H. Lee Moffitt Cancer Center & Research Institute

Legal and Clinical Issues in Prescribing Controlled Substances

Introduction

This paper has three objectives. The first is to acquaint readers with the Controlled Substances Act (CSA) of 1970 and its implications for contemporary pain management in hospital, long-term care, and ambulatory settings. It is the author’s contention that most physicians are insufficiently familiar with the CSA and the Code of Federal Regulations (CFR) that elucidates it. Therefore, they practice with unsubstantiated fear of legal repercussions and a knowledge gap in an area of potential liability.

The second objective is to review problems with definitions and nomenclature relevant to this supplement’s discussions of pain management. The main premises are that physical dependence and addiction should not be confused and that individuals who seek controlled substances for relief of excruciating pain ought not to be considered the legal or clinical equivalent of people who seek them for nontherapeutic purposes. Some of our current nomenclature fails to meet the test of these and other related distinctions.

The third objective is to describe the consensus statement of the American Academy of Pain Medicine and the American Pain Society, The Use of Opioids for the Treatment of Chronic Pain.¹

The Controlled Substances Act of 1970

In the United States, the legislative history of what we now call controlled substances began early in this century. Prior to that, it was legal, for example, to drink cocaine-laced Coca-Cola in Atlanta. When the federal government enacted the first law regulating the sale and distribution of controlled substances in 1914, it was not for purposes of public health but for economic reasons: the original opioid regulation was a tax law designed to generate public revenue.

By the 1960s, however, concern began to mount about illicit international drug trade and the nonmedical use of potentially debilitating "addictive" drugs. Thus, in 1961, the United Nations opened for signature the Single Convention on Narcotic Drugs (UNSCND), the product of an overwhelmingly favorable vote of the General Assembly and to which, by now, virtually all 185 member states of the UN have subscribed. This multilateral treaty was an effort to codify in a single place the disparate bilateral and regional treaties on the production, distribution, and consumption of narcotics. It also created the International Narcotics Control Board (INCB), which maintains statistics on drug-related subjects and advises both the Secretary-General and member governments. The American Pain Society serves as an advisor to the INCB in its capacity as a chapter of the International Association for the Study of Pain, an authoritative nongovernmental organization (NGO) competent in the subject of the INCB’s jurisdiction.

The Preamble of the UNSCND points out the dual nature of opioids in these companion statements: "...medical use of narcotic drugs continues to be indispensable for relief of pain and suffering..." and "...addiction to narcotic drugs constitutes a serious evil for the individual and is fraught with social and economic danger to mankind..." In joining the Convention, each government acknowledges these two "faces" of opioids and is expected to use them as a guide to its own regulatory practices.

By 1970, illicit drug use had reached what the government considered crisis proportions in the United States. Concern over expanding drug importation, popularity of synthetic drugs, drug-related street crime and violence, the social use of drugs, and the Vietnam war experience with addiction both on the battlefield and within the protest counter-culture converged to inspire the CSA, the nation’s first comprehensive effort at drug regulation. It consolidated previously existing laws governing the manufacture and distribution of opioids, stimulants, central nervous system depressants, hallucinogens, anabolic steroids, and the chemicals used in the production of these controlled substances. It is found in Title 21, Section 801, of the United States Code and Title 21, Chapter 1300 of the Code of Federal Regulations.² The CSA assigned enforcement responsibility to the Drug Enforcement Administration (DEA). The specifics of the Act are summarized in the DEA’s Physician’s Manual of March, 1990, which is available from regional offices of the DEA.

In order to facilitate communication of the information that follows, much of which is in the arcane language of legislation and regulation, I have chosen to make liberal use of italics. The italicized font is used to indicate my emphasis and is not found in the reference sources. The reference style adopted by governments is also unique. The title, or major division of the regulation is listed first, followed by the accepted abbreviation of the reference, followed by the part, section, and paragraph. Thus, 21 CFR 1306.07(c) indicates that the reference is Title 21 of the Code of Federal Regulations, part 1306, section 0.07, paragraph c.

