1239
Intravesical capsaicin for neurogenic bladder dysfunction SIR,-In a preliminary study of intravesical capsaicin for bladder detrusor hyperreflexia, six instillations have been done in five patients with multiple sclerosis (MS), followed by improvement in bladder control in four of them. In laboratory animals with an intact neuraxis, micturition is dependent upon a spinobulbospinal reflex activated by bladder A 8 afferents, but after spinal transection at the lower thoracic level, a new spinal reflex emerges, which in cats is mediated by C-fibre afferents. This reflex can be blocked by capsaicin in doses of 20-30 mg/kg, administered subcutaneously, that do not affect micturition reflexes in intact cats.’ Capsaicin is the pungent ingredient of red peppers. It is a specific neurotoxin for certain types of sensory nerves, notably those with unmyelinated (C-fibre) axons. It releases neuropeptides from sensitive neurons and produces a prolonged functional block. The existence of capsaicin-sensitive receptors in the bladders of laboratory animals is well established2 but their presence and functional significance in man is less certain. Following a report of the use of intravesical capsaicin to treat painful bladder disorders3 we investigated the possibility of using capsaicin to modify the reflex arc causing detrusor hyperreflexia in patients with MS and spinal cord disease. All patients gave informed consent to this experimental treatment. Case 1 (F, 57; ambulant with assistance but severe urinary urgency had necessitated an indwelling catheter since 1987). In pilot studies to establish the dose, 0’1, 1, 10, and then 100 umol/1 capsaicin (in 100 ml saline) was instilled. No long-lasting benefit was obtained and the catheter had to be reinserted within hours. In May, 1991, 100 ml of a 1 mmol/1 (0-3 g/1) solution of capsaicin dissolved in 30% alcohol in saline was given as an intravesical instillation for 30 min. For the ensuing 18 h the patient reported unusually frequent spontaneous bladder contractions but by 48 h these had subsided and she was able to manage without an indwelling catheter. This improved bladder control lasted for 5 months. She could go 2-3 h without passing urine, was never incontinent, and needed to get up only once at night. 5 months later her bladder control deteriorated so that rising to a standing position tended to induce hyperreflexic contractions although she was not incontinent. At the patient’s request the capsaicin instillation was repeated last November. Since then, the interval between her voids has increased to 3-4 h, she does not need to get up at night, and no longer feels that changes in posture induce hyperreflexic contractions. Throughout this period she has continued to take the same dose of oxybutynin. Her bladder capacity has increased from less than 150 ml before treatment with 1 mmol/l capsaicin to 750 ml. Case 2 (M, 56; ambulant with assistance but needing to wear a urinary appliance because of urge incontinence). He became continent and able to go for 4-5 h between voids after an instillation of 100 ml 1 mmol/1 capsaicin in alcohol and saline in September, 1991. Although improvement in bladder control coincided with a change in medication from terodiline to oxybutynin, when terodiline was withdrawn, 6 months later--and despite continuing the same dose of oxybutynin-bladder control deteriorated and he has now asked for the capsaicin instillation to be repeated. Case 3 (M, 45; similar to case 2 in terms of mobility and bladder control). Following 100 ml 2 mmol/1 capsaicin in alcohol and saline for 30 min in February, 1992, urge incontinence has been eliminated; he can spend the night without passing urine and intervals between voids during the day are 2-5 h. 2 months after intravesical capsaicin, his functional bladder capacity had increased from 160 to 550 ml. These three patients perform intermittent self-catheterisation three or four times a day. They had learned the technique some years earlier but found it to be of diminishing value as their bladders became more severely hyperreflexic. All three have reported an increase in post-micturition residual volumes after capsaicin instillation. The other two patients (cases 4 and 5) were wheelchair bound; they needed long-term indwelling catheters but were persistently troubled by "bypassing". Both were given the same instillation of 100 ml 1 mmol/1 capsaicin in alcohol and saline for 30 min. One patient continues to leak around her catheter daily
although it may be relevant that she had had a bladder-neck incision in the past. The other patient reports a pronounced improvement and, whereas formerly she daily leaked around the catheter, for 3 months after intravesical capsaicin this happened only infrequently and to a minor degree, so that she felt sufficiently confident to social activities. In all but one case, instillations were done in the operating-theatre with full cardiovascular monitoring and an anaesthetist on hand for analgesia or sedation if required. A balloon catheter was used to minimise the risk of leakage into the urethra and the capsaicin was left in the bladder for 30 min. Although patients reported considerable discomfort in the form of a suprapubic burning pain, worst within the first 10 min, this then subsided and at no stage did any ever ask for medication. No significant alteration in cardiovascular state was detected during or after the procedure. Blood alcohol concentrations taken over the period of the instillation and up to 4 h later never exceeded 3 mmol/1, indicating little diffusion of alcohol through the bladder wall. Because the procedure seemed to cause so little ill-effect the most recent case was treated in the laboratory rather than the operating-theatre and went home 2 h later. These preliminary results of intravesical capsaicin as a treatment for intractable detrusor hyperreflexia seem promising. Hyperreflexia is the disorder of bladder function largely responsible for incontinence of neurological origin, and a non-surgical, effective, topical treatment could have wide-ranging implications. Its use might also shed further light on the pathophysiology of detrusor instability, a condition suspected of being neurogenic.4 The numbers in this study are small because of the non-medicine status of capsaicin. An exemption from a licence certificate for the use of intravesical capsaicin to treat detrusor hyperreflexia has now been given so that a larger scale study may be undertaken. resume
