Lessons learned in the abuse of pain-relief medication: a focus on healthcare costs

Abstract

The increasing prevalence of chronic pain with its major societal impact and the escalating use of opioids in managing it, along with their misuse, abuse, associated fatalities and costs, are epidemics in modern medicine. Over the past two decades, multiple lessons have been learned addressing various issues of abuse. Multiple measures have already been incorporated and more are expected to be incorporated in the future, which in turn may curtail the abuse of drugs and reduce healthcare costs, but these measures may also jeopardize access to appropriate pain treatment. This manuscript describes the lessons learned from the misuse, abuse and diversion of opioids, escalating healthcare costs and the means to control this epidemic.

Keywords::

• abuse
• adverse consequences
• chronic pain
• diversion
• healthcare costs
• lessons learned
• misuse
• opioid use
• opioids

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Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)^™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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 www.medscape.org/journal/expertneurothera; (4) view/print certificate.

Release date: 29 April 2013; Expiration date: 29 April 2014

Learning objectives

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

• • Assess the epidemiology of prescription opioid abuse

• • Distinguish the health impact of prescription opioid abuse

• • Distinguish the economic impact of prescription opioid abuse

• • Identify means to reduce the risk of prescription opioid abuse

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Publisher, Future Science Group, London, UK.

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD, Associate Professor and Residency Director, Department of Family Medicine, University of California, Irvine, USA.

Disclosure: CP Vega, MD, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Laxmaiah Manchikanti

Pain Management Center of Paducah, KY USA; Anesthesiology and Perioperative Medicine, University of Louisville, KY, USA.

Disclosure: L Manchikanti has disclosed no relevant financial relationships.

Mark V Boswell

Department of Anesthesiology and Perioperative Medicine, University of Louisville, KY, USA.

Disclosure: MV Boswell has disclosed no relevant financial relationships.

Joshua A Hirsch

Department of Radiology, Massachusetts General Hospital; Associate Professor of Radiology, Harvard Medical School, MA, USA.

Disclosure: JA Hirsch has disclosed no relevant financial relationships.

Figure 1. Global morphine consumption in 2007.

Data taken from International Narcotics Control Board, United Nations Data. Graphic created by the Pain and Policy Study Group, University of Wisconsin/WHO Collaborating Center (2009).

Figure 2. Opioid-related deaths, 1999–2010 in all categories.

Data taken from [33].

Figure 3. Deaths from unintentional drug overdoses in the USA according to major type of drug, 1999–2007.

Adapted with permission from [211].

Figure 4. Rates^† of opioid pain reliever overdose deaths, opioid pain relief treatment admissions and kilograms of opioid pain relievers sold – USA, 1999–2010.

^†Age-adjusted rates per 100,000 population for OPR deaths, crude rates per 10,000 population for OPR abuse treatment admissions and crude rates per 10,000 population for kilograms of OPR sold.

OPR: Opioid pain reliever.

Adapted with permission from [33].

Figure 5. Annual societal costs of opioid abuse, dependence and misuse in the USA, 2007.

Adapted with permission from [218].

Figure 6. Percentage of patients and prescription drug overdoses, by risk group in the USA.

Adapted with permission from [41].

Figure 7. Guidance to opioid therapy.

CT: Computed tomography.

Adapted with permission from [5].

Over the past two decades the world has not only learned about, but continues to attempt to control escalating chronic pain and associated disability, as well as opioid use, abuse and related fatalities [1–14]. In its 2006 report, the International Narcotics Control Board (INCB) noted that medications containing narcotic or psychotropic drugs were becoming the drugs of choice for many abusers [15]. They warned that the worldwide abuse of prescription drugs would soon exceed illicit drug use [15]. In fact, a 2011 report of the INCB reported that abuse of prescription drugs was growing rapidly around the world with more people abusing legal narcotics than heroin, cocaine and ecstasy combined [201]. It is commonly stated that there has and continues to be an escalation in the utilization of all types of interventions in managing chronic pain, but opioids and other prescription-controlled substances have taken a central role in the debate on increasing healthcare costs and related fatalities [4–14,16–18]. Consequently, the overuse and abuse of prescription drugs have been emphasized as a major and growing health problem globally by leading international monitoring entities [15,201–203]. Prescription drug abuse, while most prevalent in the USA, is also a problem in many areas around the world including Canada, Australia, Europe, Southern Africa and South Asia with tens of millions of people giving up control of their lives in favor of addiction [11,12,15,19,201–204].

The past several years have seen soaring rates of prescription drug abuse across the USA, followed by rising numbers of deaths involving prescription drug overdoses [204]. Emergency department visits related to prescription drug abuse now exceed the number of visits related to illicit drug use [204]. However, it is not limited to the USA alone. Recently, it was reported that correlated to increasingly high overall prescription opioid consumption levels, nonmedical prescription opioid use and harms in Canada are high and now likely constitute the third highest level of substance-use disease burden after alcohol and tobacco [11,20]. Similarly, prescription opioid analgesics and related harms in Australia have been reported [12].

