Sustained Release Paracetamol Research Articles

Prolonged use of paracetamol and the prescribing patterns on rehabilitation facilities.

The study investigated: (a) the usage patterns of paracetamol, and (b) the association between paracetamol use and patient outcomes such as liver and kidney functions among older people. Paracetamol is a well-known analgesic and antipyretic drug, with an excellent safety profile when used within its recommended dose. It is a commonly used drug by people aged over 65years to treat chronic pain. Prolonged use of paracetamol in the elderly is poorly understood. As such, there is a genuine risk among older people of unintentional overdose. A retrospective analysis of medical records in rehabilitation wards was undertaken from 1July 2016 to 30June 2017. Patients' paracetamol use, prescribing patterns and biochemical results were analysed to assess for differences in admission and discharge biochemistry results. The TREND Statement was utilised to guide study reporting (Enhancing the QUAlity and Transparency Of health Research, 2021). A total of 1119 patients were admitted for seven or more days in a metropolitan tertiary hospital in Melbourne. Almost three-quarters (74%) of patients were administered paracetamol; 76.1% received 'Immediate-Release Paracetamol' (IRP), and 23.9% were given 'Sustained-Release Paracetamol' (SRP). A proportion (4.5%) of patients in both the IRP and SRP groups received more than the daily recommended dose. There were limited statistically significant differences between patients' admission and discharge biochemistry results; group or time differences were observed, which were indicative of improvements within the paracetamol group. Paracetamol was a commonly used medication among long-stay elderly patients. Precaution to ensure paracetamol use does not exceed recommended daily doses is required. This study suggests that paracetamol used at a therapeutic level in older patients had limited, negative associations with liver and kidney function. The clinical practice regarding prolonged use of paracetamol is ambitious. The increased risk of paracetamol toxicity among the frail elderly is a concern. Optimising the dose adjustment in the elderly is important to avoid adverse outcomes.

Turning Pain into Gain: Evaluation of a Multidisciplinary Chronic Pain Management Program in Primary Care.

ObjectiveTo measure the impact of the multidisciplinary Turning Pain Into Gain program in people experiencing chronic pain of any etiology.MethodsA mixed-methods observational study of 252 participants was used to explore the impact of Turning Pain Into Gain on medication use; quality of life and functioning, as measured by the Pain Self-Efficacy Questionnaire; and self-reported hospitalizations between 2015 and 2016.ResultsResponses from 178 participants showed an increased alignment with Australian pain medication guidelines (e.g., a 7.3% reduction in paracetamol duplication was reported with a concurrent 5.1% rise in the administration of sustained-release paracetamol formulations); improved Pain Self-Efficacy Questionnaire scores from 23.1 (out of a possible score of 60) preprogram to 35.3 postprogram; and a reduction in self-reported hospitalizations from 50 cases in the 12 months preprogram to 11 cases in the 12 months postprogram.ConclusionsPositive medication, Pain Self-Efficacy Questionnaire, and hospitalization changes provide evidence for the broader implementation of similar patient-centered programs to promote more holistic management of diverse types of chronic pain in primary care. Reduced hospitalization reflects potential for this intervention to be cost-effective, which could be investigated further.

Фармацевтическая формулировка и исследования матричных таблеток парацетамола замедленного действия и их потенциальное жаропонижающее действие у детей

Фармацевтическая формулировка и исследования матричных таблеток парацетамола замедленного действия и их потенциальное жаропонижающее действие у детей

Efficacy and safety of twice daily sustained-release paracetamol formulation for osteoarthritis pain of the knee or hip: a randomized, double-blind, placebo-controlled, twelve-week study

