Chapter 4 Narcotics
The term "narcotic," derived from the Greek word for stupor, originally referred to a variety of substances that dulled the senses and relieved pain. Today, the term is used in a number of ways. Some individuals define narcotics as those substances that bind at opiate receptors (cellular membrane proteins activated by substances like heroin or morphine), while others refer to any illicit substance as a narcotic. In a legal context, narcotic refers to opium, opium derivatives, and their semi-synthetic substitutes. Cocaine and coca leaves, which are also classified as "narcotics" in the Controlled Substances Act (CSA), neither bind at opiate receptors, nor produce morphine-like effects and are discussed in the section on stimulants. For the purposes of this discussion, the term narcotic refers to drugs that produce morphine-like effects.
Narcotics are used therapeutically to treat pain, suppress cough, alleviate diarrhea, and induce anesthesia. Narcotics are administered in a variety of ways. Some are taken orally, transdermally (skin patches), intranasally, or injected. They are also available in suppositories, and more recently in "troches," a form of narcotics that can be sucked like candy. As drugs of abuse, they are often smoked, sniffed, or injected. Drug effects depend heavily on the dose, route of administration, and previous exposure to the drug. Aside from their medical use, narcotics produce a general sense of well-being by reducing tension, anxiety, and aggression. These effects are helpful in a therapeutic setting but contribute to their abuse.
Narcotic use is associated with a variety of unwanted effects including drowsiness, inability to concentrate, apathy, lessened physical activity, constriction of the pupils, dilation of the subcutaneous blood vessels causing flushing of the face and neck, constipation, nausea, vomiting, and most significantly, respiratory depression. As the dose is increased, the subjective, analgesic (pain relief), and toxic effect become more pronounced. Except in cases of acute intoxication, there is no loss of motor coordination or slurred speech as occurs with many depressants.
Among the hazards of illicit drug use is the ever-increasing risk of infection, disease, and overdose. Medical complications common among narcotic abusers arise primarily from adulterants found in street drugs and in the non-sterile practices of injecting. Skin, lung, and brain abscesses, endocarditis (inflammation of the lining of the heart), hepatitis, and AIDS are commonly found among narcotic abusers. While pharmaceutical products have a known concentration and purity, clandestinely produced street drugs have unknown compositions. Since there is no simple way to determine the purity of a drug that is sold on the street, the effects of illicit narcotic use are unpredictable and can be fatal. Physical signs of narcotic overdose include constricted (pinpoint) pupils, cold clammy skin, confusion, convulsions, severe drowsiness, and respiratory depression (slow or troubled breathing). Most narcotic deaths are a result of respiratory depression.
Doctor's hypodermic syringe kit, circa 1900.
With repeated use of narcotics, tolerance and dependence develop. The development of tolerance is characterized by a shortened duration and a decreased intensity of analgesia, euphoria, and sedation, which creates the need to consume progressively larger doses to attain the desired effect. Tolerant users can consume doses far in excess of the dose they initially started with.
Chronic narcotic use is associated with physical dependence and a withdrawal or abstinence syndrome when drug use is discontinued. In general, shorter acting narcotics tend to produce shorter, more intense withdrawal symptoms, while longer acting narcotics produce a withdrawal syndrome that is protracted but less severe. Although unpleasant, withdrawal from narcotics is rarely life threatening. The withdrawal symptoms associated with heroin/morphine addiction are usually experienced shortly before the time of the next scheduled dose. Early symptoms include watery eyes, runny nose, yawning, and sweating. Restlessness, irritability, loss of appetite, nausea, tremors, and drug craving appear as the syndrome progresses. Severe depression and vomiting are common. The heart rate and blood pressure are elevated. Chills, alternating with flushing and excessive sweating, are also characteristic symptoms. Pains in the bones and muscles of the back and extremities occur, as do muscle spasms. At any point during this process, a suitable narcotic can be administered to dramatically reverse the withdrawal symptoms. Without intervention, the syndrome will run its course, and most of the overt physical symptoms will disappear within 7 to 10 days.
The psychological dependence associated with narcotic addiction is complex and protracted. Long after the physical need for the drug has passed, the addict may continue to think and talk about the use of drugs and feel strange or overwhelmed coping with daily activities without being under the influence of drugs. There is a high probability that relapse will occur after narcotic withdrawal when neither the physical environment, nor the behavioral motivators that contributed to the abuse have been altered.
