This document discusses diabetic polyneuropathy. It begins with an agenda outlining the topics to be covered: epidemiology, clinical presentation, pathogenic mechanisms, diagnosis, and treatment. Some key points include: - Up to 50% of diabetics may develop symptomatic neuropathy 20 years after diagnosis. The risk increases the longer a person has diabetes. - Neuropathic pain symptoms can include burning, tingling sensations, allodynia, and hyperalgesia. The pain is usually chronic. - Pathogenic mechanisms include metabolic and vascular factors that damage nerve fibers over time, such as hyperglycemia, oxidative stress, impaired blood flow. This can lead to endoneurial hypoxia, ATP depletion and nerve damage.

1. Amr Hassan, MD, FEBN
Professor of Neurology
Cairo University
Diabetic Polyneuropathy

2. AGENDA
Epidemiology
Clinical presentation
Pathogenic mechanisms
Diagnosis
Treatment
2

3. AGENDA
Epidemiology
Clinical presentation
Pathogenic mechanisms
Diagnosis
Treatment
3

4. As a proportion of all diabetics 20 years after diagnosis
No neuropathy
10%
Asymptomatic
40%
Symptomatic
50%
Incidence of Diabetic Neuropathy

5. Neuropathy Increases with Time
0%
10%
20%
30%
40%
50%
60%
70%
0 5 10 15 20 25
Years from Diabetes Diagnosis
Proportion with Neuropathy
CDC Website
Prevalence of Diabetic Neuropathy

6. Incidence of Diabetic Neuropathy
&Neuropathic pain

7. 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
Neuropathic Pain is Prevalent Across a
Range of Different Conditions

8. AGENDA
Epidemiology
Clinical presentation
Pathogenic mechanisms
Diagnosis
Treatment
8

9. 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.
How Patients Feel Neuropathic Pain?

10. 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?

11. Course

12. 12
Adapted from ADA. Diabetes Care. 2003;26:S33-S50; Abbott CA, et al. Diabetes Care. 1998;21:1071-1075; Armstrong DG, et al. Arch Intern Med. 1998;158:289-292; Armstrong
DG, et al. Ostomy Wound Manage. 1998;44:70-76; Carrington AL, et al. Diabetes Care. 2002;25:2010-2015; Feldman EL, et al. Diabetes Care. 1994;17:1281-1289; Shearer A,
et al. Diabetes Care. 2003;26:2305-2310; Veves A, et al. Diabet Med. 1991;8:917-921.
Course

13. • 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.
Sensory Symptoms of Neuropathic Pain

14. • 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.
Sensory Symptoms of Neuropathic Pain

15. • 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.
Sensory Symptoms of Neuropathic Pain

16. • 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.
Sensory Symptoms of Neuropathic Pain

17. • 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.
Sensory Symptoms of Neuropathic Pain

18. Types of diabetic neuropathies

19. 19
Types

20. 20
Rodica Pop-Busui,Diabetes Care 2017 Jan; 40(1): 136-154. https://doi.org/10.2337/dc16-2042

21. 21
Rodica Pop-Busui,Diabetes Care 2017 Jan; 40(1): 136-154. https://doi.org/10.2337/dc16-2042

22. Images: 1,4Edward J Bastyr, III, MD;
2,3Rayaz A Malik, MBChB, PhD, MRCP.
Effects of Diabetic Peripheral Neuropathy

23. Autonomic
Neuropathy
Symptomatic
• Postural hypotension
• Gastroparesis
• Diabetic diarrhea
• Neuropathic bladder
• Erectile dysfunction
• Neuropathic edema
• Charcot arthropathy
• Gustatatory sweating

24. Autonomic
Neuropathy
Subclinical abnormalities
• Abnormal pupillary
reflexes
• Esophageal dysfunction
• Abnormal cardiovascular
reflexes
• Blunted counter-
regulatory responses to
hypoglycemia
• Increased peripheral
blood flow

25. AGENDA
Epidemiology
Clinical presentation
Pathogenic mechanisms
Diagnosis
Treatment
25

26. Nature 2001;414:813-20
Pathogenic mechanisms of DPN

27. Pathogenic mechanisms of DPN

28. Pathogenic mechanisms of DPN
Rodica Pop-Busui,Diabetes Care 2017 Jan; 40(1): 136-154. https://doi.org/10.2337/dc16-2042

