Laws and Policies Affecting Pain Management in the United States

Aaron M. Gilson

James F. Cleary

Introduction

PREVALENCE OF UNRELIEVED PAIN IS A PUBLIC HEALTH PROBLEM

In The Mystery of Pain, poet Emily Dickinson wrote,

Pain has an element of blank;

It cannot recollect

When it began, or if there were

A day when it was not.

It has no future but itself,

Its infinite realms contain

Its past, enlightened to perceive

New periods of pain.^1(p650)

Dickinson’s description personifies pain and reveals that the pain experience, conversely, depersonalizes the sufferer. As intense and prolonged pain becomes a defining trait of someone’s life, pain and that person’s existence become intertwined—defining not only the present and future but also the past. This loss of self, coupled with constant suffering, sheds light onto why some people feel hopelessness because of unremitting pain.²^,³ Pain is, in fact, one of the most common physical complaints on a person’s admission into the health care system, and moderate to severe pain is frequently reported to be experienced throughout hospitalization, during treatment, and even after discharge. The Institute of Medicine (IOM) estimates that “at least 100 million Americans” live with chronic pain, including pain associated with the disease of cancer,⁴ and recent research suggests that the prevalence of pain in people with cancer can vary considerably, depending on chronicity, severity, and site of the disease.⁵ In addition, the national prevalence of chronic pain (defined as pain every day for the past 3 months) is estimated at approximately 11%, whereas around 16% reported a lot of pain or the most severe level of pain.⁶ The costs of pain, both emotional and financial, can be enormous.⁴ Untreated or undertreated severe pain from any condition or any stage of disease can limit a person’s functioning, productivity, and ability to interact socially; sometimes, pain destroys the will to live.² A recent study from the Johns Hopkins Center for Health Disparities Solutions and Department of Health Policy and Management indicated that cumulative US health care costs associated with pain exceeded $560 billion in 2010 and calculated an estimate ranging between $299 and $335 billion per year in lost productivity and wages.⁷ These estimates suggest that the financial cost of chronic pain has surpassed that of cancer, cardiovascular disease, or diabetes.⁷ Increasingly, unrelieved pain has been recognized as a significant public health problem in the United States.⁴^,⁸^,⁹

Issues of public health demand a public health approach to develop informed and organized responses to these health problems.¹⁰ A public health approach is intended to protect the community and enhance the health and quality of life of this population by making available effective and economical interventions.¹¹ Utilizing a social systems perspective, which incorporates input from various levels of the government (including administrative agencies), health care, education, and welfare systems, often is necessary to guide effective interventions.¹² As inadequate pain management becomes accepted as an important public health issue, efforts to rectify this situation will necessarily involve the systematic utilization of methods to measure outcomes of improved treatment. Some of the most frequent outcome measures, including reduction in pain scores and indicators of quality of life enhancement, must be considered alongside more long-term objectives that denote optimal levels of health status.¹³ Before such approaches and outcomes can be conceptualized and achieved, however, the numerous factors that can combine to result in unrelieved pain for patients with chronic diseases or conditions must be understood.

BARRIERS TO THE SAFE AND EFFECTIVE USE OF OPIOID ANALGESICS FOR PAIN MANAGEMENT

Unlike most countries in the world, the problem of unrelieved pain in the United States is not a function of needed medications being unavailable (see Chapter 16 for more detail about global medication unavailability). Patients who experience chronic severe pain still often do not have access to prescription opioid analgesics, which are considered essential medications for treating this level of pain.¹⁴ Of course, this does not mean that prescription opioid medications are to be considered the first-choice treatment option for every patient, a position that is apparent throughout this text, but rather one to be initiated and monitored when the clinical circumstances warrant.¹³^,¹⁵^,¹⁶ Access to effective pain management requiring prescription opioids is a direct function of the equity of health care services, and the reasons for inequity relate to a variety of issues.

Health care organizations and national experts suggest that a number of diverse factors can interfere with the legitimate medical use of opioid analgesics for the treatment of pain and can negatively affect patients’ access to safe and effective pain relief. Most studies have focused on issues in the patient or clinical domains, such as (1) patients’ and family perceptions about the use of opioids for pain relief¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶; (2) patients’ characteristics such as race or ethnicity, substance use history, or the community in which they live²⁷^,²⁸^,²⁹^,³⁰^,³¹^,³²^,³³^,³⁴; and (3) knowledge and attitudes of health care professionals about the legitimate use of opioids.³⁵^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹^,⁴²^,⁴³

When considering whether to treat pain with opioid analgesics, health care practitioners must determine how to maximize benefit and minimize harm,¹⁵ which they have generally not been trained to do.⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷ Such inadequate preparation contributes to an unfamiliarity with pain management in general and with relevant treatment modalities in particular, as well as inconsistent use of risk mitigation strategies for patients⁴⁸ and perceptions about regulatory or criminal sanctions resulting from prescribing the medications.⁴⁹ As a result, there remains an urgent need to enhance clinicians’ skills and confidence and to explore the motivations and challenges to get both practitioners and patients involved in activities promoting pain management services.

