Efficacy and Safety of Once-Daily Tramadol
Efficacy and Safety of Once-Daily Tramadol
Objective: To compare the 24-hour sustained efficacy and safety of a new tramadol once-daily formulation (tramadol OAD) using Contramid controlled-release technology with a marketed twice-daily formulation (tramadol BID).
Patients, design and setting: 431 patients with osteoarthritis of the knee were enrolled in this randomised, double-blind, multicentre, parallel study. After titration to optimum dose (range 100-400mg), patients received medication for 12 weeks.
Main outcome measures and results: Efficacy evaluations included: Western Ontario and McMaster University Osteoarthritis Index (WOMAC) scores (pain, stiffness, physical function and global), daily efficacy ratings (post-dose: tramadol OAD 24 hours; tramadol BID 12 hours), pain ratings over 24 hours, and patient and investigator overall ratings. Non-inferiority was demonstrated for the primary endpoint, mean percentage change in WOMAC pain score from baseline to week 12 (tramadol OAD 58%; tramadol BID 59%) [95% CI -7.67, 3.82]. The median optimum dose received was 200mg (both treatments). In 73% of patients, pain was mild to absent at the end of the dosing interval for both treatments (tramadol OAD 24 hours; tramadol BID 12 hours). Pain ratings over 24 hours were similar between groups, indicating 24-hour sustained efficacy for tramadol OAD. More tramadol BID patients reported dizziness/vertigo (37% vs 26%), vomiting (14% vs 8%) and headache (18% vs 13%) while tramadol OAD patients reported more somnolence (30% vs 21%).
Conclusions: This study demonstrated that this novel tramadol OAD formulation provides sustained analgesic efficacy over the entire 24-hour dosing interval and a clinically favourable safety profile, both of which will provide a clear clinical benefit.
Tramadol is a synthetic, centrally acting analgesic that has been used to treat pain effectively in a variety of indications. First introduced in Germany in 1977 and in the US in 1995, it is currently approved for use in many countries throughout the world. Tramadol and its M1 metabolite act as opiate agonists, through selective binding to the µ-opioid receptor, and weak inhibition of norepinephrine and serotonin uptake. This second mode of action is thought to increase analgesic activity by complementing opioid receptor binding.
The efficacy and safety profile of tramadol make it suitable as a long-term treatment for moderate to severe chronic pain in patients for whom paracetamol (acetaminophen), NSAIDs or cyclo-oxygenase (COX)-2 inhibitors are no longer effective or in whom treatment with NSAIDs is contraindicated. The adverse effect profile of tramadol is typical of opioids. However, tramadol has a lower potential for abuse or dependence. Gastrointestinal (GI) adverse events such as nausea, vomiting and constipation are often reported during treatment with tramadol. However, tramadol and opioids do not share the ulcerogenic, renal or cardiac adverse event potential of NSAIDs and COX-2 inhibitors.
Clinical studies have been conducted that demonstrate that tramadol provides analgesic effect in moderate to severe osteoarthritis (OA). Although some trials have high withdrawal rates, as is typically expected in trials of analgesics, with the appropriate use of statistical methods, efficacy conclusions can be drawn.
Pain along with functional limitation and stiffness are key symptoms of OA. Effective pain control is seen as essential to management of the disease, and depends on the analgesic efficacy of the treatment along with compliance with the dosing regimen. Lack of compliance with high-frequency dosing regimens can result in inconsistent plasma drug concentrations and accordingly less consistent analgesia. Current immediate-release and prolonged-release tramadol formulations require dosing several times daily. A once-daily tramadol formulation has been developed using Contramid (Labopharm Inc., Laval, Québec, Canada). This formulation has the potential to provide effective pain control and to circumvent the problem of inconsistent analgesia resulting from noncompliance with higher frequency dosing regimens.
Contramid, the novel, controlled-release technology used to develop this once-daily tramadol, is based on the chemical cross-linking of high-amylose starch molecules resulting in the formation of a matrix that encloses the active pharmaceutical ingredient within its structure. In the gastric environment the surface of the tablet transforms into a gel through which the drug diffuses at a constant rate. This characteristic of Contramid permits the design of tablets that are tailored to release tramadol continuously over a 24-hour period. This new tramadol once-daily (OAD) formulation was created with the aim of providing continuous drug delivery and corresponding analgesic efficacy over 24 hours with a once-daily dosing regimen.
The objective of this study was to demonstrate the analgesic non-inferiority and safety of this novel tramadol OAD formulation compared with tramadol twice daily (BID) over a 12-week treatment period in patients with OA of the knee.
