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There is limited data on the comparative pharmacokinetics of cannabidiol (CBD) across oral and vaporized formulations. This within-subject, double-blind, double-dummy, placebo-controlled laboratory study analyzed the pharmacokinetic profile of CBD, ∆9-tetrahydrocannabinol (∆9-THC) and related metabolites in blood and oral fluid (OF) after participants (n = 18) administered 100 mg of CBD in each of the following formulations: (1) oral CBD, (2) vaporized CBD and (3) vaporized CBD-dominant cannabis containing 10.5% CBD and 0.39% ∆9-THC (3.7 mg); all participants also completed a placebo condition. Oral CBD was administered in three formulations: (1) encapsulated CBD, (2) CBD suspended in pharmacy-grade syrup and (3) Epidiolex, allowing for pharmacokinetic comparisons across oral formulations (n = 6 per condition). An optional fifth experimental condition was completed for six participants in which they fasted from all food for 12 h prior to oral ingestion of 100 mg of CBD. Blood and OF samples were collected immediately before and for 57-58 h after each drug administration. Immunoassay screening and LC-MS-MS confirmatory tests were performed, the limit of quantitation was 0.5 ng/mL for ∆9-THC and 1 ng/mL for CBD. The mean Cmax and range of CBD blood concentrations for each product were as follows: vaporized CBD-dominant cannabis, 171.1 ng/mL, 40.0-665.0 ng/mL, vaporized CBD 104.6 ng/mL, 19.0-312.0 ng/mL and oral CBD, 13.7 ng/mL, 0.0-50.0 ng/mL. Of the three oral formulations, Epidiolex produced the greatest peak concentration of CBD (20.5 ng/mL, 8.0-37.0 ng/mL) relative to the capsule (17.8 ng/mL, 2.0-50.0 ng/mL) and syrup (2.8 ng/mL, 0-7.0 ng/mL). ∆9-THC was detected in the blood of 12/18 participants after vaporized CBD-dominant cannabis use, but neither ∆9-THC nor its metabolite THC-COOH were detected in the blood of any participants after vaporized or oral CBD-only administration. These data demonstrate that different oral and vaporized formulations produce substantial variability in the pharmacokinetics of CBD and that CBD alone is unlikely to convert to ∆9-THC or produce positive drug tests for ∆9-THC or its metabolite.
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Cannabidiol , Cannabis , Alucinógenos , Administración Oral , Método Doble Ciego , Dronabinol , Ingestión de Alimentos , Humanos , VolatilizaciónRESUMEN
The market for products containing cannabidiol (CBD) is booming globally. However, the pharmacokinetics of CBD in different oral formulations and the impact of CBD use on urine drug testing outcomes for cannabis (e.g., 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (Δ9-THCCOOH)) are understudied. This study characterized the urinary pharmacokinetics of CBD (100 mg) following vaporization or oral administration (including three formulations: gelcap, pharmacy-grade syrup and or Epidiolex) as well as vaporized CBD-dominant cannabis (containing 100 mg CBD and 3.7 mg Δ9-THC) in healthy adults (n = 18). A subset of participants (n = 6) orally administered CBD syrup following overnight fasting (versus low-fat breakfast). Urine specimens were collected before and for 58 h after dosing on a residential research unit. Immunoassay (IA) screening (cutoffs: 20, 50 and 100 ng/mL) for Δ9-THCCOOH was performed, and quantitation of cannabinoids was completed via LC-MS-MS. Urinary CBD concentrations (ng/mL) were higher after oral (mean Cmax: 734; mean Tmax: 4.7 h, n = 18) versus vaporized CBD (mean Cmax: 240; mean Tmax: 1.3 h, n = 18), and oral dose formulation significantly impacted mean Cmax (Epidiolex = 1,274 ng/mL, capsule = 776 ng/mL, syrup = 151 ng/mL, n = 6/group) with little difference in Tmax. Overnight fasting had limited impact on CBD excretion in urine, and there was no evidence of CBD conversion to Δ8- or Δ9-THC in any route or formulation in which pure CBD was administered. Following acute administration of vaporized CBD-dominant cannabis, 3 of 18 participants provided a total of six urine samples in which Δ9-THCCOOH concentrations ≥15 ng/mL. All six specimens screened positive at a 20 ng/mL IA cutoff, and two of six screened positive at a 50 ng/mL cutoff. These data show that absorption/elimination of CBD is impacted by drug formulation, route of administration and gastric contents. Although pure CBD is unlikely to impact drug testing, it is possible that hemp products containing low amounts of Δ9-THC may produce a cannabis-positive urine drug test.
