Identification and management of pain medication abuse and misuse: current state and future directions

Abstract

Long-term opioid therapy poses a risk for abuse and misuse in some patients. Identifying which patients may potentially be at risk prior to initiation of therapy, and identifying patients in whom these problems develop during therapy, are significant challenges. Outcome prediction is impeded by the complexity of the problem, where considerable heterogeneity results from psychological and socioeconomic factors, as well as interindividual variation in biological pathways due to genetic and epigenetic factors. Screening tools designed to detect opioid misuse and urine drug testing are both used clinically; scant evidence currently exists to allow the formulation of an algorithm for judicious use of these tools. Moreover, these tools may not be addressing the underlying alterations in biological pathways that occur owing to the development of chronic pain or in response to chronic opioid administration. An evidence-based algorithmic approach to risk mitigation that can be applied in a cost-effective manner to guide therapy is urgently needed.

Keywords::

• opioid abuse
• opioid misuse
• outcome prediction
• pain medication questionnaire
• screening tools
• urine drug testing

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All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at http://www.medscape.org/journal/expertneurothera; (4) view/print certificate.

Release date: 1 May 2012; Expiration date: 1 May 2013

Learning objectives

Upon completion of this activity, participants should be able to:

• • Describe the Pain Medication Questionnaire (PMQ) as a screening tool to detect opioid misuse, based on a review

• • Describe use of urine drug testing (UDT) to detect opioid misuse, based on a review

• • Describe outcome prediction among patients in whom long-term opioid therapy is being considered, based on a review

Financial & competing interests disclosure

EDITOR

Elisa Manzotti,Publisher, Future Science Group, London, UK

Disclosure:Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Laurie Barclay, MD,Freelance writer and reviewer, Medscape, LLC

Disclosure:Laurie Barclay, MD, has disclosed no relevant financial relationships.

AUTHORS

Craig T Hartrick, MD, FIPP,Biomedical Sciences (Pharmacology), Oakland University William Beaumont School of Medicine, Rochester, MI, USA

Disclosure:Craig T Hartrick, MD, FIPP, recently participated in Webinars for Indian physicians sponsored by Glenmark and Wolters Kluwer and has received research grant funding from Ortho-McNeil in the past.

Robert J Gatchel, PhD, ABPP,Department of Psychology, College of Science, The University of Texas at Arlington, Arlington, TX, USA

Disclosure:Robert J Gatchel, PhD, ABPP, has disclosed no relevant financial relationships.

Sean Conroy, MD, FIPP,Pain Division, Department of Anesthesiology, Beaumont Health System, Troy, MI, USA

Disclosure:Sean Conroy, MD, FIPP, has disclosed no relevant financial relationships.

While opioids have been used for pain for thousands of years, their prescription for chronic noncancer pain was historically limited owing to concerns over adverse effects, including the risk for addiction. However, in recent decades, long-held attitudes began to change, especially in the USA. Expert opinion and consensus statements suggested that, in some cases, long-term use of opioids in noncancer pain may not be associated with increased risk of addiction. A joint position statement from the American Pain Society and the American Academy of Pain Medicine published in 1997, while continuing to recommend judicious opioid use in these situations, also stated that tolerance was not a “prevalent limitation to long-term opioid use”. This implied that chronic opioid use rarely posed a clinical problem necessitating dose escalation unless there was disease progression [1]. While the development of tolerance to chronic opioid administration leading to an escalating dose requirement is now recognized to be common, it is not necessarily directly associated with increased risk for the development of addiction (i.e., a preoccupation with procurement and compulsive use of a drug) [2]. In fact, there is some evidence to suggest that allowing dose escalation may be associated with small improvements in outcome in highly controlled situations [3]. Less frequently, the dose escalation associated with the development of tolerance leads to a state of heightened pain intensity – opioid-induced hyperalgesia (OIH).

