Coping with Neuropathic Pain

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• Coping with Neuropathic Pain
• Interactive Small-Group Workshop

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Educational Team

• Aline Boulanger, MD, Anesthesiologist
• Director, Pain Clinics, Hôtel-Dieu, Centre
  hospitalier de lUniversité de Montréal, and
  Hôpital du Sacré-Cur de MontréalMontreal,
  Quebec
• Dominique Dion, MD, Family Physician
• Hôpital Maisonneuve-RosemontSt. Marys Hospital
  CentreMontreal, Quebec
• Martin Labelle, MD, Family Physician
• Coordinator, Workshop Design, Continuing
  Professional DevelopmentFaculty of Medicine,
  Université de MontréalMontreal, Quebec
• Robert L. Thivierge, MD, Pediatrician
• Vice Dean, Continuing Professional Development
  
  Faculty of Medicine, Université de Montréal
• Montreal, Quebec

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Collaborators

• Helen Hays, MD, Family Physician
• Associate Clinical Professor, University of
  Alberta Edmonton, Alberta
• Roman D. Jovey, MD, General Practitioner
• Pain and Addiction Medicine, The Credit Valley
  HospitalMississauga, Ontario
• Brian Knight, MD, Anesthesiologist
• University of Alberta Misericordia Community
  Hospital and Health CentreEdmonton, Alberta
• Dwight E. Moulin, MD, Neurologist
• London Regional Cancer Centre, London Health
  Sciences Centre Victoria CampusLondon, Ontario

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Workshop Schedule

• 000 Introduction - Presentation of Objectives
  - Evaluation of Participants Expectations
• 010 Stage 1 Diagnosis and Evaluation of
  Neuropathic Pain
• 025 Stage 2 Pharmacotherapy
• 050 Summary and Key Messages Review of
  Objectives and Expectations
• 055 Evaluation
• 100 End of Workshop

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General Learning Objective

• To enable general practitioners and medical
  specialists to optimize the management of
  patients with neuropathic pain

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Specific Learning Objectives

• At the end of this workshop, participants will be
  able to
• 1. Differentiate neuropathic pain from other
  types of chronic pain, based on its clinical
  characteristics
• 2. Identify the underlying diagnosis and
  comorbidities often associated with chronic pain
• 3. Prescribe appropriate single or combined
  pharmacotherapy to relieve neuropathic pain

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Your Expectations
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Stage 1

• Diagnosis and Evaluation of Neuropathic Pain

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Exercise 1

• Match Types of Pain With Conditions

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Exercise 1a
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Types of Pain
neuropathic
mixed
nociceptive
central / peripheral nervous system
visceral
somatic
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Exercise 1a
X X X X
X
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Exercise 1b
X X X X
X ? ?
X
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Pathophysiology and Investigation
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Pain 93 (2001)Spinal cord glia new players in
painLinda R. Watkins, Erin D. Milligan, Steven
F. MaierDepartment of Psychology and the Center
for Neurosciences, University of Colorado at
Boulder CO

• Glia, microglia and astrocytes, may participate
  in creating and maintaining pathological pain.
• Glia are implicated in inflammation, infection
  (viral, HIV/AIDS and ? zoster ?? fibromyalgia)
  and neuropathic pain.
• Glia are activeated by ATP, bradykinin,CGRP,CCK-B
  , EAAs (via NMDAreceptors) AMPA and kainate
  receptors, prostaglandins and substance P,
  causing production of pro-inflammatory cytokines,
  IL-1, IL-6, TNF as well as increasing levels of
  most chemicals known to induce pain. This
  activation spreads from cell to cell across gap
  junctions.
• This explains extraterritorial pain (
  non-anatomical pain, thought to be non
  organic) and the phenomenon of mirror image
  pain.

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Neuropathic Pain Pain Description

• Patient may report pain that is
• Spontaneous
• Continuous burning, pressure, squeezing
• Intermittent (paroxysms) electrical, stabbing,
  shooting
• Evoked
• Provoked or worsened by touch, brushing and/or
  cold contact Allodynia
• Sometimes accompanied by paresthesias/
  dysesthesias
• Numbness, pins and needles, tingling, itch

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Neuropathic Pain Physical Features

• Investigate
• Muscle weakness
• Sensory abnormalities
• Touch
• Rubbing
• Cold
• Vibration
• Autonomic dysfunction
• Temperature or colour changes

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Neuropathic Pain

• Implicated mechanisms
• Peripheral sensitization
• Inflammation
• Spontaneous peripheral nerve activity (Na)
• Central sensitization
• Ca channels
• AMPA and NMDA receptors
• Reduced inhibitory activity

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Medication
TCA Tricyclic antidepressant, SSRI Selective
serotonin reuptake inhibitor, SNRI Serotonin and
norepinephrine reuptake inhibitor, CBZ
Carbamazepine, OXC Oxcarbazepine, TPM
Topiramate, LTG Lamotrigine GBP Gabapentin
LVT Levetiracetam PREGAB Pregabalin.Adapted
from Beydoun A., Backonja M.M Mechanistic
stratification of antineuralgic agents. Journal
of Pain and Symptom Management, 2003255S
(p.S27) with permission from the U.S. Cancer
Pain Relief Committee
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Investigations

