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INTRODUCTION

Lack of available treatment options for medical management of chronic noncancer pain (CNCP) is an ongoing, rapidly progressing health care dilemma associated with significant morbidity and mortality.¹ Patients with CNCP commonly experience physical discomfort, anxiety surrounding unemployment, impaired family dynamics, depression, and isolation. Activities of daily living may also be adversely affected.² An estimated 60 million Americans have some type of CNCP, and 40% of these patients report inadequate pain relief.^3,4 Pain management also has a significant economic impact. Direct and indirect costs associated with managing all types of pain in the United States (U.S.) consumes between $560 and $635 billion annually.⁵

Overall, the goal of pain management should be to improve and maintain patient functioning and quality of life. Various surgical procedures, acupuncture, and relaxation techniques are all viable maintenance therapies. Clinicians are using the remaining option—pharmacologic therapies—increasingly in the 21^st century.

In 2010, clinicians prescribed enough opioid pain relievers to medicate every adult in the U.S. with a 5 mg dose of hydrocodone every 4 hours for 1 month.⁶ Heavy opioid prescribing is not just an American problem. A statistic that is often quoted, but misleading, is that 99% of the world’s hydrocodone is prescribed in the United States. Opioid preferences differ geographically. Consider that

• Milligram for milligram, hydrocodone and morphine are considered equipotent.
• Most European countries use dihydrocodeine or morphine instead of hydrocodone.
• In Canada, hydrocodone is only available in cough and cold products.
• Australia uses almost no hydrocodone, using morphine preferentially.

Another point to consider is the influence of regulatory factors on opioid prescribing and use. For decades, hydrocodone was a schedule III controlled substance in the United States. This status, which allows prescription refills, probably encouraged use of hydrocodone combinations over opioids classified as Schedule II (and unable to be refilled) based on convenience. Therefore, the 99% statistic may be true, but it is overstated and sensationalized. In 2014, U.S. authorities moved hydrocodone to schedule II after observing growing abuse potential; they took this action even though hydrocodone is the least abused opioid analgesic according prescription-per-capita data.⁷

With increased opioid prescribing for CNCP over the last 2 decades, opioid misuse and overdoses have surged. As states have established prescription drug monitoring programs (PDMPs) and increased scrutiny, an unintended effect has been a surge in heroin use as patients who experience difficulty securing prescription opioids turn to this inexpensive, widely available street opioid.^6,8 Nevertheless, the misuse of prescription opioids, often in conjunction with other agents, is now the second most common form of drug abuse. Only marijuana is abused more often.⁸ The Centers for Disease Control and Prevention presented mortality data in 2016, showing that an estimated 47,055 Americans died in 2014 from drug overdose. Rates of opioid deaths increased from 7.9 per 100,000 in 2013 to 9.0 per 100,000 in 2014, a significant 14% increase.⁹

FACTORS AND CHARACTERIZATION OF OPIOID ABUSE AND MISUSE

With the growing misuse of opioids, it is important to understand why abusers desire these medications. Opioids bind to 1 or more types of opioid receptors; their effects depend on the extent and predominance of binding.¹⁰ Several receptors influence opioids' pharmacologic effects—mu, kappa, delta, and sigma—as follows¹⁰:

• Mu receptors produce supraspinal analgesia, euphoria, physical dependence, respiratory depression, hypothermia, bradycardia, and miosis.
• Kappa receptors mediate supraspinal analgesia, miosis, and sedation.
• Delta receptors mediate analgesia.
• Sigma receptors may produce dysphoria and hallucinations.

Each receptor type is found throughout the nervous system, and mu receptors are ubiquitous in tissues throughout the body (not just the nervous system).

