WO2019159005A2

WO2019159005A2 - Tetrodotoxin multidose methods of treatment

Info

Publication number: WO2019159005A2
Application number: PCT/IB2019/000164
Authority: WO
Inventors: Donald C.k. WONG; Walter N. KORZ; Christopher C. Gallen
Original assignee: Wex Pharmaceuticals Inc
Current assignee: Wex Pharmaceuticals Inc
Priority date: 2018-02-15
Filing date: 2019-02-15
Publication date: 2019-08-22
Anticipated expiration: 2020-08-15
Also published as: WO2019159005A3

Abstract

A method of treating pain aimed at maintaining therapeutically sufficient levels of tetrodotoxin by first administering a series of daily doses in an initial reset cycle period to achieve analgesia. Following this initial reset cycle period, a series of reset augmentation cycle periods repeat administration of tetrodotoxin to maintain analgesia.

Description

TETRODOTOXIN MULTIDOSE METHODS OF TREATMENT

STATEMENT OF RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Nos. 62/631,088, filed on February 15, 2018, and 62/802,762, filed on February 8, 2019, which are each herein

incorporated by reference in its entirety.

FIELD OF THE INVENTION

The invention described herein relates generally to the use of a sodium channel blocker, for example tetrodotoxin or its analogs and/or derivatives as well as their pharmaceutically acceptable salts, as a medicament for the treatment of pain. More particularly, but not exclusively, to use such a medicament in a calibrated pattern of periodic dosing to ameliorate pain.

BACKGROUND OF THE INVENTION Tetrodotoxin is an organic marine toxin which is mainly found in testis, ovaries, eggs, liver, spleen, gastrointestinal tract, skin, muscle, eyes, and blood of puffer fish. Tetrodotoxin is also found in several diverse animal species, including goby fish, some newts and frogs, the blue ringed octopus, and even in some marine alga. See, e.g ., Bane et al. , Tetrodotoxin: Chemistry, Toxicity, Source, Distribution and Detection, Toxins 6:693-755 (2014). Tetrodotoxin

(hereinafter“TTX”) is an alkaloid found in puffer fish ( Tetradontidae ). The chemical name of TTX is [4R-(4a,4aa,5a,7a,9a,10a,10a(i,l 1 S*J2S*)]-Octahydro-l2-(Hydroxymethyl)-2-imino-5, 9: 7, lOa-dimethano- l0aH-[l,3]dioxocino[6,5-d]pyrimidine-4,7,l0,l l,l2-pentol with a molecular formula C iiH_l7N₃0₈ and a molecular weight of 319.27 Da. It is a potent non-protein neurotoxin and an indispensable tool for the study of neurobiology and physiology.

The treatment of pain conditions is of great importance in medicine. Currently, there is a world-wide need for additional pain therapy. The pressing requirement for a specific treatment of pain conditions or a treatment of specific pain conditions which is tailored to the patient, which is to be understood as the successful and satisfactory treatment of pain for the patients, is documented in the large number of scientific works which have recently and over the years appeared in the field of applied analgesics or on basic research on nociception.

In certain embodiments, the present invention provides a new method of treatment for pain, including pain types such as neuropathic pain/allodynia/hyperalgesia. In certain embodiments, the cause of pain may be specific, such as cancer-related pain or chemotherapy induced neuropathic pain.

SUMMARY OF THE INVENTION

The present invention is directed to a method that satisfies the need to treat pain in a subject mammal. The present invention is a method of treating pain by administering a sodium channel blocker, for example tetrodotoxin, to a mammal comprising: administering a first pharmaceutically acceptable formulation of tetrodotoxin during an initial reset cycle period; then administering a second pharmaceutically acceptable formulation of tetrodotoxin during one or more reset augmentation cycle periods.

An initial reset cycle period may be four days. Optionally, the total daily dose may be divided among more than one dose. The first pharmaceutically acceptable formulation can be administered twice per day on each day of the initial reset cycle period. The total daily dose of tetrodotoxin may be 7.5 pg to about 150 pg. In some embodiments the total daily dose of tetrodotoxin is selected from the group consisting of 7.5 pg to about 150 pg, 10 pg to about 135 pg, about 15 pg to 125 pg, about 15 pg to 115 pg, about 15 pg to 100 pg, about 15 pg to 90 pg, about 15 pg to 80 pg, about 15 pg to 70 pg, about 15 pg to 60 pg, and about 15 pg to about 50 pg. In an embodiment, the total daily dose of tetrodotoxin may be an initial reset cycle period dose of about 144 pg. In an embodiment, the total daily dose of tetrodotoxin may be an initial reset cycle period dose of about 50 pg. In an embodiment, the total daily dose of tetrodotoxin may be an initial reset cycle period dose of about 44 pg. In an embodiment, the total daily dose of tetrodotoxin may be an initial reset cycle period dose of about 30 pg. In an embodiment, the total daily dose of tetrodotoxin may be an initial reset cycle period dose of about 15 pg. In an embodiment, the total daily dose of tetrodotoxin may be an initial reset cycle period dose of about 7.5 pg. In some embodiments, the total daily dose of TTX is equally divided and administered in two separate administrations. In some embodiments, the two separate administrations are separated by 10 - 13 hours. In some embodiments, the total daily dose of TTX is 30 pg.

