Abstract
Background
Non-tobacco nicotine products (eg, e-cigarettes, nicotine pouches) are increasingly used by cigarette smokers and prior nonsmokers. While the detrimental effects of cigarette dependence (CD) on healing and surgical recovery are well documented, the impact of non-tobacco nicotine dependence (NTND) on outcomes after lumbar spine surgery remains poorly characterized.
Methods
We conducted a retrospective cohort study using the TriNetX database. Patients undergoing lumbar spine decompression and fusion were divided into 3 cohorts: NTND, CD, and controls (no documented nicotine dependence). Propensity score matching was performed 1:1 based on demographic and clinical characteristics. Complication rates were assessed at 90 days and 3 years postoperatively. Outcomes included anemia, deep vein thrombosis (DVT), myocardial infarction (MI), pneumonia, renal failure, pulmonary embolism (PE), sepsis, stroke, opioid abuse, pseudoarthrosis, and lumbar fracture.
Results
A total of 39,195 matched NTND and control patients were analyzed. NTND was associated with increased 90-day risks of anemia, DVT, MI, pneumonia, renal failure, sepsis, stroke, and opioid abuse, as well as higher 3-year risks of pseudoarthrosis and lumbar fracture (p < .05). In a comparison of 36, 877 matched NTND and CD patients, NTND showed higher anemia risk but lower risks of MI, PE, renal failure, sepsis, stroke, and opioid abuse at 90 days. At 3 years, NTND carried a higher pseudoarthrosis risk but lower lumbar fracture risk relative to CD (p < .0001). When NTND and CD patients were combined (n = 102,720 total), both groups demonstrated significantly higher complications risks compared with controls at both 90 days and 3 years (p < .0001).
Conclusions
NTND is associated with increased perioperative and long-term complications following lumbar spine surgery, including higher rates of infection, opioid abuse, pseudoarthrosis, and lumbar fracture. NTND demonstrates a distinct complication profile compared to CD, underscoring the need for further research on the impact of non-tobacco nicotine exposure on spinal fusion outcomes.
Keywords: Nontobacco nicotine dependence, Lumbar spine surgery, Lumbar decompression and fusion, Pseudoarthrosis, Postoperative complications
Introduction
The adverse effects of cigarette smoking on orthopaedic surgical outcomes are well-documented, with numerous studies demonstrating negative impacts on bone and soft tissue healing and functional recovery [[1], [2], [3], [4], [5]]. These complications are largely attributed to the detrimental effects of nicotine and other cigarette toxins on blood flow, immune function, and bone metabolism [[1], [6], [7]]. Nicotine alone has been shown to directly impair wound healing and bony union; however, most existing studies do not distinguish outcomes based on different nicotine sources, such as smokeless tobacco or electronic vaporizers, apart from cigarette smoking [1].
In the context of spine surgery, smoking has been causally linked to delayed fusion and pseudoarthrosis [8,9]. Toxins from cigarette smoke,most notably nicotine,compromise blood flow to the spine, reducing nutrient supply to highly metabolically active spinal tissues [[10], [11], [12]]. Postoperatively, smoking increases the risk of complications such as surgical site infections, skin necrosis, wound dehiscence, and delayed wound and bone healing [8,13].
Electronic cigarettes, commonly referred to as e-cigarettes or vapes, are marketed as safer alternatives to smoking despite containing nicotine and vaporized synthetic chemicals such as humectants and flavoring agents [14,15]. Additionally, many non-tobacco nicotine products are aggressively marketed toward younger individuals, including adolescents and previous nonsmokers. Non-tobacco nicotine products including vaporizers, pouches, gum, and patches are marketed as harm-reduction tools, yet their long-term health effects remain poorly understood [14]. Recent studies suggest that, like cigarettes, these nicotine products may impair bone and wound healing due to harmful aldehydes and oxidative stress agents that may exacerbate inflammation and hinder regeneration [15].
The ability of e-cigarettes to deliver high concentrations of nicotine in doses not readily apparent to their users raises concerns about their potential to cause significant postoperative complications in spine surgery. This concern is amplified by the widespread public perception that e-cigarettes pose lower risk than cigarettes [14]. Given the increasing prevalence of e-cigarette use and its reputation as a safer alternative to smoking, it is critical to investigate its implications for surgical outcomes.
