Physical Considerations for Treatment Complications of Alcohol and Drug Use and Misuse

Alcohol

Alcoholic liver disease is one of the major medical complications of alcohol abuse. In particular, 80% of heavy drinkers develop steatosis, 10%–35% develop alcoholic hepatitis, and approximately 10% will develop cirrhosis. Steatosis represents an abnormal retention of lipids accumulated in vesicles that displace the cytoplasm of the hepatocytes. Although liver function is usually normal, if alcohol abuse continues, steatosis may progress to cirrhosis ( Table 59.1 ).

It has been suggested that 15–20 years of alcohol abuse are necessary to develop alcoholic hepatitis, which usually results in cholestasis. When alcohol abuse is persistent for a long period and generally follows a regular pattern, an individual can often develop cirrhosis. Alcoholic liver disease represents the most common cause of liver cirrhosis in the Western world. Liver damage is related to the toxicity of alcohol being linked to its metabolism via alcohol dehydrogenase. Alcohol dehydrogenase converts nicotinamide adenine dinucleotide to nicotinamide adenine dinucleotide-reduced form, which contributes to hyperuricemia, hypoglycemia, and hepatic steatosis by inhibiting lipid oxidation and promoting lipogenesis. Another pathway of ethanol metabolism is the microsomal ethanol oxidizing system. The activity of its main enzyme, cytochrome P450 2E1 (CYP2E1), and its gene are increased by chronic consumption, resulting in metabolic tolerance to ethanol. The activity of CYP2E1 is also associated with the generation of free radicals, with resulting lipid peroxidation and membrane damage as well as depletion of mitochondrial reduced glutathione and its ultimate precursor—methionine activated to S -adenosyl- L -methionine. The involvement of free radical mechanisms in the pathogenesis of alcoholic liver disease is demonstrated by the detection of lipid peroxidation markers in the liver and the serum of alcohol-dependent individuals, as well as by experiments in alcohol-fed rodents that show a relationship between alcohol-induced oxidative stress and the development of liver pathology. In particular, oxidative stress promotes hepatocyte necrosis as well as a pro-apoptotic action via tumor necrosis factor-alpha. Furthermore, oxidative mechanisms can contribute to liver fibrosis by triggering the release of profibrotic cytokines and collagen gene expression in hepatic stellate cells.

In the last years, growing evidence has suggested the role of gut microbiota in the pathogenesis of alcoholic liver disease. The dysbiosis related to chronic alcohol consumption may induce intestinal mucosal inflammation and increased gut permeability with bacterial translocation to portal blood. The exposure of liver parenchyma to lipopolysaccharides and other products of bacterial wall stimulates innate immune receptors, such as Toll-like receptors and CD14, which activate hepatic stellate and Kupffer cells, releasing pro-inflammatory mediators that ultimately contribute to liver damage. Quantitative and qualitative microbiota alterations contribute to hepatocyte injury, already damaged by chronic alcohol exposure.

From a clinical point of view, alcohol-related damage can be present without any apparent symptoms or signs of liver disease. Otherwise, nonspecific clinical features can include nausea, vomiting, or fatigue. When liver cirrhosis is present, typical cirrhosis-related signs and symptoms can include jaundice, ascites, encephalopathy, or upper gastrointestinal bleeding.

Alcoholic hepatitis (AH) is a clinical syndrome characterized by rapid onset of jaundice and liver failure that occurs in patients with chronic alcohol abuse. The histological picture consists of ballooned hepatocytes, Mallory bodies, and lobular neutrophils. Common signs and symptoms include encephalopathy, fever, ascites, and proximal muscle loss; typically, the liver is enlarged and tender.

In its milder forms, alcohol abstinence is sufficient for clinical recovery. Severe forms of AH characterized by a Maddrey discriminant function >32, could benefit from the anti-inflammatory effect of corticosteroids or pentoxifylline. However, despite a number of trials and meta-analyses encouraging their use, their efficacy has recently been questioned by a recent randomized controlled trial (RCT) that failed to demonstrate any significant improvement in long-term survival.

Thus absolute alcohol abstinence together with supportive treatment remains the cornerstone of treatment. Recently, early liver transplantation (orthotopic liver transplantation [OLTx]) approach has been tested in AH patients with a first episode of severe alcoholic hepatitis not responding to medical therapy. Early OLTx showed to improve long-term survival in this subset of patients.

