Guideline Treatment of Diabetic

Peripheral Neuropathy (DPN)

黃雅淇 藥師

Worldwide prevalence of diabetes mellitus

Prevalence

• > 60% of diabetic foot ulcer with underlying

neuropathy

• ≒ 50% of patients with peripheral arterial

disease

• ≒ 15% in people over the age of 40 years.

• foot ulcer > 3% in the general population

Risk factors of DPN

• Poor glycemic control

• Undiagnosed diabetes

• Smoking

• Excessive alcohol intake

• Renal failure

• Low socioeconomic status

Etiology

1. 微細血管循環障礙：

2. 糖化素糖化蛋白的增加：

3. Protein kinase C過度活化：

4. Polyol徑路過度活化：

Clinical features of diabetic neuropathy

Characteristic Favors neuropathyFavors vascular

disease

site of pain Feet more than calves

Calves, thighs, and buttocks more than feet

Quality of pain Sharp, superficial, burning, tingling

Deep ache

Present at rest Common Rare

Effect of walking Pain improves Pain made worse

Pain worse in bed

Yes No

Preceded by recent change in glycemic control

Sometimes No

Patterns of nerve injury in

diabetic neuropathy

• 多發性神經病變/周圍神經病變

(最為常見，約佔75%)

• 自主神經病變• 局部性神經病變◎顱神經病變

◎神經叢病變

◎神經根病變

◎四肢單一神經病變

多發性神經病變• 最為常見，約佔75%。

• 痛覺與溫度感覺過敏或喪失:出現表皮痛、燒灼感、觸電感及麻木感，這種神經痛的現象在夜晚、天氣太冷或太熱時會更嚴重。

• 肢端麻木:尤其是腳趾與手指，通常由腳趾開始。初期可能只有輕微的感覺功能減退，會出現類似"戴手套"、"穿襪子"的感覺

• Charcot joint:病患的關節也容易產生骨折、關

節變形。

◎顱神經病變

第三對腦神經:單一眼球無法向內移動以及眼皮下垂，甚至造成複視

第六對腦神經:眼睛無法向外轉動，產生複視

◎神經叢病變

薦椎神經叢及股神經，以單側肢體受影響為主，病人出現不對稱性的疼痛

◎神經根病變

單側的單一或數個神經，較常見於胸部及腹部，胸腹部表面劇烈疼痛

◎四肢單一神經病變

手腳的單一神經病變，常為急性發作，且伴隨著相當的疼痛，可能導致病人手腕或足部下垂

局部性神經病變

Stages of Diabetic Peripheral Neuropathy

Stage Characteristics

Stage 1: No neuropathy •No symptoms

•Burning, shooting, stabbing pains with or without "pins and needles"

Stage 2: Clinical neuropathy

•Increased frequency at night•Reduced/absent reflexes

Chronically painful •Minor symptoms

Stages of Diabetic Peripheral Neuropathy

Stage Characteristics

Acutely painful

•Possible normal examination

•Numbness or no symptoms

•Painless injury

Painless with

complete or partial

loss of sensation

Painless with complete or partial loss of

sensation

•Reduced/absent

sensation

•Reduced/absent sensation

Source: Boulton AJM, Gries FA, Jervell JA. Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathy. Diabet Med.1998;15:508-514.

Physical examHave the patient remove both shoes and socks and

inspect the feet for:

• Skin status(Color, thickness, dryness, cracking)

• Temperature

• Joint mobility

• Fungal infection (toenails, between toes)

• Calluses

• Blisters

• Ulcers

• Deformities(Charcot joint, clawed toes)

• Amputations

Neurological exam

• Pin prick test

• Light touch test for sensation

• Vibration test

• Ankle reflexes

• Pressure perception test

• Ankle Brachial Index (ABI)

• 針刺感覺、輕觸覺：利用針和棉花測量感覺，通常是由遠端檢查到近端

• 振動感覺：利用128Hz 音叉測量

• Monofilament：不能感覺其壓力表示病患所測部位的保護感覺消失

• 膝、踝反射：二種關節的反射消失是週邊神經病變的指標

Ankle Brachial Index(ABI)

• detect the presence and severity of

vascular diseases such as chronic

venous insufficiency (CVI) or peripheral

arterial disease (PAD)

正常動脈血流的都卜勒超音波波型，為三相波波型。

糖尿病足部潰瘍部位，動脈血流都卜勒超音波波型，damped pattern。

Ankle Brachial Index(ABI)

ABPI value Interpretation Nature of ulcers, if present

above 1.2Abnormal

Vessel hardening from PVDVenous ulcer

use full compression

bandaging1.0 - 1.2 Normal range

0.9 - 1.0 Acceptable

0.8 - 0.9 Some arterial disease

0.5 - 0.8 Moderate arterial disease

Mixed ulcers

use reduced compression

bandaging

under 0.5 Severe arterial disease

Arterial ulcers

no compression bandaging

used

ADA treatment steps• Glycemic control

• Foot care

• Treatment of pain

SNRITricyclic AntidepressantsAnticonvulsantsExternal analgesicLocal anestheticOpioid agonistsOther Herbal

• Nonpharmacologic

• Surgical

Foot care• Check feet daily.

• Wash feet daily.

• Keep feet dry.

• avoid pressure on toes, heels, or any bony

parts of the foot

• Don't soak your feet.

• Don't use hot water, heating pad, or

massager on your feet.

• Don't walk in wet shoes.

