dr eric decloedt fccp (sa) mmed (clin pharm) division of ... · diabetic peripheral neuropathy...

Dr Eric Decloedt

FCCP (SA) MMed (Clin Pharm)

Division of Clinical Pharmacology

INCISION

Nociceptors

depolarise

Synaptic transmission:

Facilitate Inhibit

Substance P DA, NA, 5HT

Glutamate Opioids

Nerve growth factor GABA

Cannabinoids

Intensity &

Location Emotional

Cause of

symptoms

Time course Outcome Features

Acute pain Known Short-term Recovery

anticipated

Essential to

survival

Chronic pain Unknown Indeterminate Complete

remission often

not possible

Pathological

Site Psych

comorbidity

Examples

Peripheral Inflammation or

damage in

periphery

Minor Osteoarthritis

Rheumatoid arthritis

Cancer

Central Disturbance in

pain processing

Major Fibromyalgia

Spinal cord injury

Poststroke pain

Multiple sclerosis

Mixed Both Either Diabetic peripheral neuropathy

Postherpetic neuralgia

Trigeminal neuralgia

Phantom limb pain

Baron et al Nature Clinical Practice Neurology 2006

Spinothalamic projection neuron

Inhibitory neuron

Baron et al Nature Clinical Practice Neurology 2006

Zeilhofer et al Annu Rev Pharmacol Toxicol 2012

Jaggi et al Brain Research 2011

Anterior cingulate

cortex

Rostral ventromedial

medulla

Periaqueductal gray

Moisset et al Neuroimage 2007

anterior

cingulate

cortex

prefrontal

cortex

primary

somatosensory

cortex

secondary

somatosensory

cortex

Borsook et al Curr Pain Headache Rep 2011

Gottschalk et al Am Fam Physician 2001

Challenging! ◦ Complex disease spectrum with heterogeneity

◦ Variability in studies

Outcome measures

Number of participants

Treatment duration

Quality of design

◦ Data manipulation & lack of transparency

◦ Expert panel of guidelines ?truly independent & no

conflict of interest

Landefeld et al NEJM 2009

Overall the AD with best efficacy evidence

Especially amitriptyline ◦ NNT 3.6 (95% CI 3.0 – 4.5)

◦ Major NNH 28 (95% CI 17 – 68)

◦ Minor NNH 6 (95% CI 4.2 – 10.7)

Efficacy mainly demonstrated for ◦ Diabetic neuropathy

◦ Post herpetic neuralgia

Saarto et al Cochrane Database Syst Rev 2012

Inexpensive

Pain response expected ± 7 days – titrate weekly

Low dose analgesic vs higher dose AD ◦ ? Treatment of choice in comorbid depression

Cardiovascular (screening ECG)

Anticholinergic side effects

Sedation

CYP2D6 DDI

Paucity of data

2 RCT available ◦ n=101 & n=145

◦ Amitriptyline 75 – 100 mg per day

◦ Study A: bias - all not randomized, not true placebo

controls

◦ Study B: terminated early by DSMB - lack of efficacy

No evidence of efficacy for TCA or any other AD

Shlay et al JAMA 1998

Kieburtz et al Neurology 1998

Duloxetine ◦ Diabetic peripheral neuropathy

NNT 6 (5 – 10)

◦ Fibromyalgia

NNT 8 (5 – 17)

◦ Major NNH 17 (12 – 50)

Venlafaxine ◦ Diabetic peripheral neuropathy

◦ Mixed or negative study results:

post-mastectomy pain, postherpetic neuralgia, other

?lower doses used in some

Rowbotham et al Pain 2004

Sindrup et al Neurology 2003

Bair et al Postgrad Med 2011

Lynn et al Cochrane Database Syst Rev 2010

Depression and NP treatment doses similar

Duloxetine registered for diabetic NP

Cardiovascular side-effects (venlafaxine) ◦ Study setting: 5% developed ECG changes

CYP2D6 DDI

Dose adjust in renal and hepatic impairment

(duloxetine)

Response expected within 2 weeks


Limited data for effectiveness

Diabetic neuropathy & somatoform disorder :

superior to placebo ◦ Fluoxetine, paroxetine, citalopram, escitalopram

Insufficient data reported to calculate NNT

Compared to TCAs: less pain relief ◦ Imipramine > paroxetine

◦ Desipramine > amitriptyline > fluoxetine

Maina et al J Clin Psych 2002

Sindrup et al Pain 1990


Ciaramella et al Minverva Anestesiologica 2000

Diabetic

PN

HIV

PN

Post-

herpetic

PN

Central

pain

Fibro-

myalgia

NNT

NNH

(Major)

Antidepressants

TCAs

SNRIs

SSRIs

11+

5+

3+/1-

1+/1-

4+

1-

2+

1-

1+

3.6 (3.0 – 4.5)

6.0 (5 – 10)

insufficient

28 (17 – 68)

17 (12 – 50)

Insufficient

Axonal transmission inhibition phenytoin, carbamazepine, valproate, lamotrigine

Decreased release of glutamate Gabapentin, pregabalin

AED mechanism of action

Bialer et al Nature Reviews 2010

Phenytoin ◦ No evidence

Sodium valproate ◦ No convincing efficacy evidence

Lamotrigine ◦ No convincing efficacy evidence

Birse et al Cochrane Database Syst Rev 2012

Gill et al Cochrane Database Syst Rev 2011

Wiffen et al Cochrane Database Syst 2011

Carbamazepine ◦ 5 good quality RCTs, n=298

◦ Efficacy evidence

Trigeminal neuralgia, DPN, postherpetic neuralgia, central

stroke pain

NNT 2 (1.6 – 2.5)