Many of the clinical and patient factors previously mentioned can contribute to the high prevalence of unrelieved pain in the United States, including characteristics of the health care system and health care professionals.⁵⁰ Restrictive federal and state policies relating to drug control and health care practice
(often referred to as regulatory barriers) also are recognized as potential impediments to pain management, especially considering the extent that practitioners know of and adhere to such policies. Since the early 1990s, national health care organizations have frequently voiced concern about the possible detrimental effects of regulatory barriers. In 1994, the Agency for Health Care Policy and Research (AHCPR) (now the Agency for Healthcare Research and Quality) published a clinical practice guideline on cancer pain relief, which recognized the existence of regulatory barriers, and recommended that laws and regulations aimed at preventing the abuse and diversion of opioids should not hamper their appropriate use in the treatment of cancer pain⁵¹; these messages were retained a decade later when the American Pain Society updated the guideline.⁵² Around the time of the AHCPR guideline dissemination, the National Cancer Institute sponsored a workshop to define priorities in cancer pain-related research that included policy and regulatory issues.⁵³ The American Cancer Society (ACS) later convened a Cancer Pain Management Policy Review Group to discuss regulatory challenges facing cancer pain management, with an emphasis on ensuring access to appropriate treatment given the national attention on the nonmedical use of pain medications. The Review Group developed several policy statements about various aspects of cancer pain management,⁵⁴^,⁵⁵^,⁵⁶ including a description of regulatory barriers affecting quality pain treatment.⁵⁵ Calls for studies to improve pain management and identify the legal and regulatory impediments to appropriately using opioids for pain relief have come from the ACS⁵⁴ as well as the IOM⁵⁷ and the National Institutes of Health (NIH).⁵⁸ For the United States, this involves an understanding and examination of both federal and state laws.

POLICIES GOVERNING THE USE OF OPIOID ANALGESICS FOR PAIN MANAGEMENT

Governments, at both the federal and state levels, can create and change public policies that influence the health of the population. Laws reflect governmental decisions that are largely influenced by social values but provide the legal basis for actions that affect public health, including pain management. For example, given the increasing recognition of pain relief as a basic human right,⁹^,⁵⁹ health care facility licensing regulatory standards (e.g., for hospitals, nursing homes, residential care units, and hospices) have even emphasized the pain care of their patients.⁶⁰ The World Health Organization (WHO) embraces the incorporation of human rights principles, acknowledging the need to “balance effective responses to disease risks” with respect for fundamental individual freedoms.⁶¹ However, a patient receiving effective pain relief currently is viewed more as a right in the moral sense but generally not in the sense of law or regulatory content.⁶²

Legislative bodies typically create laws (i.e., statutes) that are broad and general and depend on the relevant regulatory agency to interpret and implement the laws through regulations. In fact, legislatures that avoid making considerably detailed law would likely require less frequent amendments to such laws because the accompanying regulations contain the professional or technical details that would need to be revised periodically to keep pace with changing practice standards. For medicine, for example, the legislature grants authority to the state medical board to define and implement its laws through regulation (or administrative rules); regulations must be consistent with legislative provisions. Even given this structured process, pain-related law has not kept pace with advances in medical and scientific understanding. Although professional boards may revise their pain management policies in reaction to updated professional standards, legislation has been slow to change. This has particular implication for pain management, including opioid prescribing, where such legislation tends to have extensive detail and may not reflect current medical standards (see “State Pain Policy Development: An Emerging Trend” section for examples).

