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      Sex and Gender Differences in the Effects of Novel Psychoactive Substances

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          Sex and gender deeply affect the subjective effects and pharmaco-toxicological responses to drugs. Men are more likely than women to use almost all types of illicit drugs and to present to emergency departments for serious or fatal intoxications. However, women are just as likely as men to develop substance use disorders, and may be more susceptible to craving and relapse. Clinical and preclinical studies have shown important differences between males and females after administration of “classic” drugs of abuse (e.g., Δ9-tetrahydrocannabinol (THC), morphine, cocaine). This scenario has become enormously complicated in the last decade with the overbearing appearance of the new psychoactive substances (NPS) that have emerged as alternatives to regulated drugs. To date, more than 900 NPS have been identified, and can be catalogued in different pharmacological categories including synthetic cannabinoids, synthetic stimulants (cathinones and amphetamine-like), hallucinogenic phenethylamines, synthetic opioids (fentanyls and non-fentanyls), new benzodiazepines and dissociative anesthetics (i.e., methoxetamine and phencyclidine-derivatives). This work collects the little knowledge reached so far on the effects of NPS in male and female animal and human subjects, highlighting how much sex and gender differences in the effects of NPS has yet to be studied and understood.

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          Drug and Opioid-Involved Overdose Deaths — United States, 2017–2018

          Of the 70,237 drug overdose deaths in the United States in 2017, approximately two thirds (47,600) involved an opioid ( 1 ). In recent years, increases in opioid-involved overdose deaths have been driven primarily by deaths involving synthetic opioids other than methadone (hereafter referred to as synthetic opioids) ( 1 ). CDC analyzed changes in age-adjusted death rates from 2017 to 2018 involving all opioids and opioid subcategories* by demographic characteristics, county urbanization levels, U.S. Census region, and state. During 2018, a total of 67,367 drug overdose deaths occurred in the United States, a 4.1% decline from 2017; 46,802 (69.5%) involved an opioid ( 2 ). From 2017 to 2018, deaths involving all opioids, prescription opioids, and heroin decreased 2%, 13.5%, and 4.1%, respectively. However, deaths involving synthetic opioids increased 10%, likely driven by illicitly manufactured fentanyl (IMF), including fentanyl analogs ( 1 , 3 ). Efforts related to all opioids, particularly deaths involving synthetic opioids, should be strengthened to sustain and accelerate declines in opioid-involved deaths. Comprehensive surveillance and prevention measures are critical to reducing opioid-involved deaths, including continued surveillance of evolving drug use and overdose, polysubstance use, and the changing illicit drug market; naloxone distribution and outreach to groups at risk for IMF exposure; linkage to evidence-based treatment for persons with substance use disorders; and continued partnerships with public safety. Drug overdose deaths were identified in National Vital Statistics System multiple cause-of-death mortality files † using the International Classification of Diseases, Tenth Revision (ICD-10) underlying cause-of-death codes X40–X44 (unintentional), X60–X64 (suicide), X85 (homicide), or Y10–Y14 (undetermined intent). Among deaths with drug overdose as the underlying cause, the opioid subcategory was determined by the following ICD-10 multiple cause-of-death codes: all opioids (T40.0, T40.1, T40.2, T40.3, T40.4, or T40.6) § ; prescription opioids (T40.2 or T40.3); heroin (T40.1); and synthetic opioids other than methadone (T40.4). Some deaths involved more than one opioid subcategory and were included in the rates for each; subcategories are not mutually exclusive. ¶ Changes from 2017 to 2018 in age-adjusted overdose death rates** were examined for all opioids, prescription opioids, heroin, and synthetic opioids. Death rates were stratified by age, sex, race/ethnicity, urbanization level, †† U.S. Census region, §§ and state. State-level analyses included 38 states and the District of Columbia (DC) with adequate drug specificity ¶¶ for 2017 and 2018.*** The drug or drugs involved in the drug overdose death were not specified on 12% of drug overdose death certificates in 2017 and on 8% of those from 2018. The percentage of 2018 death certificates with at least one drug specified ranged from 54.1% to 100% among states. Changes in death rates from 2017 to 2018 were compared using z-tests when deaths were ≥100 and nonoverlapping confidence intervals based on a gamma distribution when <100. ††† Changes presented in the text represent statistically significant findings, unless otherwise specified. During 2018, drug overdoses resulted in 67,367 deaths in the United States, a 4.1% decrease from 2017. Among these drug overdose deaths, 46,802 (69.5%) involved an opioid. From 2017 to 2018, opioid-involved death rates decreased 2.0%, from 14.9 per 100,000 population to 14.6 (Table 1); decreases occurred among females; persons aged 15–34 years and 45–54 years; non-Hispanic whites; and in small metro, micropolitan, and noncore areas; and in the Midwest and South regions. Rates during 2017–2018 increased among persons aged ≥65 years, non-Hispanic blacks, and Hispanics, and in the Northeast and the West regions. Rates decreased in 11 