opioid calculations: asking the right questions to find...

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.

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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

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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

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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!


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

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Quality

• Pain description in patients own words – Stabbing, shooting, throbbing, aching,

gnawing

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Region and radiation

• Where is the Pain? • Does the pain move anywhere?

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Severity

• Rating Scale – Pain right now, worse, best, average, one

hour after you take the medication.

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Temporal

• Is the pain constant? • Does the pain come and go – how many

times a day • How long does it last?

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U - You

• How does the pain affect your life? • Your ability to sleep, your appetite, your

ability to ambulate

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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

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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

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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

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metabolic Pathways

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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


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%

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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

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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

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Step 5 Reassess

• Reassess pain with a patient monitoring plan

• Fine tune the total daily dose – Adjustments in both short and long acting

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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


Acute Pain

• What Stronger? – Percocet (Oxycodone) 5/325 2 tab – Norco (Hydrocodone) 5/325 2 tab – Morphine 3 mg IV – Hydromorphone 0.5 mg

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36

Genord’s Opioid Analgesic Potency Classes

Chronic Pain/Longer term Acute Pain/Acute on Chronic Pain

• Time to use what we learnt

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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.

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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)

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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)

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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?

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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

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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

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Questions

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