Neuropathic pain diagnosis & management

1. Neuropathic Pain diagnosis &
management
(Diabetic Peripheral Neuropathy)
BY
ASHRAF OKBA
PROF. OF INTERNAL MEDICINE
AIN SHAMS UNIVERSITY- EGYPT

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3. Freynhagen R, Baron R. Curr Pain Headache Rep 2009; 13(3):185-90; Jensen TS et al. Pain 2011; 152(10):2204-5;
Julius D et al. In: McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006;
Ross E. Expert Opin Pharmacother 2001; 2(1):1529-30; Webster LR. Am J Manag Care 2008; 14(5 Suppl 1):S116-22; Woolf CJ. Pain 2011; 152(3 Suppl):S2-15.
Multiple types
of pain coexist in many
conditions
(mixed pain)
Nociceptive pain
- Somatic
- Visceral
Neuropathic pain
- Peripheral
- Central
Central sensitization/
dysfunctional pain
Pathophysiological Classification of Pain

4. What is nociceptive pain?
Nociceptive pain system is a key early warning device,
an alarm system that announces the presence of a
potentially damaging stimulus. 1
nociceptive pain is a transient pain in response to
specific noxious stimuli1
It may vary in intensity , duration , quality & may be
referred pain.1
Nociceptive pain is therefore a vital physiologic
sensation. 1
Can also be chronic (e.g., osteoarthritis)2
1. Dennis A. Ausiello et al , Pain: Moving from Symptom Control toward Mechanism-Specific Pharmacologic Management, Koltzenburg M, eds. Ann Intern Med. 2004;140:441-451.
2. David T. Felson , The sources of pain in knee osteoarthritis , Curr Opin Rheumatol 17:624 -628. 2005 Lippincott Williams & Wilkins..

5. Nociceptive pain
• An appropriate physiologic response that occurs when
specific peripheral sensory neurons (nociceptors)
respond to noxious stimuli.
• Has a protective role because it elicits reflex and
behavioral responses that keep tissue damage to a
minimum.
• Nociceptive pain may be somatic or visceral in origin.
– Somatic pain: such as gout, osteoarthritis and trauma-
induced pain, originates with the musculoskeletal or
cutaneous nociceptors and is often well localized.
– Visceral pain: such as dysmenorrhea or acute pancreatitis,
originates in nociceptors located in the hollow organs and
smooth muscles; it is often referred.

6. Neuropathic pain
• Defined by the International Association for the
Study of Pain as “Pain caused by a lesion or
disease of the somatosensory nervous system.”
• Depending on where the lesion or dysfunction
occurs within the nervous system,
• Neuropathic pain can be
– Peripheral in origin (as in painful diabetic peripheral
neuropathy and postherpetic neuralgia)
– Central in origin (for example, neuropathic pain
associated with stroke or spinal cord injury).

7. Central sensitization/dysfunctional
pain
• Defined as “Hypersensitivity of the pain system such that
normally innocuous inputs can activate and perceptual
responses to noxious inputs are exaggerated, prolonged and
spread widely”.
• Some common examples for this pain type are: fibromyalgia,
temporomandibular joint disorder, chronic migraine/tension
type headache, interstitial cystitis, irritable bowel syndrome
and complex regional pain syndrome.

8. Mixed Pain
• There are cases in which more than one type
of pain pathophysiology exist
• For example, in a lumbar herniated disc
patient with radiculopathy, it is common to
experience both nociceptive/inflammatory
pain, felt around the low back area with
movement, and neuropathic pain, felt in the
distribution territory of the effected root
(lower extremity).

9. What is neuropathic pain?
Pain caused by a lesion or disease of the somato-
sensory system1
Pain often described as tingling and prickling,
commonly associated with numbness2
Almost always a chronic condition
(e.g., post-herpetic neuralgia, post-stroke pain)2
Responds poorly to conventional analgesics
(NSAIDs)3
1. Jensen TS, et al, A new definition of neuropathic pain IASP. Pain 2011;152:2204-5.
2. Dray A. Neuropathic pain: emerging treatments ,Br J Anaesth 2008;101:48-58.
3. S BOHLEGA et al, Guidelines for the Pharmacological Treatment of Peripheral Neuropathic Pain: Expert Panel
Recommendations for the Middle East Region .J Int Med Res 2010;38:101-23.

