Abstract
Herpes zoster (shingles) is caused by reactivation of the varicella-zoster virus (VZV) from dorsal sensory or cranial nerve ganglia. The characteristic unilateral dermatomal vesicular rash of herpes zoster heals within 2 to 4 weeks and is accompanied by pain in the majority of patients. Older age is associated with an increased risk of herpes zoster because of an age-associated decline in VZV-specific cell-mediated immunity. Antiviral therapy reduces the duration of viral shedding, hastens rash healing, and decreases the duration of pain. The supplementation of antiviral therapy with opioids or corticosteroids may provide additional pain relief in herpes zoster patients with moderate to severe acute pain.
Peripheral, sympathetic, and epidural nerve blocks with local anesthetics and/or corticosteroids appear to relieve acute pain in patients with herpes zoster, but their role in preventing PHN is uncertain.
Postherpetic neuralgia refers to pain that continues after healing of the herpes zoster rash. This peripheral neuropathic pain condition causes substantial distress and disability and can last for years. Risk factors for PHN in patients with herpes zoster include older age, more intense acute pain, more severe rash, and a prodrome of dermatomal pain before the rash appears. The efficacy of gabapentin, high concentration capsaicin patch, lidocaine patch 5%, pregabalin, tramadol, tricyclic antidepressants, and opioid analgesics provide an evidence-based approach to treatment. Combination therapy with opioids-gabapentin, nortriptyline-gabapentin, opioid-nortriptyline may be more effective than either drug alone.
Keywords
herpes zoster, neuropathic pain, postherpetic neuralgia, shingles, varicella-zoster virus
The objective of this chapter is to provide an overview of the epidemiology, natural history, pathophysiology, treatment, and prevention of herpes zoster and postherpetic neuralgia (PHN). Herpes zoster (“shingles”) is a viral infection that is accompanied by acute pain in the majority of patients. The pain associated with herpes zoster does not resolve in a substantial number of patients, which results in a chronic peripheral neuropathic pain condition called PHN.
Herpes Zoster
Epidemiology of Herpes Zoster
Following a primary chicken pox infection, the varicella-zoster virus (VZV) establishes latency in sensory ganglia throughout the nervous system. Herpes zoster (shingles) is the reactivation of the virus and its spread from a single dorsal root or cranial nerve ganglion to the corresponding dermatome and neural tissue of the same segment. Herpes zoster has the highest incidence of all neurologic diseases, occurring annually in approximately 1 million people in the United States, during the lifetimes of as much as 20%–30% of the population and in as many as 50% of those living until age 85. The likelihood of recurrent zoster in immunocompetent persons was reported to be 5.7% after 8 years from the initial zoster episode.
A fundamental epidemiologic feature of zoster is a marked increase in incidence with aging. The increase in the likelihood of herpes zoster with aging starts around 50–60 years of age and increases markedly into late life in individuals older than 80 years of age. For example, the incidence of herpes zoster per 1000 person-years in a US retrospective database study was 2.1 for persons aged 40–49 years, 4.2 for 50–59, 6.0 for 60–69, 8.6 for 70–79, and 10.7 for 80 and older.
The incidence of herpes zoster is also significantly increased in patients with suppressed cell-mediated immunity. Immunocompromised patients at risk for herpes zoster include persons with Hodgkin disease, non-Hodgkin lymphomas, leukemia, bone marrow and other organ transplants, human immunodeficiency virus (HIV) infection, systemic lupus erythematosus, rheumatoid arthritis, and those individuals taking immunosuppressive medications, including tumor necrosis factor inhibitors. White race, female sex, and physical trauma are other risk factors for herpes zoster.
Patients with herpes zoster who have a vesicular rash may transmit VZV via direct contact, airborne or droplet nuclei to seronegative, nonimmune individuals, such as children who have not received the varicella vaccine or who have had an insufficient response to the vaccine, and susceptible health care workers and staff in hospital or in nursing homes. These individuals may then develop varicella. The exposure of an individual who is latently infected with VZV to herpes zoster does not cause herpes zoster or varicella.
