Ibuprofen, other NSAIDs and COVID-19: a narrative review.

At the start of the coronavirus disease 2019 (COVID-19) pandemic (March 2020), there was speculation that non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, used to manage some of the symptoms of COVID-19, could increase the susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and negatively impact clinical outcomes. In the absence of any robust mechanistic and clinical evidence, this speculation led to confusion about the safety of ibuprofen, contributing to the so-called 'infodemic' surrounding COVID-19. A wealth of evidence has been generated in subsequent years, and this narrative review aims to consider the body of in vitro and in vivo research, observational studies, systematic reviews and meta-analyses on the use of NSAIDs, including ibuprofen, in COVID-19. Overall, the direction of evidence supports that NSAIDs do not increase susceptibility to infection, nor worsen disease outcomes in patients with COVID-19. Neither do they impact the immune response to COVID-19 vaccines. There is no basis to limit the use of NSAIDs, and doing so may deprive patients of effective self-care measures to control symptoms.

Ibuprofen, Flurbiprofen, Etoricoxib or Paracetamol Do Not Influence ACE2 Expression and Activity In Vitro or in Mice and Do Not Exacerbate In-Vitro SARS-CoV-2 Infection.

SARS-CoV-2 uses the human cell surface protein angiotensin converting enzyme 2 (ACE2) as the receptor by which it gains access into lung and other tissue. Early in the pandemic, there was speculation that a number of commonly used medications-including ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDs)-have the potential to upregulate ACE2, thereby possibly facilitating viral entry and increasing the severity of COVID-19. We investigated the influence of the NSAIDS with a range of cyclooxygenase (COX)1 and COX2 selectivity (ibuprofen, flurbiprofen, etoricoxib) and paracetamol on the level of ACE2 mRNA/protein expression and activity as well as their influence on SARS-CoV-2 infection levels in a Caco-2 cell model. We also analysed the ACE2 mRNA/protein levels and activity in lung, heart and aorta in ibuprofen treated mice. The drugs had no effect on ACE2 mRNA/protein expression and activity in the Caco-2 cell model. There was no up-regulation of ACE2 mRNA/protein expression and activity in lung, heart and aorta tissue in ibuprofen-treated mice in comparison to untreated mice. Viral load was significantly reduced by both flurbiprofen and ibuprofen at high concentrations. Ibuprofen, flurbiprofen, etoricoxib and paracetamol demonstrated no effects on ACE2 expression or activity in vitro or in vivo. Higher concentrations of ibuprofen and flurbiprofen reduced SARS-CoV-2 replication in vitro.

A narrative review of the potential pharmacological influence and safety of ibuprofen on coronavirus disease 19 (COVID-19), ACE2, and the immune system: a dichotomy of expectation and reality.

The coronavirus disease 19 (COVID-19) pandemic is currently the most acute healthcare challenge in the world. Despite growing knowledge of the nature of Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2), treatment options are still poorly defined. The safety of non-steroidal anti-inflammatory drugs (NSAIDs), specifically ibuprofen, has been openly questioned without any supporting evidence or clarity over dose, duration, or temporality of administration. This has been further conflicted by the initiation of studies to assess the efficacy of ibuprofen in improving outcomes in severe COVID-19 patients. To clarify the scientific reality, a literature search was conducted alongside considerations of the pharmacological properties of ibuprofen in order to construct this narrative review. The literature suggests that double-blind, placebo-controlled study results must be reported and carefully analysed for safety and efficacy in patients with COVID-19 before any recommendations can be made regarding the use of ibuprofen in such patients. Limited studies have suggested: (i) no direct interactions between ibuprofen and SARS-CoV-2 and (ii) there is no evidence to suggest ibuprofen affects the regulation of angiotensin-converting-enzyme 2 (ACE2), the receptor for COVID-19, in human studies. Furthermore, in vitro studies suggest ibuprofen may facilitate cleavage of ACE2 from the membrane, preventing membrane-dependent viral entry into the cell, the clinical significance of which is uncertain. Additionally, in vitro evidence suggests that inhibition of the transcription factor nuclear factor-κB (NF-kB) by ibuprofen may have a role in reducing excess inflammation or cytokine release in COVID-19 patients. Finally, there is no evidence that ibuprofen will aggravate or increase the chance of infection of COVID-19.

Acute treatment of migraine with zolmitriptan 5 mg orally disintegrating tablet.

