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INTRODUCTION

In 2013, deaths from an overdose of drugs achieved the dubious distinction of surpassing automobile accidents as the leading cause of accidental deaths in the United States (U.S.).¹ According to the Centers for Disease Control and Prevention (CDC), there were 43,982 drug overdose deaths in the U.S. in 2013, of which more than half (22,767 or 51.8%) were related to prescription drugs.¹ Nearly 3 out of 4 of the prescription-related deaths (16,235 or 71.3%) involved opioid analgesics, and 6,973 (30.6%) involved benzodiazepines. *The number of deaths from prescription analgesics represents a 4-fold increase since 1999.¹ The rate of opioid-related overdoses increased an additional 14% between 2013 and 2014, fueled by a surge in deaths caused by heroin use.²

Overdose deaths were not the only end point reflecting a troubling issue; emergency department visits involving misuse or abuse of prescription opioids also increased by 153% between 2004 and 2011, while admissions to substance-abuse treatment programs for prescription opioid-related abuse more than quadrupled between 2002 and 2012.³

Clearly, the abuse of prescription drugs, especially opiates, is a significant national public health issue and officials have responded to this crisis in a variety of ways. This manuscript will review the features of prescription drug abuse and the attempts to deal with this growing concern, with an emphasis on the rescheduling of controlled drugs.

* People who died of drug overdoses often were found to have ingested a combination of benzodiazepines and opioids, accounting for the value greater than 100%.

SCOPE OF PRESCRIPTION DRUG ABUSE

According to the 2014 annual survey conducted by the Substance Abuse and Mental Health Services Administration, 27 million people aged 12 years or older used an illicit drug within 30 days of the survey, corresponding to more than 1 in 10 Americans.⁴ The 2014 results were higher than those reported in every year from 2002 through 2013. The primary drivers for the illicit drug use were marijuana and the nonmedical use of prescription drugs. There were 22.2 million current marijuana users aged 12 years or older (i.e., users in the previous 30 days), and 6.5 million Americans were current nonmedical users of psychotherapeutic drugs, representing 2.5% of the population aged 12 years or older.⁴ Of these, 4.3 million people aged 12 years or older reported current nonmedical use of prescription analgesics in the U.S., with an estimated 2.1 million people experiencing substance use disorders related to the prescription opioid analgesics. By comparison, only an estimated 467,000 people were addicted to heroin.⁵

The economic cost of prescription opioid abuse in the U.S. was approximately $55.7 billion in 2007; 46% of the cost was attributable to workplace costs (e.g., lost productivity), 45% to health care costs (e.g., abuse treatment), and 9% to criminal justice costs.¹

It should not be surprising that the increase in nonmedical use of prescription drugs has coincided with a marked increase in the number of prescriptions written for opiate products. Opiate prescriptions increased from 76 million in 1991 to 207 million in 2013, a nearly 3-fold increase.⁵ The U.S. is the biggest global consumer of prescription opiates, accounting for 81% of the world total for oxycodone and, astonishingly, almost 100% of the world total for hydrocodone.⁵ Between 2007 and 2012, more prescriptions were written in the U.S. for hydrocodone with acetaminophen than for any other drug.⁶

The pattern of opiate prescribing varies among the states.⁷ In 2012, health care providers in the highest-prescribing states (i.e., Alabama, Tennessee, and West Virginia) wrote almost 3 times as many opioid painkiller prescriptions per person as those in the lowest-prescribing states (i.e., New York and California). These regional differences are even greater for individual drugs.⁸ For example, nearly 22 times as many prescriptions were written for oxymorphone in Tennessee as were written in Minnesota. Moreover, while opiate prescribing is generally higher in the South than in the Northeast, Maine and New Hampshire had the most prescriptions per person for long-acting and high-dose opiates.