Optionally, a dose of tetrodotoxin administered in either an initial reset cycle period or a reset augmentation cycle period may be given subcutaneously, intramuscularly, intravenously, transdermally, intranasally, bucally, or orally. Routes of administration may optionally be varied, with doses administered on a particular day using different routes of administration. Further, the first and second formulations may be administered to a subject using different routes of administration.

The present invention encompasses a method of treating pain by administering a sodium channel blocker, for example tetrodotoxin, to a mammal comprising: administering a first pharmaceutically acceptable formulation of tetrodotoxin during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administered two times each day subcutaneously, and the total daily dose is 7.5 pg to about 150 pg; and then, administering a second pharmaceutically acceptable formulation of tetrodotoxin during one or more reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administered two times each day subcutaneously, and the total daily dose is from 7.5 pg to about 150 pg, and these reset augmentation cycle periods begin every thirty days after the first dose of the preceding dose period.

These and other features, aspects, and advantages of the present invention will become better understood with reference to the following description, appended claims, and

accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings.

Figure 1 depicts two months, a starting month and the following month. This figure depicts the dose pattern of a four-day initial reset cycle period, followed by four-day reset augmentation cycle periods occurring every other week. The initial reset cycle period begins on Day 2 of the starting month and ends on Day 5 of the starting month. The initial reset cycle period dose period is four days. On each initial reset cycle day, a daily initial reset cycle dose of the first pharmaceutically acceptable formulation of TTX is administered. Two weeks after the first day of the initial reset cycle period, the first reset augmentation cycle period begins, on Day 16. Two weeks later, on Day 30 of the starting month, the next reset augmentation cycle period begins, and ends on Day 2 of the next month. Two weeks later, the next reset augmentation cycle period begins on Day 13. Again, two weeks later, a next reset augmentation cycle period begins on day 27. On each reset augmentation cycle period day, a daily reset augmentation cycle period dose of the second pharmaceutically acceptable formulation of TTX is administered.

Figure 2 depicts two months, a starting month and the following month. This figure depicts the dose pattern of a seven-day initial reset cycle period, followed by four-day reset augmentation cycle periods occurring every other week. The Initial Reset Cycle Period begins on Day 1 of the starting month and ends on Day 7 of the starting month. The initial reset cycle period is seven days. On each initial reset cycle period day, a daily initial reset cycle dose of the first pharmaceutically acceptable formulation of TTX is administered. Two weeks after the first day of the initial reset cycle period, the first reset augmentation cycle period begins, on Day 15. Two weeks later, on Day 29 of the starting month, the next reset augmentation cycle period begins, and ends on Day 1 of the next month. Two weeks later, the next reset augmentation cycle period begins on Day 12. Again, two weeks later, a next reset augmentation cycle period begins on day 26. On each reset augmentation cycle day, a daily reset augmentation cycle dose of the second pharmaceutically acceptable formulation of TTX is administered.

Figure 3 depicts two months, a starting month and the following month. This figure depicts the dose pattern of a four-day initial reset cycle period, followed by four-day reset augmentation cycle periods occurring every five weeks. The Initial Reset Cycle Period begins on Day 1 of the starting month and ends on Day 4 of the starting month. The initial reset cycle period is four days. On each loading dose day, a daily initial reset cycle dose of the first pharmaceutically acceptable formulation of TTX is administered. On each Initial Reset Cycle Period dose day, the first pharmaceutically acceptable formulation of TTX comprises 15 pg of TTX. Five weeks after the first day of the initial reset cycle period, the first reset augmentation cycle period begins, on Day 29 and ends on Day 1 of the next month. Five weeks later, the next reset augmentation cycle period begins on Day 26. On each reset augmentation cycle day, a daily reset augmentation cycle dose of the second pharmaceutically acceptable formulation of TTX is administered. On each day Reset Augmentation Cycle Period dose day, the second pharmaceutically acceptable formulation of TTX comprises 15 pg of TTX.

Figure 4 depicts two months, a starting month and the following month. This figure depicts the dose pattern of a five-day initial reset cycle period, followed by five-day reset augmentation cycle periods occurring every five weeks. The Initial Reset Cycle Period begins on Day 1 of the starting month and ends on Day 5 of the starting month. The initial reset cycle period is five days. On each Initial Reset Cycle Period dose day, a daily initial reset cycle dose of the first pharmaceutically acceptable formulation of TTX is administered. On each Initial Reset Cycle Period dose day, the first pharmaceutically acceptable formulation of TTX comprises 15 pg of TTX. Five weeks after the first day of the initial reset cycle period, the first reset augmentation cycle period begins, on Day 29 and ends on Day 2 of the next month. Five weeks later, the next reset augmentation cycle period begins on Day 26. On each reset augmentation cycle day, a daily reset augmentation cycle dose of the second pharmaceutically acceptable formulation of TTX is administered.

