Opiates

Opiates are naturally occurring chemicals that bind to the opiate receptor, and include opium, morphine, and codeine. In contrast, an opioid is any xenobiotic that has activity at the opiate receptors. Such drugs include the semisynthetic opioids, such as oxycodone or hydrocodone, as well as the synthetic opioids, such as fentanyl or methadone. In addition, more recently, several novel synthetic opioids have been created including U47700, MT-45, U-50488, and numerous fentanyl derivatives, such as acetylfentanyl and carfentanil. Prior to 2013, sporadic outbreaks of fentanyl and fentanyl analogs were reported as contaminants in the US heroin supply. Since 2014, however, fentanyl became more widely detected, and the first illicit pills containing fentanyl were reported. Furthermore, fentanyl purposefully contaminating the heroin market has become commonplace, largely driven by illicit production in Mexico and China. In recent years, the United States has encountered an explosion of drug overdose deaths, largely driven by opiates. Between June 2019 and May 2020, more than 81,000 Americans died of drug overdose deaths, which is the highest number documented in any 12-month period of time. This increase is largely driven by synthetic opioids, especially fentanyl.

Opioids continue to be used medically and recreationally. Although their use is often for legitimate analgesic purposes, they are frequently abused also. Approximately one-quarter of patients prescribed opioids for chronic pain misuse them, and approximately 10% of such patients develop an opioid abuse disorder. Opioids are the most common drug of addiction in the United States. Regardless of whether they are used medicinally or recreationally, all mu agonists can produce analgesic effects at lower doses, but at higher doses, can produce toxicity including central nervous system (CNS) depression, miosis, and respiratory depression. Because of a lack of tolerance, children may be particularly susceptible to the effects of opiates, and may exhibit respiratory depression or respiratory arrest following consumption of a therapeutic dose for an adult.

Treatment of opiate overdose is primarily focused on reversing respiratory depression. Pharmacologic treatment in the emergent setting is best accomplished with the administration of naloxone. Naloxone can be administered via numerous routes, including intranasal (with an atomizer), intravenous, intramuscular, or subcutaneously. When administering intravenously, typical dosing recommendations start at 0.01 mg/kg intravenously or intramuscularly, repeated up to 0.1 mg/kg until adequate response is achieved. It is best to start at a low dose and titrate upwards, especially if the individual is thought to have chronic opiate use, to avoid precipitating withdrawal. The naloxone should be titrated until the patient is breathing and arousable. If repeat doses of naloxone are indicated, a continuous infusion may be warranted. Such an infusion is typically started at two thirds of the last reversal dose administered each hour.

Sedative Hypnotics

Benzodiazepines are xenobiotics that bind to the GABA-A receptor, resulting in hyperpolarization and subsequent decrease in neuronal excitation. Since the prototypical benzodiazepine, chlordiazepoxide, was developed in the 1960s, numerous other benzodiazepines or benzodiazepine derivatives have emerged. In recent years, illicit use of alprazolam has increased. Although alprazolam is available with a prescription, its illicit use remains common, especially among adolescents. Recreationally, alprazolam is often referred to as “Xanibars,” “Xanny Bars,” or “planks” owing to their shape. They are typically available in 2 mg tablets, but can be broken and are occasionally available in smaller doses. In addition, etizolam, a thienodiazepine that is chemically similar to benzodiazepines (and binds the same receptor), has emerged. Etizolam is currently illegal in the United States, although it is available with a prescription in other countries, such as Japan and Italy, and can commonly be purchased on the Internet in the United States. The illicit sale often describes etizolam as a “research chemical,” presumably in an attempt to try to circumvent laws. The typical therapeutic dose ranges between 0.5 to 2 mg per day, with a half-life of 5 to 7 hours, although it is metabolized to an active metabolite, alpha- hydroxyetizolam, which has a longer half-life than the parent drug. Because it is metabolized via CYP3A4 and CYP2C19, slow metabolizers of these isoenzymes may be at increased risk for toxicity.

In addition, because etizolam has less effect at the alpha -1 subunit of the GABA-A receptor, etizolam produces less sedation than alprazolam or diazepam, despite being 5 to 10 times more potent as an anxiolytic than diazepam. The primary toxicity observed includes CNS depression, ataxia, dysarthria, and respiratory depression. Numerous deaths have been reported involving etizolam. However, most of these deaths involve mixed drug ingestions, frequently including opioids or pregabalin.

