lawceDrug Rescheduling and Controlled Substances

Release Date: October 1, 2013

Expiration Date: October 31, 2015

FACULTY:

Gerald Gianutsos, PhD, JD
Associate Professor of Pharmacology
University of Connecticut School of Pharmacy
Storrs, Connecticut

FACULTY DISCLOSURE STATEMENTS:

Dr. Gianutsos has no actual or potential conflict of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-13-027-H03-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

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Payment of $6.50 required for exam to be graded.

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To provide pharmacists with a greater awareness of the process of classifying a controlled substance into a schedule and a better understanding of recent efforts to reclassify selected drugs.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Distinguish the differences among the criteria for designating controlled drugs into different schedules.
  2. Identify how federal and state laws regulating controlled substances may differ.
  3. Describe the rationale and challenges in the wake of recent attempts to schedule previously nonscheduled drugs and to place controlled drugs into a different schedule.
  4. Recognize what reclassification can mean to pharmacists.


ABSTRACT: Pharmacists share with other health practitioners a legal responsibility to minimize diversion of controlled substances. Such diversion continues to be a serious problem. The regulation of controlled substances at the federal level is governed by the Controlled Substances Act, which classifies substances into one of five schedules based upon their abuse potential and public health risk. The list of substances and their placement on the schedules are subject to change due to agency or congressional action. In addition, an inconsistent patchwork of state regulations also affects their oversight. In order to properly comply with controlled substance regulations, pharmacists need to stay abreast of federal scheduling changes as well as changes within their own state.

In 2007, almost 3.5 billion prescriptions were dispensed in the United States, with controlled substances accounting for 380 million of these prescriptions, or approximately 11% of the total.1 Prescriptions for controlled substances increased 150% from 1992 to 2003, far outpacing the rise in the U.S. population during the same period.2 Unfortunately, not all of these prescriptions have been used for legitimate medical purposes. The diversion and misuse of controlled substances, especially opiates, sky- rocketed in the first decade of the 21st century, and remains a very serious problem today. The number of Americans abusing prescription drugs increased almost 2.5-fold from 1992 to 2005.2

Although the past few years have seen a leveling off of the abuse, surveys indicate that the nonmedical use of prescription drugs by persons aged 12-17 and 18-25 years is the second most prevalent type of illicit drug use, exceeded only by marijuana.3 It is estimated that 5% of the 18- to 25-year-old population was engaged in nonmedical use of prescription drugs in 2011 and that the majority of nonmedical users of prescription pain relievers belong to older age groups than those for most abused drugs. The data indicate that there have been 1.9 million or more new nonmedical pain reliever users each year since 2002 and that the number of persons with nonmedical pain reliever dependence increased from 936,000 in 2002 to 1.4 million in 2011.3

Pharmacists play a vital role in preventing diversion of controlled substances and have an affirmative responsibility, along with the prescriber, to ensure that controlled substances are appropriately dispensed and are only used for legitimate purposes. Familiarity with the scope of laws that regulate the use of controlled substances can help to lessen the impact of nonmedical use of prescription drugs as well as minimize potential sanctions against pharmacists.

Oversight of the use and distribution of controlled substances is a complex mixture of federal and state laws and regulations, which places a well-known burden on pharmacists. That there is a list of controlled substances is familiar to all pharmacists4; however, pharmacists need to recognize that the list is subject to change, with substances being added to or occasionally subtracted from it, or possibly becoming subject to more or less stringent control. Moreover, the list of controlled drugs in a particular state may be different from the federal list or from the list in an adjacent state. Therefore, it is necessary for the pharmacist to remain aware of the dynamic nature of regulatory oversight.

This manuscript will review the regulation of the controlled substances and examine recent efforts by states and the federal government to modify their restrictions in an effort to curb the diversion and abuse of substances. Some examples of recent and ongoing efforts to revise the regulation of the controlled substances will be included.

