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 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. 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 side-effects 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-dimethylamino-1-ethyl-2-methyl-propyl-phenol hydrochloride) is a novel drug that is an agonist at the μ-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. Tapentadol has a dual mechanism of action: it acts on peripheral μ-opioid receptors, to block the upward transmission of pain signals to the brain; and it has central μ-opioid effects in the brain, affecting descending pain pathways and leading to enhancement of analgesic effects. It has 50 times less affinity to μ-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 anti-inflammatory 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 μ-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 μ-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. 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 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, 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 side-effects 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 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 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 tapentadol with opioids other than oxycodone; and the lack of broad-based 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, prolonged-release 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 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% compared with 36.8% for modified-release oxycodone 17 Tapentadol may also have a lower abuse potential than oxycodone and other opioids due to its lower affinity for the μ-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 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 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, 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. 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. 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. 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 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, 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 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. 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 modified-release 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-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 prescription of tapentadol, a Schedule-2 controlled drug. Further studies are needed to establish the role of immediate-release tapentadol in acute pain. VM has been a sponsored speaker in the past, on behalf of Grunenthal. No other external funding or competing interests declared.