Opioids: Pharmacology - PDF

Opioids PA 522 PH A RMACOTHERAPY MARAH C ZA JA , PA- C SPRING 2025 Session Objectives 1. For each medication class listed in the “PA522_Medication Table_Spring 2025” know the representative drug names, mechanism of action, indications/therapeutic uses, adverse effects (ADRs), contraindications/caut...

Opioids PA 522 PH A RMACOTHERAPY MARAH C ZA JA , PA- C SPRING 2025 Session Objectives 1. For each medication class listed in the “PA522_Medication Table_Spring 2025” know the representative drug names, mechanism of action, indications/therapeutic uses, adverse effects (ADRs), contraindications/cautions, major interactions (drugs or food), lab monitoring/follow-up, patient education, and formulations available. Morphine, Fentanyl, Methadone, Hydromorphone, Codeine, Oxycodone, Hydrocodone, Buprenorphine, Naloxone, Tramadol, Aspirin Memorize the initial dosing for the following representative drugs: diazepam oxycodone sumatriptan morphine hydrocodone propranolol fentanyl aspirin lorazepam  Session Objectives 1. Classify representative opioids by their DEA schedule and potential for abuse Chapter 24 2. List the responses to activation of μ (mu) and 𝛋 (kappa) opioid receptors (Table 24.1). 3. Classify drugs that act at the opioid receptors and note whether they act as agonists, partial agonists, or antagonists at the μ (mu) and 𝛋 (kappa) opioid receptors, respectively (Table 24.2). 4. Know the black box warnings, patient education, drug interactions, and toxicity of opioid medications. 5. Differentiate between morphine, fentanyl, methadone, hydromorphone, codeine, oxycodone, and hydrocodone in terms of opioid strength, schedule classification, approved indications, and available preparations (PO {IR, ER}, liquid, rectal, Buccal, lozenge, IV, transdermal). 6. Using a morphine milligram equivalent (MME) chart, calculate the total daily dose of opioids for a patient scenario and identify patients who may benefit from closer monitoring, reduction or tapering of opioids, prescribing of naloxone, or other measures to reduce risk of overdose. 7. Discuss the benefits of a drug that is a μ agonist and a 𝛋 antagonist. 8. Know the therapeutic uses of naloxone compared to naltrexone. 9. Given a patient scenario, consider patient-care concerns across the lifespan and apply the CDC Guidelines for Safe Opiate Prescribing (Box 24.1). Continued in a separate lecture 1. Review the characteristics, pathophysiology, and general approach to the treatment of headaches based on type and severity (Table 25.1 and 25.2). 2. Summarize the Key Prescribing Considerations for Serotonin Receptor Agonists (Tryptans) and Ergot Alkaloids. 3. Discuss the indications and drug classes used in preventive migraine therapy. 4. Differentiate between the presentation and treatment of migraines versus cluster headaches (both acute and prophylaxis). 5. Provide patient education for a person experiencing medication overuse headache.  Controlled Substances-5 schedules Schedule 1 ◦ Drugs with high potential for abuse and no currently accepted medical use in US ◦ Heroin, LSD, ecstasy, cannabis* Schedule 2 ◦ Drugs or substances with high potential for abuse, currently accepted medical use in US ◦ Cocaine, morphine, methamphetamine, methadone, oxycodone, fentanyl, amphetamine, etc Schedule 3 ◦ Drugs with less potential for abuse than Schedule 1 and 2 and currently accepted medical use in US ◦ Codeine products, ketamine, testosterone, buprenorphine Schedule 4 ◦ Drugs with low potential for abuse and have currently accepted medical use in US ◦ Benzodiazepines, zolpidem, tramadol Schedule 5 ◦ Lower potential for abuse and currently accepted medical use ◦ Cough syrups with codeine, pregabalin