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Opioid Calculations: Asking the Right questions to Find the Best Answers
Cheryl K Genord, R.Ph. Clinical Pharmacy Specialist, Pain Management
Objectives
• Understand the five step process to switch a patient from one opioid to another opioid.
• Describe different types of break-through pain and recommend an opioid regimen to treat these pains.
• Determine an appropriate strategy to change an opioid regimen, including both the regularly scheduled and rescue opioids.
2
Case Study
• Patient is taking Oxycontin 60mg tid want to convert to Morphine extended release.
• Oxycodone 20mg = Morphine 30 mg po • Oxycodone 60mg = Morphine 90 mg po
3
Medication IV Eq PO Eq
Morphine 10 30
Codeine - 200
Fentanyl 0.1 -
Hydrocodone - 30
Hydromorphone
1.5 7.5
Oxycodone - 20
Simple Calculations
• Is that all there is to Opioid Conversions • If there was this would be a pretty short
presentation • Where Calculations meets Art
4
Five Step Approach
5 McPherson ML. ASHP Bethesda, MD. 2010.
Step 1 Globally
assess the patient
Step 2 Determine total daily dose of current opioids
Step 3 Decide which
opioid analgesic will be used and calculate a
proper dose
Step 4 Individualize
dosage based on info from
Step 1
Step 5 Patient follow
up and reassessment
Step 1
• Don’t jump to calculator, assess first!
6 McPherson ML. ASHP Bethesda, MD. 2010.
P • Precipitating and Palliating
Q • Quality
R • Region
S • Severity
T • Temporal
U • You
Precipitating and palliating
• What brings on or worsens the pain • What relieves the pain
– Pharmacologic • What was the response • Any side effects
– Non-Pharmacologic • What Medications have been tried to treat
the pain
7
Quality
• Pain description in patients own words – Stabbing, shooting, throbbing, aching,
gnawing
8
Region and radiation
• Where is the Pain? • Does the pain move anywhere?
9
Severity
• Rating Scale – Pain right now, worse, best, average, one
hour after you take the medication.
10
Temporal
• Is the pain constant? • Does the pain come and go – how many
times a day • How long does it last?
11
U - You
• How does the pain affect your life? • Your ability to sleep, your appetite, your
ability to ambulate
12
Step 2 Determine daily usage
• Time to play Sherlock Holmes
• Important to I spy with my little eye
• Whole Truth and Nothing But the Truth
13
Step 3 – Decide which opioid will be used and calculate new dose
• Decide which opioid to switch to: – Renal Function – Potential for drug interactions – Patient Specific Factors
• Patient ability to swallow or apply a transdermal system • Nature of pain • Patient’s previous history of response • Safety concerns
– Formulary, financial limitations – Availability of dosage
• Get those Calculators ready! WAAAAAAIT
14
Basics of opioid Metabolism
• Production of both inactive and active metabolism
• Opioids differ in how they are metabolized • People differ in how they metabolize opioids • Extensive first-pass in liver
– Phase 1 (modification reactions) • CYP enzymes (3A4, 2D6)
– Phase 2 (conjugation reactions) • Glucuronidation
15
metabolic Pathways
16
Opioid Phase 1
Phase 2 Metabolites*
Morphine - glucuronidation M3G, M6G
Codeine CYP2D6 glucuronidation C6G, morphine
Hydrocodone CYP2D6 - hydromorphone
Hydromorphone - glucuronidation H3G
Oxycodone CYP2D6, CYP3A4
- oxymorphone, noroxycodone
Methadone CYP3A4, CYP2B6
- -
Fentanyl CYP3A4 - -
Clinical Implications
• Most opioids metabolized by CYP enzymes – Substantial drug interaction potential
• Cannot predict patient response – Need to individualize therapy – Opioid trials for tolerability/analgesic assessment
• Confounding medical conditions – Hepatic/renal impairment – Accumulation of active metabolites and increased
