pain: nociceptive and neuropathic considerations principles of drug action i marlon honeywell,...
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Pain: Nociceptive and Neuropathic Considerations
Principles of Drug Action I
Marlon Honeywell, Pharm. D
Professor of Pharmacy Practice
Florida A&M University
2
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
3
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
4
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
5
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
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7
8
Permeability Changes
9
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
10
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
11
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
12
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
13
Spinal Cord/Dorsal Horn
14
Spinal Cord Sectional
15
Dorsal Horn
16
Dorsal Horn
17
Types of Pain
Nociceptive pain Neuropathic pain
18
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
19
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
20
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
21
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
22
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
23
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
24
PNSNerve Damage(crush/stretch/viral)
Neuroma
Sprouting A/C fibersExtra Na channels
Spinal Cord (Dorsal Horn)
Brain
Pain
Excitatory
NMDA
Ca++
Inhibitory
NE/5HT/GABA
Nociceptors
Nociceptors
Substance PProstaglandinsPNS
A/C Fibers (Glial Cells)Dysfunctional Na channels ( threshold)Increased Action PotentialsEctopic Firing
TargetsNa modulators
NMDA Antagonist
MU receptor/COX Inhibitors
NE/5HT/GABA
Cascade
25
Types of Neuropathic Pain
Diabetic Neuropathy Low back pain Postherpetic Neuralgia Poststroke pain Spinal Cord Injury Cancer-related pain Multiple Sclerosis
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Prevalence of Neuropathic Pain
0 0.5 1 1.5 2 2.5
Post stroke pain
Multiple Sclerosis
Spinal Cord Injury
Cancer-related pain
Postherpetic Neuralgia
Diabetic Neuropathy
Low Back Pain
US prevalence (millions of cases)
27
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
28
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)
29
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)
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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
31
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
32
WHO Ladder
33
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
34
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
35
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)
36
Assessment/Treatment (WHO)Patient Make-up
NociceptiveNeuropathicMixed
37
Demographics
Nociceptive (n = 380)
Mixed
(n = 181)
Neuropathic
(n = 32)
Mean Age 59 14 58 14 59 16
Females % 42 46 41
Cancer Site
GI 31 14 9
Breast 12 12 6
Skin/Bone 6 4 6
Lung 10 11 6
38
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/Non-
numerical)– None, mild, moderate, severe, very severe, and maximal
39
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
40
Assessment/Treatment (WHO)
0
10
20
30
40
50
60
70
Nociceptive Neuropathic
AdmissionFirst follow-upLast follow-up
Mixed
Pain Intensity
41
WHO Duration and Efficacy
42
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
43
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
44
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
45
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
46
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
47
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.
48
Neuropathic Pain Scale
49
Neuropathic pain scale
50
Treatment
“Assessment is crucial to proper treatment”
Options– Opioids– Anticonvulsants– Tricyclics– Tramadol– Buproprion– Capsacian
51
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
52
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
53
Oxycodone
0
10
20
30
40
50
60
Steady pain Brief pain Allodyia
PlaceboOxycodone CR
Weekly visual analog scale (pain score)
54
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)
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Buproprion Pain Score
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Comparison of Global Ratings of Pain ReliefRating Placebo Buproprion SR
Pain worse 14 (34.1%) 3 (7.3%)
Pain unchanged 23 (56.1%) 8 (19.5%)
Pain improved 2 (4.9%) 15 (36.6%)
Pain much impr. 2 (4.9) 14 (34.1)
Pain free 0 1 (2.4%)
Total impr. 4 (9.8) 30 (73.2)*
* p<0.001
Patients (%) Patients (%)
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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
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Tramadol
0
0.5
1
1.5
2
2.5
Baseline Day 14 Day 28 Final Visit
PlaceboTramadol
Patient ratings of pain intensity (pain intensity score)
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Tramadol
0
0.5
1
1.5
2
2.5
Day 14 Day 28 Final Visit
PlaceboTramadol
Patient ratings of pain relief (pain relief score)
60
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
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Clonidine Pain Intensity
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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
63
Tricyclic Antidepressants
Tertiary Amines– Imipramine– Amitriptyline
Secondary Amines– Nortriptyline– Desipramine
64
Tricyclic Antidepressants
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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
66
Tricyclic Antidepressants
67
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
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Tricyclic Antidepressants
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Tricyclic Antidepressants
70
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
71
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
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Trigeminal Neuralgia
Anticonvulsant agents– Carbamazepine– Phenytoin– Clonazepam– Felbamate– Gabapentin– Lamotrigine– Oxcarbazepine
73
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 (400-800mg/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
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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
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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
76
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)
77
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
78
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
79
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
80
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
81
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
82
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
83
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
84
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
85
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
86
Diabetic NeuropathyDuloxetine (Cymbalta)
First medication specifically approved for PDN– 60mg qd-bid– Well tolerated– NE/5HT reuptake inhibitor– Nausea, Constipation, Dry mouth, Fatigue
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
88
Drug Cascade
89
On the Horizon
Antioxidants (α-Lipoic Acid)– Studies being conducted – 30 minute infusion (5x week)– Impractical clinical use– Prevention?
90
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
91
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
92
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
93
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
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