Transcript Dia 1 - International Pain School

International Pain School
Treatment
of neuropathic pain
Low technology treatment methods
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General aspects of managing
of neuropathic pain
IASP definition of neuropathic pain
Neuropathic pain is a pain caused by a lesion or
disease of the somatosensory system.
www.iasp-pain.org/resources/painDefinition
Examples of causes of neuropathic pain
Peripheral nervous system
• Radiculopathies related to • Polyneuropathies
spinal column diseases
• Nerve traumas
• Infectious diseases
– Diabetes
– Drug induced (e.g.,
antiretroviral drugs,
– HIV
neurotoxic
– Herpes zoster
chemotherapy)
– Leprosy
– Vitamin deficiency
• Cancer-related
– Immune mediated
Examples of causes of neuropathic pain
Central nervous system
• Stroke
• Spinal cord injury
• Multiple sclerosis
Both the disease itself and neuropathic pain can
cause disability.
Neuropathic pain:
underlying mechanisms
Peripheral mechanisms
Central mechanisms
• Membrane hyperexcitability
– Ectopic discharges
• Na+ channel
expression 
• Neuropeptide
release 
• Peripheral sensitization
• Membrane hyperexcitability
– Ectopic discharges
• Wind up
• Central sensitization
• Denervation hypersensitivity
• Loss of inhibitory controls
In neuropathic pain there is increased activity and decreased
inhibition in the somatosensory system. Pharmacotherapy is
based on modulation of these phenomena by decreasing the
spontaneous activity and transmitter release and enhancing the
inhibitory mechanisms.
Mechanism-based treatment?
Etiology
Mechanisms
Symptoms
Individualized mechanism-based treatment is
currently not possible.
Trial and error - testing of the evidence-based drugs,
individual tailoring.
What is expected from a doctor?
• To know the concept of neuropathic pain
• To be able to recognize neuropathic pain
• To be able to diagnose the causative
disease and to treat it, if possible
(e.g., diabetes)
• To be able to start the first line
medication to relieve neuropathic pain
• To be able to refer the patient to a specialist,
if needed (for diagnostic procedures or treatment)
Characteristics of neuropathic pain
• Typical for neuropathic pain:
– spontaneous and provoked pain (often
different from previous familiar pains)
– other positive symptoms such as paresthesiae
– negative signs (sensory deficits)
• Depending on the site of the lesion, there may be
other symptoms and clinical findings (e.g., motor
paresis, muscle cramps, autonomic nervous
symptoms)
Definitions of common features
suggestive of neuropathic pain
Feature
Definition
Paresthaesia
An abnormal sensation, whether spontaneous or evoked
Dysesthesia
Unpleasant sensation, whether spontaneous or evoked
Hypoesthesia
Decreased sensitivity to stimulation
(tactile or thermal, both are frequent)
Hyperesthesia
Increased sensitivity to stimulation
(tactile or thermal, both are rare)
Hypoalgesia
Diminished pain response to a normally painful stimulus
Hyperalgesia
An increased response to a stimulus which is normally painful
Allodynia
Pain due to a stimulus which does not normally activate the
nociceptive system
a) Mechanical (dynamic and / or static allodynia)
b) Thermal (warm and / or cold allodynia)
Diagnosis of neuropathic pain
Radicular pain (C6)
Painful polyneuropathy
Diagnosis of neuropathic pain
1. Location of pain is neuroanatomically plausible.
Pain drawing is useful!
2. Abnormal sensory function is found in clinical
examination.
3. The disease causing the neuropathic pain
can be identified by:
– General examination
– Neurological examination
(findings  location of the lesion)
– Referral to further examinations, if needed.
