Anaesthesia 2015, 70, 511–527
J. C. Andrzejowski M. D. Wiles Consultant Anaesthetists Sheffield Teaching Hospitals NHS Foundation Trust Sheffield, UK Email: [email protected]
Editorial
8.
9.
References 1. Cook TM, Andrade J, Bogod DG, et al. The 5th National Audit Project (NAP5) on accidental awareness during general 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. Anaesthesia 2015; 70: 375–9. 4. Hardman JG, Aitkenhead AR. Personal and medicolegal implications of awareness. 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/ 03/130312092648.htm (accessed 20/ 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
10. 11.
12.
13.
14.
15.
16.
study. Anesthesia and Analgesia 2004; 99: 833–9. 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. Avidan MS, Sleigh JW. Beware the Boojum: the NAP5 audit of accidental awareness during intended general anaesthesia. Anaesthesia 2014; 69: 1065–8. Cook TM, Pandit JJ. Clarifying NAP5. Anaesthesia 2015; 70: 105–6. National Institute for Health and Care Excellence. Depth of anaesthesia monitors – Bispectral Index (BIS), E-Entropy and Narcotrend-Compact M. [DG6]. London: NICE, 2012. Zand F, Hadavi SMR, Chohedri A, Sabetian P. Survey on the adequacy of depth of anaesthesia with bispectral index and isolated forearm technique in elective Caesarean section under general anaesthesia with sevoflurane. British Journal of Anaesthesia 2014; 112: 871–8. Sebel PS, Lang E, Rampil IJ, et al. A multicenter study of bispectral electroencephalogram analysis for monitoring anesthetic effect. Anesthesia and Analgesia 1997; 84: 891–9. Schneider G, Wagner K, Reeker W, H€anel F, Werner C, Kochs E. Bispectral index (BIS) may not predict awareness reaction to intubation in surgical patients. Journal of Neurosurgical Anesthesiology 2002; 14: 7–11. Alkire MT. Quantitative EEG correlations with brain glucose metabolic rate during anesthesia in volunteers. Anesthesiology 1998; 89: 323–33. Myles PS, Leslie K, McNeil J, Forbes A, Chan MTV. Bispectral index monitoring to prevent awareness during anaesthe-
17.
18.
19.
20.
21.
22.
23.
24.
sia: the B-Aware randomised controlled trial. Lancet 2004; 363: 1757–63. Escallier KE, Nadelson MR, Zhou D, Avidan MS. Monitoring the brain: processed electroencephalogram and peri-operative outcomes. Anaesthesia 2014; 69: 899–910. Smith D, Andrzejowski J, Smith A. Certainty and uncertainty: NICE guidance on ‘depth of anaesthesia’ monitoring. Anaesthesia 2013; 68: 1000–5. Russell IF. Fourteen fallacies about the isolated forearm technique, and its place in modern anaesthesia. Anaesthesia 2013; 68: 677–81. Sessler DI, Sigl JC, Kelley SD, et al. Hospital stay and mortality are increased in patients having a ‘‘triple low’’ of low blood pressure, low bispectral index, and low minimum alveolar concentration of volatile anesthesia. Anesthesiology 2012; 116: 1195–203. Morris C. Oesophageal Doppler monitoring, doubt and equipoise: evidence based medicine means change. Anaesthesia 2013; 68: 684–8. Buhre W, Rossaint R. Perioperative management and monitoring in anaesthesia. Lancet 2003; 362: 1839– 46. Marik PE, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness?: a systematic review of the literature and the tale of seven mares. Chest 2008; 134: 172– 8. Vretzakis G, Ferdi E, Argiriadou H, et al. Influence of bispectral index monitoring on decision making during cardiac anesthesia. Journal of Clinical Anesthesia 2005; 17: 509–16.
doi:10.1111/anae.13045
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
well recognised side-effects, most of which are dose-dependent. In the chronic pain setting, although opioids are ubiquitously used, concerns
have been raised regarding their long-term safety and these have been well addressed in various guidelines [1].
