Time to significant pain reduction following DETP application vs placebo for acute soft tissue injuries

Abstract

Objective:

Nonsteroidal anti-inflammatory drugs (NSAIDs) provide fast and effective acute pain relief, but systemic administration has increased risk for some adverse reactions. The diclofenac epolamine 1.3% topical patch (DETP) is a topical NSAID with demonstrated safety and efficacy in treatment of acute pain from minor soft tissue injuries. Significant pain reduction has been observed in clinical trials within several hours following DETP application, suggesting rapid pain relief; however, this has not been extensively studied for topical NSAIDs in general. This retrospective post-hoc analysis examined time to onset of significant pain reduction after DETP application compared to a placebo patch for patients with mild-to-moderate acute ankle sprain, evaluating the primary efficacy endpoint from two nearly identical studies.     

Topical diclofenac: clinical effectiveness and current uses in osteoarthritis of the knee and soft tissue injuries

Background: Diclofenac is a commonly used non-steroidal anti-inflammatory drug (NSAID) for symptom control in osteoarthritis (OA) of the knee and soft tissue injuries. Although treatment with oral diclofenac is associated with serious adverse effects involving both the gastrointestinal and renal systems, these adverse effects are thought to be limited with topical diclofenac formulations without loss of efficacy. Objective: The aim of this review is to explore the available evidence in relation to the pharmacokinetics, efficacy and reported adverse effects of the topical diclofenac formulations available. Results/conclusions: In the majority of studies examined, topical diclofenac formulations with sodium lotion, lecithin or epolamine gel, patch or plaster were either superior or equivalent to oral diclofenac formulations or placebo. Topical diclofenac significantly reduced pain and morning stiffness and improved physical function and patient global assessment without major adverse effects reported in patients with OA of the knee; and provided significant pain relief in patients with sports and soft tissue injuries involving the ankle, knee or shoulder. In the majority of studies, the predominant adverse effect involved pruritus or rash at the site of application, or nausea. The principle outcome of these studies is that topical diclofenac is a safe and practical alternative as a method of treatment in OA of the knee or as an alternative treatment for sports and soft tissue injury.     

Pharmacokinetics of Transdermal Etofenamate and Diclofenac in Healthy Volunteers

Little is known about the course of the plasma concentration and the bioavailability of non‐steroidal anti‐inflammatory drugs (NSAIDs) contained in dermal patches. We compared an etofenamate prototype patch (patent EP 1833471) and a commercially available diclofenac epolamine patch regarding the bioavailability of the active ingredients relative to respective i.m. applications and regarding their plasma concentration–time course. Twenty‐four healthy human volunteers were treated using a parallel group design (n = 12 per group) with a single dermal patch (removed after 12 hr) followed (after a latency of 48 hr) by eight consecutive dermal patches every 12 hr to reach steady‐state conditions. The patches were generally well tolerated, but one volunteer treated with etofenamate developed an allergic contact dermatitis. After the first patch, C_max was 0.81 ± 0.11 (mean ± S.E.M.) ng/mL (reached 12 hr after patch removal) for diclofenac and 31.3 ± 3.8 ng/mL for flufenamic acid (reached at patch removal), the main metabolite of etofenamate. Etofenamate was not detectable. After repetitive dosing, trough plasma concentrations after the eighth dose were 1.72 ± 0.32 ng/mL for diclofenac and 48.7 ± 6.6 ng/mL for flufenamic acid. Bioavailabilities (single dose) relative to i.m. applications were 0.22 ± 0.04% for diclofenac and 1.15 ± 0.06% for flufenamic acid. In conclusion, the relative bioavailability (compared to the respective i.m. application) of both drugs is low. The maximal plasma concentrations after topical administration of these drugs are well below the IC₅₀ values for COX‐1 and COX‐2, explaining the absence of dose‐dependent toxicities.     

Topical diclofenac and its role in pain and inflammation: an evidence-based review

ABSTRACT

Objective: Topical diclofenac is widely used in the treatment of pain and inflammation. This comprehensive review assesses the safety and efficacy of topical diclo­fenac in a range of painful and inflammatory disorders.