Natural History of Herpes Zoster
The presentation of pain in herpes zoster is variable. In the majority of patients, a prodrome of dermatomal pain precedes the appearance of the characteristic unilateral rash. This prodrome begins several days before rash onset in almost all cases, but a series of patients with prodromal pain preceding the appearance of the rash by 7 to more than 100 days has been reported. Thoracic dermatomes are the most commonly affected sites in herpes zoster and account for 50%–70% of all cases; cranial (especially the ophthalmic division of the trigeminal nerve), cervical, and lumbar dermatomes each account for 10%–20% of cases, and sacral dermatomes are affected in 2%–8% of cases. The rash becomes vesicular after several days, then forms a crust, and loss of all scabs usually occurs within 2–4 weeks.
Pain in the affected dermatome accompanies the rash in most patients. Those who did not have a painful prodrome typically begin to experience pain at rash onset or shortly afterwards ( Fig. 28.1 ). VZV-induced acute neuritis is described as burning, deep aching, tingling, itching, or stabbing. A subset of patients may develop severe pain, especially those with trigeminal nerve involvement. Acute herpetic neuralgia has a profound negative impact on functional status and quality of life and usually results in substantial health service utilization.
Dermatomal pain without a rash, referred to as zoster sine herpete, has also been described, and the finding of VZV DNA in the cerebrospinal fluid of patients with prolonged radicular pain and no rash provides evidence of this syndrome.
In addition to acute pain, the morbidity of herpes zoster includes neurologic disorders and ophthalmologic, cutaneous, and visceral complications. The types of neurologic complications include motor neuropathy, cranial polyneuritis, transverse myelitis, meningoencephalitis, and cerebral angiitis and stroke after ophthalmic zoster. Ophthalmologic complications include keratitis, uveitis, iridocyclitis, panophthalmitis, and glaucoma. Elderly and especially immunosuppressed patients are at greater risk for most of the complications of herpes zoster.
Treatment of Herpes Zoster
The main goals of the treatment of herpes zoster are to relieve acute pain and prevent PHN. Treatment of herpes zoster patients with the antiviral agents acyclovir, brivudine, famciclovir, or valacyclovir inhibits viral replication and has been shown to reduce the duration of viral shedding, hasten rash healing, and decrease the severity and duration of acute pain. The results of randomized controlled trials and meta-analyses are conflicting as to whether antiviral agents prevent PHN, partly because of heterogeneity in definitions of PHN and study design, although the duration of pain is decreased in some of these trials. Therefore, based on reduction in acute pain and the potential for reduction in pain duration, antiviral therapy is recommended as first-line treatment in herpes zoster patients who are aged 50 years and older. Famciclovir (500 mg every 8 hours for 7 days), valacyclovir (1 g 3 times daily for 7 days), and brivudine (125 mg daily for 7 days) offer more convenient dosing and higher and more reliable blood levels of antiviral activity compared with acyclovir (800 mg 5 times a day for 7–10 days).
Some patients do not have their acute pain adequately controlled with antiviral therapy and simple analgesics. How then can acute pain and the risk of chronic pain be further reduced beyond that currently achieved by antiviral therapy? Corticosteroids, opioids, gabapentin, and neural blockade have been investigated or considered as strategies to achieve these goals.
Randomized clinical trials (RCTs) demonstrated that the addition of a corticosteroid reduced acute pain but did not contribute significantly beyond the benefits achieved by antiviral therapy alone in reducing prolonged pain. The evidence from these trials indicated that corticosteroids do not prevent PHN.
An RCT of oxycodone, gabapentin, or placebo in older adults with herpes zoster showed that oxycodone but not gabapentin provided significantly greater pain relief than placebo. This trial was not powered to analyze PHN, and there are no other controlled trials of the effect of opioids or gabapentin on PHN when used during the acute phase of herpes zoster, except for a crossover study that showed greater pain relief with a single dose of 900 mg of gabapentin versus placebo.