Objective: Evaluate efficacy and safety of an investigational, twice daily sustained-release (SR) paracetamol formulation in subjects with knee or hip osteoarthritis (OA).Methods: In this multicenter, double-blind, parallel study (NCT02311881), subjects with hip or knee OA were randomly assigned to SR paracetamol 2 × 1000 mg BID, extended-release (ER) paracetamol 2 × 665 mg TID or placebo for 12 weeks. Primary endpoint was mean change from baseline through 12 weeks in WOMAC Osteoarthritis Index pain. Secondary efficacy endpoints included other WOMAC categories, Global Patient Assessment of Osteoarthritis (GPAOA), Patient Global Assessment of Response to Therapy (PGART) and responder rate.Results: A total of 676 subjects were included in the analysis population (mITT). Mean change from baseline in WOMAC pain subscale was not significantly greater with SR paracetamol BID versus placebo (LS mean [SE]: −28.25 [1.697] vs. −25.74 [1.713]; p = .163). Reduction in WOMAC physical function and stiffness subscales with SR paracetamol BID was not significantly greater than with placebo (p = .089 and .054, respectively). Significant improvement over placebo was observed for GPAOA (p = .043), PGART (p = .012), and proportion of high-improvement responders (p = .015). Safety and tolerability were consistent with the known profile of paracetamol.Conclusions: Improvement in WOMAC pain, physical function and stiffness subscales from treatment with SR paracetamol BID versus placebo in subjects with knee or hip OA was not significant. SR paracetamol BID demonstrated significant improvements in GPAOA, PGART, and high-responder rate. High placebo response may have contributed to lack of statistical separation on some outcomes. All interventions were generally well tolerated.

Bioequivalence and Safety of Twice-Daily Sustained-Release Paracetamol (Acetaminophen) Compared With 3- and 4-Times-Daily Paracetamol: A Repeat-Dose, Crossover Pharmacokinetic Study in Healthy Volunteers.

Twice‐daily sustained‐release (SR) paracetamol (acetaminophen) offers convenient administration to chronic users. This study investigated at steady state (during the last 24 hours of a 3‐day dosing period) the pharmacokinetics, bioequivalence, and safety of twice‐daily SR paracetamol compared with extended‐release (ER) and immediate‐release (IR) paracetamol. In this open‐label, randomized, multidose, 3‐way crossover study, 28 healthy subjects received paracetamol SR (2 × 1000 mg twice daily), ER (2 × 665 mg 3 times daily), and IR (2 × 500 mg 4 times daily). At steady state, twice‐daily SR paracetamol was bioequivalent to ER and IR paracetamol. The 90% confidence intervals for the ratios of geometric means were within the acceptance interval for SR/ER paracetamol (AUC0–t, 0.973–1.033; AUC0–24, 0.974–1.034; AUC0–∞, 0.948–1.011; Cmax, 1.082–1.212; Cav, 1.011–1.106) and SR/IR paracetamol (AUC0–t, 0.969–1.029; AUC0–24, 0.968–1.027; AUC0–∞, 0.963–1.026; Cmax, 0.902–1.010; Cav, 1.004–1.098). Given twice daily, the SR formulation demonstrated SR properties as expected. Mean time at or above a 4 μg/mL plasma concentration of paracetamol from 2 daily doses of the SR formulation was significantly longer than that from 4 daily doses of IR paracetamol. SR formulation also had a greater Tmax, a longer half‐life, and lower Cmin compared with ER and IR paracetamol. All formulations were well tolerated.

ISOLATION AND EVALUATION OF SEED COAT CONSTITUENTS OF MORINGA OLEIFERA

Traditionally, Moringa oleifera seed powder has been used as eco-friendly clarifying agent for drinking water. Natural polysaccharides are widely used as excipients in pharmaceutical industry. In the present In vitro study, starch and protein-mucilage fractions were isolated from the seed coats of Moringa oleifera. The isolated fractions were evaluated as binder and disintegrant in the preparation of paracetamol tablets. The prepared tablets were assessed for comparative In vitro quality control parameters such as weight variation, hardness, friability and disintegration time. The parameters were compared with paracetamol tablets prepared using potato starch as binder and disintegrant. Significant variation was observed in hardness, friability, and disintegration time among three formulations. Paracetamol tablets with protein-mucilage fraction were found to be relatively harder, less friable, and taking more time to disintegrate than the tablets made with potato starch. The tablets with isolated starch fraction were found to be almost similar to tablets prepared with potato starch with respect to hardness, friability and disintegration time. The isolated starch fraction and protein-mucilage fractions exhibited good binding and disintegrating properties and were natural in origin, nontoxic, biodegradable and bio compatible. Hence, they could be employed as binding and disintegrating agents in the formulation of paracetamol immediate release dosage forms. Since the protein fraction showed relatively higher values of hardness and disintegration time with less friability and could be explored for designing sustained release paracetamol tablets. Key words: Moringa seeds, starch fraction, protein-mucilage fraction, Paracetamol tablets, binder and disintegrant Â

Bioavailability and pharmacokinetic profile of a newly-developed twice-a-day sustained-release paracetamol formulation.

