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US005525601A United States Patent (19) 11 Patent Number: 5,525,601 Belmonte-Martinez et al. 45 Date of Patent: Jun. 11, 1996 54 COMPOSITION FORTREATING OCULAR P?ister R. ct al., Polymorphonuclear Leukocytic Inhibition PAN by Citrate, Other Mctal Chelators, and Trifluopcrazinc, Eyc Rcs, Labs, Birmingham, AL, Invest. Ophthalmol, Visual Sci. (75 Inventors: Carlos Belmonte-Martinez, Roberto Gallego-Fernandez, both of Alicante; (USA) Aug. 1984, 8:955–970, Miguel A. Pozo-Garcia, Madrid; Juana Bignall J. ct al., , nifcdipinc and cataract, Thc Sur. Gallar-Martinez, Alicantic, all of Spain gery, Newport, Dyfcd U.K., Lancct, Eng., 1986, 2/8497 (73) Assignce: Universidad de Alicante, Alicante, (42-43). Spain Pozo M. ct al., Blockadge by Calcium Antagonists of Chemical Excitation and Scnsitization of Polymodal Noci (21) Appl. No.: 434,949 ceptors in the Cat's Cornca, J. of Physiol, 1992, 450, pp. 22 Filed: May 4, 1995 179. 189. Bussey, H. and R. Talbert, Promising Uses of Calcium Related U.S. Application Data - Channel Blocking Agncts, Pharmacothcrapy (1984) 63 Continuation of Ser, No. 855,018, Jul. 7, 1993, abandoncol. 4:137. .143, 30 Foreign Application Priority Data Cat's Cornca, J, of Physiol., 1992, 450, pp. 179-189. Sep. 7, 1990 (ES Spain ...... 9002335 Moscs, R. cd. Adler's Physiology of the Eyc, The C.V. (51 Int. Cl." ...... A61K 3.1/54; A61K 31/44 Mosby Co. St. Louis, 1987, pp. 44, 56-58. 52 U.S. C...... 514/222.2, 514/356; 514/912 Goodman and Gilman's Thc Pharmacological Basis of 58) Field of Search ...... 514/222.2, 356, Therapeutics, Pergamon Press, New York, pp. 774-783, 514/912 1990. (56) References Cited Primary Examiner Zohrch Fay U.S. PATENT DOCUMENTS Attorney, Agent, or Firm. Wolf, Grccnficla & Sacks

4,552,695 11/1985 Igarashi ...... 260/239.3 4,562,075 12/1985 Rajadhyaksha ...... 514/788 4,981,871 1/1991 Abelson ...... , 514/523 57 ABSTRACT 5,202,130 4/1993 Grant ...... 424/617 Thc invcntion relatcs to thc usc of a calcium channcl FOREIGN PATENT DOCUMENTS blocking agent for thc manufacture of a mcdicament for WOA19006123 6/1990 WIPO, allcviatirtig pain, such as ocular pain. Particular calcium channcl blocking agents that can bc uscd in accordance with OTHER PUBLICATIONS the invcntion arc diltiazcm, vcrapamil, ni?cdipinc, nicar Gunderson, C., Management of thc Migrainc Paticnt, Ameri dipinc, and nimodipinc, can Family Physician, vol. 33, No. 1, 1986, pp. 137-143. J. Walton, Diffuse cxcrcise-induccd muscle pain of undc termined causc rclieved by , The Lancet, 1981, p. 993. 20 Claims, 1 Drawing Sheet U.S. Patent Jun. 11, 1996 5,525,601

SN Cd 2.5 mM O im M C d 4 O mM 5 O

4. O

3 O

2 O

O

O sec 3O sec 5,525,601 1. 2 COMPOSITION FOR TREATING OCUIAR Thc opiatc-bascd analgesics includc opium dcrived alka PAIN loids, including morphinc, codcinc, and thcir various deriva tivcs, opiatic antagonists, thc scveral morphinc dcrivatives This application is a continuation of application Scr. No. which have morphinc antagonist activity, but have analgesic 07/855,018, ?ilcd Jul, 7, 1993, now abandonccl. 5 activity. Since thcsc narcotic typc drugs arc addictivc, a number of nonaddictivc, non-opiate analgesics havc bc.cn devclopcd in FIELD OF THE INVENTION an attcmpt to produccan analgesic which is highly c?licicnt This invention relates to the topical application of calcium but not addictivc. channcl blocking agents for treating ocular pain and neuro 10 In the third broad catcgory, thc analgesics and antipyrct. gcnic inflammation and compositions uscful for such appli ics, arc thc salicylatcs and acctamidc-containing compounds cation. and thc so-callcd non-stcroidal anti-inflammatory drugs, Thcy are non-addictive pain killers, BACKGROUND OF TEI ART As to thcir mode of action, drugs that block pcrccption of 15 Pain is a well known phenomenon as an indicator of pain may bc said to act cithcr centrally (such as narcotics) or injury or tissuc damage duc to inflammation, ischcmia, peripherally. mechanical or other irritation Juan, H., Prostaglandins as Centrally acting narcotic drugs arc truc analgesics Mediators of Pain, Gen. Pharmacy, 9,403-409 (1978)). becausc thcy can relicvc pain regardless of the ctiology, The first step leading to the scnsation of pain is thc 20 Thc non-steroidal anti-inflammatory agents (NSAIAs) activation of nociceptive primary afferents by intensc thcr havc bccn described as peripheral pain rclicvers. It was mal, mechanical or chemical stimuli, Indircct studics of further suggestcd that thc analgesic propertics of thcsc drugs nociceptive transduction (activation) indicatc that it involvcs arc indcpcndcnt of their anticdcma or anti-inflammatory chemical mediators that are released or synthcs.iv.cd in actions (Capctola ct al., Supra. responsc to tissuc damage Ficlds, H. and Lcvinc, J., Pain 25 Thc action of NSAIAs as pain rclicv.crs is associated with Mechanisms and Management, Western Medical J. 141, thc biosynthesis of prostanoids. 