The use of etizolam is expected to result in a negative benzodiazepine test on most routine drug-of-abuse screens. However, comprehensive confirmatory testing is available. Treatment is largely supportive, although flumazenil may be able to reverse the effects of etizolam if clinically indicated. Flumazenil is typically dosed at 0.01 mg/kg intravenously, with a maximal dose of 0.2 mg. The use of flumazenil needs to be weighed against the risk of precipitating a life-threatening withdrawal.

Phenibut ( beta phenyl- gamma aminobutyric acid) is a sedative hypnotic frequently used for its anxiolytic and sedative properties. Although the drug was originally developed in the 1960s in Russia, its use in the United States has increased significantly in recent years. The United States Food and Drug Administration banned its retail sale in 2019, although it is still able to be easily obtained online and is available as either a powder or tablet. Phenibut primarily exerts its activity at the GABA receptors, with more agonism at the GABA-B receptor, compared with the GABA-A receptor. ^, In addition, it is an agonist at the dopamine receptor and blocks beta phenethylamine (PEA), an endogenous anxiogenic chemical.

The primary toxicity of phenibut involves a combination of sedative and stimulant effects, owing to the mixed actions at the GABA and dopamine receptors. Consequently, sedation or agitation can be encountered, as can tachycardia. Patients who purchase phenibut online may exhibit higher rates of toxicity than those who take it at therapeutic doses during clinical trials. In addition, chronic users of phenibut may develop physical dependence. ^, Abrupt discontinuation may result in withdrawal symptoms. Such withdrawal symptoms may include hypertension, tachycardia, seizures, and encephalopathy.

Kratom

Kratom, a drug derived from the tropical tree Migragyna speciose , has long been used in Africa and Southeast Asia for management of fatigue, diarrhea, and opiate withdrawal. At low doses (1 to 5 g of plant product), kratom produces mild stimulant effects, in which individuals report increase alertness and an increase in physical energy. ^, At higher doses (5 to 15 g plant product), the primary manifestation is opiate-like. Kratom contains multiple indole alkaloids, including mitragynine and 7-hydroxymitagynine, which are partial agonists at the mu opioid receptor. In addition, mitragynine is an agonist at the alpha-2 adrenergic receptor, and an antagonist at the serotonin receptors. Its use has increased recently, especially in the United States, among individuals with opiate use disorder. Such individuals have used kratom, anecdotally, to help minimize use of other opiates, which are perceived more dangerous. Kratom can be consumed orally as a pill or capsule, or the leaves may be dried and chewed or used in a tea.

Between 2010 and 2015, calls to US poison control centers regarding kratom increased from 26 in 2010 to 263 in 2015. In 2019, US poison control centers received 1357 calls regarding kratom. At present, while kratom is illegal in several countries, the DEA has listed kratom as a drug or chemical of concern, but has not officially banned its use on a federal level.

Most calls to poison control centers regarding kratom are associated with little to no toxicity. However, there are scattered case reports associating kratom with drug-induced liver injury (DILI), primarily of a cholestatic pattern. ^{, ,} Nonetheless, a detailed review of kratom-induced liver injury found that not only is the latency time to the development of DILI unclear, the prevalence is not clearly known, and definitive causality has not been established. In addition, kratom may be associated with seizures or death, but these cases are often confounded with ingestions of other drugs. In 2019, The Centers for Disease Control and Prevention (CDC) found that kratom was a cause of death in nearly 100 people over a 17-month period. The CDC analyzed reports of more than 27,000 unintentional drug overdoses; 152 of those people were found to have kratom in their system, and kratom was listed as a cause of death in 91 of them.

Phenethylamines

Amphetamine and methamphetamine were first produced in the 1800s. In the early 1900s, Merck produced 3, 4-methylenedioxy-N-methamphetamine (MDMA), although the drug was never marketed. Years later, MDMA, which has now known more commonly as ecstasy, has been used recreationally. Such drugs are collectively referred to as phenethylamines. In the 1960s, numerous substitutions on the phenethylamine ring were made to create a series of different drugs within this class. More recently, several different phenethylamines have been manufactured, including those with fused rings (eg, 2C-B), and the N-benzylphenethylamine (NBOMe) substances, in which a benzyl group substitutes for a nitrogen atom. Substitutions of the 2, 4, or 5 position on the ring frequently result in increased hallucinogenic properties. In contrast, the phenethylamines that only have a halogen substitution on the ring tend to produce effects similar to amphetamine.

