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Post-Herpetic Neuralgia
Clinical Policy Bulletins Medical Clinical Policy Bulletins
Policy History
Last Re
view
03/18/2019
Effective: 06/20/2006
Next
Review: 08/08/2019
Review
Histor
y
Definitions
Additional Information
Number: 0725
Policy *Please see amendment for Pennsylvania Medicaid at the end of this
CPB.
I. Aetna considers the use of antivirals (oral), gabapentin, intrathecal or
interlaminar epidural corticosteroids, lidocaine patch, opioids
(oral), pregabalin, and tricyclic anti-depressants medically necessary
for post-herpetic neuralgia (PHN).
II. Aetna considers capsaicin 8% patch (Qutenza) medically necessary for
neuropathic pain associated with postherpetic neuralgia in members who
have an insufficient response, intolerance, or contraindication to two drugs
from the anticonvulsant (e.g., gabapentin (Neurontin) or pregabalin (Lyrica))
and/or tricyclic antidepressant (e.g., nortriptyline or desipramine) classes.
III. Aetna considers any the following therapeutic modalities for PHN
experimental and investigational because their effectiveness for this
indication has not been established (not an all-inclusive list):
A. Acupuncture
B. Botulinum toxin
C. Combined therapy of nerve block and pulsed radiofrequency
D. Combination of trigeminal ganglion and retrobulbar nerve block
E. Cryocautery
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F. Dorsal root entry zone lesions/dorsal root ganglion destruction
G. Epidural morphine
H. Fulranumab
I. Ganglioside GM1
J. Intercostal nerve block
K. Intralesional corticosteroid
L. Intravenous antiviral therapy
M. Intravenous ketamine
N. Intravenous lidocaine
O. Intravenous vitamin C
P. Intravenous zinc sulfate
Q. Iontophoresis of vincristine
R. Laser irradiation
S. Narrow-band ultraviolet light B
T. Peripheral nerve stimulation
U. Stellate ganglion blockade
V. Sympathectomy
W. Topical ketamine
X. Topical piroxicam
Y. Transcutaneous electrical nerve stimulation (TENS)
Z. Transdermal oxycodone patch
For spinal cord stimulation for PHN, see
CPB 0194 - Spinal Cord Stimulation (../100_199/0194.html).
IV. Aetna considers the use of any of the following pharmacotherapies for the
treatment of PHN experimental and investigational because their
effectiveness for this indication has not been established (not an all-
inclusive list):
A. Biperiden
B. Carbamazepine
C. Chlorprothixene
D. Ganoderma lucidum extract
E. Nicardipine
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V. Aetna considers (i) gabapentin and (ii) low-level laser experimental and
investigational for the prevention of PHN because their effectiveness for
this indication has not been established.
See also CPB 0011 - Electrical Stimulation for Pain (../1_99/0011.html)
, CPB 0113 - Botulinum Toxin (../100_199/0113.html)
, CPB 0115 - Varicella and Herpes Zoster Vaccines
(../100_199/0115.html), CPB 0135 - Acupuncture (../100_199/0135.html),
and CPB 0735 - Pulsed Radiofrequency (0735.html).
Background
Herpes zoster (HZ) is the consequence of re-activation of the varicella zoster virus
that remains latent since primary infection (varicella). Once infected with herpes
zoster, the virus sequesters itself in the nerve roots. The virus has the potential to
reappear, traveling down the dermatome in which it resides. This flair is typically
characterized by local and radiating pain throughout the dermatome. Patients will
be treated with antivirals such as acyclovir or valcyclovir. In some of these patients,
the virus causes noticeable nerve damage and results in moderate to severe pain
which radiates as most neuropathies do. This condition is referred to as
postherpetic neuralgia.
The overall incidence of HZ is about 3 per 1000 of the population per year
increasing to 10 per 1000 per year by age 80. Approximately half of persons
reaching age 90 years will have had HZ. In approximately 6 %, a second episode of
HZ may occur; usually several decades after the first attack. The most common
complication of HZ is post-herpetic neuralgia (PHN), defined as significant pain or
dysaesthesia present 3 months or more following HZ. More than 5 % of the elderly
have PHN at 1 year after acute HZ. Reduced cell-mediated immunity to HZ occurs
with aging, which may be responsible for the increased incidence in the elderly and
from other causes such as tumors, human immunodeficiency virus infection as well
as immunosuppressant drugs. Diagnosis of PHN is usually clinical from typical
unilateral dermatomal pain and rash. Prodromal symptoms, pain, itching and
malaise, are common (Johnson and Whitton, 2004).
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The observation that patients with PHN experience different types of pain (e.g.,
continuous burning or intense paroxysmal; most often with tactile allodynia)
suggests that multiple pathophysiological mechanisms are involved, which may
include the peripheral as well as the central nervous systems. Traditional
treatments for PHN usually entail tricyclic antidepressants (TCA) such as
amitriptyline, nortriptyline, desipramine and maprotiline; antiepileptic drugs such as
gabapentin and pregabalin; topical 5% lidocaine patches (Lidoderm), which
frequently reduce allodynia; as well as long-acting oral opioid preparations and
tramadol (Ultram). Oral antiviral agents (aciclovir, famciclovir, valaciclovir) are used
during an acute attack of herpes zoster to prevent postherpetic neuralgia
(Wareham, 2006). There is evidence that intrathecal corticosteroids may be
effective in patients who are refractory to conservative measures (Wu and Raja,
2008; Hempenstall et al, 2005), but the potential for neurological sequelae should
prompt caution with their application (Christo et al, 2007). Epidural corticosteroids
have not been shown to provide effective analgesia for PHN (Christo et al, 2007).
Many alternative treatments for PHN such as cryocautery, dorsal column (spinal
cord) stimulation, iontophoresis of vincristine, intravenous administration of
ketamine, an N-methyl-D-aspartate (NMDA) antagonist; laser; peripheral nerve
stimulation as well as transcutaneous electrical nerve stimulation (TENS) have not
been adequately studied.
Iontophoresis has been suggested to be effective in treating PHN (Ozawa et al,
1999). However, in a randomized controlled trial, Dowd et al (1999) reported that
that iontophoresed vincristine is no better than iontophoresed saline in the
treatment of this condition. Although TENS has been reported to benefit some
patients with PHN (Milligan and Nash, 1985; Robertson and George, 1990), these
findings have not been validated by randomized controlled studies. Furthermore, on
behalf of the Canadian Coordinating Office for Health Technology Assessment
(CCOHTA), Reeve and Corabian (1995) evaluated the scientific evidence of the
clinical effectiveness of TENS for the treatment of acute, chronic as well as labor
and delivery pain. These researchers concluded that there is little evidence that
TENS is effective in treating chronic pain.
In a review on sympathectomy for neuropathic pain, Mailis and Furlan (2003) stated
that the practice of surgical and chemical sympathectomy is based on poor quality
evidence, uncontrolled studies and anecdotal experience. In addition, complications
of the procedure may be significant, in terms of both worsening the pain or
producing a new pain syndrome; and abnormal forms of sweating (e.g.,
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compensatory hyperhidrosis and pathological gustatory sweating). The authors
concluded that more clinical studies of sympathectomy are needed to establish the
potential risks and overall effectiveness of this procedure.
In a pilot study (n = 10), Johnson and Burchiel (2004) found that peripheral nerve
stimulation of the supra-orbital or infra-orbital branches of the trigeminal nerve is
effective in relieving trigeminal neuropathic pain following facial trauma or herpetic
infection. These investigators stated that a prospective clinical trial using this novel
approach to treat these disorders is thus warranted. A recent Cochrane review
(Mailis-Gagnon et al, 2004) on spinal cord stimulation (SCS) concluded that
although there is limited evidence in favor of SCS for failed back surgery syndrome
and complex regional pain syndrome (also known as reflex sympathetic dystrophy),
more research is needed to confirm whether SCS is an effective treatment for other
types of chronic pain. Gilden et al (2005) noted that because only a few studies
have used antiviral therapy to manage PHN and with conflicting results, larger,
double-blind studies, which give intravenous antiviral drug, are needed. Thus, well-
designed, multi-center, controlled clinical trials are needed to ascertain the
effectiveness of various alternative treatments in the treatment of PHN.
