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11 Articles in Volume 16, Issue #2
Gender and the Pain Experience
Sex and Gender Differences In the Pain Experience
Medical Management of Diabetic Neuropathy
Comorbid Substance Use Disorders: Primer for Pain Management
Marijuana Use Disorder: Common and Often Untreated
Acupuncture: New Approach for Temporomandibular Disorders
Opioid-Maintained Patients Who Require Surgery
Natural Protein Points to New Inflammation Treatment
Lessons from the Murder Conviction of Dr. Hsiu-Ying “Lisa” Tseng
Zohydro vs Hysingla: What is the Difference in These Extended-Release Agents?
Letters to the Editor: Opioid Calculator, Testosterone for SCI

Medical Management of Diabetic Neuropathy

Nerve damage may be present long before diagnosis. Early diagnosis and treatment is paramount to preventing long-term disability.

Diabetes mellitus is the leading cause of peripheral neuropathy. In fact, the National Institute of Diabetes and Digestive and Kidney Diseases reports that 60% to 70% of people with either type 1 or type 2 diabetes will develop some type of diabetic nerve pain over their lifetime, including diabetic peripheral neuropathy (DPN).1

Increasing the risk of developing a neuropathy include the duration of diabetes, poor glycemic control, smoking and excessive drinking, and preexisting cardiovascular risk factors (high cholesterol); these factors also independently correlated with progression of DPN as well as the development of cardiovascular autonomic neuropathy. Although nerve damage can be present long before the diagnosis of diabetes, the highest rates of neuropathy are among people who have had diabetes for at least 25 years.1

Increasing the risk of diabetic neuropathy include duration of diabetes, poor glycemic control, smoking and excessive drinking, and preexisting cardiovascular risk factors (high cholesterol).

Diabetic neuropathies represent a heterogeneous group of disorders whose specific abnormalities can present with diverse clinical manifestations—from distal symmetric polyneuropathy (DSPN) to mononeuropathy, diabetic amyo-trophy, autonomic dysfunction, cranial neuropathies, and entrapment neuropathies. Peripheral neuropathy is the most likely to cause pain, but proximal neuropathy can also cause pain.

Strict glycemic control remains the only available treatment option to prevent the development of diabetic neuropathy. For the treatment of DPN symptoms, there are several pharmacologic agents that can be used alone or in combination, including 3 FDA-approved therapies for painful neuropathy.

This article focuses on the epidemiology and pathogenesis as well as clinical features, diagnosis, and management of DPN, the most common form of diabetic neuropathy.

Defining Diabetic Neuropathy

Diabetic neuropathy usually has a long subclinical latency period whose identification and management are challenging. It is important, however, to identify neuropathy in its earliest stages to prevent the extreme morbidity and healthcare costs associated with its progression.

Traditionally, diabetic neuropathy has been defined as the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after excluding other causes.2 In 2009, preceding the joint meeting of the 19th Annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the Eighth International Symposium on Diabetic Neuropathy in Toronto, a panel of experts convened to provide updates on classification, definitions, diagnostic criteria, and treatments of DPN (Table 1).3


The epidemiology of diabetic neuro-pathy depends on the case definitions used. If presence of symptoms was used as a criterion, 10% to 15% of diabetic patients would have neuropathy. The prevalence increases to 50% when sensory testing and nerve conduction study criteria are included.4

The incidence and prevalence of diabetic neuropathy has been studied in several small- and large-scale trials in the United States, Canada, and Europe. The Rochester Diabetic Neuropathy Study was a longitudinal population-based study of 380 patients, of whom 102 had type 1 diabetes. The mean duration of diabetes was 14.5 years for type 1 and 8.1 years for type 2, respectively, and in this cohort the prevalence of polyneuropathy was 35.5% based on one abnormal nerve conduction test in 2 or more nerves. Only 14% of patients were symptomatic, however, and none had severe, disabling neuropathy.4

As in all small-fiber polyneuropathies, the main drawback of nerve conduction studies (NCS) is that small myelinated and unmyelinated nerve fibers, which are affected early in the disease course of diabetic neuropathy, do not contribute to the sensory action potential detected by routine NCS. The sensory action potential is altered only after involvement of larger myelinated fibers, which is often a late event in patients with diabetes. Electrophysiological data must, therefore, always be evaluated in a clinical context.