© 2015 The Association of Anaesthetists of Great Britain and Ireland
Editorial
Multimodal analgesia, particularly 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 monoaminergic system (serotonin and noradrenaline) is known to enhance the analgesia and minimise the sideeffects of opioid drugs, but generally, noradrenaline concentration is more important for analgesia than serotonin concentration, as pure serotonin inhibitors have no analgesic effects [3]. Also, increased serotonin levels may sometimes facilitate pain pathways and may result in enteric symptoms such as nausea, vomiting, diarrhoea and constipation [3]. Tapentadol (3-dimethylamino1-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 noradrenaline [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 current analgesic options. Tramadol is the only other drug currently in clinical use that has combined opioid and monoaminergic effects [5]. Understanding the differences between tapentadol and other conventional opioids, as well as tramadol, will enable us to place tapentadol appropriately in the analgesic ladder.
Pharmacodynamics Tapentadol has a dual mechanism of action: it acts on peripheral
Anaesthesia 2015, 70, 511–527
l-opioid receptors, to block the upward transmission of pain signals to the brain; and it has central lopioid effects in the brain, affecting descending pain pathways and leading to enhancement of analgesic effects. It has 50 times less affinity to l-opioid receptors than morphine, but is only 2-3 times less potent as an analgesic [4, 6]. This suggests that tapentadol’s noradrenaline re-uptake inhibiting effect plays a significant role in its analgesic effects. Preclinical studies strongly suggest that noradrenaline re-uptake inhibition has a synergistic, as opposed to a simple additive, effect on the overall analgesic potency of tapentadol [4, 7]. Clinically, this translates to fewer adverse effects than with pure opioid agonists, similar to the combination of non-steroidal antiinflammatory drugs with opioid drugs in order to achieve an opioid-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 receptors 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].
© 2015 The Association of Anaesthetists of Great Britain and Ireland
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 dental 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 immediaterelease tapentadol was found to be effective for the relief of acute pain with an overall safety and efficacy profile similar to that of immediaterelease oxycodone, but with fewer gastrointestinal side-effects [11, 12, 16]. Immediate-release tapentadol, 50-100 mg every 4-6 hours, provided equivalent analgesia to immediate-release oxycodone, 10-15 mg every 4-6 hours for moderate to severe pain [11, 14]. This has been established both for acute postoperative 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 sideeffects such as nausea, vomiting and constipation compared with oxycodone, but with no difference in the incidence of central nervous system symptoms such as somnolence and dizziness [14]. There is also a suggestion that tapentadol may have a lower incidence of pruritus compared with oxycodone (4.3% vs 11.8%), although this did not reach statistical significance [14]. Currently, 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 significantly lower with immediate-release tapentadol (20.8%) compared with oxycodone (30.6%), and the timescale for discontinuation for oxycodone was earlier than that for tapentadol [14]. When managing patients with moderate to severe pain, it is recommended to start immediate-release tapentadol at 50100 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 tapentadol with opioids other than oxycodone; and the lack of broadbased evidence in a variety of post-surgical and acute pain settings. Randomised controlled trials comparing prolonged-release tapentadol and modified-release oxycodone have been conducted in chronic pain states including chronic low back pain, chronic osteoarthritis and painful diabetic neuropathy [17, 18]. These studies suggest equianalgesic effects of prolonged-release tapentadol and modified-release oxycodone; however, prolongedrelease tapentadol was associated with a significantly lower incidence of gastrointestinal side-effects (nausea, 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 prolonged-release tapentadol was also 520
Editorial
maintained during the course of treatment lasting up to one year. The overall adverse effects-related discontinuation rate with prolongedrelease tapentadol was 22.1% compared with 36.8% for modifiedrelease oxycodone [17] Tapentadol may also have a lower abuse potential than oxycodone and other opioids due to its lower affinity for the l-opioid receptor [19]. It is prudent to start prolongedrelease tapentadol in an opioidnaive patient with chronic pain at the lowest dose, 50 mg twice daily, titrating to response up to a maximum 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 modifiedrelease 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, prolonged-release tapentadol has not been tested in all chronic pain conditions, and comparison has been limited to modified-release oxycodone and not other opioids such as morphine, transdermal fentanyl, buprenorphine or methadone. Furthermore, there is no evidence for the use of immediate-release tapentadol 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
and inhibits both serotonin and noradrenaline re-uptake. Unlike tapentadol, which is a single enantiomer 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 activation via the cytochrome P450 system (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 contributions 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 predictable than that of tapentadol. On the contrary, both the opioid and the non-opioid mechanisms of action of tapentadol reside in a single molecule 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 serotonergic pathway, we perhaps might not expect the risks of serotonergic syndrome. The common notion that tapentadol is an ‘expensive cousin’ of tramadol may be misleading, perhaps a misconception led by the overlapping mechanisms of action of opioid and monoaminergic pathways.
