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1.  Influence of topical anesthetics on oculocardiac reflex and corneal healing in rabbits 
AIM
To investigate the incidence of oculocardiac reflex (OCR) with two anesthetic regimens and its prevention using topical anesthetics in a rabbit model, and to explore the effect of topical anesthetics on corneal healing.
METHODS
Forty-eight clinically healthy adult New Zealand white rabbits of either sex were divided into two groups (Group A and B) and anesthetized with either ketamine (Group A, n =24) or propofol (Group B, n =24). he incidence of OCR was recorded in each group with a variety of ocular manipulation with or without the use of topical anesthetics (40g/L lignocaine, 5g/L proparacain, 5g/L bupivacaine). Corneal toxicity and healing following the use of each topical anesthetic was assessed one day after surgery and up to 7 days postoperatively by clinical examination of the eye, histopathology and collagen staining and transmission electron microscopy.
RESULTS
No incidence of OCR was recorded with ocular manipulation under ketamine anesthesia, whereas significant reduction in heart rate (P<0.01) was recorded under propofol anesthesia. Topical anesthetics could successfully prevent the OCR without affecting the corneal healing.
CONCLUSION
Topical anesthetics may be recommended for prevention of OCR without any local adverse effect.
doi:10.3980/j.issn.2222-3959.2010.01.04
PMCID: PMC3340647  PMID: 22553509
oculocardiac reflex; topical anesthetics; corneal healing; ketamine; propofol
2.  Tolerability of NGX-4010, a capsaicin 8% patch, in conjunction with three topical anesthetic formulations for the treatment of neuropathic pain 
Background
The objective of this study was to assess the safety, tolerability, and preliminary efficacy of NGX-4010, a capsaicin 8% patch, following pretreatment with three different topical anesthetics in patients with peripheral neuropathic pain.
Methods
This open-label, multicenter study enrolled 117 patients with post-herpetic neuralgia, HIV-associated distal sensory polyneuropathy, or painful diabetic neuropathy. Patients received pretreatment with one of three lidocaine 4%-based topical anesthetics (L.M.X.4® [Ferndale Laboratories Inc, Ferndale, MI], Topicaine® Gel [Estela Basso, Jupiter, FL], or Betacaine Enhanced Gel 4 [Tiberius Inc, Tampa, FL]) for 60 minutes followed by a single 60- or 90-minute NGX-4010 application, and were followed for 12 weeks. Tolerability and safety measures included “pain now” Numeric Pain Rating Scale (NPRS) scores, dermal assessments, medication use for treatment-related pain, adverse events (AEs), clinical laboratory parameters, physical examinations, and vital signs. The primary efficacy variable was the percentage change in mean NPRS scores for “average pain for the past 24 hours” from baseline to weeks 2 through 12.
Results
Treatment with NGX-4010 following pretreatment with any of the three topical anesthetics was generally safe and well tolerated. Nearly all patients completed ≥90% of the planned NGX-4010 application duration. The most common treatment-related AEs, application-site burning and application-site pain, were transient, mostly mild or moderate, and could be adequately managed by local cooling or short-acting oral opioid analgesics. Although slightly more patients used medication for treatment-related discomfort following pretreatment with Topicaine compared with L.M.X.4 or Betacaine, there were no statistical differences between the topical anesthetics. Neuropathic pain reduction from baseline to weeks 2 through 12 was approximately 30% and was similar among the topical anesthetics; the proportion of responders ranged from 45% to 50%.
Conclusion
Treatment with NGX-4010 following pretreatment with any of the three topical anesthetics was generally safe and well tolerated; no significant differences in the parameters measured were noted between the pretreatment groups.
doi:10.2147/JPR.S25272
PMCID: PMC3273402  PMID: 22328830
neuropathic pain; capsaicin patch; tolerability; topical anesthetics
3.  Evaluation of prilocaine for the reduction of pain associated with transmucosal anesthetic administration. 
Anesthesia Progress  1999;46(2):52-55.
This investigation evaluated the use and efficacy of prilocaine HCl (4% plain Citanest) for minimizing pain associated with the intraoral administration of local anesthesia. Clinical anecdotes support the hypothesis that prilocaine without a vasoconstrictor reduces pain during injection. To determine relative injection discomfort, use of 4% plain prilocaine was compared with use of 2% lidocaine with 1:100,000 epinephrine and 2% mepivacaine with 1:20,000 levonordefrin. Prior to routine endodontic procedures, 150 adult patients received 0.3 to 1.8 mL of local anesthetic via the same gauge needle without the use of a topical local anesthetic. Injection methods included buccal infiltration, labial infiltration, palatal infiltration, and inferior alveolar nerve block. Following each injection, patients were asked to describe the level of discomfort by scoring on a visual analog scale of 1 to 10, where 1 = painless and 10 = severe pain. Analyses via 2-way analysis of variance revealed no interaction between anesthetic and site of injection. However, there were statistically significant differences among the injection sites. Post hoc analysis revealed that prilocaine was associated with significantly less pain perception when compared to mepivacaine and lidocaine. These results suggest that differences in initial pain perception during transmucosal injection may be a function of the local anesthetic use, and prilocaine can produce less discomfort than the others tested.
Images
PMCID: PMC2148897  PMID: 10853565
4.  Efficacy of a topical anesthetic on pain and unpleasantness during scaling of gingival pockets. 
Anesthesia Progress  1994;41(2):35-39.
The efficacy of a topical anesthetic on pain and unpleasantness provoked by scaling of gingival pockets was investigated in 20 patients with mild chronic periodontitis. A eutectic mixture of local anesthetics (EMLA) and a placebo cream, both occluded by Orahesive Oral Bandages, were applied in a balanced, randomized, double-blind, split-mouth design, which enabled within-subject comparison of the anesthetic and the placebo in the upper and the lower jaw. Pretreatment interviews showed that approximately two-thirds of the patients considered gingival scaling to be associated with some degree of pain and unpleasantness. Pain intensity and unpleasantness were evaluated on 100-mm visual analog scales (VAS). Application of EMLA reduced both pain intensity and unpleasantness significantly compared to placebo cream. Median reductions in VAS pain intensity in the upper and lower jaw were 58.9% and 61.9%, and corresponding reductions in VAS unpleasantness were 31.9% and 25.6%, respectively. Generally, the patients accepted the anesthetic procedure well. The residual perception of pain and unpleasantness following topical anesthesia may be dependent on activation of nonanesthetized nociceptive fibers in the tooth pulp. However, the present study clearly demonstrates the efficacy of a topical anesthetic in a clinical situation, which may be recommended as a simple pharmacologic strategy to reduce pain and unpleasantness during scaling procedures.
PMCID: PMC2148810  PMID: 8638858
5.  362 Contact Allergy Due to Ophthalmic Drugs in Uruguay 
Background
The external eye is exposed to a large number of environmental, cosmetic and pharmacological allergens and the frequency of external eye diseases related to the prolonged use of ophthalmic medications and contact lens wear is increasing. Predisposing factors for contact allergy are: high exposure to topical drugs (eyelids & eye), high percutaneous absorption in eyelids, high potential for concomitant irritation and hand transfer of allergens due to frequent rubbing.