In addition to unifying previous laws, the CSA introduced the concept of scheduling drugs, including the clinically useful drugs of Schedules II through V (Table). Although the formal act of scheduling is conducted by the Attorney General of the United States on the recommendation of the DEA Administrator, both are bound by the recommendation of the Food and Drug Administration (FDA) Commissioner as to the scientific evaluation of the drug. The basis for scheduling, therefore, is the FDA recommendation regarding the safe and efficacious medical use in the United States, coupled with the data regarding abuse potential. The FDA’s final recommendation is usually not rendered, however, until the National Institute of Drug Abuse advises it on the "potential for physical or psychological dependence." Thus, the balance articulated in the UNSCND is reflected in US regulatory practice.

The CSA identifies three categories of "narcotic" drugs. The first is "opium, opiates, derivatives of opium and opiates" including their salts, esters, isomers, etc; the second is "cocaine, coca leaves, ecgonine" and their derivatives; and the third is "any compound, mixture, or preparation containing any quantity of any of the substances referred to" in the first two categories. Since this classification departs from that used in pharmacology, making "narcotic" a dual-use word, it is prudent to avoid the term in clinical discussions and patient notes. Use of the term "narcotic" clinically could possibly result in inadvertent exposure to inquiry. Due to this legislative redefinition, the term "narcotic" is now considered imprecise for clinical use and should not be used when the intent is to refer to opioids.

While there is generally little question about dispensing or administering opioid analgesics for acute pain, physicians frequently question the legality of treating patients on a long-term basis with opioids. Regarding control of chronic pain, the CSA stipulates circumstances under which a controlled substance may be administered. Controlled substances may be administered or dispensed "to persons with intractable pain in which no relief or cure is possible or none has been found after reasonable efforts" [21 CFR 1306.07(c)]. In the Physician’s Manual, the DEA states "Controlled substances and, in particular, narcotic analgesics, may be used in the treatment of pain experienced by a patient with a terminal illness or a chronic disorder. It is the position of the DEA that these controlled substances should be prescribed, dispensed, or administered when there is a legitimate medical need." Note that there are no limitations on the amount of drug or the time of treatment in this statement. This allows treatment of patients with opioids indefinitely, if indicated. Few physicians know this, however, and the DEA is often cited as an impediment to treating pain with opioids on a chronic basis.

The CSA contains a number of specific references to different uses of controlled substances for various purposes. In order to comprehend the intent of the Act, some digression into definitions is warranted.

Addiction is a neurobehavioral syndrome whose expression is subject to genetic and environmental influences and consists of a preoccupation with obtaining and using a substance, the compulsive use of the which places the user or others at risk of harm and inevitably results in a progressive decrease in quality of life.

Physical dependence is medically defined as a physiologic state of neuroadaptation, which is characterized by the emergence of a withdrawal syndrome upon abrupt dose reduction or cessation of the drug or upon the administration of an antagonist. This is an expected effect of chronic exposure to many controlled substances such as opioids and does not equate with addiction. Physical dependence implies nothing inherently about quality of life. In many chronic pain patients who are physically dependent on opioids, the quality of life is improved on a sustained basis as a result of the opioid treatment.

Unfortunately, the law blurs the distinction between addiction and physical dependence when it defines dependence, substituting the latter when the former is clearly implied by the legislative intent.

Without a special license as a Narcotic Treatment Program (NTP), commonly called a "methadone clinic," a physician may not administer or dispense a controlled substance for or to an addict for the purpose of maintaining the addicted state [21 CFR 1306.07(a)]. A physician or authorized hospital staff may, however, administer or dispense "narcotic drugs in a hospital to maintain or detoxify a person as an incidental adjunct to medical or surgical treatment of conditions other than addiction" [21 CFR 1306.07(c)]. There is an important point in this regulation in that it allows any physician, whether separately licensed as an NTP or not, to either maintain addiction or detoxify an addict in a hospital setting when the primary reason for hospitalization is not addiction. In any other setting, these activities are restricted to only those providers who are licensed as NTPs. Remember that this part of the law applies only to hospitalized patients and does not allow prescribing, administering, or dispensing medication for maintenance or detoxification to outpatients who are addicted. The CSA does allow, however, a physician to administer, but not prescribe, medication daily to an addict to prevent withdrawal for a period not to exceed three days while making arrangements for treatment [21 CFR 1306.07(b)].

