New application of an old drug proparacaine in treating epilepsy via liposomal hydrogel formulation.

Proparacaine (PPC) is a previously discovered topical anesthetic for ophthalmic optometry and surgery by blocking the central Nav1.3. In this study, we found that proparacaine hydrochloride (PPC-HCl) exerted an acute robust antiepileptic effect in pilocarpine-induced epilepsy mice. More importantly, chronic treatment with PPC-HCl totally terminated spontaneous recurrent seizure occurrence without significant toxicity. Chronic treatment with PPC-HCl did not cause obvious cytotoxicity, neuropsychiatric adverse effects, hepatotoxicity, cardiotoxicity, and even genotoxicity that evaluated by whole genome-scale transcriptomic analyses. Only when in a high dose (50 mg/kg), the QRS interval measured by electrocardiography was slightly prolonged, which was similar to the impact of levetiracetam. Nevertheless, to overcome this potential issue, we adopt a liposome encapsulation strategy that could alleviate cardiotoxicity and prepared a type of hydrogel containing PPC-HCl for sustained release. Implantation of thermosensitive chitosan-based hydrogel containing liposomal PPC-HCl into the subcutaneous tissue exerted immediate and long-lasting remission from spontaneous recurrent seizure in epileptic mice without affecting QRS interval. Therefore, this new liposomal hydrogel formulation of proparacaine could be developed as a transdermal patch for treating epilepsy, avoiding the severe toxicity after chronic treatment with current antiepileptic drugs in clinic.

Degree of corneal anaesthesia after topical application of 0.4% oxybuprocaine hydrochloride and 0.5% proparacaine hydrochloride ophthalmic solution in clinically normal cattle.

OBJECTIVES: The use of corneal anaesthesia is necessary for a range of clinical purposes. Therefore, we assessed and compared the efficacy of corneal anaesthesia after application of 0.4% oxybuprocaine hydrochloride and 0.5% proparacaine hydrochloride ophthalmic solution in clinically normal cattle. METHODS: The 24 clinically normal cows were allocated into two groups. Cows in group 1 (n = 12) received 0.2 mL of 0.4% oxybuprocaine hydrochloride with fluorescein ophthalmic solution in one eye and 0.2 mL of sterile saline (0.9% NaCl) with fluorescein in the contralateral eye (control). Group 2 (n = 12) received 0.2 mL of 0.4% oxybuprocaine hydrochloride with fluorescein ophthalmic solution in one eye and 0.2 mL of 0.5% proparacaine hydrochloride with fluorescein in the contralateral eye (control). In each group, corneal touch threshold was determined by Cochet-Bonnet aesthesiometer for both eyes immediately prior to topical administration of solutions, at 1 min and 5 min after administration of topical solutions and every 5 min thereafter for a total of 75 min. RESULTS: Significant corneal anaesthesia was noted immediately following topical application of both oxybuprocaine and proparacaine as compared with controls, with maximal corneal anaesthesia noted 1 min after administration. Both oxybuprocaine and proparacaine produced significant corneal anaesthesia for the duration of the 75-min study. Neither oxybuprocaine hydrochloride nor proparacaine hydrochloride treatment resulted in visible adverse effects. CONCLUSION: There are limited data available demonstrating the efficacy and duration of corneal anaesthetic agents in cattle. Both oxybuprocaine hydrochloride and proparacaine hydrochloride should be considered practical options for providing corneal anaesthesia in cattle in a clinical setting.

Nasolacrimal Duct Probing under Topical Anesthesia for Congenital Nasolacrimal Duct Obstruction in Taiwan.

