Introduction
Injection drug use is associated with infections of skin, soft tissue, and bone that, in some cases, require amputation. Local studies have noted increasing cases of severe wounds and amputations among individuals using street opioids (1–3). National and regional estimates of changes in amputation rates among individuals using opioids are lacking.
Methods
In a repeated cross-sectional analysis of the National Inpatient Sample (NIS), we estimated nationally and regionally representative amputation rates among opioid-related and nonopioid-related hospitalizations from 2016 to 2022 for individuals 18 years or older. We used International Classification of Diseases, Tenth Revision (ICD-10), Clinical Modification codes to identify opioid-related hospitalizations (F11.1-F11.2, F11.9; T40.0-T40.4, T40.6) and ICD-10, Procedure Coding System codes to identify amputations (0X6, 0Y6) that occurred during a hospitalization. We used Elixhauser Index ICD-10 code groupings to identify comorbid diabetes and peripheral vascular disease. We considered all code positions.
We calculated crude amputation rates per 10,000 hospitalizations and plotted these by year for opioid-related and nonopioid-related hospitalizations nationally and by census region. We fit a logistic regression model with an interaction term of opioid-related (yes vs. no) by year (2016 vs. 2022) and included age, gender, race/ethnicity, diabetes diagnoses, and peripheral vascular disease diagnoses as covariates to estimate (1) the standardized difference in amputation rates among opioid-related hospitalizations between 2016 and 2022, (2) the standardized difference in amputation rates among nonopioid-related hospitalizations between 2016 and 2022, and (3) the standardized difference-in-differences of amputation rates from 2016 to 2022 between opioid-related and nonopioid-related hospitalizations. We repeated this analysis with a three-way interaction term (opioid-related by year by geographic unit) to obtain standardized estimates at the census region and census division levels. Finally, we calculated the proportion of amputations by anatomical level for opioid and nonopioid-related hospitalization, including all years. All analyses used survey weights to account for the complex sampling design of NIS. Analyses were conducted with SAS 9.4 and Stata 18.0. The funder had no role in the design, conduct, or analysis of the study or the decision to submit the manuscript for publication.
Results
There were 41,010,691 hospitalizations (205,053,364 weighted) of individuals 18 years or older from 2016 to 2022 (annual range 5,533,477–6,084,184 [27,667,386–30,420,907 weighted]), 3.0% of which were opioid-related. Among opioid-related hospitalizations, the mean age was 50.3, 49.8% were male, 70.3% were non-Hispanic White, 14.1% were non-Hispanic Black, and 8.8% were Hispanic. Among nonopioid-related hospitalizations, mean age was 58.3, 42.7% were male, 64.4% were non-Hispanic White, 15.0% were non-Hispanic Black, and 11.4% were Hispanic.
Crude amputation rates increased nationally and across all census regions among both opioid-related and nonopioid-related hospitalizations (Figure), with steeper apparent increases among opioid-related hospitalizations. At the national level, crude amputation rates per 10,000 opioid-related hospitalizations increased from 55.6 to 92.3 (crude rate difference [CRD] 36.7, standardized rate difference [SRD] 34.7 [95% CI: 27.8–41.5]), while crude amputation rates per 10,000 nonopioid-related hospitalizations increased from 58.9 to 79.7 (CRD 20.8, SRD 21.5 [95% CI: 19.7–23.3]) (Table).
Figure.
Trends in crude amputation rates among opioid-related and nonopioid-related hospitalizations, 2016–2022
Table.
Changes in amputation rates among opioid-related and non-opioid related hospitalization, 2016–2022
| Opioid-related | Nonopioid-related | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Crude rate per 10,000 hospitalizations | Standardized rate difference1 | Crude rate per 10,000 hospitalizations | Standardized rate difference1 | Standardized difference-in differences2 | |||||
| 2016 | 2022 | Difference | (95% CI) | 2016 | 2022 | Difference | (95% CI) | (95% CI) | |
| National | 55.6 | 92.3 | 36.7 | 34.7 (27.8–41.5) | 58.9 | 79.7 | 20.8 | 21.5 (19.7–23.3) | 13.2 (6.4–19.9) |
| Census Region | |||||||||
| Northeast | 45.4 | 83.5 | 38.1 | 38.9 (24.4–53.3) | 51.3 | 70.0 | 18.7 | 20.5 (16.9–24.0) | 18.4 (4.4–32.4) |
| Midwest | 52.4 | 93.7 | 41.3 | 37.1 (23.9–50.3) | 54.4 | 78.0 | 23.6 | 24.5 (21.2–27.8) | 12.6 (−0.4–25.6) |
| South | 57.4 | 87.8 | 30.4 | 26.7 (15.3–38.2) | 66.2 | 84.3 | 18.1 | 19.9 (16.8–23.0) | 6.8 (−4.4–18.1) |
