Review Article

A Pain Physician's Perspective on Recent Advances in Painful

Diabetic Peripheral Neuropathy Management
Pravesh Kanthed, Swapnil Kumar Barasker1, C.M. Ravikumar
Department of Pain Medicine, Choithram Hospital and Research Centre, 1Department of Anaesthesiology, Sri Aurobindo Medical College and Post Graduate Institute,
Indore, Madhya Pradesh, India

Abstract
Diabetic peripheral neuropathy (DPN) is a prevalent neurological complication linked to diabetes mellitus, exerting a substantial impact on
the quality of life for those affected. This review article aims to discuss and review advances in the pain management of patients with DPN.
We reviewed recent DPN management literature primarily from PubMed and SCOPUS using specific keywords, focusing on original research
and recent advancements. The pathophysiology of DPN involves metabolic and vascular changes in nerve fibers, leading to direct damage
and a decrease in their natural repair capacity. Effective glycemic control plays a central role in managing DPN, along with addressing other
contributing factors such as comorbidities and lifestyle modifications. Nutraceuticals, including alpha‑lipoic acid and Vitamin B12, have
shown promising results in some studies. Antineuropathic agents such as calcium channel a2‑δ ligands, serotonin and noradrenaline reuptake
inhibitors, tricyclic antidepressants, and sodium channel blockers are commonly used in DPN pain management. Topical therapies, including
capsaicin and lidocaine patches, have also demonstrated efficacy. Opioids are generally discouraged due to weak evidence and long‑term
deleterious side effects, along with the risk of addictive potential. Neuromodulation has emerged as a modality in resistant cases not responding
to pharmacological management. Individualized treatment plans based on symptomatology, comorbidities, and side effect profiles should
be developed for DPN patients. Comprehensive management of DPN involves a multidisciplinary approach, emphasizing patient education,
regular assessment, and counseling to prevent further damage and complications.

Keywords: Diabetes, diabetic peripheral neuropathy, painful

Received: 02‑12‑2023 Revised: 27‑01‑2024 Accepted: 09‑04‑2024 Published: 02-08-2024

Introduction to infection, ulceration, poor healing capacity, amputation, and

sepsis in some cases. It also impairs the functional capability and
The number of people suffering from diabetes mellitus (DM)
quality of life of DM patients.[3,7,8]
is on the rise globally, with a major contribution from low‑ and
middle‑income countries.[1] With the number of cases increasing Maintaining optimal sugar control is pivotal in the management
rapidly, India is considered the DM capital of the world. In of DPN, aiming to prevent or decelerate its irreversible
a recent study conducted in India, the prevalence of DM and progression. Additional factors influencing DPN advancement
impaired fasting blood glucose was found to be 9.3% and 24.5%, encompass older age, prolonged duration of diabetes, increased
respectively.[2] DM is linked to an array of complications, with height, macroalbuminuria, higher mean pulse rate, usage of
diabetic peripheral neuropathy (DPN) emerging as the most β‑blockers, and persistent albuminuria.[9] The pain experienced
prevalent neurological complication. Studies indicate that in DPN can be neuropathic, resulting from direct insult to the
approximately 50% of individuals with DM may eventually somatosensory nervous system by DM, or nociceptive, caused
develop DPN, and half of them may endure persistent neuropathic
pain.[3] The prevalence of DPN in India varies between 9.6% and Address for correspondence: Dr. Pravesh Kanthed,
78%, as reported in different studies.[4,5] However, the diagnosis Choithram Hospital and Research Centre, Indore, Madhya Pradesh, India.
of DPN also depends on the screening tool or diagnostic criteria E‑mail: [email protected]
used to define it.[6] DPN causes significant morbidity, leading
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DOI: How to cite this article: Kanthed P, Barasker SK, Ravikumar CM. A pain
10.4103/ijpn.ijpn_119_23 physician's perspective on recent advances in painful diabetic peripheral
neuropathy management. Indian J Pain 2024;38:91-8.

