Opiates

Opiate drugs are any drugs, natural or synthetic, that produce the characteristic opiate effects: the combination of a dreamy, euphoric state, lessened sensation of pain, slowed breathing, constipation, and pinpoint pupils. Sometimes scientists use the more generic term "opioids" which includes drugs resembling the substances in the opium poppy as well as endogenous opioids that serve as neurotransmitters in the brain.

Opium refers to a preparation of the opium poppy (Papaver somniferum). It is obtained in a very low-tech, labor-intensive manner throughout the world. Opium farmers cut the developing seed pod of the opium poppy and collect the gummy fluid that oozes out of the cut over the next few days. The sap is refined in several ways. It may be dried into a ball and used directly (gum opium), or dried and pounded into a powder (opium powder). Raw opium appears as a brown tarry substance. Opium can also be made into an alcohol-water extract that is called tincture of opium. This is the famous laudanum of your great-great-grandmother's era, or the paregoric of that age. Opium poppies grown in Southeast Asia (Burma, Thailand, and Afghanistan), South America (Colombia), and Mexico provide the starting material for illegal heroin that enters the United States. Southeast Asian poppies mostly provide heroin for Europe, although some makes its way to the United States. The majority comes from Colombia and Mexico.

The easiest way to develop a useful drug is to start with naturally occurring compounds that have some particular effect, and pharmacologists have done just that with the opium poppy. There are at least five important opiate analgesics that are either direct products of the seed pod of the opium poppy or minor modifications of it.

Morphine is a major constituent of the seed pod. It is a potent opiate, and is used in injectable or pill form to relieve pain after surgery. Codeine is a much less potent opiate that is used mainly in pill form for milder pain. Many people have encountered it as an acetaminophen-codeine preparation that is used commonly for dental pain or in prescription cough medicine (Robitussin A-C, terpin hydrate with codeine, Cheracol, etc.). To compensate for the lower potency of codeine, some drug users simply drink an entire four-ounce bottle, which does contain an intoxicating amount. These cough syrups used to be available over the counter until recreational use became too popular.

Other compounds are prepared by chemically modifying substances in the opium. These are hydromorphone, oxycodone, and hydrocodone. Hydromorphone (Dilaudid), a very strong opiate, is an effective analgesic that is widely abused. Oxycodone is synthesized from a nonanalgesic in opium (thebaine) and ranks between morphine and codeine in its effectiveness against pain.

Heroin is certainly the most infamous opiate drug. Heroin is a chemically modified form of morphine that is created from partially purified morphine, usually in "refineries" close to sites of opium production in the countries listed above. It is broken up into small amounts, and usually appears on the street in bags of loose powder containing about 100 milligrams of white powder. The actual color can range from white to brown to black depending upon the source and quality of the preparation technique. Highly purified heroin hydrochloride is a white powder that is prized for its purity, while Mexican "black tar" heroin at the other end of the spectrum is recognized by its black appearance. The user either snorts the powder directly or dissolves it in saline and injects it. The actual composition of the powder depends upon the supplier and can range from 10 to 70 percent heroin (in combination) with various contaminants, including talc, quinine, and baking powder, making up the balance.

If heroin is just morphine that has been slightly changed chemically, what advantage does it have? In fact, once heroin enters the brain, it is converted back to morphine. However, the improved fat solubility does serve a useful purpose-it gets heroin into the brain faster. Many physicians are lobbying for its use in terminal cancer patients, as this difference means faster pain relief.

Meperidine (Demerol) is used like morphine for intense post surgical pain, but it works well even with oral use. Meperidine has a definite downside: it can cause seizures at high doses-a feature that has led to decreased use by physicians in recent years. Methadone is a uniquely long-lasting opiate that can be taken as a pill. Its unique time course makes it particularly useful for treating withdrawing addicts, as well as chronic pain. The gradual and mild onset of action staves off withdrawal signs but doesn't provide a "high." Its use for these purposes is controversial in some circles: although tolerance and physical dependence clearly develop, it provides safe and effective treatment without the same liability for abuse. Fentanyl (Sublimaze) is a very fat-soluble, very fast acting analgesic that anesthesiologists use when they put patients to sleep. It is also used in patches that release the drug slowly through the skin to provide more long-lasting pain relief. Many addicts use fentanyl in its injectable form, and it is a common cause of overdose. Fentanyl's high comes on fast, and is intense, brief, and just a step away from fatal suppression of breathing. Finally, there is propoxyphene (Darvon). This drug is such a poor opiate that most physicians won't use it, because clinical studies find it to be no more effective than a placebo. However, some people swear by it, although it's really little stronger than aspirin.

How opiates are taken

Most opiate drugs enter the bloodstream easily from many different routes because they dissolve in fatty substances and so can cross into cells. Heroin is at one extreme - it is so fat-soluble that it can be absorbed across the mucosal lining of the nose. Most other opiates are not quite that fat-soluble, and cannot be absorbed well after snorting. However, some opiates including the natural ingredients of the opium poppy form a vapor if heated and can be absorbed into the body if they are smoked-that is the basis of the use of the "opium pipe" as the traditional device of ancient as well as more recent history. Almost all opiates can be absorbed from the stomach, although injection is a much more efficient route for some, like morphine, that are more poorly absorbed from the stomach than others.

Intravenous injection is still the route that delivers opiates into the blood-stream the fastest. Since intravenous injection is more difficult and more dangerous than other routes, many users do not start this way. Instead, they start by skin-popping-injecting drugs subcutaneously (just beneath the skin). Heroin powder is dissolved and injected. Morphine, fentanyl, and meperidine almost always appear as legally prepared injection forms that have been diverted from medical use, although there is some fentanyl production from underground laboratories. Recently, snorting heroin has replaced injection, especially by new drug users. In part, users are avoiding the stigma-and risk of AIDS-that come with injecting a drug. In part, they may believe mistakenly that they cannot become addicted if they don't inject drugs. Codeine and propoxyphene are the preparations most often used orally. Among the stronger opiates, hydromorphone (Dilaudid), oxycodone (Percodan, OxyContin), meperidine (Demerol), and, of course, methadone (Dolophine) are available as pills. Sometimes drug users resort to grinding up pills of codeine, hydrocodone, or methadone and injecting the suspension in desperation if they cannot get opiates any other way. This is an extremely risky business, as the other pill components do not dissolve in saline. Injecting particles into a blood vessel can irritate the blood vessel, thus setting off a chain of reactions that leads to vascular inflammation and permanent damage. In addition, a pill particle can lodge in a small vessel and block off the blood supply to an area of the body.

How opiates move through the body

The rate at which opiates enter the brain depends mainly on how the user takes them. The fastest way to get high is to inject the drug directly into the bloodstream. The second fastest is to smoke it. When opiates are smoked or injected, peak levels in the brain occur within minutes. Fentanyl is the most fat-soluble, and achieves maximum brain concentrations in seconds (hence its popularity). Heroin is a little slower; it takes a couple of minutes. Morphine is slower still (five minutes), but not by much. The faster the buzz, the greater the danger of death by overdose, since drug levels in the brain can rise so quickly. Snorting heroin causes slower absorption because the drug must travel through the mucous membranes of the nose to the blood vessels beneath.

How about after taking a pill? The high is a much slower proposition, as the drug must be absorbed from the small intestine into the bloodstream, then pass through the liver, which can metabolize much of a dose, before it ever gets into the circulation. This all takes about thirty minutes, so there's no rush after oral administration. This lack of a "rush" is why methadone is so useful in treating addicts, and as a pain medication. Sometimes users figure out how to circumvent opiate preparations that are designed to have a slow onset-the drug OxyContin provides a now notorious example. OxyContin is a delayed-release form of oxycodone that is designed to release drug gradually, providing pain relief over hours. However, crushing the pills causes a quick release of drug, and gives a "high" that the manufacturer did not intend. OxyContin rapidly gained a reputation as the hot "new" drug of abuse. It is simply a garden-variety opiate analgesic drug that can provide effective pain relief when used properly, or be abused if taken inappropriately. There is nothing magical or unique about it.

There is much less diversity in how long this buzz lasts than in how quickly it starts. Most of the drugs mentioned above last for four to six hours. The exact time can vary from two hours (morphine) to up to six or so (propoxyphene), but all opiates are pretty similar. There are only two main exceptions. Methadone lasts for twelve to twenty-four hours, so it can be given as a single daily dose. Fentanyl goes to the other extreme: the effects are over within an hour. The duration of action depends upon how quickly the drug-metabolizing enzymes in the liver degrade the particular drug.

Opiate effects

All opiates cause a pleasant, drowsy state in which all cares are forgotten (nodding oft), and there is a decreased sensation of pain (analgesia). The feelings are the most intense after injection, which brings the rush. People under the influence of opiates will often say that they just don't worry about their troubles anymore: they are in a special, safe place where cares are forgotten. The allure is understandable, and at the beginning it is impossible to understand the misery of addiction and withdrawal.