OBJECTIVE: To determine the speed of onset of headache response and duration of response with zolmitriptan 5 mg orally disintegrating tablet (ODT) in the acute treatment of migraine. BACKGROUND: Rapid pain relief is important for migraine sufferers. The early efficacy (30 minutes) of the 5 mg dose of the zolmitriptan ODT formulation was evaluated. METHODS: In this double-blind, parallel-group trial, 670 patients were randomised to receive either zolmitriptan 5 mg ODT (n=329) or matching placebo (n=341) to treat two migraine headaches of moderate or severe intensity. RESULTS: Zolmitriptan 5 mg ODT was significantly more effective than placebo in achieving a headache response (reduction in migraine headache intensity from moderate or severe to mild or no pain) at 30 minutes (16.5% vs 12.5%; p=0.048; primary endpoint), 1 hour (p <0.0001), and 2 hours (p <0.0001). Significantly more patients achieved a sustained headache response for 24 hours with zolmitriptan 5 mg ODT than with placebo (42.5% vs 16.4%; p <0.0001). Zolmitriptan 5 mg ODT also produced a higher pain-free rate than placebo at all timepoints (0.5, 1 and 2 hours post-dose), with the differences becoming significant at 1 hour. Adverse events were reported by 37.7% of the patients treated with zolmitriptan 5 mg ODT and 18.1% of the patients treated with placebo. Those that occurred most often for the patients treated with zolmitriptan 5 mg ODT were tightness (7.0%), dizziness (6.7%), somnolence (6.7%) and paraesthesias (6.1%). CONCLUSIONS: A significant headache response as early as 30 minutes post-dose and good maintenance of this headache response at 24 hours makes zolmitriptan 5 mg ODT an excellent acute treatment for migraine. Together with the relatively low adverse event rate, these data demonstrate that zolmitriptan 5 mg ODT is a valuable therapy for migraine sufferers.

Tolerability and consistency of effect of zolmitriptan nasal spray in a long-term migraine treatment trial.

OBJECTIVES: To primarily assess the tolerability of zolmitriptan (Zomig) nasal spray 5mg in the long-term treatment of migraine, as well as determine efficacy and consistency of effect over time (up to 1 year). METHODS: This randomised, double-blind-to-dose, parallel-group, multicentre study was designed as a two-phase, crossover trial with a total duration of 1 year. In the pre-crossover phase, 1,093 patients aged 18-65 years with an established diagnosis of migraine with or without aura received intranasal zolmitriptan 5, 2.5, 1 or 0.5mg for the treatment of mild, moderate or severe migraine attacks. When a headache persisted or recurred, a second dose of zolmitriptan nasal spray (or other approved escape medication) was permitted 2 hours post-administration but no later than 24 hours after the first dose. In the post-crossover phase, once a placebo-controlled, dose-finding study had established 5mg as the dose with the optimal clinical utility, all patients were crossed over under blinded conditions to receive this dose. As this was primarily a safety study, the primary endpoints for the study were the incidence and nature of all serious adverse events (at any time before or after administration) and nonserious adverse events (within 24 hours of administration), as well as the incidence of clinically significant abnormalities in either ECG or haematology and clinical chemistry parameters. Nose and throat examinations were performed before and after the study at 30 predetermined trial centres. Other endpoint measures included headache response rate, pain-free assessments, reduction in headache intensity, time to resumption of normal activities and consistency of headache response. Efficacy rates were measured in 90-day intervals up to a period of 360 days. RESULTS: Zolmitriptan nasal spray 5mg was well tolerated, with only 1.9% of patients withdrawing from the 12-month long-term trial because of adverse events. Adverse events occurred in 22.1% of attacks treated with zolmitriptan nasal spray 5mg, and the majority were of short duration and mild or moderate intensity. Serious adverse events occurred in 0.2% of attacks treated with zolmitriptan nasal spray 5mg. There was no evidence of increased incidence of adverse events with increasing duration of treatment. Nasopharyngeal adverse events were reported in 5.5% of attacks treated with zolmitriptan nasal spray 5mg. Again, events were generally transient and of mild intensity. For the 1,093 patients who treated 13,806 attacks during the pre-crossover phase, headache response rates at 2 hours over all attacks were 73.2%, 70.5%, 49.9% and 41.5% for zolmitriptan nasal spray 5, 2.5, 1 and 0.5mg, respectively. Pain-free rates at 2 hours over all attacks were 51.5%, 48.1%, 24.7% and 21.8%, respectively. For the 783 patients receiving the 5mg dose in either the pre- or post-crossover phases, the 2-hour headache response rates were 72.9%, 74.4%, 74.6% and 74.1% for the four 90-day periods between day 0 and day 360. Normal activities were resumed within 2 hours in 60.4% of attacks. Long-term usage of zolmitriptan nasal spray 5mg was also associated with a consistently effective response, with 57.8% of patients experiencing a 2-hour headache response in over 75% of attacks. The majority of patients (70.3%) rated their overall satisfaction with zolmitriptan nasal spray 5mg as good or excellent. CONCLUSION: Zolmitriptan nasal spray 5mg provides good tolerability and efficacy in long-term use in a clinical setting, with consistently high 2-hour headache and pain-free rates. This combination of benefits translates to high patient satisfaction with this formulation of zolmitriptan.

