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INTRODUCTION

As gatekeepers of safe and appropriate medication use, pharmacists play a major role in preventing and identifying opioid misuse, abuse, and diversion. Pharmacists must carefully assess each prescription for legitimacy and appropriateness and make the final determination of whether an opioid is dispensed.

Dispensing opioid prescriptions without careful assessment may increase misuse, abuse, and diversion. Conversely, overzealous efforts to reduce misuse and diversion without careful attention to detail may result in denying prescriptions for patients with legitimate needs and pose additional barriers and safety risks for patients with pain, including seeking alternative sources of medication.

The prevalence of opioid abuse and the corresponding media sensationalism have led many pharmacists to look skeptically at every opioid prescription. The focus on avoiding being duped by a fraudulent prescription sometimes exceeds the call to help relieve genuine pain and suffering of other patients. Striking a balance between providing legitimate pain patients with medications and recognizing individuals seeking prescription opioids for illegitimate reasons is often challenging. Finding this balance requires understandings and applications of pain, reasonable pharmacotherapeutic single-ingredient and combination agents, aberrant drug-related behaviors, and legal and regulatory opioid standards in daily practice.

Corresponding responsibility

The United States (U.S.) code of Federal Regulations defines the purpose of issue of prescription and underscores the responsibility of the pharmacist in the process of filling a prescription for a controlled substance¹: "A prescription for a controlled substance to be effective must be issued for a legitimate medical purpose by an individual practitioner acting in the usual course of his professional practice. The responsibility for the proper prescribing and dispensing of controlled substances is upon the prescribing practitioner, but a corresponding responsibility rests with the pharmacist who fills the prescription. An order purporting to be a prescription issued not in the usual course of professional treatment or in legitimate and authorized research is not a prescription within the meaning and intent of section 309 of the Act (21 U.S.C. 829) and the person knowingly filling such a purported prescription, as well as the person issuing it, shall be subject to the penalties provided for violations of the provisions of law relating to controlled substances."

Terminology

Abuse, misuse, dependence, addiction, and pseudoaddiction are distinct phenomena that are frequently misunderstood with resultant confusion by professionals, patients, and politicians (Table 1).^2,3

Table 1: Definitions of Terms Related to Opioid Abuse and Misuse2,3
Term	Definition
Aberrant drug-related behavior	Any medication-related behavior that does not follow a prescribed therapeutic plan
Addiction	Chronic disease of brain reward, motivation, memory, and related circuitry Characteristics (ABCDE): Inability to consistently Abstain Impaired Behavioral control Craving Diminished recognition of significant problems (behavior and interpersonal relationships) Dysfunctional Emotional response
Chemical coping	Relying on a drug for psychological stability
Misuse	Intentional or unintentional use of medication other than as directed; may involve taking more medication than prescribed for additional pain control or taking opioids to treat insomnia
Physical dependence	Physical adaptation with chronic drug exposure where abrupt discontinuation or administration of an antagonist precipitates withdrawal symptoms
Pseudoaddiction	An iatrogenic syndrome defined as drug-seeking behaviors that simulate addiction but are driven by desire for pain relief; usually signals undertreated pain
Tolerance	Decreased analgesic response over time as the body becomes tolerant to a given dose of the drug

Aberrant drug-related behavior

Aberrant drug-related behavior is a broad term that encompasses behaviors in drug administration that deviate from the prescribed therapeutic plan.^2,3 However, not all aberrant drug-related behaviors stem from abuse or addiction. A patient may be taking more medication than prescribed to obtain pain relief. In some cases, a feeling of wellness or euphoria can be misinterpreted by the patient as analgesia.

The difference between misuse and abuse is the underlying motive. Using a medication to alter one's sensorium or get "high" is abuse, but taking more medication than prescribed for additional pain relief is misuse. Misuse can be further classified as intentional or unintentional. For example, an elderly patient crushing an extended-release (ER) formulation for ease of use is considered unintentional misuse.