An earlier systematic review of randomized controlled trials on treatments for PHN
(Volmink et al, 1996) reported that pooled analysis of the effect of TCA
demonstrated statistically significant pain relief. Pooling of the results of the 3
studies comparing the effects of capsaicin and placebo could not be performed due
to heterogeneity, which was mainly attributable to an unpublished trial which
differed in terms of the dosage and duration of treatment. When this study was
omitted, no heterogeneity was found, and the pooled analysis revealed a
statistically significant benefit. However, problems with blinding in patients using
capsaicin may have accounted for the positive effect. One small study of
iontophoresis of vincristine compared to placebo yielded a favorable result. Other
therapies evaluated included lorazepam, acyclovir, topical benzydamine as well as
acupuncture. There was no evidence that these treatments are effective in relieving
pain associated with PHN. These investigators concluded that based on evidence
from randomized trials, TCA appear to be the only agents of proven benefit for
established PHN.
A more recent evidence-based report on treatment of PHN was developed by the
Quality Standards Subcommittee of the American Academy of Neurology (Dubinsky
et al, 2004) and it had the following recommendations:
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1. Acupuncture, benzydamine cream, dextromethorphan, indomethacin,
epidural methylprednisolone, epidural morphine sulfate, iontophoresis of
vincristine, lorazepam, vitamin E and zimelidine are not of benefit.
2. Aspirin cream or ointment is possibly effective in the relief of pain in
patients with PHN, but the magnitude of benefit is low, as is seen with
topical capsaicin.
3. The effectiveness of carbamazepine, nicardipine, biperiden,
chlorprothixene, ketamine, Helium:Neon (He:Ne) laser irradiation,
intralesional triamcinolone, cryocautery, topical piroxicam, extract of
Ganoderma lucidum, dorsal root entry zone lesions and stellate ganglion
block are unproven in the treatment of PHN.
4. Tricyclic antidepressants, gabapentin, pregabalin, opioids and lidocaine
patch are effective and should be used in the treatment of PHN.
In a multi-center, randomized controlled study, van Wijck and colleagues (2006)
reported that a single epidural injection of 80 mg methylprednisolone and 10 mg
bupivacaine within the first days of herpes zoster has a modest effect in reducing
zoster-associated pain for one month; however, there were no significant differences
in pain level between the two groups at subsequent follow-ups. At 1 month, 137 (48
%) patients in the epidural group (plus standard therapy given to the control group)
reported pain compared with 164 (58 %) in the control group (oral antivirals and
analgesics). After 3 months these values were 58 (21 %) and 63 (24 %) respectively,
and at 6 months, 39 (15 %) and 44 (17 %). The main drawback of this study was that
it was neither double-blinded nor placebo-controlled, which decreased the validity of
the already modest anti-nociceptive effects of the treatment within the first month.
Moreover, this treatment is ineffective in preventing the development of long-term
PHN. Furthermore, Baron and Wasner (2006) stated that large, well-designed
prospective studies are needed to estimate the preemptive effect of neuropathic pain
treatment on PHN.
In a Cochrane review, Khaliq et al (2007) examined the safety and effectiveness of
topical lidocaine in the treatment of PHN. The investigators identified three trials
meeting inclusion criteria, involving 182 topical lidocaine treated participants and
132 control participants. Two trials gave data on pain relief, and the remaining
study provided data on secondary outcome measures. The largest trial compared
topical lidocaine patch to a placebo patch and accounted for 150 of the 314
patients included in the analysis. A meta-analysis combining two of the three
studies identified a significant difference between the topical lidocaine and control
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groups for the primary outcome measure -- a mean improvement in pain relief
according to a pain relief scale. Topical lidocaine relieved pain better than placebo
(p = 0.003). The investigators also found a statistical difference between the groups
for the secondary outcome measure of mean visual analog scale (VAS) score
reduction (p = 0.03), but only for a single small trial. In the selected studies, there
were a similar number of adverse skin reactions in both treatment and placebo
groups. The investigators reported that the highest recorded blood lidocaine
concentration varied between 59 ng/ml and 431 ng/ml between trials. The
investigators noted that the latter figure is high and posited that it may have been
due to contamination of the sample during the assay procedure.
Christo et al (2007) stated that epidural corticosteroids have not been shown to
provide effective analgesia for PHN. Furthermore, Wu and Raja (2008) stated that
the majority of interventional therapies show equivocal analgesic efficacy although
some data indicate that intrathecal methylprednisolone may be effective. The author
stated that further randomized, controlled trials will be needed to confirm the
analgesic efficacy of analgesic and interventional therapies (e.g., sympathetic nerve
blocks/other nerve blocks, intrathecal methylprednisolone, and spinal cord
stimulation) to determine their role in the overall treatment of patients with PHN.
In a Cochrane review, He et al (2008) examined the effectiveness of corticosteroids
in preventing PHN. People of all ages with herpes zoster of all degrees of severity
within 7 days after onset were included. Interventions include corticosteroids given
by oral, intramuscular or intravenous routes during the acute stage (starting within 1
week of onset of the rash) compared with no treatment or placebo, but not with
other treatments. Primary outcome measure was the presence of PHN 6 months
after the onset of the acute herpetic rash. Secondary outcome measure was pain
severity measured by a validated VAS or numerical descriptive scale after 3, 6 and
12 months; quality of life measured with the Short Form 36 questionnaire after 6
months; adverse events during or within 2 weeks after stopping treatment. Five
trials were included with altogether 787 participants. All were randomized, double-
blind, placebo-controlled parallel group studies. There was no significant difference
between the corticosteroid and control groups for the primary outcome (risk ratio
[RR] 1.27, 95 % confidence interval [CI]: 0.20 to 7.97). There was also no
significant difference between the corticosteroid plus anti-viral agents and placebo
plus anti-viral agents’ groups for the primary outcome (RR 0.90, 95 % CI: 0.40 to
2.03). No included trials evaluated pain severity with a validated VAS or numerical
descriptive scale and also no trials measured quality of life with the Short Form 36
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questionnaire. Adverse events during or within 2 weeks after stopping treatment
were reported by all 5 included trials, but after meta-analysis, there was no
significant difference in any serious adverse event (e.g., death, acute cardiac
insufficiency, rash dissemination, bacterial pneumonia or hematemesis) or non-
serious adverse event (e.g., dizziness, nausea, vomiting, hypertension or
hyperglycemia). The authors concluded that there was insufficient evidence that
corticosteroids are safe or effective in the prevention of PHN. They stated that more
randomized controlled trials with a greater number of participants are needed to
determine reliably whether there is real benefit (or harm) from the use of
corticosteroid therapy to prevent PHN; and that future trials should measure
function and quality of life.
A Clinical Evidence systematic evidence review concluded that corticosteroids for
post-herpetic neuralgia are likely to be ineffective or harmful in preventing post-
herpetic neuralgia (Wareham, 2006). The evidence review noted that, not only have
corticosteroids not been proven to be effective for this indication, but they may
cause dissemination of herpes zoster.
Chau et al (2007) evaluated the outcome of pain treatment for the elderly patients
with PHN. A total of 58 elderly outpatients with PHN were studied. The pain
intensity before and after treatment were assessed by patients themselves with
numeric pain scale (NPS). The pain treatment included (i) medication with anti-
convulsants, opioids and non-steroidal anti-inflammatory drugs (NSAIDs); (ii)
nerve block with 0.25 % bupivacaine or 1 % lidocaine twice-weekly at the
beginning of the treatment. The therapeutic outcome was expressed by pain
relief. The reduction of pain and residual pain intensity were evaluated subjectively
by the patients themselves with patients' global impression and NPS, respectively,
after treatment for 1 and 3 months (or last visit). The adverse events throughout the
treatment course were analyzed. The mean age of the patients was 75.1 years.
The number of female PHN sufferers was higher than that of male in all aged groups
and the highest incidence was found in the age group of 70 to 79 (65.5 %). The most
commonly involved dermatomes were in the thoracic region (82.7 %). All patients
suffered from severe pain (NPS 8 to 10) before treatment. The pain management
was a combination of medication and nerve block at the beginning of the treatment.