The magnitude of each patient's opioid abuse problem is related to the opioid's effect on the central nervous system (CNS); opioids may cause analgesia, euphoria, sedation, and respiratory depression. Opioids also can activate dopaminergic cells in the central nervous system. Increased dopamine stimulates euphoria and creates a desire to take the drug again. This effect is observed with both opiates and cocaine.¹¹

People do not always experience euphoria during their initial use of opioids. Subsequent dosing may introduce an exaggerated sense of well-being and freedom from anxiety and stressors. A floating sensation can predominate, and some people will then continue to seek this experience. Each opioid's effect differs depending on its potency, duration of action, and effectiveness after oral administration. The abuse liability of various formulations is directly linked to the speed with which the drugs reach the brain and begin to exert their pharmacologic effects.¹² The rate of entry of a drug into the brain is a function of 2 factors: the rate of increase in drug plasma levels and qualities that allow transfer across the blood brain barrier (e.g. size, ionization and lipophilicity).¹³

Griffiths et al. demonstrated differing abuse potentials of a single agent based on dose and administration patterns, and these are determined by the rate at which the drug enters the bloodstream and subsequently the brain.¹⁴ Experimental literature has consistently shown that formulations that slow the rate of drug binding at peripheral and central opioid receptors can potentially deter abuse. These abuse-deterrent formulations (ADFs) are designed to be tamper-proof or unattractive to potential abusers. The Food and Drug Administration (FDA) encourages development of ADFs.

An example of an ADF is NKTR-181. In December 2011, the pharmaceutical company Nektar released phase 1 trial data for this new product, which uses novel small-molecule polymer conjugate technology. This delivery system is designed to deliver the opiate to the CNS 90% more slowly than the traditional opioid formulations. Slowing a medication's delivery to the CNS reduces its pharmacologic effects. FDA has accepted this product into its fast-track abuse-deterrent drug development program (discussed below).¹⁵

Other strategies explored to reduce abuse potential of medications include the following¹³:

• Pairing opioids with aversive secondary ingredients (e.g., atropine for its anticholinergic effects with diphenoxylate)
• Adding secondary ingredients to prevent parenteral use (e.g., naloxone and buprenorphine)
• Developing prodrugs requiring metabolism in the gut to be activated to the clinically effective form

Attempts to make ADFs are not always successful. Acura Pharmaceuticals created and proposed a niacin–oxycodone combination product (Acurox), using niacin because it can cause flushing, itching, sweating, chills, and headache in high doses. The theory was that abusers would find niacin, when taken in excess, aversive. FDA did not approve Acurox, leading Acura Pharmaceuticals to reformulate the product (details described below), removing the niacin. FDA approved the reformulated product (Oxecta) in June 2011.¹⁵

Opioids can be administered using oral, intravenous (IV), intramuscular, intrathecal, epidural, intranasal (IN), rectal, transdermal, buccal/transmucosal, or sublingual routes. Abusers can manipulate opioids in a variety of ways to alter their pharmacokinetic profiles and allow faster onsets of action. Abusers usually alter opioid medications so they can use them intravenously or nasally, or smoke them. Administration using IV, IN, inhalation, or rectal routes increases the absorption rate of the drug into the bloodstream and subsequently the brain to elicit pharmacologic effects. (The authors have encountered patients who have tried to “reverse roll” fentanyl patches and insert them rectally like a suppository.) When a drug is given IV, IN, or inhaled, the maximum observed plasma concentration (C_max) is increased while the time to maximum concentration (T_max) is shortened.¹⁶ These modes of administration avoid hepatic first-pass metabolism, enzyme degradation, and other interferences in the gastrointestinal tract. For these reasons, opioid abusers' manipulations provide a quicker onset of euphoria. Oral formulations (capsules, tablets, sublingual films) can be crushed or ground for easier inhalation, or dissolved or melted for easier IV use.¹⁷

Opioid analgesics are available in many dosage forms. Many are immediate-release (IR). Manufacturers have developed some medications as controlled-release (CR) products (i.e., they deliver active ingredients at a slow, steady rate), or delayed-release (DR) products (i.e., they delay medication release until the tablet has passed through the stomach). These products do not necessarily have a longer absorption phase, but they can prolong or delay release compared with IR products.¹⁸ CR and DR increase T_max and reduce abuse potentially if taken properly.