Objective: To compare the 24-hour sustained efficacy and safety of a new tramadol once-daily formulation (tramadol OAD) using Contramid controlled-release technology with a marketed twice-daily formulation (tramadol BID).
Patients, design and setting: 431 patients with osteoarthritis of the knee were enrolled in this randomised, double-blind, multicentre, parallel study. After titration to optimum dose (range 100-400mg), patients received medication for 12 weeks.
Main outcome measures and results: Efficacy evaluations included: Western Ontario and McMaster University Osteoarthritis Index (WOMAC) scores (pain, stiffness, physical function and global), daily efficacy ratings (post-dose: tramadol OAD 24 hours; tramadol BID 12 hours), pain ratings over 24 hours, and patient and investigator overall ratings. Non-inferiority was demonstrated for the primary endpoint, mean percentage change in WOMAC pain score from baseline to week 12 (tramadol OAD 58%; tramadol BID 59%) [95% CI -7.67, 3.82]. The median optimum dose received was 200mg (both treatments). In 73% of patients, pain was mild to absent at the end of the dosing interval for both treatments (tramadol OAD 24 hours; tramadol BID 12 hours). Pain ratings over 24 hours were similar between groups, indicating 24-hour sustained efficacy for tramadol OAD. More tramadol BID patients reported dizziness/vertigo (37% vs 26%), vomiting (14% vs 8%) and headache (18% vs 13%) while tramadol OAD patients reported more somnolence (30% vs 21%).
Conclusions: This study demonstrated that this novel tramadol OAD formulation provides sustained analgesic efficacy over the entire 24-hour dosing interval and a clinically favourable safety profile, both of which will provide a clear clinical benefit.
Tramadol is a synthetic, centrally acting analgesic that has been used to treat pain effectively in a variety of indications. First introduced in Germany in 1977 and in the US in 1995, it is currently approved for use in many countries throughout the world. Tramadol and its M1 metabolite act as opiate agonists, through selective binding to the µ-opioid receptor, and weak inhibition of norepinephrine and serotonin uptake. This second mode of action is thought to increase analgesic activity by complementing opioid receptor binding.
The efficacy and safety profile of tramadol make it suitable as a long-term treatment for moderate to severe chronic pain in patients for whom paracetamol (acetaminophen), NSAIDs or cyclo-oxygenase (COX)-2 inhibitors are no longer effective or in whom treatment with NSAIDs is contraindicated. The adverse effect profile of tramadol is typical of opioids. However, tramadol has a lower potential for abuse or dependence. Gastrointestinal (GI) adverse events such as nausea, vomiting and constipation are often reported during treatment with tramadol. However, tramadol and opioids do not share the ulcerogenic, renal or cardiac adverse event potential of NSAIDs and COX-2 inhibitors.
Clinical studies have been conducted that demonstrate that tramadol provides analgesic effect in moderate to severe osteoarthritis (OA). Although some trials have high withdrawal rates, as is typically expected in trials of analgesics, with the appropriate use of statistical methods, efficacy conclusions can be drawn.
Pain along with functional limitation and stiffness are key symptoms of OA. Effective pain control is seen as essential to management of the disease, and depends on the analgesic efficacy of the treatment along with compliance with the dosing regimen. Lack of compliance with high-frequency dosing regimens can result in inconsistent plasma drug concentrations and accordingly less consistent analgesia. Current immediate-release and prolonged-release tramadol formulations require dosing several times daily. A once-daily tramadol formulation has been developed using Contramid (Labopharm Inc., Laval, Québec, Canada). This formulation has the potential to provide effective pain control and to circumvent the problem of inconsistent analgesia resulting from noncompliance with higher frequency dosing regimens.
Contramid, the novel, controlled-release technology used to develop this once-daily tramadol, is based on the chemical cross-linking of high-amylose starch molecules resulting in the formation of a matrix that encloses the active pharmaceutical ingredient within its structure. In the gastric environment the surface of the tablet transforms into a gel through which the drug diffuses at a constant rate. This characteristic of Contramid permits the design of tablets that are tailored to release tramadol continuously over a 24-hour period. This new tramadol once-daily (OAD) formulation was created with the aim of providing continuous drug delivery and corresponding analgesic efficacy over 24 hours with a once-daily dosing regimen.
The objective of this study was to demonstrate the analgesic non-inferiority and safety of this novel tramadol OAD formulation compared with tramadol twice daily (BID) over a 12-week treatment period in patients with OA of the knee.
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