Opioid Withdrawal as a Barrier to Harm Reduction: Examining How Overdose Prevention Behaviors are Affected by Withdrawal

Abstract

Background and Objectives:

In the past decade, the increasing availability and prevalence of fentanyl in the drug supply have heightened the risk of fatal overdose and increased the frequency and severity of opioid withdrawal symptoms. We aimed to examine how opioid withdrawal impacts engagement in harm reduction behaviors among people who use drugs.

Methods:

Data came from a community-based research study in Baltimore, Maryland, conducted from 2022–2024. Participants were adults who used heroin, fentanyl, or prescription opiates to get high in the past month (N=676). Structured surveys assessed withdrawal as a barrier to testing drugs for potency and overdose prevention. Logistic regression models were used to identify correlates of engagement in harm reduction during periods of withdrawal.

Results:

Half the sample (46.6%) reported that withdrawal “always” or “often” prevented them from testing drugs, and 66.6% agreed that withdrawal was a barrier to overdose prevention. Depression symptoms (adjusted odds ratio (aOR): 1.56, 95% CI 1.09–2.25), increased opioid use per week (aOR: 1.12, 95% CI 1.03–1.22), and White race (aOR: 1.75, 95% CI 1.16–2.62) were independently associated with lower engagement in drug testing and overdose prevention during withdrawal.

Conclusions:

Withdrawal significantly impacts engagement in harm reduction behaviors, even among those with high awareness and receptivity to drug testing and overdose prevention strategies. Withdrawal management and mental health support are emergent and critical components for harm reduction interventions to prevent overdose morbidity and mortality among people who use drugs.

Background

Nearly 727,000 lives have been lost to opioid overdose in the United States since the onset of the opioid epidemic in 1999 (Centers for Disease Control and Prevention 2024). In 2023, there were approximately 107,000 drug overdose deaths, with over 70% of those deaths involving fentanyl (National Center for Health Statistics 2024). The high potency and fast onset of fentanyl contribute to its higher risk of dependence, overdose, and fatality (Williamson and Kermanizadeh 2024), and withdrawal related to fentanyl causes more severe and sustained symptoms compared with non-fentanyl opioids (Sharma et al. 2024). While harm reduction strategies mitigate overdose risk, the role of opioid withdrawal in shaping drug use behaviors is not well understood. Opioid withdrawal, which occurs when someone physically dependent on opioids abruptly decreases or halts their use (Bluthenthal et al. 2020), includes severe symptoms like bone pain, nausea and vomiting, and muscle aches (Bluthenthal et al. 2020). The US Food and Drug Administration recently reinforced that effective treatments for opioid use disorder and withdrawal remain a top agency priority (U.S. Food and Drug Administration 2018). Understanding how withdrawal impacts harm reduction behaviors, particularly in the context of widespread fentanyl availability and use, is essential to address gaps in intervention efforts. This study examines the relationship between withdrawal and harm reduction engagement, including the extent to which withdrawal contributes to reduced consistency in harm reduction engagement.

Harm reduction strategies such as naloxone distribution, usage, and overdose prevention education reduce overdose and opioid-related mortality (Razaghizad et al. 2021), and the use of fentanyl test strips has been associated with modifications to the dose, speed, and/or route of drug ingestion (Peiper et al. 2019; Krieger et al. 2018; Kourvelas et al. 2024). Other strategies for testing drugs prior to use include going slow to test drugs’ strength or using a small dose first, which allow people to assess drug potency and control their intake (Winiker et al. 2020). Despite the effectiveness of these strategies, drug withdrawal has been characterized as a barrier to engagement in harm reduction practices. Studies show that up to 85% of people who inject drugs reported experiencing withdrawal symptoms during the last 6 months, with a third (35%) experiencing them weekly (Bluthenthal et al. 2020). While much of the current literature on withdrawal relates to HIV and Hepatitis C virus transmission (e.g., sharing injection equipment, lack of sterilization), research posits that withdrawal broadly alters decision-making among people who use drugs (PWUD) (Frank et al. 2023; Ross et al. 1994). For example, withdrawal increased engagement in risky injection practices such as sharing used syringes and attending risky injections settings, largely driven by an “immediate pressing need to overcome withdrawal (Mateu-Gelabert et al. 2010; Stein et al. 2007).” Previous qualitative research has explored how both active withdrawal as well as fear of precipitated withdrawal may drive opioid use and act as barriers to treatment initiation (Simpson et al. 2024).

