Pain Management Drug Therapy Workshop Yale Interdisciplinary Palliative Care Educational Project Pain Management Drug Therapy Workshop

The Concept of Total Pain

World Health Organization (WHO) Step Ladder Approach Severe Pain 7-10/10 Potent opioids (e.g. morphine) +/- non-opioids Moderate Pain 4-6/10 Weak opioids +/- non- opioids (e.g. Tylenol #3®) Mild Pain 1-3/10 Note: Ask students to provide clinical example from the wards of each level of pain. ASA, Tylenol, NSAIDS

Clinical Questions #1 Breakthrough pain dosing should be individualized, but a guide for determining the initial dose of bolus I.V. medication for a patient receiving a long acting oral form of morphine is that the initial breakthrough dose is what percentage of the total daily long-acting morphine dose? a. 10% b. 20% c. 50% d. 100%

Answer #1 a. 10% Rationale: 10% would be the minimum dose, Titrated to effect. The range is 10-20%

Breakthrough Pain Patients on long-acting med always need second, short-acting med, for breakthrough pain to take Q 4 hours or less. Generally, dose of breakthrough opioid should be: 10% of 24 hour dose of analgesics and made available Q 2-4 hours. Example: MS Contin 60mg q12hrs breakthrough dose should be immediate release morphine (MSIR), 10-15 mg Q 2-4 hrs prn.

Clinical Question #2 What is the maximum number of tablets of hydrocodone/acetominophen 5 mg/500 mg (e.g., Vicodin ®) you can safely prescribe for a 24 hour period. a. 4 b. 6 c. 8 d. There is no ceiling dose/maximum

Answer #2 c. 8 Rationale: 4,000mg of acetominophen in 24 hours is safe for most patients, BUT ceiling dose may need to be modified significantly or the drug not used in patients with: renal or liver disease history of significant alcohol intake consider starting at 50% of standard ceiling dose for elders.

Clinical Question #3 A 40 yr. old women with stage IV ovarian cancer reports mild to moderate burning pain in her hands and feet. Ibuprofen has not been effective. You suggest: a. A COX-2 inhibitor b. Topical capsaicin c. A steroid d. An adjuvant with activity in neuropathic pain Note: Ask students what this burning pain is (peripheral neuropathy) and what it may be due to (chemotherapy). Have students seen other cases of peripheral neuropathy on the wards (e.g. diabetic, alcohol)?

Answer #3 d. An Adjuvant with activity in neuropathic pain Pain characterized by sharp, shooting, electric shocks, parethesias, dysesthesias, cold extremities Neuropathic pain often responds poorly to NSAIDs and opioids Note: Ask students

Drugs for Neuropathic Pain opioids antidepressants anticonvulsants local anesthetics steroids other

Antidepressants Tricyclic antidepressants Analgesic effects separate from anti-depressant effects. Amitriptyline: most studied, but most side effects Nortriptyline & desipramine: better tolerated, less well studied SSRIs: little evidence of analgesic effect. SNRI’s inhibit both norepinephrine and serotonin reuptake efficacy in neuropathic pain syndromes or pain associated with depression (duloxetine [Cymbalta®], venlafaxine [Effexor®])

Anticonvulsants Agents for neuropathic pain Start low, go slow gabapentin (Neurontin®) pregabalin (Lyrica®) clonazepam (Klonopin®) Other newer agents Start low, go slow Watch for side effects Monitor serum levels, if available

Adjuvants to Opioid Therapy Common indication Alpha agonists Neuropathic pain Anticonvulsants Antihistamines Nausea, pruritus Benzodiazepines Pain w/Anxiety Bisphosphanates Bone pain (cancer) Corticosteroids NSAIDs / COX-2 I Musculoskeletal pain Tricyclic anti-depressants

Clinical Question #4 A 63 yr. old man with advanced prostate cancer has been stable on oral morphine 30 mg every 4 hours. He is now NPO and you are going to switch him to IV morphine. The correct IV dose is: a. 4 mg IV q 4 hours b. 6 mg IV q 4 hours c. 10 mg IV q 4 hours d. 30 mg IV q 4 hours

Answer #4 c. 10 mg IV q 4 hours Rationale: Equianalgesic ratio for morphine is 1 mg IV = 3 mg PO. When writing start time for the first dose, consider time of last oral dose. ORAL DOSE (MG) MED PAREN-TERAL DOSE (MG) 30 Morphine 10 7.5 Hydro-morphone (Dilaudid ®) 1.5 20 Oxycodone -- Hydro-codone

Parenteral Opioids IV is the route of choice if access is available. There is NO indication for IM opioids (painful, no benefit over SQ route) All standard opioids can be given SQ, by either bolus dose or by continuous infusion. PCA (basal rate plus a patient initiated dose) is an effective and well accepted modality; either IV or SQ.