states and DC and increased in three states, with the largest relative (percentage) decrease in Iowa (–30.4%) and the largest absolute decrease (difference in rates) in Ohio (–9.6); the largest relative and absolute increase occurred in Missouri (18.8%, 3.1). The highest opioid-involved death rate in 2018 was in West Virginia (42.4 per 100,000). TABLE 1 Annual number and age-adjusted rate of drug overdose deaths* involving all opioids † and prescription opioids, § , ¶ by sex, age, race/ethnicity,** urbanization level, †† U.S. Census region, §§ and selected states ¶¶ — National Vital Statistics System, United States, 2017 and 2018 Decedent characteristic All opioids Prescription opioids 2017 2018 Rate change from 2017 to 2018*** 2017 2018 Rate change from 2017 to 2018*** No. (rate) No. (rate) Absolute change Relative change No. (rate) No. (rate) Absolute change Relative change All 47,600 (14.9) 46,802 (14.6) −0.3††† −2.0††† 17,029 (5.2) 14,975 (4.5) −0.7††† −13.5††† Sex Male 32,337 (20.4) 32,078 (20.1) −0.3 −1.5 9,873 (6.1) 8,723 (5.3) −0.8 ††† −13.1 ††† Female 15,263 (9.4) 14,724 (9.0) −0.4 ††† −4.3 ††† 7,156 (4.2) 6,252 (3.7) −0.5 ††† −11.9 ††† Age group (yrs) 0–14 79 (0.1) 65 (0.1) 0.0 0.0 50 (0.1) 36 (0.1) 0.0 0.0 15–24 4,094 (9.5) 3,618 (8.4) −1.1 ††† −11.6 ††† 1,050 (2.4) 790 (1.8) −0.6 ††† −25.0 ††† 25–34 13,181 (29.1) 12,839 (28.1) −1.0 ††† −3.4 ††† 3,408 (7.5) 2,862 (6.3) −1.2 ††† −16.0 ††† 35–44 11,149 (27.3) 11,414 (27.7) 0.4 1.5 3,714 (9.1) 3,350 (8.1) −1.0 ††† −11.0 ††† 45–54 10,207 (24.1) 9,565 (23.0) −1.1 ††† −4.6 ††† 4,238 (10.0) 3,490 (8.4) −1.6 ††† −16.0 ††† 55–64 7,153 (17.0) 7,278 (17.2) 0.2 1.2 3,509 (8.4) 3,291 (7.8) −0.6 ††† −7.1 ††† ≥65 1,724 (3.4) 2,012 (3.8) 0.4 ††† 11.8 ††† 1,055 (2.1) 1,152 (2.2) 0.1 4.8 Sex and age group (yrs) Male 15–24 2,885 (13.0) 2,527 (11.5) −1.5 ††† −11.5 ††† 728 (3.3) 548 (2.5) −0.8 ††† −24.2 ††† Male 25–44 17,352 (40.0) 17,240 (39.4) −0.6 −1.5 4,516 (10.4) 3,895 (8.9) −1.5 ††† −14.4 ††† Male 45–64 11,061 (26.9) 10,986 (26.8) −0.1 −0.4 4,089 (9.9) 3,637 (8.9) −1.0 ††† −10.1 ††† Female 15–24 1,209 (5.7) 1,091 (5.2) −0.5 ††† −8.8 ††† 322 (1.5) 242 (1.2) −0.3 ††† −20.0 ††† Female 25–44 6,978 (16.3) 7,013 (16.2) −0.1 −0.6 2,606 (6.1) 2,317 (5.4) −0.7 ††† −11.5 ††† Female 45–64 6,299 (14.6) 5,857 (13.6) −1.0 ††† −6.8 ††† 3,658 (8.5) 3,144 (7.3) −1.2 ††† −14.1 ††† Race/Ethnicity** White, non-Hispanic 37,113 (19.4) 35,363 (18.6) −0.8 ††† −4.1 ††† 13,900 (6.9) 12,085 (6.0) −0.9 ††† −13.0 ††† Black, non-Hispanic 5,513 (12.9) 6,088 (14.0) 1.1 ††† 8.5 ††† 1,508 (3.5) 1,444 (3.3) −0.2 −5.7 Hispanic 3,932 (6.8) 4,370 (7.5) 0.7 ††† 10.3 ††† 1,211 (2.2) 1,122 (2.0) −0.2 ††† −9.1 ††† American Indian/Alaska Native, non-Hispanic 408 (15.7) 373 (14.2) −1.5 −9.6 187 (7.2) 125 (4.7) −2.5 ††† −34.7 ††† Asian/Pacific Islander, non-Hispanic 348 (1.6) 345 (1.5) −0.1 −6.3 130 (0.6) 115 (0.5) −0.1 −16.7 County urbanization level†† Large central metro 14,518 (13.9) 14,767 (14.1) 0.2 1.4 4,945 (4.7) 4,394 (4.1) −0.6 ††† −12.8 ††† Large fringe metro 13,594 (17.2) 13,476 (17.0) −0.2 −1.2 4,273 (5.2) 3,791 (4.6) −0.6 ††† −11.5 ††† Medium metro 10,561 (16.2) 10,328 (15.8) −0.4 −2.5 3,951 (5.9) 3,539 (5.2) −0.7 ††† −11.9 ††† Small metro 3,560 (12.9) 3,379 (12.2) −0.7 ††† −5.4 ††† 1,479 (5.2) 1,278 (4.5) −0.7 ††† −13.5 ††† Micropolitan (nonmetro) 3,462 (13.9) 3,162 (12.7) −1.2 ††† −8.6 ††† 1,440 (5.6) 1,240 (4.7) −0.9 ††† −16.1 ††† Noncore (nonmetro) 1,905 (11.2) 1,690 (10.1) −1.1 ††† −9.8 ††† 941 (5.3) 733 (4.1) −1.2 ††† −22.6 ††† U.S. Census region of residence§§ Northeast 11,784 (21.3) 12,467 (22.8) 1.5 ††† 7.0 ††† 3,047 (5.3) 2,991 (5.3) 0.0 0.0 Midwest 12,483 (19.1) 11,268 (17.2) −1.9 ††† −9.9 ††† 3,702 (5.5) 2,965 (4.4) −1.1 ††† −20.0 ††† South 16,999 (14.1) 16,413 (13.5) −0.6 ††† −4.3 ††† 6,929 (5.6) 5,936 (4.7) −0.9 ††† −16.1 ††† West 6,334 (8.0) 6,654 (8.3) 0.3 ††† 3.8 ††† 3,351 (4.1) 3,083 (3.8) −0.3 ††† −7.3 ††† States with very good to excellent reporting (n = 29)¶¶ Alaska 102 (13.9) 68 (8.8) −5.1 −36.7 51 (7.0) 38 (4.9) −2.1 −30.0 Arizona 928 (13.5) 1,106 (15.9) 2.4 ††† 17.8 ††† 414 (5.9) 362 (5.0) −0.9 ††† −15.3 ††† Connecticut 955 (27.7) 948 (27.5) −0.2 −0.7 273 (7.7) 231 (6.4) −1.3 −16.9 District of Columbia 244 (34.7) 191 (26.7) −8.0 ††† −23.1 ††† 58 (8.4) 41 (5.7) −2.7 −32.1 Georgia 1,014 (9.7) 866 (8.3) −1.4 ††† −14.4 ††† 568 (5.4) 440 (4.1) −1.3 ††† −24.1 ††† Illinois 2,202 (17.2) 2,169 (17.0) −0.2 −1.2 623 (4.8) 539 (4.2) −0.6 ††† −12.5 ††† Iowa 206 (6.9) 143 (4.8) −2.1 ††† −30.4 ††† 104 (3.4) 64 (2.1) −1.3 ††† −38.2 ††† Maine 360 (29.9) 282 (23.4) −6.5 ††† −21.7 ††† 100 (7.6) 69 (5.1) −2.5 −32.9 Maryland 1,985 (32.2) 2,087 (33.7) 1.5 4.7 711 (11.5) 576 (9.2) −2.3 ††† −20.0 ††† Massachusetts 1,913 (28.2) 1,991 (29.3) 1.1 3.9 321 (4.6) 331 (4.7) 0.1 2.2 Missouri 952 (16.5) 1,132 (19.6) 3.1 ††† 18.8 ††† 253 (4.1) 265 (4.4) 0.3 7.3 Nevada 412 (13.3) 372 (11.5) −1.8 −13.5 276 (8.7) 235 (7.2) −1.5 ††† −17.2 ††† New Hampshire 424 (34.0) 412 (33.1) −0.9 −2.6 62 (4.8) 43 (3.1) −1.7 −35.4 New Mexico 332 (16.7) 338 (16.7) 0.0 0.0 171 (8.5) 176 (8.2) −0.3 −3.5 New York 3,224 (16.1) 2,991 (15.1) −1.0 ††† −6.2 ††† 1,044 (5.1) 998 (4.9) −0.2 −3.9 North Carolina 1,953 (19.8) 1,783 (17.9) −1.9 ††† −9.6 ††† 659 (6.5) 489 (4.7) −1.8 ††† −27.7 ††† Ohio 4,293 (39.2) 3,237 (29.6) −9.6 ††† −24.5 ††† 947 (8.4) 571 (5.0) −3.4 ††† −40.5 ††† Oklahoma 388 (10.2) 308 (7.8) −2.4 ††† −23.5 ††† 251 (6.7 172 (4.3) −2.4 ††† −35.8 ††† Oregon 344 (8.1) 339 (8.0) −0.1 −1.2 154 (3.5) 151 (3.4) −0.1 −2.9 Rhode Island 277 (26.9) 267 (25.9) −1.0 −3.7 99 (8.8) 85 (7.7) −1.1 −12.5 South Carolina 749 (15.5) 835 (17.1) 1.6 10.3 345 (7.1) 375 (7.4) 0.3 4.2 Tennessee 1,269 (19.3) 1,307 (19.9) 0.6 3.1 644 (9.6) 550 (8.2) −1.4 ††† −14.6 ††† Utah 456 (15.5) 437 (14.8) −0.7 −4.5 315 (10.8) 306 (10.5) −0.3 −2.8 Vermont 114 (20.0) 127 (22.8) 2.8 14.0 40 (6.3) 27 (4.4) −1.9 −30.2 Virginia 1,241 (14.8) 1,193 (14.3) −0.5 −3.4 404 (4.7) 326 (3.8) −0.9 ††† −19.1 ††† Washington 742 (9.6) 737 (9.4) −0.2 −2.1 343 (4.3) 301 (3.8) −0.5 −11.6 West Virginia 833 (49.6) 702 (42.4) −7.2 ††† −14.5 ††† 304 (17.2) 234 (13.1) −4.1 ††† −23.8 ††† Wisconsin 926 (16.9) 846 (15.3) −1.6 ††† −9.5 ††† 362 (6.4) 301 (5.3) −1.1 ††† −17.2 ††† Wyoming 47 (8.7) 40 (6.8) −1.9 −21.8 31 (6.0) 28 (4.6) −1.4 −23.3 States with good reporting (n = 10)¶¶ California 2,199 (5.3) 2,410 (5.8) 0.5 ††† 9.4 ††† 1,169 (2.8) 1,084 (2.6) −0.2 −7.1 Colorado 578 (10.0) 564 (9.5) −0.5 −5.0 300 (5.1) 268 (4.4) −0.7 −13.7 Florida 3,245 (16.3) 3,189 (15.8) −0.5 −3.1 1,272 (6.0) 1,282 (6.0) 0.0 0.0 Hawaii 53 (3.4) 59 (4.1) 0.7 20.6 40 (2.5) 33 (2.3) −0.2 −8.0 Indiana 1,176 (18.8) 1,104 (17.5) −1.3 −6.9 425 (6.6) 370 (5.6) −1.0 ††† −15.2 ††† Kentucky 1,160 (27.9) 989 (23.4) −4.5 ††† −16.1 ††† 433 (10.2) 315 (7.2) −3.0 ††† −29.4 ††† Michigan 2,033 (21.2) 2,011 (20.8) −0.4 −1.9 633 (6.5) 556 (5.6) −0.9 ††† −13.8 ††† Minnesota 422 (7.8) 343 (6.3) −1.5 ††† −19.2 ††† 195 (3.6) 136 (2.5) −1.1 ††† −30.6 ††† Mississippi 185 (6.4) 173 (6.1) −0.3 −4.7 96 (3.2) 92 (3.1) −0.1 −3.1 Texas 1,458 (5.1) 1,402 (4.8) −0.3 −5.9 646 (2.3) 547 (1.9) −0.4 −17.4 * Deaths were classified using the International Classification of Diseases, Tenth Revision (ICD–10). Drug overdose deaths were identified using underlying cause-of-death codes X40–X44, X60–X64, X85, and Y10–Y14. Rates are age-adjusted using the direct method and the 2000 U.S. standard population, except for age-specific crude rates. All rates are per 100,000 population. † Drug overdose deaths, as defined, that have opium (T40.0), heroin (T40.1), natural and semisynthetic opioids (T40.2), methadone (T40.3), synthetic opioids other than methadone (T40.4) or other and unspecified narcotics (T40.6) as a contributing cause. § Drug overdose deaths, as defined, that have natural and semisynthetic opioids (T40.2) or methadone (T40.3) as a contributing cause. ¶ Categories of deaths are not exclusive as deaths might involve more than one drug category. Summing of categories will result in more than the total number of deaths in a year. ** Data for Hispanic origin should be interpreted with caution; studies comparing Hispanic origin on death certificates and on Census surveys have shown inconsistent reporting on Hispanic ethnicity. Potential race misclassification might lead to underestimates for certain categories, primarily American Indian/Alaska Native non-Hispanic and Asian/Pacific Islander non-Hispanic decedents. https://www.cdc.gov/nchs/data/series/sr_02/sr02_172.pdf. †† By the 2013 National Center for Health Statistics Urban-Rural Classification Scheme for Counties. https://www.cdc.gov/nchs/data_access/urban_rural.htm. §§ Northeast: Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, and Vermont. Midwest: Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, Ohio, South Dakota, and Wisconsin. South: Alabama, Arkansas, Delaware, District of Columbia, Florida, Georgia, Kentucky, Louisiana, Maryland, Mississippi, North Carolina, Oklahoma, South Carolina, Tennessee, Texas, Virginia, and West Virginia. West: Alaska, Arizona, California, Colorado, Hawaii, Idaho, Montana, Nevada, New Mexico, Oregon, Utah, Washington, and Wyoming. ¶¶ Analyses were limited to states meeting the following criteria. States with very good to excellent reporting had ≥90% of drug overdose deaths mention at least one specific drug in 2017, with the change in drug overdose deaths mentioning of at least one specific drug differing by <10 percentage points from 2017 to 2018. States with good reporting had 80% to <90% of drug overdose deaths mention at least one specific drug in 2017, with the change in the percentage of drug overdose deaths mentioning at least one specific drug differing by <10 percentage points from 2017 to 2018. States included also were required to have stable rate estimates (i.e., based on ≥20 deaths in at least two of the following drug categories: opioids, prescription opioids, synthetic opioids other than methadone, and heroin). *** Absolute rate change is the difference between 2017 and 2018 rates. Relative rate change is the absolute rate change divided by the 2017 rate, multiplied by 100. Nonoverlapping confidence intervals based on the gamma method were used if the number of deaths was <100 in 2017 or 2018, and z-tests were used if the number of deaths was ≥100 in both 2017 and 2018. ††† Statistically significant (p-value <0.05). Prescription opioid-involved death rates decreased by 13.5% from 2017 to 2018. Rates decreased in males and females, persons aged 15–64 years, non-Hispanic whites, Hispanics, non-Hispanic American Indian/Alaska Natives, and across all urbanization levels. Prescription opioid–involved death rates remained stable in the Northeast and decreased in the Midwest, South, and the West. Seventeen states experienced declines in prescription opioid–involved death rates, with no states experiencing significant increases. The largest relative decrease occurred in Ohio (–40.5%), whereas the largest absolute decrease occurred in West Virginia (–4.1), which also had the highest prescription opioid-involved death rate in 2018 (13.1 per 100,000). Heroin-involved death rates decreased 4.1% from 2017 to 2018; reductions occurred among males and females, persons aged 15–34 years, non-Hispanic