Opioids in chronic noncancer pain

Abstract

Chronic noncancer pain is highly prevalent with associated negative effects on function and quality of life of the individuals involved. Opioids have been shown to decrease pain and improve function in some patients with chronic noncancer pain, but they are not always effective and are associated with multiple complications, including drug misuse, abuse and diversion. Furthermore, the effectiveness of opioids in decreasing pain and improving function has not been proven conclusively, resulting in continued uncertainty about long-term benefits of opioids for chronic noncancer pain. Ideally, in modern medicine, clinical decisions are made based on information derived from high quality evidence. Since no such evidence exists for chronic opioid therapy in chronic noncancer pain, this review describes various aspects of opioid therapy in chronic noncancer pain, including adherence monitoring, along with a ten-step process outlining the principles of effective and safe opioid use.

Keywords::

• adherence monitoring
• chronic persistent pain
• controlled substance
• noncancer pain
• opioid
• substance abuse
• substance misuse

Chronic noncancer pain

Chronic persistent pain can cause significant impairment of physical and psychological health, and performance of social responsibilities, including work and family life [1–12]. While modern medicine has shown significant improvements in the understanding of pain (including diagnosis and treatment), chronic pain continues to be an epidemic resulting in vocational, social and family discord, which may make the difference between life and death, and is accompanied by claims of inadequate treatment [1–5,13–17].

Chronic pain has been defined by the American Society of Interventional Pain Physicians (ASIPP) as, “pain that persists 6 months after an injury and beyond the usual course of an acute disease or a reasonable time for a comparable injury to heal, that is associated with chronic pathologic processes that cause continuous or intermittent pain for months or years that may continue in the presence or absence of demonstrable pathology; may not be amenable to routine pain control methods; and healing may never occur” [1].

The prevalence and associated disability continue to increase. Harkness et al., in a 2000 publication, showed that there was a large difference in the prevalence of musculoskeletal pain over a 40-year period under investigation [9]. The results showed that overall, the prevalence of low back pain increased from 8.1 to 17.8% in males, and it increased from 9.1 to 18.2% in females. Similarly, Freburger et al. reported the rising prevalence of chronic low back pain following an evaluation of North Carolina (USA) households conducted in 1992 and repeated in 2006 [10]. The results showed an increasing prevalence of chronic impairing low back pain over the 14-year interval from 3.9% in 1992 to 10.2% in 2006, with an overall increase of low back pain of 162%, an annual increase of 11.6% associated with care-seeking and disability.

Opioids in chronic noncancer pain

Opioids have been used for thousands of years to treat pain, and continue to be one of the most commonly prescribed medications for pain. In the USA and other countries, the prescription of opioids has been restricted. Despite the regulations and restrictions, during the past 20 years or so opioids have been used increasingly to treat chronic pain, with an unprecedented number of patients receiving long-term opioids and an explosion of therapeutic opioid use, abuse and nonmedical use. Manchikanti and Singh, in a 10-year perspective on the complexities and complications of the escalating use, abuse and nonmedical use of opioids, showed an overall increase of 127% in retail sales of opioids from 1997 to 2006 in the USA, with an increase of 1177% for methadone, 732% for oxycodone and 479% for fentanyl [18]. Similarly, the increase in therapeutic opioid use in the USA, in milligrams per person, from 1997 to 2006 increased 347% overall with the highest increase for methadone of 1129% and oxycodone of 899%.

Even though opioids are used extensively, the evidence of their effectiveness in improving quality of life (QOL) is limited. Unfortunately, most of the assumptions have been made based on the ability of opioids to effectively and safely treat acute and cancer pain, supporting opioid treatment to patients with chronic pain, which has essentially removed the previously exercised caution based on fears of addiction and abuse [19]. It is argued that physicians should be encouraged to prescribe opioids because persistent pain destroys peoples’ autonomy, dignity and decision-making capacity [20]. However, the camp of physicians utilizing opioids on a careful basis recognizes that opioid therapy, specifically on a long-term basis for chronic pain, may be associated with research gaps on their utility in chronic noncancer pain and multiple side effects, drug abuse, aberrant drug-related behaviors, addiction and death [13,18–28]. In fact, it has been shown that opioid use might go against other important principles of chronic pain management, aiming at increased self-efficacy, reduced reliance on the healthcare system, reinforcement of pain behavior and passivity and loss of autonomy by externalization of the focus of control [29]. In an epidemiologic study, Eriksen et al. showed that in Denmark the results were worse pain, higher healthcare utilization and lower activity levels in opioid-treated patients compared with a matched cohort of chronic pain patients not using opioids [30]. This essentially provides prima facie evidence that when opioids are prescribed liberally, even if a small number of patients benefit, the overall population does not. Even then, due to politics and emotional issues involved in efforts to improve awareness and treatment of chronic pain, the availability of opioids has increased dramatically in the past few decades [18].

Consequently, numerous reviews have been published evaluating opioid therapy in chronic noncancer pain, with variable opinions [21,22,31–43].

Effectiveness of opioid therapy

Short-term effectiveness

Ballantyne evaluated 28 studies that showed statistically significant improvement across all the studies in measured pain scales for short-term effectiveness [20]. Furlan et al. included 41 randomized trials involving 6019 patients with a drop-out rate of 33% in the opioid groups, and concluded that opioids were more effective than placebo for both pain and functional outcomes over an average duration of 5 weeks with a range of 1–16 weeks [32]. Kalso et al. reported the short-term efficacy of opioids as good in only 44% of the patients continuing treatment, with 80% of the patients experiencing at least one adverse event [38]. Martell et al. also showed that opioids were efficacious for short-term pain relief, but with significant abuse, addiction, aberrant behaviors and side effects [31]. Chou et al. were only able to conclude that the short-acting oxycodone and long-acting oxycodone were equally effective for pain control [41].