The treatment of patients with alcohol-related cirrhosis is mainly symptomatic and no other therapies are currently available. Recently, several drugs have been tested to improve survival in patients with alcohol-related cirrhosis, including antioxidants, metadoxine, therapeutic modulation of gut microbiota, nutritional support, and phosphatidylcholine. However, although some drugs have shown to be promising, none has shown a survival improvement in these clusters of patients.

OLTx represents an option when liver cirrhosis is present. Survival after a liver transplantation for alcoholic cirrhosis is similar to—or even better than—that for other end-stage liver diseases. However, several ethical concerns are still present due to the limited availability of liver donors and the risk of relapse after transplantation. A 6-month abstinence period before listing patients is recommended to prevent unnecessary liver transplantation in patients who will spontaneously recover. However, when medical urgency does not allow a 6-month waiting time (e.g., AH or severely decompensated ESLD) an urgent OLTx evaluation may proceed in selected patients.

Independently of stage of disease, abstinence from alcohol is the cornerstone of management. Accordingly, total alcohol abstinence can improve the histology and/or survival of individuals with alcoholic liver disease and the clinical outcome of all stages of alcoholic liver disease. Persistent alcohol intake in patients with alcoholic cirrhosis is associated with a significant risk ratio of death due to bleeding esophageal varices, infection, renal failure, and/or hepatic failure. In recent decades, several medications able to reduce alcohol craving and, consequently, to increase abstinence and prevent alcohol relapse have been evaluated. Anticraving drugs approved by National Medical Agency are naltrexone, nalmefene, acamprosate, sodium oxybate, and baclofen. Among them, baclofen represents the only anticraving medication formally tested in an RCT involving patients with alcohol use disorder (AUD) with advanced liver disease. For this reason, this medication has been included in the European and American Clinical Practice Guidelines for the treatment of alcoholic liver disease.

Nicotine

Several preclinical studies suggest an influence of nicotine on the hepatic enzymatic systems. For example, the chronic exposure of rats to cigarette smoke does not alter hepatic biotransformation processes.

However, in a rat model of cirrhosis, a reduction of nicotine metabolism has been observed and linked to the decreases in CYP and flavin-containing mono-oxygenase protein expression levels. Clinical studies have often been performed considering both smoking and alcohol consumption. Whitehead et al. evaluated a large population of 46,775 men and showed a joint effect of cigarette smoking and alcohol consumption in increasing the levels of γ-glutamyl transferase, whereas alcohol but not cigarette smoking was related to an increase of transaminases. In other words, nicotine can modify the hepatic enzymatic system but not induce liver damage. Consistently, smoking does not appear to be a risk factor for cirrhosis of the liver. On the other hand, a link between smoking and hepatocellular carcinoma has been suggested because constituents of cigarette smoke are hepatic carcinogens in animals. Cigarette smoking has been suggested as an important risk factor for primary sclerosing cholangitis and gallstones, although in the latter case other cofactors should be taken into account, such as gender, alcohol consumption, and overweight. Finally, there is growing interest in the role of nicotine in those individuals with liver disease who are undergoing surgical procedures, particularly OLTx. In one study, 60% of OLTx recipients reported a lifetime history of smoking, with 15% reporting smoking post-OLTx. Of smokers who quit before OLTx, 20% reported relapse to smoking post-OLTx. This observation has been subsequently confirmed by DiMartini and colleagues, who showed that individuals with alcoholic liver disease resume smoking early post-OLTx, increase their consumption over time, and quickly become tobacco dependent. Moreover, there is growing evidence that smoking cigarettes after liver transplantation is associated with a higher risk to develop de novo malignancies, particularly of the gastrointestinal and respiratory tracts.

Opioids

Preclinical studies show that opioid substances, such as morphine, heroin, meperidine, and methadone at therapeutic doses, do not usually produce irreversible damage to human hepatocytes, whereas opiate doses during tolerance or abuse may be a cause of liver dysfunction. However, it has also been noted that chronic use at therapeutic doses of opioids such as tramadol and, most of all, morphine for the management of chronic pain, increases liver damage via oxidative stress and induction of apoptosis. Consistent with the preclinical findings, intravenous drug abusers are commonly found to have altered transaminases. However, from a clinical perspective, the most important implications of opioid abuse and dependence are related to the high prevalence of hepatitis infection. In fact, over 90% of intravenous heroin addicts carry the hepatitis C virus. Accordingly, a hepatitis C virus–related elevation of the liver enzyme can be present, along with several stages of liver damage leading to cirrhosis. Furthermore, several extrahepatic clinical features can be present (e.g., immune suppression, collagen diseases, lymphoma, and leukemia) and included in the so-called hepatitis C virus syndrome. The hepatitis B virus may hold a similar chronic and degenerative course.

