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

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*

**

* * * * * * * *

Mea

n C

han

ge

in 2

4-h

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♦ 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