LT Jeffrey G. Newman, PharmD

The opioids are a class of natural, synthetic, or semisynthetic compounds used therapeutically for their analgesic, antitussive, and antidiarrheal effects. This class of alkaloid drugs is derived from the opium poppy, 

, and its properties have been known for thousands of years. Morphine, the class prototype derived from opium, was discovered in 1803. It was named after Morpheus, the Greek god of dreams, as a result of its sedative?hypnotic properties. 

Much confusion stems from the similar names used for this class of compounds, such as 

. The term narcotic refers to morphine-like drugs having both analgesic and sedative action, whereas 

 refers to morphine-like substances derived from natural sources. The term 

, coined after the development of synthetic compounds, refers to both natural and synthetic compounds. All 3 terms may be used interchangeably for medical purposes. 

All opioids exert their actions through binding to specific opioid receptors located in either the central nervous system (CNS) or the peripheral tissues such as the gastrointestinal (GI) tract. Several receptor subtypes exist, which mediate the various analgesic and adverse effects of opioids. The opioids may easily be classified by their effects on these receptors. Agonists (also known as full agonists) activate receptors; antagonists block receptors; and mixed agonist?antagonists (also known as partial agonists) both activate and block receptors. The agonists may be further classified by the relative strength of their receptor activation, and they may be strong, moderate, or weak. 

The most common use of drugs in the opioid class is to provide analgesia for moderate-to-severe pain. Opioids as a class are more efficacious in the relief of constant pain rather than sharp, intermittent pain. In selecting the appropriate agent for a patient, a proper pain assessment should be made, considering the route of administration of the drug (oral versus parenteral), duration of action, ceiling effect (maximal efficacy), duration of therapy, and past experience with opioids. Many practitioners have concerns regarding the development of tolerance and dependence, which should be subjugated in an attempt to make the patient as comfortable as possible. Fixed dosing intervals are more effective in achieving adequate pain relief, rather than as-needed dosing. 

Intravenous morphine is remarkably efficacious in providing relief from dyspnea from pulmonary edema associated with left ventricular failure. Although the exact mechanism for this action is unknown, reduced perception of shortness of breath and an associated anxiolytic effect appear to play a role in this indication. 

Opioid doses to achieve an antitussive effect usually are lower than those required for analgesia. Opioids appear to act at different receptors from those needed for analgesia in exerting their antitussive effect, relieving cough with both central and peripheral action. The most commonly used antitussives are dextromethorphan and codeine. Dextromethorphan is available over the counter, due to its lack of analgesic and addictive qualities, and it produces less constipation than does codeine. 

The phenylpiperidine subclass of opioids consists of synthetic opiates that can control diarrhea because of their selective GI effects. Agents such as loperamide (available without a prescription) and diphenoxylate reduce peristaltic movements in the bowel and alleviate diarrhea. It is important to remember, however, that infectious causes of diarrhea should be ascertained and treated appropriately. Loperamide is available over the counter, due to its limited ability to cross the blood-brain barrier and its low abuse potential. Diphenoxylate, available by prescription only, is combined with atropine to further reduce its abuse potential. 

Parenteral opioids such as fentanyl (80 times more potent than morphine), sufentanyl, and morphine are commonly used in a premedication regimen prior to anesthesia and surgery. These agents are employed because of their sedative, anxiolytic, and analgesic properties. Morphine also is frequently utilized in the epidural route of administration for regional anesthesia. 

Euphoria is a pleasant sensation of floating and of freedom from anxiety that many patients using opioids experience. Tolerance of this effect usually develops with continued use, and some patients may experience dysphoria rather than euphoria. Dysphoria is a state characterized by a sensation of malaise and restlessness. 

Drowsiness and mental clouding are frequently reported adverse effects of opioid administration, and sleep patterns may be disrupted. CNS depression may be enhanced with concomitant administration of sedative?hypnotics and should be monitored for closely. 

