diabetic p. neuropathy

Diabetic Peripheral NeuropathyAssessment and Management

Mohammad O. Daoud, MD• Consultant Endocrinologist

• NGHA- Jeddah

Agenda

DPN : What do we know ?

Clinical presentation

Diagnostic approach /Screening

Therapeutic Guidelines

Prevalence of Polyneuropathy and Neuropathic Pain

Diabetic Peripheral Neuropathy (DPN)

(Chronic sensorimotor neuropathy)

Commonest form of DN (DM 1 & 2)

IGT and the M. Syndrome may account for 30% - 50% of idiopathic neuropathies

May be present at the time of Dx. of type 2 DM

May be completely asymptomatic

DPN The Burden

Progressive nature ; more likely with longer duration of DM

Old trial in Finland: Dx of DPN based of both clinical (pain and paresthesia) and electro-diagnostic (NCV &y and response-amplitude values) criteria.

The prevalence of definite or probable poly-neuropathy

Base line 10 yrsDM type 2 8.3 % 41.9 %Normal 2.1 % 5.8 %

Natural history of peripheral neuropathy in patients with NIDDM.Partanen J, et al ;N Engl J Med. 1995;333(2):89

DPN The Burden

It is Common

Affect about to 50 % of patients with DM

Higher morbidity, mortality with high cost-Foot ulceration, which can lead to gangrene and ultimately to limb loss. -50% to 75% of non-traumatic amputations-Up to 75% of them are preventable

Impact on patients’ quality of life

Neuropathic Pain Is Associated with Sleep Disturbance, Anxiety and Depression

Pain

Sleepdisturbances

Anxiety anddepression

Functional impairment

Nicholson B, Verma S. Pain Med 2004; 5(Suppl 1):S9-27.

Diabetic Peripheral Neuropathy

Should be suspected in:

1- Type 1 DM of more than five years' duration

2- All patients with Type 2 DM

3- Patients with "idiopathic" painful neuropathy ;

Screen for Pre-DM (up to 50% of such patients have pre-DM compared

with 14 % of the general population )

Nociceptive Vs. Neuropathic Pain

Nociceptive• Usually aching or throbbing

and well-localized• Usually time-limited

(resolves when damaged tissue heals), but can be chronic

• Generally responds to conventional analgesics

Neuropathic• Pain often described as

tingling, shock-like, and burning – commonly associated with numbness

• Almost always a chronic condition

• Responds poorly to conventional analgesics

Dray A. Br J Anaesth 2008; 101(1):48-58; Felson DT. Arthritis Res Ther 2009; 11(1):203; International Association for the Study of Pain. IASP Taxonomy. Available at: http://www.iasp-pain.org/AM/Template.cfm?Section=Pain_Definitions. Accessed: July 15, 2013; McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006; Woolf CJ. Pain 2011; 152(3 Suppl):S2-15.

http://www.iasp-pain.org/AM/Template.cfm?Section=Pain_Definitions

What is Diabetic neuropathy ?

• DNP: The damage to nerves in the body that occurs due to high blood sugar levels from diabetes.

• Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage”

Hyper-excitability

Patho-physiology of Neuropathic Pain

Neuropathic pain

Loss ofinhibitory controls

Peripheral Mechanisms

Sensitization• Peripheral• Central

Central mechanisms

Reorganization

• Membrane hyper-excitability• Ectopic discharges• Transcriptional changes

Moisset X, Bouhassira D. Neuroimage 2007; 37(Suppl 1):S80-8; Scholz J, Woolf CJ. Nat Neurosci 2002; 5(Suppl):1062-7.

What are the symptoms ?

• Pain caused by an action that is not normally painful – such as the gentle touch of someone else's hand on the skin.Allodynia

• An excessively painful reaction to being in contact with everyday objects such as clothes or sheets. Hypersthesia

• An excessively painful response to something that normally causes only mild pain.Hyperalgesia

• Pain that persists even when the cause of the pain has been taken away.Hyperpathy

• Abnormal and unpleasant sensations in the skin that are felt as intense tingling, or 'pins and needles'.

Paresthesia and dysesthesia

1. Know your Pain – Stop the Pain – What is Nerve Pain. Available at: http://lyrica.iniquus.net/NervePain.aspx. Accessed March 19, 2013.

