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INTRODUCTION

One hundred seventy five. That is the estimated number of lives lost every day to drug overdoses in the United States (U.S.).¹ Tragically, drug overdose has become the leading cause of unintentional deaths in the U.S., surpassing even motor vehicle accidents.¹

According to the Centers for Disease Control and Prevention² (CDC), 68,400 drug overdose deaths occurred during the 12-month period ending in October 2017, up from 61,062 in the previous 12-month period (12% increase) and 43,982 in 2013. Pennsylvania led the nation with 5,535 deaths, compared to a low of 63 in Wyoming. New Jersey saw an astonishing 42.7% increase during the reporting period, while 9 states saw a decline.² Nearly two-thirds of these deaths (66%) involved a prescription or illicit opioid.³ The impact of the rise in overdose deaths is so pronounced that in 2016, life expectancy in the U.S. fell for the second consecutive year, for the first time since 1963, blamed at least in part on the surge in overdose fatalities.⁴

In addition to deaths, emergency room visits related to drug overdose increased 35% in 2017 in the 16 states most affected by the opioid epidemic.⁵ At least 2 states (Wisconsin, Delaware) reported more than a doubling over the previous reporting period.⁵ Moreover, it is estimated that 2 million people in the U.S. suffer from substance use disorders related to prescription opioid pain relievers, and 591,000 suffer from a heroin use disorder (not mutually exclusive).⁶ The economic cost from opioid overdoses alone is estimated to be more than $1 trillion for the period 2001 to 2017 and is expected to rise further, with health care costs accounting for $217.5 billion of the total.⁷

A problem of this magnitude is bound to attract attention from many arenas, including legislators and policy makers. In November 2017, the President's Commission on Combating Drug Addiction and the Opioid Crisis, appointed by President Trump, issued a 138-page report¹ and underscored the seriousness of the problem by asking this question: "If a terrorist organization was killing 175 Americans a day on American soil, what would we do to stop them?"¹ The Commission made 56 recommendations in many different areas to address the growing problem.¹

Pharmacists and technicians, as first-hand observers of the problem, should also ask themselves what role they can play to halt the crisis. This continuing education activity reviews the problem of drug overdose and examines some of the efforts taken to mitigate the problem.

THE PROBLEM

Death due to drug overdose, especially opioids, has been labelled as a national epidemic,⁸ and the White House declared opioid deaths a national public health emergency in October 2017.⁹ Opioid death rates showed increased alarmingly—more than 5-fold—between 1999 and 2016.³

Although the largest increase in opioid overdose death rates over the past decade was in males between the ages of 25 and 44, the meteoric rise in deaths cuts across all demographics, increasing in men and women, all races and ethnicities, all age groups over 15, urban and rural areas, and all geographic sectors of the nation.³ White women ages 55 to 64, a group most likely to see a health care practitioner with complaints of pain, have also experienced a substantial increase in accidental opioid overdose deaths.¹⁰ For heroin, the demographics have shifted over the past 50 years. While traditionally considered to be an inner-city, minority-centered problem, today it is more likely to involve white men and women in their late 20s living outside of urban areas.¹¹

CDC describes 3 waves contributing to the rise in opioid overdose deaths⁸ : The first wave in the 1990s was associated with an increase in overdose deaths from prescription opioids related to increased prescribing, fueled, at least in part by the observation that pain was being undertreated. The second wave beginning in 2010 resulted from a surge in heroin overdose deaths, and the third wave beginning in 2013 involving synthetic opioids, especially illicitly manufactured fentanyls.

Overall, drug overdose death rates increased by 21.5% in 2016 with larger increases in some regions of the U.S.³ Heroin and prescription opioid-related overdose death rates increased by 19.5% and 10.6%, respectively, while the overdose death rate from synthetic opioids (other than methadone) more than doubled.^3, Stimulants also had a major impact with death rates from cocaine and psychostimulants increasing by 52.4% and 33.3%, respectively, in 2016.³