A new twice daily sustained-release (SR) paracetamol formulation was developed to improve convenience and enhance patient compliance for treatment of pain from chronic diseases. This research aimed to evaluate bioavailability and compare pharmacokinetic (PK) properties of the new SR paracetamol formulation (2x1,000 mg) with those of immediate-release (IR) paracetamol (2x500 mg) and existing extended-release (ER) paracetamol (2x665 mg). Two randomized, single-dose, 4-way crossover studies were conducted. A total of 28 healthy male and female volunteers participated in each study. The relative bioavailability, partial extent of absorption, overall elimination, food effect, and safety were evaluated. The estimates of relative bioavailability of new SR with IR formulation based on dose-adjusted AUC0-inf were 91% (0.86-0.96) for the fasted state and 99% (0.95-1.02) for the fed state, while these estimates comparing new SR with ER formulation were 99% (0.96-1.03) in the fasted state and 98% (0.95-1.02) in the fed state. The accumulated mean time period at or above the minimal therapeutic plasma paracetamol concentration for the new SR was from 90% to 112% longer than that of the IR formulation, in fasted and fed state, respectively. Food significantly increased Cmax of SR formulation, with ratios fast vs. fed 0.79 (p<0.0001) and 0.77 (p<0.0001) in study I and II, respectively. The new SR formulation was well absorbed, with more than 90% relative bioavailability as compared to the currently marketed IR and ER products and better sustained-release PK characteristics, which make it suitable for twice-daily paracetamol treatment.

Patient Preference for Sustained-Release versus Standard Paracetamol (Acetaminophen): A Multicentre, Randomized, Open-Label, Two-Way Crossover Study in Subjects with Knee Osteoarthritis

Guidelines for osteoarthritis (OA) management recommend paracetamol (acetaminophen) as the most appropriate first-line analgesic for mild to moderate pain. Standard paracetamol requires four times daily dosing. Drug compliance and convenience are inversely related to daily dose frequency. Compliance is a pivotal component of the successful management of OA pain and is influenced by patient preferences or beliefs. The added convenience of three times daily dosing may enhance compliance and, therefore, pain relief. This multicentre, randomized, open-label, two-way crossover, phase IV study is the first to evaluate patient preference with a sustained-release paracetamol tablet formulation designed for three times daily dosing. Compared with standard paracetamol tablets dosed four times daily, the sustained-release formulation was preferred in a 2:1 ratio, provided better overall joint pain relief, resulted in higher levels of satisfaction in subjects with OA of the knee and has the potential to improve patient compliance and, therefore, pain control.

Are N-of-1 Trials an Economically Viable Option to Improve Access to Selected High Cost Medications? The Australian Experience

Objectives To explore the economic viability of N-of-1 trials for improving access to selected high cost medications in Australia. Methods Cost and effectiveness estimates were derived from two N-of-1 trials conducted by The University of Queensland from 2003 to 2005—celecoxib versus sustained-release paracetamol for osteoarthritis in a general practice setting and gabapentin versus placebo for chronic neuropathic pain in a hospital setting. Effectiveness was determined by the proportion of responders to each medication. The costs of trials were offset against the savings generated by subsequent changes in prescribing. Decision analysis models with semi-Markov processes were used to compare different scenarios of N-of-1 trials versus usual care. Results The fixed cost of performing N-of-1 trials was approximately AUS$23,000 for each trial and the variable cost was approximately AUS$1300 per participant. Clinical outcomes favored celecoxib over paracetamol in 17% of participants and gabapentin over placebo in 24% of participants. Modeling these results showed that the cost-offsets from efficient use of medications were less than the cost of running a trial; however, the incremental costs per quality-adjusted life-year gained were AUS$6,896 and AUS$29,550 for the gabapentin/placebo and celecoxib/paracetamol trials, respectively, over a 5-year horizon. Key factors affecting the viability were the time horizon modeled, the variable cost per participant, the probability of response to the intervention medication, and rates of use in nonresponders and the usual care alternative. Conclusions The N-of-1 strategy offers a realistic and viable option for increasing access to selected high cost medications where the medications are used for the symptomatic treatment of chronic disease, have rapid onset of action, and clinical response is unpredictable without a trial.

