Appendix I: Principles of Prescription Order Writing and Patient Compliance

From the wrong drug prescribed to the wrong dosage or administration schedule advised, dispensed, or administered, the impact of medication misadventures is a costly problem. Errors of these sorts occur because human beings are involved, and such errors can be prevented only by systems that make it difficult to do the wrong thing. This appendix provides a primer on the proper approach to the medication prescription and order process and a resource for practitioners in effectively providing pharmaceutical care for their patients.

History

Early medicines were made up of multiple ingredients requiring complex preparation, and Latin was adopted as the standard language of the prescription to ensure understanding between physician and pharmacist and consistency in pharmaceutical composition. Latin no longer is the international language of medicine, but a number of commonly used abbreviations derive from old Latin usage. The symbol "Rx" is said to be an abbreviation for the Latin word recipere, meaning "take" or "take thus," as a direction to a pharmacist, preceding the physician's "recipe" for preparing a medication. The abbreviation "Sig" for the Latin Signatura, is used on the prescription to mark the directions for administration of the medication.

Current Practice

The prescription consists of the superscription, the inscription, the subscription, the signa, and the name and signature of the prescriber, all contained on a single form (Figure AI–1).

The superscription includes the date the prescription order is written; the name, address, weight, and age of the patient; and the Rx (Take). The body of the prescription, or inscription, contains the name and amount or strength of the drug to be dispensed, or the name and strength of each ingredient to be compounded. The subscription is the instruction to the pharmacist, usually consisting of a short sentence such as: "make a solution," "mix and place into 30 capsules," or "dispense 30 tablets." The signa or "Sig" is the instruction for the patient as to how to take the prescription, interpreted and transposed onto the prescription label by the pharmacist. In the U.S., prescriptions should always be written in English. Many physicians continue to use Latin abbreviations; for example, "1 cap tid pc," will be interpreted by the pharmacist as "take one capsule three times daily after meals." However, the use of Latin abbreviations for these directions only mystifies the prescription and is discouraged. This can be a hindrance to proper patient-physician communication and is an otherwise unnecessary source of potential dispensing errors. Because the pharmacist always writes the label in English (or, as appropriate, in the language of the patient), the use of such abbreviations or symbols is unnecessary. Many serious dispensing errors can be traced to the use of abbreviations (Cohen, 2007).

The instruction "take as directed" is not satisfactory and should be avoided by the physician. Such directions assume an understanding on the part of the patient that may not be realized and inappropriately exclude the pharmacist from the pharmaceutical care process. Such directions are inadequate for the pharmacist, who must determine the intent of the physician before dispensing the medication, and who shares the responsibility for the patient's safe and proper use of the medication. The best directions to the patient will include a reminder of the intended purpose of the medication by including such phrases as "for relief of pain" or "to relieve itching." The correct route of administration is reinforced by the choice of the first word of the directions. For an oral dosage form, the directions should begin with "take" or "give"; for externally applied products, the word "apply"; for suppositories, "insert"; and for eye, ear, or nose drops, "place" is preferable to "instill."

Prescriptive Authority

In many states in the U.S., healthcare practitioners other than M.D. and D.O. physicians can write prescriptions. Licensed physician's assistants (P.A.), nurse practitioners, pharmacists, and clinical psychologists can prescribe medications under various circumstances.

