MORPHINE

OFFICIAL NAMES: Morphine sulfate or morphine hydrochloride (solutions for injection), Duramorph (for spinal use), MS Contin and Oramorph SR (long-acting, controlled release oral form), Kadian (oral, sustained release), MSIR (instant release), Roxanol (liquid concentrate)

STREET NAMES: M, morph, Miss Emma, monkey, white stuff

DRUG CLASSIFICATIONS: Schedule II, opiate

OVERVIEW

Morphine is the most active part of opium, a pure chemical isolated from the dried sap of the unripe poppy pod. Even today, morphine is still made from poppies. It is the prototype opiate, the parent from which all the others sprang. But efforts over the past two centuries to separate the beneficial aspects of opiates from their social drawbacks have failed. Even totally synthetic drugs that mimic morphine and the other opiates remain utterly linked to addiction.

At the turn of the nineteenth century, opium was an important part of medical practice. By the time that Frederick Serturner, a young clerk in a small German pharmacy, extracted morphine from opium, the world was already experienced in both medicinal and recreational opium use. Serturner's extraction was the first alkaloid ever isolated, and he named it after the Greek god of dreams, Morpheus.

Morphine's discovery became well-known after Serturner published his findings in 1817. In 1837, an Endinburgh chemist and physician, William Gregory, found a cheaper way to isolate and purify it. But not until the 1850s, with the introduction of the hypodermic needle, would morphine gain wider use.

The Civil War was a ready stage for the entry of morphine into common medical practice. Medics from the North and the South used morphine for the massive practice of amputation. With no delicate, germ-free surgical technique available, any serious wound to a limb called for its swift and horrendously painful removal.

The Union army obtained 29,828 oz (846 kg) of morphine sulfate. And when Confederates realized that a blockade of their ports could part them from sources of opium, they tried getting Southern women to cultivate and produce opium from garden-grown poppies. On both sides, discharged soldiers went home as addicts after the hostilities ceased.

In the years after the war, however, women abused morphine even more than man. The spread of patent medicines and the unregulated sale of hypodermics brought opiate use into the parlors of the upper classes. Fashionable women could buy and wear syringes pinned to their clothing, as they did watches or brooches. Surveys by public health officials in Michigan and Iowa recorded that by the 1880s about 75% of all drug addicts were women seeking to ease neuralgia (sharp, severe nerve pain), cramps, and morning sickness. Meanwhile, babies and toddlers were soothed with various nostrums, or "quack medicines," containing opiates, with alcohol as another major constituent. "Mrs. Lambert's Ladies Elixir" is an example: 23% alcohol with 40 mg of morphine in every bottle. Also, "Mrs. Winslow's Soothing Syrup," with 0.05 g of morphine per bottle. Even patent medicines to cure morphine dependence were sold; inevitably they contained alcohol or opium. Thomas Edison patented and marketed his own nostrum, "Poly-Form." It contained morphine, chloroform, ether, chloral hydrate, alcohol, and spices.

By the late 1800s, one in 25 Americans used large amounts of opiates. No laws limited their use. People simply went to the local druggist for morphine, no prescription required. Abuse was considered a vice or a weakness, not a crime. But doctors did begin to recognize and criticize their own profession's ability to create a lifelong servitude to the drug. Newspapers recorded morphine as an agent for suicides and deaths by accidental overdose.

At the turn of the century, the German chemical company Bayer was capitalizing on a previously unnoticed chemical improvement on morphine. In 1898, Bayer began aggressively marketing heroin as a cough cure for the rampant disease of the time, tuberculosis. Heroin, a derivative of morphine, crosses directly into the brain, where it is converted immediately back to morphine. Unbelievably, it was said to be non-addictive. Heroin was even proposed as a way to cure morphine addicts. This turns out to be a recurring theme in the story of narcotics: to hopeful physicians, a new version brought to market appeared to be free of abuse potential, until enough people used it to prove otherwise.

In medical practice today, morphine is regarded as the standard for pain relief by which all other drugs are measured. Still, doctors may be hesitant to use morphine. They must register with the federal Drug Enforcement Administration (DEA) to dispense the drug, and paper trails lead easily to doctors who prescribe it too freely. A current debate in medicine seeks to expand the medical use of the drug, and to change state laws to recognize the legitimate place for morphine in a physician's practice.

