Palliative care physicians have long known that opioid medications can produce opioid-induced bowel dysfunction, nausea, vomiting, dry mouth and sedation. The first of these is usually treatable and the others tend to resolve over time as tolerance develops. Most efficacy studies have assessed these adverse drug events, although some have looked at cognitive function and drug misuse. Moore and McQuay [17] examined the incidence of common adverse drug events in over 4,000 patients undergoing opioid pharmacotherapy for chronic noncancer pain. Dry mouth affected 25% of patients, nausea 21%, and constipation 15%. As noted above, patients in randomized trials of opioid pharmacotherapy often discontinue participation because of adverse drug events.

Several additional adverse drug events have emerged over the last two decades that were not evident in the acute pain and palliative care settings. They include opioid-induced endocrine deficiencies with increased risks for osteoporosis and bone fracture and diabetes [18,19], cardiac complications [20], hyperalgesia [21], and immunosuppression [22]. Misuse of medications including addiction, drug diversion and abuse of medications are also adverse drug events, and they have become the fastest growing drug problem in the United States. The most alarming adverse drug event is fatal prescription drug overdose [23]. Although the literature identifies these adverse drug events, large scale, randomized controlled studies of opioid pharmacotherapy have yet to include and quantify these events comprehensively. Comprehensive systematic reviews of the emerging opioid adverse events are not currently possible. Until more definitive information emerges about who is at how much risk for which adverse drug events, the risk benefit ratio for opioid pharmacotherapy in chronic noncancer pain patients must remain undefined.

From 1997 to 2010 in the United States, sales of opioid analgesic drugs quadrupled.

Physicians prescribed 96 mg morphine equivalent per person in 1997 but 710 mg morphine equivalent in 2010 [24]. With this increased prescribing rate, the societal costs of prescription opioid abuse and misuse also grew. Birnbaum et al. [25] estimated the societal costs of prescription opioid abuse in the United States to be $55.7 billion in 2007. Workplace costs were $25.6 billion, health care expenditures accounted for $25.0 billion, and criminal justice expenses totaled $5.1 billion. Clearly, prescription opioid misuse and abuse has imposed a significant burden on American society. Yet, the total of these expenditures is only 5-10% of the total costs associated with chronic pain in the United States.

Patients who have a prescribed opioid can engage in abuse in multiple ways, collectively termed aberrant drug behaviors [26]. Instead of following instructions, they can take the drug at more or less than prescribed doses, take it more or less often than instructed, take the medication for purposes other than pain relief such as sedation or to cope with interpersonal stress, chew, crush or snort medications, hoard medication, or seek prescriptions from multiple prescribers (doctor shopping). Several community practice surveys estimate the overall rates of opioid misuse and abuse in a range from 4-26% [27]. In an 18-month study of more than 25 million patients, Cepeda et al., [28,29] estimated that three of 1,000 patients exposed to opioids exhibit doctor shopping behavior, typically eight months after first exposure.

Virtually all patients taking extended release opioid medications over long periods of time will develop drug dependence. This decreases volitional control over drug use because cessation of drug intake will cause withdrawal symptoms. This dependence is not drug addiction, but it can compel patients to seek urgent prescription refills if they have consumed their medication ahead of the scheduled refill.

Patients qualify as addicted to prescribed medication when they engage in compulsive use of a substance despite obvious harm. Addicts typically deny that a drug use problem exists, become obsessed with obtaining the medication, neglect vocational and family responsibilities, and they often use more of the medication than planned. Opioid addicts may exaggerate or lie about an acute or chronic pain condition in order to obtain a prescription. The identification of true addiction in the chronic noncancer pain population is complex and challenging.

Fishbain et al. [30] conducted an evidence based structured review of 67 studies to determine the percentage of patients using chronic opioid pharmacotherapy that developed abuse/addiction or aberrant drug related behaviors. They estimated an abuse/addiction rate of 3.27%. If patients had no previous or current history of abuse or addiction, the rate was 0.19%. The aberrant drug related behavior rate was 11.5%, but those with no previous abuse/addiction history had a rate of only 0.59%. They concluded that long-term exposure to chronic opioid pharmacotherapy would lead to abuse or addiction in a low percentage of patients, particularly if this treatment were confined to those with no history of substance abuse or addiction.

Subsequently, Boscarino et al. [31] classified a sample of 705 chronic noncancer pain patients using opioid pharmacotherapy according the proposed Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) criteria for Opioid Use Disorder. Opioid use disorder is a maladaptive pattern of opioid use leading to clinically significant impairment of distress. They reported that 21.7% qualified as moderate and 13.2% as severe on Opioid Use Disorder. Although not synonymous with classical concepts of addiction and abuse, Opioid Use Disorder gauges patients on dependence and nontherapeutic compulsive use.

Increased opioid prescribing rates have also led to increased diversion of opioid medications. Prescription drug diversion is the unlawful channeling of regulated pharmaceutical drugs from legal sources to the community or an illegal market place. The 2010 National Survey on Drug Use and Health [24] estimated that 22.6 million or 8.9% of Americans older than 12 years were current illicit drug users. New nonmedical users of prescription pain relievers numbered 2.0 million, and 55.0% of these reported that they had received prescription pain killer for free from a friend or relative. Another 11.4% bought the drug from a friend or relative, while 4.8% took them from a friend or relative without permission. Other forms of drug diversion include strategic doctor shopping on the part of patients with subsequent selling or release of the drugs in the community, theft on the part of pharmacy employees, and the purchase of prescribed medications for indigent patients [32]. Financially impoverished patients may sell all or part of their opioid medications to meet the costs of basic needs such as food, housing or even other medications.

The most salient prescribed opioid misuse problem in the United States is accidental drug poisoning death. Warner et al. [23] examined death rates in the United States from 1980-2008. They reported that in 2008, the number of drug poisoning deaths exceeded for the first time the number of deaths by motor vehicle accident in the United States. Opioid analgesics were involved in more accidental poisoning deaths than other drugs, including cocaine. The accidental drug poisoning death rate has nearly tripled since 1980. In 2008, opioid medications were involved in nearly 15,000 deaths. This problem is apparently related to medication diversion. Hall et al. [33] studied 295 patients who had died from unintentional drug overdose. Of these decedents, 275 took opioids (93.2%) but only 122 (44.4%) had prescriptions for opioid medication. From 2004-2008, the rate of emergency medicine visits for the nonmedical use of opioid medications doubled from 49 per 100,000 to 101 per 100,000. Patients at risk for accidental opioid-related overdose death may be those using methadone, those who have co-morbid substance abuse disorders, those using sedatives, anti-depressants or alcohol, and those with sleep-disordered breathing [34,35].

A significant ethical and legal conflict exists in the United States. Chronic noncancer pain disables people, degrades quality of life, increases risk of suicide, and imposes a large economic burden on society. Opioid medications offer a time- and cost-efficient way to manage many chronic noncancer pain patients who do not respond to non-opioid drugs (e.g., nonsteroidal anti-inflammatory medications, acetaminophen, and other adjuvant analgesics), who do not have access to comprehensive interdisciplinary pain care (involving medical, rehabilitative and behavioral interventions or who are otherwise undermanaged. Despite the lack of an adequate evidence base for opioid pharmacotherapy in chronic noncancer pain patients, opioid prescribing in the United States has steadily escalated over the last quarter century. With escalated opioid prescribing has come a set of problems related to partly unanticipated adverse drug events. These include widespread drug misuse by patients and others share these drugs, medication diversion, Opioid Use Disorder and alarming increases in the rate of opioid-related overdose deaths. Prescribed opioids are rapidly becoming the primary misused medications in the United States and the primary cause of accidental death. Protecting the public against illicit use of opioid medications has become a high priority. This area of clinical practice remains highly controversial, with patient advocates on both sides of the issue voicing strong opinions.

The root cause of the problem is that prescribing patterns have outpaced the availability of evidence to support such prescribing, and without such evidence adequate education of prescribers on proper assessment, patient selection and management practices is impossible [27,36]. Sound evidence-based practice requires that physicians administer interventions according to knowledge gleaned from synthesized information in the literature. This knowledge should characterize both the potential benefits of a treatment and the potential harms. Most importantly, this characterization should go beyond simple efficacy to include effectiveness. It is crucial to determine the potential long-range benefits of opioid pharmacotherapy for typical patients and also the potential long-range harms. This information is simply unavailable in the literature, and there are no comprehensive federal or other funding initiatives in place to strategically generate the needed knowledge base in the foreseeable future.

In the United States, federal and state laws and regulations govern both the distribution and prescription of opioid medications. State regulatory agencies enforce these regulations. The federal Controlled Substances Act of is a subset of the Comprehensive Drug Abuse Prevention and Control Act of 1970. It is the major federal law controlling the prescribing of opioid medications, which are controlled substances. Under this law licensed medical practitioners can prescribe controlled substances for legitimate medical purposes according to standard medical practice. There are five classifications for controlled substances. Schedule I substances have no medical benefit coupled with extreme potential for abuse, and physicians cannot prescribe them. Heroin falls under this classification. Schedule II drugs have medical benefit but also have high potential for abuse. Opioid medications for chronic noncancer pain such as morphine and oxycodone fall under this classification. Drugs scheduled as III, IV and V have medical benefit but incrementally lower potentials for abuse, although hydrocodone, the most abused opioid, is a schedule III drug currently under review for possible rescheduling to Schedule II due to its demonstrated abuse liability.