Avoiding Confusion

Doses always should be listed by metric weight of the active ingredient; doses for liquid medications should include the volume. Older systems of measure such as minims for volume (15 minims = 1 mL) and grains for weight (1 grain = 60 mg) are obscure and should not be used. Writing "μg" for micrograms can very easily be misinterpreted as "mg" (milligrams). Even the abbreviation "mcg" for micrograms can be misinterpreted (Koczmara et al., 2005). Writing out the word micrograms or milligrams is preferable. When specifying the dose to be dispensed, a zero should be used before a decimal (0.# milligrams, rather than .# milligrams) but not after (use # milligrams rather than #.0 milligrams). The metric system should be used in place of common household measurements such as "dropperful" and "teaspoon" in the directions for the patient except when the dropper is provided with the prescription, as in the case of pediatric antibiotic suspensions. Both the doctor and the pharmacist should be sure that the patient understands the measurement prescribed. For medical purposes, a "teaspoon" or "teaspoonful" dose is considered to be equivalent to 5 mL and a "tablespoon" equivalent to 15 mL, but the actual volumes held by ordinary household teaspoons and tablespoons are far too variable to be used reliably for measurement of medications. Prescribing oral medications in "drops" likewise can cause problems when accuracy of dose is important, unless the patient understands that only the calibrated dropper (for drops or teaspoon measures) provided by the manufacturer or pharmacist should be used to dispense the medication. Thus, one possible dosage for a pediatric iron product would be more accurately written "15 milligrams (0.6 mL) three times daily" instead of "one dropperful three times daily," because a true dropperful could result in iron overdose.

Abbreviations lead to dispensing errors (Teichman and Caffee, 2002). A prescription intending every-other-day dosing (qod) may be miswritten as "od" by the physician for "other-day dosing"; the pharmacist may interpret "od" as the abbreviation of the Latin for "right eye." Once-daily dosing at bedtime (qhs) may be misinterpreted as "qhr" for "every hour." The use of a slash mark (/) to separate names and doses can result in the incorrect drug or dose being dispensed; the slash mark may be interpreted as a letter or number. When medications are measured in units, or international units, the abbreviation "U" or "I" must NOT be used, as it leads to errors such as misinterpretation of "U" as 0 or 4, or "IU" as 10 or 14. The word "unit" should be written as such. Drug products available in the U.S. that are dosed in units (e.g., corticotropin) or international unit measures are "harmonized" by those responsible for drug standardization to avoid errors in dosing (see "Drug Standards and Classification"). Examples of confusion in the interpretation of a physician order abound (Kohn, 2001) and are considered further in "Errors in Drug Orders." To avoid errors, practitioners in the U.S. must write out the Rx fully in English, and pharmacists must clarify their concerns with prescribers, not patients.

Proper Patient Information

The patient's name and address are needed on the prescription order to ensure that the correct medication goes to the proper patient and also for identification and recordkeeping purposes. For medications whose dosage involves a calculation, a patient's pertinent factors, such as weight, age, or body surface area, also should be listed on the prescription. Prescribers should view this effort as one that serves their goal of protecting their patient from errors rather than a burden (safety first).

Prescribers often commit errors in dosage calculations (Lesar et al., 1997) that can be prevented (Kuperman et al., 2001; Conroy et al., 2007). When prescribing a drug whose dosage involves a calculation based on body weight or surface area, both the calculated dose and the dosage formula used, such as "240 mg every 8 hours (40 mg/kg/day)," should be included to allow another healthcare professional to double-check the prescribed dosage. Pharmacists always should recalculate dosage equations when filling such prescriptions. Medication orders in hospitals and some clinic settings, such as those for antibiotics or anti-seizure medications that are sometimes difficult to adequately dose (e.g., phenytoin), can specify the patient diagnosis and desired drug and request dosing by the clinical pharmacist.

Proper Use of Prescription Pad

All prescriptions should be written in ink; this practice is compulsory for schedule II prescriptions under the U.S. Controlled Substances Act (CSA) of 1970, because erasures on a prescription easily can lead to dispensing errors or diversion of controlled substances.

Prescription pad blanks normally are imprinted with a heading that gives the name of the physician and the address and phone number of the practice site (Figure AI–1). When using institutional blanks that do not bear the physician's information, the physician always should print his or her name and phone number on the face of the prescription to clearly identify the prescriber and facilitate communication with other healthcare professionals if questions arise. U.S. law requires that prescriptions for controlled substances include the name, address, and Drug Enforcement Administration (DEA) registration number of the physician.

