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New Delhi: Noting the possible risk of expected adverse effects in healthy subjects, the Subject Expert Committee (SEC), functioning under the Central Drug Standard Control Organization (CDSCO), has declined to recommend a proposed clinical study by Advity Research Private Limited for Fludrocortisone Tablets USP 0.2 mg.
This came after the firm presented the protocol along with published literature of Fludrocortisone Tablet USP 0.2 mg, in light of the earlier SEC recommendation dated 07.08.25.
Fludrocortisone is a mineralocorticoid used to treat adrenocortical insufficiency and salt-losing adrenogenital syndrome.
The main endogenous mineralocorticoid, aldosterone, is produced in the zona glomerulosa of the adrenal cortex—it acts on mineralocorticoid receptors in the kidneys to increase sodium reabsorption and potassium excretion, which in turn helps to regulate plasma electrolyte composition and blood pressure. In conditions of adrenal insufficiency, such as Addison’s disease, aldosterone is not produced (or is produced in insufficient quantities) and must be replaced by exogenous mineralocorticoids such as fludrocortisone.
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Fludrocortisone binding to mineralocorticoid receptors causes alterations to DNA transcription and translation of proteins that result in an increased density of sodium channels on the apical side of renal tubule cells and an increased density of Na+-K+-ATPase on the basolateral side. These increases in receptor density result in increased plasma sodium concentrations, and thus increased blood pressure, as well as a decreased plasma potassium concentration. Fludrocortisone may also exert a direct effect on plasma sodium levels via action at the Na+-H+ exchanger found in the apical membrane of renal tubule cells.
At the recent SEC meeting for endocrinology and metabolism, the expert panel reviewed the protocol along with published literature of Fludrocortisone Tablet USP 0.2 mg presented by Advity Research Private Limited.
After detailed deliberation, the committee did not recommend the study due to the possible risk of expected adverse effects of Fludrocortisone Tablet USP 0.2 mg in healthy subjects.
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The strong opioid painkiller, tramadol, is not that effective at easing chronic pain for which it’s widely prescribed, finds a pooled data analysis of the available research, published online in BMJ Evidence Based Medicine.
And it likely increases the risk of serious side effects, including heart disease, the findings indicate, prompting the researchers to conclude that the potential harms of tramadol probably outweigh its benefits, and that its use should be minimised.
Tramadol is a dual action opioid widely prescribed for the treatment of moderate to severe acute and chronic pain. As such, it’s recommended in several medical guidelines for pain management, note the researchers.
Its use has surged in recent years, and it’s now among the most commonly prescribed opioids in the US, possibly because of its perceived lower risk of side effects and the widespread belief that it is safer and less addictive than other short-acting opioids, they add.
Although tramadol has been included in previous systematic reviews, none has provided a comprehensive assessment of tramadol’s efficacy and safety in a range of chronic pain conditions, they say.
In a bid to plug this knowledge gap, the researchers scoured research databases for randomised clinical trials published up to February 2025 that compared tramadol with placebo (dummy treatment) for patients with chronic pain, including cancer pain.
Nineteen clinical trials involving 6506 participants with chronic pain were eligible for inclusion in the analysis. Five looked at the impact of tramadol on neuropathic pain; nine focused on osteoarthritis; four looked at chronic low back pain; and one focused on fibromyalgia.
The average age of the trial participants was 58, but ranged from 47 to 69. Tablets were the primary formulation used; only one trial included topical cream. Length of treatment ranged from 2 to 16 weeks while length of follow up ranged from 3 to 15 weeks.
Pooled data analysis of the trial results showed that while tramadol eased pain, the effect was small and below what would be considered clinically effective.
Eight of the trials reported on the proportion of serious side effects arising after treatment during follow up periods of between 7 and 16 weeks.
Statistical analysis of these trials results indicated a doubling in the risk of harms associated with tramadol compared with placebo, mainly driven by a higher proportion of ‘cardiac events,’ such as chest pain, coronary artery disease, and congestive heart failure.
Use of tramadol was also associated with a heightened risk of some cancers, although the follow up period was short, making this finding “questionable,” say the researchers.
