Transcript Antidepressants

Presented by:
Dr. Mike Namaka
Neuroscientist and Associate Professor
Faculty of Pharmacy/Medicine
Anesthesiology/Rehab Medicine
University of Manitoba
Program Goals and Objectives
 (1)
Understand the Pain Processing Loop (pre-synaptic, post synaptic dorsal
horn neurons and decending pain control pathways
 (2)
Definition and diagnosis of Neuropathic pain that speaks to it being a
chronic pain syndrome caused by drug, disease or injury induced causes
 (3)
Understand the Pathophysiology of Neuropathic pain: Circle of Life
addressing the hallmark cellular characteristics of neuropathic pain
 (4)
Hallmark Clinical Presentation
 (5)
Recognize the prevalence and trigger factors of neuropathic pain
 (6)
Recognize and understand the different treatment strategies: Suppress
neuronal hyperexcitability
 (7)
Apply the treatment algorithm for neuropathic pain
 (8)
Understand the relevance of the treatment algorithm for neuropathic pain
 (9)
Establish treatment outcomes: 80% of patients treated will only be able to
reduce their pain to a more tolerable level. 20% may be cured. Decrease VAS
score to <5 or 2 point drop on self reporting is considered a treatment success
Pain Processing Loop
Pain Fibers
C-Fibers
A-delta-Fibers
Properties Unmyelinated
Myelinated
Pain
Dull
Perception Poorly localized
Persistent
Stimuli
High intensity
Mechanical,
chemical and
hot (>45°C)/cold
Sharp
Well localized
Mechanical
Thermal
Kandel et al.. Principles of Neural Science (3rd edition); 1991
Lamina Ⅱ of the Spinal Cord
Dorsal horn
Substantia gelatinosa
Ventral horn
Kandel et al.. Principles of Neural Science (3rd edition); 1991
3 Points of Focus
6 NT
Brain
3
Dorsal Root Ganglia
2
Famous 6 NT
1. Noradrenalin
2. Adrenalin
3. GABA
4. Serotonin
5. Body’s own
OPIOIDS
a) Endorphins
b) Enkephalins
6. Cannabinoids
1
Dorsal Horn Post Synaptic Neuron
Pre-synaptic Sensory Afferent
Spinal Cord
Neuropathic Pain
‫الظهر‬
‫آالم‬
Боль в Спине
Dolore alla schiena
mal de dos
Neuropathic pain is a chronic pain syndrome associated
with drug, injury or disease-induced destruction of nerve
fibers involved in the synaptic transmission of pain.
Namaka, M. at al. Clinical Therapeutics. 2004 Jul;26(7):951-79
Possible Causes
 Diabetes
 Amputation
 Cancer
 Herpes
 MS
 HIV
Zoster
 Spinal injury
 Alcohol-induced
Symptoms of
Neuropathic pain
Throbbing
Shooting
Sharp
Stabbing
Aching
Burning
stabbing
numbness
shooting
throbbing
Banding
Splitting
Pins/Needles
Koltzenburg, M. et al. Current Opinion on Neurology. 2001 Oct;14(5):641-7
feeling in pins and needles
burning
Criteria for Diagnosis
&
Logistics of Treatment
• Presentation of 2-3 symptoms & DN4>4
• Pain severity is >5 on a visual analogue scale
0
• Treatment Goal:
– Bring pain down to a more tolerable level
• Reduce score down 2 points or <5
• So it does not interfere with normal daily activities
– May not be able to cure pain
• Time frame to reassess patient symptoms?
– 6-8 weeks
10
Neuronal Hyperexcitability
Nociceptive transmitters:
Substance P
CGRP
Neurokinin A
Corticotropin Releasing Factor
Cholecystokinin
Galanin (only in normal state)
Vasoactive Intestinal Peptide
ATP
Nitric Oxide
Prostaglandins (PGE2)
Ca2+
Antinoceceptive
transmitters:
Na+
Neuropeptide Y
Somatostatin
Galanin
AMPA receptor
Aspartate
K+
GABA receptor
GABA
NMDA receptor
Glutamate
ON
Hains, B.C. et al. J Neuroscience. 2003 Oct 1;23(26):8881-92
ClOff
PAIN
Dorsal Horn neurons
Hains, B.C. et al. J. Neuroscience. 2003 Oct 1;23(26):8881-92
Addressing Co-morbid Symptoms
Triad Of Pain
NeP Patients Present with
Significant Co-Morbid Symptoms
Co-Morbid Symptoms
Negatively Impact Each Other
Pain
Difficulty sleeping
Lack of Energy
Drowsiness
Concentration Difficulties
Functional
impairment
Depression
Anxiety
Poor appetite
Psychological
symptoms
0
10
20
30
40
50
% patients
Ref: Meyer-Rosberg et al. Eur J Pain. 2001;5:379-389
60
70
Sleep
disturbances
Key Questions in Regard to Triad of Pain
How well do the following list of products address the Triad?
Please categorize each product for effect on NeP, anxiety and sleep
as being no effect (0), +, ++, or +++.
NeP
SATIVEX®
SSRIs
Venlafaxine
Duloxetine
TCAs
Carbamazepine
Gabapentin
Tramadol (ZYTRAM®)
Pregabalin (LYRICA®)
Nabilone (CESAMET®)
Topical Lidocaine
Anxiety
Depression
Sleep
TCA: Antidepressants
 Amitriptyline