CHEMICAL/ORGANIC COMPOSITION

Morphine is an alkaloid, the chemical class to which many drugs belong. Pure morphine is a white powder, bitter to the taste. More than 1,000 tons of morphine are isolated from opium a year, although most of it is converted to codeine. Morphine comprises anywhere from 3% to 17%—usually about 10%—of the more than 20 alkaloids present in opium.

The many rings of the morphine molecule include a benzene ring that fits into the receptors for the brain's own opiates (the endorphins and enkephalins). The nerve cells studded with these receptors recognize the morphine molecule by the close fit of the benzene ring and the binding of a critical nitrogen atom. Many other opioids duplicate these molecular features.

In the 1970s, researchers were able to discover exactly how morphine works in the brain. When stimulated by tiny electric currents, certain nerve tracts within the core of the brain can produce a painkiller strong enough to allow abdominal surgery in lab rodents. The painkiller consists of simple amino acids that, in their naturally folded state, mimic the structure of the morphine molecule. They were named enkephalins, for "in the head," and endorphins, for "the morphine within."

INGESTION METHODS

Morphine is available by prescription in many forms. It can be taken orally as a liquid or as pills, and by injection under the skin, into the veins, or into the space surrounding the spinal cord. Rectal suppositories for pain control provide longer-lasting relief with less potential for nausea. As an abused drug, morphine can be smoked and sniffed as well as swallowed.

THERAPEUTIC USE

Morphine has a clear-cut place in medicine. For cancer, after surgeries, in childbirth, and even for chronic, daily headaches that resist all other treatments, morphine is effective in relieving symptoms. It is still the most widely prescribed drug for severe pain. Typical doses of morphine injected into muscle are 5–20 mg every four hours. Oral doses must be higher, between 8 and 20 mg.

Emergency use of morphine is by intravenous injection, avoiding any "first pass effect" (the "watering down" of drugs that occurs in the liver) or the time for passage through skin or muscle. This dosage is 4–10 mg, and the analgesia (pain relief) is nearly immediate.

Doctors may use morphine to ease childbirth. Women in early and middle labor can be given an opiate, including morphine, to be able to rest between contractions. However, giving an opioid too late into labor can make the baby sleepy on delivery. The baby may also not be able to breathe actively because morphine the morphine has slowed its respiration, but an opioid blocker, naloxone, can be given.

Patients recovering from surgery are able to control their pain by devices called patient-controlled analgesia (PCA). PCA works by way of a pump set up by a hospital technician. The pump is then operated by the patient, who presses a button to deliver doses on demand. Morphine is commonly given in these PCA devices. Pain after certain surgeries can be further lessened by injecting very low doses of morphine into the space around the spinal cord before surgery. This can reduce the severe pain after heart surgeries, for instance, which require the surgeon to separate the breast bone.

A survey of patients in hospices published in 1999 showed that none of the 55 patients receiving 300 or more milligrams of morphine a day for pain relief had difficulty breathing because of the drug. Survival times in hospice were not any different for those on these high morphine doses.

USAGE TRENDS

Morphine is infrequently found "on the street," yet it can get there by its widening use in legitimate medicine. Abuse also can appear in health professionals. Street use in combination with cocaine or methamphetamine has also been documented.

A study published in 2000 reviewed data obtained from 1990 to 1996 on the number of morphine prescriptions written, and the emergency room admissions related to its abuse. Doctors prescribed 59% more morphine in that time period. Yet the number of people seeking emergency aid for morphine abuse rose by just 3%. The study concluded that legitimate use by medical professionals attempting to help patients does not necessarily lead to increased use on the street.

In medical school, doctors learn to treat morphine with suspicion. Even when the use of the drug is clinically called for, they may be hesitant to prescribe it. Many experts on pain say that prescribing morphine for surgical recovery, or even for chronic pain, will not turn most people into drug addicts. While the medical use of morphine does indirectly increase the potential supply to the street addict, restricting its medical use harms people in pain.

A survey published in 2001 shows that primary care physicians would much rather prescribe Schedule III pain relievers—such as acetaminophen with codeine—for chronic pain not due to cancers. Thirty-five percent of the 161 doctors responding to the mailed survey stated they would never prescribe Schedule II opioids to be used around-the-clock by patients in persistent pain. Those who would be willing to give the Schedule II drugs were those who also indicated a lower degree of concern about

physical dependence, tolerance, and addiction. The survey researchers noted that few carefully designed studies have been carried out to test morphine and similar opioids in relieving chronic pain other than that from malignancies (cancerous tumors that grow uncontrollably). In addition, doctors are often scrutinized by state medical boards for prescribing Schedule II drugs.