BACKGROUND: To report the success rates of office probing for congenital nasolacrimal duct obstruction (NLDO) among children of different age groups in Taiwan. METHODS: In this single-center, retrospective study, 564 eyes of 477 patients under the age of 5 years diagnosed with congenital NLDO were treated in a stepwise manner between 2001 and 2013. For infants aged < 6 months, treatment with massage and observation was suggested, followed by deferred probing under topical anesthesia if symptoms persisted. However, in cases of severe infection, immediate probing was suggested. In children aged > 6 months, office probing was usually highly recommended. Those with probing failures received either a second probing or silicone intubation. Treatment success was defined as anatomic patency by immediate irrigation after probing and absence of epiphora or mucous discharge at the follow-up visit. RESULTS: Primary probing was successful in 457 of 564 eyes (success rate: 81%). The success rate of primary probing was negatively correlated with increasing age: 90.1% (163/181), 79.6% (164/206), 76.8% (73/95), 73.5% (36/49), 75% (18/24), and 33% (3/9) for the age groups of 0 to <6 months, 6 to <12 months, 12 to <18 months, 18 to <24 months, 24 to <36 months, and 36-60 months, respectively (p < 0.001, Fisher's exact test). The second probing was successful in 52 of 81 eyes. In total, probing was successful in 509 of 564 eyes (success rate: 90.2%). CONCLUSION: Office probing is safe and effective for treating congenital NLDO. The success rate of primary probing decreases significantly with age.

Non-antiepileptic drugs for trigeminal neuralgia.

BACKGROUND: Trigeminal neuralgia was defined by the International Association for the Study of Pain as a sudden, usually unilateral, severe, brief, stabbing recurrent pain in the distribution of one or more branches of the fifth cranial nerve. Standard treatment is with anti-epileptic drugs. Non-antiepileptic drugs have been used in the management of trigeminal neuralgia since the 1970s. This is an update of a review first published in 2006 and previously updated in 2011. OBJECTIVES: To systematically review the efficacy and tolerability of non-antiepileptic drugs for trigeminal neuralgia. SEARCH METHODS: On 20 May 2013, for this updated review, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL (2013, Issue 4), MEDLINE (January 1966 to May 2013), EMBASE (January 1980 to May 2013), LILACS (January 1982 to May 2013) and the Chinese Biomedical Retrieval System (1978 to May 2013). We searched clinical trials registries for ongoing trials. SELECTION CRITERIA: We included double-blind, randomised controlled trials in which the active drug was used either alone or in combination with other non-antiepileptic drugs for at least two weeks. DATA COLLECTION AND ANALYSIS: Two authors decided which trials fitted the inclusion criteria and independently graded risk of bias. We assessed the quality of the evidence according to the GRADE criteria for this update. MAIN RESULTS: In this 2013 update, we updated the searches, but identified only two new ongoing studies. The review includes four trials involving 139 participants. The primary outcome measure in each was pain relief. Three trials compared one of the oral non-antiepileptic drugs tizanidine, tocainide or pimozide with carbamazepine. The quality of evidence for all outcomes for which data were available was low. In a trial of tizanidine involving 12 participants (one dropped out due to unrelated disease), one of five participants treated with tizanidine and four of six treated with carbamazepine improved (risk ratio (RR) 0.30, 95% confidence interval (CI) 0.05 to 1.89). Few side effects were noted with tizanidine. For pimozide, there was evidence of greater efficacy than carbamazepine at six weeks. Up to 83% of participants reported adverse effects but these did not lead to withdrawal; the report did not provide comparable data for carbamazepine. Limited data meant that we could not assess the effects of tocainide; however, data from non-randomised studies (not included in this review) indicate that serious haematological adverse events can occur. A trial involving 47 participants compared 0.5% proparacaine hydrochloride eyedrops with placebo but did not show any significant benefits, again according to low-quality evidence. The report did not mention adverse events. The proparacaine trial was at low risk of bias; the other trials were at unclear risk of bias overall. AUTHORS' CONCLUSIONS: There is low-quality evidence that the effect of tizanidine is not significantly different than that of carbamazepine in treating trigeminal neuralgia. Pimozide is more effective than carbamazepine, although the evidence is of low quality and the data did not allow comparison of adverse event rates. There is also low-quality evidence that 0.5% proparacaine hydrochloride eye drops have no benefit over placebo. Limitations in the data for tocainide prevent any conclusions being drawn. There is insufficient evidence from randomised controlled trials to show significant benefit from non-antiepileptic drugs in trigeminal neuralgia. More research is needed.

Non-antiepileptic drugs for trigeminal neuralgia.

