Introduction

Acute pain is prevalent and often under-treated [1, 2] that results in increased suffering and distress, delayed rehabilitation and healing, and may transition to chronic pain (a process known as chronification) [3, 4]. Acute pain may occur following surgical procedures, trauma, or illness. Even when acute pain is predictable and occurs in a controlled setting (such as inpatient surgery), pain is often less-than-optimally treated. In a survey of 250 adults who had surgery as an in- or outpatient in the last 5 years, 82% reported at least some degree of pain in the period of up to 2 weeks after surgery; 21% and 18% of these respondents categorized the postsurgical pain as severe or extreme, respectively [5]. In a French survey among 750 adult patients 24 h following surgery, 87% reported postsurgical pain with half (50.9%) categorizing that pain as severe [6]. A German multicenter study (n = 2252 patients who underwent surgery or other procedure) found that 88% of patients were in pain 24 h after their treatment, with non-surgical patients experiencing slightly higher rates of under-treated pain [7]. In a survey of 50,869 patients with acute pain of various etiologies (surgery, trauma, postherpetic neuralgia, low back pain, and other conditions), 44% reported inadequate analgesia [8].

The pharmacological armamentarium for managing acute pain includes nonopioid agents, notably acetaminophen (paracetamol), nonsteroidal anti-inflammatory drugs (NSAIDs), and anticonvulsants [9], although their efficacy in acute pain is debatable; and opioids for moderate to severe or very severe pain. Risks and benefits attach to each of these agents. Acetaminophen has been associated with liver damage [10]. NSAIDs have been associated with gastrointestinal side effects and cardiovascular adverse events [11, 12]. Opioids are associated with potentially treatment-limiting side effects. In a survey of 50,869 patients with acute pain, 37% of those treated with a strong opioid discontinued their medication before pain resolved because of intolerable side effects [8]. Thus, the undertreatment of acute pain may sometimes be due to the fact an analgesic product was not tolerated, rather than the fact that no analgesics were prescribed.

Long-Acting Formulations

XARTEMIS™ XR (previously known as MNK-795, Mallinckrodt Brand Pharmaceuticals, Dublin, Ireland), is the first immediate-release (IR)/extended-release (ER) abuse-deterrent formulation comprised of a fixed-dose combination of oxycodone (7.5 mg) plus acetaminophen (325 mg) that is available on the market. While there are no consensus definitions for terms such as “long acting”, “short acting”, “immediate release”, “controlled release”, or “extended release” [13], it is generally accepted that short-acting opioids (e.g., morphine, oxycodone) have a duration of action of about 2–4 h, while a long-acting opioid maintains therapeutic serum concentration for 12–24 h (e.g., methadone, tramadol) [14, 15]. By this convention, XARTEMIS™ XR would be classified as long-acting, even though it has a short-acting component. Clinical intuition would hold that long-acting analgesics offer certain potential advantages: reduced pill burden, greater convenience [16], more sustained serum drug concentration [17], and reduction of “end-of-dose” phenomena or “analgesic gaps” between doses [18]. XARTEMIS™ XR was designed to incorporate rapidity of analgesic onset combined with long duration of action. The intended result is better overall pain control.

Analgesic effect is related to serum drug concentration; the minimum effective concentration (MEC) defines the level of serum drug level required to provide analgesia [19]. Thus, providing a consistent serum drug concentration above the MEC for a prolonged period of time may confer greater analgesia than a short-acting agent. A caveat is that head-to-head studies comparing long-acting to short-acting analgesic agents are few and the evidence is still equivocal. For example, in a study of cancer patients treated with long-acting and short-acting opioids, patients in the long-acting opioid group had significantly lower pain intensity scores (P = 0.008) and better quality of life than patients in the short-acting opioid group [16], but other studies found long-acting and short-acting opioids conferred similar analgesic benefits [20, 21]. A double-blind clinical trial that compared ER oxycodone to IR fixed-dose oxycodone/acetaminophen analgesics in patients with osteoarthritis with chronic pain found similar pain control between agents, but the patients taking the ER product reported significantly better sleep quality [22]. In a randomized, double-blind study of patients with cancer pain, patients taking sustained-release oral morphine reported significantly less tiredness than those taking IR oral morphine [23].