Methods: Double-blind, randomized, placebo- or active-controlled trials (RCT) evaluating topical diclofenac in soft-tissue injuries, soft-tissue rheumatic disorders and osteoarthritis were identified through detailed literature searches. In addition, non-RCT evidence from publications evaluating the pharmacologic characteristics of topical diclofenac were also included in this review to obtain a more complete picture of the drug's profile, its efficacy and safety.

Results: Studies demonstrate that the drug prefer­entially distributes to the target tissues in sufficient concentrations to produce a therapeutic effect. A total of 19 double-blind RCTs in more than 3000 patients, supported by single-blind or open trials, consistently show that topical diclofenac significantly reduces pain and inflammation in acute and chronic conditions compared with placebo and is comparable to other topical non-steroidal anti-inflammatory drugs (NSAIDs) and some oral NSAIDs (diclofenac, ibuprofen, naproxen). Improvements have also been observed in patients’ functional capacity and mobility. Topical diclofenac is well tolerated, resulting mostly in mild, easily resolved local skin irritation, and is associated with fewer side-effects than other topical NSAIDs and a lower rate of gastrointestinal complications than oral NSAIDs (diclofenac, ibuprofen, naproxen).

Conclusion: This evidence-based review shows topical diclofenac to be an effective and well tolerated treatment in painful and inflammatory conditions, at least in the short-term. However, only published RCT studies have been included in this analysis, which may exclude some interesting data from non-RCT studies. Future trials of topical diclofenac need to be of longer duration, be better reported and consider a broader spectrum of acute and chronic pain indications.     

An alternative topical treatment of osteoarthritis of the knee with cutaneous diclofenac solution

Background: Osteoarthritis (OA) is the most common chronic degenerative disease, which is characterised by the destruction of the articular cartilage and subchondral bone. The current treatment of OA is based primarily on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics. There are disadvantages to routinely using NSAIDs in OA. Topical NSAIDs represent a potentially important advance in this regard as they may be significantly safer than oral NSAIDs. Cutaneous diclofenac solution (Pennsaid^®) was developed for the treatment of symptomatic OA of the knee and contains diclofenac sodium as an active ingredient and dimethyl sulfoxide (DMSO), a penetration enhancer. Objective: To review: i) dermal drug application; ii) the treatment of OA with systemic and topical NSAID therapies; and iii) the clinical efficiency of Pennsaid on the topical treatment of OA of the knee. Methods: A literature search was carried out on skin, topical drug delivery, treatment of OA and assessment of published clinical studies with Pennsaid. Results and discussion: The clinical studies showed that applying the topical diclofenac solution (Pennsaid) to a painful knee with primary OA could provide symptom relief equivalent to oral diclofenac with minimal systemic side effects; however, studies are needed that compare the effectiveness of Pennsaid with different topical forms of diclofenac.     

In vitro topical delivery of non-steroidal anti-inflammatory drugs through human skin.

The objective of the present study was to evaluate in vitro the percutaneous absorption, across human skin, of 5 non-steroidal anti-inflammatory drugs (NSAIDs) formulated as gels: ketoprofen (CAS 22071-15-4), epolamine diclofenac (CAS 15307-86-5), piroxicam (CAS 36322-90-4) and niflumic acid (CAS 4394-00-7) or as emulgel: diclofenac sodium (CAS 15307-79-6) and to compare the different formulations as drug delivery systems. Because the concentrations of the NSAIDs in the different excipients were not identical, the comparison of their diffusional properties was expressed in term of release efficiency (or diffusion efficacy). The results obtained show that, across human skin under standardized experimental conditions, ketoprofen and piroxicam have the best rank order followed by niflumic acid, diclofenac sodium and epolamine diclofenac.     

Diclofenac epolamine medicated plaster in the treatment of minor soft tissue injuries: a multicenter randomized controlled trial

Abstract

Objective:

To investigate the efficacy and safety of a topical plaster containing diclofenac epolamine (DHEP) 1.3% in the treatment of patients with acute minor soft tissue injuries in China.     