Casati et al. performed a systematic review of the literature concerning the misuse of medicines in the EU, which showed an alarming increase [19]; multiple studies showed that opioids, sedatives and hypnotics have been extensively misused throughout Europe [19]. In Germany, the estimates show that between 1.3 and 1.4 million people are dependent on prescription drugs, representing approximately 1.6 or 1.7% of the German population [19]. One study showed that in Germany, approximately 25% of nursing home residents over the age of 70 are addicted to psychotropic drugs [21]. In addition, of Germans over 60 years old, between 1.7 and 2.8 million misuse psychotropic drugs or pain killers or are dependent on these substances. In a cross-sectional postal survey in the UK [22], the past 2-week prevalence of nonprescription analgesic use was 37%. In Spain, it has been shown that 11.6% of the subjects in one study had a lifetime prevalence for substance-use disorder related to an opioid other than heroin [23]. In Denmark, a literature review showed that dependence prevalence rates for chronic nonmalignant pain patients were as high as 50%, depending on the patient population studied and the criteria used [24]. In France, multiple studies showed the misuse and abuse of multiple opioids, including such drugs as transdermal fentanyl and Actiq (fentanyl citrate) [19]. There are no up-to-date data available for the nontherapeutic use of psychotherapeutic drugs in other countries. Based on the report by Casati et al., in Canada, an estimated 1.3% of the population abused prescription opioids, and in several European countries – such as France, Italy, Lithuania and Poland – between 10 and 18% of students use sedatives or tranquilizers without a prescription [19].

What has the medical profession learned?

Nonmedical use of psychotherapeutic drugs

The results of the National Survey on Drug Use and Health in the USA showed that in 2011, there was a 14% decline in prescription drug use for nonmedical purposes among people aged 18–25 years; this reflects the 300,000 fewer young adults abusing such drugs compared with last year’s survey [205]. However, prescription abuse rates among children aged 12–17 years and adults over 26 years old remain unchanged. This survey showed that approximately 8.7% of Americans aged 12 years and older were identified as current drug users, a total of 22.5 million Americans; this was not a significant change from the previous year’s percent rate of 8.9%. Like previous years, marijuana continued to be the most commonly used illicit drug and its use appears to be on the rise. According to this survey, 7% of Americans were currently marijuana users, up from 6.9% in 2010 and 5.8% in 2007 [205]. Heroin use has reduced with the number of users falling to 620,000 in 2011 from 621,000 in 2010; however, there had been a substantial increase from 373,000 users in 2007. Further, in some areas, heroin is being substituted for prescription opioids.

Overuse of therapeutic opioids

The overall production and distribution of therapeutic opioids has increased extensively in the past 20 years. Global production of morphine worldwide has more than quadrupled from 168 tons in 1993 to a projected 788 tons in 2012 [25,206]. The global production of oxycodone rose by over 4000%, from approximately 6 tons in 1993 to an estimated 261 tons in 2012 [25,206]. However, the data on the prevalence of opioid use among people with chronic pain, specifically moderate-to-severe chronic noncancer pain and other moderate-to-severe pain, are limited in the USA and around the globe.

From 1999 to 2002, 4.2% of US adults reported using opioid analgesics for pain within the past month [207]. During the same time, opioid usage was described to be 22% of adults with pain in Canada [26] and 12% in Denmark [27]. A report evaluating opioid use in Utah in the USA in 2008 illustrated that 20.8% of adults in Utah had been prescribed an opioid in the last year and 29.1% of these prescriptions were for long-term pain [28]. In one of the earliest surveys, opioid use was shown to have doubled from 8% in 1980 to 16% in 2000 [29]. In a study of commercial and Medicaid insurance plans from 2000 to 2005, the proportion of enrollees receiving a diagnosis of chronic noncancer pain increased 33% in the HealthCore population and 99% in the Medicaid population, with a 58% increase of opioid prescriptions for chronic pain in HealthCore and 29% in Medicaid [30]. Another study involving over 1% of the US population from 1997 to 2005 showed that among relevant long-term opioid users in 2005, 28.6–30.2% were also regular users of sedative hypnotics [31]. This study also showed that use of long-term opioid doubled in some healthcare plans. In a study of low back pain in the USA, overall opioid use among back pain patients increased from 11.6% in 1996 to 12.6% in 1999 [32]. The prescriptions showed an increase in oxycodone and hydrocodone and a decrease in propoxyphene [204]. In 2008, a total of 36,450 deaths were attributed to drug poisoning, a rate of 11.9 per 100,000 population. By 2005, long-term opioid therapy was being prescribed to an estimated 10 million US adults [6,33–35,208].

Elsewhere across the globe, in a study conducted in Ontario, Canada, it was illustrated that from January 1991 to May 2007, opioid analgesic prescriptions increased by 29%, from 458 to 591 prescriptions, per 1000 individuals annually [36]. The number of oxycodone prescriptions rose more than 850% during the same period, from 23 per 100,000 individuals in 1991, to 197 per 100,000 in 2007. The addition of long-acting oxycodone to the drug formulary was associated with a fivefold increase in oxycodone-related mortality and a 41% increase in overall opioid-related mortality. Multiple authorities have looked at the relationship between increasing controlled substance use, specifically opioid use and related fatalities.

In pain management settings, it has been reported that as many as 90% of patients receive opioids for chronic pain management [4–6,37]. In addition, it also has been illustrated that the majority of these patients were on opioids prior to presenting to an interventional pain management setting [37]. Furthermore, Deyo et al. illustrated that approximately 20% of patients in primary care settings were long-time opioid users with 61% receiving a course of opioids [38]. Multiple studies also have described that many of the patients in primary care settings also abuse illicit drugs [38].

The quadrupled sales of opioid analgesics between 1999 and 2010 are a perfect example of the therapeutic opioid explosion. According to the United Nations Office on Drugs and Crime, in 2009, a handful of countries – the USA, Australia, New Zealand, Canada and several European countries – used 90% of the morphine, fentanyl and oxycodone used around the globe [39]. This finding was echoed by the WHO; using 2003 figures from the INCB, they reported 79% of worldwide morphine use was accounted for by just six developed countries; the numbers were reversed when developing countries, comprising 80% of the world’s population, were shown to only use 6% [39]. As shown in Figure 1, there were similar findings in 2007 when six developed countries had the highest morphine consumption while 132 out of 160 countries were below the worldwide mean consumption for morphine.