Neurological examination:
sensory testing
Nerve fiber
type
Sensation
Clinical testing instrument
A beta
Touch
Fingers, piece of cotton wool or a soft brush
Vibration
Tuning fork (64 or 128 Hz)
Pinprick,
sharp pain
Sharp sticks
(e.g., wooden cocktail or sharp, plastic sticks)
Cold
Cold object (20°)
Warmth
Warm object (40°)
A delta
C
Testing of mechanical allodynia:
1) Dynamic: brush
2) Static: compression with finger or algometer
Neurological examination:
sensory testing
• Sensory testing is performed on unclothed skin
• Sensory testing is directed according to the information
from the history and pain drawing
• The findings in the painful area are compared with
findings in the contralateral area in unilateral pain and
in other sites on the proximal-distal axis in bilateral pain
Neurological examination:
motor testing
• Inspection: muscular wasting, movements
• Palpation of muscles (tension, tenderness)
• Muscle strength
– 0 = total paralysis
– 1 = flicker
– 2 = movement with gravity eliminated
– 3 = movement only against gravity
– 4 = movement can be overcome by resistance
– 5 = full power
• Tone (spasticity, rigidity)
• Gait
What are we treating?
Pain
Causative disease and
its treatment?
Functional
impairment?
Sleep
disturbance?
Elderly?
Anxiety?
Depression?
Concomitant diseases?
Multiple drug use?
Disability?
Information, follow-up, case management
• The patient needs information of the character of the
pain and of the causative disease and its treatment
• Follow-up and a possibility of the patient to contact the
doctor or nurse (the “case-manager”) is important to
ensure compliance and safe treatment
• Support of the patient is an essential part of the
management
• Team work is recommended
Pharmacotherapy of neuropathic pain
Pharmacotherapy is the most important treatment
for those with moderate or severe pain
•Goals:
– (partial) pain relief (>50%, >30%)
• Complete pain relief is exceptional; hence some
pain relief is a realistic goal, which needs to be
explained to the patient.
– functional improvement and better quality of life
– better sleep and mood, relief of anxiety
•Many patients have some, moderate or intolerable
side effects.
•There are many refractory patients
Principles of pharmacotherapy of
neuropathic pain
1) Individual drug selection
Cause of neuropathic pain
• Most evidence comes from studies of painful polyneuropathies
and postherpetic neuralgia, but in less studied conditions, the
drugs with evidence from the best studied conditions are tested
Other medical problems and their medication
• Be careful with the contraindications and precautions
– cardiac conduction disturbances: don’t select TCAs
– urinary retention: don’t select TCAs or duloxetine
– uncontrolled blood pressure: don’t select venlafaxine or
duloxetine
Previous drug trials
• If some drug has been adequately tested previously with poor
result, repetition of trial with the same drug is not rational
Principles of pharmacotherapy of
neuropathic pain
2) Rational dosing and sufficient information
• Tailored dosing
• Clear information of dosing and possible side effects
• “Start low, go slow, reach high”
• Escalate to effective or maximal tolerated dose
• Adequate drug trial? Slow up-titration
a. to the recommended maximal dose
b. the maximal tolerated dose
c. to the dose providing relevant pain relief
Principles of pharmacotherapy of
neuropathic pain
3) Assessment of efficacy and adverse effects
Assess efficacy
•pain relief
•relief of comorbidities (e.g., better sleep, better mood,
relived anxiety)
•functional improvement
•better quality of life
Assess adverse effects
•patients are usually ready to tolerate mild adverse effects
•with slow titration side effects are usually relieved
(e.g., dizziness
caused by gabapentinoids or tiredness caused by TCAs)
Taper useless or harmful medications
Principles of pharmacotherapy of
neuropathic pain
4) Rational polypharmacy, if needed
• If one drug provides some pain relief, another drug with
different mechanism of action can be combined with
the first drug
– e.g. an antidepressant combined with gabapentin
or pregabalin
– e.g. a systemic drug combined with a topical drug
• The doses in combination therapy may be a bit lower
than in monotherapy.
Evidence-based drugs for neuropathic
pain: mechanism(s) of action
Drug(s)
Mechanism(s) of action
Tricyclic antidepressants
(e.g., amitriptyline, nortriptyline)
Serotonin and noradreanalin reupatake
inhibition, sodium channel blocking, NMDA
antagonism
SNRIs
(e.g., venlafaxine, duloxetine)
Serotonin and noradreanalin reupatake
inhibition
Carbamazepine, oxcarbazepine
Sodium channel blocking
Topical lidocaine
Sodium channel blocking
Gabapentin, pregabalin
(”gabapentinoids”)
Regulation of voltage-dependent calcium
channels in the central nervous system
Tramadol
Serotonin and noradreanalin reupatake
inhibition, m-opioid agonism
Opioids
m-opioid agonism
Topical capsaicin
TRPV1-receptor agonism
In combination treatment - drugs with different mechanisms of action can
be given together.