The date of the prescription is an important part of the patient's medical record, and it can assist the pharmacist in recognizing potential problems. For example, when an opioid is prescribed for pain due to an injury, and the prescription is presented to a pharmacist 2 weeks after issuance, the drug may no longer be indicated. Compliance behavior also can be estimated using the dates when a prescription is filled and refilled. The CSA requires that all orders for controlled substances (Table AI–1) be dated as of, and signed on, the day issued and prohibits filling or refilling orders for substances in schedules III and IV >6 months after their date of issuance. When writing the original prescription, the physician should designate the number of refills allowed. For maintenance medications without abuse potential, it is reasonable to write for a 1-month supply and to mark the prescription form for refills to be dispensed over a period sufficient to supply the patient until the next scheduled visit to the physician. A statement such as "refill prn" (refill as needed) is not appropriate, as it could allow the patient to misuse the medicine or neglect medical appointments. If no refills are desired, "zero" (not "0") should be written in the refill space to prevent alteration of the prescriber's intent. Refills for controlled substances are discussed later, in "Refills" under "Controlled Substances."

Concern about the rising cost of healthcare has favored the dispensing of so-called "generic" drugs. A drug is called by its generic name (in the U.S., this is the U.S. Adopted Name or USAN) or the manufacturer's proprietary name, called the trademark, trade name, or brand name. In most states in the U.S., pharmacists have the authority to dispense generic drugs rather than brand-name medications. The physician can request that the pharmacist not substitute a generic for a branded medication by indicating this on the prescription ("do not substitute"), although this generally is unnecessary because the U.S. Food and Drug Administration (FDA) requires that generic medications meet the same bioequivalence standards as their brand-name counterparts. In some jurisdictions, prescriptions may not be filled with a generic substitution unless specifically permitted on the prescription. Occasions when substituting generic medications is discouraged are limited to products with specialized release systems and narrow therapeutic indices, or when substantial patient confusion and potential noncompliance may be associated with substitution.

Choice and Amount of Drug Product Dispensed

Inappropriate choice of drugs by physicians is a problem in prescribing. As learned recently with the cyclooxygenase-2 (COX-2) inhibitors, a drug's therapeutic promise or popularity is not proof of its overall clinical superiority or safety (Topol, 2004). Physicians must rely on unbiased sources when seeking drug information that will influence their prescribing habits; use of the original medical literature will ensure instruction of the prescriber's best judgment.

The amount of a drug to be dispensed should be clearly stated and should be only that needed by the patient. Excessive amounts should never be dispensed, because this not only is expensive for the patient but may lead to accumulation of medicines, which can lead to harm to the patient or members of the patient's family if used inappropriately. It is far better to have several refills of a prescription than to have more than necessary prescribed at one time.

The Prescription as a Commodity

Prescribers must be aware that patients may visit their doctor to "get" a prescription. Indeed, in an era when the time spent between physician and patient is ever shorter due to limits and pressures of physician reimbursements, patients often feel that a trip to the doctor that does not result in a new prescription somehow is a failed visit or a lost opportunity. Similarly, physicians may feel that they have fulfilled their role if the patient leaves with a prescription. Physicians must educate their patients about the importance of viewing medicines as to be used only when really needed and that remaining on a particular medicine when their condition is stable may be preferable to seeking the newest medications available.

Prescription Drug Advertising

The Federal Food, Drug, and Cosmetic Act as amended (Food and Drug Administration Modernization Act of 1997) permits the use of print and television advertising of prescription drugs. The law requires that all drug advertisements contain (among other things) summary information relating to side effects, contraindications, and effectiveness. The current advertising regulations specify that this information disclosure needs to include all the risk information in a product's approved labeling or must direct consumers to healthcare professionals to obtain this information. Typically, print advertisements will include a reprinting of the risk-related sections of the product's approved labeling (package insert), while television advertising will not. In addition, advertisements cannot be false or misleading or omit material facts. They also must present a fair balance between effectiveness and risk information.