whites, and in large central metro and large fringe metro areas (Table 2). Rates decreased in the Midwest and increased in the West. Rates decreased in seven states and DC and increased in three states from 2017 to 2018. The largest relative decrease occurred in Kentucky (50.0%), and the largest absolute decrease occurred in DC (–7.1); the largest relative and absolute increase was in Tennessee (18.8%, 0.9). The highest heroin-involved death rate in 2018 was in Vermont (12.5 per 100,000). TABLE 2 Annual number and age-adjusted rate of drug overdose deaths* involving heroin † and synthetic opioids other than methadone, § , ¶ by sex, age, race/ethnicity,** urbanization level, †† U.S. Census region, §§ and selected states ¶¶ — National Vital Statistics System, United States, 2017 and 2018 Decedent characteristic Heroin Synthetic opioids other than methadone 2017 2018 Rate change from 2017 to 2018*** 2017 2018 Rate change from 2017 to 2018*** No. (rate) No. (rate) Absolute change Relative change No. (rate) No. (rate) Absolute change Relative change All 15,482 (4.9) 14,996 (4.7) −0.2††† −4.1††† 28,466 (9.0) 31,335 (9.9) 0.9††† 10.0††† Sex Male 11,596 (7.3) 11,291 (7.1) −0.2 ††† −2.7 ††† 20,524 (13.0) 22,528 (14.2) 1.2 ††† 9.2 ††† Female 3,886 (2.5) 3,705 (2.3) −0.2 ††† −8.0 ††† 7,942 (5.0) 8,807 (5.5) 0.5 ††† 10.0 ††† Age group (yrs) 0–14 —§§§ —§§§ —§§§ —§§§ 33 (0.1) 29 (0.1) 0.0 0.0 15–24 1,454 (3.4) 1,160 (2.7) −0.7 ††† −20.6 ††† 2,655 (6.1) 2,640 (6.1) 0.0 0.0 25–34 4,890 (10.8) 4,642 (10.2) −0.6 ††† −5.6 ††† 8,825 (19.5) 9,568 (20.9) 1.4 ††† 7.2 ††† 35–44 3,713 (9.1) 3,740 (9.1) 0.0 0.0 7,084 (17.3) 8,070 (19.6) 2.3 ††† 13.3 ††† 45–54 3,043 (7.2) 2,922 (7.0) −0.2 −2.8 5,762 (13.6) 6,132 (14.7) 1.1 ††† 8.1 ††† 55–64 2,005 (4.8) 2,077 (4.9) 0.1 2.1 3,481 (8.3) 4,018 (9.5) 1.2 ††† 14.5 ††† ≥65 368 (0.7) 445 (0.8) 0.1 14.3 620 (1.2) 871 (1.7) 0.5 ††† 41.7 ††† Sex and age group (yrs) Male 15–24 1,031 (4.7) 821 (3.7) −1.0 ††† −21.3 ††† 1,877 (8.5) 1,841 (8.4) −0.1 −1.2 Male 25–44 6,428 (14.8) 6,305 (14.4) −0.4 −2.7 11,693 (27.0) 12,810 (29.2) 2.2 ††† 8.1 ††† Male 45–64 3,830 (9.3) 3,778 (9.2) −0.1 −1.1 6,524 (15.8) 7,195 (17.6) 1.8 ††† 11.4 ††† Female 15–24 423 (2.0) 339 (1.6) −0.4 ††† −20.0 ††† 778 (3.7) 799 (3.8) 0.1 2.7 Female 25–44 2,175 (5.1) 2,077 (4.8) −0.3 −5.9 4,216 (9.8) 4,828 (11.2) 1.4 ††† 14.3 ††† Female 45–64 1,218 (2.8) 1,221 (2.8) 0.0 0.0 2,719 (6.3) 2,955 (6.9) 0.6 ††† 9.5 ††† Race/Ethnicity** White, non-Hispanic 11,293 (6.1) 10,756 (5.8) −0.3 ††† −4.9 ††† 21,956 (11.9) 23,214 (12.6) 0.7 ††† 5.9 ††† Black, non-Hispanic 2,140 (4.9) 2,145 (4.9) 0.0 0.0 3,832 (9.0) 4,780 (11.0) 2.0 ††† 22.2 ††† Hispanic 1,669 (2.9) 1,768 (3.1) 0.2 6.9 2,152 (3.7) 2,766 (4.7) 1.0 ††† 27.0 ††† American Indian/Alaska Native, non-Hispanic 136 (5.2) 133 (5.1) −0.1 −1.9 171 (6.5) 191 (7.3) 0.8 12.3 Asian/Pacific Islander, non-Hispanic 119 (0.5) 85 (0.4) −0.1 −20.0 189 (0.8) 214 (1.0) 0.2 ††† 25.0 ††† County urbanization level†† Large central metro 5,820 (5.6) 5,467 (5.2) −0.4 ††† −7.1 ††† 8,511 (8.2) 9,804 (9.4) 1.2 ††† 14.6 ††† Large fringe metro 4,526 (5.8) 4,321 (5.5) −0.3 ††† −5.2 ††† 8,991 (11.6) 9,871 (12.7) 1.1 ††† 9.5 ††† Medium metro 2,973 (4.6) 3,091 (4.8) 0.2 4.3 6,254 (9.8) 6,750 (10.5) 0.7 ††† 7.1 ††† Small metro 972 (3.6) 949 (3.5) −0.1 −2.8 1,878 (7.0) 2,050 (7.6) 0.6 ††† 8.6 ††† Micropolitan (nonmetro) 801 (3.3) 780 (3.3) 0.0 0.0 1,860 (7.7) 1,925 (8.0) 0.3 3.9 Noncore (nonmetro) 390 (2.4) 388 (2.4) 0.0 0.0 972 (6.0) 935 (5.8) −0.2 −3.3 U.S. Census region of residence§§ Northeast 4,310 (7.8) 4,363 (8.0) 0.2 2.6 8,861 (16.2) 10,351 (19.1) 2.9 ††† 17.9 ††† Midwest 4,228 (6.5) 3,575 (5.5) −1.0 ††† −15.4 ††† 8,234 (12.8) 8,348 (12.9) 0.1 0.8 South 4,776 (4.0) 4,718 (3.9) −0.1 −2.5 9,906 (8.3) 10,443 (8.6) 0.3 ††† 3.6 ††† West 2,168 (2.8) 2,340 (3.0) 0.2 ††† 7.1 ††† 1,465 (1.9) 2,193 (2.8) 0.9 ††† 47.4 ††† States with very good to excellent reporting (n = 29)¶¶ Alaska 36 (4.9) 29 (3.8) −1.1 −22.4 37 (4.9) 18 –§§§ –§§§ –§§§ Arizona 334 (5.0) 352 (5.2) 0.2 4.0 267 (4.0) 522 (7.7) 3.7 ††† 92.5 ††† Connecticut 425 (12.4) 338 (9.9) −2.5 ††† −20.2 ††† 686 (20.3) 767 (22.5) 2.2 10.8 District of Columbia 127 (18) 79 (10.9) −7.1 ††† −39.4 ††† 182 (25.7) 162 (22.6) −3.1 −12.1 Georgia 263 (2.6) 299 (2.9) 0.3 11.5 419 (4.1) 349 (3.4) −0.7 ††† −17.1 ††† Illinois 1,187 (9.2) 1,050 (8.3) −0.9 ††† −9.8 ††† 1,251 (9.8) 1,568 (12.4) 2.6 ††† 26.5 ††† Iowa 61 (2.1) 37 (1.3) −0.8 −38.1 92 (3.2) 80 (2.8) −0.4 −12.5 Maine 76 (6.2) 71 (6.0) −0.2 −3.2 278 (23.5) 229 (19.8) −3.7 −15.7 Maryland 522 (8.6) 356 (5.9) −2.7 ††† −31.4 ††† 1,542 (25.2) 1,825 (29.6) 4.4 ††† 17.5 ††† Massachusetts 466 (7.0) 475 (7.0) 0.0 0.0 1,649 (24.5) 1,806 (26.8) 2.3 ††† 9.4 ††† Missouri 299 (5.3) 351 (6.1) 0.8 15.1 618 (10.9) 868 (15.3) 4.4 ††† 40.4 ††† Nevada 94 (3.1) 108 (3.5) 0.4 12.9 66 (2.2) 85 (2.8) 0.6 27.3 New Hampshire 28 (2.4) 12 –§§§ –§§§ –§§§ 374 (30.4) 386 (31.3) 0.9 3.0 New Mexico 144 (7.4) 130 (6.6) −0.8 −10.8 75 (3.7) 105 (5.4) 1.7 45.9 New York 1,356 (6.8) 1,243 (6.3) −0.5 −7.4 2,238 (11.3) 2,195 (11.2) −0.1 −0.9 North Carolina 537 (5.6) 619 (6.3) 0.7 12.5 1,285 (13.2) 1,272 (13.0) −0.2 −1.5 Ohio 1,000 (9.2) 721 (6.6) −2.6 ††† −28.3 ††† 3,523 (32.4) 2,783 (25.7) −6.7 ††† −20.7 ††† Oklahoma 61 (1.6) 84 (2.2) 0.6 37.5 102 (2.6) 79 (2.0) −0.6 −23.1 Oregon 124 (3.0) 154 (3.7) 0.7 23.3 85 (2.1) 97 (2.4) 0.3 14.3 Rhode Island 14—§§§ 24 (2.2) –§§§ –§§§ 201 (20.1) 213 (21.0) 0.9 4.5 South Carolina 153 (3.2) 183 (3.8) 0.6 18.8 404 (8.5) 510 (10.8) 2.3 ††† 27.1 ††† Tennessee 311 (4.8) 369 (5.7) 0.9 ††† 18.8 ††† 590 (9.3) 827 (12.8) 3.5 ††† 37.6 ††† Utah 147 (4.8) 