In recent years, opioid therapy for the management of chronic noncancer pain has become more widely accepted following the publication of data demonstrating the efficacy of this class of drugs in a variety of pain conditions, including osteoarthritis, neuropathic pain, and low back pain. An array of short-acting and long-acting opioids has been formulated to help prescribers more effectively tailor the management of chronic pain based on the quality and temporal profile of the pain as well as the functional goals of the individual patient. Evidence suggests that both of these groups of medications offer unique benefits to individual patients and that neither is more efficacious than the other. Rather, both short-acting and long-acting opioids should be considered in the overall pharmacotherapeutic treatment of patients with chronic noncancer pain.
In properly selected and monitored patients, opioid analgesics are recognized as a widely accepted and, sometimes, indispensable, class of agents when used as part of a comprehensive, multimodal approach to the management of various types of chronic pain [1,2].
Recent years have seen a move toward greater use of these drugs in the management of the diverse group of patients with chronic noncancer pain [3–6]. Despite the historic stigmatization of opioids and practitioners' fears about prescribing agents with abuse potential, these medications are gradually becoming more accepted in the spectrum of noncancer pain syndromes, a concept that has been endorsed by organizations including the American Pain Society, American Academy of Pain Medicine, and the American Geriatrics Society, others [7,8]. This may be attributable to greater clinical experience with this drug class, the availability of different long-acting opioid (LAO) and short-acting opioid (SAO) formulations allowing better tailoring of therapy to patient needs, and an appreciation that all long-term therapies, including interventional therapies, require consideration of risk–benefit ratios. In addition, agents commonly prescribed for diverse chronic pain conditions such as the cyclooxygenase-2-selective nonsteroidal anti-inflammatory drugs (NSAIDs), which promised analgesic efficacy without the potential gastrointestinal side effects of nonselective NSAIDs, have been associated with a significant risk of cardiovascular adverse events , turning attention back to the role of opioids in the management of many chronic pain conditions. Moreover, although management of neuropathic pain remains clinically challenging, recent evidence supports a role for opioids in rationally constructed multidrug regimens for such conditions as postherpetic neuralgia and painful diabetic neuropathy .
Health care providers must turn to available evidence and their own clinical experience for guidance on how best to employ opioids in clinical practice . A number of controlled trials have established the efficacy of different opioids in musculoskeletal conditions, including osteoarthritis , low back pain [12,13], and various neuropathic pain conditions such as diabetic peripheral neuropathy and postherpetic neuralgia . However, clinical trials often fail to reflect real-life practice  and may not offer practical guidance on how to select and position available treatments and formulations to best suit patient needs . Recent meta-analyses and systematic reviews [15–19] highlight the difficulties of appraising clinical trial data in support of opioid treatments and formulations in routine—and often long-term—chronic pain management.
This article provides a constructivist view of LAO and SAO preparations within chronic pain management; this type of approach is characterized by an organized, structured approach to practice that focuses on attaining therapeutic goals while minimizing potential harms. Examining the current state of knowledge regarding these formulations can aid the clinician in generating a cohesive framework from which to apply sound clinical judgment in the selection of appropriate agents and dosage formulations.
Patient Assessment: A Key to Successful Intervention
Comprehensive patient assessment is required to allow proper consideration of the potential benefits and risks of the available pharmacotherapeutic treatment options, including drug choice, routes, and dosing regimen [20–23]. This includes a complete medical and psychological history, differential diagnosis of presenting symptoms, and analysis of relevant comorbid conditions [20,21]. An important step in assessment for potential opioid therapy, in particular, is a discussion about patient personal or family history of substance abuse, as patients with such a historyj are more likely to develop aberrant drug-taking behaviors later in therapy [20,24].
The general principles of opioid prescribing are summarized in Table 1. Prescribers may wish to consider these key questions, based on Fine and Portenoy, to help determine the appropriateness of opioids in a particular patient :
What is the conventional management for this type of pain within the immediate practice setting and compared with national standards of care?