Speed of onset and efficacy of zolmitriptan nasal spray in the acute treatment of migraine: a randomised, double-blind, placebo-controlled, dose-ranging study versus zolmitriptan tablet.

OBJECTIVE: Zolmitriptan oral tablet is highly effective and well tolerated in the acute treatment of migraine with and without aura in adults. A nasal spray formulation has now been developed. The objective of this study was to compare the efficacy and tolerability of fixed doses of zolmitriptan administered via a nasal spray with placebo and zolmitriptan oral tablet in the acute treatment of migraine. PATIENTS AND STUDY DESIGN: This was a randomised, double-blind, double-dummy, placebo-controlled, parallel-group, multicentre, dose-ranging study. 1547 patients aged 18-65 years with an established diagnosis of migraine with or without aura (as defined by International Headache Society criteria) who had at least a 1-year history of migraine and an age of onset <50 years were included. Patients were able to distinguish typical migraine from nonmigraine headaches and had experienced an average of one to six migraine headaches per month during the 2 months preceding the study. Patients were randomised to zolmitriptan (Zomig) The use of tradenames is for product identification purposes only and does not imply endorsement.) nasal spray (5.0, 2.5, 1.0 or 0.5 mg), zolmitriptan oral tablet (2.5mg) or placebo for the treatment of three moderate or severe migraine attacks. The primary outcome measure was headache response at 2 hours following treatment, defined as reduced intensity of migraine pain (using a scale of none, mild, moderate or severe) from severe or moderate at baseline to mild or no pain at 2 hours after treatment. Secondary outcome measures included early headache response at 15, 30 and 45 minutes and headache response at 1 and 4 hours postdose, as well as pain-free rates at 15, 30 and 45 minutes and 1, 2 and 4 hours postdose. Laboratory assessments, vital signs, 12-lead ECGs and nose and throat examinations were performed at screening and follow-up visits. Adverse events were recorded throughout the study using Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) terminology. RESULTS: Each dose of zolmitriptan nasal spray produced a greater 2-hour headache response rate than placebo (70.3%, 58.6%, 54.8% and 41.5% for zolmitriptan nasal spray 5.0, 2.5, 1.0 and 0.5mg, compared with 30.6% for placebo [all p < 0.001 vs placebo]). The 2-hour headache response rate for zolmitriptan nasal spray 5.0mg was significantly higher than that of the zolmitriptan 2.5mg oral tablet (61.3%; p < 0.05), while comparisons of nasal spray 0.5, 1.0 and 2.5mg with zolmitriptan 2.5mg oral tablet were not statistically significant. The nasal spray 5.0 and 2.5mg showed a rapid onset of action, with a significant difference in headache response compared with placebo from 15 minutes through 4 hours after administration and a significant difference between the nasal spray 5.0mg and 2.5mg oral tablet from 15 minutes through to 2 hours (the other nasal spray doses were not statistically significant compared with 2.5mg oral tablet). Zolmitriptan nasal spray resulted in pain-free rates that were dose dependent. While all doses from 1.0 mg upwards produced significant pain-free outcomes from 30 minutes versus placebo, only the 5.0mg dose produced pain-free rates significantly superior to both placebo and the 2.5mg oral tablet. Zolmitriptan nasal spray was well tolerated, with the most common adverse events being unusual taste and paresthesia. The majority of adverse events were of short duration and mild or moderate intensity. Only ten patients were withdrawn from the trial because of adverse events. Serious adverse events were reported by nine patients after taking study medication, but none was considered to be causally related to study medication. Zolmitriptan was not associated with any clinically significant changes in laboratory test values or vital signs. CONCLUSION: All doses of zolmitriptan nasal spray produced significant 2-hour headache response rates compared with placebo. The 5.0 and 2.5mg doses were also significantly more effective than placebo for the majority of secondary efficacy measures. Zolmitriptan nasal spray 5.0mg provided a headache response statistically superior to both placebo and the 2.5mg tablet as early as 15 minutes after administration, while demonstrating pain-free outcomes significantly superior to placebo and the 2.5mg tablet as early as 30 minutes after administration. All doses of zolmitriptan nasal spray were well tolerated, resulting in an optimal therapeutic index and clinical recommendation for the 5.0mg dose.

