Heroin (diacetylmorphine) is a semisynthetic narcotic that was first synthesized in 1874. It was originally marketed as a safer, non-addictive substitute to morphine. Soon after its introduction, heroin was realized to be clearly as addictive as morphine, prompting the US government to institute measures to control its use. By 1914, the Harrison Narcotics Act prohibited the use of heroin without a prescription. In 1920, the Dangerous Drugs Act prohibited the use of heroin altogether, thus driving it underground. In the United States, heroin remains one of the most frequently abused narcotics.
In its pure form, heroin is a white powder with a bitter taste. Street heroin samples are frequently mixed with other substances so dealers may maximize their profits. Because of these impurities and additives, street heroin may appear in various hues and colors, ranging from white to dark brown. Heroin is occasionally sold as a black, tarry substance, especially when crude processing methods are used to manufacture it.
Heroin is most often injected intravenously or smoked; however, it also may be snorted or administered subcutaneously. Recreationally, daily heroin doses of 5-1500 mg have been reported, with an average daily dose of 300-500 mg. Addicts may inject heroin 2-4 times per day. Depending on the demographic region, the street purity of heroin can range from 11-72% (average U.S. purity is ~38%). Heroin may be cut with inert or toxic adulterants such as sugars, starch, powdered milk, quinine, and ketamine. Heroin is often mixed with methamphetamine or cocaine (“speedball”) and injected; or co-administered with alprazolam, MDMA (Ecstasy), crack cocaine, or diphenhydramine.
Pharmacodynamics and Pharmacokinetics
Heroin is a highly addictive semisynthetic opioid that is derived from morphine. When used intravenously, it is 3-5 times more potent than its parent compound and is able to modulate pain perception and cause euphoria. Similar to morphine, heroin and its metabolites have mu, kappa, and delta receptor activity. In general, stimulation of the mu receptors results in analgesia, euphoria, CNS depression, respiratory depression, and miosis. Stimulation of the delta and kappa receptors also results in analgesia, but the kappa receptors are mostly involved in spinal analgesia.
Heroin and other opioids produce their major effects on the CNS primarily through m-receptors, and also at k- and d-receptors. M1-receptors are involved in pain modulation, analgesia, respiratory depression, miosis, euphoria, and decreased gastrointestinal activity; m2-receptors are involved in respiratory depression, drowsiness, nausea, and mental clouding; k-receptors are involved in analgesia, diuresis, sedation, dysphoria, mild respiratory depression, and miosis; and d-receptors are involved in analgesia, dysphoria, delusions, and hallucinations. Heroin has little affinity for opiate receptors and most of its pharmacology resides in its metabolism to active metabolites, namely 6-acetylmorphine, morphine, and morphine-6-glucuronide.
Intravenously injected heroin creates a “rush” or a sensation of intense pleasure that begins within one minute of the injection and lasts from one to a few minutes. This “rush” is followed by a period of sedation that lasts about an hour. The initial “rush” is likely due to heroin’s high lipid solubility and rapid penetration to the brain.
The onset of action, peak effects, and duration of action vary with the different methods of use. Patients experience heroin’s effect within 1-2 minutes when injected intravenously and within 15-30 minutes when injected intramuscularly. Heroin’s peak therapeutic and toxic effects are generally reached within 10 minutes when injected intravenously, within 30 minutes when injected intramuscularly or when snorted, and within 90 minutes when injected subcutaneously. Effects generally last 3-5 hours minimally.
Heroin has an extremely rapid half-life of 2-6 minutes, and is rapidly metabolized to 6-acetylmorphine and morphine by the liver, brain, heart, and kidney and may not be detected in the blood at the time of blood draw. The half-life of 6-acetylmorphine is 6-25 minutes. Both heroin and 6-acetylmorphine are more lipid soluble than morphine and enter the brain more readily. Morphine is metabolized by the liver and excreted as a glucuronide product or in its free form by the kidneys. Morphine’s half-life is considerably longer than heroin’s, i.e., 2-3 hours. A small amount of unchanged 6-acetylmorphine is excreted in the urine for up to 24 hours after heroin use.
Because 6-acetylmorphine can originate only from heroin, its detection in the urine can mean only that the patient used either heroin or 6-acetylmorphine.
Forensic drug testing
Heroin is one of the major target drugs in workplace drug-testing programs because of its history of abuse, liability, and continued negative social impact.
The detection time of morphine in blood is 20 hours after intravenous administration of 12 or 20 mg heroin. After smoking 10.5 mg of heroin, the detection time varies between 22 minutes and 2 hours. After administration of 9 mg heroin intranasally, morphine was detectable in blood for 12 hours. In the blood of chronic users, total morphine is detectable for 29.2 hours on average (maximum 5 days), and free morphine for 14.4 hours (maximum 5 days). After administration of 3, 6, and 12 mg heroin intravenously, 6-acetylmorphine is detectable in urine during respectively 2.3, 2.6, and 4.5 hours. Total morphine is detectable for 18.5, 24.8, and 35.3 hours. After a lower than 7 mg dose, the detection time for total morphine is 7.4 to 32 hours. For doses between 10 and 15 mg, the detection time is 11 to 54 hours. In oral fluid, 6-acetylmorphine is detectable for 0.5 to 8 hours and morphine for 12 to 24 hours.