Rationale and evidence for the incorporation of heparin into the diclofenac epolamine medicated plaster

Objective: The nonsteroidal anti-inflammatory drug (NSAID) diclofenac epolamine (DHEP) formulated as a topical patch has demonstrated efficacy and safety in the localized treatment of acute pain from minor strains, sprains and contusions, and for epicondylitis and knee osteoarthritis. The glycosaminoglycan heparin enhances the activity of topical NSAIDs formulated as a medicated plaster, even in the absence of any significant release of heparin. Therefore, DHEP plus, a new formulation of the DHEP medicated plaster containing a small amount of heparin sodium as excipient, has been developed.

Methods: We reviewed the pivotal and supportive studies of the clinical development program of the new patch and evaluated the role of heparin as an enhancer in the treatment of localized pain/inflammation of musculoskeletal structures, associated with post-traumatic and/or rheumatic conditions.

Results: The data was consistent with the concept that heparin increased the clinical activity of the DHEP plus medicated plaster versus the reference DHEP medicated plaster through improved bioavailability due to enhanced movement of diclofenac from the plaster. Both DHEP formulations have the same dissolution profile, indicating that heparin does not change the physical and chemical characteristics of the plaster. Permeation testing showed that heparin is not released from the DHEP plus medicated plaster. Efficacy studies showed that the DHEP plus medicated plaster was significantly more effective in reducing pain than the reference marketed DHEP medicated plaster.

Conclusions: The benefit/risk assessment of DHEP plus 180?mg medicated plaster is favorable, with a safety profile equal to placebo and improved efficacy over the reference marketed DHEP medicated plaster.     

Pooled analysis of GI tolerability of 21 randomized controlled trials of celecoxib and nonselective NSAIDs

ABSTRACT

Objective: To compare the gastrointestinal (GI) tolerability of celecoxib and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) at approved doses in patients with common musculoskeletal conditions.

Research design and methods: This was a retrospective, pooled analysis of studies selected from the Pfizer Corporate Clinical Trials Registry. Study selection criteria were: (1) Data available as of October 31, 2004; (2) Randomized, parallel-group study design and planned treatment duration of ≥?2 weeks; (3) At least one nonselective NSAID (naproxen, ibuprofen, or diclofenac) as a comparator; (4) At least one arm with 200?mg or 400?mg celecoxib per day; (5) Patients with osteoarthritis (OA), adult rheumatoid arthritis (RA), or ankylosing spondylitis (AS).

Data were pooled by treatment and by subject from the safety analysis population of each included study. Joint primary end points were the combined incidence of tolerability-related GI adverse events (AEs) (abdominal pain, dyspepsia, nausea, diarrhea, and flatulence), and time to study discontinuation due to any GI?AE.

Results: In all, 21 studies met the selection criteria. Across the safety analysis populations of the included studies, 7797 patients received celecoxib total daily dose 200?mg/day, 6653 received celecoxib total daily dose 400?mg/day, 2953 received naproxen, 499 received ibuprofen, and 5643 received diclofenac. Tolerability-related GI AEs were reported by significantly fewer celecoxib-treated patients (16.0%) than by those treated with naproxen (24.3%), ibuprofen (24.2%), or diclofenac (19.9%) (p?<?0.0001 vs. each comparator). Time to study discontinuation due to any GI?AE was significantly longer for celecoxib than for naproxen (p?<?0.0001), ibuprofen (p?=?0.002), or diclofenac (p?=?0.048). In the RA subpopulation (n?=?2857), there was no significant difference between the celecoxib and naproxen or ibuprofen groups in incidence of tolerability-related GI AEs and GI AEs.

Limitations: The limitations are inherent to the retrospective analysis design.

Conclusions: In this pooled analysis of celecoxib at approved doses in OA, RA, and AS, fewer celecoxib-treated patients in the overall population had tolerability-related GI AEs than patients treated with naproxen, ibuprofen, or diclofenac. In addition, celecoxib-treated patients had a significantly longer time to study discontinuation due to GI AEs.     

