Available online on 15.11.2021 at http://jddtonline.info

Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access  Full Text Article                                                                                                                                           Review Article 

Tapentadol: Use and Abuse

Juvin Thomas CV ¹,  Sambath Kumar R ²*,   Venkateswaramurthy N¹, 

¹ Department of Pharmacy Practice, J.K.K. Nattraja College of Pharmacy, Kumarapalayam-638183, Tamil Nadu, India

² Department of Pharmaceutics, J.K.K. Nattraja College of Pharmacy, Kumarapalayam-638183, Tamil Nadu, India

INTRODUCTION

Tapentadol is a centrally acting, multime-chanistic analgesic with a combination of l-opioid agonist activity and norepinephrine reuptake inhibition(NRI) that is used to treat moderate to severe acute andchronic pain.^1-5 The FDA approved the immediate-release formulation (Nucynta ER) of tapentadol in December 2008, and the FDA approved the extended-release (ER) formulation (Nucynta ER) in August 2011.⁶ Tapentadol is a new analgesic that acts as both an agonist of the -opioid receptor (MOR) and a norepinephrine reuptake inhibitor in a single molecule (NRI). Its analgesic benefits start right away, at roughly 30 m for both acute and chronic nociceptive and neuropathic pain.⁷ Surprisingly, NRI blockers can suppress this last component of tapentadol activity.⁸ Furthermore, an opioid antagonist like naloxone does not reduce the efficacy of tapentadol, indicating that this molecule has a dual mode of action.^9,10 Tapentadol is not a prodrug, and its therapeutic benefits are not dependent on metabolism. It's a powerful opioid with no known active metabolites, and none of them contribute to its analgesic properties.^{11, 12} Tapentadol is metabolised via glucuronidation to tapentadol-O-glucuronide, which then conjugates with glucuronic acid to create glucuronides. It is poorly processed by cytochrome P3A4 (CYP3A4) and cytochrome P2D6, which are found throughout the human body.^{11, 12} Tapentadol is a prescription pain reliever that is taken by mouth, and its metabolites are eliminated in the urine. Between 1.25 and 1.5 hours after intake, the maximal serum concentration is recorded, and the half-life is four hours.^11,12 Because tapentadol is not considerably metabolised by the CYP450 system and does not activate or inhibit CYP enzymes, medication interactions are unlikely.^11,12

Uses:

Tapentadol is a drug that is used to treat musculoskeletal pain as well as neuropathic pain caused by diabetic peripheral neuropathy.¹³ In cases of opioid-related gastrointestinal (GI) intolerance, nausea, vomiting, or itching, tapentadol may be used instead of other opioid pain medications. Tapentadol, like tramadol, another dual-acting analgesic, delivers multimodal opioid and non-opioid analgesic effects.¹³

When compared to equal analgesic doses of conventional opioids, tapentadol has less side effects, which could be due to the fact that the analgesic pathways for this molecule are only partially mediated by opioid agonist mechanisms.¹⁴

Tapentadol's use could broaden the pharmaceutical toolkit against NP, which is notoriously difficult to treat with other analgesics or co-analgesics such antidepressants or anticonvulsants.^15-20

It is used to treat moderate to severe chronic pain as well as neuropathic pain in adults with diabetic peripheral neuropathy (DPN). It is not, however, intended for use as an analgesic for acute pain or minor pain that is not expected to last for a long time. It's also not indicated for postoperative pain unless the patient is already on long-term opioid medication before surgery.²¹

Pharmacological properties:

In vitro, the drug's MOR binding affinity was significantly lower than that of morphine, despite its analgesic effectiveness in animal models being just two to three times that of morphine.²² emphasizing the role of NRI activity in the analgesic effect In certain animal analgesia models, tapentadol's opioid and noradrenergic processes were synergistic.²³ Depending on the type of pain, the relative influence of each may vary.²⁴ Tapentadol showed analgesic effects in a variety of preclinical pain types, confirming its dual mechanism. The main metabolite of tapentadol (tapentadol-O-glucuronide) has no effect on opioid receptors, synaptosomal reuptake systems, or other binding sites.²²

Tapentadol serum concentrations peak 3–6 hours after PR pill delivery.^25,26 When the tablets are taken twice daily, steady-state levels are reached on the second day, with an accumulation ratio of 1.5.²⁵ Tapentadol PR pills can be taken with or without food, and following intravenous administration, they have a volume of distribution of 540 L, and is just 20% bound to serum proteins. The medication is extensively metabolized, primarily through glucuronidation, with the primary enzymes implicated being UGT1A6, UGT1A9, and UGT2B7, 2C9, CYP2C19, and CYP2D6 are additional enzymes that break down the medication. Tapentadol and its metabolites are mostly (99%) excreted through the kidneys.²⁵ According to population pharmacokinetic modeling, the drug's apparent oral clearance after PR pill dose is 257 L/h.²⁷ andIt has a terminal half-life of 5–6 hours on average.²⁵