• Avoid hot or cold surfaces with bare feet

Shoes by The American Diabetic Association

• Forget your flip-flops

• No heels

• Use wide shoes

• Your feet need air

• Choose lace and buckle

• Opt for “depth shoes”

• Meet your doctor

Shoes

Treatment of pain

Medication DoseCommon

Side Effects

Black Box Warnings/

Contraindications

SNRI Nausea Concurrent tramadol

use

duloxetine:

Hepatic dysfunction

Renal insufficiency,

Alcohol abuse

venlafaxine:

Cardiac disease

Withdrawal syndrome

if stopped abruptly

duloxetine 60 to 120 mg /D

venlafaxine 75 to 225 mg /D

Treatment of pain

Medication DoseCommon Side

Effects

Black Box Warnings/

Contraindications

Tricyclic Antidepressants Sedation

Dry mouth

Blurred vision

Weight gain

Urinary

retention

Cardiac disease

Glaucoma

Suicide risk

Seizures

Concurrent

tramadol use

amitriptyline 25 to 100

mg /D

nortriptyline 25

to75mg

/D

desipramine 25 to 150

mg /D

Medication DoseCommon Side

Effects

Black Box Warnings/

Contraindications

Anticonvulsants Sedation

Dizziness

Peripheral

edema

Renal

insufficiencygabapentin 900 to 3600 mg/D

Pregabalin 300 to 600 mg/D

valproate 500 to 1200 mg/D

External analgesic Skin irritation

Paresthesias

Sensitivity to

capsicum plant

Broken skin or

skin abrasion

capsaicin 0.075 %four times

daily

Local anesthetic Local

erythema

Rash

Sensitivity to

local amide

anestheticslidocaine

patch

four patches 5 %

for up to 18 hours

per day

Medication DoseCommon Side

Effects

Black Box Warnings/

Contraindications

Opioid agonists Nausea

and/or

vomiting

Constipation

Drowsiness

Dizziness

Seizures

(tramadol)

History of

substance abuse

Suicide risk

Driving

impairment at

initiation

tramadol:

Seizure disorder

Concurrent SSRI,

SNRI, or TCA use

morphine titrated to 120

mg daily

oxycodone 37 ~120 mg /D

tramadol 210 mg daily

Dextrometh

orphan

400 mg daily

tapentadol

extended

release

50 mg Q12H

Treatment of pain

Medication Dose Common Side Effects

Other

Isosorbide

dinitrate

topical spray

spray to both

feet before

bedtime

NSAIDs NSAIDs may impair nerve

circulation and worsen nerve

injury due to inhibition of

prostacyclin synthesis

ibuprofen 600 mg four

times daily

sulindac 200 mg twice

daily

Herbal Recommended DoseLevel of

Evidence

Alpha lipoic acid (ALA) 600-1800 mg daily A

Gamma-linolenic acid

(GLA)

Up to 480 mg daily B

Evening primrose oil 360 mg linolenic acid/

45 mg GLA

C

L-carnitine Up to 3 grams daily C

Vitamin B12 Variable

(250-500 mcg tid-qid)

C

Zinc 660 mg (ZnSO4) daily C

*Level of Evidence: A = Strong, B = Good, C = Conflicting evidence

Nonpharmacologic

• Probably effective:

◎Percutaneous electrical nerve stimulation

for three to four weeks

◎Spinal cord stimulation

• Probably not effective:

◎magnetic field treatment

◎low-intensity laser therapy

◎Reiki therapy

Surgical

• Dellon procedure— Decompression Surgery

44% improved to exercise the function

67% displays the improved sense function,

10% didn't improve,

2% feel that the function descends

Summary of RecommendationsRecommended Drug and Dose Not

Recommended Level A Pregabalin, 300–600 mg/D

Level B Gabapentin, 900–3600 mg/D

Sodium valproate, 500–1200 mg/D

Venlafaxine, 75–225 mg/D

Duloxetine, 60–120 mg/D

Amitriptyline, 25–100 mg/D

Dextromethorphan, 400 mg/D

Morphine sulphate, titrated to 120 mg/D

Tramadol, 210 mg/D

Oxycodone, 37 mg/day, max 120 mg/D

Capsaicin, 0.075% qid

Isosorbide dinitrate spray

Electrical stimulation, percutaneous

nerve stimulation x 3–4 weeks

Oxcarbazepine

Lamotrigine

Lacosamide

Clonidine

Pentoxifylline

Mexiletine

Magnetic field

treatment

Low-intensity laser

therapy

Reiki therapy

Referance

• AAN Summary of Evidence-based Guideline for CLINICIANS

• Treatment of painful diabetic neuropathy2015

• Clinical manifestations and diagnosis of diabetic polyneuropathy

• Peripheral Neuropathy Medication Therapy Management Data Set

• 學術專論‧糖尿病周邊神經病變

• 臨床藥物治療學‧治療糖尿病之神經病變與疼痛• 內科學誌‧糖尿病足之臨床評估與治療

Chariot Foot

• About 10% in patient with long standing of diabetes

• Charcot joint 10-15 years duration

• Started as a mild swelling, redness and a localized

increase in skin temperature, it may turn into

fracture, dislocation, foot collapse, deformity and

ulceration.

We suggest not using opioidsfor the treatment of painful

diabetic neuropathy because of the lack of evidence regarding long-term effectiveness, and because of the potential for

tolerance, addiction, and overdose.