Anaesthesia 2015, 70, 511–527
J. C. Andrzejowski
M. D. Wiles
Consultant Anaesthetists
Sheffield Teaching Hospitals NHS
Foundation Trust
Sheffield, UK
Email: john.andrzejowski@sth.nhs.uk
References
1. Cook TM, Andrade J, Bogod DG, et al.
The 5th National Audit Project (NAP5)
on accidental awareness during gen-
eral anaesthesia: patient experiences,
human factors, sedation, consent and
medicolegal issues. Anaesthesia 2014;
69: 1102–16.
2. Smith D, Goddard NG. Awareness in
cardiothoracic anaesthetic practice –
where now after NAP5? Anaesthesia
2015; 70: 130–4.
3. Lucas DN, Yentis SM. Unsettled
weather and the end for thiopental?
Obstetric general anaesthesia after the
NAP5 and MBRRACE-UK reports. Anaes-
thesia 2015; 70: 375–9.
4. Hardman JG, Aitkenhead AR. Personal
and medicolegal implications of aware-
ness. British Journal of Anaesthesia
2014; 113: 533–4.
5. Wiley. New survey reports low rate of
patient awareness during anesthesia.
ScienceDaily 12 March 2013. http://
www.sciencedaily.com/releases/2013/
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01/2015).
6. Sandin RH, Enlund G, Samuelsson P,
Lennmarken C. Awareness during
anaesthesia: a prospective case study.
Lancet 2000; 355: 707–11.
7. Sebel PS, Bowdle TA, Ghoneim MM, et
al. The incidence of awareness during
anesthesia: a multicenter United States
Editorial
Tapentadol - the evidence so far
Opioids remain as first-line drugs
for the treatment of moderate to
severe acute peri-operative pain.
Their use is mainly limited by some
518
study. Anesthesia and Analgesia 2004;
99: 833–9.
8. Avidan MS, Mashour GA. The incidence
of intra-operative awareness in the UK:
under the rate or under the radar?
Anaesthesia 2013; 68: 334–8.
9. Avidan MS, Sleigh JW. Beware the Boo-
jum: the NAP5 audit of accidental
awareness during intended general
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10. Cook TM, Pandit JJ. Clarifying NAP5.
Anaesthesia 2015; 70: 105–6.
11. National Institute for Health and Care
Excellence. Depth of anaesthesia moni-
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tian P. Survey on the adequacy of
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13. Sebel PS, Lang E, Rampil IJ, et al. A
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14. Schneider G, Wagner K, Reeker W,
H€anel F, Werner C, Kochs E. Bispectral
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Editorial
sia: the B-Aware randomised controlled
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17. Escallier KE, Nadelson MR, Zhou D,
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21. Morris C. Oesophageal Doppler moni-
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doi:10.1111/anae.13045
have been raised regarding their
long-term safety and these have
been well addressed in various
guidelines [1].
Editorial
Multimodal analgesia, particu-
larly using drugs with multiple
actions, remains a viable strategy to
minimise the opioid-related adverse
effects. They also help to reduce
exposure of patients to adverse
effects of additional drugs and also
to possible inter-drug interactions
[2]. Activation of the monoaminer-
gic system (serotonin and noradren-
aline) is known to enhance the
analgesia and minimise the side-
effects of opioid drugs, but gener-
ally, noradrenaline concentration is
more important for analgesia than
serotonin concentration, as pure
serotonin inhibitors have no analge-
sic effects [3]. Also, increased sero-
tonin levels may sometimes
facilitate pain pathways and may
result in enteric symptoms such as
nausea, vomiting, diarrhoea and
constipation [3].