In late 2016, Pain Medicine published Daniel Carr’s President’s Message to the American Academy of Pain Medicine readership, entitled “Patients with Pain Need Less Stigma, Not More.”⁶³ According to Dr. Carr, who is the founding director of the Tufts Program on Pain Research, Education and Policy, the ubiquitous clinical scenario surrounding the treatment of patients with chronic pain (especially noncancer pain) is characterized by, among other things:

“Stigma—shaming and shunning—continues to befall patients with chronic pain, as do inequities in access to care.”^63(p1391)
“[The] most damaging barrier now facing patients with chronic pain [is] the unprecedented rise in illegal diversion and abuse of opioids, often involving prescription painkillers, with pervasive societal consequences from addiction, crime, overdose, and death … [despite the] general agreement that most patients prescribed opioids for chronic noncancer pain are not these problematic outliers.”^63(p1392)
“Practice guidelines put forth or proposed by different governmental agencies are not uniform, leaving prescribers uneasy that by prescribing opioids at any dose, to any patient, they place themselves in harm’s way … unleashing a torrent of blame and stigma directed towards all opioid prescriptions, prescribers, and patients.”^63(p1392)
“Increasing numbers of legitimate patients are voicing personal narratives of long-term benefit from a chronic modest dose of an opioid, now finding such care terminated by policies based upon administrators’ interpretations of group statistics never meant to guide individual care.”^{63(pp1392-1393)}

Within these statements, Dr. Carr recognizes that health care professionals must practice in an environment of legal and regulatory influences, one that can seem particularly ambiguous when it comes to chronic pain, opioid therapy, and risk of addiction or other serious harms. In such an environment, understanding current practice policy requirements is critical.

Although practitioners generally do not receive training in legal and regulatory issues related to prescribing of opioid analgesics and can be unfamiliar with the federal and state laws that govern their practice, there has been an increasing call for clinicians to acquire knowledge about the policies under which they practice.¹³^,¹⁶^,⁶⁴^,⁶⁵ This chapter attempts to create a resource to address this need by describing the three layers of laws in the United States that create the policy framework for both the diversion and legitimate medical use of opioid analgesics: (1) international treaties governing drug control; (2) federal laws and regulations governing drug control, which includes the legal parameters for prescribing controlled substances; and (3) state laws and regulations governing drug control and health care practice, including prescribing controlled substances. The chapter also discusses other policy considerations related to prescribing practices, highlights the need for communication and implementation as a means to improve practitioners’ understanding of policy requirements, and suggests the influence that diversion of medications can have on opioid-related harms.

International Treaties: Establishing Balance between Drug Control and Medical Use

Treaties form the basic legal framework to control international and domestic production and distribution of drugs—including medications—that have a recognized abuse liability. The drugs subject to these more rigorous controls are therefore referred
to as controlled substances and include, but are not limited to, opioid analgesics. The principal treaty establishing controls for prescription opioids used to treat pain is the Single Convention on Narcotic Drugs of 1961 (Single Convention).⁶⁶^,⁶⁷ It should be understood that the term narcotic, which includes opioid analgesics, is now primarily used in legal contexts, such as in reference to the international drug control treaty or relevant laws; narcotic, which generally is defined as an agent that produces stupor or insensibility, is not considered “useful in a pharmacological context” when describing opioid medications.^68(p486) The Single Convention establishes a number of basic requirements for a country’s laws and regulations to create effective measures against drug abuse and diversion. Many of these measures relate directly to the health care setting, including:

A country’s government must duly authorize everyone involved in the medical distribution of narcotic drugs (Article 30).
Opioid medicines are to be possessed with only legal authority—that is, a valid prescription issued to a patient by a properly licensed practitioner for a legitimate medical purpose in the usual course of professional practice (Articles 30 and 33).
All licensees are qualified and adhere to their obligation to prescribe and dispense controlled medicines in full and faithful execution of the law, as well as maintain records for medication manufacture, acquisition, and disposal (Article 34).⁶⁷

Although established as international law aimed at preventing drug abuse, this treaty also recognizes that many controlled substances are indispensable to public health and that there is a need to ensure their availability for legitimate medical and scientific purposes (United Nations,⁶⁷ Preamble). Becoming a party to this treaty obligates a government to take steps to make controlled substances available in adequate amounts to effectively treat medical conditions. Most, but not all, of the world governments are parties to the Single Convention, including the United States, which means that they formally accept the obligation to develop a legislative and administrative framework to implement the treaty’s objectives.⁶⁹

The long-standing dual obligation of country governments to (1) establish a system of controls to prevent abuse, trafficking, and diversion of controlled substances and (2) simultaneously assure their medical availability, is referred to as Balance.⁷⁰ Balance maintains that opioid analgesics, although designated as controlled drugs, also are essential medicines, are absolutely necessary for adequate pain relief, and must be accessible to patients who need them for medical purposes. Within this framework, the status of these medications as “controlled substances” is not meant to diminish their medical usefulness or create the perception that practitioners should avoid their use when there is a clear clinical indication. Moreover, the principle of Balance does not sanction medication use outside an established system of control, recognizing that only properly licensed health care practitioners can use opioid analgesics for legitimate medical purposes in the course of professional practice.⁶⁷ Governments that achieve and implement balanced policy continue to maintain an opioids supply sufficient to meet medical demand and empower practitioners to rationally prescribe, dispense, and administer opioids in the course of professional practice and in response to individual patient needs. With these efforts, it is clear that medication availability is supposed to be limited exclusively to medical and scientific purposes.⁶⁷