347-357 (1984)). These chemical mediators include lactic Inflammation or trauma and resultant tissuc injurics cause acid, hypertonic saline, histaminc, 5-hydroxytryptamine, thc rclcasc of which is degradcd by cyclo potassium chloridc, acetylcholine, purincs, bradykinin and oxygenasc and lipoxygenase. The cyclo-oxygenasc pathway substance P which arc referred to as algesic agents (Juan, H., 30 lcads to thc synthesis of prostaglandin E2 (PGE2) and othcr Supra). In recent years it has been shown that prostaglandins mediators. PGE rclcasc incrcases thc cyclic AMP and ionic and leukotrines can contribute to the activation of primary calcium levcls at thc nociceptor membranc resulting in a afferent nociceptors (Fields, H. and Lcvinc, J., Supra), lowcrcd activation threshold, resulting in the rclay to thc Prostaglandins are uniquely distinguishcd from the other ccntral nervous systcm of augmented pain pcrccption (hypc chemical mcdiators in that they induce a state of hypcral 35 ralgesia) Capctolact al., Pcripheral Antialgesics: A Review, gesia by clevating the sensitivity of pain receptors to other J. Clin. Pharmacol. 23, 545-556 (1983). Inhibitors of painful or algasic stimuli. prostaglandin synthesis, such as NSAIAs, act avoiding the The stimulation of primary afferents leads to action poten scnsitizing cffects of prostaglandins on nociceptive cndings tials in their axons which propagatc to thc spinal cord. In and thcroforc, thc decrease in pain threshold. addition, excitcd primary afferents rclcase nuropcptidcs 40 In animal modcls and human studics non-stcroidal anti (substance P, calciotonin-gene-relatcd pcptide, ncurokinin inflammatory agents have bccn shown to inhibit inflamma A) at their peripheral terminals. Ncuropcptides cnhancc tory pain Tcrasawa ct al., Analgesic cffcct of topically inflammatory reactions in the injurcd tissuc, contributing to applicd pranoprofen-gel, Nippon Yakurigaku Zasshi 86(6), , cdcma, and increascd vascular pcrmcability; 433-440 (1985); Chcrevatov ct al., Topical Usc of Rhcu this phenomenon is called "neurogenic inflammation'. 45 mon-Gcl in combincd treatment of paticnts with rhcumatoid In the spinal cord, the nociceptors cnter the gray matter of arthritis, Ter: Arkh, (USSR), 59(12) 100-102 (1987); and the superficial dorsal horn to synapsc on ncrvc cells con Kyukict al., Anti-inflammatory Effect of diclofenac-sodium tributing to pain-transmission pathways such as thc ointment (cream) in topical application, Jpn. K. Pharmacol, spinothalamic and spinoreticulothalamic tracts which tcrmi 33(1), 121-123 (February 1983)). nate in two separate regions in the thalamus. The two Ophthalmic applications of various NSAIAs arc also thalamic regions in turn project to different cortical sitcs known, including thc utilization of thcir anti-inflammatory (Fields, J. and Levina, J., Supra). propertics for control of various ocular inflammations. Scc The pain transmitting and modulating system depicted so Andcrson ct al., Disposition of topical flurbiprofen in normal far depends on numerous chemical moietics for its intc and aphakic rabbit cycs, Arch, Ophthalmol, 100, 642–645 grated function Fine, P, and Harc, B., Thc Pathways and 55 (1982); Duflinct al., Inhibitors of surgically induccd miosis, Mechanisms of Pain and Analgesis, LARcvicw and Clinical Ophthalmol, 86, 966-979 (1983); and Keatics and Perspective, Hospital Formul, 20,972-985 (1985). McGowan, Clinical trial of flurbiprofen to maintain pupil Anesthetics block neuronal transmission and affcct scn lary dilation during cataract surgery, Ann. Ophthalmol, sation as well as pain. Analgesics act by intcrfering with the 60 16(10),919.921 (1984). activity of chemical mediators without affecting scnsory NSAIAs have bccn used for thc treatmcnt of non-inflam input. matory, localizcd pain, such as non-inflammatory ocular According to Remington's Pharmaceutical Scienccs, 17th pain. Scc U.S. patent application Scr. No. 07/585,664, filed Ed., analgesics can be classified as falling into at lcast thrcc on Scp. 20, 1990 in the of Gwon. loose groups: 1) the opiate-based (narcotic) analgesics; 2) 65 Calcium channcl blockcrs or antagonists arc compounds thc non-opiate analgesics; and 3) analgesics and antipyrct which dclay or prevent the cardiac contracture which is 1CS bclicvcd to be causcd by an accumulation of intraccllular 5,525,601 3 4 calcium under ischaemic conditions. Calcium overload, dur positions are substituted by methyl groups, the 4 position by ing ischaemia, can have a number of additional adverse 2-nitrophenyl and the 3 and 5 positions by carboxylic acid effects which would further compromise the ischaemic methyl ester groups. Similar compounds are disclosed in myocardium. These include less efficient use of oxygen for U.S. Pat. Nos. 3,455,945; 3,325,505; and 3,441,468 to Loew ATP production, activation of mitochondrial fatty acid oxi and 3,470,297 and 3,511,837 to Bossert, which introduced dation, and