Tapentadol PR should be used with caution in mild hepatic impairment (beginning at the lowest dose of 50 mg once daily) and is not suggested in individuals with severe renal or hepatic impairment (because to a lack of data).²⁵ Tapentadol PR dosage does not normally need to be adjusted in elderly people, while the dosage should be carefully chosen.²⁵

Pharmacodynamics:

Mu-receptors can be found in the periaqueductal gray region, the spinal cord's superficial dorsal horn, and numerous layers of the cerebral cortex. The descending modulation of pain is mediated by norepinephrine (noradrenaline).²⁸ Tapentadol is a synthetic analgesic that operates as a mu-opioid receptor agonist and a norepinephrine re-uptake inhibitor in the central nervous system (NRI)²⁹ Through mu-opioid agonistic action, it changes sensory and emotional elements of pain, slows pain transmission at the spinal cord, and affects pain perception activity. It causes analgesia by increasing the amount of norepinephrine in the brain by preventing its re-absorption into nerve cells at central nervous system sites.^{28, 30, 31}

Drugs that impede the reuptake of norepinephrine and/or serotonin are effective in the treatment of chronic pain and can boost the analgesic effects of morphine. As a result, TAP and morphine may have a synergistic impact. It has a lower analgesic potency due to its inability to connect to the mu-opioid receptor. TAP was approved for the treatment of moderate to severe pain in adults because it works for a wide range of pain types, from acute to chronic. ³²

Pharmacokinetics:

TAP is absorbed 32 % when taken orally.³⁰ Gastric pH or gastrointestinal motility had no effect on its pharmacokinetics, and it could be taken with or without food.³³ It is broadly dispersed throughout the body and does not require metabolic activation to function. TAP enantiomer (RR-form) penetrates the blood–brain barrier quickly and has a rapid onset of action.³⁰ TapentadolCmax and AUC values increased with a dosage of 50–150 mg, and plasma protein binding was roughly 20%.³⁴ After oral dosing, the plasma half-life is approximately 4 hours.³² After 1 hour, the maximal effect is reached, and the activity lasts 4–6 hours.³⁰

About 97 percent of the medication undergoes substantial first-pass hepatic metabolism.³⁰ Phase I pathways metabolize a tiny amount of TPA, but phase II pathways metabolize the majority of it.³⁵

TAP has a lesser risk of drug–drug interactions due to the limited participation of phase I metabolic pathways. TAP is deactivated after biotransformation by metabolic enzymes, meaning it has no active metabolites. The most common metabolite is glucuronide conjugate (27%), which is followed by ³⁰ After oral treatment, the sulfate conjugate (15%) of the dose is eliminated in urine in a conjugated state. CYP2C9 and CYP2C19 metabolize it to N-desmethyltapentadol (13 percent) and hydroxytapentadol (2 percent) respectively, which are then conjugated. As a result, the cytochrome P450 system plays a smaller role in TAP drug metabolism than it does in the conjugation phase. In urine, just 3% of the medication is excreted in its unmodified form. TAP and its metabolites are primarily eliminated (99%) through the kidney.^{35, 36,37}

Drug Interactions:

In combination with mixed MOR agonists/antagonists or partial MOR agonists, tapentadol PR must be used with caution.²⁵ If buprenorphine patients require tapentadol PR, temporary withdrawal of buprenorphine is a possibility; if used with buprenorphine, greater tapentadol PR dosages may be required, necessitating AE monitoring for respiratory depression.²⁵ When using tapentadol PR with respiratory depressants, the risk of respiratory depression is increased, and its sedative effects are increased by CNS depressants; if taking tapentadol PR with such medicines, consider reducing the dosage. Patients who are acutely drunk with alcohol, hypnotics, centrally acting analgesics, or psychiatric drugs should not take tapentadol PR.²⁵

Tapentadol PR is unlikely to cause clinically significant glucuronidation-mediated medication interactions.²⁵ If tapentadol PR is used with medicines that strongly block the UGT isoenzymes involved in its metabolism, exposure to tapentadol may rise. If you're stopping or starting strong enzyme inducers at the same time, proceed with caution.²⁵

