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[60] Moschella C, Jaber BL. Interaction between cyclosporine and *Hypericum perforatum* (St. John's wort) after organ transplantation. American Journal of Kidney Diseases. 2001;**38**(5):1105-1107. DOI: 10.1053/ajkd.2001.28617

[61] Hebert MF, Park JM, Chen YL, Akhtar S, Larson AM. Effects of St. John's wort (*Hypericum perforatum*) on tacrolimus pharmacokinetics in healthy volunteers. Journal of Clinical Pharmacology. 2004;**44**(1):89-94. DOI: 10.1177/0091270003261078

[62] Mai I, Störmer E, Bauer S, Krüger H, Budde K, Roots I. Impact of St John's wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal transplant patients. Nephrology Dialysis Transplantation. 2003;**18**(4):819-822. DOI: 10.1093/ndt/ gfg002

[63] Andrén L, Andreasson A, Eggertsen R. Interaction between a commercially available St John's Wort product (Movina) and atorvastatin in patients with hypercholesterolemia. European Journal of Clinical Pharmacology. 2007;**63**:913-916. DOI: 10.1007/s00228-007-0345-x

[64] Sugimoto K, Ohmori M, Tsuruoka S, Nishiki K, Kawaguchi A, Harada K, et al. Different effects of St John's wort on the pharmacokinetics of simvastatin and pravastatin. Clinical Pharmacology and Therapeutics. 2001;**70**(6):518-524. DOI: 10.1067/ mcp.2001.120025

[65] Di YM, Li CG, Xue CC, Zhou SF. Clinical drugs that interact with St. John's wort and implication in drug development. Current Pharmaceutical Design. 2008;**14**(17):1723-1742. DOI: 10.2174/138161208784746798

[66] Murphy PA, Kern SE, Stanczyk FZ, Westhoff CL. Interaction of St. John's Wort with oral contraceptives: Effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and breakthrough bleeding. Contraception. 2005;**71**(6):402-408. DOI: 10.1016/j. contraception.2004.11.004

[67] Hall SD, Wang Z, Huang SM, Hamman MA, Vasavada N, Adigun AQ, et al. The interaction between St John's wort and an oral contraceptive. Clinical Pharmacology and Therapeutics. 2003;**74**(6):525-535. DOI: 10.1016/j. clpt.2003.08.009

[68] Pfrunder A, Schiesser M, Gerber S, Haschke M, Bitzer J, Drewe J. Interaction of St John's wort with lowdose oral contraceptive therapy: A randomized controlled trial. British Journal of Clinical Pharmacology. 2003;**56**(6):683-690. DOI: 10.1046/j.1365-2125.2003.02005.x

[69] Schwarz UI, Büschel B, Kirch W. Unwanted pregnancy on self-medication with St. John's wort

**275**

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants…*

Chinese Medicine. 2006;**34**(4):545-551. DOI: 10.1142/s0192415x06004089

Obonga WO. Herb-drug interaction: A case study of effect of ginger on the pharmacokinetic of metronidazole in rabbit. Indian Journal of Pharmaceutical Sciences. 2008;**70**(2):230-232. DOI:

[77] Okonta JM, Uboh M,

10.4103/0250-474X.41462

toxlet.2004.03.001

[78] Walker R. Criteria for risk assessment of botanical food supplements. Toxicology Letters. 2004;**149**(1):187-195. DOI: 10.1016/j.

[79] Huxtable RJ. The myth of

beneficent nature: The risks of herbal preparations. Annals of Internal Medicine. 1992;**117**(2):165-166. DOI: 10.7326/0003-4819-117-2-165

*DOI: http://dx.doi.org/10.5772/intechopen.92040*

Pharmacology. 2003;**55**(1):112-113. DOI:

despite hormonal contraception. British Journal of Clinical

10.1046/j.1365-2125.2003.01716.x

[70] Lantz MS, Buchalter E, Giambanco V. St. John's wort and antidepressant drug interactions in the elderly. Journal of Geriatric Psychiatry and Neurology. 1999;**12**(1):7-10. DOI:

10.1177/089198879901200103

and pharmacodynamic drug interactions with kava (*Piper methysticum* Forst. f.). Journal of Ethnopharmacology. 2004;**93**(2):153- 160. DOI: 10.1016/j.jep.2004.04.009

[73] Shi S, Klotz U. Drug

10.1055/s-2007-969384

Clinical Pharmacokinetics. 2012;**51**(2):77-104. DOI:

interactions with herbal medicines.

10.2165/11597910-000000000-00000

[74] Hendriks H, Bos R, Woerdenbag HJ, Koster AS. Central nervous depressant activity of valerenic acid in the mouse. Planta Medica. 1985;**51**(1):28-31. DOI:

[75] Lien H-C, Sun WM, Chen Y-H, Kim H, Hasler W, Owyang C. Effects of ginger on motion sickness and gastric slow-wave dysrhythmias induced by circular vection. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2003;**284**(3):G481-G4G9. DOI: 10.1152/ajpgi.00164.2002

[76] Young HY, Liao JC, Chang YS, Luo YL, Lu MC, Peng WH. Synergistic effect of ginger and nifedipine on human platelet aggregation: A study in hypertensive patients and normal volunteers. The American Journal of

aph.10031

[71] Vaes LPJ, Chyka PA. Interactions of warfarin with garlic, ginger, ginkgo, or ginseng: Nature of the evidence. The Annals of Pharmacotherapy. 2000;**34**(12):1478-1482. DOI: 10.1345/

[72] Anke J, Ramzan I. Pharmacokinetic

*The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants… DOI: http://dx.doi.org/10.5772/intechopen.92040*

despite hormonal contraception. British Journal of Clinical Pharmacology. 2003;**55**(1):112-113. DOI: 10.1046/j.1365-2125.2003.01716.x

*Medical Toxicology*

sj.bjp.0707685

genotype on the pharmacokinetics and pharmacodynamics of gliclazide. British Journal of Pharmacology. 2008;**153**(7):1579-1586. DOI: 10.1038/ product (Movina) and atorvastatin in patients with hypercholesterolemia. European Journal of Clinical

Pharmacology. 2007;**63**:913-916. DOI:

Tsuruoka S, Nishiki K, Kawaguchi A, Harada K, et al. Different effects of St John's wort on the pharmacokinetics of simvastatin and pravastatin. Clinical Pharmacology and Therapeutics. 2001;**70**(6):518-524. DOI: 10.1067/

10.1007/s00228-007-0345-x

[64] Sugimoto K, Ohmori M,

[65] Di YM, Li CG, Xue CC,

Zhou SF. Clinical drugs that interact with St. John's wort and implication in drug development. Current Pharmaceutical Design. 2008;**14**(17):1723-1742. DOI: 10.2174/138161208784746798

[66] Murphy PA, Kern SE, Stanczyk FZ, Westhoff CL. Interaction of St. John's Wort with oral contraceptives: Effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity and

breakthrough bleeding. Contraception. 2005;**71**(6):402-408. DOI: 10.1016/j.

contraception.2004.11.004

clpt.2003.08.009

[67] Hall SD, Wang Z, Huang SM, Hamman MA, Vasavada N, Adigun AQ, et al. The interaction between St John's wort and an oral contraceptive. Clinical Pharmacology and Therapeutics. 2003;**74**(6):525-535. DOI: 10.1016/j.

[68] Pfrunder A, Schiesser M,

2003;**56**(6):683-690. DOI: 10.1046/j.1365-2125.2003.02005.x

[69] Schwarz UI, Büschel B, Kirch W. Unwanted pregnancy on self-medication with St. John's wort

Gerber S, Haschke M, Bitzer J, Drewe J. Interaction of St John's wort with lowdose oral contraceptive therapy: A randomized controlled trial. British Journal of Clinical Pharmacology.

mcp.2001.120025

[57] Borrelli F, Izzo AA. Herb-drug interactions with St John's wort (*Hypericum perforatum*): An update on clinical observations. American Association of Pharmaceutical Scientists Journal. 2009;**11**(4):710-727. DOI: 10.1208/s12248-009-9146-8

[58] Piscitelli SC, Burstein AH,

Mathôt RAA, van Gorp ECM,

DOI: 10.1053/ajkd.2001.28617

10.1177/0091270003261078

of tacrolimus and mycophenolic acid in renal transplant patients. Nephrology Dialysis Transplantation. 2003;**18**(4):819-822. DOI: 10.1093/ndt/

[63] Andrén L, Andreasson A, Eggertsen R. Interaction between a commercially available St John's Wort

[61] Hebert MF, Park JM, Chen YL, Akhtar S, Larson AM. Effects of St. John's wort (*Hypericum perforatum*) on tacrolimus pharmacokinetics in healthy volunteers. Journal of Clinical Pharmacology. 2004;**44**(1):89-94. DOI:

[62] Mai I, Störmer E, Bauer S, Krüger H, Budde K, Roots I. Impact of St John's wort treatment on the pharmacokinetics

Chaitt D, Alfaro RM, Falloon J. Indinavir concentrations and St John's wort. Lancet. 2000;**355**(9203):547-548. DOI: 10.1016/S0140-6736(99)05712-8

[59] de Maat MMR, Hoetelmans RMW,

Meenhorst PL, Mulder JW, et al. Drug interaction between St John's wort and nevirapine. AIDS. 2001;**15**(3):420-421

[60] Moschella C, Jaber BL. Interaction between cyclosporine and *Hypericum perforatum* (St. John's wort) after organ transplantation. American Journal of Kidney Diseases. 2001;**38**(5):1105-1107.

**274**

gfg002

[70] Lantz MS, Buchalter E, Giambanco V. St. John's wort and antidepressant drug interactions in the elderly. Journal of Geriatric Psychiatry and Neurology. 1999;**12**(1):7-10. DOI: 10.1177/089198879901200103

[71] Vaes LPJ, Chyka PA. Interactions of warfarin with garlic, ginger, ginkgo, or ginseng: Nature of the evidence. The Annals of Pharmacotherapy. 2000;**34**(12):1478-1482. DOI: 10.1345/ aph.10031

[72] Anke J, Ramzan I. Pharmacokinetic and pharmacodynamic drug interactions with kava (*Piper methysticum* Forst. f.). Journal of Ethnopharmacology. 2004;**93**(2):153- 160. DOI: 10.1016/j.jep.2004.04.009

[73] Shi S, Klotz U. Drug interactions with herbal medicines. Clinical Pharmacokinetics. 2012;**51**(2):77-104. DOI: 10.2165/11597910-000000000-00000

[74] Hendriks H, Bos R, Woerdenbag HJ, Koster AS. Central nervous depressant activity of valerenic acid in the mouse. Planta Medica. 1985;**51**(1):28-31. DOI: 10.1055/s-2007-969384

[75] Lien H-C, Sun WM, Chen Y-H, Kim H, Hasler W, Owyang C. Effects of ginger on motion sickness and gastric slow-wave dysrhythmias induced by circular vection. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2003;**284**(3):G481-G4G9. DOI: 10.1152/ajpgi.00164.2002

[76] Young HY, Liao JC, Chang YS, Luo YL, Lu MC, Peng WH. Synergistic effect of ginger and nifedipine on human platelet aggregation: A study in hypertensive patients and normal volunteers. The American Journal of

Chinese Medicine. 2006;**34**(4):545-551. DOI: 10.1142/s0192415x06004089

[77] Okonta JM, Uboh M, Obonga WO. Herb-drug interaction: A case study of effect of ginger on the pharmacokinetic of metronidazole in rabbit. Indian Journal of Pharmaceutical Sciences. 2008;**70**(2):230-232. DOI: 10.4103/0250-474X.41462

[78] Walker R. Criteria for risk assessment of botanical food supplements. Toxicology Letters. 2004;**149**(1):187-195. DOI: 10.1016/j. toxlet.2004.03.001

[79] Huxtable RJ. The myth of beneficent nature: The risks of herbal preparations. Annals of Internal Medicine. 1992;**117**(2):165-166. DOI: 10.7326/0003-4819-117-2-165

**Chapter 14**

**Abstract**

**1. Introduction**

**277**

Analgesic Poisoning

oxycodone, in addition to poisoning signs and treatments.

**Keywords:** fentanyl, acetaminophen, paracetamol, oxycodone, intoxication

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

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

*Mahluga Jafarova Demirkapu*

## **Chapter 14** Analgesic Poisoning

*Mahluga Jafarova Demirkapu*

## **Abstract**

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.