possibly, promotion of cell necrosis. Thus, the variations in the 4-substituent. U.S. Pat. Nos. 3,905,970 to compounds are useful in the treatment or prevention of Bossert, et al. and 3,985,758 to Marakami, et al. introduced cardiac conditions, such as pectoris, cardiac arrhyth certain mono- or dialkylamino-alkylene and nitrogen-con mias, heart attacks and cardiac hypertrophy. The compounds taining heterocyclic alkylene groups into one or both of the also possess vasodilator activity and are thus useful as 10 3.5 ester groups. U.S. Pat. Nos. 4,307,103 and 4,393,070 to antihypertensives and for the treatment of coronary vasos Sato disclose 1,4-dihydropyridines in which the 2 position is pasm. blockers of the verapamil type are not substituted by alkyl, but instead is substituted with known to lower elevated intraocular pressure. See U.S. Pat. cyano, formyl or certain other substituents and the ester No. 4,981,871. Calcium channel blockers are not suggested group in the 3 position may contain various substituted alkyl as useful for treating pain, including ocular pain. 5 groups including substituted alkylaminoalkyl, heterocyclic aminoalkyl and aroylaminoalkyl, including phthalimidoet SUMMARY OF THE INVENTION hyl. U.S. Pat. No. 4,448,964 to Muto, et al., discloses compounds in which the 3-position ester group contains As will be appreciated from the above, various analgesics, certain substituted piperidinyl alkylene groups. anesthetics, etc. have been used to treat ocular pain. How 20 ever, nowhere is it suggested that compounds having cal Other pyridine compounds having calcium channel block cium channel blocking activity may be used to treat ocular ing activity are disclosed in U.S. Pat. Nos. 4,652,573; pa1n. 4,755,512; 4,791,117; 4,794, 187; 4,814,455; 4,829,076; The present invention is based on the unexpected finding 4,871,745; 4,895,846 and 4,912,223. that compounds having calcium channel blocking activity 25 Diltiazem and the like are disclosed in U.S. Pat. Nos. efficiently relieve ocular pain, including ocular pain and 3,562,257 and 4,552,695. inflammation associated with corneal injuries. The structures of the preferred calcium channel blockers The use of a topical composition, including a calcium utilized in the method and compositions of this invention are channel blocking agent, for the relief of eye pain offers as follows: several benefits over the use of systemic agents because of 30 the decreased systemic absorption, which may decrease CHO OCH side-effects, and increased ocular absorption that can GN CH increase efficacy. CHO chochsch, OCH Moreover, certain calcium channel blockers alleviate ocu lar pain associated with chemical stimuli but do not affect 35 ach mechanical stimuli. As sustained discharges in nociceptive Verapamil fibers are maintained by chemical mediators released by injured tissues, this invention permits the attenuation of pain H elicited by these mediators without interfering with sensi HC N CH tivity to mechanical stimuli. In addition, decrease of respon 40 siveness of nociceptive terminals by calcium channel block ers reduce neurogenic inflammation resulting in the release CHOOC COOCH3 of neuropeptides by excited nociceptors. NO Accordingly, the present invention relates to a method for 45 treating ocular pain in a mammal afflicted by such pain, which method comprises applying to the eye of said mam mal an effective amount of a calcium channel blocking agent in a pharmaceutically acceptable vehicle. 50 DETALED DESCRIPTION OF THE H OCH INVENTION The present invention relates to the use of calcium chan nel blocking agents for the treatment of ocular pain. 55 OOCCH The term "calcium channel blocking agent' or "com pound having calcium channel blocking activity” or "cal N O cium channel antagonist' is used to define compounds CHCH2NCH3)2 which are known to prevent or delay the cardiac contracture Diltiazem which is caused by an accumulation of intracellular calcium. 60 Suitable calcium channel blockers include verapamil, nifedipine, diltiazem, fostedil and the various derivatives, including the analogues and homologues, thereof, having \ CH,--och, calcium channel blocking activity. Verapamil and the like S OCH5 are disclosed in U.S. Pat. Nos. 3,261,859; 4,593,042 and 65 4,681,970. Nifedipine is disclosed in U.S. Pat. No. 3,485, Fostedil 847 and is a 1,4-dihydropyridine in which the 2 and 6 5,525,601 6 -continucd of active ingredicnt, and a physiological salinc solution as a H major vehicle. Thc pH of such ophthalmic solutions should HC N CH3 preferably be maintaincd betwccn 6.5 and 7.2 with an appropriatic buffer system. Thc formulations may also con s 3. tain conventional, pharmaccutically acceptable prescrva HCOOC COOCH2CH2N-CH2 Cls tivcs, stabilizers and/or pcnctration cnhancers. The preferred vchicle that may bc uscd in the ophthalmic solutions of thc prescnt invention is purified water, morc preferably a physiological saline solution, Additional suit NO 10 