PP565 Pain Management Part 1 2011 1019 B

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Non-Malignant Pain Management: Part 1Bruce Canaday, PharmD

PP565, Fall 2011

Required Pre-Reading:

Baumann TJ, Strickland J, Herndon CM. Pain Management. In: Pharmacotherapy: A pathophysiologic approach. DiPiro JT, Wells BG, Matzke GR, Talbert RL, Yee GC, Posey LM,eds. 8th edition. New York, NY. McGraw-Hill, 2011. P1045-1059.

Objectives:After completing the required reading and participating in lecture, the student will be able to:

1. Relate the pathophysiology of pain to the use of analgesics.

2. Differentiate clinical symptoms of nociceptive and neuropathic pain.

3. Compare and contrast the risks and benefits of different therapies.

4. Select optimal opioid based on patient specific factors.

5. Given a patient case with either acute or chronic pain, identify potential treatment

options based on medication properties, pain severity and other patient specific factors.6. Construct an initial pharmacologic treatment plan including goals, medication, route of

administration and dosing schedule.7. Recommend an appropriate monitoring plan for a patient’s analgesic regimen.8. Develop a treatment regimen for a patient needing IV opioids who is on a PO regimen.

9. Recommend a rescue regimen for breakthrough pain if given a specific long-actingopioid regimen.

10. Based on a patient case, determine an appropriate alternative opioid regimen.11. Reevaluate and determine new analgesic regimen for a patient not responding

adequately to an analgesic regimen.12. Analyze a patient-controlled analgesia (PCA) regimen for efficacy, safety, accuracy, and

completeness.13. Develop a treatment plan for a patient with neuropathic pain.

14. Identify adverse effects associated with analgesia and determine the appropriatemanagement.

15. Select appropriate adjunct analgesic agents for a patient based on patient specificparameters.

ROADMAP INFORMATION and PRIOR LEARNING REQUISITES:

o Review notes from PP465 topic “Approach to the Patient in Pain”

o Must complete the areas shaded in grey prior to class

o Information can be found in the required text and drug information resources

OTHER INFORMATIONo You are responsible for brand and generic names of all medications.

o An equianalgesic dosing chart will be provided for you on the exam.

o You are not responsible for dosage strengths of medications (this will be provided for

you).

B. CanadayPP565 Fall 2011

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I. Epidemiology

A. Incidence of pain in severely ill hospitalized patients:______________________

1. % of those patients dissatisfied with pain control: ______________________

B. Estimated number of Americans partially or totally disabled due to pain:

__________________________

II. Pathophysiology: Refer to required reading or PP465 notes

A. Nociceptive Pain

1. 2 types (somatic and visceral):

a. Somatic:

b. Visceral:

2. Steps of Pain Sensation : Refer to PP465 notes

a. Stimulation

b. Transmission

c. Perception


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d. Modulation

B. Neuropathic Pain

1. Results from nerve damage or abnormal function of nervous system

2. Persistent nerve stimulation or nerve damage leads to “rewiring” of pain

circuit.

a. Results in spontaneous nerve stimulation, autonomic neuronal pain

stimulation and hyperactivity of dorsal horn neuron

b. Hyperalgesia, allodynia, shooting, burning, tingling, shock-like sensations

III. Signs and Symptoms

A. Review PP465 notes

B. Table 62-1: Acute vs. chronic

IV. Pain Assessment: PP465 Notes

A. PQRST

B. Patient interview

C. Assessment tools

V. Goals of Pain Management

A. Acute Pain

1.


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2.

B. Chronic Pain

1.

2.

3.

VI. General treatment approach (Figure 62-2)

A. Mild pain (1-3/10): Non-opioid analgesic

B. Moderate pain (4-6/10): Opioid and APAP or NSAID combination product

C. Severe pain (7-10/10): Opioid

*Consider adjunct analgesia at each step if needed


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VII. Non-opioid Agents

A. Acetaminophen (APAP)

1. Brand:

2. Availability / route (do not need to include dosage strengths):

3. FDA approved indications (related to pain):

4. Mechanism of action:

5. Adverse effects

a. Hepatotoxicity: limit to <4 grams per day (< 2 grams/day if risk for hepatic

toxicity)

6. Major drug interactions

a. Warfarin: may increase INR if doses > 1.3 grams taken daily for >1 week

7. Contraindications


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a. Use caution in alcoholic liver disease and patients drinking > 3 alcoholic

drinks/day

B. NSAIDS (Table 62-3)

Drug Brand Name(s)

