acute pancreatitis is an inflammatory condition of the pancreas characterized clinically by abdominal pain and elevated levels of pancreatic enzymes : amylase and lipase in the blood .
the incidence of acute pancreatitis in the united states is approximately 17 cases per 100,000 people .
although gallstones and alcohol cause > 90% of all cases in adults , medications have been recognized as a potential cause of acute pancreatitis . since the first reported case of acute pancreatitis in the 1950s , hundreds of commonly prescribed medications have been reported to induce acute pancreatitis .
even medications are considered a common cause of acute pancreatitis , but the numbers of reported drug - induced acute pancreatitis cases account for only 0.1% to 2% of all cases . benzodiazepines ( bzds ) are used as sedatives and to treat anxiety , seizure , withdrawal disorder , sleeping disturbance , and agitation .
because of their versatility , bzds are widely prescribed , and there are nearly 50 kinds of bzds available worldwide . however , the high incidence of bzd poisoning reflects their universal use and availability .
bzd poisoning refers to ingesting the bzd class in quantities greater than those recommended or generally used .
the most common symptoms of bzd poisoning include central nervous system depression , impaired balance , and slurred speech .
the us food and drug administration has reported that since 2001 to 2012 , 81 people ( 0.33 % ) had acute pancreatitis among 24,300 people taking zolpidem with side effects .
in addition , lai et al found these patients actively using zolpidem were at 7-fold increased odds of acute pancreatitis in taiwan .
zolpidem is a short - acting non - bzd hypnotic with fewer side effects than bzd , because zolpidem potentiates -aminobutyric acid ( gaba ) by binding only to  subunit .
in contrast to zolpidem , bzd has a higher affinity for other subunits of gaba .
therefore , we believed bzds overdose could also increase risk of acute pancreatitis . in this study
, we used data from the taiwan national health insurance research database ( nhird ) to investigate whether bzd poisoning increases the risk of acute pancreatitis .
the taiwan national health insurance ( nhi ) program integrated 13 insurance programs into a nationwide , single - payer health insurance program implemented in 1995 . in 1998 , the coverage rate reached 99% of the 23 million taiwan residents ( http://www.nhi.gov.tw/english/index.aspx ) .
the taiwan government appointed the national health research institute to establish and manage the nhird , which contains all historical reimbursement claims data , including a registry for beneficiaries , disease records , and medical services ; the database is updated each year . before releasing the data for research purposes , the national health research institute encrypts all personal identification information and provides an anonymous identification number to protect patient privacy .
this study was approved to fulfill the condition for exemption by the institutional review board ( irb ) of china medical university ( cmuh-104-rec2115 ) .
disease diagnoses in the nhird are based on the criteria of the international classification of diseases , ninth revision , clinical modification ( icd-9-cm ) .
cases of bzd poisoning before 2000 were excluded . the bzd poisoning cohort comprised patients who used bzd - based tranquilizers ( icd-9-cm 969.4 ) during 2000 to 2011 and were aged  > 20 years .
each bzd poisoning cohort patient was frequency matched to 4 comparison controls according to age and sex ( per 5 years ) ; the controls had no bzd poisoning .
the index date for the comparison controls was set by randomly appointing a month and day with the same index year as that of the matched cases .
we excluded the individual with the history of the pancreas cancer ( icd-9-cm 157 ) , chronic pancreatitis ( icd-9-cm 577.1 ) , and acute pancreatitis ( icd-9-cm 577.0 ) before the index date in bzd poisoning cohort and comparison cohort .
follow - up was terminated after 3 months or upon withdrawal from the nhi program , acute pancreatitis occurrence , or december 31 , 2011 .
in addition to demographic factors , we considered the effect of comorbidities on the risk of acute pancreatitis . a history of comorbidities before the index date was collected and included chronic obstructive pulmonary disease ( copd , icd-9-cm 491493 and 496 ) , alcohol - related disease ( ard , icd-9-cm 291 , 303 , 305.0 , 790.3 , and v11.3 ) , cardiovascular disease ( cvd , icd-9 410414 , 428 , 430438 , and 440448 ) , gallstone ( icd-9-cm 574 ) , chronic kidney disease ( icd-9-cm 585586 and 588.8588.9 ) , diabetes mellitus ( dm , icd-9-cm 250 ) , hepatitis c virus infection ( icd-9-cm v02.62 , 070.41 , 070.44 , 070.51 , 070.54 ) , hepatitis b virus infection ( hbv , icd-9-cm v02.61 , 070.20 , 070.22 , 070.30 and 070.32 ) , and hypertriglyceridemia ( icd-9-cm 272.1 ) .
to determine the structure of the study population , we calculated the means and standard deviations for number , percentage , age , age group , sex , and comorbidities .
the t test and  test was used to determine the distribution difference for continuous variables and category variables , respectively .
the incidence density of acute pancreatitis for each group was calculated as number of acute pancreatitis incidences divided by the sum of follow - up time ( per 1000 person - months ) .
the cumulative incidence curves were measured using the kaplan  meier method , and the difference in the curves was assessed using the log - rank test .
the risk of acute pancreatitis between the bzd poisoning and comparison cohorts was presented as hazard ratios ( hrs ) and 95% confidence intervals ( cis ) by using single variable and multivariate cox proportional hazards models .
in addition , we estimated the acute pancreatitis risk in the bzd poisoning cohort according to different demographic characteristics and comorbidities by conducting a stratified analysis involving the cox model .
the data management and statistical analysis was performed using sas 9.4 software ( sas institute , cary , nc ) .
the significance level was set at < 0.05 for the 2-sided testing of the p value .
the taiwan national health insurance ( nhi ) program integrated 13 insurance programs into a nationwide , single - payer health insurance program implemented in 1995 . in 1998 , the coverage rate reached 99% of the 23 million taiwan residents ( http://www.nhi.gov.tw/english/index.aspx ) .
the taiwan government appointed the national health research institute to establish and manage the nhird , which contains all historical reimbursement claims data , including a registry for beneficiaries , disease records , and medical services ; the database is updated each year . before releasing the data for research purposes , the national health research institute encrypts all personal identification information and provides an anonymous identification number to protect patient privacy .
this study was approved to fulfill the condition for exemption by the institutional review board ( irb ) of china medical university ( cmuh-104-rec2115 ) .
disease diagnoses in the nhird are based on the criteria of the international classification of diseases , ninth revision , clinical modification ( icd-9-cm ) .
cases of bzd poisoning before 2000 were excluded . the bzd poisoning cohort comprised patients who used bzd - based tranquilizers ( icd-9-cm 969.4 ) during 2000 to 2011 and were aged  > 20 years .
each bzd poisoning cohort patient was frequency matched to 4 comparison controls according to age and sex ( per 5 years ) ; the controls had no bzd poisoning . the index date for the comparison controls
was set by randomly appointing a month and day with the same index year as that of the matched cases .
we excluded the individual with the history of the pancreas cancer ( icd-9-cm 157 ) , chronic pancreatitis ( icd-9-cm 577.1 ) , and acute pancreatitis ( icd-9-cm 577.0 ) before the index date in bzd poisoning cohort and comparison cohort .
follow - up was terminated after 3 months or upon withdrawal from the nhi program , acute pancreatitis occurrence , or december 31 , 2011 .
in addition to demographic factors , we considered the effect of comorbidities on the risk of acute pancreatitis . a history of comorbidities before the index date was collected and included chronic obstructive pulmonary disease ( copd , icd-9-cm 491493 and 496 ) , alcohol - related disease ( ard , icd-9-cm 291 , 303 , 305.0 , 790.3 , and v11.3 ) , cardiovascular disease ( cvd , icd-9 410414 , 428 , 430438 , and 440448 ) , gallstone ( icd-9-cm 574 ) , chronic kidney disease ( icd-9-cm 585586 and 588.8588.9 ) , diabetes mellitus ( dm , icd-9-cm 250 ) , hepatitis c virus infection ( icd-9-cm v02.62 , 070.41 , 070.44 , 070.51 , 070.54 ) , hepatitis b virus infection ( hbv , icd-9-cm v02.61 , 070.20 , 070.22 , 070.30 and 070.32 ) , and hypertriglyceridemia ( icd-9-cm 272.1 ) .
to determine the structure of the study population , we calculated the means and standard deviations for number , percentage , age , age group , sex , and comorbidities .