Methods
Ninety three patients 56 women and 37 men, age range 10 to 81 years old, mean age 43 years old with a clinical picture compatible with ocular allergy were referred to our Allergy Unit by the Department of Ophthalmology at the University Hospital for allergological evaluation, including a thorough history, complete clinical examination as well as laboratory techniques and skin testing. Patch-testing was performed with the standard series, an ophthalmic series of allergens developed at our unit, as well as additional allergens according to the clinical situation.
Results
Contact allergy was more frequently caused by topical antibiotics and preservatives and occasionally by mydriatic agents and topical drugs for glaucoma. The allergens more frequently implicated were Neomycin (10.7%), Bacitracin (9.6%) Thimerosal 8 (8.5%) Benzalconium chloride 5 (5.3%) Phenylephrine hydrochloride 3 (3.2%), local anesthetics 3 (3.2%), Chloramphenicol (3.1%), Polymyxin (2.1%), Kanamycin (2.1%), Gentamicin (2.1%), Tobramycin (2.1%), Beta-blockers 1 (1.7%), and others (6.1%).
Conclusions
Patients with a clinical picture compatible with ocular allergy should be referred for allergologic evaluation. A comprehensive approach will often provide clues for a presumptive diagnosis and appropriate management. When a contact allergy is found it is mandatory to avoid contact with the precipitating substance. This may simply be a case of stopping or altering an ophthalmic medication. The proper use of ophthalmic preparations should decrease the incidence of allergic contact reactions.
doi:10.1097/01.WOX.0000412125.33898.0d
PMCID: PMC3513184
6.  Severity of Locomotor and Cardiovascular Derangements after Experimental High-Thoracic Spinal Cord Injury Is Anesthesia Dependent in Rats 
Journal of Neurotrauma  2012;29(5):990-999.
Abstract
Anesthetics affect outcomes from central nervous system (CNS) injuries differently. This is the first study to show how two commonly used anesthetics affect continuously recorded hemodynamic parameters and locomotor recovery during a 2-week period after two levels of contusion spinal cord injury (SCI) in rats. We hypothesized that the level of cardiovascular depression and recovery of locomotor function would be dependent upon the anesthetic used during SCI. Thirty-two adult female rats were subjected to a sham, 25-mm or 50-mm SCI at T3–4 under pentobarbital or isoflurane anesthesia. Mean arterial pressure (MAP) and heart rate (HR) were telemetrically recorded before, during, and after SCI. Locomotor function recovered best in the 25-mm-injured isoflurane-anesthetized animals. There was no significant difference in locomotor recovery between the 25-mm-injured pentobarbital-anesthetized animals and the 50-mm-injured isoflurane-anesthetized animals. White matter sparing and extent of intermediolateral cell column loss appeared larger in animals anesthetized with pentobarbital, but this was not significant. There were no differential effects of anesthetics on HR and MAP before SCI, but recovery from anesthesia was significantly slower in pentobarbital-anesthetized animals. At the time of SCI, MAP was acutely elevated in the pentobarbital-anesthetized animals, whereas MAP decreased in the isoflurane-anesthetized animals. Hypotension occurred in the pentobarbital-anesthetized groups and in the 50-mm-injured isoflurane-anesthetized group. In pentobarbital-anesthetized animals, SCI resulted in acute elevation of HR, although HR remained low. Return of HR to baseline was much slower in the pentobarbital-anesthetized animals. Severe SCI at T3 produced significant chronic tachycardia that was injury severity dependent. Although some laboratories monitor blood pressure, HR, and other physiological variables during surgery for SCI, inherently few have monitored cardiovascular function during recovery. This study shows that anesthetics affect hemodynamic parameters differently, which in turn can affect functional outcome measures. This supports the need for a careful evaluation of cardiovascular and other physiological measures in experimental models of SCI. Choice of anesthetic should be an important consideration in experimental designs and data analyses.
doi:10.1089/neu.2011.1845
PMCID: PMC3584507  PMID: 21545262
animal model; arterial blood pressure; chronic telemetry; critical care; hemodynamics; HR; hypotension; isofluorane; MAP; neurology; pentobarbital; recovery of function
7.  Effect of pre-cooling injection site on pain perception in pediatric dentistry: “A randomized clinical trial” 
Dental Research Journal  2013;10(6):790-794.
Background:
Injection of local anesthesia is one of the most important reasons for development of avoidance behavior in children. Efforts have been performed to decrease pain perception of injection. The present research evaluated the effect of cooling the injection site on pain perception before infiltration of local anesthetics.
Materials and Methods:
A prospective single-blind crossover clinical trial was used to investigate pain perception in 50 healthy pediatric patients who needed bilateral buccal infiltration of local anesthetics for dental treatment. They received a topical anesthetic agent (Benzocaine) on one side (control) for 1 min and topical anesthetic agent plus one minute of ice pack on the other side (trial) prior to the injection. A dentist blind to the study assessed the patients’ reaction during injection. Wilcoxon and Mann-Whitney U tests were used for statistical analysis. Statistical significance was defined at P < 0.05.
Results:
The means of sound, eye, and motor scales (SEM) were 4.06 ± 1.32 and 5.44 ± 1.79 for the study and control groups, respectively. The means of visual analogue scales (VAS) for the study and control groups were 42.20 ± 12.70 and 58.40 ± 16.83, respectively; with statistically significant differences between the two groups (P < 0.05).
Conclusion:
Cooling the injection site before infiltration of local anesthetics in the buccal mucosa for 1 min, reduced pain perceived by pediatric patients.
PMCID: PMC3872632  PMID: 24379869
Cooling; local injection; pain perception
8.  Effect of Time on Clinical Efficacy of Topical Anesthesia 
Anesthesia Progress  2009;56(2):36-41.
The objective of this study was to determine the effect of time on the clinical efficacy of topical anesthetic in reducing pain from needle insertion alone as well as injection of anesthetic. This was a randomized, double-blind, placebo-controlled, split-mouth, clinical trial which enrolled 90 subjects, equally divided into 3 groups based upon time (2, 5, or 10 minutes) of topical anesthetic (5% lidocaine) application. Each group was further subdivided into 2: needle insertion only in the palate or needle insertion with deposition of anesthetic (0.5 mL 3% mepivacaine plain). Each subject received drug on one side and placebo on the other. Subjects recorded pain on a 100-mm visual analog scale (VAS). The results showed that for needle insertion only, 5% lidocaine reduced pain as determined by a significant difference in mean VAS after 2 minutes (20.1 mm, P < .002), 5 minutes (15.7 mm, P < .022), and 10 minutes (13.7 mm, P < .04), as analyzed by paired t tests. For needle insertion plus injection of local anesthetic, a significant difference in mean VAS was noted only after 10 minutes (14.9 mm, P < .031), yet pain scores for both topical anesthetic and placebo were elevated at this time point resulting in no reduction in actual pain. Time of application did not result in a significant difference in effect for either needle insertion only or needle insertion plus injection of local anesthetic, as analyzed by 1-way analysis of variance (ANOVA). In conclusion, topical anesthetic reduces pain of needle insertion if left on palatal mucosa for 2, 5, or 10 minutes, but has no clinical pain relief for anesthetic injection.
doi:10.2344/0003-3006-56.2.36
PMCID: PMC2699690  PMID: 19642717
Topical anesthesia; Local anesthesia; Pain
9.  The effectiveness of topical anesthesia and vibration in alleviating the pain of oral injections. 
Anesthesia Progress  1997;44(3):87-89.