These findings expose the disparity in pain relief that patients receive between developed and developing countries. Moderate-to-severe pain patients by the millions are undertreated in developing countries, while in developed countries, these same patients are overtreated with opioids, especially in the USA, which consumes an incredible 99% of all hydrocodone and 83% of all oxycodone [38]. On a per-gram basis, those in the USA use more narcotics than any other country. The INCB estimates global pharmaceutical companies produce more than 75-times a year of oxycodone, compared with 11.5-times in 1999, of which more than 80% is consumed in the USA [202,203]. In addition, the US demand for hydrocodone – the most commonly prescribed opioid – dwarfs what is consumed by the rest of the world: 27.4 million grams each year for the USA alone versus 3237 g for Great Britain, Germany, Italy and France combined [4–6,202,203].

Opioid sales in the USA increased sevenfold from 1997 to 2010 from morphine equivalents of 96 mg per person to 710 mg per person [38]. Put another way, enough opioids are sold so that 15 mg of hydrocodone can be administered every day to every American adult for 47 consecutive days. In the 10-year period from 1997 to 2007, hydrocodone sales jumped 280%, methadone jumped 1293% and oxycodone jumped 866% in the USA (Table 1).

Both immediate-release (IR) and extended-release (ER) opioid prescriptions have increased in the USA. A staggering 256 million opioid prescriptions were filled out in 2009, of which 234 million were IR (compared with only 223.9 million 2 years earlier) and 22.9 million were ER (compared with 21.3 million 2 years earlier) [209].

These data also illustrate an eightfold increase in stimulant prescriptions from 1991 to 2009 [209]. A recent publication showed that 94% of patients presenting to an interventional pain management program were on long-term opioids in the USA [37]. Illicit drug use was also common, in patients presenting to an interventional pain management program although, it has declined significantly from a previous publication. While a large proportion of individuals (45.7%) have used illicit drugs at some point, current illicit drug use was present in only 7.9% of patients; both past and current use was similar to that of the general population. More importantly, a significant proportion of patients (48.8%) have been on opioids (high doses of more than 40 mg equivalents of morphine) on a long-term basis, initiated and maintained by primary care physicians; 35% were on benzodiazepines and 9.2% on carisoprodol prior to presenting to interventional pain management.

Consequences of excessive opioid use

The number of deaths in the USA ascribed to prescription drugs is staggering, including those caused by opioids. In 2008, 36,450 deaths were credited to a drug overdose. Of these, a specific drug was attributed in 27,153 deaths, and of these, one or more prescription drugs were implicated in 20,044 deaths; 14,800 of these 20,044 deaths involved opioids [33]. In fact, published on 19 February 2013, the latest report from the CDC showed that continuing a trend that began more than a decade ago, in 2010, 16,651 people died of overdoses involving prescription opioids compared with 4030 such deaths in 1999, an increase of 313.2%. The CDC researchers once again wrote that this analysis confirms the predominant role opioid analgesics play in pharmaceutical overdose deaths, either alone or in combination with other drugs (Figure 2) [40]. Opioid analgesics caused more overdose deaths in 2007 than heroin and cocaine combined (Figure 3) [41,210–212]. Concurrently, suicide caused by drugs increased; by 2007, there were 8400 overdose deaths in the USA that were either suicide or the deceased’s intent could not be ascertained. Approximately 3000 of those deaths involved opioids [34]. In addition, for every unintentional opioid analgesic overdose death, nine were admitted for substance abuse treatment, 35 visited emergency departments, 161 reported drug abuse or dependence and 461 reported nonmedical use of opioid analgesics [41]. Furthermore, in 2007, non-suicidal drug poisoning deaths not related to suicide exceeded either motor vehicle accidents or suicide deaths in 20 states with data from Ohio illustrating the number of deaths from unintentional drug poisoning exceeding the numbers of deaths from both suicide and motor vehicle accidents combined [34,212]. A Government Accountability Office (GAO) report also concluded that key measures of prescription pain-reliever abuse and misuse increased from 2003 to 2009 [210]. Consequently, a conclusion has been reached by many that opioid analgesic abuse contributed to increasing fatalities based on opioid abuse and increasing doses, doctor shopping and other aspects of drug abuse as illustrated in Figure 4 [33]. Furthermore, the data from emergency department visits also illustrate that the use of opioids, sedatives and nonprescription sleep aids taken more than prescribed medication or solely for the feeling they cause continued to increase through 2009 [4–6,41].

Opioid abuse has been fueled by multiple factors including legitimate and easy availability in rural as well as urban areas, high street values and comorbid mental illnesses [4–6,34].

How did we get here?

Opioid prescriptions for chronic noncancer pain skyrocketed in the late 1990s. The primary driver was the lifting of restrictions on opioid prescribing by state medical boards [213]. Once these restrictions were lifted, other changes occurred, resulting in runaway opioid prescriptions. Among the changes were new standards for both inpatient and outpatient pain management, implemented in 2000 by the Joint Commission on Accreditation of Healthcare Organizations [42] and the concept of a patient’s right to pain relief, resulting in the validation physicians needed to increase their opioid prescribing [4–6].

With the door open to acceptance, those with vested interests in opioid prescribing jumped into action. The pharmaceutical industry unleashed their marketing machine, many physicians promoted opioids and a number of organizations called for increasing opioid treatment for patients with chronic noncancer pain [4–6]. However well meaning, these positions were based on misinformation and unsound science; the justification for increased opioid prescribing was that it was safe and effective so long as the opioids were prescribed by a physician [4–6,38,39,214].