Finally, in patients with advanced liver disease, opioid administration could precipitate hepatic encephalopathy. Thus opioids should be used cautiously or possibly avoided in these patients.

Cocaine

Animal data show cocaine-induced liver damage including periportal and portal damage and elevated transaminases. In subjects using cocaine, acute hepatotoxicity and hepatocellular necrosis have been described, perhaps via oxidative stress. However, because cocaine is a sympathomimetic agent it could lead to acute ischemic hepatocellular injury or hypoxic hepatitis as a consequence of impaired hepatic perfusion. Of interest, the concurrent use of cocaine and alcohol produces another psychoactive substance called cocaethylene and can induce significant liver damage.

Amphetamine

Methylenedioxymethamphetamine (ecstasy) and amphetamine abuse can be associated with serious liver clinical features. Intoxication with amphetamine or methylenedioxymethamphetamine can be associated with severe hepatotoxicity as a consequence of ischemic hepatocellular injury. In addition, chronic abuse of amphetamines/methylenedioxymethamphetamine can be associated with either subclinical liver damage or cholestatic chronic liver damage. Histological features include confluent necrosis and ballooning degeneration in centrilobular zones. The use of steroids has been suggested according to a possible immune-mediated component of amphetamine-related hepatic damage, whereas the benefit/risk ratio of OLTx for fulminant hepatic failure is still controversial.

Benzodiazepines

Liver alterations can be present in individuals who are abusing benzodiazepines, especially those with a liver metabolism like diazepam and chlordiazepoxide. Subjects with benzodiazepine abuse or dependence can present with an increase of γ-glutamyl transferase, reflecting the chronic enzymatic induction. With a much lower frequency, benzodiazepines such as diazepam and chlordiazepoxide can induce cholestatic hepatotoxicity by a hypersensitivity mechanism. Both these drugs and other long-acting benzodiazepines with hepatic metabolism could cause excess of sedation in patients with advanced liver disease. Moreover, in these patients, all classes of benzodiazepines could precipitate or aggravate hepatic encephalopathy. Furthermore, the use of benzodiazepines needs to be evaluated carefully in those alcohol-dependent individuals with liver damage, taking into account the possibilities of both dual substance abuse (alcohol and benzodiazepines) and the need to administer benzodiazepines to treat alcohol withdrawal symptoms.

Alcohol

The effects of alcohol on the gastrointestinal apparatus include those on the esophagus, stomach, small bowel, colon, and pancreas. Excess alcohol ingestion at the esophageal level can induce the Mallory-Weiss syndrome due to vomiting. In the Mallory-Weiss syndrome, about 60%–80% of patients show very high alcohol consumption in the previous hours. Given its strong association with alcoholism, the Mallory-Weiss syndrome is more prevalent in patients with advanced alcoholic liver disease. Furthermore, patients with advanced alcoholic liver disease have more severe bleeding and are more likely to rebleed when compared to patients with nonalcoholic cirrhosis. In addition, gastroesophageal reflux is facilitated in these individuals for the existence of esophageal peristaltic dysfunction, making the development of esophagitis and/or Barrett esophagus easier. A recent study revealed that 60% of alcoholic patients show alterations in the autonomic nervous system, specifically in the sympathetic system, resulting in an altered postprandial gastric emptying. This motility dysfunction could be induced by a combination of both autonomic neuropathy and direct toxicity of ethanol on smooth muscle cell contractile proteins. Furthermore, alcohol can cause direct damage of the mucosa via alterations in epithelial transport, intercellular junction disorders, and impairment of the mucosal barrier. Both superficial and chronic atrophic gastritis are common in alcoholics. For example, 25.8% of alcohol-dependent individuals enrolled in detoxification programs present with superficial gastritis, and 24.2% have chronic atrophic gastritis. In healthy subjects, the incidence is 10.7% for superficial gastritis and 3% for chronic atrophic gastritis.