**Keywords:** fentanyl, acetaminophen, paracetamol, oxycodone, intoxication

## **1. 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 of opioid addiction is long and difficult. For this purpose, opioid agonists, such as methadone and buprenorphine, an opioid antagonist naltrexone, or abstinencebased treatment may be preferred [8]. This disease, referred to as "opioid abuse and opioid dependence" in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSMIV-TR), has been changed to "opioid use disorder" in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [9].

**2. Analgesics that often lead to poisoning**

*DOI: http://dx.doi.org/10.5772/intechopen.92941*

N-[1-(2-phenylethyl)piperidin-4-yl]propanamide.

**PDs and PKs Routes of administration**

Half-life elimination 15–25 h Adults: 2–4 h

Excretion • Urine (primarily) • Feces

*PDs and PKs of fentanyl at therapeutic doses [16, 21–23].*

**Table 2.**

**279**

International Union of Pure and Applied Chemistry (IUPAC) name: N-phenyl-

Adverse effects (**Table 3**) occur when serum fentanyl concentration rises above 2 ng/mL [16]. CNS depression occurs above 3 ng/mL, whereas profound respiratory

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 (**Table 4**). Fentanyl may be associated with the development of serotonin syndrome. This risk increases when used concomitantly with

**Intranasal i.m. i.v. Transdermal patch Transmucosal**

Onset of action 5–10 min 7–8 min Immediately 6 h 5–15 min Duration — 1–2 h 0.5–1 h 72–96 h — Absorption — —— 12–24 h Rapidly Distribution — — 4 L/kg — 25.4 L/kg

> • n-Dealkylation to *norfentanyl* (active metabolite) • Amide hydrolyzation to *despropionylfentanyl* • Alkyl hydroxylation to *hydroxyfentanyl*

Bioavailability 64% 50–76%

Children: 2.4–36 h

20–27 h 3–14 h

Protein binding Alpha-1-acid glycoprotein (mainly), albumin, and erythrocytes Metabolism In the liver (primarily via CYP3A4) and intestinal mucosa

depression usually occurs at concentrations of 10 to 20 ng/mL [16].

Fentanyl is a synthetic and lipophilic phenylpiperidine opioid agonist with molecular formula C22H28N20 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 [18–20]. 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

**2.1 Fentanyl**

*Analgesic Poisoning*

in **Table 2**.

Classical opioid receptors are distributed in the peripheral tissue as well as central nervous system (CNS) [4]. Stimulation of these receptors in the central nervous system results in analgesia, drowsiness, euphoria, a sense of detachment, respiratory depression, nausea and vomiting, depressed cough reflex, and hypothermia [4]. When these receptors are stimulated in peripheral tissues, miosis, orthostatic hypotension, constipation, urinary retention, etc. emerge [4]. After stimulation of these Gi/0-coupled opioid receptors, the adenylate cyclase enzyme is suppressed, and the level of cyclic AMP decreases [4]. In addition, the voltage-gated calcium channels in the axon ends or neuron soma are closed, and intracellular calcium levels are reduced, and potassium channels are opened, leading to an increase in potassium conductance [4]. As a result, inhibition and hyperpolarization of neurons occur when opioid receptors are stimulated [10, 11]. Analgesic or antinociceptive effects, which are indicated for use of opioids, develop at the level of the brain and spinal cord [12]. At the brain level, attenuation of impulse spread is weakened and the perception of pain is inhibited, and at the spinal cord level, the transmission of pain impulses is suppressed [12].

Non-opioid or non-steroidal anti-inflammatory drugs (NSAIDs) are used to manage mild and moderate pain, as well as to reduce fever [13]. Although NSAIDs exact mechanism of action has not been fully established, according to the previous studies, it inhibits the cyclooxygenase pathways, which are involved in prostaglandin synthesis [14]. Prostaglandins are responsible for eliciting pain sensations [14]. NSAIDs do not cause addiction and withdrawal like opioid analgesics, and tolerance to analgesic effect does not develop [13].

Poisoning may lead to more dangerous consequences when taking more than one medication [2]. It is due to pharmacokinetic (PK) and pharmacodynamic (PD) drug-drug interactions (DDIs). According to Lexicomp, there are five DDI types (**Table 1**), which are clinically important (X, D, and C) and insignificant (B and A) [15].

#### **Table 1.** *DDI types and treatment approach [15].*

## **2. Analgesics that often lead to poisoning**

## **2.1 Fentanyl**

of opioid addiction is long and difficult. For this purpose, opioid agonists, such as methadone and buprenorphine, an opioid antagonist naltrexone, or abstinencebased treatment may be preferred [8]. This disease, referred to as "opioid abuse and opioid dependence" in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSMIV-TR), has been changed to "opioid use disorder" in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

Classical opioid receptors are distributed in the peripheral tissue as well as central nervous system (CNS) [4]. Stimulation of these receptors in the central nervous system results in analgesia, drowsiness, euphoria, a sense of detachment, respiratory depression, nausea and vomiting, depressed cough reflex, and hypothermia [4]. When these receptors are stimulated in peripheral tissues, miosis, orthostatic hypotension, constipation, urinary retention, etc. emerge [4]. After stimulation of these Gi/0-coupled opioid receptors, the adenylate cyclase enzyme is suppressed, and the level of cyclic AMP decreases [4]. In addition, the voltage-gated calcium channels in the axon ends or neuron soma are closed, and intracellular calcium levels are reduced, and potassium channels are opened, leading to an increase in potassium conductance [4]. As a result, inhibition and hyperpolarization of neurons occur when opioid receptors are stimulated [10, 11]. Analgesic or antinociceptive effects, which are indicated for use of opioids, develop at the level of the brain and spinal cord [12]. At the brain level, attenuation of impulse spread is weakened and the perception of pain is inhibited, and at the spinal cord level, the

Non-opioid or non-steroidal anti-inflammatory drugs (NSAIDs) are used to manage mild and moderate pain, as well as to reduce fever [13]. Although NSAIDs exact mechanism of action has not been fully established, according to the previous studies, it inhibits the cyclooxygenase pathways, which are involved in prostaglandin synthesis [14]. Prostaglandins are responsible for eliciting pain sensations [14]. NSAIDs do not cause addiction and withdrawal like opioid analgesics, and tolerance

Poisoning may lead to more dangerous consequences when taking more than one medication [2]. It is due to pharmacokinetic (PK) and pharmacodynamic (PD) drug-drug interactions (DDIs). According to Lexicomp, there are five DDI types (**Table 1**), which are clinically important (X, D, and C) and insignificant

X Avoid combination The risks associated with simultaneous use of this drug outweigh the

C Monitor therapy The benefits associated with simultaneous use of this drug outweigh the

No intervention required

benefits. Simultaneous use of this drug is contraindicated

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

risks, and dosage adjustments of one or both drugs may be considered

transmission of pain impulses is suppressed [12].

to analgesic effect does not develop [13].

