The association of pain impact and sleep disruption with opioid withdrawal during opioid-use disorder treatment.

AIMS: Persons with opioid-use disorder (OUD) often experience opioid withdrawal and opioid craving, which can drive continued opioid use and treatment discontinuation. In addition, hyperalgesia is common among persons with OUD, yet few studies have examined the role of pain impact during OUD treatment. The purpose of the present study was to test whether opioid withdrawal and craving were elevated in the context of greater pain impact (i.e. greater pain intensity and interference), and whether these associations changed throughout treatment. METHODS: Participants in residential OUD treatment (n = 24) wore wrist actigraphy to measure sleep and completed daily measures of pain impact, opioid withdrawal and opioid craving for up to 28 days. Mixed effects models were used to examine whether daily elevations in pain impact and sleep continuity were associated with withdrawal severity and opioid craving. RESULTS: Elevations in withdrawal, but not craving, occurred on days when individuals reported higher scores on the pain impact scale. Associations between pain impact and withdrawal were present throughout treatment, but stronger during early treatment. In contrast, both withdrawal and opioid craving were elevated following nights of greater wake after sleep onset and awakenings, but these findings were often more pronounced in early treatment. CONCLUSIONS: Pain impact and sleep disturbance are 2 factors associated with opioid withdrawal and opioid craving. Novel pharmacotherapies and scalable adjunctive interventions targeting sleep and pain impact should be tested in future work to improve OUD treatment outcomes.

Polymorphisms in the A118G SNP of the OPRM1 gene produce different experiences of opioids: A human laboratory phenotype-genotype assessment.

Allelic variations in the A118G SNP of the OPRM1 gene change opioid signaling; however, evaluations of how allelic differences may influence opioid effects are lacking. This human laboratory paradigm examined whether the AA versus AG/GG genotypes determined opioid response profiles. Individuals with limited opioid exposure (N = 100) completed a five-day within-subject, double-blind, placebo-controlled, residential study. Participants were admitted (Day 1), received 4 mg hydromorphone (Day 2) and 0 mg, 2 mg and 8 mg hydromorphone in randomized order (Days 3-5) and completed self-reported visual analog scale (VAS) ratings and Likert scales, observed VAS, and physiological responses at baseline and for 6.5 h post-dose. Outcomes were analysed as peak/nadir effects over time as a function of genotype (available for N = 96 individuals; AG/GG = 13.5%, AA = 86.4%). Participants with AG/GG rated low and moderate doses of hydromorphone as significantly more positive (e.g., Good Effects VAS, coasting, drive, friendly, talkative, stimulation) with fewer negative effects (e.g., itchy skin, nausea, sleepiness), and were also observed as being more talkative and energetic relative to persons with AA. Persons with AG/GG were less physiologically reactive as determined by diastolic blood pressure and heart rate, but had more changes in core temperature compared with those with AA. Persons with AA also demonstrated more prototypic agonist effects across doses; persons with AG/GG showed limited response to 2 mg and 4 mg. Data suggest persons with AG/GG genotype experienced more pleasant and fewer unpleasant responses to hydromorphone relative to persons with AA. Future studies should replicate these laboratory findings in clinical populations to support a precision medicine approach to opioid prescribing.

COVID-19-Related Financial Hardship Is Associated With Depression and Anxiety in Substance Use Treatment Across Gender and Racial Groups.

ABSTRACT: Many individuals lost their employment during the COVID-19 pandemic and experienced financial hardship. These experiences may increase risk for co-occurring conditions, including substance use disorders (SUDs) and related symptoms of depression and anxiety. This study aimed to examine the associations between COVID-19-related financial hardship and/or job loss and co-occurring symptoms, across gender and racial groups. Respondents (N = 3493) included individuals entering SUD treatment in the United States in March-October of 2020. Results demonstrated that COVID-19-related financial hardship and unemployment in the household was associated with greater depression and anxiety severity among people in SUD treatment (p's < 0.05). Our findings highlight financial hardship and loss of employment as risk factors for co-occurring depression and anxiety. However, additive effects between marginalized identity status and COVID-19 economic hardship on co-occurring symptoms were not observed.