© 2024 Indian Journal of Pain | Published by Wolters Kluwer - Medknow 91

 Kanthed, et al.: Management of pain in diabetic peripheral neuropathy

by secondary arthropathy due to DPN. Managing pain in DPN pathways, resulting in the accumulation of acetyl‑CoA, which is
is challenging, similar to other forms of neuropathic pain. Both converted to acylcarnitines. This substrate has toxic effects on both
pharmacological and nonpharmacological agents play a role in Schwann cells and the dorsal root ganglia.[14,17] Another significant
its management. In recent times, interventions like spinal cord effect is mitochondrial dysfunction. The mitochondria, which need
stimulation (SCS) have proven to be effective in alleviating to be transported to the distal ends of neurons, are particularly
pain for patients with inadequate responses to alternative vulnerable to this process. Failure to transport mitochondria
therapies.[10] The feet and legs are predominantly affected. results in the typical distal‑to‑proximal pattern of DPN, commonly
Patient education, regular assessment, and counseling are known as the “glove stocking pattern.”[18]
crucial in preventing further damage and complications.[11‑13]
Endothelial dysfunction in DM leads to microvascular changes
Pain due to DPN also compromises the quality of life of that can cause ischemia in the nerves, as observed in autopsies
patients, commonly affecting their mood and sleep.[13] of DM patients. This ischemia may be further exacerbated by
This review article aims to discuss and review the advances other contributing metabolic factors present in DM. In addition,
in the pain management of patients with DPN. vasoconstriction often accompanies these changes, further
contributing to nerve damage.[19,20]
Methodology The general pathway related to neuropathy is common in both
We conducted a comprehensive review of the current literature Type I and Type II DM, but the propensity for DPN is greater
on the pain management of DPN. The primary source of articles in Type II DM due to multifactorial causality. One important
was PubMed and SCOPUS, among the largest and most widely difference between the development of DPN in Type I and
used databases for biomedical literature. Type II DM is the presence of metabolic syndrome and
dyslipidemia in the latter.[21]
Our search strategy involved the use of relevant keywords,
including “Diabetic Peripheral Neuropathy,” “management,”
and “treatment.” We focused mainly on articles published Pain in Diabetic Peripheral Neuropathy
within the past 10 years to ensure the inclusion of recent The cause of pain in DPN affecting some individuals and not
advances. others is still not clear. The susceptibility could be due to a
composite interaction of disease severity, genetic factors,
Inclusion criteria encompassed original research studies, female gender, high body mass index, and psychological
systematic reviews, meta‑analyses, and clinical trials factors.[22,23] Both central and peripheral mechanisms contribute
that provided insights into novel approaches, therapeutic to the neuropathic pain of DPN, as neuroimaging has revealed
interventions, or advancements in the management of changes at the spinal cord and thalamus levels.[16] Neuropathic
DPN. Exclusion criteria involved non‑English publications, pain in DPN is usually spontaneous, with burning sensations
irrelevant topics, and studies lacking substantial relevance to in the feet being the most common complaint.[24] Cluster
the review’s focus. phenotyping of neuropathic pain in DPN patients revealed that
In addition, we manually searched the references of selected sensory loss (83%) and mechanical hyperalgesia (75%) were
articles to identify any additional relevant studies not captured the most common, followed by thermal hyperalgesia (34%).[25]
by our initial search. The final selection aimed to present
a comprehensive overview of the recent advances in DPN Management
management.
Glycemic control
The basic pathophysiology of DPN is due to poorly controlled
Pathophysiology of Diabetic Peripheral levels of sugar. The effect of glycemic control has a greater
Neuropathy benefit in type I DM in comparison to Type II DM. The
presence of metabolic factors such as insulin resistance,
DM‑induced hyperglycemia induces metabolic and vascular
dyslipidemia, and chronic inflammation in Type II DM
alterations in nerve fibers, causing direct damage and
results in this difference.[26,27] Greater fluctuations in glucose
impairing their inherent reparative abilities. This phenomenon
levels may be associated with a higher propensity to develop
predominantly affects sensory and autonomic nerve fibers over
neuropathic pain.[16] Metformin’s impact on DPN is dual in
motor fibers, although the precise reason for this predilection
nature; it offers therapeutic benefits while simultaneously
remains unclear.[14,15]
inducing Vitamin B12 deficiency, potentially worsening the
In DM patients, there are multiple proposed pathways (glycolysis existing neuropathy.[28]
pathway, advanced glycosylation end products, polyol pathway,
Thus, managing glycemic control should be the first step to
hexosamine pathway, and abnormal long‑chain fatty acid and
start with the management of painful DPN.
prostaglandin metabolism), with the end result being oxidative
stress from reactive oxygen species such as superoxides, increased Comorbidities
inflammatory markers, and endothelial changes.[16] The excess The presence of dyslipidemia and hypertension may contribute
glucose and lipids lead to the saturation of normal metabolic to the worsening of DPN.[29] Statins used for dyslipidemia