One of the landmark studies in the literature regarding diabetes complications is the DCCT (Diabetes Control and Complication Trial), which enrolled 1,441 patients with type 1 diabetes in 29 centers in the United States and Canada between 1983 and 1989. Patients with severe neuropathy were excluded. At the end of the study, 19% of all enrolled patients fulfilled criteria for definite clinical neuropathy (which at that time included abnormal findings in at least 2 categories from neuropathic symptoms, sensory deficits, or impaired reflexes attributable to distal symmetric polyneuropathy).5

Another large, prospective study conducted in Europe, EURODIAB (European Diabetes Prospective Complications), enrolled 3,250 patients with type 1 diabetes from 31 centers in Europe between 1989 and 1991. At baseline, 29% of patients had evidence of neuropathy. Subsequently, neuropathy developed in 276 of 1,172 patients after a mean follow-up of 7.3 years, bringing the cumulative incidence to 23.5%.6

Pathogenesis and Risk Factors

To date, the pathogenesis of diabetic neuropathy remains unclear. Several factors have been implicated, including genetics, insulin resistance, oxidative stress, accumulation of sorbitol, abnormal glucose metabolism, advanced glycation end products, and protein kinase C activation.

Proposed vascular etiologies include nerve dysfunction secondary to disease of vasa nervorum, the microvasculature to the nerves. In addition, cardiovascular risk factors (eg, hypertension, smoking, dyslipidemia, and male gender) are independent risk factors for the development of diabetic neuropathy, especially with the presence of overt cardiovascular disease at baseline.7

It is now known that multiple factors influence the development and progression of diabetic neuropathy. In the Rochester Diabetic Neuropathy Study, researchers concluded that the order of importance for the development and progression of diabetic neuropathy appeared to be microvascular disease, total hyperglycemic exposure, and type of diabetes.4 Similarly, the DCCT not only provided definitive proof of the association between chronic hyperglycemia and neuropathy, but also found that treatment significantly decreased the risk for developing diabetic neuropathy.5

The EURODIAB study found that diabetes duration, A1c values at baseline, and changes in A1c over time were risk factors for the development of neuropathy along with cardiovascular risk factors; risk for neuropathy increased with progressive worsening of hemoglobin A1c.6

Recent studies have shown that diabetic neuropathy may be a presenting symptom of diabetes, and that a small percentage of patients may have overt neuropathy at the time of diabetes diagnosis. The AUSDIAB (Australian Diabetes, Obesity and Lifestyles) study identified 1,154 patients with impaired glucose tolerance or impaired fasting glucose among 11,247 individuals aged 25 years and older in Australia.8 These patients were screened for neuropathy using modified neuropathy symptoms, disability, pressure perception scores, and postural hypotension. An association was found between neuropathy scores and retinopathy; these findings confirm that neuropathy onset may precede the diagnosis of diabetes and that the mechanisms involved are at least partly related to microvascular complications of chronic hyperglycemia.8

Finally, DPN has been associated with significantly reduced vitamin B12 and vitamin D levels. One study found that 19% of patients with diabetes receiving metformin for 1 year had vitamin B12 levels lower than 250 ng/mL and 23% had vitamin B12 levels of 250 to 400 ng/mL (Note: reference range, 160-950 pg/mL). Peripheral neuropathy was present in 77% and 23% of these patients, respectively, and also was found in 7% of those with normal B12 levels.9

In a poster presented at the 2015 annual meeting of the American Diabetes Association, researchers studied 45 patients with type 2 diabetes (17 with painful neuropathy, 14 with painless neuropathy, and 14 with no neuropathy) compared with 14 healthy volunteers.10 After undergoing clinical, neurophysiological, and intra-epidermal nerve-fiber density (IENFD) assessments, the patients were divided into 3 groups based on the Neuropathy Impairment Score of the Lower Limb. After adjustment for age, body mass index, and sunlight exposure, vitamin D levels were significantly lower in the painful-neuropathy group, at 34.34 nmol/L(13.73 ng/ml) compared with 53.22 nmol/L (21.28 ng/ml) for painless neuropathy, 50.00 nmol/L (20 ng/ml) for no neuropathy, and 64.95 nmol/L (25.98 ng/ml) for the healthy volunteers (P=0.01).10

