Opioid Induced Neurotoxicity

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Opioid Induced Neurotoxicity

• Burton Abbott, MD

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Opioid Induced Neurotoxicity

• Introduction
• General Comments Regarding Opioids
• Opioid Receptors and Metabolites
• Predisposing Factors
• Clinical Features
• Management
• Cases
• Summary

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Opioid Induced Neurotoxicity

• Neuroexcitatory sydrome described primarily in
  cancer patients who are on high doses of opioids
• Described as resulting from opioid metabolites
• Described from 1990s to present
• Best described for meperidine
• Recently described for other opioids

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Opiates, Opioids and Narcotics

• Opiate
• A specific term
• Naturally occurring or semisynthetic drugs
  derived from the opium poppy
• e.g. morphine
• Opioid
• A more general term
• Naturally occurring, semisynthetic or synthetic
  drugs that are opioid receptor agonists
• e.g. morphine, methadone, fentanyl

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Opiates, Opioids and Narcotics

• Narcotics
• An imprecise term including opioids and other
  drugs with potential for abuse
• Pejorative connotations
• Term generally not used in pain or palliative
  care literature
• Hanks GW, Cherny N. Opioid Analgesic Therapy.
  In Oxford Textbook of Palliative Medicine 2nd
  ed. 1998

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Prevalence of Cancer Pain
From Portenoy Cancer 632298, 1989
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Opioid Induced Neurotoxicity

• Recent emphasis on treatment of pain and other
  symptoms especially in cancer
• Morphine use worldwide increased 2.5 x
  between1972 and 1987
• There appears to be a corresponding increase in
  reports of opioid related hallucinations,
  agitation, myoclonus, and seizures
• Daeninck PJ, Bruera E. Acta Anaesthesiol Scand.
  1999

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Opioid Induced Neurotoxicity

• Difficult to really tell prevalence or if it is
  increasing
• Little written prior to 1990s
• Mainly case reports up to the present time
• Anecdotally, more reports in recent years
  especially among oncologists and palliative care
  physicians

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Opioid Induced Neurotoxicity

• Thought to be relatively common among patients on
  high dose opioids
• Thwaites et al
• Retrospective study
• 48 cancer patients all on continuous parenteral
  hydromorphone infusion
• Three neuroexcitatory symptoms agitation,
  myoclonus, and seizures
• These symptoms not associated with specific
  diagnosis, age
• Agitation, myoclonus, seizures independently
  associated with
• Dose (plt0.05, plt0.001, plt0.05)
• Duration (plt0.01, plt0.05, plt0.01)
• of hydromorphone
• Thwaites et al. J Palliat Med 2004.

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Opioid Receptors

• Three types of opioid receptors m, d, k
• Several subtypes within each type
• Beneficial and adverse effects mediated through
  receptors
• Opioid drugs are agonists with varying affinity
  at these receptors
• Inturrisi CE. Clin J Pain 2002

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Opioid Receptors

• Inter-individual variation in receptor
  type/subtype
• ?differences between individuals therapeutic
  response/adverse effects with opioids
• m receptor mediates most analgesic (and adverse)
  effect
• Most common opioids are predominantly m agonists
• Naloxone is a m antagonist
• Inturrisi CE. Clin J Pain 2002

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Opioid Metabolites

• Neuroexcitation induced by opioid metabolites is
  best documented for meperidine
• BUT
• This phenomenon has been described for ALL
  opioids

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Opioid Metabolites

• Opioids undergo hepatic metabolism
  (glucuronidation or demethylation) then renal
  clearance
• Some opioid metabolites are active and some are
  neuroexcitatory
• Morphine
• predominantly metabolized by glucuronidation to
  M-3-G and M-6-G
• Also N-demethylation to normorphine
• Hydromorphone
• Predominantly metabolized to H-3-G

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Opioid Metabolites

• Meperidine is primarily metabolized via
  N-demethylation to normeperidine
• Normeperidine is a potent neuroexcitant
• Normoperidine may result in neuroexcitation
  (delirium, irritability, myoclonus, seizures)
  even after relatively little meperidine
  administration

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Opioid Metabolites
After Smith MT. Clinical and Experimental
Pharmacology and Physiology 2000
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Opioid Metabolites

• In CSF, M-3-G exceeds morphine and M6G by
  approximately 2 and 5 fold respectively
• As M-3-G or H-3-G increase, neuroexcitatory
  behaviors are seen
• M-3-G and H-3-G have no analgesic activity, but
  they are neuroexcitatory

