Background
Herpes zoster (HZ) is a viral infection that usually presents as a childhood infection of varicella (ie, chickenpox). The pathogen is human herpesvirus (HHV)-3, also known as varicella zoster virus (VZV). Following the acute phase, the virus enters the sensory nervous system, where it is harbored in the geniculate, trigeminal, or dorsal root ganglia and remains dormant for many years. With advancing age or immunocompromised states, the virus reactivates, and an eruption (ie, shingles) occurs. Even after the acute rash subsides, pain can persist or recur in affected areas. This condition is known as postherpetic neuralgia (PHN).
A painful vesicular eruption in a dermatomal distribution is typical of HZ. (See the image below.) With resolution of the eruption, pain that continues for 3 months or more is defined as PHN. Pain is intense and may be described as burning, stabbing, or gnawing.
View Image | Hypopigmented rash in thoracic dermatome of postherpetic lesion. |
HZ can reactivate subclinically with pain in a dermatomal distribution without rash.[1] This condition is known as 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.[2]
No laboratory studies are usually necessary in cases of PHN. Results of cerebrospinal fluid (CSF) evaluation are abnormal in 61% of cases.
The goal of therapy for PHN is to reduce morbidity through the use of tricyclic antidepressants (TCAs), anticonvulsants, anesthetics, analgesics, corticosteroids, and antiviral agents. Vaccination is also effective for preventing HZ outbreaks and PHN.[3]
Additional concerns include cost considerations. The financial implications for treatment of PHN are becoming more important as the population ages. In a study examining annualized costs for persistent pain in patients with HZ, Dworkin et al reported that the costs were $4917 for commercially insured patients, $2696 for Medicare patients, and $9310 for Medicaid patients.[4]
Pathophysiology
Some patients with PHN appear to have abnormal function of unmyelinated nociceptors and sensory loss (usually minimal). Pain and temperature detection systems are hypersensitive to light mechanical stimulation, leading to severe pain (allodynia). Allodynia may be related to formation of new connections involving central pain transmission neurons.
Other patients with PHN may have severe, spontaneous pain without allodynia, possibly secondary to increased spontaneous activity in deafferented central neurons or reorganization of central connections. An imbalance involving loss of large inhibitory fibers and an intact or increased number of small excitatory fibers has been suggested. This input on an abnormal dorsal horn containing deafferented hypersensitive neurons supports the clinical observation that both central and peripheral areas are involved in the production of pain.
Etiology
Risk factors for the development of PHN include the following:
Advancing age
Specific sites of HZ involvement - Highest risk: trigeminal (especially ophthalmic division), brachial plexus; moderate risk: thoracic; lower risk: jaw, neck, sacral, lumbar
Severe prodromal pain (with HZ)
Severe rash
Family history has been described as a risk factor for HZ. In a case-control study of 504 patients and 523 controls, Hicks et al found that HZ patients were more likely to report blood relatives with HZ than control subjects were (39% vs 11%). This risk was higher in patients who had multiple blood relatives with HZ than in those who had only one blood relative with HZ.[5]
Epidemiology
US and international statistics
The frequency of PHN is in the range of 9-14.3% at 1 month after the onset of shingles and about 5% at 3 month. At 1 year, 3% of patients continue to have severe pain.
A study from Iceland demonstrated variations in PHN risk that were associated with different age groups.[6] No patient younger than 50 years described severe pain at any time. Patients older than 60 years described severe pain: 6% at 1 month from the onset of shingles and 4% at 3 months.
Age- and sex-related demographics
The association between age and the development of PHN is strong.[7] Advanced age appears to be the most significant risk factor for PHN. At age 60 years, approximately 60% of patients with shingles develop PHN, and at age 70 years, 75% develop PHN.
No sex predilection for PHN is known. In some studies, women have constituted the majority of patients, but this is likely to be a reflection of the usual predominance of women in older age groups.
Prognosis
PHN is not fatal. The natural history of the condition involves slow resolution of the pain syndrome. Patients may experience significant pain for a prolonged period of time.
In most patients with PHN, the pain will respond to analgesic agents (eg, TCAs). In a subgroup of patients, severe, long-lasting pain may develop that does not respond to medical therapy. Continued research for new analgesic agents is necessary.