© 2015 The Association of Anaesthetists of Great Britain and Ireland
Editorial
Tapentadol and other anti-neuropathic agents With regard to other anti-neuropathic agents, in an animal model of neuropathic pain, the combination 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 locomotor impairement [22]. This perhaps opens up the option of using tapentadol as part of multimodal analgesia, although there are currently no comparisons between tapentadol and other anti-neuropathic agents in clinical studies.
Current guidelines and recommendations The combination of moderate opioid receptor affinity, synergistic opioid-sparing effect of noradrenaline re-uptake inhibition and lack of serotonergic activity explains the potent analgesic effect of tapentadol in both acute nociceptive and chronic neuropathic/mixed pain, along with a better gastrointestinal side-effect profile. Both immediateand 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, immediate-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
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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 morphine [25, 26].
needed to establish the role of immediate-release tapentadol in acute pain.
Conclusion
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: [email protected]
Given the current restricted evidence, tapentadol cannot be considered 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 modifiedrelease oxycodone, it can be considered as an alternative to morphine. Prolonged-release tapentadol can be used for chronic mixed-pain conditions in patients intolerant to morphine (as an alternative to either transdermal fentanyl or oxycodone). This recommendation may change in future with further evidence emerging and with changing financial 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 Consortium in April 2011 [26]. Due its superior gastrointestinal profile, it is perhaps an alternative option for combined oxycodone-naloxone, although there is no head-tohead 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 prescription of tapentadol, a Schedule-2 controlled drug. Further studies are
© 2015 The Association of Anaesthetists of Great Britain and Ireland
Competing interests VM has been a sponsored speaker in the past, on behalf of Grunenthal. No other external funding or competing interests declared.
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ity of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study. Clinical Therapeutics 2009; 31: 260–71. Hale M, Upmalis D, Okamoto A, Lange C, Rauschkolb C. Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, double-blind study. Current Medical Research and Opinion 2009; 25: 1095–104. Kleinert R, Lange C, Steup A, Black P, Goldberg J, Desjardins P. Single dose analgesic efficacy of tapentadol in postsurgical dental pain: the results of a randomized, double-blind, placebocontrolled study. Anesthesia and Analgesia 2008; 107: 2048–55. Biondi D, Xiang J, Benson C, Etropolski M, Moskovitz B, Rauschkolb C. Tapentadol immediate release versus oxycodone immediate release for treatment of acute low back pain. Pain Physician 2013; 16: E237–46. Wild JE, Grond S, Kuperwasser B, et al. Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain. Pain Practice 2010; 10: 416–27. Schwartz S, Etropolski M, Shapiro DY, et al. Safety and efficacy of tapentadol ER in patients with painful diabetic neuropathy: results of a randomized– withdrawal, placebo-controlled trial. Current Medical Research and Opinion 2011; 27: 151–62. Cepeda MS, Fife D, Ma Q, Ryan PB. Comparison of the risks of opioid
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abuse or dependence between tapentadol and oxycodone: results from a cohort study. Journal of Pain 2013; 14: 1227–41. Hartrick CT, Rozek RJ. Tapentadol in pain management. A l-opioid receptor agonist and noradrenaline reuptake inhibitor. CNS Drugs 2011; 25: 359–70. Etropolski MS, Okamoto A, Shapiro DY, Rauschkolb C. Dose conversion between tapentadol immediate and extended release for low back pain. Pain Physician 2010; 13: 61–70. Christoph T, De Vry J, Schiene K, Tallarida RJ, Tzschentke TM. Synergistic antihypersensitive effects of pregabalin and tapentadol in a rat model of neuropathic pain. European Journal of Pharmacology 2011; 666: 72–9. All Wales Medicine Strategy Group Tapentadol (Palexiaâ. http://www.aw msg.org/awmsgonline/app/appraisal info/771 (accessed 23/12/2014). Scottish Medicines Consortium. Tapentadol film-coated tablets (Palexia). http://www.scottishmedicines.org.uk/ SMC_Advice/Advice/773_12_tapent adol_Palexia/tapentadol_Palexia (accessed 23/12/2014). All Wales Medicine Strategy Group. Tapentadol (Palexiaâ SR). Reference no. 651. http://www.awmsg.org/awmsgonline/app/appraisalinfo/651 (accessed 23/12/2014). Scottish Medicines Consortium. Tapentadol prolonged-release tablets (Palexiaâ SR). http://www.scottishmedicines. org.uk/SMC_Advice/Advice/654_10_ tapentadol_SR_Palexia/tapentadol_SR_ Palexia (accessed 23/12/2014).