Diabetic Peripheral Neuropathy (DPN) Clinical Picture

Total cholesterol

Triglycerides

BMI

Diabetes duration

Change in HbA1c

HbA1c

Smoking

Hypertension1.57

1.38

1.48

1.36

1.40

1.27

1.21

1.15

Model 1:without CVDand retinopathy

Odds ratios (95% CI)

n=1101 with type 1 DM; FU: 7.3±0.6 yrs

Tesfaye et al. N Engl J Med 2005; 352: 341-50.

0 1 2 3 4

Courtesy of Prof. Solomon Tesfaye

DPNGeneral features

Symmetrical ; Usually insidious in onset

Sensory symptoms >> motor Lower limbs >> Upper (Long nerves affected earlier /Taller Patient)

Ankle reflexes ; lost first ; others follow Larger fibers; Vibration and position sense Small fibers: Pain (intense),Temp, light touch, paresthesia

Listen: Sensory Symptoms of Neuropathic Pain

Positive symptoms(due to excessive neural activity)

Dysesthesia

Sensory abnormalities and pain paradoxically co-existEach patient may have a combination of symptoms

that may change over time (even within a single etiology)

Paresthesia

Spontaneous pain

HyperalgesiaAllodynia Anesthesia

Negative symptoms (due to deficit of function)

Lesion or disease of the somatosensory nervous system

Hypoesthesia

HypoalgesiaAnalgesia

Baron R et al. Lancet Neurol 2010; 9(8):807-19; Jensen TS et al. Eur J Pharmacol 2001; 429(1-3):1-11.

How Patients Feel Neuropathic Pain?

Burning Tingling Electric shock

StabbingUncomfortable numbness

1. Know your Pain – Stop the Pain – What is Nerve Pain. Available at: http://lyrica.iniquus.net/NervePain.aspx. Accessed March 19, 2013.

Listen: Pain History in Neuropathic Pain

Jensen TS, Baron R. Pain 2003; 102(1-2):1-8.

Identify the Following:

• Duration• Frequency• Quality• Intensity• Distribution and location

of pain• Extent of interference with

daily activity

Areas of Further Exploration• Previous medical history• Exposure to toxins or

other drug treatment (e.g., cancer chemotherapy, radiation)

• Use of pain medications• Associated psychological and

mood disturbance

Diabetic Peripheral Neuropathy (DPN) Clinical Presentation

Examination:Symmetric: Gloves/ Stocking-like distribution Sensory: Loss of vibration and position perception Abnormal heat /cold perception Light touch /pinprick

DTRs: Ankle and knee reflexes

Motor: Strength/muscle atrophy/wasting: mild

Cranial nerve testingVascular and skin assessment

Diabetic Peripheral Neuropathy (DPN)

Diagnosis & Screening

Diabetic Neuropathy (DN) Diagnosis

Mainly clinical ; H & PSupported by specific diagnostic tests

Exclude non-diabetic causes (May coincide with CIDP, B12 deficiency,

alcoholic neuropathy, endocrine neuropathies)Is it

‘‘Diabetic neuropathy’’ or ‘‘Neuropathy in a diabetic patient” ?

Neuropathic Pain is Prevalent Across a Range of Different Conditions

HIV = human immunodeficiency virus1. Sadosky A et al. Pain Pract 2008; 8(1):45-56; 2. Davis MP, Walsh D. Am J Hosp Palliat Care 2004; 21(2):137-42; 3. So YT et al. Arch Neurol 1988; 45(9):945-8; 4. Schifitto G et al. Neurology 2002; 58(12):1764-8; 5. Morgello S et al. Arch Neurol 2004; 61(4):546-51; 6. Stevens PE et al. Pain 1995; 61(1):61-8; 7. Smith WC et al. Pain 1999; 83(1):91-5; 8. Freynhagen R et al. Curr Med Res Opin 2006; 22(10):1911-20; 9. Andersen G et al. Pain 1995; 61(2):187-93; 10. Siddall PJ et al. Pain. 2003; 103(3):249-57; 11. Rae-Grant AD et al. Mult Scler 1999; 5(3):179-83.

