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The Use Of
Adjuvants In
Pain
Management
Stewart W. Stein, M.D.
Medical Director, Good Shepherd Hospice
Objectives
• Understand basic principles of pain
transmission
• Understand the role of adjuvants in the
management of pain
• Understand advantages and disadvantages
of various agents in the management of
chronic pain
• Understand the use of other modalities in
pain management.
Ascending Pathways
• A-delta fibers are myelinated (insulated
with a myelin sheath). The pain is fast and
well localized, like the initial prick or
stinging sensation following an injury.
• C fibers are nonmyelinated and smaller
than A-delta fibers. They transmit pain
much slower. The pain is more lasting,
generalized and described as a dull ache.
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Ascending Pathways
• After afferent A-delta (myelinated and fast)
and C-fibers (unmyelinated and slow)
synapse with the interneurons.
• These cross over to the contralateral side
and ascend primarily via the spinothalamic
tracts to the thalmus and cortex.
Ascending Pathways
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Pathophysiology
• Nociceptor activation / Types of receptors:
• Mechanical
• Thermal
• Chemical
• Respond to stimuli that approach or exceed
harmful intensity by undergoing
conformational, electrical and biochemical
changes
WHO Pain Ladder
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• Adjuvant Analgesics
Adjuvant Analgesics
• “Non-opioids with analgesic efficacy”
• Primarily used to treat neuropathic pain
syndromes although also effective in
management of nociceptive pain when
used as adjuvants to other medications
Adjuvant Analgesics
Step 1 Agents on the WHO ladder
• Non-steroidal anti-inflammatories
(NSAIDS)
• Antidepressants (TCA’s)
• Anticonvulsants / Antiepileptics (AED’s)
• Cortisteroids
• Bisphosphonates
• Anesthetics
• N-Methyl D-aspartate antagonists (NMDA)
Acetaminophen / Paracetamol
• Mechanism of action unclear but may
inhibit cyclooxygenase in the CNS
• Acetaminophen can cause liver damage if
dose exceeds 4 grams a day
• Risk of hepatic injury is increased in
patients having pre-existing liver damage
(alcoholism, hepatitis)
• Acetaminophen has also been shown to
cause renal damage.
NSAIDS
• Mechanism of action is the inhibition of
cyclooxygenase to decrease prostaglandin
synthesis
• May have central action at the spinal cord
level
• They do have a ceiling effect
• Tolerance and physical dependence is NOT
seen!
• Can be associated with end-organ toxicity
Neuropathic Pain Syndromes
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Trigeminal neuralgia
Post-herpetic neuralgia
Diabetic neuropathy
Chemotherapy-induced neuropathy
Plexopathies
Phantom limb pain
Complex regional pain syndrome
Central post-stroke (damage to thalamus,
cortical or subcortical structures)
 Syringomyelia
 Sympathetically maintained pain syndrome
(RSD)
Adjuvant Analgesics
• Tricyclic Anti-depressants
• Inhibit reuptake of norepinephrine and
serotonin in nerve endings in the spinal cord
and in the brain
• NMDA antagonism
Antidepressants
• Tricyclic Antidepressants
• Tertiary amines:
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amitriptyline
doxepin
imipramine
clomipramine
• Secondary amines:
• desipramine
• nortriptyline
Antidepressants
• Serotoninergic agents
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Fluoxetine
Paroxetine
Sertraline
Citalopram
Escitalopram
Antidepressants
• SNRI’s (serotonin / norepinephrine
reuptake inhibitors)
• Venlafaxine
• Desvenlafaxine
• Duloxetine
Antidepressants
• Used for:
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Analgesia
Depression
Insomnia
(even pruritis)
Antidepressants:
• Mechanism of action is inhibition of
reuptake of neurotransmitters (serotonin,
norepinephrine and dopamine)
• Only tricyclic antidepressants have
analgesic properties independent of their
antidepressant activity
Antidepressants:
Side Effects
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Nausea
Sedation
Confusion
Xerostomia
Tachycardia
Drug interactions
(Anticholinergic )
Side Effects of TCA’s
?MI
• Long term use of TCA’s is associated with
a 2.2 relative risk of myocardial infarction
and a 1.7fold increase in mortality vs.
placebo or SSRI’s. (screen elderly with
EKG?)