NE and Serotonin reuptake inhibitors, metabolized to Nortriptyline
100-150 mg/day (Clin J Pain 1997;13(4):324-329)
Effective but not well tolerated, serious adverse events
 Imipramine

NE and Serotonin reuptake inhibitors
 Metabolized to Desipramine
 100 mg/day (Pain 2001;92(1-2):277-282)
 Desipramine

NE and Serotonin reuptake inhibitors
 150-200 mg/day (Pain 1991;45(1):3-9; Clin Pharmacol Ther 1990;47(3):305-312)
 Least anticholinergic and sedative effects of 1st generation TCA’s
(Pain 1991;45(1):3-9)
Antidepressants (cont’d)
 Sertraline

Selective serotonin reuptake inhibitor
 150 mg/day (Ann Clin Psychiatry 1997;9(4):255-257)
 Reduced efficacy compared to NE and Serotonin reuptake
inhibitors
 Other SSRI’s: Paroxetine, Fluoxetine, etc.
 Trazodone

Serotonin Agonist: Ineffective
 Venlafaxine

75 mg/day XR (Ann Pharmacother 2001;35(5):557-559)
 NE and Serotonin reuptake inhibitors
 Does not bind to muscarinic-cholinergic, histaminic or alpha-1adrenergic receptors hence better SE profile than TCA’s.
Duloxetine: A Balanced Dual
Reuptake Inhibitor
• Potently inhibits the
reuptake of 5-HT and NE
in vitro in a relatively
balanced manner
• Studies at clinically
relevant doses in humans
(i.e., 40-60 mg BID)
have shown that
Duloxetine decreases
5-HT concentration in the
blood and decreases the
urinary excretion of NE
and its metabolites,
consistent with blockade of
5-HT and NE uptake
processes, respectively.
5-HT Reuptake
Transporter
(Blocked)
5-HT
NE Reuptake
Transporter
(Blocked)
SNRI
NE
Theoretical Representation
Clinical significance unknown
Cymbalta® Product Monograph, Eli Lily Canada Inc., October 31, 2007.
22 22
Anticonvulsants

Phenytoin

weak to modest efficacy (Drugs 2000;60(5):1029-1052)
 15 mg/kg IV x 2 hr infusion for acute flare up of chronic neuropathic pain
(Anesth Analg 1999;89(4):985-988)

300 mg/day oral doses

Carbamazepine

400 mg-800 mg/day (Eur Neurol 2000;44(1):45-48)
 Decreases Na+ conductance and inhibits ectopic discharges
 Effective but worsening of MS symptoms (Drugs 2000;60(5):1029-1052; Eur J Pain
2002;6(Suppl A:61-68; BMJ 2000; 320(7242):1113)


Topiramate (Eur J Pain 2002;6(Suppl A):3-9)
200-400 mg/day; max 1000 mg/day (weight loss, paresthesia): titrate dose
slowly
 Block voltage-gated Na+ and Ca++ channels
 Indirect or direct enhancement of GABA(a)
 Inhibition of excitatory glutamatergic neurotransmission (kainate/ampa
receptors)
Anticonvulsants (cont’d)
 Lamotrigine




Blocks voltage sensitive Na+ channels and inhibits release of
glutamate (Eur J Neurol 1998;5(2):167-173)
Max dose: 400 mg/day
Variable efficacy results (Pain 1999;83(1):105-107)
Skin rash: taper up slowly
 Gabapentin


2400-4800 mg/day
Expensive, effective and well tolerated
 Barbituates

Analogous to Benzodiazepines: prolong inhibitory effects of
GABA
Pregabalin (Lyrica)
 Analgesic
similar to gabapentin
 Ca+ channel modulator rather than blocker
 Faster onset of action
 Now approved for central neuropathic pain
 Shorter dosage escalation periods
 Dose: 150-600mg/day in 2-3 divided doses
 Adverse Effects: blurred vision, dry mouth,
dizziness, sleepiness, weight gain,
peripheral edema.
Topical Antineuralgics
 Capsaicin
 Lidocaine
 Ketamine
Analgesics
 Ibuprofen
 Naproxen
 Indomethacin
 Rofecoxib
 Celecoxib
 Acetaminophen
MacPherson RD. Pharmacol Ther 2000;88(2):163-185
Corticosteroids
 No
evidence to support their use in
neuropathic pain.
 For example: No evidence to support
the use of corticosteroids in
postherpetic neuralgia. Its use can
cause dissemination of herpes zoster
Narcotics (Open K+ Channels)
 Morphine
LA/Codeine LA

