Treatment of cystalgia

Non-pharmacologic approaches to treating cystalgia include methods that patients can use to reduce the severity of symptoms of the disease, such as stress and anxiety reduction, exercise and physical therapy, sex therapy and counseling, bladder training, pelvic floor rehabilitation, and dietary changes [Nickel, 2004]. [ 1 ]

Drug treatment

Drug treatment of cystalgia consists of oral agents and intravesical instillations. These are analgesics, antihistamines, antidepressants, prostaglandins, immunosuppressants, etc. In case of hormonal imbalances, replacement therapy is used.

1. Antiallergic drugs

Antihistamines. Because mast cells and their mediators such as histamine are key players in inflammation and the pathogenesis of cystalgia [Moldwin and Sant, 2002], therapies that block the action of histamine have been shown to improve symptoms. These include the H1 blocker hydroxyzine hydrochloride [Moldwin and Sant, 2002], [ 2 ] as well as H2 blockers such as cimetidine, which have been shown to result in significant reductions in pain and nocturia in a limited study of patients with interstitial cystitis [Thilagarajah et al. 2001]. [ 3 ]

Cimetidine is an antidepressant with central and peripheral activity. It is used 300 mg three times a day before or during meals. It can cause a feeling of fear, flatulence, diarrhea, muscle pain, increased liver enzymes, anemia, impotence. The drug is not prescribed to children under 14 years of age, pregnant women, during breastfeeding, in case of serious liver and kidney dysfunction.

Leukotriene D4 receptor antagonists montelukast. The presence of leukotriene receptors in detrusor muscle cells [Bouchelouche et al. 2001a] [ 4 ] and elevated urinary leukotriene E4 levels in patients with cystalgia suggest a role for these proinflammatory mediators in interstitial cystitis. Bouchelouche and colleagues reported their experience in 10 women with cystalgia [ ouchelouche et al. 2001b], [ 5 ] who were treated with the leukotrine antagonist montelukast. They found that after 1 month of treatment with montelukast there was a statistically significant reduction in 24-hour urinary frequency, nocturia, and pain, which persisted for 3 months of treatment. After 3 months, 24-hour urinary frequency decreased from 17.4 to 12 micturitions (p = 0.009), nocturia decreased from 4.5 to 2.8 (p = 0.019), and pain decreased from 46.8 to 19.6 mm on the visual analogue scale (p = 0.006). No adverse effects were observed during treatment.

2. Bladder mucosa protectors

Pentosan polysulfate (Elmiron). Pentosan polysulfate works by coating the bladder mucosa and restoring normal function of the glycosaminoglycan (GAG) layer [Moldwin and Sant, 2002]. Parsons and colleagues conducted a double-blind, multicenter study in which patients with cystaligia who received pentosan polysulfate experienced a reduction in interstitial cystitis symptoms [Parsons et al. 2002b]. [ 6 ]

Pentosan polysulfate sodium is a synthetic sulfate polysaccharide, eliminates the defect of the epithelium of the mucous membrane of the bladder. For treatment, a dose of 300-400 mg per day is effective. It is administered as subcutaneous and intravenous injections. It can cause a hematoma at the injection site, pain, skin reactions, nausea, vomiting, fever are possible. The drug is not recommended after strokes, bleeding ulcers, spinal anesthesia, during pregnancy, because it can cause placental abruption, miscarriage.

3. Pain modulators

Tricyclic antidepressants. Amitriptyline has been shown to be effective in the treatment of chronic pain syndromes, including cystalgia [Hanno, 1994]. [ 7 ] Amitriptyline modulates nociceptive transmission by inhibiting presynaptic reuptake of serotonin and norepinephrine [Tura and Tura, 1990]. [ 8 ] Amitriptyline has been found to produce a 50% reduction in pain and urinary frequency [Hanno et al. 1989]. [ 9 ] Recently, a randomized, double-blind, placebo-controlled clinical trial of amitriptyline in 44 women and 6 men with cystalgia, which used a self-titration protocol (up to 100 mg/day at bedtime for 4 months), reported significant improvements in cystalgia symptoms in all cases. [Van Ophoven et al. 2004]. [ 10 ]

Anticonvulsants. Anticonvulsants such as gabapentin are often prescribed for neuropathic pain [Lukban et al. 2002]. [ 11 ] These drugs can be used to treat patients with refractory cystalgia who have not responded to other treatments [Butrick, 2003]. [ 12 ]