The International Narcotics Control Board (INCB), a United Nations-affiliated agency responsible for monitoring governments’ implementation of the Single Convention, has historically observed, and continues to note that the global medical need for opioid analgesics is not being fully met.⁷¹^,⁷²^,⁷³ Opioids remain insufficiently available to meet medical needs throughout the world for many reasons, including severely restrictive drug control policies⁷⁴^,⁷⁵^,⁷⁶^,⁷⁷^,⁷⁸^,⁷⁹; the real and overriding concern about drug abuse and addiction also has motivated the creation of laws that when put into practice hamper the appropriate medical use of opioids, including for the treatment of cancer pain⁷⁴^,⁷⁷^,⁸⁰^,⁸¹:

… the reaction of some legislators and administrators to the fear of drug abuse developing or spreading has led to the enactment of laws and regulations that may, in some cases, unduly impede the availability of opiates. The problem may also arise as a result of the manner in which drug control laws and regulations are interpreted or implemented.^71(p1)

More recently, such international organizations as the Council of Europe,⁸² the World Medical Association,⁸³ the WHO,⁷⁹ WHO HIV/AIDS,⁸⁴ the INCB,⁷⁵^,⁸⁵ the United Nations Commission on Narcotic Drugs,⁸⁶ and the United Nations Economic and Social Council⁸⁷^,⁸⁸ have called for governments to identify and address regulatory barriers in their narcotics control policies.

For example, a common requirement found in international drug control policies has been and continues to be the use of multiple-copy prescription forms (also commonly called “serialized forms”), which the Single Convention encourages when a country’s government considers such a control measure necessary or desirable (United Nations,⁶⁷ Article 30(2)(b)(ii)). This requirement typically involves the need for physicians to issue prescriptions using a special form so that a designated regulatory or enforcement agency can monitor the prescribing and dispensing of certain drugs. These forms are designed and enacted primarily to prevent forgery of narcotic prescriptions and can vary in type, from the use of prescription pads with counterfoil or carbon pages to an extreme where the physician must complete the same required prescription information repeatedly on a number of separate forms. Serialized prescription forms are government-issued, but they may be difficult to obtain and can increase the health care and social stigma associated with prescribing opioid medications.⁸⁹^,⁹⁰^,⁹¹^,⁹²^,⁹³ As early as 1990, the WHO Expert Committee on Cancer Pain Relief and Active Supportive Care addressed how special government-issued prescription forms can influence prescribing:

Record-keeping and authorization requirements should not be such that, for all practical purposes, they eliminate the availability of opioids for medical purposes. Multiple-copy prescription programmes are cited as means of reducing careless prescribing and “multiple doctoring” (patients registering with several medical practitioners in order to obtain several prescriptions for the same, or similar drugs). There is some justification for [this], but the extent to which these programmes restrict or inhibit the prescribing of opioids to patients who need them should also be questioned.^94(p39)

Some governments have concluded that multiple-copy prescription forms create burdens to physicians’ practice that can unduly limit access to covered medications, and have changed the requirements of these forms to respond to these problems—this has occurred in such countries as Austria,⁹⁵ Italy,⁹⁶ and Mexico⁹⁷ and in numerous states in the United States.⁹⁸^,⁹⁹ These positive programmatic changes are not meant to undermine the drug control capacities inherent in the serialized forms but rather to make it less likely that they hinder patient care. Other ways that countries have established overly restrictive drug monitoring and control systems include establishing extremely short medication supply limits (e.g., 3 days)⁹⁰^,¹⁰⁰^,¹⁰¹^,¹⁰²^,¹⁰³^,¹⁰⁴ and only allowing physicians with certain specialties to prescribe.¹⁰⁰^,¹⁰¹^,¹⁰²^,¹⁰³^,¹⁰⁵^,¹⁰⁶ Again, countries’ governments are addressing these potential barriers in law, which is described in detail in Chapter 16.

It is apparent that the international narcotics treaty is intended for drug control and to maintain drug availability for medical purposes, which the World Health Assembly⁵⁹^,¹⁰⁷^,¹⁰⁸^,¹⁰⁹
has historically reaffirmed. However, some countries have implemented the treaty too strictly, resulting in abuse/diversion mitigation while making the use of opioid medications for pain management difficult if not impossible.¹¹⁰ Given this reality, it may help to understand the current status of national laws and regulations. The next section describes the extent that the United States is meeting its obligation to prevent medication diversion and abuse while continuing its responsibility to ensure the appropriate medical use of opioid analgesics.