Parenteral Opioids (cont.) IV or SQ bolus doses have a shorter duration of action than oral doses; typically 1-3 hours. The peak effect from an IV bolus dose is 5-15 minutes. Dose escalation of parenteral opioids is the same as with oral—always by a percentage of the starting dose.

Clinical Question #5 Mrs. Jones has advanced cervical cancer. She has been taking Percocet-5 (2 tablets PRN) for pain with good effect. The patient is now NPO & is requiring something for pain. An appropriate starting dose of PRN IV morphine is approximately: a. 2 mg b. 3 mg c. 4 mg d. 5 mg e. 6 mg Ask students in what context they have seen IV opiates used.

Answer #5 c. 4 mg IV morphine Rationale: Most equianalgesic tables use a ratio of 20 mg po oxycodone = 10 mg IV morphine. Mathematically, answer is 5 mg IV morphine. Clinically, account for possible incomplete cross-tolerance, so reduce the dose by about 25%-50%. 4 mg is a convenient dose of IV morphine. We might also have rounded down to 3 mg. 4 mg is almost certainly safe and analgesically appropriate for opioid non-naïve patient.

Incomplete cross-tolerance If switching from one opioid to another, recommended to start the new opioid at ~50% of equianalgesic dose. Why? :Because the tolerance a patient has towards one opioid, may not completely transfer (“incomplete cross-tolerance”) to the new opioid. to 50% of new Opioid from 100%

Clinical Question #6 A 69 yr. old patient with metastatic prostate cancer to the lumbar spine is taking OxyContin® (sustained release oxycodone) 100 mg every 8 hours. What should be the opioid for his breakthrough pain and at what dose and interval? a. Oxycodone 30 mg PO every 4 hours b. Oxycodone 30 mg PO every 8 hours c. Morphine 10 mg PO every 4 hours d. Morphine 10 mg IV every 8 hours

Answer #6 a. Oxyocodone 30 mg PO every 4 hours Rationale: In general, keep PRN, short acting opioid the same drug as the long-acting opioid. Starting dose for breakthrough pain is 10% of the total daily dose (and you can always titrate). Here total daily dose = 300 mg, so 10% of this = 30 mg. The PRN interval should never be longer than the expected analgesic duration (~4 hours in this case), and can often be less.

Short Acting Opioids Oral dosing: onset in 20-30 min peak effect in 60-90 minutes duration of effect 2-4 hours Can be dose escalated or re-administered every 2-4 hours for poorly controlled pain General guideline: Moderate pain: increase 25-50% Severe pain: increase by 50-100%

B. Short Acting Opioids Parenteral or Oral: Oral only: morphine hydromorphone (Dilaudid ®) Codeine Onset & duration of action depends on route administration Oral only: oxycodone (Percocet ® , Tylox ® ) hydrocodone (Vicodin ® Lortab ®, Lorcet ®) propoxyphene (Darvon ®, Wygesic ®) Note: hydrocodone is only available as a combination product.

Clinical Question #7 Ms. Nguyen is reporting 7/10 pain now in her left leg. She had vomited after her last pain medication, morphine 10 mg IV. What is your next analgesic order? a. Dilaudid® (hydromorphone) 1.5 mg IV b. Fentanyl® Patch 25 mcg/hr q72 hours c. Dilaudid® 8 mg PO d. Percocet® 5/325 three tablets Ask students if they have experienced or seen GI side effects of opiates. Explain a bit about opiate induced n/v….mechanism, natural history, managament Mechanisms: At the base of the 4 th ventricle lies the chemoreceptor trigger zone (CTZ), a “sampling port”, to detect substances that don’t belong in the blood. Adjacent to the CTZ lies the medullary vomiting center (VC), which controls the complex muscular sequence of vomiting. When the CTZ detects a noxious chemical in the blood, a signal is sent to the VC and the vomiting reflex is initiated. Opioids can directly stimulate the vestibular apparatus—patients note a spinning sensation with their nausea. Opioids cause constipation which can lead to nausea via stimulation of afferent cholinergic pathways. Natural history: Most patients develop tolerance to the emetic effects, so that within 3-7 days, at a constant opioid dose, the emetic effect will abate. Management: Dose adjustment— if good pain relief is achieved but associated with nausea, it may be possible to lower the opioid dose, still retain good analgesia, but eliminate the nausea. Switching opioid - there is variability in emetic reaction to different opioids. Anti-emetics— start with low-cost dopamine antagonists (e.g. prochlorperazine) or anti-cholinergics (e.g. scopolamine); 5HT 3 antagonists (e.g. ondansetron) can be used for more refractory cases

Answer #7 a. Dilaudid® (hydropmorphone) 1.5 mg IV Rationale: With severe pain we need rapid onset option. Onset too slow with Fentanyl patch and orals. IV morphine plus an antiemetic might be considered, but easier option - change to another opioid (different patients have different side effect responses to various opioids). Hydromorphone 1.5 mg IV is approx. equianalgesic to 10 mg IV morphine. As patient currently in severe pain, reducing dose for potential incomplete cross tolerance not necessary.