There are two major patterns of narcotic abuse or dependence seen in the United States. One involves individuals whose drug use was initiated within the context of medical treatment who escalate their dose by obtaining the drug through fraudulent prescriptions and "doctor shopping" or branching out to illicit drugs. The other pattern of abuse is initiated outside the therapeutic setting with experimental or recreational use of narcotics. The majority of individuals in this category may abuse narcotics sporadically for months or even years. Although they may not become addicts, the social, medical, and legal consequences of their behavior are very serious. Some experimental users will escalate their narcotic use and will eventually become dependent, both physically and psychologically. The younger an individual is when drug use is initiated, the more likely the drug use will progress to dependence and addiction.
Narcotics of Natural Origin
The poppy plant, Papaver somniferum, is the source for non-synthetic narcotics. It was grown in the Mediterranean region as early as 5000 B.C., and has since been cultivated in a number of countries throughout the world. The milky fluid that seeps from incisions in the unripe seed pod of this poppy has, since ancient times, been scraped by hand and air-dried to produce what is known as opium. A more modern method of harvesting is by the industrial poppy straw process of extracting alkaloids from the mature dried plant. The extract may be in liquid, solid, or powder form, although most poppy straw concentrate available commercially is a fine brownish powder. More than 500 tons of opium or equivalents in poppy straw concentrate are legally imported into the United States annually for legitimate medical use.
There were no legal restrictions on the importation or use of opium until the early 1900s. In the United States, the unrestricted availability of opium, the influx of opium-smoking immigrants from East Asia, and the invention of the hypodermic needle contributed to the more severe variety of compulsive drug abuse seen at the turn of the 20th century. In those days, medicines often contained opium without any warning label. Today, there are state, federal, and international laws governing the production and distribution of narcotic substances.
Although opium is used in the form of paregoric to treat diarrhea, most opium imported into the United States is broken down into its alkaloid constituents. These alkaloids are divided into two distinct chemical classes, phenanthrenes and isoquinolines. The principal phenanthrenes are morphine, codeine, and thebaine, while the isoquinolines have no significant central nervous system effects and are not regulated under the CSA.
Morphine is the principal constituent of opium and ranges in concentration from 4 to 21 percent. Commercial opium is standardized to contain 10-percent morphine. In the United States, a small percentage of the morphine obtained from opium is used directly (about 20 tons); the remaining is converted to codeine and other derivatives (about 110 tons). Morphine is one of the most effective drugs known for the relief of severe pain and remains the standard against which new analgesics are measured. Like most narcotics, the use of morphine has increased significantly in recent years. Since 1998, there has been about a two-fold increase in the use of morphine products in the United States.
Morphine is marketed under generic and brand name products including MS-Contin®, Oramorph SR®, MSIR®, Roxanol®, Kadian®, and RMS®. Morphine is used parenterally (by injection) for preoperative sedation, as a supplement to anesthesia, and for analgesia. It is the drug of choice for relieving the pain of myocardial infarction and for its cardiovascular effects in the treatment of acute pulmonary edema. Traditionally, morphine was almost exclusively used by injection. Today, morphine is marketed in a variety of forms, including oral solutions, immediate and sustained-release tablets and capsules, suppositories, and injectable preparations. In addition, the availability of high-concentration morphine preparations (i.e., 20-mg/ml oral solutions, 25-mg/ml injectable solutions, and 200-mg sustained-release tablets) partially reflects the use of this substance for chronic pain management in opiate-tolerant patients.
Codeine is the most widely used, naturally occurring narcotic in medical treatment in the world. This alkaloid is found in opium in concentrations ranging from 0.7 to 2.5 percent. However, most codeine used in the United States is produced from morphine. Codeine is also the starting material for the production of two other narcotics, dihydrocodeine and hydrocodone. Codeine is medically prescribed for the relief of moderate pain and cough suppression. Compared to morphine, codeine produces less analgesia, sedation, and respiratory depression, and is usually taken orally. It is made into tablets either alone (Schedule II) or in combination with aspirin or acetaminophen (i.e., Tylenol with Codeine®, Schedule III). As a cough suppressant, codeine is found in a number of liquid preparations (these products are in Schedule V). Codeine is also used to a lesser extent as an injectable solution for the treatment of pain. Codeine products are diverted from legitimate sources and are encountered on the illicit market.
Thebaine, a minor constituent of opium, is controlled in Schedule II of the CSA as well as under international law. Although chemically similar to both morphine and codeine, thebaine produces stimulatory rather than depressant effects. Thebaine is not used therapeutically, but is converted into a variety of substances including oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, and buprenorphine. The United States ranks first in the world in thebaine utilization.