All opioid analgesics are capable of producing clinically significant respiratory depression by inhibition of brainstem respiratory pathways. This effect is dose-related and may be overcome by sensory inputs such as strong painful stimuli. Although this adverse effect should be monitored for closely in patients receiving opioids, it may be reversed by a narcotic antagonist such as naloxone. 

Virtually all opioids produce pupillary constriction (miosis), a pharmacologic action to which little or no tolerance develops. This particular adverse effect is valuable as part of the assessment process for opioid overdose. 

Opioids frequently activate the brainstem chemoreceptor trigger zone, producing nausea and emesis. Tolerance of this adverse effect, like most opioid adverse effects, usually develops, and it may be minimized by having the patient refrain from ambulation. 

Constipation is among the few adverse effects that do not diminish over time with chronic opioid use. Therefore, patients requiring longterm treatment with opioids require a bowel regimen with stimulant laxatives taken on a scheduled basis to prevent this complication. 

Tolerance of the analgesic, euphoric, and respiratory-depressant effects of opioids may begin with the first dose of a particular agent. Clinically significant tolerance, however, usually does not develop until after 2 to 3 weeks of therapeutic dosing. This phenomenon typically occurs most readily when large doses are given over short time periods, and it differs widely, depending on the agent in use. Cross-tolerance also develops, whereby a patient tolerant to morphine, for example, is tolerant of other agents in the opioid class. 

When opioids are discontinued in tolerant patients, a withdrawal or abstinence syndrome occurs. Signs and symptoms of this syndrome include rhinorrhea, lacrimation, yawning, chills, hyperventilation, myalgias, and other effects. These symptoms and their intensity depend largely on the degree of physiologic dependence that has developed. Chronically treated patients are most at risk. 

The euphoria produced by opioids may lead to their compulsive use by some patients. Despite this risk, adequate pain relief should not be withheld simply because opioids may produce this effect. To minimize the potential for psychological addiction, clinicians should establish appropriate therapeutic goals, with frequent reevaluation and monitoring of analgesic needs. 

The opioids are a clinically significant group of compounds that provide benefits in many therapeutic areas. A thorough understanding of their effects, both clinical and adverse, is required to employ them in an effort to improve patient outcomes. Pharmacists have a pivotal role to play in assisting practitioners in the proper selection and use of opioids to achieve the best results for patients. 

LT Newman is a senior assistant pharmacy officer with the US Public Health Service/Federal Bureau of Prisons. He is currently based at Springfield US Medical Center for Federal Prisoners, Springfield, Mo.

The opinions expressed in this article are those of the author and do not necessarily reflect the views of the US Public Health Service or the Federal Bureau of Prisons.

Articles

Medication Overview: Opioids

The proper use of insulin preparations in the management of various types of diabetes is of paramount importance for the hospital pharmacist. Knowledge and expertise in the use of these products can contribute greatly to positive outcomes for diabetic patients, improving their quality of life and preventing complications. 

Diabetes mellitus is a chronic, lifelong disease characterized by elevated levels of blood glucose resulting from insufficient insulin production, insulin resistance, or both. The 3 main types of diabetes are type 1, type 2, and gestational diabetes. An estimated 18.2 million persons in the United States?6.3% of the population?have diabetes. Each year, about 1.3 million persons aged 20 years or older are diagnosed with the disease, and diabetes is currently the sixth leading cause of death in the United States. All type 1 diabetics must use insulin to survive, and many type 2 patients require it for optimum blood glucose control. 

There are 3 elements that comprise the cornerstone of diabetes treatment: diet, exercise, and medications (oral hypoglycemics and/or insulin). All 3 elements working together are required to keep patients symptomfree, to maintain near-normal glucose levels, and to prevent complications. For those patients requiring insulin for their medication treatment, insulin may be categorized by strength, source, and purity and by onset, peak, and duration of action. Besides knowledge of the various categories of insulin, it is equally important for the pharmacist to have a working knowledge of potential adverse effects, the variety of available methods for insulin injection, and po-tential future developments in insulin delivery. 