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 Kanthed, et al.: Management of pain in diabetic peripheral neuropathy

are known to cause neurotoxicity, but their effect in patients Targeting total relief is naturally not feasible in DPN, and
with DM has received a mixed response ranging from no any relief >50% in 4–16 weeks of starting a drug should be
benefit to an enhanced risk of new‑onset neuropathy.[30,31] The considered successful.[13,47] Among all the first‑line drugs, the
inhibitors of the renin–angiotensin‑activating system, both best evidence is with pregabalin and duloxetine.[48]
angiotensin receptor blockers and angiotensin‑converting
enzyme inhibitors, might help in preventing and delaying the
Calcium channel a2‑δ ligands
The drugs included in this category are pregabalin and
progression of DPN.[32,33]
gabapentin. Pregabalin is the preferred choice due to a
Lifestyle modification lower frequency of dosing, more potent, and earlier titration.
The presence of obesity, a higher waist circumference, and The starting dose is usually 75 mg and titrated up to
smoking habits may further hasten the development of DPN 300–600 mg/day. In comparison to pregabalin, gabapentin
in DM patients.[21] Weight loss through lifestyle modification requires slower titration and three times dosing per day. The
or bariatric surgery results in a reduced incidence of side effects are similar for both drugs, with common ones being
DPN.[34,35] Addition of exercises possibly helps in improving dry mouth, dizziness, somnolence, euphoria, peripheral edema,
the neuropathic symptoms in patients with DPN by delaying and weight gain. Both drugs are renally excreted and require
the progression.[36,37] As per the American Diabetes Association dose modification in case of renal compromise.[3,16]
recommendations, foot care forms an important step in the care
Another recent drug in this category is mirogabalin; the initial
of patients with DM, an annual comprehensive evaluation by an
data have shown promising results in DPN pain. The dose range
expert should be performed. The patient should also regularly
is from 5 to 15 mg/day in 12 hourly dosing. The notable side
self‑examine the foot for any cracks or fissures, and it forms
effects were similar to other drugs in this group.[49,50]
important preventive care.[38]
Serotonin and noradrenaline reuptake inhibitors
Nutraceuticals Two drugs are commonly used in this group: duloxetine
Two agents are of special interest in this category: alpha‑lipoic
and venlafaxine, with the latter being less commonly used.
acid (ALA) and Vitamin B12. ALA, a naturally potent
Duloxetine has been recommended as the first‑line drug in
antioxidant, has demonstrated promising outcomes in selected
multiple guidelines for painful diabetic neuropathy.[51‑53] Due to
randomized controlled trials at a daily dosage of 600 mg
its antidepressant effect along with analgesic effect, it becomes
when compared to a placebo.[39,40] However, in a 4‑year‑long
the drug of choice in patients having depressive symptoms along