Among the medications, gabapentin was prescribed to all the patients and almost
all of them (98.3 %) required opioids simultaneously and some of them needed
additional NSAIDs at the beginning of the treatment. The most common adverse
event was somnolence (24.1 %). Among the sympathetic blocks,
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the intercostal nerve block was performed commonly (84.5 %). The therapeutic
outcome was expressed by pain relief. As to the reduction of pain, 46 cases (79.3
%) and 57 cases (98.3 %) felt moderate and much improvement after treatment for
1 and 3 months (or last visit), respectively. As to residual pain intensity, although
none of them got complete pain relief, there were 12 cases (20.7 %) and 45 cases
(77.6 %) felt the pain intensity was mild (NPS 1 to 3) after treatment for 1 and 3
months respectively. There was a statistically significant decrease in the pain
intensity between before treatment and after treatment for 1 month and 3
months. The authors concluded that these findings showed that the concurrent
combination therapy with proper medications and appropriate nerve blocks could
offer satisfactory pain relief in the majority of elderly patients with PHN. The effect
of intercostal nerve block is confounded by the concomitant use of pain
medications.
Schencking and associates (2010) reported the findings of intravenous
administration of vitamin C in the treatment of 2 patients with PHN. These 2
subjects (females aged 67 and 53 years) were from an average and unselected
patient group of a general practice with confirmed acute herpetic neuralgia who
were observed in the course of their illness. They received the basic analgesic
(according to the WHO step scheme) and viral-static therapy. Furthermore, 15-g of
vitamin C was administered intravenously every second day over a period of 2
weeks. Sudden and total remission of the neuropathic pain (measured on the basis
of VAS) could be observed. Remission of the cutaneous lesions was noted within
10 days. The use of the vitamin C appears to be an interesting component of
alternative therapeutic strategies in the treatment of HZ. Especially for therapy-
resistant cases of PHN, vitamin C administration should be examined as an
additional option. The authors concluded that to test and confirm these clinical
findings, randomized clinical trials regarding the use of vitamin C in the concomitant
treatment of zoster-associated neuralgia should be performed.
Rullan and colleagues (2017) stated that PHN is a chronic neuropathic pain that
results from alterations of the peripheral nervous system in areas affected by the
herpes zoster virus. The symptoms include pain, paresthesia, dysesthesia,
hyperalgesia, and allodynia. Despite the availability of pharmacological treatments
to control these symptoms, no treatments are available to control the underlying
pathophysiology responsible for this disabling condition. These researchers
described the study protocol for a randomized controlled clinical trial that will
examine the effectiveness of gabapentin for prevention of PHN. Patients with
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herpes zoster who are at least 50 years old and have a pain score of 4 or higher on
a VAS will be recruited. The aim is to recruit 134 patients from the practices of
general physicians. Participants will be randomized to receive gabapentin to a
maximum of 1,800 mg/day for 5 weeks or placebo. Both arms will receive 1,000-
mg caplets of valacyclovir 3 times daily for 7 days (initiated within 72 hours of the
onset of symptoms) and analgesics as needed. The primary outcome measure is
the percentage of patients with a VAS pain score of 0 at 12 weeks from rash onset.
The secondary outcomes measures are changes in quality of life (QOL; measured
by the SF-12 questionnaire), sleep disturbance (measured by the Medical
Outcomes Study Sleep Scale), and percentage of patients with neuropathic pain
(measured by the Douleur Neuropathique in 4 Questions).
In a randomized, double-blind study, Backonja et al (2008) examined the safety and
effectiveness of one application of NGX-4010, a high-concentration (8 %) capsaicin
dermal patch, in the treatment of patients with PHN. A total of 402 patients were
randomly assigned to one 60-min application of NGX-4010 (640 microg/cm (2) or a
low-concentration capsaicin control patch (3.2 microg/cm(2) [0.04 % capsaicin]).
Patients were aged 18 to 90 years, had had PHN for at least 6 months, and had an
average baseline numeric pain rating scale (NPRS) score of 3 to 9. The primary
efficacy end point was percentage change in NPRS score from baseline to weeks 2
to 8. Analysis was by intention-to-treat. Patients who were randomly assigned to
NGX-4010 (n = 206) had a significantly greater reduction in pain during weeks 2
to 8 than did patients who had the control patch (n = 196). The mean changes in
NPRS score were -29.6 % versus -19.9 % (difference -9.7 %, 95 % CI: -15.47 to
-3.95; p = 0.001). A total of 87 (42 %) patients who received NGX-4010 and 63 (32
%) controls had a 30 % or greater reduction in mean NPRS score (odds ratio [OR]
1.56, 95 % CI: 1.03 to 2.37; p = 0.03). Patients who had NGX-4010 had significant
improvements in pain during weeks 2 to 12 (mean change in NPRS score -29.9 %
versus -20.4 %, difference -9.5, -15.39 to -3.61; p = 0.002). Transient blood
pressure changes associated with changes in pain level were recorded on the day
of treatment, and short-lasting erythema and pain at the site of application were
common, self-limited, and generally mild-to-moderate in the NGX-4010 group and
less frequent and severe in the controls. The authors concluded that one 60-min
application of NGX-4010 provided rapid and sustained pain relief in patients with
PHN. No adverse events were associated with treatment except for local reactions
at the site of application and those related to treatment-associated pain.
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In a Cochrane review, Derry et al (2009) reviewed the evidence from controlled
trials on the efficacy and tolerability of topically applied capsaicin in chronic
neuropathic pain in adults. Randomized, double-blind, placebo-controlled studies of
at least 6 weeks' duration, using topical capsaicin to treat neuropathic pain were
included in this analysis. A total of 6 studies (389 participants in total) compared
regular application of low dose (0.075 %) capsaicin cream with placebo cream; the
numbers needed to treat to benefit (NNT) for any pain relief over 6 to 8 weeks was
6.6 (4.1 to 17). Two studies (709 participants in total) compared a single application
of high dose (8 %) capsaicin patch with placebo patch; the NNT for greater than or
equal to 30 % pain relief over 12 weeks was 12 (6.4 to 70). Local skin reactions
were more common with capsaicin, usually tolerable, and attenuated with time; the
numbers needed to treat to harm (NNH) for repeated low dose application was 2.5
(2.1 to 3.1). There were insufficient data to analyse either data set by condition or
outcome definition. All studies satisfied minimum criteria for quality and validity, but
maintenance of blinding remains a potential problem. The authors concluded that
capsaicin, either as repeated application of a low dose (0.075 %) cream, or a single
application of a high dose (8 %) patch may provide a degree of pain relief to some
patients with painful neuropathic conditions. Local skin irritation, which is often mild
and transient but may lead to withdrawal, is common. Systemic adverse effects are
rare. Estimates of benefit and harm are not robust due to limited amounts of data
for different neuropathic conditions and inconsistent outcome definition.
In a randomized, double-blind, controlled study with an open-label extension,
Backonja et al (2010) evaluated the safety, effectiveness and tolerability of NGX-
4010 in patients with PHN. Patients were randomized to receive NGX-4010 or
control patch in a 4-week, double-blind study. This was followed by an open-label
extension phase (up to 48 weeks total) where patients could receive up to 3
additional treatments no sooner than 12 weeks after initial treatment. The primary
efficacy variable was mean change from baseline in mean morning and evening
NPRS scores. During days 8 to 28 after the double-blind treatment, NGX-4010
patients had a mean change in NPRS scores from baseline of -32.7 % compared
with -4.4 % for control patients (p = 0.003). Mean NPRS scores decreased from
baseline during week 1 in both treatment groups, remained relatively stable through
week 12 in NXG-4010 patients, but returned to near baseline during weeks 2 to 4 in
controls. Mean change in NPRS scores from baseline during weeks 2 to 12 was
-33.8 % for NGX-4010 and +4.9 % for control recipients. A similar decrease in
NPRS scores from baseline was maintained with subsequent NGX-4010
treatments, regardless of the number of treatments received. Transient increases in
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application site pain was adequately managed with analgesics. No increases in
application site reactions or adverse events were observed with repeated
treatments. No patients discontinued the study due to an adverse event. The
authors concluded that NGX-4010 is a promising topical treatment for PHN
patients, which appears to be tolerable, generally safe, and effective.
