Opioid therapy for pain Elizabeth Whiteman M.D.

Goals and objectives Understand appropriate opioid use for pain Understand side effects of opioids Learn to treat and prevent side effects Routes of administration Equianalgesic dosing Develop competence in treating pain and use of opioids

Opioid Dosing Opioid starting dose depends on: Patient’s age, weight, cachexia Total doses of previous analgesics Frequency and severity of pain

Starting opioids Opioid naive patient start slow Oral first line if patient can swallow Short acting prn, or around the clock if constant pain Can then calculate long acting needs Convert to long acting PO and make sure patient has breakthrough short acting for prn

Sublingual formulas not good bioavailability But can use liquid morphine orally Rectal dosing if patient able Routine dosing around the clock (q4-6hr) IV or Subcutaneous infusion if need rapid titration or unable to take other route

Opioid titration Titration for increases in pain Oral morphine: 4 hr duration, 2hr peak IV/SC morphine 10-20 min peak Titrate prn: ½ of the 4hr dose (about 10% of the 24 hr dose) eg: 10mg q4hr ATC with 5mg prn q2hr

Opioids Tolerance Dependence Addiction pharmacologic property, less drug effect over time Dependence pharmacological response, uncomfortable side effects when drug is withheld Addiction Behavior problem, compulsive use and craving for psychological gain

Opioid side effects Constipation Nausea Sedation and confusion Always start laxatives with opioids Fluid intake Nausea Sedation and confusion Urinary retention Myoclonic jerks Pruitis

Myoclonic Jerking Often seen in: Treatments renal or hepatic insufficiency Treatments Benzodiazepines Control electrolytes Opioid rotation Progressive Myoclonis-seizures Reduce or rotate opioid

Delirium Can be both hypoactive or hyperactive Often seen in: Renal or hepatic insufficiency Elderly Alcohol or benzodiazepine withdrawal Patients with underlying dementia Brain metastasis Treatment Decrease or rotate opioid Assess other medication which can contribute Antipsychotic medications

Respiratory Depression Often seen in: COPD Chronic lung disease Upper airway compromise Pneumonia Treatment Reduce opioid Switch to short acting agents Avoid drug with active metabolite Use diluted naloxone (only if indicated)

Treatment of side effects Reduce opioid dose Add adjuvant drug if indicated Treat symptoms (may be temporary) Hold medicine if feel patient got too much and reassess Opioid rotation- try other agents

Special populations Frail elderly Liver patients Dementia Renal failure Drug users Pediatrics HIV patients

Drugs to avoid / caution Meperidine (Demerol) Butorphanol(Stadol) Propoxyphene(Darvon) Pentazocine(Talwin) Caution, case by case Methadone(Dolophine) Transdermal Fentanyl(Duragesic)

Duragesic patch Use if no other route po or rectal If patient is on it, assess if really working Need to have some subcutaneous fat Drug is lipophilic, distributed in fat Remember takes 48-72 hours to work Also slow to get out of system, cant just pull off patch Not for use on opioid naive patients Patient should be already on 45mg/day or more Morphine Sulfate

Methadone Good for both nociceptive and neuropathic pain Patient need to have time to titrate Lasts longer, but may need q 8 hr titration Long action 15-120 hours Need to use case by case Not as appropriate in patients with short life expectancy or risk side effects

Equianalgesic dosing When changing routes of administration be familiar with an equianalgesic table Equivalent dosing are guides, individual patients may require more dose adjustment Calculate for incomplete cross tolerance, start with 50-75% of the equianalgesic dose

Converting oral to parenteral Always calculate back to morphine/24hr Drug PO SC or IV Morphine 20mg (divide by 3) = 7mg Hydromorphone 5mg (divide by 5) = 1mg

EQUIANALGESIC DOSES OF OPIOIDS (EPEC Project 1999, Module 4) ORAL/RECTAL DOSE (MG) ANALGESIC PARENTERAL DOSE (MG) 100 Codeine 60 – Fentanyl 0.1 15 Hydrocodone – 4 Hydromorphone 1.5 2 Levorphanol 1 150 Meperidine 50 10 Methadone 5 15 Morphine 5 10 Oxycodone –

Fentanyl Patch conversion TABLE 1: DOSE CONVERSION GUIDELINES Current Analgesic Daily Dosage (mg/day) Oral morphine 60-134 135-224 225-314 315-404 IM or IV morphine 10-22 23-37 38-52 53-67 Oral oxycodone 30-67 67-112 112-157 157.5-202 Oral codeine 150-447 Oral hydromorphone 8-17 17.1-28 28.1-39 39.1-51 Intravenous hydromorphone 1.5-3.4 3.5-5.6 5.7-7.9 8-10 Intramuscular meperidine 75-165 166-278 279-390 391-503 Oral methadone 20-44 45-74 75-104 105-134 DURAGESIC recommended 25mcg/hr 50mcg/hr 75mcg/hr 100 mcg/hour Source: Ortho-McNeil, Inc. 2006-2008. All rights reserved.  1 Table 1 should not be used to convert from DURAGESIC to other therapies because this conversion to DURAGESIC is conservative. Use of Table 1 for conversion to other analgesic therapies can overestimate the dose of the new agent. Overdosage of the new analgesic agent is possible [see Dosage and Administration (2.3)].

