Opioid Induced Neurotoxicity

1. Opioid Induced Neurotoxicity John Mulder, MD

3. “It’s not being dead that I’m afraid of - it’s getting there.” -- Andy Warhol

4. The Case • 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.

5. The Case • 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.

6. The Case • Current meds: • 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

7. The Case – What Now? • Causes of symptoms? • Diagnostic options? • Treatment options?

8. Differential Diagnosis • Escalating cancer pain or new acute pain that could be misinterpreted as hyperalgesia • Neurologic or pharmacologic causes of myoclonus • Delirium due to other causes

9. Opioid Induced Neurotoxicity Opioid Induced Neurotoxicity (OIN) is a syndrome of hyperalgesia and nervous system hyperexcitability associated with opioid administration.

10. Clinical Features of OIN • 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

11. 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)

12. Mechanism of OIN • Neuroexcitation by phenanthrene metabolites (e.g. morphine-3 and -6 glucuronide) • NMDA receptoractivation 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

13. OIN Mechanisms Pronociception Hyperalgesia Anti-analgesia (e.g. M3G) Peripheral (e.g. excitatory neuropeptides) Central (e.g. NMDA-R activation)

14. Approach to Diagnosis of OIN • History of 2 of the following • at least 2 opioid dose escalations • no improvement in pain or worsened pain • volume depletion or renal insufficiency • Presence of at least 1 of the following • hyperesthesia or hyperalgesia • Allodynia • multifocal myoclonus • Seizures • delirium (somnolence, agitation, hallucinations) • Confirm diagnosis on improvement with treatment by 36 h

15. Management Strategy • Calm the CNS • Opioid rotation • Specific considerations • Opioid sparing adjuvants

16. Management Strategy • Calm the CNS • Benzodiazepines • Stop other neurotoxic medications • Consider haloperidol • Opioid rotation • Stop current opioid • Start another low risk opioid at 25% MEDD or reduce current opioid to 25% MEDD

17. 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)

18. 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

19. 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

20. Mgmt Strategy/Opioid Rotation • Methadone • NMDA-R antagonist • No active metabolites • Non-phenanthrene • Fentanyl • No active metabolites • No hyperalgesia • Non-phenanthrene • Levorphanol • more active at kappa O-R

21. 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

22. Approach to Changing Opioids in Settings of OIN ? Life-Threatening (severe myoclonus,seizures) No Yes • 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 • 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)

23. Management Strategy • Specific considerations • Consider hydration • Hemodialysis? • Consider neuroleptics • Opioid sparing adjuvants • NSAIDS, steroids, ketamine, lidocaine, gabapentin, nerve blocks, others

24. 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

25. What NOT To Do • No role for anti-convulsants • No role for naloxone • Only one pro-convulsant pathway is opioid receptor mediated, other is not • Reverse analgesic activity • Best benzodiazepines seem to be • midazolam, lorazepam, clonazepam

26. 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 opioid-induced neurotoxicity

27. Delirium Hyperalgesia OpioidsIncreased Agitation OpioidsIncreased Misinterpretedas Disease-Related Pain Misinterpretedas Pain Spectrum of Opioid-Induced Neurotoxicity Opioidtolerance Mild myoclonus(eg. with sleeping) Seizures,Death Severe myoclonus

28. 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 restlessnessthe opioid has been increased to treat its own sideeffects • 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

29. The Latest Innovation in Opioid Conversion Calculation