The goal of the research was to compare the effectiveness of vibration with that of a topical anesthetic in reducing the pain of local anesthetic injections. Injections were given adjacent to maxillary premolars in four locations in 61 patients. Before injection, sites received either placebo or topical anesthetic with or without vibration. Patients rated the injection pain on a five-point scale. The topical anesthetic caused a statistically significant decrease in pain values; however, the amount of decrease was of questionable clinical significance.
Images
PMCID: PMC2148927  PMID: 9481967
10.  Clinical study to know the efficacy of Amlexanox 5% with other topical Antiseptic, Analgesic and Anesthetic agents in treating minor RAS 
Background: To evaluate the efficacy of topical antiinflammatory agent (amlexanox 5%), along with topical antiseptic, analgesic, and anesthetic agent (benzalkonium chloride 0.01%, choline salicylate 8.7% and lidocaine hydrochloride 2%), in promoting ulcer healing, decreasing ulcer size, erythema, pain and recurrence in minor RAS.
Materials & Methods: A randomized control trial was conducted on 100 patients of RAS who fulfilled the inclusion criteria. The number, size, erythema and pain with the ulcer were recorded. Visual analogue scale (VAS) and erythema scale were used to record pain and erythema. 50 patients comprising the study group received anti inflammatory paste (amlexanox 5%) applied four times daily and the control group of 50 patients received topical antiseptic, analgesic, and anesthetic agent (benzalkonium chloride 0.01%, choline salicylate 8.7% and lidocaine hydrochloride 2%) paste, patients were evaluated after 3rd, 6th, 9th and on 30th, 60th day for recurrence.
Results: The study group had reduction in ulcer number, size; erythema, pain and frequency of ulcers during follow up. The healing period and recurrence of ulceration reduced in both the groups but the study group had significant reduction in 30th and 60th day follow up for recurrence of ulcers.
Conclusion: Amlexanox 5% can reduce the frequency, duration and symptoms associated with the aphthous ulcers with no sideeffects attributed to the drug.
How to cite the article: Darshan DD, Kumar CN, Kumar AD, Manikantan NS, Balakrishnan D, Uthkal MP. Clinical study to know the efficacy of Amlexanox 5% with other topical Antiseptic, Analgesic and Anesthetic agents in treating minor RAS. J Int Oral Health 2014;6(1);5-11.
PMCID: PMC3959130  PMID: 24653596
Amlexanox; recurrent aphthous stomatitis (RAS); visual analogue scale (VAS)
11.  Anesthetic Cartridge System Under Evaluation 
Anesthesia Progress  1981;28(1):5-10.
The problem of glass breakage in the local anesthetic cartridge system was evaluated under laboratory conditions with a mechanical testing machine. The anticipated breakage of the glass did not occur with any frequency, as the rubber stopper produced more uniform failures of the system. The glass cartridge appeared to be quite reliable and resistant to breakage.
Local anesthetics have been used for many years to provide patients temporary freedom from pain. Local anesthetic solutions are in wide use in both dentistry and medicine and are the most frequently used drugs in dentistry. Various estimates place the number of injections at approximately one half million daily or 125 million injections per year.
These drugs and the armamentarium necessary to administer them have proven to be safe and reliable. Only rarely are there reports of sensitivity to the anesthetic solution or breakage of needles.. Sterility of the solutions has not been a problem as they are carefully processed and evaluated at the factory. Although there are sporadic reports of loss of sterility, this has been attributed to the reuse of the anesthetic cartridges on more than one patient. Monheim states “The success of the cartridge system in dentistry has been due to the sincerity, honesty, and high standards of the manufacturers in giving the profession a near-perfect product.” However, on occassion a glass cartridge will break or shatter when inserting the harpoon into the rubber stopper or even during injection. Cooley et al reported on eye injuries occurring in the dental office, one of which was due to glass from a local anesthetic cartridge that exploded and propelled particles into the patient's eye. Forrest evaluated syringes, needles, and cartridges and reported that one brand (made in Britain) fractured more often than any other, but that the fracture rate was too low to be of any consequence.
It is apparent that glass cartridges will fracture or burst from time to time. This study evaluates the cartridge system with carefully controlled laboratory procedures. The cartridges were tested under various pressures and conditions in an attempt to determine the causes of failure and when such failure may be anticipated.
Images
PMCID: PMC2235753  PMID: 6939350
12.  Advanced Pre-Clinical Research Approaches and Models to Studying Pediatric Anesthetic Neurotoxicity 
Advances in pediatric and obstetric surgery have resulted in an increase in the duration and complexity of anesthetic procedures. A great deal of concern has recently arisen regarding the safety of anesthesia in infants and children. Because of obvious limitations, it is not possible to thoroughly explore the effects of anesthetic agents on neurons in vivo in human infants or children. However, the availability of some advanced pre-clinical research approaches and models, such as imaging technology both in vitro and in vivo, stem cells, and non-human primate experimental models, have provided potentially invaluable tools for examining the developmental effects of anesthetic agents. This review discusses the potential application of some sophisticated research approaches, e.g., calcium imaging, in stem cell-derived in vitro models, especially human embryonic neural stem cells, along with their capacity for proliferation and their potential for differentiation, to dissect relevant mechanisms underlying the etiology of the neurotoxicity associated with developmental exposures to anesthetic agents. Also, this review attempts to discuss several advantages for using the developing rhesus monkey model (in vivo), when combined with dynamic molecular imaging approaches, in addressing critical issues related to the topic of pediatric sedation/anesthesia. These include the relationships between anesthetic-induced neurotoxicity, dose response, time-course, and developmental stage at time of exposure (in vivo studies), serving to provide the most expeditious platform toward decreasing the uncertainty in extrapolating pre-clinical data to the human condition.
doi:10.3389/fneur.2012.00142
PMCID: PMC3473308  PMID: 23087669
development; anesthesia; neurotoxicity; mechanism; imaging
13.  The Antinociceptive and Antihyperalgesic Effects of Topical Propofol on Dorsal Horn Neurons in the Rat 
Anesthesia and analgesia  2013;116(4):932-938.
Background
Propofol (2,6-diisopropylphenol) is an IV anesthetic used for general anesthesia. Recent evidence suggests that propofol-anesthetized patients experience less postoperative pain, and that propofol has analgesic properties when applied topically. We presently investigated the antinociceptive effects of topical propofol using behavioral and single-unit electrophysiological methods in rats.