The definition of maintenance treatment under the CSA is "dispensing for a period in excess of 21 days, of a narcotic drug or narcotic drugs in the treatment of an individual for dependence upon heroin or a morphine-like drug" [21 CFR 1301.02(h)]. Analgesic indications are clearly not considered here but rather maintenance of the addicted state. The law defines detoxification as "the dispensing¼a narcotic drug or narcotic drugs in decreasing doses to an individual to alleviate adverse physiological or psychological effects incident to withdrawal from the continuous or sustained use of a narcotic drug and as a method of bringing the individual to a narcotic drug-free state¼" [21 CFR 1301.02(e)].

For the clinician concerned with pain management rather than addiction treatment, these distinctions are fraught with potential dangers. If, for example, you are treating an ambulatory patient with opioids indefinitely for severe low back pain, you are less exposed if your notes read "opioid analgesia on a chronic basis" than "opioid maintenance." The issue is that long-term maintenance treatment is a concept that, by regulation and law, belongs not to analgesic intervention but to addiction treatment; clinical practice in the latter requires the special NTP registration. Once again, confusion of terms in patient records may create legal exposure. Given the subtle difference between the language of law and that of clinical practice, physicians need to be vigilant about saying what we mean and meaning what we say.

Because of the specificity of the law, a physician may use controlled substances for the treatment of intractable pain. Furthermore, if you have an inpatient addict whom you are treating for pain from a medical condition, you may also use maintenance doses or initiate detoxification. In these circumstances, your patient need not meet the "intractable pain" test. A physician may also treat an addict for pain if the primary reason for prescribing a controlled substance is documented to be a medical condition rather than the addiction. Remember, however, that while state law cannot be less restrictive than federal law, it can be more restrictive. Hence, before you treat such cases under the CSA, you need to know whether the state in which you practice has controlled substance laws that are more restrictive than those of the CSA.

In addition to hospitalized addicts and ambulatory patients who may be addicted or not, the CSA recognizes a third category of patient: the patient in a long-term care facility (LTCF). It defines such a facility as "a nursing home, retirement care, mental care or other facility or institution which provides extended health care to resident patients" [21 CFR 1306.02(e)]. For patients who meet these criteria, including those in Medicare-certified or state-licensed hospices, Schedule II drugs can be administered by intravenous, intramuscular, subcutaneous, or intraspinal routes on order of a prescription delivered by facsimile. The sole requirement is that the prescription specifies that the patient is a resident of an LTCF covered by the law. Prescriptions for Schedule II substances written for patients in an LTCF or a patient with a medical diagnosis documenting a terminal condition may be filled in partial quantities, including individual doses. The pharmacist, however, has a corresponding responsibility to assure that the prescription is for a terminally ill or LTCF patient.

There is an important difference between an order and a prescription. For hospitalized patients, you write an order for a Schedule II medication that is to be administered to or for an ultimate user either immediately or at specified intervals, beginning immediately or as needed. A prescription, on the other hand, is an order for medication to be dispensed to the patient for self-medication. These typically go to ambulatory patients or patients in the process of discharge from hospital, in either case to be obtained and self-administered later.

The law is explicit about a physician’s legal obligations when writing prescriptions for anyone who is not a resident of an LTCF. All prescriptions for controlled substances must, for example, "be dated as of, and signed on, the day when issued¼" [21 CFR 1306.05(a)]. A pharmacist may accept a prescription written on one date for filling on a later date, but it is unambiguously illegal to post-date a prescription. Additionally, while someone without a DEA Registration may write the prescription, the registrant-physician is responsible for its compliance with the CSA and must sign it by hand. A stamped signature likeness is not legally acceptable.

