Opioid Management

Question 1

opiate vs opioid vs narcotic

Answer 1

Opiate – naturally occurring substance with
morphine-like properties
Opioid – includes synthetic substances that have affinity
for opioid receptors
Narcotic – legal term (not a pharmacologic term)

Question 2

Classes of Opioids

Answer 2

Natural opioids – morphine, codeine
Semi-synthetic opioids – hydromorphone, oxycodone, hydrocodone, (heroin)
Synthetic opioids – fentanyl, methadone, buprenorphine, meperidine,
tramadol, pentazocine, diphenoxylate, loperamide

Question 3

The Importance of Opioids…

Answer 3

Very effective for nociceptive pain (especially severe)
But…
Also high potential for abuse/addiction
And have a fairly extensive adverse effect profile

Question 4

Opioid Mechanism of Action - Review

Answer 4

All opioid analgesics are agonists or partial
agonists at µ, ẟ, or κ receptors

Pure agonists
● Act predominantly at µ receptors
● May also produce lesser effects at κ and δ
receptors

Agonist-antagonists
● Have agonist or partial effects on some
receptors, but antagonist effects on others

Pain inhibitory neuron inhibits pain pathway
GABA inhibitstje pain inhibitory neuron to allow pain to happen again
opioids inhibit th GABA inhibitor

No all opioids are analgesics

Question 5

usual oral doses for adults

Answer 5

5-20mg morphine
5-15mg oxycodone
1-4mg hydromorphone
30-60 codeine
50-100 tramadol

lots of individual intervariability

Dont memorize table
Parenteral forms are twice as potent as oral (use half of dose for parenteral)
intiiate a lower dose for older patients who are opioid naive

Question 6

Opioid Risk Assessment - Risk Tool vs CAGE

Answer 6

CAGE-AID more for substances in general

Imp to do screening for most pt planning to start it esp outpt setting
Easier to say you do this for everyone

Question 7

Approach to Opioid Initiation

Answer 7

Define goals of treatment before initiation
Individualize opioid selection, dosing, and titration according to the patientʼs health status, age, and previous exposure to opioids
Short acting opioids may be safer for opioid initiation
Start low, go slow

Less peak and withdrawal for long acting is thought
But no evidence to support and short acting, less risk of accidental overdose

Around the clock (ATC) or basal dose
● Might depend on the nature or pattern of the pain being treated
○ If pain is intermittent, PRN only might be sufficient
● Regularly scheduled IR or CR/SR release
Breakthrough (PRN) dose
● Typically 10-15% of the total daily dose (TDD)
● IR formulation (not controlled release)
More challenging to get pt off long acting
Use short acting for acute pain
● Re-assess in 24-72 hours

Question 8

Dose Titration
When to adjust:

Answer 8

Depends on half-life, time to peak effect, analgesic duration, etc.
○ Short acting IV/SQ or IR given PRN only – dose by dose
○ Short acting IV/SQ or IR given ATC – ~ 24 hours (
Alf life of these drugs around 2-3 hours, 5 half lives to ss, By 24 hours there would be st)
○ CR/SR – 48-72 hours
○ Fentanyl patch – 3-6 days

Question 9

Dose Titration
steps

An opioid-naïve, underweight patient beginning opioid treatment for pain associated with a tumour. Started 2 days ago and received regular hydromorphone 0.5 mg PO q4h and 11 breakthrough doses of hydromorphone 0.25 mg PO in the past 24 hours. No problematic adverse effects experienced.

what is new dose?

Answer 9

1. Repeat pain assessment
2. Total all of the regular and breakthrough opioid used in the past 24 hours to get the new TDD (convert if necessary)
3. Divide the new TDD into new regular doses and calculate new breakthrough dose

● Regular = 0.5 mg x 6 = 3mg
● Breakthrough = 0.25 mg x 11 = 2.75 mg
● TDD = 3 mg + 2.75 mg = 5.75 mg → if staying with hydromorphone IR,
divide by 6 (i.e., for q4h dosing) → 0.96 mg → round to 1 mg PO q4h
● New breakthrough dose → 10-15% of new TDD → hydromorphone 0.5 mg PO q1h PRN

Question 10

opioid watchfuk dose

Answer 10

Try to limit how high the dose goes upt o

Chroncic, non cancer

Restrict to less than 90mg morphine equivalents daily

used to be 200mg

Question 11

Opioid Adverse Effects

Answer 11

abuse, misuse, addiction diversion
hypotension
constipation
N/V
neurotoxicity: hyperalgesia, allodyna

Question 12

Managing Opioid Adverse Effects
Respiratory Depression

Answer 12

Tolerance development: Yes –> tolerance can lead to it

● Prevention
○ carefully select opioid based on patient characteristics (including use of other respiratory depressants)
○ Use lowest effective dose with slow opioid dose titration and close monitoring
● Treatment
○ Naloxone (opioid receptor antagonist)