**Approach Explanation**

B No action needed No intervention required

(B and A) [15].

D Consider therapy modification

A No known interaction

*DDI types and treatment approach [15].*

**Table 1.**

**278**

**DDI types**

(DSM-5) [9].

*Medical Toxicology*

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 C22H28N20 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 [18–20]. 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**.

Adverse effects (**Table 3**) occur when serum fentanyl concentration rises above 2 ng/mL [16]. CNS depression occurs above 3 ng/mL, whereas profound respiratory depression usually occurs at concentrations of 10 to 20 ng/mL [16].

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 (**Table 4**). Fentanyl may be associated with the development of serotonin syndrome. This risk increases when used concomitantly with

#### **Table 2.** *PDs and PKs of fentanyl at therapeutic doses [16, 21–23].*

#### **Table 3.**

*Common adverse reactions of fentanyl [16, 21–26].*

drugs at risk of serotonin syndrome (**Table 4**). 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, known or suspected paralytic ileus and gastrointestinal obstruction, mucositis (sublingual spray), and cardiac bradyarrhythmias [16]. Clinically important DDIs are summarized in **Table 4**.

> management and reduction of fever [27]. Acetaminophen is often found in hundreds of OTC and prescription medicines [28]. PDs and PKs are summarized in

— — SSRI

Constipation Eluxadoline — Anticholinergic agents,

— — Anticholinergic agents

Fexinidazole Ceritinib, siponimod Bradycardia-causing agents,

**Possible effects Clinically important DDI types**

*DOI: http://dx.doi.org/10.5772/intechopen.92941*

Azelastine, bromperidol, orphenadrine, oxomemazine, paraldehyde, thalidomide, mifepristone

Dapoxetine, monoamine oxidase inhibitors (MAOI)

Increase in the CNS depressant effects

*Analgesic Poisoning*

Enhancement in the serotonergic effects and serotonin syndrome

**XD C**

Blonanserin, chlormethiazole, CNS depressants, droperidol, flunitrazepam,

moderate)

lemborexant, meperidine, methotrimeprazine, opioid agonists, oxycodone, perampanel,

Ethanol, alizapride, dimethindene,

brimonidine, bromopride, tetrahydrocannabinol, cannabidiol, *Cannabis*, chlorphenesin carbamate, dronabinol, lisuride, lofexidine, magnesium sulfate, metoclopramide, minocycline (systemic), nabilone, piribedil, pramipexole, ropinirole, rotigotine, rufinamide

Almotriptan, alosetron, amphetamines, antiemetics (5HT3 antagonists), dexmethylphenidatemethylphenidate, dextromethorphan, eletriptan, ergot derivatives, buspirone, lorcaserin, ondansetron, oxitriptan, ramosetron, selective serotonin reuptake inhibitors (SSRI), serotonin 5-HT1D receptor agonists (triptans), serotonin/ norepinephrine reuptake inhibitors (SNRI), St John's

wort, Syrian rue

ivabradine, lacosamide, midodrine, ruxolitinib, succinylcholine, terlipressin, tofacitinib

ramosetron

phenobarbital, primidone, sodium oxybate, suvorexant, zolpidem, tramadol, tricyclic antidepressants (TCA), CYP3A4 inhibitors (strong,

Linezolid, meperidine, methylene blue, nefazodone, ozanimod, tramadol, TCA

95% of acetaminophen undergoes biotransformation, while 5% is excreted unchanged into the urine [29]. Approximately 45–55% of acetaminophen transforms into glucuronide conjugates via UDP-glucuronosyltransferase, 30–35% into sulfate conjugates via sulfotransferase, and only 5% into toxic metabolite NAPQI

**Table 5**.

**281**

**Table 4.**

Urinary retention

Enhancement in the bradycardia effects

Enhancement in the psychomotor impairment

*Fentanyl and clinically important DDIs [15].*

## **2.2 Acetaminophen**

IUPAC name: N-(4-hydroxyphenyl)acetamide

Acetaminophen is an NSAID with molecular formula C8H9NO2 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.**

drugs at risk of serotonin syndrome (**Table 4**). 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, known or suspected paralytic ileus and gastrointestinal obstruction, mucositis (sublingual spray), and cardiac bradyarrhythmias [16]. Clinically important DDIs

CNS Confusion, dizziness, drowsiness, fatigue, headache, sedation, abnormal dreams,

Respiratory Dyspnea, atelectasis, cough, epistaxis, hemoptysis, flu-like symptoms,

pneumonia, nasal discomfort, postnasal drip, rhinorrhea Cardiovascular Arrhythmia, pulmonary embolism (intranasal), chest pain, palpitations, deep

Hepatic Ascites, increased serum alkaline phosphatase, increased serum AST, jaundice

Ophthalmic Blepharoptosis, blurred vision, diplopia, strabismus, swelling and drying of eye,

Dermatologic Alopecia, cellulitis, decubitus ulcer, diaphoresis, erythema, hyperhidrosis, night

abnormal gait, abnormality in thinking, agitation, altered sense of smell, amnesia, anxiety, ataxia, chills, depression, disorientation, euphoria,

hallucination, hypertonia, hypoesthesia, hypothermia, insomnia, irritability, lack of concentration, lethargy, malaise, mental status changes, neuropathy, paranoia, paresthesia, restlessness, speech disturbance, stupor, vertigo,

wheezing, hyperventilation/hypoventilation, pharyngolaryngeal pain, rhinitis, sinusitis, nasopharyngitis, pharyngitis, laryngitis, bronchitis, asthma,

vein thrombosis, hypertension/hypotension, myocardial infarction, edema

Renal failure, urinary retention, dysuria, erectile dysfunction, mastalgia, urinary incontinence, urinary tract infection, urinary urgency, vaginal hemorrhage,