Two other distinct but often-confused phenomena are dependence and addiction. Dependence is physical adaptation with chronic use by which abrupt discontinuation results in withdrawal effects. Dependence also occurs with medications such as beta-blockers, antidepressants, and corticosteroids. Addiction involves uncontrollable cravings due to central nervous system neurobiological and neuroplastic changes that promulgate a host of behavioral changes of which the patient has little control. Patients may often mistake dependence for addiction, which presents an important opportunity for pharmacists to educate patients. A desire to avoid withdrawal due to physical dependence is not addiction.

Pseudoaddiction describes patient behaviors when their pain is undertreated so much that they become preoccupied with obtaining their medications with regular "clock-watching"; this may be misinterpreted as "drug seeking."⁴ In this case, patients are seeking pain relief from an ineffective regimen and/or subtherapeutic dose. Pseudoaddiction can be distinguished from true addiction in that the behaviors resolve when pain is adequately treated.

Addiction or undertreated pain?

Many times, patients with chronic pain present disheveled or poorly groomed appearances, which is unfortunately a profiling that has been inappropriately attributed to persons with opioid abuse disorder who are labeled by some as "junkies." In fact, uncontrolled pain may decrease patients' abilities to speak coherently, which could be misinterpreted or mislabeled as taking too much medication.⁵ Aberrant drug-related behavior may be present in both groups—patients who abuse opioids and those who have undertreated pain—but the difference is the motive. Additionally, aberrant behaviors are divided into those that are more suggestive of addiction and those that are less suggestive of addiction. (Table 2).³ As previously mentioned, pseudoaddiction is an iatrogenic condition arising from undertreated pain involving behaviors resembling true addiction.^2-4 Theoretically, pseudoaddiction may be associated more with the use of short-acting formulations than longer-acting ones as a result of the fluctuations in serum levels with intermittent peaks and troughs. For chronic pain patients, this creates a cycle of continuously chasing the pain. Pharmacists can recommend transitioning to a long-acting (LA) or ER formulation to maintain steady serum concentrations, thereby providing longer uninterrupted durations of analgesia, which could assist with other important pain-control factors such as achieving a full night of sleep.

Table 2: Spectrum of Aberrant Drug-related Behaviors3
More suggestive of addiction	Less suggestive of addiction
Concurrent abuse of alcohol or illicit drugs Evidence of a deterioration in the ability to function at work, in the family, or socially that appears to be related to drug use Injecting oral formulations Multiple dose escalations or other nonadherence with therapy despite warnings Obtaining prescription drugs from nonmedical sources Prescription forgery Repeated resistance to changes in therapy despite clear evidence of drug-related diverse physical or psychological effects Repeatedly seeking prescriptions from other physicians or emergency departments without informing prescriber Selling prescription drugs Stealing or borrowing drugs from others	Aggressive complaining about the need for more drugs Drug hoarding during periods of reduced symptoms Openly acquiring drugs from other medical sources Requesting specific drugs Reporting psychic effects not intended by the physician Resistance to change in therapy associated with tolerable effects accompanied by expression of anxiety related to return of severe symptoms Unapproved use of the drug to treat another symptom Unsanctioned dose escalations or other nonadherence with therapy on 1 or 2 occasions

IDENTIFYING ABUSE AND MISUSE

When presented with a prescription, pharmacists must exercise professional judgment to determine whether a prescription is issued for a legitimate medical purpose or not. It is important to consistently apply criteria for evaluating prescriptions for legitimacy so that disparities based on race, socioeconomic status, or other factors do not inadvertently lead to disparities in care.

Red flags

Pharmacists should be aware of red flags that may warn a prescription is not being obtained for a legitimate medical purpose. A red flag may trigger further investigation and is not clear evidence of wrongdoing. Some red flags may occur for legitimate reasons, such as requesting an early refill due to travel; however, if even legitimate requests become a consistent pattern, the pharmacist may be concerned. Regardless of the legitimacy of the red flags, documentation is key in all situations. 

