Opioid Analgesic

Aka: Opioid Analgesic, Opioid, Opiate, Opioid Abuse Deterrent Agent, Opioid Metabolism, Narcotic Analgesic, Narcotic

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II. Definitions

  1. Opiate
    1. Naturally occurring, derived from opium poppy
    2. Examples: Morphine, Codeine, Heroin
  2. Opioids
    1. Includes Opiates (naturally occurring)
    2. Semi-synthetic Opioids (structurally similar to Opiates)
      1. Examples: Hydrocodone, Oxycodone, Hydromorphone, Oxymorphone
    3. Synthetic Opioids
      1. Examples: Methadone, Buprenorphine, Meperidine, Fentanyl, Tramadol

III. Adverse Effects

  1. See Opioid Adverse Effect
  2. See Opioid Overdose
  3. See Opioid Abuse
  4. See Opioid Withdrawal

IV. Pharmacology: Metabolism of Opioids

  1. Common Metabolites
    1. Codeine: Metabolizes to Hydrocodone and Morphine
    2. Heroin: Metabolizes to 6-acetylmorphine (6-MAM) and then to Morphine
    3. Morphine and Hydrocodone: metabolize to Hydromorphone
    4. Hydrocodone: Metabolizes to Dihydrocodeine
    5. Oxycodone: Metabolizes to Oxymorphone
  2. Renal dysfunction
    1. Safe
      1. Fentanyl (consider reduced dose)
      2. Methadone
    2. Caution (risk of metabolite accumulation)
      1. Hydromorphone
      2. Morphine
      3. Oxycodone
    3. Unsafe (avoid)
      1. Codeine
  3. Hepatic dysfunction
    1. Safe
      1. Fentanyl
    2. Caution
      1. Hydromorphone (decrease starting dose by 50%)
      2. Oxycodone (decrease starting dose by 50%)
      3. Morphine (decreased conversion to active metabolite, increased dosing frequency may be needed)
    3. Unsafe (avoid)
      1. Codeine
      2. Methadone
  4. References
    1. Johnson (2007) Opioid Safety in Patients With Renal or Hepatic Dysfunction, Pain Treatment Topics
      1. http://paincommunity.org/blog/wp-content/uploads/Opioids-Renal-Hepatic-Dysfunction.pdf

V. Pharmacology: Mechanism

  1. Opiate receptor Agonists in-vivo are triggered by stress and pain
    1. Opium derivatives (e.g. Morphine) and synthetics mimic endogenous Opioid-like agents
      1. CNS Opiate receptor binding results in analgesia and euphoria
      2. Receptor types include mu, kappa and delta receptors
    2. Endogenous Opioid-like agents
      1. Endorphins
      2. Enkephalins
      3. Dynorphins
    3. Endogenous Opioids are synthesized from Protein precursors
      1. Pro-opiomelanocortin (POMC, also a precursor for ACTH and Melanocyte Stimulating Hormone)
      2. Proenkephalin
      3. Prodynorphin
  2. Opiate receptors are concentrated in the periqueductal gray matter (as well as other CNS regions)
  3. Opioids bind Neuron membrane receptors
    1. Calcium (2+) channels close (blocks Calcium entry into cell)
    2. Potassium (1+) channels open (allows Potassium to leave cell)
    3. Intracellular cAMP also decreases
  4. Cells become hyperpolarized
    1. Charge difference increases between intracellular and extracellular fluid
    2. Decreases likelihood of Neuron activation (firing) in response to a given Action Potential
  5. Sensory Neurons decrease activity
    1. Results in fewer afferent, sensory signals returning to CNS
    2. Pain Sensation is therefore reduced
  6. Overall Opiate Receptor Agonist Effects
    1. Analgesia
    2. Sedation
    3. Respiratory depression
    4. Gastrointestinal side effects (Nausea, Vomiting, ileus, Constipation)
    5. Miosis
    6. Antidiuretic Hormone release