While reporting contradictory results, Eisenberg et al.’s study of 23 trials showed overall relief ranging from 8 to 70 days, with all trials demonstrating opioid efficacy [33]. Deshpande et al., in a Cochrane Collaboration review of opioids for chronic low back pain, found only one trial comparing morphine or oxycodone to naprosyn, and three trials meeting inclusion criteria compared tramadol to placebo and concluded that there was no significant benefit with morphine or oxycodone, whereas tramadol was more effective than placebo for pain relief and improvement of function [34]. In a systematic review and meta-analysis, Cepeda et al. concluded that patients who received tramadol reported less pain associated with a higher degree of global improvement [35]. In a systematic literature review, Sandoval et al. reported a well-defined analgesic effect with methadone 20 mg per day over a period of 20 days compared with placebo [36].

Chou et al. evaluated over 70 short-term randomized trials for benefits or harms of opioids for chronic noncancer pain [21]. Only three trials followed patients for more than 4 months. They concluded that evidence on opioids, specifically for low back pain, fibromyalgia and daily headache, was very limited or did not show a clear benefit.

Long-term effectiveness

Martell et al. concluded that the effectiveness of opioids for a period lasting 16 weeks or longer was unclear [31]. Kalso et al. showed a mean decrease in pain intensity of at least 30% with opioids, noting that approximately 80% of patients experienced at least one adverse event [38]. In addition, they showed that only 44% of the 388 patients on open-label treatments were still on opioids after therapy for between 7 and 24 months. They concluded that only a minority of patients went on to long-term management with opioids. Noble et al. showed that oral opioids reduced pain long-term in the relatively small proportion of individuals with chronic noncancer pain who continued treatment [37]. However, for oral opioids they evaluated morphine in three studies [44–46], tramadol in one study [47], methadone in one study [48], extended-release oxymorphone in one study [49], controlled-release oxycodone in one study [50], as well as dihydrocodeine and buprenorphine [46]. For evaluation of effectiveness of transdermal fentanyl they included three studies [44,51,52]; however, only two studies utilized pain relief of 50% or greater as their significant criteria [44,46]. In this study, because of high withdrawal rates, they first analyzed withdrawal rates of the two most commonly cited reasons for leaving a study, namely adverse events and insufficient pain relief [37]. Consequently, patients who experienced long-term pain outcomes represented only a subset of the patients initially enrolled in the studies. Multiple randomized controlled trials also included open-label extension trials [45,47,49,50]. In summary, among individuals with chronic noncancer pain taking oral opioids, approximately a third did not continue long-term treatment with a follow-up time ranging from 6 to 18 months because of the intolerable adverse effects. Noble et al. were unable to formulate evidence-based conclusions on the long-term efficacy of transdermal opioids for chronic pain because only two studies contributed data on this area of analysis [37]. In reference to oral administration of opioids, they combined multiple studies for meta-analysis and found that patients treated with long-term oral opioid therapy for 16–18 months showed approximately a 63.4% mean reduction in pain scores, even though substantial heterogeneity was observed in the studies. They were unable to resolve the heterogeneity of oral opioid studies and, consequently, they summarized that long-term opioids are associated with some degree of pain relief because the smallest summary of effects sizes yielded by the sensitivity and analysis remained large for oral opioids and statistically significant.

Trescot et al. also evaluated the effectiveness of opioids for the treatment of chronic noncancer pain utilizing three systematic reviews and ten individual articles that met inclusion criteria with follow-up reported on a long-term basis of greater than 6 months [19]. The results illustrated that many patients in the included studies were dissatisfied with the adverse events or the insufficient pain relief from opioids and withdrew from the studies. For patients able to continue on opioids the evidence was weak. There was also weak evidence that long-term opioid therapy with morphine and transdermal fentanyl decreases pain and also improves functioning. They showed limited evidence for the most commonly used opioids: oxycodone and hydrocodone.

Rauck evaluated the role of long-acting and short-acting opioids for patients with chronic pain [39]. They concluded that long-term clinical trials of various formulations are needed to allow clinicians to make informed decisions about which patient groups might benefit most from either short-acting or long-acting formulations. Chou et al., in an evaluation of benefits and harms of chronic opioid therapy utilizing 70 randomized trials [21], found that only three trials followed patients for more than 4 months [53,54]. Furthermore, they commented that long-term observational evidence was also sparse and characterized by substantial heterogeneity. They concluded that evidence on opioids specifically for low back pain, fibromyalgia and daily headache was very limited or did not show a clear benefit.

In spite of multiple evaluations on the long-term effectiveness of opioid therapy, hydrocodone, one of the most commonly utilized drugs, has not been studied. Only one study that utilized a large population of 11,000 patients with chronic pain, reported that 3000 of the 11,000 patients were taking hydrocodone-containing prescriptions [55]. They found relatively low levels of abuse, indicating long-term effectiveness.