Regarding neural blockade, the results of a randomized controlled trial in patients with herpes zoster treated with oral antiviral therapy showed that a single epidural injection of steroids and local anesthetics relieved acute pain within the first month after rash onset significantly better than usual care but did not reduce the risk of developing PHN. RCTs of multiple epidural injections, continuous epidural infusions, or repetitive paravertebral injections of anesthetics and steroids during herpes zoster reduced PHN or time to complete cessation of pain. Although treatment of herpes zoster patients with multiple epidural injections or continuous epidural infusions is unlikely to be feasible in most settings, these data suggest that aggressive analgesia can be effective in patients with herpes zoster and ongoing moderate to severe pain.
Even if the risk of developing PHN is not reduced by combining antiviral therapy with analgesic or corticosteroid treatment in patients with herpes zoster, effective relief of acute pain is a critical treatment goal. For patients with moderate to severe pain, treatment with a strong opioid analgesic (e.g., oxycodone) is recommended in combination with antiviral therapy. If moderate to severe pain in patients with herpes zoster has not responded rapidly to treatment with an opioid analgesic and antiviral therapy, then the addition of a corticosteroid can be considered. For patients with pain that is inadequately controlled by antiviral agents in combination with oral analgesic medications and/or corticosteroids, referral to a pain specialist or pain center is recommended to evaluate eligibility for neural blockade.
Prevention of Herpes Zoster
The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) recommends the live attenuated zoster vaccine for the prevention of herpes zoster and PHN in immunocompetent adults 60 years of age and older. The recommendation is based on the results of the Shingles Prevention Study, a large placebo controlled trial in persons 60 years and older. In this study, the vaccine reduced incidence of herpes zoster from 11.12 to 5.42 cases (51.3%) per 1000 person-years, reduced the incidence PHN from 1.38 to 0.46 cases (66.5%) per 1000 person years, and reduced the pain burden of illness (a pain severity by duration measure) caused by herpes zoster by 61.1%. The exact duration of the protection against herpes zoster by the zoster vaccine is unknown, but recent studies suggest that the live vaccine efficacy for herpes zoster and pain burden persists through year 8 after vaccination but probably not beyond 10 years. In a large randomized placebo controlled trial of the live zoster vaccine in individuals 50–59 years old, vaccine efficacy for prevention of herpes zoster was 69.8%. The US Food and Drug Administration (FDA) licensed the live vaccine for use in immunocompetent adults 50 years of age. However, the ACIP retained the recommendation to vaccinate at 60 years of age and over because zoster vaccine administration should be timed to achieve the greatest reduction in burden of herpes zoster and its complications, which is in persons over 60 years old.
A recently developed subunit zoster vaccine containing VZV glycoprotein E and the AS01b adjuvant system was tested for efficacy against herpes zoster in a multisite randomized placebo controlled trial called the Zoster Efficacy Study in Adults 50 Years of Age or Older (ZOE-50). The intervention was two intramuscular doses of the vaccine or placebo 2 months apart. The results showed that the subunit adjuvanted vaccine reduced the incidence of herpes zoster in this age group by 97.2% with an adequate safety profile. This vaccine is not yet licensed by the FDA but looks to be an exciting addition to our interventions against herpes zoster.
Postherpetic Neuralgia
Epidemiology and Natural History
A variety of definitions of PHN have been used by clinicians and investigators, ranging from any pain persisting after rash healing to pain that has persisted at least 6 months after rash onset. The results of studies suggest that the pain associated with herpes zoster has three phases—an acute herpetic neuralgia that accompanies the rash and lasts for approximately 30 days after rash onset, a subacute herpetic neuralgia that lasts from 30 to 120 days after rash onset, and PHN, defined as pain that persists for at least 120 days after rash onset (see Fig. 28.1 ). Although this provides a validated definition for research on PHN, it is probably unnecessary to distinguish between subacute herpetic neuralgia and PHN when treating patients with pain persisting after rash healing.