| West | 67.4 | 107.8 | 40.4 | 41.0 (24.7–57.2) | 56.5 | 80.7 | 24.2 | 21.9 (17.5–26.2) | 19.1 (3.3–34.9) |
| Census Division | |||||||||
| New England | 46.1 | 86.9 | 40.8 | 45.1 (22.8–67.3) | 46.3 | 66.0 | 19.7 | 22.2 (15.6–28.7) | 22.9 (1.2–44.6) |
| Middle Atlantic | 45.1 | 82.1 | 37.0 | 36.2 (18.0–54.4) | 52.9 | 71.4 | 18.5 | 19.9 (15.7–24.1) | 16.3 (−1.3–33.9) |
| East North Central | 52.3 | 93.4 | 41.1 | 37.8 (22.1–53.5) | 55.4 | 77.9 | 22.5 | 23.9 (19.9–27.8) | 14.0 (−1.3–29.2) |
| West North Central | 52.5 | 94.5 | 42.0 | 35.0 (10.3–59.8) | 52.0 | 78.3 | 26.3 | 25.7 (19.8–31.6) | 9.3 (−15.8–34.5) |
| South Atlantic | 54.7 | 86.3 | 31.6 | 27.0 (12.9–41.1) | 61.4 | 79.8 | 18.4 | 18.8 (14.9–22.7) | 8.2 (−5.7–22.1) |
| East South Central | 55.9 | 96.3 | 40.4 | 36.9 (9.4–64.4) | 68.9 | 98.4 | 29.5 | 31.5 (23.6–39.5) | 5.4 (−21.7–32.4) |
| West South Central | 67.5 | 83.8 | 16.3 | 16.7 (−10.3–43.8) | 73.1 | 84.3 | 11.2 | 15.3 (9.6–21.0) | 1.4 (−25.2–27.9) |
| Mountain | 65.0 | 105.1 | 40.1 | 41.2 (15.1–67.2) | 54.4 | 80.6 | 26.2 | 28.5 (20.4–36.6) | 12.7 (−13.4–38.8) |
| Pacific | 68.7 | 109.3 | 40.6 | 40.7 (20.1–61.4) | 57.5 | 80.8 | 23.3 | 19.2 (14.1–24.3) | 21.5 (1.6–41.4) |
Standardized rate differences comparing amputation rate between 2016 and 2022 within group (opioid-related or nonopioid-related), standardized by age, gender, race/ethnicity, diabetes, and peripheral vascular disease.
Standardized difference-in-differences were calculated as the difference in rates between 2016 and 2022 in opioid-related hospitalizations minus the difference in rates between 2016 and 2022 in nonopioid-related hospitalizations, standardized by age, gender, race/ethnicity, diabetes, and peripheral vascular disease.
The standardized difference-in-differences analysis showed greater increases in amputation rates among opioid-related vs. non-opioid-related hospitalizations between 2016 and 2022 at the national level (13.2 [95% CI: 6.4–19.9], in the Northeast (18.4 [95% CI: 4.4–32.4]) and West census regions (19.1 [95% CI: 3.3–34.9]), and in the New England (22.9 [95% CI: 1.2–44.6]) and Pacific census divisions (21.5 [95% CI: 1.6–41.4]). Estimates for other regions and divisions were in the same direction but generally less precise, with some intervals centered near no difference and others spanning small decreases to moderate or large increases. Higher anatomical amputation levels were more common in opioid-related compared with nonopioid-related hospitalization, with 8.5% vs 5.2% of amputations at the upper extremity, 17.9% vs 14.6% at the knee or above, 25.7% vs 20.4% at the lower leg, and, conversely, 50.3% vs 61.7% at a toe or part of a foot.
Discussion
Amputation rates have increased among both opioid-related and nonopioid-related hospitalizations, with significantly greater increases among opioid-related hospitalizations nationally and in the Northeast and West census regions. Amputations among opioid-related hospitalizations also involved higher amputation levels compared with nonopioid-related hospitalizations. Street opioid contamination with xylazine—an alpha2-agonist with no approved human use that is associated with especially severe wounds—may be contributing to this increase in areas where it is especially prevalent, such as the Northeast (1–3). Increases in amputations where xylazine is less prevalent and entered the street drug supply later suggest that other factors may be driving rising opioid-related amputation rates. Possible factors include increased injection frequency associated with fentanyl and stimulant use, and the association between black tar heroin and increased skin and soft tissue infections. Concerns regarding injection-related wounds, including those associated with xylazine, may be accelerating the widespread transition to non-injection routes of administration, including opioid smoking (3–5). Limitations include the inability to directly link opioid use to amputations, a serial cross-sectional study design that limits causal inference, and the possibility that our analysis did not account for important unmeasured risk factors for amputations.
Acknowledgements:
The work presented in this article was supported by National Institutes of Health/National Institute on Drug Abuse research grants R01 DA054190 and R21 DA064011 (P.I. Dr. Ciccarone). Dr. Baggett reports author royalties from UpToDate (Wolters Kluwer) for a topic review on the health of people experiencing homelessness. Dr. Ciccarone reports financial support as a scientific advisor to Celero Systems and Emergent Biosciences.
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