Opioids for Pain: Giving the Right Drug at the Right Dose at the Right Time

1
Opioids for Pain Giving the Right Drug at the
Right Dose at the Right Time

• Curt Gedney, M.D.
• Diplomate, American Board of Hospice and
  Palliative Medicine
• Palliative Care Physician, St. Lukes RMC
  Boise/Meridian
• Primary reference http//www.eperc.mcw.edu/EPERC
  /FastFactsIndex

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Opioids for PainPart One

• Types of Pain
• Opioid Receptors
• Types of Analgesics
• The WHO Ladder of Pain Management
• Dose Escalations
• Dose Conversions

3
Opioids for PainPart Two

• Opioids Special Considerations
• Sublingual Morphine
• Transdermal Fentanyl
• Transmucosal Fentanyl
• Methadone
• Opioid Infusions
• Opioid Side Effects Delirium Neurotoxicity

4
Major Categories of Pain

• 1. Nociceptive CNS and peripheral afferent
  pathways modulated via spinal cord (dorsal horn)
• Somatic aching, constant, localized, e.g.
  musculoskeletal
• Visceral sharp, crescendo/decrescendo, e.g.
  cholecystitis, renal stones, intestinal
  obstruction, MI
• 2. Neuropathic ischemia, destruction or
  encroachment of nerve by disease or tumor
• paroxysmal shooting or shock-like pain on a
  background of burning, aching sensation

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Major Categories of Pain

• 3. Inflammatory response to tissue damage that
  potentiates pain
• 4. Soft tissue pain pressure ulcers, burns
• 5. Intracranial pressure pain brain tumor edema
  and hemorrhage

6
Types of Neuropathic Pain

• Deafferentation phantom-type pain, usually
  localized numbness, tingling or burning sensation
• Allodynia pain resulting from a non-noxious
  stimulus to normal skin, e.g. pain on light touch
  or placement of clothing
• Dysesthesia (continuous) an unpleasant abnormal
  sensation produced by a normal stimulus, e.g.
  constant burning of the hand due to malignant
  brachial plexopathy

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Types of Episodic Pain

• 1. End of dose failure
• Dose of medication does not last the desired or
  prescribed time parameters
• 2. Incident pain
• Pain on movement or with activity
• 3. Breakthrough pain
• Crescendo (escalating) pain superimposed over
  stable or managed chronic pain
• Coluzzi, PH, Cancer Pain Management Newer
  Perspective on Opioids and Episodic Pain. Am J
  Hospice and Palliative Care. 199813-22.

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Opioid PharmacologyReceptor Site Theory

• Opioid Narcotic or opiate-like drugs includes
  natural, synthetic and endogenous substances
• Receptor sites There are several opioid receptor
  sites mu (beta-endorphins), kappa (dynorphins)
  and delta (met- leu-enkephalins).

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Mu Receptors 1 2

• Effect Location
• 1. Analgesia (robust) 1. Mid-brain/SC
• 2. Respiratory depression 2. Medulla
• 3. Inhibits GI motility 3. Intestines
• 4. Euphoria 4. Limbic system

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Kappa Receptors 1,2 3

• Effect Location
• Analgesia (mild) Spinal cord
• Inhibits GI motility Intestines
• Diuresis Pituitary gland

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Delta Receptors 1 2

• Effect Location
• 1. Analgesia (minor) 1. Spinal cord
• 2. Tolerance 2. Unknown
• 3. Seizures 3. Striatum/cortex

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Drugs and Receptor Activation

• There are three opioid receptor subtypes mu,
  kappa and delta.
• The opioid receptor subtypes location helps
  explain its function
• The mu opioid receptor subtype produces the
  strongest analgesic response.
• Major anesthetics like fentanyl, morphine,
  oxycodone, hydromorphone, and tramadol
  predominantly activate the mu opioid receptor.