Effectiveness on quality of life

Quality of life improvement has been evaluated less frequently than pain relief [56]. Of the many reported studies, only one study reported a positive difference in relation to most health-related QOL (HRQOL) domains of the Short Form (SF)-36 with administration of oxycodone [56]. The 10-year follow-up by Jensen et al. showed that opioid users had lower SF-36 scores than chronic pain patients who were not using opioids [57]. Deshpande et al. concluded that pain relief could be expected to improve more in nondepressed patients [58]. Milligan et al. showed improvement in bodily pain, social functioning and physical functioning on SF-36 scores for 12 months even though QOL scores did not change [51]. In a 10-year follow-up survey of opioid use, Jensen et al. reported HRQOL and healthcare utilization in chronic noncancer pain patients, demonstrating that only 60% of those discharged on long-acting opioids were still on that treatment at follow-up [57]. In fact, they showed that users of opioids had a significantly higher occurrence of depression. Rauck et al. showed that both sustained-release morphine and oxycodone led to significant improvement on both physical and mental components of the SF-12, with physical functioning scores improving by approximately 20–30% [59].

Other studies have also shown improved physical functioning associated with pain relief after therapy with sustained-release morphine in patients with different types of chronic, moderate-to-severe noncancer pain. Caldwell et al. showed that the mean physical function score improved by 18% at week 4 compared with an improvement of 8% with placebo [45]. Adams et al. showed that sustained release morphine significantly increased the proportion of subjects who reported an improvement in the ability for moderate-intensity activities [60]. Allan et al., in an evaluation of transdermal fentanyl or sustained-release morphine, demonstrated that, while both drugs provided significant pain relief, the proportion of participants reporting more than 3 weeks of work decreased from 34 and 25% at baseline to 16% for transdermal fentanyl and sustained release morphine at end point, respectively [44]. Zenz et al. have also shown a close correlation between pain reduction and an increase in performance [46].

Overall, it appears that epidemiological studies are less positive with regard to function and QOL and report the failure of opioids to improve QOL in chronic pain patients [29]. By contrast, Eriksen et al. demonstrated worse pain, higher healthcare utilization and lower activity levels in opioid-treated patients compared with a matched cohort of chronic pain patients not using opioids [30]. Other studies have also shown that instead of improving functional status, opioid use has been associated with increased disability, medical costs, subsequent surgery and continued or late opioid use [61–64].

Apart from pain relief, functional status improvement and healthcare utilization, another important function when patients are on chronic opioid therapy is driving capability [65,66]. Fishbain et al. in a structured, evidence-based review of impairment in driving-related skills in opioid-dependent or -tolerant patients, concluded that the majority of the reviewed studies appeared to indicate that opioids do not impair driving-related skills in opioid-dependent or -tolerant patients [66]. However, the research was inconclusive in one of the five areas relating to the potential impairment in cognitive function of opioid-maintained patients. The research was conclusive that there was no impairment of psychomotor abilities of opioid-maintained patients; no impairment of psychomotor abilities immediately after being given doses of opioids; no greater incidence in motor vehicle violations or motor vehicle accidents versus comparable controls of opioid-maintained patients; and no impairment as measured in driving simulators and on-road driving by opioid-maintained patients. These opinions did not correlate with a narrative review by Strassels [65], indicating that cognitive function can be influenced by the use of opioid analgesics, although the effects vary among drugs.

Complications

Complications due to opioid administration concern all medical practitioners [22–28,67–71]. Commonly known side effects of opioids include constipation, pruritus, respiratory depression, nausea, vomiting, delayed gastric emptying, sexual dysfunction [69], muscle rigidity and myoclonus [72,73], sleep disturbance [74], pyrexia, diminished psychomotor performance [65,66], cognitive impairment [75], hyperalgesia [19,20,42,69], dizziness and sedation, all reflecting the effects of opioids on multiple organ systems [76].

Adverse events, in general, appear to fall into two broad categories: non-life-threatening and life-threatening. Hydrocodone may cause sensorineural hearing loss due to possible genetic polymorphisms [77]. More serious adverse events, such as respiratory depression and death, have been seen with the use of fentanyl buccal tablets for breakthrough pain. Drug deaths from opioids are a serious and increasing issue [23–27,70,71].

Opioids have also been described to have multiple drug interactions. A drug interaction occurs when the amount or the action of a drug is altered by the administration of another drug or multiple drugs. Multiple hepatic drug interactions may influence opioid drug levels [69,76].

Opioid tolerance & physical dependence

Tolerance, a loss of analgesic potency, is one of the common complications of opioid treatment, leading to ever-increasing dose requirements and decreasing effectiveness over time. By contrast, physical dependence is the development of an altered physiological state that is revealed by an opioid withdrawal syndrome involving autonomic and somatic hyperactivity. Two types of tolerance have been described, including innate tolerance, which is genetically determined and would be present from the initial dose of the opioid, and acquired tolerance, which is based on pharmacokinetic, pharmacodynamic and learned activity [78]. Pharmacokinetic tolerance results from changes in the metabolism of a drug after repeated administration, such as the induction of an enzyme by the administration of the drug itself, whereas pharmacodynamic tolerance is represented by the drug itself. Pharmacodynamic tolerance is represented by the classic decreased effectiveness of an opioid over time, related to upregulation of receptors. In contrast to pharmacokinetic and pharmacodynamic tolerance, learned tolerance results in a decrease in efficiency as compensated mechanisms are incorporated or learned [79]. It is illustrated by the fact that if a patient is in a setting where he or she usually consumes the drug they typically expect the drug to be less effective; whereas if the same patient takes the same amount of drug in a nonstandard setting, he or she will probably feel a greater effect.

