Opioids interact with central nervous system (CNS) receptors to produce their analgesic, euphoric, and sedative effects. Historically, on the basis of animal studies, three major opioid receptors designated mu, kappa, and sigma have been proposed [1]. The sigma receptor is no longer considered an opioid subtype because it is insensitive to naloxone, has dextrorotatory stereochemistry binding, and has no endogenous ligand. The International Union on Receptor Nomenclature recommends a change from the Greek alphabet to one similar to other neurotransmitter systems; receptors are denoted by their endogenous ligand (opiates peptides) with a subscript denoting their order of discovery: delta to OP₁ kappa to OP₂, and mu to OP₃ [2] (Table 140.1).

Most opioid analgesics are well absorbed after parenteral administration, from the pulmonary capillaries and mucosal sites. Analgesia is promptly achieved after parenteral administration and within 15 to 30 minutes after oral dosing. Peak plasma levels are generally attained within 1 to 2 hours after therapeutic oral doses. However, acute overdose may produce decreased intestinal peristalsis, resulting in delayed and prolonged absorption. Therapeutic and toxic serum drug concentrations are not well established.

All opioids undergo hepatic biotransformation, including hydroxylation, demethylation, and glucuronide conjugation. Considerable first-pass metabolism accounts for the wide variations in oral bioavailability noted with drugs such as morphine and pentazocine. Only small fractions of the parent drug are excreted unchanged in the urine. Active metabolites can contribute to the toxicological profile of specific drugs.

All opioids elicit the same overall physiologic effects as morphine, the prototype of this group. A typical morphine dose (5 to 10 mg) usually produces analgesia without altering mood or mental status in a patient. Sometimes dysphoria rather than euphoria is manifest, resulting in mild anxiety or a fear reaction. Nausea is frequently encountered, and vomiting is occasionally observed. Morphine and most of its congeners cause miosis in humans. This effect is exacerbated after an overdose, resulting in profound pupillary constriction, predominantly a central effect. Cerebral circulation does not appear to be altered by therapeutic doses of morphine unless respiratory depression and carbon dioxide retention result in cerebral vasodilation.

Respiratory failure is the most serious consequence of opiate overdose. Opioid agonists reduce the sensitivity of the medullary chemoreceptors in the respiratory centers to an increase in carbon dioxide tension and depress the ventilatory
response to hypoxia. Even small doses of morphine depress respiration, decreasing minute and alveolar ventilation [3]. The peak respiratory-depressant effect is usually noted within 7 minutes of intravenous (IV) morphine administration, but may be delayed up to 30 minutes if the drug is intramuscularly administered. Normal carbon dioxide sensitivity and minute volume usually return 5 to 6 hours after a therapeutic dose [3].

Therapeutic opiate doses cause arteriolar and venous dilation and may result in a mild decrease in blood pressure. This change in blood pressure is clinically insignificant while the patient is supine, but significant orthostatic changes are common [4]. Hypotension appears to be mediated by histamine release [5]. Myocardial damage (necrotizing angiitis) in opiate overdose associated with prolonged hypoxic coma may be mediated by cellular components released during rhabdomyolysis, direct toxic effects, or hypersensitivity to the opioids or adulterants [6].

Heroin (diacetylmorphine) has two to five times the analgesic potency of morphine [7]. Virtually all street heroin in the United States is produced in clandestine laboratories and adulterated before distribution (Table 140.2). The purity of street heroin is between 5% and 90%. Physiologically, the effects of heroin are identical to those described for morphine [8]. Heroin can be administered intravenously, intranasally, or inhaled as a volatile vapor, and can be mixed with other drugs of abuse, typically amphetamine or cocaine (“speed ball”). The plasma half-life of heroin is 5 to 15 minutes. Heroin is initially deacetylated in the liver and plasma, and then renally excreted as a conjugate, with small amounts of morphine, diacetylmorphine, and 6-monoacetylmorphine [8]. Individual variation in sensitivity and tolerance makes correlation of serum levels with clinical symptoms difficult.

The initial heroin rush is probably due to its high lipid solubility and rapid penetration into the CNS [8]. The majority of its lasting effects are attributable to its metabolites 6-monoacetylmorphine and morphine [8]. Fatal overdoses with heroin have been reported with serum morphine concentrations of 0.1 to 1.8 μg per mL [9].