Figure 5 depicts two months, a starting month and the following month. This figure depicts the dose pattern of a four-day initial reset cycle period, followed by four-day reset augmentation cycle periods occurring every five weeks. The Initial Reset Cycle Period begins on Day 1 of the starting month and ends on Day 4 of the starting month. The initial reset cycle period is four days. On each initial reset cycle dose day, a daily initial reset cycle dose of the first pharmaceutically acceptable formulation of TTX is administered in two separate

subcutaneous doses separated by 10 - 13 hours. On each Initial Reset Cycle Period dose day, the first pharmaceutically acceptable formulation of TTX comprises 15 pg of TTX. Five weeks after the first day of the initial reset cycle period, the first reset augmentation cycle period begins, on Day 29 and ends on Day 1 of the next month. Five weeks later, the next reset augmentation cycle period begins on Day 26. On each reset augmentation cycle day, a daily reset

augmentation cycle dose of the second pharmaceutically acceptable formulation of TTX is administered. The daily reset augmentation cycle dose of the second pharmaceutically acceptable formulation of TTX comprises 15 pg of TTX. On each reset augmentation cycle dose day, two separate subcutaneous doses are administered and separated by 10 - 13 hours. On a dose day, in either the initial reset cycle period or a reset augmentation cycle period, the total daily TTX dose is 30 pg. DETAILED DESCRIPTION OF THE INVENTION

In the Summary of the Invention above and in the Detailed Description of the

Invention, and in the claims below, and in the accompanying drawings, reference is made to particular features and method steps of the invention. It is to be understood that the disclosure of the invention in this specification includes all possible combinations of such features and method steps. For example, where a particular feature is disclosed in the context of a particular aspect or embodiment of the invention, or a particular claim, that feature can also be used, to the extent possible, in combination with and/or in the context of the other particular aspects and

embodiments of the invention, and in the invention generally.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

All patents and publications referred to herein are incorporated by reference in their entireties.

In some embodiments, the sodium channel blocker is an analog of TTX. In some embodiments, an analog may be one disclosed in Lin, U.S. Pat. No. 8,486,901, which is incorporated by reference in its entirety. Further embodiments may include a TTX analog as disclosed in Buschmann et al ., U.S. Pat. No. 9,018,222, which is incorporated by reference in its entirety.

Several processes for producing TTX are known. Usually TTX is extracted from marine organisms (e.g. JP 270719 Goto and Takahashi), but numerous other methods of preparation or synthesis are also described (and used for the preparation of TTX in connection to this invention) in U.S. Pat. No. 6,552,191, U.S. Pat. No. 6,478,966, U.S. Pat. No. 6,562,968 or 2002/0086997, all of which are included here by reference. TTX is a well-known compound described for example in WO02/22129 as systemically acting as analgesic. Among the publications describing TTX are, for example, Tu, Anthony (Ed.) Handbook of Natural Toxins, Vol. 3: Marine Toxins and Venoms, 1988, 185-210 and Kao (1966), Pharmacol. Rev. 18:997- 1049, Bane et al. (2014).

It is surprising that administration of tetrodotoxin, a sodium channel blocker, is highly effective for the treatment for pain, including neuropathic pain/allodynia/hyperalgesia. The present invention relates to the use of sodium channel blockers. In one embodiment the sodium channel blocker is tetrodotoxin, its analogues/derivatives, optionally in the form of its racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, in any suitable mixing ratio; in neutral form, in the form of an acid or base or in form of a salt, in particular a physiologically acceptable salt, or in form of a solvate, especially a hydrate for the production of a medicament for the treatment of pain.

A Method for Treating Pain

In certain aspects, the invention relates generally to methods for treating pain by administering multiple doses of a sodium channel blocker. Particularly, a method of treating pain by administering tetrodotoxin (hereinafter“TTX”) to a mammal comprising: administering a first pharmaceutically acceptable formulation of TTX during an initial reset cycle period; and administering a second pharmaceutically acceptable formulation of TTX to the mammal during one or more reset augmentation cycle periods.

Initial Reset Cycle Period

An initial reset cycle period is a time window wherein one or more doses of a first pharmaceutically acceptable formulation of TTX is administered to a subject, for example, a human subject in need thereof. In certain embodiments the initial reset cycle period is at least one day. In certain embodiments the initial reset cycle period is at least two days. In certain embodiments the initial reset cycle period is at least three days. In certain embodiments the initial reset cycle period is four days. In yet further embodiments, the initial reset cycle period is five days, or ten days, or more days. The doses may be given on consecutive days or regularly spaced days or irregularly spaced days.

On each day of an initial reset cycle period, a first pharmaceutically acceptable formulation of TTX is administered to a subject. In certain embodiments the first

pharmaceutically acceptable formulation is administered once per day. In certain other embodiments, the first pharmaceutically acceptable formulation is administered two or more times per day, on each day of an initial reset cycle period. In particular embodiments the amount of TTX in a given dose during an initial reset cycle period day may be from 7.5 to about 150 pg, but about 144 pg, less than about 50 pg, less than about 44 pg, less than about 30 pg, less than about 15 pg, or less than about 7.5 pg.

In some embodiments an initial reset cycle period dose is administered intravenously. In some embodiments an initial reset cycle period dose is administered intramuscularly. In other embodiments an initial reset cycle period dose is administered subcutaneously. In yet further embodiments, an initial reset cycle period dose may be administered transdermally, buccally, or orally.

In some embodiments, the initial reset cycle period is four days. In an aspect, the first pharmaceutically acceptable formulation comprises 15 pg TTX. In one aspect, the initial reset cycle period dose comprises 30 pg TTX, wherein the dose is administered in two doses of 15 pg TTX each initial reset cycle period dose day.