The importance of tolerance and physical dependence lies in concerns related to when to start a patient on long-term opioids with regard to its efficacy and maintenance over time. Tolerance was considered to be the driving force to support the street addicts’ abuse of opioids. Consequently, there was a notion that it would occur in a similar way if opioids were used on a chronic basis in patients with chronic pain. This led to the reluctance of physicians to use opioids. Physicians always prefer to use them in a restrictive manner to preserve their efficacy for a situation when they are really needed. Even though there is no research to support this point of view, it is shown that tolerance develops at a different rate depending on the specific opioid prescribed. In some cases there is lack of cross-tolerance, resulting in the opinion that tolerance to one particular opioid does not necessarily confirm tolerance to another. The clinical significance of this fact is also of paramount importance, as prescription of a new opioid at equianalgesic doses may lead to overdose. Furthermore, the knowledge from randomized opioid trials is scarce and the knowledge of long-term analgesia comes from surveys, case series, open-label studies and epidemiologic studies [80]. Spinal adaptations have been shown to play an important role in the development of the tolerance phenomenon [81], with increased activity of sensory neuropeptides (calcitonin gene-related peptide and substance P) and their downstream signaling messengers derived from metabolism of arachidonic acid, such as prostaglandins, lipoxygenase metabolites and endocannabinoids [81]. Tolerance is also complicated by the fact that NMDA receptor antagonists block development of tolerance to morphine, but not to fentanyl, or a pure d opioid receptor (DOR) agonist in mice [82]. It has also been shown that patients on chronic opioids, such as methadone, demonstrate dramatically decreased tolerance to experimental pain, despite additional high doses of morphine being administered [81].

Opioid-induced immunologic effects

Opioids have been implicated in the increased incidence of infections in heroin addicts and as a cofactor in the pathogenesis of HIV [69]. Furthermore, while exogenous opioids have been implicated in immunosuppression, their endogenous counterparts (e.g., endorphins) induce immunoactivation. Opioid administration can cause inhibitory effects on antibody and cellular immune responses, natural killer cell activity, cytokine expression and phagocytic activity. The immunologic effects of opioids are mediated by central, as well as peripheral, mechanisms [83–85]. The potential by which central opioid receptors mediate peripheral immunosuppression may involve the hypothalamic–pituitary–adrenal axis and the autonomic nervous system. Interestingly, peripheral immune cells under the influence of cytokines may release endogenous opioids modulating analgesia and inflammatory response. Furthermore, the same cells can express opioid receptors creating a bidirectional system, whereby opioids, immune cells and cytokines dynamically interact [83–85]. The central immunologic receptors include µ-opioid receptor, DOR, DOR-antagonist, k-opioid receptor and k-opioid receptor-antagonist [86–88].

Opioid-induced hormonal changes

The effects of opioid compounds on hormonal function is reasonably well understood and has been termed opioid endocrinopathy or, in the case of androgen hormone, opioid-induced androgen deficiency [89–91]. The hormonal effects of opioid usage in both men and women have been documented during oral consumption [89,91–95], transdermal [92–97], intravenous [98–101] and intrathecal [102,103] administration. Opioid endocrinopathy has also been documented in illicit drug users where serum hormone levels return to normal following withdrawal from the drug [93,98]. Multiple studies have demonstrated opioid effects on a variety of hormones, including testosterone [89,95], estrogen [90,93–95,97], luteinizing hormone [90,102], gonadotrophin-releasing hormone [100], dehydroepiandrosterone, adrenocorticotropin and corticotropin-releasing hormone [97,104]. However, the majority of work has been focused on the androgen hormones, owing to their linkage to many symptomatic side effects of opioid usage.

Opioid-induced hyperalgesia

Opioid-induced hyperalgesia is a relatively unrecognized adverse effect, and is generally defined as an increased pain sensitivity [105,106]. Simply put, the sensitization presents as increasing pain despite increasing doses of opioids. Long-term use of high doses of opioids may be associated with the development of hyperalgesia, which may be related to opioid metabolites, such as morphine 3-glucor

onide, opioid-induced cell apoptosis, leading to a loss of GABA neurons resulting in changes in spinal neuronal circuits [107], or NMDA receptor agonist [108]. Studies in opioid addicts have also shown that chronic opioid use results in an abnormal pain perception, consistent with hyperalgesia [109]. The effect of opioid dose and treatment duration on perception of a painful standardized clinical stimulus has been evaluated in 355 chronic pain patients [110]. Compared with patients not receiving opioid treatment, patients receiving opioid therapy were more likely to rate the standardized pain stimulus as being more unpleasant than painful. It was concluded that the results of the study bolstered preclinical and experimental pain models demonstrating enhanced pain perception in subjects receiving opioid therapy [110].

Opioid abuse in chronic pain

The central question when prescribing opioids for chronic, noncancer pain is how best to balance the risk of opioid abuse with the pain relief provided by these medications [18–27,70,71,111–130]. While proponents claim extremely low levels of opioid abuse [55], opioids are by far the most abused drugs, especially in chronic pain management settings [18–28]. Numerous investigations have illustrated drug abuse in 18–41% of patients receiving opioids for chronic pain [31,100,112,116–129].

Martell et al., in a systematic review of opioid treatment for chronic back pain, estimated the prevalence of lifetime substance use disorders to range from 36 to 56%, with a 43% current substance use disorder rate [31]. Furthermore, aberrant medication-taking behaviors ranged from 5 to 24%.