Evidence-based drugs for neuropathic
pain: dosing
Drug
Starting dose
Target dose
Tricyclic antidepressants
10-25 mg at bedtime
20-150 mg (in 1-3 doses)
Venlafaxine
75 mg/day
225 mg/day (in 1-2 doses)
Duloxetine
60 mg/day
120 mg/day (in 1-2 doses)
Carbamazepine
100 mg b.i.d.
200-1200 mg/day (in 2-3 doses)
Oxcarbazepine
150 mg b.i.d.
600-1800 mg/day (in 2-3 doses)
Tramadol
50 mg/day
300-400 mg/day (in 2-3 doses)
Gabapentin
300 mg at bedtime
3600 mg/day (in 3 doses)
Pregabalin
75 mg at bedtime
600 mg/day (in 2-3 doses)
Topical lidocaine
5% cream: 3 times a day
Patch: for 12h every day
5% cream: 3 times a day
Max. 3 patches at the same time
Capsaicin patch
Patch for 30-60 min every 3 month
Max. 4 patches/session
Morphine (slow-release)
10-20 mg b.i.d.
160 mg/day (in 2 doses)
Oxycodone (slow-release)
10 mg b.i.d.
120 mg/day (in 2 doses)
Algorithm for treatment of neuropathic
pain
Peripheral neuropathic pain
Local
allodynia
Gabapentin /
pregabalin
Topical
lidocaine
SNRI
Capsaicin plaster?
Trigeminal neuralgia
Central neuropathic pain
Central post-stroke pain
Carbamazepine or
oxcarbazepine
TCA
Neurosurgery
Opioids?
Abbreviations:
SNRI = serotonin and noradreanalin reuptake inhibitors
TCA = tricyclic antidepressants
Amitriptyline
Spinal cord injury pain
Pregabalin
Multiple sclerosis pain
(Cannabinoids)
Questions patients often ask
about treatment
• Are the drugs harmful to my liver, kidneys, stomach?
• Are the drugs harmful to my brain?
• Will they affect my mood?
• Will they affect my sex life? – individual importance
• Will I still be able to drive?
• Are they addictive?
• Can I use alcohol with them?
• Can I change the dose if needed?
• Is it ok to stop taking them abruptly?
• Are they expensive?
Pain and cognitive performance
Medication
Disturbed sleep
COGNITIVE
PERFORMANCE
PAIN
Anxiety and stress
Depression
• Revise previous medication, if needed
• Start with low dose, titrate individually, follow up
carefully
• Evaluate effect on pain, comorbidities and cognitive
performance
Detailed information about
drugs for neuropathic pain
Tricyclic antidepressants (TCAs)
Efficacy
• The efficacy of TCAs has been established in peripheral
neuropathic pain (pain diabetic neuropathy,
postherpetic neuralgia) and in central post stroke pain
– The pain relieving effect of TCAs in independent of
their antidepressant effect (comes quicker and with
lower dose)
Tricyclic antidepressants (TCAs)
Dosing
• Starting: 10–25 mg in a single dose at bedtime
• Effective dosages vary from 25–150 mg from
case to case
• The average dosage for amitriptyline is 75 mg/day
• Monitoring of serum drug concentrations may be
helpful
Contraindications and
precautions of TCAs
• TCAs cannot be used in recovery phase of myocardial
infarction or in patients with cardiac conduction
disturbances.
• TCAs should be used with caution in patients with history
of seizures, prostatic hypertrophy, urinary retention,
chronic constipation, narrow-angle glaucoma, increased
intraocular pressure, suicidal ideations and in patients
receiving concomitant SSRI, SNRI or tramadol treatment.