The Drug Enforcement Agency (DEA) is a part of the United States Department of Justice. Its job is to assure an adequate supply of controlled substances for legitimate medical use and research while also assuring that the prescription, dispensing, and administration of controlled substances is solely for legitimate medical purposes. American physicians who prescribed opioid medications must obtain DEA registration. The DEA may investigate individual physicians to determine whether their prescribing patterns reflect legitimate medical practice. It can revoke a physician's controlled substances registration. This happens infrequently.

Individual states have licensing boards that license and oversee medical practitioners. In general, state medical boards regulate opioid prescribing through licensure screening and promulgating medical practice guidelines. Such boards keep abreast of emerging findings in the literature and the development of new interventions or drug formulations. The Federation of State Medical Boards helps assure continuity in policy across states. In the late 1990s it produced a policy template, "Use of Controlled Substances for the Treatment of Pain" and produced its "Model Policy for the Use of Controlled Substances" [11], and it has commissioned a guide for clinicians [37].

Currently 43 states have adopted prescription drug monitoring programs. Such programs maintain a statewide electronic database that collects specific information on drugs dispensed within a state. The program can provide feedback to authorized professionals. Some states require physicians to report every controlled substance prescription they write, while others require pharmacist reporting. A doctor shopping patient seeking to fill multiple prescriptions for opioid medication will find that the dispensing pharmacist knows from the database that the patient is doing this. The United States Department of Justice fosters these programs. State licensing boards are increasingly instructing clinicians in the use of prescription monitoring program databases and asking them to query these sites on a regular basis before prescribing. An ongoing challenge is to have these databases fully secure to protect patient privacy, yet readily accessible with current information for all practitioners in routine clinical settings.

The United States Executive Branch of the federal government under President Obama has taken action on the opioid pharmacotherapy problem through the Office of National Drug Control Policy. In 2011, it announced the Prescription Drug Abuse Prevention Plan, a set of guidelines to address the misuse of prescription opioid medications [38]. This plan encourages stakeholders to take action in four domains: 1) Education; 2) Tracking and Monitoring; 3) Proper Medication Disposal; and 4) Enforcement. The education effort aims to increase awareness of the dangers of prescription drug abuse among patients, young people, parents and providers. The tracking and monitoring effort focuses on state prescription drug monitoring programs. It seeks to improve and empower such programs by giving clinicians greater access and increasing inter-state operability and communication. The effort directed at proper medication disposal is concerned with the home storage of unused opioid medication. Patients need convenient ways to dispose of opioid medications that they do not intend to use and secure ways to store medications they are using. This requires the development of environmentally save options for medication disposal. Finally, the enforcement effort recognizes that a small minority of opioid prescribing physicians act outside of standard medical practice and often enable doctor shopping. Their actions are a threat to the patients in their care and to the communities in which they practice. The guidelines put forward a plan for more aggressive pharmaceutical crime investigation and prosecution. The goals of this five year plan include reducing nonmedical use of opioids among young people, implementing a Risk Evaluation and Mitigation Strategy, implement regulations for medication disposal, enhance the registration of controlled substances information and achieve prescription drug monitoring programs in all 50 states, and decrease the number of unintentional overdose deaths.

The Food and Drug Administration (FDA), an agency within the Department of Health and Human Services, has introduced a risk evaluation and mitigation strategy for both extended release and long-acting opioid medications [39]. The 20 companies that produce opioid medications must contribute to provider and patient education by providing educational grants to continuing education trainers. This is part of the agency's efforts to address the epidemic of prescription drug abuse and accidental overdose. The goals of this strategy are to assure that prescribers know how to prescribe safely and that patients understand the risks of opioid pharmacotherapy. There are three components: 1) Training for prescribers according to an FDA blueprint; 2) A consumer friendly updated medication guide and patient counseling document; and 3) Assessment and auditing of company compliance with training requirements.

The pharmaceutical industry is also making efforts to reduce the opioid abuse problem. Most opioid abusers chew, crush or snort the drugs to maximize psychological effects. Pharmaceutical manufacturers are developing and marketing products that are tamper resistant [40,41]. One approach offers extended release morphine with sequestered naltrexone. Chewing or crushing of the tablet will cause release of the opioid antagonist naltrexone. Another product offers controlled release oxycodone in a crush resistant formulation and another in a high viscosity hard gelatin capsule; it is impossible to extract its contents with a needle. The impact of this approach to deterring prescription opioid abuse is still unknown but there is evidence of reduced street value of and opioid poisonings from the reformulated crush resistant long-acting oxycodone that has replaced the older formulation.