Pharmacologic Pain Management

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Pharmacologic Pain Management

• Brad Brazeal, MD
• Department of Anesthesiology
• Department of Psychiatry

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Clinical Challenges

• 1. Reduces or eliminates
• 2. Educate patients
• 3. Enhance patient comfort, satisfaction, and
  other treatments
  
• 4. Fewer complications and untoward psychological
  side effects

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Pharmacologic ManagementEssential Principles

• multimodel in approach
• established guidelines
• expect diverse patient response
• oral route is preferred

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Three Major Classes

• nonsteroidal anti-inflammatory drugs (NSAIDs)
• opioids
• adjuvant analgesics

• be aware of
• pharmacology
• basic principles
• simplest dosage schedules
• least invasive

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Pain Free
Step 3 Stronger Opioid Adjuvant Nonopioid
Step 2 Opioid Adjuvant Nonopioid
Step 1 Nonopioid Adjuvant
Pain
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NSAIDs
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• Acetaminophen
• low anti-inflammatory
• minimal risk of bleeding
• decreased gastrointestinal effects
• low plasma protein binding

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• Aspirin
• ulceration
• prolonged bleeding
• renal toxicity
• Reye's syndrome

• Diflunisal
• GI tolerability
• twice-daily
• renal toxicity

• Trisalicylate
• GI tolerability
• minimal effect
• platelet
• aggregation
• low peptic ulcer
• potential
• renal toxicity

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• Ibuprofen
• extensively bound to plasma proteins
• Naproxen
• more potent antipyretic and anti-inflammatory

• Ketorolac
• intramuscularly
• GI side effects
• platelet aggregation inhibition

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Adverse Effects of NSAIDs

• renal failure
• hepatic dysfunction
• dyspepsia
• fluid retention
• bleeding

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New Agents

• Cox 2 inhibitors
• Rofecoxib
• Celecoxib
• no GI distress
• minimal effects on platelet aggregation

• Tramadol
• synthetic opioid
• minimal addicting
• no effect platelet aggregation
• weak (mu)-receptor agonists
• weak inhibition of reuptake norepi/serotonin

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Classes of Opioids

• Mixed agonist- antagonists
• pentazocine
• nalbuphine
• butorphanol
• suppress (mu)-receptors, activate
  (kappa)-receptors

• full agonists
• morphine
• hydromorphone
• fentanyl
• codeine
• oxycodone
• hydrocodone
• methadone
• mu opioid agonists

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Mixed agonists/antagonists

• should never be administered to patients who are
  already receiving full agonists

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Selection of Opioids

• NSAID for mild pain
• Then combine with opioids
• Oral opioids are recommended
• meperidine should not be considered for
  long-term
  
• Optimal pain relief with the fewest adverse
  effects

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PCA

• PCA Dose/ Lockout, Min. Infusion
• Hourly Max
• Morphine 1 mg 6-10 1mg/hr 6-10 mg
• Meperidine 10 mg 6-10 - -
• Fentanyl 20 ?g 5 20 ?g 180 ?g

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Opioid doses Qday

• Morphine 10mg IV Morphine 30mg PO Methadone
  20mg PO
  
•   Demerol 75mg IV Demerol 300mg PO
•   Dilaudid 1.5mg IV Dilaudid 7.5mg PO
•   Fentanyl 100mcg iv Fentanyl 1000 mcg TD
•   Codeine 130mg iv Codeine 200mg PO
•   Vicodin 15mg PO Darvon 100mg PO

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Opioid Adverse Effects

• Constipation
• urinary retention
• sedation
• respiratory depression
• nausea
• confusion
• myoclonus

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Primary Adjuvant Agents

• Anticonvulsant
• carbamazepine, phenytoin, valproate, gabapentin,
  lamotrigine, topiramate
  
• inhibition of spontaneous synaptic firing
• neuropathic symptoms

• Antidepressants
• amitriptyline or imipramine
• potentiate action of opioids
• SSRIs
• enhancement of serotonin-dependent descending
  fibers

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Classic Dogma

• -character of pain is predicted a response
  -burning pain treated with antidepressants and
  shooting pain with anticonvulsant. Wrong.
  Tricyclic's work in both.