• Determine the type of pain (perform a clinical
  evaluation)
• The diagnosis is based primarily on historyand a
  physical examination
• Neuroimaging and electromyograms are usefulin
  cases where a neurological examinationwould
  indicate lesions to these structures

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Diagnostic ToolThe DN4 Questionnaire

• When the clinician suspects neuropathic pain,the
  DN4 questionnaire is a useful diagnostic tool
• There are four questions, with a total of ten
  itemsto check off
• The clinician asks the patient the questions and
  fills in the questionnaire. For each item, the
  clinician must answer yes or no
• At the end of the questionnaire, the clinician
  adds up the score, counting one point for each
  yes and zero for each no. The sum obtained gives
  the patients score, out of 10
• If the patients score is equal to or greater
  than 4, thetest is positive (sensitivity 82.9
  specificity 89.9)

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Bouhassira D, et al. Pain 200511429-36.
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DN4 Questionnaire

• PATIENT INTERVIEW
• QUESTION 1 Does the pain have any of the
  following characteristics?
• Burning
• Painful sensation of cold
• Electric shocks
• QUESTION 2 Is the pain associated with any of
  the following symptoms in the same area?
• Tingling
• Pins and needles
• Numbness
• Itching
• PATIENT EXAMINATION
• QUESTION 3 Is the pain located in an area where
  examination reveals either of the following?
• Hypoesthesia to touch
• Hypoesthesia to prick
• QUESTION 4 Is the pain provoked or increased by
  the following?
• Brushing

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Bouhassira D, et al. Pain 200511429-36.
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Stage 2

• Pharmacotherapy

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MR Z.

• Male 60, had R opthalmic zoster 8 months
  previously.
• He did receive appropriate antiviral drug, but he
  continues to suffer burning pain, with increased
  pain on touching the forehead. Pain score 4-5 to
  9-10/10.
• He received codeine during the acute episode, but
  no prescribed analgesic since.
• Relevant other hx Hypertension, stable angina,
  mild renal impairment creatinine 138 mmol/L
• Meds Ramipril, Atorvastatin, Atenolol, NTG SL,
  ASA 81

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Mr S.

• Male, 48 Type 2 DM diagnosed 4 years ago.
• C/o burning pain in the feet. Started 2 years
  ago. Also some numbness. Pain score gradually
  increased to 6-7/10 continuous day/night.
• He uses OTC Acetaminophen up to 5gm/day
  ibuprofen 1600mg/day. Stress aggravates the pain.
• He has mild albuminuria, poor glycemic control.
  He uses alcohol socially.
• Meds Metformin, Glyburide, ASA 81,
  Atorvastatin,
  Ramipril.

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Incidence of Chronic Post-operative Pain

• Breast surgery
• Breast/chest pain 11 to 57
• Post-mastectomy phantom pain 13 to 24
• Arm/shoulder pain 12 to 51
• Gallbladder surgery 3 to 56
• Cardiac surgery 15 to 56
• Inguinal hernia surgery 0 to 37

Perkins, Kehlet. Anesthesiology, 2000
(Review). Macrae. British Journal of
Anaesthesiology, 2001 (Review).
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MR. B.P.

• Male, 54, hurt back at work 2 years ago. NSAIDs,
  muscle relaxants and PT did not help. Due to
  ongoing severe pain he underwent discectomy 1
  year ago with no benefit.
• C/o LBP with radiation down the R leg. Burning
  pain in the back and electrical shock-like
  sensation down the leg. Pain score 8-9/10.
• MRI Fibrosis around L5 root.
• Current meds GBP 1200mg tid, amitryptiline 150mg
  hs.
• TNS is of slight benefit.

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Adjuvants / Coanalgesics

• An adjuvant is a medication that is not primarily
  indicated for the treatment of pain, but which
  has been found to be useful in pain management
• Tricyclic antidepressants
• SSRIs
• SNRIs
• NMDA blockers
• Anticonvulsants

SSRIs Selective serotonin reuptake inhibitors
SNRIs Selective norepinephrine reuptake
inhibitorsNMDA N-methyl-D-aspartate
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Rules for Prescribing Adjuvants / Coanalgesics

• Few prophylactic therapies have been studied
• Adjuvant of choice
• Antidepressant or anticonvulsant
• Often arbitrary
• When choosing a drug, consider adverse effects,
  toxicity and drug interactions

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Rules for Prescribing Adjuvants / Coanalgesics

• Introduce one adjuvant at a time
• Start with low doses
• Gradually increase
• Long process Trial and error
• If the medication is ineffective switch to
  another one
• If the medication is partially effective combine
• With slow titration patients develop tolerance to
  adverse effects

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Antidepressants

• Pain vs. depression
• Lower dose
• Faster effect
• Tricyclics more effective than SSRIs
• Improvement in 60-70 of cases