Smith MT. Clinical and Experimental
Pharmacology and Physiology 2000
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Opioid Metabolites

• Morphine-6-glucuronide
• is a potent m agonist
• Has analgesic activity
• Morphine-3-glucuronide
• Has nociceptive activity
• Is not a m antagonist
• Related to neuroexcitation (agitation, delirium,
  hyperalgesia/allodynia, myclonus, seizures)
• Christrup LL. Acta Anaesthesiol Scand. 1997

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Morphine Metabolites in Renal Insufficiency
n18 patients Followed over 4 to 26
weeks ?inverse relationship between estimated
creatinine clearance and ratio of metabolite to
morphine
Ravenscroft P, Schnider J. Clinical and
Experimental Pharmacology and Physiology 2000
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Opioid Induced Neurotoxicity

• Predisposing Factors
• High opioid doses
• Prolonged opioid use
• Recent rapid dose escalation
• Dehydration
• Renal failure
• Advanced age
• Other psychoactive drugs
• Daeninck PJ, Bruera E. Acta Anaesthesiol
  Scand. 1999

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Opioid Induced Neurotoxicity

• Differential Diagnoses
• Metabolic (Na, K, Ca)
• Hyoxemia
• Hypercarbia
• Sepsis
• Drug effect
• Uremic encephalopathy
• Hepatic encephalopathy
• Terminal Delirium

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Opioid Induced Neurotoxicity

• Management
• Consider consultation with palliative care MD on
  call
• Discontinue offending opioid
• Hydration
• Begin alternative opioid
• Consider benzodiazepine
• NO role for naloxone
• Daeninck PJ, Bruera E. Acta Anaesthesiol
  1999

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Opioid Induced Neurotoxicity

• Management
• Consider nonopioid (adjuvant) medications (e.g.
  bisphosphonates, gabapentin)
• Consider consultation with
• Radiation oncology
• Anesthesia (e.g. regional anesthesia)
• Orthopedic surgery
• Occupational therapy (e.g. splinting, seating)

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Opioid Rotation

• Retrospective study of 80 patients who had
  undergone opioid rotation for neuroexcitatibility
  symptoms
• Cognitive deterioration, hallucinations,
  myoclonus
• These symptoms improved in 58/80 (plt0.01)
• Significant improvement in pain control per VAS
• New opioid dose was significantly lower than that
  thought to be equianalgesic

de Stoutz et al. J Pain Symptom Manage 1995
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Opioid Rotation to Which Opioid?

• It is felt that any change to one of the common
  opioids indicated for chronic use is beneficial
• To a different class if possible
• Methadone, fentanyl/sufentanil
• No neuroexcitatory metabolites identified
• Less common for patient to be on any of these
  medications from the community
• Note that neuroexcitation has been described for
  all opioids

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Case 1

• Mrs. I.H. 54 y.o. woman with metastatic ovarian
  carcinoma diagnosed in 2002
• Transferred Feb. 21/05
• Received call from rural physician (Community
  Cancer Program) re out of control pain and
  widespread twitching
• The note accompanying patient
• Her pain has recently been escalating and we
  likely need a new strategy.
• Admitted at 1525 h
• Pain everywhere but worst in abdomen, R hip
  area, R leg

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Case 1 contd

• History included laparotomy R hemicolectomy,
  debulking surgery incl hysterectomy BSO,
  radiation, chemotherapy
• Stage 4 ovarian carcinoma widespread mets
• Present meds
• Hydromorphone 60 mg/h continuous SQ infusion (
  had received total of 240 mg SQ additionally that
  day)
• Fentanyl for breakthrough pain ( 400 mcg / day)
• Amitriptyline
• Ketamine
• Dexamethasone
• Huge increase in opioids in the prior 2 weeks

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Case 1 Contd

• In obvious distress
• Agitated, confused
• Myoclonic jerks
• Pupils 4mm reactive
• Afebrile
• Labs
• WBCs 11.6 CBC otherwise N
• Coags N
• Lytes N, urea 8.9, creatinine 110,
  urea/creatinine 81 (N lt 70), glucose 9.5
• Corrected Ca 2.49, Mg N
• Albumin 26
• LD 423 other liver enzymes essentially N
• Urine conc otherwise N

