Management of Neuropathic Pain

Mellar P Davis MASCC ,June 2009

Pharmacological treatment of neurologic pain relies on evidence from large randomized controlled trials

Attal 2006Dworkin 2007

Despite advances in research and clinical trials, a considerable number of individuals do not get relief

NNT- 3-5 for most drugs

Response is defined as a “30-50% reduction in pain severity

empiric drug trials – “trial and error”choices based on mechanismgulf between empiricism and mechanisticdrug choices

Baron 2006Woolf 1998

It is unclear which laboratory pain responses are most strongly associated with the experience of pain in daily life

Edwards 2003

Tools for Neuropathic Pain

• Neuropathic pain questionnaire, Leeds assessment of neuropathic signs and symptoms Neuropathic Pain Symptom Inventory

• Definite NP, possible NP, unlikely NP• Definite NP had greater pain intensity• Definite NP had greater opioid escalation

index

Mercadante 2009Mercadante 2009

Differences Between Peripheral and Central Neuropathic Pain

• Less evidence for central pain syndromes• Differences in drug classes (cannabinoids)• Central pain syndromes do not respond to

peripheral blocks or ablative procedures • Motor cortex stimulation

Pain Relief

• 30-50% pain relief may not correlate with Patient Global Impression of change (PGIC)

• Analgesia vs. function• Differential response on the several pain

mechanisms found in a single individual – Allodynia– Burning C fiber pain– Spontaneous pain

Baron 2006Baron 2006Farrar 2001Farrar 2001

Pain Relief

• Not “all or none” but continuous• Balance of pain relief, medication

burden, side effects, QOL, function• Artifact to use binomial outcomes

Dosage

• Tolerable dose vs therapeutic dose (serum levels vs empiric recommendations)

• Combinations may reduce the tolerable dose

Duration

• Maximum tolerable dose and duration of time to see maximum benefit

• Pharmacodynamic optimal time for response is largely unknown

• Maintenance period of 3 weeks, longer if suggested by RCTs

• Drug specific• Poorly related to drug half-life • Challenge in neuropathic pain

Treatment Paradigm

• Drug classes proven by RCT

TCASNRIAlpha-2-delta ligandsOpioidsTopical lidocaineSodium channel blockers

• Monotonous (single drug)

Peripheral neuropathic pain

Postherpetic neuralgia and focal neuropathy

Lidocaine patch

yes no

yes

no

TCA contraindication

Gabapentin / pregabalin

yes

Tramadol, oxycodone

TCA contraindication

TCA(SNRI)

noTCA

(SNRI)Gabapentin / pregabalin

‘Numbers Need to Treat’ Calculated for Various Drug Classes in the Treatment of Painful Neuropathy

*Optimal dose achieved. SSRI, selective serotonin *Optimal dose achieved. SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.reuptake inhibitor; TCA, tricyclic antidepressant.

Study by Sindrup and Jensen (1999)Study by Sindrup and Jensen (1999)

0 2 4 6 8

SSRIs

Gabapentin

TCAs-NE

TCAs-5HT/NE

TCAs-5HT/NE* 1.4

2

3.4

3.7

6.7

Pharmacoresistance• Pharmacorotation fails to produce

response or produces intolerable side effects

• Lowers QOL, increases symptoms• Expensive

Definition of Pharmacoresistance

“A neuropathic pain condition is resistant to pharmacotherapy when mono or a rational combination treatment using drugs proved efficacious in RCTs fails in inducing useful pain relief from the patients/physicians point of view after an appropriate duration of treatment with adequate dosage or if intolerable side effects occur”

Hansson 2009

Combination Therapy

• Rationale-non-overlapping mechanism• Paucity of data• Polypharmacy, side effects• No data for central pain syndromes

Polypharmacy

• Gabapentin plus opioids

• Gabapentin plus venlafaxine

Gilron 2005Hanna 2008Simpson 2001

Morphine, Gabapentin, or Their Combination for Neuropathic Pain

Ian Gilron, M.D., Joan M. Bailey, R.N., M.Ed.,Dongsheng Tu, PhD., Ronald R. Holden, Ph.D., Donald F. Weaver, M.D.,

Ph.D., and Robyn L. Houlden, M.D.