Shared Genetic Etiology between Cortical Brain Morphology and Tobacco, Alcohol, and Cannabis Use.

Genome-wide association studies (GWAS) have identified genetic variants associated with brain morphology and substance use behaviors (SUB). However, the genetic overlap between brain structure and SUB has not been well characterized. We leveraged GWAS summary data of 71 brain imaging measures and alcohol, tobacco, and cannabis use to investigate their genetic overlap using linkage disequilibrium score regression. We used genomic structural equation modeling to model a "common SUB genetic factor" and investigated its genetic overlap with brain structure. Furthermore, we estimated SUB polygenic risk scores (PRS) and examined whether they predicted brain imaging traits using the Adolescent Behavior and Cognitive Development (ABCD) study. We identified 8 significant negative genetic correlations, including between (1) alcoholic drinks per week and average cortical thickness, and (2) intracranial volume with age of smoking initiation. We observed 5 positive genetic correlations, including those between (1) insula surface area and lifetime cannabis use, and (2) the common SUB genetic factor and pericalcarine surface area. SUB PRS were associated with brain structure variation in ABCD. Our findings highlight a shared genetic etiology between cortical brain morphology and SUB and suggest that genetic variants associated with SUB may be causally related to brain structure differences.

Clinical correlates of drug-related dreams in opioid use disorder.

BACKGROUND AND OBJECTIVES: Drug-related dreams are commonly reported by individuals in treatment for substance use disorders, which may be distressing. Existing evidence suggests that dream recollection may be influenced by clinically relevant phenomena, such as opioid use and withdrawal, general sleep disturbance, affective symptoms, and chronic pain. However, very few studies have explored drug-related dreams among individuals who screened positive for opioid use disorder (OUD). METHODS: Adults recruited from Amazon Mechanical Turk (MTurk) who screened positive for OUD (N = 154) completed a questionnaire about drug-related dreams, as well as measures assessing sleep, opioid use history, stress, anxiety, and chronic pain. χ2 analyses, one-way analysis of variance, and bivariate correlations, correcting for the false discovery rate, were used as appropriate to explore correlates of (1) recollecting a drug-related dream, and (2) experiencing post-dream craving and distress. RESULTS: Individuals who recollected a past-week drug-related dream were more likely to report other recent sleep disturbances, including poorer sleep quality, greater insomnia symptoms, and a higher risk for sleep apnea. Post-dream craving and distress were both associated with greater insomnia symptoms, poor sleep hygiene behaviors, and greater anxiety symptoms. Individuals who had ever experienced a drug-related dream (recently, or in their lifetime) were more likely to report a history of severe withdrawal, overdose, and intravenous opioid use. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Drug-related dreams were common among individuals in the present sample and were related to other clinically relevant phenomena. Interventions that treat co-occurring OUD, pain, sleep symptoms, and affective symptoms may improve overall well-being in this population.

Early Childhood Behavioral and Academic Antecedents of Lifetime Opioid Misuse among Urban Youth.

OBJECTIVE: Opioid misuse has become an epidemic in the United States. In the present study, we examine potential malleable early childhood predictors of opioid misuse including whether childhood achievement, aggressive behavior, attention problems, and peer social preference/likability in first grade predicted opioid misuse and whether these relationships differed depending on participant sex. METHOD: Data are drawn from three cohorts of participants (N = 1,585; 46.7% male) recruited in first grade as part of a series of elementary school-based, universal preventive interventions conducted in a Mid-Atlantic region of the US. In first grade, participants completed standardized achievement tests, teachers reported on attention problems, and peers nominated their classmates with respect to their aggressive behavior and social preference/likability. At approximately age 20, participants reported on their misuse of opioids defined as lifetime use of heroin or misuse of prescription opioids. RESULTS: Higher levels of peer nominations for aggressive behavior in first grade predicted a greater likelihood of opioid misuse. An interaction between participant sex and attention problems was observed such that females higher in attention problems were more likely to misuse opioids, particularly prescription opioids, than females lower in attention problems. An interaction was also found between participant sex and peer likability such that males lower in peer-nominated likability were more likely to misuse opioids relative to males higher in likability. CONCLUSION: Given the malleable nature of attention problems, aggression, and social skills in early childhood, prevention programs that target these behaviors during this developmental period may attenuate risk for opioid misuse.

Substance Use in the Performing Artist with Chronic Pain.

OBJECTIVES: To evaluate how performing artists (PAs) with chronic pain may differ on measures of substance use compared to non-PA controls. METHODS: 157 participants reporting chronic pain (89 PAs, 68 non-PA controls) completed an online cross-sectional survey. Participants were assessed for self-reported current pain severity using the Brief Pain Inventory Short-Form, opioid misuse risk using the Screener and Opioid Assessment for Patients with Pain-Revised, opioid withdrawal using the Subjective Opiate Withdrawal Scale, and symptoms of opioid use disorder (OUD) using a modified version of the DSM-V checklist. RESULTS: PAs had lower pain severity (p <0.05, t=2.196, df=155) and lower pain interference (p <0.05, t=2.194) than non-PA controls. 24% of PAs and 13% of controls reported using opioids within the past month. Among PAs, the number of days using opioids in the past month was positively associated with hours spent practicing per week (r=0.508, p <0.05). PAs (66%) were more likely to endorse current alcohol use than controls (44.1%, t= -2.136, X2=7.72, p <0.01). Importantly, PAs (19%) were more likely than controls (3%) to endorse symptoms of at least mild OUD (X2(3)=11.3, p <0.01) and higher ratings of opioid misuse risk (t=-2.166, p <0.05). Past month opioid withdrawal was also greater in PAs than controls (t=-2.136, p <0.05), and 5.6% of PAs and 1.5% of controls reported at least one prior incidence incident of opioid overdose in their lifetime (X2 =1.80, NS). CONCLUSIONS: Among persons with chronic pain, PAs may have higher risk for opioid-related consequences, including OUD, and should be screened during health care encounters.

Method for Successfully Inducting Individuals Who Use Illicit Fentanyl Onto Buprenorphine/Naloxone.

BACKGROUND AND OBJECTIVES: Individuals exposed to fentanyl are at risk of precipitated withdrawal using typical buprenorphine/naloxone induction procedures. METHODS: This case series describes buprenorphine/naloxone inductions of four individuals who tested positive for fentanyl. RESULTS: Buprenorphine-precipitated withdrawal was observed in two individuals who completed a conventional buprenorphine/naloxone induction strategy. Two more individuals completed a revised buprenorphine/naloxone induction strategy that did not precipitate withdrawal. DISCUSSION AND CONCLUSION: Using multiple 2 mg doses of buprenorphine/naloxone in patients already in mild/moderate withdrawal improved outcomes. SCIENTIFIC SIGNIFICANCE: Persons who use illicit fentanyl might be less likely to experience precipitated withdrawal from this revised buprenorphine/naloxone induction strategy. (Am J Addict 2021;30:83-87).

Challenges for Women Entering Treatment for Opioid Use Disorder.

PURPOSE OF REVIEW: Women with opioid use disorder (OUD) face unique challenges the moment they enter treatment. This narrative review focused on recent literature regarding sex- and gender-based issues that could affect treatment outcomes in women with OUD. RECENT FINDINGS: Women respond differently to opioids based on hormonal factors, are more likely to present to treatment with mental health conditions, especially depression, and are more likely to have experienced trauma via intimate partner violence compared with men. Women also face stigma when entering OUD treatment, particularly if they have children. Future research to improve OUD treatment outcomes in women should account for sex as a biological variable and gender as a social construct. Women have a fundamentally different experience than men during the course of OUD and upon treatment entry. Programs that address childcare/family support, mental health, and trauma are warranted for women with OUD.

Preliminary evidence of different and clinically meaningful opioid withdrawal phenotypes.

Opioid use disorder (OUD) is a public health crisis. Differences in opioid withdrawal severity that predict treatment outcome could facilitate the process of matching patients to treatments. This is a secondary analysis of a randomized controlled trial (RCT) that enrolled treatment seeking heroin-users (N = 89, males = 78) into a residential study. Participants maintained on morphine (30 mg, subcutaneous, four-times daily) underwent a naloxone (0.4 mg, IM = intramuscular) challenge session to precipitate withdrawal. Area-under-the-curve (AUC) values from self-reported withdrawal ratings during the challenge session were analyzed using K-means clustering, revealing two phenotype groups. Withdrawal and retention from the subsequent 14-day double-blind, double-dummy RCT comparing three study medications (clonidine, tramadol-ER, and buprenorphine) were evaluated as a function of phenotype. Cluster analyses suggested HIGH (N = 37; mean [SD] subjective opiate withdrawal scale [SOWS]-AUC 123.7 [65.8]) and LOW (N = 52; SOWS-AUC 68.0 [47.7]) withdrawal phenotype groups. HIGH participants were significantly more female and had lower body mass indices than LOW participants; no drug-use variables were significant. Regarding RCT outcomes, HIGH phenotype participants were less likely to be retained in the study (P = 0.02) and had higher mean self-reported withdrawal (P = 0.05) than LOW phenotype participants. A significant interaction in RCT retention was observed between phenotype (P = 0.02) and study medication (P < 0.01). Self-reported withdrawal was significant for phenotype (P = 0.02); study medication trended towards significance (P = 0.07). Results suggest patients have meaningfully different experiences of opioid withdrawal that may predict differential response to opioid pharmacotherapies during supervised withdrawal. Additional prospective research to replicate and more thoroughly evaluate withdrawal phenotype correlates and sex differences is warranted.

Non-Opioid Neurotransmitter Systems that Contribute to the Opioid Withdrawal Syndrome: A Review of Preclinical and Human Evidence.

Opioid misuse and abuse is a major international public health issue. Opioid use disorder (OUD) is largely maintained by a desire to suppress aversive opioid withdrawal symptoms. Opioid withdrawal in patients seeking abstinence from illicit or prescribed opioids is often managed by provision of a µ-opioid agonist/partial agonist in combination with concomitant medications. Concomitant medications are administered based on their ability to treat specific symptoms rather than a mechanistic understanding of the opioid withdrawal syndrome; however, their use has not been statistically associated with improved treatment outcomes. Understanding the central and/or peripheral mechanisms that underlie individual withdrawal symptom expression in humans will help promote medication development for opioid withdrawal management. To support focused examination of mechanistically supported concomitant medications, this review summarizes evidence from preclinical (N = 68) and human (N = 30) studies that administered drugs acting on the dopamine, serotonin, cannabinoid, orexin/hypocretin, and glutamate systems and reported outcomes related to opioid withdrawal. These studies provide evidence that each of these systems contribute to opioid withdrawal severity. The Food and Drug Administration has approved medications acting on these respective systems for other indications and research in this area could support the repurposing of these medications to enhance opioid withdrawal treatment. These data support a focused examination of mechanistically informed concomitant medications to help reduce opioid withdrawal severity and enhance the continuum of care available for persons with OUD.

Analgesic Effects of Hydromorphone versus Buprenorphine in Buprenorphine-maintained Individuals.