Availability / routes(OTC vs. Rx, routes)Do not need to includedosage strengths

FDA ApprovedIndications(related to painmanagement)

Maximum dailydose

Ibuprofen

Naproxen

Ketorolac

Indomethacin

1. Mechanism of action (use ibuprofen as prototype)

2. Common adverse effects

a. 3 boxed warnings for all NSAIDS (use ibuprofen as prototype):

b. 1 additional boxed warning specific to ketorolac

3. Other adverse effects

a. Impaired platelet aggregation


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b. Renal impairment: vasoconstriction of afferent arteriole

4. Major drug interactions

a. ACE-I or ARB: renal impairment

b. Anticoagulants/antiplatelet agents: increased risk of bleeding

c. ASA: give ASA 30 minute before or 8 hours after NSAID dose

d. Antihypertensives: NSAIDs may increase BP

e. Lithium: increased lithium concentrations

5. Clinical considerations

a. Ketorolac: only use for 5 days

b. Can switch to another NSAID if inadequate response to one

i. Multiple subclasses of NSAIDs with structural differences (table 62-3)

c. Choice of agent: availability, cost, PK parameters, side-effects

d. Useful for bone pain

VIII. Opioids

Drug ExtendedReleaseForm.

ImmediateReleaseForm.

IV Form. Other form.

Availablewith non-opioid

Comments

Morphine X

8-12 hrs:

X

MorphineIR

X Rectal

Solution(Roxanol)

No -Gold standard opioid-Hepaticglucoronidation to 2metabolites


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MS Contin,OramorphSR,

24 hrs:Kadian,Avinza

-M-3G: adverseeffects

-M-6G: analgesia(more potent)-Renal excretion

Oxycodone -Less dependent onactive metaboliteformation

Hydrocodone -Metabolized byCYP2D6-Ceiling analgesic dose(10 mg PO)

Hydromorphone -Short half life-Safer option for renaldysfunction

Oxymorphone -No advantage over others

Codeine -Requires CYP2D6metabolism to becomeactive-Ceiling analgesiceffect: 60 mg

Fentanyl -Not for opioid naïve

Methadone -Long half-life-Multiple druginteractions-NMDA antagonism

Levorphanol -longer duration of effect-long half life may resultin accumulation

1. Mechanism of action (use morphine as prototype)

2. Common adverse effects (> 10%) (use morphine as prototype)


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a. Cardiovascular

b. CNS

c. Dermatologic

d. GI

e. Genitourinary

f. Neuromuscular

g. Respiratory

B. Selection of Opioid

C. Selection of Opioid

1. Pain intensity (per Dipiro)


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a. Milder pain: acetaminophen, NSAIDs

b. Moderate pain: opioid in combination with acetaminophen or NSAID

c. Severe pain: opioid

2. Acute vs. chronic

a. Acute: short acting

b. Chronic: long acting with rescue medication

3. Underlying disease states

a. Renal impairment: morphine not recommended

4. Formulation availability

a. IV: quicker time to onset

b. Long acting options

c. Non-PO options

5. Allergies

a. True opioid allergy is very uncommon

b. Reactions often called allergies but are adverse effects

i. Itching: due to histamine release

ii. N/V: stimulation of chemoreceptor trigger zone

c. 3 structural classes of opioids (need to know which opioids are in thesame class but not the name of the class)


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i. If someone has a true allergy to one structural class, you can try one in

another structural class.

(i) Phenanthrenes: morphine, oxycodone, hydromorphone,

oxymorphone, hydrocodone, codeine

(ii) Phenylpiperidines: meperidine, fentanyl

(iii) Diphenylheptanes : methadone, propoxyphene

D. Special considerations

1. Fentanyl transdermal patch

a. Onset of action: analgesia can begin as soon as 7-8 hours after patch

placement but concentrations level off after 12-24 hours

b. Continues to be active even once patch is removed (depot in the

subcutaneous tissue)

c. Temperature can affect the medication release

d. Should wait 5-6 days in between dose titrations

2. Fentanyl buccal lozenges, film, tablets

a. Only for opioid tolerant

b. Typically reserved for cancer patients

c. Are not interchangeable


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3. Methadone

a. NMDA antagonism: decreases neuropathic pain symptoms

b. Serotonin and norepinephrine inhibitor

c. Accumulation can occur with the medication due to long half-life

d. Wait ~5 days in between dose titrations

e. Equianalgesic dosing varies based on morphine dose

f. Multiple drug interactions

i. Major substrate of 3A4, 2B6

ii. Minor substrate of 2C9, 2C19, 2D6

iii. Moderate inhibitor of 2D6

iv. Weak inhibitor of 3A4

g. QTc prolonging

E. Opioids not recommended

1. Meperidine (Demerol)

a. Toxic metabolite: normeperidine

i. CNS toxicity: tremor, muscle twitching, seizures

ii. Accumulates more with renal insufficiency


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2. Propoxyphene (Darvon)

