JP2002537330A - Topical tricyclic antidepressant as an analgesic - Google Patents

Abstract

  (57) [Summary] The present invention relates to the use of doxepin, doxepin hydrochloride or a metabolite of doxepin or doxepin hydrochloride for the manufacture of a medicament for ameliorating pain in an individual. The present invention also relates to the use of a tricyclic antidepressant (TCA) for the manufacture of a medicament for ameliorating pain in an individual, wherein said medicament is formulated for topical application. Use of TCA and a compound of Formula I for the manufacture of a medicament for ameliorating deep or internal pain or discomfort in an individual, as well as a pharmaceutical composition comprising TCA and a compound of Formula I; and It also relates to the use of the pharmaceutical composition as an analgesic.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to the use of tricyclic antidepressants (TCAs), especially doxepin, doxepin hydrochloride, and metabolites thereof as topically applicable analgesics.

[0002]

[Prior art]

Tricyclic antidepressants (TCAs) are a class of antidepressants commonly prescribed for individuals with depression and usually formulated for oral administration. Included in the definition of TCA,
There are at least 28 different compounds (The Merck Index, 12 ^th Edition, p
age "THER-8"). In addition to their use in treating depression, a number of TCAs
Has been found to be effective in providing analgesic or pain-relieving effects, especially when administered orally, in the treatment of neuropathic pain [1].

[0003] Neuropathic pain refers to pain caused by a disease that affects the function of one or more peripheral nerves. The disease, peripheral neuropathy, is restricted to the peripheral nervous system, involves both the peripheral and central nervous systems, or acts on multiple organ systems. Peripheral neuropathy can be encountered in all age groups, may be hereditary or acquired, and is of a variety of causes, including diabetes, HIV infection, and cancer. The resulting pain can be severe pain (lasting several days), near-intense pain (weeks), or chronic (months or years) (Pathology, 2nd Edition, Rubin & Faber, JB Lippincott & Co.)
1994.).

[0004] There is evidence for the pain-relieving effects of TCA, and when administered orally in pain, amitriptyline [2,3,4,5,8,13,16], imipramine [1]
1,15], desipramine [6,7,8,9,12] and clomipramine [9,1]
0,14]. This analgesic effect is independent of the antidepressant properties [2, 3] and alters peripheral and autonomic nervous functions.
It is not related to [9]. The effects of TCA are not reproduced by another type of antidepressant. There appears to be an association between serum levels of TCA and therapeutic efficacy [9]
.

[0005] However, the use of TCA often exacerbates the condition with side effects, and such effects are as common as therapeutic effects (because of the contemplated effects, the number required for treatment (NNT) is: 2.3 to 3 depending on symptoms, NNT for side effects is 3.7 [1]). Common side effects experienced by taking these drugs orally include drowsiness, asthenia, decreased appetite, dry mouth, diarrhea, indigestion, and headache. Thus, patients often hesitate to take enough dosage to achieve substantial pain relief because of side effects. Furthermore, these side effects may discourage the use of these compounds in patients requiring long-term treatment. Therefore, the use of TCA in formulations where the therapeutic effect outweighs unwanted side effects is desirable.

[0006] doxepin is a dibenz xenon pin derivative, it belongs to a group of dibenzo xenon pin tricyclic compound, which is one of the ^{TCA (Merck Index, 12 th Edition} , compound N
o. 3492). It is generally prepared as an isomer mixture of both cis and trans isomers. Its hydrochloride, doxepin hydrochloride (1-propanamine, 3-
Dibens (b, z) oxepin-11 (6H) ylidene-N, N-dimethyl-, hydrochloride) has the molecular formula C ₁₉ H ₂₁ NO.HCl and a molecular weight of 316.

When ingested, doxepin is absorbed into the circulatory system and undergoes hepatic metabolism, resulting in the conversion to a number of metabolites, with the major active metabolite being desmethyldoxepin. However, a number of side effects are observed in patients who have taken doxepin orally, and lethargy is most commonly observed. .

In addition, doxepin hydrochloride has been formulated as a cream suitable for topical application for use as an anti-pruritic in conditions such as eczema (eczematous dermatitis, atopic dermatitis, and focal neuropathy). Dermatitis). For example, recently in the UK, 5% cream (XepinCream) cream, Biog
(available from Lan Laboratories, Hithcin, Hertfordshire, England) is licensed and commercially available. In general, topical creams are intended for short-term (up to 8 days) management of moderate pruritus. The exact mechanism by which doxepin exerts its antipruritic effect is unknown.

[0009]

[Problems to be solved by the invention]

Thus, the use of both doxepin or doxepin hydrochloride as an orally administered antidepressant and as a topically administered agent in the treatment of pruritus has been recognized. However, there is no indication that doxepin can provide an analgesic effect when administered either orally or as a topical preparation.

[0010]

Means for Solving the Problems and Embodiments of the Invention

In a first aspect, the invention provides the use of doxepin, doxepin hydrochloride, or a metabolite of doxepin or doxepin hydrochloride, for the manufacture of a medicament for ameliorating pain in an individual.

When referring to doxepin, doxepin hydrochloride, or metabolites thereof, both cis and trans isomers of doxepin or doxepin hydrochloride and mixtures of isomers thereof, any other salt of doxepin, and primary activity It is understood to include these metabolites, including metabolites, desmethyldoxepin.

If the medicament prepared according to the present invention is said to ameliorate or ameliorate pain, it is effective in reducing the intensity of pain or has an analgesic effect And it is preferred, but not necessary, that the agents so described can eliminate certain pains. The term pain is used sensibly and is intended to describe pain levels from mere discomfort to practically intolerable.

[0013] In a second aspect, the invention relates to the use of a tricyclic antidepressant (TCA) for the manufacture of a medicament for ameliorating pain in an individual, wherein the medicament is used for topical application. Provide use that is prescribed for.

When the term TCA is used, it introduces all tricyclic antidepressants. There are at least 28 different compounds in this class of compounds (The Merck Inde
x, 12 ^th Edition, see page "THER-8"). Thus, according to a preferred embodiment, the TCA is amitriptyline, imipramine, desipramine, or clomipramine. Preferably, the TCA is doxepin, doxepin hydrochloride, or a metabolite thereof.

[0015] In the present application, the present inventors have shown for the first time the analgesic effect of doxepin, a TCA applied topically in chronic human neuropathic pain [25]. With the clinical impression of a synergistic effect when agents from different classes of agents are co-administered, it was decided to test the effect of topical administration of capsaicin, doxepin, and a mixture of both on chronic neuropathic pain in humans. Capsaicin has been disclosed for its use as an analgesic for 185
It has been disclosed as early as 0 years [17], but has various analgesic effects, such as postherpetic neuralgia [18, 19, 20], diabetic neuropathy [21, 22], and surgical nerve. Its effects on impaired pain [23] have been confirmed. Capsaicin is represented by Formula I.

[0016]

Embedded image

Capsaicin causes the release of substance P from C-fiber afferent neurons, and repeated application conversely depletes substance P stores and thus reduces pain transmission from peripheral nerve fibers to higher centers [24]. Surprisingly, while doxepin, capsaicin, and the doxepin / capsaicin mixture alleviated pain as much as overall, analgesia with the doxepin / capsaicin mixture began more rapidly. The onset of analgesia with the doxepin / capsaicin mixture was apparent in the first week of treatment in some cases, as compared to two weeks for doxepin alone.

In a third aspect of the invention there is provided the use of TCA and a compound of formula I for the manufacture of a medicament for ameliorating deep or internal pain or discomfort in an individual.

Embedded image

In a fourth aspect of the present invention there is provided a pharmaceutical composition comprising TCA and a compound of formula I.

Embedded image

In a fifth aspect of the present invention there is provided the use of a pharmaceutical composition according to the fourth aspect of the present invention as an analgesic.

In a preferred embodiment of the fourth and fifth aspects according to the present invention, said TCA reduces intense discomfort associated with the application of a compound of formula I to the skin in said pharmaceutical composition Present in an amount sufficient to Preferably, the compound of formula I is present in an amount sufficient to increase the analgesic effect provided by said TCA.

In a preferred embodiment of the various aspects according to the present invention, the medicament further comprises a pharmaceutically active carrier, which makes it preferably suitable for topical application to the skin. Preferably, the medicament is a cream, jelly or ointment. Suitable carriers are well known to those skilled in the art. Suitable carriers include Bi
Includes those used in xepin cream available from oglan Laboratories Ltd. These include inert ingredients (sorbitol, cetyl alcohol, isopropyl myristate, glyceryl stearate, PEG-100 stearate, petrolatum, benzyl alcohol, titanium dioxide, and pure water) at pH 3.
A base cream of 5-5.5 can be included.

Preferably, the medicament for use according to the present invention is formulated for topical application around the source of pain or at the perceived source of pain (although in reality it is more central).

In general, patients prefer topical preparations of pain relieving compounds over oral ones. In particular, patients prefer the concept that they can apply the drug to the site where they perceive it as the source of pain, even though it may be more centered in reality. Furthermore, it is desirable to reduce the side effects experienced by patients while taking advantage of the beneficial effects of the compounds. By applying a topical formulation, patients will experience milder side effects than they would ingesting a sufficient amount of TCA to induce an analgesic effect in an oral formulation. In view of reduced side effects, topical preparations can be used for longer periods of time, and thus can be used in the treatment of chronic or long-lasting pain. Thus, such preparations would be more tolerated for patients requiring long-term treatment.

In particular, in a medicament prepared according to the invention and formulated for topical application, optionally the release of capsaicin, ie substance P from C-fiber afferent neurons, or conversely, the storage of substance P Patients using doxepin, doxepin hydrochloride, or their metabolites as an analgesic, together with compounds that deplete the drug will not experience the side effects, including lethargy, associated with oral doxepin preparations.

In a preferred embodiment, the medicament prepared according to the present invention is used for amelioration of pain in an individual suffering from neural pain, preferably chronic neural pain. These pains include running pain, burning pain,
It is understood to be characterized by symptoms including paralysis, paresthesia / paresthesia (stinging), and allodynia. In particular, chronic neuropathic pain is characterized by the presence of three of these five related constituent symptoms. Preferably, the average duration of the pain afflicted by the human being treated is 69 months.

In a preferred embodiment, the medicament prepared according to the invention is intended for long-term use. Long term means use of the drug for longer than 8 days, and includes treatment that lasts many months, if not more.

In a preferred embodiment, the use of the medicament prepared according to the present invention is
Without the significant side effects usually associated with oral administration of. These side effects include drowsiness. Preferably, the medicament produced according to the invention has previously been treated with oral TC
It is intended for use in individuals experiencing treatment deficiency with A (lack of analgesia or intolerable side effects).

Preferably, the medicament according to the invention contains 2.5 to 7.5% doxepin hydrochloride, but more preferably contains 5% doxepin hydrochloride. In the present invention according to the fourth or fifth aspect, the drug is preferably 0.01 to 0.1%, preferably 0.015 to 0.075%, more preferably 0.015 to 0.035.
% Capsaicin. In a particularly preferred embodiment, the agent is 3.
Contains 3% doxepin and 0.025% capsaicin.

In the preparation of a medicament for use as an analgesic, the advantages of these aspects of the invention in which doxepin, doxepin hydrochloride, and their metabolites are used with or without capsaicin are: Doxepin and doxepin hydrochloride are known compounds, having a history of use in individuals suffering from depression or pruritus. Thus, rather than developing novel compounds for use as analgesics, particularly in the treatment of chronic pain, the present invention provides a well-known drug with a well-known series of possible side effects and contraindications. For use in new applications.

In a randomized, double-blind, placebo-controlled experiment, the effect of doxepin hydrochloride 5% twice daily application was compared to placebo in 40 patients with neuropathic pain did. The details of this experiment are summarized in Example 1 below. The results show that there was a significant reduction in pain index when treated with topical doxepin hydrochloride compared to placebo. Minor side effects were seen in three patients. There were no significant differences in drowsiness levels between the two groups.

In another randomized, double-blind, placebo-controlled experiment, 3.3
% Of doxepin, 0.025% capsaicin, and the effect of daily application of a cream containing a mixture of 3.3% doxepin and 0.025% capsaicin, in 200 patients with neuropathic pain. Compared with placebo. Details of this experiment are summarized in Example 2 below. The results show that when treated with topical doxepin hydrochloride, topical capsaicin, and a combination of topical doxepin hydrochloride and capsaicin, there was a significant reduction in pain index compared to placebo. The results also indicate that the combination of topical doxepin hydrochloride and capsaicin initiated pain relief more rapidly than doxepin hydrochloride or capsaicin alone. Minor side effects were seen in a relatively small number of patients.

[0033] Thus, doxepin hydrochloride has analgesic effects in neuropathic pain and is usually without side effects when applied topically.

[0034] The apparent effects without central nervous system side effects may be indicative of doxepin's peripheral effects. However, the half-life of doxepin after a single oral dose is approximately 18 hours, and in the case of the major active metabolite desmethyldoxepin, the time to reach steady-state concentrations after multiple doses over two weeks. It is 34 hours including [28]. This two weeks to steady state is a gap between the onset of topical treatment and the first signs of analgesic effects, suggesting a systemic effect. Furthermore, this is
It suggests that the metabolite appears to be active. The mode of action of capsaicin in increasing the rate of onset of analgesia caused by TCAs such as doxepin is
Not completely understood.

The treatment population experienced a mean duration of pain of 69 months, many of whom had previously received oral TCA
The result obtained is even more remarkable, due to the fact that the patient has experienced inadequate treatment (lack of analgesic effects or intolerable side effects), and the goal of the treatment is itself a balance between the drug's efficacy and side effects , Stressing the quality of life.

[0036]

【Example】

Example 1 Randomized, double-blind, placebo-controlled experiment Subjects: Pain Clininc, with chronic neuropathic pain, responding to codeine-based analgesics and nonsteroidal anti-inflammatory drugs No, 40 adult patients (running pain,
There are three out of five related constituent symptoms: intense pain, paralysis, paresthesia / dysesthesia, and allodynia). All patients submitted their consent forms and obtained Regional Ethical Committee Approval. Patients taking oral antidepressants were excluded from the study. Patients who had previously failed oral TCA attempts were not excluded. Patients were assigned to one of two groups using a computer generated random number list.

Experimental drug: doxepin hydrochloride 5% (xepin cream, Bioglan Laboratories, Ltd., Hith
cin, England) (white odorless cream) and aqueous cream (placebo).

Experimental design: A randomized, double-blind, placebo-controlled experiment. Patients in each group were instructed to apply a volume of cream equal to the size of a rice grain to the pain area twice daily over a 4-week experimental period. Group A patients received doxepin and group B patients received placebo.

Measurements: Patients were given their average pain index (scale 0-10) and their level of drowsiness (also scale 0-) during the 28-day experimental period every day for the previous 24 hours.
10). The patient was also asked to record any side effects of applying the cream.

Data Analysis: A comparison of the pain index between the two groups at both the beginning and end of treatment was performed using a parametric t-test. A t-test was also used for the difference between the start and end of treatment in the two groups. P <0.05 was considered statistically significant.

