Pearls in DPNP Management
奇美醫學中心
林高章醫師
神經科
全人醫療科
Spino-thalamic tract
International Association
for the Study of Pain
Spino-limbic tract
An unpleasant sensory and emotional experience associated
with actual or potential tissue damage or described in terms of
such damage.. (IASP 1979)
Re-definition of neuropathic Pain
Pain is arising as a direct consequence of a lesion or disease
affecting the somatosensory system
(R.D, Treede et al; Neurology, 2008)
Case scenario
46 y/o man with DM type II for 5 years, HbA1C:
9.0%
Acral burning pain for 6 months and nocturnal
severe
NE: no muscle atrophy or weakness
DTR: 1+, symmetrically in four limbs
DMvibration
with painful
polyneuropathy
normal
and
joint position(DPNP)
sense
symmetrically, mild decrease on pain and
thermal sensation
-------------------------------------------------------------------NCV: Declined CMAP and SNAP of upper+ lower.
H-reflex + F-wave: prolonged response.
Characteristic of DM neuropathic pain
complaints..
•
•
•
•
•
continuous burning pain
aching, cramping, tingling
paroxysmal shooting-electric pain
allodynia, hyperalgesia
paresthesia, hyperpathia
• Hyposthesia, numb, cold feeling
• Asthenia, weakness
Positive symptoms
Negative symptoms
Current Prescription Medication Use Among Patients Treated
for Neuropathic Pain
Medications with established efficacy represent a small proportion of prescriptions.
All other 2%
Anticonvulsants 13%
Local anesthetics 6%
Antidepressants/
mood stab. 4%
Tranquilizers 9%
Opioids 4%
Opioids 4%
NSAIDs 41%
AEDs 13%
Non-narcotic
analgesics 21%
IMS global prescription data 4Q 2003 (n=143 million prescriptions).
NSAIDs
(include COX-2)
41%
Trend Among Patients Treated for Neuropathic Pain
Opioids 30%
NSAIDs 22%
AEDs 12%
2010, Euro-market
Outline
1. Tight sugar control is better in DPNP?
2. Combination therapy is superior to single drug?
3. How economic burdens in treating DPNP?
4. SNRI with Effects, applications and ADEs
5. Different guideline in countries for DPNP.
1.Tight sugar control is better in DPNP?
Prevalence of Diabetic Neuropathy
as a proportion of all diabetics 20 years after diagnosis
(WHO)
No
neuropathy
10%
Asymptomatic
40%
Symptomatic
50%
(Diabetic care, 2004)
Prevalence of Painful Diabetic Neuropathy
(Schmader et al. Clin J Pain 2002)
A large communitybased diabetic
population in UK.
(Diabetic care, 2011)
Tight glycemic control had better prognosis
The Diabetes Control Complications Trial (DCCT) :
1. Tight glycemic control may result in 60% reduction in the
risk of developing clinical neuropathy
( NEJM 1993; Ann Neurol 1995)
American Diabetes Association ( ADA) recommendation:
1. In patients with type II DM, peak pc sugar < 180 mg%,
HbA1c < 7%;
2. In patients with type I DM (13-39 y/o), mean glucose level
should be <155mg%, HbA1c < 7.2%
(Diabetes care 2005)
Odd ratio to develop DPNP
(EURODIAB)
Metabolic syndrome play a key role in
pathogenesis of diabetic peripheral neuropathies
(Diabetic care, 2009)
2. Is combination therapy is better ?
(Cochrane review, 2012)
No significance but with non-inferiority
comparison in DLX group
SNRI and Pregabalin
(TEAE)
(Pain practice, 2013)
Medical Search From 1969~2011
Summary for management of DPNP (1969-2011)
• 58 well studies, 11833 patients analyzed.
• Pain reduction (NRS): Sodium valproate(-3.29); Sativex (1.67)
• Pain reduction (VAS): Pregabalin300mg (-21.88); Topiramate
(-3.09)
• Fluoxetine: the lowest risk of ADE (p>0.05)
• Oxycodone: the highest risk of ADE (RR=1.55, p<0.05)
• 50% pain reduction: alpha-lipoic acid (RR=2.25, p<0.05)
• 50% pain reduction: amitriptyline (RR=0.98, p>0.05)
• Discontinued rate: clustered around 0.8-1.5
1. The largest and complete studied
review in DPNP
2. Provide guidance to clinicians for
treatment selection
critics
1. Heterogeneity in study methods, outcomes,
dosing and duration
2. Unmet for clinical practice (in part)
3. Compared to placebo (mostly)
COMBO
(PAIN-2013, 154: 2616-2625)
Head to Head Comparison in COMBO
Whether combination therapy is better than mono-therapy of maximal
doses in patients not responding to standard dose of Duloxetine(60mg)
or Pregabalin (300mg)?