Codeine (methylmorphine) is formulated as a sole ingredient and in combination with aspirin or acetaminophen. Codeine is rapidly absorbed by the oral route, producing a peak plasma level within 1 hour of a therapeutic dose [10]. Usually 10% of codeine is metabolized to morphine by CYP2D6; this may be greatly increased in patients with duplicated or amplified CYP2D6 genes, resulting in opioid toxicity [11]. This pathway may be inhibited by quinidine [12]. Clearance of codeine by CYP3A4 may be inhibited by clarithromycin and voriconazole [11]. Codeine and morphine appear in the urine within 24 to 72 hours. However, only morphine is detected in the urine at 96 hours [10]. The effect of codeine on the CNS is comparable with, but less pronounced than that of, morphine. Fatal ingestions with codeine alone are rare. The estimated lethal dose in a nontolerant adult is 800 mg, with a serum codeine concentration of 0.14 to 4.8 mg per dL [13].

Fentanyl, a phenylpiperidine derivative, has a potency 200 times that of morphine. Legitimate use is limited to anesthesia, and it is known to be commonly abused by hospital personnel. Rapid IV administration may result in acute muscular rigidity primarily involving the trunk and chest wall, which impairs respiration. Although motor activity resembling seizures has been associated with fentanyl use, simultaneous electroencephalogram recording during fentanyl induction of general anesthesia failed to show epileptiform activity [14]. This suggests a myoclonic rather than epileptic nature of the observed muscle activity [14].

Fentanyl is available as a transdermal delivery system that establishes a depot of drug in the upper skin layers, where it is available for systemic absorption. After removal of the patch, drug absorption from the dermal reservoir continues with an apparent half-life of 17 hours, versus 2 to 4 hours with IV administration [15].

By manipulating the chemical structure of fentanyl, α-methylfentanyl (China white), 3-methylfentanyl, and para-fluoro-fentanyl have been produced and distributed on the street as heroin substitutes. They are 200 to 3,000 times more potent than heroin [16]. α-Methyl-acetyl-fentanyl, α-methyl-fentanyl acrylate, and benzylfentanyl are 6,000 times more potent than morphine [17].

Meperidine, another phenylpiperidine derivative, is less than half as effective when given orally as compared to the parenteral route [18]. It appears to be a common drug of abuse among medical personnel, yet there are few reports of meperidine poisoning or fatalities [19]. Peak plasma levels are 30 minutes after intramuscular administration, and 1 to 2 hours after an oral dose [18]. The duration of action is 2 to 4 hours [18]. Meperidine is metabolized primarily by N-demethylation to normeperidine, an active metabolite with half the analgesic and euphoric potency of its parent and twice the convulsant property [20]. Excretion is primarily through the kidneys as conjugated metabolites [21]. Meperidine and normeperidine may be detected in either urine or serum [21]. The seizures reported with meperidine toxicity have been attributed to the accumulation of normeperidine, which has an elimination half-life of 14 to 24 hours [18,22].

A synthetic meperidine analog, methyl-phenyl-propionoxypiperidine has been used as a heroin substitute. Methyl-phenyl-tetrahydropyridine, a contaminant produced during the clandestine synthesis of this agent, led to an epidemic of Parkinsonism among IV drug abusers within days of repeated injections [23].

Diphenoxylate is structurally similar to meperidine. Diphenoxylate (2.5 mg) is formulated with 0.025 mg atropine sulfate (Lomotil) and used in the treatment of diarrhea. In therapeutic doses, the drug has no significant CNS effects. Symptoms arising from a toxic ingestion may be delayed because of decreased gastrointestinal (GI) motility and accumulation of the hepatic metabolite difenoxin, a potent opioid with a long serum half-life [24]. The ingestion of only six to eight Lomotil tablets may cause serious toxicity in children [24].

Methadone is used for chronic pain conditions and maintenance of opiate addicts. It is well absorbed orally, producing a peak plasma level within 2 to 4 hours [25]. It has a prolonged but variable duration of action; the half-life averages 25 hours, but may be as long as 52 hours during long-term maintenance therapy [25]. As little as 40 to 50 mg may produce coma and respiratory depression in a nontolerant adult [26]. A protracted clinical course is expected after an overdose [27].