Multiple investigators have also studied the issue of illicit drug use in chronic pain patients receiving controlled substances [112,118,124–129]. The results showed that illicit drug use in patients without controlled substance abuse was found in 14–16% of patients and illicit drug use in patients with controlled substance abuse was present in 34% of the patients [118,120,121]. Illicit drug use was significant in chronic pain patients in general, but illicit drug use was similar in patients using either long-acting or short-acting opioids [125]. In a study on effective monitoring of opiates in chronic pain patients evaluating 111,872 specimens collected over a 1-year time period from pain treatment facilities throughout the USA [128], and in another study evaluating 938,586 specimens, a significant proportion were shown to have abnormal drug testing with nonprescribed medications, illicit drugs and inappropriate intake of drugs [129]. In other evaluations, it was shown that adherence monitoring will in fact decrease controlled substance abuse and illicit drug use [124,127].

Along with an increase of prescriptions for controlled drugs from 1992 to 2002 of 154%, there was also a 90% increase in the number of people who admitted abusing controlled prescription drugs. Studies also evaluated opioid abuse in the insured population of the USA [131]. Opioid abuse was determined to be present in 6.7–8 per 10,000 persons insured; however, opioid abusers presented with multiple comorbidities and expenses eight-times higher than for nonabusers (US$15,884 vs 1830).

Drug diversion

Prescription drug ‘diversion’, defined as the unlawful channeling of regulated pharmaceuticals from legal sources to the illicit market place, has been a topic of widespread commentary and is of interest to regulators and providers [132]. The abuse of many different prescription drugs has been escalating since the early to mid-1990s [132–135]. Diversion can occur in many ways, including the illegal sale of prescriptions by physicians, patients and pharmacists, doctor shopping, forgery, robbery and theft. However, it has been shown that the majority of the drugs come from a single physician’s prescription and that family members share it [18]. Inciardi et al. described diversion as a disorganized for-profit industry [132]. They described it as ‘disorganized’ because there are so many different players involved in the phenomenon, including physicians, pharmacists and other healthcare professionals; drug abusers, patients, students, street dealers and white collar criminals; and tourists, saloonkeepers and all types of service personnel, to name but a few. Federal agencies maintain that the diverted drugs enter the illegal market primarily through ‘doctor shoppers’, inappropriate prescribing practices by physicians and improper dispensing by pharmacists [132]. Incidardi et al. in a study of the mechanisms of prescription drug diversion among drug-involved club- and street-based populations, concluded that while doctor shoppers and the internet receive much of the attention regarding diversion, the data showed there are numerous active street markets involving patients, Medicaid recipients and pharmacists as well [132]. They also suggested that the contributions of residential burglaries, pharmacy robberies and thefts and ‘sneak thefts’ to the diversion problem may have been understated.

In an updated manuscript, Inciardi et al. described the results of an ultra-rapid assessment of prescription opioid abuse and diversion in an urban community [133]. They described that the primary sources of prescription drugs on the street were the elderly, patients with pain and doctor shoppers, as well as pill brokers and dealers who work with all of the former. They also described that the popularity of prescription drugs in the street market was rooted in the abusers’ perceptions of these drugs as less stigmatizing, less dangerous and less subject to legal consequences than illicit drugs. Furthermore, they showed that the abuse of prescription opioids also appears to serve as a gateway to heroin use.

Proper use of opioids

Important issues in opioid therapy in chronic pain revolve around appropriate use of prescription opioids. However, confusion surrounding a specific operational definition of opioid misuse among chronic pain patients has complicated the process of effectively assessing and predicting its occurrence [111]. The typical elements of drug diversion involve theft, forgery, counterfeit prescriptions, fraud imposed against physician/pharmacy for other patients and promoting pill mills [18,116].

Screening for opioid abuse

The decision to use opioids for chronic pain patients, like all medical decisions, is based on a balance between risk and potential benefit. Screening for opioid misuse and abuse is an exercise to strengthen the patient–physician relationship. This should not be confrontational, and the patient has to understand that this is like any other laboratory test. A physician would respond to abnormal liver functions or anemia, just as a pain physician responds to a screening questionnaire, urine drug screen or pill count.

Inciardi et al. in their study of ultra-rapid assessment of prescription opioid abuse and diversion in an urban community, concluded that the diversion of prescription opioids might be reduced through physician education focusing on recognizing that a patient is misusing and/or diverting prescribed medications; considering a patient’s risk for opioid misuse before initiating opioid therapy; and understanding the variation in the abuse potential of different opioid medications currently on the market [133]. They also concluded that patient education also appears appropriate in the areas of safeguarding medications, disposal of unused medications and understanding the consequences of manipulating physicians and selling their medications. This has been echoed by Manchikanti et al. and others demonstrating that physician education, appropriate guidelines and adherence monitoring will reduce drug abuse and diversion [13,18–20,96,116–127].

Even though several investigators have described multiple screening instruments in detecting opioid abuse or misuse in chronic pain patients [111,136,137], there is no widely used screening instrument in current practice. Most look at problematic behaviors, such as focusing on opioids, escalation of opioid use, multiple phone calls and visits, lack of improvement with increased medications, multiple prescription problems (lost or stolen scripts) and opioids from multiple providers [111].