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Antidepressants
Documented Effectiveness -
Tertiary Secondary SSRIs, SNRIs
Amines Amines and others
amitriptyline desipramine paroxetine
imipramine nortriptyline citalopram bupr
opion venlafaxine
Side Effects
-
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Tricyclic Antidepressants

• Amitriptyline, desipramine or nortriptyline
• Begin at 10-25 mg at bedtime
• Increase by 10-25 mg/week
• Usual effective dose 50-150 mg/day

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Anticonvulsants

• Various modes of action
• If the drug is ineffective change for another
• If the drug is partially effective combine

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Anticonvulsants

• Gabapentin and pregabalin similarities
• No hepatic metabolism
• Strictly renal elimination
• No significant pharmacokinetic drug interactions

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Gabapentin

• Begin with 100-300 mg/day
• Once daily HS or multiple doses
• Increase by 300 mg/week
• Usual effective dose 1,800-3,600 mg/day
• Adjust dosage if creatinine clearance is
  decreased (consult product monograph)

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Pregabalin

• Pregabalin is indicated for the management of
  neuropathic pain associated with
• Diabetic peripheral neuropathy and
• Postherpetic neuralgia
• Dosage
• Recommended starting dose 150 mg/day (75 mg bid
  or 50 mg tid) with or without food
• Dose may be increased to 300 mg/day (150 mg bid)
  after one week, according to clinical response
• If necessary, dose may be increased to a maximum
  of 600 mg/day (300 mg bid) in those patients who
  experience significant and ongoing pain, and can
  tolerate pregabalin

TM C.P. Pharmaceuticals International
C.V.    Pfizer Canada Inc., licensee
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LYRICA Product Monograph. Pfizer Canada Inc.,
June 2005.
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Pregabalin

• The most common adverse events documented in
  pregabalin-treated patients were
• Dizziness
• Somnolence
• Peripheral edema
• Dry mouth
• Adverse events were usually mild to moderate in
  intensity

TM C.P. Pharmaceuticals International
C.V.    Pfizer Canada Inc., licensee
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LYRICA Product Monograph. Pfizer Canada Inc.,
June 2005.
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Pregabalin Ca Channel Modulator
Excitatory Neuron
Modulation of Ca Channel by Pregabalin
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Gabapentin vs. PregabalinDifferences

• Gabapentin
• Absorption the percentage of absorption
  decreases with the dosage increase
• Divided doses improve absorption

• Pregabalin
• Absorption proportional to the dose
• The dose-blood level curve is linear

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Topical Adjuvants

• If oral formulation is poorly tolerated
• In combination with oral adjuvants
• Several creams are suggested, but few studies are
  available
• Local anesthetics, capsaicin, doxepin, clonidine,
  ketamine, nitroglycerine, carbamazepine

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Topical Adjuvants

• Compounded preparation of Xylocaine 10
• 10 g lidocaine powder in 90 g Glaxal Base
• Applied q4h unless toxicity (tremor, tachycardia)
• Lidocaine 5 patches
• Efficacy demonstrated in postherpetic neuralgia
• Not available in Canada

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Opioids

• Evidence in neuropathic pain relief
• It may be necessary to administer higher doses
  than those used for nociceptive pain relief
• Can be combined with adjuvants
• Better efficacy in peripheral vs. central pain

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Opioids

• Codeine is by far the most commonly prescribed
  opioid in Canada. Despite lack of evidence for
  effectiveness (Tylenol 1-2-3-4 and others.)
• Codeine is a pro drug. It is metabolized in the
  liver to morphine by cytochrome P450 CYP2D6. 10
  of the population lacks an effective form of this
  enzyme.
• Dr. Art Lipman, US pharmacologist
  Codeine should be reserved for cough and
  diarrhoea.
• Oxycodone may be a much more effective opioid for
  most patients (percosets, oxycocets, also
  controlled release form, Oxycontin.)

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CNCP Opioid Pharmacotherapy

• Opioid sensitive nociceptive pain
  Opioid resistant neuropathic pain
• Opioid receptors mu, kappa, delta,
  
• mu agonistsmorphine, hydromorphone, fentanyl
• kappa agonists oxycodone, talwin (women may do
  particularly well with kappa agonists)
• delta agonists ? Sufentanil
• NMDA blockade methadone, demerol

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Chronic Pain Comorbidities

• Link between chronic pain and psychopathology
• Depression in 34 to 57 of cases
• Anxiety problems frequent
• Sleeping problems frequent

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Summary and Key Messages
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Summary and Key Messages

• There are 2 main types of pain
• Nociceptive
• Neuropathic
• The clinical presentation is sometimes mixed
• It is important to determine the type of pain
  because this suggests initial treatment
• Many etiologies cause neuropathic pain
• Treat neuropathic pain even if its origin has not
  been determined

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Summary and Key Messages

• Initial treatments of choice
• Antidepressant
• Anticonvulsant
• Use adjuvants\coanalgesics as single or combined
  therapy
• When indicated, introduce opioids early on
• Treat comorbidities aggressively
• When choosing a drug, consider adverse effects,
  toxicity and drug interactions

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