Treatment of Neuropathic Pain in Diabetic Peripheral Neuropathy

Rodica Pop-Busui, MD, PhD

Saturday, March 5, 2016
9:30 a.m. – 10:15 a.m.

Diabetic neuropathies (DNs) are the most prevalent chronic complications of diabetes, with
multiple manifestations, consistent risk factors, and complex pathogenetic mechanisms. There
are multiple types of DN and each presents with a unique array of symptoms and clinical signs,
but distal symmetrical polyneuropathy is the most prevalent form. Screening for symptoms and
signs of DN is critical in clinical practice to enable early intervention and prevent late
complications . Neuropathic pain may be the first symptom that prompts patients to seek
medical care and is present in up to 25% of individuals with DN. Characteristically, the pain is
burning, lancinating, tingling, or shooting (electric shock-like), with paresthesias, occurring in
varying combinations, and is typically worse at night. Despite the recent major advances in
elucidating the pathogenesis of diabetic neuropathy, there remains a lack of treatment options
that effectively target the natural history of DNs. However, pharmacological management for
pain using drugs of different classes is available.

Several recent guidelines and systematic reviews have addressed the evidence base for the
treatment of neuropathic pain and agents with evidence of effectiveness for DN pain will be
discussed.
 Disclosures

Grant support to University of Michigan:

Astra Zeneca: Role Investigator Initiated project
Treatment of Neuropathic Pain in Diabetic Impeto Pharmaceuticals

Peripheral Neuropathy
Rodica Pop-Busui MD, PhD
Professor of Internal Medicine,
Metabolism, Endocrinology and Diabetes,
University of Michigan, Ann Arbor, MI

Case 1 Mrs. R.S.’s Initial Physical Examination

 55 yo Hispanic female presents to the office for
progressive severe, shooting pain from both feet up to her
ankles, worse at night
 Claims her skin is “on fire,” and she cannot tolerate even
the touch of clothing or bed sheet
 Height: 5 ft 3 in; Weight: 182 lbs
 BP: 145/90 mm Hg; Pulse: 72 beats/min
 Abdominal obesity
 Unremarkable Head/Neck, Lungs, Cardiovascular,
extremities

 Reports no other known medical problems and was not

taking any medications

Mrs. R.S.’s Test Results

Mrs. R.S.: Test Results
• Fasting lipid profile:
• Comprehensive metabolic panel, TSH, CBC, folate, – Total cholesterol: 230 mg/dL
protein electrophoresis: WNL – LDL-C: 140 mg/dL
• Urine: Negative for protein – HDL-C: 40 mg/dL
– Triglycerides: 256 mg/dL
• Random glucose: 138 mg/dL
• HbA1c: 6.4% • Oral Glucose Tolerance Test
– Fasting blood glucose (FBG): 118 mg/dL
– 2-h post glucose load: 194 mg/dL
 The Peripheral Nervous System is Complex

Large Myelinated Fibers Small Myelinated &

Unmyelinated Fibers

Function Pressure, balance Nociception; protective sensation

Numbness Pain:
Symptom Tingling Burning, electric shocks
Poor balance Stabbing pain

Reflexes, proprioception Thermal, pin-prick sensation

Exam vibration

NCV Testing Historically “invisible”

Diagnostic Test (median, sural, peroneal Skin Biopsy for IENFD,
(For research nerves ) Corneal confocal microscopy,
Small myelinated QST (thermal, pain),
Large myelinated only )
fiber QST (vibration perception) Sudomotor function (Neuropad,
fiber Unmyelinated Sudoscan)
fibers

Diabetic Peripheral Neuropathy DPN Diagnosis Michigan Neuropathy Screening

Instrument

1. Appearance
Normal? Yes (0) No (1) If no:
Deformities?
Dry Skin/Callus?
Infection?
Fissure?
2. Ulceration Absent (0) Present (1)

Large myelinated 3. Vibration (c128hz) Present (0) Reduced (0.5) Absent (1)
fiber
4. Ankle Reflex Present (0) Present with Absent (1)
Reinforcement (0.5)
Small myelinated
fiber Unmyelinated Feldman et al, Diabetes Care, 1994
fibers DPN is present if a score >2 Herman, Pop-Busui and Feldman, Diabetic
Medicine 2012

Diabetic Neuropathy Pain

Mrs. R.S.’s Examination
Neuropathic pain

Neurological Hyperalgesia: exaggerated

response to painful stimuli
• Intact light touch and vibration
• Symmetrical impairment in pinprick and in cold Allodynia : pain evoked by
temperature discrimination up to ankle contact, e.g., with socks,
shoes, and bedclothes.