Reset Augmentation Cycle Period A reset augmentation cycle period is a time window after a preceding cycle period, wherein one or more doses of a second pharmaceutically acceptable formulation of TTX is administered to a subject. In certain embodiments the reset augmentation cycle period is at least one day. In certain embodiments the reset augmentation cycle period is at least two days. In certain embodiments the reset augmentation cycle period is at least three days. In preferred embodiments the reset augmentation cycle period is four days. In yet further embodiments, the reset augmentation cycle period is five days, or ten days, or more days. The doses may be given on consecutive days or regularly spaced days or irregularly spaced days.

On each day of a reset augmentation cycle period, a second pharmaceutically acceptable formulation of TTX is administered to a subject. In certain embodiments the second pharmaceutically acceptable formulation is administered once per day. In certain embodiments, the second pharmaceutically acceptable formulation is administered twice per day.

In a particular embodiment, the reset augmentation cycle period includes one or more doses per day on each day of a reset augmentation cycle period, of a second pharmaceutically acceptable formulation of TTX, administered on four consecutive days, and the reset augmentation cycle period begins 30 days after the first dose of the preceding cycle period. The preceding cycle period may be an initial reset cycle period or an earlier reset augmentation cycle period. In particular embodiments, the preceding dose period may be an initial reset cycle period or an earlier reset augmentation cycle period.

A reset augmentation cycle period may begin a week after the first dose of the preceding dose period; begin seven days after the first dose of the preceding cycle period; begin 14 days after the first dose of the preceding cycle period; begin three weeks after the first dose of the preceding cycle period; begin 21 days after the first dose of the preceding cycle period; begin four weeks after the first dose of the preceding cycle period; begin 28 days after the first dose of the preceding cycle period; begin a month after the first dose of the preceding cycle period; begin evenly spaced from a preceding cycle period; or comprise asynchronously spaced reset augmentation cycle periods. The first dose of the preceding period may be an initial reset cycle period dose or the dose of the preceding period may be a reset augmentation cycle period dose.

In particular embodiments, a reset augmentation cycle period begins unevenly spaced from a preceding reset augmentation cycle period.

In particular embodiments the total applied TTX dose during a reset augmentation cycle dose period day may be from 7.5 pg to about 150 pg, but about 144 pg, less than about 50 pg, less than about 44 pg, less than about 30 pg, less than about 15 pg, or less than about 7.5 pg.

In some embodiments, the reset augmentation cycle period is four days. In an aspect, the second pharmaceutically acceptable formulation comprises 15 pg TTX. In one aspect, the reset augmentation cycle period dose comprises 30 pg TTX, wherein the dose is administered in two doses of 15 pg TTX each reset augmentation cycle period dose day.

In some embodiments a reset augmentation cycle period dose is administered intravenously. In some embodiments a reset augmentation cycle period dose is administered intramuscularly. In certain embodiments a reset augmentation cycle period dose is administered subcutaneously. In yet further embodiments, such a dose may be administered transdermally, intranasally, bucally, or orally. Combinations

In some embodiments, the second pharmaceutically acceptable formulation of TTX may include a second active pharmaceutical ingredient. The second active pharmaceutical ingredient may be an analgesic present in a therapeutically effective amount to ameliorate pain in conjunction with TTX.

Optionally, TTX may be co-administered with an analgesic during one or more reset augmentation cycle periods. The analgesic is present at a therapeutically effective amount.

In some embodiments, the combination of TTX and an analgesic is administered in a single dose. Such administration may be by injection, e.g ., intravenous injection, in order to introduce pain control quickly. However, other routes, including the preferred oral route, may be used as appropriate. A single dose of the combination of TTX and an analgesic may also be used for treatment of acute pain.

In some embodiments, the combination of TTX and an analgesic is administered in multiple doses as determined by the method.

Dosages and Dosing Regimens

The dosage regimen is determined by the method claimed in the present invention. The amounts of TTX administered will be dependent on the human or mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compounds and the discretion of the prescribing physician. However, an effective dosage of each is in the range of 7.5 pg to about 150 pg of TTX per day, in single or divided doses. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect - e.g. , by dividing such larger doses into several small doses for administration throughout the day.

In another embodiment, TTX is administered in multiple doses. Dosing may be at least once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be every day for one, two, three, four, or more consecutive days with this regimen repeating depending on the frequency of reset augmentation cycle periods. In some embodiments, an effective daily dosage of TTX or an analog thereof is in the range of 7.5 gg to about 150 gg, about 144 gg, less than about 50 gg, about 44 gg, less than about 30 gg, less than about 15 gg, or less than about 7.5 gg. In some embodiments an effective daily dosage of TTX or an analog thereof is in the range of 15 gg to about 60 gg. In some embodiments an effective daily dosage of TTX or an analog thereof is about 60 gg. In some embodiments an effective daily dosage of TTX or an analog thereof is about 30 gg.

In some instances, dosage levels below the lower limit of the aforesaid ranges may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect - for example, by dividing such larger doses into several small doses for administration throughout the day. In such embodiments, it is understood that a daily dose is the sum of the several divided small doses administered throughout the day.

An effective amount of TTX in the first pharmaceutically acceptable formulation, the second pharmaceutically acceptable formulation, or a combination of TTX and an analgesic, may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

In a preferred embodiment, the first pharmaceutically acceptable formulation is administered subcutaneously. In a preferred embodiment, the second pharmaceutically acceptable formulation is administered subcutaneously.

In some embodiments, the first and second pharmaceutically acceptable formulations are the same.

