Pharm Unit 2 Opioid

• Opioid lecture notes for PA522 Pharmacotherapy Spring 2025
• Representative drugs to know, mechanism of action, indications/therapeutic uses, adverse effects, contraindications/cautions, major interactions, lab monitoring/follow-up, patient education, and available formulations, initial dosing.

Session Objectives:

• Classify representative opioids by their DEA schedule and potential for abuse
• List the responses to activation of µ (mu) and к (kappa) opioid receptors
• Classify drugs that act at the opioid receptors and note whether they act as agonists, partial agonists, or antagonists at the µ (mu) and к (kappa) opioid receptors.
• Know the black box warnings, patient education, drug interactions, and toxicity of opioid medications.
• 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).
• Use a morphine milligram equivalent (MME) chart to 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.
• Discuss the benefits of a drug that is a µ agonist and a ҝ antagonist.
• Know the therapeutic uses of naloxone compared to naltrexone.
• Given a patient scenario, consider patient-care concerns across the lifespan and apply the CDC Guidelines for Safe Opiate Prescribing

Controlled Substances

• Schedule 1 drugs have a high potential for abuse and no currently accepted medical use in the US, like heroin, LSD, ecstasy, and cannabis.
• Schedule 2 drugs or substances have a high potential for abuse, which are currently accepted for medical use in the US, for example, cocaine, morphine, methamphetamine, methadone, oxycodone, fentanyl, and amphetamine.
• Schedule 3 drugs have less potential for abuse than Schedule 1 and 2 drugs and are currently accepted for medical use in the US.
• Codeine products, ketamine, testosterone, and buprenorphine. Benzodiazepines, zolpidem, and tramadol.
• Schedule 4 drugs have a low potential for abuse and are currently accepted for medical use in the US, for example, benzodiazepines, zolpidem, and tramadol.
• Schedule 5 drugs have a lower potential for abuse and are currently accepted for medical use, like cough syrups with codeine and pregabalin.
• Scheduled opioids: Most opioids are Schedule 2 drugs. Tylenol with Codeine® and buprenorphine (Suboxone®) are Schedule 3 drugs. Tramadol and propoxyphene (Darvon) are Schedule 4 drugs. Cough preparations containing not more than 200 milligrams of codeine per 100 milliliters or per 100 grams (Robitussin AC®, Phenergan with Codeine®) are Schedule 5 drugs.
• Opioid definition: Any drug, natural or synthetic, that has actions similar to those of morphine. Opiate definition Includes only compounds present in opium, for example, morphine and codeine.
• The body has three families of peptides that have opioid-like properties, for example, enkephalins, endorphins, and dynorphins, which serve as neurotransmitters, neurohormones, and neuromodulators in the central nervous system (CNS) and in peripheral tissues.
• 3 types of opioid receptors in the body: μ (mu), к (kappa), and δ (delta)
• Endogenous opioid peptides act through all three opioid receptors, but opioid analgesics do not interact with δ receptors.

Opioid Receptor Types

• Analgesia: Mu and Kappa
• Respiratory Depression: Mu
• Sedation Mu and Kappa
• Euphoria: Mu
• Physical Dependence: Mu
• Decreased gastrointestinal motility: Mu and Kappa

Action of Drugs that Bind Opioid Receptors fall into three major groups:

• Pure opioid agonists. For example Morphine, codeine, meperidine, and others (μ and к): Divided into strong opioid agonists (morphine) and moderate to strong opioid agonists (codeine).
• Agonist-antagonist opioids. For example pentazocine, nalbuphine, butorphanol and buprenorphine: Alone they produce analgesia, but with an opiate, they antagonize analgesia caused by the pure agonist.
• Pure opioid antagonists For example, Naloxone, naltrexone, and others: Reversal of respiratory and CNS depression caused by overdose + Methylnaltrexone- Rx opioid-induced constipation

Therapeutic opioid effects

• Analgesia, sedation, euphoria, respiratory depression, cough suppression, and suppression of bowel motility. Drowsiness reduces anxiety, which creates a sense of well-being.
• Uses: cough suppression, acute pain (also think acute MI), and chronic pain.

Morphine, codeine, fentanyl, hydrocodone, and oxycodone.

