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

19. OVERVIEW OF BASIC STEPS
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

26. CHALLENGES IN MANAGING PAIN / DISTRESS IN SETTINGS OF NEUROTOXICITY
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

28. ADVANTAGES 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

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