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Cannabidiol , Cannabinoides , Cannabis , Alucinógenos , Administración Oral , Adulto , Analgésicos , Cannabidiol/farmacocinética , Cannabinoides/orina , Dronabinol/orina , HumanosRESUMEN
OBJECTIVES: Acute pain management in patients with opioid use disorder who are maintained on methadone presents unique challenges due to high levels of opioid tolerance in this population. This randomized controlled study assessed the analgesic and abuse liability effects of escalating doses of acute intravenous (IV) hydromorphone versus placebo utilizing a validated experimental pain paradigm, quantitative sensory testing (QST). METHODS: Individuals (N = 8) without chronic pain were maintained on 80-100 mg/day of oral methadone. Participants received four IV, escalating/incremental doses of hydromorphone over 270 min (32 mg total) or four placebo doses within a session test day. Test sessions were scheduled at least one week apart. QST and abuse liability measures were administered at baseline and after each injection. RESULTS: No significant differences between the hydromorphone and placebo control conditions on analgesic indices for any QST outcomes were detected. Similarly, no differences on safety or abuse liability indices were detected despite the high doses of hydromorphone utilized. Few adverse events were detected, and those reported were mild in severity. CONCLUSIONS: The findings demonstrate that methadone-maintained individuals are highly insensitive to the analgesic effects of high-dose IV hydromorphone and may require very high doses of opioids, more efficacious opioids, or combined non-opioid analgesic strategies to achieve adequate analgesia.
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Hidromorfona , Trastornos Relacionados con Opioides , Analgésicos Opioides/efectos adversos , Tolerancia a Medicamentos , Humanos , Hidromorfona/efectos adversos , Metadona/efectos adversos , Trastornos Relacionados con Opioides/tratamiento farmacológicoRESUMEN
Oral cannabis products (a.k.a. "edibles") have increased in popularity in recent years. Most prior controlled pharmacokinetic evaluations of cannabis have focused on smoked cannabis and included males who were frequent cannabis users. In this study, 17 healthy adults (8 females), with no cannabis use in at least the past 2 months, completed 4 double-blind outpatient sessions where they consumed cannabis brownies containing Δ9-tetrahydrocannabinol (THC) doses of 0, 10, 25 or 50 mg. Whole blood and oral fluid specimens were collected at baseline and for 8 h post-brownie ingestion. Enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-tandem mass spectrometry (LC-MS-MS) were used to measure THC and relevant metabolites. In whole blood, concentrations of THC and 11-hydroxy-THC (11-OH-THC) peaked 1.5-2 h after brownie consumption, decreased steadily thereafter, and typically returned to baseline within 8 h. Blood concentrations for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) and THCCOOH-glucuronide were higher than THC and 11-OH-THC and these metabolites were often still detected 8 h post-brownie consumption. Women displayed higher peak concentrations for THC and all metabolites in whole blood compared to men, at least partially owing to their lower body weight/body mass index. Detection of THC in oral fluid was immediate and appeared to reflect the degree of cannabis deposition in the oral cavity, not levels of THC circulating in the blood. THC concentrations were substantially higher in oral fluid than in blood; the opposite trend was observed for THCCOOH. Agreement between ELISA and LC-MS-MS results was high (i.e., over 90%) for blood THCCOOH and oral fluid THC but comparatively low for oral fluid THCCOOH (i.e., 67%). Following oral consumption of cannabis, THC was detected in blood much later, and at far lower peak concentrations, compared to what has been observed with inhaled cannabis. These results are important given the widespread use of toxicological testing to detect recent use of cannabis and/or to identify cannabis intoxication.
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Dronabinol/farmacocinética , Psicotrópicos/farmacocinética , Administración Oral , Adulto , Cannabis , Dronabinol/metabolismo , Femenino , Humanos , Masculino , Psicotrópicos/metabolismo , Saliva/metabolismo , Detección de Abuso de Sustancias/métodos , Adulto JovenRESUMEN
BACKGROUND: Prior controlled cannabis research has mostly focused on smoked cannabis and predominantly included frequent cannabis users. Oral cannabis products ("edibles") make up a large and growing segment of the retail cannabis market. This study sought to characterize the pharmacodynamic effects of oral cannabis among infrequent cannabis users. METHODS: Seventeen healthy adults who had not used cannabis for at least 60 days completed four experimental sessions in which they consumed a cannabis-infused brownie that contained 0, 10, 25, or 50 mg THC. Subjective effects, vital signs, cognitive/psychomotor performance, and blood THC concentrations were assessed before and for 8 h after dosing. RESULTS: Relative to placebo, the 10 mg THC dose produced discriminable subjective drug effects and elevated heart rate but did not alter cognitive/psychomotor performance. The 25 and 50 mg THC doses elicited pronounced subjective effects and markedly impaired cognitive and psychomotor functioning compared with placebo. For all active doses, pharmacodynamic effects did not manifest until 30-60 min after ingestion, and peak effects occurred 1.5-3 h post-administration. Blood THC levels were significantly correlated with some pharmacodynamic drug effects, but were substantially lower than what is typically observed after cannabis inhalation. CONCLUSION: Ingestion of oral cannabis dose-dependently altered subjective drug effects and impaired cognitive performance. Unlike inhaled forms of cannabis for which acute effects occur almost immediately, effects of oral cannabis were considerably delayed. In an era of legalization, education about the time course of drug effects for cannabis edibles is needed to facilitate dose titration and reduce acute overdose incidents.
