Opioid Induced Neurotoxicity John Mulder, MD

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

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.

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, Pigtail drain was removed in January, 2009 per patient request without resolution of the abscess.

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 mg hourly prn Haldol 1 mg topical qid prn

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

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

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

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

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) Opioid Induced Myoclonus

Mechanism of OIN 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 Anti-analgesia (e.g. M3G) Peripheral (e.g. excitatory neuropeptides ) Central (e.g. NMDA-R activation)

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

Management Strategy Calm the CNS Opioid rotation Specific considerations Opioid sparing adjuvants

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

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) Discontinue the Offending Opioid

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 Consider Benzodiazepines to Decrease Neuromuscular Irritability

Recognizing The Syndrome Of OIN Delirium, agitation, restlessness Myoclonus, potentially seizures Rapidly increasing opioid dose; seems to make things worse Allodynia, Hyperalgesia - pain presentation changes to “pain all over”; doesn’t make sense in terms of underlying disease

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

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 Advantage of Fentanyl or Sufentanil in Neurotoxicity

Approach to Changing Opioids in Settings of OIN ? Life-Threatening (severe myoclonus,seizures) No Yes 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) Can titrate off of offending opioid over days As you titrate down, add appropriate doses of an alternative opioid: 1.Pain Poorly Controlled: ↑ dose of new opioid 2.Pain well controlled, patient alert: ↑ new opioid, ↓ offending opioid 3.Pain well controlled, patient lethargic: ↓ offending opioid

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

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 Hydrate to Help Clear Opioid and Metabolites

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

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 Why Are We Seeing More Opioid Induced Neurotoxicity?

Seizures, Death Opioid tolerance Mild myoclonus (eg. with sleeping) Severe myoclonus Delirium Agitation Misinterpreted as Pain Opioids Increased Hyperalgesia Misinterpreted as Disease-Related Pain Opioids Increased Spectrum of Opioid-Induced 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 “crossed- over” to alternatives (incomplete cross-tolerance) Impossible to calculate dose equivalences of alternative opioids; conversion charts dangerous to use CHALLENGES IN MANAGING PAIN / DISTRESS IN SETTINGS OF NEUROTOXICITY

The Latest Innovation in Opioid Conversion Calculation