Advances in Therapy

, Volume 31, Issue 3, pp 264–275

Tamper-Resistant Opioid Formulations in the Treatment of Acute Pain

Authors

    • Millennium Laboratories, Inc. and Millennium Research Institute
Review

DOI: 10.1007/s12325-014-0099-7

Cite this article as:
Passik, S.D. Adv Ther (2014) 31: 264. doi:10.1007/s12325-014-0099-7

Abstract

Introduction

Pain—including acute or persistent acute pain—is a common condition that is increasingly being treated with opioids in the United States. The acute pain treatment setting may represent a key target for addressing the growing epidemic of prescription drug abuse occurring hand in hand with the rise in opioid prescribing. Balancing the needs of pain treatment with abuse prevention can be challenging for clinicians.

Methods

This article identified efforts to balance opioid abuse risks with opioid availability through the extensive experience of the author in this field. In addition, PubMed literature searches using terms such as “prescription opioid abuse”, “abuse-deterrent opioids”, and “tamper-resistant opioids”; and inspection of the bibliographies of relevant articles were used to identify relevant sources.

Results

These multifaceted efforts have included: improving assessment of patient risk for drug misuse, abuse, or diversion; funding of and encouraging referral to addiction treatment programs; access to and widespread use of prescription monitoring programs (PMPs); public knowledge of prescription opioid abuse; proper storage of opioid medications; and development of new formulations designed to resist tampering and deter abuse. This review discusses the problem of prescription opioid abuse and strategies to minimize risk within the context of acute pain treatment, and explores the potential role of tamper-resistant opioid formulations and other abuse deterrence strategies in the area of acute or persistent acute pain management.

Conclusion

In order to stem the tide of prescription opioid abuse and preserve the availability of opioids as a much needed analgesic option, a multifaceted approach that includes tamper-resistant opioid formulations—for chronic or acute pain—along with strategies such as improved patient risk assessment, funding for and referral to addiction treatment programs, greater use of PMPs, and raised awareness of prescription opioid abuse is needed.

Keywords

Acute painOpioid abuseOpioidsPainPain medicationsTamper-resistant formulations

Introduction

Acute and persistent acute pain are common conditions that are increasingly being treated with opioids in the United States (US). According to data from the National Health and Nutrition Examination Survey, 26% of Americans aged 20 years or older reported pain lasting longer than 24 h in the month prior to interview, of whom 32.0% said it lasted less than a month and 12.3% said it lasted from 1 to 3 months [1]. Pain-related visits have been estimated to account for more than 40 million emergency department (ED) visits annually, and most of the 73 million patients undergoing surgical procedures in the US each year experience significant acute postoperative pain [2, 3]. From 1993 to 2005, pain was the primary reason for 42% of ED visits; during this period, opioid prescribing for pain-related visits increased significantly from 23% to 37% (P < 0.001) [3]. The common practice of treating acute pain with opioids is likely an important contributor to the increasingly widespread use of prescription opioids in the US.

Hydrocodone is the most frequently prescribed medication in the US, amounting to nearly 140 million prescriptions in 2011 [4]. Among opioid prescriptions, hydrocodone- and oxycodone-containing products predominate (85%), according to a nationally representative prescription database analysis for 2009 [5]. Most opioid prescriptions were for short periods (19.1% for less than 2 weeks; 65.4% for 2–3 weeks), and 11.7% were for patients aged 10–29 years [5]. Primary-care physicians (28.8%), internists (14.6%), dentists (8.0%), and orthopedic surgeons (7.7%) were the most common prescribers; dentists were the largest prescribers of opioids for young people (patients aged 10–19 years, 30.8%) [5].

The predominance of short-term opioid prescriptions by non-pain specialists suggests that the acute pain treatment setting may provide an opportunity for addressing the continued increase in prescription opioid abuse. Overall, approximately 12 million Americans aged 12 years and older reported non-medical use of prescription painkillers in 2010, with 8%–10% of high-school seniors reporting past-year non-medical use of hydrocodone and 4%–5% reporting past-year non-medical use of oxycodone since 2002 [6, 7].