BACKGROUND: Managing acute pain in buprenorphine-maintained individuals in emergency or perioperative settings is a significant challenge. This study compared analgesic and abuse liability effects of adjunct hydromorphone and buprenorphine using quantitative sensory testing, a model of acute clinical pain, in persons maintained on 12 to 16 mg sublingual buprenorphine/naloxone. METHODS: Participants (N = 13) were enrolled in a randomized within-subject, double-blind, placebo-controlled three-session experiment. Each session used a cumulative dosing design with four IV injections (4, 4, 8, and 16 mg of hydromorphone or 4, 4, 8, and 16 mg of buprenorphine); quantitative sensory testing and abuse liability assessments were measured at baseline and after each injection. The primary analgesia outcome was change from baseline cold pressor testing; secondary outcomes included thermal and pressure pain testing, as well as subjective drug effects and adverse events. RESULTS: A significant two-way interaction between study drug condition and dose was exhibited in cold pressor threshold (F10,110 = 2.14, P = 0.027) and tolerance (F10,110 = 2.69, P = 0.006). Compared to after placebo, participants displayed increased cold pressor threshold from baseline after cumulative doses of 32 mg of IV hydromorphone (means ± SD) (10 ± 14 s, P = 0.035) and 32 mg of buprenorphine (3 ± 5 s, P = 0.0.39) and in cold pressor tolerance after cumulative doses of 16 mg (18 ± 24 s, P = 0.018) and 32 mg (48 ± 73 s, P = 0.041) IV hydromorphone; cold pressor tolerance scores were not significant for 16 mg (1 ± 15 s, P = 0.619) or 32 mg (7 ± 16 s, P = 0.066) buprenorphine. Hydromorphone and buprenorphine compared with placebo showed greater ratings on subjective measures of high, any drug effects, good effects, and drug liking. Adverse events were more frequent during the hydromorphone compared with buprenorphine and placebo conditions for nausea, pruritus, sedation, and vomiting. CONCLUSIONS: In this acute clinical pain model, high doses of IV hydromorphone (16 to 32 mg) were most effective in achieving analgesia but also displayed higher abuse liability and more frequent adverse events. Cold pressor testing was the most consistent measure of opioid-related analgesia.

Randomized comparison of two web-based interventions on immediate and 30-day opioid overdose knowledge in three unique risk groups.

BACKGROUND: In response to the opioid overdose epidemic, scalable interventions that instruct at-risk populations how to prevent and respond to overdose scenarios are needed. METHOD: The following groups of at-risk individuals were recruited online: (1) Acute Pain patients with an opioid prescription, (2) Chronic Pain patients with an opioid prescription, and (3) persons without pain who use Illicit Opioids. Participants were tested on their opioid overdose knowledge using the Brief Opioid Overdose Knowledge (BOOK) questionnaire and randomized to one of two web-based interventions that contained 25 educational content slides. One intervention consisted of embedded questions with corrective feedback (Presentation + Mastery, n = 58), the other did not (Presentation, n = 61). Participants completed the BOOK again at the end of the intervention and 30 days later. Overdose risk behaviors were assessed at baseline and 30-days. RESULTS: Relative to baseline, both Presentation and Presentation + Mastery interventions increased total BOOK scores immediately and 30 days later. There was a significant effect of Group on BOOK Knowledge, whereby those with Acute Pain had lower scores across time, regardless of intervention, relative to those with Chronic Pain and Illicit Opioid Use. Compared to baseline, all three groups reported fewer instances of using opioids alone or concurrently with alcohol at the 30-day follow-up. CONCLUSIONS: A web-based intervention increased opioid overdose knowledge and decreased overdose risk behavior immediately and at a one-month follow-up, suggesting that this brief, practical, and scalable program could have utility in several populations who are at-risk of opioid overdose.

Individuals with Chronic Pain Who Misuse Prescription Opioids Report Sex-Based Differences in Pain and Opioid Withdrawal.