Adverse effects of TCAs
• Anticholinergic adverse effects are common
– Dry mouth: drink water, salivation-producing
resoriblets
– Constipation: bulk laxatives
– Blurred vision or urinary retention: taper TCA off
• Cardiovascular adverse effects:
– Orthostatic hypotension: monitor blood pressure
(supine and standing)
– Prolongation of PR and QTc intervals: ECG screening
– Increased heart rate: taper TCA off
Adverse effects of TCAs
• Sedation, confusion and sweating can also occur
• Imipramine and nortriptyline cause fewer anticholinergic
effects and less sedation
Venlafaxine
• Efficacy of venlafaxine has been shown
in painful polyneuropathy
• Dosing: start with 75 mg once daily, and escalate
the dose with 75 mg at 2 weeks interval.
Effective dosage is 150-225 mg/day.
• Venlafaxine is contraindicated in patients with
uncontrolled hypertension, and blood pressure
monitoring is recommended during the treatment
Venlafaxine
• Venlafaxine should be used with caution in patients
with history of mania, seizures and bleeding tendency
• Adverse effects: nausea, dry mouth, headache and
sweating, abnormal dreams, decreased libido, dizziness,
insomnia, nervousness, sedation, tremor, visual
disturbance, hypertension, palpitations, anorexia and
urination hesitancy
Duloxetine
• Efficacy of duloxetine has been shown in painful
diabetic polyneuropathy
• Dosing: start with 60 mg once a day, and increase the
dose with 30-60 mg until 120 mg, when needed
(effective dose is 60-120 mg/day)
• Adverse effects: nausea, somnolence, dry mouth,
constipation, reduced appetite, diarrhoea,
hyperhidrosis, and dizziness
• Duloxetine is contraindicated in unstable
arterial hypertension.
Carbamazepine (slow release)
• Is a drug of choice for primary trigeminal neuralgia
(but no evidence of efficacy in other NP conditions)
• Dosing: slowly raise the initial dosage of 100 mg twice
daily until freedom from pain is achieved
(often 600-800 mg daily, even 1200 mg daily)
• Adverse effects: Sedation, dizziness,
gait abnormalities, liver and blood changes,
hyponatraemia, enzyme induction
• Blood count, liver enzyme and plasma sodium
monitoring is recommended
Carbamazepine (slow release)
• Carbamazepine has lots of interactions with other
drugs (e.g., oral contraceptives)
– Check the possible interactions before prescribing
carbamazepine
– Check serum drug concentration in suspected
enzyme induction
• Once the neuralgia is in remission, try to decrease the
dose slowly
Oxcarbazepine
• Is a drug of choice for primary trigeminal neuralgia
• Has fewer interactions and is better tolerated
than carbamazepine
• Dosing: slowly raise the initial dosage of 150mg twice
daily until freedom from pain is achieved
(600-1800 mg daily)
• Adverse effects: somnolence, headache, dizziness,
diplopia, nausea, vomiting and fatigue
• Hyponatremia is possible; check plasma sodium level
before commencing the treatment and after some
weeks of use of oxacarbazepine
Tramadol
• Tramadol itself has serotoninergic and noradrenergic
effect, and its active metabolite (after metabolism by
CYP2D6 enxyme) is opioid agonist
• Dosing: testi with a 50 mg capsule, and if it is well
tolerated, escalate the dose gradually up to
300-400 mg/day
• Depot and short-acting capsules can be combined
• Adverse effects: nausea, sedation, excessive sweating,
dizziness, constipation, headache
• Use with caution in patients with epilepsy or SSRI or
SNRI medication
Gabapentin
• The efficacy of gabapentin has been established in
painful diabetic neuropathy and postherpetic neuralgia
• Dosing: start with 300 mg at bedtime, and escalate with
300 mg/day or more slowly until sufficient pain relief
• Effective dose: 900-3600 mg/day (divided in 3 doses)
• Adverse effects: dizziness, somnolence, peripheral
oedema, weight gain, asthenia, headache, dry mouth
and blurred vision
• If renal function impaired, reduce the dose
• No pharmacokinetic interactions
Patient cases
Case 1: Afghan housewife
Case 1
• Patient comes to visit a psychiatric outpatient clinic,
escorted by her husband.
• Complains of continuous burning and lancinating pain
in her left arm and on the right side of the face.
• Pain is much more severe in the face than in the arm.