• Opioid: Direct agonists 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

Routes of Administration

• Enteral: Oral, Sublingual, Buccal, and Rectal
• Parenteral: Intramuscular, Subcutaneous, and Intravenous
• Topical

Opioid time course and therapeutic effects include:

• Codeine (PO): Onset in 30-45 minutes. Peak in 1-2 hours. Duration of 4-6 hours.
• Morphine (PO): Onset in 30 minutes. Peak for IR is 1-2 hours and ER is 7 hours. Duration of 4-6 hours.
• Morphine (IV): Onset in 5-10 minutes. Peak in 1-2 hours.
• Morphine (IM): Onset 10-30 minutes. Peak in 1-2 hours.
• Fentanyl (BUC): Onset in 10-15 mintues. peak in 20 minutes duration 1-2 hours
• Fentanyl (TD): Onset delayed. Peak in 24-72 hours. Duration of 72 hours.
• Hydrocodone (PO): Onset in 10-30 minutes. Peak in 30-60 minutes. Duration of 4-6 hours.
• Hydromorphone (PO): Onset in 30 minutes. Peak for IR is 90-120 minutes, and ER is 6-8 hours. Duration of 4 hours.
• Oxycodone (PO): Onset in 15-30 minutes. Peak in 60 minutes. Duration of 3-4 hours.
• Methadone (PO): Onset in 30-60 minutes. Peak in 90-120 minutes. Duration of 4-6 hours (up to 48 hours with repeated dosing.

Moderate to strong opioids include:

• Codeine (Tablets: 15, 30, 60mg Oral solution: 30mg/5mL): Usual Adult Analgesic Dose is 15-60 mg every 3 to 6h, with a maximum of 120mg in 24h.
• Oxycodone (Oxaydo, OxyContin, Roxicodone, Xtampza ER) which is available in IR tablets: 5, 7.5, 15, 30mg ER tablets: 10, 15, 20, 30, 40, 60, 80mg and ER capsules: 9, 13.5, 18, 27, 36 mg
• Usual Adult Analgesic Dose for opiate-naïve patients: 5-10mg IR every 4-6 h + Opiate-tolerant patients: 10mg ER every 12h
• Hydrocodone (Hysingla ER, Zohydro ER, Norco) which is available in IR tablets (hydrocodone with acetaminophen): 5/325, 7.5/325, 10/325 mg + ER tablets: 20, 30, 40, 60, 80, 100, 120mg and ER capsules: 10, 15, 20, 30, 40, 50mg
• Usual Adult Analgesic Dose for Acute pain: 5/325 mg IR every 4-6 h + Severe, chronic pain: 20 mg ER every 24h
• Tapentadol (Nucynta, Nucynta ER) which is available in IR tablets: 50, 75, 100mg and ER tablets: 50, 100, 150, 200, 250mg
• Usual Adult Analgesic Dose for Acute pain: 50–100 mg IR every 4–6h + Severe, chronic pain: 50mg ER every 12h

Black Box Warnings

• Codeine: In the liver, about 10% of each dose of codeine undergoes conversion to morphine, the active form of codeine. The enzyme responsible is CYP2D6 (the 2D6 isoenzyme of cytochrome P450). Among ultrarapid metabolizers, which carry multiple copies of the CYP2D6 gene, codeine is unusually effective and has led to death in some children. Severe toxicity can also develop in breast-fed infants whose mothers are taking codeine. The cause is high levels of morphine in breast milk, due to ultrarapid codeine metabolism.
• Hydrocodone includes all forms of hydrocodone which contain black box warning. Products that contain acetaminophen (Vicodin) are associated with hepatotoxicity. The extended-release forms of hydrocodone can...

Fentanyl formulations Include: Formulation/Available dose/Usual initial dose/Indication

• Buccal Tablets (Fentora): 100, 200, 400, 600, 800 mcg. Usual initial dose is 100 mcg x1, which may be repeated after 30 min. Indication is breakthrough cancer pain in opioid tolerant patients
• Intranasal (Lazanda): 100, 300, 400 mcg per actuation. Usual initial dose is 100 mcg intranasally x1. Indication is breakthrough cancer pain in opioid tolerant patients.
• Lozenge on a Stick (Actiq): 200, 400, 600, 800, 1200, 1600 mcg. Usual initial dose is 200 mcg orally x1, may repeat after 30 min. Indication is breakthrough cancer pain in opioid tolerant patients.
• Sublingual Spray (Subsys): 100, 200, 400, 600, 800 mcg per actuation. Usual initial dose is 100 mcg SL x1, may repeat after 30 min. Indication is breakthrough cancer pain in opioid tolerant patients.
• Sublingual Tablets (Abstral): 100, 200, 300 mcg. Usual initial dose is 100 mcg SL x1, may repeat after 30 min. Indication is breakthrough cancer pain in opioid tolerant patients.
• Transdermal Patch (Duragesic): 12, 25, 37.5, 50, 62.5, 75, 87.5, 100mcg/h. Individualize dose based on current opioid intake Indication is severe, chronic pain.

Fentanyl notes

• 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 already opioid tolerant.
• 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.
• Transmucosal fentanyl is 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.