Many opioid-related adverse events, such as respiratory depression, are dose related. The more constant serum concentration levels resulting from long-acting opioids avoid the peak-to-trough transitions of short-acting opioids, and have been thought to offer greater tolerability [13]. Evidence supporting reduced side effects in long-acting versus short-acting opioid agents, though, has been mixed [14, 21, 22, 24]. Comparative studies of opioid analgesic agents are complicated by the fact that pain is subjective, variable, and that patients do not respond similarly to opioids; for instance, there is no clear evidence that any one opioid agent is clinically superior to the others, although individual patients may respond better to one than another.

There are reasons why prescribers might select long-acting analgesic agents over short-acting agents for their patients: long-acting formulations may provide analgesic benefit for 12–24 h [15]; long-acting agents may provide sufficiently long pain control to permit uninterrupted sleep; and long-acting agents reduce frequent dosing, which patients may prefer and which might improve compliance which, in turn, could improve analgesic relief. There appears to be widespread clinical acceptance of long-acting opioids, as evidenced by the fact that 23 million ER prescriptions were dispensed in the United States (US) in 2009 [25].

ER formulations are available for single-entity opioids, such as hydrocodone, hydromorphone, morphine, oxycodone, and tapentadol. Transdermal buprenorphine and transdermal fentanyl may also be considered long-acting single-entity opioid analgesics. Single-entity ER hydrocodone was cleared for market by the US Food and Drug Administration (FDA) under considerable controversy, in that its Advisory Panel recommended against approval [26–28]. XARTEMIS™ XR is the only IR/ER formulation of a fixed-dose oxycodone/acetaminophen combination product on the market today.

Efficacy and Safety of the Oxycodone/Acetaminophen Fixed-Dose Product

A fixed-dose combination analgesic is a product that combines two or more agents into a single tablet or capsule to offer additive or synergistic analgesic benefits, or reduce overall adverse effects (AEs) [29]. A further benefit of opioid/nonopioid fixed-dose combination products is that they may provide analgesia using a lower dose of opioid, resulting in a so-called “opioid-sparing effect” [30]. The synergistic combination of oxycodone plus acetaminophen shown in animal models has been reflected in safe and effective pain relief in many types of clinical pain syndromes [30], including low back pain [31], rheumatic conditions [32–34], postsurgical pain [35–37], pain following dental procedures [38], acute pain [39], and cancer pain [40].

XARTEMIS™ XR was evaluated in a randomized, double-blind, placebo-controlled study of 266 bunionectomy patients [41]. Patients were administered four doses (2 tablets every 12 h) of oxycodone/acetaminophen ER product or placebo. The mean summed pain intensity difference at 48 h was 114.9 (±7.6) for the active group and 66.9 (±7.6) for the placebo group (P < 0.0001), with the treatment group achieving meaningful pain relief significantly sooner than the control patients. After the first 30 min, the treatment-group patients had ≥30% pain intensity relief at all of the time points versus placebo. Placebo-group patients took more supplemental/rescue medication (i.e., ibuprofen, 400 mg every 6 h) over 48 h than did the active-group patients (4.64 vs. 2.91 doses, respectively, P < 0.0001). More patients in the treatment than placebo group reported AEs (53.6% vs. 21.5%, respectively), but the rate of constipation was low (4.2% vs. 3.1%, respectively) which may have been attributable to the short duration of the study. Other AEs included nausea (30.7% vs. 5.5%), dizziness (13.3% vs. 1.2%), headache (9.6% vs. 4.9%), skin disorders (9.0% vs. 4.3%), vomiting (9.0% vs. 0%), and somnolence (3.6% vs. 0.6%).

In an open-label extension study of the above trial lasting at least 14 days, tolerability of XARTEMIS™ XR was consistent with that of an opioid product and AEs occurred in 43.8% of patients [42]. The most common AEs reported in this extension study were nausea (17.8%), vomiting (7.5%), and constipation (6.2%).

In an analysis of 20 studies of XARTEMIS™ XR (n = 2641 patients total), the number needed to treat for at least 50% pain relief was 4.6 (95% confidence interval, range 2.9–11) for single-entity oxycodone and 2.7 (95% confidence interval, range 2.4–3.1) for oxycodone/acetaminophen 10/650 mg (an IR product) [35].