BACKGROUND: Non-antiepileptic drugs have been used in the management of trigeminal neuralgia since the 1970s. OBJECTIVES: The objective was to systematically review the efficacy and tolerability of non-antiepileptic drugs for trigeminal neuralgia. SEARCH STRATEGY: For this updated review we searched the Cochrane Neuromuscular Disease Group Specialized Register (30 April 2010). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 2), MEDLINE (January 1966 to April 2010), EMBASE (January 1980 to April 2010), LILACS (January 1982 to April 2010) and the Chinese Biomedical Retrieval System (1978 to April 2010). We handsearched 10 Chinese journals. SELECTION CRITERIA: We searched for double-blind randomized or quasi-randomized controlled trials in which the active drug was used for at least two weeks. DATA COLLECTION AND ANALYSIS: Two authors decided which trials fitted the inclusion criteria and independently graded risk of bias. MAIN RESULTS: Four trials involving 139 participants were included. The primary outcome measure in each was pain relief. Three trials with an unclear risk of bias compared one of the non-antiepileptic drugs tizanidine, tocainide or pimozide with carbamazepine. In a trial of tizanidine involving 12 participants (one dropped out due to unrelated disease) one of five treated with tizanidine and four of six treated with carbamazepine improved, risk ratio 0.30 (95% CI 0.05 to 1.89). Few side effects were noted with tizanidine. In a study involving 12 participants there was an improvement in mean pain scores with tocainide similar to that with carbamazepine, but significant side effects limited its use. In the pimozide study more participants improved on pimozide (48/48) than with carbamazepine (27/48) (risk ratio 1.76, 95% CI 1.37 to 2.26). Up to 83% of participants reported adverse effects but these did not lead to withdrawal from the study. A trial with low risk of bias involving 47 participants compared 0.5% proparacaine hydrochloride eyedrops with placebo but did not show any significant benefits or side effects. AUTHORS' CONCLUSIONS: Of the four studies identified, one had low and three an unclear risk of bias. There is insufficient evidence from randomized controlled trials to show significant benefit from non-antiepileptic drugs in trigeminal neuralgia. More research is needed.

Non-antiepileptic drugs for trigeminal neuralgia.

BACKGROUND: Non-antiepileptic drugs have been used in trigeminal neuralgia management since the 1970s. OBJECTIVES: The objective was to review systematically the efficacy of non-antiepileptic drugs for trigeminal neuralgia. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Register, MEDLINE, EMBASE, and LILACS (all to August 2005) and the Chinese Biomedical Retrieval System, the database of the Chinese Cochrane Center (The Cochrane Library, Issue 1 2005), conference paper databases and checked bibliographies. We handsearched ten Chinese journals. SELECTION CRITERIA: We searched for randomized or quasi-randomized controlled trials. DATA COLLECTION AND ANALYSIS: Two authors decided which trials fitted the inclusion criteria and graded methodological quality independently. MAIN RESULTS: Nine trials of different non-antiepileptic drugs involving 223 participants were included. Each trial investigated one non-antiepileptic drug. Two trials tested baclofen. In one, more people gained 50% reduction from baseline than with placebo (relative risk 15.00, 95% CI 0.97 to 231.84, P value = 0.05). In the other, slightly more participants on baclofen had a 75% reduction in attacks on the 10th day compared with carbamazepine (relative risk 2.38, 95% CI 0.83 to 6.85, P value = 0.11). One trial showed no significant difference in reduction in average daily frequency of attacks with L-Baclofen compared with racemic baclofen. Tizanidine was investigated in two trials. In one, the proportion of people with reduction in the average number of paroxysms per day increased with tizanidine compared with placebo (relative risk 8.00, 95% CI 1.21 to 52.69, P value = 0.03). In the other, one of five participants improved in visual analog scale score with tizanidine and four of six with carbamazepine (relative risk 0.30, 95% CI 0.05 to 1.89, P value = 0.20). One study showed that the improvement in mean values of pain scores with tocainide was similar to that of carbamazepine. In one study more participants improved during the pimozide than the carbamazepine period (relative risk 1.78, 95% CI 1.39 to 2.28). In one study, proparacaine hydrochloride 0.5% instillation into the eyes was not significantly different from placebo (relative risk 1.06, 95% CI 0.37 to 2.99, P value = 0.92). In another, there was moderate or marked improvement in seven of nine participants treated with clomipramine and three of nine with amitriptyline after a 12-week treatment (RR 2.33, 95% CI 0.87 to 6.27). AUTHORS' CONCLUSIONS: There is insufficient evidence from randomized controlled trials to show significant benefit from non-antiepileptic drugs in trigeminal neuralgia. More research is needed.

