Transcript Dia 1 - International Pain School

International Pain School
Treatment
of neuropathic pain
High technology treatment methods
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General aspect of management
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
alcohol?
• 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)
Diagnosis of neuropathic pain
Radicular pain (C6)
Painful polyneuropathy
Diagnosis of neuropathic pain
1. Diagnosis of lesion or disease of the somatosensory system
– Without this the pain cannot be neuropathic!
2. Location of pain is neuroanatomically logical
(pain drawing is useful) Character of pain (e.g., burning,
electric shock like pain), presence of other sensory
symptoms (paresthesia, dysesthesia) and abnormal
findings in sensory testing (hypo- or hyperesthesia,
allodynia)
– Neuropathic pain screening tools (e.g., DN4) are based
on pain descriptors, and some include also simple
sensory testing
Diagnosis of neuropathic pain
3. Measurement of pain intensity and impact of pain on
functional capacity and well-being
– Treatment effect is assessed by improvement in
these aspects
What are we treating?
Pain
Causative disease and
its treatment?
Elderly?
Functional
impairment?
Sleep
disturbance?
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
* See evidence of efficacy of pharmacotherapy in systematic reviews, e.g. Cochrane
reviews, Finnerup et al. Pain 2005;118:289-305, Finnerup et al. Pain 2010 ;150:573-81
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
• Check possible interactions with the patient’s current medication
(e.g., antiretroviral drugs, SSRIs)
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
– to the recommended maximal dose
– to the maximal tolerated dose
– 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 of 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
– an antidepressant combined with gabapentin
or pregabalin
– 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 mechanism of action
can be combined.
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
• Inform patient of possible deleterious effect of drugs on alertness;
driving is not recommended during titration of drugs with possible
sedative effect
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
• 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 (but
no evidence of efficacy in other NP conditions)
• 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 oxcarbazepine
Tramadol
• Tramadol itself has serotoninergic and noradrenergic
effect, and its active metabolite (after metabolism by
CYP2D6 enzyme) is opioid agonist
• Dosing: test 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
Pregabalin
• The efficacy of pregabalin has been established in painful
diabetic neuropathy, postherpetic neuralgia and spinal
cord injury pain
• Dosing: start with 75 mg at bedtime and increase the
dose with 75 mg every 3 days until pain relief or maximal
dose (600 mg/day)
• Effective dose: 150-600 mg/day (divided in 2 doses)
• Adverse effects: include dizziness and somnolence,
peripheral edema, weight gain, asthenia, headache,
dry mouth and blurred vision
• If renal function impaired, reduce the dose
• No pharmacokinetic interactions
Strong opioids (e.g., oxycodone)
• Are regarded as the last option*
• Can be combined with antidepressants, antiepileptics
or topical treatment
* National guidelines on use of opioids for non-cancer pain are available for
many countries
Strong opioids (e.g., oxycodone)
Preconditions for an opioid trial
• The cause of pain is known
(neuropathic or nociceptive & neuropathic pain)
• Pain is severe in spite of other treatments
(which continue during opioid trial)
• The patient has no previous dependence or abuse problems
• Psychiatric problems (depression, anxiety) are adequately treated
• The patient consents to have a trial with pre-set dose schedule and
tapering off of the drug, if pain relief and improved function are
not achieved.
Strong opioids (e.g., oxycodone)
• Use only slow-release preparations
• Starting dose 10-20 mg b.i.d., dose escalation with 10-
20 mg/day every 3-5 days until pain relief, intolerable
side effects or maximal dose (80-120 mg oxycodone for
neuropathic pain)#
• Pre-treatment of constipation with lactulose
# Oxycodone is the opioid with best evidence in RCTs, but equivalent doses of
slow-release morphine can also be used due to availability and cost
Referral to a neurosurgeon?
Primary trigeminal neuralgia
Refer to a neurosurgeon if
carbamazepine or oxcarbazepine
fail to relive pain.
Ganglion thermocoagulation and
microvascular decompression are
the most common techniques.
Referral to a neurosurgeon?
Other neuropathic pains:
Consider referral to a specialist for spinal
cord stimulation, if a patient has chronic
(> 6 months) peripheral neuropathic pain,
complex regional pain syndrome or
neuropathic pain associated with partial
spinal cord injury (with preserved dorsal column) and the
pain is severe in spite of adequate drug trials.
Patient cases
Leo 78 years, history and
clinical examination
• Retired taxi-driver, widow, lives in a remote village
• The only medication is tamsulosin
due to prostatic hyperplasia
• Herpes zoster at left 5th thoracic dermatome
for 1 year ago was treated with acyclovir
• Severe pain, tenderness, disturbed sleep
• Dynamic mechanical allodynia and pinprick
hyperalgesia at the anterior part of the
painful dermatome
Leo 78 years, pharmacotherapy
• Topical lidocaine: abolished allodynia but not the
continuous spontaneous pain
• Amitriptyline was considered but not started due to prostate
hyperplasia and old age (relative contraindications)
• Gabapentin: (initial dose 300 mg at bed-time, maintenance
dose 600 mg t.i.d.) alleviated pain to mild
• Allodynia recurred with the cessation of topical lidocaine;
continues with combination medication
• Medication well tolerated, drives a car
Take home message: especially in the elderly living alone topical treatments are
recommended due their safety and tolerability, but on their own they may not
provide sufficient pain relief.
Anna 52 years, history and
examination findings
• A previously healthy nurse who has had low back pain,
which radiculates to the left L5 dermatome, for 2 months
• Clinical findings: Laseque -/+70°, no limitation of range of
movements, no motor abnormalities, tendon reflexes
normal, in sensory testing pinprick hypoalgesia at left L5
• In MRI scan a small prolapse in L IV-L V, no compression
of neural structures  conservative treatment
• In ENMG an aftermath of a mild L5 root lesion
Anna 52 years, treatment
• Information from the doctor
– No indication for surgery
– There is a mild root lesion, but the pain may be
relieved with time
– No need to restrict physical activity (“do what you
can without essentially exacerbating the pain”)
– If needed, a drug trial to relive neuropathic pain
is possible
Anna 52 years, treatment
• Counselling by a physiotherapist
– Ergonomy
– Suitable physical activity not exacerbating the pain
• Pharmacotherapy: amitriptyline up to 70mg/day
– Good pain relief (average pain from 8 to 3 on NRS 010)
– The only adverse effect was mild constipation
controlled with diet
Take home messages:
1) Sufficient and uniform information from the health care professionals
2) Monotherapy with a cheap first-line drug for neuropathic pain was successful
Summary
• Tailored medication
– Choice of the drug(s)
– Careful dose escalation
• Sufficient information for the patient and family members
• Close follow-up
• Psychosocial support, non-pharmacological methods
• Realistic goal-setting
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 & Aki 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
International Pain School
The project is supported by these organizations: