prostate cancer is the most common solid tumor in men and is the second leading cause of death among cancers .
diagnosis is performed through fragments obtained by ultrasound - guided transrectal prostate biopsy , which is usually performed on an outpatient basis .
many patients consider the procedure uncomfortable and painful ; about 65% to 90% of patients report moderate to severe pain and 20% would not repeat the procedure .
some of the factors that can cause pain during biopsy are anal discomfort generated by transducer insertion and needle penetration in the rectal wall , periprostatic tissue , and prostatic capsule .
the best means of analgesia for prostate biopsy has not yet been defined , and several techniques have been described , such as intrarectal lidocaine gel , anti - inflammatory drugs , periprostatic nerve block ( ppnb ) , and sedoanalgesia [ 4 - 19 ] .
the drug used should preferably be rapidly metabolized , have few side effects , and , if necessary , be easily reversed .
anal distension during the introduction of the transducer is an important component in the mechanism of pain generated by the procedure .
other pain - relieving techniques do not act on this mechanism , thus justifying the use of sedation .
fentanyl citrate is an opioid drug used in treating pain ; it is characterized by rapid onset , short duration , and high efficiency .
its administration is intravenous , and its action is installed within 2 - 3 minutes , lasting about 30 minutes .
it is used for sedation in combination with a benzodiazepine such as midazolam in endoscopic procedures .
midazolam is a sleep - inducing agent that can be administered intravenously , with rapid onset , short duration , and anterograde amnesia .
the study was performed in patients from the department of urology , botucatu medical school , unesp , after approval of the ethics in research board .
the inclusion criteria were as follows : abnormalities in the digital rectal examination suggesting prostate cancer , high prostate - specific antigen ( psa ; > 4.0 ng / ml in men over 55 years old and > 2.5 ng / ml in men younger than 55 years old ) , psa density greater than 0.15 , and annual psa increase greater than 0.75 ng / ml . patients with bleeding disorders , anorectal disease ( hemorrhoids , anal fissure , anal stenosis ) , urinary tract infection in treatment or diagnosed at the time of biopsy , spinal trauma , hypersensitivity to fentanyl citrate or midazolam , or who refused to provide written informed consent and were unable to answer the questionnaire were excluded from the study .
some parameters were analyzed as risk factors for pain during biopsy , such as age , race , education level , serum psa , free - psa and the free - psa / total psa ratio , rebiopsy , biopsy indication , and prostate volume .
complications such as hypotension , hypoxia , hemorrhage , urinary retention , and vasovagal reaction were also recorded .
the biopsy procedure was performed on an outpatient basis . a structured room with all the equipment required for urgent care and emergency care was necessary ( oxygen supply , laryngoscope , endotracheal tubes , respirator , defibrillator , and drugs ) .
three minutes before the procedure , 50 g of fentanyl citrate dissolved in 1 ml of distilled water and 5 mg of midazolam dissolved in a 1-ml distilled water bolus were administered in separate syringes intravenously in the upper left limb with a number 23 butterfly needle .
the procedure was performed with a 250-ml rectal enema and prophylaxis by administration of antibiotic ciprofloxacin 500 mg orally 2 hours before the procedure and after 8 hours .
the procedure was performed with the use of a transrectal probe with the patient in the left lateral decubitus position with the thighs flexed .
after the procedure , the patients remained in the recovery room until they could be discharged . in the immediate biopsy recovery period ,
all patients were evaluated by a single investigator responsible for measuring the primary pain outcome by use of a visual analogue scale ( vas ) .
the vas was used to evaluate the pain generated by the transducer introduction ( vas 1 ) and the pain generated by biopsy ( vas 2 ) .
after 7 days , the patients were evaluated again for the presence of pain ( vas 3 ) .
pain was classified as follows : absence of pain , score of 0 ; mild pain , score of 0.1 to 3 ; moderate pain , score of 3.1 to 7 ; and severe pain , score from 7.1 to 10 .
data were collected by use of a microsoft excel spreadsheet ( microsoft co. , redmond , wa , usa ) and were analyzed by using sas ver .
results were expressed as means and standard deviations ( sds ) for age , psa , prostate volume , and pain .
qualitative variables were described by frequency and percentage . to determine differences in pain levels among age , educational level , race , prostate volume , prebiopsy , rebiopsy , and anxiety ,
the kruskal - wallis test and wilcoxon rank - sum test were used when comparing two or more than two samples , respectively . in all tests ,
biopsies were performed in 118 patients , and of these , 56 patients ( 47.9% ) had undergone at least one procedure .
the average age , total psa , prostate volume , education level , and race of the patients are shown in table 1 .
of the 118 patients studied , 69 ( 58.4% ) reported anxiety in the exam and 56 ( 47.4% ) reported no anxiety . the average ( sd )
pain vas 1 was 1.951.98 mm . at this time , 75% of the patients reported pain lower than 3.1 mm , or mild pain .
pain assessment during the introduction of the probe for biopsy ( vas 2 ) had a mean of 2.732.55 mm . at the time of the vas 2 ,
75% of the patients reported pain lower than 4.5 and 50% reported pain lower than 1.5 , or mild pain .
just 5.4% and 11% of the patients reported severe pain at vas 1 and vas 2 , respectively .
evaluation of pain in the weeks following the biopsy ( vas 3 ) had a mean of 0.30.9 mm , whereas 75% of patients reported no pain .
there were huge differences among vas 1 , 2 , and 3 with high significance ( vas 2>vas 1>vas 3 , p=0.0013 ) .
pain intensity at different times ( vas 1 , vas 2 , and vas 3 ) was compared with stratification by age , race , educational level , and other possible influencing factors such as prostate volume , rebiopsy , prebiopsy anxiety , and prostate cancer diagnosis .
none of these factors had a significant influence on the pain level with this kind of sedoanalgesia .
the main complications were rectal bleeding ( 21 patients , 17.7% ) , vasovagal reaction ( 5 patients , 4.2% ) , urinary retention ( 8 patients , 6.7% ) , urethral bleeding and fever ( 1 patient , 0.8% ) , pain ( 14 patients , 11.8% ) , hematuria ( 75 patients , 63.4% ) , and hemospermia ( 51 patients , 43.2% ) .
of 14 patients who reported moderate to severe pain during the procedure , it was necessary to use a double dose to perform the procedure in 11 ( 78% ) .
there were no respiratory or cardiac complications , even in elderly patients who required an additional dose of medication ( 10 mg midazolam and 100 g fentanyl citrate ) .
with the introduction of serum psa in prostate cancer screening , there has been a significant increase in the number of biopsies , which has consequently led to a better diagnosis .
about 65% to 90% of patients report pain of moderate to severe intensity , and 20% do not repeat the examination .
sextant biopsy was considered the method of choice for many years , but nowadays it is recommended to obtain at least 12 fragments to increase the tumor diagnoses .
the high number of punctures increases the prostate cancer diagnosis , but pain , anxiety , and discomfort are proportional to the number of punctures .
the main factors responsible for pain during the biopsy are anal discomfort generated by transducer insertion and as a result of the needle penetration in the rectal wall , prostatic capsule , and periprostatic tissue .
other factors such as age , transducer size , and procedure time can affect pain intensity .
some studies have shown that younger patients or patients with smaller prostates have more discomfort during the biopsy .
additionally , prebiopsy anxiety or rebiopsy as a result of a prior biopsy procedure are mentioned as factors predisposing to a higher pain intensity .
we did not observe that these factors affected the pain scores , which may have been the result of the excellent analgesia and sedation obtained by the drugs used . in our research
, there was no control group , because it is not ethical to perform this design without analgesia .
even if there were risk factors involved in providing pain relief , this method of sedoanalgesia alleviated pain regardless of the presence or absence of these factors .
although the best means of analgesia for prostate biopsy has not yet been defined , several techniques have been described in the literature .
several studies have shown that one of the benefits of ppnb is to reduce pain safely in prostate biopsy .
because of these indicators , ppnb is considered the standard analgesia procedure for prostate biopsy . however
, patients still suffer significant emotional and physical discomfort before the procedure , which can increase the pain stimulus . moreover , ppnb does not act in the pain mechanism generated by the anal stretching that occurs when the rectal probe is introduced .
therefore , we believe that the use of intravenous sedation and analgesia is the most effective method for controlling pain during prostate biopsy .
this method of analgesia can optimize the benefits of the ppnb and may directly interfere in the anxiety and pain sensation caused by anal stretching from the transducer .
these beneficial effects of intravenous sedation and analgesia are important considering that the number of prostate biopsies has been growing steadily , especially in economically active young patients , and also that biopsy may be repeated several times in the same patient including a larger number of fragments ( 16 , 20 , or 24 fragments ) .
the drug used should preferably be rapidly metabolized with few side effects and , if necessary , be easily reversed .
we do not doubt that sedoanalgesia with the attendance of an anesthesiologist will have a higher cost than the cost of a urologist or radiologist performing the procedure alone .
however , this kind of sedoanalgesia can be performed by the urologist in a structured room with a defibrillator , material for resuscitation , and airway intubation . despite the small number of patients
in fact , the costs of sedoanalgesia and prostatic nerve block are similar . in our service
, we do not work with anesthesiologists to perform sedation and analgesia . in the united kingdom , it is common to use nitrous oxide .
however , the procedure requires the compulsory attendance of the anesthesiologist , which can be considered a drawback , because it increases the cost of the procedure .
moreover , owing to nausea and vomiting as side effects , the patients must stay in the recovery room for up to 4 hours after the procedure . with the use of midazolam and fentanyl citrate
, the patients could leave the recovery room on average 30 minutes after the procedure , which facilitated its logistics .
some studies have evaluated the use of midazolam and meperidine for sedation and analgesia for prostatic biopsy .