11–26%1

~33%2

35–53%3–5

20–43% of mastectomy patients6,7

Up to 37%8

Diabetes

Cancer

HIV

Post-surgical

Postherpeticneuralgia

Chronic low back pain

8%9

75%10

~55%11

Stroke

Spinal cord injury

Multiple sclerosis

7–27% of patients with herpes zoster1

Condition% affected by peripheral

neuropathic pain% affected by central

neuropathic pain

Is it ‘‘diabetic neuropathy’’ or ‘‘neuropathy in a diabetic patient ?Think if- Clues… Rapidly progressive /abrupt onset

Prominent motor abnormality or CN involvement

Large >> small fiber involvement

Involvement of the entire lower limbs without neuropathy of the distal upper limb.

Predominant hands/UL sensory symptoms findings

Distal Peripheral Neuropathy (DPN) Diagnosis

- Questionnaires for DN : ex:DN4- Clinical ; History & Exam - NCS- QST: quantitative sensory testing- Skin biopsy: assess (IENFD) - Corneal Confocal Microscopy

Neuropathic Pain Screening ToolsLANSS DN4 NPQ painDETECT ID Pain

SymptomsPricking, tingling, pins and needles x x x x XElectric shocks of shooting X x x x xHot or burning X x x x xNumbness x x x xPain evoked by light touching X x x xPainful cold or freezing pain x XClinical examinationBrush allodynia X XRaised soft touch threshold XAltered pin prick threshold X X

DN4 = Douleur Neuropathique en 4 Questions (DN4) questionnaire; LANSS = Leeds Assessment of Neuropathic Symptoms and Signs; NPQ = Neuropathic Pain QuestionnaireBennett MI et al. Pain 2007; 127(3):199-203; Haanpää M et al. Pain 2011; 152(1):14-27.

Neuropathic pain screening tools rely largely on common verbal

descriptors of pain}

} Some screening tools also include bedside neurological

examination

Select tool(s) based on ease of use andvalidation in the local language

Sensitivity and Specificity of Neuropathic Pain Screening Tools

*Compared with clinical diagnosisDN4 = Douleur neuropathic en 4 questions; LANSS = Leeds Assessment of Neuropathic Symptoms and Signs; NPQ = Neuropathic Pain Questionnaire; NR = not reportedBennett MI et al. Pain 2007; 127(3):199-203.

Name Description Sensitivity* Specificity*

Interview-basedNPQ 10 sensory-related items + 2 affect items 66% 74%

ID-Pain 5 sensory items + 1 pain location NR NR

painDETECT 7 sensory items + 2 spatial characteristics items 85% 80%

Interview + physical testsLANSS 5 symptom items + 2 clinical exam items 82–91% 80–94%

DN4 7 symptom + 3 clinical exam items 83% 90%

Tests incorporating both interview questions and physical tests have higher sensitivity and specificity than tools that rely only on interview questions

Interview of the patient

Question 1: Does the pain have one of the following characteristics?1) Burning2) Painful cold3) Electric shocks

Question 2: Is the pain associated with one or more of the following symptoms in the same area?

4) Tingling5) Pins and needles6) Numbness7) Itching

YES NO

YES NO

YES NO

YES NO

YES NO

YES NO

YES NO

1. Bouhassira D, Attal N, Alchaar H, et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 2005;114:29-36.

Examination of the patient

Question 3: Is the pain located in an area where the physical examination may reveal one or more of the following characteristics?

8) Hypoesthesia to touch9) Hypoesthesia to pinprick

Question 4: In the painful area, can the pain be caused or increased by:10) Brushing

YES NO

YES NO

YES NO


Interpretation of results

If the patient scores > 4; he may have neuropathic pain.

1 pointYES 0 pointNO


1. Monofilament Test

Objective: The two-site Semmes-

Weinstein (SW) monofilament test is used to identify loss of sensitivity for people with diabetes.

SW monofilaments come in several strengths, including: 4.17, 5.07, and 6.1 (1,10, and 75-g force respectively).

1. Lee S, Kim H, Choi S, Park Y, Kim Y, Cho B. Clinical usefulness of the two-site Semmes-Weinstein monofilament test for detecting diabetic peripheral neuropathy. J Korean Med Sci 2003;18:103-7.

2. Brush Test

Objective: The brush test can be used

to identify mechanical allodynia.

3. Pinprick Test

Objective: The pinprick test is used

to identify hyperalgesia and hypoesthesia.