Diagnosis and Clinical Presentation

As noted, diabetic neuropathy has a long subclinical latency period. The most common type of diabetic neuropathy is DPN; it can be sensory or motor and may involve small and large fibers. In general, small-fiber disease precedes the onset of large-fiber disease, and sensory symptoms usually precede motor symptoms.2 Small-fiber sensory neuropathies can include a number of characteristics and include hypoxia as well as distal axonopathy with dying back of the nerve as primary pathoetiology. The small-fiber sensory neuropathy includes hyperalgesia, paresthesia, burning pain, lancinating pain, loss of pain and temperature sensation, loss of visceral pain, and eventual foot ulceration, leading to an increased incidence of amputation.11

To confirm a diagnosis, the presence of diabetic polyneuropathy must be established. In patients with findings consistent with neuropathy, causes other than diabetes, such as neurotoxic medications, heavy metal poisoning, alcohol abuse, vitamin B12 deficiency (especially in those taking metformin for prolonged periods of time),9 renal disease, chronic inflammatory demyelinating neuropathy, inherited neuropathies, and vasculitis, should always be considered.12

Large-fiber neuropathy typically causes painless paresthesias with impairment of vibration and also proprioceptive dysfunction with altered touch, pressure sensation, and loss of ankle reflexes on neurological examination and abnormal nerve conduction studies. The longest peripheral nerves are involved first; therefore, lower extremity involvement occurs first. Stocking/glove pattern is characteristic of the sensory impairment, which is seen both more commonly and earliest in the lower extremities, particularly in the feet. Severe neuropathy, defined as the inability to detect the 10-g Semmes-Weinstein monofilament, is associated with increased risk for foot ulcers and amputation.

Chronic neuropathy also manifests with pain, present in 13% to 26% of patients with diabetes.13 Neuropathic pain has a significant impact on quality of life, particularly because it causes considerable interference with sleep, mood, and daily activities. Manifestations of painful neuropathy include episodic or persistent pain, typically worse at night and improved by walking.

Pain is described as burning/hot, electric, sharp, achy, and tingling sensation. The average pain is 5 out of 10 on a visual analog scale. In addition, allodynia (pain due to a stimulus that normally does not cause pain, eg, stroking) and hyperalgesia (severe pain due to a stimulus that normally causes slight pain, eg, a pinprick) may be present. These symptoms also may be accompanied by sensory loss, but patients with severe pain may have few clinical signs. The most frequent locations of pain include feet (96%), balls of feet (69%), toes (67%), dorsum of foot (54%), calves (37%), and heels (32%).14


The ADA’s 2016 Annual Standard of Care Guidelines recommend that patients with diabetes be screened annually for diabetic neuropathy using tests such as pinprick sensation, vibration perception (using a 128-Hz tuning fork), light touch perception using a 10-g monofilament pressure sensation at the distal plantar aspect of both great toes and metatarsal joints, and assessment of ankle reflexes.15

The challenge of early diagnosis and detection of diabetic neuropathy is to identify the most sensitive and specific tests. Two tools have been shown to have excellent specificity and sensitivity in the physical examination of the patient with possible diabetic neuropathy: the 10-g Semmes-Weinstein monofilament examination (SWME) and the 128-Hz tuning fork.16,17

The 10-g SWME is a noninvasive, low-cost, simple, and accurate handheld calibrated nylon thread that buckles once it has delivered a force of 10 g (Figure 1). Applied to the skin surface, it provides a standardized measure of patients’ ability to sense a point of pressure. Based on the current literature, the optimal method is to use the 10-g monofilament to test the plantar aspects of the great toe, third, and fifth metatarsal heads. Patients are instructed to say “yes” each time they sense the monofilament on their foot. If patients fail to sense the monofilament after it bends, the test site is considered to be insensate.