Methods of Treatment In some embodiments, the method is used to treat a subject undergoing treatment for chemotherapy induced neuropathic pain.

In a particular embodiment, the method is used to treat a subject undergoing treatment for cancer induced pain and wherein said subject also receives at least one low dose of an analgesic or an opioid. In some embodiments, the subject is treated with about 500 mg morphine equivalent dose of an opioid.

In one embodiment a first pharmaceutically acceptable formulation of TTX is administered, twice per day, each of four consecutive days during an initial reset cycle period to a patient in need thereof. Then, one week or one month after the first dose of the initial reset cycle period, a second pharmaceutically acceptable formulation of TTX is administered, twice per day, each of four consecutive days, during a first reset augmentation cycle period.

In particular embodiments the first and second pharmaceutically acceptable

formulations are the same formulation. In particular embodiments the first and second pharmaceutically acceptable formulations are different pharmaceutically acceptable formulations of TTX. In yet other embodiments, an initial reset cycle period dose may be administered by a different route of administration than a reset augmentation cycle dose.

In a particular embodiment, pain is treated in a subject by administering tetrodotoxin to a mammal (for example, a human subject in need thereof) comprising: administering a first pharmaceutically acceptable formulation of tetrodotoxin during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administered two times each day subcutaneously, and the total daily dose is from 7.5 pg to about 150 pg; and administering a second pharmaceutically acceptable formulation of tetrodotoxin during one or more reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administered two times each day subcutaneously, and the total daily dose is from 7.5 pg to about 150 pg, and said reset augmentation cycle periods begin every 30 days after the first dose of the preceding cycle period.

In some embodiments, pain is treated in a subject by administering tetrodotoxin to a human subject in need thereof comprising: administering a first pharmaceutically acceptable formulation of tetrodotoxin during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administered two times each day subcutaneously, and the total daily dose is from 15 pg to about 60 pg; and administering a second pharmaceutically acceptable formulation of tetrodotoxin during one or more reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administered two times each day subcutaneously, and the total daily dose is from 15 pg to about 60 pg, and said reset augmentation cycle periods begin every 30 days after the first dose of the preceding cycle period.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein the tetrodotoxin is formulated as a first pharmaceutically acceptable formulation suitable for administration during an initial reset period and the tetrodotoxin is also formulated as a second pharmaceutically acceptable formulation suitable for administration during a reset augmentation cycle period.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein there is more than one reset augmentation cycle period. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein the initial reset cycle period is four days.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein during the initial reset cycle period the tetrodotoxin is formulated for administration two times each day. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein the first pharmaceutically acceptable formulation is subcutaneously administrable.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein a daily total dose of tetrodotoxin is 7.5 pg. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein a daily total dose of tetrodotoxin is 15 pg. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein a daily total dose of tetrodotoxin is 30 pg. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein a daily total dose of tetrodotoxin is 60 pg. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein a daily total dose of tetrodotoxin is 150 pg.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein the reset augmentation cycle period comprises two doses per day, administrable on four consecutive days. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein the reset augmentation cycle period comprises two doses per day, administrable on four consecutive days, and said reset

augmentation cycle period begins 30 days after the first dose of the preceding dose period. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein a reset augmentation cycle period begins every other week. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein a reset augmentation cycle period begins every 14 days. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein a reset augmentation cycle period begins every 3 weeks. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein a reset augmentation cycle period begins every 21 days. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein a reset augmentation cycle period begins every 4 weeks. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein a reset augmentation cycle begins every 28 days. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein a reset augmentation cycle period begins once per month.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein a reset augmentation cycle period begins unevenly spaced from a preceding reset augmentation cycle period.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein the first formulation is intramuscularly administrable and the second formulation is subcutaneously administrable. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein the first formulation and the second formulation are administrable via different routes of administration.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein at least one reset augmentation cycle period is skipped. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, at least one off-cycle reset augmentation cycle period is added. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein the reset augmentation cycle period is four days.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein the second formulation is a combination with at least one additional active pharmaceutical ingredient. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein the second active pharmaceutical ingredient is an analgesic. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein the first formulation of tetrodotoxin and the second formulation of tetrodotoxin are the same.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein the tetrodotoxin is formulated as a first pharmaceutically acceptable formulation suitable for administration during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 7.5 pg; and the tetrodotoxin is also formulated as a second pharmaceutically acceptable formulation suitable for administration during reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 7.5 pg, and said reset augmentation cycle periods begin every 30 days after the first dose of the preceding dose period.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein the tetrodotoxin is formulated as a first pharmaceutically acceptable formulation suitable for administration during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 15 pg; and the tetrodotoxin is also formulated as a second pharmaceutically acceptable formulation suitable for administration during reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 15 pg, and said reset augmentation cycle periods begin every 30 days after the first dose of the preceding dose period.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein the tetrodotoxin is formulated as a first pharmaceutically acceptable formulation suitable for administration during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 30 pg; and the tetrodotoxin is also formulated as a second pharmaceutically acceptable formulation suitable for administration during reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 30 pg, and said reset augmentation cycle periods begin every 30 days after the first dose of the preceding dose period.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein the tetrodotoxin is formulated as a first pharmaceutically acceptable formulation suitable for administration during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 50 pg; and the tetrodotoxin is also formulated as a second pharmaceutically acceptable formulation suitable for administration during reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 50 pg, and said reset augmentation cycle periods begin every 30 days after the first dose of the preceding dose period.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein the tetrodotoxin is formulated as a first pharmaceutically acceptable formulation suitable for administration during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 60 pg; and the tetrodotoxin is also formulated as a second pharmaceutically acceptable formulation suitable for administration during reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 60 pg, and said reset augmentation cycle periods begin every 30 days after the first dose of the preceding dose period.