Methods
In behavioral experiments with rats, we assessed the effect of topical hindpaw application of propofol (1–25%) on heat and mechanically evoked paw withdrawals. In electrophysiology experiments we recorded from lumbar dorsal horn wide dynamic range (WDR)-type neurons in pentobarbital-anesthetized rats. We assessed the effect of topical application of propofol to the ipsilateral hindpaw on neuronal responses elicited by noxious heat, cold and mechanical stimuli. We additionally tested if propofol blocks heat sensitization of paw withdrawals and WDR neuronal responses induced by topical application of allyl isothiocyanate (AITC; mustard oil).
Results
Topical application of propofol (1–25%) significantly increased the mean latency of the thermally evoked hindpaw withdrawal reflex on the treated (but not opposite) side in a concentration-dependent manner, with no effect on mechanically evoked hindpaw withdrawal thresholds. Propofol also prevented shortening of paw withdrawal latency induced by AITC. In electrophysiological experiments, topical application of 10 and 25% propofol, but not 1% propofol or vehicle (10% intralipid), to the ipsilateral hindpaw significantly attenuated the magnitude of responses of WDR neurons to noxious heating of glabrous hindpaw skin with no significant change in thermal thresholds. Maximal suppression of noxious heat-evoked responses was achieved 15-min after application followed by recovery to the pre-propofol baseline by 30 min. Responses to skin cooling or graded mechanical stimuli were not significantly affected by any concentration of propofol. Topical application of AITC enhanced the noxious heat-evoked response of dorsal horn neurons. This enhancement of heat-evoked responses was attenuated when 10% propofol was applied topically after application of AITC.
Conclusions
The results indicate that topical propofol inhibits responses of WDR neurons to noxious heat consistent with analgesia, and reduced AITC sensitization of WDR neurons consistent with an antihyperalgesic effect. These results are consistent with clinical studies demonstrating reduced postoperative pain in surgical patients anesthetized with propofol. The mechanism of analgesic action of topical propofol is not clear, but may involve desensitization of TRPV1 or TRPA1 receptors expressed in peripheral nociceptive nerve endings, engagement of endocannabinoids, or activation of peripheral gamma-aminobutyric acid A receptors.
doi:10.1213/ANE.0b013e31827f560d
PMCID: PMC3606650  PMID: 23337417
14.  Topical anesthesia. 
Canadian Family Physician  1998;44:2152-2156.
OBJECTIVE: To consider topical anesthetic options available to primary care physicians, indications for their use, and efficacy and safety of these agents as supported by the literature. QUALITY OF EVIDENCE: Five randomized controlled trials were retrieved that compared various topical anesthetics as well as topical anesthetics versus infiltrative anesthesia. MAIN FINDINGS: A combination of lidocaine, epinephrine, and tetracaine (LET) is currently the topical anesthetic of choice for repair of simple lacerations involving the faces and scalps of children. A promising new topical preparation is bupivacaine and epinephrine, but its efficacy must be studied in larger populations before widespread use can be advocated. Using EMLA (eutectic mixture of local anesthetics) for repair of extremity lacerations requires further study and cannot yet be recommended. Continued use of topical tetracaine, adrenaline, and cocaine (TAC) is not supported in the literature, because of its greater expense, its status as a restricted narcotic, its potential for toxicity, and better availability of an equally efficacious alternative, LET. CONCLUSIONS: Children's simple facial and scalp lacerations can be safely repaired using topical LET gel. Physicians must adhere to recommendations to avoid mucous membrane contact and ensure appropriate dosing with these agents. Bupivacaine-epinephrine topical preparation is a promising analgesic agent that warrants further study.
PMCID: PMC2277899  PMID: 9805170
15.  The role of Volatile Anesthetics in Cardioprotection: a systematic review 
Medical Gas Research  2012;2:22.
This review evaluates the mechanism of volatile anesthetics as cardioprotective agents in both clinical and laboratory research and furthermore assesses possible cardiac side effects upon usage. Cardiac as well as non-cardiac surgery may evoke perioperative adverse events including: ischemia, diverse arrhythmias and reperfusion injury. As volatile anesthetics have cardiovascular effects that can lead to hypotension, clinicians may choose to administer alternative anesthetics to patients with coronary artery disease, particularly if the patient has severe preoperative ischemia or cardiovascular instability. Increasing preclinical evidence demonstrated that administration of inhaled anesthetics - before and during surgery - reduces the degree of ischemia and reperfusion injury to the heart. Recently, this preclinical data has been implemented clinically, and beneficial effects have been found in some studies of patients undergoing coronary artery bypass graft surgery. Administration of volatile anesthetic gases was protective for patients undergoing cardiac surgery through manipulation of the potassium ATP (KATP) channel, mitochondrial permeability transition pore (mPTP), reactive oxygen species (ROS) production, as well as through cytoprotective Akt and extracellular-signal kinases (ERK) pathways. However, as not all studies have demonstrated improved outcomes, the risks for undesirable hemodynamic effects must be weighed against the possible benefits of using volatile anesthetics as a means to provide cardiac protection in patients with coronary artery disease who are undergoing surgery.
doi:10.1186/2045-9912-2-22
PMCID: PMC3598931  PMID: 22929111
Cardiac; Cardioprotection; Arrhythmias; Ischemia; Volatile anesthetic gas; Anesthesia
16.  Therapy of atopic eczema 
Objectives
Major objective is the evaluation of the medical effectiveness of different therapeutical approaches and the cost effectiveness with relevance for Germany.
Methods
This health technology assessment (HTA) evaluates systemically randomized controlled studies (RCT) on the therapy of atopic dermatitis which were published between 1999 and 2004. Further it includes some important clinical studies which have been published after 2004 and other updates the English HTA report by Hoare et al. [1].
Results
Topical corticosteroids and topical calcineurin-inhibitors are the principal substances which are currently used for anti-inflammatory therapy in atopic dermatitis. These substances have shown a significant therapeutic efficacy in controlled studies. In newer controlled studies no difference was observable when corticosteroids were applied once or more than once daily onto the skin. Moreover, there is now one controlled study available which points to the fact that an interval therapy with a stronger topical corticosteroid over a limited time (some weeks) may lower the risk of recurrent flares of atopic dermatitis. Both topical calcineurin-inhibitors pimecrolimus and tacrolimus have shown a significant therapeutical efficacy in a number of placebo-controlled prospective studies. The wealth of data is high for these substances. Both substances have been shown to be efficient in infants, children and adult patients with atopic dermatitis.
