Overactive bladder (OAB) is a common and often debilitating condition characterized by symptoms such as urinary urgency, frequency, and urge incontinence. It significantly impacts the quality of life for millions of individuals worldwide, particularly affecting women and the elderly. While first-line treatments typically include behavioral therapies and anticholinergic or beta-3 agonist medications, many patients experience inadequate relief or intolerable side effects. In recent years, botulinum toxin type A (commonly known as Botox) has emerged as a promising second-line therapy for managing refractory OAB. By modulating neuromuscular signaling in the bladder, Botox offers a novel and effective approach to symptom control.

This paper explores the use of Botox in the treatment of overactive bladder, examining its mechanism of action, clinical efficacy, safety profile, and role in current urological practice.

What is botox?

Botox, or botulinum toxin type A, is a neurotoxic protein that is widely known for its cosmetic use in reducing wrinkles. However, it is also approved as a medical treatment for OAB, particularly in cases where other treatments have failed.

Botox provides a minimally invasive, effective treatment option for managing symptoms of overactive bladder in patients who have not found relief through more conventional methods.

Mechanism of action of botox

Botox works by modulating nerve activity in the bladder, thereby reducing involuntary bladder contractions that cause symptoms of overactive bladder, such as urgency, frequency, and urge incontinence.

Here’s a breakdown of its mechanisms:

Inhibition of Acetylcholine Release

• Botox blocks the release of acetylcholine, a neurotransmitter responsible for triggering muscle contractions.
• In the bladder, acetylcholine is released from parasympathetic nerves and binds to receptors on the detrusor muscle, causing it to contract.
• By preventing this release, Botox reduces involuntary contractions of the detrusor muscle, leading to improved bladder storage and fewer urgency episodes.

Desensitization of Sensory Nerve Endings

• Botox also affects afferent (sensory) nerves in the bladder wall.
• It reduces the release of other neurotransmitters involved in bladder sensation, such as substance P and calcitonin gene-related peptide (CGRP).
• This helps to decrease the sensation of urgency and pain, making the bladder feel less overactive.

Modulation of Bladder Reflex Pathways

• Botox may help to alter abnormal reflex signaling between the bladder and spinal cord that contributes to OAB symptoms.
• This results in improved control over bladder function and reduced episodes of urgency and leakage.

Temporary Effect

• The action of Botox is reversible. Over time (typically 6 to 9 months), new nerve endings form, and muscle activity gradually returns, which may require repeat injections.

Summary

Botox treats overactive bladder by:

• Blocking acetylcholine release → ↓ involuntary muscle contractions
• Reducing sensory neurotransmitters → ↓ urgency and discomfort
• Modulating reflex pathways → ↑ bladder control

This dual action on both motor and sensory pathways makes Botox an effective second-line treatment for patients with OAB who do not respond to medications.

Indications

Botox is approved and used for specific indications in the management of OAB. It is typically considered when other standard treatments have failed or are not well tolerated.

FDA-Approved Indications:

OAB in adults with ınadequate response to anticholinergic medications

1. Botox is indicated for adults with symptoms of OAB—such as urinary urgency, frequency, and urge urinary incontinence—who have:
   • Not achieved sufficient symptom relief from oral medications (e.g., anticholinergics, beta-3 agonists)
   • Experienced intolerable side effects (e.g., dry mouth, constipation, confusion)

Neurogenic Detrusor Overactivity (NDO)

1. Botox is also approved for patients with urinary incontinence due to NDO resulting from neurological conditions such as:
   • Spinal cord injury
   • Multiple sclerosis (MS)

In these cases, Botox helps reduce involuntary bladder contractions caused by disrupted neural control.

Off-Label/Investigational Uses (with growing evidence):

While not always FDA-approved for these, Botox is increasingly being explored for:

• Interstitial cystitis/bladder pain syndrome
• Detrusor overactivity in children with neurological disorders
• Male lower urinary tract symptoms (LUTS) with bladder overactivity

When Botox is Considered:

• Patients failed or cannot tolerate first-line therapies (behavioral therapy, oral medications)
• Patients are willing to undergo intravesical injections
• Patients are able to perform clean intermittent catheterization (CIC) if urinary retention occurs post-treatment

Contraindications

While Botox is generally safe and effective for treating overactive bladder, it is not suitable for everyone. Certain medical conditions and situations make its use contraindicated due to the risk of complications.

Absolute Contraindications:

• Urinary Tract Infection (UTI) at the Time of Injection: Active UTI increases the risk of complications such as worsening infection or sepsis after the injection procedure.
• Urinary Retention or Inability to Perform CIC: Botox can cause temporary urinary retention. Patients who cannot or will not perform intermittent catheterization are not good candidates.
• Known Hypersensitivity to Botulinum Toxin or Any of Its Components. Allergic reactions can occur, including anaphylaxis, which makes further use dangerous.
• Neuromuscular Disorders (in some cases): Conditions like myasthenia gravis, amyotrophic lateral sclerosis (ALS), or Lambert-Eaton syndrome may be worsened by Botox due to its effect on nerve-muscle signaling.

