Multimechanistic Single-Entity Combinations for Chronic Pain Control: A Narrative Review

Abstract

Atypical opioids such as tramadol, tapentadol, and cebranopadol combine two complementary mechanisms of action into a single molecule, creating novel analgesic agents. These are synthetic small molecules: cebranopadol is not yet market released; tramadol and tapentadol are commercially available and have immediate-release (IR) and extended-release (ER) formulations. Tramadol has been widely used in the United States in recent years and works as a prodrug in that its metabolites are active in inhibiting serotonin and norepinephrine reuptake. Tapentadol is a direct-acting agent with a faster onset of action and is a mu-opioid-receptor agonist and also inhibits noradrenaline reuptake. Cebranopadol is the newest of these drugs, a first-in-class atypical analgesic that combines mu-opioid receptor (MOR) agonism with activity at the nociception/orphanin (NOP) FQ petide receptors. Cebranopadol may be considered a partial kappa-opioid receptor agonist as well. The pharmacology of these unique single-entity agents allows them to offer analgesic benefit with fewer side effects and risks. Clinical studies have demonstrated the safety and efficacy of tramadol and tapentadol, and promising but limited studies for cebranopadol show good analgesic effect and safety. Serotonin toxicity or ‘serotonin syndrome’ may occur with accumulation of serotonin with tramadol. While the misuse of these agents is limited in the United States, tramadol misuse is prevalent in Iran and parts of Africa. Patients have been successfully rotated from one of these agents to another. All three agents show promise in the treatment of cancer and non-cancer pain and their unique formulation in a single molecule reduces the pill burden.

Tramadol and Tapentadol Induce Conditioned Place Preference with a Differential Impact on Rewarding Memory and Incubation of Craving

“…Tramadol analgesia is highly dependent on its conversion into O -desmethyltramadol (M1), its active metabolite, by the CYP2D6 isoenzyme; its opioid, noradrenergic and serotonergic activities reside mainly in the (+)-M1, (−)-tramadol and (+)-tramadol enantiomers, respectively [ 6 ]. Owing to its serotonergic component, and contrarily to tapentadol, it is associated with serotonin syndrome, besides the classic opioid-related adverse events [ 7 ]. In turn, a single parent molecule ensures tapentadol opioid and noradrenergic mechanisms of action.…”

“…While the rates of abuse and dependence are considerably lower for tramadol and tapentadol than for other opioid peers, they are not devoid of risk, as substantiated by several reports [ 3 , 4 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Although tramadol is listed as a Schedule IV controlled substance in the USA, with the rates of abuse and misuse being lower than those of other prescription opioids, it is emerging as a drug of abuse in the Middle East and African countries, as well as in other developing nations [ 7 ]. Users report a sense of happiness but also cognitive alterations [ 4 , 24 ].…”

“…A recent web-based survey on tapentadol non-medical use revealed that, besides pain relief, it is consumed for multiple psychotropic effects, including relaxation, reduction in depression or anxiety, and getting high; a subgroup of participants even reported hallucinogenic side effects at higher doses [ 30 ]. Such potential to induce physical and psychological dependence, supported by rewarding and reinforcing effects comparable to those of morphine, underpinned its classification as a Schedule II substance in the USA [ 7 , 28 ].…”

Tapentadol for the management of cancer pain in adults: an update

“…It is the first of a new class of MOR-NRI drugs and the only one of this class available 4–6▪▪,7. As well as being a MOR agonist, tapentadol blocks the reuptake of noradrenalin, potentiating the inhibitory effect of noradrenalin (which is ordinarily released by activation of the descending inhibitory pathway) 4–6▪▪,7. It thus inhibits pain signaling by acting on both ascending and descending pathways (Fig.…”

“…Other opioids, such as morphine, fentanyl, and oxycodone, produce their main analgesic effects by activating MOR 10. Tramadol also has serotonin and NRI actions leading to analgesia 1▪▪,7, although the balance of serotonin at the different 5HT receptors in the pain pathway can have variable effects on pain transmission, being facilitatory in chronic pain 4. Tapentadol has no clinically relevant effect on serotonin, so it potentially has more predictable analgesic properties across a range of clinical pain situations.…”