Postherpetic Neuralgia: Treatment and Prevention Strategies

Release Date: March 1, 2013

Expiration Date: March 31, 2015


Donna Sym, BS, PharmD
Associate Clinical Professor
Department of Clinical Pharmacy Practice
St. John’s University
College of Pharmacy and Health Sciences
Queens, New York

Rane Jabonillo, PharmD Candidate 2013
St. John’s University
College of Pharmacy and Health Sciences
Queens, New York

John Lim, PharmD Candidate 2013
St. John’s University
College of Pharmacy and Health Sciences
Queens, New York


Dr. Sym, Mr. Jabonillo, and Mr. Lim have no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.


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To enhance the clinician’s knowledge about the treatment and prevention of postherpetic neuralgia (PHN), a complication associated with herpes zoster.


After completing this activity, the participant should be able to:

  1. Describe the pathophysiology associated with PHN.
  2. Identify risk factors associated with PHN.
  3. Recognize the signs and symptoms of PHN.
  4. Outline treatment and prevention strategies for PHN.

ABSTRACT: Herpes zoster (HZ), also known as shingles, is the reactivation of a past varicella zoster infection (chickenpox). This reactivation is more common in the elderly due to a declining immune system. Complications associated with HZ include central nervous system and ocular involvement and postherpetic neuralgia (PHN), a neuropathic pain that can be debilitating and last for months. The pain associated with PHN is a result of necrosis, inflammation, and damage to the sensory nerves upon viral reactivation. Treatment and prevention strategies for PHN include oral and topical medications, alternate treatments with limited data, and a shingles vaccine.

Chickenpox is a common childhood infection caused by the varicella zoster virus (VZV). Initial entry is through the mucosa of the upper respiratory tract, continuing into the blood and lymphatic systems, and then to the skin, causing a blisterlike rash.1 Although the primary VZV infection resolves, the virus also passes into the sensory nerves of the skin (dermatome) and up to the sensory ganglia. Here it can remain in a dormant state for a life span but is dependent on an intact immune system to maintain this inactivity. Infected individuals, however, have a 10% to 20% lifetime chance of reactivating this infection, which can occur when the immune system is weakened.2 This is seen with advanced age or immunosuppression caused by diseases or medications. Upon reactivation, the virus in the sensory ganglia descends along the sensory nerves and is released by the nerve endings into the skin, where it causes clusters of vesicles known as herpes zoster (HZ) or shingles.1,3

HZ usually presents with a prodromal phase with pain and itching (pruritus) along an affected dermatome followed by an acute phase with rash and blistering skin eruptions.4 Diagnosis of HZ is usually clinical, determined by the appearance of this characteristic blistering rash.5 Occasionally, it can be misdiagnosed or confused with the rash of herpes simplex virus (HSV).6 Laboratory diagnosis may be necessary at times. VZV DNA in the lesions can be identified using tissue culture, direct fluorescent antibody (DFA) staining, and polymerase chain reaction (PCR) to confirm or clarify a diagnosis.5,6


Complications of HZ reactivation can include the central nervous system (CNS) and such effects as encephalitis, ocular involvement, and postherpetic neuralgia (PHN). PHN is defined as a neuropathic pain that persists or reoccurs 3 or more months after the acute HZ episode5,7 and can last for a variable period of time, in some cases as long as 12 months after onset.3 PHN is diagnosed clinically when patients report a symptomatic painful rash in an affected dermatomal region; they may also have continued skin color changes and scarring. In contrast, some patients may not have a history of a painful zoster rash, a condition known as zoster sine herpete.8 PHN can occur in approximately 15% of HZ patients over 60 years of age,1,3 and the risk increases with age.9 Almost 50% of patients over 70 years old will experience PHN5; conversely, it is rarely seen in children or young adults.9 The elderly (age ≥65 years) are more at risk for PHN due to an aging peripheral nervous system (PNS) and CNS, with a reduced number of functional neurons and reduced ability to tolerate damage.10 Women are also more at risk at developing both HZ and PHN.11