Tapentadol (3-dimethylamino-
1-ethyl-2-methyl-propyl-phenol hydro
chloride) is a novel drug that is an
agonist at the l-opioid receptor and
inhibits the re-uptake of noradrena-
line [4]. It became commercially
available in the USA from 2009 and
in Europe from 2010. This unique
combination of the drug effect may
add an interesting choice to the cur-
rent analgesic options. Tramadol is
the only other drug currently in clini-
cal use that has combined opioid and
monoaminergic effects [5]. Under-
standing the differences between
tapentadol and other conventional
opioids, as well as tramadol, will
enable us to place tapentadol appro-
priately in the analgesic ladder.
Pharmacodynamics
Tapentadol has a dual mechanism
of action: it acts on peripheral
© 2015 The Association of Anaesthetists of Great Britain and Ireland
l-opioid receptors, to block the
upward transmission of pain signals
to the brain; and it has central l-
opioid effects in the brain, affecting
descending pain pathways and lead-
ing to enhancement of analgesic
effects. It has 50 times less affinity
to l-opioid receptors than mor-
phine, but is only 2-3 times less
potent as an analgesic [4, 6]. This
suggests that tapentadol’s noradren-
aline re-uptake inhibiting effect
plays a significant role in its analge-
sic effects. Preclinical studies
strongly suggest that noradrenaline
re-uptake inhibition has a synergis-
tic, as opposed to a simple additive,
effect on the overall analgesic
potency of tapentadol [4, 7]. Clini-
cally, this translates to fewer
adverse effects than with pure
opioid agonists, similar to the com-
bination of non-steroidal anti-
inflammatory drugs with opioid
drugs in order to achieve an opi-
oid-sparing effect [8]. This dual
mode of action has also been shown
to make tapentadol more resistant
to tolerance than morphine [4].
It is interesting to note that the
differential effect of the medication
(contribution of l-opioid receptor
agonism or noradrenaline re-uptake
inhibition to analgesia) depends on
the pain model used. In an acute
nociceptive or sham pain model,
the contribution of l-opioid recep-
tors to anti-nociception was more
important whereas in neuropathic
pain models, the noradrenaline
re-uptake inhibition contributed
more to the analgesic effect [7, 9,
10]. Tapentadol at best shows only
a weak in-vitro 5-HT re-uptake
inhibition, which does not seem to
contribute to its clinical effects [9].
Anaesthesia 2015, 70, 511–527
Current evidence
Immediate-release tapentadol has
been tested in both phase-2 and
phase-3 trials and is licensed for use
in patients aged 18 years or over,
with moderate to severe pain. This is
based on studies looking at patients
undergoing bunionectomy and den-
tal surgery, patients with severe joint
disease awaiting joint replacement
surgery, or patients with acute low
back pain [11–15]. There is some
evidence to suggest that immediate-
release tapentadol was found to be
effective for the relief of acute pain
with an overall safety and efficacy
profile similar to that of immediate-
release oxycodone, but with fewer
gastrointestinal side-effects [11, 12,
16]. Immediate-release tapentadol,
50-100 mg every 4-6 hours, pro-
vided equivalent analgesia to imme-
diate-release oxycodone, 10-15 mg
every 4-6 hours for moderate to
severe pain [11, 14]. This has been
established both for acute postopera-
tive pain and in a chronic setting in
patients with end-stage degenerative
joint disease.
Immediate-release tapentadol
has been associated with a lower
incidence of gastrointestinal side-
effects such as nausea, vomiting and
constipation compared with oxyco-
done, but with no difference in the
incidence of central nervous system
symptoms such as somnolence and
dizziness [14]. There is also a sugges-
tion that tapentadol may have a
lower incidence of pruritus com-
pared with oxycodone (4.3% vs
11.8%), although this did not reach
statistical significance [14]. Cur-
rently, there are no data on the
risk of respiratory depression with
tapentadol compared with other
519
Anaesthesia 2015, 70, 511–527
opioids. The overall discontinuation
rate due to adverse events was signif-
icantly lower with immediate-release
tapentadol (20.8%) compared with
oxycodone (30.6%), and the time-
scale for discontinuation for oxyco-
done was earlier than that for
tapentadol [14]. When managing
patients with moderate to severe
pain, it is recommended to start
immediate-release tapentadol at 50-
100 mg 4-6 hourly and titrate to
response [11, 14].