The importance of a so-called basic therapy with emollients which have to be adapted to the current status of skin is generally accepted in clinical practice. Controlled studies show the efficacy of ”basic therapy” - although the level of evidence is quite low for this approach. The skin of patients with atopic dermatitis is colonized in the majority with Staphylococcus aureus, a gram-positive bacterium. Therefore, a therapeutical approach for the treatment of atopic dermatitis is the anti-bacterial or anti-septic treatment of the skin. Due to the lack of randomized controlled studies there is still not certain proof that antimicrobial or anti-septic treatment of non-infected eczematous skin is efficient for the treatment of atopic dermatitis. A reduction of Staphylococcus aureus is observable during an anti-inflammatory treatment of the skin with topical corticosteroids and/or the topical calcineurin-inhibitor tacrolimus. Antihistaminic drugs which are orally applied in atopic dermatitis may support the therapy of the itching skin disease. One controlled study showed a rapid reduction of itch during the use of a non-sedating antihistaminic drug. There are, however, no controlled studies which show the efficacy of antihistaminic drugs on the skin condition in atopic dermatitis.
Dietetic restrictions should be applied only after a specific allergological diagnostic clarification. The “gold standard” is still a (blinded) oral provocation test which has to show an influence of a given food on the skin condition. There is sufficient evidence that there is no general dietetic approach which shows efficacy in atopic dermatitis. The treatment of patients with lactobacillae is still controversially discussed. Available studies which showed an efficacy show methodological weaknesses so that this approach can not be generally recommended for clinical practice at the time now. Approaches reducing house dust mite in the surroundings of patients with atopic dermatitis can have an effect on the skin condition so that at least in mite sensitized patients this approach appears to be reasonable. The specific immunotherapy with house dust mite showed clinical efficacy in a controlled study and in some open studies. The education of patients with atopic dermatitis or their parents is a further efficient approach in the management of this chronic skin disease. Interdisciplinary approaches in patients’ education containing also psychological elements appear to be an attractive new approach for the treatment of atopic dermatitis.
Phototherapy is a further possibility of intervention in atopic dermatitis in adolescent or adult patients. The available evidence points to the fact that UVB radiation (both small and broad spectrum), UVA-1 radiation and balneo-phototherapy are efficient therapeutical options for atopic dermatitis. The systemic treatment with the immunosuppressive substance cyclosporine A is efficient in the treatment of severe atopic dermatitis. Cyclosoprine A is approved for the treatment of adult patients with this skin disease. The immunosuppressive substance azathioprine showed a high clinical efficacy in two controlled studies for severe atopic dermatitis in adults. There are still controversial results for the application of antagonists to leucotriens in the treatment of atopic dermatitis: in some open studies a therapeutical efficacy was described which was, however, not reproducible in a newer controlled study. The phosphodiesterase-4-inhibitor cipamphyllin was efficient in the treatment of atopic dermatitis in a controlled study but weaker than a topical class II (i. e. moderate strength) corticosteroide. The HTA assessment further describes so-called complementary therapeutical approaches which have either not properly been studied in controlled clinical trials or which have been shown to be of no value for the treatment of atopic dermatitis.
Altogether six full health-economic evaluations were found which did not cover the whole therapy spectrum of atopic dermatitis. The choice of the most cost effective treatment option of topic corticosteroids depends less on application frequency, but rather on the drug price and more used or unused quantity of the standard packages, so even smallest improvements justify a more frequent application. The results from health economic evaluations of calcineurin-inhibitors are not reliable. The therapy of severe atopic dermatitis in adults with ciclosporin shows comparable cost effectiveness in comparison to UVA/UVB therapy.
Discussion
The spectrum of therapeutical procedures has increased for atopic dermatitis but is still not sufficient. The spectrum of established substances is much smaller compared to psoriasis, another chronic and common inflammatory skin disease. There is need for the development new substances which can be applied topically and which are aimed to treat atopic dermatitis in early childhood. Another need for new developments can be found for the treatment of severe atopic dermatitis in adults.
Conclusions
The spectrum of therapeutical procedures has increased for atopic dermatitis but is still not sufficient. The spectrum of established substances is much smaller compared to psoriasis, another chronic and common inflammatory skin disease. There is need for the development new substances which can be applied topically and which are aimed to treat atopic dermatitis in early childhood. Another need for new developments can be found for the treatment of severe atopic dermatitis in adults.
Due to lack of health economic evaluations therapy decisions in the treatment of atopic dermatitis must take place on the basis of clinical decision criteria. The prescription of topic corticosteroids should prefer low priced drugs. Reliable statements about the cost effectiveness of the new calcineurin-inhibitors tacrolimus and pimecrolimus.
PMCID: PMC3011357  PMID: 21289970
17.  Management of Ocular Trauma in Emergency (MOTE) Trial: A pilot randomized double-blinded trial comparing topical amethocaine with saline in the outpatient management of corneal trauma 
Background:
It is unclear whether local anesthetic eye drops can be safely used for the topical anesthesia of patients with minor corneal injury who are discharged from the emergency department (ED).
Objectives:
To assess whether topical 0.4% amethocaine self-administered to a maximum recommended frequency of once every hour for 36–48 h is safe in the management of uncomplicated corneal injury in patients discharged from the ED.
Patients and Methods:
A pilot randomized double-blinded trial comparing topical 0.4% amethocaine with topical normal saline.
Results:
Forty-seven subjects were recruited, with 22 randomized to receive amethocaine and 25 to receive placebo (normal saline). Baseline characteristics, including corneal injury type, were similar in both groups. There were no significant functional or clinical adverse sequelae in the majority of enrolled patients who could be contacted at 2 weeks (17/22 for amethocaine and 21/25 for placebo). Follow-up for the primary study outcome was suboptimal, with only 7/22 from the amethocaine group and 9/25 from the saline group presenting for 36–48 h review; there was a statistically nonsignificant trend for persistence of the corneal defect in the amethocaine group as compared with the saline group (2/7 and 1/9, respectively).
Conclusion:
Compared with saline drops, amethocaine eye drops are not definitely safe but they are effective for topical analgesia in minor corneal injury. Until further definitive studies, topical nonsteroidal agents or long-lasting artificial tears may be preferred for the topical analgesia of minor corneal injury. Return for corneal re-evaluation will necessarily remain suboptimal in an otherwise self-limiting condition, leading to a bias even if study recruitment is good.
doi:10.4103/0974-2700.44676
PMCID: PMC2700573  PMID: 19561949
Corneal injury; ocular anesthetic; topical analgesia
18.  Mortality reduction in cardiac anesthesia and intensive care: results of the first International Consensus Conference 
Background
There is no consensus on which drugs/techniques/strategies can affect mortality in the perioperative period of cardiac surgery. With the aim of identifying these measures, and suggesting measures for prioritized future investigation we performed the first international consensus conference on this topic.
Methods
The consensus was a continuous international internet-based process with a final meeting on June 28th 2010 in Milan at the Vita-Salute University. Participants included 340 cardiac anesthesiologists, cardiac surgeons and cardiologists from 65 countries all over the world. A comprehensive literature review was performed to identify topics that subsequently generated position statements for discussion, voting and ranking.