10. What is neuropathic pain?
Neuropathic Pain
Pain caused by a lesion or disease of the
somatosensory nervous system
Peripheral Neuropathic Pain
Pain caused by a lesion or disease of
the peripheral somatosensory
nervous system
Central Neuropathic Pain
Pain caused by a lesion or disease of
the central somatosensory
nervous system
International Association for the Study of Pain. IASP Taxonomy, Changes in the 2011 List. Available at:
http://www.iasp-pain.org/AM/Template.cfm?Section=Pain_Definitions. Accessed: July 15, 2013.

11. 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

12. 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.

13. Neuropathic Pain is Characterized by
Changes in Pain Response to Painful
StimuliPainintensity
10
8
6
4
2
0
Stimulus intensity
Normal
pain response
Injury
Hyperalgesia
(increased response to a stimulus
that is normally painful)
Allodynia
(pain due to stimulus
that does not normally
provoke pain)
Adapted from: Gottschalk A et al. Am Fam Physician 2001; 63(10):1979-84.
Response
after injury

14. Characteristics of nociceptive and
neuropathic pain
Pain types Nociceptive “OA” Neuropathic “PDN”
Definition Pain caused by
physiologic activation
of pain receptors
Pain caused by a lesion
or disease of the
somato-sensory system
Localization Local and referred
pain
Confined to innervations
territory of the nervous
structure lesion
Quality of
symptoms
Ordinary painful
sensation
New strange sensations
1. Pedro Schestatsky1et al, What do general neurologists need to know about neuropathic pain? Arq Neuropsiquiatr 2009;67(3-A):741-7492.
2. David T. Felson , The sources of pain in knee osteoarthritis , Curr Opin Rheumatol 17:624 -628. 2005 Lippincott Williams & Wilkins...
OA: Osteoarthritis
PDN: Painful Diabetic Neuropathy

15. Prevalence of painful diabetic
peripheral neuropathy
Painful diabetic peripheral neuropathy occurs in
53.7% of people with diabetes in the Middle East1
Diabetes is a significant healthcare problem in North
Africa and the Middle East region, affecting:
An estimated 7.593.300 people in Egypt (16.6% of the
population in MENA Region) in 20142
A predicted 13.073.300 people in Egypt (17.7% of the
population) by 20352
1. Jambart S et al. Prevalence of Painful Diabetic Peripheral Neuropathy among Patients with Diabetes Mellitus in
the Middle East Region J Int Med Res 2011;39:366-77.
2. International Diabetes Federation. Diabetes Atlas. 6th edition,2014.

16. Simplified patho-physiology
of neuropathic pain
NeP
Peripheral mechanisms
Abnormal
discharges
Central mechanisms
1. Gilron I et al. Neuropathic pain: a practical guide for the clinician, CMAJ 2006;175:265-75.
2- Ralf Baron, et al, Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment.. Lancet Neurol 2010; 9: 807–19
Peripheral neuron
hyperexcitability1
Loss of
inhibitory controls1,2
Central mechanisms
Central neuron
hyperexcitability
(central sensitization)1
NeP = Neuropathic pain
.

17. Pathophysiology of PDN
PDN: Painful Diabetic neuropathy
DAG :Di-AcylGlycerol
LDL :Low-Density Lipoprotein
PKC: Protein Kinase C.
Rayaz .AM et al, Pathophysiology and Treatment of Painful Diabetic Neuropathy ,Current Pain and Headache Reports 2008, 12:192–197

18. The interrelationship between neuropathic pain,
sleep, and anxiety/depression
Pain
Functional
impairment
Anxiety and
depression
Sleep
disturbance
Nicholson B et al. Comorbidities in chronic neuropathic pain, Pain Med 2004;5(Suppl 1):S9-27.

19. Sleep disruption contributes to
pain
• Most experimental studies in humans and animals show that sleep
deprivation produces hyperalgesic changes1
• Concurrent management of disturbed sleep and pain in patients
with chronic pain is advisable:1
 Pain enhances arousal and disrupts sleep
 Sleep deprivation and sleep disruption increase pain sensitivity and
vulnerability to pain
 A vicious circle with sleep disorder and chronic pain maintaining and
augmenting each other may result
1. Lautenbacher S et al. Sleep deprivation and pain perception ,Sleep Med Rev 2006;10:357-69.