4. Hot/Cold Test

Objective: Hot/Cold test is used to

identify thermal allodynia (the abnormal sensation of pain from the stimulus of hot or cold).

1. Cruccu G, Anand P, Attal N, et al. EFNS guidelines on neuropathic pain assessment. Eur J Neurol 2004;11:153-162.2. Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment

recommendations. Arch Neurol 2003;60:1524-34.

5. Vibration Test

Objective: The vibration test can

evaluate the integrity of large nerve fibres.1

This test is a rapid, reliable assessment, requiring less than 60 seconds to administer. 2

1. Aring AM, Jones DE, Falko JM. Evaluation and prevention of diabetic neuropathy. Am Fam Physician 2005;71(11):2123-28.

2. Perkins BA, Olaleye D, Zinman B, Bril V. Simple screening tests for peripheral neuropathy in the diabetes clinic. Diabetes Care 2001;24(2):250-56.

Diabetic Peripheral Neuropathy (DPN) Management Guidelines

Exclude non-diabetic etiologies

Stabilize DM/ Metabolic control

Pain management ;ex Pregabaline ( Lyrica) , TCA, Duloxetine (Cymbalta) Tramdaol ,Topical :Capsaicin Combination

Consider pain clinic referral

Diabetic Peripheral Neuropathy (DPN) Management

Treat Underlying Pathogenic Mechanisms Glycemic and Metabolic Control

Intensive glycemic control was associated with a reduction of 40% - 60% in the development or progression of neuropathy(DCCT /UKPDS)Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol. 1995;38(6):869.

The reduction in complications (Risk of DPN and CAN (64% and 45%, respectively, P<0.01). persisted despite the return of the hemoglobin A1c to pretreatment levels (Legacy effect) Aggressive early intervention to produce later rewards. Neuropathy and related findings in the DCCT EDIC study. ,Martin CL, Albers JW, Pop-Busui R, DCCT/EDIC Research Group Diabetes Care. 2014 Jan;37(1):31-8.

Treat Underlying Pathogenic Mechanisms Glycemic and Metabolic Control

The incidence of neuropathy is also associated with modifiable CV risk factors ( TAG , BMI, smoking, and hypertension) (EURODIAB Trial)

Multifactorial intervention, showed a reduction in the odds ratio (to 0.32) for the development of autonomic neuropathy ) (The Steno Trial)

Mechanism-Based Pharmacological Treatment of Neuropathic Pain

Spinal cordNociceptive afferent fiber

SNRI = serotonin-norepinephrine reuptake inhibitor; TCA = tricyclic antidepressantAdapted from: Attal N et al. Eur J Neurol 2010; 17(9):1113-e88; Beydoun A, Backonja MM. J Pain Symptom Manage 2003; 25(5 Suppl):S18-30; Jarvis MF, Boyce-Rustay JM. Curr Pharm Des 2009; 15(15):1711-6; Gilron I et al. CMAJ 2006; 175(3):265-75; Moisset X, Bouhassira D. NeuroImage 2007; 37(Suppl 1):S80-8; Morlion B. Curr Med Res Opin 2011; 27(1):11-33; Scholz J, Woolf CJ. Nat Neurosci 2002; 5(Suppl):1062-7.

Impaired Descending Modulation

Central Sensitization

Ectopic Discharge

Peripheral Sensitization

Brain

Nerve lesion/diseaseNerve lesion/disease

Central Sensitization /

Perception

Nerve lesion/disease

AscendingInput

Mechanism-Based Pharmacological Treatment of Neuropathic Pain


SNRI = serotonin-norepinephrine reuptake inhibitor; TCA = tricyclic antidepressantAdapted from: Attal N et al. Eur J Neurol 2010; 17(9):1113-e88; Beydoun A, Backonja MM. J Pain Symptom Manage 2003; 25(5 Suppl):S18-30; Jarvis MF, Boyce-Rustay JM. Curr Pharm Des 2009; 15(15):1711-6; Gilron I et al. CMAJ 2006; 175(3):265-75; Moisset X, Bouhassira D. NeuroImage 2007; 37(Suppl 1):S80-8; Morlion B. Curr Med Res Opin 2011; 27(1):11-33; Scholz J, Woolf CJ. Nat Neurosci 2002; 5(Suppl):1062-7.

