An Update on the Treatment of Postherpetic Neuralgia

The Journal of Pain, Vol 9, No 1 (January), Supplement 1, 2008: pp S19-S30
Available online at www.sciencedirect.com
An Update on the Treatment of Postherpetic Neuralgia
Christopher L. Wu and Srinivasa N. Raja
Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine,
Baltimore, Maryland.
Abstract: Like other types of neuropathic pain, postherpetic neuralgia (PHN) can be resistant to
many types of pharmacologic and interventional therapies. Although many analgesic agents have
been used for the treatment of other types of neuropathic pain, tricyclic antidepressants, antiepileptic drugs, opioids, and lidocaine patch appear to demonstrate relative analgesic efficacy for
the treatment of pain from PHN. There are fewer studies on the use of interventional options for
the treatment of pain from PHN. The majority of interventional therapies show equivocal analgesic efficacy although some data indicate that intrathecal methylprednisolone may be effective.
Further randomized, controlled trials will be needed to confirm the analgesic efficacy of analgesic
and interventional therapies to determine their role in the overall treatment of patients with PHN.
Perspective: This article reviews the analgesic options for the treatment of PHN and suggests that
tricyclic antidepressants, membrane stabilizers, opioids, and lidocaine patch may demonstrate analgesic efficacy in this group of patients. These data may potentially help clinicians who attempt to
provide analgesia in patients with PHN.
© 2008 by the American Pain Society
Key words: Neuropathic pain, zoster, pharmacotherapy.
Introduction
P
ostherpetic neuralgia (PHN), a sequel of acute
herpes zoster, may be associated with severe pain
and sensory abnormalities that adversely affect a
patient’s quality of life.17 Like other types of neuropathic
pain, PHN can be resistant to many types of pharmacologic and interventional therapies. Nevertheless, more
recent data, including systematic reviews/meta-analyses
and randomized, controlled trials (RCTs), provide evidence for the analgesic efficacy of a number of pharmacologic therapies. We provide an overview on the efficacy of pharmacologic and interventional strategies for
the treatment of PHN.
Pharmacologic Therapies
A number of pharmacologic agents have been used for
the treatment of PHN. Many of these agents are also
generally used for the treatment of other types of neuSupported in part by grants NIH P01 HD 33990 and NS-26363 (SNR). SNR
has received research support, consulting fees, or honoraria in the past
year from US Public Health Service, US Food and Drug Administration,
Allergan, and Fralex. CLW has no relevant conflicts to report.
Address reprint requests to Dr. Srinivasa N. Raja, The Johns Hopkins Hospital, Carnegie 292, 600 North Wolfe Street, Baltimore, MD 21287. E-mail:
[email protected]
1526-5900/$34.00
© 2008 by the American Pain Society
doi:10.1016/j.jpain.2007.10.006
ropathic pain. We focus on the more commonly used
pharmacologic agents with evidence for analgesic efficacy in the treatment of PHN (Table 1).
Systemic Drugs
Tricyclic Antidepressants
Tricyclic antidepressants (TCAs), which are used widely
for the treatment of numerous neuropathic pain states,
including PHN, have a number of presumptive mechanisms of action, including blocking of norepinephrine
and serotonin reuptake and local anesthetic-like sodium
channel blockade.21 There have been several RCTs and a
meta-analysis of available RCTs examining the efficacy of
TCAs for the treatment of PHN. In a meta-analysis of 4
RCTs, use of TCAs (including amitriptyline, nortriptyline,
and desipramine) resulted in significant analgesic benefit for the treatment of PHN pain, with the pooled data
showing a number needed to treat (NNT) of 2.6 (95%
confidence interval [CI], 2.1–3.5) (Figs 1 and 3).38 Earlier
meta-analyses examining the efficacy of TCAs for the
treatment of PHN pain also provided similar results with
an NNT of 2.1 to 2.3.15,70 With regard to individual RCTs,
1 double-blinded, crossover trial of TCAs and opioids in
patients with PHN noted a higher NNT of 4.0 for TCAs,
and there was a lack of correlation in the analgesic responsiveness between TCAs and opioids where some patients who did not have analgesia with TCA treatment
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Therapeutic Agents for the Management of PHN: Suggested Dose Titration, Side Effects, and Clinical Comments23,28,46,77
MEDICATION
CLASS
TCAs*
Nortriptyline
Desipramine
Amitriptyline
Antiepileptics
Gabapentin
STARTING
DOSE
DOSE-ESCALATION SCHEME
COMMON SIDE EFFECTS
CONTRAINDICATIONS/CAUTION
COMMENTS
Increase by 10–25 mg weekly
with a target dose of
75–150 mg
Sedation, dry mouth, blurred vision,
weight gain, urinary retention,
constipation, sexual dysfunction
Cardiac disease, glaucoma, suicide
risk, seizure disorder
Concomitant use of tramadol,
SSRI, or SNRIs
The lower starting dose may be more
appropriate in the elderly.