Patient Education
For patient education resources, see the Infections Center, as well as Shingles and Chickenpox.
History
A painful vesicular eruption in a dermatomal distribution is typical of herpes zoster (HZ). With resolution of the eruption, pain that continues for 3 months or longer is defined as postherpetic neuralgia (PHN). The pain is intense and may be described as burning, stabbing, or gnawing.
HZ can reactivate subclinically with pain in a dermatomal distribution without a rash.[1] This condition is known as 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.[2]
Physical Examination
On examination, an 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. Allodynia—pain produced by a nonnoxious stimulus, such as a light touch by a brush—may be present over involved areas.
Changes in autonomic function (eg, increased sweating over the involved area) may be noted.
Laboratory Studies
In most cases of postherpetic neuralgia (PHN), no laboratory work is necessary .
Evaluation of cerebrospinal fluid (CSF) yields abnormal findings in 61% of patients. Pleocytosis is observed in 46%, elevated protein in 26%, and varicella zoster virus (VZV) DNA in 22%. However, these findings do not predict the clinical course of PHN.
Viral culture or immunofluorescent staining may be used to differentiate herpes simplex virus (HSV) infection from herpes zoster (HZ) in cases where it is difficult to distinguish the two conditions from each other on clinical grounds.
Antibodies to VZV can be measured. A fourfold increase in these antibodies has been used to support the diagnosis of subclinical HZ (zoster sine herpete). However, a rising titer that is secondary to viral exposure rather than reactivation cannot be ruled out.
Imaging Studies
A study by Haanpaa et al revealed the following findings from magnetic resonance imaging (MRI)[8] :
MRI lesions attributable to HZ were seen in the brainstem and cervical cord in nine (56%) of 16 patients
At 3 months after the onset of HZ, five (56%) of the nine patients with an abnormal MRI had developed PHN
Of the seven patients who had no HZ-related lesions on MRI, none had residual pain
Histologic Findings
Although HZ symptoms may be confined to a few sensory dermatomes, pathologic changes may be more widespread. Affected ganglia of the spinal or cranial nerve roots are swollen and inflamed with a primarily lymphocytic reaction. Some ganglion cells are swollen while others are degenerated.
Inflammation extends into the meninges and root entry zone and may be present in the ventral horn and perivascular space of the spinal cord. Pathologic changes in the brainstem are similar to those in the spinal root and spinal cord. In the months following infection, fibrosis occurs in the ganglia, peripheral nerve, and nerve root. Degeneration occurs in the ipsilateral posterior column.
Medical Care
The goal of therapy for postherpetic neuralgia (PHN) is to reduce morbidity through the use of antidepressants, anticonvulsants, anesthetics, analgesics, corticosteroids, and antiviral agents. Vaccination is also effective for preventing herpes zoster (HZ) outbreaks and PHN.[9]
Vaccination
Use of a live attenuated varicella zoster virus (VZV) vaccine has been shown in a clinical trial to be effective in preventing HZ and PHN. In a study by Brisson, the estimated number of 65-year-olds who would have to be vaccinated (HZ vaccine efficacy = 63%, PHN vaccine efficacy = 67%, no waning) to prevent one case of HZ was 11; to prevent one case of PHN, 43; to prevent one HZ death, 23,319; to prevent loss of one life-year, 3762; and to prevent loss of one quality-adjusted life-year (QALY), 165.[10] The results of this study showed that the main benefit of HZ vaccination is prevention of morbidity caused by pain.
In 2011, the Food and Drug Administration (FDA) lowered the approved age for use of Zostavax (Merck, Rahway, NJ) to 50-59 years; the vaccine was already approved for use in individuals aged 60 years or older. Approval was based on the results of the multicenter Zostavax Efficacy and Safety Trial (ZEST),[11] conducted in the United States and four other countries in 22,439 people aged 50-59 years. Participants were randomized in a 1:1 ratio to receive either Zostavax or placebo and monitored for at least 1 year to see if shingles developed. Compared with placebo, Zostavax reduced the risk of developing HZ by approximately 70%.