ImpairedDescendingmodulation


Ectopic Discharge

Peripheral Sensitization

Brain

Medications affecting descending modulation:• SNRIs• TCAs• Tramadol, opioids

Medications affecting central sensitization:• α2δ ligands• TCAs• Tramadol, opioids

Medications affecting peripheral sensitization:• Capsaicin• Local anesthetics• TCAs

Nerve lesion/diseaseNerve lesion/disease


Nerve lesion/disease

Note: gabapentin and pregabalin are α2δ ligands Bauer CS et al. J Neurosci 2009; 29(13):4076-88.

Nerve injury

Injury stimulatesproduction of

calcium channel

Calcium channels transported to nerve

terminals in dorsal hornIncreased numbers of calcium channels

Increased calcium influx

Increased neuronal excitability

INCREASEDPAIN SENSITIVITY

X XBinding of α2δ ligands to

α2δ inhibits calcium channel transportX

X

X

X

Role of a2d-Linked Calcium Channels in Neuropathic Pain

How Antidepressants Modulate Pain

Nerve lesion


Verdu B et al. Drugs 2008; 68(18):2611-2632.

DescendingModulation

AscendingInput

Ectopic discharge Transmission

Perception

Glial cell Activation

Inhibiting synaptic reuptake of Serotonin and NE >> enhances descending modulation inhibitory effect)

Brain

Enhancing inhibitory controls

guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association

Treatment Options for Neuropathic PainCDA -2013

CDA 2013

1 - Screen timing : At time of diagnosis (Type 2 DM) and 5 yrs after diagnosis (Type 1 DM) ; Annual screening beyond that

2- Screening for peripheral neuropathy should be conducted by assessing loss of sensitivity to the 10-g monofilament or loss of sensitivity to vibration at the dorsum of the great toe [Grade A, Level 1].

CDA 2013

3- Diabetes should be treated with intensified glycemic control to prevent the onset and progression of neuropathy [Grade A, Level 1A, for type 1 diabetes; Grade B, Level 2, for type 2 diabetes].

4 - Agents may be used alone or in combination for relief of painful peripheral neuropathy:

Anticonvulsants (Pregabalin [Grade A, Level 1], gabapentin‡, valproate‡) [Grade B, Level 2]

Antidepressants (amitriptyline‡, Duloxetine, venlafaxine‡) [Grade B, Level 2]

Opioid analgesics (tapentadol ER, oxycodone ER, tramadol) [Grade B, Level 2]

Topical nitrate spray [Grade B, Level 2]


Treatment for Neuropathic PainFirst Line Anticonvulsants

Antidepressants Second Line Opioids*Other Topical nitrate

CapsaicinTranscutaneous electrical nerve stimulation

* Most avoid opioids due to dependency, tolerance, dose escalation and diversion

Many Treatment Options Exist for Neuropathic Pain


Medication Starting Dose

Titration Maximal Dose

Concerns

Gabapentin‡ [Grade B, Level 2]

300 mg bid 600 mg qid 3,600 mg/d

Pregabalin alpha 2-delta ligand [Grade A, Level 1]

75 mg bid 300 mg bid 600 mg/d Dizziness, … Weight gain

Edema

Valproate‡ [Grade B, Level 2]

250 mg bid 500 mg bid 1,500 mg/d

Backonja M, JAMA 1998; Gilron J, NEJM 2005; Rosenstock J, Pain 2004; Lesser H, Neur 2004; Richter RW, J Pain 2005; Satoh J, Diabetic Med 2011; Kochar DK Acta Neurol Scand 2002; Kochar DK, QJM 2004

‡This drug is not currently approved by Health Canada for the management of neuropathic pain associated with diabetic peripheral neuropathy.

Anticonvulsants for Neuropathic Pain




Concerns

Amitriptyline TCA‡[Grade B, Level 2]

10 mg qhs 100 mg qhs 150 mg/d S. EffectsCardiac

Duloxetine (SNRI) [Grade B, Level 2]

30 mg od 60 mg po od 120 mg/d Drug IntxnLiver/Renal?Glycemia

Venlafaxine‡ [Grade B, Level 2]

37.5 mg bid

150 mg po bid

300 mg/d Nausea and

somnolence

Max MB, Neurology 1987; Max MB, NEJM 1992; Raskin J, Pain Med 2005; Yasuda H, J Diab Inv 2011; Rowbotham MC Pain 2004.