a. Poor analgesic

b. Active metabolite with long half-life

c. Can lead to accumulation and increased adverse effects

F. Management of opioid induced adverse effects

1. Constipation

a. Laxative + stool softener

i. Should be initiated with initiation of opioid therapy

ii. Must use laxative

iii. Most common used is Senna

(i) Starting dose 1 tablet PO daily

(ii) Titrate as needed

b. Methylnaltrexone (Relistor ®)

i. FDA Indication: Treatment of opioid induced constipation in patients

with advance illness receiving palliative care with inadequate response

to conventional laxative regimens


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ii. Mechanism of action: opioid receptor antagonist; structure does not

allow it to cross the blood brain barrier (does not induce withdrawal);

works peripherally to inhibit opioid-induced GI decreased motility

iii. Subcutaneous injection every other day as needed

iv. Adverse effects: intestinal perforation (rare), abdominal pain,

flatulence, nausea, diarrhea

2. Respiratory depression

a. If not acutely decompensated, decrease opioid dose or discontinue

b. If acutely decompensated, administer opioid antagonist

i. Naloxone

(i) Brand name:

(ii) Formulation:

(iii) Indication:

(iv)Clinical considerations

1. Rapid onset of action: IV ~2 minutes

2. Short half life: 0.5-1.5 hrs

3. Dosing

a. 0.4 mg IV in patient with unknown opioid use history


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b. 0.1-0.2 mg IV in patient on therapeutic opioid therapy

c. Repeat every 2-3 minutes until response

d. May need to repeat dose in 20-60 minutes

i. Can start an IV infusion if necessary

4. Will induce opioid withdrawal

3. Nausea/vomiting

a. Decrease dose if possible

b. Take with food if possible

c. Administer with antiemetic

4. Sedation

a. If mild sedation, decrease dose and titrate slower

b. If severe sedation (not responsive), administer opioid antagonist

5. Pruritis, rash

a. Switch to an opioid with less histamine release (hydromorphone,

oxycodone, fentanyl, methadone, oxymorphone)

b. Administer an antihistamine

c. Consider naloxone infusion

i. 0.25 mcg/kg/hr with close monitoring of pain


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ii. Used if pruritus is intolerable and other agents have been tried

IX. Opioid Dosing

A. Acute Pain

1. Start with low dose opioid around the clock (ATC)

a. Titrate up as necessary to obtain adequate pain control

2. Decrease dose or change to prn as pain subsides

B. Chronic Pain

1. Consider long acting opioid for ATC coverage

2. Provide a rescue analgesic for breakthrough pain

a. Typically 10-20% of the total daily opioid dose given every 2-4 hours prn

3. Increase upward if patient is using > 3 rescue doses/day or pain is

consistently > 3/10

a. If no side effects, increase the dose of the current analgesic

i. Base on use of rescue doses

ii. Recalculate rescue dosage

b. If side effects present, switch to another analgesic

C. Opioid conversions (See equianalgesic dose chart)


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1. Opioid rotation (switching to another opioid)

a. Indications to switch:

i. Improved convenience of alternate regimen

ii. Decrease drug related adverse effects

iii. Improve pain control and reduce toxicity

A patient is receiving 8 mg hydromorphone every 4 hours ATC. The MD wants toswitch to extended release morphine. What dose should be recommended?

b. Calculate total daily dose of opioid (include long acting and rescue doses

used)

c. Calculate the total daily equianalgesic dose of alternate agent

d. Reduce the daily dose by at least 25%

i. Due to incomplete cross-tolerance

ii. If switching to fentanyl patch, do not need to reduce (already

accounted for in specific guidelines)

iii. If switching to ExalgoTM, reduce calculated dose by 50%


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e. Determine the new regimen based on usual dosing intervals and product

availability of alternate agent

f. Calculate appropriate rescue dose

2. Converting dosage forms (PO to IV)

A patient is taking 180 mg MS Contin every 8 hours with rescue morphine IR

dose of 60 mg every 4 hours as needed (has not used in previous 4 days). Hecannot tolerate oral medications right now and needs to be started on a IV morphine infusion.

