fentanyl (Sublimaze, Subsys, Fentanyl Oralet, Actiq, Fentora, Onsolis, Abstral, Lazanda)

Introduction

Tradenames: Sublimaze, Duragesic. DEA-controlled substance: class 2.

Indications

• treatment of moderate to severe acute pain syndromes
• anesthesia related to pain control
• do not use patches for unstable or acute pain
  • for use in opioid tolerant patients

Dosage

• Intravenous (IV)
  • 2-3 ug/kg up to 50 ug, then 25 ug every 1-3 hours (higher doses may be needed in opiate tolerant patients)
  • infusion: start 20 ug/hr, titrate to effect
  • conscious sedation/adjunct to surgery:
    • 25-50 ug every 3-5 minutes, max 500 ug/4 hours higher doses used for major surgery

Injection: 0.05 mg/mL (2 mL, 5 mL, 20 mL)

Transdermal:* Tradename: Duragesic. (2 generics: Sandoz, Mylan)#

• one patch every 3 days.

Patches: 25, 50, 75 & 100 ug/hr

* reservoir for transdermal fentanyl is the skin removal of patch will NOT remove fentanyl in skin

do not cut patches, improper use may cause leakage

# Sandoz (same as Duragesic) liquid reservoir

Mylan solid reservoir

• some say Mylan generic NOT as effective as Duragesic
• FDA says both generics equivalent to Duragesic

Ionsys Works by iontophoresis

Transmucosal lollipops: Tradename: Fentanyl Oralet, Actiq.

• 5-15 ug/kg, max 400 ug.

Lollipops: 200, 300, 400 ug.

Buccal tablet: Tradename: Fentora

• Bioavailability about twice that of Actiq

Tablets: 100, 200, 400, 600, 800 mg

Buccal soluble film formulation for cancer pain: Onsolis

Sublingual: Abstral, Sublys* (spray)

Nasal spray: Lazanda 100 ug/spray

100 ug IV = 7 mg morphine IV

25 ug patch = 45-134 mg morphine PO daily

50 ug patch = 134-224 mg morphine PO daily

75 ug patch = 225-314 mg morphine PO daily

100 ug patch = 315-404 mg morphine PO daily

125. ug patch >= 405 mg morphine PO daily

Patients should be on an equivalent of at least 60 mg of oral morphine daily for at least 1 week prior to using a fentanyl patch

Pharmacokinetics

• intravenous (IV)
  • immediate onset of action
  • duration of action 30-60 minutes
  • metabolized by liver by cyt P450 3A4
  • metabolites eliminated in urine
  • short 1/2 life, less than morphine or meperidine
• oral
  • extensive first-pass metabolism
  • oral bioavailability of 33%
  • onset of action is 5-10 minutes
• transdermal
  • absorption varies with body temperature & the application of heat to the skin surface
  • onset of action is 12-24 hours
  • steady state reached in 72 hours
  • post-removal, steady state concentrations are seen for 24-48 hours
    • mean decline of 50% in 17 hours
    • skin is reservoir for drug delivery
  • reservoir is skin

elimination via liver

Adverse effects

• common (> 10%)
  • bradycardia, hypotension, respiratory depression, drowsiness, nausea/vomiting (minimal)
• less common (1-10%)
  • arrhythmias, confusion, biliary spasm, blurred vision, CNS depression, orthostatic hypotension
• uncommon (< 1%)
  • bronchospasm, circulatory depression, convulsions, pruritus, urticaria, dysesthesia, laryngospasm, depression, delirium, paradoxical CNS excitation, cold & clammy skin, dizziness, biliary spasm, urinary tract spasm
• other
  • fentanyl infusions can stimulate chest wall tightness & exacerbate respiratory failure; give prophylactic benzodiazepines
  • rash, especially with transdermal delivery
  • respiratory depression (dose & tolerance dependent), greater with IV dosing
  • dependence (physical &/or psychological)
  • constipation
  • overdose & death reported from use of transdermal patch
  • accidental exposure to fentanyl via transdermal patch, particularly by children
  • severe necrotic wounds, extending to bone, amputations with illicit fentanyl containing xylazine (veternary sedative)

Overdose:

• fentanyl detected in ~ 2/3 of opioid overdose deaths in southeastern Massachusetts Oct 2014 - March 2015
  • 82% involved illicitly manufactured fentanyl.
  • 90% without pulse when emergency medical services arrived
  • 36% with evidence overdose within seconds or minutes
  • 6% with evidence of naloxone administration by bystanders
• illicit fentanyl often contains xylazine (veternary sedative)
  • naloxone still works but some patients may respond differently
• multiple doses of naloxone may be needed to revive a patient after a fentanyl overdose

• drug adverse effects of opiates
• drug adverse effects of psychotropic agents
• drug adverse effects of sedatives

Drug interactions

• any drug that inhibits cyt P450 3A4 may increase levels of fentanyl
• any drug that induces cyt P450 3A4 may diminish levels of fentanyl
• benzodiazepines, barbiturates, alcohol in combination increase adverse CNS effects
• MAO inhibitors within 14 days are CONTRAINDICATED
  • severe & unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics
  • fatal reactions have occurred
• naloxone is a direct opiate antagonist
• scorpion venom in combination increases the toxic effects of the venom

• drug interaction(s) of benzodiazepine with opiates
• drug interaction(s) of Z-drugs with opiates
• drug interaction(s) of alcoholic beverage with opiates
• drug interaction(s) of pregabalin with opiates
• drug interaction(s) of gabapentin with opiates

Laboratory

• fentanyl in specimen
  • fentanyl in body fluid
    • fentanyl in gastric fluid
    • fentanyl in saliva
    • fentanyl in serum/plasma/blood
      • fentanyl in blood
      • fentanyl in serum/plasma
    • fentanyl in urine

Mechanism of action

• opiate agonist
• phenenylpiperidine derivative
• alters perception to pain at the level of the spinal cord & higher levels of the CNS
• alters emotional response to pain
• causes less of an increase in biliary tract pressure than morphine

Comparative biology

• a vaccine has been developed that blocks the euphoric effects of fentanyl in rats

Notes

• only 1/2 of Subsys prescriptions (sublingual spray) marketed for treatment of breakthrough cancer pain are written by oncologists
  • general practice physicians, neurologists & even dentists & podiatrists account for almost 1/2 theprescriptions

More general terms

• opiate
• opioid receptor agonist (narcotic)

More specific terms

• acetylfentanyl
• fentanyl topical; fentanyl transdermal (Duragesic, Ionsys)
• para-fluorofentanyl

Additional terms

• cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

Component of

• bupivacaine/epinephrine/fentanyl
• fentanyl/ropivacaine
• droperidol/fentanyl
• bupivacaine/fentanyl

Patient information

fentanyl overdose patient information

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3345
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=13819