The relationship between alcohol consumption and Helicobacter pylori infection is controversial. Some studies report a significantly inverse association with H. pylori infection, whereas others found no significant association. A recent study indicates that nondrinkers exhibit a significantly lower rate of H. pylori infection compared with drinkers, demonstrating a positive association. More generally, it is conceivable that although mild-moderate amounts of alcohol may exert protective effects against H. pylori infection through a bactericidal effect or stimulation of gastric acid secretion, heavy alcohol consumption promotes colonization of the gastric mucosa by H. pylori.

Alcohol abuse has been implicated in peptic ulcer disease, and is associated with a high risk of rebleeding, and increased mortality. In alcoholic patients with a history of nonvariceal upper gastrointestinal bleeding, close follow-up and long-term proton pump inhibitor therapy are recommended.

In the small intestine, acute and chronic alcohol misuse impairs the barrier function of the gastrointestinal mucosa, resulting in increased permeability and translocation of macromolecules. Dysbiosis reported in patients with AUD is characterized by a reduced abundance of Bacteroidetes and a decreased abundance of Proteobacteria, such that microbial alterations correlated with elevated serum endotoxin levels. Small intestine bacterial overgrowth (SIBO) has been also demonstrated in individuals with chronic alcohol abuse; SIBO shows a higher prevalence in alcoholic compared to nonalcoholic subjects. These bacteria may cause mucosal damage and contribute to malabsorption (for review see Vassallo et al. ) Furthermore, a bidirectional pathway of communication along the microbiome-gut-brain axis exists. Neural signaling can alter the composition and function of the gut microbiota. Conversely, gut microbiota can influence neural, endocrine, and/or immune pathways, and may impact behavior, brain activity, and neurotransmitter systems, playing a role in developing and maintaining an AUD.

Exposure of the mucosal side of the small intestine to alcohol inhibits the active transport of numerous macro- and micronutrients across the epithelial layer, such as folate and others. Moreover, alcohol affects the metabolism of carbohydrates and lipids in the brush border membrane of the small intestinal mucosa by damaging the villi where lactase and sucrase are located. The activities of both enzymes are reduced, which may exacerbate lactose intolerance. However, the activities of lactase and sucrase return to normal within weeks of abstinence. Acute alcohol reduces impending wave motility and increases propulsive wave motility, through both a direct and indirect action on local musculature and nervous plexus; this may result in reduced transit time to the colon and diarrhea. Conversely, chronic alcohol misuse may induce a reversible prolonged orocecal transit time. Both abnormalities could contribute to diarrhea, as shortened transit reduces absorption while prolonged transit predisposes to bacterial overgrowth. In contrast to the organs of the upper gastrointestinal tract, the mucosa of the large bowel is exposed only to alcohol concentrations corresponding to those in the blood. However, due to the low aldehyde dehydrogenase activity of the colonic mucosa, acetaldehyde accumulates in the colon and may contribute to the pathogenesis of alcohol-induced diarrhea and colon cancer. The morphology of the rectum is altered by chronic alcohol misuse; rectal biopsies often show crypt destruction, inflammation, and proliferation of epithelial cells. Abnormal cellular proliferation is the hallmark of malignant neoplasia.

Given ethanol’s pro-oxidant properties and its deleterious effects on gut barrier function, alcohol abuse is a potential trigger for the onset and reactivation of inflammatory bowel diseases (IBDs). Specifically, current drinkers with inactive IBD more frequently report worsening of gastrointestinal symptoms with alcohol, compared to drinkers with irritable bowel disease. Pancreatitis due to alcohol abuse is a very painful and potentially fatal condition. About one-third of acute pancreatitis cases in the United States are related to alcohol, and 60%–90% of patients with pancreatitis have a history of chronic alcohol consumption. There is dose-response association between the risk of pancreatitis and the amount of alcohol (specifically, spirits) consumption, reaching an exponential correlation beyond the threshold of five drinks per day.