the t test and  test was used to determine the distribution difference for continuous variables and category variables , respectively .
the incidence density of acute pancreatitis for each group was calculated as number of acute pancreatitis incidences divided by the sum of follow - up time ( per 1000 person - months ) .
the cumulative incidence curves were measured using the kaplan  meier method , and the difference in the curves was assessed using the log - rank test .
the risk of acute pancreatitis between the bzd poisoning and comparison cohorts was presented as hazard ratios ( hrs ) and 95% confidence intervals ( cis ) by using single variable and multivariate cox proportional hazards models .
in addition , we estimated the acute pancreatitis risk in the bzd poisoning cohort according to different demographic characteristics and comorbidities by conducting a stratified analysis involving the cox model .
the data management and statistical analysis was performed using sas 9.4 software ( sas institute , cary , nc ) .
the significance level was set at < 0.05 for the 2-sided testing of the p value .
this study included a total of 12,893 bzd poisoning patients and 4 times as many comparison controls with similar ages ( nearly 53 years ) and sex ratios ( men : 39.0% ) ( table 1 ) .
the comorbidities in the bzd poisoning cohort were more prevalent than those in the comparison cohort ( all p  <  .001 ) .
demographic characteristics and comorbidities in cohorts with and without bzd poisoning the incidence of acute pancreatitis in the comparison cohort was only 0.60 per 10,000 person - months ( table 2 ) , whereas that in the bzd poisoning cohort was nearly 10-fold higher ( 6.32 per 10,000 person - months ) .
figure 1 shows that the cumulative incidence curve for the bzd poisoning cohort was significantly greater than that for the comparison cohort ( log - rank test , p  <  .001 ) .
we observed that ard , gallstone , dm , hbv , hypertriglyceridemia , and cvd significantly influenced the increased risk of acute pancreatitis and considered model adjustment .
after adjustment for potential risk factors , the patients with bzd poisoning had a 5.33-fold increased risk of acute pancreatitis compared with patients without bzd poisoning ( hr  =  5.33 , 95% ci  =  2.2612.60 ) .
the incidence ( per 10,000 person - months ) and risk factors for acute pancreatitis cumulative incidence comparison of acute pancreatitis for patients with ( dashed line ) or without ( solid line ) bzd poisoning .
. table 3 presents the risk of acute pancreatitis in bzd poisoning patients with different demographic characteristics and comorbidities .
men and patients with bzd poisoning had a significantly increased risk of acute pancreatitis compared with female patients without bzd poisoning ( hr  =  13.2 , p  <  .001 ) , patients in the 3 age levels ( hr  =  11.8 , 10.7 , and 3.17 , all p  <  .05 ) , and patients with / without comorbidity ( hr  =  3.50 and 12.9 , all p  <  .05 ) . in addition , we estimated the acute pancreatitis risk in patients in the bzd poisoning cohort according to follow - up time .
the results revealed that acute pancreatitis in the bzd poisoning patients occurred in a follow - up time of 1 month ( hr  =  50.0 , p  <  .001 ) , and the risk of acute pancreatitis was no different between the patients with and without bzd poisoning when the follow - up time was  > 1 month ( hr  =  1.07 , p  >  .05 ) . incidence of acute pancreatitis by age , sex , comorbidity , follow - up time , and cox model measured hazards ratio for patients with bzd poisoning compared to those without bzd poisoning
this population - based retrospective cohort study reveals a significant association between bzd poisoning and an increased risk of acute pancreatitis , namely bzd poisoning significantly affects the acute pancreatitis risk .
after adjustment for potential confounding factors , patients with bzd poisoning had a 5.33-fold greater acute pancreatitis risk ( 95% ci  =  2.2612.60 ) compared with patients without bzd poisoning ( table 2 ) .
the alcohol abuse causes approximately 30% of all acute pancreatitis cases in the united states .
alcohol may promote the synthesis by pancreatic acinar cells of the digestive and lysosomal enzymes that is the key to cause acute pancreatitis or the oversensitization of acini to cholecystokinin . in our study , the patients with bzd poisoning and an alcohol - related disorder had a 11.6-fold increased risk of acute pancreatitis compared with the patients without bzd poisoning ( table 2).thus , bzd poisoning increased the risk of acute pancreatitis in the patients with alcohol - related disorders .