Further qualitative work has suggested that efforts to reduce overdose risk may be complicated by withdrawal experiences (Collins et al. 2024; Elliott et al. 2024). Although harm reduction education and resources such as naloxone are increasingly disseminated and available in the US (Freeman et al. 2018), the extent to which withdrawal affects engagement in harm reduction behaviors and increases risk of overdose is not well understood. Moreover, the discordance between self-reported consistent engagement in harm reduction behaviors and impacted engagement or consideration of harm reduction strategies during withdrawal is unknown. Contextualizing harm reduction engagement during withdrawal is a critical factor in gaining a more nuanced perspective of PWUDs’ overall risk of fatal overdose.

This study examined withdrawal as a barrier to (1) testing drugs for potency and (2) overdose prevention among PWUD as well as among the subset who endorsed consistent engagement in harm reduction behaviors. We also assessed multilevel factors associated with reduced harm reduction when experiencing withdrawal. Finally, we investigated how withdrawal impacts harm reduction behaviors among those who report high engagement in harm reduction behaviors.

Methods

2.1. Study Description

Data come from the Oasis study, a project centered on promoting engagement in risk reduction and characterizing locations where people use drugs (ClinicalTrials.gov 2025). The study was conducted at a community-based research center in Baltimore, MD. Eligible participants were individuals 18 years or older who lived in the Baltimore Metropolitan area and had used opioids like heroin, fentanyl, or prescription opiates to get high within the past month. All participants provided informed consent to participate in the study. This study was approved by the Johns Hopkins Bloomberg School of Public Health IRB [blinded].

All participants completed an in-person quantitative survey questionnaire facilitated by trained interviewers. Survey questions included sociodemographic and health information, substance use frequency and characteristics, experiences using drugs in different settings, and familiarity and engagement in harm reduction. All study participants were compensated for their time.

Data for this study were collected between December 2022 and August 2024. Recruitment strategies included production and dissemination of flyers that were sent to various local community organizations. Prior study participants at the research center were also contacted and informed that they may be eligible for new studies. This analysis includes participants who completed their baseline survey on or before August 13, 2024.

2.2. Study Variables

There were two primary outcomes in this study. Withdrawal as a barrier to testing for potency was assessed with the question: “How often does feeling sick or in withdrawal prevent you from testing your drugs? (use a small amount first, go slow, use fentanyl test strips).” For the analysis, the responses were collapsed to a three-level variable, which assessed “Always” or “Often” versus “Sometimes” versus “Rarely” or “Never.” This categorization captured those who experienced a meaningful and consistent frequency of withdrawal impacting harm reduction behaviors compared with those for whom withdrawal had minimal or no impact on these behaviors.

Withdrawal as a barrier to overdose prevention was assessed with the question: “Sometimes when I feel sick or in withdrawal from not having my fix, I don’t think about overdose prevention.” Response categories were dichotomized into responses of “Strongly agree” and “Agree” versus “Neither agree nor disagree,” “Disagree,” and “Strongly disagree.” The former category captured those who explicitly acknowledged that withdrawal was a barrier to overdose prevention, and the latter category captured those who disagreed with the statement or were ambivalent.

To further understand how withdrawal affects harm reduction efforts, we examined a subset of the sample who endorsed consistent engagement in certain harm reduction behaviors across other survey items. Respondents were asked how often they engaged in: (1) going slow to test strength of drugs, (2) using a little bit first, and (3) using fentanyl test strips. Responses categories included: “Always,” “Often,” “Sometimes,” “Rarely,” and “Never.” To capture those endorsing consistent engagement in harm reduction, responses were dichotomized to compare responses of “Always” or “Often” with “Sometimes,” “Rarely,” or “Never.” Reponses were dichotomized based on construct validity (consistent versus inconsistent/episodic engagement) and measurement considerations including central tendency response bias. In focusing on a subset of individuals who already regularly engage in harm reduction practices, we aimed to understand how these strategies may fail in a real-world context, despite appropriate awareness and receptivity to harm reduction practices.

