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