Because the proportion of herpes zoster patients with pain declines with time, estimates of the percentage of patients who develop PHN depend on its definition. In an analysis of a cohort of 27,225 herpes zoster (HZ) patients in the UK General Practice Research Database, 13.7% of patients developed PHN at least 3 months after HZ diagnosis. Of those patients, 58.5% had moderate to severe pain. In an analysis of 1669 HZ patients in a population-based study of adult residents of Olmsted County, Minnesota, 18% of patients developed PHN, defined as zoster-associated pain persisting at least 90 days. PHN occurred in 33% of individuals aged 79 years and older. Estimates of the number of prevalent cases of PHN have ranged from 500,000 to 1 million in the United States.
PHN is a chronic pain syndrome that can last for years and cause substantial suffering and reduction in quality of life. As is true of other chronic pain syndromes, patients develop depression and other types of psychological distress as well as physical, occupational, and social disability as a consequence of their unremitting pain. There is evidence that pain in PHN can be discontinuous, with pain-free intervals of varying durations occurring. Indeed, PHN can develop even in herpes zoster patients who have not had acute pain.
The quality of pain in PHN compared to herpes zoster has been examined in several studies. Sharp, stabbing pain was found to be more common in patients with zoster than in patients with PHN, whereas burning pain was more common in PHN patients and much less likely to be reported by patients with zoster. The investigators noted that the word tender was chosen by both groups of patients to describe allodynia (i.e., pain in response to a stimulus that does not normally provoke pain). These adjectives reflect the three different types of pain that have been distinguished in research on PHN—a steady throbbing or burning pain, an intermittent sharp or shooting pain, and allodynia.
Older age is the most well-established risk factor for PHN. In the UK General Practice Research Database study, not only did the incidence of PHN increase with age, but the prevalence of moderate-severe pain also increased with age, from 46% in 50–54-years-olds to 68% in 80–85-year-olds. Furthermore, the duration of PHN increased with pain severity. For individuals with severe pain 3 months after rash onset, the average duration of PHN was 12.5 months. Many independent studies have reported that patients with more severe acute pain are at greater risk for PHN. As noted above, the majority of herpes zoster patients have a painful prodrome before their rash appears, and several studies have found that these patients have a greater risk of PHN than patients who did not have a prodrome. Greater severity and duration of the herpes zoster rash are additional risk factors for the development of PHN that have been identified in multiple studies.
Pathophysiology
Except for age and psychosocial factors, the risk factors for PHN that have been identified can all be considered concomitants of a more severe infection. More severe zoster infections are accompanied by greater neural damage, and it has been proposed that this neural damage contributes prominently to the development of PHN. However, the nature of this damage and the specific mechanisms by which it causes the persisting pain of PHN remain unclear. What limited knowledge there is of the pathophysiology of PHN derives from studies of neuropathology, sensory dysfunction, and pharmacologic response. There is considerable agreement currently that different peripheral and central mechanisms contribute to PHN and that the qualitatively different types of pain that characterize PHN probably have different underlying mechanisms. This suggests that there may be pathophysiologically distinct subgroups of patients with PHN or that more than one mechanism may be involved in individual patients or both.
Watson and his colleagues have conducted an elegant series of postmortem studies of patients of who were suffering from PHN at the time of death and of patients with a history of herpes zoster whose pain did not persist beyond rash healing. In these studies, dorsal horn atrophy and pathologic changes in the sensory ganglion were found on the affected side (and not on the unaffected side) in patients with PHN but not in patients with a history of herpes zoster whose pain did not persist. In a set of studies using punch-skin biopsy, reductions in epidermal nerve fiber density were found in the affected dermatome but not on the contralateral unaffected side in patients with PHN. Notably, in both the postmortem studies and the punch-skin biopsy studies, the pathologic features were characteristic of only the affected side in patients with PHN and were not found in patients with a history of zoster whose pain did not persist.