Efficacy and tolerability of DHEP-heparin plaster in reducing pain in mild-to-moderate muscle contusions: a double-blind,randomized trial

Abstract

Objectives:

To investigate if the 180-mg diclofenac epolamine and heparin sodium 5600?IU medicated plaster (DHEP-heparin) is more effective for pain reduction in mild-to-moderate contusions than the reference diclofenac epolamine 180?mg plaster (DHEP).     

Efficacy and safety of aceclofenac in the treatment of osteoarthritis: a randomized double-blind comparative clinical trial versus diclofenac – an Indian experience

ABSTRACT

Objective: Osteoarthritis is one of the most common forms of arthritis seen in primary care. Non-steroidal anti-inflammatory drugs (NSAIDs) play an important role in the management of osteoarthritis. However, gastrointestinal (GI) side effects limit their use. Cyclooxygenase-2 (COX‐2) selective inhibitors exhibit better GI tolerability than conventional NSAIDs, but their cardiovascular safety is controversial. An NSAID with high efficacy, high GI tolerability and devoid of adverse cardiovascular effects is therefore a profile preferred by physicians. Aceclofenac is an anti-inflammatory and analgesic drug with preferential COX-2 inhibition. The objective of this study was to assess the efficacy and safety of aceclofenac in the treatment of osteoarthritis in an Indian population.

Research design and methods: The trial was controlled, comparative, randomized, and double-blind. The study included 247 patients (82 males and 165 females, 40–82 years), suffering from osteoarthritis. Patients were randomized to receive either aceclofenac (100?mg twice daily) or diclofenac (75?mg twice daily).

Main outcome measures: Clinical assessment was done at screening, randomization, and at 2 weeks, 4 weeks and 8 weeks of treatment by calculating Western Ontario MacMaster (WOMAC) scores, time taken to walk 100 feet, visual analogue scores for pain, investigator's assessment on a Likert scale and joint tenderness. Tolerability assessment was based on adverse events. Patient compliance was also assessed.

Results: Aceclofenac was found to be statistically superior to diclofenac in efficacy parameters of WOMAC scores, investigator's assessment and joint tenderness. Aceclofenac was found to be statistically superior to diclofenac in terms of epigastric discomfort, dyspepsia and abdominal pain. Compliance was also better with aceclofenac. The overall response of patients’ osteoarthritis to aceclofenac was found to be statistically superior to diclofenac by both physician and patient.

Conclusions: Aceclofenac is an effective and well-tolerated drug in osteoarthritis in the Indian setting.     

The upper gastrointestinal safety of rofecoxib vs. NSAIDs: an updated combined analysis*

SUMMARY

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are nonspecific cyclo-oxygenase (COX-1/COX-2) inhibitors and are associated with gastrointestinal (GI) toxicity attributable to COX-1 inhibition. Rofecoxib, a COX-2 specific inhibitor, was developed to provide similar efficacy and less GI toxicity than NSAIDs.

Objective: To update the results of a previously performed analysis of the incidence of upper GI perforations, symptomatic gastroduodenal ulcers, and upper GI bleeding (PUBs) with rofecoxib compared with non-selective NSAIDs.

Research design and methods: We compared the incidence of PUBs in a combined analysis of 20 randomized, double-blind, clinical trials of rofecoxib versus NSAIDs. Men and women (N = 17?072) from multinational trial sites with osteoarthritis or rheumatoid arthritis were studied. There was no upper age limit in any of the trials. Investigator-reported PUBs were reviewed by a blinded, external adjudication committee using pre-specified criteria. The incidence of confirmed PUBs, the main outcome measure, among patients treated with rofecoxib 12.5?mg, 25?mg, or 50?mg (combined, N = 10?026) was compared to that among patients treated with ibuprofen, diclofenac, nabumetone, or naproxen (combined, N = 7046).

Results: The incidence of PUBs over 24.8?months was significantly lower with rofecoxib vs. NSAIDs (cumulative incidence 1.6% vs. 3.1%, p < 0.001; rate/100 patient-years 0.74 vs. 1.87; relative risk 0.36, 95% CI 0.24, 0.54). Results of subgroup analyses and comparisons of rofecoxib with individual NSAID comparators were consistent with the primary result, as was an analysis in patients with no PUB risk factors.

