoracic dermatomes (T4–T6), ophthalmic division of trigeminal nerves, other cranial nerves and cervical dermatomes are the most commonly affected.¹⁴ This is followed by lumbar and sacral dermatomes. The pain in acute zoster is described to be a sharp, stabbing sensation. In PHN the pain is described to be a burning discomfort.

There is stimulus-independent burning, throbbing pain that is described as sharp, shooting, or electric shock-like sensation. Stimulus-evoked pain described as tactile allodynia and hyperalgesia can occur with the application of nonpainful mechanical and thermal stimuli. More than 90% of the patients with PHN will have allodynia (Table 1).

Table 1.

Dermatomal Distribution of Herpes Zoster in Immunocompetent Patients

Thoracic: up to 50% of all cases

Cranial: 10%–20%

Cervical: 10%–20%

Lumbar: 10%–20%

Sacral: 2%–8%

Generalized: <1%

Reprinted with permission from Fishman SM, Ballantyne JC, Rathmell JP (eds): Bonica's Management of Pain, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2009, pp. 338–357.

Patients with PHN often demonstrate areas of anesthesia, as well as deficits of thermal, tactile, pinprick, and vibration sensation within the affected dermatome.¹⁵ Allodynia is most prominent in areas with preserved sensation and spontaneous pain within the area of impaired or lost sensation.

Few patients present with post herpetic itch that is thought to be caused by unprovoked firing of peripheral and/or central neurons that mediate itch. This may persist with or without pain. Musculoskeletal pain can also occur due to guarding of the affected area. Myofascial trigger points, atrophy of muscles, and decreased range of motion of joints is seen in severe cases.

Evidence of facial paralysis may be seen in case of facial nerve involvement. In case of thoracic involvement truncal bulge from weakness of intercostal muscles may be seen. Reduced quality of life is a common problem is patients whose pain persists as PHN. There is a positive correlation between the impact of pain severity, medication use, and quality of life. In 385 patients older than 65 years of age, pain severely affected their ability to carry out general activities.¹⁶ PHN causes loss of physical function due to fatigue, anorexia, weight loss, reduced mobility, insomnia, and reduction in overall health. Reduced independence with activities of daily living (ADLs) result in institutionalization, loss of autonomy, and decreased social contact. PHN also affects patients psychologically.

Patients with intense pain are at a greater risk of anxiety and depression and also report difficulty concentrating.¹⁷ Many patients receive medication for depression, anxiety, insomnia, and there has been reports of suicide as a direct consequence of PHN pain.¹⁸

Diagnosis of PHN

PHN is primarily a clinical diagnosis. A history of herpes zoster rash, followed by persistent pain in the corresponding dermatome or adjoining area is typical. Others have reported PHN occurring months or even years after the initial zoster episode.¹⁹ There may even be a recurrence of rash in the same distribution of the initial rash and that can be precipitated by a specific event (surgery, emotional stress). Sometimes a clear history of rash may not be present in all patients.

In these cases definitive diagnosis is based on serial serologic assessment, which may or may not be possible in a clinical setting. Diagnostic tests have limited application in the clinical management of PHN pain; but these tests are useful for research that may help classify different phenotypes that in turn may dictate the treatment of algorithms. These include quantitative sensory testing, skin biopsy, and nerve conduction studies.

Epidemiology/Risk Factors for Developing PHN

Systematic studies determining the epidemiology of specific chronic pain conditions are rare. Estimates of the prevalence of PHN range from 500,000 to 1 million in the United States.^20,21 This could decrease if zoster vaccination becomes widespread. Prevalence estimates are variable because of different definitions. If PHN is defined as persistence of pain beyond 120 days from the onset of rash, available data indicated that 10%–25% of herpes zoster patients develop PHN. Studies indicate that majority of patients experience resolution of pain over weeks to months following onset of rash.^22–25 The presence of persistent pain 1 year after the initial diagnosis of PHN is in approximately 20% of patients over 60 year of age.^26–28

The major risk factors for PHN are older age, greater acute pain, greater rash severity^29–32 and persistence of symptoms (Table 2).³³

Table 2.