Unfortunately, abusers can deliberately circumvent these formulations' abuse-deterrent technologies for subsequent inhalation or IV use. For example, using alcohol to extract drugs from CR or DR formulations—called dose dumping—allows most or all of the dose to be released. It is potentially lethal because it hastens rapid drug release from a product that was otherwise intended to deliver active medication over 8, 12, or 24 hours. In the case of fentanyl transdermal, patches hold more than 3 days’ worth of medication, an opioid equivalent considerably more potent than that in morphine formulations.¹⁸

ADFs have been shown to produce a lower C_max and increase in T_max. They attempt to decrease “drug-liking” and IN tolerability, and theoretically reduce potential for IN abuse.¹⁹ These formulations include excipients resistant to manipulation or antagonists that block opioid effects in the CNS. For example, Embeda combines naltrexone, an opioid receptor antagonist, and morphine, an opioid receptor agonist. The naltrexone is formulated in a sequestered core so that if the capsule is taken orally as directed, the patient digests the naltrexone component in the stomach’s acidic environment, resulting in no physiologic effect. The patient's pain is relieved. However, if an individual crushes the capsule for dose dumping, injection, or IN use, the naltrexone is released and antagonizes morphine’s pain relieving and euphoric effects, rendering the opioid inactive.²⁰

Abuse potential across opioid classes differs subtly. When injected IV, opioids' overall effects are similar. Stoops et al. compared the abuse potential of oxycodone, hydrocodone, and morphine in opioid abusers.²¹ After patients were given IV oxycodone, hydrocodone, and morphine, the researchers measured behavioral, pharmacologic, and psychologic effects. Effects were similar among opioid users, nonusers, and patients physically dependent on heroin. This finding further demonstrates the potential for abuse across all opioids when given IV. Table 1 reviews common characteristics and factors that influence opioid likeability.^22-25

Table 1. Factors Influencing Opioid Attractiveness Media attention Peer preferences Low cost Availability Tampering susceptibility High attractiveness quotient (high Cmax, low Tmax)

MECHANISTIC APPROACHES IN ABUSE-DETERRENT FORMULATIONS

Approaches to Deter Physical/Chemical Tampering

Physical and chemical barriers can hamper tablet physical manipulation such as crushing, chewing, or dissolving, and can increase viscosity to prevent extraction and intravenous abuse.²⁵ Table 2 summarizes various types of ADFs.^26,27,28

Table 2. Comparison of Oral Drug Formulations that Deter or Prevent Misuse and Abuse26,27,28
Product	Active Drug	Dosage Form	Manufacturer	Abuse-Deterrent Methods				Type of Technology
				Physical Barrier	Viscosity Management	Sequestered Opioid Antagonist	Aversive Agent
Exalgo	Hydromorphone HCl	ER tablet	Mallinckrodt Pharmaceuticals, Inc.	•	•			OROS
Nucynta ER	Tapentadol	ER tablet	Janssen Pharmaceuticals, Inc.	•	•			Intac and PEO matrix
Opana ER	Oxymorphone HCl	ER tablet	Endo Pharmaceuticals, Inc.	•	•			Intac and PEO matrix
Oxycontin	Oxycodone HCl	CR tablet	Purdue Pharma, L.P.	•	•			HPMC and PEO matrix
Xartemis XR	Oxycodone HCl and acetaminophen	ER tablet	Mallinckrodt Pharmaceuticals, Inc.		•			Acuform and PEO matrix
Embeda	Morphine sulfate	ER capsule	King Pharmaceuticals, Inc. (a Pfizer co.)			•		Pellets of morphine surrounding an inner core of naltrexone
Suboxone	Buprenorphine HCl	SL film	Reckitt Benckiser Pharmaceuticals, Inc.			•		Co-formulated with sequestered naloxone
Talwin NX	Pentazocine HCL	IR tablet	Sanofi-Aventis LLC.			•		Co-formulated with sequestered naloxone
Targiniq ER	Oxycodone HCl	ER tablet	Purdue Pharma, L.P.			•		Co-formulated with sequestered naloxone
Zubsolv	Buprenorphine HCl	SL tablet	Orexo US, Inc.			•		Co-formulated with sequestered naloxone
Tussigon	Hydrocodone bitartrate	IR tablet Oral syrup	Monarch Pharmaceuticals, Inc. (a Pfizer co.)				•	Co-formulated with homatropine methylbromide
Oxecta	Oxycodone HCl	IR tablet	King Pharmaceuticals, Inc. (a Pfizer co.)		•		•	Aversion and PEO matrix
Remoxy	Oxycodone HCl	ER capsule	Pain Therapeutics (a Durect Corporation co.)		•			ORADUR and SAIB matrix
Xtampza	Oxycodone HCl	ER capsule	Collegium Pharmaceutical, Inc.	•	•			DETERx technology—wax-based microspheres resist crushing or chewing; melting or dissolving the product creates a difficult-to-inject mass.
Hysingla ER	Hydrocodone bitartrate	ER tablet	Purdue Pharma, L.P.	•	•			PEO matrix and HPC RESISTEC
Zohydro ER	Hydrocodone bitartrate	ER capsule	Pernix Therapeutics, LLC.		•			PEO matrix BeadTek
MS Contin	Morphine sulfate	ER tablet	Purdue Pharma, L.P.
Avinza	Morphine sulfate	ER capsule	Purdue Pharma, L.P.				•
Kadian	Morphine sulfate	ER capsule	Actavis Pharma, Inc.				•
Abbreviations used: HCl, hydrochloride; HPC, hydroxypropyl cellulose; HPMC, hydroxypropyl methylcellulose; OROS, Osmotic extended-Release Oral delivery System; PEO, polyethylene oxide; SAIB, sucrose acetate isobutyrate