The benefits of these types of direct-to-consumer (DTC) advertising, including Internet advertising, are controversial (Findlay, 2001). Dramatizations employed by television commercials may be a disservice to the physician's ability to educate and care for the patient if such advertisements only create brand loyalty. Alternatively, patients who learn about drugs on television may interact more effectively with their healthcare providers by asking questions about the medicines they take. Prescription drug advertising has alerted consumers to the existence of new drugs and the conditions they treat, but it has also increased consumer demand for drugs. This demand has increased the number of prescriptions being dispensed (raising sales revenues) and has contributed to the higher pharmaceutical costs borne by health insurers, government, and consumers. In the face of a growing demand for particular brand-name drugs driven by advertising, physicians and pharmacists must be able to counsel patients effectively and provide them with evidence-based drug information (Khanfar et al., 2007).

The Institute of Medicine (IOM) estimates that the annual number of medical errors in the U.S. that results in death is between 44,000 and 98,000 (Kohn et al., 2000). Although there is some controversy about these estimates (Sox and Woloshin, 2000), it is clear that the large number of medical errors includes medication errors resulting in adverse events, including death (Mangino, 2004; Tzimenatos and Bond, 2009). Databases of anonymously reported errors are maintained jointly by the Institute for Safe Medication Practices (ISMP), the U.S. Pharmacopeia Medication Errors Reporting Program (USP MERP), and the FDA's MedWatch program. Adverse drug events occur in ~3% of hospitalizations, and this number is larger for special populations such as those in pediatric and neonatal intensive care units (Chedoe et al., 2007).

By examining aspects of prescription writing that can cause errors and by modifying prescribing habits accordingly, the physician can increase the probability that the patient will receive the correct prescription. By being alert to common problems that can occur with medication orders and communicating with the patient's physician, pharmacists and other healthcare professionals can assist in reducing medication errors (Murray et al., 2009). Good practice in the preparation of medication orders in both the institutional and outpatient settings can be summarized as follows:

• Write all orders clearly using metric measurements of weight and volume.

• Include patient age and weight on the prescription, when appropriate, so dosage can be checked.

• Use Arabic (decimal) numerals rather than Roman numerals (e.g., does "IL-II" mean "IL-11" or "IL-2"?); in some instances, it is preferable for numerals to be spelled out.

• Use leading zeros (0.125 milligrams, not .125 milligrams); never use trailing zeros (5 milligrams, not 5.0 milligrams).

• Avoid abbreviating drug names; abbreviations may lead to misinterpretation.

• Avoid abbreviating directions for drug administration; write out directions clearly in English.

• Be aware of possibilities for confusion in drug names. Some drug names sound alike when spoken and may look alike when spelled out. The U.S. Pharmacopeial Convention Medication Errors Reporting Program maintains a current list of drug names that can be confused (www.usp.org). The list of alliterative drug names currently contains >750 pairs of potentially confusing names that could lead to harmful prescribing or dispensing errors. Alliterative drug names can be particularly problematic when giving verbal orders to pharmacists or other healthcare providers.

• Provide the patient's diagnosis on the prescription order. This is the single most important measure to prevent dispensing errors based on sound-alike or look-alike drug names. For instance, an order for administration of magnesium sulfate must not be abbreviated "MS," as this may result in administration of morphine sulfate. Including the therapeutic purpose and/or the patient's diagnosis can prevent this error.

• Write clearly. Poor handwriting is a well-known and preventable cause of dispensing errors. Both physician and pharmacist share in the responsibility for preventing adverse drug events by writing prescriptions clearly (When in doubt, write it out!) and questioning intent whenever an order is ambiguous (When in doubt, check it out!).

• Think.

In the U.S., the DEA within the Department of Justice is responsible for the enforcement of the Federal Controlled Substances Act (CSA). The DEA regulates each step of the handling of controlled substances from manufacture to dispensing (21 U.S.C. § 811). The law provides a system that is intended to prevent diversion of controlled substances from legitimate uses. Substances that come under the jurisdiction of the CSA are divided into five schedules (Table AI–1), but practitioners should note that individual states may have additional schedules. Physicians must be authorized to prescribe controlled substances by the jurisdiction in which they are licensed, and they must be registered with the DEA or exempted from registration as defined under the CSA. The number on the certificate of registration must be indicated on all prescription orders for controlled substances. Criminal prosecution and penalties for misuse generally depend on the schedule of a substance as well as the amount of drug in question.