Case 1
History
• Less than 3 years earlier, patient had suffered an attack
of severe vertigo and vomiting, slurred speech and
clumsiness of left hand
• most of her symptoms had subsided within a week but
slight clumsiness of left hand persisted
• she had not consulted a doctor that time
• pain in face and left arm had started gradually after
about 2 months of this episode
Case 1
Clinical examination
• slight drooping of right eyelid
• slight clumsiness, ataxia and dysmetria of right arm
• normal and symmetric muscle strength,
normal speech
• loss of pinprick and temperature sensation on right
cheek and diminished pinprick and temperature
sensation in left arm
• cardiac auscultation: normal
Case 1
Diagnosis
• (highly probable) post stroke pain
due to right lateral medullary infarction (Wallenberg
syndrome); posterior inferior cerebellar artery occlusion?
• Spino- and trigeminothalamic tract are injured in
Wallenberg syndrome (denervation sensitivity)
• Pain may start in acute or chronic (months
after stroke) stage
• Many patients have swallowing difficulties
in acute stage
Lateral medullary syndrome
Case 1
Treatment
• Nortriptyline was started (initiation 10 mg/day and
increase up to maximum tolerated dose)
• Later combined with carbamazepine (100 mg bid and
increased up to 300 mg bid) (lancinating, electric shock
like pain on the right side of the face).
Case 2: Maasai-hunter from Tanzania
Case 2
• Male Maasai warrior, 18 years
• Visits local doctor due to burning pain in his left knee
• Pain gets stronger during kneeling
• 3 months ago he had tripped over a stone on a
hunting trip and hit his left knee hard.
Case 2
Imaging
• Knee X-ray did not reveal any fractures or bone
abnormalities
Case 2
Clinical examination
• remarkable hyperesthesia, hyperalgesia and
dynamic allodynia at the anteromedial aspect of
the left knee, sensory exam of right knee normal
• patient was not able to kneel down properly
(painful)
• no impairment of tendon reflexes
Case 2
Diagnosis
• neuropathic pain due to lesion of the infrapatellar
branch of the left saphenous nerve
Infrapatellar nerve injury
Patella
Infrapatellar
nerve
Tibial
tuberosity
Lateral
Medial
Injury, Vol 43, Issue 6, 2012, Pages 779–783
Case 2
Treatment
• nortriptyline or amitriptyline 10 mg, increase
gradually up to maximum tolerated dose
• combination with topical anesthetic gel
(Lidocaine 5 %)
• physiotherapy and exercises
• surgical evaluation if neuroma suspected
Summary
• Tailored medication
– Choice of the drug (s)
– Careful dose escalation
• Sufficient information for the patient
• Realistic goal-setting
• Close follow-up
• Psychosocial support
This talk was prepared originally by:
Maija Haanpää, M.D. & Aki Hietaharju, M.D.
Helsinki & Tampere, Finland
International Pain School
Talks in the International Pain School include the following:
Physiology and pathophysiology of pain
Nilesh Patel, PhD, Kenya
Assessment of pain & taking a pain history
Yohannes Woubished, M.D, Addis Ababa,
Ethiopia
Clinical pharmacology of analgesics
and non-pharmacological treatments
Ramani Vijayan, M.D. Kuala Lumpur, Malaysia
Postoperative – low technology treatment methods
Dominique Fletcher, M.D, Garches & Xavier
Lassalle, RN, MSF, Paris, France
Postoperative– high treatment technology methods
Narinder Rawal, M.D. PhD, FRCA(Hon),
Orebro, Sweden
Cancer pain– low technology treatment methods
Barbara Kleinmann, MD, Freiburg, Germany
Cancer pain– high technology treatment methods
Jamie Laubisch MD, Justin Baker MD, Doralina
Anghelescu MD, Memphis, USA
Palliative Care
Jamie Laubisch MD, Justin Baker MD,
Memphis, USA
Neuropathic pain - low technology treatment methods
Maija Haanpää, MD, Helsinki &
Hietaharju, MD, Tampere, Finland
Neuropathic pain – high technology treatment methods
Maija Haanpää, M.D., Helsinki & Aki Hietaharju,
M.D., Tampere, Finland
Psychological aspects of managing pain
Etleva Gjoni, Germany
Special Management Challenges:
Debra Gordon, RN, DNP, FAAN, Seattle, USA
Aki
International Pain School
The project is supported by these organizations: