Pain Management and the Opioid Epidemic Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use (2017) / Chapter Skim
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4 Trends in Opioid Use, Harms, and Treatment
4 Trends in Opioid Use, Harms, and Treatment
Pages 187-266
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From page 187... ...
The opioid epidemic's toll is felt across the life span and in every sociodemographic group, but more heavily burdens vulnerable populations, such as those in economically depressed areas of the country. This chapter updates key statistics regarding use and misuse of prescription opioids, identifies risk factors for opioid-related harms, describes the recent increase in use of heroin and illicitly manufactured synthetic opioids and its relation to the prescription opioid epidemic, describes the impact of prescription opioids on illicit markets, reviews the current state of surveillance systems, and summarizes recent trends in treatment of OUD and use of naloxone to prevent overdose deaths.
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From page 188... ...
. Opioid-related death rates also were higher among those who had recently been released from prison, those who obtained opioid prescriptions from multiple pharmacies, and those who obtained prescription opioids in combination with other scheduled medications.
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. However, many people who otherwise would have been using prescription opioids have transitioned to heroin use, with a resulting three-fold increase in heroin-involved overdose deaths from 2010 to 2014 (Compton et al., 2016)
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Translating data from laboratory-based, controlled abuse liability studies to the community and clinic to examine possible increased risk is more challenging. However, several studies provide insight into "realworld" abuse liability and risk variation by compound.
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and nonfatal and fatal opioid overdose (Braden et al., 2010; Miller et al., 2015; Zedler et al., 2014)
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From page 192... ...
For example, a new and comprehensive analysis by Alpert and colleagues (2017) shows that the reformulation of OxyContin from a non-ADF to an ADF prescription opioid was linked to higher-than-expected rates of subsequent heroin use, especially in places with persistently high rates of opioid misuse.
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From page 193... ...
However, these studies are not designed to predict a fuller range of potentially harmful effects that one may want to consider in deciding whether to approve an opioid or other drug, such as unforeseen allergies, unanticipated side effects, co-use with other licit and illicit drugs, and ease of manipulation to prepare the product for misuse. For these effects, the current approach is to rely on post-marketing surveillance to capture, in a proactive, preventive way, the cumulative effects of drug-specific characteristics as the drugs are actually used or misused in the population.
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From page 194... ...
. These patterns may ultimately reflect poor coordination of care for people with pain and OUD in the community rather than causal drivers of the epidemiology of nonmedical use of prescription opioids.
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The co-use of opioid medications with one class of drugs, benzo diazapines, has been well established in preclinical, clinical, and epidemiologic studies, and contributes to up to one-third of fatal opioid overdoses in the United States (Jones and McAnich, 2015)
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From page 196... ...
Overdose deaths rise sharply when opioid dose is 50 mg or greater and benzodiazepine is also used.
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From page 197... ...
, the proportion of babies born with NAS in the United States increased five-fold from 2000 to 2012, concurrently with a significant increase in opioid use and misuse among pregnant women. Subsequent studies have found that the incidence of NAS varies significantly among states, that the geographic variations in NAS are consistent with the variations in opioid pain prescriptions, and that the incidence of NAS and maternal opioid use increased disproportionately in rural relative to urban counties (Ko et al., 2016; Villapiano et al., 2017)
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From page 198... ...
The context encompasses whether the opioid is a medication taken under the care of a health care provider (e.g., a woman receiving medication under the care of a physician for pain management, or a woman being treated by a physician for OUD with methadone or buprenorphine) , or whether the woman is misusing pain medications with or without a prescription and/or using illicit opioids such as heroin.
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From page 199... ...
No information is available for other opioid pain medications regarding signs and symptoms of NAS, its incidence and severity, and the length of treatment. Importantly, little to no information is available regarding exposure to illicitly manufactured fentanyl or fentanyl analogs in pregnant women and its effect on the risk of fatal overdose; responsiveness to OUD treatment; the maternal medication-assisted treatment (MAT)
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To the committee's knowledge, no data specific to other opioid pain medications are available. Infants undergoing NAS would be assessed and treated the same, but mothers receiving opioids for chronic pain who wished to breastfeed would
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As the opioid epidemic shifts rapidly from prescription opioids to heroin, illicitly manufactured fentanyl, and other illicit drugs, more indi 3 Public Law 93-247.
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. As is the case for pregnant women with OUD, there are important opportunities to identify and treat people in the criminal justice system who are at risk of progressing to more severe OUD and overdose.
