Management of Neuropathic Pain

Mellar P Davis
MASCC ,June 2009

Pharmacological treatment of neurologic

pain relies on evidence from large
randomized controlled trials

Attal 2006
Dworkin 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 mechanism
gulf between empiricism and mechanistic
drug choices
Baron 2006
Woolf 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 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 2006
Farrar 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
TCA
SNRI
Alpha-2-delta ligands
Opioids
Topical lidocaine
Sodium channel blockers

Monotonous (single drug)

Peripheral
neuropathic pain
yes

Postherpetic neuralgia no
and focal neuropathy

Lidocaine patch
yes

no

Gabapentin /
pregabalin
TCA
contraindication

TCA
contraindication

TCA
(SNRI)
yes

no

TCA
(SNRI)

Gabapentin /
pregabalin

Tramadol, oxycodone

Numbers Need to Treat Calculated

for Various Drug Classes in the
Treatment of Painful Neuropathy
SSRIs

6.7

Gabapentin

3.7

TCAs-NE

3.4

TCAs-5HT/NE

2
1.4

TCAs-5HT/NE*
0

*Optimal dose achieved. SSRI, selective serotonin

reuptake inhibitor; TCA, tricyclic antidepressant.
Study by Sindrup and Jensen (1999)

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 2005
Hanna 2008
Simpson 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.

Score for Pain Intensity

Mean Daily Pain

7
6
5
4
3
2
1
0

Baseline

Placebo

Gabapentin

Morphine Combination

Dose (mg)

Maximal Tolerated Dose

2500

60

2000

50
40

1500

30
1000

20

500

10

0
Single agent combination

0
Single agent combination

Gabapentin

Morphine

The Involvement of Endogenous

Opioid Mechanisms in the
Antinociceptive Effects Induced by
Antidepressant Drugs, Desipramine
and Trimipramine
Yusuf zturk, Sleyman Aydin,
Rana Beis, Tuba Herekman-Demir

Reaction Time (s)

20
16
10
8
4
0

Control

7.5

15

Desipramine

7.5

15

Rats pretreated
with Naltrindole
(1mg/kg)

Desipramine doses (mg/kg)

More Efficacious Drugs

Lower side effect profiles
New classes (CB2 receptor agonists,
anti-glia agents)
More trials of combination therapy
Rigorous studies of nonpharmacological measures

Hansson 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
Sahin 2008
Combined with SNRI

Evsoy 2008
Kim 2008
Hannan 2007

Withdrawal
duration (s)

20

10

Withdrawal
latency (s)

12

Vehicle
Amitriptylline 3 mgkg
Amitriptylline 10 mgkg
Amitriptylline 30 mgkg

Vehicle
Mirtazapine 3 mgkg
Mirtazapine 10 mgkg
Mirtazapine 30 mgkg

Base Base 30
1
2

60

90

Time (min)

120 180

Base Base 30
1
2

60

90

Time (min)

120 180

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 2008

Etodolac Attenuates Mechanical

Allodynia in a Mouse Model of
Neuropathic Pain

Naoki Inoue, Sunao Ito, Koyuki Tajima, Masaki Nogawa

Yosuke Takahashi, Takahiro Sasagawa,
Akio Nakamura, and Takashi Kyoi

Effect on Mechanical Allodynia in PSNL

Mice
0.8

Control
Etodolac 10 mg/kg
Indomethacin 1 mg/kg
Celecoxib 30 mg/kg

PWT (g)

0.6
0.4

**
**

0.2
0.0

*
Day 0

Pre 1h
4hDay 7

**

**

**

**

Pre 1h
4hDay 14

Pre 1h
4h
Day 21

Time after administration

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).

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 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
Increase in VAS (%)

500
400

Group 1
Group 2
Group 3

*
*

300
200

100
0

S1/BL

S2/BL

S3/BL

*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 (47C) stimuli.

Different Profiles of Buprenorphine

Induced Analgesia and Antihyperalgesia
in a Human Pain Model

Wolfgang Koppert, Harald Ihmsen, Nicole Krber, Andreas

Wehrfritz, Reinhard Sittl, Martin Schmelz, Jrgen Schttler

Antihyperalgesia

Analgesia

Ratio

Buprenorphine i.v.

2.6 (0.8-3.8)

Buprenorphine s.i.

1.9 (-0.1-8.1)

Fentanyl i.v.

0.6 (-0.3-2.2)

Alfentanil i.v.

0.3 (-0.3-0.5)

S-ketamine i.v.

5.5 (3.1-6.1)

100

75

50

25

Effect (%)

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

pg/mg Protein

1200

Saline
Chronic Morphine
Saline / Incision
Chronic Morphine / Incision

IL-1

900
600
300
0

pg/mg Protein

600
450

TNF

300
150
0

2h

24h
Time after Incision

72h

Paw Withdrawal
Threshold (g)

2.0

Saline prior to incision

MSO4 prior to incision

1.0

0.0

Baseline

+
PTX

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 2003
Goodin 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)

SF-36 subscales
General health (0-100)

Younger (n = 37) Older (n = 37)

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

Age groups differ at *P<0.05. Higher SF-36 subscale score

represents better functioning (e.g. less pain, better health).

Younger Adults
DNIC +
(n=24)

DNIC (n=13)

Older Adults
DNIC +
(n=11)

DNIC (n=26)

100
90
80
70
60
50

Younger Older

BP*

Younger Older

PF*

Younger Older

PR

Younger Older

GH

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 2009
Weissman-Fogel 2008
George 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

DNIC
a

In vivo
catastrophizing

B*

SF-MPQ pain
ratings

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

Pain intensity
(VAS 0-100)

100

Non-Religious condition
Religious condition

80

60

40

Non-Religious
group

Religious group

50

Pain intensity
(VAS 0-100)

40

Non-Religious condition
Religious condition

30
20
10
0
-10
-20
-30

Non-Religious
group

Religious group

Summary

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