RESUMO
In a pilot randomized trial in persons with opioid use disorder hospitalized with injection-related infections, an innovative care model combining outpatient parenteral antimicrobial therapy with buprenorphine treatment had similar clinical and drug use outcomes to usual care (inpatient intravenous antibiotic completion) and shortened hospital length of stay by 23.5 days. CLINICAL TRIALS REGISTRATION: NCT03048643.
Assuntos
Anti-Infecciosos , Buprenorfina , Transtornos Relacionados ao Uso de Opioides , Antibacterianos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Buprenorfina/uso terapêutico , Humanos , Tratamento de Substituição de Opiáceos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Pacientes AmbulatoriaisRESUMO
RATIONALE: Accurate assessment of medication adherence is critical for determination of medication efficacy in clinical trials, but most current methods have significant limitations. This study tests a subtherapeutic (microdose) of acetazolamide as a medication ingestion marker because acetazolamide is rapidly absorbed and excreted without metabolism in urine and can be noninvasively sampled. METHODS: In a double-blind, placebo-controlled, residential study, 10 volunteers received 15 mg oral acetazolamide for 4 consecutive days. Acetazolamide pharmacokinetics were assessed on day 3, and its pharmacokinetic and pharmacodynamic interactions with a model medication (30 mg oxycodone) were examined on day 4. The rate of acetazolamide elimination into urine was followed for several days after dosing cessation. RESULTS: Erythrocyte sequestration (half-life = 50.2 ± 18.5 h, mean ± SD, n = 6), resulted in the acetazolamide microdose exhibiting a substantially longer plasma half-life (24.5 ± 5.6 hours, n = 10) than previously reported for therapeutic doses (3-6 hours). After cessation of dosing, the rate of urinary elimination decreased significantly (F3,23 = 247: P < 0.05, n = 6) in a predictable manner with low intersubject variability and a half-life of 16.1 ± 3.8 h (n = 10). For each of 4 consecutive mornings after dosing cessation, the rates of urinary acetazolamide elimination remained quantifiable.There was no overall effect of acetazolamide on the pharmacodynamics, Cmax, Tmax, or elimination half-life of the model medication tested. Acetazolamide may have modestly increased overall oxycodone exposure (20%, P < 0.05) compared with one of the 2 days when oxycodone was given alone, but there were no observed effects of acetazolamide on oxycodone pharmacodynamic responses. CONCLUSIONS: Coformulation of a once-daily trial medication with an acetazolamide microdose may allow estimation of the last time of medication consumption for up to 96 hours postdose. Inclusion of acetazolamide may therefore provide an inexpensive new method to improve estimates of medication adherence in clinical trials.
Assuntos
Acetazolamida/farmacologia , Acetazolamida/farmacocinética , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/farmacocinética , Adesão à Medicação , Entorpecentes/farmacologia , Oxicodona/farmacologia , Acetazolamida/administração & dosagem , Adulto , Biomarcadores , Inibidores da Anidrase Carbônica/administração & dosagem , Estudos Cross-Over , Método Duplo-Cego , Interações Medicamentosas , Feminino , Humanos , Masculino , Entorpecentes/administração & dosagem , Oxicodona/administração & dosagemRESUMO
Oxymorphone is a semisynthetic µ-opioid agonist, marketed as a prescription analgesic purported to be twice as potent as oxycodone for pain relief. Oral formulations of oxymorphone were reintroduced in the United States in 2006 and reports of abuse ensued; however, there are limited data available on its pharmacodynamic effects. The current study aimed to examine the direct physiologic effects, relative abuse liability, analgesic profile and overall pharmacodynamic potency of oxymorphone in comparison with identical doses of oxycodone. Healthy, non-dependent opioid abusers (n = 9) were enrolled in this within-subject, double-blind, placebo-controlled, 3-week inpatient study. Seven experimental sessions (6.5 hours) were conducted, during which an oral dose of immediate-release formulations of oxymorphone (10, 20 and 40 mg), oxycodone (10, 20 and 40 mg) or placebo was administered. An array of physiologic, abuse liability and experimental pain measures was collected. At identical doses, oxymorphone produced approximately twofold less potent effects on miosis, compared with oxycodone. Oxymorphone also produced lesser magnitude effects on measures of respiratory depression, two experimental pain models and observer-rated agonist effects. However, 40 mg of oxymorphone was similar to 40 mg of oxycodone on several abuse-related subjective ratings. Formal relative potency analyses were largely invalid because of the substantially greater effects of oxycodone. Overall, oxymorphone is less potent on most pharmacodynamic measures, although at higher doses, its abuse liability is similar to oxycodone. These data suggest that the published clinical equianalgesic estimates may not be consistent with the observed direct physiologic effects of opioids, results of experimental pain models or abuse liability measures, as assessed in the human laboratory.
