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Tramadol is a synthetic racemate: the (+) enantiomer is a prodrug of a weak opioid (CYP-2D6 converts tramadol to O -desmethyl tramadol - 'M1', the only active metabolite), while the (-) enantiomer increases synaptic noradrenaline and serotonin levels by inhibiting their reuptake and promoting release (through autoreceptor activation), tramadol vs vikaden. Major effects are probably via modulation of descending pain pathways, . Tramadol was synthesised in 1962, and became available in Germany in 1977. Here, we look at its usage, , pharmacokinetics, side-effects and merits, . 1. Usage The drug is an excellent agent for moderate to severe pain, in adults and children, tramadol vs vikaden. Recommended dosage in adults parenterally (IM or slowly IV over 2-3min, , or PCA) is a 100mg bolus, then 50mg every 10-20min, , with a maximum total dose 250mg; then 50-100mg 4-6 hourly to a maximum of 600mg/day. Clearly adjust PCA appropriately, perhaps 20mg boluses with 5 min lockout, . Per os, the adult dosage is 50 - 100 mg q 4-6hr as required, , maximum 400mg/day. (For chronic pain, fewer side-effects may be seen starting gradually, with lower doses). In children, tramadol vs vikaden, the dosage recommended is an initial 1-2mg/kg (Germany). Efficacy is excellent. Parenterally, analgesic efficacy similar to that of morphine (or ketorolac), tramadol vs vikaden, based on good visual analogue score (VAS) -based randomised, double blind, tramadol vs vikaden, controlled studies in adults (with dose titration to response) summarised in Table V of Scott & Perry. In IV PCA studies, the drug is likewise similar to morphine (Scott & Perry, , Table VI), tramadol vs vikaden. There is synergy with paracetamol, , and non-steroidal anti-inflammatories. There seems to be no point in giving continuous infusions, (30% more drug required). Even this silliness appears not to be associated with more adverse events, . In children 1yr of age, but not in USA (< 16 yr age) or UK (< 12 yr). Pharmacokinetics in children over 1 year of age appear similar to those in adults. 2. Pharmacokinetics Per os : peak effect after 1-4 hr, lasts 3-6 hr; 68+% bioavailable; extensive first-pass activation and removal (by CYP, including 3A4 - induced by carbamazepine). Parenterally : V D ~260L; Excretion of tramadol (and metabolites) is renal with a t 1/2 ß tramadol vs vikaden; ~ 5.5 hr - for M1 the value is ~ 6.7+ hr. Plasma protein binding is 20%. Clearance is halved with liver or renal dysfunction. The drug is poorly dialysable. 3. Side effects, tramadol vs vikaden, interactions and cautions The major good point of tramadol is its minimal respiratory depression in therapeutic doses but you should exercise the usual caution you would with opiates, . Interactions with with monoamine-oxidase inhibitors, alcohol (acute intoxication), , hypnotics, centrally acting analgesics, opioids, and "psychotropics" (including selective serotonin reuptake inhibitors) preclude its use with such agents, . It should also not be used in epileptic patients. Potential problems include CYP 2D6 deficiency, , which may have clinical consequences (about 30% of analgesia is from M1 metabolite); tramadol vs vikaden; it may be more effective in extensive metabolisers (nobody appears to have looked at respiratory depression in this subgroup), ! Interactions occur with carbamazepine or cimetidine (3A4 effect), and quinidine, fluoxetine or amitriptyline (2D6), but the clinical relevance of all of these is unclear. Interactions might possibly occur with coumarin anticoagulants (unlikely; this may be attributable to concomitant paracetamol administration)!! Watch for rare digoxin toxicity (??). Side Effects include nausea & vomiting (6% and ~2% respectively; more common with parenteral administration), dizziness, drowsiness, tramadol vs vikaden, sweating. Nothing suggests a different tolerability profile in children, but this has not been extensively and specifically studied. Intra-operative awareness has been reported, but it would seem that the anaesthesia administered with the drug in these early reports was inadequate, . Overdose is uncommon and abuse potential low , tramadol vs vikaden. Features of overdose are what one would expect (sedation, nausea, vomiting) but importantly, overdose may result in seizures. Seizures do not appear to occur with usual doses (in the absence of drug interactions or underlying epilepsy). Tramadol crosses the placenta , but appears safe in labour without neonatal respiratory depression. There is no evidence at present for teratogenicity, but the usual cautions apply. A tiny amount enters breast milk (0.1%). Tramadol appears contra-indicated in porphyria. 4. Benefits of Tramadol
It is an effective analgesic.
No significant respiratory depression occurs (in adults OR children) at recommended doses - IV /kg is similar to placebo; 1 or 2mg/kg caused substantially less respiratory depression in 88 children (2 - 10 yr) than did pethidine 1mg/kg - respiratory rate decreased by 7-12/min versus pethidine 31/min and placebo 2/min, , with NO prolonged apnoea in the tramadol group. 90% of the pethidine group (versus 14 & 23% of the tramadol groups and 14% of placebo) needed manual ventilatory support. [Bosenberg AT & Ratcliffe S Anaesthesia 1998 Oct 53 960-4]
Tramadol appears to be antitussive.
There is no clinically significant effect on heart rate or blood pressure have been recorded (adults or children). There is no relevant effect on GIT function (apart from the relatively infrequent side effects of nausea and occasional vomiting).
Tramadol reduces post-operative shivering. (Interestingly, the sweating threshold is decreased by tramadol, in contrast to other opioids; but like other opioids it lowers the vasoconstriction threshold and shivering threshold).
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