One irony to come out of this groundswell of support for opioid prescribing is that many model guidelines, whose intent was to curtail controlled substance abuse, actually appeared to condone an increase in opioid prescribing [4–6,43]. One guideline seems to absolve prescribers from the responsibility for their actions: ‘no disciplinary action will be taken against a practitioner based solely on the quantity and/or frequency of opioids prescribed’ [213].

The result of all these factors is that opioid prescribing, including long-acting and potent forms, has increased exponentially. This increase has been driven by regulations based on weak evidence that opioids are highly effective and safe, especially when administered to those with chronic noncancer pain, as well as questionable selection criteria [4–6,214].

Today, there is still no unmistakable scientific evidence that opioids are effective for chronic noncancer pain [4–6,43–53,214]. Opioids’ lack of effectiveness is not the only troubling concern regarding chronic opioid therapy. There is mounting evidence that opioids have multiple physiological and nonphysiological adverse effects including: opioid-induced hyperalgesia, misuse and abuse, providers not trained to identify or monitor their patients for misuse and overuse and fatalities related to opioids, which have steadily been climbing [4–6,43–75,214–217].

The steady increase in fatalities caused by opioids, coupled with the scant evidence for their effectiveness, begs the question of who will be held responsible for opioids being adopted prematurely as a treatment standard [4–6]. Some have predicted that there will be a ‘postmortem’ on runaway opioid prescribing and the social ills that have accompanied it. Among those social ills are the damage done by opioid diversion, misuse and abuse. Prescribing opioids for chronic noncancer pain violates a sacred principle of medical intervention – there should be convincing evidence of a treatment’s benefit before its large-scale use.

Impact on healthcare costs

Strassels described the economic burden of prescription opioid misuse and abuse in a comprehensive review [14]. He described that estimating the incidence of consequences of opioid misuse, abuse and diversion from biomedical literature is challenging. The author identified over 2300 titles, included 41 in the review and showed that the total cost of prescription opioid abuse in 2001 was estimated at US$8.6 billion, including workplace, healthcare and criminal justice expenditures.

The existing evidence indicates that persons who abuse or misuse prescription opioids incur higher costs and healthcare resource use. A study of commercially insured beneficiaries in the USA found that mean per capita annual direct healthcare costs from 1998 to 2000 were nearly US$16,000 for abusers of prescribed and nonprescribed opioids compared with approximately US$1800 for nonusers who had at least one prescription insurance claim [76]. The study’s authors concluded that the economic burden of prescription opioid misuse and abuse is large. Furthermore, when examined by category, inpatient expenditures accounted for 46% of the total cost for abusers and 17% for nonabusers. In addition, opioid abusers were four-times as likely to visit the emergency department, had 12-times as many hospital stays and three-times as many outpatient visits than nonabusers. A study prepared for the Office of National Drug Control Policy (ONDCP) reported that the cost of drug abuse in the USA in 2002 was estimated to be US$180.8 billion [76]. This estimate included resources used to address health and crime consequences and loss of productivity resulting from disability, deaths and withdrawals from the workforce, but does not specify the contribution of illicit use of prescription opioid analgesics to the total economic burden.

Birnbaum et al., in an analysis of the costs of prescription opioid abuse, separately assessed healthcare, workplace and criminal justice expenditures [77]. In this study, the total economic burden was estimated at US$8.6 billion in 2001; healthcare costs accounted for 30% of the total burden. Birnbaum et al. also assessed the societal costs of prescription opioid abuse, dependence and misuse in the USA [78]. Once again, they identified costs by healthcare, workplace and criminal justice expenditures. They estimated the total US societal costs of prescription opioid abuse at US$55.7 billion in 2007; healthcare costs accounted for US$25 billion or 45% of total costs. These healthcare costs consisted primarily of excess medical and prescription costs, valued at US$23.7 billion. They concluded that the cost of prescription opioid abuse presents a substantial and growing economic burden for society.

The 2007 Treatment Episodes Data Set reported that the number of patients admitted to substance abuse treatment facilities due to nonheroin/opioid abuse nearly quadrupled from 23,000 to more than 90,000 from 1999 to 2007 [218]. Figure 5 shows the growing prevalence of prescription opioid abuse, dependence and misuse and shows the annual societal costs of opioid abuse, dependence and misuse in the USA in 2007.

Patients who abuse opioids accounted for over 92% of excess medical and drug costs with their caregivers accounting for the remainder. Medicaid patients and caregivers combined contributed approximately a third of total excess medical and drug costs, privately insured and uninsured patients and caregivers contributed slightly less than a third each and Medicare patients and caregivers accounted for only 4.6% [78].

Similar to the above reports, in 2006, the estimated total cost in the USA of the nonmedical use of prescription opioids was US$53.4 billion. Five drugs, including OxyContin (an ER version of oxycodone), oxycodone, hydrocodone, propoxyphene and methadone accounted for two-thirds of the total economic burden [79]. The CDC in 2008 reported that the cost of pain killer abuse can exceed US$70 billion annually, not including the social problems they perpetuate or the lost or stalled potentials of those addicted to them. It has also been shown that opioid abusers generate, on average, annual direct healthcare costs 8.7 times higher than nonabusers [219,220].