Analyses assessing trends over time have indicated substantial increases in problems related to prescription opioids. For example, chronic non-medical use of prescription pain medications increased by 74.6% from 2002–2003 to 2009–2010 [8], drug treatment admissions related to prescription opioids increased more than fivefold from 19,941 to 121,091 between 1998 and 2008 [7], ED visits related to prescription opioids more than doubled from 144,600 to 305,900 between 2004 and 2008 [9], and prescription opioid overdose deaths nearly quintupled from 3000 to just under 15,000 between 1999 and 2008 [10, 11]. Moreover, the number of overdose deaths in the US related to prescription opioids is higher than for deaths related to cocaine or heroin overdoses combined [10, 11].

A major challenge to clinicians is the difficulty of balancing the needs of pain treatment with mitigating the risks for abuse. Historically, a growing awareness and attention to the need to adequately treat pain (evidenced, for example, by the Congressional declaration of 2001–2010 as the “Decade of Pain Control and Research” and the Joint Commission on the Accreditation of Health Care Organizations mandate to assess pain as a vital sign) was quickly followed by a rise in rates of opioid prescribing and a corresponding rise in rates of prescription opioid abuse [2, 4, 12]. This has created a conflict for clinicians who may need to prescribe opioids to adequately treat pain but, on the other hand, limit opioid prescribing for the benefit of society [12]. The current climate—including a great deal of media attention—tends to focus on the risks of opioid abuse, which may inhibit opioid prescribing and leave some patients with inadequately treated pain. Although the medical community is increasingly aware of the negative consequences of overprescribing opioids, very few real alternatives exist to sufficiently relieve moderate to severe pain for certain patients and clinical situations, in particular acute pain in patients at risk for abuse. Thus, all stakeholders—patients, healthcare providers, law enforcement personnel, pharmaceutical manufacturers, and third-party payers—should share a role in reducing risks of opioid abuse while preserving the availability of opioid therapy for patients in genuine need.

The purpose of this review is to discuss the problem of opioid abuse within the context of acute pain treatment and describe the strategies implemented and the future initiatives that may help minimize that risk, with a focus on the potential role of tamper-resistant opioid formulations in the area of acute or persistent acute pain management.

Methods

This review assessed the literature qualitatively based on the author’s expertise and experience with chronic and acute pain treatment and abuse risks. In addition, PubMed searches were conducted using relevant search terms, including “prescription opioid abuse”, “abuse-deterrent opioids”, and “tamper-resistant opioids”, for articles indexed before October 2012. Governmental sources and bibliographies of relevant articles were also inspected manually to identify additional sources. Articles were selected for inclusion at the author’s discretion. This article is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by the author.

Risks of Opioid Abuse in Acute Pain Settings

Acute pain has been characterized as a “complex, unpleasant experience with emotional and cognitive, as well as sensory, features that occurs in response to tissue trauma” [13, 14]. Patients requiring opioid analgesia for acute pain are typically prescribed an immediate-release (IR) formulation. The drug prescribed often contains hydrocodone or oxycodone, which may be given in quantities greater than needed to last until the episode of acute pain resolves. The drugs may also be stored and disposed of improperly by the patient. Together, these factors can increase the risks of opioid diversion and abuse. National drug abuse surveillance data indicate that hydrocodone and oxycodone are the most commonly abused prescription opioids on a population basis—although not when adjusted for prescription volume—and that, in general, IR opioids are responsible for a higher proportion of misuse, abuse, and diversion cases than extended-release (ER) opioids (Fig. 1) [1517]. The National Survey on Drug Use and Health reports that a friend or family member, or a prescription from a single healthcare provider, are the most common sources of abused opioids [18]. Obtaining opioids from the street is especially common among young people aged 25 years or younger, with the likelihood of abusing opioids from a doctor’s prescription increasing with age [19].
https://static-content.springer.com/image/art%3A10.1007%2Fs12325-014-0099-7/MediaObjects/12325_2014_99_Fig1_HTML.gif
Fig. 1