Efficacy of sucrose to reduce pain in premature infants during eye examinations for retinopathy of prematurity.

BACKGROUND: Eye examinations for retinopathy of prematurity (ROP) are painful to the neonate. The use of topical anesthetic for eye examinations to evaluate ROP is routine in our neonatal intensive care unit (NICU), but does not completely suppress painful responses. Sweet solutions have been shown to reduce procedural pain in newborns. OBJECTIVE: To examine whether the addition of sucrose 24% to topical anesthetic improves procedural pain control during the ROP eye examination. METHODS: Neonates born at < or = 30 weeks' gestation were included in this placebo-controlled, double-blind, crossover study. Patients were randomly assigned to receive treatment with either proparacaine HCl ophthalmic solution 0.5% plus 2 mL of sucrose 24% or proparacaine HCl ophthalmic solution 0.5% plus 2 mL of sterile water (placebo) prior to an eye examination. In a subsequent eye examination, each patient received the alternate treatment. Oral sucrose and sterile water were prepared in the pharmacy in identical syringes, and physicians, nurses, and pharmacists in the NICU were blinded to the treatment given. Pain was measured using the Premature Infant Pain Profile (PIPP) scoring system, which measures both physical and physiologic measures of pain, and the scores were simultaneously assessed by 2 study nurses. PIPP scores were recorded 1 and 5 minutes before and after the eye examination and during initial placement of the eye speculum. The same ophthalmologist performed all eye examinations. Several different definitions of a pain response were investigated. RESULTS: Twenty-three infants were studied, with 12 receiving sucrose and 11 receiving placebo as the first treatment. For 3 of the 5 definitions of pain response, patients experienced significantly less pain at speculum insertion with sucrose than with placebo. After the ROP examination, pain responses were similar with either sucrose or placebo. CONCLUSIONS: Oral sucrose may reduce the immediate pain response in premature infants undergoing eye examination for ROP.

Systemic manifestations in response to mydriasis and physical examination during screening for retinopathy of prematurity.

OBJECTIVE: To determine whether adverse effects manifested via vital sign changes during the screening examination for retinopathy of prematurity (ROP) are due to the pharmacologic properties of the eye drops or to physical manipulation of the eyes. The authors also investigated the relationship between distress during the screening process and the severity of prematurity of the infant. DESIGN AND METHODS: A prospective observational study was designed that enrolled all infants either weighing < or =1500 g or who were < or =32 weeks gestational age at birth who were admitted to the neonatal intensive care unit (NICU) at Northwest Texas Hospital or Baptist St. Anthony's Hospital from June 2002 to February 2003. Thirty participants were enrolled in this study. Blood pressure, pulse, temperature, respiratory rate, and O2 saturation were recorded at different time intervals during the examination. Infants were excluded from the study if they were on the ventilator, considered acutely ill, born with significant birth defects, or currently taking inotropic drugs, or had received albuterol 2 hours before the examination. RESULTS: Oxygen saturation and pulse rate following physical manipulation of the eyes significantly varied from baseline values and the values obtained during the three instillations of topical mydriatics. No significant changes in blood pressure, temperature, or respiratory rate from their respective baseline values were observed throughout the ROP screening examination. Gestational age of the infant did not correlate with level of distress during the examination. CONCLUSION: Regardless of the severity of prematurity, infants seem to undergo significant distress during the eyelid speculum examination. Thus ophthalmologists should take into consideration the infant's discomfort caused by physical manipulation of the eyes and attempt to perform the examination as swiftly, yet safely, as possible using topical anesthetic.

