Its main role is to educate the patient in order to understand what OAB is and to assist the patient in identifying symptom management strategies. The patient must understand, from the beginning, that they are to undergo treatment over a lengthy period of time, that they must remain motivated and, especially tolerant (1,6,13-15,18).

First-line treatment is considered to be behavioral therapy, especially since it does not involve risks and its effectiveness is proven in many cases (6,13). The patient is advised to make changes in lifestyle: to lose weight, reduce fluid intake (six to eight glasses of water per day, avoiding fluid intake 2 h before bedtime), to give up coffee, spices, sour drinks and alcohol, smoking cessation, bowel regulation (avoid constipation), to increase the level of physical activity and to improve overall health. All these have been confirmed to have beneficial results (1,6,13-15,18,41,42).

Bladder training is part of the arsenal of non-pharmacological treatment, with promising results (1,6,13,15,43). It consists of urinating at regular intervals, starting with urination at 30 min, then reaching intervals of 3-4 h, once the patient manages to have control over urination. The patient must know that every minute of postponing urination during the urge is an important gain (13,15,44). The use of the micturition calendar can increase patient compliance and motivation through visual feedback and evaluate outcome (14,18).

Optimal results are obtained by combining with emergency control techniques, especially the Kegel contraction or deep breathing (as a relaxation technique), which the patient may use in order to obtain gradual control (6,15,44).

On the other hand, the use of pelvic floor muscle training (PFMT) can be substantially positive, especially in reducing episodes of urgency and incontinence, by reducing detrusor contractions through inhibitory reflection of the pelvic floor and improving urethral stability (1,6,13-15,18,45). PFMT results appear to be improved when combined with oral drug therapy (1,6). The main types of PFMT used are: Kegel exercises, pelvic-floor electrical stimulation, and pelvic floor exercise with biofeedback or vaginal weight training. There is no single and/or effective PFMT regimen, thus therapy should be individualized and performed under the supervision of a physical therapist or by advanced practice nurses (1,6,13,15). An important problem, however, is that long-term adherence to treatment (PFMT) is poor (13,46).

The first group of pharmacological drugs are represented by antimuscarinic drugs (anticholinergic), with the help of which some relaxation of the detrusor is obtained. During years of use and clinical trials, they have been shown to be safe, fairly well tolerated and effective, leading to significant improvement in symptoms and consequent quality of life (1,6,14,15). The main problem with these drugs is that muscarinic receptors, on which they act, are found in many organs of the body, which leads to the occurrence of numerous common side effects: dryness of the mucous membranes (dry mouth, dry eyes, dry vagina), constipation, heart palpitations, arrhythmia, tachycardia and cognitive impairment (somnolence, hallucinations, confusion, delirium, blurred vision, memory problems) or urinary retention (1,15,18,47,48).

Anticholinergic medication has been shown to be beneficial in relieving symptoms, as indicated in numerous studies (1,13,15,18,49,50). However, many patients cease taking medication (1,51). Most often patients discontinue medication due to constipation (approximately 50%) (52) or dry mouth (approximately 30%) (13,18).

The most common antimuscarinics used are: oxybutynin, tolterodine, fesoterodine, trospium, propiverine, solifenacin; subsequent studies failed to prove that one is more effective than the other (1,13-15,18). Extended-release (ER) drugs are considered as effective as immediate-release (IR), but with an improved safety profile, with lower side effects (13,14,18). If both types of medication are available, then ER drugs should preferentially be prescribed (6,13). Transdermal oxybutynin or oxybutynin topical gel is another option, as it avoids liver first-pass effect, with lower systemic side effects, and a low dry mouth rate. Even in this case continuing treatment over a long period of time is a problem, due to adverse skin reaction (pruritus and erythema at the site of application) (6,13,14,18).