Opioids accounted for more than 42,000 of the deaths in 2016.³ Of these, 45.9% involved fentanyl, 40.4% involved prescription opioids, and 36.6% involved heroin (multiple causes account for a total of more than 100%).^3,12 By contrast fewer than 5,000 opioid-related deaths involved fentanyl in 2010,² signaling a shift away from prescription opioids to heroin and synthetic drugs. Fentanyl was also a contributing factor in overdose deaths involving non-opioids drugs, and involved in 40.3% of cocaine-related overdose deaths, 31% of benzodiazepine-related overdose deaths, and 20.8% of antidepressant-related deaths.¹²

As a reminder for pharmacists and technicians, fentanyl is a synthetic opioid which is approximately 50 to 100 times more potent than morphine as a mu receptor agonist and higher than normal doses of naloxone are needed to reverse fentanyl toxicity, because of its potency. Other fentanyl analogs, such as sufentanil, alfentanil, remifentanil, and carfentanil also pose problems. In particular, carfentanil which is an astounding 10,000 times more potent than morphine, is emerging as a specific problem; a report from Ohio found that 8% of decedents tested positive for carfentanil, indicating that it is finding its way to the street with increasing frequency.¹³

A provisional report from CDC for 2017 indicates that a new record of 72,000 deaths may be anticipated when final data are collected, roughly a 10% increase from 2016.¹⁴ The expected toll will exceed the yearly historic peak death total from HIV, car crashes, or shootings.

History Repeats

Although the problem has reached unprecedented and disturbing levels, rampant drug abuse is not a new phenomenon. The first national opioid crisis is generally believed to have developed in the mid-to-late 19^th Century.^1,10 During this time, legal restraints that we are familiar with today did not exist, and with few if any active alternatives, physicians prescribed opiates (morphine, laudanum, paregoric, codeine, and heroin) liberally for pain or other ailments. Manufacturers also promoted patent medicines containing opiates aggressively.¹ In addition, Civil War combatants and veterans liberally received opioid-based treatments for injuries and diarrhea. In the 1800s, discoveries including methods to extract pure morphine from poppy and the hypodermic syringe were also important contributors to the crisis.¹

It is estimated that between 1840 and 1890, opioid consumption increased more than 5-fold.¹⁰ By 1900, 1 in 200 Americans were opiate addicts.¹ Eventually, the dangers were recognized and the response by physicians and pharmacists, coupled with medical education, restraint, and the advent of federal regulations and law enforcement quelled the epidemic.¹

In the 1960s, drug abuse again captured the nation's attention as drugs became "symbols of youthful rebellion, social upheaval, and political dissent."¹⁵ Then-President Richard Nixon declared in words reminiscent of what is emanating from Washington, D.C. today, that "America's public enemy number one in the United States is drug abuse. In order to fight and defeat this enemy, it is necessary to wage a new, all-out offensive."¹⁶ In the early 1970s, the tactics of the war included the establishment of the Drug Enforcement Agency (DEA) and the enactment of the Controlled Substances Act (CSA), which still regulates the manufacture, sale, distribution, and possession of abused substances.¹ The 1980s drug war was accompanied by a steep rise in incarceration of addicts under President Ronald Reagan fueled by First Lady Nancy Reagan's anti-drug "Just Say No" campaign and a growing public concern over the perceived mounting illicit use of "crack."¹⁵

The late 1980s and 1990s ushered in a number of other important changes that reverberate today. Prescribing of opiates accelerated, rapidly triggered by several factors.^1,10,17 In 1980, The New England Journal of Medicine published a letter that reported that chronic use of opiates for non-cancer pain posed relatively few risks of addiction.¹⁸ This widely cited reference, now considered low quality by most experts,¹⁹ resulted in expanded prescribing of opiates for pain. The development of potent, orally active, and long-acting opioid drugs, such as oxycontin introduced in 1995, further fueled this trend.^1,10

The medical community's view of pain management underwent a change during this period. The American Pain Society introduced a campaign entitled "Pain is the Fifth Vital Sign" in 1995 and encouraged more aggressive use of opioids for non-cancer pain.¹⁰ Similarly, Joint Commission on Accreditation of Healthcare Organizations, World Health Organization, and International Organization for the Study of Pain, among others, expressed the view that pain relief was a human right.²⁰ In 2000, Congress declared 2000 to 2010 the Decade of Pain Control and Research; its objective was to recognize a new emphasis on pain management and palliative care and it stated that "physicians should not hesitate to dispense or distribute controlled substances when medically indicated."²⁰ One consequence was a change in DEA policy permitting physicians to issue multiple prescriptions during a single office visit, up to a 90-day supply, increasing the prescribing and supply of prescription opioids, and, inevitably, diversion.

Against this backdrop, prescribing of opioid analgesics for the management of pain increased several-fold since the mid-1990s, apparently without a corresponding increase in reported pain.²¹ Between 1999 and 2002, prescriptions for oxycodone, fentanyl and morphine increased by 50%, 150%, and 60% respectively.²² In all, health care providers wrote 259 million prescriptions for opioid pain medication in 2012, equivalent to 1 prescription for every adult in the U.S.²³ More than 100 million prescriptions were written for the hydrocodone/acetaminophen combination alone in 2005, and it became the most prescribed drug for much of the decade.²⁴ Many of these prescriptions were diverted to illicit use, facilitated by unrestrained distribution, rogue pharmacies, unethical physicians, and patients whose legitimate opioid medications were stolen, or who sold them for profit.¹

In recent years, new trends have emerged. Notably heroin has become more available and cheaper and the potent, deadly fentanyls arrived,¹ transforming the foundation of drug overdose deaths away from prescription drugs to heroin and synthetic opioids.

The New Problem

Between 1999 and 2010, the annual rate of fatalities involving prescription opioids grew at an annual rate of 13.4% and represented the primary cause of overdose deaths. Between 2010 and 2016, fatalities involving prescription opioids increased by a much smaller annual rate (4.8%),^2,25 although total opioid deaths continued to exhibit a steeper rise, signaling a shift.

Over a comparable period, overdose deaths involving heroin rose by 4.1% annually between 1999 and 2010.²⁵ In 2010, 3,036 people died from an overdose involving heroin, while 10,943 died from a prescription opioid-involved overdose. However, since 2010, overdose fatalities involving heroin grew by 31.2% per year and in 2015, overdose fatalities involving heroin surpassed the number of fatalities involving prescription opioids, reaching almost 16,000 in 2017.²⁵

Heroin abuse is a problem not only because of the high risk of overdose but also the increased risk of intravenous (IV)-related transmission of HIV, hepatitis, and sexually transmitted infections. When individuals purchase injected products illegally, overdose risk is also compounded by their lack of purity and quality control and possible contamination with other drugs, including the highly potent fentanyls. A major concern is 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 has fallen markedly since the 1990s, perhaps as much as 60%.²⁶ Anecdotally, the price of a bag of heroin on the street is comparable to a pack of cigarettes.

More recently, the main culprit has evolved again to synthetic opioids, notably fentanyl and its analogs. The rate of drug overdose deaths involving synthetic opioids (other than methadone) increased by 88% per year from 2013 to 2016, doubling in 2016 compared to 2015.² In 2016, synthetic opioids became the most common opioid type involved in all opioid overdose deaths. The trend continued in 2017 with preliminary estimates from the National Center for Health Statistics reporting more than 27,000 overdose deaths from synthetic opioids for the 12 months ending November 2017,^14,25 accounting for more than half of all opioid overdose deaths.

These potent opioid receptor agonists have become a major public health concern.¹ Much of the fentanyl involved in lethal overdoses is illicitly manufactured and imported from China, often arriving through Mexico.¹ Fentanyls are frequently mixed with or substituted for heroin, often without the user's knowledge, and are more likely to be lethal because of their potency. Emergency first responders, medical and law enforcement personnel, medical examiners, and prosecutors face the challenge of treating and investigating intoxications and deaths from novel compounds whose identities are often unknown and for which analytical standards do not exist.¹ Many novel compounds do not appear in routine assays and may escape detection when a simple assay is used to identify a street drug overdose that is contaminated with fentanyl analogs, hindering appropriate identification and treatment.¹ Moreover, illicit fentanyls may be mixed into street supplies of benzodiazepines and cocaine, likely contributing to increases in overdoses involving these other substances.¹³ Since powdered fentanyl can be inhaled or absorbed through the skin, it also poses risks to first responders.

Synthetic drugs other than fentanyls are also emerging as problems. For example, deaths caused by U-47700 ("Pink"), a synthetic opioid 7.5 times more potent than morphine originally developed by Upjohn in the 1970s but never approved by U.S. Food and Drug Administration (FDA), have been increasing.¹³ Other opioid-like compounds being found in street samples include:

• the kappa agonist U-50488, desomorphine ("Krokodil," the street name for a homemade cheap heroin substitute used in Russia that turns the skin green and scaly with chronic use because of damage at the injection site)
• tapentadol (Nucynta, with a mechanism similar to tramadol)
• salvinorin A (the main psychoactive molecule form the Salvia plant), and its analog herkinorin.¹

Fault?

Many factors have contributed to the rise in drug overdose deaths (Table 1). The upward trajectory in prescriptions for opiate analgesics is often blamed for the rise in drug overdose deaths at least during the early part of the 21^st Century.¹⁰ Opioid use increased gradually during the 1980s and began a sharp upturn in 1996, 1 year after the introduction of OxyContin, an extended release formulation of oxycodone by Purdue-Frederick.¹⁰ The manufacturer promoted OxyContin to health care practitioners as a less addictive pain medication that was less subject to abuse and diversion and less likely to cause tolerance and withdrawal.²⁷ Purdue aggressively promoted the use of OxyContin to treat non-cancer pain.¹⁰ Prescriptions for the drug to treat pain grew 10-fold between 1997-2002, despite a lack of evidence demonstrating clinical superiority.²⁸ The excess supply of prescription opioids lent itself to misuse and diversion. Roughly 21% to 29% of patients who are prescribed opioids for chronic pain misuse them.⁶

Patterns of nonmedical use of prescription opioids suggest that abuse most often starts with oral dosage forms. 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 (blowing substances into the lungs), or smoking. Often these users graduate to heroin, usually through contact with other drug users, sexual partners, or drug dealers. They often find heroin more potent, readily available, and more cost-effective than prescription opioids. It is also easier to manipulate (than manufactured tablets) for the preferred non-oral routes of administration.²⁶

Data indicate that among young, urban heroin users, 86% had used prescription opioids prior to using heroin (but not necessarily legally obtained by prescription. Moreover, over the 10-year period from 2002 to 2012, individuals who reported prior non-medical use of prescription analgesics had a 19-fold higher incidence (0.39% compared to 0.02%) of starting heroin than among those who did not.^11,29

These observations point to prescription opioid misuse as a contributor to higher risk of heroin abuse, but are not necessarily an indication that the surge in heroin addiction is coming from patients progressing from legitimate treatment for pain.²¹

A study looking at oxycodone abuse in patients admitted to treatment centers found that 78% of patients were not prescribed the drug for any medical reason and 86% acknowledged that they acquired the drug only to "get high." Most users obtained the drug from illicit sources rather than prescriptions from physicians. The authors concluded that the drug is most frequently obtained from nonmedical sources as part of a broader and longer-term pattern of multiple substance abuse.³⁰

An analysis of the sources of diverted drugs found that the most common means of obtaining prescription drugs were dealers, sharing or trading among individuals, deceiving legitimate medical practitioners, illegitimate medical practice (e.g., pill mills), and theft, in that order.¹¹ Another study²⁹ of injection drug users (largely young, white males) found that most had used opioid pain relievers nonmedically prior to using heroin, most commonly hydrocodone/acetaminophen), oxycodone, and oxycodone/acetaminophen. The most common sources of the drugs were pilfering a family member's prescribed drug, misuse of their own prescribed opiate or, most commonly, acquiring the drug from family or friends, often in a group setting.⁴¹

It is important to point out that only a small percentage of users of prescription opioids initiate heroin use. An estimated 4% to 6% of people who misuse prescription opioids transition to heroin.^6,30 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.¹¹

WHAT IS BEING DONE?

Several different strategies are being implemented to try to limit the availability and improper use of prescription opiates (Table 2). The President's Commission also makes 56 recommendations (see reference 1). Some of these approaches will be reviewed here.

