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