Although the effectiveness of antimuscarinics has been clearly proven, the discontinuation rate of treatment is very high, especially due to side effects (43-83% in the first 30 days of treatment), but also low level of efficacy or cost (13,53). Thus, it is opportune to commence with small doses, on a plan as flexible as possible, and to evaluate the patient as closely as possible, at 1-3 months, in order to manage the case as correctly as possible and, especially, the patient's ability to cope with the side effects. This is crucial as the rate of side effects increases with increasing doses (1,6,13,14,54). Contraindications to antimuscarinic medication are: patients with narrow-angle glaucoma (unless approved by the ophthalmologist treating), myasthenia gravis, severe ulcerative colitis, toxic megacolon, urinary retention or intestinal obstruction. Caution should be accorded when prescribed to elderly patients or those who already have cognitive impairment, or if the patient is using other medications with anti-cholinergic properties, although studies are contradictory in this regard. Cognitive side effects are cumulative and increase with length of exposure, so antimuscarinics should be used with caution in elderly patients. In other words, each case must be managed carefully and individually, sometimes in collaboration with other clinicians in other specialties, to weigh the ratio between risks and benefits (1,6,13,15,18).

The second type of drug that is used is β3-agonists. Of the three β adrenoceptors present in the bladder, findings have shown that β3 is predominant and responsible for detrusor relaxation during the filling phase (55,56). Mirabegron is the only licensed β3-agonist available since 2013, and studies have shown favorable results on OAB symptoms. Additionally, this agonist is well tolerated. Mirabegron is considered a second-line therapy. The effectiveness is comparable to that of antimuscarinics, but with decreased side effects, especially those related to the incidence of dry mouth (1,6,15,18,57).

The side effect profile is different in β3-agonists because the mechanism of action is different. β3 adrenoceptors are also present in vascular and cardiac tissue, with studies showing some changes in heart rate and increases in blood pressure, albeit not notable ones. Other possible side effects are nasopharyngitis and UTI, which are less common (13,15,58).

The use of mirabegron as an alternative to antimuscarinic therapy is recommended especially in patients who do not respond to first-line treatment and in those who cannot tolerate side effects (6,13,15,18). There was a much greater adherence to mirabegron treatment when compared to antimuscarinics (13,59). Additionally, in patient refractory to monotherapy, antimuscarinics may be combined with mirabegron, the results being superior to monotherapy (6,13,15,18,60). In elderly patients, existing data have shown that mirabegron is safe (13).

When patients do not respond to anticholinergic medication or to β3-agonists, they are considered refractory. This category also includes patients who have used at least 2 types of anticholinergics or combination treatment without results, or those who do not tolerate side effects or have contraindications for first-line or second-line therapy. In such cases resorting to third-line therapy is inevitable: temporary chemical denervation of the bladder detrusor muscle, peripheral tibial nerve stimulation (PTNS) or neuromodulation (1,6,14,15).

OBTA is derived from Clostridium botulinum and selectively blocks presynaptic release of acetylcholine from nerve endings. This results in reduced contractility and a degree of muscle atrophy at the injection site (a temporary degree of paralysis). The result is not permanent due to the formation of new functional synapses. Another mode of action appears to be directly in the urothelium by inhibiting the release of neurotransmitters at this level, thus acting on the sensory system (1,15,18,61). OBTA is administered intravesically, by injection into certain areas of the bladder, using a cystoscope. The injection is made in 20 places at the level of the posterior wall of the bladder, above the trigone, to avoid extreme paralysis and significant urinary retention. The optimal dose is considered to be 100 units (6,13,15,18). Findings have shown that higher doses are more effective, but reported side effects have been much more common (18,62). Higher doses may be used in selected cases, but patients should be informed of the much higher likelihood of urinary retention (15).

Local or systemic side effects are reduced at the standard dose of 100 units, but the main problem is related to increased PVR (residual volume). As a result the patient must be compliant and able to perform clean intermittent self-catheterization. It is reported that urinary difficulties appear in 4-45% of patients (6,13,15,18,55,63). Other side effects of the injection are UTIs (13-44%), hematuria, dysuria, rash, transient flu-like illness or generalized muscle weakness (14,18,64). Favorable results of OBTA treatment, with marked improvement of symptoms, urodynamic parameters and significant improvement of quality of life have been reported. The duration of the favorable effect is estimated to be 6-9 months, after which a new administration of OBTA may be necessary (1,13,15,18,65). The most common causes of withdrawal are ineffective treatment (13%) and problems with secondary urinary disorders (11%) (1). Intravesical OBTA was approved by FDA in 2013 for the treatment of idiopathic OAB.