Results: 30 (75%) patients submitted the results-16 doxepin group, 14 placebo group. The average age of all patients was 52 years (range 27-80), the average duration of pain was 69 months (range 3-324 months), and statistically significant between active and placebo treatment groups. There were no significant differences. There was no statistically significant difference in mean pain index during the first week of treatment in both groups. However, in the last 10 days of treatment, the mean pain index was significantly reduced in the doxepin group (p <0.05) (Table 1). When comparing the differences between the start and end of treatment, there was no significant difference in the placebo group, but 1.18 (p <0.01) in the doxepin group.
) Was observed (Table 2). One of the patients reported momentary intense discomfort after applying the cream. There were no differences in drowsiness levels between the two groups.

Example II Subjects: This is a randomized, double-blind, placebo-controlled experiment of 200 adult patients with chronic neuropathic pain. Ethics committee approval was obtained and consent was obtained from the subject. For the purposes of this study, patients were treated with pain, including at least three of the following symptoms of neuropathic pain: running pain, intense pain, paralysis, paresthesia and paresthesia (allodynia). Was diagnosed as neuropathic pain. All patients had pain that did not respond to simple or complex codeine-containing analgesics or nonsteroidal anti-inflammatory drugs. Oral TC for all patients due to their pain
A was tried and was non-reactive or intolerant. Patients were excluded if they had a known sensitivity to doxepin or capsaicin or had a rupture of the skin in the area of pain. Patients were asked to record all experimental measurements over a week prior to randomization and provide a baseline index for these parameters. After baseline measurements, patients were randomized to a computer-generated (
Four randomized groups (A, B, C) using number lists (equal numbers)
, D).

Experimental drugs: Patients in group A received placebo (aqueous cream), group B received 3.3% doxepin hydrochloride (2 parts 5% doxepin hydrochloride with 1 part aqueous cream (Xepin, Bioglan L)
aboratories, Ltd)) and Group C has 0.025% capsaicin (Zacin, E
lan Pharma) and Group D received 0.075% capsaicin (Axsain, 3.3% doxepin / 0.025% capsaicin (Xepin, Bioglan Laboratories, Ltd) 2 parts per 2 parts). Elan Pharma) was administered. All experimental creams were white, odorless and had a similar non-greasy texture, which were housed in identical screw-cap containers, marked with appropriate random letters.
Although all cream combinations appear to mix easily, further investigation is needed to assess the stability of the mixture in terms of physical and chemical compatibility.

Experimental Design: Patients in each group were applied three times a day to the pain area in a volume of cream approximately equal to the size of a rice grain, and all experimental measurements were taken over a four week experimental period. Was instructed to be recorded. A visual representation of the amount of cream applied was used to aid reconciliation. The patient was asked not to wash the application area for one hour after application, and the applied finger was certainly asked to wash to avoid accidentally applying the test cream elsewhere. At the end of the experimental period, the patient was required to return the test cream container for compliance. If the volume of cream used was insufficient (arbitrarily set to 50% container content), these patients were excluded from the study.

Measurements: The patient was given a continuous 0-10 visual analog scale (VAS) measuring the average level of the following variables over the last 24 hours with an accuracy closest to 0.1 cm: ) Were required to be recorded: total pain, running pain, severe pain, paralysis, paresthesias, and paresthesia. In addition, they were asked to record side effects and their desire to continue study medication.

Data Analysis: The mean change in index using standard deviation and 95% confidence limits (95% CL) was calculated for the week before the experiment and each of the four weeks during the experiment. The significance of the change from baseline level was tested using the Student's t-test, with P <0.05 considered significant. Pre-experimental calculations indicate that 60 patients in each group show a 1-point reduction (90% power, and 17 further show a 2-point reduction (90
% Power)).