An investigation into the usefulness of generalized regression neural network analysis in the development of level A in vitro–in vivo correlation

Quantitative correlations between in vivo and in vitro data (IVIVC) reduce the number of human in vivo studies, thus decreasing the overall time and expenses necessary for the development of optimal drug product formulation. Although linear regression analysis represents the simplest relationship, it is recognized that IVIVC should not be limited to linear relationship. With regards to the implementation of non-linear IVIVC models and the ability of artificial neural network (ANN) computing to cope with non-linear relationships, the usefulness of ANN analysis in the development of IVIVC merits further evaluation. The present paper is an attempt to develop an IVIVC for model sustained release paracetamol matrix tablet formulations employing various correlation approaches based on linear and non-linear modeling of in vitro and in vivo data. Currently accepted compendial methodology was compared with the alternative approaches, involving general mixed effects model and generalized regression neural network (GRNN) analysis, in order to evaluate their usefulness for predicting the in vivo behavior of drug products. Although based on analogous approaches, data generated by GRNN were closer to those observed in vivo, leading to the higher level of IVIVC than obtained by convolution. It can be assumed that GRNN analysis was able to generalize complex relations between the output and input parameters and could account for the differences in drug release kinetics observed under various conditions in vitro, thus offering potential as a reliable and robust estimate of drug products in vivo behavior.

Celecoxib compared with sustained-release paracetamol for osteoarthritis: a series of n-of-1 trials

To assess the use of n-of-1 trials for short-term choice of drugs for osteoarthritis, with particular reference to comparing the efficacy of sustained-release [SR] paracetamol with celecoxib in individual patients. Evaluation of community-based patients undergoing n-of-1 trials which consisted of double-blind, crossover comparisons of celecoxib 200 or 400 mg/day with sustained-release paracetamol 1330 mg three times a day in three pairs of 2 week treatment periods per drug with random order of the drugs within pairs. Outcomes evaluated were pain and stiffness in sites nominated by the patient, functional limitation scores, preferred medication, side effects and changes in drug use after an n-of-1 trial. Participants were 59 patients with osteoarthritis in multiple sites (hip 6, knee 24, hand 6, shoulder/neck 8, back 14, foot 5), with pain for >or=1 month severe enough to warrant consideration of long-term use of celecoxib but for whom there was doubt about its efficacy. Forty-one n-of-1 trials were completed. Although on average, celecoxib showed better scores than SR paracetamol [0.2 (0.1) for pain, 0.3 (0.1) for stiffness and 0.3 (0.1) for functional limitation], 33 of the 41 individual patients (80%) failed to identify the differences between SR paracetamol and celecoxib in terms of overall symptom relief. Of the eight patients who were able to identify the differences, seven had better relief with celecoxib and one with SR paracetamol. In 25 out of 41 [61%] patients, subsequent management was consistent with their trial results. N-of-1 trials may provide a rational and effective method to best choose drugs for individuals with osteoarthritis. SR paracetamol is more useful than celecoxib for most patients of whom management is uncertain.

Formulation and evaluation of sustained release paracetamol peroral matrix tablets: optimisation and &lt;i&gt;in vitro&lt;/i&gt; evaluation

An optimised formulation of sustained release paracetamol peroral matrix tablets for a three-times-daily use was prepared with hydroxypropylmethylcellulose (HPMC). The levels of HPMC 4,000, polyethylene glycol (PEG) 6,000 and lactose were varied according to a 2 level 3-factor full factorial experimental design using the release rate of the drug from the matrices as the response variable. From the dissolution data of the eight tablet formulations that resulted from the experimental design, a polynomial regression equation was generated from which an optimum formulation was obtained. Three different batches of granules of the \'optimum formulation\' were compressed into tablets at a compression force of 15 kN with an instrumented EK-0 Korsch eccentric single punch tablet machine. Evaluation of tablet weight variation, crushing strength and friability demonstrated acceptable results. In vitro dissolution tests also revealed sustained release of the drug for an 8-hour period at the end of which almost complete release was achieved (96.22 ± 0.72%, 97.69 ± 0.20% and 98.94 ± 1.17%, respectively, for the three batches). Keywords: sustained release, paracetamol matrix tablets, hydroxypropylmethylcellulose, in vitro dissolution tests, optimization Ethiopian Pharmaceutical Journal, vol. 22 (2004): 27-38

Formulation and evaluation of sustained release paracetamol peroral matrix tablets: in vivo bioavailability evaluation in man