Rescheduling

One recent example of an approach to reduce diversion is upscheduling (i.e., moving into a more restrictive schedule of the CSA). In August of 2014, DEA rescheduled hydrocodone combination products (HCPs) from Schedule III to Schedule II.³¹ Typically, powerful opiates combined with other ingredients that presumably will reduce abuse liability are placed into Schedule III, while the single ingredient form of the drug is placed in Schedule II. This guideline was followed for hydrocodone upon inception of the CSA in 1971.³¹

As the prescribing of HCPs began to spike, DEA received many comments expressing concern from different sources including Congress and began reconsidering the placement of HCPs.³¹ After reviewing the available data and the public comments and evaluating the "eight factor test," the criteria used for determining scheduling, DEA concluded that the HCPs warranted placement into Schedule II. DEA determined that this was justified because

• HCPs have a high abuse potential, comparable to the Schedule II controlled substance oxycodone
• Abuse may lead to severe psychological or physical dependence
• HCPs have a currently accepted medical use in treatment in the U.S. (i.e., 1 of the major factors differentiating C-II drugs from C-I drugs).³¹

With the transition of the overdose problem away from prescription drugs to heroin and the fentanyls, upscheduling will probably not accomplish much more, at least for opioids. It could be a strategy to suppress the rise in abuse of non-opiates such as gabapentin.

Treatment Guidelines

Greater awareness of the risks of the opiate dependence from prescription drugs has brought new attention to opioid use in pain management. As previously mentioned, experts have largely rejected a 1980 letter that concluded that non-cancer pain patients' addiction risk from long-term opioid use is low. Data on the true risk of addiction from opioids prescribed for chronic pain is difficult to determine, with estimates ranging from 0% to 50% depending on the criteria and subpopulation used.²⁸ However, it is not surprising that higher rates of opioid abuse occur in users receiving higher doses or for longer periods. The rate of opioid abuse or dependence diagnosis reportedly ranged from 0.7% with lower-dose (less than or equal to 36 Morphine Milligram Equivalents [MME]) chronic therapy to 6.1% with higher-dose (greater than or equal to 120 MME) chronic therapy, compared to 0.004% when no opioids were prescribed.²³

Studies have also suggested that patients are at risk for continuing opioids long-term once they have used them for more than 5 days,¹⁸ and are they are unlikely to discontinue opioids after having used them for 90 days.¹⁹ These parameters highlight the importance of guidelines that minimize unnecessary initial opioid exposure and the potential challenges in reducing opioid use among patients receiving chronic therapy.

In 2016, CDC issued voluntary, evidence-based practice recommendations for prescribing opioids to patients 18 years or older in primary care settings, focusing on chronic pain treatment. The document, Guideline for Prescribing Opioids for Chronic Pain,³² was intended to improve the safety and effectiveness of pain treatment, and reduce risks associated with long-term opioid therapy. One of the general recommendations is: when opioids are needed for acute pain, prescribe no more than needed. The specific guideline is "When opioids are started, clinicians should prescribe the lowest effective dosage. Clinicians should use caution when prescribing opioids at any dosage, should carefully reassess evidence of individual benefits and risks when considering increasing dosage to ≥50 morphine milligram equivalents (MME)/day, and should avoid increasing dosage to ≥90 MME/day or carefully justify a decision to titrate dosage to ≥90 MME/day."³² CDC specifically notes that the guideline is not intended for patients who are in active cancer treatment, palliative care, or end-of-life care.³²

Other organizations concerned with health care have also weighed in with voluntary recommendations on opiate use.³³ Perhaps the most significant statement comes from the Centers for Medicare and Medicaid Services (CMS). CMS has announced it "is deeply concerned about the magnitude of the opioid misuse epidemic and its impact on our communities, and is committed to a comprehensive and multi-pronged strategy to combat this public health emergency." As part of the strategy, CMS "expects" that by 2019, all Part D sponsors will limit initial opioid prescriptions for the treatment of acute pain to no more than a 7 days' supply and would also limit Medicare beneficiaries to 90 mg of morphine equivalents per day.³⁴ However, despite efforts to curb prescribing, opiate and opioid overdose deaths continue to climb.

