Analgesic

Tramadol

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Tramadol, Ultram

  • Background
  1. Developed in Germany in 1962 and later released there in 1977
  2. Released in the U.S. in 1995
  • Indications
  1. Opioid Analgesic for moderately severe acute or Chronic Pain not relieved with other measures
    1. When Opioids are indicated, other Opioids are preferred over Tramadol
  • Mechanism
  1. Opiate Analgesic (Codeine analog)
  2. Weak mu-receptor binding, inhibiting ascending pain signals and blunting pain response
  3. Tramadol is a racemic mix of two active stereo isomers
    1. Theoretically, these isomers should provide a combination of an SNRI (e.g. Duloxetine) and an Opioid
    2. One Isomer
      1. CNS Mu-Opioid receptor agonist that is very weak
      2. Its metabolite, +O-desmethyltramadol (O-DSMT), is a potent Mu Opioid agonist
        1. O-DSMT requires CYP2D6 to be created
      3. Inhibits Serotonin reuptake
    3. Other isomer
      1. Active without metabolism
      2. Inhibits Norepinephrine reuptake
  4. However, the two isomers (one requiring metabolism by CYP2D6) results in highly variable patient effects
    1. Similar variable effects as seen with Codeine (which lead to its demise as an Analgesic)
    2. A subset of patients, with normal CYP2D6 activity, will have good analgesia
    3. Patients with decreased CYP2D6 will have poor Analgesic effect
    4. Patients with high CYP2D6 activity, will have more potent effects, and potential for toxicity
  5. Marketed as having low abuse and addiction potential
    1. However, tolerance, withdrawal and Drug Seeking Behavior also occur with Tramadol
    2. Desmethyltramadol (O-DSMT), is a Mu Opioid agonist, and Tramadol is regulated as an Opioid Analgesic
  • Contraindications
  1. See Drug Interactions below
  2. See Safety for pregnancy and Lactation precautions
  3. Seizure Disorder or increased Seizure risk factors
  4. Acute Intoxication (Alcohol, hypnotics, Opioids or psychotropic agents)
  5. All children under age 12 years old
  6. Children ages 12 to 18 years old with additional risks
    1. Tonsillectomy or adenoidectomy
    2. Obesity
    3. Sleep Apnea
  7. References
    1. FDA Drug Safety Communication (4-20-2017)
      1. https://www.fda.gov/Drugs/DrugSafety/ucm549679.htm
  • Safety
  1. Avoid in children under age 12 years
  2. Breastfeeding women
    1. Excreted in Breast Milk with risk of infant sedation
  3. Pregnancy
    1. Consider Class C Drug
    2. Risk of newborn Opioid dependency (as well as neonatal abstinence syndrome)
  • Precautions
  1. As of 2020, Tramadol has 8 black-box warnings
  2. Weak Analgesic, with abuse potential, variable effect and risk of death in ultrarapid CYP2D6 metabolizers
  3. Other agents are preferred: NSAIDs, Acetaminophen, short acting Morphine, Hydrocodone, Oxycodone
  4. Binds Serotonin (and Norepinephrine) receptors with risk of Serotonin Syndrome
  5. Overdose risk
    1. Overdoses present with Seizure, Altered Mental Status, apnea, coma and Miosis
    2. Variable metabolism with an unpredictable dose response in Overdose
      1. CYP2D6 metabolizes Tramadol to desmethyltramadol (a mu-receptor agonist)
      2. CYP2D6 activity varies widely from person to person
  • Classification
  1. Reclassified as FDA Schedule IV Opioid (US, August 2014)
  • Efficacy
  • Relatively weak Opioid
  1. One-thirtieth the potency of Morphine (very weak mu receptor agonist)
  2. Equivalent effect to Tylenol with codeine (Tylenol #3) or Ibuprofen
  3. Less effective than Hydrocodone with Acetaminophen (Vicodin 5/500)
    1. Turturro (1998) Ann Emerg Med 32(2): 139-43 [PubMed]
