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Long-term efficacy, safety and tolerability of Remoxy for the management of chronic pain Expert Rev. Neurother. 15(3), 231–238 (2015)
Joseph V Pergolizzi Jr1–3, Gianpietro Zampogna4, Robert Taylor Jr*4 and Robert B Raffa5 1 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA 2 Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA 3 Department of Anesthesiology, Georgetown University School of Medicine, Washington, DC, USA 4 NEMA Research Inc., 3384 Woods Edge Circle, Suite 102 Bonita Springs, FL 34134, USA 5 Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USA *Author for correspondence: Tel.: +1 239 908 4442 Fax: +1 239 908 4432 [email protected]
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Historically, chronic pain generally went under-treated for a variety of objective and subjective reasons, including difficulty to objectively diagnose and manage over a long period of time, potential serious adverse effects of commonly available medications, and patient, healthcare and societal concerns over opioid medications. More recently, in an effort to redress the under-treatment of pain, the number of prescriptions of opioid analgesics has risen dramatically. However, paralleling the increased legitimate use has been a concomitant increase in opioid abuse, misuse and diversion. Pharmaceutical companies have responded by developing a variety of opioid formulations designed to deter abuse by making the products more difficult to tamper with. One such product is Remoxy, an extended-release formulation of the strong opioid oxycodone. We review the efficacy, safety and tolerability of this formulation based on the available published literature. KEYWORDS: abuse . abuse-deterrent . chronic pain . opioid . oxycodone . Remoxy
Background Overview
Chronic pain is widespread and prevalent, affecting an estimated 100 million people in the USA alone according to a recent report by the Institute of Medicine [1,2]. Common etiologies and sites of chronic pain include arthritis, lower back, muscle, bone/joint and fibromyalgia, among others. Despite advances in knowledge regarding pain mechanisms and new treatment options, the under-treatment of chronic pain continues to be a major problem, creating a significant burden for patients [2,3] (their quality of life is negatively affected); a strain on the healthcare system and a significant economic burden (due to lost work productivity and overuse of healthcare resources) [4,5]. Chronic pain is also a particular challenge to treat because of its inherent pathophysiological characteristics and complexity. Oxycodone ((5R,9R,13S,14S)-4,5a-epoxy14-hydroxy-3-methoxy-17-methylmorphinan6-one) is a centrally acting opioid analgesic. In humans, oxycodone is metabolized via
10.1586/14737175.2015.1015418
CYP450-3A-catalyzed N-demethylation to noroxycodone, noroxymorphone and a- and b-noroxycodol (about 45% of the dose), via CYP4502D6-catalyzed O-demethylation to oxymorphone and a- and b-oxymorphol (about 11% of the dose), and 6-keto-reduction to a- and b-noroxycodol (about 8% of the dose), and noroxymorphone (N-desmethyloxycodone) [6]. Fast metabolizers have reduced analgesic effect, and slow metabolizers do not have improved analgesia [7,8]. This, plus additional evidence, strongly suggests that: ‘The central opioid effects of oxycodone are governed by the parent drug, with a negligible contribution from its circulating oxidative and reductive metabolites’ . . . ‘either because of their low potency or low abundance in circulation or as a result of their poor uptake into the brain’ [6]. Mechanistically, oxycodone has relatively weak affinity for m-opioid receptors and little or no affinity for d-opioid receptors, but it has demonstrated in vitro and in vivo activity at k-opioid receptors [6,9,10]. However, this generalization has been disputed because oxycodone produces effects that are typical of m-opioid
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agonists (some believe with a contribution from oxymorphone), which is a more potent opioid agonist with higher binding affinity for m-opioid receptors compared with oxycodone [11]. Some researchers suggest that the effect of oxycodone is mediated by different receptors in different situations, such as in diabetic mice vs nondiabetic mice (the k- and m1-opioid receptors, respectively) [12,13]. Clinically, oxycodone has been available as an analgesic for nearly a century and, when used properly, has been shown to be a safe and effective pain reliever against a variety of pain types. Unfortunately, oxycodone has also been used inappropriately [14–16]. Opioid consumption, abuse, misuse & diversion
Demographic changes (e.g., the aging population), the greater recognition of increased need and regulatory mandates to treat pain (as the ‘fifth vital sign’) has prompted an increase in use and greater availability of opioid analgesics to treat patients with chronic pain, but this has helped contribute to a corresponding rise in the diversion, misuse and abuse of prescription opioid analgesics [17–20]. For example, in 2012, there was an estimated 23.9 million Americans aged 12 or older (9.2% of population aged 12 or older) reported using illegal drugs in the prior month, a rise from 8.1% in 2008, but similar to rates in 2009 to 2011 [21]. A majority of the abusers (~70%) are obtaining their drugs from the legitimate prescription of their friends or relatives, which is being obtained from one doctor [21]. Costs associated with opioid abuse are in the billions, with estimates as high as US$ 55.7 billion [22]. In addition, unintentional deaths related to opioid overdose are greater than heroin and cocaine deaths combined [23]. Oxycodone abuse, misuse & diversion
Extended-release formulations of oxycodone without any abusedeterrent properties, which necessarily contain larger amounts of oxycodone than immediate-release formulations, have historically been associated with some of the highest rates of misuse, abuse and diversion of prescription medications in the USA. To reduce abuse, pharmaceutical companies have responded with a variety of new oxycodone formulations [24]. Currently marketed products include OxyContin ‘OP’ (Purdue Pharma, Stamford, CT), which is more resistant to cutting, breaking, chewing, crushing and dissolving; Oxecta (Pfizer, New York, NY), which is an immediate-release formulation resistant to crushing and dissolving. Other technologies currently in development include Oxytrex (Pain Therapeutics, Austin, TX), which includes the opioid antagonist naltrexone; and Oxycodone DETERx (Collegium Pharmaceutical, Canton, MA), which is an extended-release formulation designed to be resistant to crushing and dissolving. There is potential for reducing the abuse of these products as reports have indicated that abuse of abuse deterrent formulation (ADF) oxycodone was 41% lower than historical abuse for non-ADF oxycodone, with oral abuse 17% lower and non-oral abuse 66% lower with the introduction of Oxycontin ‘OP’ [25]. 232
Remoxy
There are a variety of ADFs in late stages of development, one of which is a novel extended-release formulation of oxycodone called Remoxy. Remoxy is an extended-release, oral oxycodone product formulated with an extraction-resistant (ORADUR) technology. The formulation has been designed to provide controlled pain relief plus a physical barrier against extraction of the ingredients using common methods, such as crushing, chewing or dissolution in alcohol. The barrier’s intention is to try and provide a level of resistance against the common methods of intentional tampering with opioid prescription medications and against accidental patient misuse. In addition, the properties of the technology allow for a means to administer the oral tablet in a twice-a-day regimen. Remoxy is currently in late stages of development and any claims regarding its efficacy or abuse deterrence has not been approved. A Complete Response Letter was received by the sponsor from the US FDA in June 2011. The clinical program is still underway, with current timelines for resubmission in 2015. Objective
Physicians are faced with the difficult decision of how to avoid furthering the prevailing under-treatment of pain [18], while simultaneously not contributing to a prevalent opioid risk [19]. We review the efficacy, safety and tolerability of an opioid product that was specifically designed to provide physicians with a viable and reasonable option. It should be noted that whatever the characteristics of an opioid product, prior to opioid initiation and as part of the opioid risk management, it is generally recommended that the physician perform a comprehensive assessment of pain, screen for risk factors, evaluate safety considerations and evaluate different treatment options on an ongoing basis. Methods
A series of search terms, including chronic pain, opioid analgesic, oxycodone, misuse, abuse, diversion and Remoxy was used to search PubMed/MEDLINE, EMBASE and The Cochrane Library. The databases were searched from database inception to the most recent entries as of May 2014. The terms were searched both individually and in various combinations. The goal was to identify and summarize published studies, regardless of design type, that were relevant to the topic. To identify articles potentially missed by the initial search, the bibliographies of the identified articles were searched and any appropriate articles were identified and included. Remoxy: efficacy
The database search identified a total of three studies, two Phase III and one post hoc analysis that reported on the efficacy of Remoxy (TABLE 1). Both Phase III trials enrolled an adequate number of patients for reaching statistical significance related to efficacy and safety (see safety section below) endpoints, contained appropriate/standard pain and patient-reported outcomes and were designed appropriately and similarly (e.g., length of Expert Rev. Neurother. 15(3), (2015)
Long-term efficacy, safety & tolerability of Remoxy for the management of chronic pain
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Table 1. Clinical studies reporting efficacy outcomes for Remoxy. Study (year)
Efficacy endpoints
Ref.