CONTROLLED SUBSTANCES ACT

The manufacture, importation, distribution, use, and possession of illicit substances are regulated at the federal level by the Controlled Substances Act (CSA), which was enacted in 1970.5 The CSA was designed to reorganize previous efforts at drug control, which produced a piecemeal pattern of enforcement through agencies with different priorities.6 The new law provided a systematic means of regulating narcotics and other dangerous drugs. While granting greater control over and penalties for distribution of psychoactive substances, it also removed mandatory minimum prison sentences and provided more support for treatment and research.6

The CSA replaced the Harrison Narcotic Act, which was enacted in 1914.7,8 The main purpose of the 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.7 The Harrison Narcotic 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."8 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 imprisonment of many physicians.7

The impetus to change the existing Harrison Narcotic Act–based laws was the belief by then President Richard Nixon and Attorney General John Mitchell that the drug problem in the U.S. in the 1960s was getting out of hand.5 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 Drug Enforcement Administration (DEA). They were also responsible for records of inventories and transactions involving controlled substances and had to maintain appropriate security. The CSA is administered by the DEA within the Department of Justice.9

Drug Schedules

Pharmacists are aware that drugs regulated by the CSA are classified into five categories or schedules. Placement into a particular schedule is based upon a drug's accepted medical use and its abuse or dependency potential.9 However, the law specifically excludes the regulation of distilled spirits, wine, malt beverages, and tobacco. Non- narcotic substances sold OTC (if approved by the FDA) are also exempted from the lists. The attorney general (AG) may exempt other substances from the list if they meet certain criteria. These include products that contain other substances that may "vitiate" the abuse potential, are not intended for use by a human or animal, or are packaged in a concentration or include adulterants whereby the substance does not present significant potential for abuse.10

The AG, as the head of the Justice Department, has the authority by rule to place a drug on a schedule due to its potential for abuse.10 The CSA requires the AG to consider eight factors in making the determination that a drug should be scheduled (TABLE 1).10 The criteria include information about current patterns of abuse, dependence liability, and scientific information about the drug's pharmacology.


In general, the abuse rate, potential public health risks, and medical value are the determinative factors that govern the placement of a drug in a particular schedule (see TABLE 2 for specific criteria).4,5 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. As the schedule number increases, the abuse potential lessens, so that Schedule V (C-V) drugs have the lowest potential for abuse. For example, the main difference between a C-I and C-II drug is its safety profile and whether there is a current recognition of its medical use in the U.S.


A list of drugs and their schedules can be found on the DEA Web site (TABLE 2).4,5 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."11

A substance can be subject to temporary scheduling for up to a year in C-I if it poses an imminent hazard to public safety.10 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 criteria12:

  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 med- ical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community.

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 concerned with drug abuse, a state or local government agency, or an individual citizen.10 When a petition is received by the DEA, the agency begins its own investigation of the drug. The DEA also may begin an investigation of a drug based upon information received from law enforcement laboratories, state and local law enforcement and regulatory agencies, or other sources of information.

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 HHS secretary "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."10 The HHS secretary 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." In doing so, the HHS solicits information from the FDA, the National Institute on Drug Abuse (NIDA), and occasionally from the scientific and medical community at large.

The HHS's findings on 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."10 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 must 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.13 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) and specified that its determinations were binding on drug control decisions made by the AG. 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.13

Anabolic Steroids

Against this backdrop, the inclusion of anabolic steroids in the CSA represents an anomaly in the law.14 Anabolic steroids are listed in C-III and are included not because of their psychological and dependence-inducing effects, the usual criteria for placing a drug on a schedule, but rather as a response to cheating in athletics. Placement in C-III consigns them to the same group as buprenorphine and codeine or hydrocodone combination products. In fact, the first congressional hearing in 1988 proposed placing methandrostenolone (Dianabol) into C-I.14

The FDA and NIDA review concluded that the steroids did not have psychoactive effects comparable to other scheduled drugs and recommended against including them within the CSA. Similarly, the American Medical Association (AMA) testified that scheduling steroids would not reduce diversion. Despite these doubts about the suitability of scheduling, steroids were placed into a CSA schedule by congressional action in 1990, rather than by the normal process of administrative action via the DEA. As noted, ordinarily a determination by the FDA that a drug should not be considered a controlled substance would preclude its being placed on a schedule.

Analogue Act

Congress enacted the Federal Controlled Substance Analogue Act in 1986 in an effort to close a loophole in the CSA that prevented prosecution for the manufacture of so-called "designer drugs." These drugs are chemicals with minor modifications of existing drugs of abuse (i.e., drugs not listed under one of the CSA schedules despite their pharmacologic similarities to known abused drugs). This change was in response to a proliferation in the 1980s of mostly black-market products made in small, clandestine laboratories, often by copying drugs that were developed from pharmaceutical research.15

Under the Analogue Act, a chemical is prohibited if it is "substantially similar" in structure and pharmacologic effect to a drug already prohibited by the CSA and can be regulated as a C-I drug. Prior to the Act, the DEA had to enact a rule banning each individual drug as it appeared on the market,15 a costly and time-consuming process that delayed getting these potentially dangerous materials off the streets.

PHARMACIST RESPONSIBILITY

The CSA provides a method to classify drugs and to impose certain requirements on those involved in the distribution system, but becomes flawed if health practitioners choose to circumvent its provisions. Pharmacists need to appreciate that the effort to minimize the diversion of prescription drugs is a shared responsibility among health professionals. Knowing that a drug is listed as a controlled substance is only the beginning. The CSA requires that a "valid prescription issued by a DEA- registered practitioner is required for dispensing a controlled substance. To be effective (i.e., valid), a prescription for a controlled substance must be issued for a legitimate medical purpose by a practitioner acting in the usual course of professional practice."16

Thus, a physician who prescribes a controlled substance that is outside of usual professional practice is writing an invalid prescription. A crucial feature that pharmacists need to consider is the DEA's interpretation of prescribing for the relief of an individual who is addicted. The law since the time of the Harrison Narcotic Act has been construed to mean that prescribing opioids for narcotic addiction is outside of the usual course of professional practice and, therefore, unlawful under the CSA, unless the physician is specifically registered in a narcotic treatment program to maintain or detoxify narcotic addicts. The definition becomes critically important. The CSA defines an addict as a person who "habitually uses any narcotic drug so as to endanger the public morals, health, safety, or who is so far addicted to the use of narcotic drugs as to have lost power of self-control with reference to his addiction."17 This definition does not make a clear distinction between chronic use for a legitimate medical purpose and illicit use. By contrast, the New York State Controlled Substances Act defines an addict as "a person who habitually uses a controlled substance for a non- legitimate or unlawful use, and who by reason of such use is dependent thereon."18

Why do pharmacists need to be concerned with the reason a prescription is written? The CSA goes on to say that "a pharmacist has a corresponding responsibility for the proper prescribing and dispensing of controlled substances."16 A pharmacist must "carefully review all purported controlled substance prescriptions to ensure that the prescription meets all of the legal requirements for a valid prescription," i.e., the prescription must be valid on its face and contain all necessary information for a prescription. In addition, "the pharmacist has a duty to inquire further as to any question surrounding the satisfaction of any or all of the legal requirements for a valid prescription depending upon the particular circum stances, including the requirement that the prescription be issued for a legitimate medical purpose by a practitioner acting in the usual course of professional practice. The pharmacist must be satisfied that the prescription is consistent with the CSA and DEA regulations before dispensing a controlled substance to the ultimate user."16

Thus, verifying that a seemingly valid prescription that is in a proper format and complies with all the information necessary for a prescription and verifying that it was, in fact, obtained from a licensed physician authorized to prescribe may not be enough to fulfill the pharmacist's responsibility if it is written for the wrong purpose.19

Although not a part of the federal law, many states place restrictions on the number of dosage forms of certain controlled substances, typically C-II or C-III drugs, which can be dispensed at one time.13 Typically, these restrictions are 100 to 120 dose units or a 30- to 34-day supply.

SCHEDULING IS NOT STATIC: RECLASSIFIED DRUGS

It should be apparent that the list of scheduled controlled substances is subject to change. A number of drugs have received recommendations for greater or lesser control. Some examples are provided below and summarized in TABLE 3.


GHB

Gamma-hydroxybutyrate (GHB, sodium oxybate) is a naturally occurring substance found in the central nervous system (CNS). The drug has a history of abuse and has been implicated in many cases of date rape. It also has value in treating narcolepsy and is prescribed for that purpose.20 This drug occupies a unique place in the DEA's regulatory scheme, being considered both a therapeutic agent and a serious public health concern. When prescribed as sodium oxybate, it is treated as a C-III drug. However, in 2000, the Hillory J. Farias and Samantha Reid Date-Rape Drug Prohibition Act placed GHB in C-I if it is used illicitly.21 This is an example of a drug that is listed in different schedules based upon its use and where the normal DEA review was bypassed by Congress. A number of states had already decided to control GHB in some way by the time Congress acted.

Carisoprodol

A recent example of the DEA initiating a schedule change is its treatment of carisoprodol (Soma). Carisoprodol is a centrally acting muscle relaxant that is metabolized to meprobamate, which is believed to be at least partially responsible for the effects of the drug and has barbiturate- like effects in vitro.22 Meprobamate is a once-popular sedative with a well-established history of abuse and is currently a C-IV controlled substance.22

In 2012, carisoprodol was reclassified as a C-IV controlled substance under federal law.23 In making this decision, the DEA analyzed data from the Drug Abuse Warning Network (DAWN), a survey of emergency room (ER) visits, and found that the frequency of nonmedical visits for carisoprodol (22.6 visits/10,000 prescriptions) was at least comparable to diazepam and higher than cyclobenzaprine.23 These ER visits most commonly occurred in individuals combining the drug with other substances, especially opiates, benzodiazepines, and alcohol. The FDA also determined that the drug was the cause of death in 88 cases in 2007. Moreover, the FDA and DEA concluded that the drug possessed pharmacologic activity similar to other known abused substances. Carisoprodol has affinity for the GABA-A receptor complex, a characteristic shared by both barbiturates and benzodiazepines.22,23 This combination of a public health risk and similarities to known drugs of abuse was justification for the reclassification. At least 11 states had already classified carisoprodol as a controlled substance at the time of the DEA's action, and it was also removed from the market in Norway in 2008.23

Opiates

Recently, the scheduling of opiates, especially hydrocodone, has been called into question, with a growing demand for more stringent regulation. In particular, the rescheduling of hydrocodone has been debated since 1999.24 In 2013, the FDA's Drug Safety and Risk Management Advisory Committee voted 19 to 10 in favor of reclassifying hydrocodone-containing compounds from C-III drugs under the CSA to C-II.25

Much of the discussion centered on the ease of obtaining a C-III drug with a high risk of abuse. During his testimony, U.S. Senator Joe Manchin (D–WV) quoted a deputy sheriff from his state describing the ease with which these drugs can be obtained and their value: "‘It seems any 18- to 25-year-old can go to any doctor, claim they have chronic pain, and get a recurring prescription for 120-plus of these pills per month.' And what they don't use themselves, they can sell for $10 to $30 each. It's about a dollar a milligram."25 This testimony, which likely comes as no surprise to pharmacists, highlights the trend toward rampant illicit use of prescription drugs discussed earlier. Other speakers provided examples of addicts visiting different ERs over the course of a weekend complaining of back pain and obtaining multiple prescriptions for hydrocodone, which could be filled at local pharmacies.25

On the other hand, the aftermath of rescheduling was described as a "Hobson's choice" in testimony by John Mendelson, MD, a physician and clinical professor of medicine at the University of California, San Francisco (UCSF). Dr. Mendelson testified that the prescribing of other C-II drugs with greater abuse liability and the use of illicit drugs will increase if the scheduling of hydrocodone becomes more stringent, along with a higher incidence of drug withdrawal in patients currently receiving hydrocodone.25 This illustrates the dilemma between the need to provide appropriate control to prevent diversion of opiates, while still meeting the needs of patients with severe pain.