State agencies may impose additional regulations, such as requiring that prescriptions for controlled substances be printed on triplicate or state-issued prescription pads or restricting the use of a particular class of drugs for specific indications. Some U.S. states, such as California, have placed marijuana, classified by the FDA as a schedule I substance, in a special category by decriminalizing its possession and sale for medical use. Under California's medical marijuana laws, patients and caregivers are exempt from prosecution by the state of California, notwithstanding contrary federal law. This legal difference of opinion between state and federal regulation is the source of considerable controversy. Generally, the most stringent law takes precedence, whether it is federal, state, or local.

Prescription Orders for Controlled Substances

To be valid, a prescription for a controlled substance must be issued for a legitimate medical purpose by an individual practitioner acting in the usual course of his or her professional practice. An order that does not meet these criteria, such as a prescription issued as a means to obtain controlled substances for the doctor's office use or to maintain addicted individuals, is not considered a legitimate prescription within the meaning of the law, and thus does not protect either the physician who issued it or the pharmacist who dispensed it. Most states prohibit physicians from prescribing controlled substances for themselves; it is prudent to comply with this guideline even if it is not mandated by law.

Execution of the Order

Prescriptions for controlled substances should be dated and signed on the day of their issuance and must bear the full name and address of the patient and the printed name, address, and DEA number of the practitioner and should be signed the way one would sign a legal document. Preprinted orders are not allowed in most states, and pre-signed blanks are prohibited by Federal law. When oral orders are not permitted (schedule II), the prescription must be written with ink or typewritten. The order may be prepared by a member of the physician's staff, but the prescriber is responsible for the signature and any errors that the order may contain.

Oral Orders

Prescriptions for schedule III, IV, and V medications may be telephoned to a pharmacy by a physician or by trusted staff in the same manner as a prescription for a noncontrolled substance, although it is in the physician's best interest to keep his or her DEA number as private as reasonably possible (see "Preventing Diversion"). Schedule II prescriptions may be telephoned to a pharmacy only in emergency situations. To be an emergency:

• Immediate administration is necessary

• No appropriate alternative treatment is available

• It is not reasonably possible for the physician to provide a written prescription prior to the dispensing.

For an emergency prescription, the quantity must be limited to the amount adequate to treat the patient during the emergency period, and the physician must have a written prescription delivered to the pharmacy for that emergency within 72 hours. If mailed, the prescription must be postmarked within 72 hours. The pharmacist must notify the DEA if this prescription is not received.

Refills

No prescription order for a schedule II drug may be refilled under any circumstance. For schedule III and IV drugs, refills may be issued either orally or in writing, not to exceed five refills or 6 months after the issue date, whichever comes first. Beyond this time, a new prescription must be ordered. For schedule V drugs, there are no restrictions on the number of refills allowed, but if no refills are noted at the time of issuance, a new prescription must be made for additional drug to be dispensed.

Preventing Diversion

Prescription blanks often are stolen and used to sustain abuse of controlled substances and to divert legitimate drug products to the illicit market. To prevent this type of diversion, prescription pads should be protected in the same manner as one would protect a personal checkbook. A prescription blank should never be pre-signed for a staff member to fill in at a later time. Also, a minimum number of pads should be stocked, and they should be kept in a locked, secure location except when in use. If a pad or prescription is missing, it should be reported immediately to local authorities and pharmacies; some areas have systems in place to allow the rapid dissemination of such information. Ideally, the physician's full DEA number should not be pre-printed on the prescription pad, because most prescriptions will not be for controlled substances and will not require the registration number, and anyone in possession of a valid DEA number may find it easier to commit prescription fraud. Some physicians may intentionally omit part or all of their DEA number on a prescription and instead write "pharmacist call to verify" or "call for registration number." This practice works only when the pharmacist may independently verify the authenticity of the prescription, and patients must be advised to fill the prescription during the prescriber's office hours. Pharmacists can ascertain the likely authenticity of a physician's DEA number using an algorithm.