Risk Factors for PHN

Well replicated

Older age

Severity of rash

Severity of acute pain

Prodromal pain

Less well replicated

Female gender

Greater sensory abnormalities in the affected dermatomes

Polyneuropathy

Psychosocial variables

Opthalmic distribution

Reprinted with permission from Fishman SM, Ballantyne JC, Rathmeli JP (eds): Bonica's Management of Pain, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2009, pp. 338–357.

PHN, post herpetic neuralgia.

Prevention

Prevention strategies include primary varicella vaccine to decrease the incidence of chicken pox zoster vaccine to decrease the incidence of acute herpes zoster, antiviral medications to treat acute zoster, and aggressive pain control for acute herpetic neuralgia.

Amitryptyline is the only medication that has shown a mild beneficial effect in the prevention of PHN. In one randomized double-blinded controlled study, 72 patients over the age of 60 with herpes zoster were assigned to amitriptyline, 25 mg daily, along with antiviral agents or to placebo within 48 hours of onset of rash.³⁴ The primary outcome that was measured was pain prevalence at 6 months and this was reduced by half in the treatment group.

Two double-blinded, randomized controlled trials of corticosteroids given for 21 days in acute herpes zoster did not show any effect on the incidence or duration of PHN. Use of gabapentinoids has not shown a beneficial effect in the prevention, although in clinical practice these are used as first-line medications.

Sympathetic blocks have been used for the acute pain in herpes zoster, and uncontrolled studies have claimed a reduction in the development of PHN. Other studies have failed to replicate this effect.

Since the pain of herpes zoster and PHN improve over time as part of their natural history, currently available research data are inadequate to definitively support the routine use of sympathetic blocks as a strategy for preventing PHN. In clinical practice injections are used to achieve effective pain control acutely in patients who are refractory to conservative therapy.

Treatment of PHN

Includes multiple modalities consisting of topical medications, systemic medications, invasive interventions, alternative modalities, physical, and psychological interventions. As is true in most chronic pain conditions, a multimodal approach offers the best chance of a successful outcome.

Medications

In clinical practice gabapentinoids including gabapentin and pregabalin, topical lidocaine and tramadol are used as first line medications. If tramadol is ineffective it is usually replaced with a newer agent tapentadol. Stronger opioids and tricyclic antidepressants (TCAs) are considered as the second-line agents primarily because of the better tolerability profile of the former group. Topical capsaicin and valproate are considered to be third-line medications. All patients need a thorough evaluation, and treatment is ideally tailored to an individual's needs.

The choice of medications used is based on the patient's comorbities, concomitant medication use, and associated symptoms.

Topical therapies

Use of topical medications is associated with relatively fewer side effects due to minimal systemic absorption of the medication.

Topical lidocaine

Lidocaine comes in 5% (700 mg) patch and in a gel cream form. The patch is one of the FDA-approved topical medications for the treatment of PHN.

Lidocaine is a sodium channel blocker, hence it inhibits the ectopic discharges in damaged nociceptors, suggested number needed to treat (NNT) is 4.4.³⁵ The patch is efficacious in the treatment of patients with clinical evidence of allodynia, even if the biopsy of the involved skin shows complete absence of nociceptors. It has an excellent safety and tolerability profile even with the use of three patches concurrently. The most frequent side effect is mild skin irritation at the site of application. It can be cut into any shape to fit the affected area, left on for 12–18 hours and off for 6–12 hours. It should not be used over active lesions. A randomized, controlled cross over trial showed that lidocaine patch was strongly preferred over a vehicle patch (78.1% versus 9.4%), with no significant difference of side effects between the treatments.³⁶

Two open-label, nonrandomized prospective studies showed that the lidocaine patch reduces the intensity of moderate to severe pain and improved the quality of life.^37,38 Lidocaine gel is also efficacious in patients with PHN and allodynia, and this should be considered if lidocaine patches are not available, affordable, or their application is problematic.