In a recent systematic review of the literature, it was demonstrated that the SWME is an optimal tool for clinical testing of diabetic neuropathy. This meta-analysis reviewed all of the studies performed on the diagnostic properties of SWME throughout the world and was shown to achieve sensitivity of 90% or above. Therefore, the SWME can be an inexpensive, accurate, and painless way for primary and specialty care physicians to identify patients with DPN during a physical examination, especially because it allows the diagnosis of diabetic neuropathy before the appearance of obvious visual signs, such as foot deformities and calluses.16

The 128-Hz tuning fork has been used to assess peripheral neuropathy, usually by comparing how long the patient detects vibration in comparison with the examiner. It determines whether vibration sense is normal, impaired, or absent. The testing is performed by first activating the tuning fork (striking it against a hard object) and then applying it to a bony prominence where neuropathy is unlikely (eg, hand, elbow, wrist).

Once the patient is familiar with the vibration, the vibrating fork is placed on the metatarsophalangeal joint. If vibration is felt by the patient, he or she will then indicate when it stops. As soon as the patient says that the vibration has stopped, the clinician should place the tuning fork on his or her wrist. If it is still vibrating, the patient has impaired vibration sense. If the patient feels no vibration, he or she has absent vibration sense and thus peripheral neuropathy. The 128-Hz tuning fork recently has been shown to provide superior predictive value for the detection of diabetic neuropathy.17

A more recent small study showed the accuracy of the clanging tuning fork as a test for diabetic neuropathy. Among patients with 8 seconds or less of vibration perception, results of monofilament testing were abnormal only in those whose vibration perception was less than or equal to 4 seconds. In the patients with vibration perception of 4 seconds or less, 50% had normal monofilament test scores, including 29% of those with absent vibratory sensation. This study showed that the 128-Hz tuning fork provides a quantitative assessment of DPN and can document severe neuropathy, even in the presence of a normal result with the SWME.18

For those not familiar with the above techniques, sudomotor examination is a highly sensitive detection tool in distal small fiber neuropathy in patients with diabetes. Quantitative sudomotor axon reflex testing (QSART, Sudoscan) is a promising diagnostic test for diabetic and idiopathic distal symmetric polyneuropathy, with diagnostic performance similar to skin biopsy for intraepidermal nerve fiber density.19

Treatment Strategies

Figure 2 is a screening/treatment algorithm that illustrates a practical approach to the patient with possible diabetes neuropathy. The primary strategy is the prevention of neuropathy; we have definitive evidence from the DCCT study that the risk for diabetic neuropathy can be decreased by up to 69% with improved glycemic control.5

In addition, because diabetic neuropathy has multifactorial pathogenesis, additional therapies should be aimed at controlling hypertension, normalizing dyslipidemia, smoking cessation, and weight reduction. However, despite the evidence in the literature and the multiple pharmacologic regimens available for diabetes treatment today, normoglycemia is not achieved in the majority of patients with diabetes patients, and other therapies aimed at the pathogenetic mechanisms of diabetic neuropathy have been investigated.

Pathogenetic Treatments

Although not FDA-approved, proposed pathogenetic treatments include alpha-lipoic acid (stems reactive oxygen species formation), benfotiamine (prevents vascular damage in diabetes), aldose-reductase inhibitors (reduces flux through the polyol pathway), protein kinase C inhibitors (prevent hyperglycemia-induced activation of protein kinase C), and nerve growth factors (stimulate nerve regeneration).20

The SYDNEY (Symptomatic Diabetic Neuropathy 2) trial showed that treatment with 600 mg daily of alpha-lipoic acid taken orally for 5 weeks reduced the chief symptoms of diabetic polyneuropathy, including pain, paresthesias, and numbness, to a clinical meaningful degree.21 In addition, a randomized placebo-controlled study, NATHAN 1, compared alpha-lipoic acid with placebo; 4 years from randomization, the neuropathic deficit in the placebo group progressed, whereas the patients treated with alpha-lipoic acid improved and the drug was well tolerated throughout the trial.14

Benfotiamine, a fat-soluble analogue of thiamine/vitamin B1, has been shown by Hammes et al to inhibit 3 different pathways involved in vascular damage in diabetes.22 In a placebo-controlled trial involving 165 patients treated with benfotiamine for 6 weeks, improvement was seen in the primary outcome measure (Neuropathy Symptom Score) in the treatment arm compared with placebo, although no improvement was found in the intent-to-treat arm of the study.

