Scand J Urol Nephrol 12: 129-131, 1978
THE USE OF DIMETHYL-SULFOXIDE (DMSO) IN THE TREATMENT O F INTERSTITIAL CYSTITIS A. Ek, A. Engberg, L. Friidin and G. Jiinsson
Scand J Urol Nephrol Downloaded from informahealthcare.com by Flinders University of South Australia on 01/15/15 For personal use only.
From the Depurtment of Urology, University Hospitul. Uppsula und the Depurtmrnt of Urology. University Hospitul, Lund, Snwien
(Submitted for publication August 24. 1977)
Ahstrrrcr. Dimethyl-sulfoxide (DMSO) was uxed in 17 pa-
tients with interstitial cystitis. The diagnosis was made on the basis of clinical and laboratory findings and the characteristic picture with Hunner ulcera. The majority of the patients had responded poorly to other forms of conservative treatment. Subjective symptoms were controlled in 2/3 of the cases but repeated treatment was needed and S patients did not respond to the therapy. The DMSO treatment is an alternative worth to try and has in some cases a dramatic and lasting effect.
More than 60 years have passed since G . L. Hunner (1914) foreseeingly described interstitial cystitis (IC) as the “elusive ulcer”. Despite many efforts the etiology of IC is essentially unknown and the 37 conservative and 7 surgical methods of treatment. listed by Bowers & Lattimer (1957), are merely an expression of the enigmatous etiology of the disease. The possibility of an immunologic mechanism is strongly suspected and circulating antibodies against human bladder muscle have been reported in some patients with interstitial cystitis (Silk, 1970). Furthermore Oravisto, Alfthan & Jokinen (1970) have demonstrated antinuclear antibodies in 85% of the cases. The final proof is, however, still lacking and immunosuppressive treatment with the exception of corticosteroids is so far disappointing. In 1972 Stewart, Branson, Hewitt, Kiser & Straffon reported that repeated intravesical instillation of a 50 % dimethylsulfoxide (DMSO) solution significantly relieved subjective symptoms in 15 of 21 women with interstitial cystitis. Further experience was added 1976 (Stewart & Shirley, 1976). DMSO was synthetized more than 57 years ago and its exceptional solvent properties rapidly found industrial application. The first reports on DMSO as a pharmacological agent appeared in 1964 (Jacob, 9- 7X?9?0
Bischel & Herschler. 1964) and since then a wide range of effects have been reported. The currently most important include membrane penetration, analgesia, anti-inflammation, bacteriostasis, vasodilatation and disolution of pathologic deposition of collagen (Brown, Wood & Jacob, 1969). Interstitial cystitis is not common but extremely troublesome both for the patient and the urologist. A prominent feature of the disease is a n intense suprapubic pain and urgency relieved only temporarily by voiding. Topically applied DMSO has been used to treat various forms of pain (Rosenbaum, Rosenbaum & Jacob. 1965) and this fact together with the results of Stewart and coworkers justified a limited trial to use DMSO as a symptomatic treatment in interstitial cystitis.
MATERIAL AND METHODS The material consists of I6 women and 1 man between 30 and 80 years (mean 64 years) and a history varying from 2 to 15 years (mean 7.5 years). The diagnosis was made on the basis of clinical and laboratory findings and characteristic cystoscopic picture with Hunner ulcera and/or bleeding when the bladder was distended. Cytology on bladder washing was always done to exclude malignant transformation of the urothelium. The majority of the patients had responded poorly to other forms of conservative treatment. All were classified as stage I 1 of the disease (Oravisto et al.) and the bladder capacity varied between 100 and 300 ml (mean 189 ml). The instillation was mostly carried out at the out-patient department using a small calibre ureteral catheter. Fifty ml of a sterile filtered 50% DMSO solution (in water) was instilled into the empty bladder where it was kept for IS min. The bladder was then emptied by voiding. The treatment was repeated every other week and an average of 4 treatments was given. A temporary rather intense sulfide breath was always noted but otherwise no serious adverse effect was seen.
