Management of LifeThreatening Opioid Neurotoxicity

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Management of Life-Threatening Opioid
Neurotoxicity
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Why Are We Seeing More Opioid Induced
Neurotoxicity?

• There has been a 3x increase in morphine
  consumption worldwide from 1986 to 1995
• There has also been an increase in reports and
  awareness of neuroexcitatory side effects
  (allodynia, hyperalgesia, myoclonus, seizures) of
  morphine and hydromorphone
• As we succeed in educating and encouraging health
  care providers to be aggressive in pain
  management, we can expect to see more
  opioid-induced neurotoxicity

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Opioid Induced Myoclonus

• Myoclonus sudden, brief, shock-like involuntary
  movements caused by muscular contractions
• All muscle groups
• Often best observed when patient sleeping
• Incidence of opioid-related myoclonus varies from
  2.7 to 87
• Most recognized with metabolites of morphine
  (particularly M3G), however also seen with
  opioids with no active metabolites (methadone,
  fentanyl)

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CASE PRESENTATION

• Ms. W.P. 73 yo woman with met. NSCCL Dx. early
  Oct. 2001
• Seen Oct. 18/01 by oncology in community hospital
  ER with low back pain, dyspnea
• At that time morphine long-acting 200 mg bid
  plus morphine 2.5 mg IV push q3h (pr,, but given
  regularly)
• Morphine long-acting increased to 300 mg bid,
  with plans for 300 mg tid, plus 5 mg IV q3h prn
• Over the next 2 days became twitchy on morphine,
  changed to hydromorphone infusion
• Over the subsequent 2 days, hydromorphone
  increased from a few mg/hr to 30 mg/hr, with no
  improvement in distress
• Increase in agitation, fluctuating LOC, non-stop
  myoclonus

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Case presentation ctd.

• Oct. 22/01 transferred to SBGH palliative care
• On exam at time of transfer (approx 1330h)
• Lethargic, disoriented, restless, emaciated.
• Resps. approx 20, reg.
• Pupils 3-4 mm, reactive
• Generalized myoclonus non-stop
• Lab Oct. 19/01 Creat 50 µmol/l (60-110) BUN
  2.9 mmol/l (2.5-6.1) Oct. 22/01 Creat 47
  µmol/l (35-97) BUN 2.9 mmol/l (2.7-7.1)lytes,
  Ca normal
• Assessed as having severe opioid neurotoxicity,
  with risk of seizures.

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Case presentation ctd.

• Hydromorphone D/Cd
• NS 500 ml IV bolus, followed by NS with KCl 10
  mEq/l 250 ml/hrIV. (This was decreased to 200
  ml/hr overnight, D/Cd Oct 23 1300h)
• Furosemide 40 mg IV q8h
• Lorazepam 0.5 mg IV push x1 dose _at_ 1345h
• Sufentanil 5 µg IV push x1 dose _at_ 1425h
• Sufentanil 10 µg/hr IV infusion started
  mid-afternoon Oct. 22 ? 20 µg/hr Oct.
  23Breakthrough sufentanil 25-50 µg SL q 30 min
  prn. Received total breakthrough of 75 µg Oct. 22
  and 250 µg Oct. 23
• Midazolam 2.5 5 mg SQ q1h prn (needed just 1
  dose, Oct. 23)
• Marked improvement in myoclonus by 1700h Oct. 22

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Case presentation ctd.

• Methadone 10 mg bid added Oct 25 ? 15 mg bid Oct
  26 at which time sufentanil DCd.
• Max methadone dose was 25 mg bid, Nov. 07
• Considerhydromorphone 30 mg/hr SQ 720 mg/day
  3600 mg/day SQ morphine if a 51 ratio
  used 7200 mg/day po morphineRipamonti
  et al J Clin Oncol 1998 mg po Morphine/day
  MorphineMethadone 30
  90 3.7
  1 90 300
  7.75 1 gt 300
  12.25 1
• Calculated methadone equivalence to 7200 mg/day
  po morphine 588 mg/d po methadone
• ie. throw out your opioid conversion tables in
  neurotoxicity

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Case presentation final

• Nov. 20/01 marked decline
• No longer able to swallow methadone switched to
  hydromorphone 6 mg SQ q4h
• Died comfortably Nov. 24/01