Propoxyphene is structurally related to methadone. It is available alone or in combination with aspirin or acetaminophen. Oral administration is followed by rapid absorption, with peak serum levels occurring in 1 hour [28]. The plasma half-life of propoxyphene and its main active metabolite, norpropoxyphene, is 6 to 12 hours and 37 hours, respectively. Norpropoxyphene is the primary metabolite excreted in the urine [29]. It is believed to play a role in the prolonged clinical course after an overdose [30]. Blood levels in fatal overdose cases range from 0.028 to 42.7 mg per L [31].

Pentazocine is a synthetic analgesic in the benzomorphan class and has been involved in the drug abuse trade [32]. It has agonist as well as weak antagonist activity at the opioid receptors. It has one third the analgesic potency of morphine [32]. Orally administered, pentazocine achieves peak plasma levels within 1 hour and is extensively metabolized in the liver with the parent compound and metabolites detectable in either urine or plasma [32]. Pentazocine (Talwin), in combination with the antihistamine tripelennamine, was known on the street as T’s and Blues and was used as a heroin substitute [33].

In an attempt to curtail pentazocine abuse, the oral preparation was reformulated to contain 0.5 mg naloxone (Talwin-NX). When Talwin-NX is parenterally administered, the effects of pentazocine are antagonized by naloxone, which has precipitated withdrawal in opiate-dependent individuals. Because the duration of action of pentazocine exceeds that of naloxone, delayed respiratory depression may occur.

Dextromethorphan, an analogue of codeine, is found in a large number of nonprescription cough and cold remedies. It is available as a single ingredient but usually formulated in combination with sympathomimetic and antihistamine drugs. Dextromethorphan is well absorbed from the GI tract, with peak plasma levels occurring 2.5 and 6.0 hours after ingestion of regular and sustained-release preparations, respectively. The therapeutic effect is 3 to 6 hours, with a corresponding plasma half-life of 2 to 4 hours. The predominant antitussive effect is attributed to the active metabolite dextrorphan [34]. Within the therapeutic dose, dextromethorphan lacks analgesic, euphoric, and physical dependence properties [35].

Hydromorphone and oxycodone are orally administered opioids used in the treatment of chronic pain conditions. A number of sustained-release formulations are available, and can result in prolonged poisoning in overdose. A formulation of hydromorphone has recently been withdrawn from the market because alcohol could accelerate the release of the drug [36]. The sustained-release properties of some formulations of oxycodone can be circumvented by crushing or dissolving the tablet, resulting in fatal narcotic overdoses in drug abusers [37].

Tramadol is structurally similar to morphine. It is a centrally acting analgesic with moderate affinity for mu receptors. The metabolite O-demethyl-tramadol appears to have a higher affinity than the parent compound. Most of the analgesic effects are attributed to nonopioid properties of the drug, probably by blocking the reuptake of biogenic amines (e.g., norepinephrine and serotonin) at synapses in the descending neural pathways, which inhibits pain responses in the spinal cord [38].

Buprenorphine is a partial agonist activity with high affinity to, and slow dissociation from, the mu receptor. It displaces other opioids and its dose–response curve has a ceiling effect, resulting in less respiratory depression in overdose, although apnea may still occur [39,40]. It has poor oral bioavailability and is administered sublingually. It is also formulated with naloxone that is active only if administered intravenously [41]. Other partial agonists include butorphanol and nalbuphine. They can precipitate opioid withdrawal (see Chapter 145) in those taking other opioids.

Miosis, respiratory depression, and coma are the hallmarks of opiate intoxication, with the magnitude and duration of toxicity dependent on the dose and degree of tolerance. The clinical effects of an overdose with any one of the agents in this class are similar. However, there are important differences between certain drugs. Overdoses resulting in toxicity often have a prolonged clinical course, in part because of opiate-induced decreased GI motility when taken orally and prolonged half-life of the drug or its active metabolite(s). Miosis is considered a pathognomonic finding in opiate poisoning, with the exception of meperidine, propoxyphene, pentazocine, and dextromethorphan use, in the case of a mixed overdose with an anticholinergic or sympathomimetic drug, or when severe acidemia, hypoxemia, hypotension, or CNS structural disorder is present.

CNS depression occurs in most severely intoxicated patients. However, codeine, meperidine, and dextromethorphan intoxications are remarkable for CNS hyperirritability, resulting in a mixed syndrome of stupor and delirium. In addition, patients with meperidine toxicity may also have tachypnea, dysphoric and hallucinogenic episodes, tremors, muscular twitching, and spasticity, whereas patients with dextromethorphan toxicity may also manifest restlessness, nystagmus, and clonus [22,42].