The pain associated with PHN is a result of necrosis, inflammation, and damage to the sensory nerves upon viral reactivation.7 Peripheral sensory nerves have axonal damage resulting in hyperexcitability such as spontaneous firing, exaggerated neural impulses in response to stimuli, and lower excitation thresholds.8 HZ can also cause damage to the CNS by direct spinal cord infection or trans-synaptic degeneration, and this may determine and correlate with the incidence of PHN.10,12 PHN has typically three types of presentations: constant pain, paroxysmal pain, and allodynia. Constant pain can be described as a deep, aching, or burning pain; paroxysmal is sudden occurrences of stabbing, sharp pain; and allodynia is pain provoked by typically nonpainful stimuli.3,7,13 Constant, long-lasting pain may be due to sensitization of the sensory nerves (nociceptors) in the CNS from repetitive painful stimuli.9 Paroxysmal pain is thought to be caused by demyelination of sensory nerve fibers permitting action potentials to spread from one axon to another. This electrical neurotransmission results in the triggering of many nociceptors, resulting in severe jolts of pain. Demyelination predominantly affects only fast-conducting afferent fibers, causing abnormally long-lasting and painful sensations with minimal stimuli, and it can also be the explanation for allodynia.1,8

Individuals may also complain about intense itching, known as postherpetic itching (PHI), particularly in HZ cases involving the head or neck. This symptom can occur before, during, or after the onset of a lesion. PHI may be a result of impulsive firing of denervated central itch-specific neurons or preserved peripheral itch-specific neurons from nearby unharmed dermatomes.1,10 Other cases can result in a complete loss of the sense of touch or pain. This may be due to a reduction of incoming signals in the periphery. Injured afferent nerves result in more electrical activity of central neurons, initially increasing sensory function but eventually resulting in a decrease or entire loss of sensory function.1


PHN can be debilitating and greatly affect the quality of life of patients. An effort has been made to treat PHN with medical therapies and other interventions; however, they have not always proven successful. This article will review the medical and interventional treatment options utilized (see TABLE 1 for dosing regimens, TABLE 2 for side-effect profiles, and TABLE 3 for comments on medical treatment options in the elderly).




Tricyclic Antidepressants (TCAs)

TCAs have been used to treat various types of neuropathic pain, and there are several randomized, controlled trials (RCTs) showing efficacy in the treatment of PHN.14 Amitriptyline has been the most studied TCA, with at least seven RCTs done since 1982 showing efficacy in PHN management. One study showed a response rate of 67% at a median dose of 75 mg/day, and other studies showed response rates ranging from 47% to 66%.8 There is evidence that other TCAs such as desipramine and nortriptyline are also effective with similar response rates,8 and a meta-analysis of RCTs has shown significant relief of PHN with TCAs.14 In a study comparing nortriptyline with amitriptyline, results showed equal efficacy, but there were fewer side effects with nortriptyline.15 In a study comparing nortriptyline with gabapentin, both treatments showed similar efficacy.16 A recent study noted that desipramine was successful in treating the pain of PHN in antidepressant-naïve patients. Desipramine was compared to amitriptyline and fluoxetine, and although there was no statistical difference in the treatment arms, the greatest reduction in pain intensity was found in patients taking desipramine (47%) compared to amitriptyline (38%) and fluoxetine (35%).17 Maprotiline has also been shown as efficacious, but when compared, amitriptyline was slightly more efficacious.3

The main limiting factor of TCAs is their extensive side-effect profile. Since PHN is prevalent mostly in the elderly, it is important to evaluate any underlying disease states and potential added risk of side effects.14

TCAs have multiple proposed mechanisms of action in the treatment of PHN. TCAs inhibit the neuronal reuptake of serotonin and norepinephrine, which inhibits pain perception of the spinal neurons. TCAs also inhibit neuronal sodium (Na+) channels, which are believed to play a role in nociception and pain sensitivity. These agents have been shown to block the action of N-methyl-d-aspartate (NMDA), a receptor associated with neuronal excitation and abnormal pain manifestations, as well as block adrenergic receptors on the nociceptive fibers.8