Friedmann et al. (2011)
Mean (SD) PI score at all time points (e.g.,) in the intent to treat population were significantly (p < 0.001) lower compared to the baseline score of 6.4 (1.8) Mean (SD) change in PI from baseline to month 6 and 12 was significant (p < 0.001) Quality of analgesia (LOCF) and study drug (LOCF) were rated good, very good or excellent by 61 and 60%, respectively, in patients at 6 months and 64 and 61%, respectively, in patients at 12 months
[26]
Roland et al. (2011)
76% (n = 429) opioid-experienced patients achieved stable dose, of these 86% successfully converted to Remoxy (£4 titration steps) 76% (n = 394) opioid-naı¨ve patients achieved a stable dose, 84% successfully initiated on Remoxy PI decreased by 35% from baseline to end of study for both opioid-experienced and opioid-naı¨ve patients
[27]
Friedmann et al. (2011)
Primary endpoint included change in PI from baseline at pre-randomization to end of the 12-week period Mean AUC for change in PI score was significantly greater for Remoxy than for placebo (p = 0.007) Quality of analgesia (p = 0.004) and global assessment of study medication (p = 0.007) significantly better with Remoxy compared with placebo
[28]
AUC: Area under the curve; LOCF: Last observation carried forward; SD: Standard deviation.
study, phases of study) to other Phase III opioid-related trials. In a Phase III, open-label study in 828 patients with chronic pain related to osteoarthritis of the hip and/or knee and low back pain were administered Remoxy twice daily (b.i.d.) up to 160 mg total (80 mg b.i.d.) per day. Patients 18–75 years of age, who were either opioid naı¨ve or opioid tolerant, were enrolled into the study and required to attend the clinic every 2 weeks for the first 2 months, followed by monthly visits for the remaining 10 months. Efficacy endpoints studied included change in pain intensity (11-point scale) from baseline to the end of weeks 2, 4, 6, 8 and end of months 3–12; quality of analgesia and global assessment of study drug [26]. Pain intensity significantly decreased at all time points (p < 0.0001), and 64 and 61% of patients rated quality of analgesia and global assessment of study drug as good, very good or excellent. In addition, decrease in pain intensity was similar between opioid naı¨ve and opioid experienced. Remoxy appears to be flexible in its dosing regimen and efficacious for at least 12 months when treating chronic pain related to osteoarthritis of the hip or knee and low back pain. A post hoc analysis of the data from the Phase III osteoarthritis and chronic low back pain study was conducted to gain clinical insight on initiating or converting to Remoxy therapy [27]. Of the 429 opioid-experienced patients and 394 opioid-naı¨ve patients, 76% in both patient populations were able to reach a stable dose of Remoxy after approximately two titration steps. In addition, the analysis indicated that approximately a 35% reduction in pain intensity was observed for both opioid-naı¨ve and opioid-experienced individuals [27]. Authors concluded that patients, regardless of the baseline opioid use, can be successfully dose initiated, dose converted and titrated to a safe and efficacious dose. In another Phase III, randomized enrichment study, 558 patients aged 40–75 years with chronic osteoarthritis were initially titrated with Remoxy and later randomized to either Remoxy or placebo for 12 weeks [28]. Subjects were initially informahealthcare.com
titrated from 5 mg twice daily to 20 mg twice daily dosing. Patients who were able to tolerate the 20 mg twice daily dose were randomized (n = 412), during which time dose titration was allowed for first 4 weeks. Dosages of patients ranged from 10 to 80 mg per day during randomization phase. Primary efficacy endpoint included change in pain intensity from prerandomization to end of study. Secondary endpoints included quality of analgesia, which was assessed weekly by asking patients ‘How would you rate the quality of your pain relief at this time?’; global assessment of medication, which was assessed weekly by asking patients ‘How would you rate the study medication you received during the past week?’; and quality of life, which was assessed using the 12-Item Short Form Health Survey and the Western Ontario and McMaster Universities OA Index. At the end of study, Remoxy performed significantly better than placebo for reduction in pain intensity (p = 0.007), with a mean area under the curve change in pain intensity score from prerandomization to end of week 12 of 30.4 for placebo versus 54.9 for Remoxy. In addition, the global assessment of medication (p = 0.007) and quality of analgesia (p = 0.004) was significantly better for Remoxy versus placebo at the end of study. Authors concluded that Remoxy appears to improve pain intensity, quality of analgesia and quality of life, while maintaining a safety profile similar to other marketed opioid analgesics. Remoxy: safety & tolerability Short-term safety
Safety was assessed in a Phase I, randomized, double-blind triple dummy study comparing Remoxy 40 mg (whole, chewed), oxycodone extended-release (ER) 40 mg whole and crushed, oxycodone immediate-release (IR) 40 mg crushed, and placebo [29]. Safety assessments included adverse events (AEs), vital signs, oxygen saturation, end-tidal carbon dioxide and clinical laboratory tests. AEs associated with Remoxy were typical of those of any opioid (e.g., constipation, nausea/vomiting sedation). The 233
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Table 2. Clinical studies reporting safety outcomes for Remoxy. Study (year)
Efficacy endpoints
Ref.
Friedmann et al. (2011)
678 patients (82%) experienced at least one AE Common AEs were those related to opioids, including constipation, nausea, and somnolence AEs were mild to moderate 40.7% reported an AE after 180 days of first treatment dose Common opioid-related AEs occurred during first 180 days 66 serious AEs were reported (five related to study drug) 3 deaths reported, non related to study drug 173 patients (21%) discontinued treatment due to AEs
[26]
Friedmann et al. (2011)
AEs reported during open label phase included: Constipation (n = 141), nausea (n = 114), dry mouth (n = 29), vomiting (n = 27), diarrhea (n = 6), somnolence (n = 107), dizziness (n = 69), headache (n = 37), pruritus (n = 69) AEs reported during randomization for placebo versus Remoxy included: Constipation (n = 9 vs 35) , nausea (n = 20 vs 41), dry mouth (n = 0 vs 5), vomiting (n = 6 vs 29), diarrhea (n = 12 vs 9), somnolence (n = 4 vs 23), dizziness (n = 9 vs 17), headache (n = 11 vs 10), pruritus (n = 6 vs 7) 146 subjects discontinued from open-label phase, 124 due to AEs 75 placebo subjects and 70 Remoxy subjects during randomization phase discontinued, 22 due to AEs in placebo group versus 43 in Remoxy group 2 serious AEs related to Remoxy, orthostatic hypotension and fecaloma
[28]
AE: Adverse events; AUC: Area under the curve; PI: Pain intensity.
