Download Neuropathic Pain

Pain: Nociceptive and
Neuropathic Considerations
Principles of Drug Action I
Marlon Honeywell, Pharm. D
Professor of Pharmacy Practice
Florida A&M University
Background
 Acceptable definition is enigma
 “Punishment from the gods”
 Derived from Latin peone and Greek
poine
– “penalty” or “punishment”
 Aristotle considered pain as a “feeling”
– Classified as passion of the soul
– Heart was the source or processing center
for pain
2
Background
 Mueller, Van Frey and Goldschieder
– Hypothesized concepts of neuroreceptors,
nociceptors and sensory input
– Nineteenth century
– Theories developed into current definition:
“an unpleasant sensory and emotional
experience associated with actual or
potential tissue damage or described in
terms of such damage
3
Background
 Subjective data
 Based on patient’s interpretation
 Often viewed by clinicians as “whatever
the patient says it is”
 Understanding how pain is generated,
transmitted and perceived is crucial
4
Action Potential
 Required for neurons to fire
 Various substances may be involved
– Sodium and potassium mostly
 Stimulus must be applied (pain)
 Action potential generated
 Impulse fired through myelinated axons
 Brain interpretation
5
6
7
Permeability Changes
8
Neurochemicals
 Other neurochemicals may be involved
– GABA
– Neurotensin
– Substance P
– Braddykinnin
– Prostaglandins
– Leukotrienes
– NE
– 5HT
 May sensitize and or activate pain receptors
 Involved in pain transmission between spinal
cord and brain in synaptic cleft
9
Process of Pain Transmission
 Stimulation
– Noxious stimulus sensitizes receptors causing
release of neurochemicals that may sensitize
or stimulate nociceptors
 Action Potential (Transmission)
– Action potential comes from the site of
painful stimulus to the dorsal horn of the
spinal cord and ascends to the brain
10
Process of Pain Transmission
 Perception
– Conscious experience of pain
 Modulation
– Inhibition of nociceptor impulses. Neurons
from the brain stem descend to the spinal
cord and release substances such as
endogenous opiods
(endorphins,enkephalins), seritonin, and
norepinephrine that inhibit transmission
11
Dorsal Horn
 Located in the spinal cord
 Responsible for the release of
neurotransmitters in the face of painful
stimuli.
– Substance P
– Neuroreceptors
– Calcitonin-gene related peptide
 Action Potential/Neuronal Firing to PNS
12
Spinal Cord/Dorsal Horn
13
Spinal Cord Sectional
14
Dorsal Horn
15
Dorsal Horn
16
Types of Pain
 Nociceptive pain
 Neuropathic pain
17
Nociceptive pain
 Somatic pain
– Arising from skin, bone, joint, muscle, or connective
tissue
– Mostly presents as throbbing and well localized
 Visceral pain
– Arising from internal organs such as large intestine
or pancreas
– Described as though it was coming from inner
structures
 Both types may involve inflammation
18
Neuropathic Pain
 Distinctly different from nociceptive
 Definition
– Group of painful disorders characterized by pain
due to dysfunction or disease of the nervous system
at a peripheral level, central level or both.