Review of zolmitriptan and its clinical applications in migraine.

Preclinical studies have shown that zolmitriptan is a selective serotonin 5-HT(1B/1D) receptor agonist (triptan). Randomised, placebo-controlled, double-blind trials in patients with migraine have shown that zolmitriptan has good efficacy measured using 2 h response and pain-free rates. Migraine-associated symptoms, including nausea, photophobia and phonophobia, are also improved with zolmitriptan. Oral zolmitriptan (2.5 and 5 mg) has an onset of action within 45 min and efficacy is sustained in most patients who respond at 2 h. The orally-disintegrating zolmitriptan tablet has the advantage that it may be taken immediately, without the need for additional fluids, any time a migraine headache occurs. Patients may benefit in terms of improved efficacy from the convenience of the disintegrating tablet, since there is evidence that taking triptan therapy as early as possible in an attack is advantageous. For similar reasons, as well as improved efficacy, a nasal spray formulation is in development. Zolmitriptan is effective in the treatment of migraine associated with menses and migraine with aura. There is no tachyphylaxis following repeated doses for multiple attacks of migraine over a prolonged period of time. Compared to placebo, the incidence of persistent migraine headache is reduced by zolmitriptan and recurrent migraine headache occurs less frequently. Zolmitriptan has also shown efficacy in the treatment of persistent and/or recurrent migraine headache. Comparative clinical studies have shown overall that zolmitriptan has similar or superior efficacy to sumatriptan in the treatment of migraine. Specifically, zolmitriptan 2.5 mg was significantly more effective than sumatriptan 25 or 50 mg according to a number of end points, including headache response at 2 h. Oral zolmitriptan is also effective in the acute treatment of cluster headache. Zolmitriptan is generally well tolerated, with most adverse events being mild-to-moderate, transient and resolving without intervention or the need for treatment withdrawal. The consistent efficacy in treating all types of migraine and the choice of available formulations make zolmitriptan acceptable to patients and a suitable first-line therapy for the treatment of migraine.

Dressing-related trauma: clinical sequelae and resource utilization in a UK setting.

BACKGROUND: Dressings are the mainstay of wound care management; however, adherence of the dressing to the wound or periwound skin is common and can lead to dressing-related pain and trauma. Dressing-related trauma is recognized as a clinical and economic burden to patients and health care providers. This study was conducted to garner expert opinion on clinical sequelae and resource use associated with dressing-related trauma in a UK setting. METHODS: THIS WAS AN EXPLORATORY STUDY WITH TWO PHASES: qualitative pilot interviews with six wound care specialists to explore dressing-related trauma concepts, sequelae, and resource utilization; and online quantitative research with 30 wound care specialists to validate and quantify the concepts, sequelae, and resource utilization explored in the first phase of the study. Data were collected on mean health care professional time, material costs, pharmaceutical costs, and inpatient management per sequela occurrence until resolution. Data were analyzed to give total costs per sequela and concept occurrence. RESULTS: The results demonstrate that dressing-related trauma is a clinically relevant concept. The main types of dressing-related trauma concepts included skin reactions, adherence to the wound, skin stripping, maceration, drying, and plugging of the wound. These were the foundation for a number of clinical sequelae, including wound enlargement, increased exudate, bleeding, infection, pain, itching/excoriation, edema, dermatitis, inflammation, and anxiety. Mean total costs range from £56 to £175 for the complete onward management of each occurrence of the six main concepts. CONCLUSION: These results provide insight into the hidden costs of dressing-related trauma in a UK setting. This research successfully conceptualized dressing-related trauma, identified associated clinical sequelae, and quantified resource utilization associated with a typical occurrence of each trauma concept. Further research is warranted into dressing-related trauma and the associated costs.

Zolmitriptan 5 mg nasal spray: efficacy and onset of action in the acute treatment of migraine--results from phase 1 of the REALIZE Study.