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INTRODUCTION: The use and availability of oral and inhalable products containing cannabidiol (CBD) as the principal constituent has increased with expanded cannabis/hemp legalization. However, few controlled clinical laboratory studies have evaluated the pharmacodynamic effects of oral or vaporized CBD or CBD-dominant cannabis. METHODS: Eighteen healthy adults (9 men; 9 women) completed four, double-blind, double-dummy, drug administration sessions. Sessions were separated by ≥1 week and included self-administration of 100 mg oral CBD, 100 mg vaporized CBD, vaporized CBD-dominant cannabis (100 mg CBD; 3.7 mg THC), and placebo. Study outcomes included: subjective drug effects, vital signs, cognitive/psychomotor performance, and whole blood THC and CBD concentrations. RESULTS: Vaporized CBD and CBD-dominant cannabis increased ratings on several subjective items (e.g., Like Drug Effect) relative to placebo. Subjective effects did not differ between oral CBD and placebo and were generally higher for CBD-dominant cannabis compared to vaporized CBD. CBD did not increase ratings for several items typically associated with acute cannabis/THC exposure (e.g., Paranoid). Women reported qualitatively higher ratings for Pleasant Drug Effect than men after vaporized CBD and CBD-dominant cannabis use. CBD-dominant cannabis increased heart rate compared to placebo. Cognitive/psychomotor impairment was not observed in any drug condition. CONCLUSIONS: Vaporized CBD and CBD-dominant cannabis produced discriminable subjective drug effects, which were sometimes stronger in women, but did not produce cognitive/psychomotor impairment. Subjective effects of oral CBD did not differ from placebo. Future research should further elucidate the subjective effects of various types of CBD products (e.g., inhaled, oral, topical), which appear to be distinct from THC-dominant products.
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Cannabidiol/administración & dosificación , Emociones/efectos de los fármacos , Uso de la Marihuana/psicología , Uso de la Marihuana/tendencias , Desempeño Psicomotor/efectos de los fármacos , Administración Oral , Adulto , Cannabidiol/farmacología , Estudios Cruzados , Método Doble Ciego , Dronabinol/administración & dosificación , Dronabinol/farmacología , Emociones/fisiología , Femenino , Humanos , Masculino , Uso de la Marihuana/epidemiología , Nebulizadores y Vaporizadores/tendencias , Desempeño Psicomotor/fisiología , VolatilizaciónRESUMEN
Cannabis products in which cannabidiol (CBD) is the primary chemical constituent (CBD-dominant) are increasingly popular and widely available. The impact of CBD exposure on urine drug testing has not been well studied. This study characterized the urinary pharmacokinetic profile of 100-mg oral and vaporized CBD, vaporized CBD-dominant cannabis (100-mg CBD; 3.7-mg ∆9-THC) and placebo in healthy adults (n = 6) using a within-subjects crossover design. Urine specimens were collected before and for 5 days after drug administration. Immunoassay (IA) screening (cutoffs of 20, 50 and 100 ng/mL) and LC-MS-MS confirmatory tests (cutoff of 15 ng/mL) for 11-nor-9-carboxy-∆9-tetrahydrocannabinol (∆9-THCCOOH) were performed; urine was also analyzed for CBD and other cannabinoids. Urinary concentrations of CBD were higher after oral (mean Cmax: 776 ng/mL) versus vaporized CBD (mean Cmax: 261 ng/mL). CBD concentrations peaked 5 h after oral CBD ingestion and within 1 h after inhalation of vaporized CBD. After pure CBD administration, only 1 out of 218 urine specimens screened positive for ∆9-THCCOOH (20-ng/mL IA cutoff) and no specimens exceeded the 15-ng/mL confirmatory cutoff. After inhalation of CBD-dominant cannabis vapor, nine samples screened positive at the 20-ng/mL IA cutoff, and two of those samples screened positive at the 50-ng/mL IA cutoff. Four samples that screened positive (two at 20 ng/mL and two at 50 ng/mL) confirmed positive with concentrations of ∆9-THCCOOH exceeding 15 ng/mL. These data indicate that acute dosing of pure CBD will not result in a positive urine drug test using current federal workplace drug testing guidelines (50-ng/mL IA cutoff with 15-ng/mL confirmatory cutoff). However, CBD products that also contain ∆9-THC may produce positive urine results for ∆9-THCCOOH. Accurate labeling and regulation of ∆9-THC content in CBD/hemp products are needed to prevent unexpected positive drug tests and unintended drug effects.
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Cannabidiol/orina , Cannabinoides/orina , Administración por Inhalación , Administración Oral , Adulto , Cannabidiol/farmacocinética , Cannabinoides/farmacocinética , Estudios Cruzados , Femenino , Humanos , Masculino , Fumar Marihuana , Farmacocinética , VolatilizaciónRESUMEN
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.