130
A . EX ct
ti/.
Scand J Urol Nephrol Downloaded from informahealthcare.com by Flinders University of South Australia on 01/15/15 For personal use only.
RESULTS Our total experience is now more than four years ranging from 1 . 5 4 years. Five patients did not respond at all and cystolysis o r cystoplasty was performed (Worth & Turner Warwick, 1973). The other 12 reported an almost dramatic improvement already after the second instillation. Pain disappeared and micturition frequency was drastically reduced. 4/12 have so far received only one series of DMSO instillations and remain improved. 3/12 achieved the same significant relief but symptoms reappeared 4-5 months later and another 4 instillations was given. These patients are still improved but seem to need further instillations. 3/12 were improved 4-7 months after the first treatment, but were later operated with cystolysis. In 2 patients the improvement lasted 2-4 months after the first series of instillations. One of these patients was only modestly improved after another 4 instillations and the other one complained of eye symptoms-which were due to presbyopia. The ophtalmologist was asked if he saw any lens precipitates but he found only small ones which were considered normal for the age. DMSO was, however, interrupted and those two patients were operated with cystolysis. All patients have been followed closely and we have not seen any serious adverse effects which can be attributed to the DMSO-treatment. The cystoscopic picture did not change despite a definite subjective improvement. Bladder capacity was essentially unchanged with exception of 2 patients where it increased moderately.
DISCUSSION DMSO is extremely water soluble and mixes well with water in all proportions. It penetrates extremely rapidly through biological tissues and enhances the penetration of other drugs. This apparently innocuous permeation of DMSO through a protein barrier is probably the result of reversible configurational changes of protein molecules due to temporary water substitution by DMSO (Rammler & Zaffaroni, 1967). Although the main part of administered DMSO is excreted unchanged by the kidneys it may be metabolized and the end product is sulfate (Gerhards & Gibian, 1967). The major toxicologic effect in the experimental Scond J Urol Nephrol I2
animal is protein precipitates in the lens of the rabbit eye (van Heyningen & Harding. 1972). Other experimental animals appears to be more resistant and large doses of DMSO, I g/kg body weight, given to human volunteers daily for 90 days have failed to reveal any lens abnormality (Brown et al.). The mechanism of action of DMSO remains obscure. The local findings in the bladder are unchanged but the patients are free of pain. Local application of DMSO induces analgesia. From i l l vitro studies it is also known that DMSO significantly lowers the conduction velocity of isolated nerves probably due to a change in the protein configuration of the nerve sheath. The nerve block is reversible when DMSO concentrations less than 80% are used (Mitchell, 1967). A local analgesia with long duration may be one explanation to the beneficial effect of DMSO on interstitial cystitis. We are well aware of that we are treating an elusive disease with a drug whose pharmacology partly is an enigma. Our results are not as good as those reported by Stewart and co-workers. Subjective symptoms are controlled in 2/3 of the cases but sooner o r later pain and urgency return and treatment has t o be repeated. In our opinion DMSO instillations should be considered preferably in older patients and when other forms of conservative treatment are failing. Careful supervision is necessary and eye catharact is an absolute contraindication. Furthermore, it is known that DMSO may potentiate the effect of ethyl alcohol (Mallach, 1967) and the patients should avoid alcoholic beaverages the first two days after an instillation. REFERENCES Bowers, J . E. & Lattimer. J. K . 1957. Interstitial cystitis. Collective review. I n / Ahstr Surg 105, 313. Brown, J . H., Wood, D. C. &Jacob, S. W. 1972. Current status of dimethyl sulfoxide (DMSO). A double blind evaluation of its therapeutic value in acute strains, sprains, bursitis and tendonitis. Bull Soc I n / Chir 31 (6), 561. Gerhards, E. & Gibian, H. 1967. The metabolism of dimethyl sulfoxide and its metabolic effects in man and animals. Ann N Y Acod Sci 141, 65. van Heyningen, R. & Harding, J . J. 1972. Some changes in the lens of the dimethylsulphoxide-fed rabbit. E.rp Eye Res 14, 91. Jacob, S. W., Bischel, M. & Herschler. R. J. 1964. Dimethyl sulfoxide effects on the permeability of biologic membranes (preliminary report). Curr Ther Re.$ 6 (3). 193. Mallach, H. J. 1967. Interaction of DMSO and alcohol. Ann N Y Acud Sci 141. 457.