Discussion: The analysis demonstrated a consistently lower incidence of confirmed PUBs with rofecoxib than with NSAIDs over 24.8?months. These results confirm those of a previous smaller combined analysis of clinical trials with rofecoxib vs. non-selective NSAIDs in OA patients only, in which the risk reduction for confirmed PUBs was approximately 50%. In addition, this analysis demonstrated risk reductions with rofecoxib vs. NSAIDs in risk subgroups and in patients who did not have any known risk factors for PUBs consistent with the primary result. Some of the studies in this analysis required scheduled endoscopies. Asymptomatic upper GI ulcers or bleeding diagnosed during scheduled procedures were not included in the primary endpoint, which may have caused a bias against rofecoxib.

Conclusions: Treatment with rofecoxib was associated with a statistically significantly (p < 0.001) lower incidence of PUBs than was treatment with NSAIDs. The difference was maintained in subgroups of patients with risk factors, as well as in those with no risk factors, for PUBs.     

Oxaprozin versus diclofenac in NSAID-refractory periarthritis pain of the shoulder

SUMMARY

Objective: To evaluate the efficacy and safety of oxaprozin in comparison with diclofenac in patients with periarthritis pain of the shoulder previously unsuccessfully treated with nonsteroidal anti-inflammatory drugs other than diclofenac and oxaprozin.

Methods: In this open, multicentre, randomised, controlled study, eligible patients with periarthritis of the shoulder were randomised to receive either oxaprozin 1200^?mg once daily (^?n?=?49) or diclofenac 50^?mg three times daily (^?n?=?47). The treatment period was 15?± 1 days. The study was planned on a hypothesis of equivalence between the two study drugs. The primary study endpoint was the change from baseline at day 15 in the patient-assessed shoulder pain score. Secondary efficacy variables included investigator-assessed shoulder function, patient-assessed quality of life on the Short-Form-36 (SF-36) Acute Health Survey and both patients’ and investigators’ overall assessment of efficacy.

Results: At day 15, the mean changes in shoulder pain score from baseline in the oxaprozin and diclofenac groups were –5.85?± SD 4.62 and –5.54 ± SD 4.41, respectively. The difference between the two groups was not statistically significant, confirming the hypothesis of the study that oxaprozin is as effective as diclofenac. Investigator-assessed shoulder function improved in both groups but more so in the oxaprozin group (^?p?=?0.028 at day 15). Quality of life as measured by SF-36 total score was also improved in both treatment groups, with a trend toward greater improvement in the oxaprozin group. Furthermore, a significantly more favourable effect on the SF-36 ‘mental health’ item was observed in oxaprozin compared with diclofenac-treated patients at day 15 (^?p?=?0.0202). As assessed by investigators, the overall efficacy of oxaprozin was superior to that for diclofenac at visit 3 (8?±?1 days) (^?p?=?0.0067). Patients also assessed the overall efficacy of oxaprozin as superior to that of diclofenac at visits 3 (8?±?1 days) (^?p?=?0.0235) and 4 (15?±?1 days) (^?p?=?0.0272). Only six adverse events, all of which were mild or moderate in intensity and occurred in four diclofenac recipients, were observed in the study.

Conclusions: As expected, once-daily oxaprozin proved to be as effective as diclofenac three times daily in reducing the primary efficacy variable of patient-assessed shoulder pain score in patients with periarthritis of the shoulder refractory to previous treatments with other NSAIDs. Oxaprozin was shown to be superior to diclofenac in improving shoulder function and was considered by investigators and patients to have greater overall efficacy than diclofenac. In addition, oxaprozin showed a trend toward superior results in improving patients’ quality of life compared with diclofenac. A trend towards better tolerability results for oxaprozin compared with diclofenac was also noted.     

NSAID induced gastrointestinal damage and designing GI-sparing NSAIDs

ABSTRACT

NSAIDs are widely used to treat pain and rheumatic conditions, but they induce adverse events in different body systems, although the major, most frequent events occur in the upper and lower gastrointestinal (GI) tracts.