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Receptor Affinity of Opioid Analgesics

• Receptor mu delta kappa NMDA
• Morphine A
• Fentanyl A
• Hydromorphone A
• Oxycodone A A?
• Methadone A A A
• Pentazocine A
• Stadol, Nubain A
• Ketamine A? A? A
• Dextromethorphan A? A? A
• A strong agonist

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N-Methyl D-Aspartate Antagonists/Inhibitors

• NMDA Antagonists block amino acid glutamate from
  binding to NMDA receptors, reducing the
  depolarization of spinal cord neurons. The
  continued firing of these neurons causes
  hyperalgesia. This hypersensitivity to a painful
  stimulus causes a windup phenomenon, a
  progressive increase in depolarization spikes
  that causes a single summation spike and the
  spontaneous firing of neurons that can persist
  for minutes.

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NMDA Inhibitors

• Reduce the occurrence of windup and decrease
  morphine tolerance at the mu receptor site. These
  drugs work the same way as tricyclics for
  neuropathic pain by preventing the uptake of
  serotonin and norepinephrine.
• Methadone oral, IV/SC
• Ketamine- IV/SC and oral,using parenteral
  solution
• Dextromethorphan
• Memantine HCl (Namenda)
• Venlafaxine and Duloxetine

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Types of Analgesics

• 1. Non-opioid or non-steroidal anti-inflammatory
  drugs (NSAIDS)work primarily at the peripheral
  nervous system level
• A. OTC ASA, acetaminophen, ibuprofen
• B. Prescription ibuprofen, naproxen,
  indomethacin, etc.
• 2. Opioids work primarily at the CNS level
• A. Opioid agonists morphine, meperidine,
  hydromorphone, fentanyl (Duragesic), levorphanol
  (Levo-Dromoran), oxymorphone (Numorphan),
  oxycodone, tramadol, codeine
• B. Opioid agonist-antagonists pentazocine
  (Talwin), nalbuphine (Nubain), butorphanol
  (Stadol), buprenorphine (Buprenex)

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Types of Analgesics-2

• 3. Adjuvant analgesics-- various actions
• A. Anticonvulsants, e.g. phenytoin,
  carbamazepine, valproate, gabapentin, pregabalin
• B. Antidepressants, e.g. tricyclicsamitriptyline,
  desipramine SNRIsvenlafaxine , duloxetine
• C. Others steroids, Baclofen, eutetic mixture of
  local anesthetics (EMLA, lidocaine, lidoderm), IV
  Lidocaine, dextromethorphan, bisphosphonates
• Peralta A Pain Management in the Elderly.
  International Jour of Pharmaceutical Compounding,
  May/June 2004 8(3)187-192.

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WHO Analgesic Ladder

• MILD (1-3) NSAID mild analgesics COX 12,
  propoxyphene, APAP, ASA
• MODERATE (4-7) Opioids, NSAIDS /- adjuvants
  oxycodone, codeine, tramadol, COX 12
• SEVERE (8-10) Opioid, NSAID Adjuvants
  morphine, meperidine, methadone, fentanyl,
  oxycodone
• World Health Organization. Cancer Pain Relief
  (2nd ed.), 1996

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Oral Opioid Dosing Intervals

• Short-acting agents (morphine, oxycodone,
  hydromorphone, codeine) have a peak analgesic
  effect in 60-90 min. with a total duration of
  analgesia of 2-4 hr.
• AHCPR Clinical Practice Guidelines (1994)
  recommends dosing intervals of 3-4 hrs.
• These agents may be dosed as often as every 2 hrs
  in pts with normal renal function.
• If agents are combined with APAP and given every
  4 hrs, a long-acting opioid should be prescribed.

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Use of Opioids in Pain Management

• Since opioids like morphine have a short
  half-life (t1/2) of 60 to 90 minutes, they reach
  steady state within 4-5 half-lives. Once steady
  state is achieved, you can titrate the dose up by
  50-100 within 24-48 hours. Once the patients
  pain is controlled, i.e. pain rating of 0-2, you
  can convert the immediate release opioid to long
  acting opioid for pain.
• Note It is imperative to initiate a bowel
  regimen when starting opioid therapy.

