We investigated sub-optimal pain relief of intradetrusor injection at 20-30min post-instillation of ≤ 1% w/v un-alkalinized lidocaine (1) in recent randomized controlled trials (RCT) of onabotulinumtoxinA, listed in the table (Fig.1B). Because Henderson Hasselbalch equation for lidocaine's pKa of 7.8 predicts higher unionized lidocaine at alkaline pH >7 for rapid intravesical absorption, we hypothesize that intradetrusor injection at ≥ 20min post-instillation of ≤ 1% w/v un-alkalinized lidocaine (1) is not as aligned with Tmax as ≤ 15min of post-instillation of >1%w/v alkalinized lidocaine (2-3).

We distilled published evidence of instilled lidocaine for pharmacokinetic-pharmacodynamic correlation and first order kinetic modelling of serum levels at 0-30min in five prospective (P), RCTs and retrospective (R) studies.

While peak anesthetic effect of applied lidocaine in urethra coincides with Tmax of 15min, instilled lidocaine exhibits Tmax of 5min in human bladder and vagina.  Therefore, alignment with Tmax ensures completion of intradetrusor injection before exponential decline of serum lidocaine levels from peak serum lidocaine levels (Cmax) fall below the efficacy threshold (Fig.1A). Instilled concentration 0.5% to ≥1% w/v dependent rise of anesthetic efficacy in RCTs (Fig.1B) is caused by proportional doubling of Cmax from 1mg/L to 2mg/L and steep rise to Cmax depicts first order kinetics of rapid absorption (A) whereas steeper upslope (Fig.1A) at larger instilled volume of 100mL vs 6mL display faster absorption rate constant (ka) following enlargement of enlarged tight junction gap between umbrella cell borders accelerating paracellular diffusion of lidocaine.  Instilled volume, pH and concentration only impact monoexponential rise to Cmax but do not impact biexponential decline from Cmax, emblem of two-compartmental pharmacokinetics. While initial steep decline (D) from Cmax depicts widespread rapid binding of lidocaine with Na+ channels in large volume of distribution (Vd) of~100L, flatter terminal slope displays slower elimination (E).

As molecular size of lidocaine is comparable to fluorescein, scant fluorescence of detrusor layer post-instillation of fluorescein portrays restricted diffusion of instilled lidocaine to the detrusor layer. Accordingly, instilled lidocaine reaches detrusor layer only after systemic dilution in blood with maximal levels at Cmax (Fig.1A). Therefore, maximal relief of intradetrusor injection pain at ≤ 15min of post-instillation correlates with Cmax whereas sub-optimal pain relief at 20min post-instillation in RCT (Fig.1B) can be attributed to 
exponential decline from Cmax at 20min. Likewise, exponential rise to Cmax causes rapid onset of lidocaine anesthesia and blood pressure dip of spinal cord injured patients at 2min post-instillation whereas lidocaine toxicity at 5min post-instillation in a pediatric case report confirms systemic absorption of ~20% of instilled dose at5 min post-instillation- product of Cmax (1mg/L)*Vd (100L). The hypothesis of Tmax alignment for intradetrusor injection pain relief can be tested by measuring serum lidocaine levels immediately post- instillation and before Tmax to plot true absorption phase of instilled lidocaine. While intact perfusion of human bladder propels first order kinetics for systemic absorption of ~20% applied lidocaine dose by 5min, pig bladder excised from perfusion only enables zero order kinetics for 1.4% dose absorption of applied lidocaine by 60min (ex-vivo). Therefore, mammalian bladder excised from perfusion may not provide any meaningful insight on anesthesia period of instilled lidocaine for intradetrusor injection.

The rapid onset of anesthesia with proportionally shorter duration 19min to ≤ 10min at lower lidocaine concentration (2% to ≤1% w/v) is emblematic of first order absorption and elimination kinetics of instilled lidocaine. Because of exponential rise and fall from Cmax(Fig.1A), optimal anesthesia for intradetrusor injection is only assured when injection timing is aligned with the Tmax of >1% w/v alkalinized lidocaine whereas intradetrusor injection misaligned with Tmax result in sub-optimal pain relief at 20min post-instillation of un-alkalinized lidocaine ≤1% w/v in published RCTs (Fig.1B).

Negrean C, Ross J, Yu W, Maciejewski C, Vigil HR, Hickling D. Lidocaine solution vs. lidocaine gel instillation for pain management during intravesical botulinum injections. Can Urol Assoc J. 2025 Jun;19(6):189-192.
Pereira E Silva R, Ponte C, Lopes F, Palma Dos Reis J. Alkalinized lidocaine solution as a first-line local anesthesia protocol for intradetrusor injection of onabotulinum toxin A: Results from a double-blinded randomized controlled trial. Neurourol Urodyn. 2020 Nov;39(8):2471-2479.
El Issaoui M, Elmelund M, Klarskov N. Alkalinised lidocaine as an anaesthetic before onabotulinumtoxinA injections. a randomised trial.BJU Int. 2025;135(4):638-647