able vchicles include but arc not restrict.cd to, viscosity agents such as polyvinyl , povidonc, hydroxypropyl methyl cellulosc, poloxamers, carboxymethyl cellulosc, car H bomer and hydroxycthyl cellulosc. HC N CH Pre?crred prescrvatives that may be uscd in thc oph 15 thalmic formulations of the prescnt invcntion include, but arc not limited to, bcnzalkonium chloridc, chlorobutanol, (CH3)2HCOOC COOCEICHOCII thimcrosal, phenylmercuric acctate and phenylmercuric nitratic, Pcnctration cnhancers may, for cxamplc, bc surface activc 20 agents; certain organic solvents, such as dimcthylsulfoxidic and othcr sulfoxidcs, dimethylacctamidc and pyrrolidonc; NO ccrtain amides of hctcrocyclic amincs, glycols (c.g., propy Nimodipinc lenc glycol); propylenc carbonatc; olcic acid; alkyl amines 25 and dcrivatives; various cationic, anionic, nonionic, and This listing represents the well known calcium channel amphotcric surface activc agents; and the like. blocking agents, i.c., those marketcd or tcstcd for human Tonicity adjustors may bc added as nccdcd or convenient, use. But thc mere listing of thesc particular, presently They include, but are not limitcd to, salts, particularly marketed or tcstcd calcium channel blocking agents, is not sodium chloridc, potassium chloridc, mannitol and glyccrin, intended to limit the scope of thc compounds which might 30 or any other suitable opthalmically acceptable tonicity be used in practicing the present invention. Any calcium adjustor. channel blocking agent can be used in accordance with this Various buffers and mcans for adjusting ph may be uscd invention, so long as the resulting preparation is ophthalmically accept Calcium channel blocking activity varics substantially from compound to compound. Generally, when adminis able. Accordingly, buffers includc acctate buffers, citratic tered systemically, calcium channel blocking agents arc 35 buffers, phosphatic buffers and boratic buffers for ophthalmic effective in a wide range of concentrations. For cxamplc, SC. diltiazem tablets contain 30 to 120 mg of activc ingredicnt In a similar vcin, an ophthalmically acceptable antioxi per tablet. dant for usc in thc present invention includcs, but is not An effective dose, when it comes to topical, ocular pain, limited to, sodium mctabisulfitc, sodium thiosulfatc, acctyl is a matter of similarly broad thcrapeutically cffective dosc 40 cysticinc, butylatcd hydroxyanisolc and butylatcd hydroxy requirements. This figure is onc controlled by a number of tolucnc. factors: the inherent activity of the drug itself; thc vehicle in Othcr cxcipicnt componcnts which may bc included in thc which it is administered, primarily topical delivery being ophthalmic preparations arc chelating agents. The preferred anticipatcd; thc size of the arca to be treatcd; and thc chclating agent is cdctate disodium, although other chclating intensity of the pain. Exact dosing data havc not been 45 agents may also bc uscd in placc or in conjunction with it. determined for all compounds within the scopc of this Thc invention is further illustratcd by thc following invention. But it is anticipated that a topical formulation non-limiting cxamples. having between 0.001% and 1.0% (weight/volumc) of a calcium channcl blocking agent will provide relic? from BRIEF DESCRIPTION OF THE DRAWINGS ocular pain. The determination of thc cffective dosc for any 50 selected compound is well within the skill of an ordinary FIG, 1 shows thc cffects of acidic stimulation when thc skilled physician, cornca has bccntrcatcd previously with 2.5 mMCd' or with In the practice of this invention, calcium channclblocking 1 mm diltia/cm. agents may be administered in any manner which will 55 EXAMPLE 1 deliver the drug directly to the locale of the pain to be treated. It is anticipated that this will be by application to the A clinical study is performed to comparc thc analgesic immediate area of distress. For examplc, thc drug could be cffect of topically administcrcd diltiazcm and placcbo foll applicd topically, or by subcutaneous injcction or by some lowing radial keratotomy surgery. Onc hundred and twenty similar means which delivers the drug directly to the affectcd 60 four malc and femalc subjects, 21 to 45 years of age, who area. It is not intended that this invention be practiccd by undergo routinc, clectivc, unilateral radial kcratotomy for administering the drug in such a way as to insure that it gcts thc correction of myopia participatcd in thc study, and to the central nervous system. In fact, that would defeat the diltiazcm was administered as a 0.03% ophthalmic solution, whole purpose of this invention which is focused on trcating Each subject receives one drop of the assigned study the pain at its source. mcdication cvery four hours while awakc one day prior to For ophthalmic application, preferably solutions are pre surgery and again cvery 20 minutes for the two hours just pared typically containing from about 0.001% to