Amitriptyline has the most
anticholinergic effects and hence
less well tolerated by the elderly.
Obtain baseline ECG in patients with
hx of cardiac disease.
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
300–600 mg in 1 wk
Somnolence, dizziness, ataxia,
peripheral edema and weight
gain, myalgia, fatigue
Decrease dose in patients with
renal impairment
No clinically significant drug
interactions, improved sleep.
Avoid sudden discontinuation.
Ataxia, dizziness, somnolence,
peripheral edema and weight
gain, blurred vision, euphoria
Decrease dose in patients with
renal impairment by 50% or
more based on CL creatinine
Known hypersensitivity to amide
local anesthetics
Caution in patients receiving class
I antiarrhythmic drugs (eg,
tocainide and mexiletine)
Caution with concomitant use of ACE
inhibitors-angioedema;
Increased risk for weight gain and
peripheral edema in patients on
thiazolidinedione antidiabetic
agents.
No significant systemic side effects.
Pregabalin
50 mg tid OR
75 mg bid
Topical
lidocaine
5%, 1–2
patches
Can use up to 3 patches 12 h/d
Local erythema, rash, blisters
Topical
capsaicin*
0.025–0.075%
Cream
Apply 3–4 times a day over
affected region
Stinging or burning at application
site
Coughing, sneezing, or other signs
of respiratory irritation if dry
residue inhaled
15–30 mg
10 –20 mg
5–15 mg
0.5–1 mg
Titrate at weekly intervals
balancing analgesia and side
effects.
Average dose: 90 mg
morphine or its equivalent
Total daily dose: 150 – 400 mg
Extended-release dosing once a
day
Nausea/vomiting, constipation,
drowsiness, dizziness, itching
History of substance abuse, suicide
risk, driving impairment during
treatment initiation
Gradual titration monitoring G.I. and
CNS side effects.
Nausea/vomiting, constipation,
drowsiness, dizziness, seizures,
hallucinations, pruritus
History of substance abuse, suicide
risk, driving impairment during
treatment initiation, seizure
disorder, concomitant use of
SSRI, SSNRI, TCA
Caution if TCA, SSRI, or SNRI are also
being used.
Caution with reduced dose in patients
with hepatic or renal disease.
Opioid agonists
Morphine
Oxycodone
Methadone
Levorphanol
Tramadol
50 mg bid or
tid
Care to avoid contact with eye or
mucosa, use gloves for application.
Pretreatment with topical 5%
lidocaine may decrease burning
associated with its use.
Update on the Treatment of Postherpetic Neuralgia
10 –25 mg
10 –25 mg
10 –25 mg
(once a
day, qhs)
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Table 1.
S21
Vertigo, headache, somnolence,
weight gain, alopecia, abdominal
pain, hepatotoxicity,
teratogenicity, pancreatitis,
thrombocytopenia
Avoid in patients with hepatic
disease or dysfunction
Avoid in women of child-bearing age
and patients and urea cycle
disorder.
Drug interaction with lamotrigine.