Despite these marked regional differences in prescribing rates, the CDC notes that health issues associated with pain do not vary much from place to place and cannot explain the variability in prescribing.⁹ Some variables that may account for differences in prescribing rates are believed to include, on one hand, a lack of agreement among health care providers in different parts of the country on when to prescribe opioid painkillers and how much to prescribe and, on the other hand, doctor shopping and the presence of profitable, high-volume pill mills that prescribe large quantities of opiates for nonmedical use.

In response to this serious issue, regulators and governmental agencies have adopted various strategies to combat prescription drug abuse (TABLE 1).One type of strategy is the development of prescription opioids that incorporate abuse-deterrent technologies. From a more public policy point of view, the National Governors Association in 2012 undertook a strategic plan designed to develop and implement a comprehensive and coordinated approach to combatting prescription drug abuse.¹⁰ Of particular interest to pharmacists is the governmental plan to make better use of prescription drug monitoring programs, enhance enforcement efforts to clamp down on the most egregious cases of overprescribing (e.g., pill mills), develop best practices in pain management, use Medicaid and Workers’ Compensation claims to identify doctor shopping, ensure proper disposal of prescription drugs, and promote public education about prescription drug abuse. Pharmacists should also be aware that they share a corresponding responsibility with prescribers to ensure that controlled substances are dispensed only for a legitimate medical reason.

Table 1. Representative Strategies Taken to Restrict Prescribing and Abuse/Diversion of Prescription Opiate Drugs Rescheduling of drugs within the DEA categories Developing abuse-deterrent formulations Expanding use of prescription drug monitoring programs Eliminating "pill mills" and physician dispensing Using triplicate prescription forms Evaluating guidelines for pain management Promoting public education about the risks posed by prescription opiates Ensuring proper disposal of unused prescription drugs DEA = Drug Enforcement Administration

Another strategy that was recently implemented to contain the diversion of prescription drugs is the rescheduling of controlled substances (i.e., moving a controlled substance from one Drug Enforcement Administration [DEA] category to a more restrictive category). Scheduling was established by the implementation of the Controlled Substances Act (CSA).

CONTROLLED SUBSTANCES ACT (CSA)

The manufacture, importation, distribution, use, and possession of illicit substances are regulated at the federal level by the CSA, which was enacted in 1970.¹¹ The CSA was designed to reorganize previous efforts at drug control, which produced a piecemeal pattern of enforcement through agencies with different priorities.¹² The new law provided a systematic means of regulating narcotics and other dangerous drugs and was a comprehensive regulatory change granting greater control over and penalties for distribution of psychoactive substances, but also removed mandatory minimum prison sentences and provided more support for treatment and research.¹²

The CSA replaced the Harrison Narcotic Act, which was enacted in 1914.^13,14 The main purpose of the Harrison Act was to enforce treaty obligations to regulate international commerce in opiates. The law provided that manufacturers, pharmacists, physicians, distributors, and others be registered, pay a fee, and be required to keep records of drugs dispensed and prescribed.¹³ The Harrison Act was not designed to control behavior or medical practice and specifically stated that, "nothing contained in this section shall apply…to the dispensing or distribution of any of the aforesaid drugs to a patient by a physician, dentist, or veterinary surgeon registered under this Act in the course of his professional practice only."¹³

Registrants were only expected to keep records of drugs prescribed or dispensed. However, shortly after the enactment of the Act, law enforcement officials interpreted the law as a prohibition on prescribing opiates for the treatment of addicts and enforced the law accordingly, resulting in mprisonment of many physicians.¹³

The impetus to change laws based on the existing Harrison Narcotic Act was driven by the belief of then President Richard Nixon and Attorney General John Mitchell that the drug issue in the U.S. in the 1960s was getting out of control.¹¹ The CSA consolidated existing laws and treaty obligations and created a system where all parties authorized to handle controlled substances had to register with the DEA, thereby transferring enforcement from the Treasury Department to the Department of Justice, which is headed by the U.S. Attorney General (AG). Registrants were also responsible for maintaining records of inventories and transactions involving controlled substances and maintaining appropriate security.¹⁵