Proportion of opioid abuse cases for immediate-release versus extended-release opioids in the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS®) System, 2008 [17]. Reprinted with permission from RADARS® System News, © 2009 RADARS System [17]. CS college survey, DD drug diversion, IHCW impaired health care workers, KI key informants, OTP opioid treatment programs, PC poison centers, SKIP survey of key informants’ patients

Thus, leftover medication from patients with resolved acute pain represents a serious possible source for abuse and diversion. In a study of postoperative pain management, two-thirds of patients interviewed responded that they had leftover medication from the initial prescription; 90.8% of these patients kept the medication at home [20]. In a pilot study investigating how patients who had been prescribed opioids in the ED stored and disposed of their medication, none of the 20 patients interviewed had safely stored their medication in a locked container or cabinet, nor had they properly disposed of unused pills [21]. Another study analyzed a subset of 192 young adults (aged 21–26 years) from the College Life Study (a large, ongoing, prospective longitudinal study) who reported that they had been prescribed an analgesic (89% had received opioids) for acute pain in the past year; overall, 27% of the patients diverted their pain medication (29% of those prescribed opioids) [22]. Those who overused their own prescribed medication were the most likely to divert it to others (63%), and the study authors noted that some patients probably had enough doses from their prescriptions to accomplish both [22].

The above findings highlight the interplay between patient behavior and clinician prescribing practices in contributing to opioid abuse. The majority of opioids in the US are prescribed by clinicians who are not in specialties related to pain management, may be inadequately trained to treat pain, and may have less training or experience in identifying and addressing issues of opioid abuse [23]. In 2009, 42% of IR opioids and 44% of long-acting opioids were prescribed in the US by primary-care physicians, in contrast to pain management-related specialties, which accounted for 6% of IR opioid and 23% of long-acting opioid prescriptions [23]. The most common specialties for prescribing IR opioids in the US are general practice/family practice/osteopathic medicine (26.7%), internal medicine (15.4%), dentistry (7.7%), orthopedic surgery (7.4%), and emergency medicine (4.7%) [24]; dentists alone may prescribe an estimated 1–1.5 billion doses of IR opioids each year [25].

While the abuse risk associated with short-term opioid prescriptions focuses primarily on the potential for diversion, an additional factor to consider is the potential for at-risk patients to develop iatrogenic opioid addiction during longer-term opioid treatment. In a study of acute pain resolution following discharge from the ED, 54.6% of patients had a pain level of 4 or greater on day 4 [26]; over the full 6-day follow-up period after ED discharge, 21% of patients had either a lack of pain resolution or worsening pain over time, with a trajectory predicting no immediate improvement or even worsening, rather than the expected improvement [26]. This lingering pain, together with a large body of literature on the development of persistent postoperative pain, indicates a subset of patients for whom an episode of what was expected to be “acute” pain may lead to longer-term pain with potentially longer-term exposure to opioid therapy [26, 27]. Whether or not the initial opioid prescription was for acute pain, prescribing pattern data from a large Veterans Affairs database analysis showed that about 10% (2,195 of 22,125) of patients prescribed IR oxycodone/acetaminophen (OC/APAP) used it long term (>9 months continually at stable doses in most cases), which was distinct from the 75% of the cohort receiving OC/APAP prescriptions for 2 months or less [28]. Using OC/APAP for a longer duration was associated with a greater number of drug abuse/dependence diagnoses [28]. This suggests that IR opioid formulations, such as OC/APAP, are being used chronically in at least some patients who may be at risk for developing opioid abuse, depending on individual patient factors. Therefore, it is important for physicians to conduct thorough risk–benefit analyses to identify individuals who may themselves be at risk for abusing prescription opioid analgesics or may have an individual living with them who may be at risk.