Almost all patients in the United States use U-100 insulin, although U- 500 is available. 

 indicates the number of units of insulin per milliliter. Therefore, 10 units of insulin is equal to 0.1 mL. U-500 insulin is reserved for use in patients requiring more than 100 units as a single injection. 

All insulin products currently marketed are 1 of 4 types: pork, beef?pork, biosynthetic human, or analogue. Pork insulin differs from human insulin by only 1 amino acid, whereas beef differs by 3 amino acid sequences. Both pork and beef?pork insulins are capable of causing antigenic reactions, and they are rarely used today. Biosynthetic insulins also are referred to as ?human? because their amino acid structure is identical to naturally occurring human insulin. Analogue insulin differs from human insulin only by substitution or position changes in the human insulin molecule. Biosynthetic and analogue insulins are created using recombinant DNA technology. 

The purity of an insulin product relates to the amount of proinsulin and other impurities present. Before 1980, most insulins contained 300 to 10,000 parts per million of impurities, an amount large enough to elicit local reactions when injected as well as systemic effects. Today, all insulins marketed in the United States are ?purified,? indicating 10 ppm or less of impurities, and none are considered antigenic. 

The most important clinical considerations in the use of insulin products relate to their onset, peak, and duration of action. The generally accepted categories are rapid-acting (or shortacting), intermediate, and long-acting. The rapid-acting insulins are the only clear-solution insulins that may be given intravenously or subcutaneously. All other insulin products are cloudy suspensions that may be injected only subcutaneously. The rapid-acting insulins include regular, lispro, and aspart. These insulins have an onset of action within an hour or less and are used to reduce the peak of glycemia that occurs after meal ingestion. Regular insulin has an onset of action of 30 to 60 minutes, peaks within 2 to 4 hours, and may last for 6 to 8 hours. Lispro and aspart insu-lins both have an onset of action of 15 minutes, with a peak in 1 hour and a duration of action of 3 to 4 hours. 

Common intermediate-acting insulins include Neutral Protamine Hagedorn (NPH; isophane), insulin zinc suspension (Lente), and combinations of NPH and regular insulins?usually a 70/30 mixture. These forms of insulin have a significantly longer delay in their onset and duration of action. In the setting of type 1 diabetes, they generally are used in combination with a rapidly acting form of insulin, although they may be given before bedtime to limit hyperglycemia over-night and in the early hours of the morning. NPH insulin has an onset of action of 1 to 3 hours, peaking within 6 to 8 hours and lasting for 12 to 16 hours, whereas Lente insulin has a slightly extended time frame with an onset of 1 to 4 hours, a peak of 6 to 10 hours, and a duration of 14 to 18 hours. 

The long-acting insulins include extended insulin zinc suspension (Ultralente) and glargine. Even after an overnight fast, the normal pancreas continues to secrete insulin. Investigators have long attempted to develop forms of long-acting insulin with pharmacokinetic properties that simulate the basal production of insulin. Ultralente has an onset of 2 to 4 hours, peaking within 8 to 10 hours and lasting for 16 to 24 hours. The newest long-acting agent, known as glargine, has an onset of action of 6 hours, peaking and lasting upwards of 24 hours. 

Although insulin use is ubiquitous, complications and adverse effects occur as with any drug regimen. Complications may include hypoglycemia, weight gain, worsening of retinopathy, and allergic reactions. Hypoglycemia is most common in diabetics using an intensive insulin regimen of 2 to 4 injections per day, and it is the most common reason why these patients fail to achieve tight glucose control. In the Diabetes Control and Complications Trial, patients on an intensive insulin regimen were 3 times more likely to experience hypoglycemia than patients in the standard treatment group. 

Weight gain also is common in insulin users, especially with intensive regimens. This effect may be due to a combination of factors, including appe-tite stimulation, reduced glycosuria from improved glycemic control, and increased food intake to prevent or treat hypoglycemia. 