majority of AEs were considered mild and the most common included pruritus, dizziness, somnolence, nausea and vomiting. No serious AEs, deaths or discontinuations due to AEs occurred during the study. Laboratory values, vital signs, mean SpO2 and end tidal CO2 remained within normal ranges. A total of 558 moderate-to-severe chronic osteoarthritis pain in the hip or knee patients were treated with Remoxy in a Phase III, double-blind, multicenter, enriched enrollment, randomized, placebo-controlled withdrawal trial design to assess Remoxy’s safety profile [28]. Subjects underwent a 2-week openlabel treatment phase, followed by a 12-week maintenance phase (weeks 1–4 allowed dose titration). Discontinuation due to AEs was reported for 124 subjects in the open-label phase, 22 for placebo and 43 for Remoxy during randomization; however, rates were similar to other opioid trials in osteoarthritis patients. During the open-label phase, the AEs observed were those typical of other opioids, which included constipation (25%), nausea (20%), somnolence (19%), dizziness (12%) and pruritus (12%). During randomization phase, AEs reported in Remoxy group included nausea (20%), constipation (17%), vomiting (14%) and somnolence (11%). Most AEs were reported to be mild or moderate in intensity. A total of 11 serious AEs were reported, two (orthostatic hypotension and fecaloma) were considered related to treatment with Remoxy. No clinically significant changes in vital signs, laboratory tests, physical exams or QTc were reported. Authors of both studies concluded that Remoxy has a similar side effect profile as other opioids and thus appears to be safe. An overview of the safety studies is provided in TABLE 2. Long-term safety & tolerability
Long-term safety and tolerability of ER oxycodone have been evaluated in patients with chronic pain related to osteoarthritis 234
of the hip and/or knee or chronic low back pain [26]. In a Phase III, open-label study, 828 patients were enrolled to receive 5–80 mg (twice daily) of Remoxy for 12 months. Safety and tolerability were evaluated based on AEs, laboratory tests, vital signs, physical examinations and electrocardiograms. AEs were assessed at each visit and were reported by the patient or observed by the investigator. A total of 823 patients received at least one dose of study medication, with 469 and 381 patients receiving study drug for more than 180 or 358 days, respectively. Opioid-related AEs were the most common in patients exposed to Remoxy for more than 6 months, which included constipation (37%, n = 172/469), nausea (28%, n = 133/469), somnolence (18%, n = 84/469), headache (16%, n = 76/469), vomiting (15%, n = 69/469), diarrhea (15%, n = 68/469) and insomnia (14%, n = 65/469). Similar occurrences were reported in patients exposed for more than 12 months. Approximately 82% of patients (n = 678) experienced at least one adverse event, and 21% discontinued due to AEs. No clinically relevant changes were observed in laboratory tests, vital signs or physical examinations. A total of 45 patients had isolated post-baseline QTc intervals >450 ms, and 103 patients had isolated postbaseline QTc interval changes greater than or equal to 30 ms; however, these were not considered clinically relevant nor related to study drug. Sixty-six serious AEs were reported, of which five (constipation, gait disturbance, gastroesophageal reflux disease, intestinal obstruction and overdose) were reported as possibly or probably related to study drug. Although the clinical significance of this study would have been greater if this had been a randomized, double-blind, placebo-controlled trial and not an open-label, this study, due to its duration, still provides valuable information regarding Remoxy’s long-term treatment safety and tolerability.
Expert Rev. Neurother. 15(3), (2015)
Long-term efficacy, safety & tolerability of Remoxy for the management of chronic pain
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Abuse potential
ADFs are designed to address some, if not all, of the common abuse behaviors reported, such as swallowing large amounts of intact product, chewing, crushing and snorting/inhaling and injecting. Methods used by abusers vary depending on the opioid and formulation chosen [30]. For oxycodone, preferred route of administration has been reported to be crushing and snorting and swallowing intact/chewed pills to achieve euphoria [31,32]. Remoxy’s technology tries to address these issues by making it more difficult to crush/chew intact pills and extract oxycodone for various routes of administration. Demonstration of Remoxy’s abuse potential was recently reported in a Phase I trial randomized, double-blind, triple-dummy, placebo- and active-controlled 6-way crossover study [29]. Forty-five healthy males and females between the ages of 18–50 years, nondependent, recreational opioid users, defined as achieving a high fivetimes in the past 12 months and once in the past 3 months were treated with 40 mg Remoxy whole or chewed in the fed state, oxycodone ER 40 mg whole or crushed in the fasted state, oxycodone IR 40 mg crushed and placebo, both in the fasted state. Treatment schedule consisted of a screening visit, a naloxone challenge and drug discrimination phase, and followed by five treatment periods. Subjects were randomly assigned to two treatment groups in a 3:1 ratio; treatments consisted of both fed and fasted states for placebo, Remoxy 40 mg (whole), Remoxy 40 mg (chewed), oxycodone ER 40 mg (whole), oxycodone ER 40 mg (crushed) and oxycodone IR 40 mg. Subjects were dosed and followed for up to 24 h post dose; calculations of area under the effect curve (AUE), maximum effect (Emax), time to maximum peak effect (TEmax) and minimum effect and time to minimum effect (Emin and TEmax) were conducted to evaluate abuse potential. The primary endpoint was the drug liking (0–100 mm visual analog scale) subscale of the drug effects questionnaire. Secondary endpoints included the Cole/Addiction Research Center Inventory Morphine Benzedrine Group scale, the take drug again assessment, price value assessment questionnaire. For the drug liking primary endpoint, mean drug-liking was statistically significantly lower for Remoxy 40 mg (whole or chewed; fed state) compared with oxycodone IR 40 mg (fasted), and oxycodone ER 40 mg (crushed; fasted) for Emax, AUE0–1 h and AUE0–2 h (p £ 0.0461). A significant delay was seen for time to peak drug liking for Remoxy 40 mg (whole and chewed) compared with oxycodone IR/ER (crushed) (p £ 0.0193). In addition, mean drug liking was significantly (p £ 0.0374) lower for Remoxy 40 mg (whole, fed) compared with oxycodone ER 40 mg (whole, fasted) for both AUE0–2 h and Emax. Secondary endpoints for drug high, good effects, and Cole/Addiction Research Center Inventory Morphine Benzedrine Group scale were statistically significantly lower for Remoxy (whole, fed) compared with those for oxycodone IR (fasted) and oxycodone ER (crushed, fasted; p £ 0.0130) for the parameters Emax, AUE0–1 h and AUE0–2 h. Although limitations of the study were small sample size and restricted to one study site, the clinical significance remains that since Remoxy informahealthcare.com
Drug Profile
taken whole or chewed showed reduced abuse potential compared with products that are known to have high abuse, Remoxy may have a reduced risk potential for abuse and help reduce some of the common oxycodone abuse routes of administration. Limitations
Due to the limited number of published studies on Remoxy’s safety and efficacy, no formal analysis or evaluation (e.g., population size, study power, endpoints) on the individual studies or the studies as a whole was conducted. Conclusion
Due to an aging population, generally increasing lifespan, and longer survival of cancer patients, among other epidemiological and medical factors, there is a large, and growing, proportion of population throughout the world that experiences, or will experience in their lifetime, chronic pain. There is no perfect analgesic to treat all chronic pain. The NSAIDs have associated gastrointestinal and other organ AEs; acetaminophen (paracetamol) has associated liver toxicity, particularly when the daily recommended dose is exceeded (often unintentionally); and other analgesics work well in some, but not the majority of chronic pain patients. Due to the severity of pain in many chronic pain patients, strong analgesics are needed. Opioids, albeit imperfect and not effective in all patients, provide temporary pain relief for some and long-term relief for others. They can often also be helpful for treating episodes of breakthrough pain. However, physicians, other healthcare providers, and society at large have become reticent about opioids for patients with chronic nonmalignant pain because of fear related to misuse, abuse and addiction. The recent publicity about prescription opioid abuse has heightened these concerns. The dilemma of treating chronic pain, yet at the same time ameliorating abuse, has generated new formulations of opioids intended to deter abuse by making the products more difficult to tamper with. Several strategies and products have been developed. One such product in development is Remoxy, which is an extended-release oral formulation of oxycodone made using a special extraction-resistant technology. On the basis of efficacy, safety and tolerability profile reported in the reviewed literature, Remoxy appears to hold promise for fulfilling a medical need, while possibly being less amenable to abuse due to tampering. Expert commentary
Development of abuse-deterrent opioids is becoming standard practice for many of the commonly abused and misused opioids in today’s market. Guidance provided by the FDA has yielded standard procedures for testing the abuse-deterrent characteristics of these formulations [33]. Although the likeability of Remoxy has been reported to be significantly lower compared to other currently available oxycodone formulations and abuse potential modeling has indicated that Remoxy would be less attractive to abusers compared to current marketed 235
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Pergolizzi, Zampogna, Taylor & Raffa
products [34], the real-world abuse potential for Remoxy is currently unknown. Large-scale epidemiological studies are needed to determine its actual abuse potential. In addition, there is a number of other abuse-deterrent oxycodone formulations currently in further development and these technologies may prove to be superior to Remoxy. Although this technology is of great value and current studies show it is safe and effective compared to placebo, its survival in the market and its abuse potential in the real world cannot be determined at this time. The results of additional clinical trials currently underway will help in determining Remoxy’s place in the treatment of chronic pain.