VI. Approach: Quantity Prescribed

  1. See Opioid Prescribing Quantity

VII. Precautions: General

  1. Informed Consent for Opioid Prescription
    1. See Opioid Prescription in Acute Pain
  2. Pregnancy
    1. Neural Tube Defects if Opioids used in early pregnancy
    2. Newborn Opioid Withdrawal (neonatal abstinence syndrome) if maternal Chronic Opioid use
    3. No evidence of Tramadol safety
    4. Buprenorphine (without Naloxone) or Methadone may be used for pregnant women with Opioid Use Disorder
    5. (2017) Presc Lett 24(11): 64
    6. (2017) Obstet Gynecol 130(2):e81-e94 +PMID:28742676 [PubMed]
    7. Reddy (2017) Obstet Gynecol 130(1):10-28 +PMID:28594753 [PubMed]
  3. Respiratory Depression
    1. Exercise caution in comorbid COPD, Obstructive Sleep Apnea and other respiratory disorders
    2. Avoid in combination with CNS Depressants (e.g. Benzodiazepines, Z-Drugs)

VIII. Precautions: Ineffective Oral Opioids (Not recommended)

  1. Darvocet N-100 (Acetaminophen 650, Propoxyphene 100)
    1. Dose: 1 PO q4-6 hours
    2. Not available in U.S. as of 2007-2010
    3. Not recommended due to low efficacy and toxicity risk
  2. Tylenol #3 (Acetaminophen 300, Codeine 30)
    1. Dose: 1-2 PO q4-6 hours
    2. Avoid due to low efficacy and increased toxicity risk

IX. Precautions: Metabolism and Drug Interactions

  1. Severe liver disease (Cirrhosis)
    1. Fentanyl is preferred (Pharmacokinetics are not significantly affected)
    2. Consider oral Opioid dose reduction to 50% and increasing dosing frequency (due to decreased first pass metabolism)
    3. Avoid Morphine (increased Bioavailability and decreased clearance)
  2. Renal Failure (or Chronic Kidney Disease 4 or 5)
    1. Fentanyl is preferred
      1. However, respiratory depression may occur with severe Uremia (reduced dose is recommended)
    2. Avoid Morphine (risk of metabolite accumulation)
  3. Elderly
    1. Increased adverse effect risk (altered Pharmacokinetics, Polypharmacy, Fall Risk)
    2. Fewer Analgesic alternatives (avoid NSAIDS)
    3. Avoid Tramadol
    4. Start oral Opioids at 25 to 50% of normal dose
  4. Serotonin Syndrome
    1. Risk with serotonergic Opioids (e.g. Tramadol, Fentanyl, Meperidine, Methadone)
    2. Avoid combining with other serotonergic agents (e.g. SSRIs)
  5. Variable metabolism of oral Opioids
    1. Most oral Opioids are metabolized to active form (e.g. Morphine) by Cytochrome P450 2D6 (CYP2D6)
      1. Codeine
      2. Tramadol (Ultram)
      3. Hydrocodone
      4. Oxycodone
    2. Ultrarapid CYP2D6 Metabolizers
      1. Accounts for 10% of caucasians (may be as high as 30% in some races)
      2. Risk of a rapid conversion to toxic levels of active Opioid (e.g., Morphine)
    3. Slow CYP2D6 Metabolizers
      1. Accounts for 10% of caucasians (or 3% of other races)
      2. Renders the oral Opioids less effective in slow metabolizing patients
    4. CYP3A4 Inhibitors (e.g. Itraconazole, Ritonavir)
      1. May increase levels of Hydrocodone, Oxycodone, Fentanyl
  6. References
    1. (2024) Presc Lett 31(6): 35
    2. (2012) Presc Lett 19(6): 33
    3. Crews (2012) Clin Pharmacol Ther 91:321-6 [PubMed]

X. Precautions: Iatrogenic Opioid Overdose prevention

  1. Avoid repeat intramuscular Opioid injection
    1. Risk of dose stacking and secondary CNS/Respiratory depression (esp. Dilaudid)
  2. Titrate dosing to pain while exercising caution in the elderly and Opioid naive
    1. See Dilaudid below for specific precautions
    2. Decrease dose to 50% in the elderly, hepatic insufficiency, Renal Insufficiency
  3. Opioid tolerant patients may still experience respiratory depression on typical Opioid doses
  4. Exercise caution when combining CNS Depressants (e.g. Opioids and Benzodiazepines)
  5. Long-acting Opioids for non-cancer Chronic Pain are associated with significantly increased mortality
    1. Ray (2016) JAMA 215(22): 215-23 [PubMed]
  6. References
    1. Beaudoin (2015) Ann Emerg Med 65(4): 4243-31 [PubMed]