20. Pain intensity increases with increasing sleep
disturbance in patients with neuropathic painPresentpainintensity
p=0.0001
603 patients with neuropathic pain of multiple etiologies
MOS = Medical Outcomes Study
Rejas J et al. Psychometric properties of the MOS (Medical Outcomes Study) Sleep Scale in patients with neuropathic pain Euro J Pain 2007;11:329-40.
Worse sleep
0 10 20 30 40 50 60
No pain
Mild
Discomforting
Distressing
Horrible
Excruciating
Mean MOS Sleep Scale 9-item index score
53.7
51.8
47.1
40.5
38.8
34.1

21. Neuropathic pain has positive
&
negative sensory symptoms1
Somatosensory system dysfunction or damage
Positive symptoms
(due to excessive activity)1
Paresthesia1
Spontaneous pain1,2
Hyperalgesia2
Allodynia2
Negative symptoms
(due to deficit of function)1,2
Hypoesthesia1,2
Hypoalgesia1,2
Analgesia2
1. Baron R,et al , Assessment and diagnosis of neuropathic pain. Curr Opin Support Palliat Care 2008;2:1-81.
2. Gilron I et al. Neuropathic pain: a practical guide for the clinician ,CMAJ 2006;175:265-75.

22. Positive
symptom
Definition1
Spontaneous pain1 Painful sensations felt with no
evident stimulus
Allodynia1 Pain due to a stimulus that does not normally provoke pain
(e.g., touching, movement, cold, heat)
Hyperalgesia1 An increased response to a stimulus that is normally painful
(e.g., cold, heat, pinprick)
Dysesthesia1 An unpleasant abnormal sensation, whether spontaneous or
evoked (e.g., shooting sensation)
Paresthesia1 An abnormal sensation, whether spontaneous or evoked (e.g.,
tingling)
Positive sensory symptoms
of neuropathic pain
Adapted from:
1. Bohlega S et al. Guidelines for the Pharmacological Treatment of Peripheral Neuropathic Pain: Expert Panel
Recommendations for MER ,J Int Med Res 2010;38:101-23

23. Negative
symptom
Definition
Hypoesthesia1 Diminished sensitivity to stimulation to non Painful
stimulus.
Anesthesia1 Total loss of sensation (especially tactile sensitivity)
Hypoalgesia1 Diminished pain in response to a normally painful
stimulus
Analgesia1 Absence of pain in response to stimulation that
would normally be painful
Negative sensory symptoms
of neuropathic pain
Adapted from:
1. Bohlega S et al. Guidelines for the Pharmacological Treatment of Peripheral Neuropathic Pain: Expert Panel
Recommendations for MER ,J Int Med Res 2010;38:101-23

24. Diagnosing Neuropathic Pain
Is Challenging
Harden N, Cohen M. J Pain Symptom Manage 2003; 25(5 Suppl):S12-7; Woolf CJ, Mannion RJ. Lancet 1999; 353(9168):1959-64.
Diagnostic
challenges
Multiple,
complex
mechanisms
Diverse
symptoms
Difficulties in
communicating and
understanding symptoms
Recognition of
comorbidities

25. Painful diabetic peripheral neuropathy
Painful diabetic
peripheral neuropathy

26. Painful diabetic
peripheral neuropathy
Numbness or insensitivity to pain or
temperature
Tingling, burning, or
prickling sensation
Sharp pains or cramps
Extreme sensitivity to touch, even light
touch
Loss of balance
and co-ordination
Muscle weakness and loss of reflexes
Symptoms are often worse at night
National Institute of Diabetes and Digestive and Kidney Diseases. Diabetic Neuropathies: The Nerve Damage of Diabetes. Available
at: http://diabetes.niddk.nih.gov/dm/pubs/neuropathies/. Accessed 18 Oct 2011.

27. The 3L approach to diagnosis
Patient verbal descriptors of pain,
questions and answers
Nervous system lesion
or abnormality
Sensory abnormalities
(skin and joints)
Listen1
Look1Locate2
1. Gilron I et al. Neuropathic pain: a practical guide for the clinician ,CMAJ 2006;175:265-75.
2. Haanpää ML et al. Assessment of Neuropathic Pain in Primary Care , Am J Med 2009;122(10 Suppl):S13-21.

28. Patients with neuropathic pain may use
these pain descriptors
“Numbness”1
“Shooting”1 “Burning”1
Be alert for common verbal
descriptors of neuropathic pain1
“Electric shock-like”1
“Tingling”1
1. Baron R ,et al , Assessment and diagnosis of neuropathic pain. Curr Opin Support Palliat Care 2008;2:1-81

29. Listen:
Recognizing Neuropathic Pain
Burning Tingling Shooting Electric shock-like Numbness
Be alert for common verbal descriptors of neuropathic pain:
Baron R et al. Lancet Neurol 2010; 9(8):807-19; Gilron I et al. CMAJ 2006; 175(3):265-75.