Patient behavior

Patients may exhibit several behaviors or signs and symptoms of abuse⁶:

• Appears with needle tracks, appears intoxicated, or exhibits withdrawal symptoms
• Requests brand name products by slang terms ("the Ms" or "the Blues")
• Presents several prescriptions for controlled and non-controlled substances (example: an opioid and an antibiotic from the emergency department) but only wants the controlled substance dispensed
• Requests early refills on multiple occasions
• Obtains prescriptions from multiple prescribers in different practices
• Pays for medications with cash

Prescription attributes

The prescription itself may also display red flags of which the pharmacist should take note⁶:

• Appears forged or altered
• Issued by a prescriber who is prescribing outside of his or her scope of practice
• Orders therapeutic combinations (e.g., 2 or more short-acting formulations)
• Written for highly abused "cocktails" (e.g., an opioid, benzodiazepine, and carisoprodol)

Risk-assessment tools

There are several validated risk assessment tools for aberrant drug-related behavior. These vary in length, complexity, and validation techniques. Opioid risk stratification tools have previously been tabulated and summarized and can be accessed at the following website: http://paindr.com/wp-content/uploads/2012/05/Risk-stratification-tools-summarized_tables.pdf.⁷ These tools can be used at the time of initiation of opioids and during therapy. If a patient is considered to have a high risk for developing misuse or abuse, frequent monitoring is warranted to ensure safety. Another approach is to optimize the use of non-opioid analgesics, which is an area in which pharmacists can provide recommendations. Further, discontinuation of opioids can be considered, depending on patient-specific considerations and factors.

Risk assessment tools for aberrant drug-related behavior include^3,8:

• Opioid Risk Tool (ORT)
• Current Opioid Misuse Measure (COMM)
• Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R)

The assessment of risks of opioid misuse is complex and can be challenging in a community pharmacy setting. Medication therapy management (MTM) is an excellent avenue in which pharmacists can address pain management; provision of MTM services to patients receiving long-term opioid therapy is also an excellent setting for pharmacists to promote broad, widespread opioid risk assessment. Risk assessment tools and questionnaires have been a common part of MTM in other disease states, such as the COPD Assessment Test for assessing the severity of chronic obstructive pulmonary disease, and would be easily applied to MTM in the setting of long-term opioid use. Through MTM, pharmacists can use risk assessment tools to identify misuse and abuse and can document findings in the patient’s chart on the MTM platform (e.g., Mirixa), which can be easily shared with the provider.

Prescription drug monitoring programs

Most states in the U.S. have prescription drug monitoring programs (PDMPs) in place. These programs are overseen by each individual state and not by the Drug Enforcement Administration (DEA). Generally, only outpatient prescriptions are reported to the PDMPs but the specific requirements for reporting vary among states. Since the implementation of PDMPs, there has been a reported decrease in rates of obtaining opioid prescriptions from multiple providers (also known as "doctor shopping").⁹ PDMPs have become important tools for pharmacists to help prevent misuse and abuse.  

Patient education and counseling

For many patients, the pharmacy is their most visited healthcare location and they see their pharmacist(s) more frequently than any other healthcare provider. Pharmacists are well positioned to improve appropriate medication use and mitigate medication-related problems.

Arguably, the first step towards combating opioid misuse and abuse is educating patients about risks. Pharmacists have professional and ethical obligations to discuss efficacy and safety of medications with patients and counsel them on appropriate use. Simply asking the patient "Do you have any questions for the pharmacist? If not, please select next and sign here." is not sufficient or acceptable. Patients should be counseled at initiation of opioids and at every subsequent fill to ensure efficacy and safety. It is possible that the patient picking up a prescription for an opioid medication has never taken an opioid before.

In addition to regular counseling about medications, there are 4 important components of patient education that must be addressed with opioids that help prevent misuse and diversion:

1. Set expectations. It is important that patients have realistic expectations about pain relief from opioids in order to avoid a situation in which a patient takes more and more medication to relieve all of his or her pain. A common misconception is that complete relief can be obtained from opioids, which may stem from the terminology "pain killers," thus setting an expectation that the medication will eliminate or "kill" all the pain. This unrealistic expectation may set patients up for failure and drive continuous dose escalations. Therefore, it is prudent to ask, "What is a realistic expectation of this therapy?" The Food and Drug Administration (FDA) requires an analgesic to demonstrate at least 30% reduction in pain intensity to gain indication approval.¹⁰ Therefore, a realistic expectation to share with patients is that 30% pain relief is considered treatment success.
   
