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Mechanism Of Action
Tapentadol is a centrally-acting synthetic analgesic. The exact mechanism of action is unknown. Although the clinical relevance is unclear, preclinical studies have shown that tapentadol is a mu-opioid receptor (MOR) agonist and a norepinephrine reuptake inhibitor (NRI). Analgesia in animal models is derived from both of these properties.
Tapentadol is 18 times less potent than morphine in binding to the human mu-opioid receptor and is 2-3 times less potent in producing analgesia in animal models. Tapentadol has been shown to inhibit norepinephrine reuptake in the brains of rats resulting in increased norepinephrine concentrations. In preclinical models, the analgesic activity due to the mu-opioid receptor agonist activity of tapentadol can be antagonized by selective mu-opioid antagonists (e.g., naloxone), whereas the norepinephrine reuptake inhibition is sensitive to norepinephrine modulators. Tapentadol exerts its analgesic effects without a pharmacologically active metabolite.
The minimum effective plasma concentration of tapentadol for analgesia varies widely among patients, especially among patients who have been previously treated with agonist opioids.
Concentration-Adverse Experience Relationships
There is a general relationship between increasing opioid plasma concentration and increasing frequency of adverse experiences such as nausea, vomiting, CNS effects, and respiratory depression.
Effects on the Cardiovascular System
There was no effect of therapeutic and supratherapeutic doses of tapentadol on the QT interval. In a randomized, double-blind, placebo- and positive-controlled crossover study, healthy subjects were administered five consecutive doses of NUCYNTA® 100 mg every 6 hours, NUCYNTA® 150 mg every 6 hours, placebo and a single oral dose of moxifloxacin. Similarly, NUCYNTA® had no relevant effect on other ECG parameters (heart rate, PR interval, QRS duration, T-wave or U-wave morphology).
Effects on the Central Nervous System (CNS)
The principal therapeutic action of tapentadol is analgesia. Tapentadol causes respiratory depression, in part by a direct effect on the brainstem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Tapentadol depresses the cough reflex by direct effect on the cough center in the medulla.
Tapentadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see OVERDOSAGE]. Other effects of tapentadol include anxiolysis, euphoria, and feeling of relaxation, drowsiness and changes in mood.
Effects on the Gastrointestinal Tract and on Other Smooth Muscle
Gastric, biliary and pancreatic secretions are decreased by tapentadol. Tapentadol causes a reduction in motility and is associated with an increase in tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm. The end result is constipation. Tapentadol can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi, and transient elevations in serum amylase. Tapentadol may also cause spasm of the sphincter of the urinary bladder.
Effects on the Endocrine System
Opioid agonists have been shown to have a variety of effects on the secretion of hormones. Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.
Effects on the Immune System
Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown.
CNS Depressant/Alcohol Interaction
Additive pharmacodynamic effects may be expected when NUCYNTA® is used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.
The mean absolute bioavailability after single-dose administration (fasting) of NUCYNTA® is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of tapentadol are typically observed at around 1.25 hours after dosing.
Dose-proportional increases in the Cmax and AUC values of tapentadol have been observed over the 50 to 150 mg dose range.
A multiple (every 6 hour) dose study with doses ranging from 75 to 175 mg tapentadol showed a mean accumulation factor of 1.6 for the parent drug and 1.8 for the major metabolite tapentadol-O-glucuronide, which are primarily determined by the dosing interval and apparent half-life of tapentadol and its metabolite.
The AUC and Cmax increased by 25% and 16%, respectively, when NUCYNTA® was administered after a high-fat, high-calorie breakfast. NUCYNTA® may be given with or without food.
Tapentadol is widely distributed throughout the body. Following intravenous administration, the volume of distribution (Vz) for tapentadol is 540 +/- 98 L. The plasma protein binding is low and amounts to approximately 20%.
Metabolism and Elimination
In humans, about 97% of the parent compound is metabolized. Tapentadol is mainly metabolized via Phase 2 pathways, and only a small amount is metabolized by Phase 1 oxidative pathways. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration approximately 70% (55% O-glucuronide and 15% sulfate of tapentadol) of the dose is excreted in urine in the conjugated form. A total of 3% of drug was excreted in urine as unchanged drug. Tapentadol is additionally metabolized to N-desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 and to hydroxy tapentadol (2%) by CYP2D6, which are further metabolized by conjugation. Therefore, drug metabolism mediated by cytochrome P450 system is of less importance than phase 2 conjugation.
None of the metabolites contribute to the analgesic activity.
Tapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys. The terminal half-life is on average 4 hours after oral administration. The total clearance is 1530 +/- 177 mL/min.
The mean exposure (AUC) to tapentadol was similar in elderly subjects compared to young adults, with a 16% lower mean Cmax observed in the elderly subject group compared to young adult subjects.
AUC and Cmax of tapentadol were comparable in subjects with varying degrees of renal function (from normal to severely impaired). In contrast, increasing exposure (AUC) to tapentadol-O-glucuronide was observed with increasing degree of renal impairment. In subjects with mild (CLCR = 50 to < 80 mL/min), moderate (CLCR = 30 to < 50 mL/min), and severe (CLCR = < 30 mL/min) renal impairment, the AUC of tapentadol-O-glucuronide was 1.5-, 2.5-, and 5.5fold higher compared with normal renal function, respectively.
Administration of NUCYNTA® resulted in higher exposures and serum levels to tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The ratio of tapentadol pharmacokinetic parameters for the mild hepatic impairment group (Child-Pugh Score 5 to 6) and moderate hepatic impairment group (Child-Pugh Score 7 to 9) in comparison to the normal hepatic function group were 1.7 and 4.2, respectively, for AUC; 1.4 and 2.5, respectively, for Cmax; and 1.2 and 1.4, respectively, for t½. The rate of formation of tapentadol-O-glucuronide was lower in subjects with increased liver impairment.