serum triglyceride concentrations exceeding 1000  mg / dl ( 11  mmol / l ) can precipitate attacks of acute pancreatitis ; however , the pathogenesis of inflammation is still unclear .
acquired hypertriglyceridemia may be secondary to obesity , dm , hypothyroidism , pregnancy , estrogen or tamoxifen therapy , glucocorticoid excess , nephrotic syndrome , and -blockers . in our study , patients with bzd poisoning and hyperglyceridemia had a significantly higher risk of acute pancreatitis ( adjusted hr  =  3.57 , 95% ci  =  0.9613.30 ) than did patients without bzd poisoning .
we also noted that people with dm had a higher risk of acute pancreatitis when they had bzd poisoning ( adjusted hr  =  2.63 , 95% ci  =  1.126.19 ) .
the gallstone is the most common cause of acute pancreatitis in the world , accounting for 35% to 40% of all cases . but only 3% to 7% of patients with gallstones develop biliary pancreatitis . there were 2 mechanisms of biliary pancreatitis : reflux of bile into the pancreatic duct caused by transient obstruction of the ampulla during passage of gallstones , or obstruction at the ampulla secondary to stone or edema caused by the passage of gallstone .
our study revealed that the bzd poisoning did not increase the risk of biliary pancreatitis , possibly because the bzd is unrelated to the obstruction of biliary tract .
although its mechanisms remain unclear , some studies have reported that cigarette smoking is an independent risk factor for acute and chronic pancreatitis .
tobacco smoking is the most common cause of copd , which is characterized by chronically poor airflow . in our study ,
although drug - induced acute pancreatitis is rare , some studies show that incidence is increasing .
therefore , the diagnosis depends on a high level of suspicion and careful drug history review .
the time course of developing acute pancreatitis relative to the drug involved . according to table 3 ,
patients with bzd poisoning exposure had a significantly higher risk of acute pancreatitis within 1 month after the event occurred ( adjusted hr  =  50.0 , 95% ci  =  6.39390.8 ) . however , the risk was nonsignificant > 1 month after the event occurred ( adjusted hr  =  1.07 , 95% ci  =  0.303.90 ) .
we found that female patients with bzd poisoning exposure had a higher risk of acute pancreatitis than did male patients ( adjusted hr  =  13.2 , 95% ci  =  3.6048.5 ) .
we noted the same trend in another cohort study : in 2015 , a cohort study identified several factors associated with acute pancreatitis and chronic pancreatitis that may be specific to older women .
heavy smoking ( 40 + years vs 0 pack - years ) was associated with a 2-fold increased odds ratio ( or ) for chronic pancreatitis . for body mass index
( 30  kg / m vs < 25  kg / m ) , the ors were 1.35 ( 1.071.70 ) for acute pancreatitis ( p for trend  =  .009 ) and 0.59 ( 0.370.94 ) for chronic pancreatitis ( p for trend  =  .01 ) .
the ors for acute and chronic pancreatitis were increased for hormone replacement therapy , heart disease , and hypertension . in taiwan
we diagnosed the patient as having bzd poisoning based on careful history taking , clinical symptoms , and urine bzd screen .
although we ca nt measure the doses of bzd , we still believed the diagnosis is correct . on the same way , the doctors diagnosed the patient as having acute pancreatitis based on clinical symptoms , blood examination , and image .
after we adjusted for the potential confounding factors , the people with bzd poisoning exposure had a 5.33-fold greater acute pancreatitis risk ( 95% ci , 2.2612.6 ) than people without bzd 's poisoning exposure .
the exact mechanism associated with bzd use and acute pancreatitis can not be fully shown , so we review some of the research in order to explain the possible mechanisms .
specific reactions to drugs are adverse effects and its pharmacodynamic mechanisms are not related to drugs directly .
these adverse events may occur , which are usually by the abnormal interaction of the drug or its metabolites , or trigger immune - mediated cytotoxicity between the drug and the pancreas .
although the accurate mechanism of drug - induced acute pancreatitis is not always known , it should have similar pathogenesis .
