CA2009402A1 - Use of benzydamine and salts thereof for relief of pain associated with herpes viral infections and laser vaporization of condylomata - Google Patents

Abstract

ABSTRACT

Benzydamine and its pharmaceutically acceptable, pharmacologically compatible acid addition salts is used in a topical formulation, more especially a cream, to relieve pain associated with herpes zoster infections, i.e., shingles, as well as in the treatment of pain following laser vaporization of condylomata of the vulva.

Description

~9402 This invention relates to the use of benzydamine and salts thereof, in the temporary relief of pain or neuralgia, associated with and following episodes of herpes zoster infection, and in the relief of pain in women following laser surgery to the vulva.

Herpes Zoster Infections (Shingles) Herpes zoster infections are caused by the varicella-zoster virus. It appears to be the con-sequence of reactivation of the latent virus from the dorsal root ganglia. It may be activated by local lesions involving the- dorsal root ganglia, by systemic disease, particularly Hodgkin's disease, or by immunosuppressive therapy. While the disease may occur at all ages, it strikes most often in the elderly. The incidence ranges between 5 and 10 cases per 1,000 persons from the sixth through the eighth decades of life.
Commonly known as "shingles", herpes zoster infections are characterized by vesicular eruption and neuralgic pain in the cutaneous areas supplied by peripheral sensory nerves arising in the affected root ganglia. Inflammatory changes occur in the --~
sensory root ganglia and in the skin of the associated dermatome. Inflammation may involve, in ~ -some cases, the posterior and anterior horns of the ~ -gray matter, the meninges, and the dorsal and ventral roots.
In both the normal and immunocompromised host, the most debilitating complication of herpes zoster is pain associated with acute neuritis and :.~f . ' ' " .-..c~

~ ';',f""j"",.'.~" ' ' ~ ' -2- 2 9~ ~2 postherpetic neuralgia. Although it is extremely uncommon in young individuals, at least 50 per cent of patients with shingles over 50 years of age report pain in the involved dermatome months after resolution of cutaneous disease.
In the immunocomprised host, treatment of herpes zoster infections can be accomplished with intravenous administration of vidarabine or acyclovir. Both drugs accelerate healing of skin lesions while decreasing the likelihood of visceral complications. The treatment of acute neuritis which accompanies the disease and postherpetic neuralgia which follows as a sequela should preferentially be of a topical nature rather than a systemic treatment.
Capsaicin is currently utilized in the therapy of neuralgia associated with herpes zoster infections. Capsaicin is an alkaloid derived from the fruit of various species of Capsicum (solanaceae). It renders skin insensitive to pain by preventing the reaccumulation of substance P in peripheral sensory neurons. (Substance P is thought to be the principal chemomediator of pain impulses from the periphery to the central nervous system).
Capsaicin is available under the Trade Mark Zostrix as a 0.025% cream.

Laser Surgery to the Vulva Laser surgery or evaporisation is used for the treatment of vulvar condylomata, vulvar intra-epithelial neoplasia and carcinoma in situ of the vulva. Laser surgery results in the destruction and -loss of the superficial layer of the dermis to a 3 2009~

depth of 1 to 5 mm depending on the disease process and the anatomical area treated. This treatment is accompanied by an intense local inflammatory reaction and pain. Healing usually takes from one to three months depending on the extent of laser evaporisation and the depth of treatment. The onset of pain is usually on the day of treatment and lasts from one to three weeks. Initial injury to nerve endings in the vulvar tissue by the thermal effects of the laser beam frequently results in initial reduction of pain.
Maximum discomfort occurs about the fourth day after vulvar surgery.
Vulvar condylomata acuminata usually affects women in their late teens and twenties. The lesions are typically multiple and involve the posterior vaginal fourchette and the perineal body, the labia minora, the clitoris, the labia majora, the perineum, and the anal mucosa. Condylomata also affect the vaginal mucosa and the cervix. These lesions are almost always sexually transmitted and most of them are caused by the Human Papilloma Virus (HPV) type 6 or 11. The virus resides within the epidermis and its malignant potential is extremely low or nonexistent. Initial treatment of vulvar condylomata acuminata often consists of topical application of Podophyllin or trichloroacetic acid.
This treatment must be repeated regularly to obtain a complete response. Patients with condylomata failing to respond to these measures or with very extensive lesions are usually treated by laser evaporisation.
8ecause the virus is in the superficial layer of the skin or epidermis, treatment can be limited to the _4_ 2~

upper 100 to 150 ~m of skin, however, even with careful technique, the depth of vaporization often reaches 1 mm.
Vulvar intraepithelial neoplasia consists of a spectrum of mild, moderate and severe vulvar dysplasia and carcinoma in situ. Although carcinoma of the vulva usually involves an older population of women, the pre-invasive condition usually affects young women in whom it tends to be multifocal in distribution around the fourchette and perineal body, labia minora, clitoris, interlabial sulci, labia majora and perineal skin. Vulvar lntraepithelial neoplasia and carcinoma in situ usually cause symptoms of vulvar pruritus and discomfort. The lesions typically are hypopigmented and present as white plaques especially after application of acetic acid but may be hyperpigmented. The diagnosis is usually confirmed by biopsy which is facilitated by colposcopy. The treatment can be by surgical excision but in yong women with multifocal lesions this may lead to scarring and alterations in sexual function. Topical 5-fluorouracil has a high failure rate due to poor compliance. The most satisfactory treatment currently in use is laser evaporisation after invasive carcinoma has been ruled out by appropriate biopsies. Laser evaporisation to the vulva is usually performed under general anesthesia is carried to a depth of 2 to 3 mm.
The current management of post laser-surgery pain varies between different clinics.
Physicians at most centres prescribe oral analgesics such as a combination of acetominophen and codeine.

_5_ At times, narcotics are prescribed. Several topical treatments are used all with less than ideal results in terms of relief of discomfort. These include topical Aloevera cream and topical tannic acid. Some physicians prescribe or recommend no local treatment in view of the lack of documented efficacy of any of the above treatments. In order to minimize the discomfort, sitz baths and abstention from usual activities and intercourse are recommended. This wide diversity in local management of laser injury reflects the absence of scientific data supporting any of the treatment regimens and current practice in this area is based on personal and anecdotal experience. -:,~
Biochemistry and Pharmacology of Benzydamine Benzydamine hydrochloride is a hydro-chloride salt of benzyldamine, i.e., l-benzyl 3-(3-dimethylamino)propoxy l-H-indazole. The compound is an odourless, white, crystalline powder which is ~-soluble in water.
Benzydamine is described in U.S. Patent 3,318,905, issued May 9, 1967.
In animals, the pharmacological activities of benzydamine include the following: local anesthetic, non-steroidal anti-inflammatory after both oral administration and local application, analgesic, antipyretic, antitussive (not a central nervous system effect), aspecific antibacterial and antifungal, antispasmodic of the papaverine type and an anthelmintic. Benzydamine also possesses inhibi- -.':
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tory activity on the polysynaptic linguomandibular reflex and on the tonic convulsions induced by electroshock or strychnine.
Benzydamine has little or no effect on blood pressure, respiration, intestinal motility and conditioned reflexes. It has no anticholinergic, antihistaminic, antiserotonin, antireserpine or ganglio-blocking activity.
The results of studies on acute, subacute and chronic toxicity revealed large ratios between the systematically administered doses of benzydamine which produced toxic effect in animals and the locally applied concentrations of the drug which are proposed for therapeutic usage in man.
In acute toxicology studies, benzydamine produced pharmacological effects and mortality at systemically administered doses far above the locally applied therapeutic concentration of 0.15~. LD5~
values in mg/kg in various species of animals were as follows: mice 33 intravenously, 110 intraperi-toneally, 218 subcutaneously, and 515 orally; rat 100 intraperitoneally, and 1050 orally. The general effects of benzydamine were similar in several species and consisted of muscle relaxation and sedation. At high doses ataxia and convulsions were detected. In dogs, benzydamine produced sedation, however, the occurrence of vomiting prevented the study of dose levels higher than 30 mg/kg.
In subacute and chronic toxicology studies, benzydamine produced a depression of growth rate and hepatomegaly in mice and rats when the drug was administered in large doses. No pathological changes .

20094~,2 in the functioning of the liver were detected.
Studies conducted to investigate lever hypertrophy revealed that this effect was due to an enzymatic induction common to numerous other therapeutic agents.
No ulcerogenic effects were observed upon treatment with benzydamine. In fact, benzydamine protected against experimentally-induced ulcerations.
At concentration greater than 0.25%, benzydamine caused a local irritating effect in the eyes of rabbits and in the dorsal subcutaneous tissue. The drug was well tolerated as a 5% aerosol.
Benzydamine has no significant effects on reproduction when administered at relatively high doses to mice, rats and rabbits in the diet, by gavage or subcutaneously.
Benzydamine has a long half-life and a low protein binding capacity. It is eliminated mainly through the urine. Benzydamine concentrates pre-ferentially in inflamed tissues where it can display its analgesic, anesthetic and anti-inflammatory properties.
The muscle relaxant activity of benzydamine is of particular interest since this has not been reported for other non-steroidal anti-inflammatory compounds such as aspirin and phenylbutazone. This property is of importance in situations where pain is associated with spasm of striated or smooth muscle fibres.
The antibacterial, antifungal and topical anesthetic activities of benzydamine represents a pharmacological advantage for topical usage. Con-C, . ~ , .: , ., ,-, .. .. .. .. . . ..

-8- 2 94 ~2 sidering that the most appropriate usage of benzyd-amine is of a topical nature, the local treatment is practically devoid of toxic risks.
Since 1965, benzydamine has been used in Europe, South America and Japan for the relief of pain and the reduction of inflammation. It has been investigated for numerous inflammatory conditions by systemic administration. As a cream formulation, benzydamine has been studied for the topical treat-ment of pain associated with injuries and other soft tissue inflammatory conditions. Benzydamine vaginal douche has demonstrated anti-inflammatory, anti-microbial and local anesthetic activity in various infective and non-infective vaginal diseases. The therapeutic activity has been investigated in various types of traumatic and non-traumatic inflammatory conditions of the mouth and throat where the principal aim of benzydamine treatment was to provide both analgesic and anti-inflammatory relief.
In particular benzydamine hydrochloride has been used as a 0.15% oral rinse typically comprising a solvent of water, glycerine and 10% ethanol; as a 3-5% ointment and as a 0.1% vaginal douche.
In accordance with the present invention it has been found that benzydamine and the pharma-ceutically acceptable, pharmacologically compatible acid addition salts thereof, may advantageously be employed to relieve pain associated with herpes zoster, more especially during the acute phase and in postherpetic sequela.

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Furthermore, and in accordance with this invention it has been found that benzydamine and the pharmaceutically acceptable, pharmacologically compatible acid addition salts thereof may advant-ageously be employed in the treatment of pain follow-ing laser vaporization of condylomata of the vulva.
More especially the benzydamine or a pharmaceutically acceptable, pharmacologically compatible salt thereof is employed for topical application in the form of a cream containing the benzydamine or salt in a cream base, in a concent-ration of 0.25 to 0.75%, and preferably about 0.5%.
The cream base is more especially an oil-in-water emulsion having a viscosity such that the cream is relatively immobile or non-flowing such that the cream rests immobile on a site to which it is applied.
In the case of emulsion it has generally been accepted that to achieve good transdermal penetration of an active ingredient, the active ingredient should be in the oil phase rather than in the aqueous phase of the emulsion. this is because the skin surface has a lipid nature, and it is thought the oil phase partitions into the lipid components of the skin thereby permitting good penetration of an active ingredient from an oil phase into the skin.
Benzydamine and its salts are water soluble and thus can be expected to dissolve in the aqueous phase of an oil-in-water emulsion rather than in the oil phase.

-10- 20094~

In view of its location in the aqueous phase one would not have expected to achieve good penetration of the skin by benzydamine or its salt, applied topically in an oil-in-water emulsion.
Furthermore, it was not to have been expected that benzydamine or its salts would relieve the intense pain associated with or following herpes zoster infections or that following laser surgery to the vulva.
The known pharmacological activity of benzydamine and its salts relies on the ability of the preparations containing benzydamine and its salts to penetrate inflammed skin tissue, and it was not expected that preparations of this type would pene-trate intact, non-inflammed skin.
Thus, for example, considering when a patient is affected by Herpes zoster, inflammatory changes occur in the sensory root ganglia and in the skin of the associated dermatome. In some instances, the inflammation may involve the dorsal and ventral roots. This inflammation causes a pain typical of that chronic pain which develops after injury to any level of the nervous sytem, in this case peripheral.
Since in Herpes zoster there is a partial, though limited damage to afferent nerve pathways, this particular pain can be classified as "deafferentation pain", from the "afferent" nerve pathways which are involved.
This type of pain is very different from the common pain which is an essential biologic signal of the extent of an injury.

-11- C~9~(~2 Pain can be "nociceptive", due to activa-tion of pain-sensitive nerve fibers, typical in cancer patients, or psychogenic, as opposed to "somatogenic". Nociceptive pain is typical of arthritis.
It appears that the benzydamine formula-tions of the invention penetrate the intact skin and the underlying dermatome and act on the inflammation of the nerve endings, thereby relieving the post-herpetic pain. In other words, the benzydamine formulations of the invention are surprisingly found to penetrate the intact skin as well as the inner mesodermic layer of the skin known as the dermis which contains numerous nerves and sensory receptors.
This mode of action is unrelated to the conventional use of benzydamine formulations on inflammed skin.
The emulsion of the invention is more especially an oil-in-water emulsion comprising a fatty phase and an aqueous phase. In particular, the emulsion may be in the form of a cream having a slightly acid pH, preferably a pH of 4.0 + 1 so that it is compatible with the tissue of the vagina.
The invention is further illustrated by reference to the accompanying drawings in which:
FIGURE 1 shows pain intensity clinical data for patients suffering postherpetic neuralgia treated with a cream of the invention;
FIGURE 2 shows pain relief clinical data for patients suffering postherpetic neuralgia treated with a cream of the invention;
'.

-12- 2 ~94 02 FIGURE 3 shows visual analogue clinical data scores for patients with postherpetic neuralgia treated with a cream of the invention;
FIGURE 4 shows visual impairment clinical data in patients with postherpetic neuralgia treated with a cream of the invention;
FIGURE 5 illustrates graphically mean total symptom score clinical data for patients suffering from laser evaporation treatments, treated with a cream of the invention;
FIGURE 6 illustrates graphically mean pain score clinical data for patients suffering from laser evaporation treatment, treated with a cream of the -invention; and FIGURE 7 illustrates the analgesic require-ment of a patient suffering pain following laser evaporation treatment of the vulva.

Clinical Trials with Benzydamine for Pain Associated with and Following Herpes Zoster Infections A Canadian pilot study was undertaken which demonstrates the efficacy of benzydamine and its salts, applied topically as a cream for the relief of deafferentation pain. Deafferentation pain results from injury to the peripheral or central nervous systems as a result of tumour compression or infilt-ration of a peripheral nerve or the spinal cord, or injury to the peripheral nerve as a result of surgery or chemotherapy. Eligible patients included those with dysesthesia or pain in defined dermatome(s) due to mastectomy, radical neck dissection, thoracotomy, -13- 20094 ~2 cisplatinum dysesthesia and herpes zoster infections.
Patients with progressive cancer requiring systemic analgesic were excluded from the study.
Patients applied a cream formulation containing 0.5~, by weight, of benzydamine hydro-chloride, 3 times a day for 2 weeks and were assessed before and after 1, 2 and 4 weeks. The patients completed a Self-Assessment Pain Questionnaire, indicating pain intensity, pain relief after use of -the cream, functional impairment, interference with sleep, concomitant pain medication. Also, patients were asked to score their spontaneous pain and pain on movement using a visual analogue scale, where the two extremes were no pain and severe pain.
This study was done at two centres; by Dr.
Danjoux of the Ottawa Civic Hospital and Dr. Yanofsky of Montreal. Of the 10 patients treated for post-herpetic neuralgia, one patient discontinued treat-ment after 3 days, 2 patients continued treatment after 2 weeks and 7 patients requested to continue treatment for 4 weeks. Reduction in pain intensity, increased pain relief and decreased functional impairment were observed after treatment with the cream.
The patients experienced moderate to severe pain before treatment with no or mild pain relief by oral analgesics. After use of the 0.5~ cream, pain intensity was, substantially reduced as shown !in Figure 1 and mild to good pain relief was noted as demonstrated in Figure 2.

~ .

~z The visual analogue scale results of Figure 3 indicate that the mean pain scores decreased from approximately 80~ before treatment to approximately 56~ for spontaneous pain and 52~ for pain on movement.
Prior to treatment with the cream of the invention, 2 patients reported complete functional impairment due to pain, 2 patients reported partial and 2 patients reported no functional impairment.
After 4 weeks of treatment, no patients reported complete impairment, as demonstrated in Figure 4.
This study demonstrates that the use of benzydamine or an acceptable salt in accordance with the invention is therapeutically beneficial for the temporary relief of pain associated with and follow-ing episodes of herpes zoster infections.

Clinical Trials with Benzydamine for Pain Following Laser Surgery to the Vulva A clinical trial was performed using 0.5~
cream of benzydamine hydrochloride for the treatment of pain associated with laser surgery to the vulva.
Doctors at the Ottawa General Hospital assessed the effect of the cream on the relief of pain and tissue healing following laser surgery for vulvar lesions. Patients undergoing laser surgery for neoplasia and carcinoma in situ were entered into the study. Patients with invasive carcinoma of the vulva, who had concurrent laser evaporisation treat-ment to the cervix or with known sensitivity to benzydamine were excluded.

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The cream was applied as needed starting immediately following laser treatment and continuing for 1 to 3 weeks. Analgesic requirements, skin healing and reactions and local pain in the area of treatment were assessed weekly. Treatment was to be continued until re-epithelialisation had occurred as assessed by the physician or pain had been resolved as indicated by the patient.
The symptoms of pain, pruritus, burning, heat, discharge, tenderness and edema were scored as follows: ~=absent, l=moderate and 2=severe. The total symptom score at each, defined as the sum of the scores for all the symptoms at each visit, increased with the area of the vulva that was treated by laser evaporisation. The mean total score for all the patients decreased by approximately one third after 2 weeks compared to day 1, as shown in Figure 5.
The mean pain score increased slightly after one week and then decreased to approximately 40~ after 2 weeks of treatment compared to the score on day 1 as demonstrated in Figure 6. During this period, pruritus increased steadily indicating that re-epithelialisation was occurring. The overall therapeutic score was defined as the total score for all three visits. Thirteen of the patients demon-strated good to excellent therapeutic effect of the cream; one patient benefited slightly;- one patient discontinued treatment after one week due to a burning sensation and one patient did not return for the last visit.

When analgesic requirement was examined, an inverse relationship between the number of Tylenol #3 tablets (Tylenol is a Trade Mark for an acetaminophen medication for pair relief) taken and the number of lOOg tubes of a cream containing 0.5~ benzydamine hydrochloride in accordance with the invention.
The Canadian study shows that topical treatment with a 0.5~ cream containing benzydamine hydrochloride in a concentration of 0.5~, by weight, results in the relief of pain following laser surgery of vulvar lesion without detrimental effects on healing.

Cream Base A suitable cream base is an oil-in-water emulsion which provides an aqueous cream.
Such a cream base is essentially immobile or non-flowable, by which is to be understood that on application of the cream to a site of the body, the cream remains on the site and does not flow away from the site under the influence of gravity. The con-sistency of the cream is such that leakage from tubes or other containers is substantially avoided.
The cream base oil-in-water emulsion should be suitable for topical application and meet the usual requirements for such an emulsion. Thus it should not be unduly irritating to the skin or mucosa and should havei adequate stability. Suitably it should be non-greasy, non-staining and washable.
In particular, the cream base may comprise an aqueous phase and a dispersed oil phase in the form of a fat or oil or both.

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The oil phase may, in particular, comprise one or more fatty acid esters of aliphatic polyols.
For example, palmityl and stearyl esters of ethylene glycol and polyethylene glycols as well as mixed fatty acid esters of such glycols. The esters may comprise basic esters with some free hydroxyl groups as well as fully esterified neutral esters and may include both saturated and unsaturated esters, as well as straight chain and branched esters depending on the choice of fatty acid. Suitable fatty acid esters also include etherified esters, namely esters in which some of the hydroxyl group have been alkoxy-lated rather than esterified, for example, ethoxy-lated esters.
In the oil or fatty phase, the fatty acid esters provide a non-ionic absorption base functioning as a primary emulsifier and as a thickening agent. The esterified esters, for example ethoxylated saturated glycerides are co-emulsifiers contributing to the enhancement of the appearance and stability of the emulsion. Saturated esters, for example saturated neutral triglycerides, provide a desired level of flowability.
The aqueous phase of the emulsion contains the active ingredient, for example, benzydamine i hydrochloride, and may suitably contain an anti-microbial preservative, for example, benzoic acid which acts as an antimicrobial agent at an acidic pH, and a buffer system, for example, a citric acid and sodium citrate.

The manner of formulating the emulsion follows known techniques in emulsion technology.
Emulsification may suitably be carried out by mixing an aqueous solution of the benzydamine or its salt with the oil phase under conditions of vigorous agitation and suitably at a temperature of 40 to 80C., preferably 50 to 70C.
The emulsion may include an emulsifier as is well known to provide the best balance of ease of emulsification and emulsion stability.
The acceptable salts of benzydamine are in particular the acid addition salts with non-toxic inorganic or organic acids. These salts should be pharmacologically compatible by which is meant salts with non-toxic inorganic or organic acids which have no adverse effects to the extent that such salts would be unsuitable for administration to living bodies. The salts should also be pharmaceutically acceptable by which is intended that the salts have the necessary physical characteristics, for example, stability, to render them suitable for formulations in pharmaceutical formulations, especially the oil-in-water emulsions with which the invention is particularly concerned. Suitable acids include hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulphuric acid, formic acid, acetic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, adipic acid, benzoic acid, o-acetoxybenzoic acid, cinnamic acid, naphthoic acid, mandelic acid, citric acid, malic acid, -19- 2oo9~ 2 tartaric acid, aspartic, glutamin acid, methane-sulphonic acid, p-toluene sulphonic acid or cyclo-hexylsulphamic acid.

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~9402 EXAMPLE
A cream was formulated having the following composition:
Benzydamine HCl 0.5 g Ethylene glycol and polyethylene glycols palmito-stearate 18.0 g Ethoxylated saturated glycerides 3.0 g Saturated neutral triglycerides 3.0 g Benzoic acid 0.2 g Citric acid, monohydrate0.2 g Sodium citrate, dihydrate 0.4 g Purified water 74.7 g The composition was formulated into tubes in 100 .
quantities. The cream was employed in clinical trials for the relief of pain associated with both herpes zoster infections and post-laser surgery to the vulva, the results of these trials having been ~ -described above by reference to Figures 1 to 7.
The chemical name of benzydamine hydro-chloride is l-benzyl 3,3-(dimethylamino)propoxy H-indazole hydrochloride, and the structural formula -is:

Cllz-cll2'R~n;

Claims (34)

1. Use of benzydamine or a pharmaceutically acceptable, pharmacologically compatible acid addition salt thereof to relieve pain associated with herpes zoster.

2. Use of benzydamine or a pharmaceutically acceptable, pharmacologically compatible acid addition salt thereof to relieve pain associated with herpes zoster during the acute phase and in postherpetic sequela.

3. Use according to claim 1 or 2, wherein said benzydamine or salt thereof is in the form of a cream for topical application.

4. Use according to claim 3, wherein said benzydamine or salt thereof comprises 0.25 to 0.75%, by weight, of said cream.

5. Use according to claim 3, wherein said benzydamine or salt thereof comprises about 0.5%, by weight, of said cream.

6. Use of benzydamine hydrochloride to relieve pain associated with herpes zoster.

7. Use of benzydamine hydrochloride to relieve pain associated with herpes zoster during the acute phase and in postherpetic sequela.