Rowbotham, Fields, and Petersen have conducted an important series of studies of sensory dysfunction and pharmacologic response that address the pathophysiology of PHN. PHN patients with prominent allodynia were found to have relatively normal sensory function as assessed by thermal thresholds and were also more likely to report pain relief following local anesthetic infiltration with lidocaine than patients with primarily constant pain. These authors conclude that at least two different mechanisms may contribute to PHN and propose that the mechanism of allodynia in PHN is abnormal activity in preserved primary afferent nociceptors that have been damaged by the VZV but that remain in continuity with their central targets. Activity in these “irritable” nociceptors may initiate and then maintain a state of central sensitization in which input from large fiber afferents that respond to nonpainful mechanical stimuli causes allodynia.
As opposed to patients with prominent allodynia, PHN patients with predominantly continuous pain were found to have sensory loss in the areas where they have the most pain. This suggests that continuous pain in PHN is caused by a different mechanism than allodynia, possibly involving central structural and functional changes accompanying deafferentation. These may include a structural reorganization of the spinal cord that involves abnormal synaptic connections, as well as functional abnormalities resulting from deafferentation involving hyperexcitability of dorsal horn neurons. A clinical trial that compared oxcarbazepine to placebo in neuropathic pain (including PHN) patients stratified participants by irritable versus nonirritable pain phenotypes. The results showed that the number needed to treat to obtain one patient with more than 50% neuropathic pain relief was 3.9 (95% confidence interval [CI] 2.3–12) in the irritable and 13 (95% CI 5.3–∞) in the nonirritable nociceptor phenotype.
Treatment
The efficacy of lidocaine patch 5%, gabapentin, pregabalin, tricyclic antidepressants (TCAs), opioid analgesics, tramadol, and high-concentration capsaicin patch has been demonstrated by the results of randomized controlled trials in patients with PHN, although a recent meta-analysis has called the benefits of opioids into question. Depending on the study, in general, these agents produce clinically significant reduction in pain in about 30%–60% of patients. The initial choice of these medications should be guided by the adverse event profiles, potential for drug interactions, and patient comorbidities and treatment preferences, especially because there are no replicated data demonstrating superior effectiveness of one drug over another. In general, the lidocaine patch 5%, gabapentin, and pregabalin can be considered first-line treatments for PHN. TCAs, opioid analgesics, tramadol, and high-dose capsaicin patch require greater caution and/or specialized expertise in the often elderly patient with PHN.
Lidocaine Patch 5%
Treatment with the lidocaine patch 5% consists of the application of up to three patches daily for a maximum of 12 hours applied directly to the area of maximal PHN pain and allodynia, which typically overlaps the affected dermatome. The lidocaine patch 5% is not approved for patients with herpes zoster, and it should not be used in patients with open lesions because the available formulation is not sterile. Importantly, whether the patient obtains satisfactory relief from lidocaine patch 5% will usually be apparent within 2–3 weeks and time-consuming dose escalation is not required. The only adverse effects involve skin reactions (e.g., erythema, rash). Systemic absorption is minimal but must be considered in patients receiving oral class I antiarrythmic drugs.
Gabapentin
To reduce the likelihood of adverse effects and increase patient compliance with treatment, gabapentin should be initiated at low dosages—100–300 mg in a single dose at bedtime or 100 mg 3 times daily—and then titrated by 100 mg 3 times daily as tolerated. Because of variability in gabapentin absorption, the final dosage should be determined either by acceptable levels of pain relief or by unacceptable adverse effects that do not resolve over a few weeks. Adverse effects of gabapentin include somnolence, dizziness, and mild peripheral edema, which requires monitoring and possibly dosage adjustment but usually not treatment discontinuation. Gabapentin may cause or exacerbate gait and balance problems and cognitive impairment in the elderly. Dosage adjustment is necessary in patients with renal insufficiency, but its generally excellent tolerability, safety, and lack of drug interactions distinguish gabapentin from the other oral medications used in the treatment of PHN.