Drug Schedules

Placement of a drug into 1 of 5 existing schedules (C-I through C-V) is based on a drug's accepted medical use and its potential for abuse or dependency.¹⁵ However, the law specifically excludes the regulation of distilled spirits, wine, malt beverages, and tobacco, as well as nonnarcotic substances sold over-the-counter (OTC), if approved by the U.S. Food and Drug Administration (FDA). The AG may exempt other substances from the list if they meet certain criteria, including the following: products containing substances that may vitiate the abuse potential; products not intended for use by a human or animal; and products packaged in a concentration or that include adulterants whereby the substance does not present significant potential for abuse.¹⁶ The CSA requires the AG to consider 8 factors in making a determination that a drug should be scheduled (Table 2).¹⁶ The criteria include information about current patterns of abuse, dependence liability, and scientific information about the drug's pharmacology. The application of this standard will be discussed below.

Table 2. Factors That Must be Considered by the DEA Before a Drug Can be Scheduled15 The drug's actual or relative potential for abuse Scientific evidence of a drug's pharmacological effects, if known The state of current scientific knowledge regarding the drug or other substance The history and current pattern of abuse of the drug The scope, duration, and significance of abuse of the drug Risks, if any, to public health associated with the drug The liability of the drug for creating psychic or physiological dependence Whether the drug is an immediate precursor of another substance that is already controlled DEA = Drug Enforcement Administration

Schedule I (C-I) drugs are considered to have the highest potential for abuse, with the highest risk of severe psychological and/or physical dependence, and to be the most dangerous of the substances listed. In addition, Schedule I drugs are deemed to have no recognized medical use in the U.S. As the schedule number increases, the abuse potential lessens, so that Schedule V (C-V) drugs have the lowest potential for abuse. A list of drugs and their schedules can be found on the DEA Web site.¹¹ These lists describe the parent chemical and do not necessarily include all the derivatives, salts, isomers, and chemical forms of each substance. The DEA states that these lists are intended as "general references and are not comprehensive listings of all controlled substances."¹⁷

A substance can be subject to temporary scheduling as a C-I drug if it poses an imminent hazard to public safety.¹⁶ Examples where this type of interim regulation has been implemented are described later under Emergency Scheduling.

Although the intent of the CSA is to classify drugs on the basis of their abuse potential, the terms "abuse" and "potential for abuse" are not defined within the CSA. However, the legislative history of the CSA explains that a drug or substance "has a potential for abuse because of its depressant or stimulant effect on the central nervous system or its hallucinogenic effect" based on the following criteria¹⁸:

1. Individuals are taking the substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community; or
2. There is significant diversion of the drug or substance from legitimate drug channels; or
3. Individuals are taking the substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such substance; or
4. The substance is so related in its action to a substance already listed as having a potential for abuse to make it likely that it will have the same potential for abuse as such substance, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community.

The application of these criteria will be described in more detail below.

Process for Scheduling

A proceeding to add, delete, or change the schedule of a drug may be initiated by the DEA, by the Department of Health and Human Services (HHS), or by petition from any interested party, including the manufacturer of a drug, a medical society or association, a pharmacy association, a public interest group, a state or local government agency, or an individual citizen.¹⁶ When a petition is received by the DEA, the agency begins its own investigation of the drug. While the AG has the authority through administrative rulemaking to place a drug on the list of controlled substances or move a drug to a different schedule, there is a shared responsibility with other agencies. The AG must first request from the secretary of the HHS "a scientific and medical evaluation, and his recommendations, as to whether such drug or other substance should be so controlled or removed as a controlled substance."¹⁶ The HHS must consider the scheduling factors noted above and "include recommendations with respect to the appropriate schedule, if any, under which such drug or other substance should be listed."¹⁶ In doing so, the HHS solicits information from the FDA, the National Institute on Drug Abuse, and occasionally from the scientific and medical community at large.