we found that there are several mechanism assumptions that include duct stenosis , direct pancreatic toxicity , the impact of bile flow , immune - mediated toxicity , metabolic effects , and thrombosis .
if acute pancreatitis occurred after drug used for 4 to 8 weeks , it may be caused by hypersensitivity .
if acute pancreatitis happened after several months of drug use , it is caused by accumulation of a toxic metabolite .
if acute pancreatitis occurred immediately after drug overdose , it usually caused by its intrinsic toxicity . following this hypothesis
, we think the mechanism of bzd poisoning  induced acute pancreatitis most likely is the intrinsic toxicity or the sphincter of oddi dysfunction .
tracing the past studies , we found the diazepam and midazolam had no effect on motility of the sphincter of oddi in human .
while there is no direct evidence that bzd has a direct toxicity for pancreas , there are studies that showed that bzds may be related to acute pancreatitis .
however , they are also found in other sites , for example , pancreatic  cells and immune cells .
some studies have implicated the gabaergic system in immune cell functions , inflammatory conditions , and diseases in peripheral tissues .
the recent research has investigated the modulation of this autocrine regulatory loop by chronic ethanol and explored the potential prevention of these effects by gaba .
we also found the use of zolpidem or zopiclone will increase the incidence of acute pancreatitis .
some studies point out the zolpidem is a short - acting agent with half - life of 2.1 to 2.4 hours .
although zolpidem and zopiclone is non - bzd class of sleeping pills , but they also are acting on the gaba receptor .
therefore , they think bzds may have an acute and direct toxic effect on the pancreas , which further precipitates the pancreatic inflammation .
first , we have no information about the amounts and types of bzds that poisoned patients .
we also could nt obtain some possible risk factors for acute pancreatitis , such as socioeconomic status , smoking habit , body mass index , and family history .
even we ca nt sure whether the patient has alcohol abuse , pancreatic trauma , gene mutation , or coprescribed drugs in detail .
however , this cohort study is national research , because nhird covers 99% of the taiwan population .
compared to bzd poisoning , the gene mutations , pancreatic trauma , and other drug poisoning are relatively rare .
we have the enough database to establish the stronger relationship between bzd poisoning and acute pancreatitis than other resource .
second , the evidence derived from a case - control study has lower quality than randomized controlled trials , because a case - control study design adjusted by the relevant confounding factors .
although we carefully study design , including adequate control for confounding factors , a key limitation is that bias could still remain if there are unmeasured or unknown confounders .
third , the diagnoses in nhi claims are used for administrative billing purposes and do not for scientific purposes .
because of the data anonymity , we are unable to contact patients with bzd poisoning directly . however , the data on the acute pancreatitis diagnosis and bzd poisoning were highly reliable .
this population - based , retrospective case - control study revealed that the event of bzd poisoning is significantly associated with an increased risk of acute pancreatitis .
our findings require confirmation through a large , population - based , unbiased study before any definite conclusions can be drawn .
 abstractwe designed a population - based retrospective cohort study to investigate the association between the event of benzodiazepine ( bzd ) poisoning and the risk of acute pancreatitis.in the present study , 12,893 patients with bzd poisoning during 2000 to 2011 were enrolled and matched with 4 comparison patients according to mean age and sex . 
 we determined the cumulative incidences and adjusted hazard ratios of acute pancreatitis.a significant association was observed between bzd poisoning and acute pancreatitis . after adjustment for potential risk factors , 
 the patients with bzd poisoning had a 5.33-fold increased risk of acute pancreatitis compared with the controls without bzd poisoning ( hr  =  5.33 , 95% ci  =  2.2612.60 ) . the results revealed that acute pancreatitis in patients with bzd poisoning occurred in a follow - up time of 1 month ( hr  =  50.0 , p  <  .001 ) , and the risk of acute pancreatitis was no different between the patients with and without bzd poisoning when the follow - up time was  > 1 month ( hr  =  1.07 , p  >  .05).this population - based study revealed the positive correlation between the event of bzd poisoning and an increased risk of acute pancreatitis . 
 the findings warrant further large - scale and in - depth investigation . 
INTRODUCTION
METHODS
Data Source
Study Population
Statistical Analysis
RESULTS
DISCUSSION
CONCLUSIONS