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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.
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 immediate-release formulation doses of tapentadol 100 mg every 6 hours, tapentadol 150 mg every 6 hours, placebo and a single oral dose of moxifloxacin. Similarly, the immediate-release formulation tapentadol had no relevant effect on other ECG parameters (heart rate, PR interval, QRS duration, T-wave or U-wave morphology).
The minimum effective plasma concentration of tapentadol for analgesia varies widely among patients, especially among patients who have been previously treated with agonist opioids. As a result, individually titrate patients to achieve a balance between therapeutic and adverse effects. The minimum effective analgesic concentration of tapentadol for any individual patient may increase over time due to an increase in pain, progression of disease, development of a new pain syndrome and/or potential development of analgesic tolerance.
Concentration-Adverse Experience Relationships
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 therapeutic 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 Cardiovascular System
Tapentadol produces peripheral vasodilation which may result in orthostatic hypotension.
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
The mean absolute bioavailability after single-dose administration (fasting) of NUCYNTA® ER is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of tapentadol are observed between 3 and 6 hours after administration of NUCYNTA® ER. Dose proportional increases for AUC have been observed after administration of NUCYNTA® ER over the therapeutic dose range.
Steady-state exposure of tapentadol is attained after the third dose (i.e., 24 hours after first twice daily multiple dose administration). Following dosing with 250 mg every 12 hours, minimal accumulation was observed.
The AUC and Cmax increased by 6% and 17%, respectively, when NUCYNTA® ER tablet was administered after a high-fat, high-calorie breakfast. NUCYNTA® ER 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%.
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 5 hours after oral administration. The total clearance of tapentadol is 1603 +/-227 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 5.5-fold higher compared with normal renal function, respectively.
Administration of tapentadol 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 t1/2. 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.
Only a minor amount of tapentadol is metabolized via the oxidative pathway. In addition, in vitro studies did not reveal any potential of tapentadol to either inhibit or induce cytochrome P450 enzymes. 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.
Drug Interaction/Alcohol Interaction
NUCYNTA® ER may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression, because respiratory depression, hypotension, hypertension, and profound sedation, coma or death may result [see WARNINGS AND PRECAUTIONS].
An in vivo study examined the effect of alcohol (240 mL of 40%) on the bioavailability of a single dose of 100 mg and 250 mg of NUCYNTA® ER tablet in healthy, fasted volunteers. After co-administration of a 100 mg NUCYNTA® ER tablet and alcohol, the mean Cmax value increased by 48% compared to control with a range of 0.99-fold to 4.38-fold. The mean tapentadol AUClast and AUCinf were increased by 17%; the Tmax and t½ were unchanged. After co-administration of a 250 mg NUCYNTA® ER tablet and alcohol, the mean Cmax value increased by 28% compared to control with a range of 0.90-fold to 2.67-fold. The mean tapentadol AUClast and AUCinf were increased by 16%; the Tmax and t½ were unchanged.
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 of NUCYNTA® ER was studied in five studies in patients with moderate to severe chronic pain and DPN. Efficacy was demonstrated in one randomized, double-blind, placebo- and active-controlled study in patients with chronic low back pain (LBP), and two randomized, double-blind, placebocontrolled studies in patients with pain related to diabetic peripheral neuropathy (DPN-1 and DPN-2).
Moderate to Severe Chronic Low Back Pain
In the LBP study, patients 18 years of age or older with chronic low back pain and a baseline pain score of ≥ 5 on an 11-point numerical rating scale (NRS), ranging from 0 to 10 were enrolled and randomized to 1 of 3 treatments: NUCYNTA® ER, active-control (an extended-release Schedule II opioid analgesic), or placebo.
Patients randomized to NUCYNTA® ER initiated therapy with a dose of 50 mg twice daily for three days. After three days, the dose was increased to 100 mg twice daily. Subsequent titration was allowed over a 3-week titration period to a dose up to 250 mg twice daily, followed by a 12-week maintenance period. There were 981 patients randomized. The mean age of the study population was 50 (range 18 to 89) years; the mean baseline pain intensity score was 8 (SD 1). Approximately half of the patients were opioid-na´ve (had not taken opioids during the three months prior to the screening visit).