Objective Individuals with chronic pain who misuse prescription opioids are at high risk for developing opioid use disorder and/or succumbing to opioid overdose. The current study conducted a survey to evaluate sex-based differences in pain catastrophizing, opioid withdrawal, and current pain in persons with co-occurring chronic pain and opioid misuse. We hypothesized that women with chronic pain who misused prescription opioids would self-report higher pain ratings compared with men and that the relationship between pain catastrophizing and self-reported current pain would be moderated by symptoms of opioid withdrawal in women only. Design Survey assessment of the relationship between pain and opioid misuse. Setting Online via Amazon Mechanical Turk. Participants Persons with ongoing chronic pain who also misused prescription opioids on one or more days in the last 30 days were eligible (N = 181). Methods Participants completed demographic and standardized assessments including the Brief Pain Inventory (BPI), Pain Catastrophizing Scale (PCS), and Subjective Opiate Withdrawal Scale (SOWS). Results Women reported higher levels of current (P < 0.001), average (P < 0.001), and worst (P = .002) pain in the last 24 hours compared with men. Women also endorsed higher scores on the PCS (P = 0.006) and marginally higher past-30-day SOWS ratings (P = 0.068) compared with men. SOWS ratings moderated the relationship between PCS and BPI Worst Pain in women (ΔR2 < 0.127, ΔF(1, 78) = 12.39, P = 0.001), but not in men (ΔR2 < 0.000, ΔF(1, 98) = 0.003, P = 0.954). Conclusions These data suggest a strong relationship between opioid withdrawal, pain catastrophizing, and the experience of pain in women with chronic pain who misuse opioids.

Review: Sex-Based Differences in Treatment Outcomes for Persons With Opioid Use Disorder.

BACKGROUND AND OBJECTIVES: In order to address the current opioid crisis, research on treatment outcomes for persons with opioid use disorder (OUD) should account for biological factors that could influence individual treatment response. Women and men might have clinically meaningful differences in their experience in OUD treatment and might also have unique challenges in achieving successful, long-term recovery. This review summarizes and synthesizes the current literature on sex-based differences in OUD treatment outcomes. METHODS: Relevant literature was identified via automated and manual searches using the terms "opioid treatment outcome sex [or gender] differences" and "opiate treatment outcome sex [or gender] differences." Search methodology was consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and were conducted within the PubMed electronic database during March and April of 2018. RESULTS: The initial PubMed search yielded 241 manuscripts and 31 original research articles that met inclusion/exclusion criteria were synthesized in this review. Several important trends emerged, including findings that women are more likely than men to present to treatment with co-occurring mental health conditions such as depression, and that women might respond particularly well to buprenorphine maintenance. DISCUSSION AND CONCLUSIONS: While much of the literature on this topic is subject to potential cohort effects, interventions that address co-occurring mental health conditions and psychosocial stress might improve treatment outcomes for women with OUD. SCIENTIFIC SIGNIFICANCE: Funding agencies and researchers should focus attention toward human laboratory studies and clinical trials that are prospectively designed to assess sex-based differences in OUD recovery. (Am J Addict 2019;28:246-261).

Systematic review of sex-based differences in opioid-based effects.

There are several biological factors that might play a role in physiological response to opioids and/or the onset of problematic opioid use; however, sex-based differences in non-analgesic opioid-based effects are poorly understood. The goal of this review is to provide a current analysis of the pre-clinical literature on sex-based differences in response to endogenous and exogenous opioids, including the interplay between sex hormones and opioid receptor-mediated neuronal activity and associated behaviours. A systematic search was performed on the following terms within PubMed between March and April 2018: 'opioid oestrogen', 'opioid progesterone', 'opioid oestradiol', and 'opioid testosterone'. Pre-clinical research on the non-analgesic, sex-based effects of opioids is disparate, both in terms of methodology and outcomes, which prohibits a cohesive summary of the results. Themes from the pre-clinical literature suggest that opioid receptor binding, coupling, and density vary as a function of hormone exposure. Findings also suggest that interactions between endogenous opioid and stress systems may differ between males and females as a function of ovarian hormones. Given the current opioid-related public health crisis, there is a pressing need to increase systematic pre-clinical and clinical research on sex-based differences in opioid-effects and opioid use disorder.

Double jeopardy: a review of weight gain and weight management strategies for psychotropic medication prescribing during methadone maintenance treatment.