Limited: short duration, limited size, poorly defined outcomes

NNH 2.6 (2.1 – 3.5)

Inconsistently reported

Wiffen et al Cochrane Database Syst Rev 2011

Carbamazepine ◦ Auto-induction – dose increase at 3 weeks

Omitted in most studies

◦ Cutaneous skin reactions

5-10% Asians: HLA-B*1502 → SJS

Gabapentin ◦ Efficacy evidence: diabetic neuropathy, post herpetic

neuralgia, mixed neuropathic pain

◦ > 30% improvement compared to placebo

NNT 5.8 (4.8 – 7.2)

◦ > 50% improvement compared to placebo

NNT 6.8 (5.6 – 8.7)

◦ Major NNH 32 (19 – 100) & minor NNH 6.6 (5.3 – 9)

Moore et al Cochrane Database Syst Rev 2011

Pregabalin ◦ Best NNT for 50% improvement at max dose (600 mg)

Postherpetic neuropathy 3.9 (3.1 – 5.1)

Peripheral diabetic neuropathy 5.0 (4.0 – 6.6)

Central neuropathic pain 5.6 (5.3 – 14)

Fibromyalgia 11 (7.1 – 21)

Usual dose 75 mg bd, increased to 150 mg bd

Adverse events dose related: Major NNH 5 - 10

Moore et al Cochrane Database Syst Rev 2011

Gabapentin ◦ Absorbed by an active and saturable transport system:

careful dose titration

◦ Not metabolized & no enzyme induction

Pregabalin ◦ Registered for neuropathic pain

◦ Linear pharmacokinetics – easier dosing

◦ Not metabolized & no enzyme induction

Diabetic

PN

HIV

PN

Post-

herpetic

PN

Central

pain

Fibro-

myalgia

NNT

NNH

(Major)

Antidepressants

TCAs

SNRIs

SSRIs

11+

5+

3+/1-

1+/1-

4+

1-

2+

1-

1+

3.6 (3.0 – 4.5)

6.0 (5 – 10)

insufficient

28 (17 – 68)

17 (12 – 50)

Insufficient

Anticonvulsants

Carbamazepine

Gabapentin

Pregabalin

3+/2-

3+/3-

5+

1-

1-

5+

5+

1-

1+/1-

2+

1+

4+

2.0 (1.6 – 2.5)

5.8 (4.8 – 7.2)

3.9 (3.1 – 5.1)

2.6 (2.1 – 3.5)

32 (19 – 100)

5 – 10

Efficacy evidence Diabetic peripheral neuropathy

Postherpetic neuropathy

Painful polyneuropathy

Tramadol ◦ 50% pain relief NNT 3.8 (2.8 – 6.3)

◦ Major NNH 8.3 (5.6 – 1.7)

Morphine, oxycodone, methadone ◦ 50% pain relief NNT 2.6 (28 to 70 day use)

◦ Minor NNH 4.2 & Major NNH 10

Duehmke et al Cochrane Database Syst Rev 2008

Eisenberg et al Cochrane Database Syst Rev 2009

Morphine ◦ Abuse potential

Tramadol ◦ Atypical : weak action at μ-receptor & inhibit 5HT & NA

re-uptake transporters

◦ No suppression of hypoxic drive

◦ Seizure risk

◦ Lower abuse potential

◦ DDI with other AD

Diabetic

PN

HIV

PN

Post-

herpetic

PN

Central

pain

Fibro-

myalgia

NNT

NNH

(Major)

Antidepressants

TCAs

SNRIs

SSRIs

11+

5+

3+/1-

1+/1-

4+

1-

2+

1-

1+

3.6 (3.0 – 4.5)

6.0 (5 – 10)

insufficient

28 (17 – 68)

17 (12 – 50)

Insufficient

Anticonvulsants

Carbamazepine

Gabapentin

Pregabalin

3+/2-

3+/3-

5+

1-

1-

5+

5+

1-

1+/1-

2+

1+

4+

2.0 (1.6 – 2.5)

5.8 (4.8 – 7.2)

3.9 (3.1 – 5.1)

2.6 (2.1 – 3.5)

32 (19 – 100)

5 – 10

Opioids

Opioids

Tramadol

2+

3+

2+

1+

2.6

3.8 (2.8 – 6.3)

10

8.3 (5.6 – 1.7)

No recipe! ◦ Co-morbid disease

◦ DDI

◦ Side effect profile

◦ Cost

◦ Patient response

Increase dose to maximum, add different class of drug

FIRST LINE - Good efficacy, lower cost ◦ TCAs & SNRIs

SECOND LINE ◦ Gapapentin (higher NNT)

◦ Pregabalin (response requires higher dose, registered)

◦ Carbamazepine (efficacy base on limited data)

◦ Tramadol (combination with AD problematic)

◦ Morpine (abuse potential)

dr eric decloedt fccp (sa) mmed (clin pharm) division of ... · diabetic peripheral neuropathy...

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