tobias - machado et al .   conducted a randomized controlled trial comparing three different types of anesthesia ( administration of 2% intrarectal lidocaine gel , ppnb , and sedation with a combination of midazolam and meperidine ) to evaluate efficacy in reducing pain during prostate biopsy . in the ppnb group ,
78.33% of the patients reported pain , with 86.7% reporting weak pain and only 3.33% reporting severe pain .
no patient had unbearable pain , and compared with the control group , there was significant reduction in pain ( p<0.001 ) . in the group receiving sedation with midazolam and meperidine , 76% of patients reported some pain , and of these 81.6% had little or no pain ; only 4.99% reported severe or unbearable pain . compared with the control group , the pain reduction in the group receiving sedation with midazolam and meperidine was significant ( p<0.001 ) .
recently , izol et al .   published a study that evaluated three different analgesia techniques on prostate biopsy .
pain intensity was assessed by vas graded in three stages : during biopsy ( vas 1 ) , immediately after the procedure ( vas 2 ) , and 1 hour later ( vas 3 ) .
a total of 100 patients were randomized into 4 groups : group 1 ( control ) , group 2 ( periprostatic block with 2% lidocaine ) , group 3 ( intrarectal lidocaine gel ) , and group 4 ( sedation and analgesia with 2 mg midazolam and 2 g / kg fentanyl intravenously ) . in the group receiving sedation and analgesia with midazolam and fentanyl , a decrease in pain intensity in these three conditions ( vas 1 , vas 2 , and vas 3 ) was observed .
groups 2 and 4 were statistically significant compared with the group that received intrarectal lidocaine gel and the gel control group ( p=0.0001 ) .
of 100 patients undergoing the procedure , only 1 patient ( belonging to the group that underwent periprostatic block ) presented with hypotension , which was quickly treated .
the study concluded that the association of midazolam with fentanyl and ppnb are effective and superior to the other techniques to relieve pain .
the authors recommended sedoanalgesia only in patients who do not tolerate pain , in saturation biopsies , and in patients who are allergic to lidocaine . in our study , the combination of midazolam and fentanyl citrate proved to be easy to apply , safe , and effective in reducing pain and discomfort both during and after the procedure . in our samples ,
the association of these two drugs proved to be an excellent method of analgesia and sedation .
midazolam acts by promoting sedation , retrograde amnesia , and relaxation of the anal muscle tone , which is one of the mechanisms responsible for pain during the procedure .
fentanyl , in turn , is a potent opioid analgesic drug during and after the procedure .
we noticed that after the procedure , when the patients were discharged , some of them did not remember having undergone it , which must be due to retrograde amnesia promoted by midazolam .
it is important to emphasize that midazolam promotes only retrograde amnesia without compromising cognition , which did not interfere in the evaluation of pain after the procedure .
the evaluation of the patient before the procedure can be carried out in the questionnaire that is routinely given before the biopsy indication . in our previous experience
, there is a contraindication to perform it in patients with low cardiac and respiratory reserve .
the average time for patient recovery is either about 30 minutes or is not different from the care given to patients with the use of ppnb .
complications due to the use of these drugs are very rare with similar rates [ 16 - 19 ] .
when complications do occur , they can be circumvented because the procedure is performed in an appropriate and structured place by providers professionally trained and qualified to treat them .
intravenous sedation and analgesia with midazolam and fentanyl citrate is a good method to reduce the discomfort and pain caused by prostate biopsy , even during probe insertion .
 purposeto assess the pain intensity of patients administered midazolam and fentanyl citrate before undergoing transrectal ultrasound - guided prostate biopsy.materials and methodsthis was a study in patients with different indications for prostate biopsy in whom 5 mg of midazolam and 50 g of fentanyl citrate was administered intravenously 3 minutes before the procedure . after biopsy , 
 pain was assessed by use of a visual analogue scale ( vas ) in three stages : vas 1 , during probe introduction ; vas 2 , during needle penetration into prostate tissue ; and vas 3 , in the weeks following the exam . 
 pain intensity at these different times was tested with stratification by age , race , education , prostate volume , rebiopsy , and anxiety before biopsy . 
 pain was ranked according to the following scores : 0 ( no pain ) , 1 - 3 ( mild pain ) , 4 - 7 ( moderate pain ) , and 8 - 10 ( severe pain ) . 
 statistical analysis was performed by using kruskal - wallis and wilcoxon two - tailed tests with a significance of 5%.resultspain intensity was not influenced by any risk factors . 
 the mean vas 1 score was 1.951.98 , the mean vas 2 score was 2.732.55 , and the mean vas 3 score was 0.30.9 , showing greater pain at the time of needle penetration than in other situations ( vas 2>vas 1>vas 3 , p=0.0013 , p=0.0001 , respectively ) . 
 seventy - five percent of patients reported a vas pain scale of less than 3.1 or mild pain.conclusionsintravenous sedation and analgesia with midazolam and fentanyl citrate is a good method for reducing pain caused by prostate biopsy , even during probe insertion . 
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
CONCLUSIONS