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Oral Opioid OrdersGood and Bad Examples

• Tylenol 3 1-2 po q4-6 hr prn mod pain, and
  Percoset 1-2 po q4-6 prn severe pain
• 1. Short-acting opioids rarely last 6 hrs.
• 2. only one opioid/non-opioid combo should be
  ordered at a time, assess for response, then
  change if needed
• 3. Subjective ratings of pain by nurses are
  inaccurate only the pt knows the truth
• 4. Be careful not to exceed 4 gm/d APAP
• Preferred order Percoset 1 po q4 hr prn pain

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Oral Opioid Orders-2

• MS Contin 60 mg q6 hr and Duragesic patch 25
  mcg/hr q72 hr
• None of the oral long-acting products should be
  prescribed less than q8 hr, and q12 hr dosing is
  preferred
• Dont use two different long-acting products at
  the same time. Instead, always order a
  short-acting product for breakthrough pain.
• Duragesic is a poor choice for poorly controlled
  pain. It can be safely dose escalated only every
  2-3 days.
• Preferred order MS Contin 90 mg q12 hr and MSIR
  15 mg 1-2 q4 hr prn pain

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Opioid Dose Escalation

• Ms. B is on a morphine drip at 5 mg/hr for cancer
  pain. Her physician has written an order to
  increase drip by 1 mg/hr, titrate to comfort.
  Her nurse increases the drip to 6 mg/hr when she
  complains of pain. Thirty minutes later she still
  has no relief. Whats the problem?

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Opioid Dose Escalation-2

• Opioids, like other drugs, should be dose
  escalated on the basis of a percentage increase.
  Going from 5 to 6 mg is only a 20 increase.
• Pts generally do not notice a change in analgesia
  when dose increases are less than 25
• For mod to severe pain, increase by 50-100
• For mild to mod pain, increase by 25-50
• Do not increase basal infusion rate (or
  long-acting oral opioids) more than 100 at a
  time or more often than every 6-8 hrs.

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Opioid Equianalgesic Table

• Morphine 30 mg po 10 mg IV
• Hydrocodone 30 mg
• Oxycodone 20 mg
• Hydromorphone 7.5 mg 1.5 mg IV
• Meperidine 75 mg IM/IV
• Fentanyl 15 mcg/hr IV/TD
• Methadone see Methadone table

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Calculating Opioid Dose Conversions

• Morphine 10 mg IV 30 mg oral Hydromorphone
  7.5 mg oral 1.5 mg IV
• 1. Change route, keeping drug the same Change 90
  mg q12 ER Morphine to Morphine IV by continuous
  infusion
• 24-hr oral Morphine dose 180 mg po
• Convert to IV 180/3 60 mg IV
• Hourly infusion rate 60/24 2.5 mg/hr
• Rec if a new drug, start at 50 of calculated
  dose to account for variation in first pass
  clearance and incomplete cross-tolerance.

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Calculating Conversions-2

• 2. Change drug, keep same route
• Change 90 mg q12 ER Morphine to oral
  hydromorphone
• 24-hr oral Morphine dose 180 mg po
• Hydromorphone dose 180/4 45 mg po
• Rec start new opioid at 50 of calculated
  equianalgesic dose for possible incomplete
  cross-tolerance
• Reduce dose 50 22 mg/24 hr 4 mg q4

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Calculating Conversions-3

• 3. Changing drug and route
• Change 90 mg q12 ER Morphine to IV hydromorphone
  as continuous infusion
• 24-hr Morphine dose 180 mg po
• IV Morphine dose 180/3 60 mg IV
• Morphine 60 mg IV 60/10 X 1.5 9 mg
  hydromorphone IV/24 hr
• Reduce dose 50 for cross-tolerance 9/2 4.5
  mg/24 hr 0.2 mg/hr IV

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Part One Summary

• Oral short-acting opioids are the mainstay of
  pain management for the majority of patients.
  They can be dose escalated as much as 50-100 per
  day because of rapid upregulation of receptors
  and short half-life. When dose requirements are
  high, long-acting opioids are more useful in
  controlling pain. Opioids are readily
  interconvertible according to established
  conversion ratios.