Another method employed by the drug seeker is to alter the face of a valid prescription to increase the number of units or refills. By spelling out the number of units and refills authorized instead of giving numerals, the prescriber essentially removes this option for diversion. Controlled substances should not be prescribed excessively or for prolonged periods, as the continuance of a patient's addiction is not a legitimate medical purpose.

The U.S. Pharmacopeial Convention, Inc. is a nongovernmental organization that promotes the public health and benefits practitioners and patients by disseminating authoritative standards and information on medicines and other healthcare technologies. This organization is home to the U.S. Pharmacopeia (USP), which, together with the FDA, the pharmaceutical industry, and health professions, establishes authoritative drug standards. These standards are enforceable by the FDA and the governments of other countries and are recognized worldwide. Drug monographs are published in the USP/National Formulary (USP-NF), the official drug standards compendia that organize drugs into categories based on pharmacological actions and therapeutic uses. The USP also provides chemical reference standards to carry out the tests specified in the USP-NF. For example, a drug to be manufactured and labeled in units must comply with the USP standard for units of that compound. Such standards are essential for agents possessing biological activity, such as insulin.

The USP also is home to the USP Dictionary of U.S. Adopted Names (USAN) and International Drug Names. This compendium is recognized throughout the healthcare industry as the authoritative dictionary of drugs. Entries include one or more of the following: U.S. Adopted Names, official drug names for the National Formulary (NF), previously used official names, International Nonproprietary Names, British Approved Names, Japanese Accepted Names, trade names, and other synonyms. In addition to names, the records in this file contain other substance information such as Chemical Abstract Service (CAS), registry number (RN), molecular formula, molecular weight, pharmacological and/or therapeutic category, drug sponsor, reference information, and structure diagram, if available. The USP maintains an electronic web site that can be accessed for useful drug naming, classification, and standards information (www.usp.org).

In the U.S., drug products also are coded under the National Drug Code (NDC). The NDC originally was established as an essential part of out-of-hospital drug reimbursement under Medicare. In the U.S., the NDC serves as a universal product identifier for drugs used in humans. The current edition of the National Drug Code Directory is limited to prescription drugs and a few selected over-the-counter products. Each drug product listed under the Federal Food, Drug, and Cosmetic Act is assigned a unique 10-digit, 3-segment number. This number, known as the NDC number, identifies the labeler/vendor, product, and package size. The labeler/vendor code is assigned by the FDA. The second segment, the product code, identifies a specific strength, dosage form, and formulation for a particular drug company. The third segment, the package code, identifies package sizes. Both the product and package codes are assigned by the manufacturer.

In addition to classification of drugs by therapeutic category, drugs also are grouped by control schedule. Drug schedules in the U.S. are listed in Table AI–1 from schedule I to schedule V and are discussed above under "Controlled Substances."

The FDA also categorizes drugs that may be used in pregnant women. These categories are similar to those used in other countries and provide guidance based on available science. The risk from a drug may be throughout pregnancy or limited to a particular period of fetal development. The categories range from A to X, in increasing order of concern, as noted here:

Pregnancy Category A: Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters). Because of the obvious nature of the risk associated with the use of medications during gestation, the FDA requires a body of high-quality data on a drug before it can be considered for Pregnancy Category A.

Pregnancy Category B: Animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and well-controlled studies in pregnant women, OR animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester.

Pregnancy Category C: Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Pregnancy Category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Pregnancy Category X: Studies in animals or humans have demonstrated fetal abnormalities, and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

Physicians should realize that the pregnancy categories by themselves provide little guidance for the physician treating pregnant women. For example, angiotensin-converting enzyme (ACE) inhibitors such as captopril cause developmental toxicity (Category X) only after the first trimester. Physicians' primary responsibility remains treating the pregnant patient. However, the risks of withholding treatment to the mother because of possible risks to the fetus have to be considered as well.

Drugs also are grouped by their potential for misuse under British and U.N. legal classifications as class A, B, or C. The classes are linked to maximum legal penalties in a descending order of severity, from A to C.