Physical Barriers

Physical barriers “shelter “or “entrap” active drug. Desirable barriers would have certain characteristics, including dosage form durability (ability to resist physical manipulation such as crushing or grinding) and resistance to common chemical solvents used in tampering.²⁵ These barriers make it more difficult for abusers to alter dosage forms for snorting, smoking, extraction, and “dose dumping” for rapid IV absorption.²⁵

Viscosity Management

Some ADFs incorporate excipients such as water-soluble/swellable cellulose derivatives, polyethylene oxide, gums, clays, and polyacid carbomers that form a gel or increase in viscosity when the product is crushed and mixed in water or other solvents.²⁵ Increased viscosity traps the drug in a gel-like substance and prevents syringe extraction for IV use.²⁵

Another approach, sorption processes such as ion-exchange resins, attaches the active ingredient to crush-resistant resin particles. If someone tampers with the product, the free drug is bound or trapped, preventing rapid release of the drug or extraction in solvents.²⁵ Modification of solubility with temperature, pH, particle size, and solvent can affect a drug’s ability to be absorbed by the body or extracted through tampering.²² An example of solubility modification is the use of meglumine, a basic solubilizing agent that increases the pH in the presence of methadone. Meglumine causes methadone to precipitate, making it difficult to extract.²⁵ Formulations incorporating solubility-modifying substances are intended to deter extraction, prevent injection, and decrease drug absorption, preventing overdose.²⁵

In Vivo Processes

In vivo mechanisms modify or interfere with drug binding or metabolism following product administration.²⁵ Inclusion of opioid antagonists, use of prodrugs, and presence of enzyme inhibitors have been used to deter abuse through in vivo mechanisms. Embeda, Suboxone, and Zubsolv (a combination of buprenorphine and sequestered naloxone), and Talwin NX (a combination of pentazocine and naloxone) are examples of products using this approach.

Opioid Antagonists

Direct incorporation of a sequestered antagonist or unsequestered naloxone into an opioid analgesic ADF prevents potential abuse by parenteral administration.²⁵ The combination of pentazocine and naloxone (Talwin-NX) was discussed above. Naloxone has exceedingly low oral bioavailability due to significant first-pass metabolism, and is therefore ineffective systemically; it does not require sequestering.²⁵ Unlike naloxone, naltrexone has good systemic availability. For this reason, Embeda uses a similar concept, but its antagonist component (naltrexone) is sequestered and released only if a potential abuser tampers with the product.²²

Other in vivo approaches include use of an inactive prodrug that requires biotransformation to be converted to its pharmacologically active form.²⁵ Although the prodrug approach may not directly prevent abuse or tampering, it may prevent the abuser from experiencing the desired effect after injecting, inhaling, or smoking the ADF.²⁵ Additionally, prodrug biotransformation in vivo may delay peak plasma concentrations and possibly lessen euphoric effects.²⁵