29. • All of these factors combine to result in:
–  endoneurial blood flow and nerve hypoxia
with altered nerve function
– ATP depletion
– Cell necrosis and activation of genes involved
in neuronal damage
Pathogenic mechanisms of DPN

30. Microvascular Damage Leads to Diabetic
Peripheral Neuropathy (DPN)
Dyck PJ, Giannini C. J Neuropathol Exp Neurol. 1996;55:1181-1193. Sheetz MJ, King GL. JAMA. 2002;288:2579-2588.
Normal nerve
Damaged nerve
Occluded vasa
nervorum
Damage to
myelinated and
unmyelinated
nerve fibers

31. 31
Transmission of pain

32. First Pain Second Pain
Sharp Dull(unpleasant)
Initial Later
Brief Long – lasting
Transmission of pain

33. Neuropathic Pain Muscle/Skeletal Pain
Price SA. Pathophysiology: Clinical Concepts of Disease Processes. 5th ed; 1997; Galer BS et al. Diabetes Res Clin Pract. 2000;47:123-128
Classification of pain

34. Woolf and Mannion. Lancet 1999;353:1959-64
Neuropathic pain
Spontaneous pain Stimulus-evoked pain
Mechanisms
Metabolic Traumatic
Toxic
Ischemic
Hereditary
Compression
Infectious
Immune-related
Syndrome
Symptoms
Pathophysiology
Etiology
Nerve damage
Mechanisms of pain

35. Pain
Sleep
disturbances
Anxiety and
depression
Functional
impairment
Nicholson B, Verma S. Pain Med 2004; 5(Suppl 1):S9-27.
Neuropathic Pain Is Associated with Sleep
Disturbance, Anxiety and Depression

36. Impact of DPN

37. Spinal cord
Nociceptive 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.
Central
Sensitization
Ectopic
Discharge
Peripheral
Sensitization
Brain
Nerve lesion/disease
Central
Sensitization
Nerve lesion/disease
Mechanism-Based Pharmacological Treatment
of Neuropathic Pain

38. 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.
Nociceptive Vs. Neuropathic Pain

39. Wind up
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.
⚫ Central sensitization
⚫ Loss of inhibitory controls
Patho-physiology of Neuropathic Pain

40. 40
Pathophysiology

41. Na+ = sodium ion channels.
Injured nerves develop higher number of Na+ channels
Mechanisms of pain: Ectopic discharges

42. 42

44. 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
Role of a2d-Linked Calcium Channels in
Neuropathic Pain

46. Mechanisms of pain: Central reorganization

47. Baron, 2001
Mechanisms of pain: Central reorganization

48. Spinal cord
Nociceptive 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
Nerve lesion/disease
Central
Sensitization /
Perception
Nerve lesion/disease
Ascending
Input
Mechanism-Based Pharmacological Treatment
of Neuropathic Pain

49. Modulation of pain

50. 50
Modulation of pain

51. 51
Modulation of pain

52. AGENDA
Epidemiology
Clinical presentation
Pathogenic mechanisms
Diagnosis
Treatment
52

53. 53
D.D. of DPN
Rodica Pop-Busui,Diabetes Care 2017 Jan; 40(1): 136-154. https://doi.org/10.2337/dc16-2042
‫و‬ ‫السكر‬ ‫عندي‬ ‫أنا‬
‫منم‬ ‫رجليا‬
...
‫شششششش‬
..
‫ده‬
DPN

54. 54
D.D. of DPN
Rodica Pop-Busui,Diabetes Care 2017 Jan; 40(1): 136-154. https://doi.org/10.2337/dc16-2042
‫و‬ ‫السكر‬ ‫عندي‬ ‫أنا‬
‫منم‬ ‫رجليا‬
...
‫شششششش‬
..
‫ده‬
DPN

55. Baron, 2001
- Questionnaires for DN : ex:DN4
- Clinical ; History & Exam
- NCS
- QST: quantitative sensory testing
- Skin biopsy: assess (IENFD)
- Corneal Confocal Microscopy
Diagnosis of DPN

56. 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
Neuropathic Pain Screening Tools

57. *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
Sensitivity and Specificity of Neuropathic Pain
Screening Tools

58. LANSS Scale
Bennett. Pain. 2001;92:147-57

59. 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
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.
Interview of the patient