•
American Journal of Medicine (2000) Jan;108(1):2-8
•
European Heart Journal (2004) 25 (1): 3-9
AED’s
(Antiepileptic Drugs)
Mechanism of action of AED’s:
• Slow recovery of voltage gated Na
channels from depolarization
(carbamazepine, phenytoin)
• Indirect or direct enhancement of inhibitory
Gama-aminobutyric acid neurotransmission
(Valproic acid, Tiagabine)
• Inhibition of excitatory glutamatergic
neurotransmission (lamotrigine)
Mechanism of action of AED’s
• Block voltage dependent Ca++ channel
(Gabapentin and Pregabalin)
• Carbonic anhydrase inhibition (Topiramate,
Zonisamide)
Mechanism of action of AED’s:
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New AED’s (Anti-Epileptic Drugs)
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Gabapentin
Topiramate
Levitiracetam
Tiagabine
Oxcarbazepine
Lamotrigine
Felbamate
Pregabalin
Use of AED’s:
• Start with a low evening dose
• Increase GRADUALLY over 4-6 weeks
depending on response. (Typically
effective at higher doses)
New AED’s
Side Effects
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Drowsiness
Unsteadiness
Aplastic anemia (CB)
Dizziness
Confusion
Rash (VPA)
Ataxia
Nausea and vomiting
Gabapentin
• Established efficacy in treatment of post
herpetic neuralgia
• Most common mistake is failure to titrate to
effective doses (900mg ineffective in
managing PDN in one series)
Gabapentin
• Titration Schedule:
• Day 1: 300mg po at HS
• Day 2: 300mg po bid
• Day 3: 300mg po tid
• Titrate 100-300mg per day over next 2
weeks to target dose of 1800mg. Continue
titration over 2 more weeks to 3600mg if
indicated for effect. Higher doses have also
been successfully used.
Pregabalin
• Advantages include predictable absorption
across the GI tract. Not metabolized or
protein-bound. Minimal drug-drug
interactions.
• Multiple studies demonstrate effective pain
relief and decreased sleep interference in
PHN and PDN
Pregabalin
• Dosing schedule
• Days 1-3: 50mg po tid
• Days 4-7: 100mg po tid
• Thereafter 200mg po tid.
• Taper dose over 7 days to discontinue
Lamotrigine
• Demonstrated efficacy in trigeminal
neuralgia.
• Utility in vascular HA’s and PDN suggested
by open label studies
Lamotrigine
• Dosing:
• Start at 25-50mg po daily
• Increase by 50mg per day per week until
effective or an arbitrary maximum is reached
(usually around 900mg daily in 2-3 divided
doses)
Topiramate
• Studies demonstrate utility in management
of cluster headache and diabetic
neuropathy
• Effective dose range is 200-400mg daily in
divided (2) doses
• Associated with weight loss
• Side effects may include abnormal
thinking, delusional and psychotic thinking,
kidney stones.
Carbamazepine
• Used in trigeminal neuralgia since the
1960’s!
• Starting dose is 200mg po bid. Effective
dose is usually 400-1000mg per day.
• Induces P450 system so potential for drugdrug interactions.
• Aplastic anemia occurs in 1:200,000. More
commonly, a reversible leukopenia or
thrombocytopenia may occur.
Oxcarbezapine
• An analog of carbamazepine that retains
many therapeutic properties of the drug
while avoiding toxicities. (No bone marrow
suppression or induction of P450 system)
• Start with 300mg at HS. Increase weekly
by 300-600mg until effective up to a
maximum of 1200-2400mg per day.
Phenytoin
• Mixed results in trials (1970’s) for PDN.
• Usual dose 200-400mg po daily
• Side effects include nausea, diplopia,
dizziness, confusion, gingival hyperplasia
and rarely Stevens-Johnson syndrome.