Intensive insulin regimens for tight glucose control also may exacerbate preexisting retinopathy, and proliferative retinopathy should be treated in patients with poor glucose control prior to initiating an intensive regimen. Allergic reactions to insulins are much less commonplace with the use of biosynthetic and analogue insulins, but they still may occur. Most reactions are local, but life-threatening anaphylaxis is still a possibility. 

Many types of devices exist for insulin users to enhance comfort and convenience. Insulin syringes that are filled by the patient are most common, but insulin may be delivered via a prefilled ?pen? device, via an external pump, or with jet injectors. The prefilled pen cartridge enables patients to dial in a dose for delivery, whereas the external pump provides a continuous basal infusion that may be supplemented with bolus injections at mealtimes or when preprogrammed glucose levels are reached. Jet injectors deliver insulin through a fine spray under high pressure rather than through conventional needles. 

Many exciting developments are on the horizon in insulin delivery that may enhance quality of life for insulin users. These developments include an implantable insulin pump, a transdermal patch, and delivery by inhalation. The surgically implanted insulin pump functions in the same manner as an external pump, delivering both basal and bolus dosing. The patch delivers insulin in a transdermal system similar to nicotine patches, with a tab that allows users to supplement dosing before meals. 

Perhaps the most promising delivery system is the inhaled insulin system. Danish researchers recently reported the results of a small clinical trial involving more than 100 patients, in which glycemic control levels were similar in patients using standard subcutaneous injections and in those using aerosolized droplets in an inhaled nasal spray. Further studies in larger patient populations are needed, but it appears that this system may be the next major development in insulin delivery. 

Today?s diabetic patients who require insulin for glycemic control have a distinct advantage over previous generations of users because of improvements in insulin purity, the advent of the human insulins, and the wide variety of delivery systems available. Research is ongoing to improve the quality of life for diabetics who use insulin. The future remains bright for patients with this chronic disease, and pharmacists can and should play a role in helping to secure this future for patients with diabetes. 

The opinions expressed in this article are those of the author and do not necessarily reflect the views of the US Public Health Service or the Indian Health Service.

Medication Overview: Insulins and Injection Devices

    Friends and family, dancing and drinking, parties and presents?the holiday season is just around the corner! Many of us will enjoy the festivities and merriment, as will our patients. All of us will have decisions to make about healthy eating and drinking during the holidays, since the temptation to overindulge is perhaps greatest at this time of year. Yet, these decisions?especially concerning the use of alcoholic beverages?are vitally important for our diabetic patients 

 the year. How can we provide the best pharmaceutical care when counseling patients about diabetes and alcohol? 

    Before we can provide guidelines for responsible drinking, we must be aware of the specific risks and potential consequences of alcohol use for diabetics. These risks include both short- and long-term effects on the body, interactions with diabetic medications, and worsening of preexisting diabetic complications. Whereas alcohol use in moderation is prudent for most patients with diabetes, there are times when saying ?no, thanks? is the best decision.

Physiologic Effects of Alcohol in Diabetics 

    When alcohol is ingested, it moves quickly from the gastric contents and intestinal lumen into the bloodstream with minimal breakdown. Blood alcohol content is measurable within 5 minutes and peaks at 30 to 90 minutes. The liver metabolizes ethanol as a toxin through the alcohol dehydrogenase pathway. Absorption and breakdown rates are affected by many factors, such as gender, ethnicity, stomach contents, and body weight. 

    Under normal conditions, when blood glucose levels begin to decline, the liver converts stored carbohydrates into glucose for release into the bloodstream. This reaction avoids or slows the rate of hypoglycemia. When alcohol is ingested, however, conversion of carbohydrates into glucose for release becomes a secondary priority. The liver detoxifies alcohol until it is cleared, and it only then begins to assist in normalizing blood sugar. This scenario can quickly lead to hypoglycemia for the diabetic who ingests alcohol. 

    Insulin and oral hypoglycemics mixed with alcohol may increase the risk of hypoglycemic reactions. Chlorpropamide and possibly other sulfonylureas may produce a disulfiramlike reaction with alcohol, leading to flushing, hypotension, nausea, tachycardia, vertigo, dyspnea, and blurred vision. Metformin should be avoided in patients with a history of chronic alcohol use because they may be more predisposed to lactic acidosis. 