Tapentadol PR and monoamine oxidase inhibitors (MAOIs) may have additive effects on noradrenaline at synapses; as a result, tapentadol PR should be avoided when on MAOI therapy or within 14 days of finishing it. Tapentadol has caused serotonin syndrome in serotoninergic drug users, though symptoms normally improve if the serotoninergic substance is stopped.CYP-mediated medication interactions are unlikely to be clinically significant with tapentadol PR because tapentadol does neither stimulate or inhibit CYP enzymes in vitro.Drug interactions via protein binding-site displacement are also rare due to low serum protein binding.²⁵

Dosage and Administration:

In a number of European countries, notably the United Kingdom,²⁵ Tapenadol PR 50–250 mg tablets are used to treat severe chronic pain in people that cannot be treated effectively with opioid analgesics. The tablets should be taken without chewing or dividing twice day (every 12 hours). The dosage should be tailored to the severity of the pain, the patient's ability to be monitored, and their prior treatment history, including the nature, mode of administration, and average daily dose of previous therapy.²⁵ Patients who are already using opioids may need a greater starting dose of tapentadol PR than those who aren't. The dosage of tapentadol PR should be titrated to achieve appropriate analgesia while minimizing adverse effects; the total daily dosage should not exceed 500 mg.²⁵ Tapentadol PR abuse/addiction should be considered for patients at higher risk of abuse, misuse, addiction, or diversion; all recipients should be closely monitored for indicators of abuse/addiction.²⁵

Dosing Issues:

Individualize the tapentadol SR dose based on the degree of the pain and the patient's reaction. Tapentadol SR tablets should be taken twice a day, with or without food, about 12 hours apart. ³⁸

Overdose Management:

There is little clinical experience with tapentadol overdose. Symptoms such as vomiting, circulatory collapse, and respiratory depression/arrest are predicted to be comparable to those seen with other opioid analgesics. In the event of an overdose, the most important thing to remember is to keep breathing. Although opioid antagonists like naloxone can be administered as a specific antidote to respiratory depression, respiratory depression after an overdose may last longer than the opioid antagonist's duration of action.³⁸

Use in pregnancy, older people and children:

Tapentadol is a category C drug that has not been tested in pregnancy. While nursing, tapentadol should be avoided. Due to a lack of safety and efficacy data, do not use in children under the age of 18. When prescribing tapentadol to older people, use caution, as with any opioids.³⁸

Interactions with medicines:

Other central nervous system depressants, such as phenothiazines, sedatives, hypnotics, or other CNS depressants (including alcohol), may cause an additive CNS depression, resulting in respiratory depression, hypotension, deep drowsiness, or coma in those who take tapentadol SR simultaneously. Avoid taking tapentadol SR with any of these medications if at all feasible. If it's inevitable, keep a close eye on things and try lowering one or both of your medications' doses. Combining MAOIs with tapentadol (or using tapentadol in individuals who have recently taken MAOIs) may induce cumulative effects on noradrenaline levels, which could lead to serious cardiovascular events. ³⁸

Serotonin toxicity:

Tapentadol only has a minor impact on serotonin reuptake.³⁹ However, there is a theoretical risk of serotonin syndrome if tapentadol is taken with other serotonergic medications such as SSRIs, SNRIs, TCAs, MAOIs, St John's wort, and triptans.³⁸

There have been a few reports of serotonin syndrome in patients who were also taking tapentadol SR.³⁸

Internet Discussion and Surveys:

Internet forums about prescription drug abuse by recreational drug users record uncensored data on the patterns and preferences of nonmedical opioid usage in real time among prescription drug abusers, providing a unique data source for assessing opioid abuse liability. The proportion of posts discussing tapentadol (0.0003) was the lowest of the nine compounds tested in a survey gathering slightly under 2,000,000 messages written by recreational drug abusers in online forums between January 1, 2011 and September 30, 2012. It was much lower than the proportions for the other comparators (oxycodone, oxymorphone, hydromorphone, hydrocodone, morphine, buprenolone, and buprenolone).⁴⁰

Adverse Events:

These side effects may be the result of the mu-opioid receptor agonism. Convulsions, hypersensitivity,nausea, dizziness, vomiting, somnolence and delayed stomach emptying have all been described infrequently.³⁰

Symptoms of mu opioid agonisms are exacerbated by TAP overdose. As a result, treatment should be focused on reversing the onset of symptoms. Supportive therapies (such as oxygen and vasopressors) should be employed to manage circulatory shock and pulmonary edema, as well as controlled ventilation for the patient.³⁰

 Drug Abuse:

Tapentadol has been in the Indian market for eight and a half years. In 2017, our centre was the subject of a single peer-reviewed study detailing two incidences of abuse.⁴¹ The Indian Pharmacovigilance Program has issued no drug safety alerts or advisories, and Tapentadol's current drug label does not indicate that it is a class H or H1 substance.⁴² Tapentadol is more likely than Tramadol to be abused. Despite these findings, real-world evidence reveals that Tapentadol has a lower rate of diversion, abuse, addiction, overdose, and street demand than other prescription opioids in the United States. ⁴³

