3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.5. Opioids
                      3.1.3.5.3. Opioid agonists
                          3.1.3.5.3.9. Other opioid agonists
 3.1.3.5.3.9.5. Tramadol 

Tramadol

[SH4:p117; NPS.org.au PPR22 July 2003; PI on MIMS]

Usage

  • Moderate to severe pain

Structure

Synthetic, centrally acting analgesic

Racemic mixture of two enantiomers

  • (-) enantiomer inhibits NE reuptake
  • (+) enantiomer blocks 5HT reuptake, stimulation of presynaptic 5HT release, and actions at mu receptor

NB:

  • M1 (the main metabolite) is an MOP agonist

Pharmacodynamics

Mechanism of action

  • Centrally acting analgesic
  • Actions on classic opioid receptors
    * Moderate affinity to MOP receptors
    * Weak affinity to DOP and KOP receptors
  • Enhance the function of spinal descending inhibitory pathway, by
    * Inhibition neuronal reuptake of NE (norepinephrine) and 5HT (5-hydroxytryptamine, aka serotonin)
    * Stimulation of presynaptic 5HT release

Thus,

Possible complementary and synergistic actions of the two enantiomers
--> Analgesia with minimal respiratory depression, low potential for tolerance development, dependence, and abuse.

NB:

  • Naloxone only antagonises about 30% of the effect of tramadol

Relative contribution to clinical effects

Clinical effects of tramadol [MCQ:Q154][Stefan Schug lecture at ASA 2002]

  • 40% due to MOP agonism
  • 40% due to NE reuptake inhibition
  • 20% due to 5HT reuptake inhibition

Potency

  • 5-10 times less potent than morphine as an analgesic
  • 100mg of tramadol is about the same efficacy as paracetamol 1000mg + codeine 60mg
    * [NPS]

Effects

  • Analgesia
  • No significant effect on CVS
    * But orthostatic hypotension has been reported [PI]
  • Minimal respiratory depression
  • No development of tolerance or addiction [SH4; PI]
    * Tolerane, dependence, and withdrawal symptoms have been reported to the Australian Adverse Drug Reactions Advisory Committee (ADRAC) [NPS]
  • Marked decrease in postoperative shivering
  • Not associated with major organ toxicity
  • No significant sedative effect
  • Not associated with histamine release

Side-effects

  • Seizure
  • High incidence of N&V
    * At least 1 in 10
  • Slows gastric emptying
    * Mild compared to other opioids
  • Serotonin syndrome
    * More likely to occur with high doses of tramadol, TCAs, SSRIs, venlafaxine, MAOi's (including moclobemide), pethidine, St John's wort [NPS]
  • Convulsions
    * More likely with tricyclic antidepressants, SSRIs, bupropion, opioids [NPS]

Pharmacokinetics

Absorption

  • IM bioavailability = 100%

Distribution

[PI]

  • Vd = 2-3 L/kg in young adults
    --> Reduced by 25% in >75 y.o.
  • Protein-binding = 20%

Metabolism

  • Tramadol is metabolised by hepatic P450 enzymes
  • Major metabolite is O-desmethyltramadol (aka M1)
  • Other metabolic pathways include:
    * N-demethylation (catalysed by CYP3A4) --> Inactive metabolite
    * Glucuronidation or sulfation in the liver

O-desmethyltramadol (aka M1)

  • Higher affinity to MOP receptors than tramadol (200 times in animal models)
    --> Up to 6 times more potent in producing analgesia (in animal models)
  • Relative analgesia contribution of tramadol and M1 in human is unknown
  • Dependent on CYP2D6 enzyme
  • Variation in CYP2D6 enzyme could result in variable M1 formation, thus analgesia

 

Elimination

  • Tramadol and metabolites are excreted mainly by kidneys
  • In young adults, 15-19% of tramadol is excreted unchanged in urine
  • In elderly, 35% of tramadol is excreted unchanged in urine
  • Clearance = 430-610 mL/min

Action profile

In young adults,

  • Tramadol half-life = 5-7 hours
  • M1 half-life = 6-8 hours

 

Physicochemical properties

  • Readily soluble in water and methanol
  • pKa 9.41

Pharmaceutics

Presentation

  • 50mg/1mL (not available in Australia), 100mg/2mL

Formulations

  • Active
    * Tramadol hydrochloride
  • Inactive
    * Sodium acetate trihydrate
    * Water

 

Clinical

Administration

  • Tramadol 3mg/kg PO, IM, or IV
    --> Effective for moderate to severe pain
  • NPS recommendation: initiate therapy with immediate-release dosage form, and switch to modified-release formulation if tolerability is established.

Chronic pain

  • Useful for chronic pain
    * No development of tolerance or addiction
    * Not associated with major organ toxicity
    * No significant sedative effect

Drug interaction

  • Interaction with coumadin anticoagulants
    * Not all reports confirm this interaction
    * Tramadol increases effects of warfarin [NPS.org]
  • Ondansetron and other 5HT antagonists may interfere with the analgesic component of tramadol
  • Drugs which selectively inhibits CYP2D6 enzymes (quinidine, phenothiazines, antipsychotic agents)
    --> Decreased concentration of M1
    --> Decreased analgesic effect

Contraindications

Drug-related seizures

  • Avoid tramadol in patients with epilepsy
  • Avoid tramadol in patients on drugs that lower the seizure threshold (e.g. antidepressant)

Special considerations

Hepatic and renal impairment

  • Elimination of tramadol and M1 is impaired in patients with hepatic or renal impairment
    --> Half-life more than double
    * [PI]
  • Dose adjustment in renal impairment
  • Avoid in severe hepatic insufficiency

Elderly

In the elderly (over 75 y.o.)

  • Vd is decreased by 25%
  • Clearance is decreased by 40%
  • Half-life is only slightly prolonged (by 15%)

Paediatrics

  • Safety has not been established