    Exercise depletes muscle glycogen stores, and they must be replenished with blood glucose. Because alcohol consumption prevents the liver from releasing glucose into the bloodstream, patients who exercise and ingest alcohol increase the risk of hypoglycemia. 

    Alcohol is considered a substance with ?empty calories? due to its lack of nutrients, and it can adversely affect a diabetic who is concerned with weight loss. A single 12-oz beer contains approximately 150 calories, and a single 5- oz glass of wine or a 1.5-oz shot of 80- proof liquor contains about 100 calories. For diabetic meal-planning purposes, 1 drink equals 2 fat exchanges. 

    For patients suffering from diabetic neuropathy, alcoholic beverages can increase the pain, burning, tingling, and numbness associated with this condition. This increase can even occur with moderate drinking (fewer than 2 drinks per week). Moderate drinking habits also may elevate blood triglyceride levels, already elevated in most diabetics. Heavy drinking (3 or more drinks per day) can worsen diabetic retinopathy. Finally, because diabetes and hypertension are often comorbid conditions, diabetics should be aware that alcohol use may raise blood pressure levels. 

    Now that we have considered the ramifications of alcohol use for the patient with diabetes, we should be prepared to provide the patient with useful guidelines concerning alcohol use and diabetes. 

Questions for a Patient to Ask Himself or Herself 

    According to the American Diabetes Association (ADA), a diabetic patient should ask 3 questions before using alcohol: 1. Is my diabetes under control? 2. Does my health care provider agree that I am free from health problems that alcohol can make worse? 3. Do I know how alcohol can affect me and my diabetes? If the answers to all 3 questions are ?yes,? the ADA suggests that an occasional drink is acceptable. The recommendation for occasional drinking is the same for persons without diabetes: no more than 2 drinks a day for men and no more than 1 drink a day for women. 

Food may slow the rate of absorption and help to prevent hypoglycemic reactions. 

Be Prepared for Low Blood Sugar Reactions.

 Have a high-carbohydrate snack ready for when the blood sugar level dips below 65 to 70 mg/dL. Remember that glucagon does not correct hypoglycemia related to alcohol use. 

 Bring your blood glucose monitor with you, and use it. 

Carefully Check the Alcohol Level of What You Are Drinking.

 Make sure that mixed drinks are measured correctly, and be sure to account for added calories and carbohydrates in fruit juices, sodas, and other mixers. Check the proof of distilled spirits and the alcohol level of beers and wines. Also, consider drinking nonalcoholic beers or wines or virgin mixed drinks. 

 Remember That the Symptoms of Hypoglycemia and Intoxication Are Similar.

 Be sure that a responsible friend or family member is present to watch for signs such as dizziness, confusion, or shakiness that may indicate a low blood glucose level. This person should know how to help you check your sugar level and get you a high-carbohydrate snack if needed. 

 Your blood sugar level can drop overnight even though you feel fine when retiring for the night. Set an alarm to wake you after a few hours? sleep so that you can check your level. 

Choose Drinks That Are Low in Sugar and Alcohol.

 Light beers and dry wines are excellent choices. When using mixers, select ones that are sugar-free, such as club soda, seltzer, water, and diet soft drinks or tonic. 

    For some people with diabetes, not using alcohol at all is the best choice. Those with diabetic complications such as neuropathy, retinopathy, uncontrolled hypertension, or elevated triglyceride levels always should say no. 

    (Some considerations about not using alcohol apply to everyone. No one should drink and operate a motor vehicle or heavy machinery under the influence of alcohol. There are other medical conditions that may contraindicate the use of alcohol, such as liver disease, peptic ulcer disease, gastritis, pancreatitis, or pregnancy.) 

    After this review of the specific risks associated with drinking and diabetes, we should be better prepared as pharmacists to provide our diabetic patients with sound advice concerning the responsible use of alcohol. As the holiday season approaches, we should be able to tell our patients that they can enjoy themselves without fear if they know a few simple precautions to take. After all, the holidays are a celebration! 