Strategies for Reducing Risks of Opioid Abuse

Tamper-Resistant Opioid Formulations

One facet of the effort to reduce prescription opioid abuse and diversion has been the development of opioid formulations by the pharmaceutical industry that are intended to deter tampering and abuse [29, 30]. However, this effort has largely only been discussed in the realm of treating chronic pain and ER opioid formulations, but lessons from the recent history of the availability of such formulations in this area could also be instructive for developing formulations with similar properties that can be used to treat acute pain. First, a distinction should be drawn between what tamper-resistant formulations can and cannot accomplish. They may inhibit some forms of abuse, such as converting an ER opioid into an IR formulation by manipulating the tablets to defeat the ER properties and gain access to the entire opioid dose or extracting the dose for injection or snorting. Although the most common means of abuse is through oral ingestion, abusers may progress from oral administration to snorting or intravenous use over time [31]. In other words, these formulations are designed to deter recreational drug abusers seeking a rapid “high,” but are less likely to prevent misuse by pain patients taking too many doses [29]. Therefore, these formulations should be viewed not as a fix for the problem of prescription opioid abuse but rather as options for patients with risk–benefit profiles that warrant use of an abuse-deterrent opioid. These formulations are an additional effort to be used in conjunction with other means for helping reduce the risk for opioid misuse and diversion. Although current formulations are primarily targeted to non-medical users, formulations that are less attractive for any type of recreational use would presumably be less likely to be diverted from legitimate medical use. Because legitimate prescription medications are so often borrowed, stolen, or obtained from friends or family members by those who seek to use them non-medically, the wider use of tamper-resistant formulations may help to reduce opioid abuse [29].

Conversion to tamper-resistant opioid formulations will require that patients, prescribers, and payers share a role in addressing this public health problem. Importantly, insurers may be resistant to pay for abuse-deterrent formulations that cost more than currently available generic formulations. The onus, therefore, falls upon the prescriber to perform risk–benefit analyses to identify patients who are at risk for abusing these drugs or may have an individual living with them who may be at risk for abuse. For instance, the Opioid Risk Tool (ORT) can be administered to patients as a standard procedure for patients being prescribed opioid analgesics to assess their potential for abuse [32]. The ORT assesses several potential risk factors for abuse, including sex, personal or familial histories of alcohol and illicit or prescription drug abuse, age, and psychiatric comorbidities. Different treatment strategies can then be used depending on the patient’s perceived risk for abusing prescription opioid analgesics. For example, a patient who is at risk for abuse and experiencing pain that is severe enough to warrant treatment with an opioid may benefit from the use of an abuse-deterrent formulation, whereas a patient who has no perceived risk for abuse may be better treated with a less costly generic formulation.

Currently, only one tamper-resistant IR opioid formulation was identified that is approved for treating acute pain. This single entity oxycodone formulation (Oxecta®; Pfizer Inc., New York, NY, USA) has been designed to deter insufflation by causing irritation to the nasal passage [33]. A clinical abuse potential study conducted with participants with histories of intranasal oxycodone abuse has demonstrated that the intranasal administration of this formulation was associated with significantly lower scores on scales that measured drug liking and desire to take the drug again than the traditional IR oxycodone formulation [34]. In addition, a combination OC/APAP analgesic with purported abuse-deterrent properties is currently under development by Mallinckrodt Inc. (Hazelwood, MO, USA) for treating acute pain. Studies conducted with the product (i.e., OC/APAP ER) have not been published in peer-reviewed journals, but they have begun to be presented at scientific meetings. OC/APAP ER has been designed with both IR and ER components that produce initial increases in oxycodone and acetaminophen plasma concentrations followed by a second phase that sustains plasma concentrations over an extended period to allow for 12-h dosing [35]. This pharmacokinetic profile addresses a major issue of using an ER opioid to treat acute pain (i.e., the delayed onset of effects associated with these products). A press release from the manufacturer has stated that this formulation has met the primary endpoint in a phase 3, pivotal clinical trial and is currently under review with the US Food and Drug Administration (FDA) [36]. Results from this acute pain bunionectomy trial have demonstrated that OC/APAP ER produces a significantly greater degree of pain relief than placebo beginning at 30 min after the first dose that was maintained throughout the 48-h study period [37]. Furthermore, in an abuse potential study conducted with recreational users of prescription opioids, OC/APAP ER was shown to produce significantly lower levels of drug liking, drug high, and good drug effects than IR OC/APAP [38].