Posterior tibial nerve stimulation (PTNS) was first described in 1983 and is a minimally invasive procedure with favorable results and low risks. It consists of intermittent stimulation applied to the posterior tibial nerve using a small needle electrode (34-G) inserted just above the medial aspect of the ankle (P-PTNS). The success rate is estimated at 60-80% (1,6,13,14,66-68). The optimal duration is not very clearly defined, but it is estimated as optimal 30 min sessions for 3 months, and the favorable effect can last up to 1 year. Repeated treatments may be required for sustained efficacy. Local discomfort is minimal and no serious side effects have been reported, being especially local and temporary (local inflammation, mild bleeding, pain) (1,13,14,18,67,69). PTNS contraindications are patients with implantable defibrillators, pacemakers, and nerve damage that can affect tibial nerve, bleeding problems, pregnancy or attempts to conceive (15). PTNS was approved by the US Food and Drug Administration (FDA) in 2005. There is also a possibility of a T-PTNS (transcutaneous stimulation) being performed (15).

Sacral neuromodulation (SNM) is recommended in selected severe cases that are refractory to other types of treatment and should be considered before resorting to other more radical ways of treatment (1,6,14,18). SNM consists of S3 nerve root stimulation using a percutaneously implantable device under fluoroscopic control, which generates electrical impulses (continuous low frequency stimulation is used to modulate bladder/pelvic floor function). The major disadvantage surgery is necessary to permanently implant a device, accompanied by related complications (pain, bleeding, infection, movement of the device or its malfunction) sometimes requiring reinterventions to revise the device (approximately 33% of cases). The final surgery occurs only after the patient's qualification for this procedure. A preliminary phase is necessary to determine whether or not the patient has a significant improvement in symptoms (50% improvement in baseline symptoms). Only such patients may benefit from a full implant (1,13-15,18,70).

The advantages are important: the symptoms are significantly improved in over 50% of patients, with marked improvement in quality of life, the favorable effect being maintained up to 3-5 years (1,13,15,18,71,72). SNM is contraindicated in patients who need frequent MRI, pregnancy or if a patient aims to conceive. The device is not cost-effective, and the patient must be very compliant because lifelong follow-up is needed (14,15,73). Sacral neuromodulation was FDA approved in 1997.

In rare severe cases, refractory to any other type of treatment, surgical treatment can be performed; a form of fourth-line therapy (6,14). It is addressed to only selected cases. Patients must be very well informed about the consequences of interventions and should be very motivated. These forms of treatment are irreversible with a significant morbidity (13,14,18).

Augmentation of the bladder (cystoplasty) is performed by adding to its intraluminal surface area a 10-15 cm loop of small bowel, preferably ileum (detubularized segment of bowel is inserted into the bivalved bladder wall). The complications of the intervention can be redoubtable, with obstructions, disinsertions of anastomoses, abscesses, or fistulas (1,13,74).

Urinary diversion is an intervention that involves implanting the ureters in an ileal segment and creating a skin stoma (13,14,18).

The long-term complications of these types of surgery are electrolyte disturbances, renal failure, urinary tract stones, ischemia of the ileum and ureteric stricture, a need for clean intermittent self-catheterization (for bladder augmentation), change in bowel symptoms, or UTI (13,14,18). Patient satisfaction after such interventions is quite high, especially due to the fact that, having to resort to surgical treatment, they faced severe symptoms, refractory to any other type of treatment (13,14,18).

Other possible treatments for OAB are currently under investigation: α-adrenoceptor antagonists, gene therapy, neurokinin receptor antagonists, nerve growth factor inhibitors, stem cell-based therapies, potassium channel opening gates, capsaicin (resiniferatoxin), vaginal estrogen as a monotherapy for OAB as well as in combination with other therapies (including behavioral and pharmaceutical) (1,6,14,75-78).