Results
Of the 17 major topics with a documented mortality effect, seven were subsequently excluded after further evaluation due to concerns about clinical applicability and/or study methodology. The following topics are documented as reducing mortality: administration of insulin, levosimendan, volatile anesthetics, statins, chronic beta-blockade, early aspirin therapy, the use of preoperative intra-aortic balloon counterpulsation and referral to high-volume centers. The following are documented as increasing mortality: administration of aprotinin and aged red blood cell transfusion. These interventions were classified according to the level of evidence and effect on mortality and a position statement was generated.
Conclusion
This international consensus conference has identified the non-surgical interventions that merit urgent study to achieve further reductions in mortality after cardiac surgery: insulin, intra-aortic balloon counterpulsation, levosimendan, volatile anesthetics, statins, chronic beta-blockade, early aspirin therapy, and referral to high-volume centers. The use of aprotinin and aged red blood cells may result in increased mortality.
PMCID: PMC3484607  PMID: 23439940
anesthesia; intensive care; cardiac anesthesia; cardiac surgery; mortality; cardiopulmonary bypass; consensus development conference; treatment outcome; focused update; prevention and control
19.  Strategies for Increasing Recruitment to Randomised Controlled Trials: Systematic Review 
PLoS Medicine  2010;7(11):e1000368.
Patrina Caldwell and colleagues performed a systematic review of randomized studies that compared methods of recruiting individual study participants into trials, and found that strategies that focus on increasing potential participants' awareness of the specific health problem, and that engaged them, appeared to increase recruitment.
Background
Recruitment of participants into randomised controlled trials (RCTs) is critical for successful trial conduct. Although there have been two previous systematic reviews on related topics, the results (which identified specific interventions) were inconclusive and not generalizable. The aim of our study was to evaluate the relative effectiveness of recruitment strategies for participation in RCTs.
Methods and Findings
A systematic review, using the PRISMA guideline for reporting of systematic reviews, that compared methods of recruiting individual study participants into an actual or mock RCT were included. We searched MEDLINE, Embase, The Cochrane Library, and reference lists of relevant studies. From over 16,000 titles or abstracts reviewed, 396 papers were retrieved and 37 studies were included, in which 18,812 of at least 59,354 people approached agreed to participate in a clinical RCT. Recruitment strategies were broadly divided into four groups: novel trial designs (eight studies), recruiter differences (eight studies), incentives (two studies), and provision of trial information (19 studies). Strategies that increased people's awareness of the health problem being studied (e.g., an interactive computer program [relative risk (RR) 1.48, 95% confidence interval (CI) 1.00–2.18], attendance at an education session [RR 1.14, 95% CI 1.01–1.28], addition of a health questionnaire [RR 1.37, 95% CI 1.14–1.66]), or a video about the health condition (RR 1.75, 95% CI 1.11–2.74), and also monetary incentives (RR1.39, 95% CI 1.13–1.64 to RR 1.53, 95% CI 1.28–1.84) improved recruitment. Increasing patients' understanding of the trial process, recruiter differences, and various methods of randomisation and consent design did not show a difference in recruitment. Consent rates were also higher for nonblinded trial design, but differential loss to follow up between groups may jeopardise the study findings. The study's main limitation was the necessity of modifying the search strategy with subsequent search updates because of changes in MEDLINE definitions. The abstracts of previous versions of this systematic review were published in 2002 and 2007.
Conclusion
Recruitment strategies that focus on increasing potential participants' awareness of the health problem being studied, its potential impact on their health, and their engagement in the learning process appeared to increase recruitment to clinical studies. Further trials of recruitment strategies that target engaging participants to increase their awareness of the health problems being studied and the potential impact on their health may confirm this hypothesis.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Before any health care intervention—a treatment for a disease or a measure such as vaccination that is designed to prevent an illness—is adopted by the medical community, it undergoes exhaustive laboratory-based and clinical research. In the laboratory, scientists investigate the causes of diseases, identify potential new treatments or preventive methods, and test these interventions in animals. New interventions that look hopeful are then investigated in clinical trials—studies that test these interventions in people by following a strict trial protocol or action plan. Phase I trials test interventions in a few healthy volunteers or patients to evaluate their safety and to identify possible side effects. In phase II trials, a larger group of patients receives an intervention to evaluate its safety further and to get an initial idea of its effectiveness. In phase III trials, very large groups of patients (sometimes in excess of a thousand people) are randomly assigned to receive the new intervention or an established intervention or placebo (dummy intervention). These “randomized controlled trials” or “RCTs” provide the most reliable information about the effectiveness and safety of health care interventions.
Why Was This Study Done?
Patients who participate in clinical trials must fulfill the inclusion criteria laid down in the trial protocol and must be given information about the trial, its risks, and potential benefits before agreeing to participate (informed consent). Unfortunately, many RCTs struggle to enroll the number of patients specified in their trial protocol, which can reduce a trial's ability to measure the effect of a new intervention. Inadequate recruitment can also increase costs and, in the worst cases, prevent trial completion. Several strategies have been developed to improve recruitment but it is not clear which strategy works best. In this study, the researchers undertake a systematic review (a study that uses predefined criteria to identify all the research on a given topic) of “recruitment trials”—studies that have randomly divided potential RCT participants into groups, applied different strategies for recruitment to each group, and compared recruitment rates in the groups.
What Did the Researchers Do and Find?
The researchers identified 37 randomized trials of recruitment strategies into real and mock RCTs (where no actual trial occurred). In all, 18,812 people agreed to participate in an RCT in these recruitment trials out of at least 59,354 people approached. Some of these trials investigated novel strategies for recruitment, such as changes in how patients are randomized. Others looked at the effect of recruiter differences (for example, increased contact between the health care professionals doing the recruiting and the trial investigators), the effect of offering monetary incentives to participants, and the effect of giving more information about the trial to potential participants. Recruitment strategies that improved people's awareness of the health problem being studied—provision of an interactive computer program or a video about the health condition, attendance at an educational session, or inclusion of a health questionnaire in the recruitment process—improved recruitment rates, as did monetary incentives. Increasing patients' understanding about the trial process itself, recruiter differences, and alterations in consent design and randomization generally had no effect on recruitment rates although consent rates were higher when patients knew the treatment to which they had been randomly allocated before consenting. However, differential losses among the patients in different treatment groups in such nonblinded trials may jeopardize study findings.
What Do These Findings Mean?
These findings suggest that trial recruitment strategies that focus on increasing the awareness of potential participants of the health problem being studied and its possible effects on their health, and that engage potential participants in the trial process are likely to increase recruitment to RCTs. The accuracy of these findings depends on whether the researchers identified all the published research on recruitment strategies and on whether other research on recruitment strategies has been undertaken and not published that could alter these findings. Furthermore, because about half of the recruitment trials identified by the researchers were undertaken in the US, the successful strategies identified here might not be generalizable to other countries. Nevertheless, these recruitment strategies should now be investigated further to ensure that the future evaluation of new health care interventions is not hampered by poor recruitment into RCTs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000368.