guidelines exist to help determine who the appropriate patients might be [36]. Because of the risks related to abuse, misuse and addiction, there is a need to balance effective chronic pain management with the appropriate use of opioids and healthcare providers should incorporate opioid risk-management strategies into their practice [37]. Office of National Drug Control Policy’s 2011 Prescription Drug Abuse Prevention Plan expands on the Obama Administration’s National Drug Control Strategy and includes action in four major areas to reduce prescription drug abuse [38]: .
Five-year view
We must consider various facts to appropriately conjure up a 5-year speculative view on the treatment of pain and role of abuse-deterrent opioids. The CDC reported that ‘in 2010, enough (opioid pain relievers) were sold to medicate every American adult with a typical dose of 5 mg of hydrocodone every 4 h for 1 month’ [35]. Even thought is seems that there is an overabundance of opioid pain relievers being prescribed, the reality is that prescriptions are being inadequately distributed to the proper populations. The sheer prevalence of pain and its apparent increase is the most prominent feature that qualifies it as a public health problem. The reality is that pain is underestimated in America because most surveys do not take into account children or acute pain [1]. Furthermore, pain continues to be under-diagnosed by physicians and under-reported by a patient, which worsens the problem. Efforts to address the rise and under-treatment of pain are constantly evolving and are coming from various stakeholders. One such example, promoted by the US Department of Health and Human Services, is Healthy People, which is a set of goals and objectives with 10-year targets designed to guide national health promotion and disease prevention efforts to improve the health of all people in the USA. Healthy People reflects the idea that setting objectives and providing science-based benchmarks to track and monitor progress can motivate and focus action. Healthy People 2020 represents the fourth generation of this initiative, building on a foundation of three decades of work. Recently released goals and objectives for Healthy People 2020 – ‘The Health Agenda for the Nation,’ issued by the Department of Health and Human Services appear to anticipate a larger public health role in pain management [1]. Healthy People 2020 Pain Relief’s objective is to increase the safe and effective treatment of pain and its goals are to reduce the proportion of patients suffering from untreated pain due to lack of access to pain treatment, reduce serious injuries from the use of pain medicines and reduce deaths from the use of pain medicines. As physicians, we are charged with patient care and that means using effective and safe pain assessment, as well as management. Managing severe chronic pain can be difficult because no single therapy provides optimal pain relief to onehundred percent of the patients one-hundred percent of the time. Opioids are indicated for the relief of severe pain when other options have proven to be inadequate and chronic opioid 236
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Education. A crucial first step in tackling the problem of prescription drug abuse is to educate parents, youth and patients about the dangers of abusing prescription drugs, while requiring prescribers to receive education on the appropriate and safe use, and proper storage and disposal of prescription drugs. Monitoring. Implement prescription drug monitoring programs in every state to reduce ‘doctor shopping’ and diversion and enhance prescription drug monitoring programs to make sure that they can share data across states and are used by healthcare providers. Proper medication disposal. Develop convenient and environmentally responsible prescription drug disposal programs to help decrease the supply of unused prescription drugs in the home. Enforcement. Provide law enforcement with the tools necessary to eliminate improper prescribing practices and stop pill mills.
For abuse risk mitigation to be effective, it must be implemented across multiple levels and must include the active participation of relevant stakeholders, including patients, practitioners, payers, industry and governments. Clinicians will need to use the strategies, tools and programs available. One potentially important step toward the goal of creating safer opioid analgesics has been the development of opioids that are formulated to deter abuse. FDA considers the development of these products a high public priority. Most abuse-deterrent technologies developed to date are designed to make product manipulation more difficult or to make abuse of the manipulated product less attractive or rewarding [33]. Categories of Opioid Abuse-Deterrent Formulations include physical barriers, chemical barriers, agonist/antagonist, aversion, delivery systems and prodrugs [33]. The FDA issued draft guidance on various categories of data needed to support certain tiers of claims in prescribing information section 9.2 of the label of an ADF [33]. It is believed that through this process only meaningful ADF products shall come to be marketed and the hope is that this will in turn materially contribute to the mitigation of the risk of abuse, misuse and addiction related to opioid analgesics. On the basis of desire to mitigate related opioid risks, the development of abuse-deterrent opioids is becoming standard practice for many of the commonly abused and misused opioids in today’s market. Over time, most, if not all, opioids will contain some form of abuse-deterrent technology. All of the current technologies have some advantage against Expert Rev. Neurother. 15(3), (2015)
Long-term efficacy, safety & tolerability of Remoxy for the management of chronic pain
abuse and misuse; however, the superiority of the technologies will only be revealed once it is brought to market. Remoxy shows promise and if it enters the market within the next few years, it may help mitigate the risk for abuse in some future patient populations.
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Financial & competing interests disclosure
J Pergolizzi is a senior partner in NEMA Research Inc., and has served as a consultant for Johnson & Johnson, Purdue Pharma LP, Baxter International Inc., Endo Pharmaceuticals Inc., Collegium Pharmaceutical, and
Drug Profile
Iroko. R Taylor Jr is an employee of NEMA Research. G Zampogna is a medical fellow at NEMA Research. RB Raffa is a speaker, consultant, and/or basic science investigator for several pharmaceutical companies involved in analgesics research but receives no royalty (cash or otherwise) from the sale of any product. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues .
Opioids are generally the go-to analgesic for moderate-to-severe pain; however, there are patient, healthcare and societal concerns over opioid use.
.
Increase in opioid abuse, misuse and diversion has paralleled the increase in opioid prescriptions in the USA.
.
Pharmaceutical companies have responded to the increase in opioid abuse, misuse and diversion by developing opioid formulations that have an increased resistance to tampering.
.
A novel tamper-resistant extended-release oxycodone, branded as Remoxy, is currently in clinical development.
.
Two Phase III trials have demonstrated Remoxy’s effectiveness in reducing pain intensity and improving quality of life when compared with placebo.
.
Long-term safety (12 months) has been demonstrated for Remoxy in a Phase III study; adverse events were typical of those of other opioids.
.
Abuse potential for Remoxy was significantly different when compared with currently available oxycodone products in small clinical studies, a reduction in drug liking as well as drug high and good effects.
.
Larger, real-life epidemiological and clinical studies may be needed to compare abuse and misuse to other opioids in the same class.