Physicians often discover with annoyance that pharmacists question the way in which prescriptions are written and presented. Two rules of thumb apply here. First, the pharmacist cannot countermand the content of an order but can rightfully challenge the way in which it was written. Second, just as the law controls the physician in prescribing controlled substances, so does it govern the pharmacist’s dispensing of it. In this sense, pharmacists are charged by law with a corresponding responsibility to ensure that the prescription is valid and intended as written. You are not being "pestered" if a pharmacist questions you about a Schedule II prescription. These inquiries are merely fulfillment of the pharmacist’s duty under the law. One should consider these a necessary and important collaboration to provide optimal care to our patients.

As is the case with patients in LTCFs, Schedule II prescriptions for ambulatory patients can be delivered by facsimile to the pharmacist, but there is a major difference: Whereas in the LTCF a facsimile is valid by itself for actual administration of the drug, a facsimile copy is insufficient for dispensing a Schedule II drug to an ambulatory patient. The facsimile can do no more than alert the pharmacist that your patient is en route with a specific prescription in the hope that it will have been prepared by the time of the patient’s arrival. Your dated and signed prescription must be presented to the pharmacist before the drug can be dispensed to the patient.

Prescribing controlled substances in emergency situations presents special problems. The Secretary of Health and Human Services has ruled that emergencies are "those situations in which the prescribing practitioner determines that: (1) immediate administration of a controlled substance is necessary, for proper treatment of the intended ultimate user, (2) that no appropriate alternative treatment is available, including administration of a drug which is not a controlled substance under Schedule II of the Act, and (3) it is not reasonably possible for the prescribing practitioner to provide a written prescription to be presented to the person dispensing the substance, prior to dispensing" [21 CFR 290.10]. In these circumstances, the physician may give an oral prescription for a Schedule II substance provided that the pharmacist makes a reasonable effort to identify the prescriber, if not known to them, and the amount is limited to enough of the substance to treat the patient during the emergency period. The prescribing physician is required by law to "cause to be delivered" an original prescription covering the amount necessary for the emergency period to the dispensing pharmacist within seven days. This prescription must have "Authorization for Emergency Dispensing" written on it. Given the knowledge we have of how to ameliorate withdrawal symptoms with drugs such as clonidine, the criteria for an emergency must be clearly documented.

With respect to Schedule II substances for ambulatory patients without terminal disease, a pharmacist may partially fill a prescription if his or her supply does not permit complete filling. If the remainder is not dispensed to the patient within the following 72 hours, however, the balance of the prescription is void and a new prescription will have to be written for the remainder.

Amid all the CSA’s specificity are two apparent oddities: Nowhere does it say when a Schedule II prescription expires, and there is no limit on the amount prescribed. Legally, therefore, a patient can be given a properly executed and signed prescription for a controlled substance and present it three years later for dispensing. Similarly, a patient can have a six-month supply of a Schedule II drug dispensed at one time. Some states, as previously noted, have more restrictive rules (vide infra).

For Schedules III and IV, the regulations are generally less strict. Prescriptions may be telephoned or sent by facsimile to the pharmacist, or the practitioner may simply walk up to the pharmacy counter and request that the drug be dispensed to the patient. It is the pharmacist’s responsibility to reduce the transaction to writing. Yet, while Schedule II prescriptions have no time limit, for Schedule III there is a six-month restriction. During that time, there may be as many as five refills. The authorization for refills can even be transferred to a second pharmacy (only once) within the six-month time limit. Beyond that time limit, if need still persists, a new prescription must be authorized by the practitioner, via any of the means listed above.

All of the preceding pertains to the CSA and federal regulations pursuant to it. States, as mentioned, may have more restrictive regulations. South Carolina, for example, has a system of dosage units for Schedule II drugs. The maximum amount of drug to be dispensed at one time is limited to 120 dosage units. A dosage unit is defined as the amount to be taken at one time (ie, the number of pills taken at once). This can lead to confusion for patients, physicians, and pharmacists, however, since "120 dosage units" is often misinterpreted as meaning 120 pills.

