Opioid therapy is the mainstay approach for the treatment of moderate to severe pain associated with cancer or other serious medical illnesses (Patt & Burton, 1998; World Health Organization, 1996). Although the use of opioid analgesics for the treatment of CNMP has been increasing in recent years (Joranson, Ryan, Gilson & Dahl, 2000) and has been endorsed by numerous professional societies (AAPM, APS, 1997; American Geriatric Society, 1998; Pain Society, 2004), the use of opioids remains controversial due to concerns about side effects, long-term efficacy, functional outcomes, and the potential for drug abuse and addiction. The latter concerns are especially evident in the treatment of CNMP patients with substance use histories (Savage, 2003).
Other concerns that may contribute to the hesitancy to prescribe opioids may be related to perceived and real risks associated with regulatory and legal scrutiny during the prescribing of controlled substances (Office of Quality Performance, 2003). These concerns have propelled extensive work to develop predictors of problematic behaviors or frank substance abuse or addiction during opioid therapy. Questionnaires to assist in this prediction and monitoring have been developed and used in research and field trials. Examples include the Prescription Drug Use Questionnaire (PDUQ; Compton et al., 1998); the Pain Assessment and Documentation Tool (PADT; Passik et al., 2004) and the Current Opioid Misuse Measure (COMM; Butler et al., 2007). These instruments are not used in practice settings at this time.
Narrative reports on the use of opioids for CNMP have underscored the effectiveness of opioid therapy for selected populations of patients and there continues to be a consensus among pain specialists that some patients with CNMP can benefit greatly from long-term therapy (Ballantyne & Mao, 2003; Trescot et al., 2006). This consensus, however, has received little support in the literature. Systematic reviews on the use of opioids for diverse CNMP disorders report only modest evidence for the efficacy of this treatment (Trescot et al., 2006; 2008). For example, a review of 15 double-blind, randomized placebo-controlled trials reported a mean decrease in pain intensity of approximately 30% and a drop-out rate of 56% only three of eight studies that assessed functional disturbance found improvement (Kalso, Edwards, Moore, & McQuay, 2004).
A meta-analysis of 41 randomized trials involving 6,019 patients found reductions in pain severity and improvement in functional outcomes when opioids were compared with placebo (Furlan, Sandoval, Mailis-Gagnon, & Tunks, 2006). Among the 8 studies that compared opioids with non-opioid pain medication, the six studies that included so-called “weak” opioids (e.g., codeine, tramadol) did not demonstrate efficacy, while the two that included the so-called “strong” opioids (morphine, oxycodone) were associated with significant decreases in pain severity. The standardized mean difference (SMD) between opioid and comparison groups, although statistically significant, tended to be stronger when opioids were compared with placebo (SMD = 0.60) than when strong opioids where compared with non-opioid pain medications (SMD = 0.31). Other reviews have also found favorable evidence that opioid treatment for CNMP leads to reductions in pain severity, although evidence for increase in function is absent or less robust (Chou, Clark, & Helfand, 2003; Eisenberg, McNicol, & Carr, 2005).
Little or no support for the efficacy of opioid treatment was reported in two systematic reviews of chronic back pain (Deshpande, Furlan, Mailis-Gagnon, Atlas, & Turk, 2007; Martell, et al., 2007). Because patients with a history of substance abuse typically are excluded from these studies, they provide no guidance whatsoever about the effectiveness of opioids in these populations.
Adding further to the controversy over the utility of opioid analgesics for CNMP is the absence of epidemiological evidence that an increase in the medical use of opioids has resulted in a lower prevalence of chronic pain. Noteworthy is a Danish study of a national random sample of 10,066 respondents (Eriksen, Sjøgren, Bruera, Ekholm, & Rasmussen, 2006).
Denmark is known for having an extremely high national usage of opioids for CNMP and this use has increased by more than 600% during the past two decades (Eriksen, 2004). Among respondents reporting pain (1,906), 90% of opioid users reported moderate to very severe pain, compared with 46% of non-opioid users; opioid use was also associated with poor quality of life and functional disturbance (e.g., unemployment).
Although this epidemiological study may be interpreted as demonstrating that opioid treatment for CNMP has little benefit, the authors acknowledge that these disquieting findings do not indicate causality and could be influenced by the possibility of widespread undertreatment, leading to poorly managed pain.
This latter interpretation is supported by a commentary on the Ericksen et al. study (Keane, 2007). Keane notes that among the 228 pain patients receiving opioids only 57 (25%) were using strong opioids, while the remainder was using weak opioids. European (as well as United States) clinical guidelines generally recommend long-acting formulations of strong opioids for the treatment of chronic moderate to severe pain, which may be supplemented with short-acting opioids for breakthrough pain (Pain Society, 2004; OQP, 2003; Gourlay, 1998; Vallerand, 2003; Fine & Portenoy, 2007).