Variables of interest focused on factors at the individual and interpersonal levels, which may guide tailored, client-centered interventions. Sociodemographic variables included age, sex assigned at birth, race/ethnicity, employment status, and homelessness in the past six months based on self-reported responses to survey questions. Health variables included symptoms of depression measured on Center of Epidemiologic Studies Depression Scale (CESD-10) with a score of 10 or greater indicating depressed mood. The CESD-10 has demonstrated good reliability and construct validity among various adult populations in community and clinical settings (Cheung, Liu, and Yip 2007; Björgvinsson et al. 2013; Zhang et al. 2012). The binary construct (>10 vs <10) was used in this analysis to improve interpretability of findings. Health variables also included HIV status, as associations between increased substance use and HIV risk behaviors have been previously established (Andresen et al. 1994; Patrick et al. 2012). Variables related to substance use included currently taking medications for substance use disorder (MOUD) (e.g., methadone, buprenorphine, naltrexone) and days per week of opioid use. Because fentanyl and heroin use co-occurred frequently in our sample, we opted to model overall opioid use frequency. The number of adults in the household using drugs was included for theoretical relevance, as prior research has social network behaviors surrounding drug use and harm reduction influence individual behavioral engagement (McDonald et al. 2011; Latkin et al. 2003).

2.3. Analysis

Overall, 676 participants were included in the current analysis. We used descriptive statistics to characterize sample demographics and reported engagement in harm reduction behaviors. Cross-tabulation analyses, which describe interactions between categorical variables, were conducted to assess (1) withdrawal as a barrier to testing for potency, and (2) withdrawal as a barrier to overdose prevention. Specifically, we were interested in evaluating discordance across categories, in which participants endorsed consistent engagement in primary harm reduction behaviors but also endorsed that withdrawal “Always” or “Often” affected their overdose prevention or testing for potency.

Bivariate and multivariate regression analyses were conducted to identify independent correlates of primary outcomes. Logistic regression was used to model withdrawal as a barrier to overdose prevention, which was categorized as a binary variable. Because withdrawal as a barrier to testing for potency was represented by a three-level outcome, ordinal logistic regression was used to model predictive effects. The odds ratio from an ordinal logistic regression represents changed odds of being in a higher category (e.g., increased engagement) versus any lower category and assumes proportional odds (i.e., that the effect is consistent across categorical thresholds of the ordinal outcome). The proportional odds assumption for all independent predictors was tested using the Brant test for parallel regression.

All sociodemographic variables were included in the final multivariable model as well as any significant covariates with a p-value < 0.10 in bivariate analyses (Chowdhury and Turin 2020). Variance Inflation Factor (VIF) was calculated to assess multi-collinearity, for which a threshold below a VIF of 10 was deemed acceptable (O’Brien 2007). A sensitivity analysis was conducted which excluded respondents who responded “Neither agree nor disagree” to withdrawal as a barrier to overdose prevention (n=48, 7.1% of analytic sample).

All data analyses were conducted in STATA 18.0 (StataCorp 2017).

Results

Sample demographics are described in Table 1. Participants were an average of 50.0 years of age (SD 10.9) and majority Black (73.1%) and male (59.2%). Most were either unemployed (42.3%) or disabled or unable to work (43.2%), and slightly less than half (43.2%) endorsed being homeless in the past six months prior to survey completion. A minority were living with HIV (7.8%). Nearly three-quarters of the sample (70.0%) had a CESD-10 score greater than 10, meeting criteria for depressive symptoms. Approximately half of the sample (48.7%) was currently taking MOUD, and participants were using opioids on average 5.7 days of the week (SD 1.9).

Table 1:

Characteristics of Full Sample of Oasis study, Baltimore, MD (N=676)

Variables	Full Sample (n=676) n(%) or Mean(SD)
Sociodemographic
Age (Years)	50.0 (10.9)
Race
Black	494 (73.1%)
White	145 (21.5%)
Other	37 (5.4%)
Sex at Birth
Male	400 (59.2%)
Female	276 (40.8%)
Employment
Employed/Retired	100 (14.8%)
Unemployed	286 (42.3%)
Disabled/Unable to work	290 (42.9%)
Homeless in past 6 months	292 (43.2%)
Health Characteristics
Living with HIV	52 (7.8%)
CESD-10 Score > 10	473 (70.0%)
Substance Use
Currently on MOUD	329 (48.7%)
Days per week using opioids	5.7 (1.9)
Interpersonal
Number of adults in household who use drugs, excluding self	1.0 (1.6)

Harm reduction characteristics and perceptions of withdrawal as a barrier to harm reduction are described in Table 2. Over half of the sample endorsed consistent (“Always” or “Often”) engagement in harm reduction behaviors, including using a small dose first (n=429, 63.5%) and going slow to test drugs’ strength (n=365, 54.0%). Approximately 10.7% endorsed consistent use of fentanyl test strips (n=72, 10.7%).

