diabetic p. neuropathy
TRANSCRIPT
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.
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
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.
Interpretation of results
If the patient scores > 4; he may have neuropathic pain.
1 pointYES 0 pointNO
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.
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
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.
ImpairedDescendingmodulation
Central Sensitization
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
Central Sensitization
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
Spinal cordNociceptive afferent fiber
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
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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]
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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
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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
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Medication Starting Dose
Titration Maximal Dose
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.
‡This drug is not currently approved by Health Canada for the management of neuropathic pain associated with diabetic peripheral neuropathy.
Antidepressants for Neuropathic Pain
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Opioids for Neuropathic Pain
Medication Starting Dose
Titration Maximal Dose
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]
10 mg bid 40 mg bid 160 mg/d
Tapentadol ER [Grade B, Level 2]
100 mg bid 250 mg bid 500 mg/d
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.
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Medication Starting Dose
Titration Maximal Dose
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
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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]
‡This drug is not currently approved by Health Canada for the management of neuropathic pain associated with diabetic peripheral neuropathy.
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