In its analysis, the FDA concluded that hydrocodone combination products had less potential for abuse than other C-II products due to the presence of other non- narcotic substances as part of the product, which would limit their intake, thus reducing the abuse liability, and also bring about undesirable toxicity. In addition, the calculated "abuse ratio" (roughly based upon reported incidences per 10,000 prescriptions) was lower for hydrocodone combination products than other C-II drugs.24 Moreover, the FDA cited evidence that the hydrocodone-acetaminophen combination resulted in better pain relief than either substance alone. While not supporting up-classification, it concluded that educational efforts and prescription monitoring programs would be effective means of curbing the abuse. At this time, the burden is on Congress to initiate reclassification. (A reminder: If the FDA concludes that a drug's schedule should not be made more stringent, the DEA is prohibited from up-classification.)

Since the response from the DEA and FDA has been slow, in 2013 the Safe Prescribing Act was introduced, which would amend the CSA to make any substance containing hydrocodone a C-II drug.26 The congressional sponsors of the proposed act noted that ER visits linked to hydrocodone abuse rose from 38,000 in 2004 to more than 115,000 in 2010.27 They further claimed that 131 million hydrocodone prescriptions were written in 2010 and that hydrocodone addictions account for more than 60% of all prescription drug addictions. In the sponsors' judgment, the advantages gained by reclassifying hydrocodone as a C-II drug included the requirement for an original, written prescription, no refills, and harsher fines and penalties for traffickers, which they believe will reduce its diversion.28 (At the time this manuscript was being prepared, the proposed Act was referred to committee and was awaiting further action.)

EDITOR'S NOTE (10/25/13): The FDA has announced its intention to recommend that hydrocodone combination products be reclassified as Schedule II drugs, citing concerns about the abuse and misuse of opioid products. See: www.fda.gov/Drugs/DrugSafety/ucm372089.htm.

Emergency Scheduling

Not all reclassifications are associated with the high profile that hydrocodone possesses. Reactions to trends in illicit use of previously uncommonly used drugs can also trigger changes in scheduling. The DEA may temporarily place a new drug into C-I, typically for a year, if it poses a threat to public safety, while it studies whether the drug should be permanently controlled. Some recent examples follow.

Bath Salts: The term "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 khat plant that rapidly gained popularity as a legal high.29 Bath salts typically are composed of one or more of three synthetic stimulants (mephedrone, 3,4-methylenedioxypyrovalerone [MDPV], methylone). These substances are reported to mimic the effects of cocaine, LSD, MDMA (ecstasy), and/or methamphetamine. The products were reputed to produce euphoria and increased sociability and sex drive.29 Users also described impaired perception, reduced motor control, disorientation, extreme paranoia, hallucinatory delirium, and violent and psychotic episodes.29,30 The products 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 order to avoid their inclusion within the CSA.29,30

In 2011, the DEA used its emergency scheduling authority under the CSA to ban the sale of bath salts.30 The emergency action temporarily placed these products into C-I for 12 months while the DEA studied whether to permanently control them. The Synthetic Drug Abuse Prevention Act, enacted in 2012, placed 26 substances, including most of the known bath salts, permanently into C-I. Bath salts were already banned in 37 states at the time of the DEA's action.30

K2: The DEA took similar steps to control so-called "fake" marijuana in 2012.31 Smokable herbal products marketed as a "legal" form of marijuana became increasingly popular, especially among teens and young adults. These products, popularly known as K2 or spice, were readily available at retail outlets, in head shops, and over the Internet, and were often sold as incense or potpourri. They consist of plant material that has been coated with synthetic research chemicals that are claimed to mimic tetrahydrocannabinol (THC), the active constituent of marijuana. The DEA became aware of an increasing number of reports from poison control centers, hospitals, and law enforcement agents regarding these products, with reports that individuals who used them experienced serious side effects, including convulsions, anxiety attacks, dangerously elevated heart rates, increased blood pressure, vomiting, and disorientation. The DEA decided to place these products into C-I.31

