Neuropathic Pain diagnosis &

management

(Diabetic Peripheral Neuropathy)

BYASHRAF OKBA

PROF. OF INTERNAL MEDICINE AIN SHAMS UNIVERSITY- EGYPT

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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

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..

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.

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).

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.

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).

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.

What is neuropathic pain?

Neuropathic PainPain caused by a lesion or disease of the

somatosensory nervous system

Peripheral Neuropathic PainPain caused by a lesion or disease of

the peripheral somatosensory nervous system

Central Neuropathic PainPain 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.

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 Opin2006; 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

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.

Neuropathic Pain is Characterized by Changes in Pain Response to Painful

StimuliP

ain

inte

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ty

10

8

6

4

2

0

Stimulus intensity

Normalpain 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

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

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.

Simplified patho-physiology of neuropathic pain

NeP

Peripheral mechanisms

Abnormaldischarges

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 neuronhyperexcitability1

Loss ofinhibitory controls1,2

Central mechanisms

Central neuron hyperexcitability

(central sensitization)1

NeP = Neuropathic pain.

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

The interrelationship between neuropathic pain, sleep, and anxiety/depression

Pain

Functionalimpairment

Anxiety anddepression

Sleepdisturbance

Nicholson B et al. Comorbidities in chronic neuropathic pain, Pain Med 2004;5(Suppl 1):S9-27.

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.

Pain intensity increases with increasing sleep disturbance in patients with neuropathic pain

Pre

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ty

p=0.0001

603 patients with neuropathic pain of multiple etiologiesMOS = Medical Outcomes StudyRejas 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

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

Analgesia 2

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.

Positive

symptomDefinition1

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

Negative

symptomDefinition

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

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

Painful diabetic peripheral neuropathy

Painful diabetic peripheral neuropathy

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.

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.

Patients with neuropathic pain may use these pain descriptors

“Numbness”1

“Shooting”1 “Burning”1

Be alert for common verbaldescriptors 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

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.

Determine Pain Intensity

31International 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 10Moderate

painWorst

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

Locate: correlate the region of pain to the lesion/dysfunction in the nervous

systemPainful 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.

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

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 withsafety pin or sharp stick

Very sharp, superficial pain

Stroke skin with brush,cotton or apply acetone

Sharp, burningsuperficial pain ALLODYNIA

HYPERALGESIA

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.

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

Probablenociceptive pain

Can you detect sensoryabnormalities using

simple bedside tests?1-3

Are verbal descriptorssuggestive of neuropathic pain?1

YesNo

Neuropathic pain syndromelikely: initiate treatment3

Yes

NoCan you identify the

responsible nervous systemlesion/dysfunction?3

Consider specialist referral, andif neuropathic pain is still

suspected consider treatment in the interim period3

Management of Neuropathic Pain

Treatment of underlying conditions

Diagnosis

Improvedsleep 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 ofcomorbidities

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

FunctionQuality

of life

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 IntMed Res 2010;38:101-23.

TCAs = tricyclic antidepressants;SNRIs = serotonin-norepinephrine reuptake inhibitors;NSAIDs = non-steroidal anti-inflammatory drugs

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International guidelines recommending pregabalin as first-line formanagement 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 evidenceLevel 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‡

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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..

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