Assuntos
Analgésicos Opioides/farmacologia , Cognição/efeitos dos fármacos , Transtornos Relacionados ao Uso de Opioides , Oximorfona/farmacologia , Medição da Dor/efeitos dos fármacos , Dor/prevenção & controle , Administração Oral , Adulto , Analgésicos Opioides/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Temperatura Baixa , Estudos Cross-Over , Método Duplo-Cego , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Oximorfona/administração & dosagem , PressãoRESUMO
Pre-clinical studies suggest that the neurokinin-1 (NK1) receptor may modulate the response to opioids, with NK(1) inactivation leading to decreased opioid reinforcement, tolerance and withdrawal. Aprepitant is a selective NK1 antagonist currently marketed for clinical use as an anti-emetic. This 6-week in-patient study used a randomized, double-blind, double-dummy, within-subject, crossover design. Subjects (n = 8; 6 male/2 female) were healthy, adult volunteers who provided subjective and objective evidence of current prescription opioid abuse (without physical dependence) and underwent careful medical and psychiatric screening. Fifteen experimental conditions, consisting of one aprepitant dose (0, 40 and 200 mg, p.o. given as a 2-hour pre-treatment) in combination with one oxycodone dose [placebo, oral (20 and 40 mg/70 kg) and intranasal (15 and 30 mg/70 kg)], were examined. Sessions were conducted at least 48-hour apart and multi-dimensional measures were collected repeatedly throughout the 6-hour session duration. Oxycodone, by both routes of administration, produced significant dose-related effects on the predicted measures (e.g. subjective measures of abuse liability, respiratory depression and miosis). Pre-treatment with aprepitant (200 mg) significantly enhanced ratings of oxycodone subjective effects related to euphoria and liking and doubled the street value estimates for the highest test doses of oxycodone by both routes. Some objective measures (respiratory function, observer-rated opioid agonist effects) were similarly enhanced by pre-treatment with the highest dose of aprepitant. All dose combinations were safely tolerated. These findings are discussed in the context of the potential utility of NK1 antagonists in the treatment of opioid use disorders.
Assuntos
Analgésicos Opioides/farmacologia , Antieméticos/farmacologia , Morfolinas/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Oxicodona/farmacologia , Administração Intranasal , Adulto , Analgésicos Opioides/administração & dosagem , Análise de Variância , Animais , Antieméticos/administração & dosagem , Aprepitanto , Área Sob a Curva , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Interações Medicamentosas/fisiologia , Tolerância a Medicamentos , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Morfolinas/administração & dosagem , Transtornos Relacionados ao Uso de Opioides/metabolismo , Transtornos Relacionados ao Uso de Opioides/psicologia , Oxicodona/administração & dosagem , Placebos , Desempenho Psicomotor/efeitos dos fármacos , Receptores da Neurocinina-1/metabolismo , Reforço Psicológico , Substância P/fisiologia , Fatores de TempoRESUMO
BACKGROUND: It is not known whether buprenorphine/naloxone (bup/nx) can be safely initiated in hospitalized patients with acute hepatitis A infection. We assessed liver function and tolerability of bup/nx induction in patients with acute Hepatitis A Virus (HAV). METHODS: Retrospective review of patients (Nâ=â31) admitted to a tertiary care facility for acute HAV who were evaluated by an addiction medicine consultant. RESULTS: No significant difference was seen in aspartate aminotransferase, alanine aminotransferase, total bilirubin, or INR trends in patients receiving bup/nx during hospitalization versus those not receiving bup/nx. Nausea was the most common reported symptom in patients receiving bup/nx. DISCUSSION AND CONCLUSIONS: With careful monitoring and induction dose adjustment, bup/nx can be administered to patients with acute HAV without hepatic encephalopathy. Similarly, patients on bup/nx before hospitalization should not have this medication held in the setting of acute HAV. SCIENTIFIC SIGNIFICANCE: This strategy may engage patients with acute HAV in treatment of OUD earlier and minimize disruptions in treatment.
Assuntos
Buprenorfina , Hepatite A , Transtornos Relacionados ao Uso de Opioides , Buprenorfina/uso terapêutico , Combinação Buprenorfina e Naloxona/uso terapêutico , Hepatite A/tratamento farmacológico , Humanos , Naloxona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Tratamento de Substituição de Opiáceos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Estudos RetrospectivosRESUMO
RATIONALE: Preclinical studies demonstrate that the NK1 receptor is involved in opioid reinforcement and withdrawal expression. Few studies have examined the impact of treatment with NK1 antagonists on opioid response in humans. OBJECTIVE: To explore the potential for a selective NK1 antagonist, tradipitant, to attenuate the abuse liability and reinforcing and analgesic effects of oxycodone in opioid-experienced individuals. METHODS: Participants with recreational opioid use, but without opioid physical dependence, were enrolled as inpatients for ~6 weeks (n = 8). A within-subject, double-blind, randomized, placebo-controlled, crossover design was employed. The pharmacodynamic response to intranasal oxycodone across a range of doses (0 to 30 mg) was examined during two counterbalanced maintenance periods (tradipitant 0 or 85 mg/bid). Oxycodone self-administration was assessed with a modified progressive ratio procedure, and analgesia was assessed with the cold pressor test. RESULTS: Oxycodone produced significant and dose-related increases on a broad array of prototypic opioid measures, including subjective ratings related to abuse liability (e.g., liking) and physiological outcomes (i.e., expired CO2). Oxycodone self-administration increased with increasing dose, as did analgesia. Tradipitant largely did not alter any of these effects of oxycodone, with the exception of producing a reduction in ratings of desire for opioids. CONCLUSIONS: Given that the vast majority of oxycodone effects were unchanged by tradipitant, these data do not provide support for the utility of NK1 antagonists as a potential treatment for opioid use disorder.