In an open-label study, Simpson and associates (2010) assessed the safety of
repeated applications of NGX-4010 over 1 year in patients with moderate to severe
PHN or human immunodeficiency virus-associated distal sensory polyneuropathy
(HIV-DSP). Patients had successfully completed a previous NGX-4010 study and
had a pain level appropriate for further treatment. Eligible patients had not been
treated with NGX-4010 within 12 weeks of study initiation. Patients received pre-
treatment with a topical local anesthetic (lidocaine 4 %) for 60 minutes followed by
either a 60-minute (PHN and HIV-DSP patients) or a 90-minute (HIV-DSP patients)
treatment with NGX-4010. Patients could receive up to 3 additional treatments at
intervals of greater than or equal to 12 weeks. Regardless of the number of
treatments received, all patients were followed-up for 48 weeks except for those
withdrawing early. A total of 106 patients were enrolled and received a total of 293
NGX-4010 treatments. The most frequently reported treatment-emergent adverse
events were transient, mild-to-moderate application site erythema, pain, edema, and
papules. Small, transient pain-related increases in blood pressure during and
immediately after NGX-4010 application were observed. There was no evidence of
an increased incidence of adverse events, dermal irritation, intolerability, or
impaired neurological function with repeated treatments. The authors concluded that
repeated treatments with NGX-4010 administered over a 1-year period are generally
safe and well-tolerated.
McCormack (2010) stated that capsaicin dermal patch is an adhesive patch
containing a high concentration (8 % w/w) of synthetic capsaicin. It is indicated in
the European Union for the treatment of peripheral neuropathic pain in non-diabetic
adults using a single 30- or 60-minute application repeated every 90 days, as
required, and in the United States for the treatment of neuropathic pain associated
with PHN. In pivotal, randomized, double-blind, multi-center trials in adults with
PHN, a single 60-minute application of capsaicin dermal patch reduced the mean
NPRS scores from baseline to a significantly greater extent than a low- concentration
(0.04 % w/w capsaicin) control patch during weeks 2 to 8. In randomized, double-
blind, multi-center trials in patients with HIV-associated neuropathy, capsaicin dermal
patch reduced the mean NPRS scores from baseline
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significantly more than control in 1 study for the 30- and 90-minute, but not the 60-
minute, application during weeks 2 to 12. In another study, the differences between
capsaicin (30- and 60-minute applications) and control did not reach statistical
significance. An integrated analysis of both studies showed that the 30-minute
application of capsaicin dermal patch was significantly better than control for the
reduction from baseline in mean NPRS scores during weeks 2 to 12. The efficacy
of capsaicin dermal patch was maintained for up to 1 year in extension studies in
which patients could receive up to 3 or 3 repeat treatments. Capsaicin dermal patch
was generally well-tolerated in clinical trials. The most common adverse events were
transient, mostly mild-to-moderate, application-site reactions.
On November 16, 2009, the Food and Drug Administration approved Qutenza
(capsaicin, 8 % patch) for the treatment of neuropathic pain associated with PHN.
The capsaicin in Qutenza (capsaicin) 8% patch is a synthetic equivalent of the
naturally occurring compound found in chili peppers. Capsaicin is an agonist for the
transient receptor potential vanilloid 1 receptor (TRPV1), which is an ion channel‐
receptor complex expressed on nociceptive nerve fibers in the skin. Topical
administration of capsaicin causes an initial enhanced stimulation of the TRPV1‐
expressing cutaneous nociceptors that may be associated with painful sensations.
This is followed by pain relief thought to be mediated by a reduction in TRPV1‐
expressing nociceptive nerve endings. Over the course of several months, there
may be a gradual re‐emergence of painful neuropathy thought to be due to TRPV1
nerve fiber reinnervation of the treated area.
Qutenza must be applied to the skin by a health care professional since placement
of the patch can be quite painful, requiring use of a local topical anesthetic, as well
as additional pain relief such as ice or use of opioid pain relievers. The patient must
also be monitored for at least 1 hour since there is a risk of a significant rise in
blood pressure following patch placement. The product inserts of Qutenza states
that the patches should be applied to the most painful skin areas, using up to 4
patches. Furthermore, the patches should be applied for 60 minutes and repeat
every 3 months or as warranted by the return of pain (not more frequently than
every 3 months).
There are no controlled studies with pregnant or lactating mothers. The safety and
efficacy of Qutenza in patients under the age of 18 has also not been studied.
Studies did involve patients over 75 years of age with similar efficacy and safety
profiles. Therefore, no dose adjustments are required in the geriatric population.
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According to the 2004 American Academy of Neurology treatment guidelines for
postherpetic neuralgia, the magnitude of benefit for topical capsaicin is below the
level that is considered clinically important in the treatment of chronic pain related
to post‐herpetic neuralgia. Since the guidelines have not been updated since 2004,
the same AAN evidence rating tool was used to evaluate the two Qutenza trials
cited in the package insert. Both studies were prospective, randomized, double‐
blind controlled trials. Primary outcomes and drop‐out rationale were clearly
defined. The endpoints were mean percent reductions in Numeric Pain Rating
Scale (NPRS) score from baseline. Pain endpoints such as these, are subject to
user bias. In addition, possible confounders in these studies were the fact that half
of the patients were allowed to continue taking their current pain regimen and the
subjects were also allowed to take extra pain medications during the treatment
period as well. Both endpoints did not reach statistically significance, only showed
pain improvement. The patients who did not complete the trials were assigned to
0% improvement which is a conservative approach when evaluating outcomes.
These trials would be classified as AAN Class II because of the potential bias and
the lack of convincing evidence to support Qutenza’ use in PHN.:
Young and colleagues (2017) noted that capsaicin has been traditionally used to
manage pain; however, the safety and effectiveness of this practice is still elusive.
These researchers examined the effect of topical capsaicin in pain management.
All double-blinded, randomized placebo- or vehicle-controlled trials that were
published in English addressing PHN were included. Meta-analysis was performed
using Revman version 5.3. Upon application of the inclusion and exclusion criteria,
only 6 trials fulfilled all the criteria and were included in the review for qualitative
analysis. The difference in mean percentage change in NPRS score ranged from
-31 to -4.3. This demonstrated high efficacy of topical capsaicin application and
implied that capsaicin could result in pain reduction. Furthermore, meta-analysis
was performed on 5 of the included studies. All the results of studies were in favor
of the treatment using capsaicin. The incidence of side effects from using topical
capsaicin is consistently higher in all included studies, but the significance of safety
data cannot be quantified due to a lack of p-values in the original studies. The
authors concluded that topical capsaicin is a promising therapeutic option for
specific patient groups or certain neuropathic pain conditions such as PHN.
In a pilot study, Nabarawy et al (2011) evaluated the effect of narrow-band ultra-
violet light B (nbUVB) in the treatment PHN. The study included 17 patients with
distressing PHN. Patients were evaluated using the Verbal Rating Scale (VRS).
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They received nbUVB sessions, 3 times a week, for a total of 15 sessions or until
the pain disappeared. Patients were followed-up for a period of 3 months after the
end of therapy. Using intention-to-treat analysis, more than 50 % improvement was
achieved in 6 (35.29 %) and 8 (47.06 %) patients, at the end of therapy and after 3
months follow-up, respectively. An improvement of less than 50 % was achieved in
11 (64.71 %) and 9 (52.94 %) patients, at the end of therapy and after 3 months
follow-up, respectively. The pain severity assessed by the VRS significantly improved
both at the end of sessions (p = 0.005) and after 3 months follow-up (p = 0.005). The
authors concluded that nbUVB may be of beneficial use in the treatment of PHN.
The drawbacks of this pilot study were small number of patients and limited follow-up
period. These preliminary findings need to be validated by well-designed studies.
Barros et al (2012) stated that herpes zoster infection may cause PHN. This
phenomenon may be reversed by (S)-ketamine (SKET), but its use results in
intolerable side effects, while its topical administration seems to be safe. In a
cross-over study, these researchers examined the effectiveness of topical (S)
-ketamine for pain management of PHN. A total of 12 patients were randomly
divided into 2 groups. There was a significant effect of time on pain intensity, but
no statistical difference in pain scores for SKET or placebo use in this sample in
this treatment regimen. Only few mild cutaneous reactions were observed with
topical SKET use.
In a Cochrane review, Han and colleagues (2013) examined the effectiveness of
corticosteroids in preventing PHN. These researchers updated the searches for
randomized controlled trials (RCTs) of corticosteroids for preventing PHN in the
Cochrane Neuromuscular Disease Group Specialized Register (April 16, 2012),
CENTRAL (2012, Issue 3), MEDLINE (January 1966 to April 2012), EMBASE
(January 1980 to April 2012), LILACS (January 1982 to April 2012), and the
Chinese Biomedical Retrieval System (1978 to 2012). They also reviewed the
bibliographies of identified trials, contacted authors and approached
pharmaceutical companies to identify additional published or unpublished data.
