Opioids and Public Health: The Prescription Opioid Ecosystem and Need for Improved Management

Evan D. Kharasch, M.D., Ph.D.; J. David Clark, M.D., Ph.D.; Jerome M. Adams, M.D., M.P.H.

Anesthesiology. 2022;136(1):10-30.

Abstract and Introduction

Abstract

While U.S. opioid prescribing has decreased 38% in the past decade, opioid deaths have increased 300%. This opioid paradox is poorly recognized. Current approaches to opioid management are not working, and new approaches are needed. This article reviews the outcomes and shortcomings of recent U.S. opioid policies and strategies that focus primarily or exclusively on reducing or eliminating opioid prescribing. It introduces concepts of a prescription opioid ecosystem and opioid pool, and it discusses how the pool can be influenced by supply-side, demand-side, and opioid returns factors. It illuminates pressing policy needs for an opioid ecosystem that enables proper opioid stewardship, identifies associated responsibilities, and emphasizes the necessity of making opioid returns as easy and common as opioid prescribing, in order to minimize the size of the opioid pool available for potential diversion, misuse, overdose, and death. Approaches are applicable to opioid prescribing in general, and to opioid prescribing after surgery.

Introduction

The current opioid crisis, emanating from inappropriate prescribing, marketing, diversion, and misuse of oral prescription opioids for acute and chronic noncancer pain,^[1] has a staggering human and economic toll.^[2–4] In the United States, there have been more than 450,000 opioid-related deaths over the past two decades, one quarter of which may be suicides.^[5] This cost the U.S. economy more than $2.5 trillion between 2015 and 2018, including an estimated $700 billion to $1 trillion in 2018 alone—representing 3.4% of the U.S. gross domestic product.^[6] Opioid misuse and fatal overdose are not limited to the United States,^[7–10] or to adults.^[11] Moreover, the problem worsened during the COVID-19 pandemic, due primarily to illicit fentanyl and analogs.^[12–14] The influence of the COVID-19 pandemic on opioid overdose, whether due to illicit fentanyl abundance, disrupted prescription drug supply chains, increasing drug toxicity, social isolation, unemployment, worsening mental or physical health, or reduced access to emergency medical and drug treatment services, continues well into 2021.^[15,16]

The opioid crisis has multiple antecedents.^[17–19] It is grounded on the pain epidemic, currently the most prevalent (40 to 100 million U.S. adults), disabling, and costly public health problem in the United States, the societal costs of which exceed the annual combined costs of heart disease, diabetes, and cancer.^[20] It is also grounded on the more debilitating subset of high-impact chronic pain, which impairs work outside the home, education, social activities, and simple self-care and daily living, and is suffered by 11 million U.S. adults, and who use a disproportionate amount of health care.^[21] It is also grounded on the overprescription and overuse of oral opioids, and in patients for whom they were not indicated or effective. Contributory also were avaricious and illegal marketing of prescription oral opioids, and economic stagnation, unemployment, poverty, lack of opportunity, social distress, and substandard living and working conditions in underprivileged areas of the country.^[22,23] The U.S. Drug Enforcement Administration (Springfield, Virginia) estimates that 163,683,029 schedule II prescriptions (retail cost $11.8 billion) were filled for "acute pain" in 2017.^[24] Overuse and misuse of prescription oral opioids and associated overdose were then followed by a rapid and fluid shift of the use- and supply-chain of abused opioids from medical to illicit (first heroin and then fentanyl) sources.^[25–27] Indeed, deaths in North America attributed to illicit fentanyl now outnumber those from heroin.^[19]

The "opioid paradox" is that opioid overdose mortality has continued to increase despite steady reductions in opioid prescribing (Figure 1).^[31] Overall opioid prescribing is decreasing, in both numbers of patients exposed and average doses prescribed (Figure 1).^[30,32] Opioid prescribing in the United States initially quadrupled from 1999 to the peak in 2012,^[33] but has decreased 43% since then (from 81 to 47 prescriptions per 100 persons in 2020).^[30] Nonetheless, average daily morphine milligram equivalents have decreased more slowly, because the average supply per prescription continues to rise.^[34] Opioid use is still common, with 15% of the U.S. population filling one or more opioid prescriptions in 2018.^[34] Despite the declining prescription numbers, overdose deaths have not declined, due to the increased use of heroin and illicit fentanyl.^[35,36]

(Enlarge Image)

Figure 1.