a. Calculate total daily dose of opioid

b. Calculate the total daily equianalgesic dose of IV formulation

i. If only changing from PO to IV but same agent, no dose reduction

(example PO morphine to IV morphine)

ii. If changing agents, then reduce dose by 25% (example PO morphine

to IV hydromorphone)

c. Calculate infusion rate for 24 hour infusion (total daily dose / 24 hours)


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d. Consider giving a loading dose if necessary (loading dose is equivalent to

infusion rate)

e. Calculate rescue dose of 50-200% of hourly infusion rate

i. Can be given every 15 minutes as needed

f. Monitor VS every 30 minutes for 4 hours after loading dose

g. Reassess frequently (every 1-4 hours depending on environment and

pain)

i. Titrate up or down as needed

D. Patient Controlled Analgesia (PCA)

1. Patients can self-administer the dose as they need it

Component Explanation Typical Example

Drug andConcentration

Morphine,hydrocodone

Morphine 1 mg/ml

Basal dose Constant infusion (notpatient controlled)

Morphine: 0.5-1.5mg/hr

Hydromorphone:0.2-0.4 mg/hr

Calculated basedon opioid regimen(see above)

0

Demand dose Dose of medication thepatient can receive whenthey press the button

Morphine: 1-5 mg

Hydromorphone:

1 mg


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0.2-0.4 mg

Lock-out time # of minutes patient hasto wait in between

demand doses (even if they hit the button themachine will not releaseanother dose until thelock-out time haspassed)

6-20 minutes 6 minutes

4-hour limit Max dose a patient canget over 4 hours. Needsto take into account thebasal and demand

doses. It is a secondway to ensure not toomuch given.

Calculated

(Basal x 4 hrs) +(demand dose / lock

out time x 60minutes x 4 hours)

(0 mg/hr x 4 hours)+ (1 mg/6 minutes x60 minutes/hour x 4hours)

40 mg

Holdparameters

Directions to nursing onwhen to stop PCA

Resp rate < 12 breaths/min or SBP < 90mmHg

Reversal agentas needed

Order a reversal agent incase patient becomesoverly sedated or RRdeclines

Naloxone 0.4 mg ampule at bedside asneeded (hold for MD administration)

Medication Equianalgesic Doses Initial Doses (for naïve patients)IV dose PO dose

Morphine 10 30 mg IR PO: 10 mg every 3-4 hrsER: Based on pts historyIV: 2.5-5 mg every 3-4 hrs

Hydrocodone NA 30 mg 10 mg every 4-6 hours

Oxycodone NA 20 mg IR: 2.5-5 mg every 6 hrsER: Based on pts history (10 mgevery 12 hours)

Hydromorphone 1.5 mg 7.5 mg IR: 2-4 mg every 3-6 hrsIV: 0.2-0.6 mg every 2-3 hrs

Codeine NA 200 mg 60 mg po every 3-4 hrs

Levorphanol 2 mg 4 mg PO: 4 mg po every 6-8 hrsIV 2 mg IV every 6-8 hrs

Methadone30-100 mg PO morphine

101-300 mg PO morphine> 300 mg PO morphine

3.75 mg2.5 mg1.5 mg

7.5 mg5 mg3 mg

PO: 5 mg po every 6-8 hrsIV: 2.5 mg po every 6-8 hrs

Oxymorphone 1 mg 10 mg PO: 10 mg po every 4-6 hrsIV: 0.5 mg IV every 4-6 hrs


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Fentanyl Patch ConversionConversion guidelines based on Duragesic® Package Insert

Daily Oral Morphine (mg/24 hrs) Fentanyl Dose (mcg/hr)

60-134 25

135-224 50

225-314 75

315-404 100

405-494 125*No need to dose reduce for cross tolerance because this was already done

Other guidelines for fentanyl transdermal conversions:

* Need to dose reduce for these conversions*

o 60 mg of PO morphine sulfate ~ 25 mcg/hr

o ½ of the total mg of PO morphine sulfate per day = dose of fentanyl mcg/hr

ExalgoTM Dosing Guidelines

Opioid ExalgoTM Oral Conversion Ratio

Hydromorphone 1Codeine 0.06

Hydrocodone 0.4Methadone 0.6

Morphine 0.2Oxycodone 0.4

Oxymorphone 0.6

Calculate the total daily opioid dose by the conversion factor. Then reduce by 50% for startingdose of ExalgoTM.


PP565 Pain Management Part 1 2011 1019 B

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