Are there other treatments with more favorable risk–benefit ratios than opioids in terms of pain control and improvement in function and quality of life (QoL) in this type of patient with this type of pain?
Are there relatively high risks related to opioid pharmacotherapy in this patient given theirpersonal and medical history? This relates not only to the risk of medication misuse, but importantly, to the role that comorbidities or drug interactions may play in therapy selection.
Are there concerns about the responsible use of medication over time? This risk assessment applies to the patient as well as the patient's home and work environments (e.g., friends and family). Appropriate use of a universal precautions approach (Table 2)  and validated tools such as the Opioid Risk Tool  or the revised Screener and Opioid Assessment for Patients with Pain  can help with a structured risk assessment in every patient being considered for opioid therapy.
Universal precautions for assessment of chronic pain
1. Differential diagnosis
2. Psychological assessment (including risk of addictive disorders)
3. Informed consent
4. Treatment agreement or “opioid contract”
5. Assessment of pain level and function before and after intervention
6. Appropriate trial of opioid with or without adjunctive medication
7. Reassessment of pain score and level of function
8. Regular assessment of the four As of pain medicine:
analgesia, activities of daily living, adverse events, aberrant behaviors
9. Periodic review of pain diagnosis and comorbid conditions
Adapted from Gourlay et al. .
Because of the variability in response to opioids among individual patients, the relative risks associated with this class of drugs, and differing degrees of prescriber comfort and experience using opioids in chronic pain treatment, it is important to consider a multidimensional and multidisciplinary approach to ensure the provision of appropriate care with these agents . Some patients can be treated in a primary care setting, while others represent a more significant challenge and may best be referred to a specialist with related specific experience in addiction or psychiatry. Commonly, there is a middle ground; many patients can be comanaged with the assistance of other specialists . The use of non-opioid and nonpharmacologic approaches should be considered and tailored for the individual patient .
LAOs and SAOs in Chronic Pain Management
Having decided that a patient is a suitable candidate for opioid-based therapy, the clinician has the choice of a wide range of agents with distinct pharmacodynamic and pharmacokinetic characteristics, such as opioid receptor selectivity of full or partial agonists, mixed agonist–antagonists, time to analgesic onset, elimination half-life, and duration of analgesic effect [20,30]. It is important to note that the agent selected for an initial opioid trial will not necessarily form the basis of longer term management. Interindividual variability in biologic responses to particular opioids (including the development of tolerance) preclude always identifying the “best” opioid for a patient at the outset of treatment [23,31,32].
Clinicians are presented not only with a choice among a variety of opioid agonists, but also with the decision to prescribe either a LAO or a SAO [1,20,32]. Throughout this review, the term LAO will be used to describe opioids that are inherently long acting, such as methadone and levorphanol, as well as modified-release formulations . Table 3 describes some of the most commonly available short-acting and long-acting formulations used for the management of chronic pain [20,33–37].
↵* Does not apply to modified-release or TD formulations.
↵† Refer to other sources for dosing strengths and recommendations.
Adapted from Fine and Portenoy  and APS .
CR = controlled release; ER = extended release; IR = immediate release; SR = sustained release; TD = transdermal; TM = transmucosal.
The pharmacokinetic properties of LAOs allow reduced frequency of dosing relative to SAOs and typically provide analgesia over an 8–72-hour dosing interval . It has been suggested that LAOs have the greatest utility in extended treatment of patients with consistent pain levels, and those in whom non-opioid treatment has failedto provide adequate or tolerable analgesia . However, the evidence base for these ideas is not strong , and appropriate selection relies primarily on clinical judgment and an evaluation of each individual patient. Many LAOs are formulated specifically to maintain analgesia through modified release of the active agent, which is designed to provide relatively consistent and prolonged plasma drug levels with fewer peak and trough fluctuations compared with short-acting formulations of the same opioid . In addition, LAOs may offer the potential for improved compliance with dosing schedule  and avoidance of patient “clock-watching” between doses, although this idea is supported more by clinical experience than evidence.