experienced significant pain relief with opioids and vice
versa.61 As with other neuropathic pain states, amitriptyline is probably the most commonly studied TCA for
the treatment of PHN pain, but other similar TCAs (eg,
nortriptyline) appear to be equally effective.38,75 A recent study noted that desipramine may also provide
clinically meaningful pain relief in antidepressantnaïve PHN patients.65 The addition of fluphenazine to
amitriptyline does not seem to provide superior pain
relief for PHN pain compared with amitriptyline
alone.35
A limiting factor in the clinical use of TCAs 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. These side effects may be of particular concern in the older population and in patients with a history of cardiac arrhythmia
or ischemic heart disease. Although there is no standard
or guideline for ECG screening prior to TCA administration, TCAs may cause ECG changes (eg, prolonged QT)
and it may be prudent to obtain a baseline ECG in patients with cardiac disease.68,73 As PHN is a disease of the
elderly and co-existing cardiac abnormalities are not uncommon in this age group, a baseline ECG may be beneficial. For minor harm, the number needed to harm
(NNH) for TCAs (vs placebo) has been reported as 5.7
(95% CI, 3.3–18.6) (Fig 4). For major harm, the NNH for
TCAs is 16.9 (95% CI, 8.9 –178).38
Antiepileptic Drugs
*Not FDA approved for this indication.
Titrate to 1000 mg/d
250 mg bid
(extended
release)
Other drugs
Divalproex
sodium*
STARTING
DOSE
MEDICATION
CLASS
Table 1.
Continued
DOSE-ESCALATION SCHEME
COMMON SIDE EFFECTS
CONTRAINDICATIONS/CAUTION
COMMENTS
ORIGINAL REPORT/Wu and Raja
Antiepileptic drugs such as gabapentin and pregabalin
have been used for the treatment of many types of neuropathic pain, including PHN. Although the precise
mechanism of analgesic action of gabapentin is uncertain, it is believed that gabapentin acts at the ␣2␦-1 subunits of voltage-dependent Ca2⫹ channel to decrease
calcium influx, which in turn inhibits the release of neurotransmitters (such as glutamate) from the central terminals of primary afferent fibers in the spinal cord.8,49
Several RCTs and a few meta-analyses have established
the analgesic efficacy of gabapentin for the treatment of
PHN pain (Figs 2 and 3). A meta-analysis of 2 RCTs revealed that the pooled NNT for gabapentin for the treatment of PHN was approximately 4.4 (95% CI, 3.3– 6.1).38
The daily dose of gabapentin ranged from 1800 mg to
2400 mg.
One study looked at gabapentin dosages up to 3600
mg/d or placebo over a 4-week titration period in 229
patients with PHN.63 This study found that those who
received gabapentin had a significant reduction in average daily pain score (from 6.3– 4.2 points), compared
with a smaller decrease (6.5– 6.0 points) for placebo;
however, patients receiving gabapentin experienced a
higher incidence of somnolence, dizziness, ataxia, peripheral edema, and infection. In another RCT with a
total of 334 patients with PHN,62 those who received
gabapentin (1800 or 2400 mg/d) had a significantly
greater improvement in pain scores from week 1 than
those receiving placebo. The most common side effects
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Update on the Treatment of Postherpetic Neuralgia
Figure 1. Responder rates for tricyclic antidepressants (TCA) in the treatment of postherpetic neuralgia. (Modified with permission
from Hempenstall K, Nurmikko TJ, Johnson RW, A’Hern RP, Rice AS. PLoS Med. 2005;2:e164.)
noted over the 7-week study period were dizziness and
somnolence. The optimal dosing schedule for gabapentin in patients with PHN is uncertain, but a systematic
review4 suggested that gabapentin treatment should be
started at a dosage of 900 mg/d by initiating 300 mg/d on
the first day, administering 600 mg/d on day 2, and 900
mg/d on day 3, with titration up to 1800 mg/d over approximately 2 weeks (and occasionally dosages up to
3600 mg/d needed for some patients) recommended for
greater efficacy. The dose should be reduced in patients
with altered renal function and titrated slowly in the
elderly. Administration of gabapentin with an opioid
may provide superior analgesia at lower doses compared
with either administered as a single agent.33
A newer gabapentinoid, pregabalin, provides analgesia presumably by a mechanism of action similar to that
of gabapentin. Although there are no meta-analyses examining the analgesic efficacy of pregabalin in PHN,
there are a few RCTs. Pregabalin at a dose of 150 to 600
mg/d provided superior pain relief to placebo and improved pain-related sleep interference in 3 doubleblinded RCTs in 776 patients with PHN.28 Common side
effects of pregabalin include dizziness, somnolence, and
peripheral edema.24,28,29 Although the optimal dosing
regimen for pregabalin is unclear, patients may notice a
reduction in pain even after the first full day of treatment, and flexible and fixed-dose pregabalin regimens
both appear to be effective for PHN.24,29
Generally, the gabapentinoids are well tolerated. The
most frequently reported side effects are somnolence,
dizziness, peripheral edema, fatigue, headache, and dry
mouth. For minor harm, the NNH for gabapentinoids
(vs placebo) has been reported as 4.1 (95% CI, 3.2–5.7)
(Fig 4). For major harm, the NNH for gabapentinoids is
17.3 (95% CI, 7.7–30.2).38
Figure 2. Responder rates for gabapentin and pregabalin in the treatment of postherpetic neuralgia. (Modified with permission
from Hempenstall K, Nurmikko TJ, Johnson RW, A’Hern RP, Rice AS. PLoS Med. 2005;2:e164.)