XI. Medications: Acute pain IV Opioids (equivalent to Demerol 50 mg IV)

  1. Fentanyl 50 mcg IV (25 mcg IV in elderly)
    1. Preferred agent in Renal Insufficiency
    2. Onset <1 minute
    3. Peaks 2 to 5 minutes
    4. Duration 30 to 60 minutes
  2. Morphine 4 mg IV (2 mg IV in elderly)
    1. Onset 1 to 2 minutes
    2. Peaks 3 to 5 minutes
    3. Duration 1 to 2 hours
  3. Hydromorphone (Dilaudid)
    1. Onset 5 to 15 minutes
    2. Peaks 10 to 20 minutes
    3. Duration 2 to 4 hours
    4. Moderate pain: 0.5 mg IV
      1. Start with 0.2 to 0.3 mg IV in the elderly or Opioid naive
      2. May repeat every 15 to 30 minutes up to 3 doses in the emergency department
        1. Spread interval to every 2-3 hours on the hospital ward
    5. Opioid tolerant or severe pain: Start with 1 mg IV
    6. Dilaudid triggers greater euphoria than Fentanyl or Morphine (higher risk of drug seeking and abuse)
    7. Dilaudid is a high potency Opioid (1 mg is equivalent to up to 10 mg Morphine)
      1. Most iatrogenic Opioid Overdoses have occurred with Hydromorphone (Dilaudid)

XII. Medications: Oral Opioids by strength

  1. Weak Opioids (WHO Step 2)
    1. Vicodin (Hydrocodone 5, Acetaminophen 500)
      1. Dose: 1-2 PO q4-6 hours
      2. Hydrocodone 10 mg equivalent to Codeine 60-80 mg
    2. Vicoprofen (Hydrocodone 7.5, Ibuprofen 200)
      1. Dose: 1-2 PO q4-6 hours
    3. Tramadol (Ultram)
      1. Dose: 50-100 mg PO q4-6 hours
      2. Tramadol 50 mg equivalent to Codeine 60 mg
      3. Higher cost, but less effective than other Opioids
      4. Metabolized by 2D6 and risk of respiratory depression in ultrarapid metabolizers
      5. Inferior to Vicodin for analgesia
        1. Turturro (1998) Ann Emerg Med 32:139-143 [PubMed]
  2. Strong Opioids (WHO Step 3)
    1. Oxycodone
      1. Adults (and over age 12 years) 5-10 mg every 4-6 hours as needed
      2. Child: 0.05 to 0.3 mg/kg/dose (up to 10 mg) every 4-6 hours as needed
    2. Percocet (Acetaminophen 325, Oxycodone 5)
      1. Dose: 1 PO q6 hours (adults)
    3. Hydromorphone (Dilaudid)
      1. Dose: 2 mg orally every 4-6 hours
    4. Morphine Sulfate (MSIR, MS Contin)
      1. Fast Release: 15 to 30 mg orally every 4 hours
      2. Sustained Release (MS Contin): 30 mg orally every 8-12 hours
    5. Fentanyl Lollipop (100 ug, 200 ug, 300 ug, 400 ug)
      1. Dose: 5 to 15 ug/kg (maximum 400 ug)
    6. Methadone (Dolophine)
      1. Dose: 15 to 60 mg orally every 6 to 8 hours