In contrast, another placebo-controlled study in a population with diabetes found no significant differences between the treatment and placebo arms in peripheral nerve function and soluble inflammatory markers. It should be noted, however, that DSPN was not evident in all of the patients at initial assessment.23

Aldose reductase is an important enzyme in the polyol pathway involved in the metabolism of blood glucose.24 Thus, aldose reductase inhibitors (ARIs) have been proposed to prevent DSPN. A number of ARIs have been tested but most have been found to have significant adverse effects and limited efficacy.25 The ARI epalrestat has been found to improve patient-reported neuropathic symptoms with an acceptable safety profile, and a 3-year randomized trial suggested a preventative role for DSPN with epalrestat.26,27

Symptomatic Treatment

Control of symptoms constitutes a considerable management problem because the efficacy of a single therapeutic agent is not the rule, and simple analgesics are usually inadequate to control the pain. A reduction in symptoms of 30% to 50% is achievable in most patients with combination therapy.

There presently are several classes of agents used in the treatment of painful diabetic neuropathy: tricyclic antidepressants (TCAs), serotonin norepinephrine reuptake inhibitors (SNRIs), calcium channel modulators (α2δ ligands), sodium channel blockers, topical agents, and opioids. To date, only 3 medications are formally approved by the FDA for treating painful diabetic neuropathy: duloxetine (Cymbalta), an SNRI; pregabalin (Lyrica), a voltage-sensitive calcium channel modulator; and tapentadol (Nucynta), an extended-release opioid. Table 2 describes the list of drugs recommended for the management of PDN.

The efficacy of the first FDA-approved drug for diabetic neuropathy, duloxetine, was analyzed in multiple trials pooled recently in a meta-analysis.28 All of these studies evaluated 60 mg of duloxetine daily or twice daily and showed beneficial effects compared with placebo starting in the first week of therapy.

These findings are supported by a Cochrane review that analysed data from 8 studies, including 2,728 patients. The review concluded that 60 mg and 120 mg daily doses of duloxetine were efficacious in the management of DPN, but lower doses were not associated with improvement. Minor side effects were commonly present and occurred more frequently with higher doses but major side effects were rare.29 The most frequent side effects were nausea, fatigue, and somnolence at both doses.

In multiple studies, pregabalin was shown to significantly reduce pain and sleep interference and achieve an improvement in quality of life of patients with DPN at doses of 150, 300, and 600 mg daily, with greater benefit at higher doses. Median time of onset of pain relief was 4 days for the 600 mg per day group and 13 days for the 150 mg per day group.

A number of side effects including mood disturbances, dizziness, peripheral edema, and somnolence have been reported and appear to be dose-dependent. Abrupt discontinuation of pregabalin can be associated with cerebral edema and encephalopathy. The discontinuation rate was higher at the 600-mg dose.

Of note, pregabalin treatment resulted in weight gain, with a 7% increase from baseline to end point, especially with the 600 mg per day dose compared with placebo.30 It may help to start low and go slow, increasing the dose slowly so patients do not quit this medication prematurely—a not uncommon phenomenon when given at recommended dosages.

The third FDA-approved drug’s efficacy was based on data from 2 placebo-controlled randomized trials. The studies found that among patients who had at least a 1-point reduction in pain intensity during 3 weeks of treatment with tapentadol ER, those who continued on the same dose titrated to balance individual tolerability and efficacy (100 to 250 mg bid) for an additional 12 weeks experienced significantly better pain control compared with those who switched to placebo.31

Several other medications have shown some efficacy in treating diabetic neuropathy. There is considerable experience with TCAs; however, there is a growing concern about a possible association of TCAs with sudden cardiac death; they also cause postural hypotension, which may be particularly problematic in patients with autonomic neuropathy.

Venlafaxine, another SNRI, was shown to be efficacious, but clinically significant electrocardiographic changes were seen with high doses. Other anti-epileptic medications, such as gabapentin, phenytoin, carbamazepine, oxcarbazepine, lamotrigine, topiramate, and valproic acid, have been shown to have some efficacy in treating painful diabetic neuropathy.32

N-methyl-D-aspartate receptor antagonists are generally used for the management of postoperative pain. Dextromethorphan has been found to be effective in alleviating the painful symptoms of diabetic neuropathy when used on its own or in combination with memantine.33 More recently, a combination of dextromethorphan and quinidine was found to be effective in a study of 379 patients with DPN.34 These findings confirmed the results of a smaller open-label study.35