Anemia, leukopenia, neutropenia, thrombocytopenia, lymphadenopathy

Dehydration, hot flash, hypercalcemia/hypocalcemia, hypokalemia,

hypomagnesemia, hyponatremia, hypoalbuminemia, hyperglycemia, weight loss

Asthenia, arthralgia, back pain, lower limb cramp, limb pain, myalgia, tremor

Constipation, nausea, vomiting, abdominal distention, abdominal pain, anorexia, decreased appetite, diarrhea, dysgeusia, dyspepsia, flatulence, gingivitis, glossitis, stomatitis, tongue disease, xerostomia, gastroesophageal reflux, gastritis, gastroenteritis, hemorrhage, ulcer, hematemesis, intestinal

Acetaminophen is an NSAID with molecular formula C8H9NO2 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

are summarized in **Table 4**.

**Systems Symptoms**

*Medical Toxicology*

Gastrointestinal

Genitourinary (GU)

Hematologic and oncologic

Endocrine and metabolic

skeletal

**Table 3.**

**280**

Neuromuscular and

(GI)

withdrawal syndrome

obstruction, rectal pain

vaginitis

visual disturbance

Miscellaneous Hypersensitivity reaction, fever, abscess

*Common adverse reactions of fentanyl [16, 21–26].*

sweats, pallor, pruritus, skin rash

IUPAC name: N-(4-hydroxyphenyl)acetamide

**2.2 Acetaminophen**

*Fentanyl and clinically important DDIs [15].*

management and reduction of fever [27]. Acetaminophen is often found in hundreds of OTC and prescription medicines [28]. PDs and PKs are summarized in **Table 5**.

95% of acetaminophen undergoes biotransformation, while 5% is excreted unchanged into the urine [29]. Approximately 45–55% of acetaminophen transforms into glucuronide conjugates via UDP-glucuronosyltransferase, 30–35% into sulfate conjugates via sulfotransferase, and only 5% into toxic metabolite NAPQI

even death [29, 35, 36]. Additional mechanisms such as mitochondrial injury, oxy-

IUPAC name: (4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one

Respiratory Atelectasis, hypoxia, pleural effusion, pulmonary edema, stridor, wheezing

Hypocalcemia, hyponatremia, hypokalemia, hypomagnesemia,

hyperuricemia, hyperglycemia, hypervolemia

hypophosphatemia, hyperchloremia, low bicarbonate levels, hypoalbuminemia,

CNS Trismus, fatigue, headache, agitation, anxiety, insomnia

GI Constipation, nausea, vomiting, abdominal pain, diarrhea Hepatic Increased serum transaminases, hyperbilirubinemia GU Nephrotoxicity, hyperammonemia, oliguria

Cardiovascular Tachycardia, hypertension/hypotension, edema

Muscle spasm, limb pain

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**,

gen, and nitrogen stress deepen hepatic cell damage [37].

*DOI: http://dx.doi.org/10.5772/intechopen.92941*

respectively.

**2.3 Oxycodone**

*Analgesic Poisoning*

**Systems Symptoms**

Ophthalmic Periorbital edema

Dermatologic Pruritus, skin rash

Anemia

Miscellaneous Hypersensitivity reaction, fever

*Common adverse reactions of acetaminophen [29, 38, 39].*

Hematologic and oncologic

Endocrine and metabolic

skeletal

**Table 6.**

**283**

Neuromuscular and

#### **Table 5.**

*PDs and PKs of acetaminophen at therapeutic doses [29–31].*

#### **Figure 1.**

*Metabolism of acetaminophen. NAPQI, N-acetyl-p-benzoquinone imine; (1) UDP-glucuronosyltransferase (1-9, 1-6, 1-1, and 2B15 isoforms); (2) CYP2E1; (3) sulfotransferase (1A1 and 1A3/1A4 isoforms) and bile salt sulfotransferase; (4) glutathione S-transferase (P and theta-1 isoforms) [33–35].*

through the CYP2E1 (**Figure 1**) [32–34]. 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.

## **2.3 Oxycodone**

IUPAC name: (4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one

#### **Table 6.**

*Common adverse reactions of acetaminophen [29, 38, 39].*

through the CYP2E1 (**Figure 1**) [32–34]. 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

*salt sulfotransferase; (4) glutathione S-transferase (P and theta-1 isoforms) [33–35].*

*Metabolism of acetaminophen. NAPQI, N-acetyl-p-benzoquinone imine; (1) UDP-glucuronosyltransferase (1-9, 1-6, 1-1, and 2B15 isoforms); (2) CYP2E1; (3) sulfotransferase (1A1 and 1A3/1A4 isoforms) and bile*

**PDs and PKs Routes of administration**

Distribution Adults: 4–6 L/kg

Protein binding 10–25% Metabolism In the liver

*Medical Toxicology*

Bioavailability 88%

**Table 5.**

**Figure 1.**

**282**

Half-life elimination Adults: 2–3 h

Excretion Urine (mainly)

**Oral i.v.**

• Metabolism to glucuronide and sulfate conjugates (primarily)

By CYP2E1 to toxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI,

Onset of action Above 1 h 5–10 min Duration 4–6 h 4–6 h

Absorption Small intestine (primarily) and stomach

Children: 5–30 L/kg

**Figure 1**)

*PDs and PKs of acetaminophen at therapeutic doses [29–31].*

Children: 4–10 h

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

CNS Dizziness, drowsiness, headache, fatigue, abnormal dreams, twitching,

Respiratory Dyspnea, cough, epistaxis, flu-like symptoms, oropharyngeal pain, rhinitis, sinusitis, pharyngitis, laryngismus, pulmonary disease Cardiovascular Flushing, tachycardia, palpitations, cardiac failure, deep vein thrombosis,

