Tramadol SR Formulations
Introduction: Different oral sustained-release (SR) formulations of tramadol have been introduced in pain treatment in order to prolong the dosage interval to improve convenience for the patient. The objective of this study was to compare tramadol pharmacokinetics and intra- and intersubject variability after replicate single-dose administrations of a multiple-units SR formulation (capsule) and a single-unit formulation (tablet).
Methods: This was a randomised, single-dose, single-centre study with an open-label, four-period, two-sequence, two-formulation, replicate crossover design in healthy subjects under fed conditions. The main outcome measures were the intra- and intersubject variance of the area under the concentration-time curve from 0 to 12 hours (AUC12) and maximum concentration (Cmax), as well as the mean AUC12 and Cmax for tramadol. Study drugs were a tramadol SR multiple-units formulation (capsule) and a tramadol SR single-unit formulation (tablet), each containing tramadol hydrochloride 100mg. The time interval from 0 to 12 hours of AUC12 of the single-dose design corresponds to the recommended twice-daily dosage interval for both study drugs during long-term treatment.
Results: The two formulations were equivalent in the area under the curve (AUC∞: 2411 vs 2527 µg • h/L). However, capsules led to a lower Cmax (148.6 vs 183.2 µg/L), to a later time to reach Cmax (5.9 vs 4.9 hours), and to a longer half-value duration (13.4 vs 10.4 hours). In addition, intrasubject variability of AUC12 was significantly smaller for capsules than for tablets (p = 0.041). Capsules also produced smaller intra- and intersubject variability in plasma concentrations during the first 2.5 and 3.0 hours after administration, respectively (p < 0.05).
Conclusion: Although tramadol SR capsules and tramadol SR tablets led to an equivalent systemic exposure to the drug, capsules provided a smoother and more extended plasma profile. In addition, in the case of capsules, bioavailability was subjected to lower variability in terms of both rate and extent of absorption.
Tramadol is a synthetic centrally acting analgesic that binds weakly to µ-receptors. At the same time, it stimulates descendent inhibitory pathways in the spinal cord by enhancing release and decreasing re-uptake of noradrenaline and serotonin. Because of this dual mechanism of action, tramadol has a similar efficacy to codeine, despite its ten times lower affinity to µ-receptors. Tramadol thus causes less clinically relevant adverse reactions than other opioids of similar analgesic efficacy.
Since its first approval in Germany in 1977, tramadol has been registered in more than 100 countries and has become one of the preferred drugs in the treatment of moderate to severe pain. Tramadol, as an oral immediate-release (IR) formulation, reaches a maximum plasma concentration (Cmax) within 2 hours after administration and has a terminal half-life (t½) of about 5-6 hours. This relatively short half-life results in a required dosage frequency of 4-6 times daily, which is particularly inconvenient for maintaining pain relief at night and in patients requiring long-term treatment. Therefore, there is a strong need for sustained-release (SR) formulations of tramadol.
Since tramadol SR formulations result in more stable plasma concentrations than IR oral forms, adverse reactions associated with abrupt plasma peaks should decrease. This was shown for the incidences of nausea and headache, which decreased significantly when a tramadol SR oral formulation was used instead of an IR oral formulation. Furthermore, since a rapidly decreasing plasma concentration after a peak is one of the reasons for intermittent exacerbation of pain, it is expected that SR formulations will reduce the incidence of end-of-dose failure. Although clinical efficacy trials comparing SR and IR formulations of tramadol have not included the incidence of pain exacerbations as an outcome, an experimental model of pain showed that a SR formulation of tramadol is more effective than an IR formulation.
Single-unit SR formulations are commonly used to provide retardation of drug release. They slowly release the drug from only one matrix body. In contrast, multiple-units SR formulations contain numerous pellets within one capsule, each of which slowly releases the drug after the pellets have been quickly discharged from the capsule in the stomach.
Introduction: Different oral sustained-release (SR) formulations of tramadol have been introduced in pain treatment in order to prolong the dosage interval to improve convenience for the patient. The objective of this study was to compare tramadol pharmacokinetics and intra- and intersubject variability after replicate single-dose administrations of a multiple-units SR formulation (capsule) and a single-unit formulation (tablet).
Methods: This was a randomised, single-dose, single-centre study with an open-label, four-period, two-sequence, two-formulation, replicate crossover design in healthy subjects under fed conditions. The main outcome measures were the intra- and intersubject variance of the area under the concentration-time curve from 0 to 12 hours (AUC12) and maximum concentration (Cmax), as well as the mean AUC12 and Cmax for tramadol. Study drugs were a tramadol SR multiple-units formulation (capsule) and a tramadol SR single-unit formulation (tablet), each containing tramadol hydrochloride 100mg. The time interval from 0 to 12 hours of AUC12 of the single-dose design corresponds to the recommended twice-daily dosage interval for both study drugs during long-term treatment.
Results: The two formulations were equivalent in the area under the curve (AUC∞: 2411 vs 2527 µg • h/L). However, capsules led to a lower Cmax (148.6 vs 183.2 µg/L), to a later time to reach Cmax (5.9 vs 4.9 hours), and to a longer half-value duration (13.4 vs 10.4 hours). In addition, intrasubject variability of AUC12 was significantly smaller for capsules than for tablets (p = 0.041). Capsules also produced smaller intra- and intersubject variability in plasma concentrations during the first 2.5 and 3.0 hours after administration, respectively (p < 0.05).
Conclusion: Although tramadol SR capsules and tramadol SR tablets led to an equivalent systemic exposure to the drug, capsules provided a smoother and more extended plasma profile. In addition, in the case of capsules, bioavailability was subjected to lower variability in terms of both rate and extent of absorption.
Tramadol is a synthetic centrally acting analgesic that binds weakly to µ-receptors. At the same time, it stimulates descendent inhibitory pathways in the spinal cord by enhancing release and decreasing re-uptake of noradrenaline and serotonin. Because of this dual mechanism of action, tramadol has a similar efficacy to codeine, despite its ten times lower affinity to µ-receptors. Tramadol thus causes less clinically relevant adverse reactions than other opioids of similar analgesic efficacy.
Since its first approval in Germany in 1977, tramadol has been registered in more than 100 countries and has become one of the preferred drugs in the treatment of moderate to severe pain. Tramadol, as an oral immediate-release (IR) formulation, reaches a maximum plasma concentration (Cmax) within 2 hours after administration and has a terminal half-life (t½) of about 5-6 hours. This relatively short half-life results in a required dosage frequency of 4-6 times daily, which is particularly inconvenient for maintaining pain relief at night and in patients requiring long-term treatment. Therefore, there is a strong need for sustained-release (SR) formulations of tramadol.
Since tramadol SR formulations result in more stable plasma concentrations than IR oral forms, adverse reactions associated with abrupt plasma peaks should decrease. This was shown for the incidences of nausea and headache, which decreased significantly when a tramadol SR oral formulation was used instead of an IR oral formulation. Furthermore, since a rapidly decreasing plasma concentration after a peak is one of the reasons for intermittent exacerbation of pain, it is expected that SR formulations will reduce the incidence of end-of-dose failure. Although clinical efficacy trials comparing SR and IR formulations of tramadol have not included the incidence of pain exacerbations as an outcome, an experimental model of pain showed that a SR formulation of tramadol is more effective than an IR formulation.
Single-unit SR formulations are commonly used to provide retardation of drug release. They slowly release the drug from only one matrix body. In contrast, multiple-units SR formulations contain numerous pellets within one capsule, each of which slowly releases the drug after the pellets have been quickly discharged from the capsule in the stomach.
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