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Analgésicos/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Narcóticos/uso terapéutico , Tratamiento de Sustitución de Opiáceos/métodos , Trastornos Relacionados con Opioides/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/fisiopatología , Adulto , Buprenorfina/uso terapéutico , Clonidina/uso terapéutico , Análisis por Conglomerados , Método Doble Ciego , Femenino , Humanos , Masculino , Morfina/uso terapéutico , Naloxona/uso terapéutico , Fenotipo , Índice de Severidad de la Enfermedad , Tramadol/uso terapéutico , Resultado del TratamientoRESUMEN
As cannabis has become more accessible, use of alternative methods for cannabis administration such as vaporizers has become more prevalent. Most prior controlled pharmacokinetic evaluations have examined smoked cannabis in frequent (often daily) cannabis users. This study characterized the urinary excretion profile of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH), the primary analytical outcome for detection of cannabis use, among infrequent cannabis users following controlled administration of both smoked and vaporized cannabis. Healthy adults (N = 17), with a mean of 398 (range 30-1,825) days since last cannabis use, smoked and vaporized cannabis containing 0, 10, and 25 mg of Δ9-tetrahydrocannabinol (THC) across six outpatient sessions. Urinary concentrations of THCCOOH were measured at baseline and for 8 h after cannabis administration. Sensitivity, specificity, and agreement between three immunoassays (IA) for THCCOOH (with cutoffs of 20, 50, and 100 ng/mL) and gas chromatography-mass spectrometry (GC/MS) results (confirmatory concentration of 15 ng/mL) were assessed. THCCOOH concentrations peaked 4-6 h after cannabis administration. Median maximum concentrations (Cmax) for THCCOOH were qualitatively higher after administration of vaporized cannabis compared to equal doses of smoked cannabis. Urine THCCOOH concentrations were substantially lower in this study relative to prior examinations of experienced cannabis users. The highest agreement between IA and GC/MS was observed at the 50 ng/mL IA cutoff while sensitivity and specificity were highest at the 20 and 100 ng/mL IA cutoffs, respectively. Using federal workplace drug-testing criteria (IA cutoff of 50 ng/mL and GC/MS concentration ≥15 ng/mL) urine specimens tested positive in 47% of vaporized sessions and 21% of smoked sessions with active THC doses (N = 68). Urinary concentrations of THCCOOH are dissimilar after administration of smoked and vaporized cannabis, with qualitatively higher concentrations observed after vaporization. Infrequent users of cannabis may excrete relatively low concentrations of THCCOOH following acute inhalation of smoked or vaporized cannabis.
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Dronabinol/orina , Detección de Abuso de Sustancias/métodos , Adulto , Cannabis , Femenino , Humanos , Masculino , Nebulizadores y Vaporizadores , VolatilizaciónRESUMEN
OBJECTIVE: This study describes changes in weight and cardiovascular risk factors over time among individuals enrolled in methadone maintenance treatment for opioid use disorder. Demographic and clinical predictors of weight gain were also evaluated. DESIGN: This study was a retrospective chart review evaluating data over a period of 3 years. SETTING: Medical records of individuals enrolled in an academic research outpatient methadone maintenance treatment program were reviewed. PATIENTS: Seventy-four individuals who were admitted and retained in methadone maintenance treatment for at least 3 consecutive years were included. OUTCOME MEASURES: Annual weight was assessed by calculating body mass index (BMI). Changes over time in cardiovascular risk factors of hypertension, diabetes, and hypercholesterolemia were also assessed. RESULTS: The percentage of patients categorized as overweight, obese, or morbidly obese BMI increased from 42 percent (n = 31) at admission to 76 percent (n = 56), 82 percent (n = 61), and 88 percent (n = 65) at 1, 2, and 3 years post-admission, respectively. Hypertension, diabetes, and hypercholesterolemia also tended to increase following admission. BMI increases tended to be greater for those with a higher dose of methadone, as well as for females and Black/African American individuals. No other predictors of weight gain were identified. CONCLUSIONS: These data indicate that methadone maintenance treatment is associated with clinically meaningful weight gain and increases in cardiovascular risk factors. Given the importance of methadone maintenance for treatment of opioid use disorder, future research should examine additional predictors and potential mechanisms of weight gain among methadone patients and develop tailored interventions including nutritional knowledge and lifestyle recommendations.
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Índice de Masa Corporal , Enfermedades Cardiovasculares , Metadona/efectos adversos , Obesidad Mórbida , Analgésicos Opioides , Enfermedades Cardiovasculares/inducido químicamente , Femenino , Humanos , Masculino , Obesidad Mórbida/inducido químicamente , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Opioids have high abuse potential and pose a major public health concern. Yet, a large percentage of individuals exposed to opioids do not develop problematic use. Individual differences in opioid abuse potential are not well understood. METHODS: This within-subject (N = 16), double-blind, double-dummy, human laboratory study evaluated individual differences in response to dose (placebo, low, medium, high) following administration of heroin and hydromorphone through intravenous and subcutaneous routes, in opioid-experienced but non physically-dependent participants. Outcomes were self-reported visual analog scale (VAS) ratings (High, Liking, Drug Effect, Good Effect, Rush), pupil diameter change from baseline, and crossover point on the Drug vs. Money questionnaire. The degree to which results were consistent across measures within an individual was assessed using a mixed-effects model from which an intraclass correlation coefficient measure of between and within-subject variance was derived. RESULTS: The mixed effects model fit was significant (p < 0.0001) and revealed that 85.5% of the explainable variance was due to between-subject effects, suggesting the responses within an individual were highly consistent. Visual inspection reveals a myriad response pattern across participants, with some demonstrating classic dose-effect responses and others not differentiating any active doses from placebo. CONCLUSIONS: Data suggest the abuse potential of opioids is significantly different between individuals but that the experience within an individual is highly consistent. Research to prospectively characterize and evaluate mechanisms underlying these differences is warranted and may provide a foundation to help identify persons at heightened risk of transitioning from opioid exposure to misuse and/or opioid use disorder.