In contrast, three tamper-resistant ER opioid formulations are currently available that are approved for treating chronic pain: OROS® hydromorphone ER (Exalgo®; Mallinckrodt Inc.) [39]; reformulated oxycodone controlled-release (OxyContin®; Purdue Pharma L.P., Stamford, CT, USA) [40]; and reformulated oxymorphone ER (Opana® ER; Endo Pharmaceuticals Inc, Chadds Ford, PA, USA) [41]. Despite the availability of these formulations, clinicians may be unwilling to prescribe, and payers may be unwilling to cover, a new formulation introduced solely for the sake of reducing abuse. Therefore, the benefits of using these agents must be weighed against the potential risks of prescribing more easily abused formulations. Reformulated oxycodone controlled-release was introduced in August 2010 and has been shown to successfully reduce abuse rates of this formulation; however, the unexpected consequence is that opioid abusers appear to have shifted to different formulations that are not as difficult to abuse [4244]. After the introduction of the reformulated oxycodone controlled-release, news reports and law enforcement officials noted an increased incidence of oxymorphone ER pharmacy theft and abuse, before the introduction of its tamper-resistant formulation in June 2012 [42, 43]. In addition, surveys of prescription opioid abusers entering treatment programs around the US reported that oxycodone controlled-release went from being the primary drug of abuse for 36% of prescription drug abusers prior to August 2010 to just 13% in the first quarter of 2012, a significant decrease (P < 0.001) [44]. However, this report noted a corresponding increase in the use of other prescription opioids (such as high-potency fentanyl and hydromorphone) as abusers’ drugs of choice and a near doubling in rates of heroin use [44].

These scenarios suggest that, although these formulations may have the desired effect of reducing abuse of a given product, addressing the prescription opioid abuse epidemic while retaining access to opioids for appropriate pain management remains a daunting challenge. Development of tamper-resistant products may help address abuse and diversion of opioids prescribed for acute pain. Ultimately, lowering overall opioid abuse will require multifaceted efforts.

Additional Strategies for Reducing Risks of Opioid Abuse

Beyond the development of formulations that are designed to resist tampering and deter abuse, various efforts to balance opioid abuse risks with availability have been employed. These multifaceted efforts have included: initiatives to improve assessment of patient risk for engaging in drug misuse, abuse, or diversion [32, 45, 46]; funding of and encouraging referral to addiction treatment programs; access to and widespread use of prescription monitoring programs (PMPs); urine drug testing (UDT) [47]; public knowledge of prescription opioid abuse; proper storage of opioid medications; and assessment and monitoring of comorbid psychiatric disorders that might involve self-medication [48, 49]. Data suggest that implementation of PMPs can have a positive effect on prescription opioid abuse and misuse by not only identifying individuals that are seeking multiple prescriptions (i.e., doctor shoppers) but also identifying excessive physicians’ prescribing and pharmacists’ dispensing of opioid analgesics [50]. Data from states with PMPs collected between 2003 and 2009 have reported a slower rate of increase in poison center exposures (0.2% vs. 1.9%; P = 0.036) and opioid treatment center admissions (2.6% vs. 4.9%; P = 0.058) than states without PMPs [51]. In 2002, the US Government Accountability Office conducted an analysis of the time needed to identify doctor shoppers and found an 80%–90% decrease in the time to initiate an investigation following the implementations of PMPs in Kentucky, Nevada, and Utah in the US [52]. Furthermore, a 2012 review of peer-reviewed research of PMPs suggests that these programs have led to a reduction in doctor shopping, changes in prescribing behaviors, and a reduction in the supply of prescription opioids, which taken together has led to a decrease in the likelihood of abusing these drugs [53].