156 (5.1) 0.3 6.3 92 (3.1) 83 (2.9) −0.2 −6.5 Vermont 41 (7.3) 68 (12.5) 5.2 71.2 77 (13.8) 106 (19.3) 5.5 39.9 Virginia 556 (6.7) 532 (6.4) −0.3 −4.5 829 (10.0) 852 (10.3) 0.3 3.0 Washington 306 (4.0) 328 (4.2) 0.2 5.0 143 (1.9) 221 (2.9) 1.0 ††† 52.6 ††† West Virginia 244 (14.9) 195 (12.3) −2.6 −17.4 618 (37.4) 551 (34.0) −3.4 −9.1 Wisconsin 414 (7.8) 327 (6.0) −1.8 ††† −23.1 ††† 466 (8.6) 506 (9.4) 0.8 9.3 Wyoming —§§§ —§§§ —§§§ —§§§ —§§§ —§§§ —§§§ —§§§ States with good reporting (n = 10)¶¶ California 715 (1.7) 778 (1.9) 0.2 ††† 11.8 ††† 536 (1.3) 865 (2.2) 0.9 ††† 69.2 ††† Colorado 224 (3.9) 233 (3.9) 0.0 0.0 112 (2.0) 134 (2.2) 0.2 10.0 Florida 707 (3.6) 689 (3.5) −0.1 −2.8 2,126 (11.0) 2,091 (10.7) −0.3 −2.7 Hawaii 10 —§§§ —§§§ —§§§ —§§§ —§§§ —§§§ —§§§ —§§§ Indiana 327 (5.3) 311 (5.0) −0.3 −5.7 649 (10.5) 713 (11.5) 1.0 9.5 Kentucky 269 (6.6) 140 (3.3) −3.3 ††† −50.0 ††† 780 (19.1) 744 (17.9) −1.2 −6.3 Michigan 783 (8.2) 633 (6.5) −1.7 ††† −20.7 ††† 1,368 (14.4) 1,531 (16.0) 1.6 ††† 11.1 ††† Minnesota 111 (2.0) 93 (1.7) −0.3 −15.0 184 (3.5) 202 (3.7) 0.2 5.7 Mississippi 34 (1.3) 39 (1.4) 0.1 7.7 81 (2.9) 72 (2.6) −0.3 −10.3 Texas 569 (2.0) 668 (2.3) 0.3 ††† 15.0 ††† 348 (1.2) 358 (1.2) 0.0 0.0 * Deaths were classified using the International Classification of Diseases, Tenth Revision (ICD–10). Drug overdose deaths were identified using underlying cause-of-death codes X40–X44, X60–X64, X85, and Y10–Y14. Rates are age-adjusted using the direct method and the 2000 U.S. standard population, except for age-specific crude rates. All rates were per 100,000 population. † Drug overdose deaths, as defined, that have heroin (T40.1) as a contributing cause. § Drug overdose deaths, as defined, that have semisynthetic opioids other than methadone (T40.4) as a contributing cause. ¶ Categories of deaths are not exclusive as deaths might involve more than one drug category. Summing of categories will result in more than the total number of deaths in a year. ** Data on Hispanic origin should be interpreted with caution; studies comparing Hispanic origin on death certificates and on Census surveys have shown inconsistent reporting on Hispanic ethnicity. Potential race misclassification might lead to underestimates for certain categories, primarily American Indian/Alaska Native non-Hispanic and Asian/Pacific Islander non-Hispanic decedents. https://www.cdc.gov/nchs/data/series/sr_02/sr02_172.pdf. †† By the 2013 National Center for Health Statistics Urban-Rural Classification Scheme for Counties. https://www.cdc.gov/nchs/data_access/urban_rural.htm. §§ Northeast: Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, and Vermont. Midwest: Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, Ohio, South Dakota, and Wisconsin. South: Alabama, Arkansas, Delaware, District of Columbia, Florida, Georgia, Kentucky, Louisiana, Maryland, Mississippi, North Carolina, Oklahoma, South Carolina, Tennessee, Texas, Virginia, and West Virginia. West: Alaska, Arizona, California, Colorado, Hawaii, Idaho, Montana, Nevada, New Mexico, Oregon, Utah, Washington, and Wyoming. ¶¶ Analyses were limited to states meeting the following criteria. States with very good to excellent reporting had ≥90% of drug overdose deaths mention at least one specific drug in 2017, with the change in drug overdose deaths mentioning of at least one specific drug differing by <10 percentage points from 2017 to 2018. States with good reporting had 80% to <90% of drug overdose deaths mention at least one specific drug in 2017, with the change in the percentage of drug overdose deaths mentioning at least one specific drug differing by <10 percentage points from 2017 to 2018. States included also were required to have stable rate estimates (i.e., based on ≥20 deaths in at least two of the following drug categories: opioids, prescription opioids, synthetic opioids other than methadone, and heroin). *** Absolute rate change is the difference between 2017 and 2018 rates. Relative rate change is the absolute rate change divided by the 2017 rate, multiplied by 100. Nonoverlapping confidence intervals based on the gamma method were used if the number of deaths was <100 in 2017 or 2018, and z-tests were used if the number of deaths was ≥100 in both 2017 and 2018. ††† Statistically significant (p-value <0.05). §§§ Cells with nine or fewer deaths are not reported. Rates based on <20 deaths are not considered stable rate estimates and are not reported. Death rates involving synthetic opioids increased from 9.0 per 100,000 population in 2017 to 9.9 in 2018 and accounted for 67.0% of opioid-involved deaths in 2018. These rates increased from 2017 to 2018 among males and females, persons aged ≥25 years, non-Hispanic whites, non-Hispanic blacks, Hispanics, non-Hispanic Asian/Pacific Islanders, and in large central metro, large fringe metro, medium metro, and small metro counties. Synthetic opioid–involved death rates increased in the Northeast, South and West and remained stable in the Midwest. Rates increased in 10 states and decreased in two states. The largest relative increase occurred in Arizona (92.5%), and the largest absolute increase occurred in Maryland and Missouri (4.4 per 100,000 in both states); the largest relative and absolute decrease was in Ohio (–20.7%, –6.7). The highest synthetic opioid–involved death rate in 2018 occurred in West Virginia (34.0 per 100,000). Discussion During 1999–2018, opioids were involved in 446,032 deaths in the United States. §§§ From 2017 to 2018, relative decreases occurred in death rates involving all drug overdoses (–4.1%), all opioids (–2.0%), prescription