trial (NATHAN 1), 600 mg/day ALA failed to show any
with painful DPN. Duloxetine is usually started at a dose of
significant improvement in comparison to the placebo.[41]
30–60 mg/day and titrated up to the dose range of 60–120 mg/day.
As previously discussed, metformin is commonly used in the The prominent side effects associated with duloxetine are
treatment of DM; it reduces the absorption of Vitamin B12.[28] nausea, dizziness, fatigue, and decreased appetite.[53] Venlafaxine
Supplementation of Vitamin B12 is commonly advised among has shown significant relief in patients with painful DPN, but
patients with DPN.[42] Primary deficiency of Vitamin B12 itself due to its associated electrocardiogram (ECG) changes, it is
can cause neuropathy, and the deficiency is common in the the less preferred drug.[16] These groups of drugs, when used in
Indian subcontinent due to a predominantly vegetarian diet in combination with antiplatelets or anticoagulants, may result in
certain parts of the country.[43] In the current literature, the role an increased tendency to bleed.[54]
of Vitamin B12 is mostly studied in patients with Type II DM
Tricyclic antidepressants
who are on metformin. In a study by Li et al.,[44] a comparison
The most common drug used in this group is amitriptyline, but
was done between Vitamin B12 (0.5 mg/three times a day)
the presence of anticholinergic side effects has discouraged
and acetyl‑L‑carnitine (ALC) (500 mg/three times a day) in
its widespread use. The easy availability and low cost are
patients with DPN, and both agents were found to be equally
favorable points in addition to its effectiveness. Amitriptyline
effective. In another trial on ALC, it was found to be effective in
is started at a dose of 10 mg/day and gradually titrated up
relieving pain and nerve fiber regeneration in DPN patients.[45]
to tolerable side effects. The recommended maximum daily
Benfotiamine, a lipid‑soluble derivative of thiamine, is another dose is 100 mg/day. The other drugs from the same group are
widely studied agent in DPN patients, but large cohort studies imipramine, desipramine, and nortriptyline. The common side
have failed to find its beneficial effects.[46] effects are sedation, dry mouth, urinary retention, orthostatic
hypotension, and ECG changes. The intensity of these effects
Antineuropathic is lower with nortriptyline.
This is the major class of drugs used in the management of pain
in DPN patients. The best evidence is in support of calcium Sodium channel blockers
channel a2‑δ ligands, serotonin and noradrenaline reuptake The literature supporting this group of drugs is scarce,
inhibitors, tricyclic antidepressants, and/or sodium channel but they have been recommended in the recent American
blockers.[13] These agents form the first‑line drugs, and the Academy of Neurology (AAN) guidelines.[13] The drugs with
choice among them is based on the concurrent symptoms and a positive effect in this class are valproic acid, lamotrigine,
comorbidities present in patients and the side effect profile.[13] lacosamide, and oxcarbazepine. Voltage‑gated sodium