https://www.ncbi.nlm.nih.gov/books/NBK572085/ Responsible Controlled Substance and Opioid Prescribing. Horn, et al. 2023 Scheduled opioids SCHEDULE 2: Most opioids fall in this category SCHEDULE 3: Products containing not more than 90 milligrams of codeine per dosage unit (Tylenol with Codeine®), and buprenorphine (Suboxone®). SCHEDULE 4: tramadol, propoxyphene, darvon SCHEDULE 5: Cough preparations containing not more than 200 milligrams of codeine per 100 milliliters or per 100 grams (Robitussin AC®, Phenergan with Codeine®)  What’s in a name? Opioid: any drug, natural or synthetic, that has actions similar to those of morphine. Opiate: applies only to compounds present in opium (e.g., morphine, codeine). The body has three families of peptides that have opioid-like properties ◦ enkephalins, endorphins, and dynorphins ◦ central nervous system (CNS) and in peripheral tissues. ◦ serve as neurotransmitters, neurohormones, and neuromodulators Opioid receptors 3 types of opioid receptors in the body: ◦ μ (mu) ◦ 𝛋 (kappa) ◦ δ (delta) Endogenous opioid peptides act through all three opioid receptors Opioid analgesics do not interact with δ receptors.  Partial-agonist-antagonist- action Drugs that bind opioid receptors fall into three major groups: pure opioid agonists (μ and 𝛋 ) ◦ subdivided into two groups: ◦ strong opioid agonists (morphine) ◦ moderate to strong opioid agonists (codeine) agonist-antagonist opioids ◦ Alone they produce analgesia, but with an opiate, they antagonize analgesia caused by the pure agonist. pure opioid antagonists ◦ Reversal of respiratory and CNS depression caused by overdose ◦ Methylnaltrexone- Rx opioid-induced constipation Opioid Effects and Uses Therapeutic Effects: ◦ analgesia, sedation, euphoria, respiratory depression, cough suppression, and suppression of bowel motility. ◦ drowsiness, mental clouding, reduces anxiety, creates a sense of well-being. Uses ◦ Cough suppression ◦ Acute Pain ◦ Also think acute MI (peripheral effects & CNS) ◦ Chronic Pain  Morphine, codeine, fentanyl, hydro- & Oxycodone Classification & MOA: Opioids, direct agonist of mu and kappa receptors in the CNS and periphery Kinetics: Hepatic metabolism, renal excretion (methadone- feces & renal) Opioids fentanyl hydrocodone oxycodone hydromorphone Opiates Morphine Codeine  Opioid time course and therapeutic effects Drug Route Onset (minutes) Peak Duration (hours) Codeine* PO 30-45 1-2 hours PO 30 IR: 1-2hours; ER: 7 hours 4-6 hours Morphine IV 5-10 1-2 hours IM 10-30 1-2 hours BUC 10-15 20 minutes 1-2 hours Fentanyl TD delayed 24-72 hours 72 hours Hydrocodone* PO 10-30 30-60 minutes 4-6 hours Hydromorphone PO 30 IR: 90-120; ER: 6-8 hours 4 hours Oxycodone* PO 15-30 60 minutes 3-4 hours Methadone PO 30-60 90-120 minutes 4-6 hours (up to 48 hours with repeated dosing) Moderate to strong opioids Codeine & Hydrocodone Fentanyl Black Box Warning: Products containing fentanyl can cause fatal respiratory depression. Many of these products are only available through restricted distribution programs secondary to misuse and abuse. IV fentanyl is used for acute pain, perioperative pain, and induction of general anesthesia Transdermal fentanyl is indicated only for persistent severe pain in patients who are already opioid tolerant. Transmucosal fentanyl Approved only for breakthrough cancer pain in patients at least 18 years old who are already taking opioids around-the-clock and have developed some degree of tolerance, ◦ 1 week or longer: 60 mg of oral morphine a day, or 30 mg of oral oxycodone a day, or 25 mg of oral oxymorphone a day, or 8 mg of oral hydromorphone a day, or 25 mcg of fentanyl per hour, or an equianalgesic dose of another opioid. Tramadol