In July 2016, 46 state governors signed the "Compact to Fight Opioid Addiction"³⁵ signaling a governmental commitment to take steps to reduce inappropriate opioid prescribing, change the nation's understanding of addiction, and ensure a pathway to recovery. Some steps proposed by the governors include

• encouraging efforts to update evidence-based opiate prescribing guidelines
• requiring prescribers to receive education on opiate prescribing
• implementing coordinated prescription drug monitoring programs
• reducing administrative barriers in health plans including Medicaid to promote comprehensive pain management including alternatives to opioids and treatment options for individuals with addiction problems
• increasing education in schools and other community-based settings to raise awareness about opioid abuse and addiction among youth and other at-risk groups
• improving understanding of the disease of addiction among health care providers and law enforcement, and
• providig addiction treatment as an alternative for non-violent individuals charged with low-level drug-related crimes.

Prescribing Limits

A number of states have enacted policies and regulations placing limits on the prescribing/dispensing of opioid drugs for acute pain, often aligning with CDC recommendations.³⁶ As of April 2018, 28 states had enacted legislation with some type of limit, guidance, or requirement related to opioid prescribing. Massachusetts passed the nation's first law in 2016. The law contained a number of provisions, including setting a 7-day supply limit for initial (first-time) opioid prescriptions. Most states restrict first-time opioid prescriptions to a certain number of days' supply. The most common limit is 7 days, but some states set limits at 3, 5, or 14 days. A few states set dosage limits in MMEs. Nearly half the states with limits specify that they apply to treating acute pain, and most states set exceptions for chronic pain treatment, cancer, and palliative care. Many states also allow exceptions for the treatment of substance use disorder or in conjunction with behavioral therapy (medication-assisted treatment). Some also allow exceptions based on the prescribing provider's professional judgment. Many of the laws stipulate that exceptions must be documented in the patient's medical record. States have also enacted laws related to prescription drug monitoring programs, access to naloxone, pain clinic regulation, provider education and training, and other efforts to curb opioid misuse. (For a state-by-state review of guidelines see reference 36.)

Tightening the controls on prescription opioids likely contributed to the trend toward other substances. The reduced availability of prescription opiates may have led to the increased abuse of heroin as a substitute for prescription drugs, particularly among young people.³⁷ Physicians curtailed opioid prescriptions without determining whether patients had developed an opioid use disorder and without guidance on tapering dependent patients.¹

Have prescribing restrictions and upscheduling of HCPs accomplished what supporters hoped and reduced the misuse of opioids? One study examined data from the first year following the upscheduling of HCPs and reported that there were 26.3 million fewer prescriptions written for HCPs and 1.1 billion fewer HCP tablets dispensed in the U.S.³⁷ 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.

Another more recent analysis from inpatient/outpatient prescribing data in a Texas hospital revealed an overall reduction in the prescribing of opioids after rescheduling of HCPs. This was accompanied by a shift away from HCPs and an accompanying increase in prescribing of codeine and oxycodone-containing products and tramadol.³⁸ Placing restrictions on prescription opioids can reduce their availability and risks of misuse.

According to CDC, the amount of opioids prescribed in the U.S. peaked in 2010.³⁹ It should be noted that this was prior to the rescheduling of HCPs and state prescribing limits. The opioid prescribing rates leveled off from 2010 to 2012, and then decreased by 13.1% from 2012 to 2015. CDC suggests that these trends may have been the result of health care practitioners' and patients' increased awareness of risks. It cites new national guidelines defining high dose opioid prescribing as greater than 200 MME/day. It also cites studies demonstrating a progressively increasing overdose risk at prescribed opioid dosages exceeding 20 - 100 MME per day as contributing to increased awareness.

CDC reported that the 2010 prescribing peak (782 MME per capita) had decreased to 640 MME per capita in 2015. Despite these decreases, the amount of opioids prescribed in 2015 remained approximately 3 times higher than in 1999 with substantial regional variation.³⁹ Some factors associated with higher regional differences included a larger percentage of non-Hispanic whites; a higher prevalence of diabetes and arthritis, which may result in an increase in treatment of pain associated with these disorders; smaller urban areas (population 10-50,000); and higher unemployment and Medicaid enrollment. CDC speculated that smaller urban areas show higher rates because access to quality health care and other treatments for pain, such as physical therapy, may be lower. Small urban areas may also be hubs for smaller, rural communities from which people may travel to receive medical care and pick up prescriptions.