Tramadol (Nonopioid Centrally Acting Analgesic)

• Is an analog of codeine but is a weak u opioid receptors agonist, and primary MOA Block uptake of norepinephrine and serotonin, which activates monoaminergic spinal inhibition of pain.
• Uses moderate to moderately severe pain. Peak in 2 hours, half-life is 5-6 hours; Hepatic metabolism and renal excretion.
• Adverse effects: Sedation, dizziness, headache, dry mouth, and constipation. Low potential for dependence, abuse, or respiratory depression and Seizures reported - should be avoided in patients with epilepsy

Agonist Adverse interactions

• Respiratory Depression: CNS depressants, Barbiturates, Benzos, Alcohol, General anesthetics, Antihistamines, Phenothiazines
• Constipation & Urinary Retention: Anticholinergics, Atropine-like drugs, Antihistamines, Phenothiazines, and TCAS
• Hypotension: Hypo-tensive Agents
• MAO-I's: Hyperpyrexic coma

Patient education

• Respiratory Depression - Do not combine with other CNS depressants (BLACK BOX WARNING)
• Hypotension - Orthostatic hypotension
• Urinary Retention - Void Q4hrs, avoid anticholinergics
• Nausea vomiting - up to 40%
• Sedation - Avoid driving
• Neurotoxicity - Hydration, dose reduction
• Tolerance and physical dependence (BLACK BOX WARNING)
• Calculate the total daily dose of opioids which helps identify patients who may benefit from closer monitoring, reduction or tapering of opioids, prescribing of naloxone, or other measures to reduce the risk of overdose.

MME Conversions

• Convert current total daily oxycodone dose to MME
• Oxycodone Equivalent Conversion Factor: OxyIR: 1 mg oxycodone = 1.5 mg MME
• To calculate MME = Total Daily Oxycodone Dose (mg) * Oxycodone Equivalent Conversion Factor = MME
• To determine the equivalent initial dose of transdermal fentanyl patch based on MME conversion: use 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
• Opioid overdose can cause, coma-hypopnea-apnea, hypoxia, hypotension, shock and death, respiratory depression, and pinpoint pupils.
• Treatment: Give Narcan and ventilation.
• Naloxone is a stronger affinity to the opioid receptors than opioids.

Withdrawal

• Fentanyl: Onset from 3-5 hours, and a peak from 8-12 hours
• Long-acting opioids: Onset is 8-12 hours
• Heroin, Morphine, Percocet, crushed long-acting: Onset is 24 hrs with a peak of 36 to 72 hours
• Methadone: Onset is 24 to 72 hours with a peak of 4 to 6 days.

Treatment of withdrawal includes:

• Loperamide for diarrhea, promethazine or ondansetron for nausea/vomiting, ibuprofen for myalgia, Clonidine for hypertension and restlessness, and 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)
• 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
• Naloxone is the fast-acting antagonist (think overdose treatment
• Buprenorphine is a μ agonist and a к antagonist which has Analgesic effects like morphine, but significant tolerance has not been observed + QT-prolongation

Opioids across the lifespan

• Infants: regular use of opioids during pregnancy can cause physical dependence in the fetus, resulting in withdrawal after delivery.
• Children: adequately assess pain with a standardized pain scale. Aspirin, as an adjuvant to opioids, should be avoided because of risk for Reye syndrome. There remains a lack of research regarding the best practice in the treatment of chronic non-cancer pain in children.
• Pregnant women: taking opioids in early pregnancy can increase the risk for congenital heart defects, spina bifida, and gastroschisis.
• Breastfeeding women: limited data suggests small amounts of opioids are excreted in breast milk, which can result in infant drowsiness.
• Older adults: persistent pain is often undertreated in the frail older-adult population. The American Geriatrics Association recommends that providers consider treating moderate to severe uncontrolled pain with opiates after a trial of acetaminophen.

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 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, or chronic pain, immediate-release formulations are preferred over extended-release and long-acting formulations.
• In opioid-naïve patients, the lowest effective dose should be 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 should not be discontinued abruptly/ When opioids are discontinued, they should be gradually tapered off.
• For patients, the taking opioids for extended durations (≥1 year), the recommended taper rate is 10% per month or slower, as this rate is better tolerated than more rapid tapers.
• For acute pain, the prescribed quantity of opioid medications should not exceed the expected duration of pain For subacute and chronic pain, the benefits and risks of continued opioid therapy should be discussed with patients within 1 to 4 weeks of initiation.
• The risk of opioid therapy should be discussed periodically during the treatment, with a clear discussion on ways to mitigate harm, including using naloxone
• Before prescribing opioid therapy for acute, subacute, or chronic pain, and periodically during opioid therapy, the prescriber should review the patient's controlled substance