doi:10.1111/anae.13080
Editorial Oxygen therapy and anaesthesia: too much of a good thing? Oxygen is given to patients around the time of surgery to prevent or treat acute hypoxaemia, the harmful consequences of which are potentially augmented in the setting of 522
the peri-operative inflammatory response. Whilst sub-acute and chronic hypoxaemia are frequently well tolerated by humans, both in health and illness [1], the adaptive
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
© 2015 The Association of Anaesthetists of Great Britain and Ireland
J. C. Andrzejowski M. D. Wiles Consultant Anaesthetists Sheffield Teaching Hospitals NHS Foundation Trust Sheffield, UK Email: [email protected]
Editorial
8.
9.
References 1. Cook TM, Andrade J, Bogod DG, et al. The 5th National Audit Project (NAP5) on accidental awareness during general 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. Anaesthesia 2015; 70: 375–9. 4. Hardman JG, Aitkenhead AR. Personal and medicolegal implications of awareness. 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/ 03/130312092648.htm (accessed 20/ 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
10. 11.
12.
13.
14.
15.
16.
study. Anesthesia and Analgesia 2004; 99: 833–9. 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. Avidan MS, Sleigh JW. Beware the Boojum: the NAP5 audit of accidental awareness during intended general anaesthesia. Anaesthesia 2014; 69: 1065–8. Cook TM, Pandit JJ. Clarifying NAP5. Anaesthesia 2015; 70: 105–6. National Institute for Health and Care Excellence. Depth of anaesthesia monitors – Bispectral Index (BIS), E-Entropy and Narcotrend-Compact M. [DG6]. London: NICE, 2012. Zand F, Hadavi SMR, Chohedri A, Sabetian P. Survey on the adequacy of depth of anaesthesia with bispectral index and isolated forearm technique in elective Caesarean section under general anaesthesia with sevoflurane. British Journal of Anaesthesia 2014; 112: 871–8. Sebel PS, Lang E, Rampil IJ, et al. A multicenter study of bispectral electroencephalogram analysis for monitoring anesthetic effect. Anesthesia and Analgesia 1997; 84: 891–9. Schneider G, Wagner K, Reeker W, H€anel F, Werner C, Kochs E. Bispectral index (BIS) may not predict awareness reaction to intubation in surgical patients. Journal of Neurosurgical Anesthesiology 2002; 14: 7–11. Alkire MT. Quantitative EEG correlations with brain glucose metabolic rate during anesthesia in volunteers. Anesthesiology 1998; 89: 323–33. Myles PS, Leslie K, McNeil J, Forbes A, Chan MTV. Bispectral index monitoring to prevent awareness during anaesthe-
17.
18.
19.
20.
21.
22.
23.
