Tapentadol

Tapentadol, sold under the brand names Nucynta and Palexia among others, is a synthetic opioid analgesic with a dual mode of action as a highly selective full agonist of the μ-opioid receptor and as a norepinephrine reuptake inhibitor (NRI).^[6] Tapentadol is used medically for the treatment of moderate to severe pain.^[2] It is highly addictive and is a commonly abused drug.^{[2][8][9][10]}

Common side effects include euphoria, constipation, nausea, vomiting, headaches, loss of appetite, drowsiness, dizziness, itching, dry mouth, and sweating.^[11] Serious side effects may include addiction and dependence, substance abuse, respiratory depression and an increased risk of serotonin syndrome.^[12][13] Combining tapentadol with certain substances, including serotonergic drugs or other central nervous system depressants such as alcohol, cannabis, benzodiazepines, and other opioids, may increase the risk of serotonin syndrome, sedation, respiratory depression, and death.^[9][14]

Analgesia occurs within 32 minutes of oral administration, and lasts for 4–6 hours.^[15] Tapentadol is taken by mouth, and is available in immediate-release and controlled-release formulations.^[16] Tapentadol’s combined mechanism of action is often compared to that of tramadol.^[15] Unlike tramadol, tapentadol is not metabolised by cytochrome P450 enzymes, but rather through glucuronidation.^[17] Due to this, tapentadol has fewer interactions with other medications and fewer side effects when compared with tramadol.^[17]

Like tramadol, tapentadol affects both the opioid system and the norepinephrine system to relieve pain.^[18] Unlike tramadol, it has only weak effects on the reuptake of serotonin and is a significantly more potent opioid with no known active metabolites.^[15][19] The potency of tapentadol is somewhere between that of tramadol and morphine,^[20] with an analgesic efficacy comparable to that of oxycodone despite a lower incidence of side effects.^[6] The CDC Opioid Guidelines Calculator estimates a conversation rate of 50mg of tapentadol equaling 10 mg of oral oxycodone in terms of opioid receptor activation.^[21]

In the late 1980s, Grünenthal developed tapentadol to improve on tramadol,^[22] which they had created in 1962.^[23] Their goal was to design a molecule that minimized serotonin activity, strongly activated the μ-opioid receptor, inhibited norepinephrine reuptake, and worked without metabolic activation.^[22] The result was tapentadol. Due to the high risk of addiction, substance misuse, and dependence,^[24][10][14] tapentadol is a Schedule II controlled substance in the United States,^[25] a Schedule 8 controlled drug in Australia,^[26] and a Class A controlled substance in the United Kingdom.^[27]