Topical capsaicin

It is commercially available in two concentrations, 0.025% and 0.075% cream, recommended dosing 3–4 times a day. Capsaicin is an extract of hot chili peppers and an agonist of the vanilloid receptor TRPV1. Initial applications cause worsening of the burning sensation, but repeated application results in desensitization of the unmyelinated epidermal nerve fibers and reduces hyperalgesia.

A 6-week blinded parallel group study followed by a 2-year open-label follow-up showed that 0.075% topical capsaicin cream was effective in relieving pain in 64% of patients at 6 weeks compared with 25% of patients who received placebo.³⁹

Capsaicin 8% patch was FDA approved in 2009 for treatment of PHN. This must be applied by a health care professional in monitored settings. To avoid patient discomfort, the affected area can be prepared with a topical local anesthetic cream 30–45 minutes prior to the application of this patch. Patients might need additional systemic analgesics for pain relief during and after the application. Up to four patches can be used concurrently. The patch is left on for 1 hour. Single applications have been shown to provide 12 weeks of pain relief. The most common adverse effects are application site redness, pain, and itching. These side effects are transient.

Serious but rare adverse reactions include increase in blood pressure.⁴⁰ In a double-blinded, randomized placebo controlled trial with an open-label extension, numeric pain rating scale decreased from baseline during week 1 in both the high-concentration capsaicin group and the placebo group; but the capsaicin patch group showed improvement through week 12.⁴⁰

Anticonvulsants

Calcium channel blockers: Gabapentin, pregabalin, and zonisamide

Gabapentin is FDA approved for the treatment of PHN. In a meta-analysis,⁴² pooled NNT for treatment of PHN is 4.4., whereas the number needed for harm (NNH) for minor harm is 4.1 and major harm is 17.3. Exact mechanism of action is not known, but it binds to the alpha-2-delta subunit of the L-type calcium channel, stabilizing the cell membrane. This effect inhibits the release of the excitatory neurotransmitters, including glutamate,⁴³ a neurotransmitter implicated in central sensitization.

In two large randomized controlled trials, use of gabapentin was shown to result in a statistically significant reduction in daily pain ratings, as well as improvements in sleep, mood, and quality of life at daily dosages of 1800–3600 mg.^44,45

Gabapentin is rapidly absorbed after oral administration. Its absorption is in part mediated by a transport mechanism that becomes saturated at higher doses. This phenomenon reduces the bioavailability of gabapentin as the dose is increased. The bioavailability of gabapentin at a dose of 300 mg is approximately 60%, but the bioavailability falls to 40% with a 600 mg dose. Peak serum concentrations are achieved approximately 3 hours after oral administration. Gabapentin is eliminated via the kidneys, and the dose needs to be adjusted for renal insufficiency. Gabapentin is started at 100–300 mg, preferably at night, and can be titrated by 100–300 mg every 3–5 days to an effective dose of 1800–3600 mg in three to four divided doses. Patients on dialysis should be started on a single dose of 100 mg, given 1 hour after dialysis treatment. This dose then can be titrated up slowly and cautiously. Side effects associated with gabapentin include somnolence, dizziness, peripheral edema, visual side effects, gait, or balance problems.

Pregabalin appears to have the same mechanism of action as gabapentin. It is FDA approved for the treatment of PHN with a NNT of 4.9.⁴⁶ Pregablin is efficacious at a dose of 150–600 mg/d, in two or three divided doses. It was shown to provide superior pain relief compared to placebo.⁴⁷ Side effects include weight gain, dizziness, and somnolence. As most patients with PHN are elderly, extra caution should be taken to titrate these medications slowly.

Sodium channel blockers: Topiramate, lamotrigine, phenytoin, carbamazepine, oxcarbazepine, levetiracetam, lidocaine, and valproic acid

These medications are considered to be third line in the treatment of PHN. In clinical practice these medications are used rarely because of the availability of agents with better tolerability and safety profiles.