US Federal Law: Preserving Balance between Drug Control and Medical Use

THE FEDERAL FOOD, DRUG, AND COSMETIC ACT

Under the authority of the Federal Food, Drug, and Cosmetic Act of 1962 (FFDCA), the U.S. Food and Drug Administration (FDA), which is part of the U.S. Department of Health and Human Services, is responsible for promoting public health by ensuring that all medications, including opioids and other controlled substances, are safe and effective for human use.¹¹¹ The FDA’s approval decisions for marketing a particular drug always involve an assessment of the benefits and risks,¹¹² including its abuse liability. The drug manufacturer must provide to the FDA all relevant data related to safety by the time a new drug application is submitted.¹¹³ When the benefits of a drug are considered to outweigh its risks, and when the labeling instructions allow for safe and effective use, only then does the FDA consider the drug safe for approval and marketing.¹¹⁴ To further reduce opportunities for adverse events, patients also are expected to use the medications according to the prescriber’s instructions.¹¹⁵ Of course, use of any medication outside of the prescriber’s instructions, for nonmedical purposes, or absent medical supervision, undermines the safety profile of that medication and increases the likelihood of harms.

When reviewing a new drug application, or after the FDA approves a medication, a determination can be made that the manufacturer also must submit plans for a risk evaluation and mitigation strategy (REMS) to ensure that the benefits of the medication outweigh its risks.¹¹⁶ In the context of pain management, the FDA approved a shared class-wide REMS for long-acting (LA) and extended-release (ER) opioid analgesics in mid-2012, which has been updated with new products every year since¹¹⁷; as of this writing, this REMS program encompasses 65 separate generic or branded LA/ER products.¹¹⁷ In addition, a REMS for transmucosal immediate-release fentanyl (TIRF) products was begun in 2011 and subsequently has been applied to additional products, at this time covering a total of ten TIRF medications.¹¹⁸ Within the primary objective of REMS programs to enhance medication safety, there remains an explicit commitment to “enable patients to have continued access to such medicines by managing their safe use” (webinar statement).¹¹⁶

A REMS program contains steps to address morbidity and mortality and, according to law, requires a timetable to assess the strategy at 18 months, 3 years, and 7 years after the strategy is approved,¹¹⁹ whereas the LA/ER REMS specifically mandates that assessments be submitted to the FDA at 6 months and 12 months and then every year thereafter.¹²⁰ Again, the goal of the REMS relates to reducing serious adverse outcomes from the misuse and abuse of, as well as to ensure appropriate access to, the covered medications.¹²⁰ Two components comprise the adopted REMS: (1) a medication guide and (2) elements to assure safe use. A one-page medication guide is designed for each covered opioid product, either generic or branded,¹²¹ and are to be provided through the pharmacy when an LA/ER opioid is dispensed outside of a hospital setting. Elements to assure safe use are satisfied through voluntary REMS-compliant training for prescribers, with the training content conforming to learning objectives outlined in the FDA Blueprint.¹²² The learning objectives relate broadly to the consideration of medication-related risks and benefits throughout treatment, including during initial patient assessment; initiating, maintaining, or discontinuing opioid therapy; and counseling patients and their caregivers.¹²² In addition, the training is designed to improve practitioners’ general and specific understanding of LA/ER opioid medications.¹²²

Various methods are being used to enhance prescribers’ awareness of available REMS training opportunities, as a means to achieve explicitly defined performance goals.¹²⁰ Such methods include developing and maintaining a REMS-related Web site, sending letters to all practitioners registered to prescribe relevant medications, and requesting that informational letters be disseminated through state health care licensing and disciplinary boards (i.e., boards of medicine, nursing, and dentistry) as well as their national associations (i.e., the Federation of State Medical Boards of the United States [the Federation], the National Council of State Boards of Nursing, and the American Association of Dental Boards) and professional societies and associations.¹²⁰ Another important resource included in these methods is the availability of a one-page counseling document, which health care practitioners are expected to give to patients when treatment involves LA/ER opioids. It is clear that these LA/ER REMS characteristics conform to general programmatic elements defined in law to include a communications plan to health care practitioners about the medications, such as (1) sending letters, (2) disseminating information about the REMS to explain certain safety protocols or to encourage implementation by health care practitioners of applicable components of the REMS, and (3) using professional societies to disseminate information about serious drug risks and protocols to enhance safety.¹²³