Nomenclature

Rarely is semantic precision as important as when dealing with questions of legal regulation and compliance. Yet, the continued imprecise use of terms related to abuse, dependence, and addiction still leads to substantial confusion in clinical care and in the medical literature on controlled substances.

To show the history of some of this confusion, consider the following information. In a paper designed to clarify substance abuse terminology published only 10 years ago, physical dependence was defined as a "physiological state of adaptation to a drug or alcohol, usually characterized by the development of tolerance to the drug effects and the emergence of a withdrawal syndrome during prolonged abstinence."³ Three factors hamper the current clinical applicability of this definition. First, relative to the characterization used, it blurs the distinction between drugs and alcohol. Second, few definitions are reliable when in their identifying components the word "usually" appears. And third, the issue of tolerance is misplaced here, as it is, in all probability, a separate clinical issue and is largely unrelated to physical dependence.

Tolerance exists when an increased amount of a substance is needed to maintain an effect or when a constant amount produces a decreased effect. Withdrawal is denoted by the development of a characteristic syndrome upon discontinuation, decrease, or reversal of a given substance, in which the same or a similar substance can be taken to avoid or relieve the syndrome.

Furthermore, the same source defines psychological dependence as "the emotional state of craving a drug either for its positive effect or to avoid negative effects associated with its absence." Cravings for various things are common and do not always connote dependence. Having offered these flawed definitions of both physical and psychological dependence, the authors go on to describe another term, "drug dependence," characterizing it as "a generic term that related to physical or psychological dependence, or both. It is characteristic for each pharmacological class of psychoactive drugs. Impaired control over drug-taking is implied."

The confusion, in light of our current knowledge, does not end here. Having to this point avoided the words addict and addiction, the authors then define an addict as a person who is "physically dependent on one or more psychoactive substances, whose long-term use has produced tolerance, who has lost control over his intake, and would manifest withdrawal phenomena if discontinuance were to occur." Whether or not this applies to street addicts is not in question here; but this definition of an addict does not apply accurately to persons under long-term opioid therapy for acute pain.

The American Psychiatric Association took a different slant on the definition of an addict problem in 1994 when it published the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).⁴ Avoiding the term addict, it defines the problem as substance dependence. A person is said to be substance dependent if he or she exhibits a maladaptive pattern of substance that leads to clinically significant impairment or distress, as manifested by any three of the following signal conditions occurring at any time in the same 12-month period: (1) tolerance, (2) withdrawal, (3) often taking the substance in larger amounts or over longer time than intended, (4) persistent desire or unsuccessful efforts to cut down or control use, (5) great deal of time spent in obtaining or using substance or recovering from drug use, (6) important social, occupational, and/or recreational activities given up or reduced because of substance use, and (7) continued substance use despite knowledge of persistent or recurrent physiological or psychological harm.

The overriding theme of the DSM-IV definition is "a maladaptive pattern of substance use leading to clinically significant impairment or distress..." (emphasis added). Too often, a practitioner merely runs down the checklist and concludes erroneously that individuals taking opioids for legitimate medical purposes are addicts because they meet three of the criteria.

This definition must be applied very cautiously to a patient on continued opioid treatment, under a physician’s supervision, for chronic pain. It may well be the underlying pain condition that causes abandonment of social or recreational activities. If the patient will go to great inconvenience to get drugs for relief, develops analgesic tolerance (which occurs very rarely in patients taking opioids for pain), or misses a work shift because of need to see a physician, that patient need not be labeled an addict.

Based on clinical observation and a careful study of the literature, the author prefers this conceptualized definition of addiction: a neurobehavioral syndrome whose expression is subject to genetic and environmental influences and consists of a preoccupation with obtaining and using a substance, the compulsive use of the which places the user or others at risk of harm and inevitably results in a progressive decrease in quality of life.