Pregabalin
Pregabalin is similar in structure to gabapentin. Pregabalin should be initiated at 100–150 mg/day in two or three divided doses. Frail older patients may require lower starting doses. The dose may be increased to 300 mg/day in two or three divided doses within 1 week depending on clinical response and any adverse effects. The maximum dose of 600 mg/day in two or three divided doses can be considered if the patient does not have adequate pain relief at the risk of significantly higher frequency of adverse effects. Dizziness, somnolence, peripheral edema, amblyopia, dry mouth, and gait disturbances are the most common adverse effects of the medication.
Tricyclic Antidepressants
To decrease the likelihood of adverse effects, all TCAs should be initiated at low dosages—10–25 mg in a single dose at bedtime—and should then be slowly titrated as tolerated. It is often claimed that the analgesic effect of TCAs occurs at lower dosages than their antidepressant effect, but there is no controlled evidence of this. Consequently, TCAs should be titrated to dosages of at least 75–150 mg daily. For titration above 100–150 mg daily, blood levels and the electrocardiogram (EKG) should be monitored. Irrespective of the TCA chosen, it is imperative that patients understand the rationale for treatment, specifically, that TCAs have an analgesic effect that has been demonstrated to be independent of their antidepressant effect. Amitriptyline is widely used for PHN. However, amitriptyline is poorly tolerated and contraindicated in elderly patients. In one of the few randomized, double-blind trials that have compared two different treatments in elderly PHN patients, nortriptyline demonstrated equivalent efficacy to amitriptyline but was better tolerated. Based on the results of this study, nortriptyline should now be considered the preferred TCA for the treatment of PHN in older adults.
Despite the efficacy of TCAs in the treatment of PHN, their cardiac toxicity and side effect profile require considerable caution when treating older patients with PHN. Dry mouth is the most common side effect, and constipation, sweating, dizziness, disturbed vision, and drowsiness also occur frequently. All TCAs must be used very cautiously in patients with a history of cardiovascular disease, glaucoma, urinary retention, and autonomic neuropathy, and a screening EKG to check for cardiac conduction abnormalities is recommended before beginning TCA treatment, especially in patients over 40 years of age. TCAs must be used cautiously when there is a risk of suicide or accidental death from overdose, and TCAs may cause balance problems and cognitive impairment in the elderly. TCAs can block the effects of certain antihypertensive drugs and interact with drugs metabolized by P450 2D6 (e.g., type 1C antiarrythmics). Because all SSRIs inhibit P450 D26, caution is necessary in the concomitant administration of TCAs and SSRIs to prevent toxic TCA plasma concentrations.
In addition, there are no published RCTs of either selective serotonin reuptake inhibitors (e.g., fluoxetine, paroxetine) or selective serotonin and norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine) in PHN; thus, it is unknown whether these classes of antidepressant medications are efficacious in PHN. However, considering that TCAs inhibit the reuptake of serotonin and norepinephrine and have well-established efficacy in PHN, it can be predicted that selective serotonin and norepinephrine reuptake inhibitors would also have efficacy in PHN.
Opioid Analgesics
There are numerous short- and long-acting opioid analgesics available, and treatment can begin with a short-acting medication at morphine oral equianalgesic dosages of 5–15 mg every 4 hours as needed. After 1–2 weeks of treatment, the total daily dosage can be converted to an equianalgesic dosage of one of the available long-acting opioid analgesics (e.g., controlled-release morphine oxycodone, oxymorphone, or tapentadol, and transdermal fentanyl, levorphanol, and methadone) while the patient continues taking the short-acting medication on an as-needed basis. Evaluation by a pain specialist should be considered when contemplating the use of opioids for PHN especially for daily dosages greater than 100 mg morphine or its equivalent given increasing concerns about the risk/benefit ratio with long-term use of opioids.
