‘It's time we stop the source and treat the troubled’, CDC Director Dr Tom Frieden .
The increase in prescription opioid abuse has gathered attention from the medical societies, politicians, and the White House [2,3▪,4]. The number of opioid prescriptions increased by 60% over the last 10 years , and in 2012, 74% of prescription drug overdose deaths (14 800 deaths) were related to opioid analgesics . According to the 2010 National Survey on Drug Use and Health, 5.1 million people were active nonmedical users of prescription opioids, 54% obtained them from a friend or relative for free, and 17% bought or took them [7▪▪]. When obtained from a friend or relative, the opioid had been prescribed by one physician 80% of the time [7▪▪].
Despite the perceived swing in the pendulum toward opioid overprescribing, a number of recent studies have reported undertreatment of pain in the setting of advanced illness and cancer [8–11]. There is also some concern that patients may suffer from underprescribing as an unintentional consequence of tighter regulations [12▪]. However, the alarming increase in the nonmedical use and opioid-related deaths demands that healthcare providers re-examine their prescribing practices in order to improve patient care and avert the introduction of excessive regulatory burden. In this review, we describe the clinical, pharmaceutical, financial, and regulatory impact of the opioid prescription abuse epidemic.
As a result of the subjective nature of pain, and its multidimensional construct comprising physical, psychological, social, and spiritual components, additional assessments are necessary for effective pain management. In light of the opioid abuse epidemic, an assessment of the patients risk for opioid misuse, monitoring for aberrant behavior, and doctor shopping are more important than ever to supplement patient-reported numeric pain scores.
In the USA, there are distinct regional variations in nonmedical opioid use. With the exception of several nonrural counties in Florida, increased nonmedical use and opioid-related deaths are found in states with large rural populations such as Kentucky, West Virginia, Alaska, and Oklahoma [13,14▪]. Possible factors contributing to greater rural misuse include increased sales and availability of opioid analgesics, economic deprivation, and tighter social networks [14▪]. Other purported causes for the national increase in opioid use include pharmaceutical marketing to physicians and consumers, and public misperception about the safety of prescription opioids . There are other examples from the developed world of geographic variation. In an analysis of insurance system data for three different regions in France, both the amount and the type of opioid varied by region . Poverty, unemployment, crime, and urbanization were associated with an increase in estimated opioid abuse as measured by a ‘doctor shopping’ index . This heterogeneity among different populations suggests that interventions to ensure safe prescribing may need to be adapted depending on the regional differences in healthcare systems and the variability in patient's expectations of ‘effective’ pain management [14▪,17].
Various adaptations [18–20] of the universal precautions  approach to pain management have been proposed for patients with cancer (Table 1). The goals of universal precautions are to maximize patient safety, pain management, and avoid opioid abuse or diversion. Included in universal precautions are assessment of risk factors, differential diagnoses, screening instruments, informed consent, opioid agreements, and longitudinal evaluations of function, compliance, and aberrant behavior. In an era of drug abuse, prescribing opioids based on the mantra of ‘pain is what the patient says it is’ seems ill-considered. The high prevalence of chemical coping, depression, somatization, concerns about opioid diversion, and the risk of opioid overdose necessitates a more comprehensive patient assessment in order to avoid unnecessary opioid dose escalation .
Screening tools for risk assessment and additional ‘objective’ measures such as prescription monitoring programs (PMPs) may help to distinguish patients who are chemically coping, suffering from pseudo addiction, or diverting their medication for nonmedical use. Chemical coping and pseudoaddiction patients present with similar behaviors and pose a treatment dilemma for the physician as they require different management strategies . Chemical copers use opioids in nonprescribed ways to deal with the stress associated with their diagnosis. These patients require a multidimensional interdisciplinary approach and co-management with substance abuse specialists when their chemical coping is at the maladaptive addiction end of the spectrum. In contrast, patients with pseudoaddiction  require appropriate increases in pain medications.
Re-assessment of patients and their opioid needs periodically are essential. For example, patients who no longer have evidence of disease but suffer from chronic pain should be managed with scheduled opioids and not as needed immediate-release opioids. Also, because of the concurrent, albeit more modest rise in benzodiazepine misuse, providers will need to monitor patients for additive side-effects that are consistent with combination opioids and benzodiazepines  such as severe sedation, cognitive dysfunction, and delirium. The increased risk of death especially when opioids are prescribed at higher doses or in combination with other substances has clearly emerged [26–28], even in patients with cancer. Unfortunately, none of the universal precautions strategies to avoid abuse is fail-safe. For example, although pill counts are recommended as a simple way to monitor misuse and ensure compliance , a recent report describes the use of pill renting to avoid the detection of misuse .