Results: No subject was excluded due to known sensitivity to doxepin or capsaicin. 151 (75.5%) patients submitted results (placebo 41
, Doxepin 41, capsaicin 33, doxepin / capsaicin 36). Demographic details are shown in FIG. The duration of pain in the doxepin / capsaicin group was longer than in the other groups (p = 0.05).

The data for all pain indexes were normally scattered, so a parametric test was used. There were no statistically significant differences in baseline indices for parameters measured between treatment groups: the total pain index before treatment was 7.13 in the placebo group, 7.29 in the doxepin group, and in the capsaicin group. 7.11 for the doxepin / capsaicin group, 7.47. Total pain was unchanged in the placebo group, but decreased 0.9 (95% CL, 0.34-1.46) (p <0.001) in the doxepin group and 1.12 in the capsaicin group ( 95% CL, 0.44-1.8) (p <0.00
1) and 1.07 reduction in the doxepin / capsaicin group (95% C.P.).
L., 0.39-1.75) (p <0.00). A statistically significant decrease in pain index was evident in all three active agent treatments from the second week of treatment (FIG. 1).

Paralysis and numbness did not change from baseline measurements in any of the four groups (FIGS. 2 and 3).

The index for intense pain remained at a baseline level of 2.34 in the placebo group, but increased 2.1 weeks later in the doxepin group (95% C.P.).
L., 1.62-2.58) (p <0.001).
8 (95% CL, 0.32-1.04). In the capsaicin group as well, a 1.6 rise from baseline was seen during the first week of treatment (95% CL, 0.86-2.34).
(P <0.01), showing a gradual decrease of 0.52 after 4 weeks of treatment (95% CL
, -0.42-1.46). In the doxepin / capsaicin group, the rise from baseline was less substantial, rising 0.32 after one week (95% CL, 0.
11-0.53) (p <0.01). This level did not decrease with increasing treatment time (FIG. 4).

The dysesthesia was not altered by placebo or doxepin. The index for dysesthesia decreased from baseline shortly after the start of capsaicin treatment, with an initial decrease of 1.2 (95% CL, 0.1-2.3) after the first week of the experiment (p <0.001). And the fourth
By week, a further gradual 0.19 decrease (95% CL, 0.49-0.87) was seen. In the doxepin / capsaicin group, there was an immediate 0.95 decrease from baseline (95% CL, 0.7-1.2) after the first week of the experiment (p <0.01), and further treatment continued There was no reduction (FIG. 5).

The running pain was not modified by placebo or doxepin. After 4 weeks, the application of capsaicin showed a running pain reduction of 0.75 from baseline (95% CL, 0-1.5) (p <0.001). Running pain was reduced by 0.73 with the doxepin / capsaicin combination (95% CL, 0.28-1
.18) (p <0.001) (FIG. 6).

As for the taste of the cream, one patient (at the time the blind rule was released)
(2.4%) wished to continue using placebo, 17 (41%) doxepin, 13 (39%) capsaicin, and 9 (25%) wishing to continue using doxepin / capsaicin.

[0054] Side effects were minor. Four (97%) of the doxepin and two (5.5%) of the doxepin / capsaicin group complained of lethargy, and one (2.4%) had a skin rash using doxepin and one (2%) (0.8%) had a headache with doxepin / capsaicin, and two more (4.9%) experienced itching with doxepin. Regarding severe discomfort after applying cream, the Capsaicin Group
(81%), 22 (61%) in the doxepin / capsaicin group,
And 4 people (17%) in the doxepin group.

[0055]

[References]

[0056]

[Table 1]

[0057]

[Table 2]

[0058]

[Table 3]

[Brief description of the drawings]

FIG. 1 shows a visual analog scale (0-10) for total pain.

FIG. 2 shows a visual analog scale (0-10) for paralysis.

FIG. 3 is a diagram showing a visual analog scale (0-10) for paresthesia.

FIG. 4 shows a visual analog scale (0-10) for severe pain.