The opioid paradox. Opioid prescriptions are declining while opioid overdose deaths are increasing.^28–30

There are inescapable public and practitioner awareness of the opioid crisis, extensively documented inappropriate outpatient oral opioid use and overprescribing, innumerable federal, state, local, and institutional regulatory, legislative, and guidance restrictions on opioid prescribing, and billions of dollars invested to combat the opioid crisis over the past 5 yr. Nonetheless, these approaches are failing to retard or reverse the epidemic of opioid-related fatalities. There has been some improvement, in that the number of Americans 12 yr or older who misused opioids decreased from 11.8 million in 2016 to 10.1 million in 2019,^[37,38] and the number who misused prescription pain relievers decreased from 11.5 million in 2016 to 9.7 million in 2019.^[37,38] In addition, the number who initiated prescription pain reliever misuse each day in 2019 (4,400)^[38] was less than in 2018 (5,230).^[39] Nevertheless, this still represents 1.6 million new misusers in just 1 yr. Moreover, these small reductions represent a feeble response compared with the plethora of recently enacted restrictive countermeasures intended against opioid prescribing and misuse.

Furthermore, the opioid overdose rate is climbing (Figure 1). Nearly 50,000 Americans died of an opioid overdose in 2019 (137 per day), then a new record.^[28,40] This was a threefold increase from 16,600 overdose deaths in 2010,^[41] and a fourfold increase from the previous decade.^[42] Even worse, opioid overdose deaths spiked again in 2020, to 66,000 (181 per day, 1 every 8 min),^[28] the highest number on record and the largest annual percentage increase in the past 20 yr. Opioids now account for 74% of all fatal drug overdoses, increased from 63% in 2015.^[29] Death rates continue to be driven primarily by overdose from synthetic opioids (mainly illicit fentanyl), which account for more than two thirds of opioid overdose deaths.^[40] Overdose due to prescription opioids has plateaued (Figure 1), but overdose death rates involving fentanyl and other synthetic opioids increased more than 10-fold from 2013 to 2019,^[40] and more than doubled between 2016 and 2020.^[28] Most recently, synthetic opioid deaths increased 38% in the year ending May 2020,^[13] and continue to rise.^[28] It is abundantly clear that current approaches to the opioid crisis are not succeeding.

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Next Section

Abstract and Introduction
Postoperative Pain and Opioids: The Problem of Variability
The Opioid Pool
Managing the Size of the Opioid Pool
Prescription Opioid Ecosystem
Practicum
References

Box 1. Partial Filling of Opioid Prescriptions
1. Partial filling of prescriptions for schedule III, IV, or V controlled substances. This is currently permitted (21 CFR Part 1306.23), provided that the total quantity dispensed in all partial fillings does not exceed the total quantity prescribed, no dispensing occurs later than 6 months after the initial prescription, and each partial filling is properly recorded. 2. Partial filling of prescriptions for schedule II controlled substances. The Comprehensive Addiction and Recovery Act of 2016 amended the Controlled Substances Act (21 U.S.C. 829, new paragraph f) to allow partial filling of prescriptions for schedule II controlled substances when requested by a patient or practitioner. Additional requirements are that partial filling is not prohibited by state law, the total quantity dispensed in all partial fillings does not exceed the total quantity prescribed, and no dispensing occurs later than 30 days after the initial prescription (unless it was an emergency oral prescription, in which case the remaining portion must be filled within 72 h). In December 2020, the Drug Enforcement Administration issued a Notice of Proposed Rulemaking (Docket No. DEA–469) to modify the Code of Federal Regulations (21 CFR Part 1306) to revise the Drug Enforcement Administration regulations to incorporate the new statutory provisions.¹⁶⁸ Where a practitioner requests that a schedule II prescription be partially filled (as the Comprehensive Addiction and Recovery Act now allows), the proposed rule states that the face of the written prescription must specify the quantity to be dispensed in the partial filling. Where a patient requests that a schedule II prescription be partially filled (as the Comprehensive Addiction and Recovery Act now allows), the proposed rule states that the pharmacy would be required to indicate on the prescription that the patient requested the partial fill. One caveat is that where a practitioner has requested the partial filling of a prescription, the patient may not request a partial filling in an amount greater than that specified by the practitioner. A patient request to the pharmacy for a partial fill would not require the consent of, or notification of, the prescribing practitioner. In addition, the Drug Enforcement Administration recognized that many postsurgery patients may have a difficult time visiting a pharmacy in person; therefore, the proposed rule would not require an in-person request by the patient in every case and would allow alternative pathways for the patient to make such a request and specify the amount to be filled (e.g., phone call by the patient to the pharmacist, or a signed written note from the patient and delivered by a family member to the pharmacist).