The distinction between tolerance and addiction is important because most opioid-tolerant patients do not exhibit signs of addiction. Conversely, evidence of tolerance is not a requirement for the development of addiction. Nevertheless, higher opioid dosing has been associated with higher rates of addiction [4]. Other predictive factors for the development of addiction include younger age, as well as pre-existing mental health disorders and prior substance abuse [4], factors that are widely included in screening tools prior to the initiation of long-term opioid therapy. However, despite a long human history of opioid use, outcome prediction with respect to the potential for addiction, abuse and misuse remains problematic.

Consistent with these gaps in knowledge regarding the potential for addiction, outcomes in chronic opioid therapy for noncancer pain remain contentious; surprisingly, there is relatively little evidence supporting the efficacy of chronic opioid therapy [5]. However, the trend for increased opioid use, already well underway prior to 1997, has increased in exponential fashion [6]. Aberrant behaviors in patients taking chronic opioid for noncancer pain are common and they have been noted in up to 24% of patients [7]. Abuse, the unlawful use or use despite detriment to the user, and misuse, the use in a manner other than prescribed, are also both commonly observed. Given the widespread use of opioids for chronic pain, the ability to predict which patients are likely to fail therapy due to abuse or misuse prior to initiation of treatment, and the importance of identifying patients exhibiting medication abuse and misuse during therapy, are both widely recognized as essential. Updated guidelines for opioid use in chronic noncancer pain from an internationally constituted consensus panel have recently been published, at least partially in response to the recognition that the weight of evidence is once again favoring heightened vigilance [8].

The risks for abuse and addiction are subject to considerable individual variability. It is likely that, in addition to the predictors previously mentioned (mental health disorders and prior substance abuse), genetic, environmental and social factors also contribute. In addition, nonadherence to therapy may vary with other remaining factors that include reluctance to take medication and fear of addiction [9]. Pathophysiological changes following injury may also be important, especially in neuropathic conditions. A phenotypic shift from opioid-predominant pain pathways to noradrenergic mechanisms following nerve injury, as noted in preclinical models [10], may reduce the effectiveness of therapy. This ineffectiveness can contribute to an apparent undermedication, resulting in pseudoaddictive drug-seeking behavior. Moreover, as glial cells in the CNS are now understood to play a major role in the development of neuropathic pain, OIH and opioid tolerance, it has been postulated that altered glial cell behavior may contribute to opioid abuse [11]. Variation in sensitivity to drug effect, drug metabolism and adaptation to the effects of chronic exposure to a drug may also contribute to the susceptibility for opioid abuse.

While the body may naturally adapt to an ongoing toxin assault, in the form of opioid or other drug therapy, by downregulation in receptor numbers or sensitivity, interindividual differences in this response may lead to the need for dose escalation in some patients. Additionally, the reward experience, as modulated by the mesolimbic dopamine pathway following opioid use, may present yet another source of variability.

Although mediated by differing mechanisms, both positive reinforcement (euphoria) and negative reinforcement (self-medication to reduce the effects of withdrawal) are possible. Neuroplasticity associated with altered behavior of dopaminergic neurons of the ventral tegmental area, which project to the nucleus accumbens and mediate reward mechanisms, drive the transition from regulated to compulsive drug use. Vulnerability to relapse, should chronic use be discontinued, is thought to be mediated by neuroplasticity in cortical glutaminergic pathways projecting to the nucleus accumbens [12]. Dopaminergic transmission is disinhibited when the inhibitory GABA interneurons are themselves inhibited by µ-opioid agonists and CB₁ cannabinoid agonists. Both prior experience and variation in the relative influences of these and other inhibitors of GABA release may add to the considerable potential for individual variability, further hampering efforts to predict patient response to chronic opioid therapy.

Undertreatment of chronic pain: one rationale for abuse-liability screening

As noted by Gatchel, there have been a number of reviews to suggest that the proper management of opioids and other pain-reducing medications (e.g., antidepressants and neuroleptics) in well-selected patients with no history of substance abuse or addiction, often leads to long-term pain relief [13]. There is, however, significant risk for some patients to develop addiction or other serious side effects due to abuse or misuse [14]. Moreover, as Katz and Barkin have pointed out, in spite of the potential usefulness of such medications, and even though there are a variety of pharmacological treatments currently available for patients suffering from persistent and chronic pain, such pain is often inadequately managed [15]. This has the unfortunate consequence of chronic pain being a substantially undertreated problem for patients and for society as a whole. Gatchel has provided a number of reasons for this inadequate pharmacological treatment, as delineated below [13]:

• • Healthcare professionals often have the fear of patients abusing or becoming addicted to the pain medications;

• • Related to the above, it has been found that many healthcare professionals have the fear of being perceived as potentially complicit in increasing the rates of abuse or addiction in patients [16];

• • There is frequently the need for multiple doses of pain medication (e.g., opioids) for continuous pain relief, which may result in inconvenience, as well as time–compliance issues, that often prevent patients from achieving adequate pain relief;

• • There are also often side effects (such as gastrointestinal, cardiovascular and organ toxicity) that limit the prescription of adequate levels of medication for effective pain relief in some patients;

• • Because the US federal government is now closely monitoring the potential misuse or abuse of controlled substances, such as opiates and other pain medications, many physicians have developed ‘opiophobia’ (or the fear of opioid prescribing, with an inherent prejudice against these types of drugs, regardless of their appropriate utility). Therefore, many physicians have limited their pain medication prescriptions owing to fear of potential regulatory investigation. Indeed, in a recent survey study of 128 healthcare providers by Hooten and Bruce, it was found that a significant proportion had unsupported beliefs and problematic attitudes about medication abuse and addiction [17].

Such findings highlight the important educational gaps related to prescribing opioids.

Owing to the above fears and concerns associated with prescribing pain medications that, unfortunately, often result in the under-treatment of patients with this therapeutic modality, there is now an increased effort being made to promote an early and proper identification of, along with careful monitoring for, potential signs of medication misuse, abuse and addiction in patients requiring such chronic medication. How does one go about the task of evaluating ‘well-selected patients?’ Fortunately, a number of assessment tests have been developed for this purpose in recent years (see Gatchel [13] and Turk et al.[18] for a review of such tests).

Variability in screening prior to initiating opioid therapy

Psychosocial screening interviews [19], screening tools designed to predict risk for addiction, abuse and misuse [20–25], and urine drug screens are used to assess the suitability of patients for long-term opioid treatment. However, few studies have compared the effectiveness of these methods in predicting treatment outcome. Moore et al. compared the Screener and Opioid Assessment for Patients with Pain (SOAPP), Diagnosis, Intractability, Risk and Efficacy Score (DIRE), Opioid Risk Tool (ORT) and a clinical interview, and they reported high sensitivity in predicting aberrant behavior with the interview and SOAPP [26]. Combining the SOAPP with a clinical interview provided a sensitivity of 90%. More recently, the ability of three risk assessment tools SOAPP – Revised [SOAPP–R], ORT and Pain Medication Questionnaire [PMQ]) and a clinical interview by one of two experienced psychologists to predict discharge from opioid treatment and the presence of aberrant behavior were compared [27]. None of these measures individually yielded the ideal test to predict aberrant drug-related behavior. The sensitivity for predicting aberrant behavior was highest for psychologist 1 (69.2%), followed by the SOAPP-R (41.4%) and PMQ (35.8%). The specificity was, however, highest for the ORT (88.1%), psychologist 2 (83.3%) and PMQ (78.1%). Combining sensitivity and specificity (receiver operator characteristic curves) gave a measure of the best overall performance with the best score by psychologist 2 (65.7%), followed by PMQ (57.0%) and the SOAPP-R (56.2%) [27].

The wide variation in the approach to screening prior to the initiation of opioid therapy adds further complexity to clinical practice. While some clinicians use virtually no screening, others use individual or combinations of the aforementioned tools, often applying them inconsistently. Moreover, findings from a recent study suggest that, even when a standardized approach to the evaluation for potential aberrant drug-related behaviors is implemented, clinical investigators tended to assign risk levels for misuse and abuse that were lower than specified in the protocol [28]. The following section highlights the importance of screening in a consistent, rational manner, and a rationale for implementation of screening procedures.