In various aspects, the present disclosure provides a use of tetrodotoxin for the treatment of gain in a mammal, wherein the mammal is a patient undergoing treatment for chemotherapy induced neuropathic pain. In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal, wherein the mammal is a patient undergoing treatment for cancer induced pain and wherein said patient also receives at least one low dose of an opioid.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein the tetrodotoxin is formulated as a pharmaceutically acceptable formulation of tetrodotoxin suitable for administration during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 7.5 pg; and, the tetrodotoxin is also formulated as a second pharmaceutically acceptable formulation suitable for administration during reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 7.5 pg, and said reset augmentation cycle periods begin every five weeks after the first dose of the preceding dose period.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein the tetrodotoxin is formulated as a pharmaceutically acceptable formulation of tetrodotoxin suitable for administration during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 15 pg; and, the tetrodotoxin is also formulated as a second pharmaceutically acceptable formulation suitable for administration during reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 15 pg, and said reset augmentation cycle periods begin every five weeks after the first dose of the preceding dose period.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein the tetrodotoxin is formulated as a pharmaceutically acceptable formulation of tetrodotoxin suitable for administration during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 30 pg; and, the tetrodotoxin is also formulated as a second pharmaceutically acceptable formulation suitable for administration during reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 30 pg, and said reset augmentation cycle periods begin every five weeks after the first dose of the preceding dose period.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein the tetrodotoxin is formulated as a pharmaceutically acceptable formulation of tetrodotoxin suitable for administration during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 50 pg; and, the tetrodotoxin is also formulated as a second pharmaceutically acceptable formulation suitable for administration during reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 50 pg, and said reset augmentation cycle periods begin every five weeks after the first dose of the preceding dose period.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein the tetrodotoxin is formulated as a pharmaceutically acceptable formulation of tetrodotoxin suitable for administration during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 60 pg; and, the tetrodotoxin is also formulated as a second pharmaceutically acceptable formulation suitable for administration during reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 60 pg, and said reset augmentation cycle periods begin every five weeks after the first dose of the preceding dose period.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein the tetrodotoxin is formulated as a pharmaceutically acceptable formulation of tetrodotoxin suitable for administration during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 100 pg; and, the tetrodotoxin is also formulated as a second pharmaceutically acceptable formulation suitable for administration during reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 100 pg, and said reset augmentation cycle periods begin every five weeks after the first dose of the preceding dose period.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein the tetrodotoxin is formulated as a pharmaceutically acceptable formulation of tetrodotoxin suitable for administration during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 120 pg; and, the tetrodotoxin is also formulated as a second pharmaceutically acceptable formulation suitable for administration during reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 120 pg, and said reset augmentation cycle periods begin every five weeks after the first dose of the preceding dose period.

In some aspects, the present disclosure provides a use of tetrodotoxin for the treatment of pain in a mammal wherein the tetrodotoxin is formulated as a pharmaceutically acceptable formulation of tetrodotoxin suitable for administration during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 150 pg; and, the tetrodotoxin is also formulated as a second pharmaceutically acceptable formulation suitable for administration during reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administrable two times each day subcutaneously, and the total daily dose is 150 pg, and said reset augmentation cycle periods begin every five weeks after the first dose of the preceding dose period.

Non-limiting, exemplary embodiments are depicted in Figures 1 through 5.

Definitions

Time periods are measured from the time of the first dose of a relevant preceding cycle period. For example, a cycle period immediately following a preceding cycle period by seven days, would begin the first dose seven days after the first dose of the preceding cycle period. Figure 1 depicts three embodiments and the time periods associated with the particular embodiment.

An initial reset cycle period is a time period where an appropriately selected active pharmaceutical ingredient is administered to a mammal in need thereof to reset the nervous system and it sensory systems, particularly, those systems affecting pain.

A reset augmentation cycle period is a time period where an appropriately selected active pharmaceutical ingredient is administered to a mammal in need thereof to augment a reset of the nervous system and it sensory systems, particularly, those systems affecting pain. The term“analogues” as used in this application is defined here as meaning a chemical compound that is a derivative of a compound which has similar biochemical activity to that compound.

The term“derivatives” as used in this application is defined here as meaning a chemical compound having undergone a chemical derivation such as substitution or addition of a further chemical group to change (for pharmaceutical use) any of its physico-chemical properties, such as solubility or bioavailability. Derivatives include so-called prodrugs, e.g. ester and ether derivatives of an active compound that yield the active compound per se after administration to a subject.