24.
sia: the B-Aware randomised controlled trial. Lancet 2004; 363: 1757–63. Escallier KE, Nadelson MR, Zhou D, Avidan MS. Monitoring the brain: processed electroencephalogram and peri-operative outcomes. Anaesthesia 2014; 69: 899–910. Smith D, Andrzejowski J, Smith A. Certainty and uncertainty: NICE guidance on ‘depth of anaesthesia’ monitoring. Anaesthesia 2013; 68: 1000–5. Russell IF. Fourteen fallacies about the isolated forearm technique, and its place in modern anaesthesia. Anaesthesia 2013; 68: 677–81. Sessler DI, Sigl JC, Kelley SD, et al. Hospital stay and mortality are increased in patients having a ‘‘triple low’’ of low blood pressure, low bispectral index, and low minimum alveolar concentration of volatile anesthesia. Anesthesiology 2012; 116: 1195–203. Morris C. Oesophageal Doppler monitoring, doubt and equipoise: evidence based medicine means change. Anaesthesia 2013; 68: 684–8. Buhre W, Rossaint R. Perioperative management and monitoring in anaesthesia. Lancet 2003; 362: 1839– 46. Marik PE, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness?: a systematic review of the literature and the tale of seven mares. Chest 2008; 134: 172– 8. Vretzakis G, Ferdi E, Argiriadou H, et al. Influence of bispectral index monitoring on decision making during cardiac anesthesia. Journal of Clinical Anesthesia 2005; 17: 509–16.
doi:10.1111/anae.13045
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
well recognised side-effects, most of which are dose-dependent. In the chronic pain setting, although opioids are ubiquitously used, concerns
have been raised regarding their long-term safety and these have been well addressed in various guidelines [1].
© 2015 The Association of Anaesthetists of Great Britain and Ireland
Editorial
Multimodal analgesia, particularly 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 monoaminergic system (serotonin and noradrenaline) is known to enhance the analgesia and minimise the sideeffects of opioid drugs, but generally, noradrenaline concentration is more important for analgesia than serotonin concentration, as pure serotonin inhibitors have no analgesic effects [3]. Also, increased serotonin levels may sometimes facilitate pain pathways and may result in enteric symptoms such as nausea, vomiting, diarrhoea and constipation [3]. Tapentadol (3-dimethylamino1-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 noradrenaline [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 current analgesic options. Tramadol is the only other drug currently in clinical use that has combined opioid and monoaminergic effects [5]. Understanding the differences between tapentadol and other conventional opioids, as well as tramadol, will enable us to place tapentadol appropriately in the analgesic ladder.
Pharmacodynamics Tapentadol has a dual mechanism of action: it acts on peripheral
Anaesthesia 2015, 70, 511–527
l-opioid receptors, to block the upward transmission of pain signals to the brain; and it has central lopioid effects in the brain, affecting descending pain pathways and leading to enhancement of analgesic effects. It has 50 times less affinity to l-opioid receptors than morphine, but is only 2-3 times less potent as an analgesic [4, 6]. This suggests that tapentadol’s noradrenaline re-uptake inhibiting effect plays a significant role in its analgesic effects. Preclinical studies strongly suggest that noradrenaline re-uptake inhibition has a synergistic, as opposed to a simple additive, effect on the overall analgesic potency of tapentadol [4, 7]. Clinically, this translates to fewer adverse effects than with pure opioid agonists, similar to the combination of non-steroidal antiinflammatory drugs with opioid drugs in order to achieve an opioid-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 receptors 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].