Opiate-based syrups were once popular for treating children with teething and dysentery.
The following narcotics are among the more significant substances that have been derived from morphine, codeine, or thebaine contained in opium.
First synthesized from morphine in 1874, heroin was not extensively used in medicine until the early 1900s. Commercial production of the new pain remedy was first started in 1898. It initially received widespread acceptance from the medical profession, and physicians remained unaware of its addiction potential for years. The first comprehensive control of heroin occurred with the Harrison Narcotic Act of 1914. Today, heroin is an illicit substance having no medical utility in the United States. It is in Schedule I of the CSA.
Four foreign source areas produce the heroin available in the United States: South America (Colombia), Mexico, Southeast Asia (principally Burma), and Southwest Asia (principally Afghanistan). However, South America and Mexico supply most of the illicit heroin marketed in the United States. South American heroin is a high-purity powder primarily distributed to metropolitan areas on the East Coast. Heroin powder may vary in color from white to dark brown because of impurities left from the manufacturing process or the presence of additives. Mexican heroin, known as "black tar," is primarily available in the western United States. The color and consistency of black tar heroin result from the crude processing methods used to illicitly manufacture heroin in Mexico. Black tar heroin may be sticky like roofing tar or hard like coal, and its color may vary from dark brown to black.
After the opium poppy pod has been scored, the liquid opium oozes out and dries on the pod. It is collected and scraped into a ball shape.
Pure heroin is rarely sold on the street. A "bag" (slang for a small unit of heroin sold on the street) currently contains about 30 to 50 milligrams of powder, only a portion of which is heroin. The remainder could be sugar, starch, acetaminophen, procaine, benzocaine, or quinine, or any of numerous cutting agents for heroin. Traditionally, the purity of heroin in a bag ranged from 1 to 10 percent. More recently, heroin purity has ranged from about 10 to 70 percent. Black tar heroin is often sold in chunks weighing about an ounce. Its purity is generally less than South American heroin and it is most frequently smoked, or dissolved, diluted, and injected.
In the past, heroin in the United States was almost always injected, because this is the most practical and efficient way to administer low-purity heroin. However, the recent availability of higher purity heroin at relatively low cost has meant that a larger percentage of today's users are either snorting or smoking heroin, instead of injecting it. This trend was first captured in the 1999 National Household Survey on Drug Abuse, which revealed that 60 to 70 percent of people who used heroin for the first time from 1996 to 1998 never injected it. This trend has continued. Snorting or smoking heroin is more appealing to new users because it eliminates both the fear of acquiring syringe-borne diseases, such as HIV and hepatitis, as well as eliminating the social stigma attached to intravenous heroin use. Many new users of heroin mistakenly believe that smoking or snorting heroin is a safe technique for avoiding addiction. However, both the smoking and the snorting of heroin are directly linked to high incidences of dependence and addiction.
According to the 2003 National Survey on Drug Use and Health, during the latter half of the 1990s, heroin initiation rates rose to a level not reached since the 1970s. In 1974, there were an estimated 246,000 heroin initiates. Between 1988 and 1994, the annual number of new users ranged from 28,000 to 80,000. Between 1995 and 2001, the number of new heroin users was consistently greater than 100,000. Overall, approximately 3.7 million Americans reported using heroin at least once in their lifetime.
Hydromorphone (Dilaudid®) is marketed in tablets (2, 4, and 8 mg), suppositories, oral solutions, and injectable formulations. All products are in Schedule II of the CSA. Its analgesic potency is from two to eight times that of morphine, but it is shorter acting and produces more sedation than morphine. Much sought after by narcotic addicts, hydromorphone is usually obtained by the abuser through fraudulent prescriptions or theft. The tablets are often dissolved and injected as a substitute for heroin. In September 2004 the FDA approved the use of Palladone® (hydromorphone hydrochloride) for the management of persistent pain. This extended-release formulation could have the same risk of abuse as OxyContin®.
Oxycodone is synthesized from thebaine. Like morphine and hydromorphone, oxycodone is used as an analgesic. It is effective orally and is marketed alone in 10, 20, 40, 80, and 160 mg controlled-release tablets (OxyContin®), or 5 mg immediate-release capsules (OxyIR®), or in combination products with aspirin (Percodan®) or acetaminophen (Percocet®) for the relief of pain. All oxycodone products are in Schedule II. Oxycodone is abused orally, or the tablets are crushed and sniffed or dissolved in water and injected. The use of oxycodone has increased significantly. In 1993, about 3.5 tons of oxycodone were manufactured for sale in the United States. In 2003, about 41 tons were manufactured.
Historically, oxycodone products have been popular drugs of abuse among the narcotic abusing population. In recent years, concern has grown among federal, state, and local officials about the dramatic increase in the illicit availability and abuse of OxyContin® products. These products contain large amounts of oxycodone (10 to 160 mg) in a formulation intended for slow release over about a 12-hour period.
Abusers have learned that this slow-release mechanism can be easily circumvented by crushing the tablet and swallowing, snorting, or injecting the drug product for a more rapid and intense high. The criminal activity associated with illicitly obtaining and distributing this drug, as well as serious consequences of illicit use, including addiction and fatal overdose deaths, are of epidemic proportions in some areas of the United States.
Samples of OxyContin® tablets.
Hydrocodone is structurally related to codeine but more closely related to morphine in its pharmacological profile. As a drug of abuse, it is equivalent to morphine with respect to subjective effects, opiate signs and symptoms, and "liking" scores. Hydrocodone is an effective cough suppressant and analgesic. It is most frequently prescribed in combination with acetaminophen (i.e., Vicodin®, Lortab®) but is also marketed in products with aspirin (Lortab ASA®), ibuprofen (Vicoprofen®) and antihistamines (Hycomine®). All products currently marketed in the United States are either Schedule III combination products primarily intended for pain management or Schedule V antitussive medications often marketed in liquid formulations. The Schedule III products are currently under review at the Federal level to determine if an increase in regulatory control is warranted.
Hydrocodone products are the most frequently prescribed pharmaceutical opiates in the United States with over 111 million prescriptions dispensed in 2003. Despite their obvious utility in medical practice, hydrocodone products are among the most popular pharmaceutical drugs associated with drug diversion, trafficking, abuse, and addiction. In every geographical area in the country, the DEA has listed this drug as one of the most commonly diverted. Hydrocodone is the most frequently encountered opiate pharmaceutical in submissions of drug evidence to federal, state, and local forensic laboratories. Law enforcement has documented the diversion of millions of dosage units of hydrocodone by theft, doctor shopping, fraudulent prescriptions, bogus "call-in" prescriptions, and diversion by registrants and Internet fraud.
Hydrocodone products are associated with significant drug abuse. Hydrocodone was ranked 6th among all controlled substances in the 2002 Drug Abuse Warning Network (DAWN) emergency department (ED) data. Poison control data, DAWN medical examiner (ME) data, and other ME data indicate that hydrocodone deaths are numerous, widespread, and increasing in number. In addition, the hydrocodone acetaminophen combinations (accounting for about 80 % of all hydrocodone prescriptions) carry significant public health risk when taken in excess.
In contrast to the pharmaceutical products derived from opium, synthetic narcotics are produced entirely within the laboratory. The continuing search for products that retain the analgesic properties of morphine without the consequent dangers of tolerance and dependence has yet to yield a product that is not susceptible to abuse. A number of clandestinely produced drugs, as well as drugs that have accepted medical uses, fall within this category.
Introduced as an analgesic in the 1930s, meperidine produces effects that are similar, but not identical, to morphine (shorter duration of action and reduced antitussive and antidiarrheal actions). Currently it is used for pre-anesthesia and the relief of moderate to severe pain, particularly in obstetrics and post-operative situations. Meperidine is available in tablets, syrups, and injectable forms under generic and brand name (Demerol®, Mepergan®, etc.) Schedule II preparations. Several analogues of meperidine have been clandestinely produced. During the clandestine synthesis of the analogue MPPP, a neurotoxic by-product (MPTP) was produced. A number of individuals who consumed the MPPP-MPTP preparation developed an irreversible Parkinsonian-like syndrome. It was later found that MPTP destroys the same neurons as those damaged in Parkinsons Disease.
A close relative of methadone, dextropropoxyphene was first marketed in 1957 under the trade name of Darvon®. Oral analgesic potency is one-half to one-third that of codeine, with 65 mg approximately equivalent to about 600 mg of aspirin. Dextropropoxyphene is prescribed for relief of mild to moderate pain. Bulk dextropropoxyphene is in Schedule II, while preparations containing it are in Schedule IV. More than 150 tons of dextropropoxyphene are produced in the United States annually, and more than 25 million prescriptions are written for the products. This narcotic is associated with a number of toxic side effects and is among the top 10 drugs reported by medical examiners in drug abuse deaths.