 Involves ectopic discharges from sodium
channels
– Changes in depolarization
– Dysfunctional secondary to nerve injury
19
Neuropathic Pain
 Formation of neuromas
– Area where the nerve injury occurs
– Ectopic discharges occur
• Can occur in neuroma, dorsal horn, glial cells
(axon)
– Reported to accumulate sodium channels at the
distal end of nerve injury
– Acquire adrenergic sensitivity
• Increased pain when area is injected with
norepinephrine
– Sensitive to catecholamines and citokines
20
Neuropathic Pain
 Neurogenic Inflammation
– Nociceptors in dorsal horn are stimulated
from nerve injury
• Release Substance P (Capsacin/Opioids)
• Prostaglandins (NSAIDS)
• Neurotransmitters spread along PNS
– May explain use of topical agents and
antiinflammatory agents
21
Neuropathic pain
 Contrast
– Nociceptive pain results from
activation of nociceptors (pain
receptors)
– Neuropathic pain results from injury
to the pain-conducting nervous system
• Nerve damage
• Responds poorly to traditional
treatment options
22
Neuropathic Pain
 Contrast
– Nociceptive pain
• Self limiting
• Protective biological function
• Usually warning of ongoing tissue damage
– Neuropathic
• Unrelenting not self limiting
• Sharp, aching, throbbing and gnawing
• Serves no protective biological function
23
Cascade
Brain 
Sprouting A/C fibers
Extra Na channels

Neuroma

Inhibitory



Pain
NMDA
NE/5HT/GABA



Ca++
Nociceptors
PNS 

Nerve Damage
(crush/stretch/viral)
PNS
Excitatory
Spinal Cord (Dorsal Horn)
Nociceptors

Targets
Na modulators
NMDA Antagonist



Substance P
Prostaglandins
A/C Fibers (Glial Cells)
Dysfunctional Na channels ( threshold)
Increased Action Potentials
Ectopic Firing
MU receptor/COX Inhibitors
 NE/5HT/GABA
24
Types of Neuropathic Pain
 Diabetic Neuropathy
 Low back pain
 Postherpetic Neuralgia
 Poststroke pain
 Spinal Cord Injury
 Cancer-related pain
 Multiple Sclerosis
25
Prevalence of Neuropathic Pain
Low Back Pain
Diabetic Neuropathy
Postherpetic Neuralgia
Cancer-related pain
Spinal Cord Injury
Multiple Sclerosis
Post stroke pain
0
0.5
1
1.5
2
2.5
US prevalence (millions of cases)
26
Epidemiology
 Seriously hospitalized patients report a
50% incidence of pain
 15% had extremely or moderately severe
pain occurring at least 50% of time
 15% were dissatisfied with overall pain
control
 70% of chronic pain patients claimed to
have pain despite treatment, with 22%
believing treatment worsened pain
27
Clinical Presentation
 Attention must be paid to mental factors
that alter threshold
–
–
–
–
–
–
–
Anxiety (lower)
Anger (lower)
Fatigue (lower)
Fear (lower)
Rest (elevate)
Mood elevation (elevate)
Sympathy (elevate)
28
Clinical Presentation
 Evaluate components of pain experience
– Behavioral (part of our reaction to
pain is learned)
– Social (expression differs in different
environments)
– Cultural (background may influence
tolerance)
29
Clinical Presentation
 Neuropathic
– Often use terms
– Burning, tingling, itching, dull, sharp, hot, etc.
– Allodynia
• Painful response to normally non-noxious stimuli
– Mechanical Allodynia
• Painful response to normally non-noxious movement
– Hyperalgesia
• Exaggerated painful response to normally noxious stimuli
– Thermal hyperalgesia
• Exaggerated painful response to normally noxious
temperature
30
WHO Guidelines
 Control of neuropathic pain begins with
proper assessment
 In 1993, Von Roenn et al. conducted a
study over a six month period
– 897 oncologists and 70,000 patients
– Primary barrier was pain assessment
 Concluded that primary goal should be to
assess patient and treat pain according to
goals discussed
31
WHO Ladder
32
WHO Guidelines
 Problems
– Only address cancer-related pain (nociceptive)
– Only used NSAIDS, APAP, ASA, and opioids
– Doesn’t completely address neuropathic pain
•
•