GI Constipation, nausea, vomiting, hiccups, upper abdominal pain, abdominal pain,

gastroesophageal reflux, gastritis, gastroenteritis

Dermatologic Pruritus, diaphoresis, hyperhidrosis, skin rash, skin photosensitivity,

arthritis, laryngospasm, pathological fracture

Miscellaneous Hypersensitivity reaction, fever, infection, sepsis, seroma, accidental injury

hypertension/hypotension, edema

Hepatic Increased serum alanine aminotransferase GU Urinary retention, dysuria, urinary tract infection

excoriation, urticaria

Ophthalmic Blurred vision, amblyopia

*Common adverse reactions of oxycodone [45–47].*

Hematologic and oncologic

Endocrine and metabolic

skeletal

**Table 9.**

**285**

Neuromuscular and

abnormality in thinking, agitation, anxiety, chills, depression, hypertonia, hypoesthesia, insomnia, irritability, confusion, lethargy, nervousness, paresthesia, neuralgia, personality disorder, withdrawal syndrome

anorexia, diarrhea, dyspepsia, dysphagia, gingivitis, glossitis, xerostomia,

Anemia, leukopenia, neutropenia, thrombocytopenia, hemorrhage

Hypochloremia, hyponatremia, hyperglycemia, weight loss, gout

Asthenia, arthralgia, ostealgia, back pain, neck pain, limb pain, myalgia, tremor,

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 [45–47]. 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**.

**Table 9**.

*Analgesic Poisoning*

*DOI: http://dx.doi.org/10.5772/intechopen.92941*

**Systems Symptoms**

#### **Table 7.**

*Acetaminophen and clinically important DDIs [15].*

Oxycodone is a semisynthetic opioid agonist, produced from thebaine and codeine found in the raw *Papaver somniferum L*. plant and approved by the FDA in 1968, with molecular formula C18H21NO4 and a molecular weight of 315.4 g/mol [41–43]. It is used alone or in combination with acetaminophen in the management of moderate to severe pain [3]. It binds to classical opioid receptors such as fentanyl and mediates similar mechanisms of action [6]. Oxycodone also inhibits the release of vasopressin, somatostatin, insulin, and glucagon and nociceptive neurotransmitters, such as substance P, GABA, dopamine, acetylcholine, and noradrenaline [44]. The analgesic effects of oxycodone are mediated by both itself and its active metabolites, noroxycodone, oxymorphone, and noroxymorphone [21]. It can be applied both orally and rectally. PDs and PKs are summarized in **Table 8**.

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 8.**

*PDs and PKs of oxycodone at therapeutic doses [21, 45–49].*

### *Analgesic Poisoning DOI: http://dx.doi.org/10.5772/intechopen.92941*

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 [45–47]. 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**.

#### **Table 9.**

*Common adverse reactions of oxycodone [45–47].*

Oxycodone is a semisynthetic opioid agonist, produced from thebaine and codeine found in the raw *Papaver somniferum L*. plant and approved by the FDA in 1968, with molecular formula C18H21NO4 and a molecular weight of 315.4 g/mol [41–43]. It is used alone or in combination with acetaminophen in the management of moderate to severe pain [3]. It binds to classical opioid receptors such as fentanyl and mediates similar mechanisms of action [6]. Oxycodone also inhibits the release of vasopressin, somatostatin, insulin, and glucagon and nociceptive neurotransmitters, such as substance P, GABA, dopamine, acetylcholine, and noradrenaline [44]. The analgesic effects of oxycodone are mediated by both itself and its active metabolites, noroxycodone, oxymorphone, and noroxymorphone [21]. It can be applied both orally and rectally. PDs and PKs are summarized in **Table 8**.

metyrapone Methemoglobinemia — — Dapsone, local anesthetics, nitric oxide, prilocaine, sodium nitrite

Ethanol, barbiturates, carbamazepine, imatinib, mipomersen, fosphenytoin-phenytoin, isoniazid,

**Possible effects Clinically important DDI types**

Hepatotoxicity — Dasatinib,

*Acetaminophen and clinically important DDIs [15].*

**PDs and PKs Oral administration**

Distribution Adults: 2.6 L/kg

Protein binding 38–45%

Metabolism In the liver

Bioavailability 60–87%

**Table 8.**

**284**

Excretion Urine (mainly)

*PDs and PKs of oxycodone at therapeutic doses [21, 45–49].*

Onset of action 10–15 min — Duration 3–6 h ≤12 h

Children: 2.1 L/kg

noroxycodol

Half-life elimination 3.2–4 h 4.5–5.6 h

High anion gap metabolic acidosis

*Medical Toxicology*

**Table 7.**

Enhancement in the anticoagulant effects **X D C**

— — Flucloxacillin

— — Vitamin K antagonists

sorafenib, probenecid

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

**Immediate release Extended release**

• Albumin (primarily) and alpha-1-acid glycoprotein

• By CYP3A4 and CYP3A5 to noroxycodone and then by CYP2D6 to

oxymorphol 6-keto-reduced to alpha and beta oxycodol

• By CYP2D6 to oxymorphone and then by CYP3A4 to noroxymorphone (active). Oxymorphone (active) can also be reduced to alpha or beta

noroxymorphone. Noroxycodone (active) can also be reduced to alpha or beta

**Drugs Clinical manifestations**

*DOI: http://dx.doi.org/10.5772/intechopen.92941*

*Analgesic Poisoning*

and death

asymptomatic Stage II (24 to 72 h):

Stage III (72 to 96 h):

system failure)

**Table 12.**

**Management steps**

**Decontamination**

**Basic measures and treatment**

**Antidotal therapy dosing**

**287**

• GI • Patch Stage IV (4 days to 2 weeks):

• Regression in symptoms and recovery phase

*Clinical manifestations of fentanyl, acetaminophen, and oxycodone poisoning [16, 61, 64–71].*

**ABC** Secure airway, breathing, and circulation as necessary

1. Ensure adequate ventilation

until ventilation is adequate 3. Require supplemental oxygen,

• Adult: 50 g orally

• Must be removed

is present

2 mg i.v. Children:

Adults:

Oxycodone Respiratory depression, sleepiness, stupor, coma, skeletal muscle flaccidity, cold

partial or complete airway obstruction, atypical snoring, and death

**Fentanyl Oxycodone Acetaminophen**

Activated charcoal: within 4 h of ingestion, unless contraindicated

1. Poisoning severity following an acute ingestion is quantified by plotting a timed serum acetaminophen concentration on the modified Rumack-Matthew nomogram 2. Antidotal therapy with N-acetyl cysteine (NAC)

**Oral dosing:** 140 mg/kg loading dose, followed by 17 doses of 70 mg/kg every 4 h **21 h i.v. protocol**: 150 mg/kg loading dose over 60 min, followed by 50 mg/kg infused over 4 h, with the final 100 mg/kg infused over the remaining 16 h • INR <2: 21 h i.v. protocol • INR >2: 21 h i.v. protocol, followed by a continuous i.v. NAC infusion at 6.25 mg/kg/h

until INR is <2

Children: 1 g/kg orally or by nasogastric tube, max. 50 g

2. Apply antidotal therapy with NLX. With a total of 5 to 10 mg, repeat administration

endotracheal intubation, and positive endexpiratory pressure, if response is inadequate to NLX or if pulmonary edema

• O2 saturation is <90%: 0.05 mg i.v. or i.m. • For apneic patients: 0.2 to 1 mg i.v. or i.m. • Patients in cardiorespiratory arrest: min.

