What's known on the subject? and What does the study add? Study Type - Harm Reduction RCT Level of Evidence 1b The combination of perianal-intrarectal lidocaine-prilocaine cream and periprostatic nerve block effectively counteracts probe and sampling related pain during transrectal prostate biopsy, but not pain due to periprostatic infiltration. The novel combination of lidocaine-prilocaine cream and lidocaine-ketorolac gel, both administered perianal-intrarectally, provides the same probe and sampling-related pain relief than combined perianal-intrarectal lidocaine-prilocaine cream and periprostatic nerve block and prevents the non-negligable pain due to periprostatic infiltration, thus leading to better overall patients' compliance to the procedure. OBJECTIVE To compare the efficacy and safety of combined perianal-intrarectal (PI) lidocaine-prilocaine (LP) cream and lidocaine-ketorolac (LK) gel with combined PI LP cream and periprostatic nerve block (PPNB) in relieving pain during transrectal ultrasonography guided prostate biopsy (TPB). PATIENTS AND METHODS In all, 200 patients were randomized to receive combined PI LP cream and LK gel (group 1) or combined PI LP cream and PPNB (group 2) before TPB. The 0-10-point visual analogue scale (VAS) was used for assessing pain at probe insertion and movements (VAS-1), periprostatic infiltration (VAS-2) when applied, and prostate sampling (VAS-3), as well as maximal procedural pain (MPP). Complications occurring ≤20 days after the TPB were recorded. RESULTS The groups were comparable for patients' age, serum PSA level, prostate volume, and cancer detection rate. All patients tolerated the procedure well. The two anaesthetic regimens provided almost equal mean VAS-1 (0.33 vs 0.37; P= 0.701) and VAS-3 (0.52 vs 0.51; P= 0.954) scores, but patients in group 2 reported significantly greater MPP scores (0.68 vs 1.53; P < 0.001) as periprostatic infiltration was the most painful part of the procedure (mean VAS-2: 1.33). Complications rate was similar in the two groups (1% vs 2%; P= 0.38). CONCLUSIONS The novel combination of PI LP cream and LK gel provided the same probe- and sampling- related pain relief as combined PI LP and PPNB; moreover, by preventing the non-negligible periprostatic infiltration pain, it provided significantly better overall patients' compliance to the procedure. Being safe and easy to administer, this novel non-infiltrative regimen has the potential to replace infiltrative anaesthesia in relieving pain during TPB