This study aims to evaluate the effects of non-tobacco nicotine dependence (NTND) on lumbar spine surgery. By identifying potential risks associated with e-cigarette use, this research seeks to provide a foundation for future studies and inform clinical guidelines on the perioperative management of patients who vape.
Material and methods
A retrospective cohort study was conducted using TriNetX, a global health research network that provides real-time access to de-identified clinical data from a vast consortium of healthcare organizations. Institutional review board approval was not required, as only de-identified, aggregated data were accessed. Patients who had undergone lumbar spinal decompression and fusion were identified using CPT and ICD codes. The complete list of CPT codes used can be found in Supplementary Table 1.
Cohort selection
Patients who underwent lumbar spinal fusion and decompression surgeries were categorized into 5 cohorts based on their preoperative diagnosis of nicotine use: noncigarette tobacco/nicotine dependence (NTND), cigarette dependence (CD), a combined NTND/CD group, and a control group.
The NTND cohort included patients with a preoperative diagnosis of nicotine dependence (ICD-10: F17), excluding those specifically dependent on cigarettes (ICD-10: F17.21), chewing tobacco (ICD-10: F17.22), or other tobacco products (ICD-10: F17.29). The CD cohort consisted of patients with a preoperative diagnosis of cigarette dependence (ICD-10: F17.21), excluding those dependent on chewing tobacco (ICD-10: F17.22) or other tobacco products (ICD-10: F17.29).
A combined NTND/CD cohort was created by including all patients who met the criteria for either the NTND or CD groups. Lastly, a control group was composed of patients who had undergone spinal surgery but had no history of nicotine dependence (ICD-10: F17) or a personal history of nicotine use (ICD-10: Z87.981).
Statistical analysis
For each outcome, risk differences, risk ratios, and confidence intervals (CIs) were calculated using the TriNetX system. Student’s t-tests were used to compare continuous variables across cohorts, while chi-square tests were employed to assess differences in categorical outcomes. Chi-square analysis was chosen over ANOVA, as postoperative complications were binary, making it a more appropriate measure for comparing proportions across cohorts. To evaluate specific pairwise comparisons, post-hoc Dunn’s tests with Holm’s correction were conducted. Dunn’s test was preferred as it avoids bias from assumptions of normality. For long-term outcomes, Kaplan-Meier survival analysis was performed to evaluate pseudoarthrosis-free and lumbar fracture-free survival at 3 years. Log-rank tests were utilized to evaluate statistical differences in survival between the NTND and control cohorts. A p-value of less than .05 was considered statistically significant for all analyses. Statistical analyses were conducted using R statistical software.
Unmatched cohort
This study assessed 43,582 NTND patients versus 413,889 control patients, 42,526 NTND patients versus 61,880 CD patients, and 108,259 NTND+CD patients versus 413,903 control patients. Mean ages were significantly different across comparison cohorts, and significant differences in the distribution of sex, race, and ethnicity were also observed. Additionally, medical comorbidities, including hypertension, dyslipidemia, obesity, and type 2 diabetes mellitus, were significantly different across all groups (Supplemental Tables 2A-C). To improve balance among cohorts, 1:1 propensity score matching was applied.
1:1 Propensity-matched cohort
To ensure comparability, cohorts were matched for age, sex, race, ethnicity, and the presence of hypertension, hyperlipidemia, obesity, and type 2 diabetes mellitus using the TriNetX built-in algorithm, which employs 1:1 nearest neighbor matching. Propensity matching resulted in a more even distribution of demographic variables and medical comorbidities across cohorts (Supplementary Tables 3A-C).
Outcomes
Complication profiles were assessed at 90 days and 3 years postoperatively. The risk of major medical complications within 90 days of surgery was evaluated, including anemia, deep vein thrombosis (DVT), myocardial infarction (MI), opioid abuse, pulmonary embolism (PE), pneumonia, renal failure, sepsis, stroke, and blood transfusion. Long-term outcomes, including rates of pseudoarthrosis and lumbar fracture, were assessed at 3 years postoperatively.