However, there are two main
gaps in the evidence for the use of
immediate-release tapentadol before
it can be recommended as an early
intervention in the management of
acute surgical and non-surgical
pain: the lack of comparison of ta-
pentadol with opioids other than
oxycodone; and the lack of broad-
based evidence in a variety of
post-surgical and acute pain set-
tings.
Randomised controlled trials
comparing prolonged-release tapent-
adol and modified-release oxyco-
done have been conducted in
chronic pain states including chronic
low back pain, chronic osteoarthritis
and painful diabetic neuropathy [17,
18]. These studies suggest equianal-
gesic effects of prolonged-release
tapentadol and modified-release
oxycodone; however, prolonged-
release tapentadol was associated
with a significantly lower incidence
of gastrointestinal side-effects (nau-
sea, vomiting and constipation).
Additionally, there was a lower
incidence of central nervous system
side-effects (dizziness, headache,
somnolence) and pruritus [17, 18].
The therapeutic response for pro-
longed-release tapentadol was also
520
maintained during the course of
treatment lasting up to one year.
The overall adverse effects-related
discontinuation rate with prolonged-
release tapentadol was 22.1% com-
pared with 36.8% for modified-
release oxycodone [17] Tapentadol
may also have a lower abuse poten-
tial than oxycodone and other opi-
oids due to its lower affinity for the
l-opioid receptor [19].
It is prudent to start prolonged-
release tapentadol in an opioid-
naive patient with chronic pain at
the lowest dose, 50 mg twice daily,
titrating to response up to a maxi-
mum dose of 250 mg twice daily
(the maximum studied dose) [18].
Studies have shown that prolonged
release tapentadol 100-250 mg twice
daily was non-inferior to modified-
release oxycodone 20-50 mg [20].
This suggests that a reasonable
opioid conversion would be 50 mg
tapentadol = 10 mg oxycodone =
20 mg oral morphine. Both
immediate- and prolonged-release
tapentadol have been found to be
equianalgesic [21]. Again, pro-
longed-release tapentadol has not
been tested in all chronic pain con-
ditions, and comparison has been
limited to modified-release oxyco-
done and not other opioids such as
morphine, transdermal fentanyl,
buprenorphine or methadone. Fur-
thermore, there is no evidence for
the use of immediate-release tapent-
adol for breakthrough pain in
chronic pain conditions, precluding
it from the management of cancer
pain.
Contrast with tramadol
In comparison with tapentadol,
tramadol is a weak opioid agonist
© 2015 The Association of Anaesthetists of Great Britain and Ireland
Editorial
and inhibits both serotonin and
noradrenaline re-uptake. Unlike ta-
pentadol, which is a single enantio-
mer with no active metabolites,
tramadol is a racemic mixture
of (+) and ( ) enantiomers and is
also actively metabolised. The
parent compound of tramadol has
a predominantly monoaminergic
effect but the opioid effect mainly
resides on the (+)- enantiomer of
O-desmethyl-tramadol [4, 5]. Hence
the overall analgesic effect of
tramadol relies on its variable acti-
vation via the cytochrome P450 sys-
tem (absent in up to 15% of the
Caucasian population) and its
metabolites have less effect on the
monoaminergic pathway compared
with the parent molecule. Because
of this complexity, the relative con-
tributions of the opioid and the
monoaminergic pathways to the
analgesic effect of tramadol is very
variable [4, 5]. These factors make
the analgesic effect of tramadol
both less effective and less predict-
able than that of tapentadol. On the
contrary, both the opioid and the
non-opioid mechanisms of action
of tapentadol reside in a single mol-
ecule that is metabolised into an
inactive metabolite [4]. Due to this,
tapentadol is also less prone to
adverse drug interactions [4]. Also,
because of the lack of clinically
significant effects on the serotoner-
gic pathway, we perhaps might not
expect the risks of serotonergic
syndrome. The common notion
that tapentadol is an ‘expensive
cousin’ of tramadol may be mis-
leading, perhaps a misconception
led by the overlapping mechanisms
of action of opioid and monoamin-
ergic pathways.