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Analgésicos Opioides/administración & dosificación , Heroína/administración & dosificación , Hidromorfona/administración & dosificación , Individualidad , Trastornos Relacionados con Opioides/psicología , Autoinforme , Administración Intravenosa , Adulto , Analgésicos Opioides/efectos adversos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Emociones/efectos de los fármacos , Emociones/fisiología , Femenino , Heroína/efectos adversos , Humanos , Hidromorfona/efectos adversos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Trastornos Relacionados con Opioides/diagnósticoRESUMEN
BACKGROUND: Understanding mechanisms of physiological opioid withdrawal symptoms can inform treatment strategies. This secondary analysis evaluated the association between mydriasis (dilated pupils), a commonly-assessed opioid withdrawal metric, with self- and observer-rated opioid withdrawal severity. METHOD: Ninety-five participants with opioid physical dependence were stabilized with morphine before receiving an injection of the opioid antagonist naloxone to precipitate withdrawal. Pupil diameter, the Subjective Opiate Withdrawal Scale (SOWS), and the Clinical Opiate Withdrawal Scale (COWS) were collected at baseline and in 15-minute intervals for 120 min following naloxone administration. Pearson product-moment correlations and linear regressions characterized the relationships between pupil measurements (baseline and peak naloxone-induced) and self- and observer-rated measures of withdrawal. Repeated-measures ANOVAs tested whether self and observer-rated withdrawal severity corresponded to unique patterns in pupil changes. RESULTS: Baseline pupil diameter significantly correlated with SOWS and COWS peak scores. Peak naloxone-induced pupil diameter significantly correlated with SOWS scores only. Peak changes in pupil from baseline did not correspond to peak changes in self- and observer-rated withdrawal scales. CONCLUSIONS: This study suggests that pupil diameter measurements were more closely associated with acute opioid withdrawal severity than changes in pupil diameter. Prospective research examining the mechanisms underlying the relationship between pupil diameter and opioid withdrawal severity are warranted.
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Analgésicos Opioides/efectos adversos , Trastornos Relacionados con Opioides/fisiopatología , Pupila/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/diagnóstico , Adulto , Femenino , Humanos , Masculino , Morfina/uso terapéutico , Naloxona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Tratamiento de Sustitución de Opiáceos , Trastornos Relacionados con Opioides/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/tratamiento farmacológicoRESUMEN
BACKGROUND: The Strategy to Reduce the Incidence of Postoperative Delirium in the Elderly trial tested the hypothesis that limiting sedation during spinal anaesthesia decreases in-hospital postoperative delirium after hip fracture repair. This manuscript reports the secondary outcomes of this trial, including mortality and function. METHODS: Two hundred patients (≥65 yr) undergoing hip fracture repair with spinal anaesthesia were randomised to heavier [modified Observer's Assessment of Alertness/Sedation score (OAA/S) 0-2] or lighter (OAA/S 3-5) sedation, and were assessed for postoperative delirium. Secondary outcomes included mortality and return to pre-fracture ambulation level at 1 yr. Kaplan-Meier analysis, multivariable Cox proportional hazard model, and logistic regression were used to evaluate intervention effects on mortality and odds of ambulation return. RESULTS: One-year mortality was 14% in both groups (log rank P=0.96). Independent risk factors for 1-yr mortality included: Charlson comorbidity index [hazard ratio (HR)=1.23, 95% confidence interval (CI), 1.02-1.49; P=0.03], instrumental activities of daily living [HR=0.74, 95% CI, 0.60-0.91; P=0.005], BMI [HR=0.91, 95% CI 0.84-0.998; P=0.04], and delirium severity [HR=1.20, 95% CI, 1.03-1.41; P=0.02]. Ambulation returned to pre-fracture levels, worsened, or was not obtained in 64%, 30%, and 6% of 1 yr survivors, respectively. Lighter sedation did not improve odds of ambulation return at 1 yr [odds ratio (OR)=0.76, 95% CI, 0.24-2.4; P=0.63]. Independent risk factors for ambulation return included Charlson comorbidity index [OR=0.71, 95% CI, 0.53-0.97; P=0.03] and delirium [OR=0.32, 95% CI, 0.10-0.97; P=0.04]. CONCLUSIONS: This study found that in elderly patients having hip fracture surgery with spinal anaesthesia supplemented with propofol sedation, heavier intraoperative sedation was not associated with significant differences in mortality or return to pre-fracture ambulation up to 1 yr after surgery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00590707.