Results
Demographics
Patients who underwent lumbar spine decompression and/or fusion were identified and categorized into cohorts. The NTND versus Control cohort included 43,582 NTND patients and 413,889 control. The NTND versus CD cohort consisted of 42,526 NTND patients and 61,880 CD patients. The NTND+CD versus Control cohort compromised 108,259 NTND+CD patients and 413,903 control patients.
Initial comparisons (Table 1) revealed significant baseline differences in virtually all variables between cohorts. Propensity score matching (PSM) was conducted to account for these differences, as these key variables are known drivers of postoperative outcomes. Due to the pairwise nature of the analysis, sample sizes varied across comparisons. NTND and CD cohorts were matched separately to Control patients, resulting in 39,165 patients per cohort for the NTND versus Control comparison, 36,877 per cohort for the NTND versus CD, and 102,720 total patients in the NTND+CD versus Control analysis (Supplementary Tables 3A-C).
Table 1.
Postoperative complication risks at 90 days and 3 years among nontobacco nicotine (NTND), cigarette-dependence (CD), and control cohorts
| Complication | Cohort incidence (risk) |
Risk difference | p-value | Risk ratio (95% CI) | |
|---|---|---|---|---|---|
| NTND (n=39,195) | Control (n=39,195) | ||||
| 90 days | |||||
| Anemia | 3,984 (0.102) | 3,647 (0.093) | 0.009 | <.001 | 1.092 (1.047, 1.140) |
| DVT | 429 (0.011) | 349 (0.009) | 0.002 | .004 | 1.229 (1.068, 1.415) |
| MI | 417 (0.011) | 213 (0.005) | 0.005 | <.001 | 1.958 (1.661, 2.308) |
| Opioid abuse | 253 (0.006) | 54 (0.001) | 0.005 | <.001 | 4.685 (3.494, 6.283) |
| PE | 390 (0.010) | 357 (0.009) | 0.001 | .225 | 1.092 (0.947, 1.260) |
| Pneumonia | 1,015 (0.026) | 412 (0.011) | 0.015 | <.001 | 2.464 (2.199, 2.760) |
| Renal Failure | 1,174 (0.030) | 853 (0.022) | 0.008 | <.001 | 1.376 (1.262, 1.502) |
| Sepsis | 521 (0.013) | 319 (0.008) | 0.005 | <.001 | 1.633 (1.422, 1.876) |
| Stroke | 497 (0.013) | 189 (0.005) | 0.008 | <.001 | 2.630 (2.225, 3.107) |
| Transfusion | 1,200 (0.031) | 1,212 (0.031) | 0.000 | .804 | 0.990 (0.915, 1.071) |
| 3 years | |||||
| Lumbar fracture | 1,610 (0.041) | 1,365 (0.035) | 0.006 | <.001 | 1.179 (1.099, 1.266) |
| Pseudoarthrosis | 3,619 (0.092) | 2,665 (0.068) | 0.024 | <.001 | 1.358 (1.294, 1.425) |
| Complication | Cohort incidence (risk) |
Risk difference | p-value | Risk ratio (95% CI) | |
|---|---|---|---|---|---|
| NTND (n=36,877) | CD (n=36,877) | ||||
| 90 days | |||||
| Anemia | 3,779 (0.102) | 4,515 (0.122) | −0.020 | <.001 | 0.837 (0.804, 0.872) |
| DVT | 418 (0.011) | 393 (0.011) | 0.001 | .377 | 1.064 (0.927, 1.220 |
| MI | 406 (0.011) | 615 (0.017) | −0.006 | <.001 | 0.660 (0.583, 0.748) |
| Opioid abuse | 230 (0.006) | 461 (0.013) | −0.006 | <.001 | 0.499 (0.426, 0.584) |
| PE | 382 (0.010) | 458 (0.012) | −0.002 | .008 | 0.834 (0.729, 0.955) |
| Pneumonia | 990 (0.027) | 1,017 (0.028) | −0.001 | .541 | 0.973 (0.893, 1.061) |
| Renal Failure | 1,146 (0.031) | 1,532 (0.042) | −0.010 | <.001 | 0.748 (0.694, 0.806) |
| Sepsis | 505 (0.014) | 793 (0.022) | −0.008 | <.001 | 0.637 (0.570, 0.711) |
| Stroke | 486 (0.013) | 557 (0.015) | −0.002 | .027 | 0.873 (0.773, 0.985) |
| Transfusion | 1,146 (0.031) | 945 (0.026) | 0.005 | <.001 | 1.213 (1.114, 1.320) |
