Update on extended-release opioids in pain management

Abstract

Chronic pain is frequently treated with our most potent analgesics, the opioids. While immediate-release opioids given every 3 – 4 h provide adequate analgesia for most patients with cancer pain and some patients with chronic nonmalignant pain, extended-release (ER) opioid formulations have been developed in the hope that patients with chronic pain would have improved analgesia, reduced side effects, more convenience, improved compliance, improved sleep and reduced nighttime pain. A more recent goal of the ER opioid product is to reduce prescription opioid addiction risk. This editorial will review the evidence that modern ER opioid formulations have advanced toward these goals.

Keywords::

• cancer pain
• chronic opioids
• chronic pain
• extended-release opioids

Extended-release (ER) opioids are currently used in the treatment for both chronic nonmalignant and cancer pain [1]. Although opioids have been used throughout history to treat various ailments, the use of oral, regularly scheduled, immediate-release (IR) opioids (short-acting) in modern medicine for the treatment of cancer pain was pioneered, researched and championed 50 years ago by Dame Cicely Saunders [2]. Her views concerning opioids for chronic cancer pain are still relevant today and, in spirit, underlies the basic reason for the development of ER versions of opioids; ‘[c]onstant pain calls for constant control and at this stage that means the regular giving of drugs' [3]. Systematic study of IR opioids for the control of cancer pain continued in the 1970s with IR oral morphine replacing oral heroin for cancer pain management in North America [4]. A decade later, a blinded, prospective, clinical efficacy and pharmacokinetic study demonstrated the validity of an ER oral morphine tablet to provide both adequate morphine plasma levels and analgesia over the 12-h dosing interval among patients with terminal cancer [5]. The use of ER opioids for pain management rested with cancer patients until the mid-1990s when opioids were first used, then studied, in the management of chronic nonmalignant pain (CNMP). Although there are no data to recommend any particular opioid or IR versus ER formulation, some clinicians still advocated the use of ER opioids in the hope of improved analgesia and reduced side effects [6]. The question remains today, despite a rapid explosion of ER opioid products in the past 20 years, does the use of ER opioids for chronic pain management represent an improvement in patient care and safety compared with the seminal work using IR opioids a half-century ago [7]. For the purposes of this editorial, ER opioids refers to all opioids formulated to provide plasma levels of opioid sustained over a 12- or 24-h period and transdermal fentanyl and transdermal buprenorphine formulations to be used every 72 h.

Chronic pain is frequently treated with our most potent analgesics, the opioids. While IR opioids given every 3 – 4 h provide adequate analgesia for most patients with cancer pain and some patients with CNMP, ER opioid formulations have been developed in the hope that chronic pain patients would have improved analgesia, reduced side effects, more convenience, improved compliance, improved sleep and reduced nighttime pain [8]. A more recent goal of the ER opioid product is to reduce the risk of prescription opioid abuse [9,10]. What is the evidence that modern ER opioid formulations have achieved these goals?

First, ER opioid formulations have successfully reduced the dosing interval compared with IR drugs. This has been accepted and appreciated by patients who enjoy less burden by using less pills per day [11,12]. Thus, the modern ER opioid is more convenient for the patients compared with IR opioids. It is hoped that a more convenient dosing regimen would translate into improved patient compliance [13,14]; yet, a recent study among patients with advanced cancer found that more than one-quarter of patients did not take their ER opioid at the prescribed frequency [15]. Careful monitoring of the patient for compliance is still needed, especially among the elderly, since an older age is associated with increased risk of noncompliance in this study of cancer patients [15].

Second, ER opioids have clearly matched the analgesic efficacy of their IR counterparts [1,5,8,11,14]. But have they resulted in improved analgesia compared to IR opioids? It is evident that some ER formulations result in less plasma peak-to-trough fluctuation of opioid concentrations [16]; yet, there are no clear data regarding analgesia to recommend ER versus IR opioid formulations for the treatment of chronic pain [14,17]. There are very few studies directly comparing IR with ER opioid formulations for chronic pain, and even less that follow patients over a period of many months [17]. Many patients still prefer the ER formulations, with a perceived improvement in quality of life; yet, some patients prefer and may benefit from the IR opioid preparations [18]. It is interesting that learned experts reviewing the same clinical trials do not agree on the question of ER versus IR opioids for chronic pain. For example, the recent American Pain Society clinical guidelines on chronic opioid therapy indicate that there is not enough evidence to choose between ER and IR products for chronic pain, while the British Pain Society guidelines recommend the use of ER products where possible [19,20]. Clearly, clinical trials directly comparing ER and IR opioid formulations, and conducted over a period of months to 1-year, need to be completed to provide additional guidance. It is important to note, however, that the use of transdermal fentanyl has a direct warning not to be administered to opioid-naïve patients.