ORIGINAL REPORT/Wu and Raja
S23
Figure 3. Meta-analysis of the number needed to treat to provide a significant analgesic benefit for the treatment of postherpetic
neuralgic pain. (Adapted from Hempenstall K, Nurmikko TJ, Johnson RW, A’Hern RP, Rice AS. PLoS Med. 2005;2:e164; Davies PS, Galer
BS. Drugs. 2004;64:937-947.)
Tramadol
The analgesic effects of tramadol are centrally mediated and related to its weak opioid agonist (␮-receptor)
action and monoamine (norepinephrine and serotonin)
reuptake inhibition. Earlier placebo-controlled studies
have demonstrated the efficacy of tramadol in treating
diabetic neuropathic pain and polyneuropathies.36,69 A
more recent RCT in 127 patients with PHN10 suggested
that 6 weeks of treatment with sustained-release tramadol (100 – 400 mg/d; average dose ⫽ 275 mg) was associated with a reduction in pain and improved quality of life
compared with placebo. The NNT was 4.8 (95% CI, 3.5–
6.0), and the drug was relatively safe (Fig 3).
Adverse effects of tramadol include nausea, vomiting,
constipation, and dizziness. Less common side effects in-
clude vertigo, urinary retention, pruritus, somnolence, and
headache. For minor harm, the NNH for tramadol (vs placebo) has been reported as 7.2 (Fig 4). For major harm, the
NNH for tramadol is 10.8.38 About 7% of the population
exhibit a reduced activity of the CYP2D6 isoenzyme of cytochrome P-450. In these individuals (poor metabolizers),
concentrations of tramadol were approximately 20% higher
versus “extensive metabolizers.” In addition, concomitant
therapy with inhibitors of CYP2D6 such as SSRIs (eg, fluoxetine, paroxetine), SNRIs (venlafaxine, duloxetine), and
TCAs (amitriptyline, nortriptyline) could result in increases
in tramadol concentrations due to varying degrees of inhibition of the metabolism of tramadol. Concomitant use of
SSRIs and MAO inhibitors may enhance the risk of adverse
events, including seizures and serotonin syndrome.
*NNH for major harm could not be calculated from available data.
Figure 4. Meta-analysis of the number needed to harm to elicit significant adverse effects associated with analgesic therapy.
(Adapted with permission from Hempenstall K, Nurmikko TJ, Johnson RW, A’Hern RP, Rice AS. PLoS Med. 2005;2:e164.)
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Opioid Analgesics
Although opioid analgesics are accepted as a cornerstone for the treatment of nociceptive and cancer pain,
their role in the management of neuropathic pain such
as PHN has been intensely debated. Some clinicians consider neuropathic pain to be resistant to the analgesic
effects of opioids. The controversy of efficacy in relieving
neuropathic pain reflects the use of multiple definitions
and pain assessments of neuropathic pain in both clinical
and experimental trials, methodologic issues in available
RCTs, and interindividual differences in opioid responsiveness. In addition, many other factors, such as opioidrelated side effects, development of tolerance, exaggerated fear of addiction, and government health policies,
contribute to the controversy regarding the use of opioids for nonmalignant neuropathic pain.
