Diabetic p. neuropathy

Diabetic Peripheral Neuropathy
Assessment and Management
Mohammad O. Daoud, MD
• Consultant Endocrinologist
• NGHA- Jeddah

Agenda
DPN : What do we know ?
Clinical presentation
Diagnostic approach /Screening
Therapeutic Guidelines

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 yrs
DM 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
Sleep
disturbances
Anxiety and
depression
Functional
impairment
Nicholson B, Verma S. Pain Med 2004; 5(Suppl 1):S9-27.

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 of
inhibitory 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.

Clinical Picture

Total cholesterol
Triglycerides
BMI
Diabetes duration
Change in HbA1c
HbA1c
Smoking
Hypertension
1.57
1.38
1.48
1.36
1.40
1.27
1.21
1.15
Model 1:
without CVD
and 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

DPN
General 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-exist
Each patient may have a combination of symptoms
that may change over time (even within a single etiology)
Paresthesia
Spontaneous pain
Hyperalgesia
Allodynia Anesthesia
Negative symptoms
(due to deficit of function)
Lesion or disease of the somatosensory nervous system
Hypoesthesia
Hypoalgesia
Analgesia
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
Stabbing
Uncomfortable
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

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 testing
Vascular and skin assessment

(DPN)
Diagnosis & Screening

Diabetic Neuropathy (DN)
Diagnosis
Mainly clinical ; H & P
Supported 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 virus
1. 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
Postherpetic
neuralgia
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 Tools
LANSS DN4 NPQ painDETECT ID Pain
Symptoms
Pricking, tingling, pins and needles x x x x X
Electric shocks of shooting X x x x x
Hot or burning X x x x x
Numbness x x x x
Pain evoked by light touching X x x x
Painful cold or freezing pain x X
Clinical examination
Brush allodynia X X
Raised soft touch threshold X
Altered pin prick threshold X X
DN4 = Douleur Neuropathique en 4 Questions (DN4) questionnaire;
LANSS = Leeds Assessment of Neuropathic Symptoms and Signs; NPQ = Neuropathic Pain Questionnaire
Bennett 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 and
validation in the local language

Sensitivity and Specificity of Neuropathic Pain
Screening Tools
*Compared with clinical diagnosis
DN4 = Douleur neuropathic en 4 questions; LANSS = Leeds Assessment of Neuropathic Symptoms and Signs;
NPQ = Neuropathic Pain Questionnaire; NR = not reported
Bennett MI et al. Pain 2007; 127(3):199-203.
Name Description Sensitivity* Specificity*
Interview-based
NPQ 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 tests
LANSS 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) Burning
2) Painful cold
3) Electric shocks
Question 2: Is the pain associated with one or more of the following
symptoms in the same area?
4) Tingling
5) Pins and needles
6) Numbness
7) 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 touch
9) 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.

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
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 antidepressant
Adapted 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/disease
Central
Sensitization /
Perception
Ascending
Input

Mechanism-Based Pharmacological Treatment
of Neuropathic Pain
Adapted 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
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
Central
Sensitization

Note: gabapentin and pregabalin are α2δ ligands
Bauer CS et al. J Neurosci 2009; 29(13):4076-88.
Nerve injury
Injury stimulates
production of
calcium channel
Calcium channels
transported to nerve
terminals in dorsal horn
Increased numbers
of calcium channels
Increased
calcium influx
Increased neuronal
excitability
INCREASED
PAIN SENSITIVITY
X X
Binding of α2δ ligands to
α2δ inhibits calcium
channel transport
X
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.
Descending
Modulation
Ascending
Input
Ectopic
discharge Transmission
Perception
Glial cell
Activation
Inhibiting synaptic reuptake of Serotonin and NE >>
enhances descending modulation inhibitory effect)
Brain

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 Pain
First Line Anticonvulsants
Antidepressants
Second Line Opioids*
Other Topical nitrate
Capsaicin
Transcutaneous 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

Medication Starting
Dose
Titration Maximal
Dose
Concerns
Amitriptyline TCA
‡[Grade B, Level 2]
10 mg qhs 100 mg qhs 150 mg/d S. Effects
Cardiac
Duloxetine (SNRI)
[Grade B, Level 2]
30 mg od 60 mg po od 120 mg/d Drug Intxn
Liver/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

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]
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.

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

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 -2011
Pharmacological 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 Neurology
Bril V et al. Neurology 2011; 76(20):1758-65.
1st line
(level A)
• Pregabalin
2nd line
(level B)
• Gabapentin
• Duloxetine
• Amitriptyline
• Opioids
• Tramadol

AAN Guidelines
American 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)
DPN
Postherpetic
neuralgia
Trigeminal
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 antidepressant
Adapted 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 Line
For peripheral neuropathic pain, treat with:
1) Pregabalin or gabapentin
2) TCA (nortriptyline or desipramine)
For focal neuropathy such as postherpetic neuralgia, treat
with: topical lidocaine (patch or 5% gel or cream)
2nd Line
1) 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 or
inadequate 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 unavailable
Note: there is insufficient support for the use of nsNSAIDs in neuropathic pain
nsNSAID = non-specific non-steroidal anti-inflammatory drug; SNRI = serotonin-norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant
Dworkin 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
STEP1
STEP2
STEP3

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 week
60 mg bid 4 weeks
Venlafaxine 37.5 mg qd ↑ by 75 mg
each week
225 mg/day 4–6 weeks
TCAs
(desipramine
nortriptyline)
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
Dworkin RH et al. Mayo Clin Proc 2010; 85(3 Suppl):S3-14.

Goals in the Treatment of
Neuropathic Pain
2o goals
1o goal:
>50%
pain relief*
… but be
realistic!
Sleep Mood
Function
Quality
of life

Highly 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 Messages
DPN

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

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