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 Kanthed, et al.: Management of pain in diabetic peripheral neuropathy

channels, specifically Nav1.6 expression, have been found to over an hour resulted in significant pain relief with better results
be upregulated in research models, making them an attractive on repeated infusions.[70] However, the lack of discrete evidence
alternative to traditional drugs.[55,56] The upregulated expression in support of lignocaine infusion further limits its utilization.
of DRG neurons Nav1.7 and Nav1.8 are the other important The benefits are only during the infusion therapy and a few
implicated receptors in painful DPN.[57] However, practical hours following.[71,72] Ketamine is used at a subanesthetic
research has not resulted in widespread clinical implications, dose, and the relief is short‑lasting, with benefits lasting up
possibly due to genetic polymorphism and the absence of to 2 weeks. The optimal dosing regimen is not available, but
quality randomized control trials supporting their use. higher doses have a better analgesic effect with resultant greater
side effects such as nausea, vomiting, and psychomimetic
Opioids
effects.[73] The role of magnesium in controlling neuropathic
The current recommendations are against the use of opioids
pain has not been widely studied, and the available literature
for pain management in patients with DPN.[13] The reason for
focuses more on acute pain rather than chronic neuropathic
this is the weak supporting evidence and long‑term deleterious
pain.[69,74] In a crossover trial, ketamine and its combination
side effects. The role of opioids in managing chronic pain
with magnesium failed to show any benefit in patients with
for a prolonged duration has long been questioned and
chronic neuropathic pain compared to placebo.[75] Another
discouraged.[58,59] Tapentadol and tramadol, both weaker
intravenous therapy available is Vitamin B12, but the research
opioids and having a similar mechanism of action of inhibiting
results are disparate, and thus, no recommendation exists.[76,77]
serotonin and norepinephrine reuptake, have some research
supporting their use for chronic pain in DPN.[60,61] However, Lumbar sympathectomy
the risk of abuse and addiction is still pertinent.[62] Lumbar sympathectomy (LS) can be performed using
Topical therapy radiofrequency ablation (thermal, pulsed, and cooled) or
• Capsaicin is an alkaloid extracted from red chili, which chemical neurolysis (alcohol and phenol). Often, both
acts on the transient receptor potential vanilloid 1 techniques are combined for better coverage and prolonged
receptor as an agonist. It is available as a gel or patches relief.[78] LS is more commonly used for complex regional
in concentrations of 0.025% and 0.075%. The best pain syndrome of the lower limbs and pain induced by
supporting evidence is with the 8% patch. Its role in peripheral arterial disease. In a trial comparing pulsed
localized neuropathic pain has been well established in radiofrequency (PRF) with transcutaneous electrical nerve
conditions such as painful DPN and postherpetic neuralgia. stimulation (TENS) for painful DPN, the results favored
The major challenge in India is the availability of the 8% PRF.[79] The exact mechanism of action of LS in relieving
patch. The associated hindrances in its utilization are DPN pain is still under research, but it should be considered
handling the patch, localized increased pain due to burning an option in resistant cases.
and itching, and transient raised blood pressure. The 8% Neuromodulation
patch is applied to the targeted painful site after lidocaine It is not uncommon to come across patients who experience
application for 30 min and may result in pain relief for up inadequate pain relief from conventional nonpharmacological
to 12 weeks.[63,64] Another special indication is for patients and pharmacological management of DPN.[80] A relatively
having intolerable side effects due to systemic therapy recent advancement is the application of neuromodulation
• Lidocaine patch: Lidocaine acts as a blocker of the devices for these patients. However, the wider implementation
voltage‑gated sodium channel. It is available as a 5% of neuromodulation in the Indian subcontinent is hindered by
patch or plaster to be applied over the painful DPN site. its cost and limited acceptance in the medical community.
The systemic absorption is minimal through topical Neuromodulation techniques include both invasive and
application, which explains the role of peripheral sodium noninvasive modalities. These techniques are based on the
channels (Nav1.7 and 1.8) in the pathophysiology of pain gate theory of pain proposed by Melzack and Wall.
in DPN patients[65‑67]
• Topical preparations of systemic drugs are also available, Transcutaneous electrical nerve stimulation
including pregabalin, gabapentin, and amitriptyline. The TENS is a noninvasive technique of cutaneous neuromodulation.
evidence favoring their use is not robust, and research Along with the gate theory, the release of endogenous opioids
results are still ambiguous. However, their potential is still contributes to its analgesic effects.[81] However, there are
being explored, particularly in patients with a nonviable challenges with TENS due to different stimulation protocols
systemic route of administration.[68] used in various trials and uncertain response patterns reported
in the literature.[82,83] The AAN recommends the use of TENS
Intravenous therapy in patients with painful DPN but calls for further studies to
Two drugs have been widely utilized through the intravenous establish its efficacy.[84]
route: lidocaine and ketamine. Their use is limited to resistant
cases that do not respond to traditional therapy. They come Spinal cord stimulation
under the blanket of intravenous neuromodulation therapy.[69] SCS is an invasive pain management technique rooted in the
In a study by Kim et al., lignocaine (3 mg/kg) administered gate theory of pain. Beyond its impact on Aβ fibers, it engages

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 Kanthed, et al.: Management of pain in diabetic peripheral neuropathy