Gabapentin and pregabalin are two antiepileptics used to treat PHN as well as other types of neuropathic pain. They have similar efficacy to TCAs but have a milder side-effect profile.14 As previously mentioned, nortriptyline versus gabapentin had similar efficacy, but the side effects were less in the gabapentin arm.16 There are several RCTs and meta-analyses that have confirmed the efficacy of gabapentin.14 In comparing gabapentin to placebo, there was a greater reduction in pain score for the gabapentin arm. Gabapentin given in combination with an opioid may prove superior for PHN pain relief than either agent given alone, and may require lower doses of each. Doses varied in these studies and were titrated over time to a maximum dose. Clinicians should keep in mind that altered renal function may require dose adjustments, and titration in the elderly should be done slowly.14

There is less evidence available for pregabalin, as it is the newer agent; however, there have been RCTs confirming efficacy.14 In a study comparing pregabalin with placebo, the pregabalin arm was associated with ≥50% reduction in pain while the placebo arm only had a 20% reduction. Pain relief was observed as early as 1 day after treatment initiation. Unfortunately, the pregabalin treatment arm was also associated with a higher rate of discontinuation due to side effects (32%) over placebo (5%).3 Another small study compared gabapentin with pregabalin.18

Patients on a current gabapentin regimen were switched to a pregabalin regimen, receiving one-sixth the dose of the gabapentin arm. There was no significant change in analgesic effect after the switch, but there was a decrease in pain when the pregabalin dose was increased. There was a higher rate of peripheral edema associated with pregabalin, and side effects increased with increased dosing.18

Other antiepileptics, although effective in many other types of neuropathic pain, have not been effective in the treatment of PHN.8 Conversely, divalproex showed promise for PHN treatment. A small RCT compared placebo to 1,000 mg of divalproex sodium daily as monotherapy over 8 weeks.19 Improvement in pain was reported in 58.2% of divalproex patients, whereas only 14.8% of placebo patients reported improvement. Divalproex was well tolerated.19

The proposed mechanism of action for pregabalin and gabapentin is inhibition of the Ca2+ channel by acting upon the alpha-2-delta subunit. This decreases influx of calcium into the neuron, which leads to a decrease in the release of neurotransmitters from the primary afferent fibers in the spinal cord.14 The proposed mechanism of action for divalproex is its inhibition of GABA (gamma-aminobutyric) transaminase and the enzymes involved in the synthesis and degradation of GABA, which increases GABA levels. Additionally, divalproex prolongs recovery of voltage-gated sodium channels.19


The use of opioid analgesics in the treatment of neuropathic and PHN pain has been an intensely debated subject. Some clinicians believe the effects of opioid analgesia are ineffective for neuropathic pain.14 Conversely, numerous studies have proven their efficacy at pain relief in patients with PHN.8 A proposed mechanism by which opioids treat PHN is by directly inhibiting primary nociceptive afferent and spinal dorsal horn neurons.8 Although effective, many clinicians are concerned with their side-effect profile, the development of tolerance over time, and the potential for drug abuse associated with opioid medication therapy.14

Tramadol is considered a weak opioid agonist with an additional mechanism of action—monoamine reuptake inhibition of neurotransmitters such as serotonin and norepinephrine to modulate pain perception.14 Tramadol has been extensively studied for the treatment of pain associated with diabetic neuropathy and polyneuropathies.20 A study by Boureau et al compared the efficacy of sustained-release tramadol (100-400 mg/day) to placebo in reducing the pain of PHN. Tramadol showed efficacy in improvement of PHN and increased quality of life.21

More traditional opioids have also been studied in the treatment of PHN. Watson et al showed efficacy of analgesia with oxycodone in a double-blind, crossover RCT.22 Treatment with sustained-release oxycodone 10 mg every 12 hours over a 4-week period provided significant pain reduction, both chronic and intermittent, from PHN.22 In a study by Raja et al, morphine sulfate controlled release (maximum dose 240 mg/day) was compared with nortriptyline (maximum dose 160 mg) and placebo.23 Patients on nortriptyline and morphine had greater decreases in pain ratings than with placebo, but the decreases were greater with morphine, and patients preferred morphine over the TCA. Opioids did not impair cognitive function but did have more gastrointestinal side effects and a higher discontinuation of drug.23 A study by Rowbotham et al showed a dose-related increase in efficacy using levorphanol, a potent orally available mu-receptor agonist.24 In a double-blind RCT of patients with refractory neuropathic pain including PHN, those who received a high dose (mean dose 8.9 mg/day) of levorphanol had a greater level of analgesia compared to patients receiving a low dose (mean dose 2.7 mg/day). However, patients in the high- dose group experienced more personality side effects and withdrew from the study.24