While the opiate user is in a dreamy, pleasant state, breathing slows, pupils are constricted, and he typically experiences nausea and perhaps even vomits. Although the effects on breathing can be quite dangerous, the other physiologic effects are fairly benign. For example, opiates do not produce big changes in blood pressure in healthy individuals. Most of the effects are caused by the way opiates act on the brain, specifically on opiate receptors in the parts of the brain involved with the control of breathing and other involuntary functions. For example, opiate users vomit because morphine stimulates a center in the brain (the chemoreceptor trigger zone) whose job it is to cause vomiting in response to ingestion of a toxic substance.

One very important effect of opiates on the body has made life easier for generations of foreign travelers. Opiates increase the tension in certain muscles in the gastrointestinal tract so that the normal propulsive movements that move food along cannot operate effectively-hence their well-known ability to cause constipation. This can be a good thing if you are in Mexico and have traveler's diarrhea. Diphenoxylate (Lomotil) utilizes a neat chemical trick to stop diarrhea without affecting the brain. The typical opiate molecule is slightly changed so that it is not fat-soluble enough to enter the brain. This gives you a very safe, very effective medicine that numerous pharmaceutical companies have tried to improve upon with little success, and indeed it is widely used to treat mild diarrhea. Through a similar action, opiates constrict the muscles of the urinary bladder, and can cause difficulties in urination.

How opiates work

The efforts of the opium poppy to make opium alkaloids may reflect ingenious plant evolution to match the biology of their predators/pollinators. The poppy plant figured out how to make a compound that acted in their brains. The poppy is not alone-many plants make compounds that are psychoactive. The marijuana plant, numerous species of hallucinogenic mushrooms, and the coca shrub, to name a few, also influence the behavior and physiology of animals that ingest them. Furthermore, production of opioids is not limited to plants-certain frogs produce opioid-like compounds in their skin, perhaps for the same reason(s).

Opiates act on specific receptor molecules for the endorphin/enkephalin class of neurotransmitters in the brain. These endogenous opioids are chemical neurotransmitters that control movement, moods, and physiology. They help to control many bodily activities, including digestion, regulation of body temperature, and breathing. They also help to process pain sensations, and they activate reward circuits, which is why stimulating them makes you high. All of these behaviors arise when neurons in different parts of the brain release endorphins or enkephalins. Normally, each neuron is doing its job, firing away only if it is called upon; activation of all the endogenous opioid neurons virtually never happens. Taking heroin is like every endogenous opioid neuron in the brain firing all at once.

Which of the many endogenous opioid neurons in the brain are responsible for the opiate high? The first is a small group of neurons in the hypothalamus of the brain. The neurons that use the main endorphin neurotransmitter beta-endorphin all start here, and they spread out throughout the brain. There is a theory that these neurons become active during extremely intense stress, for the purpose of calming us down. The theorists speculate that in the body's most extreme time of stress, when it is on the verge of death, a sense of calm relaxation is about all that is called for. The beta-endorphin neurons fire like crazy and induce an opioid-like pleasant state. Scientists are at least partway toward proving that beta-endorphin can do this. We do know that injecting beta-endorphin in the brain creates many aspects of this state, including slowed breathing, analgesia, and drowsiness.

The enkephalins are a different story. Many different kinds of neurons use enkephalins to communicate with other neurons. They appear in parts of the brain involved in processing painful sensations, controlling breathing, and other actions influenced by the opiates. They are also found in the gastrointestinal tract, where they regulate digestive function. Most important, they are found in several places involved in the reward system, and may be important there. However, they probably do not function as a cohesive unit like endorphin neurons.

Endorphins and enkephalins are different members of a closely related "family" of neurotransmitters. There is a third member of the family, the dynorphins, which share some actions, like analgesia, but actually cause unpleasant rather than pleasant feelings. These three neurotransmitters share receptors. This is perhaps a resourceful evolutionary trick played by the brain to get the most "bang for the buck" out of neurotransmitters and their receptors. By combining different opioid peptides with their receptors, a large number of possible combinations can produce a great diversity of effects.

They cause a diversity of effects by sharing three different kinds of receptor molecules. The main opiate receptor (named with the Greek letter mu) provides the major effects of opiates: analgesia, euphoria, respiratory depression - almost everything opiates do. The main backup receptor (delta) cooperates with mu in some places to help produce these same effects. There is a third receptor (kappa), and this is the weird one. The drugs that are specific for this receptor produce analgesia, but they do not produce a high. This should be it, you might think: the perfect nonaddicting analgesic drug. There is only one problem: stimulation of this receptor alone causes the opposite of euphoria, or dysphoria. Unfortunately, all of the other clinically useful drugs we use now are specific for the mu receptor, and they are all addictive-the addicting properties of opiates cannot be distinguished from their painkilling properties.

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