30. Determine Pain Intensity
31
International Association for the Study of Pain. Faces Pain Scale – Revised. Available at: http://www.iasp-
pain.org/Content/NavigationMenu/GeneralResourceLinks/FacesPainScaleRevised/default.htm. Accessed: July 15, 2013;
Iverson RE et al. Plast Reconstr Surg 2006; 118(4):1060-9.
0
0–10 Numeric Pain Intensity Scale
No
pain
1 2 3 4 5 6 7 8 9 10
Moderate
pain
Worst
possible pain
Simple Descriptive Pain Intensity Scale
No
pain
Mild
pain
Moderate
pain
Severe
pain
Very severe
pain
Worst
pain
Faces Pain Scale – Revised
31

31. Locate: correlate the region of pain to
the lesion/dysfunction in the nervous
system
Painful diabetic peripheral neuropathy
Morales-Vidal et al ,Diabetic Peripheral Neuropathy and the management of Diabetic Peripheral Neuropathic
Pain, Postgrad Med 2012 ;Vol 124 , Issue 4 , P 145 - 153.

32. Look for the presence of sensory and/or
physical abnormalities
o First, inspect the painful body area and compare it with the
corresponding healthy area1:
Differences in color, temperature, sweating2
o Then, conduct simple bedside tests to confirm sensory
abnormalities associated with
neuropathic pain1-3:
Gauze or a piece of cotton wool
Pinprick
Pinch
Thermal (hot or cold object)
Pain when straight leg is raised2
1. Haanpää ML et al. Assessment of Neuropathic Pain in Primary Care ,Am J Med 2009;122(10 Suppl):S13-21.
2. Gilron I et al. Neuropathic pain: a practical guide for the clinician ,CMAJ 2006;175:265-75.
3. Baron R ,et al , Assessment and diagnosis of neuropathic pain. Curr Opin Support Palliat Care 2008;2:1-81

33. Look: Simple Bedside Tests
Baron R. Clin J Pain 2000; 16(2 Suppl):S12-20; Jensen TS, Baron R. Pain 2003; 102(1-2):1-8.
Light manual pinprick with
safety pin or sharp stick
Very sharp,
superficial pain
Stroke skin with brush,
cotton or apply acetone
Sharp, burning
superficial pain ALLODYNIA
HYPERALGESIA

34. Examples of tests applied for neuropathic pain
•Touch tests can detect1,2:
–Differences in
skin temperature
(hypo- or hyperthermia)
–Hypersensitivity
(allodynia, e.g.,
gauze test)
–Unpleasant abnormal
sensations (dysesthesia)
–Sensory deficit
(hypoesthesia)
•Tests to evoke pain1,2:
–The response to
these tests is the
presence of positive
sensory symptoms
–Touch (allodynia)
–Pinprick, pinch
(hyperalgesia)
–Pain when straight leg
is raised 2
1. Gilron I et al. Neuropathic pain: a practical guide for the clinician ,CMAJ 2006;175:265-75.
2. Baron R, Tölle TR. Assessment and diagnosis of neuropathic pain, Curr Opin Support Palliat Care 2008;2:1-8.

35. Making a differential diagnosis
1. Gilron I et al. Neuropathic pain: a practical guide for the clinician, CMAJ 2006;175:265-75.
2. Baron R, Tölle TR. Assessment and diagnosis of neuropathic pain, Curr Opin Support Palliat Care 2008;2:1-8.
3. Haanpää ML et al. Assessment of Neuropathic Pain in Primary Care Am J Med 2009;122(10 Suppl):S13-21.
Yes
No
Probable
nociceptive pain
Can you detect sensory
abnormalities using
simple bedside tests?1-3
Are verbal descriptors
suggestive of neuropathic pain?1
Yes
No
Neuropathic pain syndrome
likely: initiate treatment3
Yes
No
Can you identify the
responsible nervous system
lesion/dysfunction?3
Consider specialist referral, and
if neuropathic pain is still
suspectedconsider treatment in
the interim period3

