Tapentadol — BrandWiki

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). Tapentadol is used medically for the treatment of moderate to severe pain.[2] It is highly addictive and is a commonly abused drug.[2][7][8][9]

Frequently reported adverse effects include euphoria, constipation, nausea, vomiting, headaches, loss of appetite, drowsiness, dizziness, itching, dry mouth, and sweating.[10] More severe adverse reactions can occur, including addiction and dependence, substance abuse, respiratory depression, and an elevated risk of serotonin syndrome.[11][12] Concurrent use of tapentadol with serotonergic drugs or central nervous system depressants – including alcohol, cannabis, benzodiazepines, and other opioids – can heighten the risks of excessive serotonin accumulation, profound sedation, dangerously slowed breathing and death.[8]

Analgesia occurs within 32 minutes of oral administration, and lasts for 4–6 hours.[13] Tapentadol is taken by mouth, and is available in immediate-release and controlled-release formulations.[14] Tapentadol's combined mechanism of action is often compared to that of tramadol.[13] Unlike tramadol, tapentadol is not metabolised by cytochrome P450 enzymes, but rather through glucuronidation.[15] Due to this, tapentadol has fewer interactions with other medications and fewer side effects when compared with tramadol.[15]

Like tramadol, tapentadol affects both the opioid system and the norepinephrine system to relieve pain.[16] Unlike tramadol, it has only weak effects on the reuptake of serotonin and is a significantly more potent opioid with no known active metabolites.[13][17] The potency of tapentadol is somewhere between that of tramadol and morphine,[18] with an analgesic efficacy comparable to that of oxycodone despite a lower incidence of side effects. 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.[19]

In the late 1980s, Grünenthal developed tapentadol to improve on tramadol, which they had created in 1962. 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. The result was tapentadol. Due to the high risk of addiction, substance misuse, and dependence,[20][9] tapentadol is a Schedule II controlled substance in the United States,[21] a Schedule 8 controlled drug in Australia,[22] and a Class A controlled substance in the United Kingdom.[23]

Medical use

Tapentadol is used for the treatment of moderate to severe pain for both acute (following e.g. injury or surgery) and chronic musculoskeletal pain.[24] It is also specifically indicated for controlling the pain of diabetic neuropathy when around-the-clock opioid medication is required.

Extended-release formulations of tapentadol are not indicated for use in the management of acute pain and are instead indicated only for the relief of severe, disabling pain, that is long-term in nature and cannot be controlled by any other pharmacological means.[25][26]

Tapentadol is pregnancy category C. There are no adequate and well-controlled studies of tapentadol in pregnant women, and tapentadol is not recommended for use in women during and immediately prior to labor and delivery.[27] There are no adequate and well-controlled studies of tapentadol in children.[27]

Contraindications

Tapentadol is contraindicated in people with epilepsy or who are otherwise prone to seizures. It raises intracranial pressure so should not be used in people with head injuries, brain tumors, or other conditions which increase intracranial pressure. It increases the risk of respiratory depression so should not be used in people with asthma.[24]

As with other μ-opioid agonists, tapentadol may cause spasms of the sphincter of Oddi, and is therefore discouraged for use in patients with biliary tract disease such as both acute and chronic pancreatitis. People who are rapid or ultra rapid metabolizers for the CYP2C9, CYP2C19, and CYP2D6 enzymes may not respond adequately to tapentadol therapy. Due to reduced clearance, tapentadol should be administered with caution to people with moderate liver disease and not at all in people with severe liver disease.[27]

Adverse effects

The most commonly reported side effects of tapentadol therapy are constipation, nausea, vomiting, headaches, loss of appetite, drowsiness, dizziness, itching, dry mouth, and sweating.[25][12] Tapentadol has also been noted to induce feelings of relaxation and euphoria,[11][28] and it may cause serious side effects such as respiratory depression, serotonin syndrome, addiction and substance dependence.[10]

Interactions

Combination with selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, serotonin releasing agents, and serotonin receptor agonists may lead to potentially lethal serotonin syndrome.[43] Combination with MAOIs may also result in an adrenergic storm. Use of tapentadol with alcohol or other central nervous system depressants such as benzodiazepines, barbiturates, nonbenzodiazepines, phenothiazines, gabapentinoids and other opiates may result in increased impairment, sedation, respiratory depression, and death.[25][10]

Tapentadol is partially metabolized by the hepatic enzymes CYP2C9, CYP2C19, and CYP2D6 so it innately has interactions with drugs that enhance or repress the activity/expression of one or more of these enzymes, as well as with substrates of these enzymes (due to competition for the enzyme); some enzyme mediators/substrates require dosing adjustments to one or both medications.[44]

Pharmacology

Pharmacodynamics

Tapentadol is a synthetic opioid with a dual mechanism of action: it acts as a full agonist of the μ-opioid receptor (MOR) and as a norepinephrine reuptake inhibitor (NRI).[45] This unique pharmacological profile allows it to treat both nociceptive and neuropathic pain, and it is theorised that the effects on norepinephrine are a substantial benefit for people taking it.[46] Tapentadol does not affect serotonin, unlike tramadol, which prevents the reuptake of serotonin and norepinephrine, similarly to certain antidepressants known as serotonin–norepinephrine reuptake inhibitors (SNRIs), such as desvenlafaxine and duloxetine.[47]

Tapentadol exhibits high binding selectivity and affinity for MOR, which is the principal target of the endogenous neuropeptide β-endorphin.[48]

History

Tapentadol was invented at the German pharmaceutical company Grünenthal in the late 1980s led by Helmut Buschmann;[63] the team started by analyzing the chemistry and activity of tramadol, which had been invented at the same company in 1962.[64]

