Transcript Alive-HCA Partnership

Opioid Induced
Neurotoxicity
John Mulder, MD
“It’s not being dead that I’m
afraid of - it’s getting there.”
-- Andy Warhol
The Case
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26 y/o Asian male presented to the ER Feb, 2009
writhing in pain (abdominal).
Anxious, breathing labored secondary to pain, though
answered questions appropriately with short phrases.
Cachetic, marked lower abdominal, scrotal, and leg
edema. Nauseated, and manifested random muscular
twitching.
Recent history of agitation, brief moments of
disorientation.
BP 102/65. Pulse 129, oximetry 97% room air.
The Case
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Angiosarcoma of the spleen diagnosed January, 2008,
followed by chemotherapy.
Ruptured spleen April of 2008, leading to extensive
surgery, including splenectomy and partial
panceatectomy.
Developed large subphrenic abscess in December,
2008, treated with antibiotics and drainage.
Admitted to hospice in December, 2008.
Pigtail drain was removed in January, 2009 per patient
request without resolution of the abscess.
The Case
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Current meds:
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Hydromorphone infusion, 25 mg/hour, 4mg
demand q15 min
Klonapin 2 mg at hs
Elavil 40 at hs
Lexapro 40 mg at hs
Ativan 2 mg at hs
Phenergan 25 mg qid
Remeron 15 mg at hs
Roxanol 40-80 mg hourly prn
Haldol 1 mg topical qid prn
The Case – What Now?
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Causes of symptoms?
Diagnostic options?
Treatment options?
Differential Diagnosis
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Escalating cancer pain or new acute
pain that could be misinterpreted as
hyperalgesia
Neurologic or pharmacologic causes of
myoclonus
Delirium due to other causes
Opioid Induced Neurotoxicity
Opioid Induced Neurotoxicity (OIN) is a
syndrome of hyperalgesia and nervous
system hyperexcitability associated with
opioid administration.
Clinical Features of OIN
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A history of increased pain, delirium,
allodynia, hyperalgesia, myoclonus, and,
in extreme cases, seizure activity and
death
Symptoms are non-tolerant
Resistance to sedation and respiratory
depression
mu opioid receptor antagonist resistant
Increasing opioids make symptoms worse
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)
Mechanism of OIN
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Neuroexcitation by phenanthrene metabolites (e.g.
morphine-3 and -6 glucuronide)
NMDA receptor activation by opioids
Release of neurotransmitters (spinal dynorphin,
substance P, nociceptin)
M6G concentrations shown to be loosely associated
with neurologic adverse effects of morphine
M3G concentration and M3G:Morphine ratio have
been suggested but not confirmed as mediators for
OIN
OIN Mechanisms
Pronociception
Hyperalgesia
Peripheral
(e.g. excitatory neuropeptides)
Anti-analgesia
(e.g. M3G)
Central
(e.g. NMDA-R activation)
Approach to Diagnosis of OIN
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History of 2 of the following
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Presence of at least 1 of the following
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at least 2 opioid dose escalations
no improvement in pain or worsened pain
volume depletion or renal insufficiency
hyperesthesia or hyperalgesia
Allodynia
multifocal myoclonus
Seizures
delirium (somnolence, agitation, hallucinations)
Confirm diagnosis on improvement with treatment by
36 h
Management Strategy
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Calm the CNS
Opioid rotation
Specific considerations
Opioid sparing adjuvants
Management Strategy
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Calm the CNS
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Benzodiazepines
Stop other neurotoxic medications
Consider haloperidol
Opioid rotation
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Stop current opioid
Start another low risk opioid at 25% MEDD
or reduce current opioid to 25% MEDD
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)
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
Recognizing The Syndrome Of OIN
• Delirium, agitation, restlessness
• Myoclonus, potentially seizures
• Allodynia, Hyperalgesia - pain presentation
changes to “pain all over”; doesn’t make sense in
terms of underlying disease
• Rapidly increasing opioid dose; seems to make
things worse
Mgmt Strategy/Opioid Rotation
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Methadone
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Fentanyl
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NMDA-R antagonist
No active metabolites
Non-phenanthrene
No active metabolites
No hyperalgesia
Non-phenanthrene
Levorphanol
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more active at kappa O-R
Advantage 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
Approach to Changing Opioids in Settings of OIN
? Life-Threatening (severe myoclonus,seizures)
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1.
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No
Yes
Can titrate off of offending
opioid over days
As you titrate down, add
appropriate doses of an
alternative opioid:
• Abrupt withdrawal of offending
opioid
• Aggressive hydration
• prn dosing of either fentanyl,
sufentanil, or methadone
• Don’t 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)
Pain Poorly Controlled: ↑ dose
of new opioid
Pain well controlled, patient
alert: ↑ new opioid, ↓offending
opioid
Pain well controlled, patient
lethargic: ↓offending opioid
Management Strategy
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Specific considerations
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Consider hydration
Hemodialysis?
Consider neuroleptics
Opioid sparing adjuvants
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NSAIDS, steroids, ketamine, lidocaine,
gabapentin, nerve blocks, others
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 hydration:
NS 500 ml bolus followed by 250 ml/hr plus
furosemide 40 mg IV q6h
What NOT To Do
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No role for anti-convulsants
No role for naloxone
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Only one pro-convulsant pathway is opioid
receptor mediated, other is not
Reverse analgesic activity
Best benzodiazepines seem to be
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midazolam, lorazepam, clonazepam
Why Are We Seeing More
Opioid Induced Neurotoxicity?
• There has been a dramatic increase in morphine
consumption worldwide
• 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 opioidinduced neurotoxicity
Spectrum of
Opioid-Induced Neurotoxicity
Opioid
tolerance
Mild myoclonus
(eg. with sleeping)
Delirium
Opioids
Increased
Severe myoclonus
Seizures,
Death
Hyperalgesia
Agitation
Misinterpreted
as Pain
Opioids
Increased
Misinterpreted
as Disease-Related Pain
CHALLENGES IN MANAGING PAIN
/ DISTRESS IN SETTINGS OF
NEUROTOXICITY
• A 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 “crossedover” to alternatives (incomplete cross-tolerance)
• Impossible to calculate dose equivalences of
alternative opioids; conversion charts dangerous to
use
The Latest Innovation in Opioid Conversion Calculation