Efficacy of Opioids for Neuropathic Pain
Despite previous clinical uncertainty regarding the
analgesic efficacy of opioids for the treatment of neuropathic pain, a number of high quality studies demonstrate that opioids are effective in relieving neuropathic pain (Fig 3).26,28,66,79,82 Guidelines and consensus
statements2,25,54 have indicated that opioid analgesics
are a recognized option for the treatment of neuropathic pain including PHN. Although the efficacy of
opioids for neuropathic pain, derived from NNTs, is
comparable to TCAs and better than antiepileptics,
their side effects, concerns of misuse and abuse, and
tolerance have, however, led to the recommendation
by the IASP Neuropathic Pain Special Interest group,
the European and Canadian consensus panels that this
class of drugs be considered as second or third line
analgesics.2,25,54
Initial proof of principle of the effectiveness of opioids
for neuropathic pain was achieved using brief intravenous infusion studies of morphine, lidocaine, and placebo in PHN.66 In a double-blinded, placebo-controlled
RCT, the analgesic effect of a short-acting intravenous
opioid, fentanyl, was compared with an active (diazepam) and inert (saline) placebo in 53 patients with various types of neuropathic pain including 3 with PHN.
Compared with the 2 control phases, patients had significantly superior average and maximum pain relief while
receiving placebo, and the analgesic effect was independent of the degree of sedation.20 In another doubleblinded, placebo-controlled RCT of an intravenous opioid in neuropathic pain,82 phantom limb pain was
significantly diminished by morphine but not by lidocaine or active control (diphenhydramine). Another double-blinded RCT evaluating the analgesic efficacy of oral
levorphanol (a potent ␮-opioid agonist) for the treatment of a variety of neuropathic pains refractory to conventional therapy67 demonstrated that patients randomized to receive a high-strength/dose of levorphanol
had a greater decrease in pain compared with a lowstrength/dose of levorphanol. Long-term treatment of
chronic noncancer pain (neuropathic in 51% of patients)
with transdermal fentanyl53 provided a stable degree of
Update on the Treatment of Postherpetic Neuralgia
pain control and was generally well-tolerated with a low
incidence of serious side effects such as drug abuse and
respiratory depression. A recently published meta-analysis26 also indicates that opioids demonstrate significant
efficacy versus placebo in treatment of neuropathic pain in
intermediate-term studies. It is possible that opioid responsiveness of neuropathic pain is in part related to dosage as
higher doses of opioids may be necessary to decrease neuropathic pain compared with nociceptive pain.7
Efficacy of Opioids for Postherpetic
Neuralgia
Both intravenous and oral opioids have been shown to
provide significant pain relief for patients with neuropathic pain.66,75,76 The analgesic efficacy of oral oxycodone for PHN pain was evaluated in a double-blinded,
crossover RCT.75 Patients were randomly assigned to receive either placebo or sustained-release oxycodone 10
mg every 12 hours over a period of 4 weeks. Treatment
with oxycodone resulted in a significant reduction in allodynia, steady pain, and paroxysmal spontaneous pain,
while providing significantly improved pain relief.75 Oxycodone treatment also resulted in superior scores for
global effectiveness, disability, and masked patient
preference relative to placebo. A randomized, doubleblinded, crossover trial in patients with PHN61 found an
NNT of 2.7 for opioids. Therefore, RCTs suggest that PHN
pain responds to opioid therapy. However, questions remain as to whether the beneficial effects persist with longterm therapy. Further studies are needed to determine the
beneficial effects of prolonged treatment with opioids.27
For the treatment of PHN and other neuropathic pain,
opioids may be considered as part of a comprehensive
plan that includes pharmacologic and nonpharmacologic options.12 Opioids may be considered if the pain is
moderate to severe and has a significant impact on function or quality of life, and reasonable and conservative
therapy has already been tried. There are several general
principles of chronic opioid therapy that may facilitate
effective PHN pain control. The dose of opioid should be
titrated to optimize efficacy and minimize side effects. In
general, a fixed-dose regimen using a long-acting or sustained-release formulation opioid with prn (on an asneeded basis) administration of short-acting opioids for
breakthrough pain is preferable over a prn-only analgesic regimen. The clinician should document the treatment plan and outcomes. Some clinicians use an “opioid
contract” to describe treatment parameters, the mutually agreed-on treatment plan, and informed consent.5,55
Patients may exhibit opioid-related side effects including
endocrine dysfunction,18 loss of libido, and immunosuppression.6 Clinicians should also consider prophylactic