| 3 years | |||||
| Lumbar fracture | 1,515 (0.041) | 1,976 (0.053) | −0.125 | <.001 | 0.767 (0.718, 0.818) |
| Pseudoarthrosis | 3,346 (0.091) | 1,425 (0.039) | 0.052 | <.001 | 2.348 (2.211, 2.494) |
| Complication | Cohort incidence (risk) |
Risk difference | p-value | Risk ratio (95% CI) | |
|---|---|---|---|---|---|
| NTND + CD (n=102,720) | Control (n=102,720) | ||||
| 90 days | |||||
| Anemia | 12,129 (0.118) | 10,126 (0.099) | 0.019 | <.001 | 1.198 (1.168, 1.228) |
| DVT | 1,138 (0.011) | 959 (0.009) | 0.002 | <.001 | 1.187 (1.089, 1.293) |
| MI | 1,332 (0.013) | 568 (0.006) | 0.007 | <.001 | 2.345 (2.126, 2.586) |
| Opioid abuse | 934 (0.009) | 136 (0.001) | 0.008 | <.001 | 6.868 (5.738, 8.219) |
| PE | 1,137 (0.011) | 938 (0.009) | 0.002 | <.001 | 1.212 (1.112, 1.321) |
| Pneumonia | 2,518 (0.025) | 1,098 (0.011) | 0.014 | <.001 | 2.293 (2.137, 2.460 |
| Renal failure | 3,531 (0.034) | 2,358 (0.023) | 0.011 | <.001 | 1.497 (1.422, 1.576) |
| Sepsis | 1,668 (0.016) | 841 (0.008) | 0.008 | <.001 | 1.983 (1.826, 2.154) |
| Stroke | 1,333 (0.013) | 602 (0.006) | 0.007 | <.001 | 2.214 (2.012, 2.437) |
| Transfusion | 3,004 (0.029) | 3,248 (0.032) | −0.002 | .002 | 0.925 (0.881, 0.971) |
| 3 years | |||||
| Lumbar fracture | 5,171 (0.050) | 3,616 (0.035) | 0.015 | <.001 | 1.430 (1.372, 1.491) |
| Pseudoarthrosis | 8,094 (0.079) | 7,439 (0.072) | 0.006 | <.001 | 1.088 (1.056, 1.121) |
NTND, nontobacco nicotine-dependent; CD, cigarette-dependent; DVT, deep vein thrombosis; MI, myocardial infarction; PE, pulmonary embolism.
In the NTND cohort, the mean age was 53.1 ± 14.9 years with 18,505 (47.2%) male and 19,516 (49.8%) female patients. A total of 29,310 (74.8%) were White, 3,483 (8.9%) were Black, and 1,844 (4.7%) were Hispanic. Similar findings were observed in both the CD and Control cohorts, which are presented in Supplemental Tables 3A-C, along with prematching and further demographic characteristics.
Short-term (90-day) postoperative complications
Postoperative complications within 90 days were compared across NTND, CD, and Control cohorts using chi-square analysis (Table 1, Table 2). Significant differences were observed across all complications, with the largest differences in opioid abuse, pneumonia, and sepsis.
Table 2.
Chi-square analysis of postoperative complication rates among nontobacco nicotine, cigarette-dependent, and control cohorts
| Complication | Chi-square statistic | p-value |
|---|---|---|
| Anemia | 51.8 | <.0001 |
| DVT | 8.80 | <.0001 |
| MI | 178.0 | <.0001 |
| Opioid abuse | 387.3 | <.0001 |
| PE | 10.3 | <.0001 |
| Pneumonia | 283.3 | <.0001 |
| Renal failure | 175.9 | <.0001 |
| Sepsis | 230.0 | <.0001 |
| Stroke | 137.0 | <.0001 |
| Transfusion | 44.9 | <.0001 |
| Lumbar fracture (3 yrs) | 104.0 | <.0001 |
| Pseudoarthrosis (3 yrs) | 918.4 | <.0001 |
Chi-square tests revealed that opioid abuse occurred significantly more frequently in NTND and CD patients compared to Controls (χ2 = 387.8, p < .001). Similarly, pneumonia (χ2 = 283.3) and sepsis (χ2 = 230.0) rates occurred significantly more frequently in NTND and CD patients compared to Controls (p < .001 for both). Interestingly, both DVT (χ2 = 8.80, p = .013) and PE (χ2 = 10.3, p = .0058) showed the smallest yet still significant differences across cohorts.