8. Use according to claim 6 or 7, wherein said benzydamine hydrochloride is in the form of a cream for topical application.

9. Use according to claim 8, wherein said benzydamine hydrochloride comprises 0.25 to 0.75%, by weight, of said cream.

10. Use according to claim 8, wherein said benzydamine hydrochloride comprises about 0.5%, by weight, of said cream.

11. Use of benzydamine or a pharmaceutically acceptable, pharmacologically compatible acid addition salt thereof, in the manufacture of a medicament for the treatment of pain associated with herpes zoster.

12. Use of benzydamine hydrochloride in the manufacture of a medicament for the treatment of pain associated with herpes zoster.

13. A pharmaceutical cream formulation for the treatment of neuralgia associated with herpes zoster infections comprising as active ingredient an accept-able amount for the treatment of neuralgia associated with herpes zoster infections of benzydamine or a pharmaceutically acceptable, pharmacologically compatible acid addition salt thereof in a pharma-ceutically acceptable cream.

14. A formulation according to claim 13, in which said active ingredient is benzydamine hydro-chloride.

15. A formulation according to claim 13 or 14, wherein said active ingredient is present in a concentration of about 0.25 to 0.75%, by weight.

16. A formulation according to claim 13 or 14, wherein said active ingredient is present in a concentration of about 0.5%, by weight.

17. A formulation according to claim 13 or 14, wherein said cream is a substantially immobile aqueous cream.

18. A formulation according to claim 15, wherein said cream is a substantially immobile aqueous cream.

19. A formulation according to claim 16, wherein said cream is a substantially immobile aqueous cream.

20. Use of benzydamine or a pharmaceutically acceptable, pharmacologically compatible acid addition salt thereof in the treatment of pain following laser vaporization of condylomata of the vulva.

21. Use of benzydamine hydrochloride in the treatment of pain following laser vaporization of condylomata of the vulva.

22. Use according to claim 20, wherein said benzydamine or salt is in the form of a cream for topical application.

23. Use according to claim 20, wherein said benzydamine hydrochloride is in the form of a cream for topical application.

24. A pharmaceutical cream formulation for the treatment of pain following laser vaporization of condylomata of the vulva comprising as active ingredient an acceptable pain relieving amount for relief of pain following laser vaporization of condylomata of the vulva, of benzydamine or a pharma-ceutically acceptable, pharmacologically compatible acid addition salt thereof in a pharmaceutically acceptable cream.

25. A formulation according to claim 24, in which said active ingredient is benzydamine hydrochloride.

26. A formulation according to claim 24 or 25, wherein said active ingredient is present in a concentration of about 0.25 to 0.75%, by weight.

27. A formulation according to claim 24 and 25, wherein said active ingredient is present in a concentration of about 0.5%, by weight.

28. A formulation according to claim 24 or 25, wherein said cream is a substantially immobile aqueous cream.

29. A formulation according to claim 26, wherein said cream is a substantially immobile aqueous cream.

30. A formulation according to claim 27, wherein said cream is a substantially immobile aqueous cream.

31. Use of benzydamine or a pharmaceutically acceptable, pharmacologically compatible acid addition salt thereof in the manufacture of a medica-ment for the treatment of pain following laser vaporization of condylomata of the vulva.

32. Use of benzydamine hydrochloride in the manufacture of a medicament for the treatment of pain following laser vaporization of condylomata of the vulva.

33. A method of relieving pain associated with herpes zoster infections comprising applying to a site of pain resulting from herpes zoster infection, an aqueous cream containing an effective pain relieving amount of benzydamine or a pharmaceutically acceptable, pharmacologically compatible acid addition salt thereof.

34. A method of relieving pain following laser vaporization of condylomato of the vulva, comprising applying to a site of pain resulting from laser vaporization of condylomata of the vulva an aqueous cream containing an effective pain relieving amount of benzydamine for a pharmaceutically acceptable, pharmacologically compatible acid addition salt thereof.