60. 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

61. 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
If the patient scores > 4; he may have neuropathic pain.
1 point
YES 0 point
NO

62. Adapted from Dyck PJ. Muscle Nerve 1988; 11:21-32.
Rating Description
0 No neuropathy
1 Subclinical diabetic peripheral neuropathy
2a
Clinical diabetic peripheral neuropathy with
symptoms, mild to moderate
2b
Clinical diabetic peripheral neuropathy insensate
foot, loss of feeling/negative symptoms
3 Disability/late stage
Diabetic Peripheral Neuropathy Severity Scale

63. AGENDA
Epidemiology
Clinical presentation
Pathogenic mechanisms
Diagnosis
Treatment
63

64. 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
Goals in the Treatment of Neuropathic Pain

65. Level of Risk
Most invasive
Least invasive
Interventional
techniques
Oral
medications
Topical
medications
Psychologic/
physical
approaches
Injections
Treatment should begin at an appropriate point
along the risk continuum
Management of Neuropathic pain

66. • Cognitive-behavioral strategies
– Meditation
– Biofeedback
– Relaxation therapy
• Physical rehabilitation
• Acupuncture
• TENS
Management of Neuropathic pain

67. Spinal cord
Nociceptive 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.
Central
Sensitization
Ectopic
Discharge
Peripheral
Sensitization
Brain
Nerve lesion/disease
Central
Sensitization
Nerve lesion/disease
Mechanism-Based Pharmacological Treatment
of Neuropathic Pain

68. Spinal cord
Nociceptive 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
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/disease
Nerve lesion/disease
Central
Sensitization
Nerve lesion/disease
Mechanism-Based Pharmacological Treatment
of Neuropathic Pain

69. 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
Role of a2d-Linked Calcium Channels in
Neuropathic Pain

70. 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

71. Nerve lesion
Spinal cord
Nociceptive afferent fiber
Verdu B et al. Drugs 2008; 68(18):2611-2632.
Descending
Modulation
Ascending
Input
Ectopic
discharge Transmission
Perception
Glial cell
Activation
Brain
Inhibiting synaptic reuptake of Serotonin and
NE enhances descending modulation of pain
SNRI

72. American Academy of Neurology
(AAN) Guidelines
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

73. European Federation of Neurological Societies
Guidelines
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.

74. 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
SNRI = serotonin-norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant
Dworkin RH et al. Mayo Clin Proc 2010; 85(3 Suppl):S3-14.
International Association for the Study of Pain (IASP)
Pharmacological Management of Neuropathic Pain : 1st line

75. 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
STEP
1
STEP
2
STEP
3
International Association for the Study of Pain (IASP)
Pharmacological Management of Neuropathic Pain

76. 76
Guidelines od ADA 2017

77. 77
Rodica Pop-Busui,Diabetes Care 2017 Jan; 40(1): 136-154. https://doi.org/10.2337/dc16-2042
Guidelines od ADA 2017

78. Sign/Symptom Treatment
Bladder dysfunction Voluntary urination;
catheterization
Retrograde ejaculation Antihistamine
Erectile dysfunction Sildenafil, tadalafil
Dyspareunia Lubricants; estrogen
creams
Genitourinary Autonomic Neuropathy

79. • Treatment
– Other causes of gastroparesis or enteropathy
should first be ruled out
– Gastroparesis - Small, frequent meals,
metoclopramide, erythromycin
– Enteropathy - loperamide, antibiotics, stool
softeners or dietary fiber
Gastrointestinal Autonomic Neuropathy

80. 80
Algorithm for management of DSPN
Rodica Pop-Busui,Diabetes Care 2017 Jan; 40(1): 136-154. https://doi.org/10.2337/dc16-2042

81. • Treatment
– Discontinue aggravating drugs
– Change posture (make postural
changes slowly, elevate bed)
– Increase plasma volume
– Mineralocorticoid fludrocortisone and a
high salt diet can be helpful in severe
cases
Cardiovascular Autonomic Neuropathy

82. • DPN are Highly prevalent Under-diagnosed entity
• Detailed H& E with basic Screening tools are essential
& useful tools for screening and Dx
• 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
82
Conclusions

83. THANK YOU
amrhasanneuro@kasralainy.edu.eg