Antidepressants for Neuropathic Pain


Opioids for Neuropathic Pain



Dextromethorphan [Grade B, Level 2]

100 mg qid 200 mg qid 960 mg/d

Morphine SR [Grade B, Level 2]

15 mg bid 60 mg bid 180 mg/d

Oxycodone ER [Grade B, Level 2]


Tapentadol ER [Grade B, Level 2]


Tramadol [Grade B, Level 2]

50 mg qid 50 mg qid 400 mg/d

Sang CN Anesthesiology 2002; Gilron I, NEJM 2005; Gimbel JS Neurology 2003; Harati Y, Neurology 1998.




Topical nitrate sprays [Grade B, Level 2]

30 mg spray to legs QHS

30 mg spray to legs bid

60 mg/d

Capsaicin cream 0.075% cream applied tid-qid

5-6 times per day

5-6 times /day

Transcutaneous electrical nerve stimulation

- - -

Yuen KC Diabetes Care 2002; Agrawal RP Diabetes Res Clin Pract 2007; Agrawal RP Diabetes Res Clin Pract 2009; Low PA Pain 1995; Capsaicin Group Arch Intern Med 1991; Hamza MA, Diabetes Care 2000.

Other Treatments for Neuropathic Pain


4. The following agents may be used alone or in combination for relief of painful peripheral neuropathy:

– Anticonvulsants (pregabalin) [Grade A, Level 1], gabapentin‡, valproate‡) [Grade B, Level 2]

– Antidepressants (amitriptyline‡, duloxetine, venlafaxine‡) [Grade B, Level 2]

– Opioid analgesics (tapentadol ER, oxycodone ER, tramadol) [Grade B, Level 2]

– Topical nitrate spray [Grade B, Level 2]


2013Recommendation

American Academy of Neurologists (AAN) Guidelines -2011Pharmacological Treatment of Painful Diabetic Peripheral

Neuropathy

The AAN recognizes that specific care decisions are the prerogative of the patient and the physician caring for the patient, based on all of the circumstances involved.AAN = American Academy of NeurologyBril V et al. Neurology 2011; 76(20):1758-65.

1st line (level A)

• Pregabalin

2nd line(level B)

• Gabapentin• Duloxetine• Amitriptyline

• Opioids• Tramadol

AAN GuidelinesAmerican Academy of Neurologists-2011

Summary of recommendations:

1. Bril V, England J, Franklin GM, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy: Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2011;76:1-1.

Level A: Effective

Level B: Probably Effective

Probably Not Effective

European Federation of Neurological Societies Guidelines (EFNS-2010) Pharmacological Treatment of Neuropathic Pain

1st line

• α2δ ligands (gabapentin, pre-gabalin)

• SNRIs (duloxetine, venlafaxine ER)

• TCAs

2nd or 3rd line

• Opioids• Tramadol*

• α2δ ligands (gabapentin, pregabalin)

• TCAs• Lidocaine

plasters

• Capsaicin• Opioids

• Cabamazepine• Oxcarbazepine

• α2δ ligands (gabapentin, pregabalin)

• TCAs

• Surgery

• Cannabinoids (MS)

• Lamotrigine• Opioids• Tramadol

(SCI)

DPNPostherpetic

neuralgiaTrigeminal neuralgia Central pain

Note: recommended treatments may not all be licensed for the indication. Prescribers should also be aware of contraindications and cautions when using certain agents in certain patients (e.g., elderly).*Tramadol may be considered first-line in patients with acute exacerbations of pain, especially for the tramadol/acetaminophen combination. DPN = diabetic peripheral neuropathy; EFNS = European Federation of Neurological Societies; ER = extended release; MS = multiple sclerosis; SCI = spinal cord injury; SNRI = serotonin-norepinephrine reuptake inhibitor; TCA = tricyclic antidepressantAdapted from: Attal N et al. Eur J Neurol 2010; 17(9):1113-e88.

Middle East Region Expert Panel Recommendations:Treatment Algorithm for Peripheral Neuropathic Pain

*In patients with focal post-herpetic neuropathy with allodynia, or any peripheral neuropathic pain associated with a small, localized area of allodynia NMDA = N-methyl-D-aspartate; SNRI = serotonin-norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant; XR = extended release Bohlega S et al. J Int Med Res 2010; 38(2):295-317.