Areas covered: This review is focused on damage caused by NSAIDs in the upper and lower GI tracts, the different mechanisms of damage and the GI-sparing NSAIDs designed to minimize adverse events based on understanding of these mechanisms.

Expert commentary: Among the new NSAIDs, COX-2 selective inhibitors have been extensively investigated, and some were approved for human use. Celecoxib demonstrated its safety for the entire GI tract, compared to traditional NSAIDs. However, coxibs, like traditional NSAIDs, are toxic to the cardiovascular (CV) system. Other GI-sparing agents include nitric oxide-NSAIDs and phosphatidylcholine-associated NSAIDs. Testing in animal models and humans they showed GI advantages over the parent NSAID compounds, but none obtained regulatory approval or were further investigated. Hydrogen sulfide-releasing NSAIDs are currently under clinical development, and more data are needed before clinical use. Alternative therapies, such as modulating gut microbiota, are being explored. Currently, clinicians must continue prescribing traditional NSAIDs or coxibs, associated with/without proton pump inhibitor therapy, based on the presence of GI/CV risk factors.     

The anti-inflammatory effect of diclofenac is considerably augmented by topical capsaicinoids-containing patch in carrageenan-induced paw oedema of rat

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most used drugs in musculoskeletal disorders, but their systemic adverse effects limit their therapeutic benefit in local inflammation. On the other hand, topical preparations of capsaicinoids are widely used for musculoskeletal disorders as a complementary therapy. In this study, the effects of both topical capsaicinoids-containing patch and local subcutaneous capsaicin application on the anti-inflammatory action of NSAID were examined. Carrageenan-induced paw oedema of rats was used as the inflammation model. The volume and weight of the paw oedema and plasma extravasation in the paw were determined after carrageenan injection. The systemic application of diclofenac (3 mg/kg), which is an NSAID, significantly decreased the volume and weight of the paw oedema. Topical capsaicinoids-containing patch application or local capsaicin injection (2, 10, 20 μg/paw) alone did not cause any effect on oedema volume and weight. However, the combination of diclofenac with topical capsaicinoids-containing patch significantly increased the effectiveness of diclofenac on inflammation. Evans blue content of the paws that represents plasma extravasation was decreased by capsaicinoids-containing patch with and without diclofenac and diclofenac combination with the lowest dose of capsaicin injection. The results of this study indicate that topical application of capsaicinoids-containing patch enhances the anti-inflammatory effect of diclofenac and its beneficial effect may not purely relate to its capsaicin content. In the treatment of local inflammatory disorders, the combination of NSAID with topical capsaicinoids-containing patch could increase the anti-inflammatory efficiency of drug without systemic side effects.     

An exploratory microdialysis study investigating the effect of repeated application of a diclofenac epolamine medicated plaster on prostaglandin concentrations in skeletal muscle after standardized physical exercise

Aim

Muscle injuries and extensive exercise are associated with cyclo-oxygenase dependent formation of inflammatory prostaglandins. Since the effect of topical administration of non-steroidal anti-inflammatory drugs (NSAIDs) on local cyclo-oxygenase is unknown, the present exploratory, open label, non-randomized study set out to measure exercise induced release of prostaglandins before and after epicutaneous administration of diclofenac.

Methods

Microdialysis was used to determine the local interstitial concentration of PGE₂ and 8-iso-PGF_2α as well as diclofenac concentrations in the vastus lateralis under rest, dynamic exercise and during recovery in 12 healthy subjects at baseline and after a treatment phase applying a total of seven plasters medicated with 180 mg of diclofenac epolamine over 4 days.

Results

At baseline PGE₂ concentrations were 1169 ± 780 pg ml⁻¹ at rest and 1287 ± 459 pg ml⁻¹ during dynamic exercise and increased to 2005 ± 1126 pg ml⁻¹ during recovery. After treatment average PGE₂ concentrations were 997 ± 588 pg ml⁻¹ at rest and 1339 ± 892 pg ml⁻¹ during exercise. In contrast with the baseline phase no increase in PGE₂ concentrations was recorded during the recovery period after treatment (PGE₂ 1134 ± 874 pg ml⁻¹). 8-iso-PGF_2α was neither affected by exercise nor by treatment with diclofenac. Local and systemic concentrations of diclofenac were highly variable but comparable with previous clinical pharmacokinetic studies.