In addition to federal programs, Medicaid, workers’ compensation and private insurers are also involved. The prevalence of opioid abuse is estimated to be over ten-times higher for Medicaid beneficiaries than private insurance populations [80]. A Washington state study of opioid deaths involving prescription drugs between 2004 and 2007 found that 1668 persons died from prescription opioid-related overdoses during the time period with 6.4 deaths per 100,000 population per year; 45.4% of deaths were among persons enrolled in Medicaid [81]. In another study, it was shown that escalating problems such as overdose, addiction and even death were reported in association with workers’ compensation claims, with 55–85% of injured workers across the country receiving opioids for chronic pain relief [82]. The report found workers’ compensation claims in the state of Michigan, USA, which included prescriptions for certain opioid medications were nearly four-times more likely to develop into catastrophic claims. The study also determined that opioid use was an independent predictor of whether a compensation claim would generate costs greater than US$100,000.

The cost of substance abuse in general in the USA was reported in 2005 with federal, state and local government spending as a result of substance abuse and addiction being at least US$467.7 billion [221]. Almost three-quarters (71.1%) of total federal and state spending on substance abuse was in two areas: healthcare and justice system costs. Reports published in the USA show an escalating problem of prescription drug use, abuse and diversion in the Medicare and Medicaid programs [222].

Increasing healthcare costs and increasing misuse and related costs in Canada have been described. Canada is home to the overall second highest level of prescription opioid use globally. Total prescription opioids consumed in Canada increased from 8713 standardized, defined daily-doses in 2002 to 26,380 standardized, defined daily-doses in 2008–2010 – a 203% increase, which appears to be steeper than that observed in the USA [206].

Roxburgh et al., whilst describing prescription opioid analgesics and related harms in Australia, were concerned with the growing use of opioids among medical professionals and the increase in opioid analgesic prescriptions, specifically morphine and oxycodone, over the past decade [12]. While North America ranks first, Australia’s consumption of opioid analgesics is ranked 10th internationally; however, per capita consumption of oxycodone and morphine preparations in Australia is relatively high, ranked third and fifth respectively, internationally, compared with Canada, which ranks first for oxycodone and Australia, which ranks first for morphine [201]. This study showed prescriptions for morphine declined, while those for oxycodone increased markedly. Further, prescriptions for both were highest among older Australians. They reported 465 oxycodone-related deaths from 2001 through 2009. While treatment episodes for problematic morphine use remained relatively stable with 0.07 per 1000 population in 2007–2008, episodes for problematic oxycodone use doubled, from 0.01 per 1000 population in 2002–2003 to 0.02 per 1000 population in 2007–2008 [12].

Promoting pain treatment, including using opioids, is endorsed by the Institute of Medicine committee. Despite this, they recognize that there is a serious crisis with opioid abuse and diversion, as well as the fact that chronic opioid therapy has not been proven viable for treating chronic pain. The opioid crisis continues to accelerate, as does chronic pain’s prevalence, healthcare costs and adverse consequences from opioids [4–6]. Even with such mounting evidence, there are still those who advocate increased opioid use based on a supposed undertreatment of pain. In fact, Stein et al. summarized the evidence succinctly, noting that ‘many arguments in favor of opioids are solely based on traditions, expert opinion, practical experience, and uncontrolled anecdotal observations’ [50].

The CDC have reported the percentage of patients with prescription drug overdoses by risk-group in the USA [41]. This report showed that approximately 80% were prescribed low doses (<100-mg of morphine equivalent dose per day) by a single practitioner. These account for only an estimated 20% of all prescription overdoses (Figure 6). By contrast, among the remaining 20% of patients, the 10% prescribed high doses of opioids by single prescribers (>100-mg morphine equivalent dose per day) [83,84], account for an estimated 40% of prescription opioid overdoses [62,85] and the remaining 10% of patients seeing multiple doctors and typically involved in drug diversion, account for 40% of overdoses [73]. In fact, 76% of nonmedical users report obtaining drugs that had been prescribed to someone else while only 20% report that they acquired the drug from their own doctor [41]. Finally, among persons who died of opioid overdoses, a significant proportion did not have a prescription in their records for the opioid that killed them; in West Virginia, Utah and Ohio (USA), 25–66% of those who died of pharmaceutical overdose used opioids originally prescribed to someone else [73,86,212].

Thus, in modern medicine, adverse consequences of appropriately prescribed and used opioids are underappreciated with all the blame diverted to abuses and overuses. This is, in addition to the lack of evidence regarding the long-term benefits, the alarming evidence that the increased prescribing of opioids is fueling an epidemic of addiction and overdose deaths, based on a lack of education and misinformation, leading essentially to overprescribing [211]. Due to multiple adverse consequences with opioids even when they are prescribed appropriately, a more cautious stance towards opioid prescribing for chronic noncancer pain has been advocated [4–6,38,41,44–48,57,60,61,87,88,208,210,214]. In fact, the majority of injuries and deaths may arise from people using opioids exactly as prescribed, not just those misusing or abusing them [214]. It is even more important that most studies indicate that patients on long-term opioid therapy are unlikely to stop them, even if analgesia and function are poor and safety issues arise [6]. On the other hand, patients also report excellent pain relief and improvement in function with other modalities or interventions [88,89].

Taking higher doses and a combination of short-acting and long-acting opioids are likely to be abused and also cause serious dose-related adverse effects, including death. In addition, there is no evidence to support the previous teaching that long-acting opioids can provide better analgesia and less abuse risk than IR products [6,33,44–49,214].

Multiple studies have reported an association between opioid prescribing and overall health status with increased disability, increased medical costs, subsequent surgery and continued or late opioid use [4–6,34,77,88–100]. Overall, it appears that epidemiologic studies are less positive regarding functional improvement and quality-of-life for chronic pain patients on opioids [100]. In Denmark, where opioids are freely prescribed for chronic pain, an epidemiological study conducted [88] showed that those receiving opioids for chronic pain, when compared with a matched cohort of chronic pain patients not receiving opioids, had higher pain levels, higher healthcare utilization and lower activity levels [101].