Opioid Dose Escalation Always increase by a percentage of the present dose based upon patient’s pain rating and current assessment 50-100% increase Severe pain 7-10/10 25-50% increase Moderate pain 4-6/10 25% increase Mild pain 1-3/10

Frequency of dose escalation The frequency of dose escalation (oral opioids) depends on the particular opioid … Short acting oral: q 2-4 hours Long acting oral, except methadone: q 24 hours methadone: q 72 hours transdermal fentanyl: q 72 hours.

Clinical Question #8 Mr. MacLean comes to your floor in excruciating pain (10/10). He receives morphine 4 mg IV, but reports no relief at all after 15 minutes. The intern or fellow then orders morphine 6 mg IV. After another 20 minutes the patient reports that she still has no relief. You note that the patient is wide awake (no sedation) with continued 10/10 pain. What would you recommend? a. Tell the patient that the interval between doses is 4 hours and they will have to wait b. Administer another dose of morphine 6 mg IV in one hour c. Administer another dose of morphine 9-12 mg now d. Call for a pain or palliative care consult

Answer #8 c. Administer another dose of morphine 9-12 mg now. Rationale: Patient has no unacceptable side effects, so no immediate reason to change to another drug. Patient is in a pain crisis. We should titrate aggressively (i.e., 50-100% increase in each dose at approximately 15 minute intervals) until a response is observed. Note:some protocols for pain crisis in cancer patients suggest that 1-2 doses of ketorolac (Toradol®) 30 mg IV be considered (if not otherwise contraindicated) in addition to the opioid.

Clinical Question #9 Ms. Santini, a 45 yr. old woman with colon cancer metastatic to the liver, had been admitted for uncontrolled pain. Her pain is now controlled and stable on PCA morphine of 10 mg/hr. The boluses are 5 mg q15 minutes PRN and work very well but she rarely needs to use the bolus doses for breakthrough pain. She is to be discharged home on oral opioids. What opioid/formulation and what dose would you recommend? a. MS Contin 120 mg PO Q 12 hours b. MS Contin 240 mg PO Q 12 hours c. MS Contin 360 mg PO Q 12 hours d. Fentanyl patch 50 mcg Q 72 hours e. Dilaudid 8 mg PO Q 8 hours

Equianalgesic Doses: Opioid Analgesics ORAL DOSE (MG) ANALGESIC PARENTERAL DOSE (MG) 30 Morphine 10 7.5 Hydromorphone (Dilaudid ®) 1.5 20 Oxycodone -- Hydrocodone Note: before showing table ask students: What is the most potent opiate they know? Which ones are they comfortable using? Do they know equianalgesic doses? Handout laminated card.

Answer #9 c. MS Contin 360 mg PO every 12 hours Rationale: Patient already on morphine, so use same opioid. Using long-acting formulation is the oral equivalent of a continuous infusion. Total daily dose of morphine IV is 240 mg and the oral equivalent is 720 mg of morphine, can be given as 360 mg of MS Contin PO every 12 hours.

C. Long Acting Opioids Oral Transdermal morphine: oxycodone MS Contin® Kadian® Oramorph SR oxycodone Oxycontin® Oxycodone SR oxymorphone Opana SR methadone Transdermal Fentanyl Patch (Duragesic®) – Dosing Q 72 hours

Clinical Question #10 What breakthrough pain opioid/formulation would you recommend for Ms. Santini if she takes MS Contin 360 Mg Q 12 hours? a. Morphine elixir 20 mg PO every 2-4 hours PRN b. Morphine immediate release tablets 40 mg PO Q 2-4 hours PRN c. Morphine immediate release tablets 60 mg PO Q 2-4 hours PRN d. Morphine immediate release tablets 70 mg PO Q 2-4 hours PRN

Answer #10 d. Morphine immediate release tablets 70 mg PO every 2-4 hours PRN. Rationale: Breakthrough pain requires a short-acting formulation. Preferable to use same opioid as long-acting. PRN initially 10% of the total daily dose = 10% of 720mg = 72mg. Dosing interval is q2-3h PRN. We don’t expect that pts will need to take 12 doses in 24hr (our pain regimen would be really off). If patient requires >5 PRN doses/day, either the PRN dose needs adjusting or the basal dose or both.

Name one new fact you learned about the use of narcotics from this presentation and how you might use it clinically as a Sub- I Note: Ask for response from each student

References Portions of this presentation were originally developed by David E. Weissman, MD, Drew Rosielle, MD, Kathy Biernat, MS and Judi Rehm for: EPERC End of Life/Palliative Education Resource Center And: Yale Cancer Center Supportive Oncology Program Connecticut Challenge Survivorship Clinic Kenneth Miller, MD & Thomas Quinn, APRN

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