Considerations for the Use of Acetaminophen in Fixed-Dose Products

Acetaminophen is the most frequently consumed analgesic in the US [43, 44]. The FDA has launched various public health initiatives regarding this familiar drug’s potential hepatotoxicity, and it recommends that adult doses be limited to no more than 4000 mg per day, which is higher than the 3000 mg maximum daily dose on current products marketed by McNeill Consumer Healthcare, a Johnson & Johnson company [45, 46]. Since this total daily dose is cumulative from all sources, the FDA further limits the dose of acetaminophen allowed in prescription combination products [47]. Despite these efforts, however, consumers may be unaware of potential acetaminophen toxicity or be unaware of all of the sources of acetaminophen in their medicine cabinets [48–50].

XARTEMIS™ XR contains 325 mg of acetaminophen per tablet, which falls within the new FDA requirements (2 tablets = 650 mg acetaminophen, 4 tablets = 1300 mg acetaminophen/day). However, patient education is still necessary when prescribing a product that contains acetaminophen. Clinicians who prescribe a product containing acetaminophen should be diligent about informing patients about toxicity and dose limits.

The risk of hepatotoxicity was evaluated in a large retrospective cohort study of 1,228,356 adults taking either oxycodone/acetaminophen or hydrocodone/acetaminophen products compared to controls taking opioids only [51]. After adjusting for confounders, the opioid-only group did not exhibit a lower rate of hepatotoxicity-related hospitalizations at 12 months than did the groups taking oxycodone or hydrocodone combination products with acetaminophen. To date, there are no strong population-based data indicating that fixed-dose combination products containing acetaminophen elevate the patient’s risk of hepatotoxicity-related hospitalization. Nevertheless, diligence must be exercised.

Drug Delivery Technology

The XARTEMIS™ XR product was designed as a dual-layer product to allow for biphasic drug delivery as well as provide resistance to some tampering methods. A partial amount of the agents is released immediately for rapid onset of pain relief, followed by a gradual, sustained release of the remainder over 12 h [52]. Each tablet contains a release-controlling polymer that swells in the stomach, extending drug release. When taken as a single dose (two tablets, oxycodone/acetaminophen), the IR layer delivers approximately 3.75/325 mg of oxycodone/acetaminophen followed by the release from the ER layer of approximately 11.25/325 mg of oxycodone/acetaminophen.

The use of the polymer technology was evaluated in a phase I study to determine if food intake might affect the pharmacokinetic properties. A study of 48 health volunteers (men and women, ages 18–55 years, body mass indices ranging from 19 to 30) in an open-label, single-center, three-period, six-sequence, crossover study over 13 weeks found small differences in maximum serum concentration (C max) for oxycodone and acetaminophen in fed versus fasted subjects, but these differences were deemed not large enough to have clinical relevance [53]. The area-under-the-time curve (AUC) 0 to infinity and AUCo–t were nearly identical in fed and fasted subjects. The bioavailability of both oxycodone and acetaminophen was within the acceptable limit of 80–125% for the 90% confidence interval for the geometric least squares mean ratio for AUC and C max for high-fat state versus fasted state. Thus, it does not appear that the level of food intake will affect the product’s pharmacokinetics; the package insert indicates dosing without regard to food [54].

The Potential Role of Extended-Release Combination Products for Chronic Pain Syndromes

XARTEMIS™ XR is indicated for acute pain [54]. Although many guidelines recommend opioid analgesics for chronic pain conditions [55–57], including for geriatric patients [58, 59], the use of opioids for chronic nonmalignant pain remains controversial [60–62]. In a retrospective review, fixed-dose IR oxycodone–acetaminophen combination products were the most frequently prescribed drugs for patients with chronic noncancer pain [63], and they have demonstrated safety and efficacy in the treatment of chronic pain syndromes [30, 32, 34]. It must be noted that this is off-label use and the authors are not advocating such use.

Abuse Potential of Extended-Release Oxycodone/Acetaminophen

In 2009, the FDA stated that there was a need for a class-wide Risk Evaluation and Mitigation Strategy (REMS) for ER opioids, and such was proposed the following year and approved in 2012 [64]. A key consideration for REMS is that ER single-entity opioid formulations contain more opioid per dosage unit than do comparable IR formulations, and larger doses are thought to be associated with an elevated risk of abuse [65]. Moreover, long-acting single-entity opioids have been associated with higher rates of overdose [66]. There is no comparable class-wide REMS for IR opioids, which may have led to the otherwise unsupported notion that IR opioids products are somehow “safer” than ER opioids. Fixed-dose combination products can contain a relatively small amount of opioid, which in theory is less attractive to potential abusers. Currently XARTEMIS™ XR does not have a REMS requirement.