Curtailing opioid abuse & healthcare costs

Opioid abuse and extensive use may be curtailed by various means. The first and foremost is to close pill mills and promote responsible opioid prescribing by educating physicians and the public. It is essential to realize that psychotherapeutic drug abuse, including opioids, is superseding illicit drug use. Drug dealers are no longer the primary source of illicit drugs. It appears that the greatest problem now is diversion through family and friends; their source is more likely to be one physician, not doctor shopping. Further, consideration must be given to the highly interactive pattern of effect and impact that exists in the general area of substance abuse, mental health and overall healthcare.

Misuse, abuse and diversion should be addressed on four fronts: education, establishing medical necessity, supply and drugs.

Supply is dependant on physicians and patients, thus education of both is extremely important. The increased abuse of opioid analgesics likely reflects the misguided belief that, because these medications are prescribed by physicians, they are safer than illicit drugs. It is also likely that part of this increased abuse is due to much greater access to and availability of opioid analgesics [86,102]. This is likely to reflect more aggressive management of noncancer pain, facilitated, in part, by the regulatory mandate from Joint Commission on Accreditation of Healthcare Organizations, liberalization of medical board regulations, and by lingering concerns regarding the safety of non-opioid analgesics and their tolerability [102].

Education and knowledge can be a double-edged sword. Physicians must recognize that some patients misrepresent genuine pain in order to obtain, misuse and divert these medications, resulting in serious or even lethal public health problems [102]. Thus, enhancing and updating clinical teaching and training for physicians, nurses, dentists and pharmacists in the areas of pain management, opioid pharmacology and abuse/addiction, perhaps through interactive web-based training, should be the first and foremost line of action [102]. It has been suggested that pain management education for health professionals has been and continues to be insufficient. Consequently, a more comprehensive and contemporary curriculum for prescribers seems warranted [102]. Appropriate guidance must be applied because, as the literature illustrates, guidelines do not sufficiently influence clinical practice of opioid prescribing in chronic pain management. The lack of appropriate guidelines and education leads to stringent regulations enacted by legislators that mainly focus on curtailing abuse, which may also reduce access to needed therapy. Education is of paramount importance to curtail and properly manage opioid use and abuse.

Education and understanding the physiology and pharmacology of chronic pain and the multiple modalities available for managing it, as well as comorbid factors, will assist physicians in establishing indications and medical necessity for chronic opioid therapy. Prior to initiating opioid therapy, it requires a comprehensive initial evaluation, including a screening process and special provisions for managing pain and those most at risk for abuse and dependence, a family history of substance abuse disorders and alcohol abuse, evaluation of the previous history through prescription monitoring program (PMP) results or results from physicians when the PMP is not available, baseline urine drug testing, and, finally, initiation of monitoring for adherence.

Medical necessity is a dynamic process. This includes assessing and establishing other treatment modalities such as physical and behavioral modalities, assessing the risk–benefit ratio of opioid therapy, establishing treatment goals, obtaining informed consent and agreements, titrating the initial dose, maintaining through stable phases and monitoring adherence. Further, outcomes must be assessed on a regular basis once medical necessity is established and opioid therapy may be discontinued either for nonadherence or failure to respond. Supply is closely tied to adherence monitoring. Adherence monitoring consists of continuous vigilance from the initial evaluation to discharge utilizing numerous means including screening tools, urine drug testing, PMPs and appropriate agreements or contracts.

PMPs collect state-wide data about prescription drugs and track their flow. To date, 48 states have approved PMPs, but there is a significant difference in the manner and frequency with which the data are collected. The National All Schedules Prescription Electronic Reporting was signed into law in 2005, created by the American Society of Interventional Pain Physicians and enacted by Congress [223]. This law requires states to collect prescription information for Schedule II, III and IV medications. It also requires states to have the capability to share this information with one another. This can decrease cross-border narcotic trafficking. Even though there is no definite evidence that PMPs reduce overuse and abuse, partly due to interstate commerce laws and a multitude of other issues, most appreciate the benefit of monitoring programs and the ability to make proper decisions with information in hand in conjunction with other regulations [4–6,41,103–105].

Consequently, multiple screening tools to monitor opioid adherence have been developed for predicting and identifying aberrant drug-related behaviors [4–8]. The majority of the screening tools used to evaluate pain are based on psychopathology, but some also assess drug misuse and abuse. There is currently no ideal instrument that can screen for misuse and abuse of drugs while also being able to reliably predict the potential for substance abuse.

Urine drug testing is part of adherence monitoring to curtail the abuse of opioids as well as other controlled substances [67–71]. Urine drug testing provides relatively good specificity, sensitivity, ease of administration and cost; 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 application in chronic pain management settings. Furthermore, additional issues exist related to excessive use, misuse, abuse and financial incentives [70]. However, recent diagnostic accuracy reports of urine drug testing illustrated that immunoassay in an office setting is appropriate, convenient, and cost effective [69]. With appropriate monitoring tools, this can be performed cost effectively without laboratory confirmation in the majority of the patients unless the patient does not provide a proper history and the problem of abuse continues.

The fourth issue in curtailing opioid abuse is the development of abuse deterrent formulations (ADFs) of opioids. This can potentially curtail abuse but still have opioids readily available for pain management for those who need them. The potential for abuse depends on the formulation, route of administration and rapid rise of plasma concentration resulting in drug linking and reinforcement [67]. Various types of ADFs of opioids are being developed, but they will not necessarily decrease abuse in those who consume the drug intact. Some ADFs employ physical barriers that resist common methods of tampering, such as crushing the pill and subjecting the pill to various chemical manipulations to extract the active ingredients so that they can be chewed. A combination of opioid agonists and opioid antagonists have also been tried; however, these have not been very successful.

