Non-Malignant Pain Management: Part 1

Bruce 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 patients 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-acting opioid 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 appropriate management. 15. Select appropriate adjunct analgesic agents for a patient based on patient specific parameters. 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 INFORMATION o 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).

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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 include dosage strengths

FDA Approved Indications

(related to pain management)

Maximum daily dose

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.
Drug

Opioids
Extended Release Form. X 8-12 hrs: Immediate Release Form. X Morphine IR IV Form. Other form. Available with nonopioid No Comments

Morphine

Rectal Solution (Roxanol)

-Gold standard opioid -Hepatic glucoronidation to 2 metabolites B. Canaday PP565 Fall 2011 7

MS Contin, Oramorph SR, 24 hrs: Kadian, Avinza Oxycodone

-M-3G: adverse effects -M-6G: analgesia (more potent) -Renal excretion

-Less dependent on active metabolite formation -Metabolized by CYP2D6 -Ceiling analgesic dose (10 mg PO) -Short half life -Safer option for renal dysfunction -No advantage over others

Hydrocodone

Hydromorphone

Oxymorphone

Codeine

Fentanyl

-Requires CYP2D6 metabolism to become active -Ceiling analgesic effect: 60 mg -Not for opioid nave

Methadone

Levorphanol

-Long half-life -Multiple drug interactions -NMDA antagonism -longer duration of effect -long half life may result in 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 the same 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 to switch 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). He cannot 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 Drug and Concentration Basal dose Constant infusion (not patient controlled) Explanation Typical Morphine, hydrocodone Morphine: 0.5-1.5 mg/hr Hydromorphone: 0.2-0.4 mg/hr Calculated based on opioid regimen (see above) Demand dose Dose of medication the Morphine: 1-5 mg patient can receive when Hydromorphone: they press the button 1 mg Example Morphine 1 mg/ml 0

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0.2-0.4 mg

Lock-out time

# of minutes patient has to wait in between demand doses (even if they hit the button the machine will not release another dose until the lock-out time has passed) Max dose a patient can get over 4 hours. Needs to take into account the basal and demand doses. It is a second way to ensure not too much given. Directions to nursing on when to stop PCA

6-20 minutes

6 minutes

4-hour limit

Calculated

(0 mg/hr x 4 hours) + (1 mg/6 minutes x (Basal x 4 hrs) + 60 minutes/hour x 4 (demand dose / lock hours) out time x 60 minutes x 4 hours) 40 mg Resp rate < 12 breaths/min or SBP < 90 mmHg

Hold parameters Reversal agent as needed

Order a reversal agent in Naloxone 0.4 mg ampule at bedside as case patient becomes needed (hold for MD administration) overly sedated or RR declines
Equianalgesic Doses IV dose PO dose 10 30 mg NA NA 1.5 mg NA 2 mg 3.75 mg 2.5 mg 1.5 mg 1 mg 30 mg 20 mg 7.5 mg 200 mg 4 mg 7.5 mg 5 mg 3 mg 10 mg Initial Doses (for nave patients) IR PO: 10 mg every 3-4 hrs ER: Based on pts history IV: 2.5-5 mg every 3-4 hrs 10 mg every 4-6 hours IR: 2.5-5 mg every 6 hrs ER: Based on pts history (10 mg every 12 hours) IR: 2-4 mg every 3-6 hrs IV: 0.2-0.6 mg every 2-3 hrs 60 mg po every 3-4 hrs PO: 4 mg po every 6-8 hrs IV 2 mg IV every 6-8 hrs PO: 5 mg po every 6-8 hrs IV: 2.5 mg po every 6-8 hrs PO: 10 mg po every 4-6 hrs IV: 0.5 mg IV every 4-6 hrs
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Medication Morphine Hydrocodone Oxycodone Hydromorphone Codeine Levorphanol Methadone 30-100 mg PO morphine 101-300 mg PO morphine > 300 mg PO morphine Oxymorphone

Fentanyl Patch Conversion

Conversion 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 o 60 mg of PO morphine sulfate ~ 25 mcg/hr of the total mg of PO morphine sulfate per day = dose of fentanyl mcg/hr

ExalgoTM Dosing Guidelines

Opioid ExalgoTM Oral Conversion Ratio Hydromorphone 1 Codeine 0.06 Hydrocodone 0.4 Methadone 0.6 Morphine 0.2 Oxycodone 0.4 Oxymorphone 0.6 Calculate the total daily opioid dose by the conversion factor. Then reduce by 50% for starting dose of ExalgoTM.

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