Management of Life-Threatening Opioid Neurotoxicity

Management of Management of

Life-Threatening Life-Threatening

Opioid NeurotoxicityOpioid Neurotoxicity

• There has been a 3x increase in morphine consumption There has been a 3x increase in morphine consumption worldwide from 1986 to 1995worldwide from 1986 to 1995

• There has also been an increase in reports and awareness There has also been an increase in reports and awareness of neuroexcitatory side effects (allodynia, hyperalgesia, of neuroexcitatory side effects (allodynia, hyperalgesia, myoclonus, seizures) of morphine and hydromorphonemyoclonus, seizures) of morphine and hydromorphone

• As we succeed in educating and encouraging health care As we succeed in educating and encouraging health care providers to be aggressive in pain management, we can providers to be aggressive in pain management, we can expect to see more opioid-induced neurotoxicityexpect to see more opioid-induced neurotoxicity

Why Are We Seeing More Opioid Induced Neurotoxicity?Why Are We Seeing More Opioid Induced Neurotoxicity?

• Myoclonus: sudden, brief, shock-like involuntary Myoclonus: sudden, brief, shock-like involuntary movements caused by muscular contractionsmovements caused by muscular contractions

• All muscle groupsAll muscle groups

• Often best observed when patient sleepingOften best observed when patient sleeping

• Incidence of opioid-related myoclonus varies from Incidence of opioid-related myoclonus varies from 2.7% to 87%2.7% to 87%

• Most recognized with metabolites of morphine Most recognized with metabolites of morphine (particularly M3G), however also seen with opioids (particularly M3G), however also seen with opioids with no active metabolites (methadone, fentanyl)with no active metabolites (methadone, fentanyl)

Opioid Induced MyoclonusOpioid Induced Myoclonus

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

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.


– 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 @ 13:45h

– Sufentanil 5 μg IV push x1 dose @ 14:25h

– 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


– 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

– Consider:hydromorphone 30 mg/hr SQ = 720 mg/day ≈ 3600 mg/day SQ morphine if a 5:1 ratio used ≈ 7200 mg/day po morphine

Ripamonti et al J Clin Oncol 1998: #mg po Morphine/day Morphine:Methadone 30 – 90 3.7 : 1 90 – 300 7.75 : 1 > 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

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

Seizures,Death

Opioidtolerance

Mild myoclonus(eg. with sleeping)

Severe myoclonus

Delirium

Agitation

Misinterpretedas Pain

OpioidsIncreased

Hyperalgesia

Misinterpretedas Disease-Related Pain

OpioidsIncreased

Spectrum of Opioid-Induced Neurotoxicity

Mayer D. et al Proc. Natl. Acad. Sci. USA Vol. 96, pp. 7731-7736 Jul. 1999

Mao, J. et alPain 62 (1995) 259-274

A Spinal Cord Model of Injury-Induced Hyperalgesia

Mao, J. et alPain 62 (1995) 259-274

A Spinal Cord Model of Morphine Tolerance

Harrison, C. et alBr. J. Anaesth. 1998; 81: 20-28



Agonist(fentanyl)

Receptor(μ-opioid)

G-protein 2nd messengerResponse

(analgesia)

The process of signal transduction, with specific examples shown in parentheses


Approach To The Patient Approach To The Patient

With Opioid NeurotoxicityWith Opioid Neurotoxicity

1.1. Recognize the syndromeRecognize the syndrome

2.2. Discontinue the offending opioidDiscontinue the offending opioidNote: naloxone does not reverse neuroexcitatory Note: naloxone does not reverse neuroexcitatory effects, and may in fact exacerbate themeffects, and may in fact exacerbate them

3.3. Hydrate to help clear opioid and metabolitesHydrate to help clear opioid and metabolites

4.4. Consider benzodiazepines to decrease Consider benzodiazepines to decrease neuromuscular irritabilityneuromuscular irritability

5.5. Explore options to address the sufferingExplore options to address the suffering

OVERVIEW OF BASIC STEPSOVERVIEW OF BASIC STEPS

Recognizing The Syndrome Of O.I.N.

• Delirium, agitation, restlessnessDelirium, agitation, restlessness

• Myoclonus, potentially seizuresMyoclonus, potentially seizures

• Rapidly increasing opioid dose; seems to make things Rapidly increasing opioid dose; seems to make things worseworse

• Allodynia, Hyperalgesia - pain presentation changes to Allodynia, Hyperalgesia - pain presentation changes to “pain all over”; doesn’t make sense in terms of “pain all over”; doesn’t make sense in terms of underlying diseaseunderlying disease

• Simply decreasing the dose only postpones the need Simply decreasing the dose only postpones the need to switch opioidsto switch opioids

• Adding a benzodiazepine without addressing the Adding a benzodiazepine without addressing the opioid ignores potential reversibilityopioid ignores potential reversibility

• Stepwise conversion (days) in mild neurotoxicity Stepwise conversion (days) in mild neurotoxicity

• Abrupt discontinuation if life-threatening Abrupt discontinuation if life-threatening neurotoxicity (seizures imminent)neurotoxicity (seizures imminent)

Discontinue the Offending OpioidDiscontinue the Offending Opioid

• Morphine and hydromorphone metabolites are Morphine and hydromorphone metabolites are renally excretedrenally excreted

• Oral, SQ, or IV… depends on the severity and Oral, SQ, or IV… depends on the severity and venous accessvenous access

• Example of aggressive hydration:Example of aggressive hydration:NS 500 ml bolus followed by 250 ml/hr plus NS 500 ml bolus followed by 250 ml/hr plus furosemide 40 mg IV q6hfurosemide 40 mg IV q6h

Hydrate to Help Clear Opioid and MetabolitesHydrate to Help Clear Opioid and Metabolites

• Clonazepam: long-acting; p.o. Clonazepam: long-acting; p.o.