The ClinicalTrials.gov Web site is a searchable register of federally and privately supported clinical trials in the US and around the world, providing information about all aspects of clinical trials
The US National Institutes of Health provides information about clinical trials
The UK National Health Service Choices Web site has information for patients about clinical trials and medical research
The UK Medical Research Council Clinical Trials Units also provides information for patients about clinical trials and links to information on clinical trials provided by other organizations
MedlinePlus has links to further resources on clinical trials (in English and Spanish)
The Australian Government's National Health and Medical Research Council has information about clinical trials
WHO International Clinical Trials Registry Platform aims to ensure that all trials are publicly accessible to those making health care decisions
The Star Child Health International Forum of Standards for Research is a resource center for pediatric clinical trial design, conduct, and reporting
doi:10.1371/journal.pmed.1000368
PMCID: PMC2976724  PMID: 21085696
20.  Tolerability of NGX-4010, a capsaicin 8% dermal patch, following pretreatment with lidocaine 2.5%/prilocaine 2.5% cream in patients with post-herpetic neuralgia 
BMC Anesthesiology  2011;11:25.
Background
Post-herpetic neuralgia (PHN) is a common type of neuropathic pain that can severely affect quality of life. NGX-4010, a capsaicin 8% dermal patch, is a localized treatment that can provide patients with significant pain relief for up to 3 months following a single 60-minute application. The NGX-4010 application can be associated with application-site pain and in previous clinical trials pretreatment with a topical 4% lidocaine anesthetic was used to enhance tolerability. The aim of the current investigation was to evaluate tolerability of NGX-4010 after pretreatment with lidocaine 2.5%/prilocaine 2.5% anesthetic cream.
Methods
Twenty-four patients with PHN were pretreated with lidocaine 2.5%/prilocaine 2.5% cream for 60 minutes before receiving a single 60-minute application of NGX-4010. Tolerability was assessed by measuring patch application duration, the proportion of patients completing over 90% of the intended treatment duration, application site-related pain using the Numeric Pain Rating Scale (NPRS), and analgesic medication use to relieve such pain. Safety was assessed by monitoring adverse events (AEs) and dermal irritation using dermal assessment scores.
Results
The mean treatment duration of NGX-4010 was 60.2 minutes and all patients completed over 90% of the intended patch application duration. Pain during application was transient. A maximum mean change in NPRS score of +3.0 was observed at 55 minutes post-patch application; pain scores gradually declined to near pre-anesthetic levels (+0.71) within 85 minutes of patch removal. Half of the patients received analgesic medication on the day of treatment; by Day 7, no patients required medication. The most common AEs were application site-related pain, erythema, edema, and pruritus. All patients experienced mild dermal irritation 5 minutes after patch removal, which subsequently decreased; at Day 7, no irritation was evident. The maximum recorded dermal assessment score was 2.
Conclusion
NGX-4010 was well tolerated following pretreatment with lidocaine 2.5%/prilocaine 2.5% cream in patients with PHN. The tolerability of the patch application appeared comparable with that seen in other studies that used 4% lidocaine cream as the pretreatment anesthetic. This study is registered at http://www.clinicaltrials.gov as number NCT00916942.
doi:10.1186/1471-2253-11-25
PMCID: PMC3292968  PMID: 22182397
21.  Optimization of Topical Therapy for Leishmania major Localized Cutaneous Leishmaniasis Using a Reliable C57BL/6 Model 
Background
Because topical therapy is easy and usually painless, it is an attractive first-line option for the treatment of localized cutaneous leishmaniasis (LCL). Promising ointments are in the final stages of development. One main objective was to help optimize the treatment modalities of human LCL with WR279396, a topical formulation of aminoglycosides that was recently proven to be efficient and safe for use in humans.
Methodology/Principal Findings
C57BL/6 mice were inoculated in the ear with luciferase transgenic L. major and then treated with WR279396. The treatment period spanned lesion onset, and the evolution of clinical signs and bioluminescent parasite loads could be followed for several months without killing the mice. As judged by clinical healing and a 1.5-3 log parasite load decrease in less than 2 weeks, the 94% efficacy of 10 daily applications of WR279396 in mice was very similar to what had been previously observed in clinical trials. When WR279396 was applied with an occlusive dressing, parasitological and clinical efficacy was significantly increased and no rebound of parasite load was observed. In addition, 5 applications under occlusion were more efficient when done every other day for 10 days than daily for 5 days, showing that length of therapy is a more important determinant of treatment efficacy than the total dose topically applied.
Conclusions/Significance
Occlusion has a significant adjuvant effect on aminoglycoside ointment therapy of experimental cutaneaous leishmaniasis (CL), a concept that might apply to other antileishmanial or antimicrobial ointments. Generated in a laboratory mouse-based model that closely mimics the course of LCL in humans, our results support a schedule based on discontinuous applications for a few weeks rather than several daily applications for a few days.
Author Summary
When initiating the cutaneous disease named cutaneous leishmaniasis (CL), Leishmania parasites develop within the parasitophorous vacuoles of phagocytes residing in and/or recruited to the dermis, a process leading to more or less chronic dermis and epidermis-damaging inflammatory processes. Topical treatment of CL could be a mainstay in its management. Any improvements of topicals, such as new vehicles and shorter optimal contact regimes, could facilitate their use as an ambulatory treatment. Recently, WR279396, a third-generation aminoglycoside ointment, was designed with the aim to provide stability and optimal bioavailability for the molecules expected to target intracellular Leishmania. Two endpoints were expected to be reached: i) accelerated clearance of the maximal number of parasites, and ii) accelerated and stable repair processes without scars. A mouse model of CL was designed: it relies on the intradermal inoculation of luciferase-expressing Leishmania, allowing for in vivo bioluminescence imaging of the parasite load fluctuation, which can then be quantified simultaneously with the onset and resolution of clinical signs. These quantitative readout assays, deployed in real time, provide robust methods to rapidly assess efficacy of drugs/compounds i) to screen treatment modalities and ii) allow standardized comparison of different therapeutic agents.
doi:10.1371/journal.pntd.0000034
PMCID: PMC2100369  PMID: 18060082
22.  Corticosteroid therapy in the treatment of pediatric patients with atopic dermatitis 
Health political background
In developed countries 2.5% of the population - mainly children - are affected by atopic dermatitis. During the past few years its prevalence amongst school children has risen decisively and now lies between 8% to 16%. It is the most frequent chronic skin disease amongst school-aged children.
Scientific background
Current methods of treating atopic dermatitis among children focus on containing and preventing the illness’s further progression. Preventing dry skin, relieving symptoms (such as pruritis and inflammation of the skin) and identifying and avoiding provocating factors are elementary goals of treatment. Successful treatment can substantially increase the children’s quality of life. Possible therapies of children affected by atopic dermatitis include both topically and systemically applied pharmaceuticals. During the past ten years the use of corticosteroids has been the standard topical anti-inflammatory therapy in case of aggravating inflammations. In 2002 a new group of pharmaceutical substances (topical calcineurin inhibitors tacrolimus and pimecrolimus) was authorised in Germany for topical anti-inflammatory treatment of patients. Because of its high prevalence atopic dermatitis represents a major expense factor to the German health care system. In 1999 the costs of the treatment of atopic dermatitis with corticosteroids in Germany amounted to 230 million Euro. If other direct costs for the treatment are included, for example hospitalisation or doctor appointments, the total costs amount to 3.57 billion Euro.