As noted, opioid use has its limitations because of its side-effect profile.14 Cognitive effects of chronic opiate use are part of the controversy. Several studies have shown no long-term cognitive effects with chronic opioid administration up to 12 months, and in fact the opioids proved to increase cognitive ability in those with severe PHN due to pain relief and improvement in mood.25 Constipation can be prevented by a prophylactic regimen of stool softener and a stimulant laxative. Clinicians must also be careful with dosing and titration of opioids. A low-dose regimen should be started with a long-acting agent for baseline relief supplemented with an as-needed agent for breakthrough pain. Titration should be slow with a goal to maximize efficacy and minimize adverse reactions.14

Topical Analgesics

Topical analgesics are often used in the treatment of PHN. Galer et al showed efficacy of a lidocaine topical patch 5% (LTP).26 Compared to a placebo, 68.7% of patients preferred LTP, as there were no significant associated adverse events.26 LTP was used as add-on therapy and proved to be effective in reducing ongoing pain.27 The patch should be applied over the area associated with the most pain, but analgesia has also been noted in patients applying the patch on areas devoid of nociceptors.28 Lidocaine is effective owing to inhibition of sodium channels responsible for initiation of the pain signal.8

Topical capsaicin has also been used for treatment. It is derived from chili peppers and is classified as an irritant, normally used for arthritic joint pain. It works by stimulating nociceptors causing depolarization and desensitizes the nerve fibers to pain stimuli.29 Watson et al used capsaicin 0.075% cream in a double-blind study, along with a open-label, 2-year follow-up period, and showed capsaicin to be effective in the treatment of PHN with minor side effects like burning and stinging at the contact site.30 Of note, it is difficult to blind capsaicin because it is well known that there will be a sensation when applied.31 A high-concentration capsaicin dermal patch (8%) was also studied.32 It was applied for 1 hour at the painful site, and a topical anesthetic was applied prior to capsaicin application. The patch was used alone or in combination with other neuropathic pain medications. The dermal patch resulted in reduction in PHN pain that lasted for 12 weeks and was well tolerated.32

Other topical agents that have been studied for the treatment of PHN include topical nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, as well as topical cannabinoids, particularly N-palmitoylethanolamine. Although these agents may have some effect on PHN pain, there are scant scientific data at this time to support efficacy and any recommendation for use in the treatment of PHN pain.33


There are limited data with the alternative treatment options discussed below. Most studies have included a small number of patients, and some are just published case reports in only one patient.

IV Vitamin C

A published case report discusses the success of IV ascorbate in a 78-year-old male suffering from PHN for 8 months.34 He experienced paroxysmal pain occurring in 5-minute episodes 8 to 10 times per day. He failed multiple treatments with antidepressants and anticonvulsants. All his laboratory data were within normal range except for a low plasma concentration of vitamin C (4.9 mg/L) due to his poor nutritional status. He received 2.5 g IV of ascorbate daily on alternating days for a total of three doses, and his PHN resolved in 1 week and was maintained at a 3-month follow-up visit. His vitamin C plasma concentration was 14.9 mg/L after treatment and was 11.6 mg/L at the 3-month follow-up visit. It has been shown in rats that ascorbic acid enhances adenylyl cyclase-cAMP, which in turn enhances the production and release of beta-endorphin from its hypothalamic neurons. Beta-endorphin appears to be effective in lessening neuropathic pain. Ascorbate is also an antioxidant that scavenges reactive oxygen species, which are thought to play a role in neuropathic pain.34

Vincristine Administration by Iontophoresis

Iontophoresis is a technique for delivering ionogenic drugs through the skin using an electronically operated direct current machine. Vincristine is a positively charged medication that is repelled from a positive electrode (anode), which in turn will migrate into the skin. Several studies using this technique have produced mixed results, some showing a benefit and others showing none. A prospective, double-blind, placebo-controlled trial administered vincristine by iontophoresis to 11 out of 20 patients.35 A lint pad was soaked with vincristine (0.01%), covered by a sponge, and then covered by the anode and placed over the dermatomes affected by PHN. The 9 other patients received a saline lint pad. A direct current of 2 to 5 mAmp was applied for 60 minutes.