The high prevalence of alcoholism  and other risk factors such as a family history of abuse and psychiatric disorders suggests that all patients with cancer should undergo a risk assessment when they are started on opioids . Patients identified as high risk will require closer monitoring and greater utilization of clinical resources, such as the interdisciplinary team. Commonly used tools include the opioid risk tool (ORT), CAGE-AID, and screener and opioid assessment for patients with pain-revised (SOAPP-R). For widespread adoption, these tools will need to be brief and easily administered. Currently the CAGE, ORT, and screener and opioid assessment for patients with pain-short form, (SOAPP-SF )  take less than 5 min to complete and can be self-administered. Almost one in five patients with advanced cancer are identified as having a ‘positive’ CAGE score for alcoholism , and in patients receiving chemoradiation for head and neck cancer, a positive CAGE score is a risk factor for prolonged opioid use after completion of radiation therapy .
Urine drug screening
A systematic review found relatively weak evidence for the efficacy of written opioid agreements and urine drug testing in reducing opioid misuse by patients with chronic nonmalignant pain . A more recent observational study found the addition of ‘objective’ data [urine drug screening (UDS) and prescription monitoring] improved the identification of patients at higher risk of opioid abuse or diversion . Although there are very few studies in patients with cancer-related pain, the use of UDS is likely to increase in palliative care patients. A retrospective chart review of patients with cancer showed that moderate-to-high risk stratification using a screening tool (ORT) strongly predicted abnormal urine drug screen results . As UDS utilization increases, clinicians need to become familiar with the interpretation of abnormal results and their management . In the vulnerable palliative care population that is often burdened by multiple stressors, it is especially important to avoid false accusations of opioid misuse and diversion.
Prescription monitoring programs and doctor shopping
The practice of doctor shopping for opioids has increased over the last decade [40,41]. Healthcare information systems such as electronic prescriptions and PMPs attempt to minimize the information gaps between providers. A 2013 survey of practitioners using electronic prescribing of controlled substances found a perceived reduction of medication errors, altered prescriptions, and lost prescriptions . Although electronic prescribing was found to be less burdensome than expected, the limited adoption by clinical practices and pharmacies attenuates this system's ability to improve patient's safety and decrease diversion . In an analysis of 146 million opioid prescriptions dispensed in 2008, 0.7% of patients presumed to be doctor shoppers, on average, obtained 32 opioid prescriptions from 10 different prescribers . Although these patients cannot be identified with absolute certainty as ‘doctor shoppers’, their care can be characterized as dangerously uncoordinated . Providers are now able to access PMPs in 46 individual states; however, the majority of physicians do not access this information. Surveys show physicians and pharmacists are more likely to use PMPs to detect abuse, diversion, or doctor shopping if the PMP is electronic and easily accessible [44,45]. Unfortunately, pharmacists using the PMP were no more likely to refer the patient back to the prescriber, contact the provider, or refuse to fill the prescription . Additionally, as of 2008, there was no significant effect on the morphine milligram equivalents per capita dispensed in states with PMP [46▪]. This discrepancy between design and practice highlights the need for improved training on the interpretation and management of suspicious PMP findings. Although some have recommended mandates or regulations requiring the review of PMP prior to prescribing, this may discourage the general practitioners from prescribing controlled substances .
As a result of the misuse of commonly prescribed opioids, the pharmaceutical industry is pursuing tamper-proof formulations. In a preliminary, industry-supported study, rates of abuse, therapeutic errors, and diversion fell for brand extended-release oxycodone after the introduction of a reformulated extended-release oxycodone [47,48]. Also, in a move to combat the increase in overdose deaths, the Food and Drug Administration approved a hand-held injector device in 2014 that would allow family members or caregivers to administer naloxone outside of a healthcare setting . Finally, cost should be considered when prescribing any specific formulation of opioid. In an executive summary costing report by the UK's National Institute for Health and Clinical Excellence (NICE), the implementation of oral immediate or sustained release formulations first line, rather than transdermal opioids, was likely to generate the largest savings . Because newer tamper-proof opioids are likely to further increase the costs to patients and health systems, these formulations should be prescribed based on the individual risk assessment.