Compliance may be defined as the extent to which the patient follows a regimen prescribed by a healthcare professional. The assumption that the doctor tells the patient what to do and then the patient meticulously follows orders is unrealistic. The patient is the final and most important determinant of how successful a therapeutic regimen will be and should be engaged as an active participant who has a vested interest in its success. Whatever term is used—compliance, adherence, therapeutic alliance, or concordance—physicians must promote a collaborative interaction between doctor and patient in which each brings an expertise that helps to determine the course of therapy. The doctor is the medical expert; the patient is the expert on himself and his beliefs, values, habits, and lifestyle. The patient's quality-of-life beliefs may differ from the clinician's therapeutic goals, and the patient will have the last word every time when there is an unresolved conflict.

Even the most carefully prepared prescription for the ideal therapy will be useless if the patient's level of compliance is not adequate. Noncompliance may be manifest in drug therapy as intentional or accidental errors in dosage or schedule, overuse, underuse, early termination of therapy, or not having a prescription filled (Hagstrom et al., 2004); therapeutic failures can result (Hobbs, 2004). Noncompliance always should be considered in evaluating potential causes of inconsistent or nonexistent response to therapy. The reported incidence of patient noncompliance varies widely but usually is in the range of 30-60% (Zyczynski and Coyne, 2000); the rate for long-term regimens is ~50% but can be impacted by pharmaceutical care management (Klein et al., 2009).

Hundreds of variables that may influence compliance behavior in a specific patient or condition have been identified. A few of the most frequently cited are discussed here, along with some suggestions for improving compliance, although none provides 100% compliance (Table AI–2).

The Patient–Provider Relationship

Patient satisfaction with the physician has a significant impact on compliance behavior and is one of few factors that the physician can directly influence. Patients are more likely to follow instructions and recommendations when their expectations for the patient–provider relationship and for their treatment are met. These expectations include not only clinical but also interpersonal competence, so cultivating good interpersonal and communication skills is essential. Cultural sensitivity is of growing importance, as healthcare providers see more patients from countries and cultures different from their own.

When deciding on a course of therapy, it can be useful to discuss a patient's habits and daily routine as well as the therapeutic options with the patient. This information may suggest cues for remembrance, such as storing a once-daily medicine atop the books on the bedside table for a patient who reads nightly, or in the cabinet with the coffee cups if it is to be taken in the morning (noting that the humid environment of a bathroom can be the worst place to store a medication in terms of its physical and chemical preservation). The information also can help tailor the regimen to the patient's lifestyle. A lack of information about a patient's lifestyle can lead to situations such as prescribing a medication to be taken with meals three times daily for a patient who only eats twice a day or a medication to be taken each morning for a patient who works a night shift and sleeps during the day. Rarely is there only one treatment option for a given problem, and it may be better to prescribe an adequate regimen that the patient will follow instead of an ideal regimen that the patient will not. Involving patients in the control of any appropriate aspects of their therapy may improve compliance, not only by aiding memory and making the dosage form or schedule more agreeable or convenient, but also by giving patients a feeling of empowerment and emphasizing their responsibility for the treatment outcome.

It is not unreasonable for the physician to ask the patient whether he or she intends to adhere to the prescribed therapy and to negotiate to get a commitment to do so. Attempts should be made to resolve collaboratively any conflicts that may hinder compliance.

Patients and Their Beliefs

Behavioral models suggest that patients are more likely to be compliant when they perceive that they are susceptible to the disease, that the disease may have serious negative impact, that the therapy will be effective, and that the benefits outweigh the costs, and when they believe in their own efficacy to execute the therapy. From the standpoint of compliance, the actual severity of and susceptibility to an illness is not necessarily an issue; rather, the patient's perception of severity affects compliance (Dijkstra et al., 2008).

Patients' beliefs can lead them to deliberately alter their therapy, whether for convenience, for personal experiments, because of a desire to remove themselves from the sick role, as a means to exercise a feeling of control over their situation, or for other reasons. This reinforces the need for excellent communication and a good patient–provider relationship to facilitate the provision of additional or corrective education when the beliefs would suggest poor compliance as an outcome.

