Analgesic Poisoning

According to the 2018 Annual Report of the American Association of Poison Control Centers (AAPCC), published in 2019, the most common cause of poisoning was medicines in all human exposures. According to the data in this report, the most common group of drugs that cause poisoning in humans are analgesics. The first three drugs that cause poisoning among analgesics are fentanyl, acetaminophen, and oxycodone, respectively. Fentanyl and oxycodone are analgesic drugs with an opioid nature. Opioid analgesics are the drugs of choice for acute and chronic pain management, but after repeated exposure, they cause addiction as a result of stimulation in the brain reward center, are used in higher doses to achieve the same effect, and lead to withdrawal syndrome when medication is not taken. Acetaminophen, which takes the second place in analgesic-related poisoning, is a non-opioid analgesic and antipyretic drug. Acetaminophen is often found in hundreds of over-the-counter (OTC) medications. In addition to being an OTC drug, acetaminophen often causes poisoning as it is cheap and easily accessible. This chapter reviews pharmacological properties of fentanyl, acetaminophen, and oxycodone, in addition to poisoning signs and treatments.


Introduction
Poisoning is a medical emergency representing a major health problem worldwide, and the rate of poisoning of both prescription and over-the-counter (OTC) drugs is increasing day by day [1]. According to the American Association of Poison Control Centers (AAPCC) 2018 Annual Report, the most common cause of drug poisonings was analgesics in all human exposures [2]. Analgesics are used to manage mild, moderate, and severe, as well as acute and chronic, pain [3]. Generally, opioid and non-opioid drugs are used for analgesia [3]. According to the AAPCC 2018 Annual Report, most frequent causes of analgesic poisoning are fentanyl, acetaminophen, and oxycodone, respectively [2]. Fentanyl and oxycodone are opioid analgesics, whereas acetaminophen is a non-opioid analgesic [3].
Opioids are potent analgesics, but their use is limited as they cause addiction, withdrawal, and tolerance [4]. Opioids exert their effects by stimulating classical opioid receptors [μ (mu), δ (delta), and κ (kappa)] that are widely distributed in the body [5,6]. These receptors show seven transmembrane domain structures specific to G-protein-coupled receptors, are induced by morphine and antagonized by naloxone (NLX), and had similar analgesic effect [4]. According to the studies, μ receptor was also related with addiction [7]. Opioid addiction develops in both psychic and physical dependence [4]. After physical dependence development, opioid consumption is maintained to prevent withdrawal symptoms [4]. Treatment D

Consider therapy modification
The rate of benefit and risk due to simultaneous use of this drug needs to be evaluated, and aggressive monitoring of the patient, empirical dosage changes, or selection of alternative agents should be considered

Analgesics that often lead to poisoning 2.1 Fentanyl
International Union of Pure and Applied Chemistry (IUPAC) name: N-phenyl-N- [1-(2-

phenylethyl)piperidin-4-yl]propanamide
Fentanyl is a synthetic and lipophilic phenylpiperidine opioid agonist with molecular formula C 22 H 28 N 20 and a molecular weight of 336.5 g/mol [16]. Fentanyl, 100 times more potent than morphine, was developed in the 1950s and approved by the FDA in 1968 [17]. Fentanyl is used for pain management, induction and maintenance of general anesthesia, recovery from general or regional anesthesia, and analgesia and sedation in intensive care unit patients [18][19][20]. It is applied by injection (i.v., i.m., epidural, intrathecal), transdermal (device and patch), transmucosal (buccal film and tablet, sublingual spray and tablet, lozenge), and intranasal means [16]. Pharmacodynamics and pharmacokinetics are summarized in Table 2.
Since it is an opioid drug, fentanyl has the potential for abuse [4]. As mentioned above, with repeated use of fentanyl, tolerance develops, which allows higher doses to achieve the same effect [4]. Therefore, fentanyl can be administered at toxic doses when abused. In addition, toxicity may develop with fentanyl used for therapeutic purposes [2]. These usually occur after accidental ingestion, following use in opioid non-tolerant patients and improper dosing [2]. Known and expected adverse reactions occur more severely, whether administered for abuse or therapeutic purposes [16]. The most important of these is respiratory depression, which can have fatal consequences. Concomitant use of fentanyl with drugs inhibiting CYP3A4 (e.g., erythromycin, ketoconazole, voriconazole, ritonavir) may cause potentially fatal respiratory depression (

Acetaminophen
IUPAC name: N-(4-hydroxyphenyl)acetamide Acetaminophen is an NSAID with molecular formula C 8 H 9 NO 2 and a molecular weight of 151.16 g/mol and approved by the FDA in 1951 [27]. Acetaminophen is used by oral, injection (i.v.), and rectal means for mild to moderate pain  Table 4.
through the CYP2E1 (Figure 1) [32][33][34]. NAPQI, produced in small amounts in therapeutic dose intakes, and hepatic glutathione are immediately transformed into nontoxic cysteine and mercapturate metabolites via glutathione S-transferase and excreted into the urine [34]. With intakes above the maximum daily dose (4 g in adults and 75 mg/kg in children), the increased formation of NAPQI depletes hepatic glutathione, covalently binds to critical cellular proteins and other vital molecules, and thereby causes acute liver toxicity (hepatic damage, liver failure) or  even death [29, 35,36]. Additional mechanisms such as mitochondrial injury, oxygen, and nitrogen stress deepen hepatic cell damage [37]. Mild to moderate elevations in serum aminotransferase (aspartate aminotransferase, alanine aminotransferase) levels are the first sign of liver damage; sometimes it can even occur in chronic treatment at the maximum daily dose [35,36]. These elevations are generally asymptomatic and resolve rapidly with stopping therapy or reducing the dosage [35] and most commonly arise after taking more than 7.5 g as a single overdose [38]. If hepatotoxicity is not too severe, serum aminotransferase levels fall promptly, and recovery is rapid [39]. Instances of unintentional overdose in children are often due to errors in calculating the correct dosage or use of adult-sized tablets instead of child or infant formulations [39]. Concomitant use of acetaminophen (single) and acetaminophen-containing (combined) products may also cause toxicity [39]. Acetaminophen overdose may be manifested by renal tubular necrosis, hypoglycemic coma, and thrombocytopenia [39]. Acetaminophen has been associated with a risk of rare but serious skin reactions. These are Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis, and they can be fatal [39,40]. Population that are particularly at risk and need attention are children, since they have less glucuronidation capacity of the drug than adults, and patients with alcoholism, hepatic impairment or active hepatic disease, chronic malnutrition, severe hypovolemia, and severe renal impairment [29,38]. Adverse reactions and clinically important DDIs of acetaminophen are summarized in Tables 6 and 7, respectively.
Toxic effects occur when the serum oxycodone concentration is approximately 0.69 mg/L in single oxycodone administration and 0.72 mg/L in the oxycodonecombined drug administration [50]. When the serum oxycodone concentration is  Table 7.

Immediate release Extended release
Onset of action 10-15 min - about 0.93 mg/L in a single-drug administration and 1.55 mg/L in the combined drug administration, it is fatal [51]. Common adverse reactions are summarized in Table 9.
Since oxycodone is an opioid drug, like fentanyl, it has the potential for abuse and develops tolerance. Repeated use of oxycodone causes the development of tolerance, which can lead to overdose and death [45][46][47]. Serious, life-threatening, or fatal respiratory depression may occur with use of oxycodone orally [45]. Accidental ingestion of even one dose of oxycodone preparations by children can result in death [47]. Long-term use during pregnancy can result in neonatal opioid withdrawal syndrome [45]. Concomitant use of oxycodone with CYP3A4 inducers (e.g., carbamazepine, phenytoin, and rifampin) may result in increasing clearance and decreasing plasma concentrations of oxycodone, with possible lack in therapeutic effectiveness [45]. Concomitant use of oxycodone with CYP3A4 inhibitors may result in reduced clearance and increased plasma concentrations of oxycodone, possibly resulting in increased or prolonged opiate effects, including an increased risk of fatal respiratory depression [52]. These effects could be more pronounced with concomitant use of oxycodone and inhibitors of both CYP2D6 and CYP3A4 [52]. Population that are particularly at risk and need attention are children; geriatric, cachectic, or debilitated patients; and patients with renal and hepatic impairment, underlying pulmonary conditions, and significant genetic variability in CYP2D6 activity [45,53]. There is no evidence to prove hepatotoxicity when used alone, whereas oxycodone-acetaminophen and other opioid-acetaminophen combinations can lead to acute liver damage caused by unintentional overdose with acetaminophen [54]. Clinically important DDIs are summarized in Table 10