In 2017, the FDA approved Shingrix (zoster vaccine recombinant, adjuvanted) for the prevention of shingles in adults aged 50 years or older. Approval was based on findings from a phase III clinical trial program assessing its efficacy, safety, and immunogenicity in 38,000 patients. Data from a pooled analysis of two clinical trials demonstrated efficacy against shingles greater than 90% across all age groups, as well as sustained efficacy over a follow-up period of 4 years.[12, 13, 9]
Pharmacotherapy
In 2017, the FDA approved Lyrica CR (pregabalin extended-release tablets) for the management of PHN. The approval was based on data from a randomized placebo-controlled trial conducted in 801 patients with PHN, which included a 6-week single-blind dose-optimization phase followed by a 13-week double-blind phase.[14] Compared with patients in the placebo group, more patients in the Lyrica CR group experienced at least a 50% improvement in pain intensity (73.6% vs 54.6%).
In a retrospective cohort study comparing the efficacy and safety of pregabalin with those of gabapentin in the treatment of PHN, Shi et al found pregabalin to be more effective, with a comparable incidence of adverse events.[15] Sleep quality and analgesia were better with pregabalin, and adverse emotions were lessened.
Antidepressants used in the treatment of PHN include tricyclic antidepressants (TCAs; eg, amitriptyline and nortriptyline) and serotonin-norepinephrine reuptake inhibitors (SNRIs; eg, duloxetine and venlafaxine).[16, 17]
A trial conducted by Gilron et al demonstrated that the combination of gabapentin and nortriptyline was more efficacious than either drug alone as monotherapy for neuropathic pain.[18]
Antivirals used in the management of PHN include acyclovir, famciclovir, and valacyclovir. A network meta-analysis by Liu et al concluded that all of the available oral antivirals were well tolerated but that oral famciclovir was the most effective for the treatment of acute pain and PHN and oral valacyclovir was the most effective treatment for alleviating pain after 28-30 days.[19]
In a small study (N = 24) by Kanai et al, lidocaine 4% ophthalmic drops were administered to patients with ophthalmic PHN in a crossover manner.[20] A significant reduction in eye and forehead pain was observed in patients who received the drops. The onset of analgesic onset was noted via a visual analogue scale (VAS) within 15 minutes after administration and persisted for a median of 36 hours (range, 8-96 h).
Topical lidocaine patches have only minimal side effects and may be useful for relief of pain in this setting; they may be particularly helpful as adjuvant therapy in combination with agents such as gabapentin.[21]
One study found that a single 60-minute treatment with the high-concentration capsaicin patch NGX-4010 reduced PHN for up to 12 weeks regardless of concomitant systemic neuropathic pain medication use.[22]
Other treatments
Chen et al (N = 77) found vitamin C plasma concentrations to be lower in 38 patients with PHN (n = 38) than in healthy volunteers (n = 39).[23] In this study, restoration of vitamin C concentrations decreased spontaneous pain (but not brush-evoked pain) by 3.1 on a numeric pain scale in the PHN group as compared with the placebo group. The authors concluded that vitamin C status is a factor in PHN and is a component involved in spontaneous pain relief.
Surgical Care
Dorsal root entry zone (DREZ) lesioning has been employed as a means of treating PHN.[24] Long-term improvement rates of 20% have been citedreported. Gait disturbances are experienced by 12% of treated patients.
Other inventions include the following:
Author
W Alvin McElveen, MD, Director, Stroke Unit, Lakewood Ranch Medical Center; Neurologist, Manatee Memorial Hospital
Disclosure: Nothing to disclose.
Coauthor(s)
Douglas Sinclair, DO, Consulting Staff, Department of Neurology, Blake Medical Center and Bradenton Neurology, Inc
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Robert A Egan, MD, NW Neuro-Ophthalmology
Disclosure: Received honoraria from Biogen Idec and Genentech for participation on Advisory Boards.
Acknowledgements
Ralph F Gonzalez, MD Private Practice, Bradenton Neurology, Inc; Consulting Staff, Department of Neurology, Blake Hospital, Lakewood Ranch Medical Center, Manatee Memorial Hospital
Ralph F Gonzalez, MD is a member of the following medical societies: American Academy of Neurology and Florida Medical Association
Disclosure: Nothing to disclose.
){kind=link}