The most common adverse effects of opioid analgesics are constipation, sedation, and nausea; in addition, cognitive impairment, and problems with mobility can occur in elderly patients. Opioid analgesics must be used very cautiously in patients with a history of substance abuse or suicide attempts, since accidental death or suicide can occur with overdose. Patients treated with opioid analgesics may develop analgesic tolerance (i.e., a reduction in analgesic benefit over time), although a stable dosage can often be achieved. All patients develop physical dependence (i.e., withdrawal symptoms develop with abrupt discontinuation or rapid dose reduction), and must be advised that they should not abruptly discontinue their medication. The risk of substance abuse developing in patients who do not have a history of substance abuse is not known.
Tramadol
Tramadol is a norepinephrine and serotonin reuptake inhibitor with a major metabolite that is a mu opioid agonist. Tramadol should be initiated at low dosages—50 mg once or twice daily—and then titrated every 3–7 days by 50–100 mg/day in divided doses as tolerated. The maximum dosage of tramadol is 400 mg daily; in patients aged over 75, the maximum dosage of tramadol is reduced, for example, to 300 mg daily in divided doses.
The adverse effects of tramadol include dizziness, nausea, constipation, somnolence, and orthostatic hypotension. These occur more frequently when the dosage is escalated rapidly and with concurrent administration of other drugs with similar side effect profiles. There is an increased risk of seizures in patients treated with tramadol who have a history of seizures or who are also receiving antidepressants, opioids, or other drugs that can reduce the seizure threshold. Serotonin syndrome may occur if tramadol is used concurrently with other serotonergic medications, especially selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors. Tramadol may cause or exacerbate cognitive impairment in the elderly, and dosage adjustment is necessary in patients with renal or hepatic disease. Abuse of tramadol is relatively uncommon but does occur.
High-Concentration Capsaicin Patch
Application of the high-concentration capsaicin patch should be performed in specialist clinics by personnel trained in the proper application of the patch. Because of the high concentration, capsaicin can be aerosolized and inhaled, resulting in coughing or sneezing, or get into mucous membranes or the eyes, resulting in irritation. After application of a topical anesthetic, the patch is applied to the most painful area for an hour and then removed. The application can be repeated every 3 months depending on the analgesic response to the patch. Adverse events include acute pain during the procedure, which is usually transient, application-site skin reactions (e.g., erythema), and transient increases in blood pressure.
Sequential and Combination Pharmacologic Treatment
There have been a few clinical trials in which medications have been directly compared with one another in patients with PHN. Such comparisons not only make it possible to directly determine whether treatments vary in their efficacy, safety, and tolerability, but when conducted in the same patients, it also enables evaluating the extent to which treatment response to one medication predicts response to another. For example, treatment responses to opioid analgesics and TCAs were uncorrelated in a recent three-period, placebo-controlled crossover trial, which suggests that when patients have not responded to one of these types of medication, they may still respond to the other.