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Antidepressants

• Selective Serotonin
• Reuptake Inhibitors (SSRIs)
• Fluoxetine (Prozac)
• Fluvoxamine (Luvox)
• Paroxetine (PaxilTM)
• Sertraline (Zoloft)
• Citilopram (Celexa) Atypical Antidepressants
• Amoxapine (Asendin)
• Bupropion (Wellbutrin)
• Maprotiline (Ludiomil)
• Mirtazapine (Remeron)
• Nefazodone (Serzone)
• Trazodone (Desyrel)
• Venlafaxine (Effexor)

• Tricyclic Antidepressants (TCAs)
• Tertiary Amine Tricyclic Drugs
• Amitriptyline (Elavil)
• Clomipramine (Anafranil)
• Doxepin (Sinequan)
• Imipramine (Tofranil)
• Trimipramine (Surmontil)
• Secondary Amine Tricyclic Drugs
• Desipramine (Norpramin)
• Nortriptyline (Pamelor)
• Protriptyline (Vivactil)

Not indicated for depression in the U.S.
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Pharmacology of TCAs and SSRIs

• TCAs
• Block presynaptic reuptake of various
  neurotransmitters, particularly serotonin and
  norepinephrine, less commonly dopamine
  
• Block postsynaptic cholinergic, histamine,alpha-
  and beta-adrenergic, and serotonergic receptors

Kaplan and Sadock, Comprehensive Textbook of
Psychiatry, 1995.
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Pharmacology of TCAs and SSRIs (contd)

• SSRIs
• Inhibit serotonin reuptake, with variable but
  significant effects on norepinephrine or dopamine
  reuptake
  
• Produce low incidence of TCA-like side effects
  dueto lack of anticholinergic,
  antihistaminergic, andantialpha-adrenergic
  receptor activities

Kaplan and Sadock, Comprehensive Textbook of
Psychiatry, 1995.
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Most Common Side Effects

• TCAs SSRIs
• Orthostatic hypotension Nausea
• Dry mouth Diarrhea
• Constipation Insomnia
• Blurred vision Somnolence
• Sedation or activation Dry mouth
• Increased heart rate Tremor
• Fatigue Anxiety
• Weakness Increased sweating
• Urinary hesitancy Sexual dysfunction
• Ataxia Weight gain
• Muscle tremors/twitches
• Sexual impairment
• Dizziness
• Weight gain

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SSRI Effects on P450 Isoenzymes
Enzyme Fluoxetine Paroxetine Sertraline
CYP1A2 Unlikely Unlikely Unlikely
CYP2C9/10 ? NCS NCS CYP2C19 Moderate ? NCS (Di
azepam, Phenytoin, Warfarin, Dilantin)
CYP2D6 Substantial Substantial Mild
(Beta Blockers, Codeine to Morphine, Class IC
anti-arrhythmic metabolism) CYP3A3/4 Mild Unlikely
Unlikely (Benzos (Midazolam, Triazolam, Alprazol
am, Clonazepam), Lidocaine, Quinidine, verapamil,
diltiazem, Amiodarone, Demethylation of Codeine,
Fentanyl)

Adapted from Preskorn, J Clin Psychiatry, 1996.
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TCA Pharmacokinetics

• Generally linear pharmacokinetics
• Wide variation in steady-state levels
• Narrow therapeutic index
• Therapeutic range not established for many TCAs
• Half-life 24 h
• Clearance induced by comedication carbamazepine,
  phenytoin inhibited by SSRIs via P450

Cohen and DeVane, Am Pharmacother, 1996.
Preskorn, J Clin Psychiatry, 1993.
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Antidepressants and chronic pain-effective
analgesia in neuropathic pain and other syndromes

• Antidepressants use in a variety of pain
  presentations
  
• Strong evidence from reviews indicate tri-cyclic
  are effective treatment for several conditions
  
• Neuropathic pain-overall about 50 to 90 percent
  of patients achieve at least 50 percent pain
  relief
  
• Amitriptyline median preferred dose of 75
  mg-lower than traditional dose for depression,
  onset in one to seven days - distinct effect from
  mood
• Secondarily-antidepressants can be used for what
  is thought as side effects-example sleep.
  