The PMQ as an example of a screening instrument for potential medication misuse

Gatchel and colleagues initially developed the PMQ in order to assess the risk of medication misuse in chronic pain patients in a series of four studies [24,25,29,30]. In the initial study of this series, Adams et al. reported that there was a positive relationship between high PMQ scores (high scores = higher potential risk) and concurrent measures of substance abuse, psychopathology and physical-life functioning [29]. An advantage of the PMQ found in this study was that it had good psychometric properties (with a test–retest reliability coefficient of 0.86; and with good internal consistency reflected by a Chronbach’s α of 0.73). It was also shown to have good validity (e.g., concurrent validity with indices of substance abuse/use as well as known opioid abuse). Another attractive feature of the PMQ is that it is a relatively brief 26-item self-report instrument that can be easily completed by patients (it also requires only a third-grade reading level).

Subsequently, in a replication of this initial aforementioned study, Holmes and colleagues revealed some additional important characteristics that were associated with patients with high PMQ score [24]. These characteristics included the following: the request for early refills for prescription medications was 3.2-times more than in patients with low PMQ score; the history of substance abuse problems were 2.6-times greater than in patients with low PMQ score; the dropout rate from an interdisciplinary pain management program was 2.3-times greater than in patients with low PMQ score; and, overall, there was a diminished biopsychosocial functioning level relative to patients with low PMQ score. Additional studies by Dowling et al.[30] and Beulow et al.[25] replicated these results, as well as demonstrated reasonable cutoff points for those that had a significant issue with potential medication misuse (PMQ score ≥20), or a serious potential (PMQ score ≥30).

As summarized by Gatchel, the use of screening instruments such as the PMQ can greatly aid healthcare professionals in overcoming their reluctance to prescribe pain medication for fear of causing patient misuse or abuse in a number of ways [31]. These are listed below:

• • Using the PMQ, or other screening instruments, and consistently including it in the patient’s medical chart, will help healthcare professionals to have a good record of demonstrating ‘due diligence’ in monitoring prescription use and potential misuse in the event of any potential Drug Enforcement Agency audit of their records for potential overprescribing of such medications;

• • By providing specific cutoff scores by the means of screening ‘flags’ for potential medication misuse, the treating clinician can increase quality assurance in terms of tailoring the treatment program to the specific needs of patients, which may include more education about the harm or misuse and subsequent tolerance issues of such medications;

• • Patients who score high on the PMQ (or other instruments) may then trigger the request for more drug screenings for them during the course of treatment;

• • Finally, related to the above, a high PMQ (or other screening instrument) score will alert the clinician not to provide early refills of medications, nor to merely refill them over the phone. It will trigger the request that any refills must be accompanied by an in-office visit during which the clinician can evaluate any signs of potential misuse. Again, of course, such meetings should be diligently recorded in the patient’s medical chart in the case of a Drug Enforcement Agency audit.

Other self-report & observational screening methods

Turk et al. conducted a systematic review of published evidence for identifying at-risk patients to guide clinicians’ decisions and practice for prescribing opioid treatment for chronic pain patients [18]. These and other screening methods are summarized in Table 1.

Predicting the potential of medication misuse is much more complex than using a single assessment tool

It should be pointed out that many patients who abuse or misuse pain medications are extremely likely to have other psychosocial issues (such as personality disorders, clinical depression and anxiety disorders) that need to be concurrently treated along with the pain condition itself for which the medication is being prescribed. Fortunately, there are now interdisciplinary pain management programs that have been shown to be both treatment- and cost-effective in managing such chronic pain patients, as well as any medication issues that arise [32,33]. Indeed, it should be clearly understood that a major component of the treatment of chronic pain is that the use of pain medications should be only one component of a more comprehensive interdisciplinary evaluation/treatment pain management program. These interdisciplinary pain management programs need to include pharmacotherapy, behavioral medicine/cognitive behavioral treatment, physical therapy and occupational therapy, all coordinated by a physician–nurse team [34,35]. It is also important to note that an appropriate ‘exit strategy’ needs to be in place at all times in order to discontinue the use of pain medications when a patient is not meeting appropriate goals of the comprehensive treatment program, or if problematic behaviors develop and persist over time.