Scand J Urol Nephrol Downloaded from informahealthcare.com by Flinders University of South Australia on 01/15/15 For personal use only.
Mitchell. S . W.. J r . 1967. The effects ofdimethyl sulfoxide on nerve conduction. Ailti N Y Ac.titl S 1 . i 141. 242. Oravisto, K . J . . Alfthan. 0 . S. & Jokinen, E. J . 1970. Interstitial cystitis. Clinical and immunological findings. Sctitid J Urol N e p l i r o l 4 , 37. Rammler. D. H . & Zaffaroni. A. 1967. Biological implications of DMSO based on a review of its chemical properties. Ailti N Y Acrid Sc,i 141. 13. Rosenbaum. W. M.. Rosenbaum, E. E. & Jacob. S . W . 1965. The use of dimethylsulfoxide (DMSO) for the treatment of intractable pain in surgical patients. Sitr,gory 58. 2.58.
Silk, M. R. 1970. Bladder antibodies in interstitial cystitis. .I Urol 103. 307. Stewart. B. H.. Branson. A. C., Hewitt. C. B.. Kiser. W. S. & Straffon, R. A . 1972. The treatment of patients with interstitial cystitis. with special reference to intravesical DMSO. J 1Jrol 107. 377. Stewart. B. H . & Shirley. S.W. 1976. Further experience with intravesical Dimethyl Sulfoxide in the treatment of interstitial cystitis. J Urol 116. 36. Worth, P. H . L. & Turner Warwick. R. 1973. The treatment of interstitial cystitis by cystolysis with observations on cystoplacty. R r . I U r o l 4 5 . 6.5.
THE USE OF DIMETHYL-SULFOXIDE (DMSO) IN THE TREATMENT O F INTERSTITIAL CYSTITIS A. Ek, A. Engberg, L. Friidin and G. Jiinsson
Scand J Urol Nephrol Downloaded from informahealthcare.com by Flinders University of South Australia on 01/15/15 For personal use only.
From the Depurtment of Urology, University Hospitul. Uppsula und the Depurtmrnt of Urology. University Hospitul, Lund, Snwien
(Submitted for publication August 24. 1977)
Ahstrrrcr. Dimethyl-sulfoxide (DMSO) was uxed in 17 pa-
tients with interstitial cystitis. The diagnosis was made on the basis of clinical and laboratory findings and the characteristic picture with Hunner ulcera. The majority of the patients had responded poorly to other forms of conservative treatment. Subjective symptoms were controlled in 2/3 of the cases but repeated treatment was needed and S patients did not respond to the therapy. The DMSO treatment is an alternative worth to try and has in some cases a dramatic and lasting effect.