The prescription of combination pharmacotherapy for PHN is common in clinical practice. The efficacy of this practice has been the subject of recent studies of additive or synergistic benefits of combination treatment. In a 5-week double-blind crossover trial, patients with diabetic polyneuropathy or PHN were randomized to daily active placebo (lorazepam), sustained-release morphine, gabapentin, and a combination of gabapentin and morphine. Baseline mean daily pain (0–10) was 5.72. At maximum tolerated dose, pain was rated at 4.49 with placebo, 4.15 with gabapentin, 3.70 with morphine, and 3.06 with the gabapentin–morphine combination ( P < .05 for the combination vs. placebo, gabapentin, and morphine). Results for PHN alone were not reported. Constipation, sedation, and dry mouth were the most common adverse effects. In a 6-week double-blind crossover trial, patients with diabetic polyneuropathy or PHN were randomized to receive one of three sequences of daily oral gabapentin, nortriptyline, and their combination. Baseline mean pain intensity was 5.4 (0–10 scale). For patients with PHN, pain with combination treatment (mean 2.5, CI 1.4–3.6) was lower than with nortriptyline (mean 2.9, CI 1.7–4.0) or gabapentin alone (mean 3.4, CI 2.2–4.5), but the overall effect of drug treatment was not significant ( P = .054), possibly because of small sample size. The most common adverse event was dry mouth secondary to nortriptyline. In an evaluation of a nortriptyline-morphine combination, compared with each drug alone, patients with neuropathic pain, including PHN, were randomized to receive oral nortriptyline, morphine, and their combination in a double-blind crossover trial during 6-week periods. Average daily pain (0–10) at baseline was 5.3. At maximum tolerated dose of the drugs, the average daily pain was 2.6 for combination versus 3.1 for nortriptyline ( P = .046) and 3.4 for morphine ( P = .002). Combination treatment resulted in moderate-severe constipation in 43% versus 46% with morphine ( P = .82) and 5% with nortriptyline ( P < .0001). Combination treatment resulted in moderate-severe dry mouth in 58% versus 49% with nortriptyline ( P = .84) and 13% with morphine ( P < .0001). Somnolence was also among the most frequent adverse effects.
These results suggest that combination therapy may provide additional pain relief in some individuals with PHN who have responded to one or another agent. Disadvantages of combination therapy include an increased risk of adverse effects as the number of medications is increased.
Alternatives to Topical and Oral Medications
A considerable percentage of PHN patients will not respond to medications when used alone and in combination. For these patients, there are a large number of alternative treatments that deserve consideration, and referral to a pain management center should be contemplated sooner rather than later.
Noninvasive treatments include cold application, transcutaneous electrical nerve stimulation (TENS), percutaneous electrical nerve stimulation (PENS), psychological treatments, and acupuncture. These interventions have little risk and may be useful in some patients, but whether they are effective in a population of patients with PHN is unknown and needs to be tested in controlled clinical trials. Some PHN patients may have associated myofascial pain in addition to neuropathic pain. The presence of myofascial pathology is indicated by taut muscle bands (i.e., a group of tense muscle fibers extending from a trigger point to the muscle attachments) and trigger point(s) (i.e., a hyperirritable spot in skeletal muscle that is painful on compression) in the affected dermatome. These patients are good candidates for a trial of PENS.
Invasive treatments may be considered when patients have failed to obtain adequate relief from noninvasive treatment approaches. Invasive treatments include peripheral and central neural blockade, central nervous system (CNS) drug delivery, spinal cord stimulation, and neurosurgical techniques. Neural blockade techniques include sensory nerve, plexus, and sympathetic nerve blocks and epidural and intrathecal blockade with lidocaine-like drugs and/or corticosteroids. Many PHN patients note initial relief of pain with nerve blocks, but few experience long-lasting relief. A study examining intrathecal administration of methylprednisolone in patients with PHN received considerable attention because of the dramatic benefits that were described. However, attempts to replicate these results have not been successful, and intrathecal administration of methylprednisolone is not approved by the FDA, and the well-known risks of intrathecal steroids include neurologic complications and adhesive arachnoiditis. CNS drug delivery attempts to place the drug (e.g., morphine) as close as possible to central pain receptors in the spinal cord corresponding to the affected dermatome(s). Spinal cord stimulation requires implantation of an electrode in the thoracic or lumbar epidural space and the placement of a percutaneous electrical stimulator. These interventions represent rational approaches to pain relief but they have not been proven effective in controlled trials, partly because the design and conduct of such trials are difficult, and they carry procedural risks, especially in older patients. In general, these interventions have a limited role in PHN treatment and should be contemplated in patients who have failed all other treatments and continue to have disabling pain.
It is important to conclude by emphasizing that the medications and invasive treatments that are currently available are rarely associated with the complete relief of PHN and evidence of their beneficial effects on quality of life is limited. Medical and invasive management of the patient with PHN should therefore be considered components of a more comprehensive treatment approach, which may include various nonpharmacologic treatments such as psychological counseling.
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