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. The authors of this study note that during the same period, there was a surge in the number of young people in these states seeking treatment for OUD related to use of prescription opioids and heroin, suggesting that "the increase in acute HCV infections in central Appalachia is highly correlated with the region's epidemic of prescription opioid abuse and facilitated by an upsurge in the number of persons who inject drugs in these four states" (Zibbel et al., 2015, p. 457)
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. The authors conclude that all "available information indicates that early prescription opioid abuse and addiction, followed by initiation to IDU [injection drug use]
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Findings indicated that in these communities, which had endemic prescription opioid misuse (with little heroin use) , diverted prescription opioids were used in multiple injection events per day.
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From page 206... ...
in 2013 was among non-Hispanic whites aged 18 to 44, a demographic that one decade earlier had been heavily affected by nonmedical use of prescription opioids, as reviewed earlier in this chapter. Importantly, there are geographic differences in heroin overdose rates, with the greatest burden being exhibited in the Northeast (6.3 per 100,000)
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From page 207... ...
. Interactions and Transitions from Prescription Opioids to Heroin One of the most urgent concerns posed by the widespread increase in prescription opioid use and consequent misuse beginning around 2000 is how this epidemic is influencing current trends in the use of heroin and fentanyl and mortality due to overdose involving these drugs.
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. While societal factors have certainly contributed to this trend, a major concern is how prescription opioids contributed to this problem both by serving as "gateway" drugs to heroin use (Muhuri et al., 2013)
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Prescription Opioids as a Gateway The gateway theory of the movement of prescription opioid users to heroin is predicated on the fact that opioid medications produce the same neuropharmacologic effects as heroin, so the substances are natural substitutes. Use of both heroin and prescription opioids involves tolerance, crosstolerance, and withdrawal.
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From page 210... ...
The differences in potency and onset of effects among orally ingested opioid medications, snorted or injected prescription opioids, and injected heroin places a person making the switch away from oral routes at much higher risk for overdose. Moreover, to someone tolerant to and misusing prescription opioids, ER opioid formulations and heroin offer a much more rapid onset of effects relative to prescription IR formulations.
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From page 211... ...
Part of the reason for the price difference between illicit prescription opioids and heroin is that heroin supplies coming into the United States are largely unrestricted (other than by the sorts of supply-related control measures that may restrict opioid medications)
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From page 212... ...
In asking whether people who use heroin begin doing so before or after using prescription opioids, these authors identified a complete reversal from the 1960s: almost all people who initiated heroin use in the 1960s started with heroin, whereas almost all those who began using heroin in the 2000s began with the use of prescription opioids (Cicero et al., 2014)
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veterans who reported no previous history of nonmedical prescription opioid or illicit opioid use, Banerjee and colleagues (2016) found that nonmedical use of prescription opioids was associated positively and independently with subsequent initiation of heroin use.
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Based on these estimates, starting from 2010 and assuming 100,000 new heroin users annually, the prescription opioid epidemic could at least double the number of heroin users in the United States by 2025.
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Two questions remain: How costly, in terms of heroin mortality, has this connection been? and What does this mean if prescription opioid supplies are curtailed?
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From page 216... ...
With more new heroin users entering the market every year, it has become much easier for people to start using heroin directly, without first using prescription opioids. Thus, in addition to individuals who formerly misused prescription opioids, individuals whose heroin use began recently include those who were not influenced by the gateway effect of prescription opioid medications.
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that are packaged and sold in bulk from abroad to drug trafficking organizations or even as counterfeit pills made to look like popularly diverted prescription opioid medications. Thus, part and parcel of creating the supply of prescription opioids for treatment of chronic
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From page 218... ...
However, large-scale misuse of prescription opioids created new demand that substantially reinvigorated, expanded, and diversified those markets. The illegal opioid markets saw ebbs and flows before the expansion of prescription opioid misuse.
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, or both. In the past few years, two "new" and potentially very important product forms -- fentanyl and counterfeit opioid pills -- have proliferated in North American black markets for illegal opioids.
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Present-Day Illicit Opioid Markets Today's illicitly manufactured fentanyl may have multiple sources that are diversifying and expanding. Much illicitly manufactured fentanyl is reputedly produced in the same areas (and perhaps even the very same factories)
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Fentanyl, as noted, is cheaper than heroin, and heroin is cheaper than prescription opioids, so fentanyl-laced counterfeit pills are markedly cheaper than are diverted pharmaceuticals. That this is so is not really surprising, given that production costs for many pharmaceuticals are just a tiny fraction of their sales price in the United States.