about 1.0% before surgery. Each subject then undergocs unilateral radial 5,525,601 7 8 keratotomy. Following surgery, each subject receives one during the complete 30s period of stimulus application were drop of the study medication in the operated eye every four calculated. Frequency values were expressed in impulses. hours while awake for 14 consecutive days. Postoperative The experimental protocol was as follows: initial identifi examinations occur at days 1, 3, 7 and 14. cation of the unit was made by mechanical stimulation of the cornea, sliding a wet, fine brush on the corneal surface. The Efficacy is assessed by evaluation of pain intensity, pain receptive field was then mapped and after a pause of at least relief, subjective global analgesic efficacy. Symptoms of 3 min, force threshold was estimated with the esthesiometer, ocular inflammation (burning/stinging, tearing, etc.) are also starting from the lowest intensity (0.1 mN) and increasing recorded. the force exerted until a consistent response was evoked in The results of this study show statistically significantly different points of the receptive area. Conduction latencies greater pain relief at hours 2, 3 and 4 in the diltiazem group 10 were measured afterwards by electrical stimulation of the over the group treated with placebo. This appears to suggest center of the receptive field and of the limbus. After at least that diltiazem, administered preoperatively, might block the 5 min, a drop of a citric acid solution at pH 5.5 was applied perception of pain. on the corneal surface for 30s, to determine chemosensitiv ity of the recorded unit. A 3-5 min period was allowed EXAMPLE 2 15 between chemical stimulation with each stimulating solu tion. A total of 14 fibers was employed. Average extracorneal A54 year old woman, hard contact lens wearer, has a one conduction velocity was 8.1tl.6 m/s (mean+S.E, n=13) and day history of sharp shooting pain in both eyes. Diltiazem 0.7-0.3 at the intracorneal course. Mechanical threshold was was prescribed as a sole treatment of pain. On instillation of 1.47+0.32 mN (n=14). the medication, the patient reports relief of pain for approxi 20 In five polymodal fibers, the receptive field was flushed mately two and a half hours. Upon recurrence of pain, a with a saline solution at pH 7.5 applied every 20s during 2 second dose of diltiazem provides pain relief. min. Immediately afterwards, a single (60 ul) dose of saline EXAMPLE 3 at pH 5.5 was applied and maintained for 1 min on the 25 corneal surface before being washed away with saline at pH A 32 year old female patient with a history of gas 7.5. After a 3 min pause, the procedure was repeated by permeable contact lens wear has a two-to-three day history applying this time a conditioning solution at pH 6.5 every 20 of pain in her left eye. The patient is treated with diltiazem s during 2 min, ;and then a drop of saline at pH 5.5. Impulse for pain. The patient reports relief of pain for two hours. activity was recorded throughout the experiment. 30 In eight fibers the response to a pH 4.5 solution applied EXAMPLE 4 during 30s was initially ascertained. Then, 60 ul of a 2 mM Cd' solution at pH 7.3 was applied with 15 s intervals An experiment was carried out in adult cats anaesthetized during 5 min. At the end of this period, a 2 mM Cd' with sodium pantobarbitone (Nembutal, 40 mgfkg, I.P.). In solution of pH 4.5 was applied as the acidic stimulus. order to keep a deep arreflexic state during the experiment, 35 Mechanical responsiveness and threshold were also mea a dilute solution of the anaesthetic (15 mg/ml) was infused sured. If the response to acid was still present, application of through the radial vein. The animal was secured to a 2 mM Cd' at pH 7.3 every 15s was resumed during another stereotaxic frame, tracheotomized and left to breathe spon 5 min period. When a reduction or a suppression of the taneously. End-tidal CO was continuously monitored to impulse discharge to acid was detected, washing of the remain around 4%. Rectal temperature was maintained cornea with saline at pH 7.3 was performed at 1 min between 36°-38 C. with a heating blanket. intervals and the response to a citric acid solution of pH 4.5 The superior and lateral walls of the orbital cavity were explored every 5 min until partial or total recover was removed and the extrinsic muscles of the eye resetted to achieved. The same experimental procedure was used to expose the ciliary nerves. A ciliary nerve was carefully assay effects of diltiazem 1 mM in six separate corneal dissected under a binocular microscope and placed on 45 polymodal units. Ag-AgC1 electrodes. Conventional electrophysiological The results are reported in FIG. 1. In this Figure the equipment, consisting of a.c. amplifier with modifiable effects of acidic; stimulation when the cornea has been filters, oscilloscope and loudspeaker, was used to record treated previously with 2.5 mM Cd" or with 1 mM