National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK
CLARE J. FOWLER DOREEN JEWKES W. IAN MCDONALD
Department of Physiology, University College London
BRUCE LYNN
Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
W. C.
DE
GROAT
1. de Groat WC, Kawatani T, Hisamitsu T, et al. Mechanisms underlying the recovery of urinary bladder function following spinal cord injury. J Autonomic Nervous System 1990; 30: S71-78. 2. Maggi CA, Santicioli P, Borsini F, Giuliani S, Meli A. The role of capsaicin-sensitive innervation of the rat urinary bladder in the activation of the micturition reflex. Naunyn-Schmiedeberg’s Arch Pharmacol 1986; 322: 276-83. 3. Maggi CA, Barbanti G, Santicioli P, et al. Cysometric evidence that capsaicin-sensitive nerves modulate the afferent branch of micturition reflex in humans. J Urol 1989; 142: 150-54. 4. Editorial. Neurobiology of incontinence. Lancet 1989; ii: 1078-79.
All-trans retinoic acid and side-effects SIR,-All-trans retinoic acid (ATRA) in acute promyelocytic (APL) not only induces complete remission, but also
leukaemia
improves the early death rate through reduction of coagulopathy and bleeding complications of APL. 1-3 Dr Akiyama and colleagues (Feb 1, p 308) report hypercalcaemia with ATRA, and other side-effects have also been recorded, including rashes.’ Severe dermatological reactions can lead to withdrawal of the drug in use. With respect to ATRA, its withdrawal would indicate the need to use more conventional chemotherapeutic regimens that often exacerbate the coagulopathy of APL. We have been faced with this consideration and report our findings in a patient with APL. A 70-year-old woman presented with pancytopenia. Bonemarrow aspirate showed 75% blasts and abnormal promyelocytes, many of which contained Auer rods. Acute promyelocytic leukaemia was diagnosed. Coagulation abnormalities were present, with prothrombin time 19 s (normal 11-13), thrombin time 17 s (11-13), fibrinogen 1 gll (1-6-3-9), and fibrinogen degradation products 126 jig/ml (
Intravesical capsaicin for neurogenic bladder dysfunction SIR,-In a preliminary study of intravesical capsaicin for bladder detrusor hyperreflexia, six instillations have been done in five patients with multiple sclerosis (MS), followed by improvement in bladder control in four of them. In laboratory animals with an intact neuraxis, micturition is dependent upon a spinobulbospinal reflex activated by bladder A 8 afferents, but after spinal transection at the lower thoracic level, a new spinal reflex emerges, which in cats is mediated by C-fibre afferents. This reflex can be blocked by capsaicin in doses of 20-30 mg/kg, administered subcutaneously, that do not affect micturition reflexes in intact cats.’ Capsaicin is the pungent ingredient of red peppers. It is a specific neurotoxin for certain types of sensory nerves, notably those with unmyelinated (C-fibre) axons. It releases neuropeptides from sensitive neurons and produces a prolonged functional block. The existence of capsaicin-sensitive receptors in the bladders of laboratory animals is well established2 but their presence and functional significance in man is less certain. Following a report of the use of intravesical capsaicin to treat painful bladder disorders3 we investigated the possibility of using capsaicin to modify the reflex arc causing detrusor hyperreflexia in patients with MS and spinal cord disease. All patients gave informed consent to this experimental treatment. Case 1 (F, 57; ambulant with assistance but severe urinary urgency had necessitated an indwelling catheter since 1987). In pilot studies to establish the dose, 0’1, 1, 10, and then 100 umol/1 capsaicin (in 100 ml saline) was instilled. No long-lasting benefit was obtained and the catheter had to be reinserted within hours. In May, 1991, 100 ml of a 1 mmol/1 (0-3 g/1) solution of capsaicin dissolved in 30% alcohol in saline was given as an intravesical instillation for 30 min. For the ensuing 18 h the patient reported unusually frequent spontaneous bladder contractions but by 48 h these had subsided and she was able to manage without an indwelling catheter. This improved bladder control lasted for 5 months. She could go 2-3 h without passing urine, was never incontinent, and needed to get up only once at night. 5 months later her bladder control deteriorated so that rising to a standing position tended to induce hyperreflexic contractions although she was not incontinent. At the patient’s request the capsaicin instillation was repeated last November. Since then, the interval between her voids has increased to 3-4 h, she does not need to get up at night, and no longer feels that changes in posture induce hyperreflexic contractions. Throughout this period she has continued to take the same dose of oxybutynin. Her bladder capacity has increased from less than 150 ml before treatment with 1 mmol/l capsaicin to 750 ml. Case 2 (M, 56; ambulant with assistance but needing to wear a urinary appliance because of urge incontinence). He became continent and able to go for 4-5 h between voids after an instillation of 100 ml 1 mmol/1 capsaicin in alcohol and saline in September, 1991. Although improvement in bladder control coincided with a change in medication from terodiline to