Box 2. Perioperative Practitioner Engagement in the Prescription Opioid Ecosystem
Anesthesiologists and surgeons engage multiple facets of the perioperative opioid ecosystem. Anesthesiologists can have prominent roles in each step or even comprehensively oversee the process. Postoperative opioid needs (demand) can be diminished by optimized intraoperative/postanesthesia care unit (PACU) anesthesia care, opioid supply can be more carefully managed, consumption can be reduced by education about expectations and alternatives, and opioid stewardship can be enhanced by education about storage, disposal, and return. 1. Educate patients pre- and postoperatively on pain, pain management, and opioid use Establishment of a therapeutic alliance between patients, anesthesiologists, and surgeons is needed, with clear expectation as to who will provide the needed education. Perioperative education is often completely missing, but even when present may inadequately set expectations for pain relief, incompletely outline the use of opioids as one tool among many to control pain, and fail to review risks and proper handling of leftover opioids.¹⁵⁰ Educational materials are immediately and publicly available (c.f., "Safe and Effective Pain Control after Surgery" from the American College of Surgeons, Chicago, Illinois¹⁷⁴; and "Opioids and Pain Management" from the Michigan Opioid Prescribing Engagement Network, Ann Arbor, Michigan¹⁷⁵). Preoperative education may reduce postoperative pain scores and opioid use,¹⁴⁸ or hasten opioid cessation.¹⁴⁹ Patient education supervised by anesthesiologists should be a key component of a comprehensive perioperative opioid use and risk reduction strategy.¹⁷⁶ 2. Educate patients pre- and postoperatively on opioid stewardship, storage, and disposal Preoperative anesthesia assessments, discharge planning, and outpatient PACU and inpatient ward discharge visits afford opportunities to educate patients and caregivers whose focus is undistracted and attuned. Topics should include pain expectations, opioid and nonopioid analgesics and optimal use, avoidance of dangerous opioid drug interactions, proper storage of unused opioids, the idea that opioids are "loaned," not "given," and the need for proper disposal or return ("give-back") and the responsible and effective methods for doing so, as well as the benefit to them and society. There is also the need to educate the educators. 3. Evaluate patient preoperative opioid use Consider preoperative opioid tapering for patients on chronic opioids. Chronic preoperative opioid use is common¹⁷⁷ and a risk factor for worse surgical outcomes, surgical complications, poor pain control, greater suffering, opioid-related respiratory depression, perioperative dose escalation and prolonged postoperative opioid use, longer length of stay, greater costs, more frequent readmissions, and more difficult to control postoperative pain.^178,179 Tapering preoperative opioids has been suggested, with less acute and chronic postoperative pain and opioid consumption and enhanced functional recoveries among the hoped-for outcomes.¹⁷⁸ Unfortunately, it is simply not known for whom and to what degree preoperative opioid taper is appropriate. There is limited evidence for the effectiveness of tapering, and there are few successfully proven protocols.¹⁷⁸ Recent evidence suggested that reducing opioid use preoperatively did not result in lower postoperative opioid use.¹⁷⁹ In addition, there may be risks. Opioid discontinuation, whether abrupt or with dose reduction, significantly increased risk of suicide (hazard ratio 4 to 5), and patients with abrupt discontinuation were more likely than others to overdose on heroin (vs. prescription opioids).¹⁰¹ Discontinuation of long-term opioids was associated with a threefold greater risk of overdose death.⁹⁸ Shorter time to discontinuation was associated with greater risk of opioid-related adverse events.⁹⁹ Identify patients with opioid use disorder. First consideration should be given to stabilizing patients by referral for medication-assisted treatment, counseling, support, and other evidence-based interventions. Undertreatment of opioid use disorder, inadequate availability of treatment, and underutilization of and access to medication-assisted therapies such as methadone and particularly buprenorphine are well-known. Those having more urgent surgery should have opioid use gauged and surgical and anesthesia teams notified in order to optimize care. Patients on medication-assisted treatment will require that to be managed, generally with continuation throughout the perioperative period (definitely methadone, although buprenorphine is more controversial and with limited evidence).^180,181 Discontinuation of medication-assisted treatment may confer critical risks of return to illicit drug use or overdose.