•
•
•
Anticonvulsants
Tricyclics
Buproprion
Tramadol
Capsacian
– Majority of patients can be relieved by WHO
guidelines
33
WHO Guidelines

State that assessment is crucial to controlling
pain
– Subjective patient-clinician interaction
– Pain scale
– Reevaluation of patient response to
treatment modalities
– Constant adaptation to changes in patient
condition
34
Assessment/Treatment (WHO)
 Grond et al. conducted a study evaluating
treatment of neuropathic pain adhering
to WHO guidelines
– 593 cancer patients
• 32 with neuropathic pain
• 380 with nociceptive pain
• 181 (mixed)
35
Assessment/Treatment (WHO)
Patient Make-up
Nociceptive
Neuropathic
Mixed
36
Demographics
Mean Age
Nociceptive Mixed
(n = 380)
(n = 181)
59  14
58  14
Neuropathic
(n = 32)
59  16
Females %
42
46
41
GI
31
14
9
Breast
12
12
6
Skin/Bone
6
4
6
Lung
10
11
6
Cancer Site
37
Assessment/Treatment (WHO)
 Average duration of evaluated pain treatment
– Nociceptive – 51 days
– Mixed – 53 days
– Neuropathic pain – 38 days
 On admission
– Pain localization, aetiology and pathophysiological type
were assessed
• Patient history
• Pain questionnaire
• Physical examination
• Diagonistic testing
• Verbal rating scale (Not neuropathic-specific/Nonnumerical)
– None, mild, moderate, severe, very severe, and
maximal
38
Assessment/Treatment (WHO)
 213 patients with pure or mixed neuropathy
– 254 anatomically distinct neuropathic pain
syndromes
• 47% had burning
• 58% also had a paroxysmal characteristic
 Of the neuropathic pain syndromes
– 72% were caused by cancer
– 12% by cancer treatment
– 4% with cancer disease
– 9% unrelated to cancer
– 3% unknown aetiology
 Pain intensity was evaluated
39
Assessment/Treatment (WHO)
Pain Intensity
70
60
50
40
Admission
First follow-up
Last follow-up
30
20
10
0
Nociceptive
Mixed
Neuropathic
40
WHO Duration and Efficacy
41
Assessment/Treatment (WHO)
 Conclusions
– Neuropathic pain may be relieved by the
WHO guidelines
– Opioids, Non-opioid and adjuvants
(anticonvulsants, buproprion etc.) may be
used
– Other studies need to be conducted
– Better assessment tools may be needed
• Specific pain scale
42
Neuropathic pain scale
 In 1997, Galer et al. developed a neuropathic
pain scale
– First scale with the primary purpose of measuring
neuropathic pain
– Designed to measure distinct qualities associated
with neuropathic pain
•
•
•
•
•
Sharp
Hot
Dull
Cold
Itchy
43
Neuropathic pain scale
 Four Neuropathic conditions evaluated
– 288 patients
– Post-herpetic neuralgia (128)
– Reflex sympathetic dystrophy (69)
– Traumatic peripheral nerve injury (67)
– Painful diabetic polyneuropathy (24)
 Lidocaine and phentolamine were used
 All neuropathic diagnostic groups had
comparable levels of pain intensity
44
Neuropathic pain scale
 Found that most of the pain descriptors
improved in response to lidocaine and
phentolamine
 Further studies may be required to
determine if this scale may be uniformly
used for different dimensions of pain
45
Neuropathic pain scale
 Study limitations
– Used on a clinical population instead of
being population based
– Was not randomized or double blind
– Did not account for every type of
neuropathic pain quality
 Although study limitations exist,Current
conclusions support the preliminary use
of this scale
46
Neuropathic pain scale
 Several different aspects of pain
– Distinction might be clearer if one thinks in terms of
“Intensity of sweet”
• Taste of pie
• One may agree that the pie is good but should be
sweeter
• One may disagree that the pie is too sweet
• Loudness of music
• May agree about what is more quiet or louder
(intensity), but disagree about how it makes them
feel
– Pain is the same. One may feel extremely hot, but
not at all dull. Another may feel dull pain, but no
heat or itching may be associated.