Productivity Audit. J Occup Environ Med 2003;45(12):1234-46
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Long-term efficacy, safety and tolerability of Remoxy for the management of chronic pain Expert Rev. Neurother. 15(3), 231–238 (2015)
Joseph V Pergolizzi Jr1–3, Gianpietro Zampogna4, Robert Taylor Jr*4 and Robert B Raffa5 1 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA 2 Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA 3 Department of Anesthesiology, Georgetown University School of Medicine, Washington, DC, USA 4 NEMA Research Inc., 3384 Woods Edge Circle, Suite 102 Bonita Springs, FL 34134, USA 5 Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USA *Author for correspondence: Tel.: +1 239 908 4442 Fax: +1 239 908 4432 [email protected]
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Historically, chronic pain generally went under-treated for a variety of objective and subjective reasons, including difficulty to objectively diagnose and manage over a long period of time, potential serious adverse effects of commonly available medications, and patient, healthcare and societal concerns over opioid medications. More recently, in an effort to redress the under-treatment of pain, the number of prescriptions of opioid analgesics has risen dramatically. However, paralleling the increased legitimate use has been a concomitant increase in opioid abuse, misuse and diversion. Pharmaceutical companies have responded by developing a variety of opioid formulations designed to deter abuse by making the products more difficult to tamper with. One such product is Remoxy, an extended-release formulation of the strong opioid oxycodone. We review the efficacy, safety and tolerability of this formulation based on the available published literature. KEYWORDS: abuse . abuse-deterrent . chronic pain . opioid . oxycodone . Remoxy
Background Overview
Chronic pain is widespread and prevalent, affecting an estimated 100 million people in the USA alone according to a recent report by the Institute of Medicine [1,2]. Common etiologies and sites of chronic pain include arthritis, lower back, muscle, bone/joint and fibromyalgia, among others. Despite advances in knowledge regarding pain mechanisms and new treatment options, the under-treatment of chronic pain continues to be a major problem, creating a significant burden for patients [2,3] (their quality of life is negatively affected); a strain on the healthcare system and a significant economic burden (due to lost work productivity and overuse of healthcare resources) [4,5]. Chronic pain is also a particular challenge to treat because of its inherent pathophysiological characteristics and complexity. Oxycodone ((5R,9R,13S,14S)-4,5a-epoxy14-hydroxy-3-methoxy-17-methylmorphinan6-one) is a centrally acting opioid analgesic. In humans, oxycodone is metabolized via
10.1586/14737175.2015.1015418
CYP450-3A-catalyzed N-demethylation to noroxycodone, noroxymorphone and a- and b-noroxycodol (about 45% of the dose), via CYP4502D6-catalyzed O-demethylation to oxymorphone and a- and b-oxymorphol (about 11% of the dose), and 6-keto-reduction to a- and b-noroxycodol (about 8% of the dose), and noroxymorphone (N-desmethyloxycodone) [6]. Fast metabolizers have reduced analgesic effect, and slow metabolizers do not have improved analgesia [7,8]. This, plus additional evidence, strongly suggests that: ‘The central opioid effects of oxycodone are governed by the parent drug, with a negligible contribution from its circulating oxidative and reductive metabolites’ . . . ‘either because of their low potency or low abundance in circulation or as a result of their poor uptake into the brain’ [6]. Mechanistically, oxycodone has relatively weak affinity for m-opioid receptors and little or no affinity for d-opioid receptors, but it has demonstrated in vitro and in vivo activity at k-opioid receptors [6,9,10]. However, this generalization has been disputed because oxycodone produces effects that are typical of m-opioid
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agonists (some believe with a contribution from oxymorphone), which is a more potent opioid agonist with higher binding affinity for m-opioid receptors compared with oxycodone [11]. Some researchers suggest that the effect of oxycodone is mediated by different receptors in different situations, such as in diabetic mice vs nondiabetic mice (the k- and m1-opioid receptors, respectively) [12,13]. Clinically, oxycodone has been available as an analgesic for nearly a century and, when used properly, has been shown to be a safe and effective pain reliever against a variety of pain types. Unfortunately, oxycodone has also been used inappropriately [14–16]. Opioid consumption, abuse, misuse & diversion
Demographic changes (e.g., the aging population), the greater recognition of increased need and regulatory mandates to treat pain (as the ‘fifth vital sign’) has prompted an increase in use and greater availability of opioid analgesics to treat patients with chronic pain, but this has helped contribute to a corresponding rise in the diversion, misuse and abuse of prescription opioid analgesics [17–20]. For example, in 2012, there was an estimated 23.9 million Americans aged 12 or older (9.2% of population aged 12 or older) reported using illegal drugs in the prior month, a rise from 8.1% in 2008, but similar to rates in 2009 to 2011 [21]. A majority of the abusers (~70%) are obtaining their drugs from the legitimate prescription of their friends or relatives, which is being obtained from one doctor [21]. Costs associated with opioid abuse are in the billions, with estimates as high as US$ 55.7 billion [22]. In addition, unintentional deaths related to opioid overdose are greater than heroin and cocaine deaths combined [23]. Oxycodone abuse, misuse & diversion
Extended-release formulations of oxycodone without any abusedeterrent properties, which necessarily contain larger amounts of oxycodone than immediate-release formulations, have historically been associated with some of the highest rates of misuse, abuse and diversion of prescription medications in the USA. To reduce abuse, pharmaceutical companies have responded with a variety of new oxycodone formulations [24]. Currently marketed products include OxyContin ‘OP’ (Purdue Pharma, Stamford, CT), which is more resistant to cutting, breaking, chewing, crushing and dissolving; Oxecta (Pfizer, New York, NY), which is an immediate-release formulation resistant to crushing and dissolving. Other technologies currently in development include Oxytrex (Pain Therapeutics, Austin, TX), which includes the opioid antagonist naltrexone; and Oxycodone DETERx (Collegium Pharmaceutical, Canton, MA), which is an extended-release formulation designed to be resistant to crushing and dissolving. There is potential for reducing the abuse of these products as reports have indicated that abuse of abuse deterrent formulation (ADF) oxycodone was 41% lower than historical abuse for non-ADF oxycodone, with oral abuse 17% lower and non-oral abuse 66% lower with the introduction of Oxycontin ‘OP’ [25]. 232
Remoxy
There are a variety of ADFs in late stages of development, one of which is a novel extended-release formulation of oxycodone called Remoxy. Remoxy is an extended-release, oral oxycodone product formulated with an extraction-resistant (ORADUR) technology. The formulation has been designed to provide controlled pain relief plus a physical barrier against extraction of the ingredients using common methods, such as crushing, chewing or dissolution in alcohol. The barrier’s intention is to try and provide a level of resistance against the common methods of intentional tampering with opioid prescription medications and against accidental patient misuse. In addition, the properties of the technology allow for a means to administer the oral tablet in a twice-a-day regimen. Remoxy is currently in late stages of development and any claims regarding its efficacy or abuse deterrence has not been approved. A Complete Response Letter was received by the sponsor from the US FDA in June 2011. The clinical program is still underway, with current timelines for resubmission in 2015. Objective
Physicians are faced with the difficult decision of how to avoid furthering the prevailing under-treatment of pain [18], while simultaneously not contributing to a prevalent opioid risk [19]. We review the efficacy, safety and tolerability of an opioid product that was specifically designed to provide physicians with a viable and reasonable option. It should be noted that whatever the characteristics of an opioid product, prior to opioid initiation and as part of the opioid risk management, it is generally recommended that the physician perform a comprehensive assessment of pain, screen for risk factors, evaluate safety considerations and evaluate different treatment options on an ongoing basis. Methods
A series of search terms, including chronic pain, opioid analgesic, oxycodone, misuse, abuse, diversion and Remoxy was used to search PubMed/MEDLINE, EMBASE and The Cochrane Library. The databases were searched from database inception to the most recent entries as of May 2014. The terms were searched both individually and in various combinations. The goal was to identify and summarize published studies, regardless of design type, that were relevant to the topic. To identify articles potentially missed by the initial search, the bibliographies of the identified articles were searched and any appropriate articles were identified and included. Remoxy: efficacy
The database search identified a total of three studies, two Phase III and one post hoc analysis that reported on the efficacy of Remoxy (TABLE 1). Both Phase III trials enrolled an adequate number of patients for reaching statistical significance related to efficacy and safety (see safety section below) endpoints, contained appropriate/standard pain and patient-reported outcomes and were designed appropriately and similarly (e.g., length of Expert Rev. Neurother. 15(3), (2015)
Long-term efficacy, safety & tolerability of Remoxy for the management of chronic pain
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Table 1. Clinical studies reporting efficacy outcomes for Remoxy. Study (year)
Efficacy endpoints
Ref.