Post-hoc Dunn’s tests confirmed statistical significance of all pairwise complication comparisons; however, given the large sample size, risk ratios (RR) were used to assess clinical relevance (Table 1, Fig. 1). NTND patients had a 4.69 times higher risk of opioid abuse (RR: 4.69, 95% CI: 3.84–6.28) compared to Controls, while CD patients presented with the highest overall risk. Sepsis was 1.63 times more likely in NTND patients than Controls (RR: 1.63, 95% CI: 1.22–1.87), and pneumonia risk was 2.44 times higher in NTND patients compared to Controls (RR: 2.44, 95% CI: 2.19–2.76). Full risk ratios and statistical comparisons are detailed in Table 2.
Fig. 1.
Risk ratios (RR) with 95% confidence intervals comparing postoperative complication rates between NTND and Control cohorts at 90 days and 3 years. The dotted line at RR = 1 represents the null effect.
Long-term (3-year) postoperative complications
At 3 years, significant differences were observed in pseudoarthrosis and lumbar fractures between NTND cohorts and Controls (Table 1). Chi-square tests confirmed that pseudoarthrosis rates were significantly higher in NTND and CD groups compared to Controls (χ2 = 918.4, p < .001), and lumbar fracture rates also differed significantly between groups (χ2 = 104.0, p < .001) (Table 1).
Post-hoc Dunn’s tests confirmed that all cohort pairwise comparisons were significant. However, given the same large sample size limitations observed in the short-term analysis, risk ratios were calculated to further assess clinical validity (Table 1). NTND patients had a 1.36 times higher risk of pseudoarthrosis compared to Controls (RR:1.36, 95% CI: 1.29–1.42), with CD patients showing a similar elevated risk (RR: 2.34, 95% CI: 2.21–2.49). Additionally, lumbar fractures were 1.43 times more likely in the NTND cohort compared to Controls.
Kaplan-Meier survival analysis was conducted to assess pseudoarthrosis-free and lumbar fracture-free survival at 3 years (Fig. 2, Fig. 3). NTND patients had a lower probability of remaining pseudoarthrosis-free compared to Controls, with a steep decline in survival over time. In contrast, the survival curve for lumbar fractures showed a more gradual, yet significant, difference between NTND and Control. Log-rank tests confirmed the significant survival differences between NTND and Control groups (p < .0001).
Fig. 2.
Kaplan-Meier curve comparing pseudoarthrosis-free survival between NTND and Control cohorts over 3 years (log-rank p <.0001). The Y-axis reflects the proportion of patients without pseudoarthrosis at each time point.
Fig. 3.
Kaplan-Meier curve comparing fracture-free survival between NTND and Control cohorts over 3 years (log-rank p <.0001). The Y-axis reflects the proportion of patients without fracture at each time point.
Discussion
While prior studies have established the detrimental effects of cigarette smoking on bone healing and surgical outcomes [1,8], less is known about the risks posed by nontobacco nicotine products. In this exploratory, retrospective analysis, we observed significant associations between NTND and adverse postoperative outcomes following lumbar spine decompression and fusion. These results corroborate the previously reported negative effects of nicotine on postsurgical recovery and extend the evidence to a broader range of nicotine delivery modalities [[7], [16]].
Our study leveraged TriNetX, a federated, de-identified clinical research platform that aggregates electronic health records from large, diverse healthcare organizations across the United States. TriNetX has been validated in multiple prior orthopaedic and surgical studies as a reliable source for large-scale retrospective analyses, similar in scope to other widely used databases such as NSQIP, PearlDiver, and HCUP. Its ability to perform real-time cohort selection and propensity score matching enables efficient exploration of associations across expansive patient populations, though it remains subject to coding accuracy and residual confounding inherent to retrospective datasets [17,18].