Relative Contraindications (Use with Caution):

• Pregnancy and Breastfeeding: Safety has not been established, and use is generally avoided unless clearly necessary.
• Bleeding Disorders or Use of Anticoagulants: Increased risk of bleeding during the cystoscopic injection procedure.
• Previous Adverse Reactions to Botulinum Toxin: Including generalized muscle weakness or breathing difficulties.
• Severe or Progressive Neurological Disease: In patients already dealing with bladder dysfunction related to a progressive neurologic condition, further suppression could complicate management.

Side effects

While Botox is generally safe and effective for treating overactive bladder, like any medical treatment, it can cause side effects. These may range from mild and temporary to more serious, though rare.

Common Side Effects (Usually Mild to Moderate):

• UTI: The most frequently reported side effect. May occur due to the bladder instrumentation during injection or temporary urinary retention.
• Urinary Retention: Inability to completely empty the bladder, which may require CIC. Risk increases with higher doses.
• Dysuria: Pain or discomfort during urination.
• Hematuria: Blood in the urine, usually mild and self-limiting after the injection.
• Increased Post-Void Residual (PVR) Volume: The amount of urine left in the bladder after urination may rise, sometimes necessitating catheter use.

Less Common Side Effects:

• Fatigue: General tiredness or weakness.
• Muscle Weakness Rare and more likely in patients with underlying neuromuscular disorders.
• Urinary Urgency or Frequency: In some cases, OAB symptoms may persist or briefly worsen before improving.

Rare but Serious Side Effects:

• Generalized Botulinum Toxin Effects (Systemic Spread): Though extremely rare, Botox can spread beyond the bladder and affect other muscles, causing: Difficulty swallowing, breathing problems, muscle weakness in other areas
• Allergic Reactions: Including rash, itching, or more serious reactions like anaphylaxis.

Important Notes:

• Most side effects are temporary and resolve within a few days to weeks.
• Patients should be monitored for urinary retention, especially in the first 2 weeks post-injection.
• Follow-up assessments are important to manage any complications early.

How to administer?

Botox is administered via intravesical injection—directly into the bladder wall—using a cystoscopic procedure. This procedure is typically performed by a urologist in an outpatient or office-based setting.

Step-by-Step Procedure:

Pre-Procedure Preparation

• Patient evaluation:
  • Confirm indication (refractory OAB or neurogenic detrusor overactivity).
  • Rule out active UTI (treat before proceeding).
  • Ensure the patient understands the possibility of urinary retention and may need to self-catheterize.
• Informed consent is obtained.
• Prophylactic antibiotics may be given (per guidelines).

Botox Preparation

• The standard dose is:
  • 100 units for idiopathic OAB.
  • 200 units for neurogenic detrusor overactivity.
• Botox is reconstituted with sterile non-preserved saline (typically 10 mL for 100 units).

Procedure

• The bladder is filled with sterile water or saline for better visualization.
• A flexible or rigid cystoscope is inserted via the urethra.
• A needle is passed through the cystoscope into the bladder wall.
• Injection sites:
  • Typically 20 injections of 0.5 mL each, spaced throughout the detrusor muscle (excluding the trigone to avoid vesicoureteral reflux).
• Total injected volume is usually 10 mL.

Post-Procedure Care

• The patient is monitored briefly, then allowed to go home.
• UTI symptoms and urinary retention should be watched for over the next several days.
• A post-void residual (PVR) check may be done 1–2 weeks post-procedure.
• If PVR is high, intermittent catheterization may be necessary.

Onset and Duration of Action

• Improvement begins: Within 5–7 days
• Peak effect: Around 2–6 weeks
• Duration: Typically lasts 6–9 months
• Re-treatment: Usually after 12 weeks, if symptoms return

Important Considerations

• Patients must be willing and able to perform self-catheterization if necessary.
• Repeated treatments are safe and common but should not be given more frequently than every 12 weeks.
• Botox is not a cure—it controls symptoms but requires periodic maintenance.

Post-operative follow-up

After Botox injections for overactive bladder, follow-up care is important to monitor for complications and assess treatment effectiveness:

First Follow-Up (1–2 weeks post-injection):

• Assess for urinary retention (post-void residual volume).
  • Monitor for signs of UTI or discomfort.
  • Evaluate symptom improvement (urgency, frequency, incontinence).

Second Follow-Up (4–6 weeks post-injection):

• Reassess symptom control and response to treatment.
  • Confirm that the desired effects have occurred (reduced urgency, less frequent urination).
  • Discuss potential repeat injections if necessary (usually after 6–9 months).