In contrast, SAOs typically have durations of action of 2–4 hours and often are used during initial dose titration and for patients whose pain is not consistent . Titration with a SAO may prevent long periods of discomfort for the patient should side effects develop. Additionally, the starting dose for many patients may be less than the lowest available strength of a prescribed LAO, necessitating the use of a SAO for titration purposes. After dose initiation and titration is accomplished with SAOs, the patient is often converted to an equivalent dose of a LAO, although some patients may prefer to use these agents for around-the-clock (ATC) control of continuous pain as well as for intermittent use on an as-needed (prn) basis . It should be noted that transdermal fentanyl is specifically contraindicated in opioid-naïve patients .
The group of SAOs known as rapid-onset opioids (ROOs), including oral transmucosal fentanyl citrate and fentanyl buccal tablets, have been designed as rescue medication for cancer-related breakthrough pain (BTP), defined as sudden, severe flares of pain that occur against a backdrop of well-controlled baseline pain [42,43]. The pharmacokinetic and pharmacodynamic profiles of ROOs provide for quick onset and offset of action and allow for effective management of sudden and intense episodes of pain [44,45]. Particular care, however, should be taken when prescribing these potent agents, which are currently Food and Drug Administration (FDA) approved for cancer-related BTP only. Their rapid onset of effect and lack of a correlation between the baseline and breakthrough doses requires that they are titrated independently and that patients are opioid tolerant as defined by the FDA [46–48]. Further, acceptance of the use of ROOs for the treatment of BTP in patients with chronic noncancer pain is varied , although these agents have demonstrated efficacy and safety in short-term studies of patients with noncancer BTP [49,50], concerns remain about their long-term effectiveness and potential for abuse. It, however, remains to be determined whether there is any greater or lesser risk of problematic drug-related behaviors in cancer and noncancer pain patients who have BTP. Therefore, the decision to prescribe ROOs, regardless of underlying pain pathophysiology, should follow sound principles of practice for all opioid therapies, and include risk assessment, a benefit–risk evaluation, and recognition that some patients may have few, if any, BTP treatment alternatives that are as efficacious as ROOs.
Relative Efficacy of LAOs and SAOs in Long-Term Treatment
Few studies have directly compared LAOs and SAOs for the management of chronic pain, and no strong body of literature demonstrates more or less benefit for either type of opioid preparation in relation to analgesia, functionality, QoL, or aberrant behaviors. For example, a study comparing controlled-release (CR) oxycodone administered twice daily (every 12 hours) with immediate-release (IR) oxycodone/acetaminophen dosed every 6 hours in 167 subjects with chronic osteoarthritis demonstrated no significant differences between the formulations on pain scores . In another study of CR vs IR oxycodone, similar analgesic efficacy was observed for up to 10 days of treatment in 47 patients with chronic back pain . Finally, two studies, comparing four times-daily oxycodone IR with twice-daily oxycodone CR in patients with cancer pain and low back pain, concluded that both formulations can achieve levels of stable analgesia in more than 80% of patients . Several literature reviews also failed to identify clear differences in benefit between LAOs and SAOs [15–19]. One of these reviews, which focused on the efficacy and safety of these groups of agents in noncancer pain, examined 16 randomized trials and 8 observational studies, which together provided data on more than 2,500 patients. Insufficient evidence was found to determine whether one class was more effective or was associated with better adverse event rates than the other .
Clinical trials typically are constructed to answer questions about a specific drug (proving efficacy/equivalence of analgesia, profiling safety/tolerability), rather than to identify the best regimen, formulation, schedule, and long-term treatment plan to manage patient pain [52,53]. Moreover, clinical trials are frequently of relatively short duration (commonly <16 weeks) and therefore cannot provide an evidence base in support (or in refute) of long-term use of opioid therapy . It is not surprising, therefore, that reviews and meta-analyses of the clinical trial literature fail to provide concrete evidence supporting or contraindicating long-term use of either type of opioid in chronic pain. Many reviews attest to the paucity of literature and inconsistency of findings, which serves to cloud the evidence base for using these drugs in daily practice [15,18,54]. The lack of conclusive findings in these analyses points to the need for individualization of care for each patient, as no argument can be made that one or another opioid is generally more effective . Few contest the efficacy, as demonstrated in clinical studies and in routine care, of opioids in relieving the discomfort of chronic pain syndromes, but many question the relevance of published clinical trial data in the routine, and often long-term, management of chronic pain [1,2].
