Knowledge
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Tramadol is a synthetic opioid agonist and neurotransmitter-modulating analgesic.
A. Physiochemistry
- Synthetic analgesic of 'amino-cyclo-hexanol' group.
- Racemic mixture of two enantiomers + and -:
- (-) Inhibits NAd reuptake
- (+) Enhances 5HT release, inhibits 5HT reuptake, weak mu (& less kapaa/delta) agonist.
- Oral (50 mg capsules, 100 mg tablets) & parenteral (100 mg/2mL) preparations.
- pKa 9.4
B. Pharmacokinetics
- Dose - 5-10x less potent than morphine: 50-100 mg q6h, max 400-600 mg/day.
- 2-3 mg/kg loading, then 1-2 mg/kg q6h.
- PCA IV tramadol: 20 mg/mL then step down to oral (Prof Schug, Perth: 25-50 mg q1h PCA, using up to 1500 mg/24h).
- analgesic efficacy and potency comparable to pethidine
- Caudal: 2 mg/kg
- Absorption - IV, IM, po (80% biov)
- Distribution - 3 L/kg (80% crosses placenta).
- Protein binding - 20%
- Onset 30 min; Offset 6 h
- peak [plasma] after po: 2h
- Metabolism - t½ 6h (12h in renal impairment);
- 85% p450 (CYP-2D6 - also converts codeine → morphine & metabolises ondansetron!)
- Demethylation to 'O-demethyl-tramadol' (M1) t½ 9h - has some activity as it has 6x greater mu affinity than tramadol. Some consider tramadol a prodrug because of this.
- 90% excreted in urine, 10% in faecies.
- metabolism inhibited by quinidine
- Clearance - 9 mL/kg/min
C. Pharmacodynamics
- Mech - weak mu agonists (30% of action) (very weak kappa & delta); inhibits NAd reuptake (through indirect activation of post-synaptic alpha-2 adrenoreceptors) and stimulates 5HT release, so activates desc NAd and 5HT pathways (70%), modulating pain pathways.
- Naloxone antagonises only 30% tramadol analgesic effect. Ondansetron antagonises a further 30% of tramadol analgesic effect.
- CNS - analgesia, good for neuropathic pain, low(er) incidence of tolerance & dependence, lowers seizure threshold, dizziness, sweating.
- stops shivering?
- CVS - few CVS effects. Some tachycardia and flushing.
- Resp - little respiratory depression.
- Renal - caution in renal failure.
- GIT - Nausea & vomiting (30-40%, like morphine), minimal constipation, minimal biliary spasm.
- SEs - interacts with MAOI, SSRIs.
- Quinidine may decrease efficacy of tramadol by inhibiting CYP-2D6, thus decreasing production of M1. Codeine my compete for the same enzyme with a similar result.
- Carbamazepine induces CYP-2D6 decreasing effect by increasing metabolism.
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Sugammadex is pharmacologically great. A modified γ-cyclodextrin Selective Relaxant Binding Agent that reverses rocuronium muscle relaxation 10-times faster than neostigmine (see: Is sugammadex as good as we think?).
At launch, its biggest obvious disadvantage was simply the new drug's high cost. Now as sugammadex has become more widely used, sugammadex-anaphylaxis has risen as a new, prominent concern.
In Japan, where there was a uniquely rapid take-up of sugammadex, it became one of the commonest causes of anaphylaxis. Oriharia (2020) demonstrated an incidence of sugammadex anaphylaxis in Japan of 1 in 5,000 – a risk that most medically communities would consider too high for routine use of a drug with acceptable alternatives.
Given that in some regions (notably Australia & New Zeleand) rocuronium itself has a high-risk of anaphylaxis, the combination of rocuronium-sugammadex may present a greater risk than even old-school drugs such as suxamethonium.
In other countries, such as the United Kingdom, there has not been quite the same incidence of sugammadex-anaphylaxis. Is this simply because of the lower initial use than in Japan, or are there environmental and phenotypical differences as have been implicated for rocuronium anaphylaxis?
Worryingly, if the Japanese experience is representative, then for some locations the combination of rocuronium-sugammadex may in fact have a higher risk of anaphylaxis than using suxamethonium alone.
The true risk of sugammadex-anaphylaxis is still unclear for many populations. However with the looming expiry of the sugammadex patent in 2023, we will see a rapid increase in its use and subsequently reveal any latent anaphylaxis risk.
summary
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- Remifentanil infusions above 0.20-0.25 μg/kg/min are associated with hyperalgesia (OIH = Opioid Induced Hyperalgesia) and tolerance (AOT = Acute Opioid Tolerance) respectively.
- Some of these effects can be mitigated by multimodal analgesia (notably ketamine), and possibly by gradual weaning of a remifentanil infusion.
- The findings have been predominately identified in rats and volunteer human studies. The clinical and longterm significance is still uncertain.
- Although OIH and AOT arise from different physiological mechanisms, they are clinically difficult (if not impossible) to differentiate.
- The clinical priority for management is prevention.
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