• BMJ volume 314 15 March 1997

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Review of Newer Antidepressants in Chronic Pain

• Summary-
• - findings often inconsistent
• - effective doses dependent and may be narrow
• - one type of chronic pain may respond to a
  drug whereas another may not
  
• - one cannot generalize efficacy by type of
  antidepressants
  
• Harvard review of psychiatry 7 257-277-a.
  Ansari

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• Therefore-
• Dose - there may be some rationale for use of
  higher doses of serotonergic agents
  
• SSRI/TCA combinations - may be of use
• Comparison with TCAs - results mixed and
  evidence insufficient to indicate newer agents
  consistently as effective as TCAs. Given the
  more favorable side effects of newer agents, they
  should be considered.
• Harvard review of psychiatry 7 257-277-a.
  Ansari

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Evidence based data on pain relief with
antidepressants

• Literature search placebo controlled -
  meta-analysis
  
• divided by pain etiology and classified
  antidepressants by perceived neurotransmitter
  affect (question classification)
  
• Summary-antidepressants have anti-nociceptive
  effects
  
• greater evidence in neuropathic pain and
  psychogenic pain
  
• mixed agents more consistent effect than
  serotonergic agents
  
• note - some etiologies probably have mixed
  mechanisms thus making it difficult to say
  effectiveness in all cases within syndromes
  
• Very few studies with newer agents compared to
  tricyclics

Annals of Medicine, 32(5)305-316, 2000 July,
Fishbain
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Chronic Neuropathic Pain mechanisms and treatment

• Mechanism based approach rather than current
  practice of established randomized controlled
  studies based on the etiology
  
• spontaneous pain (allodynia and hyperalgesia)
• evoked pain (mechanical and thermal stimuli)

The clinical journal of pain, 16S118-S130,
Attal, 2000
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Chronic Neuropathic Pain mechanisms and
treatment Cont.

• Peripheral mechanisms-abnormal spontaneous
  activity (dysregulation of sodium channels)
  
• Central mechanisms-central sensitization (dorsal
  horn NMDA-allodynia)
  
• central disinhibition (down regulation of glycine
  and GABA receptors)
  
• topographic reorganization (non-nociceptive
  messages terminate in laminae II)

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Other Mechanisms

• Potentiation of morphine analgesia may be by
  spinal alpha-2A activation with norepinephrine
  
• Journal of Neuroscience, 20(24)9040-9045, 2000
  December 15- Bohn
  
• Japanese Journal of Pharmacology, 82(2)130-137,
  2000 February- Ghelardini
  
• Receptor dimerization may help clarify the
  mechanism of action of opioids and other drugs
  
• Neuropsychopharmacology, 23(4)S5-S18, 2000
  October- Jordan

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Fluoxetine
Sertraline
Nefazodone (2A)
Paroxetine
Fluvoxamine
TCA
Reboxetine
Venlafaxine
Citalopram
Noradrenaline
Serotonin
anxiety irritability
vigilance
impulse
mood emotion cognition function
appetite sex aggression
motivation
drive
Dopamine
Bupropion
Mirtazapine (2A)
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Anticonvulsant / Mood Stabilizers

• Lithium
• Tegretol - Trileptal
• Depakote
• Lamictal
• Neurontin
• Topamax
• Gabitril
• Benzodiazepines
• Antipsychotics

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Secondary Adjuvant Agents

• Clonidine
• alpha 2 receptor agonist
• neuropathic
• Neuroleptics
• (Methotrimeprazine)
• Psychostimulants
• Steroids
• NMDA Antagonists
• ketamine
• dextromethorphan
• amantadine

• Benzodiazepine
• diazepam and lorazepam
• acute anxiety or muscle spasm
• Local anesthetics
• lidocaine
• mexiletine
• Antihistamines
• hydroxyzine
• antiemetic and sedative
• Caffeine
• increase analgesia with aspirin

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Antipsychotics

• Typical
• High Potency
• haloperidol
• fluphenazine
• thiothixene
• Low Potency
• Chlorpromazine
• Thioridazine

• Atypical
• Clozapine
• Risperidone
• Olanzapine
• Quetiapine
• Ziprasidone