Across matched comparisons, NTND was associated with increased short-term complication rates, including pneumonia, sepsis, and opioid use, as well as higher long-term risks of pseudoarthrosis and lumbar fracture. These results corroborate prior studies linking nicotine exposure to impaired immune response and bone healing [15], and highlight potential perioperative risks that may extend beyond traditional cigarette use. However, the absolute difference in complication rates were marginal in some cases, and the large sample size increases the likelihood of statistical significance for findings with unknown clinical importance. Additionally, multiple outcomes were assessed without prespecification of primary endpoints, increasing the risk of type I error.
The observed associations may reflect underlying physiological and behavioral effects of nicotine exposure. The elevated opioid abuse rates among NTND patients may reflect increased postoperative pain sensitivity, as nicotine has been shown to modulate pain pathways and enhance opioid reinforcement [19,20]. Prior studies suggest that nicotine may sensitize patients to nociceptive stimuli, increasing both perceived pain and opioid requirements following surgery [21]. These established neurochemical changes may contribute to a greater risk of prolonged opioid use or abuse in nicotine-dependent individuals.
At 3 years, significantly higher rates of pseudoarthrosis and lumbar fractures were observed among NTND and CD patients. This association may reflect nicotine’s known deleterious effects on bone metabolism. Nicotine has been shown to impair osteoblast function, inhibit angiogenesis, and promote bone resorption, each of which compromise spinal fusion and structural bone integrity [22,13]. It is important to note that the current analysis cannot distinguish between nicotine-induced biological effects and confounding behavioral or clinical factors. Nevertheless, these associations are biologically plausible and warrant further prospective investigation.
These findings raise concern regarding the potential perioperative effects of nontobacco nicotine use and underscore the importance of further investigation. While our results suggest meaningful associations between NTND and adverse surgical outcomes, additional prospective research is critical to delineate the specific impact of nicotine delivery methods and dosing patterns. Such evidence will be essential to guide clinical decision-making around screening, counseling, and perioperative risk mitigation strategies. Nevertheless, clinicians should be aware that nontobacco nicotine products are widely used and may not be disclosed unless patients are specifically prompted. Our findings highlight the need for more detailed nicotine exposure assessments during preoperative risk stratification and the value of future studies examining the effects of vaping, pouches, and other delivery modalities individually.
Our study has several limitations. Its retrospective design precludes causal inference. The definition of NTND relies on ICD-10 coding, which do not distinguish between specific nicotine delivery methods or quantify nicotine exposure. Patients my use multiple products simultaneously or fail to report use entirely, leading to misclassification. The analysis also involved multiple comparisons without adjusting for the number of statistical tests performed, thereby increasing the risk of identifying false-positive associations. Finally, although we applied propensity score matching to balance known covariates, residual confounding may persist. including factors such as socioeconomic status, comorbid psychiatric conditions, or variability in surgical technique. Future studies should prioritize prospective studies with detailed nicotine exposure profiling to assess whether specific delivery systems carry differential perioperative risk.
Conclusion
This study identifies significant associations between NTND and adverse postoperative outcomes following lumbar spine surgery. NTND patients experienced higher rates of infection and opioid use as well as elevated long-term risks of pseudoarthrosis and lumbar fractures. Given that spinal fusion success is highly dependent on bone healing these findings raise concern that nicotine, regardless of delivery method, may compromise surgical recovery in this vulnerable patient population.
Declaration of competing interest
One or more of the authors declare financial or professional relationships on ICMJE-NASSJ disclosure forms.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Footnotes
FDA device/drug status: Not applicable.
Author disclosures: CS: Nothing to disclose. MR: Nothing to disclose. MB: Nothing to disclose. MKP: Nothing to disclose. AT: Nothing to disclose. RL: Nothing to disclose. AS: Nothing to disclose. JPC: Nothing to disclose. HHW: Nothing to disclose. SH: Consulting fees: SI-Bone, Inc (C), Life Spine, Inc (C), Orthofix Medican, Inc (C), Alphatec Spine, Inc (C). MSK: Nothing to disclose.
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.xnsj.2025.100790.
Appendix. Supplementary materials
References
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