More than 60 years have passed since G . L. Hunner (1914) foreseeingly described interstitial cystitis (IC) as the “elusive ulcer”. Despite many efforts the etiology of IC is essentially unknown and the 37 conservative and 7 surgical methods of treatment. listed by Bowers & Lattimer (1957), are merely an expression of the enigmatous etiology of the disease. The possibility of an immunologic mechanism is strongly suspected and circulating antibodies against human bladder muscle have been reported in some patients with interstitial cystitis (Silk, 1970). Furthermore Oravisto, Alfthan & Jokinen (1970) have demonstrated antinuclear antibodies in 85% of the cases. The final proof is, however, still lacking and immunosuppressive treatment with the exception of corticosteroids is so far disappointing. In 1972 Stewart, Branson, Hewitt, Kiser & Straffon reported that repeated intravesical instillation of a 50 % dimethylsulfoxide (DMSO) solution significantly relieved subjective symptoms in 15 of 21 women with interstitial cystitis. Further experience was added 1976 (Stewart & Shirley, 1976). DMSO was synthetized more than 57 years ago and its exceptional solvent properties rapidly found industrial application. The first reports on DMSO as a pharmacological agent appeared in 1964 (Jacob, 9- 7X?9?0
Bischel & Herschler. 1964) and since then a wide range of effects have been reported. The currently most important include membrane penetration, analgesia, anti-inflammation, bacteriostasis, vasodilatation and disolution of pathologic deposition of collagen (Brown, Wood & Jacob, 1969). Interstitial cystitis is not common but extremely troublesome both for the patient and the urologist. A prominent feature of the disease is a n intense suprapubic pain and urgency relieved only temporarily by voiding. Topically applied DMSO has been used to treat various forms of pain (Rosenbaum, Rosenbaum & Jacob. 1965) and this fact together with the results of Stewart and coworkers justified a limited trial to use DMSO as a symptomatic treatment in interstitial cystitis.
MATERIAL AND METHODS The material consists of I6 women and 1 man between 30 and 80 years (mean 64 years) and a history varying from 2 to 15 years (mean 7.5 years). The diagnosis was made on the basis of clinical and laboratory findings and characteristic cystoscopic picture with Hunner ulcera and/or bleeding when the bladder was distended. Cytology on bladder washing was always done to exclude malignant transformation of the urothelium. The majority of the patients had responded poorly to other forms of conservative treatment. All were classified as stage I 1 of the disease (Oravisto et al.) and the bladder capacity varied between 100 and 300 ml (mean 189 ml). The instillation was mostly carried out at the out-patient department using a small calibre ureteral catheter. Fifty ml of a sterile filtered 50% DMSO solution (in water) was instilled into the empty bladder where it was kept for IS min. The bladder was then emptied by voiding. The treatment was repeated every other week and an average of 4 treatments was given. A temporary rather intense sulfide breath was always noted but otherwise no serious adverse effect was seen.
130
A . EX ct
ti/.
Scand J Urol Nephrol Downloaded from informahealthcare.com by Flinders University of South Australia on 01/15/15 For personal use only.
RESULTS Our total experience is now more than four years ranging from 1 . 5 4 years. Five patients did not respond at all and cystolysis o r cystoplasty was performed (Worth & Turner Warwick, 1973). The other 12 reported an almost dramatic improvement already after the second instillation. Pain disappeared and micturition frequency was drastically reduced. 4/12 have so far received only one series of DMSO instillations and remain improved. 3/12 achieved the same significant relief but symptoms reappeared 4-5 months later and another 4 instillations was given. These patients are still improved but seem to need further instillations. 3/12 were improved 4-7 months after the first treatment, but were later operated with cystolysis. In 2 patients the improvement lasted 2-4 months after the first series of instillations. One of these patients was only modestly improved after another 4 instillations and the other one complained of eye symptoms-which were due to presbyopia. The ophtalmologist was asked if he saw any lens precipitates but he found only small ones which were considered normal for the age. DMSO was, however, interrupted and those two patients were operated with cystolysis. All patients have been followed closely and we have not seen any serious adverse effects which can be attributed to the DMSO-treatment. The cystoscopic picture did not change despite a definite subjective improvement. Bladder capacity was essentially unchanged with exception of 2 patients where it increased moderately.
