Rodica PopBusui MD PhD Professor of Internal Medicine Metabolism Endocrinology and Diabetes University of Michigan Ann Arbor MI Disclosures Grant support to University of Michigan ID: 931825
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Slide1
Treatment of Neuropathic Pain in Diabetic Peripheral Neuropathy
Rodica Pop-Busui MD,
PhDProfessor of Internal Medicine,Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI
Slide2Disclosures
Grant support to University of Michigan:
Astra Zeneca
: Role Investigator Initiated project
Impeto
Pharmaceuticals
Slide3OBJECTIVES
Brief overview and significance of the clinical problemLearn simple and effective diagnostic steps
for patients with diabetic neuropathies (DN).
Understand how to treat the pain associated with DN.
Slide4IDF Diabetes Atlas 6
th edition: www.idf.org/diabetesatlas accessed February 2016
Global Prevalence of Diabetes Mellitus
Diabetic Neuropathies up to 50%
Diabetes Care 2010;33:2285-
2293
Diabetes Care 2006;29:1294-
1299
Diabetes Care 2014;37:2643-
2646
Diabetes Care 2013;36:3903-3908
May
be present in subjects with impaired glucose
tolerance
or metabolic syndrome
< 2% of the primary prevention cohort in the DCCT26-34% in the EDIC cohort after 26 years of T1DMCirculation, 2009, 119: 2886-93; Diabetes Care 2010, 33:1090-6
Two large T2DM cohorts: ACCORD and BARI-2D: prevalence rates of DN ~ 48-52%Diabetes Care,2010, 33:1578-84; Diabetes Care. 2010, 33:721-7; Diabetes Care 2013;36:3208-15
Up to 20% will develop painful neuropathy
Slide5Large Myelinated Fibers
Small Myelinated & Unmyelinated Fibers
Function
Pressure, balance
Nociception; protective sensation
Symptom
Numbness
Tingling
Poor balance
Pain:
Burning, electric shocksStabbing pain
Slide6Neuropathic Pain in DN
Hyperalgesia: exaggerated response to nonpainful
stimuli.Allodynia: pain evoked by contact, e.g., with socks, shoes, and
bedclothes.
Slide7Large Myelinated Fibers
Small Myelinated & Unmyelinated Fibers
Examination
Reflexes, proprioception
vibration
Thermal, pin-prick sensation
Diagnostic Test
(For
research only )
NCV Testing
(median,
sural, peroneal nerves )QST (vibration perception)
Historically “invisible”
S
kin Biopsy for IENFD,
Corneal confocal microscopy, QST (thermal discrimination, pain), Sudomotor function
Slide81. Appearance
Normal?
Yes (0)
No (1)
If no:
Deformities?
Dry Skin/Callus?
Infection?
Fissure?
2. Ulceration
Absent (0)
Present (1)
3. Vibration (c128hz)
Present (0)
Reduced (0.5)
Absent (1)
4. Ankle Reflex
Present (0)
Present with Reinforcement (0.5)
Absent (1)
Feldman et al, Diabetes Care,
1994
Herman, Pop-Busui and Feldman, Diabetic Medicine 2012
DPN is present if a score >2
DPN Diagnosis
Michigan Neuropathy Screening
Instrument
Slide9GRADINGThe
modified Likert scale (0=no pain;
10=worst possible pain) The visual analogue scale (VAS) McGill Pain Scale Short Form-2,
The Neuropathic Pain Symptom Inventory (NPSI), The Neuropathic Pain Scale The Neuropathy Total Symptom Score-6 (NTSS-6) Diabetic Neuropathy Pain
Slide10Context
- pain beliefs
- expectation
- placeboMood- depression- catastrophising
- anxiety
Cognitive Set
- hyper vigilance
- attention
- distraction
-
catastrophising
Chemical & Structure
-
neurodegeneration
- metabolic
eg opiodergic, dopaminergic- maladaptive plasticityInjury
- peripheral & central- sensitisationA or C nociceptive inputAmplified input
Pain
Experience
Nociceptive
Modulation
Nociception
leads to pain;
How much
pain is experienced depends upon
Slide11Consequences of Pain
Severe pain, polypharmacyPhysical disabilities
Low quality of life
Slide12How to Treat Neuropathic Pain in Diabetes?