Codeine metabolized to Morphine
 Works at the periaqueductal and periventricular grey matter,
ventromedulla and spinal cord to produce analgesia
 Long acting products apparently more efficacious
 Meperidine

Synthetic
 Anticholinergic and SSRI
 Caution with use of other SSRI’s
 Tramadol (Zytram XL)

Weak opioid /NE/Serotonin reuptake inhibitor (SNRI)
 Effective in Neuropathic Pain
 Less dependency
 Less adverse effects (Anesth Analg 2002;94(3):619-625; Eur J Pain 2000;4(Suppl A):15-21)
Incidence of OIC:
PROBE-1 Survey*



Survey of opioid GI side effects
amongst chronic pain patients
taking opioids
Constipation ranked as the most
frequent and bothersome,
despite the use of laxatives
33% of patients missed,
decreased or stopped taking
opioids
Prevalence (%)
N=322
Rank in
“bothersomenes
s”
Constipation
81
1
Straining to
pass bowel
movements
58
2
Fatigue
50
3
Small/hard
bowel
movements
50
4
Insomnia
40
5
Opioid GI
side effect
Bell TJ, et al. Pain Med 2009;10:35.
*322 patients taking daily oral opioids and laxatives completed the 45-item on-line questionnaire.
Multiple Mechanisms of OIC
Opioids
μ-, δ-, κ-opioid receptors
↓ enteric nerve activity
↓ propulsive motor activity
↓ distension-induced peristalsis
↑ muscle tone
↑ non-propulsive contractions
↓ ion and fluid secretion
Adapted from Holzer P. Regulatory Peptides 2009;155;11.
®
TARGIN
(oxycodone HCl / naloxone
HCl)
Controlled Release Tablets
The oxycodone component is indicated for the relief of
moderate to severe pain in adults who require continuous
around the clock opioid analgesia for several days or more. The
naloxone component is indicated for the relief of opioid-induced
constipation (OIC).
®
TARGIN ?
What Is
Mechanism of Action*

Oxycodone: opioid receptor agonist in
the CNS and GI tract


*Clinical significance has not been wholly elucidated .
Naloxone: opioid receptor antagonist,
acts locally in the GI tract
Bioavailability of oral naloxone: <3%
Cannabinoids
 Receptors:
CB1 & CB2
 Anandamide
 Available products:
 Marijuanna: Δ9-THC (delta-9tetrahydrocannabinol)
– dronabinal (Marinol)
– nabilone (Cesamet): a synthetic analog of Δ9-
THC
– THC:CBD (Sativex)
Receptors

The CB1 receptors are mainly
located in the brain:
–
–

Location of
CB receptors
1
basal ganglia, hippocampus,
cerebral cortex & cerebellum
also spinal cord & primary
afferent nociceptors
The CB2 receptors are
exclusively located in
periphery:
–
–
spleen & tonsil
mast cells
Lynch M. Pain Management & Research, Volume 10 Suppl A, Autumn 2005
brain
brainstem
PAG
RVM
spinal
dorsal root cord
ganglion
primary
afferent
receptor
SATIVEX® Formulation: CBD/THC 1:1

Extracts of 2 Cannabis sativa L strains
– Equal amounts of
 Tetranabinex®: high-THC strain
– 27 mg/mL delta-9-THC
 Nabidiolex®: high-CBD strain
– 25 mg/mL CBD

Buccal spray
– Ethanol/propylene glycol vehicle
– 2.7 mg THC and 2.5 mg CBD per spray

Therapeutic dose
– High inter-patient variability
– Administered on self-titration regimen
Refractory Treatments
 Dextromethorphan

(NMDA glutamate receptor antagonist: 30 mg po qid)
 Structurally an opiate and the dextro-isomer of levorphanol
(Drug Info Perspectives 1998;18(3):8-14)
 Buproprion


150 mg SR OD
Blockade of NE and Dopamine reuptake
(Clin J Pain 2000;16(1):6-11)
 Ketamine


(non-competative NMDA glutamate receptor antagonist)
40mg – 410 mg IV/day: Oral Dose 40% of IV dose (J Pediatr Hematol
Oncology 2001;23(9):616-619)

More effective than Dextromethophan but less tolerated
(MacPherson RD. Pharmacol Ther 2000;88(2):163-185)
Refractory Treatments (cont’d)
 Clonidine

Alpha-2 adrenergic agonist
(J Pharmacol Exp Ther 2001;299(3):811-817)

Decreases release of glutamate
(J Pharmacol Exp Ther 2001;299(3):939-944)