• <20 kg: 0.1 mg/kg i.v. or intraosseous (i.

Adolescents suspected of opioid addiction: • 0.04 to 0.4 mg per dose repeated every 3–5 min and titrated to patient response

o.), max. 2 mg per dose • ≥20 kg: 2 mg i.v. or i.o.

• Recovery in stage I symptoms

Fentanyl Respiratory depression, somnolence, sleepiness, stupor, coma, amnesia, skeletal

Acetaminophen Stage I (0.5 to 24 h): nausea, vomiting, diaphoresis, pallor, lethargy, malaise or

• Increase in hepatic enzymes (aspartate aminotransferase, alanine

muscle flaccidity, cold and clammy skin, constricted pupils, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring,

aminotransferase) and total bilirubin, PT elongation, oliguria (occasionally)

• Jaundice, hepatic encephalopathy, a marked elevations of hepatic enzymes (exceed 10,000 IU/L) and total bilirubin (above 4.0 mg/dL), hyperammonemia, prolongation of the PT/INR, hypoglycemia, lactic acidosis, death (multiorgan

sweat, constricted pupils, bradycardia, hypotension, QT interval prolongation,

#### **Table 10.**

*Oxycodone and clinically important DDIs [15].*

## **2.4 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 11.**

*Toxicity, teratogenicity, and carcinogenicity of fentanyl, acetaminophen, and oxycodone.*

#### **Table 12.**

**2.4 Fentanyl, acetaminophen, and oxycodone toxicity, clinical manifestations,**

the International Agency for Research on Cancer), clinical manifestations, and management of fentanyl, acetaminophen, and oxycodone poisoning are

**Drugs Fentanyl Acetaminophen Oxycodone** LD50 (mouse, i.p.) (mg/kg) 76 367 320 TDLo (human, oral) (mg/kg) 0.1 490 0.14 FDA pregnancy category C C B Classification by the IARC NA 3 NA

The toxicity, teratogenicity (FDA pregnancy category), and carcinogenicity (by

**and management**

summarized in **Tables 11**–**13**, respectively.

*LD50, median lethal dose; TDLo, lowest toxic dose; NA, not assigned [55–63]*

*Toxicity, teratogenicity, and carcinogenicity of fentanyl, acetaminophen, and oxycodone.*

*Oxycodone and clinically important DDIs [15].*

**Possible effects Clinically important DDI types**

Azelastine, bromperidol, orphenadrine, oxomemazine, paraldehyde, thalidomide

Increase in the CNS depressant effects

*Medical Toxicology*

Enhancement in the serotonergic effects and serotonin syndrome

Urinary retention

**Table 10.**

**Table 11.**

**286**

Enhancement in the bradycardia effects

Enhancement in the psychomotor impairment

**XD C**

Blonanserin, chlormethiazole, CNS depressants, droperidol, flunitrazepam, lemborexant, methotrimeprazine, perampanel, phenobarbital, primidone, sodium oxybate, suvorexant, voriconazole, zolpidem, CYP3A4 inhibitors (strong)

MAOI — Serotonergic agents

— — Anticholinergic agents

— — Succinylcholine

Constipation Eluxadoline — Anticholinergic agents,

— — SSRI

Alizapride, brimonidine,

bromopride, tetrahydrocannabinol, cannabidiol, *Cannabis*, dimethindene, dronabinol, lisuride, lofexidine, magnesium sulfate, metoclopramide, metyrosine, minocycline (systemic), nabilone, piribedil, pramipexole, ropinirole, rotigotine, rufinamide, CYP3A4 inhibitors (moderate)

ramosetron

*Clinical manifestations of fentanyl, acetaminophen, and oxycodone poisoning [16, 61, 64–71].*

Acetaminophen, a non-opioid analgesic, found in hundreds of prescription and OTC medicines, with analgesia and antipyretic effects, often causes hepatotoxicity

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

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/

Department of Medical Pharmacology, Faculty of Medicine, University of Tekirdag

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

(hepatic damage, liver failure) or even death. Toxicity develops due to the

successfully heals liver damage.

*DOI: http://dx.doi.org/10.5772/intechopen.92941*

*Analgesic Poisoning*

continuous training of health protectors.

**Author details**

**289**

Mahluga Jafarova Demirkapu

Namık Kemal, Tekirdag, Turkey

provided the original work is properly cited.

\*Address all correspondence to<EMAIL_ADDRESS>
**Table 13.**

*Management of acute fentanyl, acetaminophen, and oxycodone toxicity [72–82].*

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:

## **3. 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.

#### *Analgesic Poisoning DOI: http://dx.doi.org/10.5772/intechopen.92941*

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.