Table 2:

Harm Reduction and Withdrawal Characteristics of Full Sample (N=676)

Variables	Full Sample n (%)
Harm Reduction Behaviors
Small dose first
Always/Often	429 (63.5%)
Sometimes/Rarely/Never	247 (36.5%)
Going slow to test drugs’ strength
Always/Often	364 (54.0%)
Sometimes/Rarely/Never	312 (56.0%)
Using fentanyl test strips
Always/Often	72 (10.7%)
Sometimes/Rarely/Never	604 (89.3%)
Withdrawal as a barrier to testing drugs for potency (e.g., using a small amount first, going slow, using test strips)
Always/Often	315 (46.6%)
Sometimes	159 (23.5%)
Rarely/Never	202 (29.9%)
Withdrawal as a barrier to thinking about overdose prevention
Strongly Agree/Agree	450 (66.6%)
Neither/Disagree/Strongly Disagree	226 (33.4%)

When asked about the extent to which withdrawal was a barrier to general harm reduction practices, nearly half the sample (46.6%) endorsed that withdrawal was “Always” or “Often” a barrier to testing drugs for potency, with another quarter (23.5%) reporting that it “Sometimes” was a barrier. Similarly, two-thirds of the sample (66.6%) strongly agreed or agreed that withdrawal was a barrier to overdose prevention.

Figure 1 explores the extent to which those who consistently engage in harm reduction also report that withdrawal is a barrier to testing for potency or overdose prevention precautions. Among those who reported consistently (“Always” or “Often”) using a small dose first, 27.5% reported that withdrawal “always” or “often” prevented them from testing drugs, 27.3% reported that withdrawal “sometimes” had this effect, and 63.9% agreed that withdrawal caused them to not think about overdose prevention (Figure 1). Of those who reported consistently going slow to check drugs’ strength, withdrawal “always” or “often” (26.3%) or “sometimes” (23.6%) prevented them from testing drugs, and 60.3% reported that withdrawal caused them to not think about overdose prevention. Finally, among those who reported consistent use of fentanyl test strips, withdrawal “always” or “often” (27.8%) or “sometimes” (26.4%) prevented them from testing drugs, and a majority (63.9%) reported that withdrawal was a barrier to thinking about overdose prevention.

Figure 1:

Degree to which withdrawal is a barrier among those endorsing consistent engagement in harm reduction behaviors among people who use opioids in Baltimore, MD

Results from logistic and ordinal logistic regression models are displayed in Table 3. In bivariate analyses, White race (OR: 2.06, 95% CI: 1.34–3.18) compared to Black, reporting homelessness in the past six months (OR 1.49, CI 1.08–2.07), moderate depression symptoms (OR: 1.65, CI 1.17–2.32), and increased days per week using opioids (OR: 1.16, 95% CI: 1.07–1.26) were significantly associated with perceiving withdrawal as a barrier to overdose prevention. Increasing age (OR: 0.98, 95% CI: 0.96–0.99) and living with HIV (OR: 0.47, 95% CI: 0.26–0.83) were negatively associated with endorsing withdrawal as a barrier to overdose prevention. In multivariate analyses adjusting for age, race, sex at birth, unemployment status, HIV status, and homelessness status, only having moderate depression symptoms (aOR: 1.56, 95% CI: 1.09–2.25) and increasing days per week using opioids (aOR: 1.12, 95% CI: 1.03–1.22) were significantly associated with endorsing withdrawal as a barrier to overdose prevention. The mean VIF was 1.43, indicating an acceptable level of multicollinearity among the predictors.

Table 3:

Correlates of endorsing withdrawal as a barrier to overdose prevention and testing for potency among people who use opioids in Baltimore, MD (N=676)