Researchers have investigated alternative metabolic approaches. Enzyme-inhibiting constituents can slow the rate at which a pharmacologically inactive drug is biotransformed to its active metabolite.²² Similar to sequestered antagonists, sequestered metabolic blocking agents would only be released upon administration of a tampered product. This novel method may prevent rapid accumulation of the active drug and potentially reduce euphoria.²⁵ Ethanol-soluble sequestration coatings may expose the enzyme inhibitor in the presence of alcohol and prevent ethanol-accelerated dissolution.²⁵ Unlike antagonist-containing formulations, enzyme inhibitors may not cause immediate withdrawal symptoms.²⁵

Approaches to Modifying Product Favorability

Modifying a product’s favorability makes the drug less desirable for abuse.²² Unlike physical and chemical barriers, these approaches do not prevent actual product alteration.²⁵ Examples of these products include Oxecta and Tussigon. Following FDA’s rejection of Acurox (discussed above), the agency approved the manufacturer’s reformulated product, Oxecta. Oxecta employs gel-forming polymers and sodium lauryl sulfate to prevent syringeability and discourage insufflation respectively when crushed.²⁶ Similarly, Tussigon was developed to be co-formulated with homatropine.²⁸ When taken in excessive quantities, the abuser may experience intolerable anticholinergic adverse effects such as blurry vision, dry mouth, constipation, and tachycardia.

Formulations may incorporate constituents that trigger unpleasant, noxious effects in abusers who intentionally tamper with dosage forms. Aversive agents such as laxatives (e.g., bisacodyl, casanthanol, senna), cutaneous vasodilators (e.g., niacin, D-beta-hydroxybutyrate), emetics and nauseants (e.g., zinc salts, ipecac, cephaeline), bittering agents (e.g., menthol, eucalyptus oil, denatonium benzoate, denatonium saccharide), and mucous membrane irritants (e.g., capsaicinoids, resiniferatoxin, olvanil, sodium lauryl sulfate) are intended to discourage nonmedical use and decrease desirability of a tampered product.²⁵

Visual deterrents also modify product favorability using color additives, dyes, and pigments. Tampering changes the product's appearance, making it visually undesirable.²⁵ Additives such as clay minerals may be used not only as visual deterrents, but also as obstructions to syringeability and extraction of drugs after exposure to aqueous solution.²² Coloring additives may stain the nasal and oral cavities when abusers snort or inhale the altered drug, causing embarrassment.²⁵

IMPACT OF ABUSE-DETERRENT FORMULATIONS

ADFs are intended to create mechanistic barriers that hinder abuse and misuse, and impede the abuser from achieving a rapid euphoric effect.^25,26,29 Extended-release oxycodone hydrochloride, known as OxyContin, was introduced in the mid-1990s. It rapidly became one of the most commonly abused opioid analgesics because it contained large amounts of oxycodone in a small tablet. Successful dose manipulation could yield a large dose of oxycodone in a small pile of “snortable” powder; this became the eventual impetus for ADF development.^22,25,26 By 2010, OxyContin was reformulated, rendering crushing and extraction more difficult. It became the first FDA-approved ADF, and abuse decreased.^25,26,29

OxyContin’s reformulation forced most abusers to abandon it, but they often turned to other opioid products such as extended-release oxymorphone, oxycodone 30 mg tablets, hydromorphone, and fentanyl. Heroin use also increased proportionately, but most especially with the advent of established PDMPs.³⁰ Opioids abusers, faced with a restricted opioid supply, turned to heroin as a cheap, readily available alternative. Regardless of the ADF, opioid abusers have and likely will continue to manipulate these products, often staying several steps ahead of manufacturers and new ADFs.²⁹

Some have postulated that ADFs may have a substantial impact on the opioid epidemic only if other non-ADF opioids are no longer available.²⁹ In addition to the legal and political implications of requiring all opioids to be manufactured as ADFs, this theory has created a mindset among some stakeholders that all ER and IR opioid formulations should contain abuse-deterrent technology.³¹ Although ADFs are mechanistically successful, they are typically more expensive, reduce the route of administration and formulation options, and inevitably increase the cost of health care (e.g., insurance copayments, benefits coverage).^22,26,32