Claims her skin is “on fire,” and she cannot tolerate

even the touch of clothing or bed sheet Document that is due to DN!
 Diabetic Neuropathy Pain
Nociception leads to pain; How much pain
is experienced depends upon
GRADING  Context  Mood
- pain beliefs Pain - depression
- expectation Experience - catastrophising
- placebo - anxiety
The modified Likert scale (0=no pain; 10=worst
possible pain)  Cognitive Set
 Chemical & Structure
The visual analogue scale (VAS) - neurodegeneration
- hyper vigilance
- metabolic eg
- attention
opiodergic,
McGill Pain Scale Short Form-2, - distraction
dopaminergic
- catastrophising
The Neuropathic Pain Symptom Inventory (NPSI), - maladaptive plasticity
The Neuropathic Pain Scale  Injury
The Neuropathy Total Symptom Score-6 (NTSS-6) - peripheral &
A or C nociceptive
central
- sensitisation
Nociceptive input

Modulation Amplified input

Consequences of Pain

How to Treat Neuropathic Pain in Diabetes?

Severe pain, polypharmacy
Physical disabilities
Low quality of life

Pain Diary: A 30% Reduction Management of Painful DPN

is a Clinically Important Improvement*
Neurostimulatory Interventional
30 Pharmacotherapy Regional
% change in mean pain score

20
10 Anesthesia
0
-10 Clinically
important
-20
change
-30
-40 Treatment Approaches
-50 Physical
-60
-70 Rehabilitation
-80
Very Much Minimally No Change Minimally Much Very Much
Complementary/
Worse / Much Worse Improved Improved Improved Alternative
Worse
PGIC category
Psychological Lifestyle
PGIC=Patient’s Global Impression of Change N=2724

Farrar, Pain 2001;94:149-158 Bril et al, Neurology 2011

 Treating Neuropathic Pain

Only 2 medications, pregabalin and duloxetine, have received

regulatory approval for the treatment of neuropathic pain in
diabetes by the United States Federal Drug Agency (FDA),
Health Canada, and the European Medicines Agency (EMA).

The opioid, tapentadol, has regulatory approval in the United

States and Canada.

Treatment of Painful DPN- AAN Recommendations, Bril et al, 2011

Drug Class Agent Dose NNT Range Common AEs Major AEs
Evidence: Pharmacotherapy For Neuropathic
Initial Effective 30-50%
Pain- Number Needed to Treat improvement
**

Anticonvulsants
Publication bias:
25-75 mg, 300-600 • Somnolence  Angioedema
1-3x/day mg/day 3.3—7.7 • Dizziness  Hepatotoxicit
Studies published in peer- Pregabalin
• Peripheral y
reviewed journals reporting edema  Rhabdomyoly
greater effects than did the • Headache sis
unpublished studies • Ataxia  Suicidal
• Fatigue thoughts and
• Xerostomia behaviour
• Weight gain  Seizures after
rapid
discontinuatio
n
 Thrombocyto
penia

Has linear and dose proportional absorption in the therapeutic dose range (150-600 mg/day) due to a non-
saturable transport mechanism , minimal titration, more rapid action
Finnerup et al , Lancet Neurology, 2015,14: 162-73

Drug Class Agent Dose NNT Range Common AEs Major AEs
Drug Class Agent Dose NNT Range Common AEs Major AEs
Initial Effective 30-50%
Initial Effective 30-50% improvement
improvement **
**
Antidepressants- SNRI

Anticonvulsants 20-30 60-120 mg/day 3.8 -11  

Duloxetine Nausea Stevens-
100-300 1800-3600 • Somnolence  Stevens- mg/day  Somnolence Johnson
Gabapentin mg, 1- mg/day 3.3-7.2 • Dizziness Johnson  Dizziness syndrome
 Constipation  Hepatotoxicity
3x/day • Ataxia syndrome
 Dyspepsia  Hypertensive
• Fatigue  Suicidal
 Diarrhea crisis
thoughts and  Xerostomia  GI hemorrhage
behaviour  Anorexia  Delirium
 Seizures  Headache  MI
after rapid  Diaphoresis  Arrhythmias
discontinuati  Insomnia  Glaucoma
 Fatigue  Suicidal
on
 Decreased thoughts Shift to
libido mania
 Seizures

Requires gradual titration to the clinically effective dose,

 Drug Class Agent Dose NNT Range Common AEs Major AEs Tricyclic Agents (NNT ~ 2.5)
Initial Effective 30-50%
improvement
Amitriptyline
**
- A most recently updated Cochrane Review based on evidence reported
Antidepressants- SNRI that in fact there is no good quality, unbiased evidence for a beneficial
 
effect for amitriptyline .
Venlafaxine 37.5 75-225 mg/day 5.2-8.4 Nausea Same as
mg/day  Somnolenc duloxetine
e These facts should be balanced in treatment decision making as only a minority
 Dizziness of people will achieve satisfactory pain relief .
 Constipatio
n
 Dyspepsia There is an increased risk of myocardial ischemia and arrhythmogenesis
 Diarrhea associated with tricyclic agents
 Xerostomia
 Anorexia Secondary amines- nortriptyline and desipramine,
 Headache
 Diaphoresis
- Have a less troublesome side-effect profile
 Insomnia
 Fatigue - Effectiveness appeared unrelated to the antidepressant effect
 Decreased - Their use is preferable, particularly in the elderly and side-effect
libido prone patients.
Cochrane Database Syst Rev 2015;7:CD008242