In an 8-week randomized controlled trial, patients treated with valproic acid, 1000 mg/d, had significant pain relief compared to the patients treated with placebo.⁴⁸

Intravenous lidocaine was tested in two randomized controlled trials, neither lidocaine 1 mg/kg (48 patient episodes) or 5 mg/kg (48 patient episodes) infused over 2 hours, was associated with superior pain relief compared to saline infusion.⁴⁹

Antidepressants

Tricyclics: Amitriptyline, nortriptyline, and desimipraine

These medications have proven efficacy in the management of PHN but are not FDA approved for the treatment of PHN. In a meta-analysis pooled data shows that the NNT for TCA is 2.1–2.6^42,46; NNH is 5.7 for minor harm and 16.9 for major harm.

These medications have a number of postulated mechanisms of action that include blocking of norepinephrine and serotonin reuptake, and sodium channel blockade.

Amitriptyline is the most studied TCA medication for PHN. Available evidence and clinical experience suggest that nortriptyline and desipramine^42,46,50,51 are better tolerated compared to amitriptyline. Thus, these secondary amine tricyclics are generally preferred, especially in elderly and frail patients. Amitriptyline and nortriptyline can be helpful with insomnia due to their sedating side effects. Desipramine has less sedating side effects than the above two medications.

A major limiting factor in the clinical use of these medications is their side effects, including dry mouth, fatigue, dizziness, sedation, constipation, urinary retention, and palpitations. Other side effects include orthostatic hypotension, weight gain, blurred vision, and QT prolongation. Hence, these medications should be used cautiously in elderly patients and in patients with history of cardiac arrhythmia or heart disease. These medications should be started at 10–25 mg nightly and can be titrated every 2 weeks as tolerated to 75–100 mg as a single evening dose.

Selective serotonin reuptake inhibitor: Duloxetine and venelafaxine

Duloxetine (Cymbalta®, Lilly USA, Indianapolis, IN) and venlafaxine (Effexor®, Pfizer, Mission, KS) has been shown to be beneficial in the treatment of peripheral neuropathy and diabetic neuropathy.⁵² Efficacious dose of duloxetine is 60–120 mg/d in one or two divided doses. Patients should have monitoring of their liver function tests periodically while taking this medication.

Efficacious dose of Effexor is 75–225 mg/d. This medication at higher doses can cause increase in blood pressure.

Opioid Analgesics

Recent evidence has shown that this class of drug is efficacious in the treatment of neuropathic pain conditions including PHN. This is now recommended as second- or third-line analgesics in neuropathic pain including PHN.

The efficacy of these agents is comparable to antidepressant and anticonvulsant medications.

Opioid medications are considered second and third line medications due to the development of tolerance and concerns of misuse and abuse.^52–54 These concerns may not be valid given that the target population is primarily older adults. A more important issue will be the tolerability in terms of sedation and constipation experienced with these agents.

Analgesic efficacy of oral oxycodone was evaluated in a double-blinded crossover trial in which it caused significant reduction in allodynia, steady pain, and spontaneous paroxysmal pain.⁵⁵

Oxycodone treatment also resulted to superior scores of global effectiveness, disability reduction, and patient preference, compared to placebo. A quantitative review of pooled results for opioid therapy yielded a NNT 2.67 (2.07–3.77).⁵⁶

If opioids are prescribed patient should be carefully counseled regarding common side effects such as nausea, sedation, constipation, pruritis, opioid tolerance, physical dependence, opioid abuse, opioid-induced hyperalgesia, hypogonadism, and immune suppression.

The clinical recommendation for the use of opioids analgesic in the treatment of PHN are the following: use the lowest dose possible. Initiation of therapy with short-acting agents. Once the patient demonstrates tolerability, change it to long-acting opioids.

Regular assessment of efficacy and tolerability is recommended. If the medication is not effective, it should be promptly weaned off.