Of course, before initiating the ‘exit strategy’ for a patient who is perceived as misusing or abusing a medication, there are other methods that should be instituted at the first sign of aberrant behaviors. Urine toxicology screens are probably the ‘gold standard’ for deducing substance use. Therefore, as suggested by Turk et al., routine screening of chronic pain patients before prescribing opioids, as well as throughout the course of treatment, may be the best recommended policy [18]. However, drug testing results must be interpreted with some caution. The lack of an initial positive urine screen cannot be used as a definite predictor of future aberrant drug behaviors. Thus, even patients with an initial negative screen may later demonstrate behaviors that appear to be indicative of substance misuse [36]. By contrast, initial positive urine toxicology may not predict future aberrant behaviors. Indeed, Katz et al. also found that 72% of patients with positive baseline screens indicating drug misuse did not demonstrate any apparent behaviors after treatment was initiated [36]. Thus, as summarized by Turk and colleagues [18]:

“Although urine toxicology screening is effective in detecting drug misuse, the results by themselves are not sufficient. The critical question remains unanswered: how do we distinguish between those who are at risk versus those who are not? Although universal precautions are prudent when prescribing long-term use of opioids, the identification of those chronic pain patients at risk for opioid misuse would permit physicians to take extra precautions.”

A great deal of additional research is still required to precisely identify those patients/populations at greater risk for abusing prescription pain medications. Of course, it should be clearly noted that the term ‘risk’ is not synonymous with substance abuse disorder or addiction; it only suggests the potential of such problematic behavior. Nevertheless, the identification of at-risk patients warrants additional attention, more in-depth evaluation of the patient, discussions of the potential problem with the patient, and continual monitoring of the patient (such as urine toxicology tests if needed). In addition, with the growing effectiveness of interdisciplinary pain management programs, we are now no longer limited to a unimodal therapy approach, such as just the use of opioids. We have other multiple interventions methods to use, with opioids simply being an adjunctive one.

When opioids or other pain medications are prescribed, it is absolutely incumbent on the clinician to carefully monitor these patients, by documenting changes in symptoms, functioning and any aberrant behaviors that may arise. In addition, because a patient’s status may change over time, it may be necessary to monitor and modify the treatment plan when necessary. It is important to use multiple sources of information in order to best estimate the initial risk potential or the continued potential risk of patients. These should include demographic factors, the observation of patient’s behaviors, the reports by a patient’s significant others, medical records and mood disorders, as well as the results of urine toxicology screens. Finally, there will have to be better education of clinicians who prescribe opioids, or hesitate to do so because of personal fears related to such prescriptions.

As previously mentioned, even when multiple measures are used to screen for potential drug-related aberrant behavior, risks are not eliminated. The evidence for the effectiveness of treatment agreements between the patient and a single prescribing physician (so-called ‘opioid agreements’) is weak [37]. Cooperative regulatory initiatives among adjacent states in the USA allow for the tracking of opioid prescription and dispensing for individual patients. This alerts prescribing physicians when their patients are receiving opioids from other legal sources. To date, these relationships remain incomplete and it is up to individual states to monitor opioid prescription.

Drug monitoring programs

Patients may seek opioid prescriptions from multiple providers without their physician’s knowledge, hampering oversight and accountability. Yet the physician’s responsibility to the patient and the community remains great, with fatalities due to prescription drug overdose in the USA surpassing deaths associated with illicit drug use [38]. In many jurisdictions, when prescriptions for opioids are filed, they are recorded electronically; this information is made available to practitioners. Prior to writing an opioid prescription the physician can query the database to when and where opioid prescriptions have been filed for the patient and who wrote those prescriptions. As of June 2011, 34 states have such systems in operation [39]. Violations of the opioid agreements can be documented. Those patients that ‘doctor shop’ can be identified. Whether or not these programs are effective in reducing opioid abuse is unclear, but the potential exists for significant improvement in this problem once information can be efficiently shared across state lines.

Identifying individuals that may be obtaining prescription medications for nonmedical use (e.g., to sell) can be more complicated. Likewise, illicit drug procurement and use requires alternative investigative approaches; urine drug testing (UDT), as was previously mentioned, is one of the more effective methods in this regard.