A comparative study of proxymetacaine-fluorescein and lignocaine-fluorescein use during applanation tonometry.

AIMS: To evaluate the relative merits of proxymetacaine-fluorescein (PROX-FLU) and lignocaine-fluorescein (LIG-FLU) when used to perform applanation tonometry. METHODS: This prospective, masked, double blind study assessed several aspects of the tonometry process-the duration of the stinging sensation and degree of discomfort, the extent of reflex lacrimation induced, the need for subsequent tear film manipulation to ensure an accurate tonometry reading, and total time to complete tonometry-for each preparation. RESULTS: PROX-FLU caused significantly less discomfort and reflex lacrimation than LIG-FLU and accurate tonometry was more rapidly completed when it was used. PROX-FLU was preferred by 98% of the study patients. CONCLUSION: PROX-FLU is a well tolerated and useful alternative to the more widely used LIG-FLU mixture.

Clinical effects of oleoresin capsicum (pepper spray) on the human cornea and conjunctiva.

OBJECTIVE: To evaluate the effects of oleoresin capsicum (OC) on the human cornea and conjunctiva and to test the effectiveness of topical anesthetics for relief of pain. DESIGN: Prospective, randomized clinical trial. METHODS: Forty-seven subjects were examined before and at 10 minutes and 1 hour after exposure to pepper spray during a training exercise. Eleven subjects were reexamined at 1 week after exposure. A short, subjective questionnaire was given asking subjects to rate their pain, blurring of vision, and tearing. After exposure, subjects were randomly given a placebo, a topical nonsteroidal antiinflammatory agent, or a topical anesthetic. MAIN OUTCOME MEASURES: Visual acuity and corneal sensitivity with a Cochet-Bonnet aesthesiometer (scale of 1-6 cm) was measured and the eyes were examined with a portable slit lamp using fluorescein. Symptoms of pain, blurring of vision, and tearing were recorded in a ranking of 0 to 10. RESULTS: Visual acuity was unaffected by exposure to pepper spray. Corneal sensitivity was reduced from a pretest mean of 5.7 cm to a posttest mean of 0.6 cm 10 minutes after exposure. At 1 hour, the mean corneal sensitivity had recovered to 2.9 cm. Twenty-one percent of eyes had evidence of punctate epithelial erosions, but no corneal abrasions were found. All subjects reported significant pain, blurring of vision, and tearing at 10 minutes that was much improved by 1 hour. Topical flurbiprofen 0.03% improved symptoms in two of 11 subjects, whereas topical proparacaine hydrochloride 0.5% improved symptoms in 16 of 29 eyes. At 1 week after exposure, corneal sensation returned to baseline, and no corneal abnormalities were noted. CONCLUSIONS: The predominant symptom after exposure to OC was pain. Topical flurbiprofen was not helpful in reducing symptoms of exposure, whereas topical proparacaine was effective in relieving pain in most subjects. Corneal sensitivity was dramatically reduced at 10 minutes after exposure and was improved after 1 hour. At 1 week, corneal sensation had returned to normal, as had slit-lamp appearance on all subjects examined.

Cycloplegia in African-American children.