opioids (–13.5%), and heroin (–4.1%); a relative increase occurred in the rate of overdose deaths involving synthetic opioids (10.0%). Decreases in all opioid-involved death rates were largely driven by those involving prescription opioids. The number of filled opioid prescriptions peaked in 2012 and decreased thereafter ( 4 ). Efforts to reduce high-dose opioid prescribing ¶¶¶ ( 4 ) have increased and have contributed to decreases in prescription opioid–involved deaths. Factors that might be contributing to the decrease in heroin-involved deaths include fewer persons initiating heroin use ( 5 ), shifts from a heroin-based market to a fentanyl-based market ( 6 ), increased treatment provision for persons using heroin, and expansion of naloxone access ( 5 , 7 ). Increases in synthetic opioid–involved deaths are likely driven by proliferation of IMF or fentanyl analogs in the illicit drug supply ( 3 , 5 , 6 ). According to the Drug Enforcement Administration, fentanyl was the most identified synthetic opioid found during drug seizures in the first half of 2017 ( 6 ); in addition, fentanyl reports in all regions increased during 2014–2018.**** This is consistent with current findings indicating recent increases in synthetic opioid–involved death rates in all regions except the Midwest. The findings in this report are subject to at least five limitations. First, postmortem toxicology testing varies by jurisdiction; improvements in testing might account for some reported increases. Second, the percentage of 2017 and 2018 death certificates with at least one drug specified varied among states and over time, limiting opioid subcategory rate comparisons. Third, because heroin is metabolized to morphine ( 8 ), some heroin deaths might have been misclassified as morphine deaths, resulting in an underreporting of heroin deaths. Fourth, potential race misclassification might have led to underestimates for certain categories, particularly American Indian/Alaska Natives and Asian/Pacific Islanders. †††† Finally, adequate drug specificity data were available from only 38 states and DC, which might limit generalizability of state-based analyses. From 2017 to 2018, small decreases occurred in all overdose deaths and in deaths involving all opioids, prescription opioids, and heroin; however, deaths involving synthetic opioids continued to increase in 2018 and accounted for two thirds of opioid-involved deaths. Findings also highlight increases in deaths among non-Hispanic blacks and Hispanics, indicating the need for culturally tailored interventions that address social determinants of health and structural-level factors. In addition, changing substance use patterns, including the resurgence of methamphetamine use, particularly among persons using opioids ( 9 ) and the mixing of opioids with methamphetamine and cocaine in the illicit drug supply ( 6 ), have continued to make the drug overdose landscape more complicated and surveillance and prevention efforts more challenging. To sustain decreases and prevent continued increases, continued urgent action is needed. Overdose Data to Action §§§§ is a 3-year cooperative agreement through which CDC funds health departments in 47 states, DC, two territories, and 16 cities and counties for surveillance and prevention efforts. These measures include obtaining more timely data on all drug overdoses, improving toxicology to better identify polysubstance-involved deaths, enhancing linkage to treatment for persons with opioid use disorder and risk for opioid overdose, improving prescription drug monitoring programs, implementing health systems interventions, partnering with public safety, and implementing other innovative surveillance and prevention activities. Because of the reductions observed in deaths involving prescription opioids, continued efforts to encourage safe prescribing practices, such as following the CDC Guideline for Prescribing Opioids for Chronic Pain ( 10 ) might be enhanced by increased use of nonopioid and nonpharmacologic treatments for pain. Additional public health efforts to reduce opioid-involved overdose deaths include expanding the distribution of naloxone, addressing polysubstance use, and increasing the provision of medication-assisted treatment. Enhanced and coordinated multisectoral surveillance of the illicit drug supply ¶¶¶¶ to track emerging threats, including the type and amount of specific drugs, could also help prevent overdoses. A comprehensive, multisectoral surveillance, prevention, and response approach remains critical for sustaining and expanding preliminary successes in reducing opioid-involved overdose deaths and specifically curtailing synthetic opioid–involved deaths and other emerging threats. Summary What is already known about this topic? In 2017, 68% of the 70,237 U.S. drug overdose deaths involved an opioid. During 2016–2017, deaths involving all opioids and synthetic opioids increased; deaths involving prescription opioids and heroin remained stable. What is added by this report? Opioids were involved in approximately 70% (46,802) of drug overdose deaths during 2018, representing decreases from 2017 in overdose death rates involving all opioids (2% decline), prescription opioids (14%), and heroin (4%); rates involving synthetic opioids increased 10%. What are the implications for public health practice? Surveillance of overdose and polysubstance use trends and the illicit drug supply to track emerging threats, enhancing linkage to treatment, and a multisectoral response are critical to sustaining and accelerating declines in opioid-involved deaths.