Urine drug testing

UDT is a valuable clinical tool available to practitioners to help guide clinical decision-making. The goals of UDT are to: detect the presence of the opioid prescribed; detect the presence of nonprescribed opioids or illicit drugs; and sometimes detect unexpected concentrations of the prescribed opioid. When the prescribed drug is not detected it may indicate that the patient is selling or trading the drug. This is not only illegal, but can be considered both drug misuse and abuse, as it is harmful to the community.

Which patients should be subjected to UDT, how frequently UDT should be repeated, whether the UDT should be scheduled or random, and what other testing may aid in these decisions, such as repeat PMQ or COMM testing, are yet to be determined [40]. These questions have not only clinical importance in improving patient care, but considerable economic value, as frequent indiscriminate use of UDT can be costly. The practice patterns regarding implementation of UDT to monitor long-term opioid therapy vary widely [41]. There is little agreement with respect to the timing of testing or even the rationale for testing. One protocol for drug testing has been advanced; however, it is not based on evidence beyond expert opinion [42]. The need for an evidence-based algorithmic approach to monitoring opioid therapy that minimizes the associated costs seems clear.

The two main types of UDT available to clinicians include immunoassay drug testing and laboratory-based specific drug identification. Immunoassay drug testing is relatively inexpensive, offers rapid results and is readily available in the office setting (point-of-care). Immunoassays are based on the principle of competitive binding and use antibodies to detect the presence of a drug or metabolite in a urine sample. These antibodies then form antibody–antigen complexes when exposed to a drug or drug metabolite. The ability of an immunoassay to detect a drug or metabolite is a function of the concentration of the substance in the urine and the predetermined cutoff concentration. This result is reported as a positive or negative value without quantification.

Point-of-care immunoassay urine drug-testing devices are readily available and offer rapid results at a lower cost than laboratory testing. Unfortunately, some commonly prescribed opioids may elude detection by these devices. Typically, they effectively identify the presence of a drug class in the urine. Although this nonspecific class identification may be acceptable for a work-related (employment) urine drug test, it is usually unacceptable for the clinical setting, where a practitioner is trying to determine what drugs are specifically present, not just the class. Some additional disadvantages of this type of testing include: the subjective nature of the qualitative results (predetermined cutoffs report a drug as positive or negative without quantitative reflection); the potential malfunction of the test device after exposure to uncontrolled circumstances during product shipping and delivery; a limited list of drugs or drug classes that can be detected; and a lack of potential expert laboratory support for test interpretation (which is usually readily available from commercial laboratories) [43].

Commercial laboratories use either liquid chromatography (LC) or gas chromatography (GC), followed by mass spectrometry (MS) to determine both the presence and amount of drugs present in a urine sample (GC/MS or LC/MS). The chromatography portion of the test is used to separate different components of a specimen, and the MS is used to identify the individual drug/metabolite components within the specimen. Advantages to laboratory-based drug identification processes include not only the qualitative identification of specific drugs and metabolites, but also quantitative levels (with GC/MS and LC/MS) of these compounds. Some companies offer algorithms to compare the recorded values against expected demographic-specific values, although validation of these algorithms remains limited [44]. Chromatographic/spectrometry methods can also be used as a confirmatory tool following initial immunoassay testing. Skillful interpretation of UDT has become an important aspect of clinical practice. False-positive as well as false-negative results represent significant pitfalls for practitioners.

Summary

Providing long-term opioid therapy to chronic pain patients while minimizing abuse and misuse remains challenging despite thousands of years of practical experience. The complexity of the problem arises from many factors, including socioeconomic considerations, psychosocial determinants, variation in clinical practice and interindividual variation in biological pathways. The need for an evidence-based algorithmic approach that can be applied in a cost-effective manner to guide maintenance therapy is critical. At present, clinical judgments can be raised beyond anecdotal experience and intuition through the use of screening tools such as the PMQ and the use of UDT, but there is little evidence to support any current algorithm regarding their implementation.