   Pharmacists can inform patients that opioids alone are often not sufficient to treat pain and are, instead, part of a pain-management plan that includes non-pharmacologic modalities and perhaps concomitant non-opioid analgesics. Furthermore, pharmacists can remind patients that, if their pain does not improve or gets worse, they should contact their prescriber but should not take more medication than prescribed.
   
   
2. Explain what "as needed" means. When opioids are prescribed on an "as needed" basis, patients should know they may take less, but not more, than the maximum daily allowance in any given day. Patients should also know that taking fewer doses one day does not mean they can take more doses the next day.
   
   
3. Discuss risks of dependence and addiction. When counseling patients about adverse effects of opioids, pharmacists should discuss the risks of physical dependence, tolerance, and addiction. Patients should be educated on all 3 phenomena and the differences among them.
   
   
4. Advise on storage and disposal. Patients should be educated on how to safely store and dispose unused medications to prevent diversion or misuse. Controlled substances, especially opioids, should be locked securely in a patient's home to avoid theft. For more information on drug disposal, refer to DEA Registrant Drug Disposal information available at https://www.deadiversion.usdoj.gov/drug_disposal/.¹¹

Communicating with prescribers

If in doubt about the authenticity of a prescription, pharmacists should contact the prescriber for clarification. When calling to verify the validity or legitimacy of a prescription, it is important to keep in mind that individuals who forge prescriptions may give their own number as a call-back number. Therefore, pharmacists should look up the clinic or prescriber's number to verify it directly. Furthermore, when calling clinics or prescribers, pharmacists should notify patients of the need for clarification in a professional manner and should not let them overhear the conversation regarding concerns of legitimacy. Such a conversation may be humiliating to legitimate patients who are already suffering and dealing with stigma. On the other hand, if the prescription is fraudulent, the person may become agitated and threaten the pharmacy staff if the conversation is overheard.

Pharmacists should also contact prescribers about medication-related problems such as drug-drug, drug-food, and drug-disease interactions. For example, for a patient currently on opioids, a prescription for a benzodiazepine or carisoprodol carries a very high risk whether prescribed intentionally or not and whether prescribed by the prescriber of the opioid or by a different prescriber: carisoprodol is metabolized by a cytochrome P450 (CYP) enzyme to meprobamate, which is a sedative-hypnotic that predated commonly used barbiturates; it has a high risk for respiratory depression and a very high abuse potential. In fact, prescribers should be contacted about all drug-drug interactions involving CYP enzymes and opioids: there have been numerous reports of harm and death in patients who were on a stable dose of an opioid and initiated a potent CYP inhibitor. In cases such as these, pharmacists have been held liable for failure to identify and intervene on drug-drug interactions, which underscores the need for pharmacists to be diligent about verifying the safety and legitimacy of every medication dispensed.¹²

ABUSE-DETERRENT FORMULATIONS

The societal and economic impacts that have been caused by the current opioid epidemic have forced the FDA to advocate that pharmaceutical companies research and develop new, innovative, and "safer" opioid formulation options. Once long-term opioid therapy is chosen—after eliminating other analgesic options alone or combined with opioid therapy—ER or LA opioids offer significant benefits over their immediate-release (IR) counterparts. Advantages of ER/LA products include reduction in overall baseline pain, improved sleep, and convenience. Note that IR opioids could additionally be used to manage intermittent, breakthrough pain episodes.

All opioids are susceptible to manipulation in such a way that bypasses their intended route of administration. However, this practice may be more dangerous with ER opioids as they offer a higher "payload" of opioid, greatly increasing the risk of overdose if used intentionally or unintentionally in a way other than intended. This is one of the major premises behind the creation and continued development of abuse-deterrent formulations (ADFs). ADFs include all opioids that have 1 or more properties that increase the difficulty of abuse, make abuse less attractive and/or less rewarding.^13,14 The FDA distinguishes ADFs on the basis of several categories: physical/chemical barriers, agonist/antagonist combinations, aversion technologies, delivery system technologies, new molecular entities and prodrugs, different combinations of these ADFs, or novel approaches.^13,14 Table 3 describes each of these categories,¹⁴ and Table 4 highlights different physical and chemical barriers commonly used by many opioid products.¹⁵