Urine drug testing

Urine drug testing is one of the simplest and least invasive approaches to biological sample screening in analysis for drugs and their metabolic products. Urine drug testing is utilized to depict drug levels to detect the presence of opioids and other drugs prior to, and/or at the beginning of, treatment that may be indicative of (the pattern/extent of) previous and current drug use; to establish relative baselines from which treatment compliance may be evaluated; and/or to suggest or indicate illicit drug use. Urine drug testing allows for the presence or absence of certain drugs to be evaluated with (relatively) good specificity, sensitivity, ease of administration and cost compared with other noninvasive approaches. However, controversies exist regarding the clinical value of urine drug testing, partly because most current methods are designed for, or adapted from, forensic or occupational deterrent-based testing for illicit drug use and are not entirely optimal for applications in the chronic pain management setting. With appropriate consideration of the caveats against interpretation arising from limits of sensitivity or specificity, urine drug testing can be a useful tool to aid in both the ability to evaluate patients’ compliance with prescribed regimens of controlled substances and to diagnose the misuse or abuse of prescribed drugs or use of illicit agents.

It is critical to understand the metabolism of opioids to avoid falsely accusing patients of abuse. For instance, codeine is metabolized to morphine and hydrocodone to hydromorphone. However, it has only been recognized recently that morphine (in high doses) can be metabolized to hydromorphone [138]. The hydromorphone is usually approximately 2% of the morphine dose (which can be determined by quantitative testing), and is usually seen in patients taking at least 100–200 mg of morphine per day. In a retrospective case–control study, 66% of patients on morphine showed evidence of hydromorphone in the urine drug test; this was seen more commonly in females, despite the fact that they were taking lower doses of morphine [139]. Table 1 illustrates various metabolites of opioids and the lack of understanding that may lead to misinterpretation and mismanagement of patients [140–142].

In principle, urine drug tests can detect the parent drug and/or its metabolite(s) and, therefore, demonstrate recent use of prescription medications and illegal substances. For most clinical applications, initial testing is done with class-specific immunoassay drug panels, which typically do not identify individual drugs within a class. However, this may, and perhaps should, be followed by a more specific technique, such as a gas chromatography/mass spectrometry, high-performance liquid chromatography or liquid chromatography tandem mass spectometry to identify or confirm the presence or absence of a specific drug and/or its metabolite(s). Numerous differences between various tests and even among the laboratories and manufacturers of various rapid drug-screen tests include the number of drugs tested, crossreactivity patterns, cut-off concentrations and drug interferences. Clinicians should remember that the cut-off concentrations used for drugs in federally regulated testing, particularly opioids, may be too high for clinical purposes. Immunoassays are based on the principle of competitive binding and use antibodies to detect the presence of a particular drug or metabolite in a urine sample. Immunoassay drug testing is provided either in the laboratory or by means of rapid drug testing at the point of service. Almost all immunoassays are subject to crossreactivity. Immunoassay tests for cocaine are highly predictive of cocaine use, whereas tests for amphetamine/methamphetamine are highly crossreactive and may detect other sympathomimetic amines (e.g., ephedrine and pseudoephedrine) and, therefore, are frequently unreliable and may lack predictive or diagnostic value. Similarly, standard tests for opiates are very responsive for morphine and codeine, but cannot distinguish which specific substance is present, nor can they distinguish between their metabolites. Furthermore, these assays show a lower sensitivity for semi-synthetic/synthetic opioids, such as oxycodone, methadone, fentanyl and buprenorphine. Consequently, mass spectrometric measurements allow high quality, precise measures of a variety of drugs that are relevant to chronic pain management.

Steps in appropriate prescription of opioids

Box 1 illustrates an algorithmic approach for long-term opioid therapy in chronic pain with a ten-step process that includes initial evaluation, establishment of the diagnosis, establishing medical necessity for opioids, assessing the risk–benefit ratio, establishing treatment goals, informed consent and agreement, initial dose adjustment, maintenance in the stable phase, adherence monitoring and assessment of outcomes.

Theoretically, opioids have no maximum or ceiling dose, but there is little evidence to guide safe and effective prescribing at higher doses and there is no standardized definition of what constitutes a ‘high’ or ‘low’ dose. Chou et al., by panel consensus in the American Pain Society (APS) guidelines, defined high-dose opioid therapy as greater than 200 mg daily of oral morphine or equivalent, based on maximum opioid doses studied in randomized trials and average opioid doses observed in observational studies [40].

Furthermore, multiple arguments may be made with regard to the definition of mild, moderate and high disease. These definitions vary from practitioner to practitioner and guideline to guideline. A conservative approach for a low dose is up to 60 mg of morphine equivalence; a moderate dose is 61–120 mg of morphine equivalence; and a high dose is 121–200 mg of morphine equivalence [143–149]. However, these recommendations vary widely.

Recognizing that many of our patients are already on long-term opioid therapy, steps I, II and III may have already passed. In those cases, if appropriate, acceptable and trustworthy evaluations are available, one may pass steps I–III and go to step IV. However, if reliable information is not available, the patients have to be assessed or re-assessed starting all over again. Finally, the ten-step process provides an exit strategy in step X, rather than maintaining the loop forever.

Evaluation

Appropriate history, physical examination and medical decision-making based on the initial evaluation of a patient’s presenting symptoms are essential. Some of the aspects specific to controlled substance abuse and chronic pain include evaluation of the effect of pain on physical and psychological function, such as activities of daily living.

Appropriate initial evaluation leads to establishment of a diagnosis utilizing x-rays, MRI, CT scan or neurophysiologic studies, psychological assessment and precision diagnostic interventions.