ADE’s
17
Smith HS. Mayo Clin Proc. July 2009;84(7):613-624. 18
19 Smith HS. Mayo Clin Proc. July 2009;84(7):613-624.
Morphine
• Morphine M3G (55%) and M6G (10%) • Morphine not altered significantly in renal insufficiently, but
metabolites will accumulate • M6G 2-4x more potent than morphine, with higher levels in
CNS • M3G lacks analgesic properties but has neuroexcitatory
effects • Effects of M6G and M3G magnified in kidney disease • Avoid use in renal dysfunction, especially hemodialysis • Bioavailability increased in cirrhotics • Monitor response in hepatic dysfunction
– Suggest increasing dosing interval
20
Smith HS. Mayo Clin Proc. July 2009;84(7):613-624 Johnson SJ. Pain Treatment Topics. June 2007
Codeine
• Codeine (prodrug) C6G (81%) and morphine (10%)
• All compounds renally excreted and can accumulate
• CYP2D6 poor/rapid metabolizers do not respond well to codeine – Poor: no conversion into morphine (no analgesia) – Rapid: too much conversion (intoxication)
• Chronic codeine dosing is proposed to accumulate to toxic levels in ⅔ of HD patients
• Avoid codeine in patients with renal dysfunction, on dialysis, or with severe hepatic dysfunction
21
Smith HS. Mayo Clin Proc. July 2009;84(7):613-624 Johnson SJ. Pain Treatment Topics. June 2007
Hydrocodone/Hydromorphone
• Hydrocodone (prodrug) metabolized into hydromorphone via 2D6 – Poor metabolizers experience little analgesia
• Hydromorphone H3G (37%) • H3G no analgesic properties but can cause
neuroexcitation (≈M3G) • Renally excreted/accumulate in dysfunction • Water soluble, small VD, low molecular
weight – Re-dosing after HD may be appropriate
• Avoid hydrocodone in hepatic failure
22
Smith HS. Mayo Clin Proc. July 2009;84(7):613-624 Johnson SJ. Pain Treatment Topics. June 2007
Oxycodone
• Oxycodone noroxycodone (3A4) and oxymorphone (2D6)
• Primary effects governed by parent drug • Renal impairment increases concentration of
oxycodone by 50% • High efficiency dialyzers enhance plasma clearance
by 48% • Re-dosing after HD may be appropriate • Dose reductions 30-50% in severe hepatic impairment
23
Smith HS. Mayo Clin Proc. July 2009;84(7):613-624 Johnson SJ. Pain Treatment Topics. June 2007
Methadone/Fentanyl
• Fully synthetic, structurally unrelated to morphine • Do not produce active metabolites • Inactive metabolites by (3A4) • Exerts both analgesic and toxic effects through parent
compound – Methadone acts also on NMDA receptors
• Fentanyl affected more by hepatic blood flow than impairment – Can be used in hepatic dysfunction
• Avoid methadone in severe hepatic failure – Risk of accumulation
• Minimal, if any, adjustments for renal dysfunction
24
Smith HS. Mayo Clin Proc. July 2009;84(7):613-624 Johnson SJ. Pain Treatment Topics. June 2007
Step 3 – Decide which opioid will be used and calculate new dose
• It is time to get those Calculators ready! • Look back at least 24 hours and obtain average
daily dose of all opioids • Convert all opioids to equivalent units using the
Equianalgesic Dosing Table • Using knowledge of drug therapy selection and
patient specific factors, switch it up! – Renal/Hepatic impairment – Drug Interaction – Patient specific factors
• Determine what to use – Long acting and/or short acting or both 25
McPherson ML. ASHP Bethesda, MD. 2010.
Titrating opioid Regimens with Around the clock and rescue
Types of Breakthrough Pain • Spontaneous –no precipitation stimulus – occurs without warning
and is acutely severe. (neuropathic) – Immediate release opioids plus co-analgesics
• Incident pain – volitional – Patient precipitated movement – Immediate release opioids on as needed basis prophylactically – Rescue dose = 10%-15& of daily dose q4hprn
• Incident pain – nonvolitional – Sneezing, bladder spasm, coughing – Immediate release opioids on as needed basis – Rescue dose = 10%-15% of daily dose q4hprn
• End of Dose – Pain that recures before the next schedulce dose – Increase dose and/or frequency in ATC opioid
26
McPherson ML. ASHP Bethesda, MD. 2010.
Conversion Examples
• Morphine 20mg IV: – ____ mg PO morphine
• Oxycodone 60mg PO: – ____ mg PO hydrocodone
• Hydromorphone 2.25mg IV: – ____ mg IV fentanyl
• Hydrocodone 30mg PO: – ____ mg IV morphine
27
Medication IV Eq PO Eq
Morphine 10 30
Codeine - 200
Fentanyl 0.1 -
Hydrocodone - 30
Hydromorphone 1.5 7.5
Oxycodone - 20
Fentanyl Patch Conversion
• USA
• CAN
28
Drug Daily Dosage PO MS 60-134 135-224 225-314 315-404 IV MS 10-22 23-37 38-52 53-67 PO Oxy 30-67 68-112 113-157 158-202 PO HM 8-17 18-28 29-39 40-51 IV HM 1.5-3.4 3.5-5.6 5.7-7.9 8-10
Fentanyl 25 mcg/h 50 mcg/h 75 mcg/h 100 mcg/h
Janssen Pharmaceuticals, Inc; Oct 2011
Drug Daily Dosage PO MS 60-134 135-224 225-314 315-404 IV MS 20-44 45-60 61-75 76-90 PO Oxy 30-67 68-112 113-157 158-202 PO HM 8-16 17-28 29-39 40-51 IV HM 4-8.4 8.5-14.4 14.5-19.5 19.6-25.5
Fentanyl 25 mcg/h 50 mcg/h 75 mcg/h 100 mcg/h
What about Chronic pain conversions
• Hydromorphone – Conversion ratio of parenteral hydromorphone
to oral hydromorphone of 1:2 • Morphine
– Conversion ratio of pareteral morpine to oral morphine of 1:3
29
Step 4 Individualize dosage
• After calculations, time to individualize! • Three options:
– No change, increase, decrease • Things to consider (from “PQRSTU”)
– Type of pain (cancer, acute, chronic, neuropathic) – Age of patient – Location/status of patient – Worsening or improving – Incomplete cross tolerance (0-50%) – Breakthrough needs (10-15% of total per dose)
• More art than science • Divide total dose for the new dosing interval
30 McPherson ML. ASHP Bethesda, MD. 2010.
Incomplete Cross Tolerance
• Tolerance – continued exposure to a drug reduces its effectiveness.