Table 3: Abuse-deterrent Properties14
Property	Description	Examples of commercially available products*
Physical/chemical barriers	Physical barriers may prevent chewing, crushing, cutting, grating, or grinding Chemical barriers may resist extraction of the opioid using common solvents (e.g., water, alcohol) Both barriers can limit drug release following manipulation of the product or change the physical form of the drug	Oxaydo Nucynta ER OxyContin Hysingla Zohydro Exalgo Remoxy MorphaBond RoxyBond Vantrela OxyContin Xtampza ER
Agonist/antagonist combinations	An opioid agonist co-formulated with an antagonist to interfere with, reduce, or diminish euphoria associated with abuse The antagonist should only be released upon manipulation of the product as to not precipitate withdrawal	Suboxone, Zubsolv, Bunavail (buprenorphine co-formulated with naloxone)a Embeda (morphine sulfate co-formulated with naltrexone) Troxyca ER (oxycodone co-formulated with naltrexone) Talwin NX (pentazocine co-formulated with naloxone)a
Aversion technologies	Substances added to the product to produce unpleasant effects if the formulation is manipulated or used at higher doses than directed	Oxaydo (oxycodone formulated with sodium lauryl sulfate, which causes nasal burning and throat irritation when snorted)
Delivery system innovations	Specific drug-release designs that offer resistance to abuse	Examples may include sustained-release depot injectable formulations or subcutaneous implants
New molecular entities and prodrugs	Any new molecular entities and/or prodrugs that can help deter abuse including the need for enzymatic activation, different receptor binding profiles, slower penetration into the central nervous system, or other novel effects	Apadaz NKTR-181
Combinations	Agents utilizing 2 or more of the above methods	Oxaydo
Novel approaches	Encompasses novel approaches or technologies that are not captured in the previous categories
*See Table 4 for more details on formulations. ER, extended release. a Products co-formulated with naloxone only have the mu-receptor antagonism effects when used intranasally or intravenously. Naloxone is not systemically absorbed when taken orally, thus these products may still be abused orally.

Table 4: Physical and Chemical Barriers That Help Deter Abuse15
Barrier	Description	Examples of commercially available products and technologies
Physical barriers
Polyethylene oxide (PEO)	High molecular weight, non-ionic, hydrophilic polymer-based matrix High glass transition temperature range (-50 to -57 °C) allows it to undergo ductile deformation instead of brittle fracture under mechanical stress, preventing pulverization by crushing When it comes into contact with water, PEO hydrates rapidly and turns into a viscous solution or gel Not soluble in most household solvents Thermally processed PEO matrices do not break but flatten	Oxaydo Nucynt ER utilizing INTACT technology OxyContin utilizing RESISTEC Hysingla ER utilizing RESISTEC Zohydro utilizing BeadTek technology Exalgo utilizing OROS technology
Sucrose acetate isobutyrate	Hydrophobic, water-insoluble, thermally-stable liquid used to prepare sustained-release gel capsules Remains highly viscous over a wide temperature range (-80 to 100 °C)	Remoxy utilizing ORADUR technology
Superabsorbent materials	Usually contain crosslinked acrylic polymers that absorb large quantities of water (hence termed "superabsorbents") Small size and high radius of curvature help resist crushing Swells rapidly into a hard gel when exposed to an aqueous environment (e.g., ethanol)	MorphaBond RoxyBond
Lipids	Commonly used for solubility enhancement, sustained-release matrices, and self-emulsifying systems Lipid-based formulations can be useful because of their lipophilicity and low solubility in ethanol	Vantrela ER utilizing OraGuard technology
Foam-forming agents	Composed of effervescent mixtures containing an organic acid and base, a surfactant, and high and low viscosity polymers formulated in the tablet If milled and added to a solvent, a stiff foam is generated that cannot be drawn into a syringe Adding additional solvents causes more foam to grow Foam is also formed upon contact with the nasal mucosa, which leads to a coughing reflex when snorted/inhaled
Ceramic particles	Nanoparticles of titanium dioxide and other related ceramic compounds that are spherical with a hollow core, allowing for high loading of drug Increases resistance to diversion attempts such as grinding
Chemical barriers
Salt formation between opioid free bases and fatty acids	Capsules containing microspherical particles consisting of fatty acid salts of opioid bases, with excess fatty acids and waxes, which cause the opioids to become more lipophilic Microparticles do not dissolve in water or organic solvents Difficult to extract drug from the intimately mixed composition Also allows for slow release of drug, even if chopped or crushed	OxyContin ER utilizing DETERx technology Xtampza ER utilizing DETERx technology
Complexation with ion-exchange resins	Forming a complex between a drug and resin is the process that reversibly interchanges ions between a liquid and solid phase Allows for regulated release of the drug by chemical and physical mechanisms, as release of active ingredient is triggered by ion-exchange reactions with counter ions present in the gastrointestinal tract, thus decreasing the ability to "dose dump" Ion-exchanging process continues until equilibrium is reached and, because of this, it does not lead to a proportional increase in drug release if increased doses are taken	Nobuse technology KCTP (Kinetically Controlled Tamper Protection) technology