The possibility of inappropriate opioid treatment is further supported by another Danish study that assigned pain patients who were on opioid therapy to either a multidisciplinary pain center (MPC) or to general practitioners (GP) who had received initial supervision from the MPC staff (Eriksen, Becker, & Sjegren, 2002). At intake, a substantial number of patients in both groups were apparently receiving inappropriate opioid therapy for chronic pain (60% were being treated with short-acting opioids and 49% were taking opioids on demand). At the 12 month follow-up, 86% of MPC patients were receiving long-acting opioids and 11% took opioids on demand.
There was no change in the administration pattern in the GP group. These findings suggest that a significant proportion of opioid-treated CNMP patients may be receiving inappropriate opioid treatment and that educating general practitioners in pain medicine may require more than initial supervision.
It is generally acknowledged that there is a wide degree of variance in the prescribing patterns of opioids for chronic pain (Lin, Alfandre, & Moore, 2007; Trescot et al., 2006). Some opioid treatment practices persist despite evidence that they might be harmful or have little benefit, such as the over-prescribing of propoxyphene among the elderly (Barkin, Barkin, & Barkin, 2006; Singh, Sleeper, & Seifert, 2007). Nursing home patients being treated with opioids have been found to be inadequately assessed for pain and to be more likely treated with short-acting rather than long acting opioids (Fujimoto & Coluzzi, 2000). A substantial number of physicians are reluctant or unwilling to prescribe long-acting opioids to treat CNMP, even when it may be medically appropriate (Nwokeji, et al., 2007).
Controversy about the long-term effectiveness of opioid treatment also has focused on the potential clinical implications of opioid-induced hyperalgesia. As noted earlier, exposure to opioids can result in an increased sensitivity to noxious stimuli in animals, and an increased perception of some types of experimental pain in humans (c.f., Koppert & Schmeltz, 2007; Angst & Clark, 2006). Anecdotal reports of hyperalgesia occurring with very high or escalating doses of opioids (Angst & Clark, 2006) has been viewed as a clinical correlate of these experimental findings.
The extent to which this phenomenon is relevant to the long-term opioid therapy administered to most patients with chronic pain is unknown. Although experimental evidence suggests that opioid-induced hyperalgesia might limit the clinical utility of opioids in controlling chronic pain (Chu, Clark, & Angst., 2006), there have been no reports of observations in the clinical literature to suggest that it should be a prominent problem. More research is needed to determine whether the physiology underlying opioid-induced hyperalgesia may be involved in a subgroup of patients who develop problems during therapy, such as loss of efficacy (tolerance) or progressive pain in the absence of a well defined lesion.
Outcome studies of long term use of opioids are compromised by methodological limitations which make it difficult to acquire evidence of efficacy (Noble, Tregear, Treadwell, & Schoelles, 2007). Methodological limitations may be unavoidable because of the ethical and practical challenges associated rigorous studies such as randomized controlled trials. Guidelines for opioid therapy must now be based on limited evidence; future evidence may be acquired by utilizing other study designs (Noble et al., 2007) such as practical clinical trials (Tunis, Stryer, & Clancy, 2003). These studies should include at least three criteria to reflect a positive treatment response: i.e., reduction of pain severity (derived from subjective reports or scores on pain scales), recovery of function (improved scores on instruments that measure some aspect of function), and quality of life.
Guidelines for the use of opioids for the treatment of chronic pain have been published (AAFP et al., 1996–2002; OQP, 2003), and recent guidelines have emphasized the need to initiate, structure and monitor therapy in a manner that both optimizes the positive outcomes of opioid therapy (analgesia and functional restoration) and minimize the risks associated with abuse, addiction and diversion (Portenoy et al., 2004). These guidelines discuss patient selection (highlighting the likelihood of increased risk among patients with prior histories of substance use disorders), the structuring of therapy to provide an appropriate level of monitoring and a presumably lessened risk of aberrant drug-related behavior, the ongoing assessment of drug-related behaviors and the need to reassess and diagnose should these occur, and strategies that might be employed in restructuring therapy should aberrant behaviors occur and the clinician decide to continue treatment.
They also note that therapy should be undertaken initially as a trial, which could lead to the decision to forego more therapy, and that an “exit strategy” must be understood to exist should the benefits in the individual be outweighed by the burdens of treatment.
The relatively recent recognition that guidelines for the opioid treatment of chronic pain must incorporate both the principles of prescribing as well as approaches to risk assessment and management may represent an important turning point for this approach to pain management. Acknowledging that prescription drug abuse has increased during the past decade, a period during which the use of opioid therapy by primary care physicians and pain specialists has accelerated, pain specialists and addiction medicine specialists now must collaborate to refine guidelines, help physicians identify the subpopulations that can be managed by primary care providers, and discover safer strategies that may yield treatment opportunities to larger numbers of patients.