HPE Chronic pain – part two | Page 8

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 8 | 2020 | hospitalpharmacyeurope.com