Friedmann et al. (2011)
Mean (SD) PI score at all time points (e.g.,) in the intent to treat population were significantly (p < 0.001) lower compared to the baseline score of 6.4 (1.8) Mean (SD) change in PI from baseline to month 6 and 12 was significant (p < 0.001) Quality of analgesia (LOCF) and study drug (LOCF) were rated good, very good or excellent by 61 and 60%, respectively, in patients at 6 months and 64 and 61%, respectively, in patients at 12 months
[26]
Roland et al. (2011)
76% (n = 429) opioid-experienced patients achieved stable dose, of these 86% successfully converted to Remoxy (£4 titration steps) 76% (n = 394) opioid-naı¨ve patients achieved a stable dose, 84% successfully initiated on Remoxy PI decreased by 35% from baseline to end of study for both opioid-experienced and opioid-naı¨ve patients
[27]
Friedmann et al. (2011)
Primary endpoint included change in PI from baseline at pre-randomization to end of the 12-week period Mean AUC for change in PI score was significantly greater for Remoxy than for placebo (p = 0.007) Quality of analgesia (p = 0.004) and global assessment of study medication (p = 0.007) significantly better with Remoxy compared with placebo
[28]
AUC: Area under the curve; LOCF: Last observation carried forward; SD: Standard deviation.
study, phases of study) to other Phase III opioid-related trials. In a Phase III, open-label study in 828 patients with chronic pain related to osteoarthritis of the hip and/or knee and low back pain were administered Remoxy twice daily (b.i.d.) up to 160 mg total (80 mg b.i.d.) per day. Patients 18–75 years of age, who were either opioid naı¨ve or opioid tolerant, were enrolled into the study and required to attend the clinic every 2 weeks for the first 2 months, followed by monthly visits for the remaining 10 months. Efficacy endpoints studied included change in pain intensity (11-point scale) from baseline to the end of weeks 2, 4, 6, 8 and end of months 3–12; quality of analgesia and global assessment of study drug [26]. Pain intensity significantly decreased at all time points (p < 0.0001), and 64 and 61% of patients rated quality of analgesia and global assessment of study drug as good, very good or excellent. In addition, decrease in pain intensity was similar between opioid naı¨ve and opioid experienced. Remoxy appears to be flexible in its dosing regimen and efficacious for at least 12 months when treating chronic pain related to osteoarthritis of the hip or knee and low back pain. A post hoc analysis of the data from the Phase III osteoarthritis and chronic low back pain study was conducted to gain clinical insight on initiating or converting to Remoxy therapy [27]. Of the 429 opioid-experienced patients and 394 opioid-naı¨ve patients, 76% in both patient populations were able to reach a stable dose of Remoxy after approximately two titration steps. In addition, the analysis indicated that approximately a 35% reduction in pain intensity was observed for both opioid-naı¨ve and opioid-experienced individuals [27]. Authors concluded that patients, regardless of the baseline opioid use, can be successfully dose initiated, dose converted and titrated to a safe and efficacious dose. In another Phase III, randomized enrichment study, 558 patients aged 40–75 years with chronic osteoarthritis were initially titrated with Remoxy and later randomized to either Remoxy or placebo for 12 weeks [28]. Subjects were initially informahealthcare.com
titrated from 5 mg twice daily to 20 mg twice daily dosing. Patients who were able to tolerate the 20 mg twice daily dose were randomized (n = 412), during which time dose titration was allowed for first 4 weeks. Dosages of patients ranged from 10 to 80 mg per day during randomization phase. Primary efficacy endpoint included change in pain intensity from prerandomization to end of study. Secondary endpoints included quality of analgesia, which was assessed weekly by asking patients ‘How would you rate the quality of your pain relief at this time?’; global assessment of medication, which was assessed weekly by asking patients ‘How would you rate the study medication you received during the past week?’; and quality of life, which was assessed using the 12-Item Short Form Health Survey and the Western Ontario and McMaster Universities OA Index. At the end of study, Remoxy performed significantly better than placebo for reduction in pain intensity (p = 0.007), with a mean area under the curve change in pain intensity score from prerandomization to end of week 12 of 30.4 for placebo versus 54.9 for Remoxy. In addition, the global assessment of medication (p = 0.007) and quality of analgesia (p = 0.004) was significantly better for Remoxy versus placebo at the end of study. Authors concluded that Remoxy appears to improve pain intensity, quality of analgesia and quality of life, while maintaining a safety profile similar to other marketed opioid analgesics. Remoxy: safety & tolerability Short-term safety
Safety was assessed in a Phase I, randomized, double-blind triple dummy study comparing Remoxy 40 mg (whole, chewed), oxycodone extended-release (ER) 40 mg whole and crushed, oxycodone immediate-release (IR) 40 mg crushed, and placebo [29]. Safety assessments included adverse events (AEs), vital signs, oxygen saturation, end-tidal carbon dioxide and clinical laboratory tests. AEs associated with Remoxy were typical of those of any opioid (e.g., constipation, nausea/vomiting sedation). The 233
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Table 2. Clinical studies reporting safety outcomes for Remoxy. Study (year)
Efficacy endpoints
Ref.
Friedmann et al. (2011)
678 patients (82%) experienced at least one AE Common AEs were those related to opioids, including constipation, nausea, and somnolence AEs were mild to moderate 40.7% reported an AE after 180 days of first treatment dose Common opioid-related AEs occurred during first 180 days 66 serious AEs were reported (five related to study drug) 3 deaths reported, non related to study drug 173 patients (21%) discontinued treatment due to AEs
[26]
Friedmann et al. (2011)
AEs reported during open label phase included: Constipation (n = 141), nausea (n = 114), dry mouth (n = 29), vomiting (n = 27), diarrhea (n = 6), somnolence (n = 107), dizziness (n = 69), headache (n = 37), pruritus (n = 69) AEs reported during randomization for placebo versus Remoxy included: Constipation (n = 9 vs 35) , nausea (n = 20 vs 41), dry mouth (n = 0 vs 5), vomiting (n = 6 vs 29), diarrhea (n = 12 vs 9), somnolence (n = 4 vs 23), dizziness (n = 9 vs 17), headache (n = 11 vs 10), pruritus (n = 6 vs 7) 146 subjects discontinued from open-label phase, 124 due to AEs 75 placebo subjects and 70 Remoxy subjects during randomization phase discontinued, 22 due to AEs in placebo group versus 43 in Remoxy group 2 serious AEs related to Remoxy, orthostatic hypotension and fecaloma
[28]
AE: Adverse events; AUC: Area under the curve; PI: Pain intensity.