bulk laxative when commencing opioid treatment. Finally, possible cognitive and neuropsychological side effects associated with chronic use of opioids remain a major concern and area of controversy. Several trials
indicate that long-term use of opioids does not have a
detrimental effect on cognitive function— on the contrary, some aspects of cognitive functioning actually im-
ORIGINAL REPORT/Wu and Raja
prove because of a decrease in pain and improvement in
mood.6,71 Patients receiving long-term treatment with
opioids (up to 12 months) did not demonstrate any decrease in neuropsychological tests or experimental assessments of driving ability.6,71
Constipation, nausea, and sedation are common adverse effects associated with opioid use. A significant
side effect with chronic opioid use is hormonal change
that may result in sexual dysfunction. More recently,
issues related to drug diversion or aberrant drug-seeking behavior in the use of opioids for chronic noncancer pain have been of concern, but it is less likely to be
a significant issue in the elderly population most affected by PHN. For minor harm, the NNH for opioids (vs
placebo) has been reported as 3.6 (95% CI, 2.2–10.2)
(Fig 4). For major harm, the NNH for opioids is 6.3 (95%
CI, 4.2–12.8).38 The successful long-term administration of opioids for the treatment of chronic pain, including that of neuropathic origin, has been reported
in several studies; however, there are several tangentially related issues (eg, dose escalation, adverse
events, quality of life, use in persons with a history of
chemical dependency) with long-term use that are discussed elsewhere.43,60,78,79
Topical Therapies
Topical Local Anesthetics
Local anesthetic may provide analgesia in neuropathic
pain states where an accumulation of neuronal-specific
sodium channels may contribute to pain, including that
of PHN.50 A topical adhesive patch containing 5% lidocaine (700 mg) has been used for the treatment of PHN
pain.16 A randomized, controlled crossover trial demonstrated that lidocaine patch was strongly preferred over
a placebo patch (78.1% vs 9.4%) with no significant difference noted between the active and placebo treatments in the incidence of side effects.31 Two open-label,
nonrandomized, prospective studies19,32 showed that
the lidocaine patch 5% (applied over the area of maximal pain) reduced the intensity of moderate-to-severe
PHN pain and improved quality of life.19 Although there
are few studies, the available clinical trials in PHN patients with allodynia suggest that the lidocaine patch is
effective in providing pain relief from PHN with minimal
systemic absorption and few side effects, the most frequent being mild skin irritation at the site of application.30,31,64 Another study suggested that the NNT (for
more than 50% relief of ongoing pain) was 4.4.51 Patients may respond well to topical lidocaine even if the
skin is completely deprived of nociceptors.74
Topical Capsaicin
Capsaicin, the pungent ingredient in hot chili pepper,
results in excitation of nociceptive afferents when applied topically. However, repeated applications of capsaicin results in desensitization of unmyelinated epidermal
nerve fibers and hypalgesia.57 A 6-week, blinded, parallel-group study, followed by a 2-year, open-label fol-
S25
low-up period, indicated that a 0.075% topical capsaicin
cream was effective in relieving pain in 64% of patients
at 6 weeks, compared with 25% in patients receiving
placebo.77 An earlier study in a small group of patients
showed similar efficacy.9 The topical application has to
be used 3 to 4 times a day and is often associated with
local irritation and an unpleasant burning sensation that
may decrease with repeated applications. The pooled
NNT was 3.3 (Fig 3). For minor harm, the NNH for capsaicin (vs placebo) has been reported as 3.9 (95% CI, 2.5–
8.6) (Fig 4); for major harm, the NNH for capsaicin is 4.7
(95% CI, 3.1–9.2).38
Other Therapies
A number of other oral therapies, such as NMDA receptor antagonists (dextromethorphan, memantine), ketamine, topical NSAIDs and TCAs, vincristine iontophoresis, homeopathy, and acupuncture have been explored.
However, there is little scientific evidence to make recommendations about the efficacy of these therapies.
More recently, some promising data indicates that divalproex sodium (valproic acid and sodium valproate) may
provide significant pain relief in PHN with a relatively
low incidence of side effects.46
Consensus Recommendations/Guidelines
and Combination Therapies
Recent guidelines of evidence-based treatment of
neuropathic pain (including PHN) includes the recommendation of the first-, second-, and third-line options
of pharmacotherapy.2,25,54 Consensus panels have generally considered TCAs, antiepileptics, and topical lidocaine as first-line analgesics for PHN. Opioids and tramadol are recommended as second-line treatments
that can be considered for first-line under certain select circumstances.25 Topical capsaicin and valproate
are considered as third-line therapies.