Any of the phenethylamines can cause sympathomimetic toxicity, including tachycardia, hypertension, diaphoresis, and agitation. Fever and rhabdomyolysis can result from increased neuromuscular agitation. In addition, both the 2C class and the NBOMe class of phenethylamines bind numerous serotonin receptors, including the 5HT2 receptor. Such serotoninergic agonism is responsible for the increased hallucinogenic effects of these phenethylamines, compared with other phenethylamines, such as amphetamine. In addition, the serotonin agonism can result in seizures and serotonin syndrome. ^,

Treatment is largely supportive, and is focused on ensuring adequate airway protection. Benzodiazepines should be titrated until resolution of neuromuscular excitation. Although benzodiazepines can be given for tachycardia and hypertension, once the patient is sedated, in general, additional benzodiazepines are not necessary if only mild hyperadrenergic vital signs persist. Sedation should ideally be titrated until the patient is lightly arousable. If fever and neuromuscular excitation persist either intermittently or persistently despite sedation, endotracheal intubation and paralysis with a nondepolarizing neuromuscular blocker should be instituted. Urine output should be monitored, and fluid resuscitation should occur. Seizures are best treated with benzodiazepine. Electrolytes, including sodium, as well as creatinine kinase, should be checked, and patients with hyperadrenergic features should also receive an electrocardiogram. Although a urine drug screen can be performed, most of the novel phenethylamines will result in a negative amphetamine screen.

Marijuana

Cannabis is a collective term that refers to any substance derived from the plant Cannabis sativa . Cannabis contains more than 400 unique chemicals, including more than 60 cannabinoids. Although numerous cannabinoids exist, the most relevant cannabinoids include cannabinol, cannabidiol (CBD) and tetrahydrocannabinol (THC). The plant Cannabis sativa commonly grows in tropic areas, but the plants have been able to be cultivated indoors in artificial environments. Marijuana is typically derived from the flowerheads and leaves of the plant, whereas hashish contains the resin, and hash oil contains a concentrated resin extract. These products can be consumed via numerous routes including traditional smoking, vaping, or oral consumption. Although nicotine is the most commonly utilized xenobiotic among adolescents who vape, cannabis has been reported in up to one-third of these adolescents.

In recent years, the concentration of THC in cannabinoids has increased substantially. In the 1960s, a typical dose of marijuana contained 10 mg of THC. In contrast, some joints currently may contain 150 mg of THC, and possibly even up to 300 mg if laced with hashish oil. The use of marijuana remains common among adults and adolescents. Among adolescent trauma patients, nearly half used marijuana. Calls to poison control centers involving illicit drug exposures in children under age 10 years increased significantly between 2006 and 2016. Among this population, marijuana use was common, and increased with time.

There are several cannabinoid receptors, including the CB1 and CB2 receptor. The CB1 receptor is primarily found throughout the nervous system and smooth muscle and the myocardium, whereas the CB2 receptors are primarily in mononuclear cells, smooth muscle, vascular endothelium, and the myocardium. Tetrahydrocannabinol is an agonist at both the CB1 and CB2 receptors. In contrast, CBD has weak affinity for the CB1 receptors and no direct effect on the CB2 receptors. Consequently, CBD does not produce the same degree of intoxication as THC. When smoked, approximately half of the THC is absorbed through the lungs, and quickly reaches systemic circulation. In contrast, following oral consumption, only 25% to 30% of the THC reaches systemic circulation, and peak concentrations may not occur for up to 2 hours. There are a few conditions (Lennox-Gastaut syndrome and Dravet syndrome), for which there are moderate data for the use of marijuana. However, most use is recreational or for less-well established conditions.

Endogenous cannabinoids control neural circuits in the prefrontal cortex and hippocampus. In adolescents, the use of marijuana has been demonstrated to affect these circuits, resulting in impaired neurocognitive functioning. The use of marijuana can result in significant impairment in driving performance, and can last up to 7 hours. This impairment is more common in occasional users than regular users, suggesting a tolerance may develop. In addition, legalization may be associated with an increase in prevalence, particularly among trauma patients.

Following legalization of marijuana, there has been an increase in children with unintentional exposures. The ingestion of edible marijuana products by children may result in significant toxicity, including CNS depression, ataxia, encephalopathy, and respiratory depression.