Available research suggests, cumulatively, that implementation of REMS-compliant prescriber training contributes to increases in practitioner knowledge; better patient awareness of mediation risks; and lower occurrence of abuse, overdose, and death while not creating a barrier to appropriate medication access.³⁶^,¹²⁴^,¹²⁵ When searched on March 22, 2017, almost 80 REMS-compliant continuing education (CE) training courses were available either at no cost or for a nominal fee, some extending into 2018 (https://search.er-la-opioidrems.com/Guest/GuestPageExternal.aspx), whereas Cepeda et al.¹²⁵ indicated that more than 500 such courses were offered in 2013 and 2014. Despite these opportunities, proportionally few prescribers have completed REMS-compliant training.¹²⁵ Many reasons account for this low completion rate, including the voluntary nature of the training, participation in non-REMS-compliant CE training (which does not cover all of the content outlined in the FDA Blueprint), and incomplete documentation such as failure to submit a posttest evaluation and the prescribing of an LA/ER opioid in the last year.¹²⁵

The FDA is responsible for reviewing and sanctioning product labeling,¹²⁶ with the purpose of providing information for the patients’ safe and effective use of the medication.¹¹⁴ The FDA also has an obligation to ensure that postmarketing promotional materials are consistent with the approved labeling information.¹²⁷ Historically, the FDA’s statutory authority applied primarily to the evaluation of premarketing testing and, after drug approval, the agency’s role was limited. However, in September 2007, the FFDCA was expanded to comprise active postmarket risk identification for approved drugs.¹²⁸ Activities under this mandate include ongoing analysis of drug safety data from disparate data sources as well as adverse event surveillance using electronic data from the federal government (e.g., the FDA Adverse Event Reporting System) and the private sector (e.g., the Researched Abuse, Diversion and Addiction-Related
Surveillance [RADARS] system).¹¹⁴ Information from these sources can lead to safety-related label changes to address new safety data. For example, in 2013, LA/ER opioid medications underwent an indication revision. As a result, LA/ER opioids are no longer indicated for the treatment of moderate to severe pain but rather “for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.”¹²⁹ This change has the benefit of characterizing a more explicit clinical circumstance warranting opioid therapy and implicitly reinforces the standard that these medications are to be initiated only after other modalities have been at least considered and ruled out as unsatisfactory. Overall, the collaborative process engendered through the 2007 legislative change is designed to improve the quality and efficiency of postmarketing drug safety risk-benefit analysis and to allow for the public disclosure of safety and effectiveness data in a timely, systematic, and transparent manner.¹¹⁴

A potentially important contribution to the FDA regulatory process comes from a 2017 report from the National Academies of Sciences, Engineering, and Medicine on opioid medications and pain management.¹³⁰ The report contains a series of recommendations that, among other things, advises the FDA to conduct a full review of currently marketed and approved opioid products to further ensure the benefit and safety of those modifications both on patients and to public health.¹³⁰ Accomplishing this objective is further enhanced when the review is conducted within a framework of what is called a “comprehensive systems approach,” in which the following factors are urged to be considered:

“Benefits and risks to individual patients, including pain relief, functional improvement, the impact of off-label use, incident opioid use disorder (OUD), respiratory depression, and death;
Benefits and risks to members of a patient’s household, as well as community health and welfare, such as effects on family well-being, crime, and unemployment;
Effects on the overall market for legal opioids and, to the extent possible, impacts on illicit opioid markets;
Risks associated with existing and potential levels of diversion of all prescription opioids;
Risks associated with the transition to illicit opioids (e.g., heroin), including unsafe routes of administration, injection-related harms (e.g., HIV and hepatitis C virus), and OUD; and
Specific subpopulations or geographic areas that may present distinct benefit-risk profiles.”^130(pp6-26)

To the extent that this recommended approach is informed by available evidence that considers the benefit/risk profiles with those for whom the medications are indicated and prescribed, as well as those for whom the medications are not prescribed (e.g., use for nonmedical purposes), this would be a highly valuable and illustrative decision-making process. Another important consideration for an FDA review will be to ascertain whether the prescribing conforms to current practice standards, including patient risk stratification and ongoing treatment monitoring as well as whether patients were compliant with practitioner instructions or product labeling directions. Along with additional attention to illegal drug markets and diversion activity (see the “Taking Diversion into Account” section), there can be a more complete understanding of the degree to which demonstrated harms result from legitimate medical, compared to nonmedical, use.

Of course, prescribing decisions are part of medical practice. The FFDCA is intended neither to regulate medical practice¹³¹ nor to interfere with the authority of a licensed health care practitioner to use controlled substances for a legitimate medical purpose.¹³² It is the responsibility of the states, and not the US federal government to regulate professional health care practice. However, both the state and the federal government share drug control responsibilities.