Pharmacokinetic Drug Interactions
Tapentadol is mainly metabolized by Phase 2 glucuronidation, a high capacity/low affinity system; therefore, clinically relevant interactions caused by Phase 2 metabolism are unlikely to occur. Naproxen and probenecid increased the AUC of tapentadol by 17% and 57%, respectively. These changes are not considered clinically relevant and no change in dose is required.
No changes in the pharmacokinetic parameters of tapentadol were observed when acetaminophen and acetylsalicylic acid were given concomitantly.
In vitro studies did not reveal any potential of tapentadol to either inhibit or induce cytochrome P450 enzymes. Furthermore, a minor amount of NUCYNTA® is metabolized via the oxidative pathway. Thus, clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur.
The pharmacokinetics of tapentadol were not affected when gastric pH or gastrointestinal motility were increased by omeprazole and metoclopramide, respectively.
Plasma protein binding of tapentadol is low (approximately 20%). Therefore, the likelihood of pharmacokinetic drug-drug interactions by displacement from the protein binding site is low.
Animal Toxicology And/Or Pharmacology
In toxicological studies with tapentadol, the most common systemic effects of tapentadol were related to the mu-opioid receptor agonist and norepinephrine reuptake inhibition pharmacodynamic properties of the compound. Transient, dose-dependent and predominantly CNS-related findings were observed, including impaired respiratory function and convulsions, the latter occurring in the dog at plasma levels (Cmax) which are in the range associated with the maximum recommended human dose (MRHD).
The efficacy and safety of NUCYNTA® in the treatment of moderate to severe acute pain has been established in two randomized, double-blind, placebo- and active-controlled studies of moderate to severe pain from first metatarsal bunionectomy and end-stage degenerative joint disease.
Orthopedic Surgery – Bunionectomy
A randomized, double-blind, parallel-group, active- and placebo-controlled, multiple-dose study demonstrated the efficacy of 50 mg, 75 mg, and 100 mg NUCYNTA® given every 4 to 6 hours for 72 hours in patients aged 18 to 80 years experiencing moderate to severe pain following unilateral, first metatarsal bunionectomy surgery. Patients who qualified for the study with a baseline pain score of ≥ 4 on an 11-point rating scale ranging from 0 to 10 were randomized to 1 of 5 treatments. Patients were allowed to take a second dose of study medication as soon as 1 hour after the first dose on study Day 1, with subsequent dosing every 4 to 6 hours. If rescue analgesics were required, the patients were discontinued for lack of efficacy. Efficacy was evaluated by comparing the sum of pain intensity difference over the first 48 hours (SPID48) versus placebo. NUCYNTA® at each dose provided a greater reduction in pain compared to placebo based on SPID48 values.
For various degrees of improvement from baseline to the 48-hour endpoint, Figure 1 shows the fraction of patients achieving that level of improvement. The figures are cumulative, such that every patient that achieves a 50% reduction in pain from baseline is included in every level of improvement below 50%. Patients who did not complete the 48-hour observation period in the study were assigned 0% improvement.
Figure 1: Percentage of Patients Achieving Various
Levels of Pain Relief as Measured by Pain Severity at 48 Hours Compared
to Baseline- Post Operative Bunionectomy
The proportions of patients who showed reduction in pain intensity at 48 hours of 30% or greater, or 50% or greater were significantly higher in patients treated with NUCYNTA® at each dose versus placebo.
End-Stage Degenerative Joint Disease
A randomized, double-blind, parallel-group, active- and placebo-controlled, multiple-dose study evaluated the efficacy and safety of 50 mg and 75 mg NUCYNTA® given every 4 to 6 hours during waking hours for 10 days in patients aged 18 to 80 years, experiencing moderate to severe pain from end stage degenerative joint disease of the hip or knee, defined as a 3-day mean pain score of ≥ 5 on an 11-point pain intensity scale, ranging from 0 to 10. Pain scores were assessed twice daily and assessed the pain the patient had experienced over the previous 12 hours. Patients were allowed to continue non-opioid analgesic therapy for which they had been on a stable regimen before screening throughout the study. Eighty-three percent (83%) of patients in the tapentadol treatment groups and the placebo group took such analgesia during the study. The 75 mg treatment group was dosed at 50 mg for the first day of the study, followed by 75 mg for the remaining nine days. Patients requiring rescue analgesics other than study medication were discontinued for lack of efficacy. Efficacy was evaluated by comparing the sum of pain intensity difference (SPID) versus placebo over the first five days of treatment. NUCYNTA® 50 mg and 75 mg provided improvement in pain compared with placebo based on the 5-Day SPID.
For various degrees of improvement from baseline to the Day 5 endpoint, Figure 2 shows the fraction of patients achieving that level of improvement. The figures are cumulative, such that every patient that achieves a 50% reduction in pain from baseline is included in every level of improvement below 50%. Patients who did not complete the 5-day observation period in the study were assigned 0% improvement.
Figure 2: Percentage of Patients Achieving Various
Levels of Pain Relief as Measured by Average Pain Severity for the Previous 12
hours, Measured on Study Day 5 Compared to Baseline- End Stage
Degenerative Joint Disease
The proportions of patients who showed reduction in pain intensity at 5 days of 30% or greater, or 50% or greater were significantly higher in patients treated with NUCYNTA® at each dose versus placebo.
Last reviewed on RxList: 12/4/2014
This monograph has been modified to include the generic and brand name in many instances.
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