  • Dosing
  • Immediate Release
  1. Starting dose: 50 mg every 6 hours
  2. Usual dose: 50-100 mg every 4-6 hours
  3. Maximum dose per day
    1. Healthy patient: 400 mg/day
    2. Over age 75 years: 300 mg/day
    3. Renal Insufficiency or on Dialysis (Creatinine Clearance <30 ml/min)
      1. Reduce dosing frequency to every 12 hours
      2. Do not exceed 200 mg per day
  • Dosing
  • Extended Release
  1. Starting Dose: 100 mg orally daily
  2. Range: 100-300 mg orally daily
  3. Maximum: 300 mg/day
  • Disadvantages
  1. More expensive and lower efficacy than other Opioids
  2. SNRI properties with risk of Serotonin Syndrome when combined with other agents (see below)
    1. However, lacks the evidence for neuropathic pain management seen with other SNRIs
  3. Risk of abuse and is Schedule 4 FDA Controlled substance, similar to Hydrocodone as of 2014
    1. Tramadol Overdose has been associated with deaths (especially when combined with Alcohol)
  4. Overdose only partially reversed by Naloxone
    1. Naloxone may also increase risk of Seizures in Overdose
  5. References
    1. Orman and Hayes in Herbert (2016) EM:Rap 16(2): 1-2
    2. (2019) Presc Lett 26(8): 44
  • Adverse Effects
  1. Most common
    1. Nausea (16-40%) or Vomiting (5-17%)
    2. Constipation (9-46%)
    3. Somnolence or drowsiness (7-25%)
    4. Dizziness or Vertigo (33%)
    5. Headache (12-32%)
    6. Xerostomia (5-13%)
    7. Dyspepsia (1-13%)
    8. Neuromuscular weakness (<12%)
  2. Serious adverse effects
    1. Serotonin Syndrome
      1. Avoid use with other serotonergic medications within prior 2 weeks (e.g. SSRI, SNRI, MAO inhibitors)
    2. Seizures
      1. Tramadol lowers the Seizure threshold
      2. Seizure may also occur with tramadol Overdose
      3. Higher risk with other agents that lower Seizure threshold or delay hepatic metabolism
    3. Anaphylactoid reaction
    4. Abuse potential
    5. Hyponatremia
    6. Hypotension
    7. Hypoglycemia
      1. Uncommon (<1 per 1000 per year)
      2. Typically occurs in first 10 days of starting
      3. Fournier (2015) JAMA Intern Med 175(2):186-93 +PMID:25485799 [PubMed]
    8. Respiratory Depression in Children
      1. Seen with Ultrafast CYP2D6 metabolizers
      2. Avoid Tramadol use in children
      3. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm463499.htm
  • Drug Interactions
  1. CYP 2D6 Inhibitors
    1. Block metabolism of Tramadol to active ingredient
      1. Increased adverse effects and decreased efficacy when used in combination with Tramadol
      2. Unique to Tramadol (other Opioids do not have some interaction)
    2. Paroxetine (Paxil)
    3. Fluoxetine (Prozac)
  2. Opioids
    1. Avoid use with other Opiates (no benefit)
  3. Serotonin Syndrome (try to avoid combination with other serotonergic agents)
    1. MAO inhibitors (absolute contraindication)
    2. Linezolid (Zyvox)
    3. Selective Serotonin Reuptake Inhibitors (SSRI)
    4. Serotonin Norepinephrine Reuptake Inhibitors (SNRI)
    5. Tricyclic Antidepressants
  4. Seizures
    1. Opioids
    2. Bupropion
    3. Selective Serotonin Reuptake Inhibitors (SSRI)
    4. Tricyclic Antidepressants
    5. Antipsychotic Medications
  5. Warfarin
    1. Tramadol may increase INR
    2. Recheck INR three days after starting Tramadol
  6. References
    1. (2012) Presc Lett 19(3): 17 [PubMed]
  • Resources
  1. Tox and the Hound: Tramadont
    1. https://toxandhound.com/toxhound/tramadont/
  • References
  1. LoVecchio (2019) Crit Dec Emerg Med 33(9): 32
  2. Henderson and Malashock (2016) Crit Dec Emerg Med 30(10): 28
  3. Mason and Armenian in Herbert (2019) EM:Rap 19(10): 3-4