dilt impulse discharges. Conduction velocities were calculated iazem. A reduction of the response to a high (H")o stimu from the delay of the evoked response to suprathreshold 50 lating solution (pH 4.5) was obtained after treatment with electric shocks (0.1-0.5ms, 0.5-3 mA), applied with a pair calcium blocking agents. In contrast, impulse discharges of polished silver electrodes on the limbus or the cornea. elicited by mechanical stimulation remained unchanged as Mechanical stimulation was performed manually, using a did the mechanical threshold of the fibers. The effect of Ca" wet, fine brush. To measure mechanical threshold, a cali blockers was reversible and after washing out of the cornea brated Cochet-Bonnet esthesiometer was employed. The 55 for a variable time (20 to 40 min) the response to acid was receptive field was mapped using the tip of the esthesiometer fully recovered. Verapamil (100 iM) failed to modify exci adjusted at suprathreshold values Belmonte and Giraldez, J. tatory effects of acid on corneal nociceptors. FIG. 1 also Physiol, 321,355 (1981). illustrates the influence of increased (Ca") A reduction of Chemical substances were assayed by applying with a the amplitude of the firing response to a pH 4.5 citric acid pipette on the receptive field 60 microliters of the test 60 solution was obtained after exposure of the cornea to 40 mM solution for 60 s. After treatment, the area was washed Ca' whereas mechanical sensitivity remained unaltered. repeatedly with balanced saline. Concentrations of chemi The effect was reversible after washing of the cornea for 5 cals used were as follows: Acetic acid, 10 mmol.1' dis min with the control solution. Increases in (H) occur solved in distilled water, citric acid. Impulse discharges were during tissue injury and hypoxia and may contribute to stored on an FM tape for later off-line computer analysis. 65 stimulation and/or sensitization of nociceptors and thus to Taking the first impulse in the response as zero time, mean pain. The fact that responses of a single fiber to acid could discharge rates during the initial 10s of the response and be blocked pharmacologically with Ca' antagonists with 5,525,601 9 10 out interfering with mechanical responsivcn.css opcins thcra min, 10 mg/kg of fluoresccin wcrc injected into the marginal peutical possibilitics in the managemcnt of pain of pcriph vein of thc car; the rabbits werc ancsthctivcd 15 min latcr eral origin. (kctaminc, 30 mg/kg and xylacinc, 3 mg/kg, i.v.) and aquc ous humor was obtaincd by paraccntesis of thc anticrior chambcr lluoresccin content was mcasurcd with a fluorim EXAMPLE 5 ctcr (Perkin Elmer, LS-5); Aqucous humor protcins were This cxperiment was carricci out in adult cats. Nervc dictermincd by thc Bradford method. In addition to capsai activity was rcoordcd cither from nervc filaments containing cin, thc animals reccived 60 ul of a solution of diltiazcm in several cornca/scnsory fibers or from single corncal afferent onc cyc and of thc vehicle (124 mM NaCl, 5 mM KC1, units identified as polymodal nociceptors. Corncal reccptive 10 pH-7.3 adjustcd with 20 mM HEPES) in thc contralateral fields innervatcd by active fibers werc stimulatcd mechani cyc. In other cascs (control cycs), thc vehicle was applicd in cally with a Cochct-Bonnct esthcs.iomcter and chcmically both cycs, Trcatment with diltiazcm was administcrcd as: with 10 mM acctic acid. Verapamil (1 mM) or ni?cdipinc (l 1) A single dose of diltiazcm 1 mM (10 rabbits), 2.8 mM mM) werc applied topically 5 min latcr. Mechanical and (9 rabbits) and 10 mM (9 rabbits), applicd 15 min chemical stimulation were rcpcated twicc with 5 min intcr 15 bcforc capsaicin. vals; then, the cornca was washed for 30 min and scnsitivity 2) Rcpcatcd doscs of diltiazcm 1 mM, applicd 15 min to acid and to mechanical stimulation again tcstcd. Number bcforc and 120 min and 240 min a?tcr capsaicin (5 of impulscs during 60s following application of acid was rabbits). counted. The cffcct of drugs was cxpresscd as pcrccnt 3) A single dose of thc vehicle in both cycs (8 rabbits), 15 reduction of the control responsc to acid. 20 min bc?orc capsaicin, Verapamil, assayed in three single units produccd in two Diltiazcm administration and mcasurcmcnt of irritation of them an increase in ongoing firing frequency (from 0.01 paramcters werc made by independent investigators, that to 0.10 and from 0.04 to 0.15) and no changcs in thc ignored thc treatmcnt given to or reccived by thc cxplored remaining unit. It reduced in all fibers thc responsc to acid animal. to an average valuc of 19.7% of control. Mcchanical thresh 25 Group 2 old increased in two of the units and rcmaincci unaltcrcd in Forty-two pigmentcd rabbits arc uscd for this cxpcrimcnt. the third. A reduction of size of thc rcceptivc ficla was Animals werc cxposcd to ultraviolct radiation (254 nm for 5 noticed in all instances after verapamil. min), pupil diameter, cpithclial dcbris, cpithclial