Consultation

Physicians should be willing to refer a patient as clinically indicated for additional evaluation to achieve treatment objectives. Special attention should be given to those patients who are at risk of misusing their medications and those whose living arrangements create a risk for medication misuse or diversion. The management of patients with a history of substance abuse or with a coexisting psychiatric disorder may require extra care, monitoring, documentation and consultation with, or referral to, an addictionologist. The lack of availability of well-trained psychologists, psychiatrists and addictionologists may make this referral difficult to obtain.

Informed consent & controlled substance agreement

At the initial visit, the physician should discuss the risks and benefits of the use of controlled substances with the patient or surrogate, including the risk of tolerance and drug dependence. It is advisable to employ the use of a written agreement between physician and patient outlining patient responsibilities. Agreements are helpful, specifically if the patient is determined to be at high risk for medication abuse or has a history of substance abuse. Possible items of a controlled substance agreement between a physician and patient include:

• • One prescribing doctor and one designated pharmacy; Urine/serum drug screening when requested;

• • No early refills and no medications called in;

• • If medications are lost or stolen, then a police report could be required before considering additional prescriptions.

The reasons for which opioid drug therapy may be discontinued, such as violation of a documented doctor/patient agreement, should be delineated.

Documentation & medical records

The physician should keep accurate and complete medical records, which include all aspects of interventional pain management and medical care. These comprise of, but are not limited to:

• • Medical history and physical examination

• • Diagnostic, therapeutic and laboratory results

• • Evaluations and consultations

• • Treatment objectives;

• • Discussion of the risks, benefits and limitations of treatments

• • Details of different treatments and medications, including date, type, dosage and quantity prescribed

• • Instructions to the patient

• • Periodic reviews of outcomes, including documentation of functional status, preferably using validated tools.

Records should remain current and be maintained in an accessible manner and readily available for review, not only for the physician and other members of the practice, but also for authorities.

To be in compliance with controlled substance laws and regulations required to prescribe, dispense or administer controlled substances, the physician must have an active license to practice medicine and comply with applicable regulations. Physicians should not prescribe scheduled drugs for themselves or immediate family, except in emergency situations.

The following criteria should be considered carefully in providing controlled substances:

• • Complete initial evaluation, including history and physical examination;

• • Psychological evaluation;

• • Physiological and functional assessment, as necessary and feasible;

• • Definition of indications and medical necessity:

  – Pain of moderate-to-severe degree

  – Suspected organic problem

  – Documentation of failure to respond to noncontrolled substances, adjuvant agents, physical therapy and interventional techniques

  – For patients with interventional techniques as the primary modality, controlled substance drugs may be used as a second-line treatment

  – For nonopioid controlled substances, appropriate documentation of psychological disorders should be maintained

  – Continued opioid prescription requires monitoring of the ‘4 As’:

  – Analgesia

  – Activity

  – Aberrant behavior

  – Adverse effect

• • The use of the lowest possible dose to provide adequate analgesia with minimum side effects should be the goal of opioid therapy;

• • In general, do not combine opioids with sedative-hypnotics, benzodiazepines or barbiturates for chronic noncancer pain unless there is a specific medical indication for the combination;

• • Adherence to the controlled substance agreement, with patients understanding the risks and benefits of controlled substances and the policy and regulations of the practitioner, including controlled substances being prescribed by only one practitioner and being obtained from only one pharmacy;

• • Monitoring for drug abuse or diversion should be routine and, if confirmed, referral to rehabilitation centers may be made, with termination of prescriptions of controlled substances;

• • Use caution when prescribing acetaminophen-containing opioids, especially given the ubiquitousness of acetaminophen in over-the-counter medications. Short-term use (<10 days) should be less than 4000 mg/day, while chronic use should probably be limited to 2500 mg/day.

While there are no universally accepted tools to assess opioid responsiveness, it is important to use a tool that monitors both function and pain relief.

Although opioids may be useful for the treatment of chronic pain, aberrant behavior and/or no improvement in function and pain after an adequate trial of opioids should trigger a consideration to discontinue the opioids, tapered over several weeks to avoid withdrawal symptoms. Evidence of diversion or illegal use warrants an immediate discontinuation of the medication. Clonidine 0.1 mg per os or transdermal can be offered to counteract the majority of withdrawal symptoms [13].

Expert commentary

Therapeutic opioid use and abuse, coupled with nonmedical use of other psychotherapeutic drugs, has shown an explosive growth in recent years and has been a topic of great concern and controversy across the globe. Yet, during the past 10 years, the increasing use of opioids, issues of drug abuse and diversion, inept prescription of opioids and soaring medical costs have all been discussed in the context of chronic opioid therapy. In addition, evidence of the increasing prevalence of chronic pain [10] and healthcare costs add to the concerns of chronic opioid therapy. In recent years, the expanded use of opioid analgesics for the treatment of chronic noncancer pain and the introduction of high-dose, extended-release opioid formulations have both improved access to these drugs and increased misuse, abuse and diversion [111]. The challenge has been to eliminate or significantly curtail the abuse of controlled prescription drugs while still assuring the proper treatment of those patients who can be helped by these medications. Development of effective drugs without side effects, tamper-resistant opioids, peripherally acting opioids and advances with intrathecal drug delivery systems, in conjunction with adherence monitoring, may improve appropriate opioid management [132,133,150,151]. Development of opioid guidelines by multiple organizations have and will continue to impact opioid therapy leading to appropriate use and avoiding abuse and misuse.