Variables	Withdrawal as barrier to overdose preventiona OR (95% CI)	aOR* (95% CI)a	Withdrawal as barrier to testing for potencyb OR (95% CI)	aOR* (95% CI)b
Sociodemographic
Age (Years)	0.98 (0.96–0.99)	1.00 (0.98–1.02)	0.98 (0.97–1.00)	1.00 (0.99–1.02)
Race
Black	REF	REF	REF	REF
White	2.06 (1.34–3.18)	1.65 (0.99–2.73)	2.05 (1.45–2.91)	1.75 (1.16–2.62)
Other	1.22 (0.60–2.48)	1.06 (0.50–2.24)	1.61 (0.85–3.06)	1.31 (0.67–2.57)
Sex at Birth
Male	REF	REF	REF	REF
Female	0.98 (0.71–1.36)	0.95 (0.67–1.33)	1.12 (0.84–1.49)	1.11 (0.83–1.50)
Employment
Employed/Retired	REF	REF	REF	REF
Unemployed	1.37 (0.84–2.24)	1.24 (0.74–2.09)	1.07 (0.70–1.63)	0.86 (0.55–1.35)
Disabled/Unable	0.80 (0.49–1.28)	0.89 (0.54–1.47)	0.85 (0.56–1.30)	0.83 (0.53–1.29)
Homeless, past 6 months	1.49 (1.08–2.07)	1.04 (0.72–1.52)	1.59 (1.19–2.11)	1.32 (0.96–1.81)
Health Characteristics
Living with HIV	0.47 (0.26–0.83)	0.63 (0.35–1.15)	0.64 (0.37–1.10)	0.78 (0.45–1.37)
CESD-10 Score > 10	1.65 (1.17–2.32)	1.56 (1.09–2.25)	1.56 (1.14–2.15)	1.45 (1.04–2.02)
Substance Use
Currently on MOUD	1.27 (0.92–1.75)	--	0.98 (0.74–1.30)	--
Days per week using opioids	1.16 (1.07–1.26)	1.12 (1.03–1.22)	1.09 (1.01–1.17)	1.04 (0.97–1.13)
Interpersonal
Number of adults in household who use drugs, excluding self	0.97 (0.84–1.11)	--	1.02 (0.90–1.15)	--

^*OR = Odds Ratio, aOR = Adjusted Odds Ratio

^aLogistic regression

^bOrdinal logistic regression

Bold values denote statistically significant findings at the 0.05 level (two-sided).

In the ordinal logistic models, bivariate associations were identified between White race compared with Black (aOR: 1.93, 95% CI: 1.03–3.62), moderate depression symptoms (OR: 1.56, 95% CI: 1.14–2.15), homelessness in the past six months (OR: 1.59, 95% CI: 1.19–2.11), increased days of the week using opioids (OR: 1.09, 95% CI: 1.01–1.17), and withdrawal as a barrier to testing for potency. In these models, an odds ratio greater than 1 suggests an increased likelihood of reporting more severe overdose prevention disengagement due to withdrawal. In the multivariable ordinal logistic model, adjusting for sociodemographic and health characteristics, only White race (aOR: 1.75, 95% CI: 1.16–2.62) and CESD-10 (OR: 1.45, 95% CI: 1.04–2.02) remained independently associated with withdrawal as a barrier to testing for potency.

In a sensitivity analysis, excluding participants who selected “Neither agree nor disagree” to the question “Sometimes when I feel sick or in withdrawal from not having my fix, I don’t think about overdose prevention” yielded similar results. CESD-10 remained independently associated with endorsing withdrawal as a barrier to overdose prevention (aOR: 1.63, 95% CI: 1.11–2.41), as did increased days of the week using opioids (aOR: 1.13, 95% CI: 1.03–1.24).

Discussion

Drug-related withdrawal greatly impacted study participants’ engagement in overdose prevention and drug testing behaviors. Despite reporting consistent engagement in harm reduction behaviors (“Often” or “Always”), many participants cited withdrawal as a barrier to overdose prevention as well as a barrier to testing for potency. This discordance highlights that withdrawal is a critical risk factor for overdose, even among those who are familiar with and otherwise regularly engage in harm reduction strategies.

Findings align with previous literature that predominantly used qualitative methods to describe the impact of withdrawal on increased risk relating to decreased HIV-related harm reduction behaviors (Mateu-Gelabert et al. 2010; Stein et al. 2007). Our study extends the scope of this prior research to examine the impact of withdrawal on a broader range of harm reduction strategies pertaining to overdose prevention (using a small dose first, going slow, using fentanyl test strips), which remains of critical concern given widespread accessibility and potency of fentanyl and other synthetic opioids, which drive both overdose fatality and severity of withdrawal symptoms. Additionally, this study is one of few to provide quantitative insight into the potential and actual impacts of withdrawal on harm reduction engagement.

Importantly, mental health concerns, specifically depressive symptoms, emerged as a consistent predictor of decreased harm reduction engagement. Having a positive CESD-10 screen was independently associated with 56% increased odds of endorsing withdrawal as a barrier to overdose prevention and 45% increased odds of actively reporting reduced testing for potency during withdrawal. While associations between opioid misuse and increased withdrawal symptomatology have been established in the literature (Rogers et al. 2021), this study appears to be the first to posit an association between depressive symptoms and reduced overdose prevention and potency testing behaviors due to withdrawal. A prior study linked depressive symptoms with increased opioid misuse to avoid withdrawal (Bouvier et al. 2019). It is plausible that depression may affect both patterns of substance use and the extent to which individuals value their lives and thus their risk of overdose, which may also impact experiences of withdrawal. Further research should investigate interactions between mental health burden and withdrawal experiences.