A GAO report extensively dealt with opioid abuse and recommended that the director of the ONDCP establish outcome metrics and implement a plan to evaluate proposed educational efforts and ensure that agencies share lessons learned among similar efforts. The ONDCP did not explicitly agree or disagree with the GAO’s recommendations, but noted that it will continue to work for improved coordination of educational efforts and evaluation of outcomes.

Franklin et al. showed that this guidance is effective in bending prescription opioid dosing and reducing mortality [106]. This study, showed a substantial decline in both the morphine equivalent dose per day of long-acting schedule II opioids by 27% and the proportion of workers on doses equal to or greater than 120-mg per day of morphine equivalent dosage by 35%, compared prior to 2007 [106]. Furthermore, there was also a 50% decrease from 2009 to 2010 in the number of deaths.

Guidelines provide different types of recommendations; however, none are based on evidence and most of them are based on consensus. Appropriate guidelines are an approach developed in each practice and must include the following: standardized screening procedures and special provisions for managing pain in those most at risk for abuse and dependence, including adolescents and young adults, individuals with a current or previous substance-use disorder, including nicotine and alcohol, and individuals with a family history of substance use disorders [102]. In addition, the guidelines should have indications for when and how long to prescribe non-opioid analgesics, or nonpharmacological methods or both for pain control versus when and for how long to prescribe opioid analgesics. Other indications should include when short- versus long-acting opioids should be prescribed and reasonable limits on the number of pills or amount of liquid prescribed, such that the prescribed amounts match the number of treatment days required.

Furthermore, an approach for continuing opioid pain management for chronic noncancer pain should include the following: when and how to use urine screening to manage the risk of diversion, abuse and addiction; when and how to use patient contracts to manage risk of diversion through a single-source prescriber and pharmacies; proper use of state prescription drug monitoring programs to reduce doctor shopping; criteria for deciding how long a patient should receive opioid analgesics and criteria for deciding whether and under what circumstances to refill or discontinue opioid prescriptions [102].

Since the patient is a crucial part of the abuse, overuse or diversion, patients and the general public must also be educated and made more aware and responsible for the use, storage and disposal of opioid analgesics [102]. Furthermore, the media should evaluate the influence of news reporting on the popularity of and misconceptions about psychoactive substances, particularly prescription opioids [102]; the media can be influential in curtailing abuses [4,5].

Figure 7 illustrates practical steps in managing chronic opioid therapy for noncancer pain in an algorithmic fashion. American Society of Interventional Pain Physicians guidelines and subsequent literature about the efforts of PMPs through National All Schedules Prescription Electronic Reporting and education are based on understanding various aspects of chronic pain and its management.

Following the appropriate recommendations with better education and appropriate prescription patterns should reduce misuse, abuse, overuse and diversion, while at the same time, promote proper pain management while maintaining access. Thus, it may be possible to not only curtail abuse, but also continue to provide appropriate avenues for proper pain management. This can be achieved with higher education standards for physicians, the public and legislators; cooperation from the pharmaceutical industry to curtail aggressive promotion; and clear and positive guidelines from regulators.

Expert commentary

Physicians have dramatically increased their prescribing of opioids for chronic noncancer pain over the past two decades. However, this change in practice and escalating use of opioids was driven by factors unrelated to their effectiveness. Even though physicians and the general public were given the impression that long-term opioid therapy had been proven safe and effective for chronic noncancer pain, the evidence indicates otherwise. Without showing significant effectiveness and with major adverse effects, patients may continue to experience significant chronic pain and dysfunction despite opioid therapy. The lack of evidence regarding its benefits and adverse effects, coupled with strong evidence for increased opioid prescribing, is fueling an epidemic of addiction and overdose deaths.

Addressing the problem of curtailing opioid abuse, while maintaining access to these drugs for patients in need of them, requires appropriate evaluation and monitoring. Critical factors in chronic opioid use relate to various issues with education taking priority, followed by adherence monitoring through PMPs, urine drug testing and vigilance and finally achieving a balance between curtailing opioid abuse and overuse, and meeting appropriate needs.

Five-year view

Based on the available data, it appears that there are multiple strides being made in the area of education to curtail opioid abuse and understand their appropriate use. In the next 5 years, we believe that there will be an escalation of numerous regulations from the Drug Enforcement Administration, US FDA, boards of medical licensure or similar agencies globally as well as legislatures. We may also see major developments in the area of ADFs and appropriate dispensing of medications through a proper mechanism with tamper-resistant dispensers. Thus, when education, supply, demand and drugs are implemented in combination, in the next 5 years, a reasonable approach may be developed to curtailing abuse, while at the same time improving access and effective management. While it is a basic necessity for physicians to use all skills to relieve pain and suffering, while also doing no harm, it is also essential to consider various modalities of treatments including cognitive behavioral therapy. As the Institute of Medicine described, effective pain management, while essential, is never about the clinician’s intervention alone, but about the clinician, and patient and their family working together.

Table 1. Retail sales of opioid medications (grams of medication) from 1997 to 2007.

