Tramadol - damned with faint praise?

Journals Reviewed: A miscellany, including BJA 2000 Vol 84(3)!
Abstracted by: Dr K. Tang MB BCh (Registrar, University of the Witwatersrand)

Summary of abstracts

Tramadol has been around for ages. One is tempted to ask the question "Why is it not used more often?" Here we look at a couple of minor articles on its caudal use and its effect on immunity, and two substantial reviews of the agent. You may also wish to briefly browse our editorial comment.

Pharmacokinetics of tramadol in children after intravenous (IV) or caudal epidural administration

Tramadol 2mg/kg was injected either IV or into the caudal space in 14 ASA I and II children, aged 1-12 yr, undergoing elective limb, urogential or thoracic surgery. Serum concentrations of tramadol and its (M1) metabolite were measured at intervals for up to 20 hrs.

Results: The median age of children in the IV group was 2,42 yr (range 1,2-6,6 yr), which was significantly different from that in the caudal group, who had a median age of 6,0 yr (range 5,5 - 12 yr). Pharmacokinetic variables were similar to those reported in adults. There is extensive systemic absorption of tramadol after caudal administration. Serum [M1] showed a time course typical of a metabolite after both modes of administration, but concentrations were lower in the caudal group.

Despite its tiny size and the different ages in the intravenous and caudal groups, this study suggests (as one would expect from knowledge of tramadol metabolism) that pharmacokinetic behaviour of tramadol in children over the age of one year doesn't differ substantially from that in adults. This study provides confirmatory evidence that it's silly to administer tramadol caudally!

Article 1: Pharmacokinetics of Tramadol in children after IV or caudal epidural administration
Source: BJA 84 (3) : 346-9 (2000)
Article type: Clinical study
Authors: Murthy BV, Pandya KS, Booker PD, Murray A, Lintz W, Terlinden R.

The Effects of Tramadol and Morphine on Immune Responses and Pain After Surgery in Cancer patients

The effects of morphine (10mg) IM and tramadol (100mg) IM on pain and immune function during the post-operative period was studied in 30 patients undergoing abdominal surgery for uterine carcinoma. These patients had not received radiotherapy, chemotherapy or immunosuppressive drugs. Phytohemagglutinin-induced T-lymphocyte proliferation and natural killer (N-K) cell activity were evaluated immediately before and after surgery and at 2hr after drug administration.

Results: In the morphine-treated group, proliferative values remained lower than basal levels for 2hr after treatment. Proliferative values returned to basal levels in the tramadol group. N-K cell activity was not affected significantly by surgery nor by morphine. Tramadol significantly enhanced N-K cell activity. Both drugs produced comparable reduction in post-operative pain, assessed using VAS scores.

An intriguing study, suggesting that different agents, despite similar analgesic properties, may have different effects on immune function. Caution should be exercised in interpreting studies like this, as the end-points are so soft - we don't expect that changes in such crude markers of immune function will have clinical import. In addition, the short duration of the study makes its relevance questionable.

Article 2: The Effects of Tramadol and Morphine on Immune Responses and Pain After Surgery in Cancer patients
Source: Anesth Analg 2000; 90 :1411-4
Article type: Clinical study
Authors: Sacerdote P, Bianchi M, Gaspani L, Manfredi B, Maucione A, Terno G, Ammatuna M, Panerai AE.

Two Recent Reviews

We now turn to two good recent reviews - a comprehensive review of recent clinical studies by Scott & Perry, and a thorough review by Shipton. Both are worth a read - go and get the original articles! Here, we briefly summarise their content:

Tramadol - the essentials

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). 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.

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, the dosage recommended is an initial 1-2mg/kg (Germany).

Efficacy is excellent. Parenterally, analgesic efficacy similar to that of morphine (or ketorolac), based on good visual analogue score (VAS) -based randomised, double blind, 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).

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 one should note that researchers used modified VAS scores (Hannallah, Oucher six faces, or Toddlers preschooler postoperative pain scale = TPPPS). Tramadol is a good analgesic for dental extraction (1.5mg/kg drops with 0.5mg/kg midazolam anxiolytic max 7.5mg). Two mg/kg is similar to IM pethidine (1mg/kg) or nalbuphine 0.1mg/kg after lower abdominal surgery. 92-100% had no or slight pain 1 hour after first dose. Caudal 2mg/kg similar to 2mg/kg bupivacaine or the combination but more pain occurred after 3 hours in one study in the tramadol-alone group. Tramadol has been used in Germany 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 ~ 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, 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); 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, 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 . 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

  1. It is an effective analgesic.

  2. No significant respiratory depression occurs (in adults OR children) at recommended doses - IV 0.6mg/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. [Bösenberg AT & Ratcliffe S Anaesthesia 1998 Oct 53 960-4]

  3. Tramadol appears to be antitussive.

  4. 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).

  5. 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).

Article 3: Tramadol: a review of its use in perioperative pain
Source: Drugs 2000 Jul 60(1) 139-76.
Article type: Review
Authors: Scott LJ Perry CM.

Article 4: Tramadol--present and future
Source: Anaesth Intensive Care 2000 28 363-74.
Article type: Review
Author: Shipton EA.

Editorial pointers

We commend the above reviews to your attention. They are good overviews of the current clinical status of tramadol. Again we must ask why tramadol is not used more enthusiastically. It appears to have equivalent analgesic efficacy compared with morphine, when used in the correct dose, and has the major advantage of causing minimal respiratory depression. Earlier studies implicating tramadol in intra-operative awareness appear totally unfounded. There seems to be no reason to shy away from its use in children over the age of one year, and one has to ask why its use is not being carefully investigated in children under the age of one year, where respiratory depression is a substantial cause for concern!

Its activation by CYP 2D6 should be noted. About eight percent of Caucasian populations will have less opiate effect from tramadol because they lack this CYP isoenzyme; conversely some people of Middle Eastern or East African origin may experience increased effects. However, the dual mechanism of action of tramadol should not preclude its use in such individuals, and one should always titrate analgesics to effect rather than relying on fixed doses.

Perhaps those faint and sporadic cheers we now hear for tramadol will eventually be converted to a roar of applause. Come on chaps, we're listening..


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