Mean Daily Pain

Baseline

Scor

e fo

r Pai

n In

tens

ity

Placebo Gabapentin Morphine Combination0

2

1

3

5

4

7

6

Maximal Tolerated Dose

Gabapentin MorphineSingle agent combination Single agent combination

Dos

e (m

g)

0

500

1000

1500

2000

2500

0

60

50

40

30

20

10

The Involvement of Endogenous Opioid Mechanisms in the

Antinociceptive Effects Induced by Antidepressant Drugs, Desipramine

and Trimipramine

Yusuf Özturk, Süleyman Aydin, Rana Beis, Tuba Herekman-Demir

Desipramine doses (mg/kg)

Control 7.5 15 7.5 150

4

8

10

16

20

Rea

ctio

n Ti

me

(s)

Rats pretreated with Naltrindole

(1mg/kg)

Desipramine

More Efficacious Drugs

• Lower side effect profiles• New classes (CB2 receptor agonists,

anti-glia agents)• More trials of combination therapy• Rigorous studies of non-

pharmacological measures

Hansson 2009Hansson 2009

Non-TCA, SNRI Antidepressant: Mirtazapine

• Therapeutic with initial dose• Pain control• Sleep, anxiety and appetite improvement• Fewer drug interactions• No QTc effects, hypertension• Anti-emetic• Tolerance to sedation• ? Tolerable in very advanced cancer• Combined with SNRI Sahin 2008Sahin 2008

Evsoy 2008Evsoy 2008Kim 2008Kim 2008Hannan 2007Hannan 2007

With

draw

al

dura

tion

(s)

With

draw

al

late

ncy

(s)

Time (min)

0

6

12

0

10

20

VehicleAmitriptylline 3 mgkgAmitriptylline 10 mgkgAmitriptylline 30 mgkg

Base 1

Base 2

30 60 90 120 180

Time (min)

VehicleMirtazapine 3 mgkgMirtazapine 10 mgkgMirtazapine 30 mgkg

Base 2

30 60 90 120 180Base 1

Combinations

• NSAIDs plus alpha-2-delta ligand• Opioid plus minocycline (anti-glia)• CB2 agonist plus opioid (anti-glia)• (+) opioid antagonists (anti-glia)• etodolac

Glia and Opioids: Minocycline

• Attenuates morphine induced respiratory depression

• Reduces conditioned place preference• Potentiate morphine analgesia• Blocks morphine induced upregulation of

Cox-1

Hutchinson 2008Hutchinson 2008

Etodolac Attenuates Mechanical Allodynia in a Mouse Model of

Neuropathic Pain

Naoki Inoue, Sunao Ito, Koyuki Tajima, Masaki NogawaYosuke Takahashi, Takahiro Sasagawa,

Akio Nakamura, and Takashi Kyoi

Effect on Mechanical Allodynia in PSNL Mice

Each symbol represents the mean PWT for 10 mice. Drugs were administered orally once a day for two weeks from seven days after PSNL. *P<0.05, **P<0.01 (vs. control, Steel test).

ControlEtodolac 10 mg/kgIndomethacin 1 mg/kgCelecoxib 30 mg/kg

Time after administrationDay 7 Day 14 Day 21

Day 0 Pre 1h4h

0.0

0.2

0.4

0.6

0.8PW

T (g

)

*** **

** ** **

**

Pre 1h4h

Pre 1h4h

Opioid Induced Hyperalgesia

• Quantitative sensory testing• Reduced heat pain thresholds • Exacerbated temporal summation of a second

pain• Dose effect• Opioid tolerance• Narrow therapeutic window

Chen 2009Chen 2009

Altered Quantitative Sensory Testing Outcome in Subjects with Opioid

Therapy

Lucy Chen, Charlene Malarick, Lindsey Seefeld,Shuxing Wang, Mary Houghton,Jianren Mao

Exacerbated Temporal Summation of the Second Pain in Group 3 Subjects

*P<0.05, as compared with group 1 and group 2 subjects. S1/BK, S2/BL, S3/BL: the percent increase in VAS (visual analogue scale) score in response to the second, third, and fourth stimulation over that of the first stimulation in a train of four noxious heat (47°C) stimuli.

Incr

ease

in V

AS

(%)

S1/BL S2/BL S3/BL0

100

200

300

400

500

*

*

*Group 1Group 2Group 3

Different Profiles of Buprenorphine Induced Analgesia and Antihyperalgesia

in a Human Pain Model

Wolfgang Koppert, Harald Ihmsen, Nicole Körber, Andreas Wehrfritz, Reinhard Sittl, Martin Schmelz, Jürgen Schüttler

Antihyperalgesia Analgesia Ratio

Buprenorphine i.v.

Buprenorphine s.i.

Fentanyl i.v.

Alfentanil i.v.

S-ketamine i.v.