These investigators included all RCTs involving corticosteroids given by oral,
intramuscular, or intravenous routes for people of all ages with HZ of all degrees of
severity within 7 days after onset, compared with no treatment or placebo but not
with other treatments. They did not include quasi-RCTs (trials in which a
systematic method of randomization such as alternation or hospital number was
used). Two authors identified potential articles, extracted data, and independently
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assessed the risk of bias of each trial. Disagreement was resolved by discussion
among the co-authors. A total of 5 trials were included with 787 participants in total.
All were randomized, double-blind, placebo-controlled, parallel-group studies. They
conducted a meta-analysis of 2 trials (114 participants) and the results gave
moderate quality evidence that oral corticosteroids did not prevent PHN 6 months
after the onset of herpes (RR 0.95, 95 % CI: 0.45 to 1.99). One of these trials was
at high-risk of bias because of incomplete outcome data, the other was at low-risk
of bias overall. The 3 other trials that fulfilled inclusion criteria were not included in
the meta-analysis because the outcomes were reported at less than 1 month or
not in sufficient detail to add to the meta-analysis. These 3 trials were generally at
low-risk of bias. Adverse events during or within 2 weeks after stopping treatment
were reported in all 5 included trials. There were no significant differences in
serious or non-serious adverse events between the corticosteroid and placebo
groups. There was also no significant difference between the treatment groups
and placebo groups in other secondary outcome analyses and subgroup analyses.
The review was first published in 2008 and no new RCTs were identified for
inclusion in subsequent updates in 2010 and 2012. The authors concluded that
there is moderate quality evidence that corticosteroids given acutely during zoster
infection are ineffective in preventing PHN. In people with acute HZ the risks of
administration of corticosteroids do not appear to be greater than with placebo,
based on moderate quality evidence. Corticosteroids have been recommended to
relieve the zoster-associated pain in the acute phase of disease. These
investigators stated that if further research is designed to evaluate the effectiveness
of corticosteroids for HZ, long-term follow-up should be included to observe their
effect on the transition from acute pain to PHN; and future trials should include
measurements of function and quality of life.
Reviews on “Evidence-based guidance for the management of postherpetic
neuralgia in primary car” (Harden et al, 2013), “Management of herpes zoster and
post-herpetic neuralgia” (Gan et al, 2013) and “Herpes zoster: Diagnostic,
therapeutic, preventive approaches” (Bader, 2013), and “Options for treating
postherpetic neuralgia in the medically complicated patient” (Bruckenthal and
Barkin, 2013) mentioned the use of topical lidocaine, but not intravenous lidocaine,
as a therapeutic option.
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Furthermore, an UpToDate review on “Postherpetic neuralgia” (Bajwa et al, 2014)
states that “The effectiveness of therapies such as TENS and acupuncture has not
been proven. Intravenous lidocaine may provide benefit in patients who do not
respond to other therapies; however, small controlled trials have not convincingly
demonstrated that this therapy is superior to placebo”.
In a Cochrane review, Wiffen et al (2104) evaluated the analgesic effectiveness and
adverse events of levetiracetam in chronic neuropathic pain conditions in adults.
These investigators searched the Cochrane Central Register of Controlled Trials
(CENTRAL) (2014, Issue 6) (via the Cochrane Library), MEDLINE, EMBASE, and two
clinical trials databases (ClinicalTrials.gov. and the World Health Organization Clinical
Trials Registry Platform) to July 3, 2014, together with reference lists of retrieved
papers and reviews. They included randomized, double-blind studies of 2 weeks
duration or longer, comparing levetiracetam with placebo or another active treatment
in adults with chronic neuropathic pain conditions. Studies had to have a minimum of
10 participants per treatments arm. Two review authors independently extracted
effectiveness and adverse event data and examined issues of study quality. They
performed analysis using 3 tiers of evidence. First tier evidence derived from data
meeting current best standards and subject to minimal risk of bias (outcome
equivalent to substantial pain intensity reduction; intention-to-treat analysis without
imputation for drop-outs; at least 200 participants in the comparison; 8 to 12 weeks
duration; parallel design); 2nd tier evidence from data that failed to meet 1 or more of
these criteria and that these researchers considered at some risk of bias but with at
least 200 participants in the comparison; and 3d tier evidence from data involving
fewer than 200 participants that was considered very likely to be biased or used
outcomes of limited clinical utility, or both. These investigators included 6 studies: 5
small, cross-over studies with 174 participants, and 1 parallel group study with 170
participants. Subjects were treated with levetiracetam (2,000 mg to 3,000 mg daily) or
placebo for between four and 14 weeks. Each study included participants with a
different type of neuropathic pain; central pain due to multiple sclerosis, pain following
spinal cord injury, painful polyneuropathy, central post-stroke pain, PHN, and post-
mastectomy pain. None of the included studies provided 1st or 2nd tier evidence.
The evidence was very low quality, down-graded because of the small size of the
treatment arms, and because studies reported results using last observation carried
forward (LOCF) imputation for withdrawals or using only participants who completed
the study according to the protocol, where there were greater than 10 % withdrawals.
There were insufficient data for a pooled efficacy analysis in particular neuropathic
pain
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conditions, but individual studies did not show any analgesic effect of levetiracetam
compared with placebo. These researchers did pool results for any outcome
considered substantial pain relief (greater than or equal to 50 % pain intensity
reduction or “complete” or “good” responses on the verbal rating scale) for 4 studies
with dichotomous data; response rates across different types of neuropathic pain
was similar with levetiracetam (10 %) and placebo (12 %), with no statistical
difference (RR 0.9; 95 % CI: 0.4 to1.7). They pooled data across different
conditions for adverse events and withdrawals. Based on very limited data,
significantly more participants experienced an adverse event with levetiracetam
than with placebo (number needed to treat for an additional harmful event (NNH)
8.0 (95 % CI: 4.6 to 32)). There were significantly more adverse event withdrawals
with levetiracetam (NNH 9.7 (6.7 to 18)). The authors concluded that the amount of
evidence for levetiracetam in neuropathic pain conditions was very small and
potentially biased because of the methods of analysis used in the studies. There
was no indication that levetiracetam was effective in reducing neuropathic pain, but
it was associated with an increase in participants who experienced adverse events
and who withdrew due to adverse events.
In a Cochrane review, Gaskell et al (2014) evaluated the analgesic effectiveness
and adverse events of oxycodone for chronic neuropathic pain and fibromyalgia.