1st LineFor peripheral neuropathic pain, treat with:1) Pregabalin or gabapentin2) TCA (nortriptyline or desipramine)For focal neuropathy such as postherpetic neuralgia, treat with: topical lidocaine (patch or 5% gel or cream)

2nd Line1) SNRI (duloxetine; venlafaxine XR)2) Tramadol or other opioid analgesic

(preferably controlled-release)

Partial or non-response to 2nd line treatment

For patients with partial orinadequate pain relief:

May add additional drugs(but do NOT combine

SNRIs and TCAs)

Refer to specialist

2010 International Association for the Study of Pain (IASP) Pharmacological Management of Neuropathic Pain

Initiate treatment with one or more first-line treatments:• α2δ ligands (gabapentin, pregabalin)• SNRIs (duloxetine, venlafaxine)

*Use tertiary amine TCAs such as amitiptyline only if secondary amine TCAs are unavailableNote: there is insufficient support for the use of nsNSAIDs in neuropathic painnsNSAID = non-specific non-steroidal anti-inflammatory drug; SNRI = serotonin-norepinephrine reuptake inhibitor; TCA = tricyclic antidepressantDworkin RH et al. Mayo Clin Proc 2010 ; 85(3 Suppl):S3-14; Freynhagen R, Bennett MI. BMJ 2009; 339:b3002.

• TCAs* (nortriptyline, desipramine)• Topical lidocaine

(for localized peripheral pain)

• If there is partial pain relief, add another first-line medication• If there is no or inadequate pain relief, switch to another

first-line medication

If first-line medications alone and in combination fail, consider second-line medications (opioids, tramadol) or third-line medications (bupropion, citalopram, paroxetine, carbamazepine, lamotrigine, oxcarbazepine, topiramate, valproic acid, topical capsaicin, dextromethorphan, memantine, mexiletine) or referral to pain specialist

STEP

1

STEP

2

STEP

3

2010 International Association for the Study of Pain (IASP) Prescribing Recommendations for First-Line Medications

Medication Starting dose Titration Max. dosage Trial duration

α2δ ligands Gabapentin 100–300 mg at bedtime

or tid↑ by 100–300 mg tid every 1–7 days

3600 mg/day 3–8 weeks + 2 weeks at max. dose

Pregabalin 50 mg tid or 75 mg bid ↑ to 300 mg/day after 3–7 days, then by 150 mg/day every 3–7 days

600 mg/day 4 weeks

SNRIs Duloxetine 30 mg qd ↑ to 60 mg qd after

1 week60 mg bid 4 weeks

Venlafaxine 37.5 mg qd ↑ by 75 mg each week

225 mg/day 4–6 weeks

TCAs (desipraminenortriptyline)

25 mg at bedtime ↑ by 25 mg/day every 3–7 days

150 mg/day 6–8 weeks, with ≥2 weeks at max. tolerated dosage

Topical lidocaine

Max. 3 5% patches/day for 12 h max.

None needed Max. 3 patches/day for 12–18 h max.

3 weeks

SNRI = serotonin-norepinephrine reuptake inhibitor; TCA = tricyclic antidepressantDworkin RH et al. Mayo Clin Proc 2010; 85(3 Suppl):S3-14.

Goals in the Treatment of Neuropathic Pain

2o goals

*Note: pain reduction of 30–50% can be expected with maximal doses in most patients Argoff CE et al. Mayo Clin Proc 2006; 81(Suppl 4):S12-25; Lindsay TJ et al. Am Fam Physician 2010; 82(2):151-8.

1o goal:>50%

pain relief*… but be realistic!

Sleep Mood

Function Quality of life

To Conclude…

Ensuring Treatment AdherenceHighly prevalent

Under-diagnosed entity= Morbidity and mortality

Painful DPN occurs in 65% of DM patients in Saudi Arabia

Detailed H& P with basic Screening tools are essential & useful tools for screening and Dx

Key MessagesDPN

Key Messages

• Neuropathic pain can be recognized by common verbal descriptors and simple bedside tests = H&P

• Most treatment guidelines consider antidepressants and α2δ ligands as first-line therapy for most types of neuropathic pain

• Combination therapy is recommended for patients with a partial response to monotherapy

diabetic p. neuropathy

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