Altogether, findings emphasize the critical importance of integrating mental health evaluation or care with harm reduction services. Given a high burden of co-morbid mental health disorders with substance use, these individuals are at particularly heightened risk of overdose and mortality. Harm reduction interventions should account for mental health as an important mediating factor between intervention delivery and consistent uptake. Intervention frameworks such as integrated or collaborative care models, in which mental health and substance use treatment are integrated into primary care settings, may bridge this gap. Promoting infrastructure for referrals for mental health care at community harm reduction centers may also be a useful strategy.

In multivariable models, increased weekly opioid use was also associated with endorsing withdrawal as a barrier to overdose prevention, with 12% increased odds of endorsement for each additional day of opioid use per week. Biological mechanisms can account for greater tolerance with increased opioid use, thereby worsening withdrawal symptoms (Haertzen, Meketon, and Hooks Jr 1970). While individuals who use opioids are already at higher risk of overdose, this risk of overdose is further compounded by decreased engagement in drug testing behaviors during withdrawal, as observed in our study. Finally, White race was associated with 75% increased odds of endorsing withdrawal as a barrier to testing for potency. The association between White race and reduced harm reduction engagement during withdrawal may reflect underlying sociocultural differences in harm reduction outreach, stigma, and healthcare access, for which further research is warranted.

This study had several limitations. The cross-sectional nature of the study precludes any causal inferences between withdrawal and active reductions in harm reduction behaviors. In addition, the study did not assess the frequency of withdrawal states among participants, which would have led to a more robust understanding of the overall impact of withdrawal on participants. We also did not adjust models for intentional fentanyl use, given highly prevalent heroin co-use and low fentanyl-only use preferences. Finally, there are additional dimensions of withdrawal –for example, anticipated withdrawal, as well as subjective vs objective perceptions– that were not assessed in this study. Future work should include more nuanced measurement and quantification of withdrawal states, as well as probe at other dimensions of withdrawal mentioned above that likely affect engagement in risk reduction behaviors.

Nearly one-third of individuals endorsing consistent harm reduction engagement also reported substantially decreased testing for potency during withdrawal. This underscores that withdrawal is a critical barrier to sustained harm reduction participation, even when adequate education and resources are available. To enhance effectiveness of harm reduction programs, intervention designs must consider fluctuating needs and priorities of PWUD in a real-world context, in which situational conditions such as withdrawal may attenuate the effectiveness of interventions. For example, withdrawal management techniques (e.g., cognitive behavioral therapy, craving identification and management) may be further characterized and incorporated into overdose prevention education (Stalcup et al. 2006; Soyka 2017). These strategies should be disseminated widely among providers and community centers with many PWUD clientele. Further, survey measures should not only assess overall harm reduction engagement but explicitly probe at harm reduction behaviors during periods of withdrawal. Such measures would provide a more nuanced understanding of harm reduction engagement among PWUD and inform targeted interventions during high-risk periods such as withdrawal.

In the context of the opioid epidemic that continues to claim over 100,000 lives per year (National Center for Health Statistics 2024), our findings underscore the urgent need for harm reduction interventions to consider withdrawal as a crucial and independent factor increasing overdose risk and mortality. While harm reduction strategies have been shown to mitigate risk, their effectiveness may be diminished during withdrawal, even among individuals who otherwise consistently engage in risk reduction practices. Integrating mental health support into harm reduction services and adapting interventions to consider fluctuating real-world priorities of PWUD are critical next steps. Future research may more precisely quantify experiences of withdrawal and measure withdrawal severity, as well as evaluate and disseminate withdrawal management strategies to clinical and social services providing harm reduction education to PWUD. Future research may also capture more granular assessments of route of administration and specific types of opioids used to support tailored harm reduction efforts. It is essential that current harm reduction interventions align with PWUDs’ lived experiences and explicitly address heightened risk of overdose associated with withdrawal.

Highlights.

1. Withdrawal reduced engagement in drug testing and overdose prevention behaviors.

2. Depressive symptoms predicted reduced overdose prevention during withdrawal.

3. Increased opioid use was associated with decreased overdose prevention during withdrawal.

4. Withdrawal management and mental health care should be core intervention components.