Possible mechanisms involved in the pathophysiology of alcoholic pancreatitis include inhibition of secretion from acini, microtubular dysfunction, induction of oxidative stress, production of pro-inflammatory cytokines, alteration of cell permeability, increased lysosomal fragility, inhibition of apoptosis, and enhancement of necrosis. Alcoholic pancreatitis is characterized by a higher risk of recurrence, progression to chronic pancreatitis, and development of diabetes mellitus, compared to pancreatitis with different etiologies. Finally, an increased risk of pancreatitis is present in individuals with acute alcohol intoxication and secondary hyperlipidemia. This hyperlipidemia, together with hemolytic anemia and the consequent increase of bilirubin, is called Zieve syndrome ( Table 59.2 ).

Nicotine

Smoking could worsen gastroesophageal reflux disease; specifically, nicotine might be responsible for lower esophageal sphincter pressure. A large case control study found a dose-response association between smoking and reflux symptoms: individuals who smoked more than 20 cigarettes daily had a significantly increased risk for reflux symptoms compared with nonsmokers. However, tobacco smoking cessation seems to improve severe gastroesophageal reflux symptoms only in individuals with normal body mass index (BMI), but not in other individuals.

Epidemiological data show that cigarette smoking increases both the incidence and relapse rate of peptic ulcer disease and delays ulcer healing in humans. Nicotine may tilt the balance between aggressive and defensive factors of the gastric and duodenal mucosal integrity, favoring aggressive factors (e.g., increased gastric acid secretion, increased biliary reflux, increased susceptibility to H. infection, free radical exposure) and attenuating defensive factors (decreased pancreatic bicarbonate secretion, dysregulated gastrointestinal immune system, decreased blood flow in the gastrointestinal mucosa). In particular, H. pylori infection is more common in smokers and eradication therapy is less effective. Several mechanisms could explain the association between smoking and failure of eradication of H. pylori : low adherence to treatment, reduced gastric mucosal blood flow, reduced effectiveness of antibiotics due to a more acidic environment which could increase non-replicative bacteria, altered protein pump inhibitor (PPI) metabolism in smokers .

Regarding the effects of nicotine on the gut, smoking is the only well-established environmental risk for IBDs. An increased risk for both Crohn disease and ulcerative colitis has been observed in former smokers, whereas current smoking seems to predispose to Crohn disease and protect against ulcerative colitis, as shown by a large prospective study.

Various mechanisms have been considered to explain the beneficial effect of nicotine on ulcerative colitis, including effects on the epithelial mucus (increased mucin synthesis), gut motility (reduction of circular muscle activity), eicosanoid metabolism, inhibition of pro-inflammatory cytokine production, and parasympathetic nervous system.

Therefore, nicotine, a major component of tobacco, has been examined as a possible pharmacological agent in the treatment of ulcerative colitis.

On the other hand, smoking has a detrimental effect on the course of Crohn disease. The reason for the opposite association with smoking status compared with ulcerative colitis is still unclear. This opposite effect could be related to several causes: smoking’s immunosuppressive effects on macrophages, which might further compound any deficiency in the host response to luminal bacteria (a possible mechanism of the pathogenesis of Crohn disease); smoking-induced compositional changes of the gut microbiota; smoking-induced modification of key proteins that activate the immune response and induce inflammation; interaction of smoking with genes associated with risk for IBDs.

Smoking is able to influence gut microbiota composition; specifically, gut microbial diversity in tobacco smokers is lower compared to nonsmoker controls. The changes in gut microbiota composition after smoking cessation seem to be similar to the differences observed in microbiota of obese compared to lean subjects.

Finally, epidemiological evidence shows an association between cigarette smoking and pancreatic diseases.

Smoking has been found to be a considerable risk factor for chronic pancreatitis both alone and associated with alcohol consumption; smoking accelerates the progression of pancreatic disease in a dose-dependent fashion, regardless of the level of alcohol consumption.

The mechanism is perhaps mediated by signal transduction pathways in the pancreatic acinar cell, leading to enhanced levels of intracellular calcium release and thereby resulting in cytotoxicity and eventual cell death. In addition, the induction of pancreatic injury by nicotine may involve the activation and expression of the proto-oncogene H-ras, which may lead to the development of pancreatic carcinoma in cigarette smokers.