majority of AEs were considered mild and the most common included pruritus, dizziness, somnolence, nausea and vomiting. No serious AEs, deaths or discontinuations due to AEs occurred during the study. Laboratory values, vital signs, mean SpO2 and end tidal CO2 remained within normal ranges. A total of 558 moderate-to-severe chronic osteoarthritis pain in the hip or knee patients were treated with Remoxy in a Phase III, double-blind, multicenter, enriched enrollment, randomized, placebo-controlled withdrawal trial design to assess Remoxy’s safety profile [28]. Subjects underwent a 2-week openlabel treatment phase, followed by a 12-week maintenance phase (weeks 1–4 allowed dose titration). Discontinuation due to AEs was reported for 124 subjects in the open-label phase, 22 for placebo and 43 for Remoxy during randomization; however, rates were similar to other opioid trials in osteoarthritis patients. During the open-label phase, the AEs observed were those typical of other opioids, which included constipation (25%), nausea (20%), somnolence (19%), dizziness (12%) and pruritus (12%). During randomization phase, AEs reported in Remoxy group included nausea (20%), constipation (17%), vomiting (14%) and somnolence (11%). Most AEs were reported to be mild or moderate in intensity. A total of 11 serious AEs were reported, two (orthostatic hypotension and fecaloma) were considered related to treatment with Remoxy. No clinically significant changes in vital signs, laboratory tests, physical exams or QTc were reported. Authors of both studies concluded that Remoxy has a similar side effect profile as other opioids and thus appears to be safe. An overview of the safety studies is provided in TABLE 2. Long-term safety & tolerability
Long-term safety and tolerability of ER oxycodone have been evaluated in patients with chronic pain related to osteoarthritis 234
of the hip and/or knee or chronic low back pain [26]. In a Phase III, open-label study, 828 patients were enrolled to receive 5–80 mg (twice daily) of Remoxy for 12 months. Safety and tolerability were evaluated based on AEs, laboratory tests, vital signs, physical examinations and electrocardiograms. AEs were assessed at each visit and were reported by the patient or observed by the investigator. A total of 823 patients received at least one dose of study medication, with 469 and 381 patients receiving study drug for more than 180 or 358 days, respectively. Opioid-related AEs were the most common in patients exposed to Remoxy for more than 6 months, which included constipation (37%, n = 172/469), nausea (28%, n = 133/469), somnolence (18%, n = 84/469), headache (16%, n = 76/469), vomiting (15%, n = 69/469), diarrhea (15%, n = 68/469) and insomnia (14%, n = 65/469). Similar occurrences were reported in patients exposed for more than 12 months. Approximately 82% of patients (n = 678) experienced at least one adverse event, and 21% discontinued due to AEs. No clinically relevant changes were observed in laboratory tests, vital signs or physical examinations. A total of 45 patients had isolated post-baseline QTc intervals >450 ms, and 103 patients had isolated postbaseline QTc interval changes greater than or equal to 30 ms; however, these were not considered clinically relevant nor related to study drug. Sixty-six serious AEs were reported, of which five (constipation, gait disturbance, gastroesophageal reflux disease, intestinal obstruction and overdose) were reported as possibly or probably related to study drug. Although the clinical significance of this study would have been greater if this had been a randomized, double-blind, placebo-controlled trial and not an open-label, this study, due to its duration, still provides valuable information regarding Remoxy’s long-term treatment safety and tolerability.
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Abuse potential
ADFs are designed to address some, if not all, of the common abuse behaviors reported, such as swallowing large amounts of intact product, chewing, crushing and snorting/inhaling and injecting. Methods used by abusers vary depending on the opioid and formulation chosen [30]. For oxycodone, preferred route of administration has been reported to be crushing and snorting and swallowing intact/chewed pills to achieve euphoria [31,32]. Remoxy’s technology tries to address these issues by making it more difficult to crush/chew intact pills and extract oxycodone for various routes of administration. Demonstration of Remoxy’s abuse potential was recently reported in a Phase I trial randomized, double-blind, triple-dummy, placebo- and active-controlled 6-way crossover study [29]. Forty-five healthy males and females between the ages of 18–50 years, nondependent, recreational opioid users, defined as achieving a high fivetimes in the past 12 months and once in the past 3 months were treated with 40 mg Remoxy whole or chewed in the fed state, oxycodone ER 40 mg whole or crushed in the fasted state, oxycodone IR 40 mg crushed and placebo, both in the fasted state. Treatment schedule consisted of a screening visit, a naloxone challenge and drug discrimination phase, and followed by five treatment periods. Subjects were randomly assigned to two treatment groups in a 3:1 ratio; treatments consisted of both fed and fasted states for placebo, Remoxy 40 mg (whole), Remoxy 40 mg (chewed), oxycodone ER 40 mg (whole), oxycodone ER 40 mg (crushed) and oxycodone IR 40 mg. Subjects were dosed and followed for up to 24 h post dose; calculations of area under the effect curve (AUE), maximum effect (Emax), time to maximum peak effect (TEmax) and minimum effect and time to minimum effect (Emin and TEmax) were conducted to evaluate abuse potential. The primary endpoint was the drug liking (0–100 mm visual analog scale) subscale of the drug effects questionnaire. Secondary endpoints included the Cole/Addiction Research Center Inventory Morphine Benzedrine Group scale, the take drug again assessment, price value assessment questionnaire. For the drug liking primary endpoint, mean drug-liking was statistically significantly lower for Remoxy 40 mg (whole or chewed; fed state) compared with oxycodone IR 40 mg (fasted), and oxycodone ER 40 mg (crushed; fasted) for Emax, AUE0–1 h and AUE0–2 h (p £ 0.0461). A significant delay was seen for time to peak drug liking for Remoxy 40 mg (whole and chewed) compared with oxycodone IR/ER (crushed) (p £ 0.0193). In addition, mean drug liking was significantly (p £ 0.0374) lower for Remoxy 40 mg (whole, fed) compared with oxycodone ER 40 mg (whole, fasted) for both AUE0–2 h and Emax. Secondary endpoints for drug high, good effects, and Cole/Addiction Research Center Inventory Morphine Benzedrine Group scale were statistically significantly lower for Remoxy (whole, fed) compared with those for oxycodone IR (fasted) and oxycodone ER (crushed, fasted; p £ 0.0130) for the parameters Emax, AUE0–1 h and AUE0–2 h. Although limitations of the study were small sample size and restricted to one study site, the clinical significance remains that since Remoxy informahealthcare.com
Drug Profile
taken whole or chewed showed reduced abuse potential compared with products that are known to have high abuse, Remoxy may have a reduced risk potential for abuse and help reduce some of the common oxycodone abuse routes of administration. Limitations
Due to the limited number of published studies on Remoxy’s safety and efficacy, no formal analysis or evaluation (e.g., population size, study power, endpoints) on the individual studies or the studies as a whole was conducted. Conclusion
Due to an aging population, generally increasing lifespan, and longer survival of cancer patients, among other epidemiological and medical factors, there is a large, and growing, proportion of population throughout the world that experiences, or will experience in their lifetime, chronic pain. There is no perfect analgesic to treat all chronic pain. The NSAIDs have associated gastrointestinal and other organ AEs; acetaminophen (paracetamol) has associated liver toxicity, particularly when the daily recommended dose is exceeded (often unintentionally); and other analgesics work well in some, but not the majority of chronic pain patients. Due to the severity of pain in many chronic pain patients, strong analgesics are needed. Opioids, albeit imperfect and not effective in all patients, provide temporary pain relief for some and long-term relief for others. They can often also be helpful for treating episodes of breakthrough pain. However, physicians, other healthcare providers, and society at large have become reticent about opioids for patients with chronic nonmalignant pain because of fear related to misuse, abuse and addiction. The recent publicity about prescription opioid abuse has heightened these concerns. The dilemma of treating chronic pain, yet at the same time ameliorating abuse, has generated new formulations of opioids intended to deter abuse by making the products more difficult to tamper with. Several strategies and products have been developed. One such product in development is Remoxy, which is an extended-release oral formulation of oxycodone made using a special extraction-resistant technology. On the basis of efficacy, safety and tolerability profile reported in the reviewed literature, Remoxy appears to hold promise for fulfilling a medical need, while possibly being less amenable to abuse due to tampering. Expert commentary
Development of abuse-deterrent opioids is becoming standard practice for many of the commonly abused and misused opioids in today’s market. Guidance provided by the FDA has yielded standard procedures for testing the abuse-deterrent characteristics of these formulations [33]. Although the likeability of Remoxy has been reported to be significantly lower compared to other currently available oxycodone formulations and abuse potential modeling has indicated that Remoxy would be less attractive to abusers compared to current marketed 235
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Drug Profile
Pergolizzi, Zampogna, Taylor & Raffa
products [34], the real-world abuse potential for Remoxy is currently unknown. Large-scale epidemiological studies are needed to determine its actual abuse potential. In addition, there is a number of other abuse-deterrent oxycodone formulations currently in further development and these technologies may prove to be superior to Remoxy. Although this technology is of great value and current studies show it is safe and effective compared to placebo, its survival in the market and its abuse potential in the real world cannot be determined at this time. The results of additional clinical trials currently underway will help in determining Remoxy’s place in the treatment of chronic pain.