stipping, Nifedipine was testcd in thrcc filaments displaying mul cpithclial granulcs, cpithclial hazc, cpithclial cxfoliation, tiunit discharges; in one of them, application of nifedipinc 30 stromal havc, stromal opacitics, conjunctival vasodilation, produced a clear increase of ongoing activity; the other two sluggishncss of pupillary responsc and blcariness were responded to the administration of the drug cithcr with a cxplorcd with thc slit lamp 8 and 24 hours after cxposurc to small and short-lasting frequcncy increase or with no changc UV radiation, according to Pitts ct al. (Invest Ophthalmol in spontaneous activity. Discharges cvokcd by subscqucnt Vis Sci. 16:932, 1977). Onc cyc of cach animal was trcatcd applications of acid were markedly reduccdby mi?cdipine in 35 with 60 ul of topical diltiazcm while the othcr rc.ceived the the thrcc filaments cxplored, to an average valuc of 15% of vchiclc, at the following times and doscs: control. Responses to mechanical stimulation pcrsistcd after 1) Treatment with a single dosc of diltiazcm 1 mM, 15 nifedipinc. Nevertheless, the prescncc of many different min bcforc UV exposurc. units in the recording precluded a dctcrmination of thresh old; also, thc possibility that a portion of thc fibers were 40 2) Trcatment with a single dosc of diltia/cm1 mM, 5 min inactivated by the drug cannot be cxcluded in thcsc cxpcri a?cr UV cxposurc. mental conditions. 3) Trcatmcnt with 1 mM diltia/cm administercd 15 min From these preliminary experimcnts it can be concluded bcforc and 7 h, 15 h and 22 h after UV radiation, that nifedipine and verapamil reduce chemical responsive 4) Trcatment with a single dosc of 10 mM dialtiazem, 15 ness of nociceptors as occurs with diltiazem. IIowcvcr, in 45 min bc?orc UV cxposurc. contrast to diltiazem, both drugs, at thc doscs cmploycd, As in Group 1, diltiazcm administration and mcasure show a bricf discharge of impulses upon instillation. Also, a ments were made by indcpcndent investigators. certain degree of inactivation of mechanical responsiveness Rcsults was observed with verapamil, Topical capsaicin produccd an immediatic motor response 50 composcd by scratching movements with thc forcpaw (wipcs) directed to the cyc; thc animal closed totally or EXAMPLE 6 partially thc cyc (blepharospasm) and maintained afterwards This experiment is directed to demonstratic that calcium a certain degrec of palpebral closure. Miosis and conjunc blockers reduce ocular pain and inflammatory reactions in tival hypercmia were also present. Thcsc phenomena lasted rabbits. Two types of experiments arc done: 55 for about 1-1.5 h, Statistical comparisons (paired t-test) Group 1 werc made bctwccn the cyc that was pre-treatcd with dilt In a first group of experiments, forty-onc (41) adult albino ia/cm and thc contralateral, vehicle-treatcd cycs. Significant rabbits are employed. Animals received in both cycs 60 l of differences in motor responses (number of wiping move 1% capsaicin (8.5% Tween 80, 1.5% cthanol in isotonic mcnts, blcpharospasm and palpcbral opening) were noticed saline) with a 5 min interval bctween cycs. Number of 60 at thc thrcc doscs testcd. Miosis tcnds to be less marked in wiping movements, blepharospasm (resistance to opening of thc cyc trcatcd with diltiazcm than in contralateral cycs but the eye), pupil diameter, conjunctival vasodilation and sizc differences arc conclusive. Conjunctival hypcremia is of palpebral opening were measurcd (-, +, ++, H, H+) rcduccd significantly by diltia/cm, The subjective cvalua at pre-established times: immediately after capsaicin and 15 tion of discomfort also shows a significantly rcduccd value min, 60 min, 180 min and 280 min after instillation of thc 65 in cycs treated with diltiazcm. Significant differenccs in drug. Also, a subjective evaluation of thc discomfort shown fluorcs.ccin or protein content in aqucous humor were by thc animal to manipulations of the cyc was madc. At 285 noticed betwcen diltiazem-treated and control cycs. 5,525,601 11. 12 Ultraviolet radiation produced an inflammatory reaction limiting the overal scope hereof; rather, the ambit of the of the anterior uvea that was not detectable at 8 hours but present invention is to be governed only by the lawful was clearly apparent 24 hours after exposure. In preliminary construction of the appended claims. experiments we had detected that the inflamatory effect of We claim: UV radiation was more prominent in pigmented rabbits; for 5 1. A method for alleviating ocular surface pain in a this reason that species was selected for this study. Differ mammalian eye comprising administering to a mammalian ences in severity of pupillary, corneal and inflammatory eye having ocular surface pain an amount of a calcium reactions noticed with 1 mM diltiazem were not significant. channel blocking agent effective to alleviate the ocular A dose of 10 mM diltiazem improved epithelial and stromal surface pain. signs of damage and