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Spectrum of Opioid-Induced Neurotoxicity
Seizures,Death
Opioidtolerance
Mild myoclonus(eg. with sleeping)
Severe myoclonus
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Mayer D. et al Proc. Natl. Acad. Sci. USA Vol.
96, pp. 7731-7736 Jul. 1999
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A Spinal Cord Model of Injury-Induced Hyperalgesia
Mao, J. et alPain 62 (1995) 259-274
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A Spinal Cord Model of Morphine Tolerance
Mao, J. et alPain 62 (1995) 259-274
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Harrison, C. et alBr. J. Anaesth. 1998 81 20-28
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Harrison, C. et alBr. J. Anaesth. 1998 81 20-28
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Harrison, C. et alBr. J. Anaesth. 1998 81 20-28
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Agonist(fentanyl)
Receptor(µ-opioid)
G-protein
2nd messenger
Response(analgesia)
The process of signal transduction, with specific
examples shown in parentheses
Harrison, C. et alBr. J. Anaesth. 1998 81 20-28
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Approach To The Patient With Opioid Neurotoxicity
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OVERVIEW OF BASIC STEPS

• Recognize the syndrome
• Discontinue the offending opioidNote naloxone
  does not reverse neuroexcitatory effects, and may
  in fact exacerbate them
• Hydrate to help clear opioid and metabolites
• Consider benzodiazepines to decrease
  neuromuscular irritability
• Explore options to address the suffering

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Recognizing The Syndrome Of O.I.N.

• Delirium, agitation, restlessness

• Myoclonus, potentially seizures

• Allodynia, Hyperalgesia - pain presentation
  changes to pain all over doesnt make sense in
  terms of underlying disease

• Rapidly increasing opioid dose seems to make
  things worse

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Discontinue the Offending Opioid

• Simply decreasing the dose only postpones the
  need to switch opioids
• Adding a benzodiazepine without addressing the
  opioid ignores potential reversibility
• Stepwise conversion (days) in mild neurotoxicity
• Abrupt discontinuation if life-threatening
  neurotoxicity (seizures imminent)

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Hydrate to Help Clear Opioid and Metabolites

• Morphine and hydromorphone metabolites are
  renally excreted
• Oral, SQ, or IV depends on the severity and
  venous access
• Example of aggressive hydrationNS 500 ml bolus
  followed by 250 ml/hr plus furosemide 40 mg IV q6h

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Consider Benzodiazepines to Decrease
Neuromuscular Irritability

• Clonazepam long-acting p.o.
• Lorazepam intermediate duration of action p.o.,
  SL, IV, (IM for seizures)
• Midazolam short-acting SQ, IV, SL, (IM
  generally not used this route)
• Be cautious with additive respiratory depressant
  effects if also giving opioids by bolus

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Explore Options to Address the Suffering

• This can include
• Switching opioids
• Steps to ? opioid requirements
• adjuvants (eg/gabapentin, corticosteroids,
  ketamine, bisphosphonates)
• Procedural intervention- epidural, spinal,
  intrathecal catheters
• Radiation,chemotherapy
• Orthopedic intervention
• Seating, positioning

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Explore Options to Address the Suffering ctd
May be other issues to address that have been
treated with opioids as physical pain
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CHALLENGES IN MANAGING PAIN / DISTRESS IN
SETTINGS OF NEUROTOXICITY

• Quite possible that a substantial proportion of
  the current offending opioid dose is being
  targeted at treating opioid-induced hyperalgesia
  or restlessness the opioid has been
  increased to treat its own side effects
• tolerance to the offending opioid, not
  crossed-over to alternatives (incomplete
  cross-tolerance)
• Impossible to calculate dose equivalences of
  alternative opioids conversion charts dangerous
  to use

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ADVANTAGES OF FENTANYL OR SUFENTANIL IN
NEUROTOXICITY

• No known active metabolites
• Different opioid class (anilinopiperidines) than
  morphine and hydromorphone (benzomorphans)
• Not common (though not impossible) to develop
  signs of neurotoxicity
• Sufentanil patients will not be on this as an
  outpatient
• will not be presenting with related neurotoxicity
• tolerance will not have developed
• Rapid onset, short-acting facilitates titration
  in difficult, unstable circumstances

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METHADONE

• Racemic mixture of 2 stereoisomers
• only the R-enantiomer has analgesic properties
• S-enantiomer NMDA receptor antagonist? Role in
  mitigating effects of M3G

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Approach to Changing Opioids in Settings of O.I.N.
? Life-Threatening (severe myoclonus,seizures)
No
Yes

• Abrupt withdrawal of offending opioid
• Aggressive hydration
• prn dosing of either fentanyl, sufentanil, or
  methadone
• Dont try to calculate an appropriate starting
  dose based on current opioid use. Start low and
  titrate up
• After a few hours, consider starting a regular
  administration (infusion, perhaps oral methadone)

• Can titrate off of offending opioid over days
• As you titrate down, add appropriate doses of an
  alternative opioid
• Pain Poorly Controlled ? dose of new opioid
• Pain well controlled, patient alert ? new
  opioid, ?offending opioid
• Pain well controlled, patient lethargic
  ?offending opioid

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Equivalency Ratios in Converting to
MethadoneInterpret With Caution
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The Latest Innovation in Opioid Conversion
Calculation