Drug	1997	1998	1999	2000	2001	2002	2003	2004	2005	2006	2007^‡	% change from 1997 to 2007
Methadone	518,737	692,675 (34%)	964,982 (39%)	1,428,840^† (48%)	1,892,691 (32%)	2,649,559 (40%)	3,683,881 (39%)	4,730,157 (28%)	5,362,815 (13%)	6,621,687 (23%)	7,228,219 (9%)	1293
Oxycodone	4,449,562	6,579,719 (48%)	9,717,600 (48%)	15,305,913 (58%)	19,927,286 (30%)	22,376,892 (12%)	26,655,152 (19%)	29,177,530 (9%)	30,628,973 (5%)	37,034,220 (21%)	42,977,043 (16%)	866
Fentanyl base	74,086	90,618 (22%)	107,141 (18%)	146,612^† (37%)	186,083 (27%)	242,027 (30%)	317,200 (31%)	370,739 (17%)	387,928 (5%)	428,668 (11%)	463,340 (8%)	525
Hydromorphone	241,078	260,009 (8%)	292,506 (12%)	346,574^† (18%)	400,642 (16%)	473,362 (18%)	579,372 (22%)	655,395 (13%)	781,287 (19%)	901,663 (15%)	1,011,028 (12%)	319
Hydrocodone	8,669,311	10,389,503 (20%)	12,101,621 (16%)	14,118,637 (17%)	15,594,692 (10%)	18,822,619 (21%)	22,342,174 (19%)	24,081,900 (8%)	25,803,543 (7%)	29,856,368 (16%)	32,969,527 (10%)	280
Morphine	5,922,872	6,408,322 (8%)	6,804,935 (6%)	7,807,511 (15%)	8,810,700 (13%)	10,264,264 (16%)	12,303,956 (20%)	14,319,243 (16%)	15,054,846 (5%)	17,507,148 (16%)	19,051,426 (9%)	222
Codeine	25,071,410	26,018,054 (4%)	23,917,088 (-8%)	23,474,865^† (-2%)	23,032,641 (-2%)	22,633,733 (-2%)	21,865,409 (-3%)	20,264,555 (-7%)	18,960,038 (-6%)	18,762,919 (-1%)	18,840,329 (0.4%)	-25
Meperidine (Pethidine)	5,765,954	5,834,294 (1%)	5,539,592 (-5%)	5,494,898^† (-1%)	5,450,204 (-1%)	5,412,389 (-1%)	5,239,932 (-3%)	4,856,644 (-7%)	4,272,520 (-12%)	4,160,033 (-3%)	3,936,179 (-5%)	-32
Total	50,713,010	56,273,194 (11%)	59,445,465 (6%)	35,962,089.84 (15%)	75,294,939 (11%)	82,874,845 (10%)	92,987,076 (12%)	98,456,163 (6%)	101,251,950 (6%)	115,272,706 (14%)	126,477,091 (10%)	149

Number in parentheses is percentage of change from previous year.

^†For year 2000, data are not available, the average of 1999 and 2001 was taken.

^‡Data for the year 2007 was taken from [224].

Data taken from [225].

Key issues

• • Chronic pain, disability and opioid use and abuse are highly prevalent and expensive across the world.

• • There have been dramatic increases in the prescribing of opioids for noncancer pain over the past two decades, which coincides with various factors including the liberalization of regulations, new standards by Joint Commission on Accreditation of Healthcare Organizations, aggressive marketing by the pharmaceutical industry and a belief that opioids are safe and effective when prescribed by physicians and taken appropriately.

• • Drug poisoning deaths are escalating; from 16,849 in 1999 to 36,500 in 2008 in the USA.

• • For every unintentional overdose death related to an opioid analgesic, nine persons were admitted for substance abuse treatment, 35 visited emergency departments, 161 reported drug abuse or dependence and 461 reported the nonmedical use of opioid analgesics in 2007.

• • Implementing strategies that target those persons at greatest risk will require strong coordination and collaboration at the federal, state and local levels, as well as the engagement of healthcare professionals, policy-makers, patients and the public at large.

• • Education, supply, demand and drugs are crucial factors in curtailing abuse and promoting appropriate use.

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Lessons learned in the abuse of pain-relief medication: a focus on healthcare costs

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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.

You are seeing a 40-year-old woman with chronic low back pain. She just moved to your area and requests refills of oxycodone, hydrocodone, and a muscle relaxant. She provides you the empty bottles from her last prescription but no other documentation. You suspect that this patient might be abusing prescription drugs. Based on the current review by Manchikanti and colleagues, what should you consider regarding the epidemiology of this problem?

• □ A Prescription drug abuse is a problem limited to the United States

• □ B Rates of psychotherapeutic drug abuse have grown most dramatically among 18- to 25-year-old adults

• □ C Both immediate-release and sustained-release opioid prescriptions have increased in the United States

• □ D Misuse of other prescription drugs is rare among abusers of prescription opioids

2. What should you consider regarding the health consequences of opioid misuse as you talk to this patient?

• □ A Opioid analgesics are associated with more overdose deaths than cocaine and heroin combined

• □ B Approximately 2000 deaths due to drug overdoses are reported in the United States on an annual basis

• □ C Most deaths related to opioids are suicides

• □ D For every death due to opioid overdose, there are 20 other adults who abuse prescription opioids

3. What should you consider regarding the economic consequences of opioid misuse as you talk to this patient?

• □ A Economic costs associated with opioid abuse are limited to the outpatient setting

• □ B Morphine abuse constitutes the largest share in the cost of opioid abuse

• □ C The type of medical insurance has no effect on the rate of opioid abuse

• □ D Most overdoses occur when low-dose opioids are prescribed by a single practitioner

4. Based on the current review, what is the best course of action to take with this patient?

• □ A Provide her with all her opioid prescriptions because current guidelines say to treat aggressively to the level of the patient’s pain

• □ B Provide her only with long-acting opioids because these have the best evidence of efficacy for back pain

• □ C Perform a urine drug test now

• □ D Prescribe a combined opioid agonist-antagonist to lower her risk of opioid misuse