Although review of clinical trial data suggests that many patients discontinue long-term opioid therapy due to either insufficient pain relief or adverse effects, the same studies establish that there are many patients who clearly respond well . Both issues, while often not completely analyzed due to the constraints of trial protocols, may be corrected in real-world clinical practice through opioid rotation, dose titration, or administration of additional pharmacologic or nonpharmacologic therapies (see Multimodal Analgesia in this supplement) [1,21–23].
Practical Considerations in Deciding on an Appropriate Treatment Strategy
Patients with chronic pain represent a highly heterogeneous group in terms of age, pain etiology and symptoms, comorbidities, and ability to tolerate discomfort. In addition, the biopsychosocial nature of pain, impact of adverse effects of treatment, context of treatment (e.g., interdisciplinary rehabilitative model vs single modality medical model), and patient preferences affect the relative merits of any treatment choice. Decisions depend on pain fluctuation, activity levels, functional goals, social circumstances, and other variables , including patient adherence and medication use behaviors. Although LAOs offer less frequent dosing, which can improve compliance  it is important not to choose an agent merely on the presumption that perceived “convenience” will promote adherence , or that patients prescribed SAOs for ATC dosing may only use the medication reactively, after pain levels increase, thereby reducing overall daily pain control . Similarly, it is important not to restrict the use of SAOs only for acute pain.
The lack of a consistent evidence base requires a flexible approach that tailors choice of opioid formulation to individual needs, goals, clinical context, and social environment, all of which may be important for constructing a pain management plan and the derived outcomes of treatment . For example, in carefully selected patients and with appropriate monitoring, LAOs may provide relief for patients whose pain interferes with their ability to sleep through the night , or for patients in whom the peak–trough effects of SAOs cause end-of-dose failure, causing pain to recur before the next scheduled dose. Other patients with chronic pain may prefer the faster onset of most SAOs and the psychological comfort of controlling pain with more frequent dosing, particularly in cases of more intermittent pain. Comprehensive patient assessment plays a key role in the anticipation of these factors. Finally, empirical observation suggests that individual patients with chronic pain may have specific preferences based upon their own experiences with either a LAO or SAO [5,17,19,31].
Practical Issues in Opioid Initiation, Titration, and Rotation
The goal of opioid-based therapy, like all other treatments, is to optimize the balance between benefit and risk. Proper initiation and titration of dosage are keys to achieving this goal.
A low-dose SAO often is favored for initial opioid therapy ; because of their short half-lives and IR profiles, SAOs can be titrated to effective analgesia more rapidly and—in an unmonitored setting—safely than a LAO . Titration to a new dose should not occur until after drug plasma levels have reached steady state (approximately five half-lives), which, for LAOs, is longer than for SAOs . A patient's response to previous opioid trials in terms of efficacy and side effects also can be informative, allowing for more appropriate selection of an initial opioid and dose for that patient . There is some support for use of LAOs in initial titration for opioid-experienced patients, although this strategy requires close monitoring for adverse effects .
Although there is some literature on rapid titration with CR formulations, these observations were made under closely monitored conditions in patients with cancer rather than noncancer pain [55,56]. One of the few studies to address use of LAOs vs SAOs in patients with noncancer pain suggests that, although dose titration with LAOs may offer some utility in carefully selected cases, it carries a potential for increased adverse effects, particularly nausea and emesis, relative to SAOs . The risk of respiratory depression can be significant if opioids are not carefully titrated, and this risk is heightened in patients who are not opioid experienced . Importantly, the guidance offered here relates to usual outpatient care, and not pain crises, in which inpatient admission or close supervision may be indicated . In all clinical settings where opioid therapy is initiated and doses are increased, safety is the first priority.
Some formulations are not appropriate, and indeed, could be dangerous, when used for treatment initiation. For example, transdermal fentanyl patches carry a black box warning against use in opioid-naïve patients . Because of the high drug concentration and rate of delivery, this formulation can cause severe respiratory depression in patients who are not opioid experienced . Methadone is characterized by significantly different and complicated pharmacodynamic and pharmacokinetic properties compared with those of other opioids. For example, methadone has a long and variable half-life (12–120 h), with steady-state serum concentrations achieved after 4–5 half-lives [20,57]; therefore, time and patience are required when adjusting methadone doses. Furthermore, conversion to methadone from other opioids demands significantly greater attention to dosing due its unpredictable pharmacokinetics and the potential for torsade de pointes, serotonin toxicity, and numerous known drug–drug interactions that result from its complicated mechanism of action and uncertain metabolism [20,57,58].
Once an opioid and formulation have been selected, the dosage should be titrated individually to the level that provides maximal analgesia with minimal adverse effects for each patient. Dosage adjustment may be required several times during a course of therapy should tolerance, new pain syndromes, or severe adverse effects develop. Dose escalation of ATC opioids should be made gradually; in general, it is recommended that a dose be increased 30–50%, or up to 100% , if pain is uncontrolled, the patient's history indicates an ability to tolerate such an increase, and a responsible caregiver is available to monitor for serious adverse effects. The opioid dose usually is not increased before achieving steady-state serum concentrations, which vary depending on the opioid and the formulation. In the case of a patient receiving opioids both ATC and prn, the supplemental opioid is added to the fixed-dose amount. Careful assessment of patient response to the new regimen is required during titration, and it is recommended that the method and timing of titration be consistent irrespective of the specific opioid or formulation. Of note, if patients are receiving both a LAO and a SAO, both opioids should be titrated concurrently .
Ongoing Assessment, Switching, and Maintenance
Ongoing patient assessment is an essential aspect of opioid therapy. The “4 A's”—analgesia, activities of daily living, adverse effects, and aberrant behaviors—were developed to provide a framework for health care providers to routinely assess critical outcome measures and gauge treatment success . The “4 A's” emphasize that pain relief, functional goals, side effects of treatment, and adherence to the treatment plan should be routinely evaluated and documented to allow the clinician to adjust the therapeutic regimen accordingly. Consistent reassessment is particularly important in the community setting where primary care physicians often assume large responsibility for patient follow-up, including administering therapeutic regimens, determining their efficacy, monitoring adverse events, checking on adherence, and evaluating the effects of pain management strategies on patients' QoL .
Achieving a balance between analgesic and adverse effects is often a matter of trial and error, and is unique in each individual patient. Even when the initial opioid formulation successfully controls pain, a change in therapy (beyond upward titration) may be required due to a change in clinical status or social circumstances, emergence of new pain pathology, behavioral issues, comorbidities, drug–drug interactions, side effects, or analgesic tolerance [26,60]. The management of poorly responsive pain is complex and may require more aggressive treatment, identification of an opioid with a more favorable balance between analgesia and side effects, or use of multiple pharmacologic and nonpharmacologic strategies in combination . Alternatively, the individual patient's pain may not be opioid responsive, necessitating the implementation of predefined exit strategies from opioid therapy and administration of alternative analgesic approaches .
An inadequate response also may be due to the presence of unrecognized and/or untreated BTP, which is often managed with a prn short-acting or rapid-onset rescue opioid. The dose of the short-acting medication is generally 5–15% of the total daily opioid dose , whereas, as mentioned earlier, ROOs require an independent titration strategy; studies have found that there is no correlation between the baseline and rapid-onset dose . Differentiating between the baseline pain and flares of BTP is critical, as frequent BTP episodes may indicate inadequate treatment of persistent baseline pain . When escalating the dose of the regularly scheduled opioid, it is important to remember that the rapid-acting or SAO dose may require a similar increase .