The term“analgesic” refers to a substance that acts to relieve pain. Analgesics, without limitation, may be drawn from any of the following: Cyclo-oxygenase-2 inhibitors (e.g.

valdecoxib, rofecoxib, or celecoxib); antimigraine agents (e.g. sumatriptan, methylsergide maleate, frovatriptan, naratriptan, almotriptan, ergotamine, rizatriptan, zolmitriptan, or dihydroergotamine); non-steroidal anti-inflammatory agents (e.g. ibuprofen, naproxen, sulindac, ketoprofen, tolmetin, etodolac, diclofenac, flurbiprofen, ketorolac, piroxicam, indomethacin, or nabumetone); salicylates (e.g. aspirin or magnesium salicylate); or narcotic agents (e.g.

morphine, oxycodone, fentanyl, oxymorphone, hydromorphone, meperidine, buprenorphine, methadone, tramadol, butorphanol, tapentadol, propoxyphene, alfentanil, liposomal morphine, sufentanil, remifentanil, or pentazocine). The term“effective amount” or“therapeutically effective amount” refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment. A therapeutically effective amount may vary depending upon the intended application {in vitro or in vivo ), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells (e.g, the reduction of platelet adhesion and/or cell migration). The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

A“therapeutic effect” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

The terms“QD,”“qd,” or“q.d.” mean quaque die , once a day, or once daily. The terms “BID,”“bid,” or“b.i.d.” mean bis in die , twice a day, or twice daily. The terms“TID,”“tid,” or “t.i.d.” mean ter in die , three times a day, or three times daily. The terms“QID,”“qid,” or “q.i.d” mean quater in die , four times a day, or four times daily.

The term“pharmaceutically acceptable formulations” refer to compositions that contain pharmaceutically acceptable salts of TTX and optionally pharmaceutically acceptable carriers and/or pharmaceutically excipients, and/or non-active ingredients known generally to the art to serve non-therapeutic purposes in medicaments.

Pharmaceutically acceptable formulations may include formulations wherein at least one component is a composition disclosed by Zhang et al. in U.S. Pat. No. 8,124,608, which is incorporated by reference in its entirety. Pharmaceutically acceptable formulations may include formulations wherein at least one component is a composition disclosed by Lin et al. in U.S. Pat. No. 8,222,258, which is incorporated by reference in its entirety. Pharmaceutically acceptable formulations may include formulations wherein at least one component is a composition disclosed by Lin et al. in U.S. Pat. No. 8,530,481, which is incorporated by reference in its entirety.

The term“pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Preferred inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Preferred organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. The term“cocrystal” refers to a molecular complex derived from a number of cocrystal formers known in the art. Unlike a salt, a cocrystal typically does not involve hydrogen transfer between the cocrystal and the drug, and instead involves

intermolecular interactions, such as hydrogen bonding, aromatic ring stacking, or dispersive forces, between the cocrystal former and the drug in the crystal structure.

“Pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the invention is contemplated. Additional active pharmaceutical ingredients, such as other drugs, can also be incorporated into the described compositions and methods.

It is understood that some embodiments according to the method include the specified ranges of TTX or other active pharmaceutical ingredient amounts per dosage unit. It is further understood that use of a medicament according to the method includes the manufacture of a medicament wherein the medicament contains from 7.5 to about 150 pg of TTX or a

pharmaceutically acceptable analog thereof per dosage unit.

While preferred embodiments of the invention are shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the described embodiments of the invention may be employed in practicing the invention. Therefore, the spirit and scope of the appended claims should not be limited to the description of the preferred versions contained herein.

The reader’s attention is directed to all papers and documents which are filed concurrently with this specification and which are open to public inspection with this specification, and the contents of all such papers and documents incorporated herein by reference. All the features disclosed in the specification (including any accompanying claims, abstract, and drawings) may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

EXAMPLES

The embodiments encompassed herein are now described with reference to the following examples. These examples are provided for the purpose of illustration only and the disclosure encompassed herein should in no way be construed as being limited to these examples, but rather should be construed to encompass any and all variations which become evident as a result of the teachings provided herein.

Example 1

Initial Reset Cycle period: On day zero, a subject is given two subcutaneous injections of 7.5 pg tetrodotoxin each. The injections are separated by approximately 12 hours. The next day, the subject is given two subcutaneous injections of 7.5 pg tetrodotoxin each. The next day, the subject is given two subcutaneous injections of 7.5 pg tetrodotoxin each. The next day, the subject is given two subcutaneous injections of 7.5 pg tetrodotoxin each. On day 28, the first reset augmentation cycle period begins. Twice a day on each of day 28, 29, 30, and 31, the subject is given two subcutaneous injections of 7.5 pg TTX each. On day 56, the second reset augmentation cycle period begins. Twice a day on each of day 56, 57, 58, and 59, the subject is given two subcutaneous injections of 7.5 pg TTX each. A reset augmentation cycle period begins every 28 days from day 56 as needed to control pain. Treatment cycle days are numbered from day zero of the first injection on the first day of the initial reset cycle period. See Figure 3. Example 2

Initial Reset Cycle period: On day zero, a subject is given two subcutaneous injections of 7.5 pg tetrodotoxin each. The injections are separated by approximately 12 hours. The next day, the subject is given two subcutaneous injections of 7.5 pg tetrodotoxin each. The next day, the subject is given two subcutaneous injections of 7.5 pg tetrodotoxin each. The next day, the subject is given two subcutaneous injections of 7.5 pg tetrodotoxin each. On day 14, the first reset augmentation cycle period begins. Twice a day on each of day 14, 15, 16, and 17, the subject is given two subcutaneous injections of 7.5 pg TTX each. On day 28, the second reset augmentation cycle period begins. Twice a day on each of day 28, 29, 30, and 31, the subject is given two subcutaneous injections of 7.5 pg TTX each. A reset augmentation cycle period begins every 14 days from day 14 as needed to control pain. See Figure 1.