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Opioids for PainPart Two

• Opioids Special Considerations
• Sublingual Morphine
• Transdermal Fentanyl
• Transmucosal Fentanyl
• Methadone
• Opioid Infusions
• Opioid Side Effects Delirium Neurotoxicity

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Sublingual Morphine

• Advantage Longer duration of action (4 hr) vs.
  IV (1-2 hr)
• Disadvantages
• 1. Data do not support more rapid absorption
  through sublingual mucosa than by oral route
• 2. Mean time to maximum concentration is shorter
  with PO than with SL morphine
• Bioavailability of SL morphine is only 9 vs.
  23.8 with an oral solution
• Absorption through oral mucosa is best with
  potent, non-ionized and lipid soluble drugs. SL
  morphine has low potency, is highly ionized and
  one of the least lipid soluble opioids, making it
  a poor choice as a SL med.

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Fentanyl Dose Conversions

• Mr. L is an 80 year-old man with cancer who has
  been on a morphine drip in the hospital at 3
  mg/hr. Upon discharge back to the nursing home
  the drip is dcd and he is placed on a 50mcg/hr
  Fentanyl patch. The next day he is found in pain,
  nauseous, jittery and diaphoretic. What happened
  to Mr. L?

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Dosage Conversion Oral Morphine to Transdermal
Fentanyl

• PO Morphine Transdermal fentanyl
• (mg/24 hr) (mcg/hr)
• 45-134 25
• 135-224 50
• 225-314 75
• 315-404 100
• 1035-1124 300
• Source Janssen Pharmaceutica

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Dosage Conversion Oral Morphine to Transdermal
Fentanyl

• Mcg/hr dose of Duragesic ½ X mg/day dose of
  oral morphine
• Example
• Duragesic 100 mcg/hr dose Q72 hrs Oral Morphine
  SA 100 mg Q12 hrs or
• Duragesic 2400 mcg or 2.4 mg/day MS 200 mg/day
  (ratio 180)
• Levy, MH. Pain Management Center, Fox Chase
  Cancer Center at NHO Annual Meeting, Oct., 1992

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Fentanyl Conversion-2

• In PDR, conversion of morphine to fentanyl is
  135-224 mg of morphine 50 mcg/hr fentanyl
  patch. The patient was receiving 3 X 24 72 mg
  IV morphine X 3 216 mg oral morphine/24 hrs.
  So, according to PDR, the appropriate conversion
  dose is 50 mcg/hr fentanyl.

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Fentanyl Conversion-3

• An Alternate Formula, published by Breitbart et
  al (2000) uses a fixed dose conversion ratio
• 2 mg oral morphine 1 mcg/hr transdermal
  fentanyl
• So 216 mg oral morphine is approximately
  equianalgesic to 100 mcg/hr fentanyl
• So the patient was underdosed on discharge from
  the hospital, so was in pain

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Fentanyl Conversion-4

• Therapeutic blood levels of fentanyl are not
  reached for 13-24 hours after patch is applied.
• So the patient was having withdrawal symptoms.
  Other breakthrough meds should have been used
  until the fentanyl had reached therapeutic
  levels.
• Note also Drug will continue to be released into
  the blood for at least 24 hrs after patch
  removal, so when replacing the patch, the new
  drug should be titrated up accordingly.
• Upward titrations of fentanyl should be done no
  more often than every 48-72 hours.