• Induces P450 cytochrome system
Valproic acid
• Demonstrated efficacy in migraine HA’s.
• Side effects include nausea, vomiting,
sedation, rash, ataxia and appetite
stimulation
• 40% develop increased transaminases.
• 1:50,000 will develop HEPATIC FAILURE
Also part of the equation ….
• NNT: The number of patients that need to
be treated with a particular drug in order for
one patient to experience a 50% reduction
in pain
• NNH: The number of patients that need to
be treated with a particular drug in order for
one patient to drop out due to adverse
effects
TCA (amitriptyline)
• NNT = 2-3
• NNH = 14.7
AED (gabapentin)
• NNT = 5.1 (Includes all doses, high and
low)
• NNH = 26.1
Opioids
• Morphine NNT = 2.5
• Oxycodone NNT = 2.6
• Tramadol NNT = 3.9
• NNH for tramadol = 9.0
• NNH morphine and oxycodone = not
significant
Bisphosphonates
• Pamidronate and Zolendronic acid
• Localize to bone and inhibit osteoclastic
activity
• Widely studied in treatment of metastatic
bone pain
• Risk of osteonecrosis of the mandible.
Corticosteroids
• Inhibit arachodonic acid (prostaglandin
synthesis) resulting in anti-infalmmatory
action
• Also a membrane stabilizer (blocking cfiber transmission)
NMDA Receptors
• Located mostly in the dorsal horn of the
spinal cord
• Activated by chronic, painful stimulus
leading to allodynia, hyperalgesia, and
neuropathic pain.
• Also responsible for opioid tolerance.
Therefore:
• Blocking NMDA results not only in
improved pain control but also reverses
opioid tolerance to varying degrees.
NMDA receptor antagonists:
• Methadone
• Ketamine
• Dextromethorphan
Ketamine
• Useful in refractory neuropathic pain states
• Useful to “reset” opioid sensitivity in an
opioid-tolerant patient
• Also very useful for procedures such as
painful wound care
Neuropathic pain:
How do we proceed?
• If we were to look only at pain relief, the
order would be:
TCA
opioids
tramadol
gabapentin / pregabalin (recall NNT)
BUT….
• If criteria are to be both relief of pain AND
quality of life, the order would be:
Gabapentin / pregabalin
Tramadol
Opioids
TCA’s
Nerve Blocks:
Celiac Plexus Block
• Used with upper abdominal malignancies
• Variable benefit
• (alcohol neurolysis most common)
Nerve Blocks:
Mandibular / Maxillary /
Gasserian ganglion block
• Used in head and neck cancer pain.
Phenol / alcohol used for neurolysis
• Radiofrequency ablation also used
• Post neurolytic dysesthesia can occur
Axial therapy
• Both presynaptic and post synaptic opioid
receptors within the dorsal horns of the
spinal matter inhibit synaptic transmission
from the peripheral afferent nociceptor to
the second order spinal neuron.
Axial Therapy
• Intrathecal
• subarachnoid
• Epidural
• requires 10 times the intrathecal volume to
spread medication over several dermatomal
segments
Axial Therapy
• Advantages:
• Effective
• Markedly reduced side effects.
• Disadvantages:
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Surgical procedure
Infection
CSF leak
Axial vs. Oral Opiate Dosing
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Oral morphine = 300mg
IV morphine = 100mg
Epidural = 10mg morphine
Intrathecal = 1mg morphine
Other Modalities
Vertebroplasty
• Cement (polymethyl methacrylate) is injected
into the damaged vertebra and acts as an
internal splint. Useful in osteoporosis and
cancer-associated fractures
Other Modalities
• TENS
• Stimulates large “A” fibers that then close the
gate for pain coming in from “C” fibers. Used in
acute and chronic pain syndromes.
• Low intensity: not reversed by naloxone
• High intensity: reversed by naloxone
Other Modalities
• Acupuncture: Possibly acts on reward
center (dopamine and serotonin)
• May increase muscle blood flow
• May reduce gastric acid and correct gastric
arrhythmia, thereby reducing nausea and
vomiting.
Questions
& Comments