On November 6, 2013, these investigators searched CENTRAL, MEDLINE and
EMBASE databases. They reviewed the bibliographies of all included studies and
of reviews, and also searched 2 clinical trial databases, ClinicalTrials.gov and the
World Health Organization (WHO) International Clinical Trials Registry Platform, to
identify additional published or unpublished data. They included RCTs with double-
blind assessment of participant outcomes following 2 weeks of treatment or longer
(although the emphasis of the review was on studies of 8 weeks or longer) that
used a placebo or active comparator. Two review authors independently extracted
efficacy and adverse event data, examined issues of study quality, and assessed
risk of bias. They performed analysis using 3 tiers of evidence. First tier evidence
was derived from data meeting current best standards and subject to minimal risk
of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat
analysis without imputation for dropouts; at least 200 participants in the
comparison, 8 to 12 weeks duration, parallel design), 2nd tier from data that failed
to meet 1 or more of these criteria and were considered at some risk of bias but
with adequate numbers in the comparison, and 3rd tier from data involving small
numbers of participants that was considered very likely to be biased or used
outcomes of limited clinical utility, or both. These researchers included 3 studies
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with 254 participants; 204 had painful diabetic neuropathy and 50 PHN. Study size
ranged from 45 to 159 participants. Two studies used a cross-over design and 1 a
parallel group design; study duration was 4 or six weeks. Controlled release
oxycodone (oxycodone CR) was used in all 3 studies, with doses titrated up to a
maximum of between 60 and 120 mg daily; mean doses achieved ranged between
37 and 45 mg daily. All studies used a placebo comparator, although in 1 study, an
active placebo (benztropine) was used. All studies had 1 or more sources of
potential major bias. No study reported the proportion of participants experiencing
at least 50 % pain relief or who were very much improved, while 1 reported the
proportion with at least 30 % pain relief, 2 reported at least moderate pain relief,
and 1 reported the number of participants who considered treatment to be
moderately effective. No study provided 1st or 2nd tier evidence for an efficacy
outcome. Third tier evidence indicated greater pain intensity reduction and better
patient satisfaction with oxycodone than with placebo in all 3 studies, but such
evidence was derived mainly from group mean data, with LOCF imputation or
completer analysis, in small studies lasting less than 8 weeks (very low-quality
evidence). Adverse events were more common with oxycodone CR than with
placebo. At least 1 adverse event was experienced by 86 % of participants taking
oxycodone CR and 63 % taking placebo, and the NNH was 4.3. The effect of
oxycodone on serious adverse events reported was uncertain in comparison with
placebo (oxycodone 3.4 % versus placebo: 7.0 %; RR 0.48 (95 % CI: 0.18 to 1.23;
very low-quality evidence); 1 death was reported with oxycodone CR but was not
attributed to treatment. Adverse event withdrawals did not differ significantly
between groups, occurring in 11 % of participants with oxycodone CR and 6.4 %
with placebo (RR 1.69 (0.83 to 3.43); very low quality evidence). Withdrawals due
to lack of efficacy were less frequent with oxycodone CR (1.1 %) than placebo (11
%), with an NNT to prevent 1 withdrawal of 10 (RR 0.12 (0.03 to 0.45); very low
quality evidence). These investigators found no relevant studies in chronic
neuropathic pain conditions other than painful diabetic neuropathy or PHN, or in
fibromyalgia. The authors concluded that no convincing, unbiased evidence
suggests that oxycodone (as oxycodone CR) is of value in treating people with
painful diabetic neuropathy or PHN. There is no evidence at all for other
neuropathic pain conditions, or for fibromyalgia. Adverse events typical of opioids
appear to be common.
Ing and colleagues (2015) stated that PHN remains a therapeutic challenge for the
clinician. Many modalities have been utilized with limited success. In this pilot
randomized study of patients who were refractory to previous medicinal treatment,
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the patients were treated with TENS with a biofeedback capability. After every 2
treatments with the sham and true device, the patients were required to fill out a
standard neuropathic pain scale score. The patients were allowed to select the
other device after 3 consecutive treatments if they felt an inadequate decrease in
their pain. The true device was chosen over the sham device by all patients. The
majority of these patients treated by the true device reported a statistically
significant decrease in pain scores (p < 0.001). The authors concluded that further
investigation of this Food and Drug Administration (FDA)-class 2 electronic device
for relief of pain is needed for patients with a history of recalcitrant PHN.
Fujiwara et al (2018) stated the acute phase of shingles is characterized by severe
pain, and one of the complications of shingles known as postherpetic neuralgia (PHN)
is associated with prolonged pain. Although factors predicting the development of
PHN, as well as its preventative measures, have been investigated, there is no single
treatment effective for PHN. Some studies showed effectiveness of epidural injection
to alleviate pain associated with acute-phase shingles. In these studies, epidural
injection was performed by interlaminar (IL) approach. However, transforaminal (TF)
approach may be more effective as it enables injection of steroids and local
anesthetics closer to the dorsal root ganglion where inflammation primarily occurs.
There have not been any studies comparing the analgesic effects of epidural
injection approaches for pain associated with acute-phase shingles. This randomized
prospective trial study compared the analgesic effects of IL and TF epidural injection
approaches for pain associated with acute-phase shingles. Nara Medical University
Hospital, Department of Anesthesiology. Forty patients with acute-phase shingles
were randomly assigned to receive epidural steroid injections by TF or IL approaches.
Patients were evaluated at the baseline, as well as at 1 month and 3 months after the
treatment using the VAS and SF-36 scores. Patients with VAS score of over 40 at the
3-month follow-up were considered as having PHN, and the number of patients with
PHN was compared between the IL and TF groups. Except the mental component of
the SF-36 score and severity of skin rash, patient characteristics were not significantly
different between the groups. VAS scores at 1 and 3-month follow-up were
significantly lower than those at the baseline, and there was no difference between
the groups. All SF-36 scores were not significantly different between groups at 1-
and 3-month. There was no significant difference in the occurrence of PHN between
the groups. Study limitations included a small sample size that did not reach the
number of patients needed by the power analysis in the study. Also, the follow-up
period of 3 months was relatively short. The authors concluded that VAS scores, the
SF-36 RCS and
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MCS scores improved in both groups, however, there was no difference in the
analgesic effects of the IL and TF epidural steroid injections at 1 and 3 months for
acute-phase shingles patients.
Combination of Trigeminal Ganglion and Retrobulbar Nerve Block for the Treatment of Post-Herpetic Neuralgia
Huang and colleagues (2017) noted that varicella zoster virus reactivation can
cause permanent histological changes in the central and peripheral nervous
system. Neural inflammatory changes or damage to the dorsal root ganglia sensory
nerve fibers during reactivation can lead to PHN. For PHN of the first division of the
5th cranial nerve (ophthalmic division of the trigeminal ganglion), there is evidence
of inflammatory change in the ganglion and adjacent ocular neural structures.
First division trigeminal nerve PHN can prove to be difficult and sometimes even
impossible to manage despite the use of a wide range of conservative measures,
including anti-convulsant and anti-depressant medication. Steroids have been
shown to play an important role by suppressing neural inflammatory processes.
Thus, these researchers chose the trigeminal ganglion as an interventional target
for an 88-year old woman with severe ophthalmic division PHN after she failed to
respond to conservative treatment. Under fluoroscopic guidance, a trigeminal
ganglion nerve block was performed with lidocaine combined with dexamethasone;
and a retrobulbar block with lidocaine and triamcinolone settled residual
oculodynia. At 1-year follow-up, the patient remained pain-free and did not require
analgesic medication. The authors concluded that to their knowledge, this was the
first reported case of ophthalmic division PHN successfully treated with a
combination of trigeminal ganglion and retrobulbar nerve block using a local
anesthetic agent and steroid for central and peripheral neural inflammatory
processes. This preliminary finding need to be validated by well-designed studies.
Ganglioside GM1 for the Treatment of Post-Herpetic Neuralgia
Koju and Lei (2016) noted that PHN is a commonest and difficult-to-manage
complication of Herpes zoster. This comparative study included 140 cases of PHN
admitted in the department of dermatology in Renmin Hospital of Wuhan University,
Wuhan, China, from March 2014 to February 2015, divided into a control and a
study group. In addition to the combination of anti-viral, analgesic, and
neurotrophic agents given to the control group, additional ganglioside GM1 was
given to patients in the study group. Pain assessment was performed at the time of
admission, and then on the 3rd, 7th and 10th day of treatment, on both groups,
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using a 10 cm VAS. There was a significant statistical difference between the pain
VAS score of the 2 groups, on the 7th day (3.73 ± 1.66 versus 3.03 ± 1.86, p =
0.024) and on the 10th day (3.25 ± 1.78 versus 2.20 ± 1.59, p = 0.006) of
treatment. The number of patients who have good/and complete response (37.5
%) were largely higher in the study group than those in the control group (15 %, p <
0.05). The authors concluded that these findings demonstrated that the
administration of ganglioside GM1 may potentially serve as a neoadjuvant therapy
to reduce the severity and duration of pain in PHN patients.
Fulranumab for the Treatment of Post-Herpetic Neuralgia
Wang and colleagues (2017) stated that fulranumab is an antibody that specifically
neutralizes the biological activity of human nerve growth factor. In a multi-center,
phase II, randomized, double-blind, placebo-controlled study, these researchers
evaluated the safety and effectiveness of fulranumab in PHN and post-traumatic
neuropathy (PTN) patients. Patients (18 to 80 years of age) with inadequately
controlled moderate-to-severe pain received study medication (subcutaneous
injection) every 4 weeks. Patients with PHN were randomized (3:2:2:3) to receive
either placebo or one of 3 doses of fulranumab: 1 mg (1 mgQ4 wk), 3 mg (3 mgQ4
wk), or 10 mg (10 mgQ4 wk); PTN patients were randomized (1:1) to receive either
placebo or fulranumab 10 mgQ4 wk. The FDA placed a clinical hold (December 23,
2010) on all trials of anti-nerve growth factor drugs, including fulranumab, due to
identified risks of osteonecrosis or rapidly progressing osteoarthritis; therefore, only
49 (of 150 planned) PHN patients and 34 (of 50 planned) PTN patients completed the
double-blind efficacy evaluation. There was no significant difference (p > 0.05,
fulranumab versus placebo) for change in 7-day average of daily pain intensity
scores from double-blind baseline to end of 12-week double-blind efficacy phase in
PHN or PTN patients (primary end-point). No significant difference was found with
fulranumab versus placebo (p > 0.05) in other efficacy measures in either PHN or
PTN patients.The most common treatment-emergent adverse events (AEs; greater
than 10 % incidence) in PTN patients were sinusitis, carpal tunnel syndrome, and
headache, whereas in PHN patients it was arthralgia. The authors concluded that
fulranumab did not demonstrate effectiveness in either PHN or PTN patients but was
generally well-tolerated in this small under-powered and abbreviated study.