A comparative in vivo bioavailability evaluation of a newly formulated sustained release paracetamol peroral matrix tablets and a marketed conventional rapidly disintegrating paracetamol tablets was carried out according to a two-period, two-treatment, two-sequence, randomised crossover design with a 4-day washout period between the treatments using urinary drug excretion data. The in vivo study was conducted on 10 healthy human male volunteers aged between 24-30 years. The subjects swallowed either the sustained release or the conventional paracetamol tablets at equal dose levels and urine samples were collected at different times over a 24-hour period. Based on the urinary drug excretion data, the mean relative bioavailability of the sustained release tablets with respect to the conventional tablets was 0.949 ± 0.287, indicating that the bioavailability was not significantly different from that of the conventional tablets (P = 0.2701). Moreover, by using the sustained release tablets, it was possible to prolong the elimination half-life of the drug from 2.589 h to 3.840 h. Keywords: sustained release, paracetamol matrix tablets, comparative bioavailability, urinary drug excretion, elimination half-life Ethiopian Pharmaceutical Journal, vol. 22 (2004): 39-46

The Safety Profile of Sustained Release Paracetamol During Therapeutic Use and Following Overdose

Sustained release (SR) formulations of paracetamol (acetaminophen) have been introduced in several countries to provide lasting pain relief and reduced risk of rebound pain. However, few studies have evaluated the safety of paracetamol SR formulations. To assess the available published safety data regarding SR formulations of paracetamol, the EMBASE and MEDLINE databases were searched from 1980 to June 2003 for published worldwide human experience with paracetamol SR formulations. All publications that included any information about ingestion of any paracetamol SR formulation were systematically reviewed and abstracted by trained staff. The literature searches returned a total of 14 references containing safety data on paracetamol SR. In addition, the Toxic Exposure Surveillance System (TESS) of the American Association of Poison Control Centers (AAPCC) database was searched for human exposure cases. The TESS database yielded 3003 cases from 1994 to 2002 that involved a paracetamol SR product. The available information indicates that the adverse event and safety profile of paracetamol SR is very similar to immediate release (IR) formulations of paracetamol. During therapeutic use, minor effects such as gastrointestinal upset and headache may occur. The rate of these effects varies substantially among studies but overall does not appear to be different between the SR and IR formulations of paracetamol. Overdose with paracetamol SR is expected to cause liver injury similar to overdose with IR formulations. The number of human exposure cases has increased since introduction of the SR formulation; however, sales of the SR formulation amounted to 7.5% of all paracetamol sales but accounted for 2.5% of the cases reported to poison centres. There were two deaths recorded in the TESS database: both were the result of multiple drug ingestion. No cases of death or unusual types of toxicity have been described from an overdose of paracetamol SR alone.

A study of the analgesic efficacy and safety of use of paracetomol formulations after third molar surgery

Objective To compare the analgesic efficacy and safety of a sustained release (SR) paracetamol formulation (Panadol Extend) with a standard immediate release (IR) formulation (Panadol) after third molar surgery. Design A multi-centre, double-blind, randomised clinical trial. Methods Patients received either a single oral dose of SR paracetamol or IR paracetamol for pain after the removal of at least one impacted third molar requiring bone removal under general anaesthesia. Post-operative pain and pain relief assessments were undertaken at time intervals up to 8 hours. Global assessments of effectiveness were made at 4 and 8 hours. Any adverse events were also recorded. Results Of 627 randomised patients, 314 were treated with SR paracetamol and 313 with IR paracetamol. In the per protocol population at 4 hours, 35.1% of the 252 patients on SR paracetamol rated the study medication as very good or excellent compared with 27.7% of the 258 patients on IR paracetamol. There were few statistically significant differences among the secondary parameters but where they did occur they favoured SR paracetamol. Trends in favour of SR paracetamol were observed among the secondary parameters and these tended to emerge at the later time points. For example, while there was no statistically significant difference in time to re-medication between the treatment groups, the estimated time to re-medication was longer for patients treated with SR paracetamol (4 hr 5 min) compared with IR paracetamol (3 hr 10 min). The high rate of re-medication observed is consistent with that reported for IR paracetamol using the post-operative dental pain model. No difference was observed between the SR paracetamol and IR paracetamol treatment groups in distribution, incidence or severity of adverse events. Conclusions SR paracetamol and IR paracetamol are clinically and statistically equivalent. While SR paracetamol and IR paracetamol were similar in terms of both onset of analgesia and peak analgesic effect, SR paracetamol had a longer duration of activity than IR paracetamol. The safety profiles of SR paracetamol and IR paracetamol were found to be very similar.