Although we discuss drugs individually, combination
therapy of more than 1 drug class may be useful in providing additive if not synergistic analgesia although
there is a lack of good evidence for which combinations
may be superior (or harmful). The benefits of combination therapies are supported by a recent study indicating
that in patients with PHN and diabetic neuropathy, the
combination of gabapentin and morphine achieved better analgesia at lower doses of each drug than either of
the 2 drugs as a single agent.33
Psychological Interventions
Neuropathic pain reduces quality of life, including
mood, physical, and social functioning. Depression and
pain coping strategies such as catastrophizing and social
support predict pain severity in chronic pain states. Investigation of cognitive-behavioral factors affecting the adaptation of elderly individuals experiencing PHN suggest
that catastrophizing predicts the level of pain, an effect
that is independent of depressive symptoms.39 Although
S26
controlled trials have examined the role of cognitive behavioral therapy in many chronic pain states, we are not
aware of any studies specific to patients with PHN. The
importance of psychosocial support and long-term follow-up for severe cases should, however, not be overlooked as sometimes it is the final thing that remains for
the most intractable cases.
Interventional Strategies
A wide variety of interventional options, such as sympathetic and other nerve blocks, intrathecal injections
(eg, methylprednisolone), and spinal cord stimulation
have been examined as potential treatments for PHN.
Interventional options are part of a comprehensive (invasive and noninvasive) strategy for the treatment of
PHN. The analgesic efficacy of some interventional strategies (eg, sympathetic nerve blocks) is uncertain; however, studies indicate that some interventional options
(ie, intrathecal methylprednisolone) may be more effective than others.
Sympathetic Nerve Blocks
Selective sympathetic nerve blocks have traditionally
been used for the treatment of many chronic pain conditions. Sympathetic nerve blocks have been one of the
more common interventional strategies used for pain
relief for both acute herpes zoster and PHN. Although
the precise mechanisms by which the sympathetic nervous
system contributes to neuropathic pain are unclear, experimental data indicate that abnormal activation of the ␣-adrenergic receptors in primary afferent neurons, direct interactions between primary afferent neurons and efferent
sympathetic nerves resulting from neuronal regeneration
and sprouting after nerve injury and tissue trauma may all
contribute to sympathetically mediated pain.42,81 Some
data suggest a link between sympathetic activity and pain
in PHN, as patients with PHN demonstrate increased levels
of pain and worsening of their allodynia after local administration of adrenergic agonists.11
Thus, administration of sympathetic nerve blocks may
theoretically interrupt the sympathetic-sensory interactions that may contribute to the pain of herpes zoster
and PHN. Regional sympathetic blockade with local anesthetics can be achieved by trained pain management
specialists. The incidence of severe complications from
sympathetic nerve blocks is extremely low, and, depending on the location of the nerve block, may consist of
local anesthetic toxicity (eg, seizures), pneumothorax, intraspinal/neuraxial injection, or neurologic injury.
Sympathetic Nerve Blocks for
Postherpetic Neuralgia
Sympathetic nerve blocks have also been used in patients with PHN, although with much less analgesic effectiveness compared with that used for acute herpes
zoster.81 Early retrospective studies seemed to indicate
that sympathetic nerve blocks might provide transient
pain relief: 41% to 50% of patients with longstanding
PHN who received sympathetic nerve blocks noted
Update on the Treatment of Postherpetic Neuralgia
marked improvement or complete relief,13,14 but longterm follow-up revealed that far fewer patients actually
obtained significant prolonged pain relief. Only 14% of
patients who received sympathetic nerve blocks later
than 2 months after rash onset became pain free, compared with 92% of those who received sympathetic
nerve blocks within 2 months of rash onset.80
Despite the apparent effectiveness of sympathetic
nerve blocks in decreasing the pain of acute herpes zoster and possibly PHN, there are significant methodologic
issues in the evaluation of the analgesic efficacy of sympathetic nerve blocks for relief of PHN.40,45,81 One of the
most glaring problems is the lack of double-blinded
RCTs. Such trials are particularly necessary in this disease
state, because the natural course of acute herpes zoster
for a majority of patients is complete resolution of pain
within a few weeks. In addition, inadequate assessments
of pain severity, lack of control for other important covariates (eg, age, rash severity, acute pain severity, concurrent use of antiviral agents), varying definitions of
acute herpes zoster and PHN, and systemic effects of
local anesthetics all contribute to the controversy of the
analgesic efficacy of sympathetic nerve blocks for both
acute herpes zoster and PHN.81 Despite these methodologic issues in examining the effectiveness of sympathetic nerve blocks for acute herpes zoster and PHN, it
does appear that there may be a role for sympathetic
nerve blocks in the treatment of pain from acute herpes
zoster, as it may diminish pain and theoretically prevent
the development of PHN. The role of sympathetic nerve
blocks for established PHN is controversial, as the longterm analgesic efficacy is marginal.