This is not to suggest that addiction never occurs as a result of analgesic treatment. Indeed, recently the American Society of Addiction Medicine devised a definition of addiction specifically for the context of opioid treatment for pain. It emphasizes dysfunctional use, with adverse consequences consisting of loss of control over opioids and preoccupation with obtaining opioids despite adequate analgesia.

Another concept that physicians need to be familiar with is that of opioid pseudoaddiction. A common clinical occurrence, this iatrogenic syndrome is the erroneous interpretation by a healthcare professional of a patient’s request for analgesia as drug seeking behavior for nontherapeutic purposes. It is not a diagnosis; that is, patients should not be labeled "pseudoaddicts" because it is not a feature of the patient. Rather, the term is a description of a clinical phenomenon that is an error or fault on the part of the practitioner. This situation is rectified when someone believes the patient and provides appropriate analgesia and thus the behaviors that were misinterpreted stop.⁵

This brief excursion into definitions, while it may seem to be no more than a semantic explication, should be taken as neither esoteric nor arcane. It is intended, rather, to alert the clinician to the importance of understanding and using precise terminology in our conversation, consultations, notes, and thinking.

American Academy of Pain Medicine/American Pain Society Consensus Statement

The American Academy of Pain Medicine is the only AMA-recognized specialty society of physicians practicing pain medicine. The American Pain Society is the US chapter of the International Association for the Study of Pain. It is composed of physicians, nurses, psychologists, and other healthcare providers and scientists who share an interest in the study of pain.

In 1996, the American Academy of Pain Medicine and the American Pain Society each adopted a joint consensus statement regarding principles of good medical practice that should guide the prescribing of opioids. The Statement was jointly released in 1997. It recommends that physicians observe five steps when prescribing opioids in order to both benefit individual patients and ensure compliance with the CSA.

Thorough Patient Evaluation. Before initiating opioid intervention for chronic pain management, the physician should conduct a thorough evaluation of the patient. This should ascertain the patient’s pain history, including previous diagnostic findings, previous interventions, and drug history. A directed physical examination should follow. Coexisting conditions should be identified and assessed.

Individualized Treatment Plan. Guided by the evaluation, the physician should devise a treatment plan tailored to the patient and the current problem. This should be concluded only after considering alternative treatment modalities. Use of opioids should be undertaken only after explanation of rationale, risks, and benefits. A written agreement specifying the conditions under which prescribing will continue may be helpful.

Consultation as Needed. Both prior to and during opioid therapy, the physician should consider consulting with other clinicians. Pain specialists, psychologists, addiction medicine specialists, and others may have valuable contributions to make to the individualized treatment regimen depending on both the original evaluation and the patient’s physiological and psychological reactions to treatment.

Periodic Review of Treatment Efficacy. Periodic assessment should be made not only of analgesic effectiveness, but also of functional status, opioid side effects, quality of life, and indications of misuse.

Documentation. Written records should support the reason for opioid treatment, overall treatment plan, reports of consultants, periodic reviews of patient status, and adjustments made in treatment plan. Given the strictures of the CSA, the need for documentation of opioid treatment can scarcely be overemphasized. It is not only a record of the patient’s treatment, but also a record of the physician’s compliance with the law that will be the most compelling evidence in case of a regulatory audit of analgesic practice.

Conclusions

It is now accepted that opioids can be useful for treating a variety of pain states, including those associated with surgery, trauma, cancer, cancer therapies, and chronic pain not associated with malignancy. Fortunately for patients, this is a time of great change in public and professional policy regarding the treatment of pain. Unlike many other aspects of medical practice, the use of opioids carries with it legal ramifications that require physicians to understand regulation and legal definitions. This paper is presented in an attempt to provide requisite understanding of both legal and medical definitions, applicable law, controlled substances regulation, and principles of good medical practice to allow the compassionate dedicated physician to adequately treat pain with opioids when it is clinically indicated.