Long-Term Follow-Up (every 6–9 months):

• Monitor for any return of symptoms.
  • Schedule repeat injections if Botox effect diminishes.

Regular follow-ups help ensure effective management of overactive bladder symptoms and early detection of potential complications.

How long do the effects of botox?

The effects of botulinum toxin type A in treating overactive bladder are temporary but long-lasting for many patients.

Typical Duration of Effect:

• Onset of action: Within 4 to 7 days after the injection
• Peak effectiveness: Around 2 to 6 weeks post-injection
• Duration of symptom relief: Typically lasts 6 to 9 months, Some patients may see effects for up to 10 months, while others may require reinjection sooner (after about 4–5 months)

Note

Individual responses may vary based on factors like:

• Severity of OAB
• Underlying neurological conditions
• Bladder capacity and muscle function
• Dose administered (100 vs. 200 units)

Does botox need to be repeated?

Yes, Botulinum toxin type A treatment for OAB does need to be repeated, as its effects are temporary.

Why Repeat Treatments Are Needed:

• The therapeutic effects of Botox wear off over time as nerve endings regenerate, and bladder muscle activity gradually returns.
• Symptoms such as urgency, frequency, and urge incontinence may reappear, signaling the need for a repeat injection.

Recommended Interval Between Injections:

• Reinjection should not occur sooner than 12 weeks, even if symptoms return early, to minimize the risk of side effects (e.g., urinary retention, resistance).
• Urologists will assess symptom recurrence, post-void residuals, and patient tolerance before scheduling repeat treatments.

Individual Factors That Influence Frequency:

• Severity of OAB or neurogenic bladder
• Dosage used (e.g., 100 units for idiopathic OAB, 200 units for neurogenic cases)
• Patient’s response to previous injections
• Willingness and ability to manage potential urinary retention

Summary

• Yes, repeat Botox treatments are usually required.
• Typical repeat interval: Every 6–9 months
• Minimum safe interval: Every 12 weeks

What if botox is not effective for OAB?

If Botox treatment fails to relieve symptoms of OAB—either due to lack of response, side effects, or diminishing benefit—there are several alternative treatment options to consider, depending on the patient’s medical history, symptom severity, and preferences.

Step Before Considering Alternatives:

• First, confirm that:
  • The correct dose was used (100 units for idiopathic OAB; 200 units for neurogenic).
  • Injections were placed correctly in the detrusor muscle.
  • The patient was given adequate time (2–6 weeks) to see results.

Best Alternative Treatments to Botox:

1. Sacral Neuromodulation (SNM)

• Example: InterStim™, Axonics®
• Involves implanting a small device (like a pacemaker) that delivers electrical impulses to sacral nerves (S3), which control bladder function.
• Effectiveness: High success rates (~70%+), often long-lasting.
• Suitable for patients with refractory OAB or urinary retention.

2. Percutaneous Tibial Nerve Stimulation (PTNS)

• A non-surgical, minimally invasive procedure.
• Delivers electrical stimulation to the tibial nerve near the ankle, indirectly affecting bladder control.
• Typically performed weekly for 12 weeks, then monthly for maintenance.
• Less invasive than SNM but requires regular clinic visits.

3. Combination Drug Therapy

• If monotherapy was ineffective, consider combining:
  • Anticholinergics + beta-3 agonists (e.g., oxybutynin + mirabegron).
• Can improve symptom control in some patients, though side effects may limit use.

4. Bladder Augmentation Surgery (Augmentation Cystoplasty)

• A major surgical option used in very severe, treatment-resistant cases.
• Part of the bowel is used to enlarge bladder capacity.
• Rarely needed, reserved for extreme refractory OAB or neurogenic bladder.

Considerations Before Switching:

• Evaluate patient’s bladder diary, post-void residuals (PVR), and comorbidities.
• Consider psychological and lifestyle factors that may contribute to treatment resistance.
• Reassess the initial diagnosis to ensure symptoms are not caused by another condition (e.g., bladder outlet obstruction, interstitial cystitis, UTI).

Summary

Botox is an FDA-approved treatment for OAB in adults who do not respond to or cannot tolerate conventional therapies. It works by injecting the toxin directly into the bladder muscle, where it blocks nerve signals that cause involuntary contractions, thus reducing symptoms like urinary urgency, frequency, and incontinence. The effects typically last 6–9 months, after which repeat injections may be needed. While Botox is generally safe, it can cause side effects like urinary retention, urinary tract infections, and dysuria. It is typically recommended for patients who have failed other treatments, offering a minimally invasive alternative to surgery.

Prof. Dr. Emin ÖZBEK

Urologist

Istanbul- TURKIYE