Abuse Deterrent Formulations

FDA has indicated its support of the development of innovative formulations that may reduce the abuse of opioids.⁴⁰ Abuse deterrent formulations are designed to make manipulation of the dosage form more difficult or to make abuse of the manipulated product less attractive or less rewarding.⁴¹ Manufacturers use many different strategies, including physical and chemical barriers (e.g., forming a gelatinous mass when in contact with liquid or being resistant to crushing to a fine powder), agonist/antagonist combinations, unique delivery systems, and prodrugs.

An analysis of trends following the introduction of reformulated OxyContin suggested a reduction in diversion, abuse, overdose fatalities, and doctor shopping. While these data suggest a decrease in the illicit use and risks from overdose of this drug, the author suggests that addicts may have started substituting with heroin and other illicit agents instead of OxyContin.

Education

The President's Commission includes among its recommendations additional efforts to improve the awareness among health care practitioners.¹ It recommends that the Executive Branch and Congress work to allow DEA to require that all prescribers desiring to be relicensed to prescribe opioids participate in an approved continuing medical education program on opioid prescribing. At least 23 states already require practitioners to obtain continuing education credits in 1 or more of the following: prescribing controlled substances, pain management, and identifying substance use disorders.³⁶

FDA also requires manufacturers of extended release and long-acting opioid dosage forms to sponsor educational programs for prescribers and patients.¹⁰ The President's Commission also recommends that appropriate agencies train pharmacists on best practices to evaluate the legitimacy of opioid prescriptions, and not penalize pharmacists for denying inappropriate prescriptions.

SUMMARY AND FINAL COMMENTS

The U.S. has witnessed a shocking surge in drug-related overdose deaths, especially from opioids. Numerous strategies, involving many different sectors, have been proposed to deal with this burgeoning public health menace (Table 2). A recent analysis using a mathematic predictive model reached the reasonable conclusion that no single policy change is likely to reduce overdose deaths substantially over the next 5 to 10 years.⁴² Instead, the most significant impact, according to the authors, could be achieved by employing a "portfolio" of approaches involving among other strategies; wider availability of rescue naloxon; an increase in medication-based (i.e. buprenorphine, methadone) and psychosocial treatment programs; and reduced prescribing for current addicts along with reducing the entry of new addicts. The model also recognizes that reducing the supply of prescription opioids may actually increase heroin related deaths, at least in the short term.

Are there unintended consequences from these necessary and well-intentioned efforts to stem the tide of drug-related overdose deaths? Several authors have commented that the pendulum may be swinging too far and does not consider the many factors that drive addictive behaviors, returning to the "opiophobia" of the early 1990s, and leaving many patients suffering from pain and patients and health care professionals with fewer alternatives and a growing stigma.^43-45 Scott M. Fishman, MD, chief of the Division of Pain Medicine at the University of California, Davis, has described the issue by saying "(w)e have 2 public health crises going on at the same time: 1 is undertreated pain and the other is prescription drug abuse ... and no one knows with any certainty if one is driving the other".²⁴ It is incumbent on pharmacists and pharmacy technicians to help determine the proper balance and participate in the search for a solution.

REFERENCES

1. The President's Commission On Combating Drug Addiction And The Opioid Crisis. Report. November 1, 2017. Accessed at: https://www.whitehouse.gov/sites/whitehouse.gov/files/images/Final_Report_Draft_11-1-2017.pdf, September 15, 2018.
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3. Centers for Disease Control and Prevention. U.S. drug overdose deaths continue to rise; increase fueled by synthetic opioids. March 29, 2018. Accessed at: https://www.cdc.gov/media/releases/2018/p0329-drug-overdose-deaths.html, September 15, 2018.
4. Fox M. U.S. life expectancy falls for second straight year-as drug overdoses soar. NBC News. December 21, 2017. Accessed at: https://www.nbcnews.com/storyline/americas-heroin-epidemic/u-s-life-expectancy-falls-second-straight-year-drug-overdoses-n831676, September 15, 2018.
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6. National Institute on Drug Abuse. Opioid overdose crisis. March 2018. Accessed at: https://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis, September 15, 2018.
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14. Ahmad FB, Rossen LM, Spencer MR, et al. Provisional drug overdose death counts. National Center for Health Statistics. September 12, 2018. Accessed at: https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm, September 15, 2018.
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16. Nixon RM. Remarks about an intensified program for drug abuse prevention and control.
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