The abuse potential for long-acting compared to short-acting opioid formulations remains to be elucidated. For instance, opioid abusers tend to prefer the effects of IR products compared to ER products [67], but they may opt to abuse ER products if they can extract the drug, because ER single-entity products contain larger quantities of opioid. Since opioids are often abused by people who are not patients, but by those who obtain prescription pain relievers from family or friends [68], opioid selection is often based on what is available.

The biphasic-layered structure of XARTEMIS™ XR may resist or deter potential abuse. Abuse-deterrent formulations represent an important effort to reduce opioid abuse [69, 70], but long-term longitudinal studies are needed to ascertain their true impact on opioid abuse. The new product contains a smaller amount of oxycodone per tablet (7.5 mg) and that appears to be relatively difficult to extract due to the incorporation of the PolyOx™ (The Dow Chemical Company Midland, MI, USA) polymer [71]. The acetaminophen content of the tablets may deter some abusers, who may be concerned about the potential hepatotoxic risk of high doses.

Although the combination of acetaminophen with an opioid may make the drug less attractive to abusers, combination products may still be abused and, in such cases, the abuser may suffer from acetaminophen poisoning. For example, patients who crush combination products to “snort” or to inhale them may absorb potentially toxic concentrations of acetaminophen [72, 73]. There is relatively little research into the pharmacokinetics of nasal acetaminophen.

Clinical Perspective

XARTEMIS™ XR is the only available long-acting formulation of the frequently prescribed combination of oxycodone and acetaminophen. While IR oxycodone/acetaminophen and other opioid/nonopioid fixed-dose products are available, they are all short-acting formulations. But pain may last for several days or weeks before it diminishes or resolves, and an ER formulation allows for more convenient dosing, decreases the pill burden, and offers more steady serum concentrations than do IR products. It is easy to speculate on potential advantages of this sort of ER product: it may allow for patients to get a full night’s sleep, it may improve their ability to resume everyday activities with prolonged pain relief, and it may be better accepted by patients who often dislike having to take pills every 4–6 h. The opioid-sparing benefits of this combination product provide analgesic relief with a relatively small quantity of opioid. Thus, there are some immediate reasons to welcome this product.

However, ER opioid formulations do have some drawbacks. For example, ER formulations are generally not appropriate to treat breakthrough pain. If one was to treat breakthrough pain with ER formulations, increasing the dose, as is generally the practice, exposes the patient to more than necessary medication, which can lead to more sedation and side effects. Appropriate treatment depends on the type and duration of breakthrough pain and generally includes short-acting opioids such as oxycodone and morphine with fentanyl formulations used for very short duration, rapid-onset breakthrough pain. Another drawback is the potential for abuse. While public health initiatives have done much to decrease opioid abuse [74, 75], it remains a serious problem. For some outside the clinical community, eliminating or vastly restricting opioid analgesics seems like a viable solution to prescription analgesic abuse, but this would leave much moderate-to-severe pain untreated. Responsible prescribing involves balanced and measured steps. As a Schedule II controlled substance, this new oxycodone/acetaminophen product will be closely regulated and it lacks some of the features that make opioid analgesics particularly “likeable” in the eyes of potential abusers. No opioid analgesic is totally abuse-proof, but this formulation might be less likely to become a prime target for potential abusers. However, much work is still necessary on the part of clinicians to educate patients and their caregivers and families about the appropriate use of all opioid formulations and potential for misuse of opioid therapy.

Long-acting oxycodone/acetaminophen seems to be an important new option. It might offer equianalgesic benefits to patients with acute pain without exposing them to the greater quantity of opioids contained in single-entity opioid therapy. It will offer more stable serum concentrations, and its convenient dosing might improve patient adherence.

Conclusion

To the armamentarium for pain control has been added a long-acting fixed-dose combination product of oxycodone/acetaminophen (7.5/325 mg), XARTEMIS™ XR, which is indicated for the management of moderate to severe acute pain. The synergistic combination of oxycodone with acetaminophen demonstrated in animal models is well established as being safe and effective in numerous painful conditions, including postsurgical and posttraumatic pain. The new long-acting formulation should offer more stable serum drug concentrations than short-acting formulations and provide 12 h or more of pain relief. Its abuse potential may be less because of the lower amount of oxycodone per tablet and the difficulty associated with extracting it. As usual, good clinical practice dictates individualized patient care and counseling patients about potential AEs, acetaminophen toxicity and dose limitations, and potential for opioid misuse and abuse.