4. Hormonal modulators

Leuprolide acetate. Many women of reproductive age with cystalgia frequently report worsening of symptoms during the menstrual cycle [Powell-Boone et al. 2005]. [ 13 ] This may be related to the fact that estradiol activates estrogen receptors expressed on bladder mast cells, which in turn increases secretion of the proinflammatory molecule [Spanos et al. 1996]. [ 14 ] In such cases, leuprolide acetate may be useful since it is a gonadotropin-releasing hormone agonist that causes a decrease in estradiol secretion. In 15 patients with irritable bladder symptoms and pelvic pain without endometriosis, symptoms improved in eight of nine patients treated with leuprolide acetate and in five of six patients treated with oral contraceptives Lentz et al. 2002]. [ 15 ]

5. Anti-inflammatory drugs

Anti-TNF therapy. Recently, various studies have focused on the neuroinflammatory mechanism of pain in order to further target specific pathogenetic links with therapy. A hypothetical model of cholinergic anti-inflammatory pathway based on bacterial LPS as a stimulator has been proposed and therapies are being developed to specifically target and disrupt this neuroinflammatory loop, such as anti-NGF to reduce SP or anti-TNF-α or neuromodulation to break the loop and achieve symptomatic relief [Saini et al. 2008]. [ 16 ]

Animal studies have shown that virus-induced neurogenic inflammation can result in a 20-fold increase in degranulated mast cells in the lamina propria, which is primarily dependent on TNF-α [Chen et al. 2006]. [ 17 ] Furthermore, TNF-α can promote mast cell enlargement and induce urothelial inflammation [Batler et al. 2002]. [ 18 ] These data have led to the suggestion that anti-TNF therapy may be useful, although there are no clinical data to support its use.

Pain relief. Most patients with cystalgia experience chronic pain, although to varying degrees. Pain can be treated with opioids either alone or in combination with hydroxyzine to enhance the analgesic response and reduce side effects [Hupert et al. 1980]. [ 19 ]

Immunosuppressants. Immunosuppressants may be used as second-line therapy in the treatment of cystalgia. For example, prednisone may be used in treatment-resistant cases [Soucy and Gregoire, 2005]. [ 20 ] Other medications such as cyclosporine have been shown to relieve symptoms of severe cystalgia [Sairanen et al. 2005]. In an open-label study of 11 patients with intractable cystalgia, treatment with cyclosporine for up to 6 months significantly reduced urinary frequency and bladder pain in the majority of patients [Forsell et al. 1996]. [ 21 ] Recently, in a randomized trial of 64 patients with cystalgia who met NIDDK criteria, patients received cyclosporine or pentosan polysulfate for 6 months. The clinical response rate was determined using the Global Response Assessment and was found to be 75% for cyclosporine compared with 19% for pentosan polysulfate (p < 0.001) [Sairanen et al. 2005]. [ 22 ]

6. Bladder mucosa protectors

Hyaluronic acid. Intravesical administration of hyaluronic acid is thought to protect the bladder surface. Morales and colleagues reported symptomatic improvement of 56% at week 4 and 71% at week 7 in 25 patients treated with intravesical instillation of hyaluronic acid [Morales et al. 1996]. [ 23 ] After week 24, efficacy declined.

7. Other drugs

L-arginine. Patients with cystalgia have decreased urinary nitric oxide synthase and urinary nitric oxide levels [Hosseini et al. 2004]. [ 24 ] These patients respond to treatment with oral L-arginine, a precursor of nitric oxide synthesis. In one double-blind, randomized, placebo-controlled trial, 21 of 27 patients with cystalgia received 1500 mg L-arginine for 3 months and compared with 25 of 26 patients taking placebo: greater global improvement in the L-arginine group (48%, 10 of 21) compared with the placebo group (24%, 6 of 25) at 3 months (p = 0.05) with a decrease in pain intensity (p = 0.04) [ Korting et al. 1999]. [ 25 ] In another randomized, double-blind, crossover study using 2.4 g L-arginine in 16 patients with interstitial cystitis for 1 month, there was a 2.2 reduction in total symptom score, but no significant difference in urinary frequency or nocturia [Cartledge et al. 2000]. [ 26 ]

L-arginine is an injection solution, administered intravenously at a rate of 10 drops per minute, after 10-15 minutes the process is accelerated to 30 drops. The daily dose is from 1.5 to 2.5 g for 3 months. Children can use it from 3 years of age. Contraindicated for people with allergies to the components of the product, severe renal dysfunction. Side effects include body aches, joint pain, nausea, vomiting, dizziness, and blood pressure surges.