Claims

CLAIMS We claim:

1. A method of treating pain by administering tetrodotoxin to a mammal comprising:

(a) administering a first pharmaceutically acceptable formulation of tetrodotoxin during an initial reset cycle period; and

(b) administering a second pharmaceutically acceptable formulation of tetrodotoxin during one or more reset augmentation cycle periods.

2. The method according to claim 1, wherein the initial reset cycle period is four days.

3. The method according to claim 2, wherein during the initial reset cycle period the formulation is administered two times each day.

4. The method according to claim 2, wherein the first formulation is administered

subcutaneously.

5. The method according to claim 2, wherein a daily total dose of tetrodotoxin is 7.5 to 150 pg.

6. The method according to claim 2, wherein a daily total dose of tetrodotoxin is less than about 50 pg.

7. The method according to claim 2, wherein a daily total dose of tetrodotoxin is less than about 30 pg.

8. The method according to claim 2, wherein a daily total dose of tetrodotoxin is about 15 pg.

9. The method according to any one of claims 1 to 8, wherein the reset augmentation cycle period comprises two doses per day, administered on four consecutive days.

10. The method according to any one of claims 1 to 8, wherein the reset augmentation cycle period comprises two doses per day, administered on four consecutive days, and said reset augmentation cycle period begins 30 days after the first dose of the preceding dose period.

11. The method according to any one of claims 1 to 8, wherein a reset augmentation cycle period begins every other week.

12. The method according to any one of claims 1 to 8, wherein a reset augmentation cycle period begins every 14 days.

13. The method according to any one of claims 1 to 8, wherein a reset augmentation cycle period begins every 3 weeks.

14. The method according to any one of claims 1 to 8, wherein a reset augmentation cycle period begins every 21 days.

15. The method according to any one of claims 1 to 8, wherein a reset augmentation cycle period begins every 4 weeks.

16. The method according to any one of claims 1 to 8, wherein a reset augmentation cycle begins every 28 days.

17. The method according to any one of claims 1 to 8, wherein a reset augmentation cycle period begins once per month.

18. The method according to any one of claims 1 to 8, wherein a reset augmentation cycle period begins unevenly spaced from a preceding reset augmentation cycle period.

19. The method according to any one of claims 1 to 8, wherein the first formulation is administered intramuscularly and the second formulation is administered subcutaneously.

20. The method according to any one of claims 1 to 8, wherein the first formulation and the second formulation are administered via different routes of administration.

21. The method according to any one of claims 1 to 8, wherein at least one reset augmentation cycle period is skipped.

22. The method according to any one of claims 1 to 8, wherein at least one off-cycle reset augmentation cycle period is added.

23. The method according to any one of claims 1 to 8, wherein the second formulation is a combination with at least one additional active pharmaceutical ingredient.

24. The method according to claim 23 wherein the second active pharmaceutical ingredient is an analgesic.

25. The method according to claim 1, wherein the reset augmentation cycle period is four days.

26. The method according to claim 25, wherein a daily total dose of tetrodotoxin is 7.5 to 150 hg·

27. The method according to claim 25, wherein a daily total dose of tetrodotoxin is less than about 50 pg.

28. The method according to claim 25, wherein a daily total dose of tetrodotoxin is less than about 30 pg.

29. The method according to claim 25, wherein a daily total dose of tetrodotoxin is about 15 pg.

30. The method according to any one of claims 1 to 8, wherein the first formulation of tetrodotoxin and the second formulation of tetrodotoxin are the same.

31. A method of treating pain by administering tetrodotoxin to a mammal comprising:

(a) administering a first pharmaceutically acceptable formulation of tetrodotoxin during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administered two times each day subcutaneously, and the total daily dose is 7.5 - 150 pg; and

(b) administering a second pharmaceutically acceptable formulation of tetrodotoxin during one or more reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administered two times each day subcutaneously, and the total daily dose is 7.5 - 150 pg, and said reset augmentation cycle periods begin every 30 days after the first dose of the preceding dose period.

32. The method according to any one of the preceding claims wherein the mammal is a patient undergoing treatment for chemotherapy induced neuropathic pain.

33. The method according to any one of the preceding claims wherein the mammal is a patient undergoing treatment for cancer induced pain and wherein said patient also receives at least one low dose of an opioid.

34. A method of treating pain by administering tetrodotoxin to a mammal comprising:

(a) administering a first pharmaceutically acceptable formulation of tetrodotoxin during an initial reset cycle period, wherein the initial reset cycle period is four days, the formulation is administered two times each day subcutaneously, and the total daily dose is 7.5 - 60 pg; and (b) administering a second pharmaceutically acceptable formulation of tetrodotoxin during one or more reset augmentation cycle periods, wherein the reset augmentation cycle period is four days, the formulation is administered two times each day subcutaneously, and the total daily dose is 7.5 - 60 pg, and said reset augmentation cycle periods begin every five weeks after the first dose of the preceding dose period.

35. The method of claim 34, wherein the total daily dose of tetrodotoxin is 60 pg.

36. The method of claim 34, wherein the total daily dose of tetrodotoxin is 30 pg.