This treatment was administered daily, 5 days per week for 4 weeks. Patients treated with this technique had PHN for more than 6 months involving intercostal and lumbar dermatomes, and were unresponsive to conventional medical therapy. This technique showed no side effects and no evidence of systemic absorption of vincristine. All patients were allowed to continue existing PHN medications. Pain relief was moderate or greater in 40% of vincristine patients and 55% in saline patients. Moderate or greater pain relief was maintained in 30% of vincristine patients and 33% of saline patients on day 90. Consequently, these data demonstrated that vincristine administered by iontophoresis showed no increased benefit over saline in the treatment of PHN.35

Botulinum Toxin

A prospective, randomized, placebo-controlled, double-blind study administered subcutaneous injections of botulinum toxin A in affected dermatomes.36 This treatment showed beneficial effects in significantly decreasing pain in PHN and reducing opioid use compared with lidocaine and placebo at day 7 and at 3 months posttreatment. It also increased sleep times of treated patients.36

Interventional Options

Sympathetic Nerve Blocks: It is speculated that the sympathetic nervous system may contribute to neuropathic pain. One possible mechanism may be the abnormal activation of alpha-adrenergic receptors in primary afferent neurons. When adrenergic agonists were administered locally to patients with PHN, their levels of pain and allodynia were increased. Another postulated mechanism may be that neuronal regeneration after injury causes an interaction between primary afferent neurons and efferent sympathetic nerves, resulting in sympathetic pain. Therefore, a logical remedy to PHN would be the administration of sympathetic nerve blocks (SNBs) utilizing local anesthetics. Early studies of SNB resulted in initial relief of pain, but the relief was not sustained months after. This method of treatment is controversial because long-term relief is marginal.14

Intrathecal and Epidural Nerve Blocks: Intrathecal or epidural administration of methylprednisolone acetate, lidocaine, or a combination of both has been used in the treatment of refractory PHN with some success,14 but long-lasting relief of pain is questionable.9 Intrathecal administration of the combination may show a more favorable relief of pain.9,14 Although these methods of treatment have shown some benefit, they are not approved for the treatment of PHN; their safety is debated and caution is advised.14 The risks of adhesive arachnoiditis caused by intrathecal steroid administration continues to be a controversial issue.9

Paravertebral Block (PVB): PVB has been used for the management of pain in acute phase HZ and may prevent the incidence of PHN. In one study, the control group received acyclovir 800 mg orally 5 times daily for 7 days and analgesics as needed (i.e., diclofenac 50 mg orally up to 4 times daily).9 The study group utilized the above oral medications in combination with a PVB of the local anesthetic (bupivacaine 0.25%, 10 mL) mixed with methylprednisolone (40 mg).9 These injections were administered every 48 hours for a week for a total of 4 doses for HZ-associated pain within 7 days of onset of rash in patients older than 50 years. At 1-month posttherapy follow-up, 13% of the PVB-treated patients reported zoster-related pain and/or allodynia, compared with 45% in the control group (P <.001). At 3- and 6-month posttherapy follow-up, significantly fewer patients in the PVB group had PHN than in the control group (P = .001 and .003, respectively); at 1 year the occurrence of PHN was 2% in the PVB group compared to 16% in the control group (P = .017). This study is promising in that historically there are a few well-designed randomized controlled trials suggesting that epidural, intrathecal, and SNBs can prevent PHN, but additional studies are necessary.9

Spinal Cord Stimulation (SCS): It is speculated that SCS can block neuropathic pain by producing an electrical field over the spinal cord, which is transmitted by a subcutaneously implanted generator with implanted electrodes in the epidural space. SCS has been used to treat chronic neuropathic pain and has resulted in long-term pain relief of up to 2 years. Temporary percutaneous SCS has been successful in treating PHN patients, but more studies are needed.14

Acupuncture: Acupuncture has been considered for the treatment of neuropathic pain, and there are small studies with controversial results for its use in the treatment of pain associated with acute HZ and PHN. Additional well-controlled studies are needed.5,37