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Sedación Consciente/métodos , Sedación Profunda/métodos , Delirio del Despertar/prevención & control , Complicaciones Posoperatorias/prevención & control , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Anestesia Raquidea , Sedación Consciente/efectos adversos , Relación Dosis-Respuesta a Droga , Delirio del Despertar/etiología , Delirio del Despertar/mortalidad , Femenino , Fuerza de la Mano , Fracturas de Cadera/mortalidad , Fracturas de Cadera/cirugía , Humanos , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/efectos adversos , Estimación de Kaplan-Meier , Masculino , Maryland/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/mortalidad , Propofol/administración & dosificación , Propofol/efectos adversos , Recuperación de la FunciónRESUMEN
AIM: To determine whether extended-release injectable naltrexone (XR-NTX), incentives for opiate abstinence, and their combination reduce opiate use compared to a usual care control and whether the combination reduces opiate use compared to either treatment alone. DESIGN: Randomized 2 × 2 single-site controlled trial conducted from November 2012 through May 2016. After a detoxification and oral naltrexone induction, participants were assigned to a Usual Care, Abstinence Incentives, XR-NTX, or XR-NTX plus Abstinence Incentives group for a six-month intervention period. SETTING: A model therapeutic workplace where participants could work on automated computer programs that targeted job-skills training for 4 h every weekday for 24 weeks and earn about $10 per hour. PARTICIPANTS: 84 heroin-dependent adults who were unemployed and medically approved for naltrexone. Most participants were male (71.4%), African American (80.1%), and cocaine dependent (71.4%). MEASUREMENTS: The primary outcome measure was the percentage of urine samples negative for opiates that were collected at once weekly assessments (24 per participant) that were not part of the intervention and for which participants were paid $10 for completing. INTERVENTION: Participants who attended the workplace provided thrice-weekly urine samples. Abstinence Incentives participants had to provide opiate-free urine samples to maintain maximum pay. XR-NTX participants received one injection every 4 weeks and were required to take injections in order to work and to maintain maximum pay. Usual Care participants were not offered XR-NTX and opiate urinalysis results did not affect pay. FINDINGS: A large percentage (65 of 149; 43.6%) of individuals failed the induction protocol required for randomization and to be eligible to receive XR-NTX. When missing urine samples were considered positive, there was no significant interaction between XR-NTX and Abstinence Incentives. XR-NTX plus Abstinence Incentives participants provided significantly more opiate-negative samples (81.3%, SD 39.0%) than XR-NTX participants (64.5%, SD 47.9%; aOR 10.4, 95% CI 1.3-85.5; P = .030). When urine samples were not replaced, there was a significant interaction between XR-NTX and Abstinence Incentives (aOR 77.0, 95% CI 1.3-4432;P = 0.036); XR-NTX plus Abstinence Incentives participants provided significantly more opiate-negative samples (99.6%, SD 0.1%) than XR-NTX participants (85.0%, SD 35.7%; aOR 147.6, 95% CI 6.3-3472; P = 0.002), Abstinence Incentives participants (91.9%, SD 27.3%; aOR 121.7, 95% CI 4.8-3067; P =0.004), and Usual Care participants (78.7%, SD 41.0%; aOR 233.4, 95% CI 9.4-5814; P <.001). No other group differences were significant. CONCLUSION: XR-NTX plus incentives for opiate abstinence increased opiate abstinence, but XR-NTX alone did not. XR-NTX can promote opiate abstinence when it is combined with incentives for opiate abstinence in a model therapeutic workplace.
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Cocaína/orina , Heroína/orina , Naltrexona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Trastornos Relacionados con Opioides/tratamiento farmacológico , Adulto , Negro o Afroamericano/psicología , Preparaciones de Acción Retardada/administración & dosificación , Femenino , Humanos , Inyecciones , Masculino , Persona de Mediana Edad , Motivación , Trastornos Relacionados con Opioides/etnología , Trastornos Relacionados con Opioides/psicología , Detección de Abuso de Sustancias , Lugar de TrabajoRESUMEN
Currently, an unprecedented number of individuals can legally access cannabis. Vaporization is increasingly popular as a method to self-administer cannabis, partly due to perception of reduced harm compared with smoking. Few controlled laboratory studies of cannabis have used vaporization as a delivery method or evaluated the acute effects of cannabis among infrequent cannabis users. This study compared the concentrations of cannabinoids in whole blood and oral fluid after administration of smoked and vaporized cannabis in healthy adults who were infrequent users of cannabis. Seventeen healthy adults, with no past-month cannabis use, self-administered smoked or vaporized cannabis containing Δ9-tetrahydrocannabinol (THC) doses of 0, 10 and 25 mg in six double-blind outpatient sessions. Whole blood and oral fluid specimens were obtained at baseline and for 8 h after cannabis administration. Cannabinoid concentrations were assessed with enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-tandem mass spectrometry (LC-MS-MS) methods. Sensitivity, specificity and agreement between ELISA and LC-MS-MS results were assessed. Subjective, cognitive performance and cardiovascular effects were assessed. The highest concentrations of cannabinoids in both whole blood and oral fluid were typically observed at the first time point (+10 min) after drug administration. In blood, THC, 11-OH-THC, THCCOOH and THCCOOH-glucuronide concentrations were dose-dependent for both methods of administration, but higher following vaporization compared with smoking. THC was detected longer in oral fluid compared to blood and THCCOOH detection in oral fluid was rare and highly erratic. For whole blood, greater detection sensitivity for ELISA testing was observed in vaporized conditions. Conversely, for oral fluid, greater sensitivity was observed in smoked sessions. Blood and/or oral fluid cannabinoid concentrations were weakly to moderately correlated with pharmacodynamic outcomes. Cannabis pharmacokinetics vary by method of inhalation and biological matrix being tested. Vaporization appears to be a more efficient method of delivery compared with smoking.
