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Created February 8, 2021, last updated almost 4 years ago.
Collection: 139, Score: 1102, Trend score: 0, Read count: 1523, Articles count: 7, Created: 2021-02-08 10:14:09 UTC. Updated: 2021-02-09 02:57:46 UTC.Notes
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.
Daniel Jolley
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Collected Articles
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Tramadol, a centrally acting analgesic structurally related to codeine and morphine, consists of two enantiomers, both of which contribute to analgesic activity via different mechanisms. (+)-Tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the mu opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake, enhancing inhibitory effects on pain transmission in the spinal cord. The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate. Tramadol is available as drops, capsules and sustained-release formulations for oral use, suppositories for rectal use and solution for intramuscular, intravenous and subcutaneous injection. ⋯ Tramadol may prove particularly useful in patients with a risk of poor cardiopulmonary function, after surgery of the thorax or upper abdomen and when non-opioid analgesics are contraindicated. Tramadol is an effective and well tolerated agent to reduce pain resulting from trauma, renal or biliary colic and labour, and also for the management of chronic pain of malignant or nonmalignant origin, particularly neuropathic pain. Tramadol appears to produce less constipation and dependence than equianalgesic doses of strong opioids.
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Anesthesia and analgesia · Jan 2017
ReviewTrends in Tramadol: Pharmacology, Metabolism, and Misuse.
Tramadol is a unique analgesic medication, available in variety of formulations, with both monoaminergic reuptake inhibitory and opioid receptor agonist activity increasingly prescribed worldwide as an alternative for high-affinity opioid medication in the treatment of acute and chronic pain. It is a prodrug that is metabolized by cytochrome P450 (CYP) enzymes CYP2D6 and CYP3A4 to its more potent opioid analgesic metabolites, particularly the O-demethylation product M1. The opioid analgesic potency of a given dose of tramadol is influenced by an individual's CYP genetics, with poor metabolizers experiencing little conversion to the active M1 opioid metabolite and individuals with a high metabolic profile, or ultra-metabolizers, experiencing the greatest opioid analgesic effects. ⋯ Tramadol's simultaneous opioid agonist action and serotonin (5-HT) and norepinephrine reuptake inhibitory effects result in a unique side effect profile and important drug interactions that must be considered. Abrupt cessation of tramadol increases the risk for both opioid and serotonin-norepinephrine reuptake inhibitor withdrawal syndromes. This review provides updated important information on the pharmacology, pharmacokinetics, CYP genetic polymorphisms, drug interactions, toxicity, withdrawal, and illicit use of tramadol.
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Serotonin syndrome is a mild to potentially life-threatening syndrome associated with excessive serotonergic activity within the central nervous system. Serotonin syndrome is associated with medication use, drug interactions, and overdose. While serotonin syndrome is often associated with the use of selective serotonin inhibitors (SSRI), an increasing number of reports are being presented involving the use of tramadol. ⋯ In conclusion, with the increasing incidence of serotonin syndrome, prescribing physicians should be aware of and educate their patients on the potential side effects of tramadol. It is important that the prescribing physician reviews patient medications for concurrent serotonergic drugs and monitors for potential abuse.
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Tramadol is commonly prescribed for pain control because it presents a lower risk for addiction and respiratory depression compared to other opioids. However, tramadol's serotonin and norepinephrine reuptake inhibitory effects result in a unique adverse effect profile. Two such adverse events are serotonin syndrome and seizures. ⋯ Serotonin syndrome and seizures can be effectively treated by administering benzodiazepines, providing supportive care, and discontinuing tramadol and other contributing agents. Cyproheptadine should be administered in moderate to severe cases of serotonin syndrome. Our objective is to summarize the literature on the pharmacology, epidemiology, risk factors, clinical presentations, and evidence-based management of tramadol-related seizures and serotonin syndrome.
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Tramadol-an atypical opioid analgesic-has a unique pharmacokinetic and pharmacodynamic profile, with opioidergic, noradrenergic, and serotonergic actions. Tramadol has long been used as a well-tolerated alternative to other drugs in moderate pain because of its opioidergic and monoaminergic activities. However, cumulative evidence has been gathered over the last few years that supports other likely mechanisms and uses of tramadol in pain management. ⋯ Given the broad spectrum of molecular targets, tramadol as a unimodal analgesic relieves a broad range of pain types, such as postoperative, low back, and neuropathic pain and that associated with labor, osteoarthritis, fibromyalgia, and cancer. Moreover, tramadol has anxiolytic, antidepressant, and anti-shivering activities that could improve pain management outcomes. The aim of this review was to address these issues in the context of maladaptive physiological and psychological processes that are associated with different pain types.
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There is a warning associated with all serotonergic antidepressants and its concomitant use with tramadol due to the concern for a drug-drug interaction resulting in serotonin syndrome (SS). The prescribing of antidepressants with tramadol may be unnecessarily restricted due to fear of causing this syndrome. ⋯ Review of the available case reports of tramadol combined with antidepressant drugs in therapeutic doses indicates caution in regard to the potential for SS but does not constitute a contraindication to their use. Tramadol is only contraindicated in combination with MAOIs but not other antidepressants in common use today. These case reports do suggest several factors associated with a greater risk of SS, including increased age, higher dosages, and use of concomitant potent cytochrome P450 2D6 inhibitors. Tramadol can be safely combined with antidepressants; however, monitoring and counseling patients are prudent when starting a new serotonergic agent or when doses are increased.
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Review Meta Analysis
The effect of ondansetron on the efficacy of postoperative tramadol: a systematic review and meta-analysis of a drug interaction.
It is likely that there is an interaction between tramadol and ondansetron that decreases the early-postoperative analgesic efficacy of tramadol.
pearl