Dextromethorphan (DXM)

Although previous sections of this manuscript have cited examples of drugs whose control has become more tightly regulated, this outcome is not always the case. DXM is a cough suppressant that is often abused, especially by teens and young adults who extract the active ingredient from cough syrups using recipes available on the Internet. Abusers describe varied effects ranging from mild stimulation to distorted perceptions and dissociative sedation, and deaths have been reported from misuse of DXM.32 Calls for tighter control of this OTC product have surfaced from many quarters.

Despite the problems of abuse, the FDA's advisory committee voted in 2010 against placing DXM in a controlled schedule, citing that it is a small problem in a limited age group and that the abuse has remained flat.33 However, some states have decided to schedule DXM, while others (e.g., Texas, North Dakota) have age restrictions on its sale, an alternative position endorsed by the advisory group.33

STATE REGULATIONS

States can also act to treat a drug as a controlled substance in the absence of action by the DEA or other federal agencies. As noted in some of the examples above, local conditions frequently cause states to take steps prior to efforts by the DEA. If a state chooses to deviate from federal law, it must be more restrictive.

Tramadol

A recent example of state action is the regulation of tramadol (Ultram). Tramadol is a weak mu opiate receptor agonist that also inhibits norepinephrine reuptake and has serotonergic effects.34 However, its main metabolite, O-desmethyltramadol, has a higher affinity for mu receptors. More than 2.5 million individuals over the age of 12 years reported nonmedical use of tramadol in 2011.35

Although unscheduled at the federal level, tramadol is considered to be a C-IV controlled substance in at least 10 states, among them Kentucky and Tennessee.35 Continuing this trend, New York placed tramadol (Ultram, Ultracet) into C-IV in 2013.36 As a result, it has become significantly more difficult to obtain tramadol in the state. Under New York law, C-IV substances are limited to a 30-day supply, require a hand-signed prescription on a New York State serialized blank, cannot be e-prescribed, and have a refill limit. It may be expected that other states will follow suit and place the drug into a schedule while awaiting further federal action. For this reason, pharmacists must be mindful of state activities that may affect previously noncontrolled substances.

What to Do About Marijuana?

While the DEA took action against fake marijuana in 2012, a particularly controversial issue that bears watching is the continuing effort to reschedule real marijuana. Marijuana is currently a C-I drug, and many attempts to reschedule the drug have surfaced since 1972. State legislatures have become increasingly more willing to legalize marijuana, particularly supporting the use of medical marijuana.36 In 2013, New Hampshire became the 19th state to do so, but at this time, state medical marijuana laws are in conflict with the federal law.37 These state initiatives have spurred new efforts to modify federal marijuana restrictions either by removing the drug from the controlled substances list entirely or at least relaxing its regulation and rescheduling it into C-II or C-III, so that it can be obtained with a prescription.

The DEA has thus far resisted these attempts, citing a high potential for abuse and limited existing clinical evidence for efficacy of marijuana in its most recent refusal,38 and these decisions have been consistently supported by the courts. Although discussion is beyond the scope of this lesson, an Appellate Court decision to deny a request for rescheduling had been appealed to the U.S. Supreme Court at the time this manuscript was being prepared,39 and the outcome will be significant.

SUMMARY AND CONCLUSION

Controlled substances represent a multilayered problem for pharmacists. Dispensing them carries different and more onerous regulatory requirements than noncontrolled substances, and there is a widespread concern about the growing problem of diversion of prescription drugs.19 The federal and state lists of controlled substances and the restrictions placed on dispensing these drugs are constantly evolving, and important changes can be expected in the near future. Potentially, the most noteworthy changes could involve hydrocodone combination products (becoming more stringent) and marijuana (becoming less stringent). Pharmacists share a responsibility to prevent the diversion of abused drugs and need to be familiar with what is considered to be a controlled substance.

REFERENCES

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