In a study conducted by Cone et al the authors found that following heroin administration, 6-acetylmorphine was excreted rapidly with an average half-life of 0.6 h. This resulted in a very short detection time for 6-acetylmorphine with a range of 2-8 h at the most sensitive cutoff limit. In contrast, free morphine and total morphine were detectable up to approximately 24 h after heroin administration. The average half-life for free morphine was 3.6 h and for total morphine was 7.9 h. After morphine and codeine administration, no 6-acetylmorphine was detected by GC/MS above the 0.81-ng/mL detection limit of the assay.
The authors concluded that the presence of 6-acetylmorphine in urine could be interpreted with confidence to mean that heroin, or 6-acetylmorphine, was administered within 24 h of specimen collection and that the presence of 6-acetylmorphine in urine was not caused by morphine or codeine administration.
Interpretation of Blood Concentrations
Following a single 12 mg intravenous mg dose of heroin, a peak heroin concentration of 0.141 mg/L was obtained at 2 minutes, while the 6-acetylmorphine and morphine concentrations were 0.151 and 0.044, respectively. A single 5 mg intravenous dose of heroin produced a peak plasma morphine concentration of 0.035 mg/L at 25 minutes, while intravenous doses of 150-200 mg have produced plasma morphine concentrations of up to 0.3 mg/L. Intranasal administration of 12 mg heroin in 6 subjects produced average peak concentrations of 0.016 mg/L heroin in plasma within 5 minutes; 0.014 mg/L of 6-acetylmorphine at 0.08-0.17 hours; and 0.019 mg/L of morphine at 0.08-1.5 hours.
Interpretation of Urine Test Results
Positive morphine urine results generally indicate use within the last two to three days, or longer after prolonged use. Detection of 6-acetylmorphine in the urine is indicative of heroin use. High concentrations may indicate chronic use of the drug. It is important to hydrolyze urine specimens to assess a urine morphine concentration.
Smith et al. studied the urine excretion profiles for total morphine (Tmor), free morphine (Fmor), and 6-acetylmorphine (6-AM) using gas chromatography-mass spectrometry (GC-MS) in 920 urine samples collected from 11 male human subjects following single doses of heroin. Eight received intravenous doses of 3, 6, and 12 mg heroin HCI and four smoked 3.5-, 5.2-, 7-, 10.5-, or 13.9-mg doses of heroin (base). In addition, 183 urine-based blind quality-control samples were added to the study set to assess assay performance. Excretion half-life for Tmor was 3.11 h. As previously reported urine concentrations varied greatly between subjects and within subjects with time after dosing but were much more predictable when values were reported as amount of drug per unit of creatinine. The range (median) values for percent of heroin excreted into urine as Tmor was 12.8-88.5% (51.0).
The effects experienced by the user depend heavily on the dose of morphine or heroin, the route of administration, and previous exposure. Following an intravenous dose of heroin, the user generally feels an intense surge of euphoria (“rush”) accompanied by a warm flushing of the skin, dry mouth, and heavy extremities. The user then alternates between a wakeful and drowsy state (“on the nod”).
Psychological effects include euphoria, feeling of well-being, relaxation, drowsiness, sedation, lethargy, disconnectedness, self-absorption, mental clouding, and delirium.
Physiological effects include analgesia, depressed heart rate, respiratory depression, CNS depression, nausea and vomiting, reduced gastrointestinal motility, constipation, flushing of face and neck due to dilatation of subcutaneous blood vessels, cramping, sweating, pupils fixed and constricted, diminished reflexes, and depressed consciousness.
Heroin, like morphine and other narcotics, reduces the brain’s responsiveness to changes in PCO2 and hypoxia, thus resulting in respiratory depression. It also reduces peripheral vascular resistance (resulting in mild hypotension), causes mild vasodilation of the cutaneous blood vessels (resulting in flushing), and stimulates histamine release (resulting in pruritus). Heroin’s inhibitory effects on baroreceptor reflexes results in bradycardia, even in the face of hypotension.
Finally, heroin decreases gastric motility, inhibits the effect of acetylcholine on the small intestine, and diminishes the colonic propulsive waves, resulting in gastric-emptying time that is prolonged by as much as 12 hours and constipation.
Side Effect Profile
Drowsiness, inability to concentrate, apathy, lessened physical activity, constipation, urinary retention, nausea, vomiting, tremors, itching, bradycardia, severe respiratory depression, and pulmonary complications such as pneumonia. Medical complications among abusers arise primarily from adulterants found in street drugs and in non-sterile injecting practices, and may include skin, lung and brain abscesses, collapsed veins, endocarditis, hepatitis and HIV/AIDS. Overdose can include slow, shallow breathing, clammy skin, convulsions, extreme somnolence, severe respiratory depression, apnea, circulatory collapse, cardiac arrest, coma, and death.