Prescription opioid abuse is a well-known public health problem in the United States, with significant morbidity and death, as well as the social and legal ramifications of substance abuse and addiction.^44,45 Prescription opioids are an important therapy option for the management of acute and chronic pain in some patients, but they are not for everyone.^46,47 The most prevalent reason for prescription opioid usage is pain alleviation.^48,49 The need for proper access to opioid medication must be balanced against the possible dangers, including opioid misuse and addiction, according to a recent recommendation from the US Department of Health and Human Services on opioid analgesic dosage decrease or termination.⁵⁰ Current efforts to combat the opioid crisis and manage chronic pain are centered on developing novel medications that treat pain effectively while posing a lower risk of abuse and addiction.⁵¹ Although conventional opioids generally interact with the mu-opioid receptor, the pharmaceutical opioid classes have significant variances in potencies, pharmacokinetic properties, and propensity for abuse and addiction.^51,52

Tapentadol affects both ascending and descending brain pathways, modulating pain signals.⁵³ Since 2008 and 2011, the medicine has been offered in immediate-release (IR) and extended-release (ER) versions in the United States.^54,55 However, it is used less frequently than other opioid formulations. The IR formulation is for the treatment of acute pain that necessitates the use of an opioid analgesic and for which other therapies are ineffective.⁵⁴ ER indications include neuropathic pain associated with diabetic peripheral neuropathy, which requires daily, around-the-clock, long-term opioid medication and for which alternate treatment alternatives are insufficient.⁵⁵ Despite the fact that continuous opioid therapy has been found to increase the risk of drug addiction,⁵⁶ In pre-marketing investigations of tapentadol IR15, dependency was not recorded, and it occurred in less than 1% of patients treated with tapentadol ER in 10 Phase 2 and 3 clinical studies.⁵⁴

Postmarketing Evaluation of Tapenadol:

Abuse of tapentadol was reported substantially less frequently (P 0.001) than abuse of the other drugs. Except for fentanyl IR, which had the lowest unadjusted abuse prevalence, tapentadol IR had a significantly lower abuse prevalence than all other comparators. With the exception of hydromorphone ER, tapentadol ER misuse was less common. Tapentadol as a chemical, as well as its IR and ER forms, had low prescription-adjusted estimates, which were among the lowest recorded and among the lowest of the Schedule II comparators. Except for hydromorphone ER (P = 0.06), tapentadol ER had a lower prescription-adjusted risk than the other drugs.⁴⁰

The limited potential for abuse and misuse of tapentadol found in post-marketing investigations could be explained by its pharmacologic characteristics and finite upper dose constraints, but the specific explanation is unknown.^54,55 Because tapentadol is almost entirely metabolized in phase II, it has no clinically significant cytochrome P450 drug interactions.⁵⁴ Tapentadol is also unaffected by cytochrome P450 phenotypic outliers, such as poor or extensive isoenzyme metabolizers, making for a simpler transition when switching from other opioids that avoid the phase I metabolism pathway (e.g., morphine, oxymorphone, and hydromorphone) and potentially avoiding mathematical errors when switching from other opioids that avoid the phase I metabolism pathway (e.g., morphine, oxymorph)^{57, 58}

Furthermore, tapentadol has little or no effect on serotonin reuptake blockage, reducing the risk of medication interactions and side effects associated with serotonin agonist activity and serotonin withdrawal.³⁹ Tapentadol has been demonstrated to be efficacious and well-tolerated in patients with chronic pain when used as indicated, with a lower rate of gastrointestinal side effects than other powerful opioids.⁵⁹

CONCLUSION:

Tapentadol is a one-of-a-kind synthetic opioid molecule with NRI properties. It causes acute nociceptive as well as persistent neuropathic analgesia. However, after glucuronidation, it is largely present in the form of conjugated metabolites and is excreted fast and completely via the kidneys. Precautions are urged against using central nervous system depressants concurrently, or using tapentadol within 14 days of stopping monoamine oxidase inhibitors.

Tapentadol abuse, addiction seeking behavior, withdrawal, and physical dependency are the most serious issues. The main challenge with tapentadol use is controlling the ratio of MOR agonist to NRI. Finally, tapentadol provides both nociceptive and neuropathic pain relief, but there are concerns about abuse and reliance.

Conflicts of Interest: Nil

Funding statement: Nil

Acknowledgement: we would like to express our thanks to the head, Department of pharmacy practice and our 

Department staffs to their valuable suggestions and recommendations. 

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