pearls in dpnp management 奇美醫學中心 林高章醫師 神經科 全人醫療科
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Pearls in DPNP Management
奇美醫學中心
林高章醫師
神經科全人醫療科
International Association for the Study of Pain
An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.. (IASP 1979)
Pain is arising as a direct consequence of a lesion or disease affecting the somatosensory system
(R.D, Treede et al; Neurology, 2008)
Re-definition of neuropathic Pain
Spino-thalamic tract
Spino-limbic tract
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
normal vibration and joint position sense
symmetrically, mild decrease on pain and thermal sensation
--------------------------------------------------------------------
NCV: Declined CMAP and SNAP of upper+ lower.
H-reflex + F-wave: prolonged response.
DM with painful polyneuropathy (DPNP)
Case scenario
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
Anticonvulsants 13%
Antidepressants/ mood stab. 4%
Opioids 4%
NSAIDs (include COX-2) 41%
Non-narcotic analgesics 21%
Tranquilizers 9%
Local anesthetics 6%
All other 2%
Medications with established efficacy represent a small proportion of prescriptions.
IMS global prescription data 4Q 2003 (n=143 million prescriptions).
Opioids 4%NSAIDs 41%AEDs 13%
Trend Among Patients Treated for Neuropathic Pain
2010, Euro-market
Opioids 30%NSAIDs 22%AEDs 12%
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 Prevalence of Diabetic NeuropathyDiabetic Neuropathyas a proportion of all diabetics 20 years after diagnosisas a proportion of all diabetics 20 years after diagnosis
Noneuropathy
10%
Asymptomatic40%
Symptomatic50%
(Diabetic care, 2004)
(WHO)
Prevalence of Prevalence of Painful Painful Diabetic NeuropathyDiabetic Neuropathy
(Schmader et al. Clin J Pain 2002)
A large community- based 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 ri
sk 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%, H
bA1c < 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
critics
1. Heterogeneity in study methods, outcomes, dosing and duration
2. Unmet for clinical practice (in part)3. Compared to placebo (mostly)
1. The largest and complete studied review in DPNP
2. Provide guidance to clinicians for treatment selection
(PAIN-2013, 154: 2616-2625)
COMBO
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
404 人Duloxetine
60mg/d
407 人Pregabalin300mg/d
8 wks
BPI-MSFNPSIHADS
>50% RRTEAE
End Point
療效佳
不佳
double dosesfor either drug
combinetherapy
8 wks
PS improve >2Respond > 30-50%
>18 yrs, >3M, PS>=4 M-61, DM-11y, pain-2yrs
Intensive study
339 人
看看複合治療是否更佳
(PAIN-2013, 154: 2616-2625)
•BPI-MSF-brief pain inventory- modified SF(10)•NPSI-neuropathic pain scale inventory•HADS-hospital anxiety and depression scale•TEAE-time-emergent adverse effect
Demographics
Basic information
Results
RespondersD>P (<0.01*)
Non-respondersC>H (>0.05)
Outcomes in responders/ non-responders
Summary in COMBO-DN study
404 人Duloxetine
60mg/d
407 人Pregabalin300mg/d
8 wks
BPI-MSFNPSIHADS
>50% RRTEAE
End Point Results
*D>P*D>P*D>P*D>P
*Nausea D>P*Dizzy P>DDrowsy P=DDrop-out P=D
療效佳
不佳
double dosesfor either drug
combinetherapy
8 wks
PS improve >2Respond > 30-50%
Intensive study
339 人
看看複合治療是否更佳
* significant, p< 0.05
3. How economic burdens in treating DPNP?
(Dove press, 2013)
Drug-selection burdenand 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
台灣衛生署
2013
******
*
****
*
Poster: Raskin J, et al. 25th American Pain Society (APS) Annual Scientific Meeting; San Antonio, TX; May 3–6, 2006.
Duloxetine Reduces 24-Hour Average Pain Severity in DPNPDuloxetine Reduces 24-Hour Average Pain Severity in DPNP
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0 1 2 3 4 5 6 7 8 9 10 11 12
Placebo(n=330)
Duloxetine20 mg QD(n=111)
Duloxetine60 mg QD(n=334)
Duloxetine60 mg BID(n=333)
** P ≤ .05vs placebo
MMRMWeeks
Imp
rove
men
t
*
**
* * * * * * * *
Mea
n C
han
ge
in 2
4-h
ou
rA
vera
ge
Pai
n S
ever
ity
Sco
re
♦ A reduction of approximately 2 points or 30% represents a clinically important difference (mean baseline score was 5.83)
13
Pooled data from 3 studies
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>=460mg 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)
2nd lineOpioids
Tramadol
1st lineDuloxetineGabapentinPregabalin
TCAVenlafaxine ER
Summary of recommendation for DPNP treatment (AAN, 2011)
US FDA approved (2009): Duloxetine and Pregabalin
♦ Neuropathic pain is associated with increased excitation and decreased inhibition of ascending pain pathways
♦ Descending pathways modulate ascending signals
♦ NENE and 5-HT5-HT are key neurotransmitters in descending inhibitory pain pathways
♦ Increasing the availability of NENE and 5-HT5-HT may promote pain inhibition centrally
SNRI SNRI Play a Major Role in Pain ModulationPlay a Major Role in Pain Modulation
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.
5-HT5-HT
NENE
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/dEFNS:150~225mg
=>secondary use to duloxetine
AAN: 60-120mgEFNS:60-120mg
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 encompassing15-25% 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 non-responders 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.
(Diabetic care, 2010)QST-quantitative sensory tests
(Pain, 2013)
Estimating the severity of DPN