Fentanyl, acetaminophen, and oxycodone toxicity, clinical manifestations, and management
The toxicity, teratogenicity (FDA pregnancy category), and carcinogenicity (by the International Agency for Research on Cancer), clinical manifestations, and management of fentanyl, acetaminophen, and oxycodone poisoning are summarized in Tables 11-13, respectively.  Table 10.
Oxycodone and clinically important DDIs [15].  Antidotal therapy with NAC in acetaminophen poisoning should be applied orally (nonpregnant patients with a functional GI tract and no evidence of hepatotoxicity) or i.v. (patients with vomiting, contraindications to oral administration, and hepatic failure) if:

Drugs
• Serum acetaminophen concentration is above the "treatment" line of the treatment nomogram • Serum acetaminophen concentration is unavailable or will not return within 8 h of time of ingestion and acetaminophen ingestion is suspected • Time of ingestion is unknown and serum acetaminophen level is >10 mcg/mL (66 μmol/L) • There is evidence of any hepatotoxicity with a history of acetaminophen ingestion • Patient has risk factors for hepatotoxicity, and the serum acetaminophen concentration is >10 mcg/mL (66 μmol/L) [80][81][82]

Conclusions
Drugs used in the treatment or prevention of diseases can lead to unintentional or intentional toxicity. Toxicity may be due to high-dose single-drug or multipledrug intake. According to the AAPCC 2018 Annual Report, opioid and non-opioid analgesics often cause single-drug poisoning. The top three of analgesic poisoning are fentanyl, acetaminophen, and oxycodone, respectively.
Opioid analgesics, such as fentanyl and oxycodone, which are preferred in severe pain management, show central and peripheral effects by binding to classical opioid receptors that are widely distributed in the body. Repeated exposure causes an addiction; higher-dose usage to produce the same effect, i.e. tolerance; and withdrawal when stopping intake. Therefore, the dose and severity of toxicity differ between those who take opioid analgesics for the first time and those who are addicted. In poisoning with opioid analgesics, death due to respiratory depression is frequently observed. For this reason, in case of poisoning with opioid analgesics, first of all, adequate ventilation should be provided, subsequent antidote treatment with naloxone should be applied, the patient should be closely monitored for vital functions, and appropriate treatment should be performed when necessary. Since the effect of naloxone is short, application should be repeated when necessary. Supplementary oxygen, endotracheal intubation, and positive end-expiratory pressure should be considered if adequate response cannot be obtained despite a total of 5 to 10 mg of naloxone. Although high doses are not preferred, toxicity is more severe in patients using X and D interactive drugs together.
Acetaminophen, a non-opioid analgesic, found in hundreds of prescription and OTC medicines, with analgesia and antipyretic effects, often causes hepatotoxicity (hepatic damage, liver failure) or even death. Toxicity develops due to the overproduction of toxic NAPQI, which occurs during acetaminophen metabolism in the liver, which quickly consumes the glutathione necessary to convert it to the nontoxic metabolite and covalently binds to cell proteins and other vital molecules. Toxicity is more severe in patients with less glucuronidation capacity and/or concomitant use of X-and D-type interacting drugs. The use of activated charcoal within the first 4 h of acetaminophen poisoning and antidote treatment with NAC successfully heals liver damage.
After stabilizing the patient, it is necessary to investigate whether poisoning is performed unintentionally or intentionally. If there is substance abuse or suicidal tendency, the patient should be consulted to a psychiatrist, and psychosocial and/or medication for addiction treatment should be started. In unintentional poisonings, adults should be educated/warned by their health protectors about the drugs (effects, duration of action, daily maximum dose, conditions to be considered, side effects, and storage conditions) they use for themselves and/or their children, and additional arrangements should be made to increase the health literacy of the society. If poisoning has developed due to the X-and D-type interactions of the drugs used in therapeutic doses, it should be considered to be subject to periodical/ continuous training of health protectors.