First synthesized in Belgium in the late 1950s, fentanyl, with an analgesic potency of about 80 times that of morphine, was introduced into medical practice in the 1960s as an intravenous anesthetic under the trade name of Sublimaze®. Thereafter, two other fentanyl analogues were introduced: alfentanil (Alfenta®), an ultra-short (5-10 minutes) acting analgesic, and sufentanil (Sufenta®), an exceptionally potent analgesic (5 to 10 times more potent than fentanyl) for use in heart surgery. Today, fentanyls are extensively used for anesthesia and analgesia. Duragesic®, for example, is a fentanyl transdermal patch used in chronic pain management, and Actiq® is a solid formulation of fentanyl citrate on a stick that dissolves slowly in the mouth for transmucosal absorption. Actiq® is intended for opiate-tolerant individuals and is effective in treating breakthrough pain in cancer patients. Carfentanil (Wildnil®) is an analogue of fentanyl with an analgesic potency 10,000 times that of morphine and is used in veterinary practice to immobilize certain large animals.
Illicit use of pharmaceutical fentanyls first appeared in the mid-1970s in the medical community and continues to be a problem in the United States. To date, over 12 different analogues of fentanyl have been produced clandestinely and identified in the U.S. drug traffic. The biological effects of the fentanyls are indistinguishable from those of heroin, with the exception that the fentanyls may be hundreds of times more potent. Fentanyls are most commonly used by intravenous administration, but like heroin, they may also be smoked or snorted.
The effort to find an effective analgesic with less dependence-producing consequences led to the development of pentazocine (Talwin®). Introduced as an analgesic in 1967, it was frequently encountered in the illicit trade, usually in combination with tripelennamine and placed into Schedule IV of the CSA in 1979. An attempt at reducing the abuse of this drug was made with the introduction of Talwin Nx®. This product contains a quantity of antagonist (naloxone) sufficient to counteract the morphine-like effects of pentazocine if the tablets are dissolved and injected.
While butorphanol can be made from thebaine, it is usually manufactured synthetically. It was initially available in injectable formulations for human (Stadol®) and veterinary (Torbugesic® and Torbutrol®) use. More recently, a nasal spray (Stadol NS®) became available, and significant diversion and abuse of this product led to the 1997 control of butorphanol in Schedule IV of the CSA. Butorphanol is a clear example of a drug gaining favor as a drug of abuse only after it became available in a form that facilitated greater ease of administration (nasal spray vs. injection).
Narcotics Treatment Drugs
German scientists synthesized methadone during World War II because of a shortage of morphine. Although chemically unlike morphine or heroin, methadone produces many of the same effects. It was introduced into the United States in 1947 as an analgesic (Dolophine®). Today, methadone is primarily used for the treatment of narcotic addiction, although a growing number of prescriptions are being written for chronic pain management. It is available in oral solutions, tablets, and injectable Schedule II formulations.
Methadone's effects can last up to 24 hours, thereby permitting once-a-day oral administration in heroin detoxification and maintenance programs. High-dose methadone can block the effects of heroin, thereby discouraging the continued use of heroin by addicts in treatment. Chronic administration of methadone results in the development of tolerance and dependence. The withdrawal syndrome develops more slowly and is less severe, but more prolonged than that associated with heroin withdrawal. Ironically, methadone used to control narcotic addiction is encountered on the illicit market. Recent increases in the use of methadone for pain management have been associated with increasing numbers of overdose deaths.
Closely related to methadone, the synthetic compound levo alphacetylmethadol, or LAAM (ORLMM®), has an even longer duration of action (from 48 to 72 hours) than methadone, permitting a reduction in frequency of use. In 1994, it was approved as a Schedule II treatment drug for narcotic addiction. Both methadone and LAAM have high abuse potential. Their acceptability as narcotic treatment drugs is predicated upon their ability to substitute for heroin, the long duration of action, and their mode of oral administration. Recent data regarding cardiovascular toxicity of LAAM has limited the use of this drug as a first-line therapy for addiction treatment.
This drug is a semi-synthetic narcotic derived from thebaine. Buprenorphine was initially marketed in the United States as an analgesic (Buprenex®). In 2002, two new products (Suboxone® and Subutex®) were approved for the treatment of narcotic addiction. Like methadone and LAAM, buprenorphine is potent (30 to 50 times the analgesic potency of morphine), has a long duration of action, and does not need to be injected. Unlike the other treatment drugs, buprenorphine produces far less respiratory depression and is thought to be safer in overdose. All buprenorphine products are currently in Schedule III of the CSA.