Editorial
Tapentadol and other
anti-neuropathic agents
With regard to other anti-neuro-
pathic agents, in an animal model
of neuropathic pain, the combina-
tion of pregabalin and tapentadol
showed a synergistic effect, whereas
the combination of pregabalin and
either morphine or oxycodone
showed only an additive effect and
resulted in increased contralateral
paw withdrawal threshold and loco-
motor impairement [22]. This per-
haps opens up the option of using
tapentadol as part of multimodal
analgesia, although there are
currently no comparisons between
tapentadol and other anti-neuro-
pathic agents in clinical studies.
Current guidelines and
recommendations
The combination of moderate opi-
oid receptor affinity, synergistic
opioid-sparing effect of noradrena-
line re-uptake inhibition and lack
of serotonergic activity explains the
potent analgesic effect of tapent-
adol in both acute nociceptive and
chronic neuropathic/mixed pain,
along with a better gastrointestinal
side-effect profile. Both immediate-
and prolonged-release tapentadol
are approved by the US Food and
Drug Administration for acute and
chronic pain, respectively. In the
UK, tapentadol was first approved
in May 2011. Currently, immedi-
ate-release tapentadol is not
endorsed by either the All Wales
Medicine Strategy Group or the
Scottish Medicines Consortium
guidelines for moderate to severe
acute pain, and it has not yet been
reviewed by the National Institute
© 2015 The Association of Anaesthetists of Great Britain and Ireland
for Health and Care Excellence
[23, 24]. Both the Welsh and the
Scottish guidelines have approved
prolonged-release tapentadol for
moderate to severe chronic pain
that can only be managed by
strong opioids other than mor-
phine [25, 26].
Conclusion
Given the current restricted evi-
dence, tapentadol cannot be consid-
ered as a first-line opioid in
moderate to severe chronic pain
that can be adequately managed
with opioids only; however, due to
its equianalgesic effect to modified-
release oxycodone, it can be consid-
ered as an alternative to morphine.
Prolonged-release tapentadol can be
used for chronic mixed-pain condi-
tions in patients intolerant to mor-
phine (as an alternative to either
transdermal fentanyl or oxycodone).
This recommendation may change
in future with further evidence
emerging and with changing finan-
cial constraints.
Its cost-effectiveness has been
considered comparable to that of
modified-release oxycodone (drug
prices correct as per the submission
to the Scottish Medicines Consor-
tium in April 2011 [26].
Due its superior gastrointestinal
profile, it is perhaps an alternative
option for combined oxycodone-nal-
oxone, although there is no head-to-
head comparison. Recently, tramadol
has been reclassified as a Schedule-3
controlled drug, which could restrict
its current widespread use [5]. This
may also have an impact on the pre-
scription of tapentadol, a Schedule-2
controlled drug. Further studies are
Anaesthesia 2015, 70, 511–527
needed to establish the role of imme-
diate-release tapentadol in acute pain.
Competing interests
VM has been a sponsored speaker
in the past, on behalf of Grunenthal.
No other external funding or com-
peting interests declared.
S. Ramaswamy
Research Fellow
S. Chang
Consultant Anaesthetist
St Bartholomew’s Hospital
London, UK
V. Mehta
Consultant in Pain Medicine
Pain & Anaesthesia Research Centre
St Bartholomew’s Hospital
London, UK
Honorary Senior Lecturer,
Queen Mary University
London, UK
Email:
vivek.mehta@bartshealth.nhs.uk
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doi:10.1111/anae.13080
responses to acute hypoxaemia are
limited and intervention may be
required to prevent harm. One of
the many roles of the anaesthetist is
to protect patients from significant