Conclusions

We can hypothesize an effect of topical diclofenac epolamine plaster on limiting the increase of local concentrations of the pro-inflammatory prostaglandin PGE₂ induced in the muscle of healthy human subjects following standardized physical exercise. No effect of diclofenac treatment on 8-iso-PGF_2α concentrations was observed, mainly since isoprostane is produced by a free radical-catalyzed lipid peroxidation mechanism independent of cyclo-oxygenases.     

A comparison of the skin irritation potential of transdermal fentanyl versus transdermal buprenorphine in middle-aged to elderly healthy volunteers

ABSTRACT

Objective: Establishing local tolerability of transdermal opioid systems is important as more systems become available for use in a range of indications. We compared the skin irritation potential of a single application of transdermal fentanyl (Durogesic D-trans; DDTDF) and transdermal buprenorphine (Transtec; TDB) patches in healthy volunteers.

Methods: 46 healthy males and females (mean age [range]: 59.6 [50–69] years) with healthy skin received a single dose of both the DDTDF 25?μg/h patch and the TDB 35?μg/h patch in a randomised order under naltrexone cover. The incidence and severity of erythema was assessed at various timepoints after patch removal.

Results: There was a non-significant trend towards a higher incidence of erythema 60?min after patch removal with TDB compared with DDTDF. The severity of erythema at 60?min and the incidence of erythema at 72?h after patch removal were significantly higher with TDB than with DDTDF (?p = 0.01 and 22% versus 4.9%, p = 0.04, respectively). In general, the results from the chromametric assessment of treated skin were in agreement. The incidence of topical adverse events (AEs) was lower with DDTDF than with TDB (one versus six events) and subjects preferred the DDTDF patch and felt it was less noticeable on the skin. The DDTDF patch was considered less painful to remove, and, consistent with that, the TDB patch was judged to have better adhesion. Twenty-one subjects reported systemic AEs with DDTDF plus naltrexone and 22 with TDB plus naltrexone, most of which were considered treatment-related, 34 and 60 AEs, respectively.

Conclusions: Local tolerability of transdermal opioid systems should be considered when making a therapeutic choice. Even after a single application in healthy volunteers, differences in local tolerability, assessed both clinically and by chromametry, and patch comfort were shown between DDTDF and TDB, in favour of DDTDF.     

Ocular permeation and inhibition of retinal inflammation: an examination of data and expert opinion on the clinical utility of nepafenac

ABSTRACT

Background: The efficacy of topical nonsteroidal anti-inflammatory drugs (NSAIDs) for inflammation in the anterior segment, and pain control after cataract surgery, is well established. However, their effectiveness in the posterior segment has not been as well studied. Nepafenac ophthalmic suspension, 0.1% is a new topical NSAID pro-drug that has been approved by the US Food and Drug Administration (FDA) for the treatment of pain and inflammation after cataract surgery. Preclinical data suggest nepafenac may also provide unique efficacy in the posterior segment.

Scope: We searched the PubMed database from 1966 to 2005 for various combinations of the search terms ‘nepafenac’, ‘ophthalmic’, ‘inflammation’, ‘anterior segment’, and ‘posterior segment’. We review here the three articles identified in the search, and also include findings from three recent clinical trials.

Results: Nepafenac's corneal permeability characteristics are superior to those of ketorolac tromethamine, diclofenac sodium, and bromfenac sodium. Nepafenac is hydrolyzed by intraocular tissues to amfenac, a potent cyclooxygenase inhibitor. In addition to a limited hydrolysis in the cornea, significant bioactivation occurs in the iris/ciliary body and retina/choroid. Nepafenac administration significantly suppresses PGE₂ synthesis in the retina/choroid. Topical nepafenac administration also significantly inhibits prostaglandin (PG)-mediated blood–retinal barrier breakdown and concurrent protein extravasation into the vitreous. In these studies, topical ketorolac and diclofenac failed to inhibit these key markers of inflammation. Nepafenac's clinical effectiveness in the posterior segment may be explained by its superior corneal permeation, biodistribution, and bioactivation to amfenac by the target tissues (i.e., iris, ciliary body, retina, and choroid) known to generate PGs.