The findings of the HHS regarding scientific and medical issues are binding on the DEA and if the HHS secretary "recommends that a drug or other substance not be controlled, the AG shall not control the drug or other substance."¹⁶ This means that if the HHS concludes that a drug does not pose a sufficient risk of abuse or danger to the public health, the drug cannot be scheduled. The AG also does not have discretion if an international treaty ratified by the U.S. mandates that a drug be controlled. The original version of the proposed CSA law would have given the discretion for making the necessary scientific and medical findings to the AG and an advisory committee appointed by the AG.¹⁹ The scientific and medical communities were concerned that complete authority for medical decisions would be given to a law enforcement agency and thus testified against the proposal. In the final version, Congress placed the responsibility for medical and scientific determinations in the Department of Health, Education, and Welfare (now HHS). In addition, other provisions of the bill and its legislative history specified that the CSA was not intended to interfere with either medical practice or the availability of these drugs for patient care.¹⁹

Once scheduled, the DEA has the authority to consider moving a drug from one schedule into another, either making it more or less strictly controlled (e.g., moving a C-III drug to Schedule II or Schedule IV), or it can place a drug that was previously unscheduled into a controlled drug category or remove a drug’s controlled drug designation, following the same process as described above. One recent example of the use of this approach in an attempt to reduce diversion is the upscheduling (i.e., moving into a more restrictive schedule) of hydrocodone combination products (HCPs).

Hydrocodone Combination Products

The DEA published its final rule on August 22, 2014, rescheduling HCPs from Schedule III to Schedule II.²⁰ Hydrocodone, without other added ingredients, became a Schedule II drug upon inception of the CSA in 1971, while combination products containing hydrocodone became Schedule III drugs at the same time. Typically, opiates that are combined with other non-opiate analgesics or that are used as antitussives are classified as Schedule III drugs.²⁰ A few months earlier (October 2013), the FDA approved Zohydro (hydrocodone), a single-entity, extended-release product, as a Schedule II substance. In 2004, a decade before the rescheduling finally occurred, the DEA submitted a request to the HHS for an evaluation of the available scientific and medical information and scheduling recommendation for HCPs. In 2008, the HHS recommended that HCPs remain controlled in Schedule III. In 2009, the DEA requested that the HHS reevaluate their data and provide another scientific and medical evaluation and scheduling recommendation based on additional information.²⁰

In 2012, a further impetus to reevaluate HCPs was provided by congressional action. The FDA Safety and Innovation Act was enacted, which included a section directing the FDA to hold a public meeting to "solicit advice and recommendations" pertaining to the scientific and medical evaluation of its scheduling recommendation to the DEA regarding drug products containing hydrocodone, combined with other analgesics or as an antitussive.²⁰ Additionally, the FDA was required to solicit stakeholder input "regarding the health benefits and risks, including the potential for abuse" of HCPs "and the impact of upscheduling these products."²⁰ In January of 2013, the FDA held a public Drug Safety and Risk Management Advisory Committee (DSaRM) meeting, at which the DEA made a presentation and provided an opportunity for the public to provide comment. As a result, 768 comments were submitted to the FDA by patients, patient groups, advocacy groups, and professional societies. The DSaRM ultimately voted 19 to 10 in favor of recommending that HCPs be placed into Schedule II and the DEA enacted the rule.²⁰

The HHS summary of its findings concluded the following: “1) Individuals are taking HCPs in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community; 2) there is significant diversion of HCPs; and 3) individuals are taking HCPs on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such drugs.”²⁰ The FDA added that comments from the DSaRM and the public supported the conclusion that, based on “the health benefits and risks, …HCPs have high potential for abuse.”²⁰

Many of the positive comments described personal experiences with loved ones who had a history of abuse and addiction and included the experiences of many youths and young adults who had tragically died as the result of the abuse and misuse of HCPs or other prescription opioids. The commenters indicated varied paths to abuse and addiction, sometimes beginning with a practitioner prescribing HCPs for treatment and other times by recreational use of pills that were available as a result of practitioner overprescribing. Many comments were of the opinion that controlling HCPs as a Schedule II substance would help prevent their abuse and diversion.