2.6 (0.8-3.8)

1.9 (-0.1-8.1)

0.6 (-0.3-2.2)

0.3 (-0.3-0.5)

5.5 (3.1-6.1)

Effect (%)100 75 50 25 0 25 50

Chronic Morphine Administration Enhances Nociceptive Sensitivity and

Local Cytokine Production After Incision

DeYong Liang, Xiaoyou Shi, Yanli Qiao, Martin S Angst, David C. Yeomans, and J David Clark

SalineChronic MorphineSaline / IncisionChronic Morphine / Incision

0

pg/m

g P

rote

in

300

600

900

1200IL-1

0

pg/m

g P

rote

in

150

300

450

600TNF

Time after Incision2h 24h 72h

0.0

Paw

With

draw

al

Thre

shol

d (g

)

PTX

Baseline - +

1.0

2.0 Saline prior to incisionMSO4 prior to incision

- +

Alternative Medications

• Melatonin• S-adenosyl methionine• L-carnitine• Vitamin D

Neuropathic Pain: Seed or Soil

• Individuals differ widely in their ability to moderate pain

• Range from substantial inhibition to substantial facilatation

• Diffuse noxious inhibitory controls (DNIC)

Diffuse Noxious Inhibitory Control

• Ability to modulate phasic pain when experiencing chronic pain

• Supraspinal generated inhibition of spinal wide dynamic range neuron

• Reduced in fibromyalgia, temporomandibular disorder, irritable bowel syndrome

Diffuse Noxious Inhibitory Control

• Reduced with age• Influenced by certain domains of quality of life• ? premorbid background to neuropathic pain

syndrome• ? Improved by non-pharmacologic

approaches to pain• ? Altering pain catastrophizing

Edwards 2003Edwards 2003Goodin 2009Goodin 2009

Individual Differences in Diffuse Noxious Inhibitory Control (DNIC): Association with Clinical Variables

Robert R. Edwards, Timothy J Ness, Douglas A Weigent,

Roger B Fillingim

Scores on SF-36 Subscales (mean ± SD)

Age groups differ at *P<0.05. Higher SF-36 subscale score represents better functioning (e.g. less pain, better health).

SF-36 subscales Younger (n = 37) Older (n = 37)

General health (0-100) 79.1 ± 13.8 77.6 ± 18.2

Physical functioning (0-100) 93.2 ± 19.2* 84.6 ± 15.4

Physical role (0-100) 95.3 ± 15.4* 81.1 ± 31.7

Bodily pain (0-100) 76.2 ± 16.5 73.7 ± 16.1

50

60

70

80

90

100

Younger Older Younger Older Younger Older Younger Older

BP* PF* PR GH

Younger Adults Older AdultsDNIC +(n=24)

DNIC -(n=13)

DNIC +(n=11)

DNIC -(n=26)

Catastrophizing

• Interferes with the endogenous opioid system • Distraction which mobilizes the endogenous

opioid system is less effective in high catastrophizing individuals

• Catastrophizing produces a pro-inflammatory response

• Interact with pain genotype (COMT) as a predictor for high pain sensitivity

Campbell 2009Campbell 2009Weissman-Fogel 2008Weissman-Fogel 2008George 2008George 2008

Associations Between Catastrophizing and Endogenous Pain Inhibitory

Processes: Sex Differences

Burel R Goodin, Lynanne Mcguire, Mark Allshouse, Laura Stapleton, Jennifer A Haythornthwaite, Noel Burns,

Lacy A Mayes, and Robert R Edwards

In vivo catastrophizing

SF-MPQ pain ratings

DNIC

a B*

c’

Religion, Spirituality and Chronic Pain• Organized religion reduced chronic pain• Spirituality without affiliated regular worship

attendance increased chronic pain prevalence• Individuals with chronic pain are more likely

to use prayer, spiritual support for coping

An fMRI Study Measuring Analgesia Enhanced by Religion as a Belief

System

Katja Wiech, Miguel Farias, Guy Kahane,Nicholas Shackel, Wiebke Tiede, Irene Tracey

Pai

n in

tens

ity

(VA

S 0

-100

)

Religious groupNon-Religious group

40

60

80

100Non-Religious conditionReligious condition

Pai

n in

tens

ity

(VA

S 0

-100

)

Religious groupNon-Religious group

-30

0

20

50Non-Religious conditionReligious condition

-20

-10

10

30

40

Summary

• Tools• Standard treatment• Limitations and treatment resistance• Combinations• OIH • Diffuse noxious inhibitory control• Catastrophizing• Religious convictions and imagery• Alternative therapies