Question 13

Managing Opioid Adverse Effects
Constipation

Answer 13

Tolerance development: No
● Prevention
○ Ensure adequate hydration, maintain high activity level, high fibre diet
● Prevention/Treatment
○ Laxatives – senna, bisacodyl, PEG, lactulose, etc
■ Especially with long-term, larger amounts of opioids
○ Methylnaltrexone (peripherally acting opioid antagonist)

long term high dose opioids is a risk (a few months or indefinite)

Question 14

Managing Opioid Adverse Effects
Nausea and Vomiting

Answer 14

Treatment
○ Opioid dose reduction (+/- addition of co-analgesic)
○ Opioid rotation
○ Switch from oral route to other route of admin
○ Dopamine antagonists (domperidone, metoclopramide, prochlorperazine)
○ Anticholinergics (scopolamine) not as effective, still an option
○ Ondansetron
○ Successful treatment of constipation

antiemetics will usually not stay on these for long

Variety of diff mechanismis at play
Depending on underlying mech
Affects how quickly they respond

Question 15

Managing Opioid Adverse Effects
Pruritis

Answer 15

Tolerance development: Yes

Treatment
○ Difficult to control - might be central
○ Antihistamines (e.g., diphenhydramine) might be helpful
○ Opioid rotation also might be helpful
○ Naloxone can provide relief in refractory cases

Scopolamine anticholingeric effects
Same effect as antihistamine

Question 16

Managing Opioid Adverse Effects
Cognitive Effects
neuroendocrine fx
sleep disturbances

Answer 16

Cognitive Effects Tolerance development: Yes
● Refrain from complex tasks requiring cognitive and psychomotor
function such as driving during acute dose increases.
● Stimulants (e.g., methylphenidate) might be beneficial in some. Stimulants to pt who don’t have tolerance readily

Neuroendocrine effects Tolerance development: No
● Testosterone supplementation might be necessary in men
● Less research in women, but oral contraceptives or
dehydroepiandrosterone might be beneficial
Potential AE: hypogonadism
Males may need testosterone or reevaluate if opioids is still necessary

Sleep disturbances Tolerance development: No
● Appropriate sleep hygiene

Question 17

Opioid Allergies
● Most reported “allergies” to opioids are not true allergies, but rather
adverse effects

Answer 17

○ e.g., opioids cause histamine release with subsequent itch and rash (and sometimes bronchial constriction in patients with obstructive pulmonary disease)
● If true allergy to one type of opioid, unlikely to have cross-sensitivity
to opioid in a different structural class
● If history of true allergy to codeine or morphine (natural opioids), a semi-synthetic or synthetic may be cautiously tried
Potent histamine releasers
Result in rash, bronchoconstriction if already have pulmonary obsrtcutive disease
Even in diff clinical classes, low risk of cross-sensitivity
Oxycodone, fentanyl, less hisamine release

History of chart documented allergies
Very low rates of IgE mediated reactions
Chemical or clinical class cross reactivity was not significant
Previously overestimated

Question 18

see summary of tx options of OIH

Answer 18

slide 35

Question 19

Opioid Rotation

Answer 19

Switch from one opioid to another
○ Goal: improved balance between analgesia and adverse effects
○ may be useful if adverse effects believed to be due to
accumulation of opioid metabolites

● Can be done by one of a couple methods:
○ Direct substitution – offending opioid stopped and new one started
○ Gradual substitution – over a few days, the offending analgesic is replaced by a new one

Take advantage of incomplete cross tolerance
Direct is what is most commonly done
Gradual seen with methadone
Accumulation of toxic metabolites

Question 20

Opioid Rotation
Always start by performing a pain assessment… Then to rotate:
1. Calculate the opioid TDD
● Include regular and average of breakthrough usage
2. Calculate the morphine equivalent daily dose (MEDD)
● Using morphine equivalence conversion factor
3. Convert to new agent (using conversion factor) and reduce the
dose for incomplete cross-tolerance
● The amount decrease depends on current pain control, threshold
of MEDD, and presence of opioid toxicity
○ If previous opioid dose was high (≥ 90 MEDD) – consider ↓ 50%
○ Previous opioid dose was low or moderate (< 90 MEDD) – consider ↓ 25 - 40%
4. Choose appropriate regimen of new drug

A patient who has been receiving codeine CR 150 mg PO q12h has been
experiencing intolerable pruritis. Their pain has been adequately controlled and
they seldom require any breakthrough. The decision has been made to try a
rotation to hydromorphone.