guidelines exist to help determine who the appropriate patients might be [36]. Because of the risks related to abuse, misuse and addiction, there is a need to balance effective chronic pain management with the appropriate use of opioids and healthcare providers should incorporate opioid risk-management strategies into their practice [37]. Office of National Drug Control Policy’s 2011 Prescription Drug Abuse Prevention Plan expands on the Obama Administration’s National Drug Control Strategy and includes action in four major areas to reduce prescription drug abuse [38]: .
Five-year view
We must consider various facts to appropriately conjure up a 5-year speculative view on the treatment of pain and role of abuse-deterrent opioids. The CDC reported that ‘in 2010, enough (opioid pain relievers) were sold to medicate every American adult with a typical dose of 5 mg of hydrocodone every 4 h for 1 month’ [35]. Even thought is seems that there is an overabundance of opioid pain relievers being prescribed, the reality is that prescriptions are being inadequately distributed to the proper populations. The sheer prevalence of pain and its apparent increase is the most prominent feature that qualifies it as a public health problem. The reality is that pain is underestimated in America because most surveys do not take into account children or acute pain [1]. Furthermore, pain continues to be under-diagnosed by physicians and under-reported by a patient, which worsens the problem. Efforts to address the rise and under-treatment of pain are constantly evolving and are coming from various stakeholders. One such example, promoted by the US Department of Health and Human Services, is Healthy People, which is a set of goals and objectives with 10-year targets designed to guide national health promotion and disease prevention efforts to improve the health of all people in the USA. Healthy People reflects the idea that setting objectives and providing science-based benchmarks to track and monitor progress can motivate and focus action. Healthy People 2020 represents the fourth generation of this initiative, building on a foundation of three decades of work. Recently released goals and objectives for Healthy People 2020 – ‘The Health Agenda for the Nation,’ issued by the Department of Health and Human Services appear to anticipate a larger public health role in pain management [1]. Healthy People 2020 Pain Relief’s objective is to increase the safe and effective treatment of pain and its goals are to reduce the proportion of patients suffering from untreated pain due to lack of access to pain treatment, reduce serious injuries from the use of pain medicines and reduce deaths from the use of pain medicines. As physicians, we are charged with patient care and that means using effective and safe pain assessment, as well as management. Managing severe chronic pain can be difficult because no single therapy provides optimal pain relief to onehundred percent of the patients one-hundred percent of the time. Opioids are indicated for the relief of severe pain when other options have proven to be inadequate and chronic opioid 236
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Education. A crucial first step in tackling the problem of prescription drug abuse is to educate parents, youth and patients about the dangers of abusing prescription drugs, while requiring prescribers to receive education on the appropriate and safe use, and proper storage and disposal of prescription drugs. Monitoring. Implement prescription drug monitoring programs in every state to reduce ‘doctor shopping’ and diversion and enhance prescription drug monitoring programs to make sure that they can share data across states and are used by healthcare providers. Proper medication disposal. Develop convenient and environmentally responsible prescription drug disposal programs to help decrease the supply of unused prescription drugs in the home. Enforcement. Provide law enforcement with the tools necessary to eliminate improper prescribing practices and stop pill mills.
For abuse risk mitigation to be effective, it must be implemented across multiple levels and must include the active participation of relevant stakeholders, including patients, practitioners, payers, industry and governments. Clinicians will need to use the strategies, tools and programs available. One potentially important step toward the goal of creating safer opioid analgesics has been the development of opioids that are formulated to deter abuse. FDA considers the development of these products a high public priority. Most abuse-deterrent technologies developed to date are designed to make product manipulation more difficult or to make abuse of the manipulated product less attractive or rewarding [33]. Categories of Opioid Abuse-Deterrent Formulations include physical barriers, chemical barriers, agonist/antagonist, aversion, delivery systems and prodrugs [33]. The FDA issued draft guidance on various categories of data needed to support certain tiers of claims in prescribing information section 9.2 of the label of an ADF [33]. It is believed that through this process only meaningful ADF products shall come to be marketed and the hope is that this will in turn materially contribute to the mitigation of the risk of abuse, misuse and addiction related to opioid analgesics. On the basis of desire to mitigate related opioid risks, the development of abuse-deterrent opioids is becoming standard practice for many of the commonly abused and misused opioids in today’s market. Over time, most, if not all, opioids will contain some form of abuse-deterrent technology. All of the current technologies have some advantage against Expert Rev. Neurother. 15(3), (2015)
Long-term efficacy, safety & tolerability of Remoxy for the management of chronic pain
abuse and misuse; however, the superiority of the technologies will only be revealed once it is brought to market. Remoxy shows promise and if it enters the market within the next few years, it may help mitigate the risk for abuse in some future patient populations.
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Financial & competing interests disclosure
J Pergolizzi is a senior partner in NEMA Research Inc., and has served as a consultant for Johnson & Johnson, Purdue Pharma LP, Baxter International Inc., Endo Pharmaceuticals Inc., Collegium Pharmaceutical, and
Drug Profile
Iroko. R Taylor Jr is an employee of NEMA Research. G Zampogna is a medical fellow at NEMA Research. RB Raffa is a speaker, consultant, and/or basic science investigator for several pharmaceutical companies involved in analgesics research but receives no royalty (cash or otherwise) from the sale of any product. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues .
Opioids are generally the go-to analgesic for moderate-to-severe pain; however, there are patient, healthcare and societal concerns over opioid use.
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Increase in opioid abuse, misuse and diversion has paralleled the increase in opioid prescriptions in the USA.
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Pharmaceutical companies have responded to the increase in opioid abuse, misuse and diversion by developing opioid formulations that have an increased resistance to tampering.
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A novel tamper-resistant extended-release oxycodone, branded as Remoxy, is currently in clinical development.
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Two Phase III trials have demonstrated Remoxy’s effectiveness in reducing pain intensity and improving quality of life when compared with placebo.
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Long-term safety (12 months) has been demonstrated for Remoxy in a Phase III study; adverse events were typical of those of other opioids.
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Abuse potential for Remoxy was significantly different when compared with currently available oxycodone products in small clinical studies, a reduction in drug liking as well as drug high and good effects.
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Larger, real-life epidemiological and clinical studies may be needed to compare abuse and misuse to other opioids in the same class.
Productivity Audit. J Occup Environ Med 2003;45(12):1234-46
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