Field of the Invention

The present invention is directed to compositions and methods that are useful in relieving pain and providing anesthesia. More particularly, it relates to compositions containing a combination of a sodium channel activator and a local anesthetic. The invention is also directed to an improved method for relieving pain by concurrently administering these agents.

Background of the Invention

Sodium channel activators have been the subject of considerable research aimed at the development of new analgesic and anesthetic agents. Among the activators studied are the veratrum alkaloids, an abundant group of steroid-like polycyclic nitrogen-containing ring structures found in liliaceous plants. Krayer, et al. , Physiol. Rev. 26:336-446 (1946); Krayer, et al. , "Veratrum Alkaloids" in Pharmacology in Medicine, V.A. Drill, ed., (1958). One of these alkaloids, veratridine, has been widely used as a neuropharmacological tool for studying the electrical properties of nerve and muscle fibers. Ulbricht, W., Rev. Physiol. 67: 18-71 (1969); Ohta, et al. , J. Pharmacol. Exp. Ther. 754: 143-154 (1973); Catterall, W.A., Ann. Rev. Pharmacol. Toxicol. 20: 15-43 (1980). Veratridine has been reported to inhibit nerve impulses and to act preferentially on C-fibers in mammalian peripheral nerves in vitro. U.S. Patent No. 5,288,723, issued February 22, 1994; Schneider et al. , Anesthesiology 74:270-280 (1991). Recent work has suggested that veratridine, when used alone, produces severe and long- lasting, dose-dependent motor and proprioceptive block and modest analgesia of short duration (Vladimirov et al. , Regional Aesthesia, 20 (2S), 129 (1995)). In contrast, local anesthetics such as bupivacaine and lidocaine induce about equal impairment of motor and nociceptive functions. In studies designed to better characterize the effects of sodium channel activators, the inventors compared the functional block of rat sciatic nerves after local injection of bupivacaine with that produced by the injection of a combination of bupivacaine and veratridine. Surprisingly, these agents were found to work together to produce an anesthetic effect with highly desirable characteristics and which neither agent produces when used alone.

Summary of the Invention

The present invention is based upon the discovery that sodium channel activators and local anesthetics act synergistically to induce analgesia. The effect produced by the combination is surprising in three different respects. First, nerve impulses are inhibited by the combination for a duration that is greater than would be expected based upon adding the individual effects of the agents. Second, analgesia is potentiated by the combination to a much greater extent than motor system blockade. This selective action is particularly desirable in that it should permit treated patients to move with minimal pain and discomfort after surgery. Finally, the combination exhibits little or no systemic toxicity and is therefore well suited for the long-term treatment of chronic pain.

Based upon the observations noted above, the present invention is directed to a pharma¬ ceutical composition comprising a sodium channel activator and a local anesthetic. Either natural or synthetic sodium channel activators may be used, with members of the veratrum alkaloids, such as veratridine, being generally preferred. Other sodium channel activators may also be used including aconitine and members of the grayanotoxins or pyrethroids.

The composition is useful in relieving pain in a subject, preferably a human, when administered in one or more unit doses. A preferred composition would contain the sodium channel activator veratridine and the local anesthetic is bupivacaine. Typically, veratridine will be adrninistered at a dosage of between about 0.10 mM and 1.0 mM in a volume of between 1 cc and 50 cc, depending upon the nerve to be anesthetized. Bupivacaine will typically be present at a concentration of about 0.5 mM to 20 mM, with lower doses (0.5 mM to 5.0 mM) being preferred. Although not essential to the invention, epinephrine may be included in the composition as an agent to help to protect against systemic toxicity. The composition may be formulated in a manner suitable for any route of administration, but preferred routes are parenteral administration, topical administration and transdermal administration.

The present invention is also directed to a kit containing, in close confinement, two or more components, e.g. vials, bottles or packets. The first component contains a sodium channel activator (e.g., veratridine or other members of the veratrum alkaloids) and the second component contains a local anesthetic (e.g., bupivacaine). Optionally, epinephrine may be included in the kit as a third component.

In another embodiment, the present invention is directed to an improved method for relieving pain in a subject, preferably a human, by administering a composition comprising a sodium channel activator and a local anesthetic. Any of the agents mentioned above may be used in the method but veratridine and bupivacaine are among the agents preferred. Typically the concentration of veratridine in the administered composition will be between about 0.10 mM and about 1.0 mM. The preferred concentration of bupivacaine is between about 0.5 and about 5.0 mM, although higher dosages can also be used. If desired, epinephrine may also be administered as part of the method and such administration will be preferred in cases where systemic tocxicity may be a problem. The preferred routes for administering agents are parenterally, topically and transdermally.