A joint statement issued by 21 health oganizations and the Drug Enforcement Administration acknowledges the balancing act that medical use of morphine engenders. "Preventing drug abuse is an important societal goal," the statement says, but "it should not hinder patients' ability to receive the health care they need and deserve."

Scope and severity

In 1999, four million people in the United States were using prescription drugs outside medical use. Of these, 2.6 million were misusing pain relievers, according to the National Institute on Drug Abuse (NIDA). Doctors must be able to recognize the occasional patient who is seeking morphine to feed an addiction. Physicians must be wary of being manipulated. Allegations of overprescription of scheduled drugs is the leading reason physicians are investigated, as well as the leading reason for the suspenstion of a doctor's license.

Age, ethnic, and gender trends

Older people receive prescriptions at three times the rate of the rest of the population. But the National Household Survey on Drug Abuse recorded the sharpest increase in nonmedical use of prescription drugs in young adults and teens.

The sexes are known to react differently to opiates. In humans, women are more likely to misuse opiates. Research in animals shows that females require higher doses to relieve pain (the sex steroid hormones change the brain's organization early in life to create this difference). Female rats also appear to enjoy morphine more than males. The females continued to choose to receive the drug even at doses so high that their breathing was halted, doses that the males chose to avoid.

MENTAL EFFECTS

Morphine blocks the deep, aching perception of chronic pain, without interrupting the fast signals sent by an acute injury. As pain signals rise through the spinal cord to reach the brain, morphine interrupts them at a "relay station" within the core of the brain, called the thalamus. Morphine also blocks pain messages as they enter the spinal cord.

This interruption is not complete: the message of pain still reaches the brain. However, morphine blocks the emotions surrounding pain: people receiving the drug still know they are having pain, but it bothers them less.

Two views are offered to explain the action of morphine on pain. One says that the opiates work on all types of pain. The other says that opiates cannot work on a certain type of pain, called neuropathic, which is the pain created by damaged nerves themselves. When opiates do work in neuropathic pain, some experts say, it is only because the drugs improve the patient's mood. In the early 1990s, one research team found that half of pains judged as neuropathic did respond to morphine. The changes in mood reflected the relief of pain, the researchers noted, regardless of the type of pain.

Researchers say that the euphoria produced by morphine is due to its action on dopamine. Dopamine is a neurotransmitter—nerve messenger—in the brain that acts in those parts of the brain that register pleasure.

The other mental effects of morphine take place at the arousal centers of the brain, in the brainstem, to produce a sleepiness and relaxation. However, some patients experience restlessness instead of drowsiness, with increased limb movement rather than relaxation. Confusion and slurred speech almost always accompany morphine at higher doses. Meanwhile, the so-called "pinpoint pupils" of opiate overdose are created by morphine's action on the iris, resulting in blurred vision and impaired ability to see in the dark.

Acting in the brainstem, as well as in the respiratory centers of the brain, morphine slows respiration and suppresses the cough reflex.

PHYSIOLOGICAL EFFECTS

In the gastrointestinal system, morphine slows the stomach and smooth muscle of the gut, causing constipation and loss of appetite. It slightly lowers body temperature, causing flushing and sweating. Morphine also causes sensations of itching or prickling of the skin, especially after intravenous use. Morphine can decrease libido and interfere with a woman's menstrual cycle.

Recent findings are leading researchers to try local applying opiates to joints affected by arthritis.

Harmful side effects

The slowed breathing caused by morphine is dangerous in those who already have trouble breathing. Indeed, the slowing of respiration is considered the most dangerous action of the opiate drugs. At high doses, the respiratory suppression caused by morphine and other potent opioids can lead, in extreme instances, to death.

Morphine's effects in the digestive tract can also be severe, especially for cancer patients already rendered nauseous by chemotherapy. Nausea and vomiting are commonly encountered at therapeutic doses of morphine (although there are medicines to counter this). Morphine may also cause constipation.

Long-term health effects

Morphine can be highly addictive. When an addict stops using, the signs of all opiate withdrawal include anxiety, restlessness, yawning, flu-like symptoms including muscle and bone pain, diarrhea, insomnia, vomiting, cold flashes, goose bumps, and involuntary movement of the legs. All aspects of withdrawal are physiologically opposite to the acute effects of the drug. It takes days or even weeks for the recovering addict to regain balance.