Anticholinergic drugs. Oxybutynin and tolterodine are commonly used anticholinergic drugs to treat symptoms associated with overactive bladder in interstitial cystitis. They both act primarily on the muscarinic-3 (M3) receptor subtype, which causes contraction of the bladder detrusor. Unfortunately, the salivary glands also have an M3 receptor, and therefore dry mouth is a major side effect, especially with oxybutynin [Cannon and Chancellor, 2002]. [ 27 ] The US Food and Drug Administration (FDA) has approved an extended-release once-daily formulation of tolterodine (Detrol LA). [ Van Kerrebroeck et al. 2001 ] [ 28 ]

Dimethyl sulfoxide (DMSO). DMSO may have analgesic, anti-inflammatory, collagenolytic, and muscle relaxant effects and is virtually a standard treatment for cystalgia. In a controlled crossover study, 33 patients with interstitial cystitis were randomly assigned to receive either 50% DMSO or placebo (saline). The drug was administered intravenously every 2 weeks for two sessions of four procedures each. The results were assessed urodynamically and symptomatically. Subjective improvement was noted in 53% of patients receiving DMSO compared with 18% receiving placebo, and objective improvement in 93% and 35%, respectively [Perez-Marrero et al. 1988]. [ 29 ]

Bacillus Calmette – Guerin (BCG). BCG is most commonly used to treat recurrent or multifocal bladder cancer. A prospective, double-blind, placebo-controlled study in patients with cystalgia showed a 60% response rate in patients receiving BCG compared with 27% in patients receiving placebo [Peters et al. 1997]. [ 30 ] In another randomized, placebo-controlled, double-blind study in 260 patients with refractory cystalgia, BCG demonstrated an overall response rate of 21% versus 12% for placebo (p = 0.062) [Mayer et al. 2005]. [ 31 ] Other multicenter studies are ongoing to define the role of BCG in the treatment of patients with interstitial cystitis.

Other drugs such as chondroitin sulfate, vanilloid, and intravesical botulinum toxin may also be used alone or may be combined into a "drug cocktail" for intravesical instillation. Intravesical therapy is necessary for patients who do not respond to oral treatment or who experience severe side effects from drug therapy [Forrest and Dell, 2007]. [ 32 ]

Trioginal vaginal capsules are used to treat cystalgia. The estrogen estriol in its composition helps to restore and renew the mucous membrane. The vaginal capsule is inserted once a day, pre-wetting it in a small amount of water. Local reactions are possible: irritation, itching, as well as tension in the mammary glands, increased vaginal discharge. Do not use if cancer is suspected, endometriosis, thrombosis, jaundice, pregnancy, breastfeeding, hypersensitivity to the components of the drug, to children under 18 years of age.

Physiotherapy treatment

As part of a comprehensive treatment, manual therapy is used to strengthen the main treatment and as a supporting treatment. Several times a day, the area of the projection onto the organ is massaged with light movements, thereby relieving muscle tone.

Effective in cystalgia are gymnastics, soft tissue massage, including myofascial release and bladder retraining, usually used in patients with little or no pain [Whitmore, 1994], [ 33 ] allowing to train the pelvic floor muscles. These are leg swings, twists around the waist, handstands as for push-ups, "bridge", abdominal exercises. Intensive physical therapy should be used at the beginning of an exacerbation of the disease and repeated at least once a year.

There is also a special technique developed by gynecologist Arnold Kegel. After emptying the bladder, you need to squeeze the muscles, stay in this state for a while, and relax. Repeat several times. Then tense and immediately release the pelvic muscles, accelerating. Ten approaches to each exercise 5 times a day will give results, reduce the symptoms of urinary incontinence.

Good results are obtained from the use of amplipulse therapy, acupuncture, reflexology, [ 34 ] biofeedback to control pelvic floor dysfunction [ 35 ]

Folk remedies

Of the folk methods, decoctions and infusions of herbs are mainly used, whose effect is calming. Mint, lemon balm, and oregano are used for treatment. Pour boiling water over the raw materials and let it brew for 20-30 minutes, drink 100 ml three times a day. Tinctures of valerian, hops, and motherwort are sold in pharmacies; use them according to the instructions. Half-half, bearberry, knotweed, and corn silk fight inflammation.

Homeopathy

Homeopathic remedies are also used to treat cystalgia, one of which is cystosan. Neuroregulating, anti-inflammatory granules, which include belladonna, equiset, clematis, himafila. In acute conditions, 3-5 granules are used 6 times a day, then 1-3 with a frequency of 2-3 times, taking breaks of 1-2 days a week. There is no data on contraindications and side effects.

Homeopaths prescribe Sepia (cuttlefish) for this diagnosis, and the woman's type is defined as tired, thin, irritable during menopause.