oxybutynin, when terodiline was withdrawn, 6 months later--and despite continuing the same dose of oxybutynin-bladder control deteriorated and he has now asked for the capsaicin instillation to be repeated. Case 3 (M, 45; similar to case 2 in terms of mobility and bladder control). Following 100 ml 2 mmol/1 capsaicin in alcohol and saline for 30 min in February, 1992, urge incontinence has been eliminated; he can spend the night without passing urine and intervals between voids during the day are 2-5 h. 2 months after intravesical capsaicin, his functional bladder capacity had increased from 160 to 550 ml. These three patients perform intermittent self-catheterisation three or four times a day. They had learned the technique some years earlier but found it to be of diminishing value as their bladders became more severely hyperreflexic. All three have reported an increase in post-micturition residual volumes after capsaicin instillation. The other two patients (cases 4 and 5) were wheelchair bound; they needed long-term indwelling catheters but were persistently troubled by "bypassing". Both were given the same instillation of 100 ml 1 mmol/1 capsaicin in alcohol and saline for 30 min. One patient continues to leak around her catheter daily
although it may be relevant that she had had a bladder-neck incision in the past. The other patient reports a pronounced improvement and, whereas formerly she daily leaked around the catheter, for 3 months after intravesical capsaicin this happened only infrequently and to a minor degree, so that she felt sufficiently confident to social activities. In all but one case, instillations were done in the operating-theatre with full cardiovascular monitoring and an anaesthetist on hand for analgesia or sedation if required. A balloon catheter was used to minimise the risk of leakage into the urethra and the capsaicin was left in the bladder for 30 min. Although patients reported considerable discomfort in the form of a suprapubic burning pain, worst within the first 10 min, this then subsided and at no stage did any ever ask for medication. No significant alteration in cardiovascular state was detected during or after the procedure. Blood alcohol concentrations taken over the period of the instillation and up to 4 h later never exceeded 3 mmol/1, indicating little diffusion of alcohol through the bladder wall. Because the procedure seemed to cause so little ill-effect the most recent case was treated in the laboratory rather than the operating-theatre and went home 2 h later. These preliminary results of intravesical capsaicin as a treatment for intractable detrusor hyperreflexia seem promising. Hyperreflexia is the disorder of bladder function largely responsible for incontinence of neurological origin, and a non-surgical, effective, topical treatment could have wide-ranging implications. Its use might also shed further light on the pathophysiology of detrusor instability, a condition suspected of being neurogenic.4 The numbers in this study are small because of the non-medicine status of capsaicin. An exemption from a licence certificate for the use of intravesical capsaicin to treat detrusor hyperreflexia has now been given so that a larger scale study may be undertaken. resume
National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK
CLARE J. FOWLER DOREEN JEWKES W. IAN MCDONALD
Department of Physiology, University College London
BRUCE LYNN
Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
W. C.
DE
GROAT
1. de Groat WC, Kawatani T, Hisamitsu T, et al. Mechanisms underlying the recovery of urinary bladder function following spinal cord injury. J Autonomic Nervous System 1990; 30: S71-78. 2. Maggi CA, Santicioli P, Borsini F, Giuliani S, Meli A. The role of capsaicin-sensitive innervation of the rat urinary bladder in the activation of the micturition reflex. Naunyn-Schmiedeberg’s Arch Pharmacol 1986; 322: 276-83. 3. Maggi CA, Barbanti G, Santicioli P, et al. Cysometric evidence that capsaicin-sensitive nerves modulate the afferent branch of micturition reflex in humans. J Urol 1989; 142: 150-54. 4. Editorial. Neurobiology of incontinence. Lancet 1989; ii: 1078-79.
All-trans retinoic acid and side-effects SIR,-All-trans retinoic acid (ATRA) in acute promyelocytic (APL) not only induces complete remission, but also
leukaemia
improves the early death rate through reduction of coagulopathy and bleeding complications of APL. 1-3 Dr Akiyama and colleagues (Feb 1, p 308) report hypercalcaemia with ATRA, and other side-effects have also been recorded, including rashes.’ Severe dermatological reactions can lead to withdrawal of the drug in use. With respect to ATRA, its withdrawal would indicate the need to use more conventional chemotherapeutic regimens that often exacerbate the coagulopathy of APL. We have been faced with this consideration and report our findings in a patient with APL. A 70-year-old woman presented with pancytopenia. Bonemarrow aspirate showed 75% blasts and abnormal promyelocytes, many of which contained Auer rods. Acute promyelocytic leukaemia was diagnosed. Coagulation abnormalities were present, with prothrombin time 19 s (normal 11-13), thrombin time 17 s (11-13), fibrinogen 1 gll (1-6-3-9), and fibrinogen degradation products 126 jig/ml (