ABUSE-DETERRENT FORMULATIONS AND THE FDA

In April 2014, FDA published evaluation and labeling guidelines for manufacturers for ADFs. These guidelines deal with development of new products, but do not discuss the approval of generic ADFs. FDA defines an abuse-deterrent property as one that meaningfully deters abuse, even if it does not fully prevent abuse. It is important to distinguish this term from tamper-resistant, which refers to packaging requirements applicable to certain drug classes. Because of the relatively new development of ADFs, FDA will generally only establish findings through comparisons of other products currently on the market.^33,34

Table 3 summarizes categories of ADFs.^26-28 Study designs examining new ADFs should include positive controls, comparator drugs, outcomes, data analysis, and appropriate subject selection. Researchers who evaluate abuse-deterrent properties should consider modes of previous abuse and potential for future abuse of new formulations. Three categories of premarketing studies must be performed:

1. Laboratory-based in vitro manipulation and extraction studies
2. Pharmacokinetic studies
3. Clinical abuse potential studies

Table 3. FDA Categories for Abuse-Deterrent Formulations

Physical/chemical barriers to prevent chewing, crushing, cutting, grating or grinding of dosage

Agonist/antagonist combinations to help interfere with, reduce or defeat associated euphoria with abuse

Aversion or additional substances that can be added to a product to produce and unpleasant effect if abused

Delivery system (e.g., depot injections or implants) to help control the release of drug or the method of drug delivery can be resistance to abuse

New molecular entities and prodrugs to help slow central nervous system penetration

Combinations of two or more of any of the previously listed methods

Novel approaches to encompass new technologies not previously stated

Manufacturers must conduct postmarketing studies to evaluate the proposed ADF's impact on abuse potential using formal studies, data, and supportive information. Further details about the components required or to be considered for each study can be found in the FDA publication, Abuse-Deterrent Opioids — Evaluation and Labeling, Guidance for Industry.³³

FDA has also established labeling guidelines for manufacturers to make health professionals and patients aware of certain potentially higher abuse medications. Labels should state the product is abuse-deterrent and not abuse-proof. Manufacturers must include findings from each stage of the product's premarketing studies and updated information from postmarketing findings. Labeling should include appropriate routes of administration and the type of abuse the product was designed to deter. FDA also expects manufacturers to demonstrate utility of their ADFs by comparing them with already-approved ADFs. If FDA determines the product does not deter opioid misuse after release of postmarketing data, it may require labeling revisions.³³

In October 2014, FDA met to discuss the development, assessment, and regulation of opioid abuse-deterrent formulations. The meeting's goals were to create incentives for development of opioids with abuse-deterrent properties, and ensure appropriate development and availability of generics.³⁴ FDA recognizes the many problems associated with opioid misuse and will continue to work to incentivize manufacturers to move ADFs to market safely and effectively.

TARGET POPULATION AND INCORPORATION OF UNIVERSAL PRECAUTIONS

Clinicians should use caution when treating patients who have a history of a substance use disorder(s) before considering opioid therapy for long-term pain management.^35-37 Risk assessments and screening tools are vital. Using validated screening tools such as the Current Opioid Misuse Measure and Screener and Opioid Assessment for Patients in Pain–Revised may help clinicians evaluate risk for misuse and potential adverse outcomes.²⁶ Implementation of universal precautions involves several standard risk mitigation strategies:

• Using opioid treatment agreements, informed consents, and urine drug screens
• Reviewing prescription drug monitoring reports
• Assessing and re-assessing the “5As” (analgesia, adverse effects, activity, aberrant behavior, and affect)
• Timely, scheduled follow-up appointments

Appropriate and timely monitoring of long-term opioid therapy is vital when managing chronic pain; risk stratification is also important. Monitoring must continue throughout treatment. Clinicians have used behavioral assessments and pill counts to monitor long-term opioid therapy.³⁸ In the authors’ opinion, however, pill counts are an ineffective way to monitor adherence, as savvy patients may borrow medication from friends to inflate their counts artificially.