Opioids

Opioid-induced gastrointestinal dysfunctions are well known. In particular, nausea and vomiting are severe adverse effects of opioids. Among individuals being treated with opioids, 8%–35% have reported nausea, whereas 14%–40% have had vomiting. Opioids act at the chemoreceptor trigger zone (area postrema in the medulla), triggering emetic mechanisms mediated by the vomiting center in the medulla. By an action on mu receptors, opioids result in inhibition of gastric motility and a delay in gastric emptying, leading to gastroesophageal reflux/heartburn. The inhibitory effect of opioids on the ileocecal sphincter and defecation reflexes contributes to opioid-induced constipation. Cases of severe constipation in heroin addicts leading to stercoral perforation of the colon have been described. A large observational study carried out on heroin-dependent patients treated with methadone or buprenorphine showed a high prevalence of constipation and consequently, an impaired quality of life in this population.

Opioids do not seem able to induce detrimental effects on the gastrointestinal mucosa. Conversely, it has been suggested that morphine protects against stress-induced gastric ulceration in a dose-dependent manner. Opioids can increase sphincter tonicity and result in sphincter of Oddi dysfunction. Sphincter of Oddi dysfunction may be manifested clinically by alteration of liver tests, pancreaticobiliary pain, and pancreatitis. For example, a study conducted in a group of 91 hospitalized heroin addicts evidenced hyperamylasemia in 19% of the individuals. However, it also has been suggested that hyperamylasemia after heroin usually arises from sources other than the pancreas.

Cocaine

Gastrointestinal complications of cocaine abuse occur less frequently than those in the cardiovascular and nervous systems. Esophageal lesions are characterized by alternating pink and white linear bands imparting a candy-cane appearance to the mucosa. The injury produces chest pain, as well as dysphagia, odynophagia, and abdominal pain. However, when individuals with candy-cane esophagus have chest pain, myocardial ischemia should remain the first possible diagnosis.

Smoking cocaine and its alkaloid-free base crack-cocaine has been reported to induce deep gastric ulcerations, intestinal perforations, and consequently, severe gastrointestinal hemorrhage.

These perforations occur in a predominantly male population of drug addicts who are 8–10 years younger than the usual group of individuals with pyloroduodenal perforations. H. pylori infection may be a contributing factor to these perforations. Cocaine injected intravenously has been shown to cause bowel ischemia without evidence of thrombosis, embolism, or atherosclerosis. The intestinal vasculature contains alpha-adrenergic receptors, which are stimulated by norepinephrine, leading to mesenteric vasoconstriction and focal ischemia. Few cases of cocaine-induced pancreatitis have been reported; a thrombotic microangiopathy has been hypothesized to be the main pathophysiologic mechanism.

The practice to swallow multiple packets filled with illicit drugs, mainly cocaine, in order to avoid controls, is increasingly widespread among “body packers.” This practice may have disastrous consequences, including gastrointestinal obstruction or perforation, signs of systemic drug toxicity from a ruptured packet, or even death after rupture in 56% of cases.

Amphetamines

Amphetamines act as an indirect sympathomimetic amine and may include decreased gut motility with consequent constipation (Matochik et al., Schifano et al. ).

As with cocaine, methamphetamines increase release of monoamines in the sympathetic nervous system, inducing splanchnic vasoconstriction and necrotizing vasculitis. Cases of amphetamine-related ischemic colitis causing gastrointestinal bleeding have been described.

Typically, misuse of crystal meth, the smokable form of methamphetamine hydrochloride, can have an important effect on teeth. In a few months, healthy teeth can turn grayish-brown, twist, and begin to fall out. The mechanism is due to the dry mouth caused by amphetamine sympathomimetic action, which in turn makes users thirsty and crave sugary soft drinks. The problem is aggravated by caustic substances used in the drug preparation, such as lithium and red phosphorus.

Benzodiazepines

Oral benzodiazepine poisoning produces minimal effects on the gastrointestinal tract. Benzodiazepines may promote gastroesophageal reflux by reducing lower esophageal sphincter pressure. Vomiting, nausea, diarrhea, epigastric distress, abdominal pain, gaseous distension, and dysphagia can occur after the administration of high doses of benzodiazepines. Conversely, several studies have evidenced possible protective effects of benzodiazepines against ethanol-induced gastric mucosa damage and stress-induced gastric ulcerations for the involvement of central-type benzodiazepine receptors located in the stomach. Finally, peripheral benzodiazepine receptors are expressed also in human pancreatic islets, and prolonged binding to peripheral benzodiazepine receptors may cause human beta-cell functional damage and apoptosis. Recently, a positive correlation between the event of benzodiazepine poisoning and an increased risk of acute pancreatitis has been found.