0.1 mg po bid
 Combination Therapy

Lamotrigine + oral morphine
(J Pain Symptom Manage 2000;19(5):398-403)

Ketamine and Opiods or Gabapentin and CBZ, etc
FOURTH
LINE
THIRD
LINE
SECOND LINE
FIRST LINE
Treatment Algorithm
Antidepressants
• Amitriptyline
• Nortriptyline
• Imipramine
• Desipramine
• Venlafaxine
• Fluoxetine
• Paroxeting
• Sertraline
Failure of
amitriptyline and
at least 2 other
antidepressants
Refactory treatments
• Tizanidine
• Ketamine
• Baclofen
• Clonidine
• Dextromethorphan
• Mexiletine
• Amantadine
• Lithium
• Memantine
AEDs
• Gabapentin
• Carbamazepine
• Lamotrigine
• Topiramate
• Phenytoin
Failure of
gabapentin
and at least 2
other AEDs
Failure of
gabapentin
and at least 2
Other AEDs
Failure of
narcotics
Pregabalin
Narcotics
• Morphine
• Codeine
• Methadone
• Tramadol
• Oxycodone
• Alfentanil
Failure of
Refractory treatment
Combo Therapy
Topical antineuralgics
• Capsaicin
• Ketamine
• Lidocaine
Consult pain service
Surgical intervention
SNRI’s
Tramadol
Cymbalta
Analgesics
Adjunctive therapy
• Ibuprofin
• Naproxen
• Indomethacin
• Celecoxib
• Rofecoxib
• Acetaminophen
• Aspirin
• Acetaminophen/
codeine
Tramacet
Nabilone
Sativex
Chronic Neuropathic Pain Guidelines
CPS Consensus Statement Spring 2007
CPS
Guideline
First Line
Second
Line
Third Line
Fourth
Line
Recommendations
TCAs
SNRI
Gabapentin or
pregabalin
Topical lidocaine
Additional
Information
Carbamazepine drug of choice
for tic douloureux, but
otherwise not recommended.
Lidocaine 5% gel or cream
useful for focal neuropathy,
e.g. PHN.
Patch not available in Canada.
Do not add SNRIs to TCAs.
Tramadol or CR opioid
analgesics
Fourth line agents*
* Includes: Cannabinoids, methadone, lamotrigine, topiramate, valproic acid
1. Moulin et al. Pain Res Manage 2007;12 No 1:13-21.
Add
additional
agents
sequentially if
partial but
inadequate
pain relief
Systematic Review/Guideline Summary
Guideline
AAN 20041
PHN
EFNS 20062
PHN
EFNS 20062
Painful
Polyneuropathy
EFNS 20062
Central pain
Pain 20053
NeP
CMAJ 20064
NeP
First Line
Therapy
Second Line
Therapy
Low Evidence or
Safety Concerns
Gabapentin, opioids, pregabalin,
topical lidocaine, and TCAs (class-I
evidence)
Opioids, topical aspirin and capsaicin
creams possibly effective, although
magnitude of benefit is low
NMDA antagonists and
methylprednisolone
Gabapentin, pregabalin, TCAs
(evidence level A) and topical
lidocaine (evidence level B)
Capsaicin, tramadol, valproate
(evidence level B) and opioids
(evidence level A)
Gabapentin, pregabalin TCAs
(evidence level A)
Lamotrigine, opioids, SNRIs, tramadol
(evidence level A)
Topical capsaicin, carbamazepine,
levodopa, mexilitine, NMDA
antagonists, oxycodone, SSRIs,
topiramate, valproate
Amitryptiline, gabapentin,
pregabalin
(evidence level B)
Cannabinoids, lamotrigine, (evidence
level B) and opioids.
Mexiletine, opioids, valproate
Tramadol or oxycodone or polytherapy
Mexiletine and NMDA antagonists
Tramadol or opioids analgesic or
polytherapy
Carbamazepine, phenytoin, NMDA
antagonists, methadone, mexiletine
TCA/(SNRI) or
Gabapentin/pregabalin or topical
lidocaine
Gabapentin/pregabalin or TCA/SNRI
or topical lidocaine
NMDA antagonists, lorazepam and
mexiletine
EFNS: European Federation of Neurological Societies
1. Dubinsky et al. Neurology 2004;63:959-65. 2. Attal et al. EJN 2006;13:1153-69. 3. Finnerup et al. Pain 2005;118:289-305. 4. Gilron et al. CMAJ 2006;175:265-75.
Realistic Treatment Goals

Realize there is no absolute cure
 Reduce pain to a more tolerable level
– Reduce VAS impact by 2 points or <5
– So it does not interfere with normal activities

Reassess patient symptoms: 6-8 weeks
1
10
Visual Analogue Scale (VAS)
Thank You
Questions ?