47
Neuropathic Pain Scale
48
Neuropathic pain scale
49
Treatment
 “Assessment is crucial to proper
treatment”
 Options
–
–
–
–
–
–
Opioids
Anticonvulsants
Tricyclics
Tramadol
Buproprion
Capsacian
50
Opioids
 Generally, opioids have been found to have a
decline in effectiveness in treatment of
neuropathic pain
– Nerve injury reduces spinal the activity of
spinal opioid receptors or opioid signal
transduction
– Morphine doesn’t effectively reduce
neuropathic pain (conflicting studies)
– Oxycodone has been found effective in some
studies
– Some opioids may reduce pain at higher
doses
51
Oxycodone
 Watson et al. found controlled release
oxycodone to be effective in treatment of
post herpetic neuralgia
– steady pain, paroxysmal spontaneous pain
and allodynia characterized
– 10-30mg q12h (titrated)
– 50 patients enrolled and 38 completed study
– Found global effectiveness, disability and
patient preference all showed superior scores
52
Oxycodone
60
50
40
Placebo
Oxycodone CR
30
20
10
0
Steady pain
Brief pain
Allodyia
Weekly visual analog scale (pain score)
53
Buproprion
 Burpropion is safe and effective in treatment of
neuropathic pain
– 150-300mg/day
– Semenchuk et al. conducted a study involving 41
nondepressed patients with neuropathic pain
– 30 patients (73%) taking buproprion SR (150mg)
had an improvement in pain
• One patient was pain free
– Mean average pain score was 5.7
– Mean average declined by 1.7 in pts taking
buproprion
• (p<0.001)
54
Buproprion Pain Score
55
Comparison of Global Ratings
of Pain Relief
Rating
Pain worse
Pain unchanged
Pain improved
Pain much impr.
Pain free
Total impr.
* p<0.001
Placebo
14 (34.1%)
23 (56.1%)
2 (4.9%)
2 (4.9)
0
4 (9.8)
Buproprion SR
3 (7.3%)
8 (19.5%)
15 (36.6%)
14 (34.1)
1 (2.4%)
30 (73.2)*
Patients (%)
Patients (%)
56
Tramadol
 Safe and effective for treatment of pain
secondary to diabetic neuropathy
– Harati et al. conducted study of 131 patients
– 65 received tramadol and 66 received
placebo
– Average dose was 210mg/day (significantly
more effective)
– Treatment group was better in physical and
social functioning
– Side effects were nausea, constipation,
headache and somnolence
57
Tramadol
2.5
2
1.5
Placebo
Tramadol
1
0.5
0
Baseline
Day 14
Day 28
Final Visit
Patient ratings of pain intensity (pain intensity score)
58
Tramadol
2.5
2
1.5
Placebo
Tramadol
1
0.5
0
Day 14
Day 28
Final Visit
Patient ratings of pain relief (pain relief score)
59
Transdermal clonidine
 Byas-Smith et al. found that a subset of
patients with diabetic neuropathy describing
pain as sharp and shooting may respond to
clonidine
– 2 phase study involving 41 patients
– Dose was titrated (0.1mg/day-0.3mg/day)
– In phase I, the 12 responders graduated to phase II
(1 week with patch, 1 week without, random)
– In phase II, the 12 responders had 20% less pain
than placebo confirming response to drug
– Side effects included dry mouth, site irritation, and
tiredness
60
Clonidine Pain Intensity
61
Amantadine
 N-methyl D-aspartate (NMDA) receptor
antagonists can block pain transmission in the
dorsal horn
–
–
–
–
Reduction in pain transmission in animals
3 individual cases of pain relief reported
Available for long term use in humans
Single intravenous doses of 200mg
• Complete pain resolution in individual cases
– Further studies may be needed
– Other agents: ketamine and dextromethorphan
62
Tricyclic Antidepressants
 Tertiary Amines
– Imipramine
– Amitriptyline
 Secondary Amines
– Nortriptyline
– Desipramine
63
Tricyclic Antidepressants
64
Mechanism of Action
 Inhibit the reuptake of biogenic amines
– Norepinephrine (NE)
– Seritonin (5HT)
 Work in descending inhibitory pathways
originating from the brainstem to the
spinal cord using the aforementioned
neurotransmitters
 Basically, inhibit transmission from
spinal cord to brainstem
65
Tricyclic Antidepressants
66
Tricyclic Antidepressants
 Double-blind, placebo controlled trial of