In 2015, the FDA released guidance and criteria for pharmaceutical companies to follow in order for those companies to include abuse-deterrent labeling in their medication package inserts.¹³ Essentially, the FDA now recommends these companies conduct 3 premarket studies—labeled categories 1, 2, and 3—and post-market studies—labeled category 4—in order for the companies to include abuse-deterrent labeling.¹³ The premarket studies include laboratory-based in vitro manipulation and extraction studies (category 1), pharmacokinetic studies (category 2), and clinical abuse potential studies (category 3).¹³ The results of these premarket studies need to be confirmed by category 4, post-market trials. Of note, to date, no company has achieved category 4 status for any opioid product.

As of 2017, there are 10 opioids that have been designated by FDA-approved product labeling detailing abuse-deterrent studies related to their ADFs. These include 5 oxycodone products (OxyContin, Targiniq ER, Xtampza ER, Troxyca ER, and RoxyBond), 3 morphine products (Embeda, MorphaBond, and Arymo ER), and 2 hydrocodone products (Hysingla ER and Vantrela ER). Table 5 outlines the major differences among the formulations.^16-28 Notably, most of the formulations have been designed with physical and chemical abuse-deterrent properties, including the use of RESISTEC technology by OxyContin CR and Hysingla ER, CIMA Lab technology by Vantrela ER, SentryBond technology by both MorphaBond and RoxyBond, Guardian technology by Arymo ER, and DETERx technology by Xtampza ER. Embeda ER and Troxyca ER are the only opioids that utilize the agonist/antagonist approach (both are co-formulated with naltrexone) with FDA-approved abuse-deterrent labeling.

Table 5: Opioids with Abuse-deterrent Properties
Brand name	Generic name	Formulation	Year of FDA approval	Manufacturer	Abuse-deterrent technology
Hydrocodone products
Hysingla16,17	Hydrocodone bitartrate	Extended-release tablets	2014	Purdue Pharma L.P.	RESISTEC technology Physiochemical properties allow increased resistance to crushing, breaking, and dissolution Forms a viscous hydrogel on contact with liquid
Vantrela ER18,19	Hydrocodone bitartrate	Extended-release tablets	2017	Teva Pharmaceuticals USA, Inc.	CIMA Lab technology that is based on a multi-layer polymer coating permitting extended drug release This extended release is maintained when crushed Other abuse deterrent properties include increased resistance to extraction for IV use and dose dumping in alcohol
Morphine products
Embeda ER20	Morphine sulfate co-formulated with naltrexone hydrochloride	Extended ­release capsules	2009a	Pfizer Inc.b	Co-formulation with opioid antagonist naltrexone Naltrexone is released from sequestered bead core when capsule contents are manipulated by crushing
MorphaBond ER21,22	Morphine sulfate	Extended-release tablets	2015	Daiichi Sankyo, Inc.	SentryBond technology Formulated with inactive ingredients that make it difficult to adulterate tablet Resistant to cutting, crushing, or breaking Forms a viscous material on contact with liquid
Arymo ER23,24	Morphine sulfate	Extended-release tablets	2017	Egalet US Inc.	Guardian technology Polymer matrix tablet that resists manipulation Forms a viscous hydrogel on contact with liquid
Oxycodone products
OxyContin CR25	Oxycodone	Controlled-release tablets	2013c	Purdue Pharma L.P.	RESISTEC technology Allows increased resistance to crushing, breaking, and dissolution Forms a viscous hydrogel on contact with liquid
Xtampza ER26	Oxycodone	Extended-release capsules	2016	Collegium Pharmaceutical, Inc.	DETERx microsphere technology Inactive ingredients form lipophilic salt permitting homogenous distribution of the active drug in each waxy microsphere Microspheres solidify within a needle Capsules can be emptied into G-tube or sprinkled on food
Troxyca ER27	Oxycodone co-formulated with naltrexone	Extended-release capsules	2016	Pfizer	If capsules are crushed or chewed, up to 100% of sequestered naltrexone is released, blocking opioid receptors and preventing mu receptor agonism
RoxyBond28	Oxycodone	Immediate-release tablets	2017	Daiichi Sankyo, Inc.	SentryBond technology Incorporates inactive ingredients making the tablet more difficult to manipulate, even if subjected to physical manipulation and/or chemical extraction
FDA, United States Food and Drug Administration; IV, intravenous. a Embeda was originally approved by the FDA in 2009; labeling for abuse-deterrent features was approved in 2014. b Pfizer discontinued Avinza following approval for updated labeling on Embeda. c OxyContin was originally approved in 1996, but it was reformulated in 2010 with abuse-deterrent technology and became the first opioid with FDA-approved labeling describing abuse-deterrent characteristics in 2013.