Brief Description of the Figures

Figure 1 : Relative Effects of Bupivacaine and a Combination of Bupivacaine and Veratridine: Figure 1 shows the results of experiments in which solutions of bupivacaine (BUPI) or bupivacaine and veratridine (VTD) were injected near the sciatic nerve of rats. Experimental groups contained 6 rats each and were injected with: 0.25 mM veratridine; 7.7 mM bupivacaine; 15.3 mM bupivacaine; and 7.7 mM bupivacaine + 0.25 mM veratridine. General behavior, posture, gait and motor function of hindlimbs, and responses to noxious heat stimulation (51 °C) of the hairy skin at the hind foot were monitored before and at different times after injections. The non- injected limb served as the control in each animal. Only one injection occurred on each rat's sciatic nerve. Functional changes are expressed as a percentage of maximal possible effect (%MPE, mean +/- SE). In control experiments, 0.1 ml of solution containing 7.7 mM bupivacaine 4- vehicle of veratridine (4% DMSO in saline) (n=6) was injected.

The results indicate that the combination of veratridine and bupivacaine exhibits a greater potentiation of nociception than of motor function. Specifically, nociceptive block is prolonged by approximately 68% whereas motor block is prolonged by only about 18%. The effect of veratridine cannot be explained by summation, because injection of veratridine alone is virtually ineffective. Using bupivacaine alone at a dosage of 7.7 mM, complete motor block lasted for 54.5 + /- 4.0 minutes and nociceptive block for 55.2 + /- 0.7 min. At 15.3 mM, bupivacaine

produced a complete motor block lasting for 67.5 +/- 2.5 min. and a nociceptive block lasting for 73.5 +/- 2.5 min.

When administered at a concentration of 0.25 mM, veratridine alone produced a partial (less than 100% MPE), short lasting (32.8 +/- 1.4 min.) impairment of motor function without any change in nociceptive response. When bupivacaine (7.7 mM) and veratridine (0.25 mM) were administered together, there was a prolongation of both motor and nociceptive components of block, but the increase in duration of motor impairment (118.5 +/- 0.6 min.) was minor (7.7 mM bupivacaine alone, 100.3 +/- 2.1 min.). In contrast, nociceptive block (138 +/- 6.4 min.) became significantly longer compared to administration of 7.7 mM bupivacaine alone (81.7 +/- 1.7 min.). The effect of injecting bupivacaine with the vehicle used for veratridine (4% DMSO in saline) did not produce an effect statistically different from that seen with the injection of bupivacaine alone. In all instances, 0.1 ml was injected near the sciatic notch of test animals.

Figures 2 A and 2B: Duration of Motor and Nociceptive Block: Figure 2 shows a comparison of the durations of motor and nociceptive block produced by injecting rats with bupivacaine, veratridine, or a combination of bupivacaine plus veratridine. The results were obtained from the experiments described in connection with Figure 1.

Figures 3 A and 3B: Effects of Low Dose Administration of Bupivacaine and a Combination of Bupivacaine and Veratridine: The experimental model described above in connection with Figure 1 was also used in experiments designed to determine the effect of low (threshold) doses of bupivacaine and veratridine. Specifically, experiments were conducted to determine whether it is possible to obtain selective nociceptive block after co-injection of a low dose of bupivacaine with veratridine, similar to the results which were obtained after co- injection of an "anesthetic" dose of bupivacaine. Solutions (0.1 ml) were injected near the sciatic nerve of rats in the same manner as described for Figure 1. Experimental groups were injected with: 1.925 mM bupivacaine; 3.85 mM bupivacaine; 0.0625 mM veratridine; and 1.925 mM bupivacaine + 0.0625 mM veratridine. The non-injected hind limb of each animal served as a control. Using bupivacaine alone at a dosage of 1.925 mM, it was found that complete motor block lasted for 15.17 +/- 6.07 minutes and complete nociceptive block lasted for 27.0 +/- 4.05 minutes. When the dosage of bupivacaine was raised to 3.85 mM, the duration of complete

motor block increased to 35.57 +/- 8.01 minutes and the duration of complete nociceptive block increased to 36.43 +/- 5.34 minutes. Veratridine alone at a concentration of 0.0625 mM produced a complete motor block lasting for 7.83 +/- 4.69 minutes whereas complete nociceptive block was not achieved at all. When 1.925 mM bupivacaine was combined with 0.0625 mM veratridine, complete nociceptive block lasted for a duration of 36.5 +/- 2.5 minutes but total motor blockade was not observed at any time during the experiments. Figure 3 shows the changes in motor (3A) and nociceptive (3B) functions of the sciatic nerve observed after the administration of either bupivacaine alone or bupivacaine in combination with veratridine. The results of this study confirmed that the addition of a low dose of veratridine is able to potentiate preferentially the nociceptive component of the regional block induced by bupivacaine. In addition, it was observed that the administration of a subthreshold dose of bupivacaine (1.925 mM) itself led to a preferential inhibition of nociception, i.e. complete motor blockade lasted for a shorter duration than complete nociceptive block and, in some rats, complete motor blockade was never observed. Finally, the addition of veratridine to subthreshold doses of bupivacaine was found to produce a profound antagonism of the motor component of the sciatic bupivacaine block. Not one rat was found to experience complete motor blockade and partial impairment of motor function was of a greatly reduced duration.