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. The proliferation of a counterfeit prescription opioid market into the foreseeable future is likely.
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From page 223... ...
If the average dose per day for NSDUH respondents equals the DDDs underpinning the 39,487 DDDs per million figure, then dividing that 1 billion by the 4.6 billion DDDs posited above, one might speculate that very roughly 20 to 25 percent of prescription opioids in the United States are used nonmedically.
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From page 224... ...
.8 It is worth noting as well that some people who had acquired the drugs most recently by some relatively innocuous means may also have purchased them or obtained them by fraud at other times. Respondents who reported use within the past 30 days account for the majority of days of use, and the NSDUH asks respondents to "Please enter all of the ways that you got the prescription pain relievers you used in the past 30 days." In 2014, fully 39 percent of those individuals reporting days of use indicated that they had bought the drugs at some point in the past month, from a dealer, friend or relative, or the Internet.
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more comprehensive estimate, drawing on the Arrestee Drug Abuse Monitoring (ADAM) system, among other sources, puts the figure closer to 1,000,000.
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Department of Health and Human Services, state agencies, and other stakeholders consider the potential effects of these interventions on illicit markets -- including both the diversion of prescription opioids from lawful sources and the effect of increased demand for illegal opioids such as heroin among users of prescription opioids -- and take appropriate steps to mitigate those effects (Recommendation 4-1)
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was a public health surveillance system created in 1972 that monitored drug-related hospital emergency department visits (DAWN-ED) in order to report on the impact of drug use in metropolitan areas and nationally.
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In retrospect, the product-level detail in DAWN could have informed decision makers across institutions of the nature and challenge of the prescription opioid and illicit drug crises. In researching the reasons for the defunding of DAWN, the committee learned of several factors, including frustrations with the sampling frame, incompleteness of data, concerns among industry about the product-level data, cost, and the lack of representation of small-town and suburban communities.
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From page 229... ...
The timing of these data losses exacerbated the inability to detect changes in misuse and mortality driven by prescription opioids, and it continues to hinder the nation's capacity to track illicit drug trends and their public health consequences. Cost-effective and nimble data collection systems may be reliable and even timely, but need to be examined rigorously for validity.
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From page 230... ...
Centers for Disease Control and Prevention invest in data collection and research relating to population-level opioid use patterns and consequences, especially nonmedical use of prescription opioids and use of illicit opioids, such as heroin and illicitly manufactured fentanyl (Recommendation 4-3)
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From page 231... ...
depression; abuse induces withdrawal if abstinence, during liability the drug is injected; which withdrawal, for Subutex and relapse, and early Suboxone, withdrawal dropout may occur; in patients dependent overdose fatality due to on methadone self-discontinuation and or short-acting hypersensitized μ opioid prescription opioids receptors * Subutex (a single-agent buprenorphine product)
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, in which a randomized controlled trial examined buprenorphinenaloxone treatment of varying durations and counseling of varying intensities among patients dependent on prescription opioids. It was found that patients receiving individual counseling for OUD in conjunction with the medication (weekly 45- to 60-minute sessions with a trained mental health or substance abuse professional)
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From page 233... ...
Instistence on provision of counseling is an important factor in access to buprenorphine. According to state regulations and accrediting standards, opioid treatment programs are required to provide a minimum of counseling services each month.
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. Methadone is a full opioid agonist that was invented in Germany in the late 1930s for use during World War II as a cheaper and easier-to-manufacture analgesic alternative to the opioids available at the time (Strang and Tober, 2003)
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From page 235... ...
, in pill form and as sublingual film, and in varying flavors. A systematic review of 16 randomized controlled trials on the efficacy of buprenorphine found that it is associated with improved outcomes compared with placebo for individuals and pregnant women with OUD (Thomas et al., 2014)
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Importantly, DATA 2000 did not require prescribers with a waiver to prescribe buprenorphine for OUD to provide other treatment services (i.e., counseling, group therapy) as well.
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From page 237... ...
. How this gap impacts special populations such as pregnant women is unknown, but anecdotally, FIGURE 4-9 Number of opioid treatment programs certified by the Substance Abuse and Mental Health Services Administration (SAMHSA)
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(See the section below on pharmacotherapies for treatment of pregnant women with OUD.) In addition, significant disparities in the use of buprenorphine have been documented.
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From page 239... ...
. A systematic review and meta-analysis identified six randomized clinical trials of SIH and concluded that among patients with OUD involving heroin, those receiving SIH compared with control groups (most often receiving methadone maintenance treatment)
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From page 240... ...
