Management of
Life-Threatening
Opioid Neurotoxicity
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
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)
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.
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 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. 23
Breakthrough = 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
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
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
Spectrum of Opioid-Induced Neurotoxicity
Opioid
tolerance
Mild myoclonus
(eg. with sleeping)
Delirium
Opioids
Increased
Severe myoclonus
Seizures,
Death
Hyperalgesia
Agitation
Misinterpreted
as Pain
Opioids
Increased
Misinterpreted
as Disease-Related Pain
Mayer D. et al Proc. Natl. Acad. Sci. USA
Vol. 96, pp. 7731-7736 Jul. 1999
A Spinal Cord Model of InjuryInduced Hyperalgesia
Mao, J. et al
Pain 62 (1995) 259-274
A Spinal Cord Model of
Morphine Tolerance
Mao, J. et al
Pain 62 (1995) 259-274
Harrison, C. et al
Br. J. Anaesth. 1998; 81: 20-28
Harrison, C. et al
Br. J. Anaesth. 1998; 81: 20-28
Harrison, C. et al
Br. J. Anaesth. 1998; 81: 20-28
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
Approach To The Patient
With Opioid Neurotoxicity
OVERVIEW OF BASIC STEPS
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
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
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)
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
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
Explore Options to Address the Suffering
•
This can include:
– Switching opioids
– Steps to ↓ opioid requirements
o adjuvants (eg/gabapentin, corticosteroids,
ketamine, bisphosphonates)
o Procedural intervention- epidural, spinal,
intrathecal catheters
o Radiation,chemotherapy
o Orthopedic intervention
o Seating, positioning
Explore Options to Address the Suffering ctd
May be other issues to address that have been treated with opioids
as physical pain
PHYSICAL
PSYCHOSOCIAL
SUFFERING
SPIRITUAL
EMOTIONAL
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
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
METHADONE
• Racemic mixture of 2 stereoisomers
• only the R-enantiomer has analgesic properties
• S-enantiomer: NMDA receptor antagonist
? Role in mitigating effects of M3G
Approach to Changing Opioids in Settings of O.I.N.
? Life-Threatening (severe myoclonus,seizures)
No
•
•
1.
2.
3.
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
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)
Equivalency Ratios in Converting to Methadone:
Interpret With Caution
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
The Latest Innovation in Opioid Conversion Calculation