Detailed Description of the Invention The present invention is directed to a composition for alleviating pain which comprises a combination of a sodium channel activator and a local anesthetic. Sodium channel activators that may be used include, without limitation, the veratrum alkaloids, the grayanotoxins, the pyrethroids and aconitine. The preferred veratrum alkaloid is veratridine which is a commercially available natural product derived from a mixture of compounds called veratrine. A monograph on veratridine can be found in The Merck Index, 11th edition (1989) under reference no. 9855.

Local anesthetics that are presently available and which are suitable for compositions include bupivacaine, ropivacaine, mepivacaine, tocainide, etc. The preferred local anesthetic is bupivacaine. Veratrum alkaloids and local anesthetics can be used in the form of a free base or, alternatively, in the form of a non-toxic pharmaceutically acceptable salt. The particular form

of the agents used in the composition will depend, in part, on the route of administration. For example, in transdermal formulations a free base would generally be preferred whereas parenteral solutions would generally use water-soluble salts.

Compositions may be formulated for any route of administration but parenteral administration will generally be preferred. Suitable compositions for such administration will include aqueous solutions in which agents are used in water-soluble form, for example, water- soluble salts. In addition, oily suspensions of the active compounds may be administered. Suitable lipophilic solvents or vehicles include fatty oils (e.g. sesame oil) or synthetic fatty acid esters (e.g. ethyl oleate or triglycerides). Aqueous injection suspensions may contain substances which increase the viscosity of the suspension and include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers. In general, injections will be made in close proximity to the nerve or nerves where anesthesia is desired. In cases where long-term anesthesia is needed, extended release formulations of agents, e.g. microsphere carriers or lipid-based emulsions, may be injected or inserted. Other formulations and dosage forms that are preferred include those suitable for topical and transdermal administration. Methods for preparing these are well known in the art (see e.g. U.S. Patent No. 5,387,615; 5,192,550; 4,868,218; 5,128, 145; and foreign patent documents EP-A404807; EP-A509761 ; and EP-A593807).

When veratridine is used in compositions, it will typically be present at a concentration of between about 0.10 and 1.0 mM. Bupivacaine will typically be present at a concentration of between about 0.5 mM and 20 mM, with lower doses (0.5 to 5.0 mM) being preferred. In some instances, it may be desirable to include an agent that reduces the likelihood of systemic toxicity. Epinephrine is suitable for this purpose and may be included in preparations at a ratio of about 1:200,000 mass to volume. The dosage of the composition to be administered will depend upon factors specific to individual patients and can be determined using procedures well known in the art. In the case of veratridine, therapeutically effective amounts include 0.027 to 0.63 mg/kg of body weight and, more preferably, 0.027 to 0.27 mg/kg of body weight.

Individual preparations containing a sodium channel activator, e.g. veratridine, and local anesthetic, e.g. bupivacaine, may be provided in the form of a kit, comprising a carrier (e.g. a box or bag) compartmentalized to receive one or more components (bottles, vials, packets, etc.) in close confinement. Such a kit will typically be supplied to physicians or similar health

care personnel and will contain written instructions concerning the way in which the enclosed drugs should be administered, potential side effects, etc. The agents provided in the kit may be mixed immediately before administration to a patient or, they may be administered in immediate succession. Other agents besides sodium channel activators and local anesthetics that may be provided in the kit include agents that mitigate systemic toxicity such as epinephrine.

The present invention is also directed to a method for relieving pain in a patient, typically a human, in need of such relief. The method may be performed before a surgical procedure or for the purpose of relieving pain either after surgery or at other times. The method entails administering compositions such as those described above, i.e. compositions that include a sodium channel activator such as veratridine and a local anesthetic such as bupivacaine. The combined administration of these agents allows lower doses of anesthetic to be used to achieve the same degree of pain relief which reduces the likelihood that unwanted side effects such as systemic toxicity will be experienced.

As discussed in connection with the compositions above, any dosage form and route of administration is compatible with the method but parenteral, topical and transdermal administration will generally be preferred. The method may include the administration of other therapeutic agents or agents designed to protect against systemic toxicity, e.g. epinephrine. The duration of administration will depend upon clinical conditions and the nature of the pain experienced by the patient. Such considerations will also be largely deteπninative of the dosage form used. For example, patients experiencing long-term chronic pain can probably best be treated using dosage forms or formulations designed for the slow release of therapeutic agent.

Further teachings relevant to the practice of the method and of the above-described compositions may be found in the references cited above and particularly in U.S. Patent

5,288,723; Schneider et al. , Anesthesiology 74:270-280 (1991); Thalhammer et al. , Anesthesiology 82:1013-1025 (1995); Vladimirov, et al. , Regional Anesthesia 20(2S)A29 (1995) and Vladimirov, et al. , Anesthesiology 86:945-956 (1997). These references and all others cited herein are fully incorporated by reference.

It will be understood by those of skill in the art that the invention may be performed within a wide and equivalent range of conditions, parameters and the like, without effecting the spirit or scope of the invention or any embodiment thereof.