For young people, after childbirth or other injuries to the genitals, Staphysagria (Stephan's seed) is suitable. For pain above the pubis, Natrium muriaticum is prescribed, against the background of a gynecological disease - Platina.

The dosage of the drugs and the rules for taking them are determined by a homeopathic doctor.

Surgical treatment of cystalgia

Surgical intervention is used in severe cases that do not respond to conservative therapy. Surgical treatment may include:

• sacral neuromodulation - by acting on the neurons of the spinal cord, pain is eliminated;
• transurethral resection - a cystoscope is inserted through a small puncture in the urethra, with the help of which not only diagnostics are performed, but also cauterization and removal of tumors;
• laser fulguration - destruction of pathological foci using a laser; The study [ 36 ] proved the effectiveness of laser therapy in the treatment of cystalgia. No intra- or postoperative side effects were found. In the treatment of cystalgia, radiation from a helium-neon optical laser AFL-1 with a wave of 632.8 mM and an output power of 18-20 mW was used.
• cystectomy with formation of an intestinal reservoir - removal of the bladder, used in cases of cancer;
• urine diversion.

Surgery is used as a last-line therapy when conservative options are ineffective.

• Bladder instillations

Although bladder distension can be used as a diagnostic procedure for cystalgia, it can also be used for therapeutic purposes [Moldwin and Sant, 2002]. Most patients reported worsening symptoms for 2–3 weeks after hydrodistension, but then experienced a decrease in symptoms after this time period. Glemain and colleagues tested the effectiveness of hydrodistension for the symptomatic treatment of interstitial cystitis with follow-up at 6 and 12 months [Glemain et al. 2002]. [ 37 ] The treatment success rate was 60% at 6 months, decreasing to 43.3% at 12 months. Erickson and colleagues reported that the mean symptom score in newly diagnosed patients was reduced after hydrodistension, but only a small number of patients experienced at least a 30% reduction in symptoms [Erickson et al. 2007]. [ 38 ]

Instillations of heparin and dimexide into the bladder provide good results.

Dimexide - has an antiseptic, analgesic effect, is used in a 50% aqueous solution. The drug in a volume of 50 ml is administered 1-2 times a week for 4-8 courses. Contraindicated in atherosclerosis, cardiovascular insufficiency, glaucoma, cataracts, stroke, heart attack. May cause burning, itching.

• Transurethral resection of visible lesions

Transurethral resection (TUR) is reserved for patients with visible Hunner lesions. Fall reported his experience with TUR in 30 patients with classic cystalgia and found that complete TUR of all visible lesions resulted in initial pain relief in all and decreased frequency in 21 patients [Fall, 1985]. [ 39 ] Although recurrence of disease was reported in one third of patients, the remaining two thirds were still pain free even after 2–20 months. In another study, Peeker and colleagues performed 259 TURs in 103 patients with cystalgia [Peeker et al. 2000a]; [ 40 ] Improvement was seen in 92 and symptom relief lasted for more than 3 years in 40%.

• Laser coagulation

Transurethral ablation of bladder tissue aims to eliminate visible Hunner's ulcers. The use of neodymium:YAG laser has been proposed as an alternative to TUR for patients with cystalgia. Shanberg and colleagues initially treated five patients with refractory cystalgia with neodymium laser, of whom four experienced cessation of pain and urinary frequency within a few days [Shanberg et al. 1985]. [ 41 ] Follow-up at 3–15 months revealed no recurrence except for mild recurrent urinary symptoms.

• Neuromodulation

Recently, unilateral sacral nerve stimulation (S3) has emerged as a promising treatment option for cystalgia. Peters demonstrated that patients with interstitial cystitis refractory to conventional therapy responded well to sacral nerve stimulation [Peters, 2002]. [ 42 ] More recently, Comiter confirmed the positive results of sacral neuromodulation on voiding and pelvic pain in patients with cystalgia [Comiter, 2003]. [ 43 ]

• Cystectomy

When all conservative efforts fail, surgical removal of the bladder represents the last and most extreme treatment option [Moldwin and Sant, 2002]. Three types of cystectomy for cystalgia can be performed: supratrigonal, subtrigonal cystectomy, or radical cystectomy including urethral removal. Van Ophoven and colleagues, for example, reported their experience with trigon-preserving cystectomy and orthotopic substitution enteroplasty in 18 patients using ileocecal (n = 10) or ileal (n = 8) segments [Van Ophoven et al. 2002]. [ 44 ] After 5 years, 14 (77.78%) patients were pain-free, 15 (83.33%) reported complete resolution of dysuria.