PURPOSE: The selection of a cycloplegic agent depends on the desired outcome, the characteristics of the patient receiving the drug, and the associated risks. The Orinda Longitudinal Study of Myopia (OLSM) has used 1% tropicamide to assess the ocular components and cycloplegic refractions in a large cohort of predominantly Caucasian children. Although tropicamide has provided adequate cycloplegia and mydriasis for the OLSM cohort, conventional clinical wisdom and scientific investigations have suggested that tropicamide might not produce adequate cycloplegia and mydriasis for subjects with darker iris pigmentation. In this study one drop of 1% tropicamide followed by one drop of 1% cyclopentolate was used to determine their effectiveness in producing adequate cycloplegia and mydriasis for cycloplegic refraction and ocular component measurements in a group of African-American children. METHODS: Nineteen children [age range 5.5 to 15.6 years, mean 8.4 years +/- (SD) 2.5 years] were tested at Family HealthCare of Alabama, Eutaw, AL. Their accommodative responses were measured using a Canon R-1 autorefractor prior to and at 30, 45, and 60 min after instillation of one drop of 0.5% proparacaine, 1% tropicamide (Mydriacyl), and 1% cyclopentolate (Cyclogyl) in both eyes. A target of 20/155 letters in a 4x4 grid positioned behind a +6.50 diopter (D) Badal lens provided accommodative stimuli of 1.00 D, 2.00 D, and 4.00 D. RESULTS: All results are presented as mean +/-1 SD. Pupils, measured from video frames, dilated rapidly and maximally at 30 min after instillation of eye drops (7.3+/-0.5 mm) Predilation, the mean accommodative responses were 0.17+/-0.29 D for the 1.00 D stimulus, 1.01+/-0.40 D for the 2.00 D stimulus, and 2.77+/-0.74 for the 4.00 D stimulus. At 30 min after drop instillation, the responses were 0.07+/-0.14 D for the 1.00 D stimulus, 0.36+/-0.35 D for the 2.00 D stimulus, and 0.77+/-0.61 for the 4.00 D stimulus. Results were very similar at 45 and 60 min after drop instillation. CONCLUSIONS: Combining 1% tropicamide and 1% cyclopentolate was very effective in providing both cycloplegia and mydriasis adequate for ocular biometry and cycloplegic refractions 30 min after drop instillation in African-American children.

Topical anesthetic abuse after radial keratotomy.

A 49-year-old woman developed corneal epithelial defects and stromal infiltration shortly after a 4-cut radial keratotomy (RK) for myopia. Although cultures grew staphylococci and appropriate antibiotic treatment was applied, the epithelial defects increased in size. The corneal epithelium did not heal fully for more than 2 months. Penetrating keratoplasty 1 year later was followed by epithelial breakdown and perforation, as was a second keratoplasty. Despite repeated questioning, the patient did not admit until 18 months after her initial surgery that she had begun self-treatment with dilute proparacaine shortly after RK and continued it after her keratoplasties. The elective use of topical anesthetics to control pain after refractive surgery should be approached with caution, and patients should be warned of the possible consequences of their misuse.

Dilute topical proparacaine for pain relief after photorefractive keratectomy.

PURPOSE: The purpose of the study is to determine whether there is a nonanesthetic and nontoxic concentration of topical proparacaine that can be applied repeatedly to the cornea to reduce pain after photorefractive keratectomy (PRK). METHODS: Part I: To determine a nonanesthetic concentration, the corneal sensitivity of 50 healthy volunteers was assessed using aesthesiometry before and after a drop of either 0.01%, 0.025%, 0.05%, 0.1%, or 0.2% topical proparacaine. Ten volunteers similarly were tested with multiple doses of 0.05% proparacaine. To evaluate toxicity, ten healthy volunteers self-administered 0.05% proparacaine to one eye and placebo to the other eye every 15 minutes for 12 hours on day 1 and every hour for 12 hours on days 2 through 7. Subjects were assessed throughout the week using visual acuity, slitlamp examination, aesthesiometry, and ultrasonic pachometry. Part II: In a prospective, double-masked study, 34 patients who underwent PRK (48 eyes) self-administered either topical 0.05% proparacaine or placebo for 1 week after PRK as needed to reduce pain. Patients recorded their pain score before and after drop use and answered a pain-relief questionnaire. RESULTS: Part I: Proparacaine concentrations greater than or equal to 0.1% eliminated sensation from some corneas; concentrations of less than or equal to 0.05% were never fully anesthetic. No corneal toxicity was observed except for some minimal punctate staining in both treatment and placebo eyes. Part II: Patients in the treatment group had significantly more pain relief (P < 0.001) for a longer period (P < 0.001) than did patients in the control group. Average change in pain score was significantly greater in the treatment group (P < 0.002). No significant difference in the number of days needed to reach complete epithelial healing was found between the two groups (P < 0.18). CONCLUSIONS: Dilute (0.05%) topical proparacaine is nonanesthetic and nontoxic, and can be used safely for at least 1 week to reduce pain after PRK.