Conclusions: Nepafenac's ability to inhibit PG synthesis in the retina/choroid following topical administration indicates the drug also targets suppression of PG synthesis in the posterior segment. Nepafenac may therefore have a clinical role in conditions that are caused by PG-mediated vascular leakage, such as anterior chamber inflammation and cystoid macular edema following cataract surgery.     

Non-steroidal anti-inflammatory induced upper gastrointestinal event rates in patients awaiting joint replacement in the United Kingdom. An epidemiologically-based burden of disease model

SUMMARY

Objective: To quantify the likely morbidity associated with upper gastrointestinal (GI) ulceration associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients awaiting hip and knee replacement surgery.

Method: A burden of disease model was constructed, using Hospital Episode Statistics from the Department of Health in England, selected patient cohorts drawn from a pooled anonymised general practice database (MediPlus) and NSAID risk assessments from the published literature. Based on mean derived waiting times from the point of referral to admission for procedure and estimates of both patient exposure to NSAIDs, and the age-specific risk associated with this treatment, the excess risk associated with NSAIDs was then calculated.

Results: In 2001-2, there were approximately 109000 hip and knee replacements carried out in the UK. The mean waiting time for hip and knee replacement, measured from the point of first referral by the GP, was found to be 443 days (95% CI 419-467). 73% (95% CI 72-74) of patients were found to be taking NSAIDs, equating to a total risk exposure of?～?96000 patient years. By applying known age-specific bleeding risks it was estmated that there were around 637 upper GI bleeds directly attributable to NSAID treatment in this cohort, with between 51 and 89 deaths resulting.

Conclusions: In order to improve outcomes in this high-risk patient group, action must continue to reduce overall waiting times, while simultaneously adopting treatment regimes that are inherently less likely to cause upper gastrointestinal bleeding.     

A Comparison of Adverse Renovascular Experiences Among Osteoarthritis Patients Treated with Rofecoxib and Comparator Non-selective Non-steroidal Anti-inflammatory Agents

Summary

Background: Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclo-oxygenase (COX) isoenzymes, i.e. COX-1 and COX-2. Rofecoxib, an agent that selectively inhibits COX-2, has been shown to provide equivalent anti-inflammatory and analgesic efficacy to comparator non-selective NSAIDs in osteoarthritis (OA) and other pain models with a significant improvement in gastrointestinal (GI) safety and tolerability. Based on renal physiology studies, it was predicted that rofecoxib would have renovascular effects similar to those observed with non-selective NSAIDs -specifically edema, blood pressure elevation, attenuation of the effects of ACE inhibitors, and (in rare circumstances), acute renal failure might be manifest in a small percentage of patients.

Objective: To assess the renovascular safety profile of rofecoxib in OA patients compared to that of non-selective NSAID comparators.

Methods: Renovascular adverse experiences (AEs) in over 5000 participants in Phase IIb/III OA clinical trials were reviewed and compared between rofecoxib and non-selective NSAID comparators (ibuprofen 800mg tid, diclofenac 50mg tid, nabumetone 1500mg qd).

Results: The incidence of lower extremity edema (LEE) AEs was generally similar between rofecoxib 12.5mg/day, rofecoxib 25mg/day, and non-selective comparator NSAIDs. Treatment discontinuations due to LEE AEs and clinically significant weight gain (> 2 kg) associated with LEE AEs were infrequent and generally similar in all active treatment groups. Congestive heart failure (CHF) was rare in all treatment groups. The incidence of hypertension AEs was low in all active treatment groups. Discontinuations due to hypertension AEs and hypertension AEs requiring a change or adjustment in blood pressure medications were similar and uncommon in all treatment groups. There was only a single report of acute renal failure (in the ibuprofen treatment group).

Conclusions: In the rofecoxib phase IIb/III OA database, the renal safety profile for rofecoxib, a selective inhibitor of COX-2, was generally similar to that of the comparator, non-selective NSAIDs which were studied.