Tramadol has several enantiomers, and each forms metabolites after processing in the liver. These tramadol variants have varying activities at the μ-opioid receptor, the norepinephrine transporter, and the serotonin transporter, and differing half-lives, with the metabolites having the best activity. Using tramadol as a starting point, the team aimed to discover a single molecule that minimized the serotonin activity, had strong μ-opioid receptor agonism and strong norepinephrine reuptake inhibition, and would not require metabolism to be active; the result was tapentadol.[64]

In 2003 Grünenthal partnered with two Johnson & Johnson subsidiaries, Johnson & Johnson Pharmaceutical Research and Development

Abuse and controls

There have been calls for tapentadol to be only marketed in countries where appropriate controls exist,[74] but after performing a critical review, the United Nations Expert Committee on Drug Dependence in 2014 advised that tapentadol not be placed under international control but remain under surveillance.[75]

As mentioned, the enhanced potency of tapentadol makes it considerably more susceptible to abuse compared to other opioids.[34] This increased potency is one of the key factors that contribute to its higher potential for misuse.[8][36][76] Furthermore, tapentadol is

Veterinary use

Tapentadol has been demonstrated as a potentially effective analgesic in experimental studies however, further research is needed before it can be recommended for clinical use. Tapentadol is mainly metabolized as tapentadol-O-glucuronide in dogs and tapentadol-O-sulfate in cats. Intravenous, but not oral, administration has been shown to be effective in the dog, inducing sedation, salivation, ataxia, diarrhoea, and thermal antinociception. In cats intravenous, intramuscular, and subcutaenous administration has resulted in mild sedation and salivation. IV produced longer and greater sedation in the cat than IM and SC.[84]

References

Tapentadol (Monograph) American Society of Health-System Pharmacists (AHFS), 19 April 2023^
Tapentadol Consumer Medicine Information NPS MedicineWise, September 2020^
Anvisa. RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial

Addiction and abuse

The World Health Organization determined that there was little evidence to judge the abuse potential of tapentadol when it was introduced.[31] Although early pre-clinical animal trials suggested that tapentadol had a reduced abuse liability compared to other opioid analgesics,[25] the US Drug Enforcement Agency placed tapentadol into Schedule II,[32] the same category as stronger opioids more commonly used recreationally, such as morphine, oxycodone, and fentanyl.[27][33] Since these initial trials, however, evidence has shown that tapentadol is commonly abused, misused and diverted,[20] that it is addictive,[34] and that it poses a high risk of physical and/or mental dependence.[2][7][8][10]

Given that tapentadol is a highly selective full agonist of the μ-opioid receptor, and given that is not a pro-drug, with no ceiling effect, studies have found that it is significantly more abusable than tramadol,[28] and similar to hydrocodone and other full agonists of the μ-opioid receptor (such as oxycodone and hydromorphone) in terms of addiction and dependence liability.[28][35] Tapentadol is water soluble, which creates the potential for further abuse of the drug. There have been reports of users crushing, chewing, inhaling or injecting immediate-release tapentadol tablets, which can lead to respiratory depression, coma and death.[8][36]

Dependence and withdrawal

The risk of experiencing severe withdrawal symptoms is high if a patient has become physically or mentally dependent and discontinues tapentadol abruptly.[37] These symptoms can range from mild discomfort to more serious health issues, making abrupt cessation dangerous.[38] When a person has been using tapentadol regularly for an extended period of time, tapering off the drug gradually is generally recommended.[39][40] This approach allows the body to adjust to lower doses over time, minimizing the risk of withdrawal symptoms and ensuring a safer transition away from tapentadol. Gradual withdrawal helps to avoid the shock to the system that comes with abrupt discontinuation, ultimately making the process more manageable for a person who has developed a dependence.[41]

The symptoms of tapentadol withdrawal are typical of other opioids and can include

Pharmacokinetics

Following oral administration, tapentadol typically provides onset of analgesia within 32 minutes, with effects lasting approximately 4 to 6 hours.[13][10][55] Approximately 32% of an oral dose of tapentadol escapes first-pass metabolism in the liver, entering systemic circulation to exert pharmacological effects on both the central nervous system (CNS) and peripheral nervous system (PNS).[56][25]

The free base conversion factor for tapentadol hydrochloride is 0.86.[57] Food intake has a minor impact on the drug's peak plasma concentration: increasing it by approximately 8% for immediate-release (IR) and 18% for extended-release (ER) formulations. These differences are not clinically significant, and tapentadol may be taken with or without food.[58][13]

Tapentadol displays dose-dependent plasma concentrations; however, higher doses (e.g., 250 mg) may produce disproportionately elevated Cmax values relative to lower doses, suggesting non-linear pharmacokinetics at higher concentrations.[30]

In receptor binding studies, tapentadol demonstrated a Ki of 60 nM for cloned human μ-opioid receptors, with strong agonist activity comparable to morphine, as measured by [35S]GTPγS binding assays.[59] Its inhibitory effect on norepinephrine reuptake (Ki = 480 nM) complements its opioid activity, while its weak serotonergic effects distinguish it from dual-acting agents like tramadol.[59][25] In vitro studies using human tissue indicate that tapentadol has approximately one-third the binding affinity of morphine for the human μ-opioid receptor, reflecting its comparatively lower opioid potency.[60][61][62] Nonetheless, it retains clinically meaningful opioid activity, contributing to its analgesic effects.

Commercial formulations contain only the (R,R)-stereoisomer, which is the weakest in terms of opioid receptor activation.[31] Drugs with high MOR affinity, such as tapentadol, carry an abuse potential comparable to other strong opioids like morphine, oxycodone, and hydromorphone.[35]