Pain: Nociceptive and Neuropathic Considerations Principles of Drug Action I Marlon Honeywell,...

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

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

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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

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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)

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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

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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)

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Assessment/Treatment (WHO)Patient Make-up

NociceptiveNeuropathicMixed

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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

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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

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0

10

20

30

40

50

60

70

Nociceptive Neuropathic

AdmissionFirst follow-upLast follow-up

Mixed

Pain Intensity

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WHO Duration and Efficacy

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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

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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

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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


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

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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.

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Neuropathic Pain Scale

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Treatment

“Assessment is crucial to proper treatment”

Options– Opioids– Anticonvulsants– Tricyclics– Tramadol– Buproprion– Capsacian

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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

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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

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Oxycodone

0

10

20

30

40

50

60

Steady pain Brief pain Allodyia

PlaceboOxycodone CR

Weekly visual analog scale (pain score)

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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)

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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

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Tricyclic Antidepressants

Tertiary Amines– Imipramine– Amitriptyline

Secondary Amines– Nortriptyline– Desipramine

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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

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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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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

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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

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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)

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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

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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

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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

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Drug Cascade

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On the Horizon

Antioxidants (α-Lipoic Acid)– Studies being conducted – 30 minute infusion (5x week)– Impractical clinical use– Prevention?

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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

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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

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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

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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

Pain: Nociceptive and Neuropathic Considerations Principles of Drug Action I Marlon Honeywell,...

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