An overview of analgesics: opioids, tramadol, and tapentadol (Part 2)

Abstract

Pain can be caused by several mechanisms, and the development of chronic pain (also known as pain chronification) is a complex and often unpredictable process. Opioids, tramadol, and tapentadol provide pharmacological solutions to chronic pain of cancer or non-cancer origins, particularly if central sensitization is present. It may also be indicated for short-term use in acute pain. Despite large studies and meta-analyses of opioids for a variety of pain conditions, the evidence for its clinical effectiveness is still unclear. This is, however, mostly due to significant heterogeneity and bias between studies assessed. The dual analgesic mechanisms of tramadol and tapentadol appear to be effective options for pain relief, with an overall lower incidence of opioid-related adverse effects. Tapentadol has an analgesic effect comparable to the strong opioids, which appears to be mediated by its greater mu opioid receptor activity and more selective noradrenaline reuptake inhibition. Tramadol produces less analgesia than tapentadol, but it is also associated with reduced opioid-related adverse effects and dependence. The opioids and tramadol may be significantly affected by polymorphisms of CYP2D6, while this effect is lessened with tapentadol.

Repeated Administration of Clinical Doses of Tramadol and Tapentadol Causes Hepato- and Nephrotoxic Effects in Wistar Rats

“…Tramadol ((1 RS ,2 RS )-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol) and tapentadol (3-[(1 R ,2 R )-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol) are fully synthetic analgesic opioids that synergistically combine mu-opioid receptor (MOR) agonism with monoamine reuptake inhibition, justifying their classification as “atypical opioids” [ 1 , 2 , 11 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Such dual mechanism of action optimizes analgesia and minimizes opioid-typical side effects, such as drowsiness, nausea, vomiting, constipation, motor incoordination and respiratory depression [ 1 , 2 , 11 , 19 , 27 ], explaining their indications for the treatment of post-surgical, musculoskeletal, inflammatory, cancer and neuropathic pain, as well as mixed pain states [ 1 , 19 , 27 , 28 , 29 , 30 , 31 , 32 ]. Also, owing to the synergistic combination of their mechanisms of action, these opioids allow the dose administered to be reduced without compromising analgesic efficacy, thus reducing the potential for abuse and addiction [ 11 , 33 ].…”

“…Tramadol is commercially available as a racemate; while (+)-tramadol provides for serotonin (5-HT) reuptake inhibition, (−)-tramadol accounts for noradrenaline (NA) uptake inhibition [ 1 , 2 , 11 , 19 , 32 , 34 , 35 , 36 , 37 ]. It undergoes extensive hepatic metabolism, mainly through O- and N-demethylation and conjugation reactions, yielding at least 14 phase I and 12 phase II metabolites [ 1 , 2 , 11 , 35 , 37 , 38 , 39 ].…”

“…Tapentadol has been developed from the structures of tramadol, O -desmethyltramadol and morphine, having been more recently made available on the market [ 1 , 40 , 41 ]. It acts mainly on NA reuptake inhibition and has minimal 5-HT activity, thus minimizing serotonin syndrome liability [ 1 , 2 , 25 , 27 , 30 , 32 , 33 , 36 , 39 , 42 , 43 , 44 , 45 ]. It is metabolized mainly through phase II glucuronidation and sulphonation reactions [ 1 , 2 , 25 , 36 , 39 , 43 , 44 , 45 ].…”

“…It is argued to be an upgrade of comparable opioids, particularly tramadol, whose drawbacks have inspired tapentadol design [ 1 , 2 ]. However, its shorter market history limits the amount of clinical and toxicological information on its use, hindering a true comparison between both opioids [ 1 , 2 , 32 , 42 ].…”

Repeated Administration of Clinically Relevant Doses of the Prescription Opioids Tramadol and Tapentadol Causes Lung, Cardiac, and Brain Toxicity in Wistar Rats

“…Opioids currently represent a mainstay option for the treatment of moderate to severe forms of pain. In this context, tramadol and tapentadol, synthetic and structurally related opioids, are widely prescribed in acute and chronic settings, finding application in the treatment of several clinical conditions, such as postoperative, musculoskeletal, neuropathic, cancer and mixed pain states [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. However, the misuse and abuse of prescription opioids, such as tramadol and tapentadol, is increasing due to their easy access, leading to addiction and toxicity cases.…”