Slide13Pain Diary: A 50-30% Reduction
is a Clinically Important Improvement*
N=2724
Clinically
important
change
PGIC=Patient’s Global Impression of
Change
Farrar, Pain 2001;94:149-158
Slide14Management
of Painful DPN
Bril
et al, Neurology 2011
Pharmacotherapy
Physical
Rehabilitation
Interventional Regional Anesthesia
Complementary/
Alternative
Lifestyle
Neurostimulatory
Psychological
Treatment Approaches
Slide15Treating Neuropathic Pain FDA approved:
Pregabalin* Duloxetine*
Tapentadol **
* Approved also by Health Canada, European Medicines Agency (EMA). ** It is an opioid,
Slide16Treatment of Painful DPN- AAN Recommendations, Bril et al, 2011
Slide17Finnerup et al , Lancet Neurology, 2015,14: 162-73
Evidence: Pharmacotherapy For Neuropathic Pain- Number Needed to Treat
Publication bias:Studies published in peer-reviewed journals reporting greater effects than did the unpublished studies
Slide18Drug Class
Agent
Dose
NNT Range 30-50% improvement **
Common AEs
Major AEs
Initial
Effective
Anticonvulsants
Pregabalin
25-75 mg, 1-3x/day
300-600 mg/day
3.3—7.7
Somnolence
Dizziness
Peripheral
edema
Headache
Ataxia
FatigueXerostomia
Weight
gain AngioedemaHepatotoxicityRhabdomyolysisSuicidal thoughts and behaviourSeizures after rapid discontinuationThrombocytopeniaHas 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
Slide19Drug Class
Agent
Dose
NNT Range 30-50
% improvement **
Common AEs
Major AEs
Initial
Effective
Antidepressants-
SNRI
Duloxetine
20-30 mg/day
60-120 mg/day
3.8 -11
Nausea
Somnolence
Dizziness
Constipation
Dyspepsia
DiarrheaXerostomia
Anorexia
Headache
DiaphoresisInsomniaFatigueDecreased libidoStevens-Johnson syndromeHepatotoxicityHypertensive crisisGI hemorrhageDeliriumMIArrhythmiasGlaucomaSuicidal thoughts Shift to maniaSeizures
Slide20Drug Class
Agent
Dose
NNT Range 30-50% improvement **
Common AEs
Major AEs
Initial
Effective
Anticonvulsants
Gabapentin
100-300 mg, 1-3x/day
1800-
3600 mg/day
3.3
-7.2
Somnolence
Dizziness
Ataxia
Fatigue
Weight gain
Stevens-Johnson syndrome
Suicidal thoughts and behaviour
Seizures after rapid discontinuationRequires gradual titration to the clinically effective dose,
Slide21Drug Class
Agent
Dose
NNT Range 30-50% improvement **
Common AEs
Major AEs
Initial
Effective
Antidepressants-
SNRI
Venlafaxine
37.5 mg/day
75-225 mg/day
5.2-8.4
Nausea
Somnolence
Dizziness
Constipation
Dyspepsia
Diarrhea
XerostomiaAnorexia
HeadacheDiaphoresis
Insomnia
FatigueDecreased libidoSame as duloxetine
Slide22Amitriptyline - A most recently updated Cochrane Review
based on evidence reported that in fact there is no good quality, unbiased evidence for a beneficial effect for amitriptyline .
These facts should be balanced in treatment decision making as only a minority of people will achieve satisfactory pain relief .