supraspinal mechanisms and modifies neurotransmitter levels However, the current literature on its efficacy for DPN is
for analgesic effects, although the exact mechanism remains limited, primarily focusing on entrapment neuropathies, raising
incompletely elucidated.[85] While commonly applied for questions about its benefit in painful DPN.
postlaminectomy pain syndrome, SCS is also utilized in
On the other hand, PRP has demonstrated positive outcomes,
conditions such as complex regional pain syndrome, painful
showing improvements in nerve function and a reduction
DPN, and angina pectoris.
in pain and numbness associated with DPN.[98,99] PRP is
SCS has evolved over time, and different waveforms are believed to promote the regeneration process and healing
used for painful DPN, including tonic, high‑frequency, and of damaged tissue. While PRP‑based treatment typically
burst waveforms.[86] The tonic waveform, also known as the necessitates multiple sessions, studies have indicated
conventional mode, was the first waveform used in SCS. It significant improvement in DPN even after a single session.[98]
induces a paraesthesia‑like sensation that can be externally Nevertheless, conflicting results exist in the literature,[100]
adjusted by patients. Several studies have demonstrated the which may be attributed to variations in the modality or
safety and effectiveness of the tonic waveform in providing technique used to prepare PRP. Although PRP holds promise
more than 50% pain relief after implantation at 6 months and as a potential modality for DPN, its widespread use still faces
in the long term.[87] However, SCS requires a significant initial challenges and requires further exploration. The current
investment, and short‑term economic benefits are limited, evidence suggests potential benefits, but a more extensive body
as demonstrated in a trial comparing SCS with medical of research is needed to establish its role in managing DPN.
management by Slangen et al.[88]
Newer evidences
The high‑frequency waveform is paresthesia independent, The choice of pharmacological agents for neuropathic pain
making it more comfortable for patients. In high‑frequency in DPN is usually based on the patient’s comorbidities. The
waveform SCS, stimulation is performed at 10 kHz and has interindividual differences in response to pharmacological
been found to be superior to conventional SCS. Multiple studies treatment can be attributed to different pain phenotypes in
have shown not only pain relief but also overall improvement patients with painful DPN. Two common pain phenotypes
in quality of life and decreased opioid consumption over identified in DPN are paresthesia‑like pain and paroxysmal
long‑term follow‑up.[10,89] The burst waveform has not been pain. Duloxetine is the recommended drug for the
widely utilized, and limited research is available showing paresthesia‑like pain phenotype, whereas pregabalin is
its favorable response.[90] The burst stimulation waveform recommended for the paroxysmal pain phenotype.[101,102]
consists of five stimulus bursts, each lasting 1 ms, delivered at Other pain phenotypes in patients with neuropathic pain
an internal frequency of 500 Hz, and delivered at 40 Hz with a include irritable nociceptor, which responds to intravenous
passive recharge pattern and waveform.[91] The analgesic effect lidocaine [103] and oxcarbazepine. [104] Another important
is not solely dependent on paresthesia, as with tonic SCS, and strategy in managing patients with a poor response to
other mechanisms play an equally vital role.[92] However, SCS pharmacological treatment is the combination of drugs based
is an invasive and costly procedure with potential adverse on the phenotype.[101]
effects such as lead migration, infection, and battery failure.[93]
The assessment of patients with painful DPN should
Intrathecal drug delivery system not be solely based on pain scales but should include
The intrathecal drug delivery system involves delivering multidimensional scales such as the diabetes quality of life or
drugs directly to the site of action in the cerebrospinal fluid, the Diabetes‑Specific Quality‑of‑Life Scale, which provide a
bypassing first‑pass metabolism. The most commonly used better evaluation of the improvement in patient’s quality of
drugs are morphine or ziconotide, although the relevance of life.[105] These tools or scales should be used in any research
ziconotide in patients with painful DPN is limited due to a lack related to DPN.
of supporting evidence.[94]
Other modalities Conclusion
Peripheral nerve stimulation has not shown a positive response In summary, successful DPN pain management necessitates a
in painful DPN.[86] Frequency‑modulated electromagnetic holistic approach, addressing glycemic control, comorbidities,
neural stimulation (FREMS) is a noninvasive technique lifestyle adjustments, and pharmacological interventions.
that involves delivering transcutaneous electromagnetic Neuromodulation, specifically SCS, has demonstrated efficacy
stimulation. Limited research available has shown a conducive in patients with inadequate responses to pharmacological
response of FREMS in painful DPN.[95,96] interventions, albeit with an initial cost constraint. Future
research should prioritize the development of targeted and
Regenerative Therapies personalized therapies, coupled with a deeper exploration of
Perineural injection therapy encompasses two common
DPN’s underlying mechanisms to enhance patient outcomes.
modalities: prolotherapy and platelet‑rich plasma (PRP).
Prolotherapy involves the injection of hypertonic dextrose (5%) Financial support and sponsorship
for neuropathic pain conditions, like carpal tunnel syndrome.[97] Nil.

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 Kanthed, et al.: Management of pain in diabetic peripheral neuropathy

Conflicts of interest sciatic nerve fiber morphology and endoneural microvessels in mouse
models relevant for obesity, peripheral diabetic polyneuropathy, and the
There are no conflicts of interest. metabolic syndrome. J Neurosci Res 2012;90:122‑31.
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