Tramadol

This analgesic medication has a weak mu receptor agonist effect like opioids, and it also inhibits the reuptake of serotonin and norepinephrine like the TCA. It has shown efficacy in the treatment of neuropathic pain with a pooled NNT of 4.8.⁴⁶ Tramadol is dosed as 100 mg every 6 hours as needed for pain. The maximum recommended dose in an elderly frail patient is 300 mg/d. Tramadol is also available as an extended-release preparation. Superior pain relief and improved quality of life has been seen with tramadol in a randomized controlled trial.⁵⁷ Tramadol should be avoided in patient who have history of seizures. Adverse effects include vomiting, dizziness, constipation, urinary retention, somnolence, and headache.

Tapentadol

This analgesic has a weak mu receptor agonist effect like opioids and has predominant norepinephrine than serotonin reuptake inhibition. A 10-day, phase 3, randomized, double-blinded, active and placebo-controlled study compared efficacy and tolerability of tapentadol immediate release and oxycodone immediate release in patients awaiting joint replacement.

Tapentadol immediate release, 50 and 75 mg, were associated with analgesia that was not inferior to that provided by oxycodone immediate release 10 mg with better gastrointestinal tolerability.⁵⁸ We do not have any scientific evidence regarding its use in neuropathic pain. In our practice we use this medication in patients with PHN and find it fairly effective.

Combination Therapy

One recent study has demonstrated that the combination of gabapentin and morphine was superior to either of these medications used alone in relieving pain in PHN.⁵⁹ The goal of combination therapy is to is improve the efficacy and tolerability of treatment while minimizing side effects of the individual medications (Table 3).

Table 3.

Pharmacologica Options for the Management of PHN in our Clinical Practice

Medication	Starting dose	Dose-titration	Common side effects	Caution/Comments	Pooled NNT ^a
Gabapentin	100–300 mg	Start qhs and increase to tid dosing; increase by 100–300 mg every 3 days to total dose of 1800–2400 mg/d in three divided doses	Somnolence, dizziness, fatigue, ataxia, peripheral edema, and weight gain	Decrease dose in patients with renal impairment. QOD dosing in dialysis patients. Avoid sudden discontinuation.	4.4
Pregabalin	50 mg tid or 75 mg bid	300–600 mg/d in 7–10 days in two divided doses	Somnolence, fatigue, dizziness, peripheral edema, and weight gain, blurred vision, and euphoria	Decrease dose in patients with renal impairment.	4.9
Topical lidocaine	5% patch	Can use up to 3 patches 12 h/d	Local erythema, rash, blisters	Known hypersensitivity to amide local anesthetics. Do not use on skin with open lesions.	2.0
Tramadol	50 mg every 6 hours prn	Can titrate up to 100 mg q 6 hrs max. daily dose: 400 mg Extended-release dosing once a day.	Nausea/vomiting, constipation, drowsiness, and dizziness	Be careful in patients with seizure disorder and concomitant use of SSRI, SNRI, and TCAs. Decrease dose in patients with hepatic or renal disease.	4.8
Tapentadol^b	50 mg every 4–6 hrs prn	Can titrate up to 100 mg q 4 hrs Maximum daily dose is 600 mg	Nausea/vomiting, constipation, drowsiness, and dizziness	Be careful in patients on SSRI, SNRI, MAOI and TCA's. Decrease dose in patients with moderate hepatic and renal impairment.	Data not available
TCAs^c Nortriptyline Desipramine Amitryptiline	10–25 mg qhs. Start at a lower dose in elderly	Increase by 10–25 mg weekly with a target dose of 75–150 mg; once in 24 hrs dose	Sedation, dry mouth, blurred vision, weight gain, urinary retention, constipation, sexual dysfunction	Cardiac arrhythmic disease, glaucoma, suicide risk, seizure disorder. Risk of serotonin syndrome with concomitant use of tramadol, SSRI, or SNRIs. Amitriptyline has the most anticholinergic effects.	2.6
Opioids Morphine Oxycodone^d Methadone Fentanyl^e patch	15 mg q 6 hrs prn 5 mg q 6 hrs prn 2.5 mg tid 12 μg/hr	Titrate at weekly intervals balancing analgesia and side effects. If patient tolerating the medications can titrate faster.	Nausea/vomiting, constipation, drowsiness and itching	Driving impairment and cognitive dysfunction during treatment initiation. Be careful in patients with sleep apnea. Additive effects of sedation with neuromodulating medications.	2.7
Topical Capsaicin	0.025–0.075% Cream	Apply 3–4 times a day over affected region	No systemic side effects. Burning and stinging sensation at the application sute.	Avoid contact with eyes, nose and mouth. Application of lidocaine gel locally may be helpful prior to capsaicin cream application.	3.3
Capsaicin^f patch	8% single application patch	Need topical local anesthetic application prior to patch application. Patch applied for 60 minutes	Local site irritation, burning, temporary increase in pain	Done in a physician's office under monitored circumstances. Patient may need oral analgesics for a short period of time following the application of the patch.	Not available