Low-Level Laser for the Prevention of Post-Herpetic Neuralgia
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In a retrospective study, Chen and colleagues (2016) examined if low-level laser
therapy (LLLT) could reduce the incidence of PHN. These researchers reviewed the
incidence of PHN at the 1st, 3rd, and 6th months after rash outbreak in 3 groups: (i)
the acute group of patients who received LLLT during the first 5 days
(n = 48); (ii) the sub-acute group of patients who received LLLT during days 6 to
14 of the eruption (n = 48); and (iii) the control group of patients who did not
receive LLLT (n = 154). After adjusting for confounding factors, including age, sex,
and use of famciclovir, the incidence of PHN was significantly lower in the acute
group versus the control group after 1 month (OR 0.21, p = 0.006, 95 % CI: 0.068
to 0.632), 3 months (OR 0.112, p = 0.038, 95 % CI: 0.014 to 0.886), and 6 months
(OR 0.123, p = 0.021, 95 % CI: 0 to 0.606). The sub-acute group only had a lower
incidence (OR 0.187, p = 0.032, 95 % CI: 0.041 to 0.865) after 3 months when
compared with the control group. The authors concluded that applying LLLT within
the first 5 days of herpes zoster eruption significantly reduced the incidence of PHN.
They stated that LLLT may have the potential to prevent PHN, but further well-
designed RCTs are needed. The main drawback of this study was its retrospective
design; thus, lacking double-blind randomization, and the placebo effect may be a
major concern. Additional drawbacks were the lack of standardized and prospective
evaluation measures.
Transdermal Oxycodone Patch for the Treatment of Post-Herpetic Neuralgia
In a Cochrane review, Gaskell and associates (2016) evaluated the analgesic
effectiveness and adverse events (AEs) of oxycodone for chronic neuropathic pain
in adults. These investigators searched the Cochrane Central Register of
Controlled Trials (CENTRAL), Medline, and Embase from inception to November 6,
2013 for the original review and from January 2013 to December 21, 2015 for this
update. They also searched the reference lists of retrieved studies and reviews,
and 2 online clinical trial registries. This update differed from the earlier review in
that these researchers included studies using oxycodone in combination with
naloxone, and oxycodone used as add-on treatment to stable, but inadequate,
treatment with another class of drug. They included randomized, double-blind
studies of 2-week duration or longer, comparing any dose or formulation of
oxycodone with placebo or another active treatment in chronic neuropathic pain.
The authors concluded that there was only very low-quality evidence that
oxycodone (as oxycodone MR) is of value in the treatment of painful diabetic
neuropathy or PHN. There was no evidence for other neuropathic pain conditions;
and AEs typical of opioids appeared to be common.
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In a randomized, double-blind, multi-center, phase IIa vehicle-controlled cross-over
trial, Gavin and colleagues (2017) evaluated the effectiveness, systemic exposure,
safety and tolerability of a transdermal oxycodone patch containing tocopheryl
phosphate mixture (TPM) in patients with PHN. While the TPM/oxycodone patch
did not significantly improve “average” NPRS scores versus vehicle patch, patients
reporting high levels of paresthesia (n = 9) showed a trend toward improved pain
reduction. The TPM/oxycodone patch resulted in a low systemic exposure to
oxycodone and was well-tolerated. The authors concluded that TPM/oxycodone
patch delivered oxycodone to the site of perceived pain in subjects suffering from
PHN but did not provide analgesia for the broad PHN indication.
Combined Therapy of Nerve Block and Pulsed Radiofrequency
In a prospective, randomized clinical trial, Li and co-workers (2018) examined the
combined effects of nerve block therapy (NBT) and pulsed radiofrequency (PRF) in
patients with PHN. A total of 60 PHN patients were divided into 4 groups (n = 15
each): the conventional puncture group (group CP), the nerve block therapy group
(group NB), the PRF group (group PRF), and the combined treatment group (PRF
combined with nerve block therapy (group CT). To evaluate the extent of remission of
hyperalgesia, these investigators recorded the VAS scores during cotton swab
reaction before and after treatment and in the resting and active pain states. In
addition, blood samples were collected and plasma cytokine and neuropeptides
such as interleukin-6 (IL-6), substance P (SP), and β-endorphin (β-EP) were
measured by enzyme-linked immunosorbent assay (ELISA) at the admission (basic
state), before the operation, and at 12 hours post-operatively. The number of AEs
(nausea, vomiting, constipation, puncture point hemorrhage, swelling and redness)
within 12 hours of the treatment were also documented. The results showed that VAS
scores during cotton swab reaction decreased after treatment in all patients (p
< 0.05). Compared to group CP, plasma IL-6 and SP levels decreased (p < 0.05)
and β-EP levels increased (p < 0.05) in groups NB, PRF, and CT. There were no
significant differences in AEs among groups (p > 0.05). These researchers found
that PRF in combination with NBT increased β-EP levels and decreased plasma IL-
6 and SP, thereby alleviating pain and hyperalgesia in PHN patients. The
authors concluded that these findings suggested that combined therapy of NBT and
PRF was safe and effective for PHN patients.
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The authors stated that the drawbacks of this study included its design as a single-
center study and its small sample size (n = 15 in the combined NBT and PRF
group). They did not evaluate the effects of liver or renal dysfunction on the
treatment effects either. These researchers stated that their study might have
limited statistical power to detect difference among the groups. They stated that
future multi-center studies with larger sample sizes are needed to validate these
findings.
Intravenous Zinc Sulfate
Lin and colleagues (2018) noted that gabapentinoids (gabapentin and pregabalin)
are 1st-line drugs for PHN, but some PHN patients have inadequate therapeutic
response. Zinc deficiency has been identified as a risk factor for PHN. Zinc can
alleviate pain through binding to Ca(v)3.2 T-channels and N-methyl-D-aspartate
receptors. Mechanisms of gabapentinoids on neuropathic pain include inhibiting N-
methyl-D-aspartate receptors and calcium channels. The afore-mentioned findings
provided a molecular pain-relieving basis for zinc supplements as an add- on
therapy to pregabalin. These investigators report 2 zinc-deficient PHN patients who
received zinc sulfate intravenously as an add-on therapy to pregabalin and
responded well. These preliminary findings need to be validated by well-designed
studies.
CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
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Code Code Description
62324 - 62325 Injection(s), including indwelling catheter placement, continuous infusion
or intermittent bolus, of diagnostic or therapeutic substance(s) (eg,
anesthetic, antispasmodic, opioid, steroid, other solution), not including
neurolytic substances, interlaminar epidural or subarachnoid, cervical or
thoracic
62326 - 62327 Injection(s), including indwelling catheter placement, continuous infusion
or intermittent bolus, of diagnostic or therapeutic substance(s) (eg,
anesthetic, antispasmodic, opioid, steroid, other solution), not including
neurolytic substances, interlaminar epidural or subarachnoid, lumbar or
sacral ( caudal)
CPT codes not covered for indications listed in the CPB (not all-inclusive):
0228T Injection(s), anesthetic agent and/or steroid, transforaminal epidural,
with ultrasound guidance, cervical or thoracic; single level
+ 0229T each additional level
0230T Injection(s), anesthetic agent and/or steroid, transforaminal epidural,
with ultrasound guidance, lumbar or sacral; single level
+ 0231T each additional level
62281 Injection/infusion of neurolytic substance (eg, alcohol, phenol, iced
saline solutions), with or without other therapeutic substance; epidural,
cervical or thoracic
62282 epidural, lumbar, sacral (caudal)
63650 Percutaneous implantation of neurostimulator electrode array, epidural
63655 Laminectomy for implantation of neurostimulator electrodes,
plate/paddle, epidural
64400 Injection, anesthetic agent; trigeminal nerve, any division or branch
64420 Injection, anesthetic agent; intercostal nerve, single
64421 intercostal nerves, multiple, regional block
64479 Injection(s), anesthetic agent and/or steroid, transforaminal epidural,
with imaging guidance (fluoroscopy or CT); cervical or thoracic, single
level
+ 64480 cervical or thoracic, each additional level (List separately in addition to
code for primary procedure)
64483 lumbar or sacral, single level
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Code Code Description
+ 64484 lumbar or sacral, each additional level (List separately in addition to
code for primary procedure)
64510 Injection, anesthetic agent; stellate ganglion (cervical sympathetic)
64555 Percutaneous implantation of neurostimulator electrodes; peripheral
nerve (excludes sacral nerve)
64575 Incision for implantation of neurostimulator electrodes; peripheral nerve
(excludes sacral nerve)
64600 - 64640 Destruction by neurolytic agent (eg, chemical, thermal, electrical or
radiofrequency, somatic nerves
64650 Chemodenervation of eccrine glands; both axillae
64653 other area(s) (eg, scalp, face, neck), per day
64680 - 64681 Destruction by neurolytic agent, with or without radiologic monitoring,
sympathetic nerves
64802 - 64818 Sympathectomy
67500 Retrobulbar injection; medication (separate procedure, does not include
supply of medication)
67505 Retrobulbar injection; alcohol
+ 95873 Electrical stimulation for guidance in conjunction with chemodenervation
(List separately in addition to code for primary procedure)
+ 95874 Needle electromyography for guidance in conjunction with
chemodenervation (List separately in addition to code for primary
procedure)
96910 Photochemotherapy; tar and ultraviolet B (Goeckerman treatment) or
petrolatum and ultraviolet B
97033 Application of a modality to one or more areas; iontophoresis, each 15
minutes
97810 - 97814 Acupuncture
Other CPT codes related to the CPB:
96365 - 96379 Therapeutic, prophylactic, and diagnostic injections and infusions
(excludes chemotherapy and other highly complex drug or higly complex
biologic agent administration)
99601 - 99602 Home infusion/specialty drug administration, per visit
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Code Code Description
HCPCS codes covered if selection criteria are met:
J1020 Injection, methylprednisolone acetate, 20 mg
J1030 Injection, methylprednisolone acetate, 40 mg
J1040 Injection, methylprednisolone acetate, 80 mg
J1094 Injection, dexamethasone acetate, 1 mg
J1100 Injection, dexamethasone sodium phosphate, 1 mg
J1320 Injection, amitriptyline HCL, up to 20 mg
J1700 Injection, hydrocortisone acetate, up to 25 mg (Hydrocortone Acetate)
J1710 Injection, hydrocortisone sodium phosphate, up to 50 mg (Hydrocortone
Phosphate)
J1720 Injection, hydrocortisone sodium succinate, up to 100 mg (Solu-Cortef)
J2650 Injection, prednisolone acetate, up to 1 ml (Key-Pred 25, Key-Pred 50,
Predcor-25, Predcor-50, Predoject-50, Predalone-50, Predicort-50)
J2920 Injection, methylprednisolone sodium succinate, up to 40 mg (Solu-
Medrol)
J2930 Injection, methylprednisolone sodium succinate, up to 125 mg (Solu-
Medrol)
J3300 Injection, triamcinolone acetonide, preservative free, 1 mg
J3301 Injection, triamcinolone acetonide, not otherwise specified, 10 mg
J3302 Injection, triamcinolone diacetate, per 5 mg (Aristocort)
J3303 Injection, triamcinolone hexacetonide, per 5 mg (Aristospan)
J7336 Capsaicin 8% pat ch, per sq cm
HCPCS codes not covered for indications listed in the CPB (not all-inclusive): No
specific code:
Fulranumab, Ganglioside GM1, transdermal oxycodone patch
A4595 Electrical stimulator supplies, 2 lead, per month, (e.g. TENS, NMES)
E0720 Transcutaneous electrical nerve stimulation (TENS) device, two lead,
localized stimulation
E0730 Transcutaneous electrical nerve stimulation (TENS) device, four or more
leads, for multiple nerve stimulation
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Code Code Description
E0731 Form-fitting conductive garment for delivery of TENS or NMES (with
conductive fibers separated from the patient's skin by layers of fabric)
J0133 Injection, acyclovir, 5 mg
J0190 Injection, biperiden lactate, per 5 mg
J0585 Botulinum toxin type A, per unit
J0587 Botulinum toxin type B, per 100 units
J2001 Injection, lidocaine HCL for intravenous infusion, 10 mg
J2060 Injection, lorazepam, 2 mg
J2270 Injection, morphine sulfate, up to 10 mg
J2271 Injection, morphine sulfate, 100 mg
J2274 Injection, morphine sulfate, preservative-free for epidural or intrathecal
use, 10 mg
J2275 Injection, morphine sulfate (preservative-free sterile solution), per 10 mg
J9370 Vincristine sulfate, 1 mg
S0093 Injection, morphine sulfate, 500 mg (loading dose for infusion pump)
ICD-10 codes covered if selection criteria are met:
B02.21 - B02.29 Zoster [herpes zoster] with other nervous system involvement
M79.2 Neuralgia and neuritis, unspecified [neuropathic pain associated with
postherpetic neuralgia]
The above policy is based on the following references:
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2. Robertson DR, George CF. Treatment of post herpetic neuralgia in the elderly.
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3. Volmink J, Lancaster T, Gray S, et al. Treatments for postherpetic neuralgia --
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91.
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4. Reeve J, Corabian P. Transcutaneous electrical nerve stimulation (TENS) and
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Page 31 of 35
19. Baron R, Wasner G. Prevention and treatment of postherpetic neuralgia.
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29. Li Q, Chen N, Yang J, et al. Antiviral treatment for preventing postherpetic
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31. Schencking M, Sandholzer H, Frese T. Intravenous administration of
vitamin C in the treatment of herpetic neuralgia: Two case reports. Med
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32. Backonja M, Wallace MS, Blonsky ER, et al; NGX-4010 C116 Study Group.
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neuropathic pain in adults. Cochrane Database Syst Rev. 2009;
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34. U.S. Food and Drug Administration (FDA). FDA approves new drug
treatment for long-term pain relief after shingles attacks. FDA News. Silver
Spring, MD: FDA; November 17, 2009. Available at:
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Accessed April 15, 2011.
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postherpetic neuralgia: A randomized, double-blind, controlled study with
an open-label extension. Pain Med. 2010;11(4):600-608.
37. Webster LR, Malan TP, Tuchman MM, et al. A multicenter, randomized,
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2011;56(1):44-47.
42. Irving G, Backonja M, Rauck R, et al. NGX-4010, a capsaicin 8% dermal
patch, administered alone or in combination with systemic neuropathic
pain medications, reduces pain in patients with postherpetic neuralgia.
Clin J Pain. 2012;28(2):101-107.
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43. Schencking M, Vollbracht C, Weiss G, et al. Intravenous vitamin C in the
treatment of shingles: Results of a multicenter prospective cohort study.
Med Sci Monit. 2012;18(4):CR215-CR224.
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505.
45. Chun-jing H, Yi-ran L, Hao-xiong N. Effects of dorsal root ganglion
destruction by adriamycin in patients with postherpetic neuralgia. Acta Cir
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57. Gaskell H, Derry S, Stannard C, Moore RA. Oxycodone for neuropathic pain
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Physicians Surg Pak. 2016;26(7):633-634.
58. Chen YT, Wang HH, Wang TJ, et al. Early application of low-level laser may
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Page 35 of 35
Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan
benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,
general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care
services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in
private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible
for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to
change.
Copyright © 2001-2019 Aetna Inc.
http://www.aetna.com/cpb/medical/data/700_799/0725.html 03/26/2019
AETNA BETTER HEALTH® OF PENNSYLVANIA
Amendment to Aetna Clinical Policy Bulletin Number: 0725 Post-Herpetic
Neuralgia
There are no amendments for Medicaid.
www.aetnabetterhealth.com/pennsylvania revised 03/18/2019
Proprietary
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