The number of patients completing the study was 51% in the placebo group, 54% in the NUCYNTA® ER group and 43% in the active-control group. Lack of efficacy was the most common reason for discontinuation among placebo-treated patients (21%), whereas adverse events were the most common reason for discontinuation among the active treatment groups (17% and 32% for NUCYNTA® ER and active-control, respectively).
After 15 weeks of treatment, patients taking NUCYNTA® ER had a significantly greater pain reduction compared to placebo. The proportion of patients with various degrees of improvement is shown in Figure 1. The figure is cumulative, such that patients, whose change from baseline is, for example 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement.
Figure 1: Percentage of Patients Achieving Various Levels of Improvement in Pain Intensity - Study LBP1
1 The last week of Study LBP was Week 15.
Neuropathic Pain Associated with Diabetic Peripheral Neuropathy
In the two DPN studies, patients 18 years of age or older with pain due to diabetic peripheral neuropathy and a pain score of ≥ 5 on an 11-point numerical rating scale (NRS) ranging from 0 (no pain) to 10 (worst possible pain) were enrolled. Following an open-label treatment period in which NUCYNTA® ER was administered to all patients for three weeks and titrated to an individually stable dose, patients who had tolerated the drug and demonstrated at least a 1-point improvement in pain intensity on the NRS at the end of the open-label titration period were randomized to either continue the NUCYNTA® ER dose (100 mg to 250 mg twice a day) reached during the open-label titration period, or receive placebo for 12 weeks of maintenance treatment. During the first 4 days of the double-blind maintenance period patients were permitted to take tapentadol ER 25 mg up to two times a day as additional medication. After the first 4 days, patients were allowed to take tapentadol ER 25 mg once daily as needed for pain, in addition to the patient's assigned study drug. Patients recorded their pain in a diary twice daily.
Study DPN-1: A total of 591 patients entered open-label treatment and 389 patients met the criteria for randomization into the double-blind treatment period. The mean age of the randomized population was 60 (range 29 to 87) years; approximately two-thirds of the patients were opioid-na´ve (had not taken opioids during the three months prior to the screening visit).
During the titration period, 34% of patients discontinued open-label NUCYNTA® ER. The most common reasons for discontinuation in the doubleblind treatment period were lack of efficacy in the placebo group (14%) and adverse events in the NUCYNTA® ER group (15%).
After 12 weeks of treatment, NUCYNTA® ER provided a significantly greater reduction in pain intensity from baseline to the end of the 12-week double-blind period compared to placebo. Figure 2 displays the proportion of randomized patients achieving various degrees of improvement in pain intensity from the start of the open-label titration period to the last week of the randomized withdrawal period. The figure is cumulative, such that patients, whose change from baseline is, for example 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement.
Figure 2: Percentage of Patients Achieving Various Levels
of Improvement in Pain Intensity - DPN-1
Study DPN-2: A total of 459 patients entered open-label treatment and 320 patients met the criteria for randomization into the double-blind treatment period. The mean age of the randomized population was 59 (range 28 to 83) years; approximately two-thirds of the patients were opioid-na´ve (had not taken opioids during the three months prior to the screening visit).
During the titration period, 22% of patients discontinued open-label NUCYNTA® ER and 6% of patients were not subsequently randomized because they failed to have at least 1-point improvement in pain intensity. The most common reason for discontinuation in the double-blind treatment period was adverse events in both the placebo group (9%) and the NUCYNTA® ER group (14%).
After 12 weeks of treatment, NUCYNTA® ER provided a significantly greater reduction in pain intensity from baseline to the end of the 12-week double-blind period compared to placebo. Figure 3 displays the proportion of randomized patients achieving various degrees of improvement in pain intensity from the start of the open-label titration period to the last week of the randomized withdrawal period. The figure is cumulative, such that patients, whose change from baseline is, for example 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement.
Figure 3: Percentage of Patients Achieving Various Levels
of Improvement in Pain Intensity-DPN-2
Last reviewed on RxList: 10/5/2012
This monograph has been modified to include the generic and brand name in many instances.
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