## **Author details**

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,

**Fentanyl Oxycodone Acetaminophen**

For vomiting

• Serum acetaminophen concentration is above the "treatment" line of the

8 h of time of ingestion and acetaminophen ingestion is suspected

• Serum acetaminophen concentration is unavailable or will not return within

• Time of ingestion is unknown and serum acetaminophen level is >10 mcg/mL

• There is evidence of any hepatotoxicity with a history of acetaminophen

• Patient has risk factors for hepatotoxicity, and the serum acetaminophen

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

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

concentration is >10 mcg/mL (66 μmol/L) [80–82]

**Supportive care** For possible coma, seizures, hypotension, and non-cardiogenic pulmonary edema

*Management of acute fentanyl, acetaminophen, and oxycodone toxicity [72–82].*

are fentanyl, acetaminophen, and oxycodone, respectively.

severe in patients using X and D interactive drugs together.

and hepatic failure) if:

**Management steps**

*Medical Toxicology*

**Table 13.**

(66 μmol/L)

ingestion

**3. Conclusions**

**288**

treatment nomogram

Mahluga Jafarova Demirkapu Department of Medical Pharmacology, Faculty of Medicine, University of Tekirdag Namık Kemal, Tekirdag, Turkey

\*Address all correspondence to<EMAIL_ADDRESS>
© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Acharya G, et al. Fentanyl

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s10900-014-9895-x

36th Annual Report. Clinical Toxicology. 2019;**57**(12):1220-1413. DOI: 10.1080/15563650.2019.1677022

Practice & Research. Clinical Anaesthesiology. 2003;**17**(1):91-110

[1] Bakhaidar M, Jan S, Farahat F, Attar A, Alsaywid B, Abuznadah W. Pattern of drug overdose and chemical poisoning among patients attending an emergency department, western Saudi Arabia. Journal of Community Health. 2015;**40**(1):57-61. DOI: 10.1007/

[8] Bart G. Maintenance medication for opiate addiction: The Foundation of recovery. Journal of Addictive Diseases. 2012;**31**(3):207-225. DOI: 10.1080/

[9] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. [DSM-5]. Arlington, VA: American Psychiatric Publishing; 2013. pp. 541-546

[10] Jordan B, Devi LA. Molecular mechanisms of opioid receptor signal transduction. British Journal of Anaesthesia. 1998;**81**:12-19. DOI:

10550887.2012.694598

10.1093/bja/81.1.12

[11] North RA, Williams JT,

Sciences of the United States of America. 1987;**84**:5487-5491. DOI:

[12] Malaivijitnond S, Varavudhi P. Evidence for morphine-induced galactorrhea in male cynomolgus monkeys. Journal of Medical

j.1600-0684.1998.tb00061.x

pp. 257-275

1971;**231**:232

Primatology. 1998;**27**:1-9. DOI: 10.1111/

[13] Hersh EV, Dionne RA. Nonopioid analgesics. In: Dowd FJ, Johnson B, Mariotti A, editors. Pharmacology and Therapeutics for Dentistry. 7th ed. St. Louis, Mosby: Elsevier; 2017.

[14] Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature: New Biology.

[Online]. Available from: www.uptodate.

[15] UpToDate, Inc. Lexi-Interact

com/drug-interactions/?source= responsive\_home#di-druglist

10.1073/pnas.84.15.5487

Surprenant A, Christie MJ. Mu and delta receptors belong to a family of receptors that are coupled to potassium channels. Proceedings of the National Academy of

[2] Gummin DD, Mowry JB, Spyker DA, Brooks DE, Beuhler MC, Rivers LJ, et al. 2018 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS):

[3] Schug SA, Garrett WR, Gillespie G. Opioid and non-opioid analgesics. Best

[4] Demirkapu MJ, Yananli HR. Opium Alkaloids [Online First]. IntechOpen; 2020. DOI: 10.5772/intechopen.91326. Available from: https://www.intechopen.

[5] Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE. The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-

dependent chronic spinal dog. The Journal of Pharmacology and Experimental Therapeutics. 1976;**197**:517-532

[6] Lord JA, Waterfield AA, Hughes J, Kosterlitz HW. Endogenous opioid peptides: Multiple agonists and receptors. Nature. 1977;**267**:495-499

[7] Hutcheson DM, Matthes HW, Valjent E, Sánchez-Blázquez P,

**290**

Rodríguez-Díaz M, Garzón J, et al. Lack of dependence and rewarding effects of deltorphin II in mu-opioid receptordeficient mice. The European Journal of Neuroscience. 2001;**13**:153-161. DOI: 10.1111/j.1460-9568.2001.01363.x

com/online-first/opium-alkaloids [Published: 27 February 2020]

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[17] Raffa RB, Pergolizzi JV Jr, LeQuang JA, Taylor R Jr, Colucci S, Annabi MH. The fentanyl family: A distinguished medical history tainted by abuse. Journal of Clinical Pharmacy and Therapeutics. 2018;**43**(1):154-158. DOI: 10.1111/jcpt.12640

[18] Dowell D. Regarding CDC's Guideline for Prescribing Opioids for Chronic Pain [Written Communication]. Atlanta, GA: Centers for Disease Control and Prevention; 2019

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[21] DePriest AZ, Puet BL, Holt AC, Roberts A, Cone EJ. Metabolism and disposition of prescription opioids: A review. Forensic Science Review. 2015; **27**(2):115-145

[22] Heikkinen EM, Voipio HM, Laaksonen S, Haapala L, Räsänen J, Acharya G, et al. Fentanyl pharmacokinetics in pregnant sheep after intravenous and transdermal administration to the ewe. Basic & Clinical Pharmacology & Toxicology. 2015;**117**(3):156-163. DOI: 10.1111/ bcpt.12382

[23] Krinsky CS, Lathrop SL, Zumwalt R. An examination of the postmortem redistribution of fentanyl and interlaboratory variability. Journal of Forensic Sciences. 2014;**59**(5):1275-1279. DOI: 10.1111/1556-4029.12381

[24] Knoll J, Fürst S, Kelemen K. The pharmacology of azidomorphine and azidocodeine. The Journal of Pharmacy and Pharmacology. 1973;**25**(12):929-939

[25] Van Bever WF, Niemegeers CJ, Janssen PA. Synthetic analgesics. Synthesis and pharmacology of the diastereoisomers of N-(3-methyl-1-(2-phenylethyl)-4 piperidyl)-N-phenylpropanamide and N- (3-methyl-1-(1-methyl-2-phenylethyl)-4 piperidyl)-N-phenylpropanamide. Journal of Medicinal Chemistry. 1974;**17**(10): 1047-1051

[26] US National Institutes of Health; DailyMed. Current Medication Information for Fentanyl Citrate (Fentanyl Citrate) Lozenge. 2012. Available from: http://dailymed.nlm. nih.gov/dailymed/drugInfo.cfm?setid= 552ba162-76ed-4bc9-8c2c-fac7a1804da0 [Accessed: 01 June 2017]

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Section 5