© 2015 The Association of Anaesthetists of Great Britain and Ireland
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 dental 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 immediaterelease tapentadol was found to be effective for the relief of acute pain with an overall safety and efficacy profile similar to that of immediaterelease oxycodone, but with fewer gastrointestinal side-effects [11, 12, 16]. Immediate-release tapentadol, 50-100 mg every 4-6 hours, provided equivalent analgesia to immediate-release oxycodone, 10-15 mg every 4-6 hours for moderate to severe pain [11, 14]. This has been established both for acute postoperative 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 sideeffects such as nausea, vomiting and constipation compared with oxycodone, but with no difference in the incidence of central nervous system symptoms such as somnolence and dizziness [14]. There is also a suggestion that tapentadol may have a lower incidence of pruritus compared with oxycodone (4.3% vs 11.8%), although this did not reach statistical significance [14]. Currently, there are no data on the risk of respiratory depression with tapentadol compared with other 519
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opioids. The overall discontinuation rate due to adverse events was significantly lower with immediate-release tapentadol (20.8%) compared with oxycodone (30.6%), and the timescale for discontinuation for oxycodone was earlier than that for tapentadol [14]. When managing patients with moderate to severe pain, it is recommended to start immediate-release tapentadol at 50100 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 tapentadol with opioids other than oxycodone; and the lack of broadbased evidence in a variety of post-surgical and acute pain settings. Randomised controlled trials comparing prolonged-release tapentadol and modified-release oxycodone have been conducted in chronic pain states including chronic low back pain, chronic osteoarthritis and painful diabetic neuropathy [17, 18]. These studies suggest equianalgesic effects of prolonged-release tapentadol and modified-release oxycodone; however, prolongedrelease tapentadol was associated with a significantly lower incidence of gastrointestinal side-effects (nausea, 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 prolonged-release tapentadol was also 520
Editorial
maintained during the course of treatment lasting up to one year. The overall adverse effects-related discontinuation rate with prolongedrelease tapentadol was 22.1% compared with 36.8% for modifiedrelease oxycodone [17] Tapentadol may also have a lower abuse potential than oxycodone and other opioids due to its lower affinity for the l-opioid receptor [19]. It is prudent to start prolongedrelease tapentadol in an opioidnaive patient with chronic pain at the lowest dose, 50 mg twice daily, titrating to response up to a maximum 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 modifiedrelease 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, prolonged-release tapentadol has not been tested in all chronic pain conditions, and comparison has been limited to modified-release oxycodone and not other opioids such as morphine, transdermal fentanyl, buprenorphine or methadone. Furthermore, there is no evidence for the use of immediate-release tapentadol 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
and inhibits both serotonin and noradrenaline re-uptake. Unlike tapentadol, which is a single enantiomer 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 activation via the cytochrome P450 system (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 contributions 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 predictable than that of tapentadol. On the contrary, both the opioid and the non-opioid mechanisms of action of tapentadol reside in a single molecule 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 serotonergic pathway, we perhaps might not expect the risks of serotonergic syndrome. The common notion that tapentadol is an ‘expensive cousin’ of tramadol may be misleading, perhaps a misconception led by the overlapping mechanisms of action of opioid and monoaminergic pathways.
© 2015 The Association of Anaesthetists of Great Britain and Ireland
Editorial
Tapentadol and other anti-neuropathic agents With regard to other anti-neuropathic agents, in an animal model of neuropathic pain, the combination 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 locomotor impairement [22]. This perhaps opens up the option of using tapentadol as part of multimodal analgesia, although there are currently no comparisons between tapentadol and other anti-neuropathic agents in clinical studies.
Current guidelines and recommendations The combination of moderate opioid receptor affinity, synergistic opioid-sparing effect of noradrenaline re-uptake inhibition and lack of serotonergic activity explains the potent analgesic effect of tapentadol in both acute nociceptive and chronic neuropathic/mixed pain, along with a better gastrointestinal side-effect profile. Both immediateand 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, immediate-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
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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 morphine [25, 26].
needed to establish the role of immediate-release tapentadol in acute pain.
Conclusion
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: [email protected]
Given the current restricted evidence, tapentadol cannot be considered 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 modifiedrelease oxycodone, it can be considered as an alternative to morphine. Prolonged-release tapentadol can be used for chronic mixed-pain conditions in patients intolerant to morphine (as an alternative to either transdermal fentanyl or oxycodone). This recommendation may change in future with further evidence emerging and with changing financial 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 Consortium in April 2011 [26]. Due its superior gastrointestinal profile, it is perhaps an alternative option for combined oxycodone-naloxone, although there is no head-tohead 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 prescription of tapentadol, a Schedule-2 controlled drug. Further studies are
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Competing interests VM has been a sponsored speaker in the past, on behalf of Grunenthal. No other external funding or competing interests declared.
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Editorial Oxygen therapy and anaesthesia: too much of a good thing? Oxygen is given to patients around the time of surgery to prevent or treat acute hypoxaemia, the harmful consequences of which are potentially augmented in the setting of 522
the peri-operative inflammatory response. Whilst sub-acute and chronic hypoxaemia are frequently well tolerated by humans, both in health and illness [1], the adaptive
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
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