The Use Of Adjuvants In Pain Management

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The Use Of Adjuvants In Pain Management
Stewart W. Stein, M.D. Medical Director, Good
Shepherd Hospice
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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.

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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.

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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

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WHO Pain Ladder
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• Adjuvant Analgesics

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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

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Adjuvant AnalgesicsStep 1 Agents on the WHO
ladder

• Non-steroidal anti-inflammatories (NSAIDS)
• Antidepressants (TCAs)
• Anticonvulsants / Antiepileptics (AEDs)
• Cortisteroids
• Bisphosphonates
• Anesthetics
• N-Methyl D-aspartate antagonists (NMDA)

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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.

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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

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Neuropathic Pain Syndromes

• 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)

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Adjuvant Analgesics

• Tricyclic Anti-depressants
• Inhibit reuptake of norepinephrine and serotonin
  in nerve endings in the spinal cord and in the
  brain
• NMDA antagonism

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Antidepressants

• Tricyclic Antidepressants
• Tertiary amines
• amitriptyline
• doxepin
• imipramine
• clomipramine
• Secondary amines
• desipramine
• nortriptyline

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Antidepressants

• Serotoninergic agents
• Fluoxetine
• Paroxetine
• Sertraline
• Citalopram
• Escitalopram

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Antidepressants

• SNRIs (serotonin / norepinephrine reuptake
  inhibitors)
• Venlafaxine
• Desvenlafaxine
• Duloxetine

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Antidepressants

• Used for
• Analgesia
• Depression
• Insomnia
• (even pruritis)

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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

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AntidepressantsSide Effects

• Nausea
• Sedation
• Confusion
• Xerostomia
• Tachycardia
• Drug interactions
• (Anticholinergic )

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Side Effects of TCAs

• ?MI
• Long term use of TCAs is associated with a 2.2
  relative risk of myocardial infarction and a
  1.7fold increase in mortality vs. placebo or
  SSRIs. (screen elderly with EKG?)
• American Journal of Medicine (2000)
  Jan108(1)2-8
• European Heart Journal (2004) 25 (1) 3-9

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• AEDs
• (Antiepileptic Drugs)

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Mechanism of action of AEDs

• 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)

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Mechanism of action of AEDs

• Block voltage dependent Ca channel (Gabapentin
  and Pregabalin)
• Carbonic anhydrase inhibition (Topiramate,
  Zonisamide)

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Mechanism of action of AEDs
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New AEDs (Anti-Epileptic Drugs)

• Gabapentin
• Topiramate
• Levitiracetam
• Tiagabine
• Oxcarbazepine
• Lamotrigine
• Felbamate
• Pregabalin

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Use of AEDs

• Start with a low evening dose
• Increase GRADUALLY over 4-6 weeks depending on
  response. (Typically effective at higher doses)

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New AEDsSide Effects

• Drowsiness
• Unsteadiness
• Aplastic anemia (CB)
• Dizziness
• Confusion
• Rash (VPA)
• Ataxia
• Nausea and vomiting

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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)

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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.

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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

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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

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Lamotrigine

• Demonstrated efficacy in trigeminal neuralgia.
• Utility in vascular HAs and PDN suggested by
  open label studies

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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)

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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.

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Carbamazepine

• Used in trigeminal neuralgia since the 1960s!
• Starting dose is 200mg po bid. Effective dose is
  usually 400-1000mg per day.
• Induces P450 system so potential for drug-drug
  interactions.
• Aplastic anemia occurs in 1200,000. More
  commonly, a reversible leukopenia or
  thrombocytopenia may occur.

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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.

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Phenytoin

• Mixed results in trials (1970s) 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

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Valproic acid

• Demonstrated efficacy in migraine HAs.
• Side effects include nausea, vomiting, sedation,
  rash, ataxia and appetite stimulation
• 40 develop increased transaminases.
• 150,000 will develop HEPATIC FAILURE

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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

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TCA (amitriptyline)

• NNT 2-3
• NNH 14.7

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AED (gabapentin)

• NNT 5.1 (Includes all doses, high and low)
• NNH 26.1

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Opioids

• Morphine NNT 2.5
• Oxycodone NNT 2.6
• Tramadol NNT 3.9
• NNH for tramadol 9.0
• NNH morphine and oxycodone not significant

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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.

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Corticosteroids

• Inhibit arachodonic acid (prostaglandin
  synthesis) resulting in anti-infalmmatory action
• Also a membrane stabilizer (blocking c-fiber
  transmission)

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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.

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Therefore

• Blocking NMDA results not only in improved pain
  control but also reverses opioid tolerance to
  varying degrees.

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NMDA receptor antagonists

• Methadone
• Ketamine
• Dextromethorphan

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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

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Neuropathic painHow do we proceed?

• If we were to look only at pain relief, the order
  would be
• TCA
• opioids
• tramadol
• gabapentin / pregabalin (recall NNT)

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BUT.

• If criteria are to be both relief of pain AND
  quality of life, the order would be
• Gabapentin / pregabalin
• Tramadol
• Opioids
• TCAs

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Nerve BlocksCeliac Plexus Block

• Used with upper abdominal malignancies
• Variable benefit
• (alcohol neurolysis most common)

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Nerve BlocksMandibular / 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

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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.

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Axial Therapy

• Intrathecal
• subarachnoid
• Epidural
• requires 10 times the intrathecal volume to
  spread medication over several dermatomal segments

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Axial Therapy

• Advantages
• Effective
• Markedly reduced side effects.
• Disadvantages
• Surgical procedure
• Infection
• CSF leak

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Axial vs. Oral Opiate Dosing

• Oral morphine 300mg
• IV morphine 100mg
• Epidural 10mg morphine
• Intrathecal 1mg morphine

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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

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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

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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.

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Questions Comments