Once clinicians establish appropriate screening, treatment plans, and monitoring and follow-up schedules, it is reasonable to consider ADFs in high-risk patients. These include patients who are at risk or have a history of substance abuse (e.g., heroin or prescription opioids) and those who have unstable living conditions, have low incomes, or are targets for theft.²⁹ Patients are deemed at higher risk for opioid misuse or addiction if they currently consume more alcohol than advised/recommended, routinely smoke marijuana, use illicit street drugs, or “doctor shop” for prescription controlled substances.³⁶ Other risk factors for opioid misuse may include age younger than 40 years, active mental health disorders, and a family history of addiction to any substance.³⁶

Although patients with active mental health disorders or a histories of addiction are not absolutely contraindicated for opioid therapy, opioids should be reserved for neuropathic pain conditions refractory to nonopioid adjuvant analgesic agents. They need frequent stringent monitoring and timely follow-up.^35,36 When active abuse (e.g., illicit street drugs, prescription medications, alcohol) is confirmed, clinicians should refer the patient to a substance abuse specialist immediately, and withhold opioid therapy until the addiction has been treated and is in remission.³⁷ From a public health standpoint, issuing a naloxone overdose kit is a serious consideration to minimize the risk of an accidental overdose and mortality.

LEARNING FROM EXPERIENCE

On July 7, 2012, FDA released a final risk evaluation and mitigation strategies (REMS) that applies to manufacturers developing new ER/long-acting opioids. As part of the REMS, manufacturers will provide training to prescribers of their products, and to the extent practicable, be conducted by accredited, independent continuing medical education (CME) providers.³⁹ This new impetus for provider education will hopefully help clinicians understand newer opioids' utility and existing abuse potential.

It is important to learn from experience and consider ADF's advantages and repercussions. For example, OxyContin has been available in a tamper-resistant formulation since 2010. The National Poison Data System collected data from 2010 to 2012 to assess OxyContin, oxycodone, and heroin trends. OxyContin prescription abuse dropped 36%; however, oxycodone IR abuse increased 20%. Heroin overdose increased by 42% over the same time period.⁴⁰ This illustrates that improving drug formulations alone will not solve drug abuse problems. It is also impossible to predict diversion, overdose, and product tampering during clinical development of new ADFs. Postmarketing study is needed to identify these characteristics fully.¹⁸

Clinicians need to focus on identifying patients who are at risk for abuse, especially when patients have comorbid pain and addiction. Clinicians also need to consider nonmedication treatment modalities apart from and combined with medication strategies. Appropriate prescribing to reduce and prevent unnecessary exposure to opioid medications is needed. Clinicians must encourage patients to use addictive medications on an as-needed basis if possible, and to augment opioids with other nonopioid treatments to reduce the potential for addiction.

While strict guidelines and widely accepted decision trees are lacking to help guide clinicians’ decisions, the 10-step universal precautions process for safe opioid prescribing, summarized in Table 4, standardizes management of patients with persistent pain syndromes.⁴¹ Care should be individualized to each patient’s needs; by employing universal precautions, clinicians can approach each case in a similar fashion, minimizing bias. Every patient needs to trust his or her clinician and have realistic goals. PDMPs and urine drug screening can help identify patients who are abusing or diverting opioids.

Table 4. Universal Precautions in Opioid Prescribing

Diagnosis with the appropriate differential

Psychological assessment including risk of any addictive disorder

Obtain informed consent (written/signed)

Obtain a treatment agreement between provider and patient (verbal or written/signed)

Pre/post intervention assessment of pain level and function

Assess appropriateness of a trial of opioid therapy +/- adjunctive medications

Reassessment of the patient's pain score and level of

Regularly asses the "5 As" of pain medicine - analgesia, adverse effects, activity, aberrant behavior, and affect

Periodically review steps 1–8

Documentation of assessments and therapeutic plans

CONCLUSION

The use of ADFs should not be viewed as a panacea for opioid abuse and misuse. These new technologies can mitigate opioid abuse, but all stakeholders must be careful so barriers to opioid access do not cause rampant use of illicit substances such as heroin. With FDA support, ADFs will continue to enter the market. Presently, all ADFs are proprietary, which translates to a significant cost burden to patients, insurance companies, and society at large. Monetary cost needs to be weighed against the tremendous societal costs of substance abuse. Health professionals in every practice area require continued education on new abuse-deterrent technologies available to patients while also employing adjuvant nonopioid therapeutic options. Clinicians must use universal precautions to make even a small dent in the opioid abuse epidemic.

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