It is difficult to predict whether a particular patient will be compliant, because there is no consistent relationship with isolated demographic variables such as age, sex, education level, intelligence, personality traits, and income. Certain of these variables have been implicated in specific situations, but they cannot be applied to the population as a whole. Social isolation generally has been found to be associated with poor compliance, although family members or other people close to the patient can undermine compliance as easily as they can support it. As noted above, the actual severity of the patient's disease is not predictive of compliance behavior, but characteristics of the disease can make adherence less likely, as with certain neurodegenerative or psychiatric illnesses.

Pharmacists have a legal and professional responsibility to offer medication counseling in many situations—even though practice environments are not always conducive to its provision—and can educate and support patients by discussing prescribed medications and their use. Because they often see the patient more frequently than does the physician, pharmacists who take the time to inquire about a patient's therapy can help identify compliance and other problems, educate the patient, and notify the physician as appropriate. Indeed, data from the Asheville Project indicate that a pharmacist-based medication management program provides significant advantages with respect to compliance, health outcomes, and cost (Bunting et al., 2008).

Elderly patients often face a number of barriers to compliance related to their age. Such barriers include increased forgetfulness and confusion; altered drug disposition and higher sensitivity to some drug effects; decreased social and financial support; decreased dexterity, mobility, or sensory abilities; and the use of a greater number of concurrent medicines (both prescription and over-the-counter) whose attendant toxicities and interactions may cause decreased mental alertness or intolerable side effects. There are drugs known to be inappropriate to prescribe to elderly patients (Curtis et al., 2004; Fick et al., 2003) and some that may adversely affect compliance. Despite these obstacles, evidence does not show that elderly patients in general are significantly less compliant than any other age group. Still, as the U.S. population ages, elderly patients will consume a disproportionate fraction of medicines and healthcare resources, so there is great opportunity and motivation to improve their drug-taking habits. Physicians must be careful in choosing medications for the elderly (O'Mahony and Gallagher, 2008; Lopez and Goldoftas, 2009). Pharmacists must pay particular attention to thorough and compassionate counseling for elderly patients and should assist patients in finding practical solutions when problems, such as polypharmacy, are noted.

The Therapy

Increased complexity and duration of therapy are perhaps the best-documented barriers to compliance. The patient for whom multiple drugs are prescribed for a given disease or who has multiple illnesses that require drug therapy will be at higher risk for noncompliance, as will the patient whose disease is chronic. The frequency of dosing of individual medications also can affect compliance behavior. Simplification, whenever possible and appropriate, is desirable.

The effects of the medication can make adherence less likely, as in the case of patients whose medicines cause confusion or other altered mental states. Unpleasant side effects from the medicine may influence compliance in some patients but are not necessarily predictive, especially if patient beliefs or other positive factors tend to reinforce adherence to the regimen. A side effect that is intolerable to one patient may be of minor concern to another. The cost of medicine can be a heavy burden for patients with limited economic resources, and healthcare providers should be sensitive to this fact (Restrepo et al., 2008). Mobile devices (e.g., iPhone) running drug formulary/therapeutic software now can provide the costs of medications, as can physicians who are familiar with the patient's insurance plan. Mobile phone systems that provide reminders and collect patient response information are being introduced and may become more popular as patients become increasingly tech savvy.

The era of e-prescribing has begun. Its implementation is still expensive, but the subsequent benefits to patients and savings in personnel costs, along with its integration with electronic medical records, drug inventory control, and billing, point to the wide use of e-prescribing in the future. Computerized prescription ordering eliminates some of the subjective features of prescribing. Thus, if the proper information is entered correctly in the electronic system, medication errors due to illegible handwriting, incorrect dose, incorrect medication for medical condition, and drug interactions can be reduced, because each prescription can be linked to high-quality drug databases that check that the information on the prescription is appropriate for the patient (e.g., age, weight, gender, condition, lab values, disease being treated, concurrent medications) and that known warnings and potential problems are brought to the attention of the physician, pharmacist, and patient. Such systems must not be used as a substitute for personal attention to the individual patient by healthcare workers but, rather, as an adjunct measure that ensures safe, high-quality, efficient care.