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Oral Transmucosal Fentanyl Citrate

• OTFC- a solid formulation of fentanyl, a lozenge
  on a handle
• Lipid soluble and 80 non-ionized, so very
  suitable for transmucosal absorption
• Bioavailability higher if absorbed through oral
  mucosa than if swallowed
• Rapid onset of analgesia (3-5 min), with peak
  effect at 20-40 minutes, short half-life

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OTFC-2

• Available in 200, 400, 600, 800, 1200 1600 mcg
  dosage strengths
• Place between cheek and gum, move gently side to
  side for 15 min.
• Always start at 200 mcg and titrate up
• If first dose inadequate, take a second dose 30
  min later. If that is effective, switch to 400
  mcg doses.
• Pt should take no more than two units per pain
  period during initial titration period.

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Methadone for Pain Why?

• Acts as both a mu receptor agonist and an NMDA
  receptor antagonist. Its NMDA action makes it
  very useful in the treatment of neuropathic pain.
• Methadone is sometimes effective for refractory
  pain when morphine or hydromorphone are not.
• A special license to prescribe methadone is not
  required, except for those treating addiction.

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Methadone Unique Qualities

• Has an extended half-life, up to 190 hours, yet
  duration of analgesia is 6-12 hours after steady
  state is achieved.
• Rapid titration guidelines do not apply to
  methadone. Dose should not be increased more
  frequently than every 5-7 days. It is not
  indicated in poorly controlled pain where rapid
  dose adjustments are needed.
• Patients with a prolonged QT interval, or who
  have other risk factors for Torsades, may need
  EKG monitoring.

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Starting Methadone

• After a single dose, there is a short
  distribution phase (with acute pain relief) with
  a half-life of 2-3 hrs and a slow elimination
  phase (half-life 15-60 hrs).
• Dosing must account for accumulation of the drug
  over days.
• No dose reduction is required with renal failure.
• Drug interactions Rifampin, phenytoin,
  carbamazepine, and several antiretroviral meds
  decrease methadone levels. Amitriptyline,
  fluconazole, erythromycin, metronidazole,
  fluoxetine and grapefruit juice increase levels.

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Starting-2

• 1. Begin methadone 5 or 10 mg po bid or tid for
  5-7 days. With elderly, begin at 2.5 mg QD/BID
  and titrate up more slowly.
• 2. If pain persists, increase dose by 50,
  continue for 5-7 days, and increase dose every
  5-7 days until pain controlled.
• 3. Use short-acting opioid with short half-life
  (e.g. morphine 10 mg) every 1-2 hrs prn for
  breakthrough pain and to provide relief during
  titration phase.

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Conversion to Methadone

• Conversion Ratio of oral Morphine to oral
  Methadone
• 31, 3mg morphine to 1 mg methadone
• for doses of morphine up to 100 mg/day
• 101-300 mg 51
• 301-600 mg 101
• 601-800 mg 121
• 801-1000 mg 151
• gt1001 mg 201

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Conversion to Methadone-2

• Calculate equianalgesic dose of methadone from
  total current opioid dose.
• Day 1 Replace 1/3 of opioid dose with oral
  methadone on bid or tid schedule.
• Day 2 Replace next 1/3 of opioid dose.
• Day 3 Complete change to methadone.
• Reference J Pall Med 2002 5127-138.

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Opioid Infusions in the Imminently Dying Patient

• 1. Calculate an equianalgesic dose of currently
  used opioids. E.g. 60 mg q12 po 120 mg/24 hr
  40 mg IV/24 hr 2 mg/hr basal rate
• 2. If the current opioid dose is ineffective,
  escalate the basal dose by 25-100
• 3. Give a loading dose when starting the infusion
  if equianalgesic dose is being escalated or if pt
  is opioid naïve (4-10 mg loading dose prior to
  starting 2 mg/hr infusion)
• 4. Choose a bolus rescue or PCA dose. A dose
  50-150 of the hourly rate is a place to start.
  In this example, bolus at 1-3 mg.

