|Journals Reviewed: A miscellany, including BJA 2000 Vol 84(3)!
|Abstracted by: Dr K. Tang MB BCh (Registrar, University of the
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
You may also wish to briefly browse our editorial comment.
Pharmacokinetics of tramadol in children after intravenous (IV) or caudal epidural
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.
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!
Pharmacokinetics of Tramadol in children after IV or caudal epidural
BJA 84 (3) : 346-9 (2000)
Clinical study |
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
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.
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.
The Effects of Tramadol and Morphine on Immune Responses and Pain After
Surgery in Cancer patients |
Anesth Analg 2000; 90 :1411-4 |
Clinical study |
Sacerdote P, Bianchi M, Gaspani L, Manfredi B, Maucione A, Terno G, Ammatuna M,
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
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.
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
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.
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
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
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 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]
- 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
Tramadol: a review of its use in perioperative pain |
Drugs 2000 Jul 60(1) 139-76. |
Scott LJ Perry CM.
Tramadol--present and future |
Anaesth Intensive Care 2000 28 363-74.
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,