Chronic pain affects an estimated 100 million people in the United States . Opioid analgesics, particularly extended-release (ER) formulations, are commonly used to treat pain severe enough to require long-term daily, around-the-clock dosing, and for which alternative treatment options are inadequate . Extended-release opioids may provide more consistent control of pain by minimizing fluctuations in plasma concentrations of the drug, thus reducing breakthrough pain . Extended-release analgesics may also reduce the number of sleep disturbances that result from nighttime breakthrough pain .
Although usually a safe and effective treatment option for patients with chronic pain who are appropriately managed and monitored, ER opioid formulations are associated with high rates of misuse (the use of prescription medications for medical purposes, but not as indicated or prescribed), abuse (the use of drugs for nonmedical purposes, e.g., to get high), and diversion (the channeling of regulated pharmaceuticals to the illicit marketplace, including selling or giving a drug product to any individual for any purpose, even therapeutic) . This is in large part because oral ER opioids may carry a large opioid load . Abusers often manipulate (e.g., cut, crush, or dissolve) ER formulations to more rapidly release most, if not all, of the active drug, with the goal of achieving a more rapid drug high . Further, unintentional misuse can occur when patients or their caregivers manipulate ER formulations for any number of reasons, including to reduce the dose or make the medication easier to swallow. Manipulation of most ER opioid formulations, regardless of intent, can result in greater exposure to the drug than intended, which can lead to adverse consequences or even death [6–10].
An additional challenge to healthcare providers is managing chronic pain in patients who have difficulty swallowing. There are an estimated 11 million people in the United States who experience chronic pain with dysphagia . Although ER formulations offer many benefits in treating chronic pain, there are limited alternative dosing options for patients who have difficulty swallowing. Currently available alternative modes of administration (e.g., rectal or transmucosal/buccal) for treating chronic pain are limited by such factors as variable absorption rates [11, 12], ceiling doses, and boxed warnings provided in package inserts advising against crushing or chewing pellet formulations when sprinkled onto food [6, 7, 13].
Treatment of pain in this patient population is further complicated because newer analgesics that are abuse deterrent may be formulated as hard, monolithic tablets and with agents that gel when exposed to water (e.g., polyethylene oxide), making the exterior of the tablet “sticky” when moistened and more difficult to swallow. There have been several reports of currently marketed abuse-deterrent tablet formulations that have become stuck in patients’ throats, causing choking, gagging, or regurgitation [8, 10]. Therefore, patients with chronic pain who have difficulty swallowing may manipulate their opioid analgesic to make it easier to swallow. In a survey of more than 1000 patients, 29% reported having difficulty swallowing pills and 10% reported that they sometimes or always manipulate their opioids (e.g., cut, break, crush) to facilitate swallowing . For incapacitated patients, caregivers may manipulate the medication on behalf of the patient. Unfortunately, patients and caregivers are often unaware that this misuse of an ER opioid by manipulation can lead to an increased risk for adverse reactions, overdose, and death .
Although rates of misuse and abuse have stabilized over the past few years, they are still high; in 2014, approximately 4.3 million people aged 12 years and older reported past-month nonmedical use of prescription opioids in the United States , and a comprehensive literature review found that 22–29% of patients misuse opioids . Because of concerns about public health, the US Food and Drug Administration (FDA) considers the development of abuse-deterrent opioids to be a priority . To help guide development of new abuse-deterrent opioid analgesics, the FDA released a final guidance document in 2015 on the evaluation of abuse-deterrent opioids, which outlined four categories needed to comprehensively evaluate prospective abuse-deterrent opioids in the premarket and postmarket contexts . The FDA guidelines included laboratory-based in vitro manipulation and extraction studies (category 1), in vivo pharmacokinetic studies assessing manipulated drugs (category 2), human abuse-potential studies (category 3), and postmarketing studies (category 4) .
Different approaches have been used in the development of abuse-deterrent technologies to make opioids tamper resistant, including incorporating components that create a physical or chemical barrier, thus making misuse and abuse associated with tampering with these medications more difficult . However, many of these formulations may still be vulnerable to misuse and abuse. For example, reformulated ER oxycodone was designed to be more difficult to crush than the original version, and incorporates a gelling agent (polyethylene oxide) which activates on exposure to water. As a result, the selection of reformulated oxycodone as a primary drug of abuse via snorting and injecting reduced significantly (p < 0.001) [17, 18]. However, 76% of abusers of reformulated ER oxycodone report abusing the formulation via the oral route (which could include manipulation prior to oral abuse) . In a separate but similar analysis of oral abusers of various crush-resistant tablets with gelling properties, 42% of patients undergoing substance-abuse treatment reported that they manipulate these drugs before using them orally (e.g., chewing, dissolving in mouth, or drinking after dissolving in liquid) .
In addition, there are limited abuse-deterrent options for patients who experience difficulty swallowing. Thus, there is a need for abuse-deterrent opioid treatment options that are not easily manipulated but can be administered by multiple modes (e.g., intact, sprinkled, and via enteral tubes). These formulations may also help to mitigate the misuse of these opioid analgesics associated with product manipulation by patients as well as their caregivers (e.g., crushing ER opioids to facilitate swallowing in patients with dysphagia).
The objective of this article is to review the literature describing a novel treatment option for chronic pain, oxycodone DETERx® (Xtampza® ER, Collegium Pharmaceutical, Inc., Canton, MA, USA), which was formulated to have abuse-deterrent properties and offer multiple administration options. Included in this review are data supporting the use of oxycodone DETERx for the treatment of moderate-to-severe chronic pain.