Fentanyl patch Key Considerations All equianalgesic ratios/formulas are approximations; clinical judgment is needed when making dose or drug conversions. The risk of sedation/respiratory depression with transdermal fentanyl is probably increased in the elderly or patients with liver and renal impairment due to its long half-life, thus, choose the lower end of the dosing spectrum. When in doubt, go low and slow, using prn breakthrough doses generously while finding the optimal dosage of a long-acting drug. Other teaching points about Duragesic: Start at the lowest dose, 12 mcg/hr, in an opioid naïve patient; there is no maximum dose. Therapeutic blood levels are not reached for 13-24 hours after patch application and drug will be continue to be released into the blood for at least 24 hours after patch removal. Opioid withdrawal symptoms can occur during dose conversions—care must be taken to avoid this by use of breakthrough opioids. Some patients will need to have their patches changed every 48 hours. The recommended upward dose titration interval is no more frequently than every 72 hours. Place patches on non-irradiated, hairless skin. Direct heat applied over the patch can increase drug absorption with increased toxic effects. (FAST FACTS AND CONCEPTS #2, David E Weissman MD, EPERC, 2008.

Cases Case 1 Mrs. D is a 45-year-old attorney who has breast cancer metastatic to bone. She is comfortable on a continuous infusion of morphine at 6 mg/h SC. Your goal is to change to oral medications before discharging her home. What should your oral morphine prescription be? Calculate a 10% prn breakthrough dose as well. cases: adapted from EPEC Project , 1999. Train the Trainer course

Case 2 Mr. T is a 73-year-old man with lung cancer, a malignant pleural effusion, and chronic chest pain. He has undergone therapeutic thoracentesis and pleurodesis. He is currently receiving meperidine, 75 mg IM q 6 h, for pain. You want to change to oral morphine. Without adjusting for cross-tolerance, what dose and schedule would you choose? Calculate a 10% prn breakthrough dose also.

Case 3 Ms. M is a 41-year-old teacher who has ovarian cancer with ascites and has been taking 2 tablets of acetaminophen/hydrocodone (500 mg/5 mg) every 4 hours and 1 tablet of acetaminophen/oxycodone (325 mg/5 mg) every 6 hours for pain relief. Morphine makes her nauseated. You are concerned about acetaminophen toxicity and want to change to an alternative oral approach. Without adjusting for partial cross-tolerance, what dose of hydromorphone would you choose?

Case 4 Mrs. A is hospitalized post op head and neck ca surgery Case 4 Mrs. A is hospitalized post op head and neck ca surgery. She is receiving adequate pain control with hydromorphone 0.4mg/hr PCA pump. She is unable to take nutrition and medications by mouth. What dose and schedule fentanyl patch would you prescribe to provide her with an approximately equal amount of analgesia?

Cases Case 5 Mr. B has been taking 3 capsules containing oxycodone (5 mg per capsule) and acetaminophen every 3 hours at home for relief of bone pain from metastatic lung cancer. He is now admitted to the hospital with a chemotherapy-induced aplasia. You do not want him taking an antipyretic (acetaminophen). Without correcting for partial cross-tolerance, how much oral morphine elixir would you prescribe to provide analgesia similar to that which he received from the oxycodone?

Case 6 Mrs. C has been taking codeine, 60 mg by mouth every 4 hours, and methadone, 40 mg orally every 6 hours, to adequately control abdominal pain from bulky retroperitoneal metastases. She is now admitted with a chemotherapy-induced stomatitis. Your attending physician suggests that you place her on a constant infusion of intravenous morphine. Without adjusting for partial cross-tolerance, what hourly rate of intravenous morphine will you choose to continue to keep her pain well controlled?

Answers Case 1 Morphine Sulfate ER 200mg PO bid or Morphine sulfate IR 70mg PO q4hr ATC Don’t forget breakthrough dose (10% daily dose) Morphine sulfate IR 40mg PO q1hr prn breakthrough pain

Case 2 Morphine sulfate SR 45mg PO BID Breakthrough: Morphine Sulfate 10 mg IR q1hr prn breakthrough NOTE: use equianalgesic conversion chart for conversion of meperidine. Based on EPEC table, slide 19.

Case 3 Case 4 Case 5 Hydromorphone 4mg po q4hr ATC Hydromorphone 1-2mg po q1hr prn breakthrough Case 4 Fentanyl transdermal patch 100mcg/hr q 72 hr Case 5 Morphine 30mg PO q4hr ATC

Case 6 Total morphine in 24hr= 98mg, so Morphine sulfate IV 4mg/hr continuous

Resources Ballantyne,J, Mao,J, Opiod Therapy for chronic pain, NEJM 349:20, Nov 13, 2003. Moryl,N, Coyle,N, Foley,K, Managing an Acute Pain Crisis in a patient with Advanced Cancer, JAMA, Vol 299, no 12, March 26,2008. www.globalrph.com/narcotic.cgi EPEC Module 4, Pain Management, EPEC Project, 1999. UNIPAC 3, Assessment and Treatment of Pain in the Terminally Ill, AAHPM, Weissman,D, Fast fact #2 Converting to/from Transdermal fentanyl, 2nd ed, EPERC Medical College of Wisconsin, 2008. (www.eperc.mcw.edu/EPERC)