US FEDERAL CONTROLLED SUBSTANCES LAW

Controlled substances laws provide an additional layer of control over the distribution of prescription drugs that have an abuse liability (i.e., using criteria related to the potential to produce psychological or physical dependence), establishing a closed distribution system to minimize their abuse, trafficking, and diversion. The federal Controlled Substances Act (CSA)¹³³ is part of the Comprehensive Drug Abuse Prevention and Control Act of 1970,¹³⁴ and is the principal drug control law in the United States and conforms to the international treaties—it establishes criminal penalties for the illicit possession, manufacture, and trafficking of controlled substances and prohibits their nonmedical use while, at the same time, recognizing that they are necessary for public health and that their medical availability must be ensured. The CSA creates a comprehensive regulatory framework designed to ensure that controlled substances are only produced and distributed through proper channels and for proper medical purposes. In fact, the CSA is a culmination of more than 50 pieces of federal legislation adopted since 1914 relating to drug control and diversion.¹³⁴

The CSA specifies five classification schedules for controlled substances, each carrying different penalties for unlawful uses. A drug’s medical usefulness and abuse liability form the basis for the decision to assign it to a particular schedule.¹³⁵ Schedule I drugs have no currently accepted medical use, no accepted safety for use under medical supervision, and a high potential for abuse (e.g., ecstasy; heroin, LSD, marijuana, methaqualone, and peyote) and are available only for scientific research. Drugs that have an FDA-approved medical use are placed in Schedules II through V according to potential for abuse in the following manner:

Schedule II medications have the highest potential for abuse and include such opioids as codeine, fentanyl, hydrocodone (including combination products since 2014),¹³⁶ hydromorphone, meperidine, methadone, morphine, and oxycodone (including combination products) as well as nonopioids such as short-acting barbiturates (e.g., pentobarbital), amphetamine, methamphetamine, methylphenidate, and cocaine.
Schedule III medications have a lower abuse potential than Schedule II drugs and include opioids such as dihydrocodeine and codeine combinations with aspirin or acetaminophen as well as nonopioids such as buprenorphine, intermediate-acting barbiturates (e.g., butalbital), and the synthetic cannabinoid dronabinol.
Schedule IV medications have a lower abuse potential relative to drugs in Schedule III and include opioids such as dextropropoxyphene, pentazocine, and tramadol as well as nonopioids such as benzodiazepines (e.g., alprazolam and diazepam), LA barbiturates (e.g., phenobarbital), and certain nonamphetamine stimulants (e.g., pemoline).
Schedule V medications have a lower abuse potential compared to drugs in Schedule IV and include compounds or preparations containing limited quantities of opioids such as codeine or opium, which may be used for over-the-counter preparations to treat cough or diarrhea, respectively, as well as antidiarrheals containing diphenoxylate and difenoxin, and pregabalin.

Under federal law, the Drug Enforcement Administration (DEA) is the primary federal agency responsible for enforcing the CSA and, thus, has regulatory authority over controlled substances. The DEA is an agency of the federal Department of Justice, headed by the attorney general of the United States.

To conduct research with, or manufacture, distribute, handle, dispense, administer, or prescribe, controlled substances, a person or business must be registered with the DEA (and, in some cases, also with the relevant state agencies).¹³⁷^,¹³⁸ Licensed and registered practitioners can prescribe, dispense, or administer controlled substances only for legitimate medical purposes and in the usual course of professional practice¹³⁹^,¹⁴⁰; the DEA and federal courts have interpreted this to mean that prescriptions must be issued “in accordance with a standard of medical practice generally recognized and accepted in the United States.”^141(p139) Registrants’ distribution of Schedule I and II controlled substances are made using a special order form (DEA Form 222) to monitor all transfers of these controlled substances within the “closed” system.¹⁴²^,¹⁴³

A number of federal standards are relevant to pain treatment involving controlled medications. For example, prescriptions for Schedule II medications must be written and may not be refilled,¹⁴⁴^,¹⁴⁵ whereas five refills are permitted for drugs in Schedules III and IV.¹⁴⁶^,¹⁴⁷

