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Management of Life-Threatening Opioid Neurotoxicity

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Presentation on theme: "Management of Life-Threatening Opioid Neurotoxicity"— Presentation transcript:

1 Management of Life-Threatening Opioid Neurotoxicity

2 Why Are We Seeing More Opioid Induced Neurotoxicity?
There has been a 3x increase in morphine consumption worldwide from 1986 to 1995 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

3 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)


5 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

6 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 ( ) Oct. 22/01: Creat 47 μmol/l (35-97) BUN 2.9 mmol/l ( ) lytes, Ca++ normal Assessed as having severe opioid neurotoxicity, with risk of seizures.

7 Case presentation ctd. 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 h) Furosemide 40 mg IV q8h Lorazepam 0.5 mg IV push x1 13:45h Sufentanil 5 μg IV push x1 14:25h Sufentanil 10 μg/hr IV infusion started mid-afternoon Oct. 22 → 20 μg/hr Oct. 23 Breakthrough = sufentanil 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

8 Case presentation ctd. 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 – : – : > : 1 Calculated methadone equivalence to 7200 mg/day po morphine ≈ 588 mg/d po methadone ie. throw out your opioid conversion tables in neurotoxicity

9 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

10 Misinterpreted as Pain Misinterpreted as Disease-Related Pain
Spectrum of Opioid-Induced Neurotoxicity Opioid tolerance Mild myoclonus (eg. with sleeping) Severe myoclonus Seizures, Death Delirium Agitation Misinterpreted as Pain Opioids Increased Hyperalgesia Misinterpreted as Disease-Related Pain Opioids Increased

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

12 A Spinal Cord Model of Injury-Induced Hyperalgesia
Mao, J. et al Pain 62 (1995)

13 A Spinal Cord Model of Morphine Tolerance
Mao, J. et al Pain 62 (1995)

14 Harrison, C. et al Br. J. Anaesth. 1998; 81: 20-28

15 Harrison, C. et al Br. J. Anaesth. 1998; 81: 20-28

16 Harrison, C. et al Br. J. Anaesth. 1998; 81: 20-28

17 Agonist (fentanyl) Receptor (μ-opioid) G-protein 2nd messenger Response (analgesia) The process of signal transduction, with specific examples shown in parentheses Harrison, C. et al Br. J. Anaesth. 1998; 81: 20-28

18 Approach To The Patient With Opioid Neurotoxicity

Recognize the syndrome Discontinue the offending opioid Note: naloxone does not reverse neuroexcitatory effects, and may in fact exacerbate them Hydrate to help clear opioid and metabolites Consider benzodiazepines to decrease neuromuscular irritability Explore options to address the suffering

20 Recognizing The Syndrome Of O.I.N.
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

21 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)

22 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

23 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

24 Explore Options to Address the Suffering
This can include: Switching opioids Steps to ↓ opioid requirements adjuvants (eg/gabapentin, corticosteroids, ketamine, bisphosphonates) Procedural intervention- epidural, spinal, intrathecal catheters Radiation,chemotherapy Orthopedic intervention Seating, positioning

25 Explore Options to Address the Suffering ctd
May be other issues to address that have been treated with opioids as physical pain SUFFERING EMOTIONAL PSYCHOSOCIAL PHYSICAL SPIRITUAL

Quite possible that a substantial 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


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

29 METHADONE Racemic mixture of 2 stereoisomers
only the R-enantiomer has analgesic properties S-enantiomer: NMDA receptor antagonist ? Role in mitigating effects of M3G

30 ? Life-Threatening (severe myoclonus,seizures)
Approach to Changing Opioids in Settings of O.I.N. ? 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)

31 Equivalency Ratios in Converting to Methadone: Interpret With Caution
Morphine Total Daily mg po Morphine:Methadone Ratio 30 – 90 3.7 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 0.74 1.5 >300 Ripamonti et al; Annals Oncol 1998

32 The Latest Innovation in Opioid Conversion Calculation

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