NNT, number of pain patients that need to be treated to achieve a 50% reduction in pain intensity in one patient.

Has not been studied in neuropathic pain, found to be effective in PHN and other chronic pain conditions in our clinical practice.

Obtain baseline ECG in patients with history of cardiac disease.

Has a long and unpredictable half-life, hence need for extra caution in elderly patients.

May need to start a patient on short-acting opioid medications before changing over to a fentanyl patch.

Single application is found to be effective for about 3 months.

PHN, post herpetic neuralgia; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; MAOI, monoamine oxidase inhibitor; TCAs, tricyclic antidepressants; ECG, electrocardiogram.

Invasive Treatments for PHN

A considerable percentage of PHN patients do not respond to currently available pharmacologic therapy. These patients should be referred to pain management centers for consideration of invasive treatments.

The following types of interventions have been reported in management of PHN.

Sympathetic nerve blocks

This intervention can be used for the treatment of PHN. Retrospective data indicates that these blocks may provide temporary relief. In these studies 41%–50% of patients with PHN noted short-term pain following the intervention.⁶⁰

Neuraxial blocks

A few studies have yielded encouraging results with the use of subarachnoid methylprednisolone,⁶¹ but concern regarding the association between this therapy and the development of adhesive arachnoiditis precludes its routine use. In clinical practice epidural injection with local anesthetic and steroids are used in patients with refractory pain due to PHN.

Peripheral nerve blocks

Intercostal nerve blocks have been reported to provide long lasting pain relief in patients with thoracic PHN.⁶¹ We use it occasionally in our practice if a particular patient has not responded to more conventional treatment modalities.

Spinal cord stimulation

Effect of spinal cord stimulation was studied prospectively in a case series of 28 patients (4 with herpes zoster and 24 with PHN). Long-term pain relief was obtained in 82% of the patients with PHN.⁶² The patient serves as their own controls by intermittently switching their spinal cord stimulator off then monitoring themselves for the reappearance of pain.

Cryotherapy

This involves freezing of peripheral nerves. In a small unblinded study, cryotherapy was used for facial PHN pain. No significant benefit was seen.⁶³ The authors did not provide information regarding inclusion criteria, concomitant therapies, or how the response was assessed. A second trial reported considerable benefit in 11 of 14 patients who had undergone cryotherapy to the intercostal nerves for PHN.⁶⁴ The duration of pain relief was less than 2 weeks.

Surgical Intervention

Surgical intervention including electrical stimulation of the thalamus, anterolateral cordotomy, and electrocoagulation of the dorsal root are associated with substantial risks and no consistent benefits.

Physical Therapy and Use of TENS

There have been conflicting responses to transcutaneous electrical nerve stimulatin (TENS) therapy in patients with PHN. There are few small case series that showed beneficial effects with the use of this treatment, but other studies failed to demonstrate any benefit. The patients who have favorable response to the trial therapy are provided with this modality for home use and are recommended to place the electrodes on the contra-lateral side of the affected area.