Steady or repeated use of morphine causes tolerance as well as withdrawal (also called physical dependence). More and more drug is needed to produce the same effect as the original dose. A tolerant morphine user can take massive doses that would kill a first timer. Compared to the therapeutic range of 5–20 mg, several hundred milligrams a day is not unusual in either cancer patients or street addicts. In extreme cases, four or five grams of morphine may be taken a day.

A newly discovered risk of opiate abuse relates to a role of endogenous opiates—opiates naturally produced by the body—as growth factors. External opiates like morphine will block such functioning, possibly harming a growing embryo as well as the mother's adaptation to pregnancy.

Endogenous opiates also help form new brains cells. Morphine abuse will interfere with this process, ultimately destroying the formation of new cells.

REACTIONS WITH OTHER DRUGS OR SUBSTANCES

The respiratory depression induced by morphine can add to that of alcohol, barbiturates, benzodiazepines (such as Valium), and even with antihistamines taken for allergies. Combined effects of these drugs with morphine can dangerously compromise breathing. Tricyclic antidepressants can hamper the metabolism of morphine.

TREATMENT AND REHABILITATION

Overdoses of morphine resulting in unconsciousness can be rapidly reversed with the opiate antagonist naloxone (Narcan). Given by intravenous injection, naloxone works in a minute or two by occupying the opiate receptors in the brain, without any action of its own other than to block morphine or other opioids. A dose of0.4–0.8 mg (to a maximum of 10 mg) is given every three to five minutes to revive an overdosed person.

Abruptly stopping the abuse of morphine will result in withdrawal. While not life threatening, as are withdrawal from alcohol or other depressants, going "cold turkey" is immensely unpleasant. The recovering addict may become suicidal from the suffering experienced.

Medical means of getting an addict off morphine allows withdrawal with less drastic symptoms. Methadone, legally administered through drug rehabilitation programs, can be substituted for morphine just as it is for heroin. A totally synthetic opioid, methadone lasts longer within the body than either morphine or heroin. Methadone closely mimics the basic opiate structure.

Methadone is given orally (different from the usual means of abuse), and thereby also substitutes for the paraphernalia that accompany illicit drug use. Methadone helps relieve the craving for more drug and delays the appearance of withdrawal symptoms as long as it is in the body. Doses are gradually decreased. If the dose of morphine that was abused is known, then 1 mg of methadone can substitute for 4 mg of morphine. Otherwise, a dose of 10–50 mg a day is generally used, and can be reduced by 20% per day.

Clonidine (Catapres) is another drug used to treat opiate addiction. It can relieve the anxiety, runny nose, salivation, sweating, abdominal cramps, and muscle aches of opiate withdrawal. Side effects are dry mouth, dizziness, and drowsiness. Clonidine is initially taken at0.8–1.2 mg a day, maintained for a few days, and then gradually decreased. Combined with the opiate blocker naltrexone, clonidine can allow a more rapid detoxification (the removal of morphine from the body). Detox in a single day can be accomplished by heavy sedation or anesthesia while giving naltrexone to an unconscious addict. This controversial method has not been studied in controlled trials.

Recovering addicts who fear a moment of weakness can strenghten themselves with the long-acting opioid antagonist naltrexone. Using naltrexone makes it impossible to get high from taking other opioids. But naltrexone must be taken before any other opioids are used, or withdrawal will occur. The usual dose of naltrexone is 25–50 mg orally, in the morning. Depression has been reported with its use, and it also raises toxin levels in the liver. Headache and nausea are encountered with naltrexone use.

LAAM, the abbreviation of levo alpha acetyl methadol, is another opiate blocker that has been used to wean addicts. It persists up to 72 hours.

Getting past withdrawal is only the first step in confronting morphine abuse. The psychological need for the drug must be addressed as well. Narcotics Anonymous and other programs are devoted to this challenge. A peer group that replaces the one that encouraged the addiction is a key feature of successful rehabilitation.

For those who are taking morphine to control pain, the same principle of tapering off the dose applies, with gradual lowering of the dosage over a period of a few weeks. However, short-term use of morphine for acute pain in a medical setting rarely requires weaning.