amitriptyline, desipramine (selective NE
blocker), and fluoxetine (SSRI)
 Mean doses: amitriptyline 105mg,
desipramine 111mg, fluoxetine 40mg
 Moderate or significant pain relief in
74% of amitriptyline, 61% of
desipramine, 48% of fluoxetine, and 41%
of placebo-treated patients
67
Tricyclic Antidepressants
68
Tricyclic Antidepressants
69
Tricyclic Antidepressants
 Have significantly better efficacy than the
SSRIs for the relief of pain in patients
with peripheral neuropathies
 Tertiary amines seem to be slightly more
effective than secondary amines, but with
worse adverse events profile
 Antineuropathic properties are
independent of antidepressant properties
70
Trigeminal Neuralgia
 Trousseau, 1853. Describes attacks of pain in
trigeminal pathway. Called it neuralgia
epileptica
 First report of efficacy of phenytoin in
trigeminal neuralgia in 1942
 First report of efficacy of Carbamazepine is in
1962 by Blom
 Animal studies found that both drugs depress
synaptic transmission from spinal cord
71
Trigeminal Neuralgia
 Anticonvulsant agents
– Carbamazepine
– Phenytoin
– Clonazepam
– Felbamate
– Gabapentin
– Lamotrigine
– Oxcarbazepine
72
Trigeminal Neuralgia (Clinical
Trials of Carbamazepine)
 Campbell et al. 1966
– Three centers, cross-over, eight weeks (4 two week
periods), 70 patients
– Found pain relief on scale and transformed into %
change
– 58% improvement on carbamazepine (400800mg/day) 26% on placebo (p<0.01)
 Killian et al. 1968
– Cross over, 10 day trial. 30 pts.
– 70% improvement on CBZ (400-1000mg/d).
Minimal placebo response
73
Clinical Trials
 Nicol. 1969
– Partial Cross over study.
– Pain relief measured on scale
– 15/33 in CBZ (100-2400mg/d) from start, 6/33 on
placebo from start, and 12/17 on placebo from start
followed by CBZ.
– Showed excellent response in pain relief
 Three studies provided evidence for approval
of CBZ for tx of trigeminal neuralgia
74
Trigeminal Neuralgia
 CBZ
– Drug of choice
– Efficacy established in three small, double-blind,
placebo-controlled, cross-over trials
– 70-80% have good initial response
– Efficacy correlated with serum levels
• 6-10mcg/cc
– Oxidized to 10-11 epoxide (side effects)
• 30-40% have problems after 1 year secondary
tolerance or side effects
– Auto induction (induces own metabolism)
• Dosage adjustment
75
Oxcarbazepine







Keto-analog of carbamazepine
Reduced to monohydrate derivative
Twice daily dosing
No auto induction
Effective starting dose
27% cross-sensitivity with CBZ
MUCH LESS SIDE EFFECTS THAN CBZ
– Reduction instead of oxidation
 Conversion (1mg of CBZ = 1.5mg of
oxcarbazepine)
76
Oxcarbazepine
 Open label trial of 15 patients refractory
to CBZ
 Pts converted to OXC monotherapy
 67% of patients completely controlled on
900-1800mg/day; 20% controlled with
occasional exacerbations on dosages of
more than 2 grams/day
77
Oxcarbazepine
 Comparative trial of OXC vs. CBZ
 15 patients titrated to OXC (900-
2100mg/day) or CBZ (400-1200mg/day)
 Efficacy assessed on scale
 Comparable effects in 12 patients;
efficacy superior on OXC in 2 pts and
inferior in 1 pt
 OXC offers an alternative to CBZ for the
treatment of trigeminal neuralgia
78
Oxcarbazepine advantages vs.
CBZ
 No black box warnings in pkg insert;
monitoring of liver enzymes and
hematological parameters not required
 Few drug-drug interactions because of
minimal interaction with CYP450 system
 Does not induce own metabolism
79
Trigeminal Neuralgia
 Other anticonvulsants
– No double blind trials
– Phenytoin: moderate efficacy at high serum
concentration
– Clonazepam: 25 pts. 40% controlled, 23%
significant improvement. Another study 13/19
patients had excellent or good improvement
– Sodium valproate: 20 pts. Complete relief in 6;
significant improvement in 3
– Anecdotal reports suggest efficacy of FBM, GB,
LTG
80
Diabetic Neuropathy
 Double blind, placebo-controlled, cross-
over trial of six weeks (3 two-week
periods); 30 pts.