Acupuncture

There are no studies clearly showing any benefit for this treatment modality.

Psychological Interventions

It has been clearly demonstrated that PHN adversely affect overall quality of life by affecting physical and emotional functioning. Although the effects of cognitive behavioral therapy and psychosocial treatments have not been specifically studied in patients with PHN, these have shown to be beneficial in various chronic pain conditions. Hence, these should be tried in patients with PHN whenever indicated.

PHN as a Model for Neuropathic Pain

In 1900, Henry Head and A.W. Campbell documented location of the zoster rashes in drawings on the skin of several hundred patients and performed autopsies.^65,66 By correlating their drawing and the identification of the zoster affected ganglion, they established the familiar mapping of sensory dermatomes that is used in every day clinical medicine. Since zoster and PHN are so common and easily diagnosed, this has been extensively studied in the investigation and treatment of neuropathic pain. Weddell and Noordenbos⁶⁷ confirmed long-lasting reduction in myelinated axons and increase in small unmyelinated axon profiles in intercostals nerves of four PHN patients in a 1959 study. They hypothesized that “hyperesthesia is due to the loss of fast conducting and the preservation of slow conducting afferent fibers.”

This work resulted in the concept that interactions between different types of sensory neurons might influence the pain perception and laid the foundation for Melzack and Wall's development of the gate theory in 1965.⁶⁸ As the PHN pain is so burdensome and can be recalcitrant to current treatment options, patients easily volunteer for clinical studies. Most of the patients with PHN would recover from the itch and pain with time, and research on these patients to determine as to what led to this symptom resolution will guide us not only to better treatment of PHN patients but also other types of neuropathic pain.

Patients with and without various symptoms after zoster can be studied to determine if genetic influence plays a role in the manifestation of these symptoms. Similarly, interindividual differences in efficacy of a given pharmacological regimen can be correlated with the genetic factors.

Conclusion

Treatment of PHN can be often frustrating to the patient and challenging to the clinician. At the present time there is good evidence to support the use of various pharmacological therapies, including topical lidocaine, capsacin, and use of anticonvulsants, antidepressants along with opioids either used individually or in combination therapy. The benefits of each of these drugs need to be carefully balanced against the patient's underlying medical condition, age, and ability to tolerate side effects. In patients with intractable pain, invasive modalities are tried including spinal cord stimulation. It is also important to realize the impact that PHN can have on the quality of life of the patient and the caregivers; and hence, we should offer psychological and integrative interventions earlier in the course of treatment.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

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Post Herpetic Neuralgia

Abstract

Abstract

Background:

Objective:

Conclusion:

Introduction

Pathogenesis of PHN

Clinical Manifestation of Herpes Zoster and PHN

Diagnosis of PHN

Epidemiology/Risk Factors for Developing PHN

Prevention

Treatment of PHN

Medications

Topical therapies

Topical lidocaine

Topical capsaicin

Other topical treatments

Anticonvulsants

Calcium channel blockers: Gabapentin, pregabalin, and zonisamide

Sodium channel blockers: Topiramate, lamotrigine, phenytoin, carbamazepine, oxcarbazepine, levetiracetam, lidocaine, and valproic acid

Antidepressants

Tricyclics: Amitriptyline, nortriptyline, and desimipraine

Selective serotonin reuptake inhibitor: Duloxetine and venelafaxine

Opioid Analgesics

Tramadol

Tapentadol

Combination Therapy

Invasive Treatments for PHN

Sympathetic nerve blocks

Neuraxial blocks

Peripheral nerve blocks

Spinal cord stimulation

Cryotherapy

Surgical Intervention

Physical Therapy and Use of TENS

Acupuncture

Psychological Interventions

PHN as a Model for Neuropathic Pain

Conclusion

Footnotes

Author Disclosure Statement

References