We performanced a NMA about managing urological postoperative CRBD which 18 recent studies were included from 2014-2021 and the effectiveness of 16 intetventions were compared in Bayesian network model by ADDIS softwore. Although our network meta-analysis was limited by the small number of studies and the heterogeneity of the included studies, we obtained comparative effectiveness of these interventions in the incidence and severity of postoperative CRBD. The major findings of our study were as follows: (1) Nefopam was ranked best in managing moderate to severe CRBD at 1h, (2) Nefopam was ranked best in terms of severity and (3)there was low conmsistency in our NMA. Despite the lack of evidence and poor quality, we report our NMA because head-to-head comparisons of many of the investigated drugs for the treatment and prevention of CRBD after urological surgery are still lacking.
CRBD is catheter-induced bladder irritation due to muscarinic receptor-mediated involuntary contraction of bladder smooth muscle. When the catheter and urine bag are connected, bladder urine is expelled, and the tip of the catheter contacts the bladder wall, causing irritation and erosion of the bladder wall[20] and the incidence of CRBD in catheterized patients reaches 90%[1].CRBD occurs after all perioperative catheterization procedures but is more common in urologic procedures, especially after transurethral resection of bladder tumors(TURBt) and transurethral resection of prostate(TURP)[21].The mechanisms of CRBD is relative to muscarinic receptors. Muscarinic receptors in the bladder were heterogeneously distributed, with M2 receptors being the main one and M3 receptors being less. Activation of M2 receptors causes contraction of detrusor smooth muscle to cause dysuria, urgency, frequency and burning sensation in the suprapubic region[22], which is similar to OAB. Since the similarity between CRBD and OAB, many interventions which were used to manage OAB, were assessed whether they are effective in CRBD.
Nefopam is non-opioid and non-steroidal and derives from a non-sedative benzoxazocine has been used to treat mild to moderate postoperative pain in different clinical settings[23, 24].Nefopam induces antitoxicity and inhibits central hyperalgesia in animal experiments[25].Its main mechanisms of analgesic effect include inhibition of serotonin, norepinephrine, and dopamine reuptake, as well as decreased activation of postsynaptic glutamate receptors by regulating calcium and sodium channels[26].
According to our outcomes, Nefopam is as the best drug to manage CRBD beacuse a combination of multiple mechanisms might contribute to prevent CRBD. First, This may be related to the triple receptor reuptake inhibition of nefopam. The major source of serotonin-containing terminals in the spinal cord is the raphe nucleus. The lumbosacral autonomic nucleus, also known as the motor nucleus of the sphincter, receives serotonergic input from the raphe nucleus, and stimulation of the raphe nucleus has been found to inhibit the bladder contractile reflex in cat and rat studies[27, 28]. Selective serotonin uptake inhibitors have inhibitory effects on overactive bladder. Therefore, we speculate that nefopam may also inhibit bladder activity by increasing serotonin in the central nervous system. Second, extracellular calcium influx through calcium channels is an important condition for activation of the detrusor via muscarinic receptors and noradrenergic pathways[29], and the effects of nefopam on calcium channels may inhibit detrusor hyperactivity.
CRBD has aroused a large attention of urologists because of higher incidence. Moataz et al established a descriptive epidemiological profile of patients with CRBD and determined its predictors[30]. They concluded that improving surgical technique can reduce the incidence of CRBD. Eun et al made a review of managing CRBD which concluded that many drugs included Gabapentin, Solifenacin, Tolterodine and so no could improve CRBD after surgery, however, most of these studies were conducted after intubation of patients taking the drug under anesthesia[20]. At present, there are few studies on the treatment of CRBD in patients with short-term or long-term catheterization of urinary system diseases, and no prospective study of these patients has been reported[20]. In a recent study, Marie et al also performed a review of CRBD, describing the effectiveness of many drugs included Gabapentin, Magnesium, Dexmedetomidine and Ketamine, which suggested perioperative drug therapy is beneficial for preventing postoperative CRBD but there were controversies about rank of effectiveness of various interventions[21].There was a NMA also analysed the effect of some drugs and it concluded that Gabapending 1200mg ranked the best in reducing incidence of CRBD and Tolterodine ranked the best in term of severity, which was different from our conclusion. We think the reasons is following: (1) We included drugs and interventions were more, (2)The RCTs we included were published in the recent ten years however the former NMA did not include the recent five years studies and (3) the technology of surgery and nursing has made a great progress, which reduced the incidence of CRBD.
Our NMA comprehensively analyzed RCTs related to CRBD in the past decade, ranked almost all interventions, and provided references for the treatment of CRBD, But it has limitations that must be considered when interpreting our findings. First, differences in patient characteristics and study designs in RCTs need to be considered when interpreting the outcomes. For example, Patients underwent different urological procedures, which led to marked differences in the incidence of postoperative CRBD, so that heterogeneous existed across the study. Second, each drug had side effects including dizziness, nausea, vomiting, etc. However, we could not compare them in our NMA. Therefore, side effects should also be taken into account when choosing a therapeutic drug. However, it is interesting that Nefopam is not only the best drug in our study but also as a effective drug to manage pain after surgery such as Laparoscopic Cholecystectomy and arthroscopic orthopedic surgery[31, 32] with a lower incidence of postoperative adverse effects in recent study. Third, most studies were small RCTs with more than half of them at unclear or high risk of bias. The number of studies for each intervention was small. Subgroup analyses or sensitivity analyses were not possible due to the small number of studies. Paucity of head to head comparisons between two interventions decreases the quality of network estimate by increasing loop-specific heterogeneity[33].