Five-year view

Based on the data available, it appears that there has been an escalation over the past 10 years not only of the therapeutic use of opioids and other psychotherapeutics, but also of their abuse and nonmedical use. The question raised is, what could happen in the next 5–10 years? While we may see some new developments in the coming years with tamper-resistant and safe opioids, the cost of these drugs may become a deterrent to their use in clinical practices. In the next 5 years, it is expected that along with a reduction in overuse, misuse and abuse, physicians will be much more cautious, which will reduce abuse and misuse, but may also reduce legitimate access, although in a minority of the population. Thus, it is important not to overlook the highly interactive pattern of effect and impact that is produced in the general areas of substance abuse, mental health and overall healthcare. We believe that the challenges of modern medicine and fundamental values will continue to prosper during the coming decade. Based on the ‘Hippocratic’ tradition, a physician must use his medical skills for the relief of pain and suffering, while doing no harm. Thus, the next decade will continue with palliation of pain, because a cure for all types of pain is far from being a reality. However, owing to renewed enthusiasm and exploding use, abuse and healthcare costs, valid evidence will be accumulated during the next decade.

Table 1. Metabolites of opioids and their impact on the interpretation of urine drug testing.

Metabolites	Comment
Hydrocodone
Hydromorphone Dihydrocodeine	If codeine to hydrocodone ratio <10, codeine is not the sole source
Normorphine
Norhydrocodone Hydrocodol	Level generally lower than its hydrocodone source and below detection if only codeine was ingested
Hydromorphol
Oxycodone
Oxymorphone
Noroxycodone
Oxycodols and their respective oxide
Morphine
Hydromorphone (minor) Morphine-3-glucuronide	If codeine to morphine ratio <6, codeine is probably not the sole source
Morphine-6-glucuronide
Normorphine	Level generally lower than its hydrocodone source and below detection if only codeine was ingested
Methadone
2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine
2-Ethyl-5-methyl-3,3-diphenylpyrrolidine
Hydromorphone
Dihydromorphine	Level generally lower than its hydrocodone source and below detection if only codeine was ingested
Hydromorphone-3-glucuronide
Oxymorphone
Oxymorphone-3-gluucornide
Oxymorphol
Codeine
Hydrocodone (minor) Norcodeine	If codeine to hydrocodone ratio <10, codeine is not the sole source
Morphine	If codeine to morphine ratio <6, codeine is probably not the sole source
Propoxyphene
Norpropoxyphene
Fentanyl
Norfentanyl
Tramadol
O-desmethyl-tramadol
Nortramadol
Butorphanol
Hydroxybutorphanol
Norbutorphanol
Buprenorphine
Norbuprenorphine
Norbuprenorphine-3-glucuronide
Buprenorphine-3-glucuronide
Heroin
Morphine
Codeine (contaminant)
6-Monoacetylmorphine

Adapted from [140–142].

Box 1. Ten-step process: an algorithmic approach for long-term opioid therapy in chronic pain.

Step I

Comprehensive initial evaluation

Step II

Establish diagnosis

• • X-rays, MRI, computed tomography, neuro-physiologic studies

• • Psychological evaluation

• • Precision diagnostic interventions

Step III

Establish medical necessity (lack of progress or as supplemental therapy)

• • Physical diagnosis

• • Therapeutic interventional pain management

• • Physical modalities

• • Behavior therapy

Step IV

Assess risk–benefit ratio

• • Treatment is beneficial

Step V

Establish treatment goals

Step VI

Obtain informed consent and agreement

Step VII

Initial dose adjustment phase (up to 8–12 weeks)

• • Start low dose

• • Utilize opioids, NSAIDs and adjuvants

• • Discontinue

  – Lack of analgesia

  – Side effects

  – Lack of functional improvement

Step VIII

Stable phase (stable–moderate doses)

• • Monthly refills

• • Assess for four As

  – Analgesia

  – Activity

  – Aberrant behavior

  – Adverse effect

• • Manage side effects

Step IX

Adherence monitoring

• • Prescription monitoring programs

• • Random drug screens

• • Pill counts

Step X

Outcomes

• • Successful – continue

  – Stable doses

  – Analgesia, activity

  – No abuse, side effects

• • Failed – discontinue

  – Dose escalation

  – No analgesia

  – No activity

  – Abuse

  – Side effects

  – Noncompliance

Key issues

• • Opioids are used extensively in managing chronic pain, although there is only weak (or limited) evidence of their effectiveness for pain relief and functional improvement.

• • There is significant evidence of opioid abuse with or without concomitant illicit drug use.

• • Opioid pharmacology is variable and understanding it is essential for the proper management of patients.

• • Among the rules of opioid administration, comprehensive evaluation and diagnostic assessment is crucial, including diagnosis by interventional techniques.

• • Establishing goals of treatment and using a controlled substance agreement are essential in the practice of pain management with opioids.

• • Periodic review of all patients on opioids is essential, using appropriate adjustments, with routine assessment of analgesia, activity, aberrant behavior and adverse effects.

• • Documentation, keeping accurate and complete medical records, with all the essential elements to provide proper patient care and also meet regulatory and legal requirements, is essential.

• • The rationalization and importance of these recommendations lies in the fact that most available evidence documents a wide degree of variance in the prescribing patterns of opioids for chronic pain. The strength of available evidence in the use of opioids for chronic noncancer pain is weak.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.