36. Management of Neuropathic Pain
Treatment of
underlying
conditions
Diagnosis
Improved
sleep quality
Improved
overall quality
of life
Improved
physical
functioning
Improved
psychological
state
Reduced pain
Haanpää ML et al. Am J Med 2009; 122(10 Suppl):S13-21; Horowitz SH. Curr Opin Anaesthesiol 2006; 19(5):573-8; Johnson L. Br J Nurs 2004; 13(18):1092-7;
Meyer-Rosberg K et al. Eur J Pain 2001; 5(4):379-89; Nicholson B et al. Pain Med 2004; 5(Suppl 1):S9-27.
The earlier a diagnosis is made, the more opportunities there are to improve patient outcomes
Pharmacological and
non-pharmacological
treatment of
neuropathic pain
Treatment of
comorbidities

37. 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

38. Treatment for painful
diabetic peripheral neuropathy
Treatment is both preventative and symptomatic,
and is based on:
– Stabilizing glycemic levels1
– Analgesics specific to neuropathic pain:2
o First-line therapies include alpha-2-delta ligands
(pregabalin, gabapentin) and TCAs
o Second-line therapies include SNRIs and opioids
– Standard NSAIDs are generally ineffective;
opioids may be useful in certain cases3
1. Corbett CF. Practical management of patients with painful diabetic neuropathy. Diabetes Educ 2005;31:523-38. .
2. Dray A. Neuropathic pain: emerging treatments, Br J Anaesth 2008;101:48-58.
3. S BOHLEGA et al, Guidelines for the Pharmacological Treatment of Peripheral Neuropathic Pain: Expert Panel Recommendations for the Middle East Region .J Int
Med Res 2010;38:101-23.
TCAs = tricyclic antidepressants;
SNRIs = serotonin-norepinephrine reuptake inhibitors;
NSAIDs = non-steroidal anti-inflammatory drugs
WEGYLYR1014021

39. International guidelines recommending pregabalin as first-line for
management of neuropathic pain
¶For focal neuropathy, such as post-herpetic neuropathy; *No differentiation between different types of neuropathic pain; **For
painful diabetic peripheral neuropathy only
†Level A evidence; ‡Level B evidence
Level A: established as effective, ineffective, or harmful (or as useful/predictive or not useful/not predictive) for the given condition in the specified population based on at least 2 consistent Class I studies (RCTs);
Level B: probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population based on at least one Class l study (RCT)7
EFNS = European Federation of Neurological Societies; IASP = International Association for the Study of Pain; CPS = Canadian Pain Society;
AAN = American Academy of Neurology; TCAs = tricyclic antidepressants; SNRIs = serotonin-norepinephrine reuptake inhibitors;
RCT = randomized controlled trial.
Guideline First-line recommendations Second-line recommendations
Middle East
Region1
(2010 PDN)
Pregabalin, gabapentin, TCAs,
lidocaine (topical)¶
SNRIs (duloxetine or venlafaxine-XR), opioid
analgesics (e.g., tramadol, oxycodone)
French-speaking
Maghreb2
(2010 )
Pregabalin, gabapentin, TCAs,
lidocaine (topical)
Duloxetine
EFNS3
(2009)
Pregabalin, gabapentin, TCAs,
duloxetine, venlafaxine ER,
lidocaine (topical)
Tramadol, opioids
IASP*4
(2010)
Pregabalin, gabapentin, TCAs,
duloxetine, venlafaxine, lidocaine
(topical)
Opioid analgesics, tramadol
CPS*5 (2007) Pregabalin, TCAs, gabapentin SNRIs, lidocaine (topical)
AAN**6
(2011 PDN)
(Class A Evidence) : Pregabalin† (Class B Evidence) : Gabapentin, duloxetine,
venlafaxine,sodium valproate, amitriptyline,
tramadol, oxycodone, capsaicin‡
WEGYLYR1014021
1. S.BOHLEGA et al, Guidelines for the pharmacological Treatment of Peripheral Neuropathic Pain: Expert Panel Recommendations for the Middle East Region .J Int Med Res 2010;38:101-23.
2. Griene B et al. Pharmacological treatment of peripheral neuropathic pain: expert panel recommendations for the French-speaking Maghreb region Douleur analg 2011;24:112-20.
3. Attal N et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2009 revision ,Eur J Neurol 2010;17:1113-e88.
4. Dworkin RH et al. Recommendations for the Pharmacological Management of Neuropathic Pain: An Overview and Literature Update , Mayo Clin Proc 2010;85(3 Suppl):S3-14.
5. Moulin DE et al. Pharmacological management of chronic neuropathic pain – Consensus statement and guidelines from the Canadian Pain Society , Pain Res Manag 2007;12:13-21.
6. Bril V. et al. Treatment of Painful Diabetic Neuropathy Neurology 2011;76:1-8 Neurology 2011;76:1-8..

40. Thank You