Drug Class Agent Dose NNT Range Common AEs Major AEs

Opioid and atypical opioid analgesics Initial Effective 50%

improvement
**

Tramadol: - low affinity binding to the μ opiate receptor Opioids

- inhibits reuptake of norepinephrine and serotonin
- analgesia only partially antagonized by naloxone. Tramadol 50 mg, 1- 210 mg/day 3.1-6.4  Somnolence  Confusion
2x/day  Nausea  Seizures
 Vomiting  Cardiac
Tapentadol: - centrally-acting analgesic through both μ-opioid receptor (MOR)  Constipation arrhythmias
 
agonism and noradrenaline reuptake inhibition . Light Hypertension
headedness  Hypersensitivity
Extended-release tapentadol was approved by FDA for the treatment  Dizziness reactions
of diabetic neuropathic pain based on data from 2 randomized-  Headache  Stevens-
withdrawal, placebo-controlled Phase 3 trials . Johnson
- Most recent systematic review and meta-analysis by the syndrome
Immediate- Immediate- N/A   Respiratory
Special Interest Group on Neuropathic Pain found the evidence of Tapentadol Release: release: 
Somnolence
Nausea depression

the effectiveness of tapentadol inconclusive 50-100 mg, 4-
6x/day
Day 1: 700 mg; after
Day 1, 60 mg/day 
Vomiting
Constipation
 Serotonin
syndrome
 Dizziness  Seizures
Extended- Extended-release:  Hypertension
Release: 50 mg, 2x/day  Neonatal Opioid
50 mg, Withdrawal
2x/day syndrome
Lancet Neurol 2015;14:162-173

Treating Neuropathic Pain Over the counter agents

There is modest evidence in support of topical agents (capsaicin, lidocaine

patches).
No compelling evidence exists in support of glycemic control or life-style
management as therapies for neuropathic pain in diabetes or pre-
diabetes.
No compelling evidence exists in support of interventional/regional anesthesia,
neurostimulatory, or complementary/alternative medicine.
There are multiple over the counter agents (herbal supplements,
vitamins, minerals) that are occasionally recommended for
neuropathic pain.
Currently, the available evidence is questionable re benefits and
given the possibility for harm (associated with lack of
consistency in regulation of active substance or the fillers),
prescribing these agents in the absence of evidence obtained
from properly designed randomized clinical trials is not
recommended.
 Is pain due to DSPN confirmed? No/Not sure Few Take Home Messages
Refer to Neurology/Pain
Clinic  DN is a very prevalent diabetes complication
Yes
Assess comorbidities, potential for AEs,,
* It may be present at the time of T2D diagnosis and in patients w/
drug interactions, costs to select initial impaired glucose tolerance/metabolic syndrome
therapy from the 3 choices below

 It can be easily diagnosed using:

* Voltage gated α2-δ ligand (pregabalin,
gabapentin)
** Serotonin-norepinephrine reuptake
inhibitor (duloxetine, venlafaxine)
No clinically meaningful effect
Secondary amine Tricyclic
Antidepressant (nortriptiline
Desipramine)
* Appropriate history to unveil specific symptoms
* Targeted physical examination and simple instruments to confirm
neuropathy pattern (distal-to-proximal), symmetrical findings, and, if
not, predominant sensory over motor deficits

 Sophisticated techniques and referrals to neurology are rarely needed,

a. Switch to another agent from above b. Try combining agents from above
c. May add tramadol or tapentadol unless symptoms and signs are atypical .
if a and b fail

No clinically meaningful effect/ Refer to Pain Clinic

Not tolerated

Few Take Home Messages

 Only 2 medications, pregabalin and duloxetine, have received regulatory
approval for the treatment of neuropathic pain in diabetes by the United
States Federal Drug Agency (FDA), Health Canada, and the European
Medicines Agency (EMA).

 The opioid, tapentadol, has regulatory approval in the United States and
Canada, but evidence regarding its effectiveness is inconclusive.

 Despite the demonstrated effectiveness of opioids in the treatment of

neuropathic pain, there are ongoing concerns with respect to abuse,
addiction, diversion, and other psychosocial issues.

 For these reasons, opioids should not be used before failure of other agents
that do not have these associated concerns and referral to a pain clinic
should be considered before opioid use.