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Dronabinol/sangre , Dronabinol/farmacocinética , Fumar Marihuana/sangre , Psicotrópicos/sangre , Psicotrópicos/farmacocinética , Saliva/química , Detección de Abuso de Sustancias/métodos , Volatilización , Adulto , Cannabis/química , Cromatografía Liquida , Método Doble Ciego , Dronabinol/administración & dosificación , Dronabinol/efectos adversos , Ensayo de Inmunoadsorción Enzimática , Femenino , Alucinaciones/etiología , Humanos , Masculino , Fumar Marihuana/efectos adversos , Fumar Marihuana/legislación & jurisprudencia , Concentración Osmolar , Psicotrópicos/administración & dosificación , Psicotrópicos/efectos adversos , Sensibilidad y Especificidad , Factores Sexuales , Espectrometría de Masas en Tándem , Vómitos/etiología , Adulto JovenRESUMEN
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.
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Analgesia/métodos , Analgésicos Opioides/farmacología , Buprenorfina/farmacología , Hidromorfona/farmacología , Trastornos Relacionados con Opioides/tratamiento farmacológico , Dolor/tratamiento farmacológico , Adulto , Analgésicos Opioides/uso terapéutico , Buprenorfina/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Masculino , Resultado del TratamientoRESUMEN
BACKGROUND: There is strong association of Alzheimer's disease (AD) pathology with gait disorder and falls in older adults without dementia. The goal of the study was to examine the prevalence and severity of AD pathology in older adults without dementia who fall and sustain hip fracture. METHODS: Cerebrospinal fluid (CSF) was obtained from 168 hip fracture patients. CSF Aß42/40 ratio, p-tau, and t-tau measures were dichotomized into normal vs. abnormal, and categorized according to the A/T/N classification. RESULTS: Among the hip fracture patients, 88.6% of the cognitively normal (Clinical Dementia Rating-CDR 0; n = 70) and 98.8% with mild cognitive impairment (CDR 0.5; n = 81) fell in the abnormal biomarker categories by the A/T/N classification. CONCLUSIONS: A large proportion of older hip fracture patients have CSF evidence of AD pathology. Preoperative determination of AD biomarkers may play a crucial role in identifying persons without dementia who have underlying AD pathology in perioperative settings.
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Péptidos beta-Amiloides/líquido cefalorraquídeo , Fracturas de Cadera/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/psicología , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/psicología , Estudios de Cohortes , Femenino , Fracturas de Cadera/complicaciones , Fracturas de Cadera/psicología , Humanos , Masculino , Pruebas de Estado Mental y Demencia , Factores de RiesgoRESUMEN
Importance: Postoperative delirium is the most common complication following major surgery in older patients. Intraoperative sedation levels are a possible modifiable risk factor for postoperative delirium. Objective: To determine whether limiting sedation levels during spinal anesthesia reduces incident delirium overall. Design, Setting, and Participants: This double-blind randomized clinical trial (A Strategy to Reduce the Incidence of Postoperative Delirum in Elderly Patients [STRIDE]) was conducted from November 18, 2011, to May 19, 2016, at a single academic medical center and included a consecutive sample of older patients (≥65 years) who were undergoing nonelective hip fracture repair with spinal anesthesia and propofol sedation. Patients were excluded for preoperative delirium or severe dementia. Of 538 hip fractures screened, 225 patients (41.8%) were eligible, 10 (1.9%) declined participation, 15 (2.8%) became ineligible between the time of consent and surgery, and 200 (37.2%) were randomized. The follow-up included postoperative days 1 to 5 or until hospital discharge. Interventions: Heavier (modified observer's assessment of sedation score of 0-2) or lighter (observer's assessment of sedation score of 3-5) propofol sedation levels intraoperatively. Main Outcomes and Measures: Delirium on postoperative days 1 to 5 or until hospital discharge determined via consensus panel using Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) criteria. The incidence of delirium was compared between intervention groups with and without stratification by the Charlson comorbidity index (CCI). Results: Of 200 participants, the mean (SD) age was 82 (8) years, 146 (73%) were women, 194 (97%) were white, and the mean (SD) CCI was 1.5 (1.8). One hundred participants each were randomized to receive lighter sedation levels or heavier sedation levels. A good separation of intraoperative sedation levels was confirmed by multiple indices. The overall incident delirium risk was 36.5% (n = 73) and 39% (n = 39) vs 34% (n = 34) in heavier and lighter sedation groups, respectively (P = .46). Intention-to-treat analyses indicated no statistically significant difference between groups in the risk of incident delirium (log-rank test χ2, 0.46; P = .46). However, in a prespecified subgroup analysis, when stratified by CCI, sedation levels did effect the delirium risk (P for interaction = .04); in low comorbid states (CCI = 0), heavier vs lighter sedation levels doubled the risk of delirium (hazard ratio, 2.3; 95% CI, 1.1- 4.9). The level of sedation did not affect delirium risk with a CCI of more than 0. Conclusions and Relevance: In the primary analysis, limiting the level of sedation provided no significant benefit in reducing incident delirium. However, in a prespecified subgroup analysis, lighter sedation levels benefitted reducing postoperative delirium for persons with a CCI of 0. Trial Registration: clinicaltrials.gov Identifier: NCT00590707.