• When switching opioid – see increase in opioid sensitivity
• When converting from one opioid to another –reduce the calculated dose by 25-50%
31
What to do increase, decrease or keep the dose the same
• Increase the calculated dose – Severe cancer pain in hospital
• Same as calculated dose – Did not switch to a different opioid – Old opioid has not been used for more than one
week • Decrease the calculated doses
– Cross Tolerance – Elderly patient – Going home
32
Pop Quiz - Individualize dosage
72 yo w/osteoarthritis & difficulty swallowing – Hydrocodone/APAP tablets to elixir
27 yo POD2 s/p ACL reconstruction – Fentanyl IV to hydrocodone/APAP
55 yo w/ evolving metastatic breast cancer – MS-IR to long acting oxycodone
94 yo, ECF resident w/ chronic back pain – Oxycodone to hydromorphone
63 yo w/ shoulder pain, developed rash – MS-IR to oxycodone
33
Step 5 Reassess
• Reassess pain with a patient monitoring plan
• Fine tune the total daily dose – Adjustments in both short and long acting
34
Subjective Parameters Objective Parameters Monitoring for therapeutic effectiveness
-Pain rating -Performance of ADLs, sleep, ambulate
-Sleeping longer -ambulating further -Limiting use of rescue opioids
Monitoring for potential toxicity
-Complaints of constipation, nausea, sedation, confusion, hives
-Level of arousal/sedation -Respiratory rate -Pinpoint pupils -Bowel movement frequency
McPherson ML. ASHP Bethesda, MD. 2010.
Acute Pain
• What Stronger? – Percocet (Oxycodone) 5/325 2 tab – Norco (Hydrocodone) 5/325 2 tab – Morphine 3 mg IV – Hydromorphone 0.5 mg
35
36
Genord’s Opioid Analgesic Potency Classes
Chronic Pain/Longer term Acute Pain/Acute on Chronic Pain
• Time to use what we learnt
37
Case 1
• DG is a 62yo man recently diagnosed with colon caner admitted for surgical resection of the lesion. Post op he was given hydromorphone 1-2 mg IV q4h. – Day 1 hydromorphone 12 mg IV – Day 2 hydromorphone 11mg IV – Day 3 hydromorphone 8 mg IV
• He reports his pain as 3 after taking hydromorphone. • On day 4 he is preparing for discharge. CR has a
history of itching with oxycodone and morphine. Oral Hydromorphone has been effective in the past.
• What oral opioid regimen should be tried prior to discharge.
38
Case 1
• Step 1 Assess – DG has used less on day 2 than day 1. – Good pain control with hydromorphone – Pain is consistent with normal post op course. – He has used po hydromorphone in the past
and it has been effective. • Step 2 Total Daily Dose
– 24 hours day 2 – Hydromorphone 8mg IV. (TDD)
39
Case 1
• Step 3 Determine new opioid and calculate new dose – Morphine and Oxycodone makes pt itch so transition to po
hydromorphone – Calculate equianalgesic dose X mg TDD oral HM 7.5 mg oral HM ________________ = _______________ 8 mg IV HM 1.5 mg IV HM X = 40 mg
• Step 4 – Individualize – Well controlled – no need to increase – Pain is getting better every day expect reduce dose requirement each
day. – No need to decrease dose for incomplete cross tolerance – Hydromorphone is available in 2,4,and 8mg tab. Dosed as q4h – 4 mg q4h (24 mg TDD)
40
Case 2
• LP is a 68 yo man with end-stage lung cancer. He is receiving MS Contin 120mg Q12h as well as Percocet 5/325 1-2 q4h prn. LP tells you that when he experiences unanticipated unprovoked pain he takes 2 Percocet tab about 4 times per day. This pain occurs at different times during the day and is achy and throbbing in nature. The Percocets are not effective (PS 8 down to 6). LP is growing weaker and is now experiencing shortness of breath occasionally as well
• What would you recommend?
41
Case 2
• Step1 – Patient is having spontaneous/incidental pain
that does not seem to be neuropathic in nature.
– Pain does not seem to be end of dose pain – Percocet 2 tablets has been used for this
pain. • Step 2
– Morphine 240mg/day – Percocet 40mg/day
42
Case 2
• Step 3 Determine new opioid and calculate new dose Breakthrough pain – 10%-15% total daily dose – 24-32mg of
Morphine = 16-24 mg of Oxycodone Percocet is too low at 10mg dose.
• Step 4 – Individualize – Before looking at increasing long-acting need to get
breakthrough dose appropriate • Morphine 30mg IR
– If patient becomes weaker could switch to oral solution – too weak to swallow concentrated solution could be instilled in the buccal cavity
43
Questions
44