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            Drug and Opioid-Involved Overdose Deaths — United States, 2013–2017

            The 63,632 drug overdose deaths in the United States in 2016 represented a 21.4% increase from 2015; two thirds of these deaths involved an opioid ( 1 ). From 2015 to 2016, drug overdose deaths increased in all drug categories examined; the largest increase occurred among deaths involving synthetic opioids other than methadone (synthetic opioids), which includes illicitly manufactured fentanyl (IMF) ( 1 ). Since 2013, driven largely by IMF, including fentanyl analogs ( 2 – 4 ), the current wave of the opioid overdose epidemic has been marked by increases in deaths involving synthetic opioids. IMF has contributed to increases in overdose deaths, with geographic differences reported ( 1 ). CDC examined state-level changes in death rates involving all drug overdoses in 50 states and the District of Columbia (DC) and those involving synthetic opioids in 20 states, during 2013–2017. In addition, changes in death rates from 2016 to 2017 involving all opioids and opioid subcategories,* were examined by demographics, county urbanization levels, and by 34 states and DC. Among 70,237 drug overdose deaths in 2017, 47,600 (67.8%) involved an opioid. † From 2013 to 2017, drug overdose death rates increased in 35 of 50 states and DC, and significant increases in death rates involving synthetic opioids occurred in 15 of 20 states, likely driven by IMF ( 2 , 3 ). From 2016 to 2017, overdose deaths involving all opioids and synthetic opioids increased, but deaths involving prescription opioids and heroin remained stable. The opioid overdose epidemic continues to worsen and evolve because of the continuing increase in deaths involving synthetic opioids. Provisional data from 2018 indicate potential improvements in some drug overdose indicators; § however, analysis of final data from 2018 is necessary for confirmation. More timely and comprehensive surveillance data are essential to inform efforts to prevent and respond to opioid overdoses; intensified prevention and response measures are urgently needed to curb deaths involving prescription and illicit opioids, specifically IMF. Drug overdose deaths were identified in the National Vital Statistics System multiple cause-of-death mortality files, ¶ with death certificate data coded using the International Classification of Diseases, Tenth Revision (ICD-10) codes X40–44 (unintentional), X60–64 (suicide), X85 (homicide), or Y10–Y14 (undetermined intent). Among deaths with drug overdose as the underlying cause, the type of drug or drug category is indicated by the following ICD-10 multiple cause-of-death codes: opioids (T40.0, T40.1, T40.2, T40.3, T40.4, or T40.6)**; natural/semisynthetic opioids (T40.2); methadone (T40.3); heroin (T40.1); synthetic opioids other than methadone (T40.4); cocaine (T40.5); and psychostimulants with abuse potential (T43.6). †† Some deaths involved more than one type of drug, and these were included in rates for each drug category; thus, categories are not mutually exclusive. §§ Annual percent change with statistically significant trends in age-adjusted drug overdose death rates ¶¶ for all 50 states and DC from 2013 to 2017 and in age-adjusted death rates involving synthetic opioids for 20 states that met drug specificity criteria*** were analyzed using Joinpoint regression. ††† Age-adjusted overdose death rates were examined from 2016 to 2017 for all opioids, prescription opioids ( 5 ), heroin, and synthetic opioids. Death rates were stratified by age, sex, racial/ethnic group, urbanization level, §§§ and state. State-level analyses included DC and 34 states with adequate drug specificity data for 2016 and 2017. ¶¶¶ Analyses comparing changes in death rates from 2016 to 2017 used z-tests when the number of deaths was ≥100 and nonoverlapping confidence intervals based on a gamma distribution when the number was 80% of drug overdose death certificates named at least one specific drug in 2013–2017; 2) change from 2013 to 2017 in the percentage of death certificates reporting at least one specific drug was <10 percentage points; and 3) ≥20 deaths involving synthetic opioids other than methadone occurred each year during 2013–2017. States whose reporting of any specific drug or drugs involved in an overdose changed by ≥10 percentage points from 2013 to 2017 were excluded because drug-specific overdose numbers and rates might have changed substantially from 2013 to 2017 as a result of changes in reporting. ¶ Left panel: Joinpoint regression examining changes in trends from 2013 to 2017 indicated that 35 states and the District of Columbia had significant increases in drug overdose death rates from 2013 to 2017 (Alabama, Alaska, Arizona, Arkansas, Connecticut, Delaware, District of Columbia, Florida, Georgia, Hawaii, Illinois, Indiana, Iowa, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Minnesota, Missouri, New Jersey, New York, North Carolina, Ohio, Pennsylvania, Rhode Island, South Carolina, South Dakota, Tennessee, Texas, Vermont, Virginia, Washington, West Virginia, and Wisconsin). All remaining states had nonsignificant trends during this period. Right panel: Joinpoint regression examining changes in trends from 2013 to 2017 indicated that 15 states had significant increases in death rates for overdoses involving synthetic opioids other than methadone from 2013 to 2017 (Connecticut, Illinois, Iowa, Maine, Maryland, Minnesota, Nevada, New York, North Carolina, Oregon, Rhode Island, Virginia, Washington, West Virginia, and Wisconsin). The five remaining states analyzed had nonsignificant trends during this period. Significant increases in trends were not detected in some states with large absolute increases in death rates from 2013 to 2017 because of limited power to detect significant effects. The figure shows age-adjusted rates of drug overdose deaths and deaths involving synthetic opioids other than methadone, by state in the United States during 2013 and 2017. From 2016 to 2017, opioid-involved overdose deaths increased among males and females and among persons aged ≥25 years, non-Hispanic whites (whites), non-Hispanic blacks (blacks), and Hispanics (Table 1). The largest relative change occurred among blacks (25.2%), and the largest absolute rate increase was among males aged 25–44 years (an increase of 4.6 per 100,000). The largest relative change among age groups was for persons aged ≥65 years (17.2%). Counties in medium metro areas experienced the largest absolute rate increase (an increase of 1.9 per 100,000), and the largest relative rate increase occurred in micropolitan counties (14.9%). Death rates increased significantly in 15 states, with the largest relative changes in North Carolina (28.6%), Ohio (19.1%), and Maine (18.7%). From 2016 to 2017, the prescription opioid-involved death rate decreased 13.2% among males aged 15–24 years but increased 10.5% among persons aged ≥65 years (Table 1). These death rates remained stable from 2016 to 2017 across all racial groups and urbanization levels and in most states, although five states (Maine, Maryland, Oklahoma, Tennessee, and Washington) experienced significant decreases, and one (Illinois) had a significant increase. The largest relative changes included a 29.7% increase in Illinois and a 39.2% decrease in Maine. The highest prescription opioid-involved death rates in 2017 were in West Virginia (17.2 per 100,000), Maryland (11.5), and Utah (10.8). Heroin-involved overdose death rates declined among many groups in 2017 compared with those in 2016 (Table 2). The largest declines occurred among persons aged 15–24 years (15.0%), particularly males (17.5%), as well as in medium metro counties (6.1%). Rates declined 3.2% among whites. However, heroin-involved overdose death rates did increase among some groups; the largest relative rate increase occurred among persons aged ≥65 years (16.7%) and 55–64 years (11.6%) and among blacks (8.9%). Rates remained stable in most states, with significant decreases in five states (Maryland, Massachusetts, Minnesota, Missouri, and Ohio), and increases in three (California, Illinois, and Virginia). The largest relative decrease (31.9%) was in Ohio, and the largest relative increase (21.8%) was in Virginia. The highest heroin-involved overdose death rates in 2017 were in DC (18.0 per 100,000), West Virginia (14.9), and Connecticut (12.4). Deaths involving synthetic opioids propelled increases from 2016 to 2017 across all demographic categories (Table 2). The highest death rate was in males aged 25–44 years (27.0 per 100,000), and the largest relative increases occurred among blacks (60.7%) and American Indian/Alaska Natives (58.5%). Deaths increased across all urbanization levels from 