On the other hand, 41% of comments during the hearing opposed the proposal to reschedule HCPs. The majority of the opposition came from pharmacists, pharmacy students, and ultimate users. Of all comments submitted by pharmacists and pharmacy students, 60% were in opposition to the rule, and pharmacists and pharmacy students comprised 31% of the commenters in opposition. Comments submitted by ultimate users were overwhelmingly negative (91%) and comprised 14% of the comments opposed to rescheduling.²⁰

The comments opposed to rescheduling HCPs covered a variety of reasons. The HHS summarized these comments into the following general categories: 1) concerns regarding the authority of the DEA to reschedule HCPs; 2) concerns regarding prescribing practices; 3) concerns regarding patient access to pain relievers; 4) concerns regarding the impact on long-term care facilities (LTCs); 5) concerns that rescheduling HCPs will not prevent abuse or diversion; 6) concerns that rescheduling HCPs will increase provider and pharmacist workload; 7) concerns regarding the economic impacts on manufacturers, distributors, pharmacies, physicians, and ultimate users; 8) concerns that alternatives to rescheduling had not been explored and/or implemented first; and 9) concerns about the amount of time to comply with the rule.²⁰ Since the most relevant comments for pharmacists are probably the added burden on health care providers and the access of patients to pain medications, these will be addressed in more detail.

The DEA received a number of comments asserting that upscheduling HCPs would result in patients being limited to a 30-day supply of medication, which would necessitate monthly visits with their provider. Pharmacists and physicians expressed a belief that rescheduling HCPs would result in larger quantities of dose units being authorized on each prescription to prevent patients from running out of medication and being in pain. As a result, there was a concern that larger quantities of unused medication would be available for diversion. Similarly, the inability to refill a C-II drug could result in prescriptions for more potent medications being issued. The DEA responded with a reminder that the that a practitioner may issue multiple prescriptions for C-II drugs in order to provide up to a 90-day CSA does not impose limits on the quantity that may be prescribed on an individual prescription and supply of medication. Furthermore, the DEA stated, “regulations do not require patients to be seen monthly by their provider. Rather, practitioners must determine on their own, based on sound medical judgment and in accordance with established medical standards, how often to see their patients when prescribing controlled substances.”²⁰

The DEA also heard from pharmacists, physicians, ultimate users, and the general public, who were concerned about the increased administrative burden on pharmacists that might occur if HCPs were moved into Schedule II, including the need for separate prescriptions for every HCP; the need for pharmacists to count the C-II prescriptions because pharmacy technicians are not legally allowed to do so in some states; and increased workload associated with recordkeeping and inventory requirements.²⁰ There was concern that the extra time needed would occur at the expense of reduced time for patient counseling and safety. The DEA was not persuaded, responding that the “processes and procedures associated with dispensing a controlled substance are not relevant factors to the determination of whether a substance should be controlled or under what schedule a substance should be placed if it is controlled.”²⁰

Concerns were also expressed over triplicate prescriptions for C-II drugs, noting that emergency physicians do not typically carry nor do they want to carry triplicate prescription forms. This could result in less effective drugs being prescribed for pain management. The DEA noted that these currently are state requirements (i.e., for Texas, California, and New York) and not mandated by the CSA.²⁰

After reviewing the available data and considering the 8 factors and the public comments, the DEA concluded that the HCPs warranted placement into Schedule II. The DEA determined that this was justified because HCPs have a high potential for abuse, which is comparable to the Schedule II controlled substance oxycodone; abuse may lead to severe psychological or physical dependence; and HCPs have a currently accepted medical use in treatment in the U.S. (i.e., one of the major factors differentiating C-II drugs from C-I drugs).²⁰

Tramadol

A controlled substance may not only be subject to movement from one category to another, but a marketed, approved drug that is not in an existing schedule may be moved into one. An example of this is tramadol. The DEA placed tramadol in Schedule IV, effective August 18, 2014; the drug had been approved for use (non-controlled) in the U.S. in 1995.²¹