Tricyclic Agents Cochrane Database Syst Rev 2015;7:CD008242 There is an increased risk of myocardial ischemia and arrhythmogenesis associated with tricyclic agents
Secondary amines-
nortriptyline
and
desipramine
,
- Have a less troublesome side-effect profile
- Effectiveness appeared unrelated to the antidepressant effect
- Their use is preferable, particularly in the elderly and side-effect prone patients.
Slide23Opioid and atypical opioid analgesicsTramadol: - low affinity binding to the μ opiate
receptor - inhibits reuptake of norepinephrine and serotonin - analgesia only partially antagonized by naloxone.
Tapentadol: - centrally-acting analgesic through both μ-opioid receptor (MOR)
agonism and noradrenaline reuptake inhibition . Extended-release tapentadol was approved by FDA for the treatment of diabetic neuropathic pain based on data from 2 randomized- withdrawal, placebo-controlled Phase 3 trials
.
- Most
recent systematic review and meta-analysis by the
Special
Interest Group on Neuropathic
Pain
found the evidence of
the
effectiveness of
tapentadol inconclusive
Lancet Neurol 2015;14:162-173
Slide24Drug Class
Agent
Dose
NNT Range 50% improvement **
Common AEs
Major AEs
Initial
Effective
Opioids
Tramadol
50 mg, 1-2x/day
210 mg/day
3.1-6.4
Somnolence
Nausea
Vomiting
Constipation
Light headedness
Dizziness
Headache
Confusion
Seizures
Cardiac arrhythmias
HypertensionHypersensitivity reactionsStevens-Johnson syndromeTapentadolImmediate-Release:50-100 mg, 4-6x/dayExtended-Release:50 mg, 2x/dayImmediate-release:Day 1: 700 mg; after Day 1, 60 mg/dayExtended-release:50 mg, 2x/dayN/A
SomnolenceNauseaVomitingConstipationDizzinessRespiratory depression
Serotonin syndrome
Seizures
Hypertension
Neonatal Opioid Withdrawal syndrome
Slide25Treating Neuropathic Pain
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.
Slide26There 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.
Over the counter agents
Slide27Clinical Case 1
55 yo Hispanic female presents to the office for progressive severe, shooting pain from both feet up to her ankles, worse at nightClaims her skin is “on fire,” and she cannot tolerate even the touch of clothing or bed sheet
Reports no other known medical problems and was not taking any medications
Slide28Case 1 : Initial Physical Examination
Height: 5 ft 3 in; Weight: 182 lbs
BP: 145/90 mm Hg; Pulse: 72 beats/min
Abdominal obesityUnremarkable Head/Neck, Lungs, Cardiovascular, extremities
Slide29Case 1 : Initial Test Results
Comprehensive metabolic panel, TSH, CBC, folate, protein electrophoresis: WNL
Urine: Negative for protein
Random glucose: 138 mg/dLHbA1c: 6.4%
Slide30What is the most appropriate next diagnostic step?
Clinical Case 1
b) Assess vibration and pin-prick sensation
bilaterally starting at the great toes.
c) Assess light touch sensation with 10-
gmonofilament
on
dorsal
aspect of great toes bilaterally
.
d) Refer for nerve conduction studies and neurological
consultation
.
Assess
8-point light touch sensation with 10-g monofilament on plantar aspect of both feet.
Slide31Case 1: Diagnosis
What would you do next?
Slide32Few Take Home Messages DN is a very prevalent diabetes complication
It may be present at the time of T2D diagnosis and in patients w/ impaired glucose tolerance/metabolic syndromeIt can be easily diagnosed using:Appropriate history to unveil specific symptomsTargeted physical examination and simple instruments to confirm
neuropathy pattern (distal-to-proximal), symmetrical findings, and, if not, predominant sensory over motor deficitsSophisticated techniques and referrals to neurology are rarely needed, unless symptoms and signs are atypical .
Slide33Few 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.