DISCUSSION DMSO is extremely water soluble and mixes well with water in all proportions. It penetrates extremely rapidly through biological tissues and enhances the penetration of other drugs. This apparently innocuous permeation of DMSO through a protein barrier is probably the result of reversible configurational changes of protein molecules due to temporary water substitution by DMSO (Rammler & Zaffaroni, 1967). Although the main part of administered DMSO is excreted unchanged by the kidneys it may be metabolized and the end product is sulfate (Gerhards & Gibian, 1967). The major toxicologic effect in the experimental Scond J Urol Nephrol I2
animal is protein precipitates in the lens of the rabbit eye (van Heyningen & Harding. 1972). Other experimental animals appears to be more resistant and large doses of DMSO, I g/kg body weight, given to human volunteers daily for 90 days have failed to reveal any lens abnormality (Brown et al.). The mechanism of action of DMSO remains obscure. The local findings in the bladder are unchanged but the patients are free of pain. Local application of DMSO induces analgesia. From i l l vitro studies it is also known that DMSO significantly lowers the conduction velocity of isolated nerves probably due to a change in the protein configuration of the nerve sheath. The nerve block is reversible when DMSO concentrations less than 80% are used (Mitchell, 1967). A local analgesia with long duration may be one explanation to the beneficial effect of DMSO on interstitial cystitis. We are well aware of that we are treating an elusive disease with a drug whose pharmacology partly is an enigma. Our results are not as good as those reported by Stewart and co-workers. Subjective symptoms are controlled in 2/3 of the cases but sooner o r later pain and urgency return and treatment has t o be repeated. In our opinion DMSO instillations should be considered preferably in older patients and when other forms of conservative treatment are failing. Careful supervision is necessary and eye catharact is an absolute contraindication. Furthermore, it is known that DMSO may potentiate the effect of ethyl alcohol (Mallach, 1967) and the patients should avoid alcoholic beaverages the first two days after an instillation. REFERENCES Bowers, J . E. & Lattimer. J. K . 1957. Interstitial cystitis. Collective review. I n / Ahstr Surg 105, 313. Brown, J . H., Wood, D. C. &Jacob, S. W. 1972. Current status of dimethyl sulfoxide (DMSO). A double blind evaluation of its therapeutic value in acute strains, sprains, bursitis and tendonitis. Bull Soc I n / Chir 31 (6), 561. Gerhards, E. & Gibian, H. 1967. The metabolism of dimethyl sulfoxide and its metabolic effects in man and animals. Ann N Y Acod Sci 141, 65. van Heyningen, R. & Harding, J . J. 1972. Some changes in the lens of the dimethylsulphoxide-fed rabbit. E.rp Eye Res 14, 91. Jacob, S. W., Bischel, M. & Herschler. R. J. 1964. Dimethyl sulfoxide effects on the permeability of biologic membranes (preliminary report). Curr Ther Re.$ 6 (3). 193. Mallach, H. J. 1967. Interaction of DMSO and alcohol. Ann N Y Acud Sci 141. 457.
Scand J Urol Nephrol Downloaded from informahealthcare.com by Flinders University of South Australia on 01/15/15 For personal use only.
Mitchell. S . W.. J r . 1967. The effects ofdimethyl sulfoxide on nerve conduction. Ailti N Y Ac.titl S 1 . i 141. 242. Oravisto, K . J . . Alfthan. 0 . S. & Jokinen, E. J . 1970. Interstitial cystitis. Clinical and immunological findings. Sctitid J Urol N e p l i r o l 4 , 37. Rammler. D. H . & Zaffaroni. A. 1967. Biological implications of DMSO based on a review of its chemical properties. Ailti N Y Acrid Sc,i 141. 13. Rosenbaum. W. M.. Rosenbaum, E. E. & Jacob. S . W . 1965. The use of dimethylsulfoxide (DMSO) for the treatment of intractable pain in surgical patients. Sitr,gory 58. 2.58.
Silk, M. R. 1970. Bladder antibodies in interstitial cystitis. .I Urol 103. 307. Stewart. B. H.. Branson. A. C., Hewitt. C. B.. Kiser. W. S. & Straffon, R. A . 1972. The treatment of patients with interstitial cystitis. with special reference to intravesical DMSO. J 1Jrol 107. 377. Stewart. B. H . & Shirley. S.W. 1976. Further experience with intravesical Dimethyl Sulfoxide in the treatment of interstitial cystitis. J Urol 116. 36. Worth, P. H . L. & Turner Warwick. R. 1973. The treatment of interstitial cystitis by cystolysis with observations on cystoplacty. R r . I U r o l 4 5 . 6.5.