Adjustments to an analgesic regimen also may be related to patient preferences . For example, a SAO may be used for initial dose titration in patients whose treatment goals include eventual maintenance using a LAO. Some patients may find that once their pain is adequately controlled, they would prefer a treatment using an alternative route of administration. General principles for switching include consulting an equianalgesic table for guidance on dosing, determining the clinically relevant start point for the switch, and consideration of further dose adjustments and rescue medication for BTP. One should be cautious, however, when referring to an equianalgesic table as many are based on studies conducted in opioid-naïve patients, suggesting that these tables may not be useful in treating opioid-experienced patients. Moreover, interindividual variability and incomplete cross-tolerance resulting from genetic polymorphisms and alternative isoforms of opioid receptors demand that care be taken when switching between opioids . Patient responsiveness to each new agent should be reassessed according to both therapeutic response and side effects .
Risk management, vigilance for aberrant behaviors, and signs of dependency and misuse of opioid therapies are discussed in greater detail in Current Risk Assessment and Management Paradigms in this supplement. Primary care practitioners, as well as pain specialists, must be aware of these issues and discuss them with patients at all stages of opioid-based pain management. The prescriber can help assess risk and aberrant behaviors through measures such as random urine drug testing, utilization of prescription monitoring programs, and random pill counts [21,28,62]. Throughout patient management, thorough patient documentation of all aspects of the treatment protocol, clinical evaluation, and outcomes of management strategies is essential .
Detailed attention to appropriate agent selection and dosing regimen, careful titration, and vigilant ongoing assessment has led to the increased acceptance of opioids as a safe and effective component of the multimodal treatment of chronic noncancer pain. In the absence of a set of patient characteristics or predictive test for successful opioid treatment, a short-term trial is the only way the clinician can determine the efficacy and safety of this medication class in a specific patient. An opioid trial has the greatest chance of success if incorporated into an overall management plan that includes structured follow-up to evaluate continued effectiveness over time. Opioid treatment may be further optimized through the inclusion of behavioral, psychological, functional, rehabilitative, and appropriate interventional therapies, along with adjuvant analgesics, when indicated.
In addition, the availability of SAO and LAO formulations allows for tailoring of therapy to patient needs. Individualization of therapy can help reduce an overreliance on rigid dosing schedules, allowing patients to focus on activities of daily life rather than their pain or their medication use. This becomes part of an overall behavioral conditioning program, aimed at reducing “illness behavior” and correcting perceptions of disability and fragility that often are associated with chronic pain.
There are a number of data gaps and unmet patient needs in the management of chronic pain. Published evidence supports the efficacy and safety of opioid medications but often fails to provide practical guidance for agent selection or the predictability of long-term benefit. Well-constructed, methodologically sound, long-term trials of opioid therapy in heterogeneous populations are needed. Such trials will help the clinician contribute to the goal of improving pain control in the many patient groups currently experiencing suboptimal pain management or inappropriate exposure to an otherwise efficacious class of analgesic agent. In the absence of long-term data regarding the efficacy of opioid therapy for chronic noncancer pain, clinicians must rely on empirical evidence and employ an “N-of-1” trial paradigm to gauge treatment success in the individual patient.
Dr. Fine discloses that he has held advisory board positions for pharmaceutical companies involved in the development and/or marketing of opioid analgesics, including Cephalon, King, Ortho-McNeil/Pricara, and Purdue Pharma. He has served as a medical-legal expert for Johnson & Johnson.
Dr. Mahajan has no disclosures to report.
Dr. McPherson has no disclosures to report.
This supplement has been sponsored by an unrestricted grant from King Pharmaceuticals®, Inc. Editorial support was provided by Megan Fink, Ariel Buda-Levin MS, John Lapolla MS, Maggie Van Doren PhD, Jim Kappler PhD, as well as Innovex Medical Communications.
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