The DEA justified its decision by applying the 8-factor test (Table 2),²¹ and the analysis included several findings. First, health surveillance program data showed an increasing trend of emergency department visits between 2004 and 2010 (i.e., rising from 4849 to 16,251 in that period). Similarly, seizures of tramadol in the course of law enforcement activity also increased during the same period, exceeding seizures for pentazocine, already controlled as a C-IV substance.²¹

Second, tramadol shares many pharmacological properties with other opioids that were scheduled under the CSA, including reinforcing properties. The HHS concluded that the abuse potential of tramadol would be expected to be similar to other opioids, including diversion from legitimate sources and use without medical supervision.²¹ The opioid activity of tramadol is believed to be primarily caused by its metabolite, O-desmethyltramadol or Ml, and shows a longer action as a result of the accumulation of this active metabolite.²¹ The DEA noted that tramadol and Ml primarily bind to the mu-opioid receptor, which is the same receptor site for most opiates. The DEA also noted that, although tramadol has a weaker affinity for the receptor (i.e., 10-fold less potent than codeine and 6000-fold weaker than morphine [a C-II drug]), the Ml metabolite had high intrinsic efficacy at the human opioid receptors and was comparable to the relative intrinsic efficacy of both morphine and fentanyl.²¹ HHS concluded, therefore, that tramadol was similar to other controlled substances.²¹ Tramadol had already been classified as a controlled substance by several states before the DEA acted.

Illustrating the tension between preventing diversion and abuse on one hand and providing relief for patients with pain on the other, an association for consulting pharmacists opposed the rescheduling of tramadol, stating that controlling tramadol would limit access to needed pain medications for older adult patients, especially those in LTCs.²¹ Comments submitted to the DEA regarding the proposed rescheduling also indicated that many LTCs require that the prescriber phone or deliver orders for controlled substances. Therefore, making tramadol a controlled substance would necessitate that the facility track down the prescriber, who is often not an employee; this, in turn, may impede the delivery of the pain reliever to the patient. However, the DEA showed little concern for dispensing and responded, “processes and procedures associated with dispensing a controlled substance are not relevant factors to the determination whether a substance should be controlled or under what schedule a substance should be placed if it is controlled.”²¹ The DEA further reiterated that if a prescriber has determined that a controlled substance (schedules C-III, C-IV, and C-V) is medically necessary, an agent of the prescriber may phone or fax a prescription order for that controlled substance. A state Board of Pharmacy that supported the scheduling of tramadol concurred, writing, ‘‘scheduling a medication does not make it impossible to prescribe, dispense, and administer the medication. However, it does alert practitioners, dispensers, and perhaps even some patients that the medication has some potential dangers for addiction and misuse.”²¹

Emergency Scheduling

Not all reclassifications are associated with the high profile that hydrocodone possesses. Reactions to trends in the illicit use of previously uncommon drugs can also trigger changes in scheduling. The DEA may temporarily place a new drug into Schedule I, typically for a year, if it poses a threat to public safety, while the DEA determines whether the drug should be permanently controlled. An example is the scheduling of bath salts.

Bath salts refer to a family of drugs containing one or more synthetic chemicals related to cathinone, an amphetamine-like stimulant found naturally in the Catha edulis (khat) shrub that rapidly gained popularity as a legal high.²² Bath salts are typically comprised of 1 or more of 3 synthetic stimulants (i.e., mephedrone, 3,4-methylenedioxypyrovalerone [MDPV], methylone), which are reported to mimic the effects of cocaine, lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), and/or methamphetamine. The products reputedly produce euphoria and increased sociability and sex drive.²² They were marketed as bath salts or plant food or other seemingly innocuous entities and promoted under compelling trade names, such as Vanilla Sky, Ivory Wave, and Cloud Nine. The products usually carried the disclaimer "not for human consumption" in an attempt to avoid their inclusion within the CSA.²²