OBJECTIVES: The objective of phase 1 (reported here) of this two-phase study was to assess the efficacy of zolmitriptan 5 mg nasal spray, in terms of ability to provide relief from all migraine symptoms, in a controlled setting, designed to replicate clinical practice. BACKGROUND: Zolmitriptan nasal spray has been shown to be fast acting and highly effective in the treatment of migraine, as assessed using standard endpoints, such as headache response and pain-free rates. METHODS: In the double-blind first phase of the study, patients with migraine were randomized to receive zolmitriptan 5 mg nasal spray or placebo to treat a single migraine attack. Attacks were treated according to patients' normal patterns of use, in order to closely reflect clinical practice; that is, no specific regimen was dictated in terms of time to treatment or at what level of pain intensity the headache should be treated. Patients could take a second dose of study medication or an agreed escape medication if adequate pain relief had not been achieved 2 hours after the first dose. The primary efficacy endpoint was total symptom relief (freedom from pain, nausea, photophobia, and phonophobia) 1 hour after the first dose. Secondary efficacy endpoints included headache response, pain-free status and sustained pain-free status, and ability to perform normal activities. RESULTS: The intention-to-treat population comprised 461 zolmitriptan nasal spray recipients and 451 placebo recipients. The total symptom relief rate 1 hour post-dose was significantly higher in the zolmitriptan 5 mg nasal spray group than in the placebo group (14.5% vs. 5.1%; P < .0001); the difference between the groups was significant from 30 minutes post-dose. Treatment with zolmitriptan nasal spray, compared with placebo, also produced a higher headache response rate from 10 minutes post-dose (15.1% vs. 9.1%; P = .0079) and a higher pain-free rate from 30 minutes post-dose (7.7% vs. 3.2%; P = .0039). Zolmitriptan nasal spray was also significantly superior to placebo in terms of sustained pain-free status and patients' ability to perform normal activities. Zolmitriptan nasal spray was well tolerated. CONCLUSIONS: These findings confirm the efficacy demonstrated by zolmitriptan nasal spray in previous clinical trials.

Treatment satisfaction with zolmitriptan nasal spray for migraine in a real life setting: results from phase two of the REALIZE study.

In phase one of the REALIZE study, zolmitriptan nasal spray demonstrated a significant headache response from 10 min post-dose and total symptom relief from 30 min post-dose. The objective of phase two was to investigate patients' dosing patterns, satisfaction and preference following open-label treatment with the nasal spray. Up to 3 attacks were treated. The ITT population consisted of 851 patients. The median time from onset of symptoms to treatment was 1 h 15 min (primary endpoint). Most patients reported being satisfied or very satisfied with zolmitriptan nasal spray (75.7%). Furthermore, the majority of patients would be willing to use zolmitriptan nasal spray in the future (59.8%) and preferred zolmitriptan nasal spray over previous therapies (57.8%). Zolmitriptan nasal spray was well tolerated. Most patients were satisfied with zolmitriptan nasal spray, were willing to continue using it and preferred it to previous therapies.

Zolmitriptan nasal spray exhibits good long-term safety and tolerability in migraine: results of the INDEX trial.

BACKGROUND: Previous studies have shown that zolmitriptan 5 mg nasal spray has a fast onset of action, high efficacy, and good tolerability in the acute treatment of migraine. Objective.-This open-label, noncomparative, multicenter, multinational phase III study was designed to further evaluate the long-term safety and tolerability of zolmitriptan 5 mg nasal spray in a population of migraineurs largely naive to triptan nasal sprays who treated multiple migraine attacks over a 1-year period. METHODS: Patients were required to have an established diagnosis of migraine with or without aura (based on International Headache Society criteria), a high frequency of migraine attacks, and were allowed to treat migraine with any baseline headache intensity. A secondary objective of the study was to assess the long-term efficacy of zolmitriptan nasal spray. A subgroup analysis aimed to determine whether rhinitis had any influence on outcomes of treatment. RESULTS: The safety population consisted of 538 patients who treated 20,717 migraine attacks with zolmitriptan 5 mg nasal spray. Overall, adverse events occurred in 32.8% of attacks, and led to treatment withdrawal in 4.5% of patients. The most common adverse events were unusual taste (19.0%) and paresthesia (6.8%). Adverse events were generally of mild intensity, transient, and well tolerated, showing a decline in incidence over time. Serious adverse events were rare. The presence of rhinitis and use of a second dose of trial medication had no effect on the incidence of adverse events. At 2 hours, 53.8% of attacks treated with zolmitriptan nasal spray 5 mg were rendered pain free. The highest 2-hour pain free rates were seen for headaches of mild baseline intensity (83.3%), followed by headaches of moderate (56.5%), and severe (32.2%) baseline intensity. The 2-hour pain-free rate remained consistent throughout the study period. The presence of rhinitis had no effect on efficacy. CONCLUSIONS: Zolmitriptan 5 mg nasal spray demonstrated a well-tolerated and efficacious profile in the acute treatment of multiple migraine attacks over a 1-year period.