Other Nerve Blocks
Use of epidural block has been reported for the treatment of acute herpes zoster.1,41 Several prospective observational trials1,41 suggest that epidural blockade in
combination with an antiviral agent, is a very effective
treatment modality for acute herpes zoster that shortens
the total duration and severity of pain. High thoracic
epidural block was shown to be as effective as sympathetic stellate ganglion block in relieving moderate to
severe acute herpes zoster pain. Other nerve blocks, such
as intercostal nerve blocks, have been reported to provide long lasting pain relief for PHN.22 However, the
quality of many of these studies is questionable.
A preliminary study44 randomly assigned patients with
intractable PHN of longer than 1 year’s duration to receive 60 mg methylprednisolone acetate administered
either epidurally or intrathecally. Patients randomly assigned to receive intrathecal methylprednisolone had
significantly superior pain relief and lower levels of interleukin-8 within the cerebrospinal fluid. A subsequent
study47 by the same group of investigators randomized
277 patients with long-lasting PHN pain refractory to
conventional therapy to receive an intrathecal injection
of either methylprednisolone and lidocaine, lidocaine
alone, or no treatment (no injection/control). Over a follow-up period of 2 years after injection, patients who
received the intrathecal methylprednisolone-lidocaine
ORIGINAL REPORT/Wu and Raja
combination showed a significant improvement in global
pain relief (vs the control group) and mean pain scores for
both burning and lacinating pain, with a decrease in diclofenac use within 4 weeks of injection (vs the lidocainealone group and the control group). Compared with the
other 2 groups, the methylprednisolone-lidocaine group
had significantly lower areas of maximal pain and allodynia. Despite the potential of intrathecal methylprednisolone in relieving pain from PHN, clinicians should recognize that intrathecal injection of methylprednisolone
acetate has not been approved for the treatment of PHN
with the methylprednisolone acetate containing benzyl alcohol and polyethylene glycol preservatives. Moreover, the
safety of intrathecal administration of methylprednisolone
has been debated and hence caution is advised in the use of
this therapy. Finally, a single epidural injection of steroids
and local anesthetics in the acute phase of herpes zoster
may have a modest effect in reducing zoster-associated
pain for 1 month after injection but is not effective for
prevention of long-term postherpetic neuralgia.72
Other Interventional Strategies
Spinal Cord Stimulation
Spinal cord stimulation (SCS) has been used for the
treatment of chronic neuropathic pain.37,48 The mechanism of action of SCS is unclear; postulated mechanisms
are based on the gate-control theory of pain, in which
stimulation of large myelinated A-␤ fibers would interfere at the dorsal horn with transmission of nociceptive
information carried by the small unmyelinated C and
myelinated A-␦ fibers from the periphery. According to
this model, SCS blocks pain of neuropathic origin by producing an electrical field over the spinal cord. The electrical pulse is transmitted to the spinal cord from a subcutaneously implanted generator via implanted
electrodes placed directly into the epidural space.48
Other proposed mechanisms of SCS-mediated analgesia include suppression of sympathetic overdrive and inhibition
of nociceptive processing via GABA-ergic interneurons.37,48
Although there are limitations in the quality and quantity
of data available, current evidence from the literature suggests that SCS is effective in the management of certain
types of neuropathic pain.34 In appropriate patients, SCS
may provide long-term pain relief (2 years) in up to 60% to
80% of patients with chronic pain.48 Some PHN patients
obtained relief with temporary percutaneous SCS.37
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S27
Other Surgical Options
Continuous infusions of analgesic agents (typically an
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Treatment of PHN is often difficult and frustrating for
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