Asunto(s)
Anestesia Raquidea , Anestésicos Intravenosos/administración & dosificación , Delirio/prevención & control , Fracturas de Cadera/cirugía , Complicaciones Posoperatorias/prevención & control , Propofol/administración & dosificación , Anciano , Anciano de 80 o más Años , Periodo de Recuperación de la Anestesia , Anestesia Raquidea/efectos adversos , Anestésicos Intravenosos/efectos adversos , Comorbilidad , Delirio/inducido químicamente , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Complicaciones Posoperatorias/inducido químicamente , Propofol/efectos adversosRESUMEN
BACKGROUND: Opioid-related overdose has increased 137% in the past decade. Training nonmedical bystanders to administer naloxone (Narcan™) is a widely-researched intervention that has been associated with decreases in overdose rates in the communities in which it has been implemented. A recent review advocated for noninjectable formulations of naloxone, however patient preference for naloxone formulations has not yet been examined (Strang et al., 2016). METHODS: Two cohorts of respondents (N1â¯=â¯501, N2â¯=â¯172) who reported currently being prescribed an opioid for pain management were recruited through the crowd-sourcing program Amazon Mechanical Turk (MTurk) to assess their preference for naloxone formulations. All respondents were provided a description of different formulations and asked to indicate all formulations they would be willing to administer for overdose reversal and to then rank formulations in order of preference. RESULTS: Results were remarkably similar across both cohorts. Specifically, respondents preferred noninjectable formulations (intranasal, sublingual, buccal) over injectable (intravenous, intramuscular) formulations. A small percent (8.9%-9.8%) said they would never be willing to administer naloxone. An identical percent of respondents in both cohorts (44.9%) rated intranasal as their most preferred formulation. CONCLUSIONS: Two independent cohorts of respondents who were receiving opioid medications for pain management reported a preference for noninjectable over injectable formulations of naloxone to reverse an opioid overdose. Though initial preference is only one of many factors that impacts ultimate public acceptance and uptake of a new product, these results support the additional research and development of noninjectable naloxone formulations.
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Analgésicos Opioides/envenenamiento , Sobredosis de Droga/tratamiento farmacológico , Naloxona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Dolor/tratamiento farmacológico , Prioridad del Paciente , Administración Bucal , Administración Intranasal , Administración Intravenosa , Administración Sublingual , Adolescente , Adulto , Analgésicos Opioides/uso terapéutico , Femenino , Humanos , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
AIMS: To review systematically the published literature on extended-release naltrexone (XR-NTX, Vivitrol® ), marketed as a once-per-month injection product to treat opioid use disorder. We addressed the following questions: (1) how successful is induction on XR-NTX; (2) what are adherence rates to XR-NTX; and (3) does XR-NTX decrease opioid use? Factors associated with these outcomes as well as overdose rates were examined. METHODS: We searched PubMed and used Google Scholar for forward citation searches of peer-reviewed papers from January 2006 to June 2017. Studies that included individuals seeking treatment for opioid use disorder who were offered XR-NTX were included. RESULTS: We identified and included 34 studies. Pooled estimates showed that XR-NTX induction success was lower in studies that included individuals that required opioid detoxification [62.6%, 95% confidence interval (CI) = 54.5-70.0%] compared with studies that included individuals already detoxified from opioids (85.0%, 95% CI = 78.0-90.1%); 44.2% (95% CI = 33.1-55.9%) of individuals took all scheduled injections of XR-NTX, which were usually six or fewer. Adherence was higher in prospective investigational studies (i.e. studies conducted in a research context according to a study protocol) compared to retrospective studies of medical records taken from routine care (6-month rates: 46.7%, 95% CI = 34.5-59.2% versus 10.5%, 95% CI = 4.6-22.4%, respectively). Compared with referral to treatment, XR-NTX reduced opioid use in adults under criminal justice supervision and when administered to inmates before release. XR-NTX reduced opioid use compared with placebo in Russian adults, but this effect was confounded by differential retention between study groups. XR-NTX showed similar efficacy to buprenorphine when randomization occurred after detoxification, but was inferior to buprenorphine when randomization occurred prior to detoxification. CONCLUSIONS: Many individuals intending to start extended-release naltrexone (XR-NTX) do not and most who do start XR-NTX discontinue treatment prematurely, two factors that limit its clinical utility significantly. XR-NTX appears to decrease opioid use but there are few experimental demonstrations of this effect.