Pooled data analysis of all the trial results indicated that tramadol treatment was associated with a heightened risk of several milder side effects, including nausea, dizziness, constipation, and sleepiness.
The researchers acknowledge that the outcome results were at high risk of bias, but this increases the likelihood that the findings overestimate the beneficial effects and underestimate the harmful effects of tramadol, they suggest.
They point out: “Approximately 60 million individuals worldwide experience the addictive effects of opioids. In 2019, drug use was responsible for approximately 600,000 deaths, with nearly 80% of these fatalities associated with opioids and approximately 25% resulting from opioid overdose.
“In the United States, the number of opioid-related overdose deaths increased from 49,860 in 2019 to 81,806 in 2022. Given these trends and the present findings, the use of tramadol and other opioids should be minimised to the greatest extent possible.”
They conclude: “Tramadol may have a slight effect on reducing chronic pain (low certainty of evidence) while likely increasing the risk of both serious (moderate certainty of evidence) and non- serious adverse events (very low certainty of evidence). The potential harms associated with tramadol use for pain management likely outweigh its limited benefits.”
Reference:
Barakji JA, Maagaard M, Petersen JJ, et alTramadol versus placebo for chronic pain: a systematic review with meta-analysis and trial sequential analysisBMJ Evidence-Based Medicine Published Online First: 07 October 2025. doi: 10.1136/bmjebm-2025-114101
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A new study published in The Lancet Respiratory Medicine found that morphine did not reduce chronic dyspnea in patients with cardiorespiratory disease, but online group singing improved quality of life.
Consenting adults (1:1, stratified by site and causal disease) with a modified Medical Research Council breathlessness score of 3 or higher due to cardiorespiratory conditions were randomly assigned to receive 5–10 mg twice daily oral long-acting morphine or placebo (as well as a blinded laxative) for 56 days in this trial conducted across 11 centers.
Using a numerical rating scale (NRS; 0 = not breathless at all; 10 = worst conceivable breathlessness), the main result was the worst breathlessness score for the previous 24 hours on day 28. Quality of life, morphine-related toxicities, physical activity levels, and worst cough NRS were secondary outcomes. The patients were eligible to be included in effectiveness and safety analyses if they received at least one dosage of the trial medication.
Only 3 individuals did not get the allotted therapy out of the 143 people who were randomly randomized to receive either morphine or a placebo (67 participants) between March 18, 2021, and October 26, 2023. The participants were primarily White (132 [94%]), male (93 [66%]), and their mean age was 70·5 (SD 9·4) years. By day 28, 66 (99%) of the morphine group and 64 (88%) of the placebo group achieved 90% or higher adherence.
With the exception of the better cough seen on day 56, researchers did not find any indication of a difference in the worst breathlessness at day 28 (morphine 6·19 [95% CI 5·57 to 6·81] vs placebo 6·10 [5·44 to 6·76]; adjusted mean difference 0·09 [95% CI –0·57 to 0·75], p=0·78]) or any secondary measure.
After multiple-measures adjustment, the increase in moderate to vigorous physical activity at day 28 (adjusted mean difference 9·51 min/day [0·54–18·48]) was not statistically significant.
Significant adverse events (15 vs. three, of which three in the morphine group and none in the placebo group were judged to be attributable to the study), study medication withdrawals (13 vs. two), and adverse events were more common in the morphine group (251 vs. 162). No one died as a result of therapy. Overall, the findings of this study states that there is no proof that morphine lessens the severity of the severe dyspnea.
Reference:
Johnson, M. J., Williams, B., Keerie, C., Tuck, S., Hart, S., Bajwah, S., Chaudhuri, N., Pearson, M., Cohen, J., Evans, R. A., Currow, D. C., Higginson, I. J., Hall, P., Atter, M., Norrie, J., Fallon, M. T., & MABEL collaborative. (2025). Morphine for chronic breathlessness (MABEL) in the UK: a multi-site, parallel-group, dose titration, double-blind, randomised, placebo-controlled trial. The Lancet. Respiratory Medicine. https://doi.org/10.1016/S2213-2600(25)00205-X
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