Expert commentary

Since objective data from well-designed clinical trials are not yet available, some clinicians, especially those who are ‘opiophobic’, opt for routine UDT on every patient at every visit. There is, however, long-standing evidence that random screening may result in better outcomes [45]. Moreover, this practice of frequent testing in all patients results in significant economic burden. Studies designed to stratify patients based upon risk, and then adjust the frequency of testing based upon need, could justify the use of UDT in a cost-effective manner while improving the efficiency of healthcare delivery. The current lack of such studies is clearly not due to insufficient interest or a small at-risk population. Rather, it may relate at least in part to the wide variation in a multitude of complex biological factors that may not be adequately assessed with current screening tools.

The apparent need to escalate doses of an opioid over time, while perhaps not causative, is positively correlated with addiction and aberrant behaviors. Opioid administration causes structural and functional alterations in the pathways associated with affect and reward within weeks of instituting therapy [46]. Opioid rotation has been advocated and is commonly used clinically when dose escalation becomes necessary despite the paucity of objective data to support its effectiveness [47]. Switching treatment from one opioid to another may exploit subtle differences in opioid receptor subtype activation patterns [48]. However, more dramatic phenotype changes are likely to affect all opioids, thus limiting the effectiveness of opioid rotation.

The mechanisms underlying both opioid tolerance and the development of OIH likely relate to alterations in central immune signaling [49]. Surrogate biomarkers for altered pain sensitivity and/or changes in diffuse inhibitory control, either due to genetic factors or neuroplasticity, may eventually prove to be useful adjunctive measures in determining risk for abuse and misuse. Examples may include, but are certainly not limited to, the response to pressure algometry or other sensory challenge (such as plunging one’s hand into an ice water bath). These are simple tests, rapidly and inexpensively performed, that can be repeated over time to assess phenotypic shifts: alterations in pain thresholds, pain tolerance and/or central sensitization in response to chronic opioid administration. Central sensitization may also be assessed using psychometric testing [50]. Adding measures such as these to current screening tools and UDT may help further efforts to develop a practical algorithmic approach to guide chronic opioid therapy.

The choice of opioid agent may also be significant. The partial µ-opioid agonist buprenorphine is increasingly being used in opioid addiction. It also has utility as an analgesic for long-term use. While associated with less than full µ-opioid receptor efficacy (and a potentially better safety profile), buprenorphine also has effects on other opioid receptors: κ-opioid receptor antagonist; δ-opioid receptor agonist; and partial ORL-1 agonist. Preclinical evidence supports divergence from the effects seen following chronic pure µ-opioid use, suggesting reduced desensitization with reduced downregulation of µ-opioid receptors [51]. At least anecdotally, tapentadol extended-release does not seem to be associated with the same degree of tolerance development compared with pure µ-opioid agents, perhaps because the drug is relatively new and there is limited experience with it, or perhaps because of the dual mode of action where norepinephrine reuptake is inhibited [52]. While a synergistic effect on analgesia due to norepinephrine reduces the overall µ-opioid agonist requirement [53], the α-2-adrenergic effects may also act to modify central immune processing [54]. Nevertheless, both buprenorphine and tapentadol should be considered to be associated with tolerance, and both have abuse and misuse potential.

Five-year view

Significant progress toward the development of an integrated evidence-based algorithm for screening and monitoring chronic opioid administration that minimizes costs, while reducing risk for abuse and misuse, may well be expected within the next 5 years. Anticipated advances in the fields of neuroimmunology, genetics and epigenetics may play important roles [55]. Phenotypic behavioral change due to altered central immune processing following chronic opioid use may be more efficiently predicted using direct genetic markers rather than surrogate testing. For example, alterations in COMT haplotypes are known predictors of pain sensitivity. Once rapid and inexpensive genetic testing becomes common, data-mining approaches applied to the problem may identify some of the innate biological predictive features, thus facilitating risk stratification. Additionally, there are medications currently clinically available (although commonly used for other indications) that modify glial cell behavior. It may be possible to pre-emptively mute some of the alterations in glial function associated with chronic opioids by administering these adjunctive medications concurrently with the opioids.