The requirement for a written prescription is additionally fulfilled through federal law’s allowance of prescribers to issue electronic prescriptions for Schedule II controlled substances¹⁴⁸; electronic prescriptions remain an option that is not designed to completely supplant written paper prescriptions. For this reason, pharmacists and health care facilities are required to have the technologic infrastructure to process e-prescriptions as a means to create a transparent environment that is auditable and DEA-compliant.¹⁴⁹ Regulatory requirements governing this process are quite elaborate. Every aspect of the technology requires certification by the DEA, such as supervised pre-enrollment, maintaining records, the cryptographic signing module, the authentication software and hardware, and the routing of the prescription to the pharmacies (with those pharmacies needing a certified technology platform).¹⁴⁸ Generally, many practitioner obligations involve maintaining information and transmission security, including the need to promptly report security breaches.¹⁵⁰ The same legal responsibilities exist when issuing electronic prescriptions as with hard-copy prescription forms for controlled substances, especially the need to issue for a legitimate medical purpose and in the course of professional practice. Clearly, electronic prescriptions must be issued in conformity to applicable laws, as with any other prescription. All states have modified their laws to accommodate this federal authorization,¹⁵¹ and as of January 1, 2015, about 70% of pharmacies and 4% of practitioners have the ability to issue electronic prescriptions for controlled substances (Rick Camp, marketing director of Surescripts, as a comment to HealthIT Buzz’s “The Electronic Prescribing of Controlled Substances Is on the Rise,” https://www.healthit.gov/buzz-blog/health-information-exchange-2/electronic-prescribing-controlled-substances-rise/).

Federal law also allows oral or faxed (but not electronic) transmission of prescriptions for Schedule II controlled substances in medical emergencies under specific circumstances,¹⁵² as well as for the partial dispensing and faxing (but not oral or electronic data transmission) of prescriptions under certain specific clinical circumstances.¹⁵³ There are penalties, both criminal and civil, for violating federal requirements.

Although prescriptions for certain controlled substances must be in writing, and refills are limited, the fact that a drug has been approved for medical use does not change when it becomes a controlled substance. This principle is conveyed by the CSA statement that

many of the drugs included within this title have a useful and legitimate medical purpose and are necessary to maintain the health and general welfare of the American people.¹⁵⁴

Overall, the legislative history, as well as language contained in the CSA itself (and its related regulations), makes it clear that efforts to prevent drug abuse and diversion are not to interfere with legitimate medical practice and appropriate patient care.¹⁵⁵

The Controlled Substances Act Ensures Availability of Controlled Substances for Medical Purposes

The CSA authorizes the DEA to establish production quotas for a number of opioids and other controlled substances as a means to stem diversion resulting from excessive unused supplies.¹⁵⁶ Such quotas also must maintain sufficient supplies to accommodate all medical and scientific needs as well as to establish and maintain reserve stock.¹⁴⁰ Despite this apparent standard, however, insufficiently low quotas have occurred for various controlled substances. For example, 30 years ago, the DEA set a very low quota for methylphenidate to restrict its production in an effort to control diversion.¹⁵⁷ As a result, the methylphenidate supply was inadequate to treat patients with attention-deficit/hyperactivity disorder and narcolepsy, which are legitimate medical uses. An official statement was promulgated in response to this action, establishing the principle of an “undisputed proposition” of drug availability:

The CSA requirement for a determination of legitimate medical need is based on the undisputed proposition that patients and pharmacies should be able to obtain sufficient quantities of methylphenidate, or of any Schedule II drug, to fill prescriptions. A therapeutic drug should be available to patients when they need it. To accomplish this, a smooth flow of distribution is required … the harshest impact of actual or threatened shortages falls on the patients who must take methylphenidate, not on the manufacturers to whom the quotas directly apply. Actual drug shortages, or even threatened ones, can seriously interfere with patients’ lives and those of their families.^{157(pp50593-50594)}

Following this statement, the DEA recalculated the methylphenidate quotas to accommodate its demand for medical purposes. The same situation later occurred for amphetamines as a treatment for attention-deficit/hyperactivity disorder.¹⁵⁸

The DEA has, over time, expressed a willingness to grant additional quotas for controlled substances necessary to treat medical conditions, including prescription opioids for pain.¹⁵⁹^,¹⁶⁰^,¹⁶¹ In fact, in response to concerns about natural disasters or other unanticipated situations resulting in prolonged interruption of medication availability:

DEA included in all schedule II aggregate production quotas, and certain schedule I aggregate production quotas, an additional 25% of the estimated medical, scientific, and research needs as part of the amount necessary to ensure the establishment and maintenance of reserve stocks. The established aggregate production quotas reflect these included amounts.^1(p59980)

However, the most recent proposed quotas have removed the 25% buffer that were in effect over the last few years, an action that some have interpreted to exemplify a potentially problematic supply reduction (see Anson¹⁶² for example). It is possible, though, that activities such as increased sales to meet prescription demand or product development will prompt the DEA to revise the quotas. Such quota revisions are indeed permissible under federal law.¹⁶³

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