There are several opioids currently being tested in clinical trials or are in development that incorporate novel abuse-deterrent properties and technologies. REL-1015 (Levocap ER) has been developed by Relmada; it is an ER levorphanol product currently in phase 3 trials.^15,29 This product utilizes SECUREL technology that helps prevent it from being crushed through its physical and chemical properties, as well as increases the difficulty for abusers of intravenous drugs to extract the active drug from the dosage form.^15,29 FT227 is an ER hydromorphone product that has been developed by Avandel Pharmaceuticals and is currently in phase 2 trials.^15,30 This product uses Trigger Lock technology that contains sustained-release Micropump particles that are resistant to crushing; are resistant to drug extraction through alcohol, water, and other mediums; and prevent injection through viscosifying ingredients.^15,30

KemPharm currently has 4 opioid prodrug product candidates in clinical trials that use their Ligand Activated Therapy (LAT) technology, including Apadaz (hydrocodone/acetaminophen), KP201/IR (IR hydrocodone), KP511/ER (ER hydromorphone), and KP511/IR (IR hydromorphone).³¹ LAT technology is a novel prodrug platform in which 1 or more molecules or ligands are chemically attached to an FDA-approved parent drug, creating a prodrug designed to improve its abuse-deterrent attributes.³¹ Once the medication is administered orally, normal metabolic processes in the gastrointestinal tract separate the ligand from the prodrug and release the parent drug so that it may exert its therapeutic effect.³¹ Notably, in preclinical studies of KP511/ER, in rats, hydromorphone blood levels increased more slowly and to a lesser extent after oral administration of increasing excessively large doses of KP511/ER compared to oral doses of hydromorphone HCL.³² This represents an important step toward achieving protection against oral overdose.

A new chemical entity, NKTR-181, has been developed by NEKTAR. It is a long-acting, mu-opioid receptor agonist that has an abuse-deterrent property integrated into its chemical structure.³³ It is thought that rapid entry into the blood-brain barrier by almost all currently available mu-opioid receptor agonists is the reason for such fast and concentrated release of dopamine in the locus coeruleus, which, in turn, causes immediate euphoria and is the primary mediator of addiction. NKTR-181 is essentially a pegylated form of oxycodone that allows for reduced permeability across the blood-brain barrier, vastly slowing its rate of entry into the brain.³³ The benefit would be to attenuate the rapid dopamine release, which would minimize euphoria and possibly decrease the neuroplastic changes associated with the development of addiction.³¹ Pre-clinical data has shown that NKTR-181's pegylated structure does reduce the rate of entry into the brain compared to standard opioids, regardless of the route of administration, and it is currently undergoing phase 3 trials to determine its approval status.³³

Currently, the only IR opioid product that has FDA-approved abuse-deterrent labeling is RoxyBond, which was approved in April 2017.²⁸ This advancement is significant because IR products possess a similar risk of abuse to ER products if taken in sufficient quantities. Additionally, IR products are generally less expensive, more readily available, and are not generally available in ADFs, all of which increase their potential for abuse. The continued development of IR products with abuse-deterrent properties is an important area of research.