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Case 1 contd

• CT massive abdominal and retroperitoneal
  adenopathy
• Assessed as having severe neuropathic pain and
  opioid induced neurotoxicity
• Treatment on Day 1
• Stopped hydromorphone, ketamine, amitriptyline
• NS bolus 500 ml ? 250 ml/h x 2 hours then 125
  ml/h
• Furosemide 20 mg IV
• Sufentanil 25 mcg SQ x 1
• Sufentanil 10 mcg/h SQ
• Methadone 2.5 mg po TID
• Lorazepam 0.5-1 mg SL Q4H prn (used 4 doses /
  day early in stay then little used)
• Dexamethasone continued

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Case 1 contd

• Feb 21 1730 h feeling much better jerking
  improved
• Feb 22 -much less pain sensorium cleared
• - sufentanil inc. to 12 mcg/h SQ
• - methadone inc. to 5 mg po BID
• Feb 23-28- no evidence of neuroexcitation
• - persisting pain
• - steady inc. in both methadone and sufentanil
• Feb 28 - Methadone 7.5 mg po TID
• - Sufentanil 40 mcg/h
• - Anesthesia consult

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Case 1 contd

• Feb 28 Anesthesia consult constant severe pain
  resistant to aggressive opioid management Pain
  likely due to tumor involving lumbosacral plexus
• - no change in systemic medications
• - epidural marcaine 1.25 mg/ml
• hydromorphone 60 mcg/ml
• rate 10 ml/h
• Mar 1 Improved pain control of low back and
  right leg, but persisting higher in back

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Case 1- contd

• Over the next week, generally good baseline pain
  control apart from periodic exacerbations
• Relatively stable doses of opioids from that
  point
• No further myoclonus, agitation, hyperalgesia
• To attempt to treat the periodic exacerbations,
  anesthesia started ketamine IV then ketamine in
  epidural
• March 6 generally comfortable, had a good night
• March 9 Passed away peacefully

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Spectrum of Opioid-Induced Neurotoxicity
Seizures
Opioidtolerance
Mild myoclonus(eg. with sleeping)
Severe myoclonus
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Case 2

• Ms. W.P. 73 yo woman with metastatic NSCLC
  Diagnosed 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 q3h (prn 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 2 contd

• Oct. 22/01 transferred to SBGH palliative care
• On exam at time of transfer (approx 1330h)
• Lethargic but easily rousable, disoriented,
  restless.
• Resps. approx 20, reg.
• Pupils 3-4 mm, reactive
• Generalized myoclonus non-stop
• Normal electrolytes, calcium, urea, creatinine
• Assessed as having severe opioid induced
  neurotoxicity.

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Case 2 contd

• Hydromorphone D/Cd
• NS 500 ml IV bolus, followed by NS with KCl 10
  mEq/l 250 ml/hr IV. (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
• Marked improvement in myoclonus by 1700h Oct. 22

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Case 2 contd

• Methadone 10 mg po bid added Oct 25 ? 15 mg po
  bid Oct 26 at which time sufentanil D/Cd.
• Good pain control
• No neuroexcitation symptoms
• Max methadone dose was 25 mg po bid, Nov. 07
• Nov. 20 marked decline
• No longer able to swallow methadone switched to
  hydromorphone 6 mg SQ q4h
• Died comfortably Nov. 24

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Consider the following

• Hydromorphone 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 equivalence to 7200 mg/day po
  morphine 588 mg/d po methadone
• ie. throw out your opioid conversion tables with
  opioid neurotoxic patients

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Opioid Induced Neurotoxicity

• A substantial part of the current opioid had been
  started to treat opioid induced
  hyperalgesia/restlessness
• That is the opioid was increased to treat its
  own adverse effects
• Significant tolerance to the offending opioid
  that is not crossed over to alternative opioids
• It is not possible to calculate dose
  equivalencies of the new opioid do not use
  conversion charts in these situations

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Summary

• Recognize the syndrome
• High opioid dose
• Rapid escalation of opioid has not reduced
  symptoms
• Pain everywhere that is not explained
  pathoanatomically
• Myoclonus
• Agitation
• Confusion

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Summary

• Consult a palliative care physician is on call
  through SBGH paging
• Hydrate
• The implicated metabolites are renally cleared
• Consider discontinuation of other psychoactive
  drugs
• Consider a benzodiazepine
• DO NOT give naloxone
• Consider rotation of the opioid caution with
  initial doses of new opioid
• Non-opioid means to treat pain

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• Questions?