Topical capsaicin (Qutenza) and lidocaine 5% patch (Lidoderm) have been used in the management of painful diabetic neuropathy. The Capsaicin Study Group found significant improvements in pain relief and a decrease in pain intensity in a double-blind placebo-controlled trial of 277 patients.36 However, the appearance of epidermal denervation in patients treated with capsaicin with impaired subsequent nerve regeneration in subjects with diabetes37 makes the use of this therapy difficult, especially in patients with established neuropathy. The effectiveness of the lidocaine patch was demonstrated in a very small trial of 56 patients, in which 4 patches were used for up to 18 hours per day.38

An isosorbide dinitrate spray has been found to reduce pain in diabetic neuropathy by 18%, as evaluated through pain sores, in a short-term placebo-controlled trial. Some guidelines suggest that its use should be considered in patients with DPN.39,40

Lastly, research has suggested that onobotulinum toxin type A (Botox) may provide relief of diabetic neuropathic pain through its modulatory effects on afferent sensory fiber firing. Although preliminary, a double-blind crossover trial of intradermal Botox injections demonstrated a significant reduction in pain and improvement in sleep in 18 patients with DPN.41 The result of this trial will need to be verified in larger studies.

Investigators are also studying a number of novel treatments for DPN, including erythropoietin analogues, angiotensin II receptor type 2 antagonists, and N-type calcium and sodium channel blockers.42

Guidelines Recommendations

The American Academy of Neurology published an evidence-based guideline for treating diabetic neuropathy in 2011.40 The guideline is based on the results of a systematic review of the literature from 1960 to August 2008, with recommendations linked to the strength of the evidence. The basic question asked was: “What is the efficacy of a given treatment to reduce pain and improve physical function and quality of life (QoL) in patients with DPN?”

In the review, the recommendations are divided into levels A and B. First-line therapies for painful DPN include a tricyclic antidepressant (eg, amitriptyline), duloxetine, pregabalin, or gabapentin, taking into account patient comorbidities and cost. Combinations of first-line therapies may be considered if pain persists. If pain is still inadequately controlled, opioids (tramadol) may be added in a combination treatment.

In 2012, the FDA-approved a non-medication treatment for diabetic neuropathy—Sensus Pain Management device. The device uses low frequency electric impulses through the body (TENS) to help improve circulation and nerve damage. According to the manufacturer, NeuroMetrix, “the device is worn on the calf, works at the press of a single button, and is equipped with a rechargeable battery that should last about 2 weeks based on the recommended once-daily, hour-long treatment sessions.”


Diabetic peripheral neuropathy is a very common complication of diabetes with a long subclinical latency period that is present in up to 50% of patients. However, recent literature has shown that diabetic neuropathy may be a presenting symptom of diabetes (ie, in patients with impaired glucose tolerance), and a small percentage of patients may have overt neuropathy at the time of diabetes diagnosis. The exact pathogenesis remains unclear and may involve metabolic and vascular dysfunction. The diagnosis of DPN revolves around a careful history and physical examination aided by the use of diagnostic and screening tools, such as the 10-g SWME and the 128-Hz tuning fork. It is important to identify neuropathy in its earliest stages to prevent the extreme morbidity and healthcare costs associated with its progression.

The clinical presentation of DPN includes paresthesias, loss of ankle reflexes, and pain, which can significantly impact quality of life. Multiple studies have proven that intensive treatment of diabetes has benefits across all complications of diabetes mellitus, including diabetic neuropathy. Primary prevention of diabetic neuropathy remains optimal glycemic control, as well as control of hypertension and dyslipidemia. In addition, patient education has a very important role in preventing diabetic foot ulcer. Essential elements of patient education include daily foot checking, prompt calls for examination with new injury, never walking barefoot or on stocking feet, wearing only prescribed footwear, and breaking in new shoes slowly.

Therapeutic strategies are aimed mainly at symptomatic relief of pain, with 3 FDA-approved drugs, pregabalin, duloxetine, and tapentadol, given alone or in combination with other therapeutic agents such as anticonvulsants, TCAs, opioids, and topical capsaicin. These therapies should be chosen carefully, with attention to the patient’s comorbidities and careful follow-up.

Last updated on: March 18, 2016
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