conjunctival hyperemia, while the pupil 10 2. The method of claim 1 wherein said mammalian eye is was not greatly affected by the UV exposure or by diltiazem. a human eye. The results of the present experiments indicate that dilt 3. The method of claim 1 wherein said administration is iazem, at relatively low doses (1-2.8 mM) reduced pain topical administration directly to said eye. reactions to anterior segment irritation. This observation is 4. The method of claim 1 wherein said calcium channel in agreement with previous electrophysiological data, shor 15 ing a decrease by diltiazem of nociceptive activity evoked blocking agent is selected from the group consisting of by acidic stimulation in corneal nociceptive afferents. At diltiazem, Verapamil, nifedipine, fostedil, , nica higher doses (2.8-10mM), an attenuation of conjunctival rdipine and derivatives thereof. inflammatory reaction to chemical irritation of the eye was 5. The method of claim 1 wherein said calcium channel also observed. Experiments with UV radiation further sup 20 blocking agent is administered in solution in a pharmaceu port the observation that diltiazem at doses over 1.8 mM tically acceptable ophthalmic vehicle. exerts an anti-inflammatory action. 6. The method of claim wherein said effective amount For example, since the functional properties of the dif is from about 1 to about 10 mg per eye per day. ferent types of peripheral nociceptors appear to be the same 7. The method of claim 5 wherein said vehicle contains in different tissues (skin, Bessou & Perl, J. Neurophysiol. 25 from about 0.01 to about 20 mg per ml of said calcium 32:1025, 1969;joints, Schaible & Schmidt, J. Neurophysiol. channel blocking agent. 54:1109, 1985; muscle, Mense, J. Physiol. 267:75, 1977; 8. The method of claim 1 wherein said pain is associated testis, Kumazawa & Mizumura, J. Physiol. 299:219, 1980; with a wound or inflammation in said eye. cornea, Belmonte & Giraldez, J. Physiol. 321:355, 1981; 9. The method of claim wherein said calcium channel teeth, Jyvasjarvi, Knifiki & Mengel, Progress Brain Res., 30 blocker is diltiazem. 74:237, 1988). The method of the present invention may be 10. The method of claim 1 wherein said calcium channel used to treat pain in other parts of the body than the eye. blocker is verapamil. Moreover, certain pain will require systemic rather than 11. The method of claim 1 wherein said calcium channel topical administration and, therefore, treating pain systemi blocker is nifedipine. cally is within the scope of the present invention. Again 35 12. The method of claim 1 wherein said pain is associated since polymodal nociceptors of the eye, i.e., the class of with radial keratotomy. nociceptive nerve terminals that respond to lesive mechani 13. The method of claim 1 wherein said pain is associated cal, thermal and chemical stimuli are analogous to those with treatment by a laser. found in the skin and mucosae or in the teeth, (this is not 14. The method of claim 12 wherein said laser is an surprising, considering that these tissues share a common 40 excimer laser. embryological origin). It is to be expected that the pain 15. The method of claim 1 wherein said pain is associated attenuating effects produced by calcium channel blockers on with corneal abrasion. the eye are also present in the skin and mucosae if the 16. A method for alleviating nonvascular associated pain medication can reach the superficial nociceptive nerve end in a mammal comprising administering to said mammal ings, as will occur when penetration is enhanced by artificial 45 having nonvascular associated pain an amount of a calcium means or when the mucosae or skin are damaged. The same channel blocking agent effective to alleviate the nonvascular will be true in the tooth when intradental nociceptive fibers associated pain. of the dental pulp are exposed. Therefore, this invention can 17. The method of claim 16 wherein said calcium channel be extended to the local treatment of superficial pain and blocking agent is selected from the group consisting of neurogenic inflammation of the skin and mucosae. 50 diltiazem, verapamil, nifedipine, fostedil, nimodipine, nica The foregoing description details specific formulations rdipine and deterivatives thereof. and methods that can be employed to practice the present 18. The method of claim 16 wherein said calcium channel invention. Having detailed specific compositions for the blocker is diltiazem. topical formulations of the present invention and specific 19. The method of claim 16 wherein said calcium channel instructions for their use in the treatment of ocular pain, the 55 blocker is verapamil. art skilled will well enough know how to devise other 20. The method of claim 16 wherein said calcium channel formulations and how to adapt the treatment (formulations, blocker is nifedipine. doses) to a special situation. Thus, however detailed the foregoing may appear in text, it should not be construed as