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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 There has been a 3x increase in morphine consumption worldwide from 1986 to 1995There 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 hydromorphoneThere 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 neurotoxicityAs 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?

3 Myoclonus: sudden, brief, shock-like involuntary movements caused by muscular contractionsMyoclonus: sudden, brief, shock-like involuntary movements 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 2.7% to 87%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)Most recognized with metabolites of morphine (particularly M3G), however also seen with opioids with no active metabolites (methadone, fentanyl) Opioid Induced Myoclonus

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5 CASE PRESENTATION Ms. W.P. 73 yo woman with met. NSCCL Dx. early Oct –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 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 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 – : 1 90 – : 1 > : 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 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

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

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

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

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

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17 Agonist (fentanyl) Receptor (μ -opioid ) G-protein2 nd 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

19 1.Recognize the syndrome 2.Discontinue the offending opioid Note: naloxone does not reverse neuroexcitatory effects, and may in fact exacerbate them 3.Hydrate to help clear opioid and metabolites 4.Consider benzodiazepines to decrease neuromuscular irritability 5.Explore options to address the suffering OVERVIEW OF BASIC STEPS

20 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 worseRapidly increasing opioid dose; seems to make things worse Allodynia, Hyperalgesia - pain presentation changes to pain all over; doesnt make sense in terms of underlying diseaseAllodynia, Hyperalgesia - pain presentation changes to pain all over; doesnt make sense in terms of underlying disease

21 Simply decreasing the dose only postpones the need to switch opioidsSimply decreasing the dose only postpones the need to switch opioids Adding a benzodiazepine without addressing the opioid ignores potential reversibilityAdding a benzodiazepine without addressing the opioid ignores potential reversibility Stepwise conversion (days) in mild neurotoxicityStepwise conversion (days) in mild neurotoxicity Abrupt discontinuation if life-threatening neurotoxicity (seizures imminent)Abrupt discontinuation if life-threatening neurotoxicity (seizures imminent) Discontinue the Offending Opioid

22 Morphine and hydromorphone metabolites are renally excretedMorphine and hydromorphone metabolites are renally excreted Oral, SQ, or IV… depends on the severity and venous accessOral, 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 q6hExample 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

23 Clonazepam: long-acting; p.o.Clonazepam: long-acting; p.o. Lorazepam: intermediate duration of action; p.o., SL, IV, (IM – for seizures)Lorazepam: intermediate duration of action; p.o., SL, IV, (IM – for seizures) Midazolam: short-acting; SQ, IV, SL, (IM – generally not used this route)Midazolam: short-acting; SQ, IV, SL, (IM – generally not used this route) Be cautious with additive respiratory depressant effects if also giving opioids by bolusBe cautious with additive respiratory depressant effects if also giving opioids by bolus Consider Benzodiazepines to Decrease Neuromuscular Irritability

24 This can include:This can include: –Switching opioids –Steps to opioid requirements oadjuvants (eg/gabapentin, corticosteroids, ketamine, bisphosphonates) oProcedural intervention- epidural, spinal, intrathecal catheters oRadiation,chemotherapy oOrthopedic intervention oSeating, positioning Explore Options to Address the Suffering

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

26 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 effectsQuite 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)+ + 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 useImpossible to calculate dose equivalences of alternative opioids; conversion charts dangerous to use CHALLENGES IN MANAGING PAIN / DISTRESS IN SETTINGS OF NEUROTOXICITY

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28 No known active metabolitesNo known active metabolites Different opioid class (anilinopiperidines) than morphine and hydromorphone (benzomorphans)Different opioid class (anilinopiperidines) than morphine and hydromorphone (benzomorphans) Not common (though not impossible) to develop signs of neurotoxicityNot common (though not impossible) to develop signs of neurotoxicity 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 neurotoxicity will not be presenting with related neurotoxicity tolerance will not have developed tolerance will not have developed Rapid onset, short-acting – facilitates titration in difficult, unstable circumstancesRapid onset, short-acting – facilitates titration in difficult, unstable circumstances ADVANTAGES OF FENTANYL OR SUFENTANIL IN NEUROTOXICITY

29 METHADONE 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 antagonist ? Role in mitigating effects of M3GS-enantiomer: NMDA receptor antagonist ? Role in mitigating effects of M3G

30 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 Dont 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

31 Morphine Total Daily mg poMorphine:Methadone Ratio 30 – > Ripamonti et al; J Clin Oncol 1998 Hydromorphone Total Daily mg poHydromorphone:Methadone Ratio > Ripamonti et al; Annals Oncol 1998 Equivalency Ratios in Converting to Methadone: Interpret With Caution

32 The Latest Innovation in Opioid Conversion Calculation


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