NMDA Receptor Antagonists

NMDA receptor antagonists can decrease pain associated with PHN. Magnesium and ketamine are both NMDA receptor antagonists. Magnesium antagonizes NMDA receptor channels by blocking calcium influx in a voltage-gated manner. It has been used in the treatment of neuropathic pain given via the IV route, but this treatment remains controversial, and side effects can include increases in serum magnesium concentrations, causing serious or fatal complications.38 The epidural route of administration, especially the transforaminal epidural route, is also not well studied, but has been used because of the advantage of target specificity and the need for less drug. Magnesium was used in a 60-year-old female with PHN who had failed multiple medical therapies.38 A dose of 100 mg of magnesium sulfate and 1 mL of 0.2% ropivacaine (total volume 2 mL) was injected using the transforaminal epidural injection technique. This procedure was repeated twice more at 1-week intervals. The patient was free of symptoms 1 week after the last injection and at a 6-month follow-up.38

Ketamine, an NMDA antagonist, also reverses hyper-algesia but has a poor side-effect profile when administered systemically; effects include somnolence, hallucination, and nystagmus. Topical administration of ketamine has minimal side effects, and a 1% topical ointment has been used to treat PHN, but ultimately there was no statistical improvement of pain with topical ketamine compared to placebo.39


As discussed, treatment strategies for PHN have a poor response rate, may not be tolerated, or produce controversial data with few good studies. PHN can have a devastating impact on patients, affecting their activities of daily living, all four health domains (physical, social, psychological, functional), and their quality of life.4 Strategies to prevent HZ and PHN are critical. Early diagnosis and aggressive treatment of HZ may reduce the incidence of PHN.5,8 Antiviral agents such as acyclovir, valacyclovir, and famciclovir reduce viral replication, which may decrease PHN.4 Timely administration (within 72 hours) at the onset of HZ is necessary,3,4,36 and even then, antivirals do not prevent all PHN cases.4,8

The live, attenuated Oka/Merck VZV vaccine (Zostavax) has been shown to be effective at reducing HZ by boosting preexisting cell-mediated immunity to VZV in older adults.40 In the Shingles Prevention Study, this vaccine showed a reduction in the incidence of HZ by 51% and reduced the incidence of clinically significant PHN by 67%; it was also well tolerated.4,36,40 The most common adverse reactions (≥1%) were headache and injection-site reactions.41 The CDC and the Advisory Committee on Immunization Practices (ACIP) recommend Zostavax for all persons aged ≥60 years, including those reporting a previous episode of HZ or who have chronic medical conditions and no contraindications to the vaccine.6

In December 2009, the Zostavax package insert was revised to recommend against coadministration of this vaccine with Pneumovax 23, the vaccine used to immunize against pneumococcal disease caused by the serotypes included in the vaccine. Simultaneous administration of the two resulted in reduced immunogenicity of Zostavax, so they should be separated by at least 4 weeks.41 Many states permit specially trained pharmacists to immunize eligible patients. A vaccine locator can be found at by entering a zip code.


As discussed, PHN is a complication of HZ reactivation, and a pain assessment should be made to evaluate its severity and impact on the patient's well-being and physical function. Some treatment modalities are well studied and effective, and other treatment options have scant data. The efficacy of TCAs, gabapentin, pregabalin, and LTP has been consistently demonstrated in multiple RCTs, and these are considered first-line treatment options. Opioids can be resorted to initially and are often used when pain is severe.3 They can also be used in combination with other first-line agents. This will give the patient more immediate pain relief while waiting for the other first-line medication to take effect.36,42 Alternatively, opioids may be postponed.36 Second-line treatments include topical capsaicin and aspirin cream.3,36 Alternative treatment options may have some benefit, but there is a paucity of evidence to recommend these treatments long-term.3,36 Combination therapy should also be considered to achieve additive or even synergistic effects, but further studies are needed to provide more information on which combinations are most beneficial.14

Prevention of PHN by timely administration of antiviral agents should be considered at the presentation of HZ. Administration of the zoster vaccine reduces reactivation of HZ and PHN.3,4,36,40 The options discussed in this article can potentially prevent or treat PHN and improve the quality of life of patients with neuropathic pain.


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