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Opioid Infusions-2

• 5. Choose a dosing interval. Peak effect from an
  IV bolus is 5-10 min, so dosing interval should
  be 10-20 min.
• 6. Reassess for desired effect vs. side effects
  every 10-15 min. until stable. Adjust bolus dose
  every 30-60 min. until desired effect is
  achieved.
• 7. Reassess need for a change in basal rate no
  sooner than every 6-8 hrs. Take total bolus doses
  into account, but never increase basal rate by
  more than 100 at one time. Be sure to give a
  loading dose to rapidly achieve steady-state
  blood levels.
• When pts become anuric close to death, d/c
  continuous dosing in favor of bolus dosing to
  prevent metabolite accumulation and delirium.

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Opioid Infusion Titration Orders

• Bad example MS 2-10 mg/hr, titrate to pain
  relief
• Places full responsibility for dose titration on
  the nurse
• Provides no guidance re how fast to titrate (q
  hr, q shift?) or dose titration intervals (should
  the dose be raised from 2 to 3 mg or 2 to 10 mg?)
• Sets up potential for overdosage by too zealous
  dose escalation
• Provides only one option for poorly controlled
  painincreasing basal rate
• Makes no sense to dose escalate more frequently
  than every 8 hrs, since it takes that long to
  achieve steady-state blood levels after a basal
  dose change
• Preferred MS 2 mg/hr and MS 2 mg q15 min prn
  breakthrough pain (or 2 mg via PCA dose) and RN
  may dose escalate the prn dose to a maximum of 4
  mg within 30 minutes for poorly controlled pain.

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Opioid Side Effects Delirium

• Occurs in as many as 80 of inpatients on
  opioids often goes undiagnosed and untreated.
• Manifests as confusion or hallucinations
• Risk is highest in late-stage or actively dying
  cancer pts who have become dehydrated and whose
  renal clearance is compromised.

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Delirium Treatment

• Fluids to correct dehydration
• You may try decreasing opioid dose, but not at
  the expense of pain control.
• A better way is to switch to an equianalgesic
  dose of a different opioid.
• Use antipsychotics such as haldol or
  chlorpromazine. Avoid benzodiazepines, as pts may
  have a paradoxical reaction.

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Opioid Side Effects Myoclonus and Neurotoxicity

• More risk as pt gets closer to death
• Manifests as muscle twitching or psychomotor
  agitation
• May try reducing opioid dose, but not at expense
  of pain control
• Opioid switch
• Benzodiazepines such as lorazepam or clonazepam
  can be effective.

52
Opioid Toxicity

• Occurs as opioid dose is increased in response to
  perception that pt is still in pain
• If myoclonus occurs, the appropriate opioid dose
  has been exceeded.
• Or toxicity presents as generalized, rather than
  localized, painthe opioid overwhelms the CNS

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Opioid Toxicity Treatment

• DO NOT increase opioid dose, even though the pt
  has generalized pain.
• Try a reduction in dosage of 25. If this is
  effective you may further reduce the dose until
  symptoms are resolved.
• If pain increases on the lesser dose, either
  restore the previous dose and add benzos or
  switch to an equianalgesic dose of a different
  opioid.

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Part Two- Summary

• Sublingual morphine, while easy to use, appears
  to have less effectiveness than oral forms.
  Transmucosal fentanyl, though more expensive, can
  provide long-term pain relief.
• Transdermal fentanyl is helpful for patients with
  chronic pain who cannot tolerate oral medication
  with its side effects, but is not useful for
  acute or uncontrolled pain.
• Methadone is cheap and particularly useful for
  neuropathic pain. It must be used cautiously with
  respect to its long half-life.

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Summary (cont.)

• Opioid infusions, both IV and subcutaneous, are
  very useful for hospitalized patients with severe
  pain, as well as for patients who are imminently
  dying.
• Delirium and neurotoxicity are common side
  effects of opioids, and can be treated with dose
  reduction, opioid switching, and administration
  of IV fluids and antipsychotics (delirium) or
  benzodiazepines (myoclonus).