PERSONAL AND SOCIAL CONSEQUENCES

Because addicts are so intent on finding their next fix, they often neglect basic aspects of hygiene and nutrition. Infections and illness often result. Skin infections as well as more serious bloodborne infections follow use of unsterile needles. Deadly viruses are also shared through dirty needles. Babies born to addicted mothers usually go through withdrawal that their immature systems cannot handle. Finally, risk of arrest or of death by violence usually goes along with a lifestyle that includes illegal drugs. The death rate of those abusing narcotics is estimated to increase by 2% for each year spent abusing the drug, with abuse of ten years carrying a 20% risk of death by overdose or drug-related crime.

LEGAL CONSEQUENCES

Under the Controlled Substances Act, morphine is a Schedule II drug. Doctors must be licensed by state medical authorities to prescribe it legally. They must also register with the Drug Enforcement Administration (DEA) and obtain a DEA number to use when writing the prescriptions. The DEA number helps keep track of how many prescriptions a doctor writes. Any trafficking in morphine—or any other Schedule II drug—results in federal penalties of up to 20 years. If death or serious injury results, the penalties for a first offense are 20 years to life and fines of up to $1 million. In 1988, the penalties were slightly changed: now those who are caught with only a small quantity of morphine face civil fines of up to $10,000.

Legal history

Opium smoking in the United States spread with the immigration of Chinese workers in the western frontier—they built most of the train tracks, for instance—but it still was perfectly legal. In 1879, the Memphis, Tennessee public health agency targeted opium dens by making it illegal to sell, own, or borrow "opium or any deleterious drug" or the paraphernalia related to smoking them. Critics writing at the time pointed to the hypocrisy in denying the Chinese their accustomed comfort while white citizens could freely purchase morphine—indeed, could inhale, drink, or inject it. Not until 1909 did federal law outlaw smoking opium, and the agent itself.

Federal guidelines, regulations, and penalties

In 1914, the Harrison Narcotic Act outlawed heroin in the United States. The federal Controlled Substances Act of 1970 classified morphine as a Schedule II drug, which means it has potential for abuse but also accepted medical uses.

In 2000, Congress considered the Pain Relief Promotion Act, which would have amended the Controlled Substances Act to say that relieving pain or discomfort—within the context of professional medicine—is a legitimate use of controlled substances. The bill died in in the Senate. Sponsors of the bill plan to reintroduce it.

In the medical community, there is a growing awarness of the legitimate use of opiates to reduce pain. State medical boards are adopting new guidelines to reflect this, as well as to urge aggressive treatment for pain. These new guidelines allow physicians to document their reasons for using opiates.

See also Codeine; Heroin; Meperidine; Opium; Oxycodone

RESOURCES

Books

Hodgson, Barbara. Opium: A Portrait of the Heavenly Doom. San Francisco: Chronicle Books, 1999.

Metzger, Thomas. The Birth of Heroin and the Demonization of the Dope Fiend. Port Townsend, WA: Loompanics Unlimited, 1998.

Periodicals

Giannini, A. James. "An Approach to Drug Abuse, Intoxication and Withdrawal." American Family Physician 61 (May 1, 2001): 2763-2774.

Gorman, Christine. "The Case for Morphine." Time online. 1997 (February 13, 2002). <www.time.com/time/magazine/1997/dom/970428/medicine.the_case_for.html>.

Kolata, Gina. "When Morphine Fails to Kill." The New York Times July 23, 1997.

Potter, Michael. "Opioids for Chronic Nonmalignant Pain." The Journal of Family Practice 50 (February 1, 2001): 145-151.

Other

Lane, Laura. "Benefits from Opioids Outweigh Risks, Study Says." CNN.com health. April 4, 2000 (February 12, 2002). <http://www.cnn.com/2000/HEALTH/04/04/pain.killer.wmd/>.

Medina, James L. "Narcotic Abuse." eMedicine Online Consumer Journal. March 4, 2001 (February 13, 2002). <http://www.emedicine.com/aaem/topic321.htm>.

Organizations

American Academy of Pain Medicine, 4700 W. Lake Avenue, Glenview, IL, USA, 60025, (847) 375-4731, (877) 734-8750, [email protected], <http://www.painmed.org>.

Pain & Policy Studies Group, 406 Science Drive, Suite 202, Madison, WI, USA, 53711-1068, (608) 263-7662, (608) 263-0259, [email protected], <hhttp://www.medsch.wisc.edu/painpolicy/about.htm>.

Roberta L. Friedman, Ph.D.