ER/LA OPIOID ANALGESIC RISK EVALUATION AND MITIGATION STRATEGY

ER/LA opioid analgesics are often used for patients with chronic pain because they offer several advantages. Compared to their short-acting counterparts, they offer prolonged analgesia and more consistent plasma concentrations with gradual peaks and troughs, which minimizes end-of-dose breakthrough pain and theoretically reduces the risk and severity of side effects.³⁴ All of these benefits, however, only occur if the opioids are prescribed appropriately and taken in an appropriate fashion, meaning they are not manipulated in ways that allow the user to receive a higher "payload" of opioid.

In addition to incorporating ADFs into opioids, opioid abuse and misuse can be mitigated through programs such as the ER/LA Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS). This program was first introduced and approved by the FDA in July 2012. The ultimate goal of this specific REMS program is to reduce serious adverse outcomes resulting from inappropriate prescribing, misuse, and abuse of ER or LA opioid analgesics while maintaining patient access to pain medications.³⁵

The FDA requires several elements of the REMS program to be followed when ER/LA opioids are prescribed to patients. First, a medication guide must be dispensed with every ER/LA opioid analgesic prescription.³⁵ There are also extensive training requirements in place to ensure safe use of the drugs, including required training and continuing education for healthcare providers who prescribe ER/LA opioid analgesics.³⁵ The content of the training courses is directed by the FDA's "Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics."³⁶ Although the content is directed toward prescribers of ER/LA opioids, the Blueprint is applicable and relevant to other healthcare professionals, including pharmacists.

Pharmacists have an important role to uphold the true objective of this REMS initiative. Since community pharmacists are far more accessible to patients than other clinicians, they have the best opportunity for face-to-face counseling with patients and caregivers. Considering pharmacist education, overall expertise, and background, they are, without a doubt, the most well-suited medication experts to deliver important messages intended by the REMS program. All patients receiving prescriptions for opioids should be counseled thoroughly regarding the inherent risks of use and the major dangers if used inappropriately—and even if used appropriately. It is important for community pharmacists to use multiple techniques to identify patients who are potentially misusing or abusing prescription opioids, including utilizing state PDMPs and recognizing risky or red-flag behavior. It is equally important for pharmacists to serve as a double-check to providers by understanding differences in opioid potencies and always ensuring that doses prescribed are appropriate for a specific patient (e.g., opioid-naïve vs. opioid-tolerant patients).

There are growing numbers of pharmacists who work alongside other healthcare providers in pain management clinics, which gives these pharmacists opportunities to emphasize the REMS program initiative. They should take full advantage of the opportunity to work in this team-centered environment and offer their expertise in pharmacotherapeutics, pharmacokinetics, and pharmacogenetics to help determine and guide optimal and appropriate pain management treatments. These pharmacists are also in positions to provide extensive and thorough counseling to patients in clinic before any prescriptions are initiated.³⁷

REFERENCES

1. Drug Enforcement Administration Office of Diversion Control. Code of Federal Regulations. Section 1306.04: Purpose of issue of prescription. http://www.deadiversion.usdoj.gov/21cfr/cfr/1306/1306_04.htm. Accessed October 5, 2017.
2. American Academy of Pain Medicine; American Pain Society; American Society of Addiction Medicine. Definitions related to the use of opioids for the treatment of pain: consensus statement. https://www.asam.org/advocacy/find-a-policy-statement/view-policy-statement/public-policy-statements/2011/12/15/definitions-related-to-the-use-of-opioids-for-the-treatment-of-pain-consensus-statement. Revised February 1, 2001. Accessed October 5, 2017.
3. Passik SD. Issues in long-term opioid therapy: unmet needs, risks, and solutions. Mayo Clin Proc. 2009;84(7):593-601.
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