In 2011, the DEA used its emergency scheduling authority under the CSA to ban the sale of bath salts for a year.²³ The Synthetic Drug Abuse Prevention Act, enacted in 2012, placed 26 substances, including most of the known bath salts, permanently into Schedule I. Bath salts were already banned in 37 states at the time of the DEA's action.²³

State Programs

In addition to rescheduling, states have taken other approaches to try to reduce diversion.⁸ For example, many states, including New York and Tennessee, required prescribers to check the state’s Prescription Drug Monitoring Program before prescribing opiate analgesics. This resulted in reductions in the number of patients seeking multiple prescribers: a 75% decrease in New York and a 36% decrease in Tennessee. Florida began increasing its oversight of pain clinics and stopped the practice of health care providers dispensing painkillers from their offices. Florida saw a 50% decrease in oxycodone-related overdose deaths 2 years later.⁸

CONSEQUENCES OF RESTRICTIONS

Have restrictions on HCPs accomplished what supporters hoped and reduced the misuse of these drugs? A recent study reported that the rate of opioid prescribing in the U.S. stabilized between 2010 and 2012 (before the rescheduling of HCPs).³ Opioid prescribing within some medical specialties has decline, and some states and localities, where the most decisive action has been taken, have seen a decline in the rate of deaths from overdose.³

More directly, another recently published study examined data from the first year following the upscheduling of HCPs. The study reported that there were 26.3 million fewer prescriptions written for HCPs and 1.1 billion fewer HCP tablets dispensed in the U.S.²⁴ The authors attributed much of the change in dispensing to the lack of refills, since C-II drugs, unlike C-III drugs, cannot be refilled. There was a modest increase in non-HCP opiates dispensed during this period, but it did not offset the reduction in HCPs.

This mirrored an earlier result in Florida, which passed legislation in 2011 to address the proliferation of pill mills in the state by prohibiting physician office dispensing of C-II and C-III drugs.²⁵ Following passage of the legislation, overdose deaths caused by HCPs and oxycodone dropped by 22% and 51%, respectively.²⁵ It would appear that placing restrictions on prescription opioids can reduce their availability and risks of misuse. However, there are also concerns about unintended negative consequences of reducing HCP availability.

The Heroin Connection?

In addition to the increase in the abuse of prescription opiates over the past decade, the number of heroin users nearly doubled between 2005 and 2012, growing from 380,000 to 670,000,²⁶ while the number of heroin overdose deaths nearly tripled between 2010 and 2014.² There is a particularly great concern regarding heroin abuse because of the high risk of overdose and increased risk of intravenous (IV)-related transmission of HIV, hepatitis, and sexually transmitted infections. The overdose risk is compounded by the lack of purity and quality control of the injected products purchased illegally and the possible contamination with other drugs, including the highly potent opiate fentanyl. In 2010, there was a nearly 50% increase in fatal heroin overdoses when compared with the relatively stable level seen earlier in the decade and these outcomes have invaded suburban areas.²⁶ There has been some concern that the reduced availability of prescription opiates may have contributed to the increased abuse of heroin as a substitute for prescription drugs, particularly among young people.²⁷

It is reasonable to suggest that a reduction in the illicit supply of HCPs could prompt opiate addicts to seek other pharmacologically similar products. Data from the CDC show that that people who are abusing or are dependent on prescription opioids are 40 times more likely to be abusing or dependent on heroin.³ Similarly, several studies indicate that the pattern of opiate use has changed.

In the 1960s, more than 80% of addicts reported that their first opioid use was heroin; while in the 2000s, 75% of users initiated opioid use with prescription products.³ However, other lines of evidence fail to support the idea that a decreased supply of HCPs is the primary driver of the increase in heroin abuse. Recent evidence suggests that the shift toward heroin use among some nonmedical users of prescription opioids was already occurring before there was an emphasis on measures to curb prescription opioid abuse, including the upscheduling of HCPs and the introduction of abuse-deterrent formulations.³ Some other possible reasons for an increase in heroin use are that heroin has become cheaper, more potent, and more available than it has been in the past, prompting more people to use it.