Methadone maintenance treatment (MMT) is an important treatment tool for the opioid epidemic. One challenge is that many persons who present for MMT also have co-occurring psychiatric disorders. Individually, both methadone and psychiatric medications carry risk of weight gain. Therefore, concurrent prescribing of methadone and psychiatric medications places dual diagnosis patients at even greater risk. As a parallel obesity epidemic grows, results from clinical trials assessing weight gain and weight management strategies among MMT and psychiatric patients can both inform and guide clinical practice. This study reviews findings from a literature search for recent clinical trials that focused on weight gain and weight management strategies during MMT with concurrent psychotropic medication use. While several studies have documented weight gain during MMT and psychotropic medication treatment, this study failed to identify recent work that explored concurrent prescribing. Most weight management strategies involved the use of additional medications and available data suggests that MMT and concurrent use of psychotropic medications increases the risk for obesity. More robust research is needed on weight gain and potential mitigation strategies when these treatment modalities are jointly utilized. Clarification of underlying biological mechanisms and development of non-pharmacological interventions merit further consideration.

Harm Reduction for Opioid Use Disorder: Strategies and Outcome Metrics.

Tweet: The authors discuss harm reduction strategies and associated outcome metrics in relation to the ongoing opioid crisis.

Fentanyl, Heroin, Methamphetamine, and Cocaine Analyte Concentrations in Urine Drug Testing Specimens.

Importance: The US is experiencing a protracted drug overdose crisis primarily associated with exposure to illicitly manufactured fentanyl (IMF), methamphetamine, and cocaine. Overdose risk and treatment responses may be directly affected by absolute drug exposure concentrations and drug use prevalence. Objective: To quantify changes in absolute drug exposure concentrations from 2013 to 2023. Design, Setting, and Participants: This cross-sectional study analyzed urine drug testing (UDT) results from urine specimens collected between January 1, 2013, and August 22, 2023, in 49 states and the District of Columbia. Urine specimens were obtained from patients aged 18 years or older who presented to substance use disorder treatment clinics. The UDT was ordered by clinicians based on medical necessity. Exposures: Urine specimens were analyzed for the following drugs or metabolites (analytes tested in parentheses): fentanyl (fentanyl), heroin (6-monoacetylmorphine), cocaine (benzoylecgonine), and methamphetamine (methamphetamine) using liquid chromatography with tandem mass spectrometry. Main Outcomes and Measures: Relative concentrations of fentanyl, heroin, cocaine, and methamphetamine. Creatinine-normalized drug concentration values were log-transformed prior to visualization and statistical analyses. The Mann-Kendall trend test was performed to examine trends over time. To estimate the geospatial and temporal patterns of drug concentration, a second series of models (1 for each drug) with an interaction effect for clinic location and collection year were fit. Results: A total of 921 931 unique UDT samples were collected from patients (549 042 males [59.6%]; median [IQR] age, 34 [27-44] years). The adjusted fentanyl concentration in urine specimens was 38.23 (95% CI, 35.93-40.67) ng/mg creatinine in 2023 and 4.61 (95% CI, 3.59-5.91) ng/mg creatinine in 2013. The adjusted methamphetamine concentration was 3461.59 (95% CI, 3271.88-3662.30) ng/mg creatinine in 2023 and 665.27 (95% CI, 608.51-727.32) ng/mg creatinine in 2013. The adjusted cocaine concentration was 1122.23 (95% CI, 1032.41-1219.87) ng/mg creatinine in 2023 and 559.71 (95% CI, 524.69-597.06) ng/mg creatinine in 2013. The adjusted heroin concentration was 58.36 (95% CI, 48.26-70.58) ng/mg creatinine in 2023 and 146.59 (95% CI, 136.06-157.92) ng/mg creatinine in 2013. Drug concentrations varied across US Census divisions. Conclusions and Relevance: This cross-sectional study found that absolute concentrations of fentanyl, methamphetamine, and cocaine in urine specimens increased from 2013 to 2023, with a decrease in heroin concentration during that period. The findings suggest that exposure to these substances, as well as the illicit drug supply, has fundamentally changed in many parts of the US, highlighting the need to reinforce surveillance initiatives and accelerate efforts to treat individuals with IMF and/or stimulant exposure.