Hydrocodone is the single most commonly prescribed medication in the USA, followed by levothyroxine, simvastatin, and lisinopril . From 2007 to 2011, spending on opioids increased by US$1.6 billion, and opioid analgesics were the third most prescribed therapeutic class behind antidepressants and lipid regulator drugs. A literature review  of the economic burden associated with opioid abuse found estimates of US$8.6 billion per year for workplace, healthcare, and criminal justice expenditures. A more recent estimate from 2007 increased the total societal cost to US$55.7 billion .
Increased laboratory testing
The healthcare costs associated with increased urine drug screens may be significant and their justification will require additional research showing improved clinical outcomes or lower health utilization. Except for individual authors and institutions , there are no recommendations or guidelines from the oncological or palliative care organizations regarding UDS.
Increased healthcare utilization
Patients who misuse opioids have significantly higher healthcare utilization and costs . Data from the national epidemiologic survey on alcohol and related conditions suggest that the nonmedical use of opioids may increase the risk for alcohol use disorder, depression, bipolar, and anxiety disorders . In a separate study reviewing claims data, patients identified with potentially problematic opioid use had significantly more office visits (3.7 vs. 2.4), inpatient admissions (0.9 vs. 0.4), higher outpatient costs (US$10 055 vs. US$7358), and total healthcare costs (US$38 553 vs. US$26 193) than controls . For every unintentional overdose death (14 800 deaths) in 2008, 9 patients (133 200 patients) were admitted for substance abuse treatment, there were 35 related emergency room visits (518 000 visits), 161 people (2.4 million people) reported drug abuse or dependence, and 461 people (∼6.8 million people) reported the nonmedical use of opioids .
Amidst a global emphasis on the palliative care, worldwide opioid consumption has not increased proportionately in low-to-middle income countries , secondary to formulary limitations and regulatory restrictions . Although formulary limitations may be perceived as a viable pathway for ensuring public safety, adequate pain control may be markedly compromised . Developing nations especially may be impacted by the current concerns about opioid prescription abuse as most lack access to necessary opioid analgesics and are burdened by regulatory barriers.
In an effort to improve both physician and patient education regarding pain management, the federal government implemented the opioid risk evaluation and mitigation strategies (REMS). Although physicians recognize that these programs assist in ensuring safe use, most also report concern for increased burden on clinical practice, with little impact on patient outcome . Additionally, there is some effort directed toward pill repositories or returns to prevent open access to opioids . Initiatives by the DEA such as The National Prescription Drug Take-Back Day  aim to provide a safe, convenient means of disposing prescription drugs, while also educating the general public about the potential for abuse of medications.
Given the emphasis the Joint Commission and the Federation of State Medical Boards (FSMBs) have placed on the patient's right for pain relief [12▪,57] over the last decade, physicians may have concerns about underprescribing opioids. Unfortunately, the importance placed on the patient's expression of pain has not been coupled with other crucial clinical considerations such as substance abuse risk.
In a recent survey of pain clinic patients, 45% noted at least one episode of diversion (defined as lost, stolen, shared, or sold). The same study found a higher likelihood of diversion with a family history of drug abuse or history of criminal behavior . A unique statewide North Carolina law enforcement group dedicated to investigating criminal violations involving prescription drugs noted a 400% increase in diversion investigations in a 5-year period and a 300% increase in overdose deaths being investigated as homicide or manslaughter. In a 2-year period, investigations involving healthcare professionals increased 35% . Similar concerning behavior among healthcare workers has prompted the healthcare systems and academic institutions to implement drug diversion prevention initiatives .
The opioid prescription abuse epidemic demands that physicians, including those managing patients with cancer-related pain, prescribe opioids based on a comprehensive patient assessment. Implementing universal precautions that include informed consent, an assessment of risk factors for abuse, increased vigilance and structure for those at risk, and a periodic re-assessment of patient and tumor related factors causing pain are essential to providing optimal clinical care. Additionally, provider and patient education, prescription monitoring, and regulations that do not impede appropriate access to opioids are most likely to improve both pain management and public safety.
Conflicts of interest
E.D.F. and S.R. have no conflicts of interest to declare.
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Papers of particular interest, published within the annual period of review, have been highlighted as:
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