2016 to 2017. Twenty-three states and DC experienced significant increases in synthetic opioid-involved overdose death rates, including eight states west of the Mississippi River. The largest relative rate increase occurred in Arizona (122.2%), followed by North Carolina (112.9%) and Oregon (90.9%). The highest synthetic opioid-involved overdose death rates in 2017 were in West Virginia (37.4 per 100,000), Ohio (32.4), and New Hampshire (30.4). Discussion In the United States, drug overdoses resulted in 702,568 deaths during 1999–2017, with 399,230 (56.8%) involving opioids. †††† From 2016 to 2017, death rates from all opioids increased, with increases driven by synthetic opioids. Deaths involving IMF have been seen primarily east of the Mississippi River; §§§§ however, recent increases occurred in eight states west of the Mississippi River, including Arizona, California, Colorado, Minnesota, Missouri, Oregon, Texas, and Washington. Drug overdose death rates from 2013 to 2017 increased in most states; the influence of synthetic opioids on these rate increases was seen in approximately one quarter of all states during this same 5-year period. Overdose deaths involving cocaine and psychostimulants also have increased in recent years ( 1 , 6 ). Overall, the overdose epidemic continues to worsen, and it has grown increasingly complex by co-involvement of prescription and illicit drugs ( 7 , 8 ). ¶¶¶¶ For example, in 2016, synthetic opioids (primarily IMF) were involved in 23.7% of deaths involving prescription opioids, 37.4% involving heroin, and 40.3% involving cocaine ( 9 ). In addition, death rates are increasing across multiple demographic groups. For example, although death rates involving opioids remained highest among whites, relatively large increases across several drug categories were observed among blacks. The findings in this report are subject to at least five limitations. First, at autopsy, substances tested for vary by time and jurisdiction, and improvements in toxicologic testing might account for some reported increases. Second, the specific types of drugs involved were not included on 15% of drug overdose death certificates in 2016 and 12% in 2017, and the percentage of death certificates with at least one drug specified ranged among states from 54.7%–99.3% in 2017, limiting rate comparisons between states. Third, because heroin and morphine are metabolized similarly ( 10 ), some heroin deaths might have been misclassified as morphine deaths, resulting in underreporting of heroin deaths. Fourth, potential race misclassification might have led to underestimates for certain categories, primarily for American Indian/Alaska Natives and Asian/Pacific Islanders.***** Finally, most state-specific analyses were restricted to DC and a subset of states with adequate drug specificity, limiting generalizability. Through 2017, the drug overdose epidemic continues to worsen and evolve, and the involvement of many types of drugs (e.g., opioids, cocaine, and methamphetamine) underscores the urgency to obtain more timely and local data to inform public health and public safety action. Although prescription opioid- and heroin-involved death rates were stable from 2016 to 2017, they remained high. Some preliminary indicators in 2018 point to possible improvements based on provisional data; ††††† however, confirmation will depend on results of pending medical investigations and analysis of final data. Overall, deaths involving synthetic opioids continue to drive increases in overdose deaths. CDC funds 32 states and DC to collect more timely and comprehensive drug overdose data, including improved toxicologic testing in opioid-involved fatal overdoses. §§§§§ CDC is funding prevention activities in 42 states and DC. ¶¶¶¶¶ CDC also is leveraging emergency funding to support 49 states, DC, and four territories to broaden their surveillance and response capabilities and enable comprehensive community-level responses with implementation of novel, evidence-based interventions.****** Continued efforts to ensure safe prescribing practices by following the CDC Guideline for Prescribing Opioids for Chronic Pain †††††† are enhanced by access to nonopioid and nonpharmacologic treatments for pain. Other important activities include increasing naloxone availability, expanding access to medication-assisted treatment, enhancing public health and public safety partnerships, and maximizing the ability of health systems to link persons to treatment and harm-reduction services. Summary What is already known about this topic? The U.S. opioid overdose epidemic continues to evolve. In 2016, 66.4% of the 63,632 drug overdose deaths involved an opioid. What is added by this report? In 2017, among 70,237 drug overdose deaths, 47,600 (67.8%) involved opioids, with increases across age groups, racial/ethnic groups, county urbanization levels, and in multiple states. From 2013 to 2017, synthetic opioids contributed to increases in drug overdose death rates in several states. From 2016 to 2017, synthetic opioid-involved overdose death rates increased 45.2%. What are the implications for public health practice? Continued federal, state, and local surveillance efforts to inform evidence-based prevention, response, and treatment strategies and to strengthen public health and public safety partnerships are urgently needed.
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              Mu opioids and their receptors: evolution of a concept.

              Opiates are among the oldest medications available to manage a number of medical problems. Although pain is the current focus, early use initially focused upon the treatment of dysentery. Opium contains high concentrations of both morphine and codeine, along with thebaine, which is used in the synthesis of a number of semisynthetic opioid analgesics. Thus, it is not surprising that new agents were initially based upon the morphine scaffold. The concept of multiple opioid receptors was first suggested almost 50 years ago (Martin, 1967), opening the possibility of new classes of drugs, but the morphine-like agents have remained the mainstay in the medical management of pain. Termed mu, our understanding of these morphine-like agents and their receptors has undergone an evolution in thinking over the past 35 years. Early pharmacological studies identified three major classes of receptors, helped by the discovery of endogenous opioid peptides and receptor subtypes-primarily through the synthesis of novel agents. These chemical biologic approaches were then eclipsed by the molecular biology revolution, which now reveals a complexity of the morphine-like agents and their receptors that had not been previously appreciated.
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                Author and article information

                Journal
                Brain Sci
                Brain Sci
                brainsci
                Brain Sciences
                MDPI
                2076-3425
                03 September 2020
                September 2020
                : 10
                : 9
                : 606
                Affiliations
                [1 ]Institute of Neuroscience-Cagliari, National Research Council (CNR), Cittadella Universitaria, 09042 Monserrato, Cagliari, Italy
                [2 ]Department of Morphology, Surgery and Experimental Medicine, Section of Legal Medicine and LTTA Center, University of Ferrara, 44121 Ferrara, Italy; mto@ 123456unife.it
                [3 ]Department of Anti-Drug Policies, Collaborative Center for the Italian National Early Warning System, Presidency of the Council of Ministers, 00187 Rome, Italy
                [4 ]Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Cagliari, Italy; rafy.mostallino@ 123456tiscali.it (R.M.); castelli@ 123456unica.it (M.P.C.)
                [5 ]National Institute of Neuroscience (INN), University of Cagliari, 09124 Cagliari, Italy
                [6 ]Center of Excellence “Neurobiology of Addiction”, University of Cagliari, 09124 Cagliari, Italy
                Author notes
                Author information
                https://orcid.org/0000-0002-2663-666X
                https://orcid.org/0000-0001-8751-2882
                https://orcid.org/0000-0003-3249-4706
                Article
                brainsci-10-00606
                10.3390/brainsci10090606
                7564810
                32899299
                e028aaf5-e147-42e4-8991-e52b22e7ea0c
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 10 July 2020
                : 31 August 2020
                Categories
                Review

                nps,sex/gender differences,cannabinoids,cathinones,phenethylamines,opioids,new synthetic drugs

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