¹⁸² 4. Implement evidence-based anesthesia that confers benefit and reduces risk Use patient-specific intraoperative and PACU anesthetic regimens that provide excellent perioperative pain relief, optimize patient recovery trajectory, minimize postdischarge pain and opioid requirements, and ideally confer continued and long-term benefit after discharge.⁵⁹ Remember that the majority (80%) of surgical patients report inadequate pain treatment,^46,106–108 acute surgical pain causes suffering, diminished patient satisfaction, and is associated with surgical complications and regret,^43,109–112 and is a major risk factor for chronic postoperative pain and persistent postoperative opioid use.^{102,113–118} Opioids are the most efficacious systemic analgesics available for moderate to severe pain. Multimodal approaches may have benefit and spare opioids when evidence based. Choose strategies that maximize pain control while minimizing the need for postoperative discharge oral opioids and associated potential long-term harm.¹⁰² Adequate analgesia, not withholding needed opioids, should be the primary goal.¹³³ Opioid-sparing by itself is not likely meaningful to patients unless accompanied by improved patient-centric outcomes like better pain relief or the sparing of undesirable opioid-related side effects.¹⁸³ Opioid-free anesthesia has not been shown to have benefits beyond opioid-sparing strategies, to influence or prevent persistent postoperative opioid use, or to prevent postoperative opioid overprescription.^92,95 Regional anesthesia and other nonopioid multimodal strategies generally reduce postoperative pain opioid requirements for several hours to days; catheter-based systems can extend benefits of some blocks for a week or more. Newer techniques of percutaneous neuromodulation may be promising.¹⁸⁴ Current approaches need improvement. Multimodal analgesia decreases acute but not chronic postoperative pain.¹²³ Epidural anesthesia may not protect against persistent opioid use.¹²⁵ Nerve block for total knee or shoulder arthroplasty did not decrease persistent postoperative opioid use,^126,127 and perioperative gabapentinoids have no effect on chronic postoperative pain.¹²⁸ Intraoperative methadone, with or without ketamine, for some inpatient and outpatient procedures, can result in less postoperative pain and opioid use, with benefits that last for weeks to months.^185–189 5. Right-size postdischarge oral opioid prescriptions Postoperative patients should ubiquitously receive nonopioid analgesics but may experience moderate to severe pain needing opioids. Adequate postoperative pain treatment is imperative, and fundamental for preventing conversion from acute to chronic pain.¹¹⁵ Opioid-sparing and multimodal techniques may reduce immediate perioperative opioid needs, but little patient benefit accrues if discharge opioid amounts are not tailored, and particularly if under- or overprescribed. Withholding needed opioids is not appropriate. Interindividual variability in pain severity and duration and analgesic response confounds one-size-fits-all postdischarge oral opioid prescribing. Communication with surgical teams about appropriate discharge opioids while adding nonopioid analgesics, taking responsibility where possible for designing and implementing opioid-sparing discharge analgesic plans, and arranging transitional pain management care are all responsibilities anesthesia groups and acute pain services might assume. Commensurate with responsibility for proper opioid prescribing is patient education about opioid stewardship, safe use, storage, disposal, and return of unused opioids. 6. Consider implementing transitional pain management This addresses the period between discharge and the re-establishment of care with the patient's primary provider for patient care and education about postoperative pain, opioids and other pain drugs, opioid stewardship, and opioid return/disposal. The first transitional pain service was developed to reduce chronic postsurgical pain by identifying high-risk patients and providing coordinated and comprehensive care from a multidisciplinary team of pain physicians, psychologists, physiotherapists, and advanced practice nurses.¹²⁹ Patients are seen preoperatively, postoperatively, or as outpatients for up to 6 months after surgery. A service can bypass potentially long waiting times for postoperative patients to be referred and seen in chronic pain clinics. Expanded aims are to reduce opioid consumption in preoperatively opioid-naïve and opioid-experienced patients.^130,131 Services may include opioid, nonopioid, and multimodal analgesia management to improve pain and opioid weaning, nonpharmacologic interventions including acupuncture and physiotherapy, and psychologic interventions around pain education and coping.¹³¹ This may enhance communication between surgical team, primary providers, and chronic pain specialists, and is amenable to telehealth implementation.