• Lorazepam: intermediate duration of action; p.o., SL, Lorazepam: intermediate duration of action; p.o., SL, IV, (IM – for seizures)IV, (IM – for seizures)

• Midazolam: short-acting; SQ, IV, SL, (IM – Midazolam: short-acting; SQ, IV, SL, (IM – generally not used this route)generally not used this route)

• Be cautious with additive respiratory depressant Be cautious with additive respiratory depressant effects if also giving opioids by boluseffects if also giving opioids by bolus

Consider Benzodiazepines to Decrease Consider Benzodiazepines to Decrease Neuromuscular IrritabilityNeuromuscular Irritability

• This can include: This can include:

– Switching opioidsSwitching opioids

– Steps to Steps to ↓↓ opioid requirements opioid requirements

o adjuvants (eg/gabapentin, corticosteroids, adjuvants (eg/gabapentin, corticosteroids, ketamine, bisphosphonates)ketamine, bisphosphonates)

o Procedural intervention- epidural, spinal, Procedural intervention- epidural, spinal, intrathecal cathetersintrathecal catheters

o Radiation,chemotherapyRadiation,chemotherapy

o Orthopedic interventionOrthopedic intervention

o Seating, positioningSeating, positioning

Explore Options to Address the SufferingExplore Options to Address the Suffering

May be other issues to address that have been treated with opioids May be other issues to address that have been treated with opioids as physical pain as physical pain

Explore Options to Address the Suffering ctdExplore Options to Address the Suffering ctd

SUFFERINGSUFFERINGEMOTIONALPSYCHOSOCIAL

PHYSICAL

SPIRITUAL

• Quite possible that a substantial proportion of the current Quite possible that a substantial proportion of the current offending opioid dose is being targeted at treating offending opioid dose is being targeted at treating opioid-induced hyperalgesia or restlessnessopioid-induced hyperalgesia or restlessness

the opioid has been increased to treat its own sidethe opioid has been increased to treat its own side effects effects

• + + tolerance to the offending opioid, not “crossed-over” + + tolerance to the offending opioid, not “crossed-over” to alternatives (incomplete cross-tolerance)to alternatives (incomplete cross-tolerance)

• Impossible to calculate dose equivalences of alternative Impossible to calculate dose equivalences of alternative opioids; conversion charts dangerous to useopioids; conversion charts dangerous to use

CHALLENGES IN MANAGING PAIN / DISTRESS CHALLENGES IN MANAGING PAIN / DISTRESS IN SETTINGS OF NEUROTOXICITYIN SETTINGS OF NEUROTOXICITY

• No known active metabolitesNo known active metabolites

• Different opioid class (anilinopiperidines) than morphine Different opioid class (anilinopiperidines) than morphine and hydromorphone (benzomorphans)and hydromorphone (benzomorphans)

• Not common (though not impossible) to develop signs of Not common (though not impossible) to develop signs of neurotoxicityneurotoxicity

• Sufentanil – patients will not be on this as an outpatient… Sufentanil – patients will not be on this as an outpatient… will not be presenting with related neurotoxicitywill not be presenting with related neurotoxicity tolerance will not have developedtolerance will not have developed

• Rapid onset, short-acting – facilitates titration in difficult, Rapid onset, short-acting – facilitates titration in difficult, unstable circumstancesunstable circumstances

ADVANTAGES OF FENTANYL OR ADVANTAGES OF FENTANYL OR SUFENTANIL IN NEUROTOXICITY SUFENTANIL IN NEUROTOXICITY

METHADONEMETHADONE

• Racemic mixture of 2 stereoisomersRacemic mixture of 2 stereoisomers

• only the R-enantiomer has analgesic propertiesonly the R-enantiomer has analgesic properties

• S-enantiomer: NMDA receptor antagonistS-enantiomer: NMDA receptor antagonist? Role in mitigating effects of M3G? Role in mitigating effects of M3G

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• 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

Morphine Total Daily mg po Morphine:Methadone Ratio

30 – 90 3.7

90 - 300 7.75

> 300 12.25

Ripamonti et al; J Clin Oncol 1998

Hydromorphone Total Daily mg po Hydromorphone:Methadone Ratio

3 - 6 0.30

6 - 24 0.89

24 - 100 0.74

100 - 300 1.5

>300 1.5

Ripamonti et al; Annals Oncol 1998

Equivalency Ratios in Converting to Methadone:Interpret With Caution

The Latest Innovation in Opioid Conversion Calculation

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Management of Life-Threatening Opioid Neurotoxicity