Answer 20

1. Calculate Opioid TDD = 300 mg codeine
2. Convert to MEDD = 300 mg x 0.15 (from table) = 45 mg morphine
3. Convert to hydromorphone = 45 mg x 0.2 = 9 mg hydromorphone
   Reduce dose for incomplete cross-tolerance (pain adequately managed,
   experiencing AE, dose could be considered “moderate”)
   ∴ reduce dose by 40% → 9 mg x 0.6 = 5.4 → round to 6 mg hydromorphone TDD
4. New regimen → 6 mg TDD → hydromorphone CR 3 mg PO q12h
   + breakthrough (6 mg x 10%) → 0.6 → round to 0.5 mg →
   hydromorphone IR 0.5 mg PO q4h PRN

Amount decreased takes a bit of judgement
Depend on pain control and AE
Reason of rotation and how much opioid were they getting
<50 MEDD decrease by 25%
50MEDD decrease by 40%
AE –> greater threshold for dose decreasing

Question 21

Opioid Discontinuation - When to Stop

Answer 21

● Pain condition has resolved
○ Patient received definitive treatment for condition
○ A trial of tapering is warranted to determine if original pain condition has
resolved
● Risks outweigh benefits
○ Overdose risk has increased
○ Clear evidence of diversion
○ Aberrant drug-related behaviours have become apparent
● Adverse effects outweigh benefits
○ Adverse effects impairs functioning below baseline level
○ Patient does not tolerate adverse effects
● Opioid ineffective
○ Does not lead to improved function or at least 30% reduction in pain intensity
○ Opioid more for regulating mood than pain control (particularly anxiety)

Question 22

Opioid Discontinuation - How to Stop

Answer 22

● Acute pain
○ Usually does not require a taper if opioid used for short period
○ Consider taper if opioid taken for > 1 week at regular interval
■ Optimize non-opioids as needed/able during taper
■ Should complete taper in 1-3 weeks
■ e.g., ↓ TDD by ≤ 25% q2-3days (likely able to stop by day 7)
● Chronic pain
○ Taper to eventually discontinue vs taper to lower dose
○ Generally should be a slower taper than with acute pain
■ (> 2-3 weeks to 3-24 months)
- rates should be individualized, decrease 10% per month is reasonable if on for >1yr

Question 23

Opioid Tapering

The longer they’ve been on opioid, th elonger the taper should be

Answer 23

● Rapid taper
○ ↓ dose 10-20% q1-3days; often completed in 1-2 weeks
○ Withdrawal symptoms more likely than with slower taper
■ Use of opioid withdrawal scale and protocol recommended
○ May be a good option for patients at very high risk of AE, are highly motivated to discontinue quickly, or on low doses
Acute settings, but sometimes for chronic too

● Slow and gradual taper
○ ↓ dose 5-10% q2-4weeks; often completed in 1-6 months
○ Once ⅓ of original dose reached, slowing down the taper (e.g., 5% dose
reduction q4-8weeks) may improve chance of success
■ May require formulation change
More common
At least 1 month tapering per year of opioid they are on
10 years –> taper over at least 10 months
Slower tapers increase chance of success

● Opioid agonist therapy (e.g., with buprenorphine/naloxone or methadone)
○ useful approach to tapering/switching patients with opioid use disorder, concurrent psychiatric conditions (e.g., depression), long-term opioid use (e.g.
>5yrs), pregnancy

Question 24

Drug Interactions

Answer 24

Pharmacodynamic
● Other CNS depressants - drosiness
(e.g., ethanol, benzodiazepines, etc)
● Serotonergic agents
(e.g., SSRIs, SNRIs, etc.)
○ Especially for opioids with a
serotonergic component
e.g., tramadol, methadone (higher serotonic effect)

Pharmacokinetic
● CYP 3A4 or 2D6 for some
no CYP metabolism for morphine

Question 25

what causes diminshed opioid analgesic effect?

Answer 25

Few possible reasons getting diminsed effect
Too much opioid –> neurotoxicity
Pain state itself is worsening
Dose escalation of opioid, longer acting
Lookat multimodal pain management, non opioids
NMDA pathway, use an NMDA antagonist might be useful
Eg. Dextromethorphan (titrate to effect), amphetamine

Hyperaglesia: NMDA antagonist, lower dose, rotate to diff opioid,
Longer acting lower on priority list

If hyperalgesia, increase dose = increased pain experience, worse pain control

If tolerant, increase dose = better pain control

When withdrawaing, can get pain sensation, does not mean they have indication for opioid again

Titrate dose down, withdrawal itself can be painful for patient

Question 26

equivalence to oral morphine 30mg

Useful to know

Morphine
Oxycodone
Codeine
Hydromorphone

Conversion factors for exam

Answer 26

morphine 30mg CF 1
codeine 200mg CF 0.15
oxycodone 20mg CF 1.5
hydromorphone 6mg CF 5

Question 27

equivaloence with fentanyl patches

Answer 27

60-134 mg morphine = 25mcg/h
135-179mg = 37mcg/h
180-224 = 50
225-269 = 62
270-314 = 75
315-359 = 89
360-404 = 100

12mcg usually used for dose adjustment

Do not need to decrease dose for incomplete cross-tolerance

Switching back to opioid, this may be more aggressive
12mcg/hour around 40mg of morphine missing
These estimates are cautious when switching to fentanyl patch, but aggressive when switching to an
oral opioid → caution warranted
- Dose reduction for incomplete cross-tolerance NOT required when switching to transdermal fentanyl
with this particular table