FIG. 5 shows a visual analog scale (0-10) for paresthesia.

FIG. 6: Visual analog scale for running pain (0-10)
FIG.

[Procedural Amendment] Submission of translation of Article 34 Amendment

[Submission date] February 20, 2001 (2001.2.20)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Contents of correction]

[Claims]

Embedded image For use in the manufacture of a medicament for ameliorating neuropathic pain with a compound of formula (I).

Embedded image A pharmaceutical composition comprising:

Embedded image A method for providing an analgesic treatment, comprising the step of continuously or simultaneously administering a compound of the present invention.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/02 A61P 25/02 25/04 25/04 // C07D 223/20 C07D 223/20 313/12 313/12 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA ( BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG , KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZWF terms (reference) 4C034 DS03 4C062 JJ19 4C076 AA09 CC01 DD29 DD34 DD37 DD38 DD45 DD46 EE23 4C086 AA01 AA02 BA10 BC32 MA01 MA02 MA04 MA05 MA28 MA63 NA06 NA10 ZA08 ZA20 4C206 FA09 GA09 MA01 MA02 MA04 MA05 MA48 MA83 NA06 NA10 ZA08 ZA20

Claims (50)

[Claims] 1. Use of doxepin, doxepin hydrochloride or a metabolite of doxepin or doxepin hydrochloride for the manufacture of a medicament for ameliorating pain in an individual. 2. The use of T for the manufacture of a medicament for ameliorating pain in an individual.
Use of CA, wherein said medicament is formulated for topical application. 3. The use according to claim 2, wherein the TCA is amitriptyline, imipramine, desipramine, or clomipramine. 4. The use according to claim 2, wherein the TCA is doxepin, doxepin hydrochloride, or a metabolite of doxepin or doxepin hydrochloride. 5. Side effects usually associated with oral administration of TCA are reduced.
5. Use according to any of the preceding claims, wherein the use is not present. 6. Use according to any one of the preceding claims, wherein the individual has previously experienced a treatment deficiency with oral TCA. 7. The use according to any one of claims 1 to 6, wherein the agent further comprises a compound capable of causing the release of substance P from C-fiber afferent neurons. 8. The use according to any one of claims 1 to 7, wherein the agent further comprises a compound capable of causing local depletion of substance P from C-fiber afferent neurons. 9. Use according to claim 7 or claim 8, wherein the amelioration of pain in the individual is started rapidly. 10. The use according to claim 9, wherein said onset occurs within two weeks. 11. The method of claim 1, wherein the drug is of the formula I: The use according to any one of claims 7 to 10, further comprising a compound of the formula: 12. The compound of formula I wherein the compound is capsaicin.
Use as described in. 13. Use according to any one of the preceding claims, wherein the medicament further comprises a pharmaceutically active carrier, which makes it preferably for topical application to the skin. . 14. The use according to any one of the preceding claims, wherein the medicament is formulated for topical application around a source of pain or at a perceived source of pain. 15. TCA and Formula I: A use of a compound of claim 1 for the manufacture of a medicament for ameliorating deep or internal pain or discomfort in an individual, wherein TCA has an ameliorating effect on said pain. 16. Use according to any one of the preceding claims, wherein the pain in the individual is a neural pain, preferably a chronic neural pain. 17. Use according to any one of the preceding claims, wherein the average duration of pain suffered by the individual to be treated is 69 months. 18. Use according to any one of the preceding claims, wherein the individual requires prolonged treatment. 19. Use according to any one of the preceding claims, wherein the medicament contains 2.5 to 7.5%, preferably 5%, of doxepin hydrochloride. 20. The method according to claim 11, wherein the drug is 0.01 to 0.1%, preferably 0.0