    The author is senior assistant pharmacy officer with the US Public Health Service (PHS)/Indian Health Service, Whiteriver PHS Hospital, Whiteriver, Ariz. The opinions expressed in this article are those of the author and do not necessarily reflect the views of the USPHS or the Indian Health Service.

Counseling Diabetic Patients About Alcohol Use

	Did I take my medicine today? If you ever find yourself asking this question, you are certainly not alone. Many people?25% to 50%?do not follow all the directions when it comes to taking their medicines properly. This is called noncompliance. Noncompli-ance is more than just skipping a pill. It can mean:

	? Not taking the medications at the correct time of day

	? Not taking the drug as directed, eg, with food

	Each year new medications are found that improve the health and well-being of millions of people, from lowering blood pressure to treating diabetes. But no matter how potent the pill or strong the syrup, no medicine can make you well if it is not taken the right way.

	Not taking medications properly is costly in terms of both money and lives. The National Pharmaceutical Council estimates that noncompliance with prescribed medications costs more than $100 billion a year in increased emergency room visits, hospital and nursing home admissions, and lost productivity. In addition, about 125,000 people die each year from noncompli-ance?almost twice the number of deaths from automobile accidents.

	Most people mean to take their medication as directed. But the following things sometimes get in the way:

	? Feel uncomfortable taking medicines in front of other people

	? No one has explained what the medicine is for or how to take it

	? Have to take medicines many times throughout the day

	There are ways to address any of these reasons for not taking your medicines the right way. One good thing to remember is to talk with your doctor and pharmacist. They can offer many solutions to help.

	Keep a calendar in the kitchen and make a mark each time you take your medications. Ask a family member or friend to remind you to take your pills. Use a weekly pill box?you have to fill it only once a week, and there are different compartments for different times of the day. If the tablets and capsules are gone, you took them! There are even medication reminder watches and caps for the prescription drug bottle that beep when it?s time to take your medicines. Ask your pharmacist for recommendations.

Feel uncomfortable taking medicines in front of other people

	Keep your medicine bottles in your purse or a small travel pill box in your pocket or briefcase, and simply excuse yourself to go to the rest room or other private area to take your medicines.

	Many pharmaceutical companies have financial assistance programs that can help?ask your doctor or pharmacist for suggestions. It is also a good idea to review your insurance program that covers prescription drugs so that you know your options. And remember, the cost of not taking your medicines properly is usually much higher than the cost of the medicines themselves.

No one has explained what the medicine is for or how to take it

	The more you know about your medicine and how it should be used, the more likely you?ll be to use it. And this is where your doctor and pharmacist can help the most. Be sure to ask as many questions as you need to fully understand what the medicine is for and how to take it the right way. Many pharmacies have counseling areas where you can ask questions in private. Be sure to ask for and read any printed materials available for your medicine or condition. You can also use the Internet to look up information on your medicine or condition. But be careful which Web sites you visit. The information on some sites is not reliable. Government or pharmaceutical company sites are a good place to start, or your doctor or pharmacist may be able to recommend a trustworthy source.

	The first thing to do when side effects occur is to talk with your health care provider. Sometimes simply adjusting the dose or the time of day you take your medicine is all that?s required. Other times, a change in medicine may be needed.

	Pillboxes of various shapes and sizes can come in handy. Fill them once a week, and make a consistent effort to take them wherever you go.

	Talking with your physician or pharmacist is the first place to start. Many medications are now made so that you have to take them only once or twice a day. Your doctor may be able to otherwise simplify your regimen.

	Taking your medications exactly as prescribed can greatly enhance the quality of your life and keep you healthy and feeling good.

	The author is senior assistant pharmacy officer with the US Public Health Service (PHS)/Indian Health Service, Whiteriver PHS Hospital, Whiteriver, AZ. The opinions expressed in this article are those of the author and do not necessarily reflect the views of the Indian Health Service.