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 (TCA’s)
• Anticonvulsants / Antiepileptics (AED’s)
• 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 SyndromesTrigeminal neuralgiaPost-herpetic neuralgiaDiabetic neuropathyChemotherapy-induced neuropathyPlexopathiesPhantom limb painComplex regional pain syndromeCentral post-stroke (damage to thalamus, cortical
or subcortical structures) SyringomyeliaSympathetically 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
• SNRI’s (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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Antidepressants:Side Effects
• Nausea
• Sedation
• Confusion
• Xerostomia
• Tachycardia
• Drug interactions
• (Anticholinergic )
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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
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AED’s(Antiepileptic Drugs)
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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)
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Mechanism of action of AED’s
• Block voltage dependent Ca++ channel (Gabapentin and Pregabalin)
• Carbonic anhydrase inhibition (Topiramate, Zonisamide)
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Mechanism of action of AED’s:
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New AED’s (Anti-Epileptic Drugs)
• Gabapentin
• Topiramate
• Levitiracetam
• Tiagabine
• Oxcarbazepine
• Lamotrigine
• Felbamate
• Pregabalin
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Use of AED’s:
• 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 AED’sSide 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 HA’s 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 1960’s!
• 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 1:200,000. 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 (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
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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
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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 pain:How do we proceed?
• If we were to look only at pain relief, the order would be:TCAopioidstramadolgabapentin / 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 / pregabalinTramadolOpioidsTCA’s
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Nerve Blocks:Celiac Plexus Block
• Used with upper abdominal malignancies
• Variable benefit
• (alcohol neurolysis most common)
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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
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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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