synthesised analgesics, but extremely weak affinity
for the mu-receptor of the molecule itself and higher
affinity of its active metabolite O-desmethyltramadol
(M1) suggested that its analgesic effect did not rely
exclusively on this mechanism. 10 M1 is mainly
responsible for the mu-opioid-related analgesic
effect, having an estimated 300-fold higher affinity
for mu receptors than the parent compound but
lesser penetration across the blood–brain barrier. 10
The discovery of noradrenaline and serotonin
reuptake inhibition in synergy with weak mu-opioid
receptor agonism as the major components of its
analgesic effects led the pharmacologist Robert Raffa
to suggest the new term ‘atypical opioid’ for
tramadol. 11 The same author has subsequently
suggested that: “the categorisation of all analgesics
that have any component of opioid mechanism of
action into the same class is anachronistic”. 12 Other
than tramadol, buprenorphine and tapentadol have
important mechanisms of analgesic action, not
relying exclusively on mu-receptor agonism, thereby
separating these from typical/conventional opioids
such as morphine, oxycodone, hydromorphone and
fentanyl. 12 This new terminology is not only
pharmacologically useful as it describes different
mechanisms of action but has also clinical
consequences as these differences result in different
effects, adverse effects and toxicity. The following
will outline this for the three currently used atypical
opioids (tramadol, buprenorphine and tapentadol).
Tramadol
As outlined above, tramadol is the prototype of the
atypical opioid. Its analgesic effects rely on three
mechanisms of action: the mu-receptor agonist
effect of its active metabolite O-desmethyltramadol
(M1), as well as its effects as a noradrenaline and
serotonin reuptake inhibitor. 11,13 The latter two
mechanisms strengthen descending inhibitory
pathways of pain control 14 and contribute (at least
in basic science experiments) to 60% of its analgesic
effect. 15
Thereby, tramadol shows the characteristics of all
atypical opioids in achieving more analgesic efficacy
than its mu-opioid effects suggest. In the postoperative
setting given via patient-controlled
anaesthesia, tramadol has similar efficacy to typical
mu-opioids such as morphine, fentanyl and
oxycodone. 16 It has also been used in cancer pain 17
and in chronic pain of non-malignant origin; here it
improved physical function with reduced disability, 18
and also in osteoarthritis. 19 Lastly, due to its
mechanism of action, tramadol may be used in the
treatment of neuropathic pain (number needed to
treat = 4.4). 20
With regard to adverse events, tramadol has
a very different profile from typical opioids. There
are fewer respiratory depressing effects (for example,
compared with oxycodone) 21–24 but they can occur, in
particular with overdose. 25 Tramadol also has fewer
inhibitory effects on gastrointestinal motor function,
leading to less constipation than with typical
opioids 13 and suppresses immune function to a lesser
extent than morphine. 26,27
While the reliance on mechanisms other than
mu-opioid receptor agonism offers the advantages
outlined above, the mechanism of serotonin
reuptake inhibition adds other adverse effect
profiles. Tramadol, by its serotonergic effects, lowers
the seizure threshold 28 and causes more seizures
than typical opioids, in particular in overdose. 25
Concomitant therapeutic use of tramadol and
serotonergic drugs such as SSRIs, SNRIs and MAOIs
may cause serotonin toxicity. 29,30 Last, but not least,
serotonergic effects contribute to an increased rate
of nausea and vomiting 16 and an increased rate of
confusion and delirium in elderly patients. 31
Tramadol relies on an active metabolite for the
weak mu-receptor antagonism, as its formation is
dependent on cytochrome P450 2D6 (CYP2D6), an
enzyme with very high polymorphism. 32 Therefore,
poor metabolisers have only a minor component of
mu-agonism contributing to the analgesic effect 33
and require higher doses of tramadol, 34 whereas
ultra-fast metabolisers are at increased risk of
mu-receptor-mediated adverse effects including
possible respiratory depression. 35
Tapentadol
In the development of tapentadol, the disadvantages
of tramadol were avoided because tapentadol has no
active metabolite 36 and a clinically irrelevant
serotonergic effect. 37 Its analgesic effect (one-third
that of morphine) is based on the extensive synergy
between a weak mu-opioid agonism (1/18 of the
affinity of morphine) and noradrenaline reuptake
inhibition. 38,39 As with tramadol, the noradrenergic
mechanism potentiates descending pain inhibition. 40
The analgesic efficacy of tapentadol is similar to
typical opioids (oxycodone and morphine being the
main comparators) in chronic osteoarthritis, chronic
low back pain, 41 cancer pain 42 and neuropathic pain
in diabetic polyneuropathy, 43 as well as acute pain
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