Third, opioid side effects, such as constipation, nausea, vomiting and sedation, may occur with both IR and ER formulations, and there appears to be little difference between the two preparations [8,21,22]. Indeed, when followed for 6 – 12 months on chronic opioid therapy, most CNMP patients discontinue ER opioids because of lack of efficacy or due to opioid-related side effects [23]. It has been suggested that with a more gradual opioid titration the rate of failure due to opioid side effects may be reduced, but even with this careful approach, discontinuation of ER opioids still approaches one-third of patients [24]. The inability to provide adequate analgesia because of opioid adverse effects continues for many patients, and more research is required if advances in opioid therapy are to be made. The one exception is that transdermal fentanyl seems to have a much lower incidence of constipation compared with other ER opioids [25,26].

Fourth, the majority of patients with chronic pain have interrupted sleep patterns [27]. Thus, the ER opioid, with constant delivery of opioid analgesic through the night was anticipated to provide an improved sleep experience for the pain patients. Unfortunately, only a handful of studies examine the effect of opioids on sleep in CNMP patients, and even fewer studies examine the difference between IR and ER opioids. Two studies appear to be widely quoted in favor of ER opioids having a beneficial effect on sleep among pain patients [28,29]. Rosenthal et al. completed an elegant study of the effect of ER morphine (24-h formulation) on both pain and sleep and found that both objective and subjective parameters of sleep improved with ER opioid in patients with chronic osteoarthritis pain [28]. Unfortunately, the study period was 14 days, and whether the beneficial effects on sleep continue for patients on long-term opioid therapy is unknown. Caldwell et al. also used patients with pain secondary to osteoarthritis and recorded both analgesic activity and effect on sleep over a period of 8 weeks [29]. The study was double-blind, placebo-controlled and compared ER oxycodone with IR oxycodone/acetaminophen. Subjective rating of sleep quality was better for ER oxycodone compared with the IR formulation; however the clinical significance of the small numerical difference (3.8 vs 3.3; 1 = very poor; 5 = excellent) is unclear [29]. Additional and much longer-term clinical trials are needed to compare the effect of ER versus IR opioids on sleep function and quality. Further, there has been increased interest and study on the negative effect of chronic opioid therapy on sleep. The use of chronic opioids has been associated with abnormal breathing patterns in many patients, including obstructive sleep apnea, central sleep apnea, ataxic breathing and hypoxemia [30]. Central sleep apnea (cessation of breathing for > 10 s) has been reported to be prevalent among 30 – 70% of pain patients on chronic opioid therapy [31]. Thus, ER opioids used for patients with chronic pain may help or hinder the quality and quantity of sleep. Without additional prospective trials, definitive conclusion on the effect of opioid therapy on sleep cannot be made [32].

Finally, it was hoped that the development of the ER opioid product would, with decreased fluctuations in opioid plasma levels, result in less risk of opioid addiction for the pain patients. The proposed logic suggests that since i.v. opioids are more desirable to addicts compared with oral opioids, then ER opioids must be less desirable compared with IR opioids. Indeed, the early packaging information for Oxycontin (an ER formulation of oxycodone) gave statements suggesting reduced abuse liability [18,33]. There are, however, very little data to suggest that ER opioids carry a reduced risk of abuse among pain patients [18]. Two published studies (oxycodone and hydromorphone) comparing IR with ER opioids in patients with a history of recreational opioid use suggest that the ER formulations may have a reduced risk potential for abuse [34,35]. On the contrary, a recent comparison of markers of abuse liability in volunteer pain patients with a pattern of self-escalation of opioid dose concluded that long-acting opioids do not have any lower abuse potential than the IR opioids or placebo [36]. Thus, ER opioids have not resulted in significant lowering of addiction to prescription opioid drugs. In fact, the higher doses contained in the ER products have been prized and sought after by abusers of opioids. It is these ER products that may be manipulated such that a large dose with rapid onset may ensue and excite the abuser [37]. It is not surprising that ER opioids (including transdermal fentanyl) have a higher rate of abuse (normalized for number of units dispensed) than the IR opioids [38]. It is hoped, but clearly not yet proven, that the opioid abuse-deterrent formulations may decrease the ability of addicts to abuse these products [8,34,39].

In conclusion, ER opioids have certainly helped in providing many pain patients with the convenience of once- or twice-daily drug dosing and possibly have improved compliance with prescription medications. It is the author's personal opinion that most patients prefer the convenience of ER dosing, although this does not seem to translate into improved analgesia or improved sleep. The ability to use fewer tablets with the ER products allows an easier ‘pill count' and helps this author to monitor for patient compliance. However, we still need long-term clinical opioid trials among patients with chronic pain to compare the efficacy, side-effect profile (especially regarding effects on sleep) and risk abuse potential of IR versus ER opioid formulations. Until then, the clinicians must rely on clinical judgment using trials of opioids for each patient, with the final decision on which opioid product to use (IR, ER and specific opioid) reflecting analgesia obtained, side-effect profile, patient preference, physician preference and social context. Dame Cicely Saunders said it best a half century ago, ‘We have to handle [an opioid] in which we have confidence, whose effects and side-effects we know, so that we can fit the dose to the patient, use it regularly to keep pain constantly in remission, and add a variety of adjuvants that we know equally well' [2].

Declaration of interest

The author has no current financial relationship or interest with any organization relevant to this editorial. No outside agencies contributed in any manner to this paper. The paper was conceived and written entirely by the author.