An analysis of heroin purchases revealed that the purchase price fell in the 2000s compared with purchase prices of $1237 in 1992 and $2690 in 1982 (i.e., dropping as low as $465 in 2012).³ A recent study showed that a $100 decrease in the price of a pure gram of heroin is associated with a 2.9% increase in the number of hospitalizations for heroin overdose, which highlights the economic impact of its abuse.²⁸

Analysis of patterns of nonmedical use of prescription opioids suggests that abuse most often starts with oral dosage forms of opioids. Once dependence is established, tolerance to opioids develops and it becomes more costly to maintain abuse; many users then employ more efficient routes of administration, such as IV injection, insufflation, or smoking. Often these users graduate to heroin, usually through contact with other drug users, sexual partners, or drug dealers, finding heroin more potent, available and cost-effective than prescription opioids and easier to manipulate for the preferred non-oral routes.³

It is important to point out that only a small percentage of nonmedical users of prescription opioids initiate heroin use. A study²⁹ found that only 3.6% of nonmedical prescription opioid users became heroin users within 5 years after beginning the use of nonmedical prescription opioids. However, if only a small percentage of this very large population converts to heroin, it will inflate the number of heroin users by several hundred thousand.³

Effect on Pain Management

Another concern is that tighter controls of prescription opiates intended to prevent their misuse may also reduce access for patients with a legitimate need for pain control. This is a large population with an estimated 100 million people in the U.S. experiencing pain in a typical year, including 9 to 12 million people with chronic pain and others with short-term pain from injuries, illness, or medical procedures.³⁰

In a survey of health care practitioners conducted shortly before the rescheduling of HCPs took effect, more than two-thirds of the respondents believed that the rescheduling would reduce access to the drugs for patients with legitimate needs for treating pain, while more than half felt that there would be an increase in the use of less appropriate therapy.³¹ The American Dental Association has argued that HCP rescheduling would leave codeine as the only available C-III opiate pain reliever and that it is a less-than-ideal choice to relieve pain following dental surgery.⁶

The experience in Florida following the state’s efforts to better regulate the prescribing of opioids supports this viewpoint. After the enactment of more stringent regulations on opioid prescription drugs, patients with chronic pain reported both difficulty obtaining care from practitioners and encountering reluctance by practitioners to prescribe the high-dose opioids they had previously received. In addition, there are reports of pharmacists refusing to carry high-dose opioid products in their pharmacies and refusing valid prescriptions.²⁵

CONCLUSION

Abuse and diversion of prescription drugs, especially opioids, has become a serious public health issue and different strategies have been proposed to counteract this issue, ranging from developing abuse-deterrent formulations to regulatory changes, such as rescheduling. Pharmacists and pharmacy technicians should be aware of changes that can impact the profession and the workplace and monitor changes at both the federal and state levels.

Although not directly related to rescheduling, the pharmacist is also advised to pay attention to changes in opiate policy being considered in 2016 by the FDA, as well as recent prescribing guidelines issued by the CDC.³² These include creating clear guidelines for opiate use, reviewing labeling and post-marketing surveillance requirements, and prioritizing abuse-deterrent formulations, overdose treatments, the development of non-opiate pain relievers, and strengthened labelling for short-acting opioids.³⁰

REFERENCES

1. Centers for Disease Control and Prevention (CDC). Prescription Drug Overdose Data. CDC Web site. http://www.cdc.gov/drugoverdose/data/overdose.html. Accessed March 23, 2016.
2. Centers for Disease Control and Prevention (CDC). Increases in Drug and Opioid Overdose Deaths – United States, 2000-2014. Morbidity and Mortality Weekly Report (MMWR). 2016;64(50):1378-82. CDC Web site. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6450a3.htm?s_cid=mm6450a3_w. Accessed March 30, 2016.
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