Research question
How effective and efficient are topical anti-inflammatory treatments of children with atopic dermatitis?
Methods
A systematic literature search was performed in 35 international databases which yielded 1335 articles. Following a two-part selection process according to predefined criteria 24 publications were included in the assessment.
Results
Of 19 randomised controlled clinical trials, which were included in the assessment, only two evaluated the effect of topical corticosteroids in comparison to tacrolimus, which is one of the calcineurin inhibitors. Both studies show that tacrolimus is more effective than hydrocortisone acetate in children with moderate to severe atopic dermatitis. No study was found that directly compares corticosteroids with pimecrolimus in the treatment of paediatric patients with atopic dermatitis. However, two trials show that an intermittent treatment with pimecrolimus can reduce the need for topical corticosteroids. Two publications focusing on the costs of atopic dermatitis, provide model calculations comparing the use of topical corticosteroids and calcineurin inhibitors. The calculations show that the treatment with topical corticosteroids is inferior to the treatment with pimecrolimus in children with mild to moderate atopic dermatitis. Furthermore the treatment with tacrolimus appears to be more expensive however also more effective in comparison to topical corticosteroids.
Discussion
During the past five decades topical corticosteroids have represented the first choice therapy when it comes to atopic dermatitis. Their effectiveness has been proven by several studies. Amongst newer generations of topical corticosteroids the occurrence of adverse side effects seems to be less frequent. Due to the fact that they have only recently been authorised experience with tacrolimus and pimecrolimus is limited. So far the only adverse side effect of the calcineurin inhibitors appears to be a burning sensation of the skin. One point for discussion concerns the economical aspects of the treatment of atopic dermatitis. The cost-effectiveness of pimecrolimus has been based on the calculated costs per quality-adjusted life year, which were lower than the frequently hawked value of 50,000 USD. It is up to policy makers to decide on the actual value of a quality-adjusted life year.
Conclusions/recommendations
From a medical as well as an economical viewpoint, there appears to be insufficient evidence stating that inflammatory steroid-free substances are more effective and/or efficient than topical corticosteroids. Based on the results of the studies that have been included in this assessment therapies based on calcineurin inhibitors seem to constitute a good alternative in case a child is unresponsive or intolerable to topical corticosteroids and for the treatment of intertriginous areas.
PMCID: PMC3011329  PMID: 21289943
23.  Nonpreserved amniotic membrane transplantation for bilateral toxic keratopathy caused by topical anesthetic abuse: a case report 
Introduction
Corneal damage associated with abuse of topical anesthetics is a rare clinic entity. Topical anesthetic abuse is one of the causes of ring keratitis. Ring keratitis is easily overlooked because it can mimic acanthamoeba keratitis or other infectious keratitis. The outcome is often poor, leading to persistent epithelial defects, corneal scarring, and perforations.
Case presentation
We report the clinical presentation, diagnosis, and treatment of a 65-year-old Caucasian man, who worked as a health care worker, with bilateral toxic keratopathy caused by topical anesthetic abuse. Nonpreserved amniotic membrane transplantation was performed for both eyes of the patient.
Conclusion
It is important to identify and treat patients who abuse topical anesthetics before permanent vision loss ensues. Nonpreserved amniotic membrane transplantation may be useful in relieving pain and improving corneal surface in anesthetic agent abusers.
doi:10.1186/1752-1947-4-262
PMCID: PMC2924861  PMID: 20698973
24.  Anesthetic efficacy of Oraqix® versus Hurricaine® and placebo for pain control during non-surgical periodontal treatment 
Objectives: To evaluate the efficacy of Oraqix® during scaling and root planing (SRP) in comparison with 20% benzocaine and placebo. Study Design: 15 patients requiring 4 sessions of SRP were enrolled. For each patient, Oraqix®, Hurricaine®, vaseline or no anesthetic product were randomly assigned each to a quadrant. Treatment pain was evaluated on a 100 mm Visual Analog Scale (VAS) and on a Verbal Rating Scale (VRS). The amount of product administered, the need to re-anesthetise, patient and operator satisfaction and the onset of side-effects were also recorded. Results: Oraqix® was significantly better than nothing, with a reduction of VAS score to 13.3 units, but without significant differences with Vaseline or Hurricaine®. Oraqix® was better in VRS reduction than not using any anesthetic (p=0.001) or using vaseline (p=0.024), but similar to Hurricaine® (p=0.232). Conclusions: Oraqix® effectively controls pain in SRP procedures, with few side-effects and a good acceptance on the part of patients and clinicians.
Key words:Controlled clinical trial, topical anesthetic, scaling and root planing.
doi:10.4317/medoral.19202
PMCID: PMC4015044  PMID: 24316699
25.  Liposomal lidocaine to improve procedural success rates and reduce procedural pain among children: a randomized controlled trial 
Background
Historically, children have been undertreated for their pain, and they continue to undergo painful cutaneous procedures without analgesics. A new topical anesthetic, liposomal lidocaine 4% cream (Maxilene, RGR Pharma, Windsor, Ont.), has become available. It has pharmacologic properties that are superior to other topical anesthetics, including an onset of action of only 30 minutes. We sought to determine the success rate of cannulation, analgesic effectiveness, procedure duration and rate of adverse skin reactions when liposomal lidocaine is used before intravenous cannulation of children.
Methods
In this double-blind randomized controlled trial, children aged 1 month to 17 years received liposomal lidocaine or placebo before cannulation. Success on first cannulation attempt was recorded, and, among children 5 years and older, pain was evaluated before and after the attempt by the child, parents and research assistant using a validated measure (Faces Pain Scale-Revised). For children younger than 5 years, pain was evaluated by the parents and research assistant only. The total duration of the procedure and adverse skin reactions were also recorded.
Results
Baseline characteristics did not differ (p > 0.05) between children who received liposomal lidocaine (n = 69) and those who received placebo (n = 73). Cannulation on the first attempt was achieved in 74% of children who received liposomal lidocaine compared with 55% of those who received placebo (p = 0.03). Among children 5 years of age and older (n = 67), lower mean pain scores during cannulation were reported by those receiving liposomal lidocaine (p = 0.01). Similarly, lower mean pain scores during cannulation were reported by the parents and research assistant for all children who received liposomal lidocaine than for all those who received placebo (p < 0.001). The mean total procedure duration was shorter with liposomal lidocaine (6.7 v. 8.5 minutes; p = 0.04). The incidence of transient dermal changes was 23% in both groups (p = 1.0).
Conclusions
Use of liposomal lidocaine was associated with a higher intravenous cannulation success rate, less pain, shorter total procedure time and minor dermal changes among children undergoing cannulation. Its routine use for painful cutaneous procedures should be considered whenever feasible.
doi:10.1503/cmaj.045316
PMCID: PMC1150261  PMID: 15967972

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