20. Use according to any one of the preceding claims, containing 15 to 0.075%, more preferably 0.015 to 0.035% capsaicin. 21. The use according to claim 20, wherein the agent contains 3.3% doxepin and 0.025% capsaicin. 22. TCA and formula I: A pharmaceutical composition comprising: 23. The pharmaceutical composition according to claim 22, for use as an analgesic. 24. A pharmaceutical composition according to claim 22 or 23 for topical application around a source of pain or discomfort. 25. The pharmaceutical composition according to any one of claims 22 to 24, further comprising a pharmaceutically acceptable carrier, suitable for topical application to the skin. 26. A pharmaceutical composition according to any one of claims 22 to 25 for ameliorating deep or internal pain. 27. A pharmaceutical composition according to any one of claims 22 to 26 for ameliorating skeletal, muscular or joint pain. 28. A pharmaceutical composition according to any one of claims 22 to 27 for ameliorating neuropathic pain, especially painful diabetic neuropathy or postherpetic neuralgia. 29. The method according to any one of claims 22 to 28, wherein the TCA is present in an amount sufficient to reduce the severe discomfort associated with applying the compound of Formula I to the skin. Pharmaceutical composition. 30. The pharmaceutical composition according to any one of claims 22 to 29, wherein the compound of formula I is present in an amount sufficient to increase the analgesic effect provided by TCA. 31. The compound of formula 22 wherein the compound of formula I is capsaicin.
0. The pharmaceutical composition according to any one of the preceding claims. 32. A pharmaceutical composition according to any one of claims 22 to 31 for application in the form of a cream, jelly ointment, gel, lotion, paste or by patch. 33. A method for providing an analgesic treatment, comprising the step of administering doxepin, doxepin hydrochloride, or doxepin or a metabolite of doxepin hydrochloride to a patient in need of the analgesic treatment. 34. The method of claim 33, wherein doxepin, doxepin hydrochloride, or a metabolite of doxepin or doxepin hydrochloride is administered topically to a patient in need of analgesic treatment. 35. In a patient in need of an analgesic treatment, TCA and formula I: A method for providing an analgesic treatment, comprising the step of continuously or simultaneously administering a compound of the present invention. 36. The method of claim 35, wherein the TCA and the compound of Formula I are applied topically to the skin or around a source of pain. 37. The method of claim 36, wherein the TCA and the compound of Formula I are applied simultaneously as a single preparation comprising TCA, the compound of Formula I, and a pharmaceutically acceptable carrier. 38. The method of claim 37, wherein the formulation is a cream, jelly, ointment, gel, lotion, paste, or for application by a patch. 39. The method of any one of claims 35 to 38, wherein the analgesic treatment is for ameliorating deep pain or internal pain. 40. The method of any one of claims 35-39, wherein the analgesic treatment is for ameliorating skeletal, muscle, or joint pain. 41. The method according to any one of claims 35 to 39, wherein the analgesic treatment is for ameliorating neural pain, especially painful diabetic neuropathy or herpetic neuralgia. 42. The method of any one of claims 35 to 41, wherein the TCA is present in an amount sufficient to reduce severe discomfort associated with the application of the compound of Formula I. 43. The method of any one of claims 35 to 42, wherein said TCA is present in an amount sufficient to increase the analgesic effect provided by the compound of formula I. 44. The compound of formula 35 wherein the compound of formula I is capsaicin.
The method according to any one of claims 3 to 7. 45. A method of ameliorating deep or internal pain, comprising the step of locally administering TCA to a subject suffering from the pain around the source of the pain. 46. The method of claim 45, wherein said TCA is applied to the skin. 47. The method of claim 45 or 46, wherein said pain is skeletal, muscular, or joint pain. 48. The method according to claim 47, wherein said pain is neuropathic, especially painful diabetic neuropathy or postherpetic neuralgia. 49. The method of any one of claims 45 to 48, wherein said TCA is administered with a pharmaceutically acceptable carrier. 50. The method of claim 49, wherein the TCA is administered as a cream, jelly, ointment, gel, lotion, paste, or as a patch application.