A key strategy for reducing the risk of opioid abuse is assessing patient risk [54]. Factors associated with a patient’s risk for opioid abuse exist in three basic categories: factors related to the drug, individual psychosocial variables, and/or genetic vulnerability to addiction [23].

Several risk assessment tools have been developed to aid clinicians in assessing abuse risk for patients receiving or being considered for chronic opioid therapy [54]. However, this type of assessment rarely seems to occur in clinical practice for patients who are prescribed opioid therapy for short-term, acute pain. Nevertheless, the 2012 guidelines for responsible opioid prescribing note that principles of risk stratification to prevent opioid misuse and abuse for patients with chronic pain may also be applied to “patients who are treated for acute pain management, but also have other risk factors and for whom pain may become chronic” [55]. These guidelines state that all clinicians prescribing opioids should be knowledgeable about the risk factors for opioid abuse [55].

The need for increased prescriber education regarding pain management, opioid pharmacology, and issues involved in abuse and addiction is recognized as an integral part of any comprehensive effort to curb the problem of prescription opioid abuse and diversion [7, 56]. Both the President’s national plan for addressing prescription drug abuse (Epidemic: Responding to America’s Prescription Drug Abuse Crisis [57], released in April 2011), and the class-wide risk evaluation and mitigation strategy (REMS) for extended-release and long-acting opioids [58, 59] mandated by the FDA, contain elements addressing prescriber education, along with education for patients and parents of adolescents or young adults regarding the appropriate use, storage, and disposal of opioids [11]. Although these educational approaches are an important step in reducing the risk of prescription opioid abuse while maintaining the availability of opioids for appropriate patients, education alone will not be sufficient [7, 59]. Other key elements in the national response to this issue include the continued implementation of PMPs in all states to identify aberrant patient, physician, and pharmacist behaviors, the development of prescription drug disposal programs to help limit drug diversion, and increased law enforcement efforts against “pill mills” (i.e., clinical practices knowingly and illegally prescribing opioids in high volume to drug abusers) and people contributing to prescription drug trafficking [7, 11, 57].

Conclusion

Opioids prescribed for acute pain—usually intended for short-term therapy—represent a major source of available opioids for diversion and abuse. ER opioids generally prescribed for chronic pain have been developed in tamper-resistant formulations to limit their desirability to drug abusers. Development of an opioid product with tamper-resistant properties may be a beneficial alternative to IR opioids when immediate analgesia and around-the-clock pain relief are needed, as it may reduce the potential for opioid diversion and abuse in the acute pain setting. In addition, such a formulation may help to reduce the number of pills by decreasing the daily doses compared to currently available IR formulations that generally have 4- to 6-h dosing intervals. In order to stem the tide of prescription opioid abuse and preserve the availability of opioids as a much needed analgesic option, a multifaceted approach that includes tamper-resistant opioid formulations—for chronic or acute pain—along with strategies such as improved patient risk assessment, funding for and referral to addiction treatment programs, greater use of risk management tools (e.g., PMPs, UDT), and raised awareness of prescription opioid abuse is needed. Applying the lessons learned from the development of abuse-deterrent ER opioids for chronic pain to the development of an abuse-deterrent opioid that can be used for treating acute pain will be important.

Acknowledgments

Technical editorial and medical writing assistance was provided by Marci Mikesell, PhD, Synchrony Medical Communications, LLC, West Chester, PA, USA, under the direction of the author. Funding for this support and the article processing charges was provided by Mallinckrodt Inc., Hazelwood, MO, USA. The author participated in the conceptualization of this review and the writing of the manuscript, takes responsibility for the integrity of the work as a whole, and has approved the final version to be submitted.

Conflict of interest

Dr. Passik is a full-time employee of Millennium Laboratories, Inc., San Diego, CA, USA.

Compliance with ethics guidelines

This article is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by the author.

Supplementary material

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Supplementary material 1 (PDF 266 kb)

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