One of NIDA's first endeavors was to fund a number of research demonstration projects in 1974 implementing treatment programs for pregnant women with OUD. This research provided the foundation for the model of care that emerged in the 1980s.
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, it is estimated that no more than 12 programs provide specialized treatment for pregnant women. Moreover, treatment for pregnant women often is fragmented and may be impeded when collaboration is lacking among the opioid treatment facility, obstetrician, pediatrician, and hospital.
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There are 14 institutions in the United States conducting pain management ECHOs. See http:// echo.unm.edu for more information.
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From page 243... ...
A long history of concern regarding withdrawal during pregnancy also merits consideration. Adverse fetal events that occurred in the 1970s as a result of withdrawing pregnant women from methadone led to recommendations that withdrawal be initiated only in the second trimester because of safety concerns, such as fetal demise in the first trimester of pregnancy and prematurity in the third trimester.
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Pregnant women referred to treatment by the criminal justice system were the least likely to receive MAT, especially in states with prenatal child abuse laws (Angelotta et al., 2016)
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As of 2014, 136 opioid overdose prevention and response programs collectively managed 644 naloxone distribution sites throughout the United States, distributing naloxone kits to 152,283 lay
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. Increasing the availability of n aloxone, therefore, is a central component of population-level efforts to prevent opioid overdose deaths, as illustrated by the U.S.
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In the face of unprecedented numbers of opioid overdoses and the infiltration of fentanyl into the illicit drug supply, the FDA and other federal agencies would be well advised to take steps to ensure that organizations and institutions with privileged access to those with high overdose risk have free (or lowest-cost) naloxone so as to maximize the reach and sustainability of their efforts.
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From page 248... ...
The downstream effects and societal impact of these intertwined epidemics require consideration by the FDA and other agencies with authority to affect the flow of prescription opioid medications and illicit opioids before, during, and after the introduction of new, similar opioid products into the marketplace. Important research gaps exists in such areas as surveillance; ethnographic studies of drug use behaviors; epidemiologic studies of exposure, natural histories describing transitions in routes of administration and use, and risk of new illicitly manufactureed synthetic opioids; evolving OUD treatment trajectories; changes in opioid markets; and measurement of the impact of use of opioids, particularly heroin and illicit fentanyl, on society and the economy.
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From page 249... ...
The National Institute on Drug Abuse and the U.S. Centers for Disease Control and Prevention should invest in data col lection and research relating to population-level opioid use patterns and consequences, especially nonmedical use of prescription opioids and use of illicit opioids, such as heroin and illicitly manufactured fentanyl.
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From page 250... ...
2016. A detailed exploration into the association of prescribed opioid dosage and prescription opioid overdose deaths among patients with chronic pain.
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From page 251... ...
2016c. Prescription opioid overdose data.
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From page 252... ...
2008. Rela tive abuse liability of prescription opioids compared to heroin in morphine-maintained heroin abusers.
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From page 253... ...
2013. Crowdsourcing black market prices for prescription opioids.
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From page 254... ...
2016. FDA requires strong warnings for opioid analgesics, prescription opioid cough products, and benzodiazepine labeling related to serious risks and death from combined use.
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From page 255... ...
2015. Prescription opioid use and misuse among older adult Rhode Island hospital emergency department patients.
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From page 256... ...
2013a. Heroin use and heroin use risk behaviors among nonmedical users of prescription opioid pain relievers -- United States, 2002–2004 and 2008–2010.
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From page 257... ...
2015. The prescription opioid and heroin crisis: A public health approach to an epidemic of addiction.
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From page 258... ...
2015. Injection and sexual HIV/ HCV risk behaviors associated with nonmedical use of prescription opioids among young adults in New York City.
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From page 259... ...
2017. Opioid agonist treatment for patients with dependence on prescription opioids.
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From page 260... ...
2009. A comparison of drug overdose deaths involving methadone and other opioid analgesics in West Virginia.
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From page 261... ...
2016a. Increases in drug and opioid overdose deaths -- United States, 2000–2014.
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From page 262... ...
2008. Predicting length of treatment for neonatal abstinence syndrome in methadone exposed infants.
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From page 263... ...
2017. Associa tion between concurrent use of prescription opioids and benzodiazepines and overdose: Retrospective analysis.
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From page 264... ...
2015. Trends in abuse and misuse of prescription opioids among older adults.
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2015. Defining risk of prescription opioid overdose: Pharmacy shopping and overlap ping prescriptions among long-term opioid users in Medicaid.
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