Opioids including heroin increase the number of shifts in sleep-waking states, and decrease total sleep time, sleep efficiency, delta sleep, and REM sleep. However, in these studies, it is difficult to differentiate the effects of the opioid medication from the effects of the underlying disorders (e.g., cancer, addiction/dependence, postoperative pain). A study of 7 healthy volunteers treated with IV morphine showed reductions in slow wave sleep and a mild decrease in REM, but no increase in awakenings or arousals. A randomized, double-blind study involving 42 healthy volunteers given 5 mg methadone or 15 mg sustained release morphine, showed that both opioids increased the percentage of time spent in light sleep and substantially decreased (30% to 50%) the percentage of time in deep sleep (stages 3 and 4).
Duration of Effects
Depending on the morphine dose and the route of administration, onset of effects is within 15-60 minutes and effects may last 4-6 hours. The duration of analgesia increases progressively with age although the degree of analgesia remains unchanged. Following heroin use, the intense euphoria lasts from 45 seconds to several minutes, peak effects last 1-2 hours, and the overall effects wear off in 3-5 hours, depending on dose.
Tolerance, Dependence and Withdrawal Effects
Both morphine and heroin have high physical and psychological dependence. With regular use, tolerance develops early to the duration and intensity of euphoria and analgesia. Withdrawal symptoms may occur if use is abruptly stopped or reduced. Withdrawal can begin within 6-12 hours after the last dose and may last 5-10 days. Early symptoms include watery eyes, runny nose and sweating. Major withdrawal symptoms peak between 48-72 hours after the last dose and include restlessness, irritability, dysphoria, loss of appetite, tremors, severe sneezing, diarrhea, nausea and vomiting, elevated heart rate and blood pressure, chills alternating with flushing and excessive sweating, goose-flesh, abdominal cramps, body aches, muscle and bone pain, muscle spasms, insomnia, and severe depression.
Alcohol increases the CNS effects of morphine such as sedation, drowsiness, and decreased motor skills. There is a higher risk of respiratory depression, hypotension and profound sedation or coma with concurrent treatment or use of other CNS depressant drugs such as barbiturates, benzodiazepines, hypnotics, tricyclic antidepressants, general anesthetics, MAO inhibitors, and antihistamines. Morphine may produce an increased degree of respiratory depression. Small doses of amphetamine substantially increase the analgesia and euphoriant effects of morphine and may decrease its sedative effects. Antidepressants may enhance morphine’s analgesia. Partial agonists such as buprenorphine, nalbuphine, butorphanol, and pentazocine will precipitate morphine withdrawal.
Effects on Physical and Cognitive Function/Performance
General Performance Effects: Laboratory studies have shown that morphine and/or heroin may cause sedation and significant psychomotor impairment for up to 4 hours following a single dose in normal individuals. Early effects may include slowed reaction time, depressed consciousness, sleepiness, and poor performance on divided attention and psychomotor tasks. Late effects may include inattentiveness, slowed reaction time, greater error rate in tests, poor concentration, distractibility, fatigue, and poor performance in psychomotor tests. Subjective feelings of sedation, sluggishness, fatigue, intoxication, and body sway have also been reported. Significant tolerance may develop making effects less pronounced in long-term users for the same dose. In a laboratory setting, heroin produced subjective feelings of sedation for up to 5-6 hours and slowed reaction times up to 4 hours, in former narcotic addicts. Euphoria and elation could also play a role on perception of risks and alteration of behaviors.
Effects on Driving: Morphine, heroin and other opioids may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car, and patients must be cautioned accordingly. In several driving under the influence case reports, where the subjects tested positive for morphine and/or 6-acetylmorphine, observations included slow driving, weaving, poor vehicle control, poor coordination, slow response to stimuli, delayed reactions, difficultly in following instructions, and falling asleep at the wheel.
Neurocognitive Effects: The empirical literature examining the neurocognitive effects of acute and chronic opioid use suggests that the use of these drugs has both acute and long-term effects on cognitive performance. Neuropsychological data indicate deficits in attention, concentration, recall, visuospatial skills and psychomotor speed with both acute and chronic opioid use. The long-term effects of opiate use appear to have the greatest impact on executive functions, including the ability to shift cognitive set and inhibit inappropriate response tendencies.
Chronic use of opiates is associated with a wide a range of cognitive deficits, including the domains of attention, inhibitory control, planning, decision-making, learning and memory. Although opiate users show marked impairment in various aspects of cognitive function, substance-specific differences are most pronounced in functions of inhibitory control and feedback processing. Compromised cognitive function in both substance-user populations is reflected in abnormal patterns of brain activation both at rest and during cognitive performance.
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