XIII. Medications: Oral Opioids by duration

  1. Short acting Opioids
    1. Codeine (not recommended)
      1. Onset 30 to 60 minutes
      2. Duration 4 to 6 hours
    2. Tramadol (not recommended)
      1. Onset 1 hour
      2. Duration 4 to 6 hours
    3. Hydrocodone (e.g. Vicodin orally every 6 hours)
      1. Onset 30 to 60 minutes
      2. Duration 4 to 6 hours
    4. Oxycodone IR (e.g. Percocet orally every 6 hours)
      1. Onset 10 to 15 minutes
      2. Duration 3 to 6 hours
    5. Morphine Sulfate IR (e.g. MSIR 10 mg orally every 4 hours)
      1. Onset 30 minutes
      2. Peaks 1 hour
      3. Duration 3 to 5 hours
    6. Hydromorphone (e.g. 4 mg orally every 4 hours)
      1. Onset 15 to 30 minutes
      2. Peaks 30 to 60 minutes
      3. Duration 3 to 4 hours
  2. Long acting Opioids
    1. Methadone 20 mg oral every 8 hours
    2. Morphine Sulfate
      1. Controlled release (MS Contin) 30 mg PO q12 hours
      2. Sustained release (Oramorph) PO q8-12 hours
      3. Sustained release (Kadian) PO q12-24 hours
      4. Extended release (Avinza) PO q24 hours
    3. Oxycodone SR (Oxycontin) 20 mg PO every 12 hours

XIV. Medications: MME - Morphine Equivalent Opioid Doses

  1. See Morphine Milligram Equivalent

XV. Medications: Transdermal Opioid

  1. Fentanyl (Duragesic) Patch
    1. Dose: 25 to 100 mcg/hour patch q72 hours
    2. Fentanyl 50 mcg/hour equivalent Morphine IV 25 mg/day

XVI. Medications: Transmucosal Opioid

  1. Precaution
    1. Indicated for breakthrough Cancer Pain in those using >60 mg/day of Morphine or equivalent
  2. Fentanyl
    1. Sublingual tab (Abstral) 100 mcg
    2. Sublingual spray (Subsys) 100 mcg
    3. Nasal spray (Lazanda) 100 mcg

XVII. Medications: Rectal Opioids

  1. General
    1. Do not use lubricant to insert (decreased absorption)
  2. Morphine suppository or tablet 10 to 30 mg rectally every 4 hours
  3. MS Contin 30 mg rectally every 12 hours
    1. Available preparations: 15, 30, 60, 100, 200 mg

XVIII. Medications: By origin (natural Opiates, semi-sythetic and synthetic Opioids)

  1. Naturally occurring Opiates (opium poppy derivatives, subset of Opioids)
    1. Morphine
    2. Codeine
    3. Heroin (Morphine metabolite)
  2. Semi-synthetic Opioids (structurally similar to Opiates)
    1. Hydrocodone
    2. Oxycodone
    3. Hydromorphone
    4. Oxymorphone
  3. Synthetic Opioids
    1. Methadone
    2. Buprenorphine
    3. Meperidine
    4. Fentanyl
    5. Tramadol

XIX. Medications: Opioid Abuse deterrents (e.g. Tamper resistant)

  1. Precautions
    1. Abuse deterrents are inconsistent among products
      1. Long-acting Hydrocodone (Zohydro) is not tamper resistant
    2. Abuse deterrents are not shown to reduce abuse
      1. abuse deterrent may simply offset abuse to other substances (e.g. Heroin)
    3. Abuse deterrents increase Opioid costs up to four fold
  2. Agents with abuse deterrents
    1. Opioids with abuse Antagonists
      1. Buprenorphine with Naloxone (Suboxone, Zubsolv)
    2. Opioids with tamper resistance (e.g. break into clumps when crushed or thick gel when wet)
      1. Long-Acting Oxycodone (Oxycontin)
      2. Extended Release Hydromorphone (Exalgo)
    3. Implantable Opioids
      1. Buprenorphine implant (Probiphine)
  3. References
    1. (2014) Presc Lett 21(5): 28

XX. Medications: Adjunctive

  1. Alternative non-Opioids
    1. See Chronic Pain Management
    2. Acetaminophen (Tylenol)
    3. NSAIDs
    4. COX-2 Inhibitors
    5. Ketamine
  2. Stool Softeners or Laxatives
    1. See Bowel Regimen in Chronic Narcotic Use

XXI. References

  1. Dachs (2003) AAFP Board Review, Seattle
  2. Hipskind and Kamboj (2016) Crit Dec Emerg Med 30(10): 15-23
  3. Velasco and Kiel (2023) Crit Dec Emerg Med 37(1): 4-9
  4. (2000) Tarascon Pocket Pharmacopoeia
  5. (2000) Med Lett Drugs Ther 42(1085):73-8 [PubMed]

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