The attitude toward other concurrent medications may also change over the next 5 years. Many, if not most, clinicians currently exclude patients taking any illicit drugs from receiving opioid prescriptions, and include this in their opioid agreement with the patient, either verbally or in written form. There are a number of reasons to support this position. Considerable controversy exists, however, over what to do with patients who test positive on UDT for marijuana. Marijuana acts on both CB1 receptors, which modulate pain and euphoria, and CB2 receptors on glial cells. Curiously, there is preclinical evidence to support the use of CB2-specific cannabinoid agonists in pain because they lack the neurological adverse effects associated with marijuana mediated via CB1 receptors as they do not seem to be subject to the same degree of tolerance development; and they are potent glial modifiers with the potential to reduce altered central immune signaling [11]. The clinical development of CB2-specific agents may dramatically alter the way we administer chronic opioids.

Table 1. Other examples of self-report and clinical interview screening methods for assessing potential medication misuse.

Study (year)	Screening tool	Ref.
Clinical interview
Wu et al. (2006)	Addictions Behaviors Checklist	[56]
Compton et al. (1998)	Prescription Drug Use Questionnaire	[57]
Michna et al. (2004)	Prescription Opioid Therapy Questionnaire	[58]
Paper and pencil self-report
Butler et al. (2007)	Current Opioid Misuse Measure	[59]
Webster et al. (2005)	Opioid Risk Tool	[20]
Coombs et al. (1996)	Screening Instrument for Substance Abuse Potential	[60]
Butler et al. (2004)	Screener and Opioid Assessment Measure for Patients with Pain	[61]
Butler et al. (2008)	Screener and Opioid Assessment Measure for Patients with Pain – Revised	[22]
Friedman et al. (2003)	Screening Tool for Addiction Risk	[62]
Belgrade et al. (2006)	Diagnosis, Intractability, Risk, and Efficacy Score	[23]

Key issues

• • There is a lack of knowledge regarding the underlying mechanisms for the development of opioid abuse and misuse.

• • Considerable interindividual variation makes outcome prediction complex.

• • Current approaches to risk mitigation rely on risk stratification and surveillance for aberrant behaviors.

• • The tools used to stratify risk and monitor therapy may not be effectively addressing the core issues underlying opioid abuse and misuse.

• • There is no evidence-based algorithm for consistent and efficient use of the screening tools currently available.

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Identification and management of pain medication abuse and misuse: current state and future directions

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. Your patient is a 68-year-old male with chronic low back pain from disc herniation who has failed surgery and conservative therapies and who has been on long-term opioid therapy. Based on the review by Dr. Hartrick and colleagues, which of the following statements about use of the Pain Medication Questionnaire (PMQ) is most likely correct?

• □ A There is no correlation of PMQ scores with concurrent measures of substance abuse, psychopathology, and physical-life functioning

• □ B The PMQ has a test-retest reliability coefficient of 0.86, but poor internal consistency and fair validity

• □ C Administration of the PMQ requires considerable time by trained staff

• □ D Reasonable cutoff points are ≥20 for those that have a significant issue with potential medication misuse, or ≥30 for a serious potential

2. Based on the review by Dr. Hartrick and colleagues, which of the following statements about use of urine drug testing (UDT) to detect possible opioid misuse in the patient described in question 1 is most likely correct?

• □ A The goals of UDT are to detect the presence of the opioid prescribed and of non-prescribed opioids or illicit drugs, and to detect unexpected concentrations of the prescribed opioid

• □ B Failure to detect the prescribed drug usually indicates that the patient is a rapid metabolizer

• □ C Timing of UDT and the rationale for UDT are well standardized across multiple clinical settings

• □ D Laboratory-based specific drug identification is less expensive than immunoassay UDT

3. Based on the review by Dr. Hartrick and colleagues, which of the following statements about outcome prediction among patients in whom long-term opioid therapy is being considered would most likely be correct?

• □ A Tolerance is required before addiction can develop

• □ B Higher opioid dosing is not associated with higher rates of addiction

• □ C Younger age, pre-existing mental health disorders, and prior substance abuse are predictive factors for the development of addiction

• □ D Clinicians have no way of checking on prior opioid prescriptions