No Laughing Matter: Nitrous Oxide for Transrectal Prostate Biopsy

Patient-adjusted nitrous oxide (N₂O), commonly called laughing gas, did not reduce anxiety associated with transrectal prostate biopsy but significantly reduced pain as compared with standard anesthesia, a small randomized study showed.

Scores on a standardized anxiety questionnaire, the primary endpoint, did not differ significantly between patients randomized to N₂O or standard care. However, patents in the N₂O group reported significantly less pain, and urologists who performed the biopsies rated patient tolerance of the procedure significantly better with the addition of N₂O.

Procedure time and complication rates did not differ between the two groups, reported Heidi J. Rayala, MD, PhD, of Beth Israel Deaconess Medical Center in Boston, and colleagues in the Journal of Urology.

“To our knowledge, this is the first prospective, randomized, controlled study assessing the effects of low-dose (20-45%) N₂O on patient experience during transrectal prostate biopsy,” the authors wrote. “Notably, there was not an observed decrease in the study’s primary endpoints related to patient anxiety. However, there was an observed reduction in secondary endpoints of patient-perceived pain. Overall, SANO [self-adjusted nitrous oxide] was well tolerated with no significant side effects and no impact on the ease of the operating urologist’s performance of the procedure.”

“These results suggest that the option of adjuvant N₂O may improve patients’ experience of care as they undergo diagnostic evaluation for prostate cancer,” the team added.

N₂O has been used in a variety of office-based urologic procedures, including transrectal ultrasound (TRUS)-guided prostate biopsy, flexible cystoscopy, shock wave lithotripsy, and ureteral stenting, noted Raed A. Azhar, MD, of King Abdulaziz University in Jeddah, Saudi Arabia, in an accompanying editorial comment. N₂O has proven to be a cost-effective, self-administered analgesic that triggers release of opioid peptides from gray matter.

Published studies have supported the safety and efficacy of N₂O as an analgesic and anxiolytic in office-based procedures, which minimizes use of narcotics and intravenous anesthetics, Azhar continued. A previous randomized study showed that a 50-50 mix of N₂O and oxygen significantly reduced pain intensity and increased patient satisfaction during TRUS prostate biopsy.

“Considering the sparse guidelines that support the use of N₂O for sedation in outpatient procedures, a large, multicenter, randomized, clinical trial including more diverse patient groups is needed,” he added.

The authors of a second editorial comment called the study “relevant, timely, and needed.”

“As the field shifts from transrectal to transperineal PBx [prostate biopsy] to reduce or eliminate antibiotic use while maintaining low rates of infectious complications and potentially yielding more accurate biopsies, it’s important to acknowledge that transperineal PBx may result in a longer and more painful experience,” wrote Lorenzo Storino Ramacciotti, MD, and Andre Luis Abreu, MD, both of the University of Southern California in Los Angeles. “This could exacerbate the considerable anxiety, uncertainty, fear, and embarrassment already faced by patients undergoing PBx.”

“Effectively managing patients’ pain and anxiety is crucial for the broader acceptance and implementation of transperineal PBx,” they added “A realistic alternative towards optimizing patient experience during prostate biopsy, balancing procedural safety, efficiency, cost-effectiveness, and ultimately improving patient care is essential.”

N₂O History

TRUS-guided prostate biopsy remains a foundational procedure for prostate cancer diagnosis, and the role has gained prominence with increasing emphasis on active surveillance, exceeding more than 1 million procedures a year in the U.S., Rayala and co-authors noted in their introduction to the study. Multiple approaches to relieve procedure-associated pain and anxiety have met with mixed results. One study in the post-biopsy setting showed that almost 20% of men considered future prostate biopsies a “major or moderate problem.”

One of the oldest inhaled anesthetics, N₂O has a history in urologic procedures dating back to the 1930s. Widely used delivery systems in the U.S. and Europe employ a 50-50 mix of N₂O and oxygen, Rayala and co-authors continued. A recent study in the setting of clinical depression showed that 25% N₂O decreased the incidence of adverse effects. The findings begged the question of whether N₂O levels <50% can preserve efficacy while reducing side effects.

Rayala and colleagues conducted a randomized study of patient-controlled N₂O analgesia with concentrations of 20-45%. Patients randomized to the control arm received oxygen plus a standard periprostatic bupivacaine block. N₂O levels were adjusted to patients’ desired effect.

The primary outcome was the mean score on the State Trait Anxiety Index (STAI). Pain was assessed before and after biopsy by means of a visual analog scale (VAS).

Key Findings

The investigators randomized 133 patients undergoing TRUS prostate biopsy. The mean N₂O value required to achieve patient-signaled comfort was 39%, reached after probe insertion. The two groups were similar with respect to prebiopsy anxiety and pain.

The results showed that the N₂O group had a mean STAI score of 11 compared with 12 for patients randomized to oxygen. VAS-assessed anxiety scores also did not differ between the two groups, nor did scores for pain catastrophizing.

Patient-rated pain was significantly less (P=0.03) and operators’ perception of patient tolerance of the procedure was significantly better (P=0.02) with N₂O. Post-biopsy pain correlated significantly with post-biopsy anxiety in both groups (P<0.001).

The authors acknowledged several limitations of the study: use of a non-validated operator survey, inherent limitations of a single-center study, and potential lack of generalizability of the N₂O because of institutional barriers.

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