Nonopioid Centrally Acting Analgesic MOA: analog of codeine -weak µ opioid receptors agonist ◦ Primary MOA: Blocks uptake of norepinephrine and serotonin, activating monoaminergic spinal inhibition of pain. Uses: approved for moderate to moderately severe pain. Kinetics: Peak in 2 hours, half-life is 5-6 hours; Hepatic metabolism and renal excretion. Adverse effects: are sedation, dizziness, headache, dry mouth, and constipation. ◦ Low potential for dependence, abuse, or respiratory depression. ◦ Seizures reported-should be avoided in patients with epilepsy Agonist Adverse interactions Respiratory Depression Constipation & Urinary CNS depressants Barbiturates Retention Anticholinergics Benzos Atropine-like drugs Alcohol Antihistamines General anesthetics Phenothiazines Antihistamines TCAs Phenothiazines Hypotension MAO-I's Hypotensive Agents Hyperpyrexic coma  Patient education Respiratory Depression – don’t combine with other CNS depressants (BLACK BOX WARNING) Hypotension – orthostatic hypotension Urinary Retention – void Q4hrs, avoid anticholinergics Nausea/vomiting in up to 40% Sedation – avoid driving Neurotoxicity – hydration, dose reduction Tolerance and physical dependence (BLACK BOX WARNING) Morphine milligram equivalents (MME)  Morphine milligram equivalents A 58-year-old female with advanced breast cancer that has metastasized to her bones presents for follow-up. She has been managing her severe pain with oral oxycodone immediate-release tablets (OxyIR) 15 mg every 6 hours as needed for breakthrough pain, and her total daily dose of oxycodone is 60 mg. Due to inadequate pain control and increasing difficulty with swallowing, her oncologist has recommended transitioning her to transdermal fentanyl patches. Calculate the Morphine Milligram Equivalents (MME) for her current oxycodone dose Bonus: Determine the appropriate initial dose of transdermal fentanyl patch for her The math Convert current total daily oxycodone dose to MME: Oxycodone Equivalent Conversion Factor: ◦ OxyIR: 1 mg oxycodone = 1.5 mg MME ◦ Total Daily Oxycodone Dose: 60 mg MME = Total Daily Oxycodone Dose (mg) * Oxycodone Equivalent Conversion Factor ◦ MME = 60 mg * 1.5 ◦ MME = 90 MME Fentanyl patch dose Determine the equivalent initial dose of transdermal fentanyl patch based on MME conversion: Fentanyl Equivalent Conversion Factor: ◦ Transdermal fentanyl: 1 mcg/hr = 2.4 mg MME per 24 hours ◦ Initial Dose (mcg/hr) = MME / Fentanyl Equivalent Conversion Factor ◦ Initial Dose (mcg/hr) = 90 MME / 2.4 mg MME per 24 hours ◦ Initial Dose (mcg/hr) = 37.5 mcg/hr Since there isn't a standard 37.5 mcg/hr fentanyl patch available, we need to round the calculated initial dose to the nearest available strength… Misuse of Opioids Opioid overdose Signs and symptoms Coma – hypopnea-apnea à hypoxiaà hypotension à shock and death Respiratory depression Pinpoint pupils https://www.youtube.com/watch?v=oW9nNJxJ3O4 (1min38sec) Treatment ◦ Ventilation ◦ Narcan  Naloxone: Narcan https://www.nhcgov.com/FAQ.aspx?QID=582 Naloxone: Narcan https://www.drugfreenorthernmichigan.net/recovery/naloxone-saves-lives.html Naloxone: Narcan  Withdrawal Drug Onset (from peak effect of drug) Peak of withdrawal Fentanyl 3-5 hours 8-12 hours Long-acting opioids 8-12 hours - Heroin, Morphine, Percocet, 24 hours 36-72 hours crushed long-acting Methadone 24-72 hours 4-6 days  Treatment of withdrawal Symptomatic treatment in opioid withdrawal ◦ loperamide for diarrhea ◦ promethazine or ondansetron for nausea/vomiting ◦ ibuprofen for myalgia ◦ clonidine for hypertension, restlessness ◦ Hydroxyzine for anxiety Methadone ◦ starting dose is 10 mg oral methadone Q4 to 6 hours ◦ total dose in 24 hours equals the dose for the next day (Rarely >40 mg in 24 hour ◦ Day 2: once or twice a day. ◦ Day 3: titration to determine a maintenance dose Buprenorphine (sublingual) start at 4 to 12 mg – outpatient, can be planned induction ◦ Start ~24 hrs since last use otherwise can precipitate withdrawal symptoms ◦ 24 to 48 hours after the last use of long-acting agonists such as methadone Opioid Agonists vs antagonists Naloxone is the fast-acting antagonist (think overdose treatment) Buprenorphine μ agonist and a 𝛋 antagonist Analgesic effects are like those of morphine, but significant tolerance has not been observed. *QT-prolongation Opioids across the lifespan  2022: CDC Clinical Practice Guidelines for Prescribing Opioids (12 guidelines) Nonopioid therapies should be maximized as first-line and adjunct therapy if no contraindications exist. Nonopioid therapies are preferred for subacute and chronic pain. Maximize non-opioid therapy over opioids first. Discuss risk vs benefit Before prescribing opioids for acute pain, the realistic benefits of opioid therapy and the risks of opioid therapy should be thoroughly discussed with the patient. If opioid therapy is prescribed for acute, subacute, Prefer short acting or chronic pain, immediate-release formulations are >long acting for preferred over extended-release and long-acting acute pain! formulations. https://www.cdc.gov/mmwr/volumes/71/rr/rr7103a1.htm?s_cid=rr7103a1_w  2022: CDC Clinical Practice Guidelines for Prescribing Opioids In opioid-naïve patients, the lowest effective dose should be Use lowest dose! prescribed. The recommended starting dose for opioid-naïve patients is 5 to 10 morphine milligram equivalents (MME) per dose or a daily dosage of 20 to 30 MME/day. Unless there are signs of impending overdose, opioid therapy Do NOT stop abruptly! should not be discontinued abruptly. When opioids are discontinued, they should be gradually tapered Taper slow for best off. For patients taking opioids for extended durations (≥1 year), results the recommended taper rate is 10% per month or slower, as this rate is better tolerated than more rapid tapers. https://www.cdc.gov/mmwr/volumes/71/rr/rr7103a1.htm?s_cid=rr7103a1_w  2022: CDC Clinical Practice Guidelines for Prescribing Opioids For acute pain, the prescribed quantity of opioid Shortest duration for pain medications should not exceed the expected duration of pain. For subacute and chronic pain, the benefits and risks of Discuss risk vs benefit for chronic continued opioid therapy should be discussed therapy! with patients within 1 to 4 weeks of initiation. The risk of opioid therapy should be discussed Continue to discuss periodically during the treatment, with a clear while prescribing! discussion on ways to mitigate harm, including using naloxone. https://www.cdc.gov/mmwr/volumes/71/rr/rr7103a1.htm?s_cid=rr7103a1_w  2022: CDC Clinical Practice Guidelines for Prescribing Opioids Before prescribing opioid therapy for acute, subacute, or chronic pain, and periodically during opioid therapy, the prescriber should review the patient's controlled substance Always check PDMP prescription history using prescription drug monitoring program (PDMP) data. Extreme caution is advised when prescribing opioid pain Caution BZDs + Opioids medication and benzodiazepines (or other central nervous system depressants) concurrently due to the risk of respiratory compromise. If opioid use disorder is suspected or diagnosed, treatment Offer treatment-don’t should be offered. Detoxification without medications for abruptly stop! opioid use disorder is not recommended. https://www.cdc.gov/mmwr/volumes/71/rr/rr7103a1.htm?s_cid=rr7103a1_w More to come Headache Substance Use Disorders Pain Management Questions for now??