Summary in COMBO-DN study
>18 yrs, >3M, PS>=4
M-61, DM-11y, pain-2yrs
PS improve >2
Respond > 30-50%
404人
Duloxetine
60mg/d
看看複合治療是否更佳
療效佳
8 wks
407人
Pregabalin
300mg/d
不佳
8 wks
Intensive study
End Point
BPI-MSF
NPSI
HADS
>50% RR
TEAE
•BPI-MSF-brief
pain inventorymodified SF(10)
•NPSIneuropathic pain
scale inventory
•HADS-hospital
anxiety and
depression scale
•TEAE-timeemergent
adverse effect
339人
double doses
for either drug
combine
therapy
(PAIN-2013, 154: 2616-2625)
Demographics
Basic information
Results
Responders
D>P (<0.01*)
Non-responders
C>H (>0.05)
Outcomes in responders/ non-responders
Summary in COMBO-DN study
* significant, p< 0.05
PS improve >2
Respond > 30-50%
404人
Duloxetine
60mg/d
看看複合治療是否更佳
療效佳
8 wks
407人
Pregabalin
300mg/d
不佳
8 wks
Intensive study
339人
double doses
for either drug
combine
therapy
End Point
BPI-MSF
NPSI
HADS
>50% RR
TEAE
Results
*D>P
*D>P
*D>P
*D>P
*Nausea D>P
*Dizzy P>D
Drowsy P=D
Drop-out P=D
3. How economic burdens in treating DPNP?
(Dove press, 2013)
Drug-selection burden
and co-morbid burden
In DPNP
(Dove press, 2013)
範例: TWN-(15,000 X30 X 1,500,000 X25%=1,687 X1011)=1687億NT/年
4. SNRI with effects/ADE and applications
2013
台灣
衛生署
Duloxetine Reduces 24-Hour Average Pain Severity in DPNP
Mean Change in 24-hour
Average Pain Severity Score
Improvement
Pooled data from 3 studies
0.0
Placebo
(n=330)
-0.5
Duloxetine
20 mg QD
(n=111)
*
-1.0
-1.5
*
-2.0
*
*
-2.5
*
*
-3.0
-3.5
0
1
2
3
Duloxetine
60 mg QD
(n=334)
*
* * * *
* * *
*
*
* * *
* * *
* *
4
5
6
7
8
9
10
11
12
Duloxetine
60 mg BID
(n=333)
* P ≤ .05
13
Weeks
♦ A reduction of approximately 2 points or 30% represents a clinically
important difference (mean baseline score was 5.83)
Poster: Raskin J, et al. 25th American Pain Society (APS) Annual Scientific Meeting; San Antonio, TX; May 3–6, 2006.
vs placebo
MMRM
COMBO study
(TEAE)
(PAIN-2013, 154: 2616-2625)
5. Different guideline among countries in DPNP
Common prescribed drugs in DPNP
健保條件:
NCV proved
VAS>=4
60mg at most
(Mayo Clinic, 2006)
1st line medications in neuropathic pain
• ADA (2005, 2009): TCAs (amitriptyline, imipramine), duloxetine
• CPS (2009): TCAs, gabapentin, pregabalin
• AACE (2007): duloxetine, pregabalin, TCAs, capsaicin, AEDs
• EFNS (2006):TCAs, gabapentin, pregabalin
• Cochrane review (2004, 2005): TCAs; (2007): TCAs, venlafaxine
• AAN (2004): amitriptyline, nortriptyline, desipramine, maprotiline,
gabapentin, pregabalin, topical lidocaine, opioids
• IASP(2007): TCAs, SNRIs, gabapentin, pregabalin
EFNS guideline (2010-revised)
1st line
Duloxetine
Gabapentin
Pregabalin
TCA
Venlafaxine ER
2nd line
Opioids
Tramadol
Summary of recommendation for DPNP treatment (AAN, 2011)
US FDA approved (2009): Duloxetine and Pregabalin
SNRI
Play a Major Role in Pain Modulation
♦ Neuropathic pain is
associated with increased
excitation and decreased
inhibition of ascending
pain pathways
♦ Descending pathways modulate
ascending signals
♦ NE and 5-HT are key
neurotransmitters in descending
inhibitory
pain pathways
5-HT
NE
♦ Increasing the availability of NE
and 5-HT may promote pain
inhibition centrally
1. Figure adapted from: Fields HL and Basbaum AI. Central nervous system mechanisms of pain modulation. In: Wall PD and Melzack R,
eds. Textbook of Pain, 4th ed. Churchill Livingstone: London, UK;1999,310.
SNRI
•
•
•
•
•
•
Safety and effective in major depression and DPNP
Less and few ADE than TCA
Effective fast than SSRI and TCA (or tetracyclic~ludiomil)
Contraindication- MAOI, narrow-angled glaucoma
Be aware of use in younger adults or teen age
No influence on BW, sugar change, or BP
AAN:75~225mg/d
EFNS:150~225mg
AAN: 60-120mg
EFNS:60-120mg
=>secondary use to
duloxetine
titrate from 30mg/d to
60mg (1wk)
Eflexor ER
Cymbalta
Taiwan guidance for total pain management-2010
• Painful polyneuropathy (PPN)
-TCA、Gabapentin、*Pregabalin (A)
-SNRI (*^duloxetine、venalfaxine) 、tramadol、lamotrigine
(B)
(Carbamazepine (C )
-Capsaicin、mexiletine、oxcarbazepine、SSRI、topiramate
(ineffective, level A)
台灣
*衛生署適應症
^健保局適應症
Take Home Message
1. DPNP is a common disorder encompassing
15-25% of whole diabetic patients.
2. Tight sugar control is inadequate to AVOID neuropathy on
EBM without co-morbid risks control at the same time.
3. The licensed medications in Taiwan are Duloxetine and
Pregabalin, with which should be tailored to individuals
depending on risks-versus-benefits.
4. Empirical combination therapy may be beneficial in nonresponders to single drug treatment.
5. Education and explanation are always mandatory importance.
Thank you for listening
QST for DPNP
(AACE-2013)
NCV has limitation to small fiber or
sensory neuropathy….
If NCV is not done, the probable or possible Dx of
DPNP is made.
If NCV is done with normal data, a validated
measure (QST) of small fiber neuropathy is needed.
QST-quantitative sensory tests
(Diabetic care, 2010)
(Pain, 2013)
Estimating the severity of DPN