 Pain relief on scale
 63% had moderate-complete relief on
CBZ vs. 20% on placebo
 Median dose = 600mg
81
Diabetic Neuropathy
(Phenytoin)
 Saudek et al. 1977
– Double blind, cross-over, placebo-controlled trial of
4 weeks (4 one week periods) 12 pts
– Pain relief on linear analog scale
– No significant difference between phenytoin (600mg
loading followed by 300mg/day) and placebo
 Chadda et al.
– DB, CO, PC trial (2 two week periods)
– 74% had moderate-complete relief of pain
(300mg/day) vs. 26% patients during placebo
treatment
 Watched carefully…..causes sedation,
dizziness, nystagmus
82
Diabetic Neuropathy
(Gabapentin)
 Multicenter, eight-week, placebo-controlled
trial in 165 pts. Titrated to 3600mg/day
– Significant reduction in daily pain scores; pts and
clinicians favored results globally
– 8% drop out secondary to side effects,
predominantly somnolence and dizziness
 Multi center, eight week trial (225 pts)
– Same results
– 13% drop out for same adverse effects
83
Diabetic Neuropathy
(Capsaicin)
 Multicenter, double-blind vehicle controlled
trial
 252 patients on topical 0.075% capsaicin vs.
vehicle cream applied 4x daily for eight weeks
 Statistically significant improvement in drug
vs. placebo (69.5 vs. 53.4%)
 Bias in study; pts knew active agent because of
hypoallergia due to pepper content
 Side effects: transient burning, sneezing and
coughing
84
Diabetic Neuropathy
(Mexelitine)
 216 patients randomized to 3 dosages of
mexelitine or placebo. Significant
reduction in sleep disturbances and
nighttime pain was seen in group taking
highest dose (600mg/day)
 Side effects: cardiac problems
 Should be reserved for pts unresponsive
or intolerant to standard therapy
85
Diabetic Neuropathy
Duloxetine (Cymbalta)
 First medication specifically approved for
PDN
–
–
–
–
60mg qd-bid
Well tolerated
NE/5HT reuptake inhibitor
Nausea, Constipation, Dry mouth, Fatigue
86
Diabetic Neuropathy: Pregabalin
(Lyrica)
 Inhibits voltage regulated calcium channels
 FDA approved for Diabetic Neuropathy
 Structurally related to gabapentin
– Side effects: dizziness, weight gain, sleepiness,
and trouble concentrating
87
Drug Cascade
88
On the Horizon
 Antioxidants (α-Lipoic Acid)
– Studies being conducted
– 30 minute infusion (5x week)
– Impractical clinical use
– Prevention?
89
On the Horizon
 Ruboxistaurin
– Eli Lilly
– PKC Beta Inhibitor
– Phase III clinical trials
– Enzyme recently found to be active in
morbidity in Diabetes
– PDN, Diabetic retinopathy, Diabetic
neuropathy
90
On the Horizon
 Sildenafil
– Used predominantly in erectile dysfunction
– Recently noted that neuronal nitric oxide
(NO) synthetase is a factor in pathogenesis of
PDN
– Decrease in Nitrous oxide
– PDE inhibitor has been shown to
significantly increase pain threshold in rats.
– Possible trials in humans soon
91
Conclusions
 CBZ is drug of choice for trigeminal neuralgia
and often effective for lancing pain in a number
of other conditions
 OXC has shown preliminary efficacy in
treatment of trigeminal neuralgia, although
further studies are required
 TCA’s and GBP have demonstrated efficacy in
diabetic neuropathy and herpetic neuralgia
 More trials may be required
92
Recommendations
 Start at lowest dose and gradually titrate
 If a patient experiences partial pain relief with
one drug as monotherapy, a combination of
two or more different classes of drugs can often
yield better results
 In general, when a patient remains pain free
for 3 months on a current treatment regimen,
consideration to a slow taper should be given if
the patient becomes refractory
93