Assuntos
Analgésicos Opioides/administração & dosagem , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Oxicodona/administração & dosagem , Medição da Dor/efeitos dos fármacos , Receptores da Neurocinina-1 , Administração Intranasal , Adolescente , Adulto , Analgesia/métodos , Analgesia/psicologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas dos Receptores de Neurocinina-1/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/psicologia , Medição da Dor/métodos , Medição da Dor/psicologia , Reforço Psicológico , Autoadministração , Resultado do Tratamento , Adulto JovemRESUMO
RATIONALE: Epidemiological data indicate that drivers testing positive for an opioid drug are twice as likely to cause a fatal car crash; however, there are limited controlled data available. OBJECTIVES: The primary aim of this study was to assess the effects of a therapeutic dose range of oxycodone alone and in combination with alcohol on simulated driving performance. METHODS: Healthy participants (n = 10) completed this within-subject, double-blind, placebo-controlled, randomized outpatient study. Six 7-h sessions were completed during which oxycodone (0, 5, 10 mg, p.o.) was administered 30 min before alcohol (0, 0.8 g/kg (15% less for women), p.o.) for a total of 6 test conditions. Driving assessments and participant-, observer-rated, psychomotor and physiological measures were collected in regular intervals before and after drug administration. RESULTS: Oxycodone alone (5, 10 mg) did not produce any changes in driving outcomes or psychomotor task performance, relative to placebo (p > 0.05); however, 10 mg oxycodone produced increases in an array of subjective ratings, including sedation and impairment (p < 0.05). Alcohol alone produced driving impairment (e.g., decreased lateral control) (p < 0.05); however, oxycodone did not potentiate alcohol-related driving or subjective effects. CONCLUSIONS: These preliminary data suggest that acute doses of oxycodone (5, 10 mg) do not significantly impair acuity on laboratory-based simulated driving models; however, 10 mg oxycodone produced increases in self-reported outcomes that are not compatible with safe driving behavior (e.g., sedation, impairment). Additional controlled research is needed to determine how opioid misuse (higher doses; parenteral routes of administration) impacts driving risk.
Assuntos
Dirigir sob a Influência/psicologia , Etanol/efeitos adversos , Modelos Psicológicos , Oxicodona/efeitos adversos , Desempenho Psicomotor/efeitos dos fármacos , Adulto , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Sinergismo Farmacológico , Etanol/administração & dosagem , Feminino , Humanos , Masculino , Transtornos Relacionados ao Uso de Opioides/psicologia , Oxicodona/administração & dosagemRESUMO
RATIONALE: Dozens of preclinical studies have reported cannabinoid agonist potentiation of the analgesic effects of µ-opioid agonists. OBJECTIVES: The aim of this study was to determine if a cannabinoid agonist could potentiate opioid analgesia in humans using several laboratory pain models. METHODS: Healthy participants (n = 10) with/out current drug use/pain conditions completed this within-subject, double-blind, placebo-controlled, randomized outpatient study. Nine 8-h sessions were completed during which dronabinol (0, 2.5, 5 mg, p.o.) was administered 1 h before oxycodone (0, 5, 10 mg, p.o.) for a total of 9 test conditions. Outcomes included sensory threshold and tolerance from four experimental pain models (cold pressor, pressure algometer, hot thermode, cold hyperalgesia), along with participant- and observer-rated, performance and physiological effects. RESULTS: Oxycodone produced miosis (p < 0.05) and analgesic responses (e.g., pressure algometer [p < 0.05]), while dronabinol did not (p > 0.05). Depending on the dose combination, dronabinol attenuated or did not alter oxycodone analgesia; for example, dronabinol (2.5 mg) decreased the analgesic effects of oxycodone (10 mg) on pressure tolerance. Conversely, dronabinol increased oxycodone subjective effects (e.g., drug liking) (p < 0.05); oxycodone (5 mg) ratings of "high" were potentiated by 5 mg dronabinol (p < 0.05; placebo = 1.1 [± 0.7]; 5 mg oxycodone = 4.7 [± 2.2]; 5 mg dronabinol = 9.9 [± 8.4]; 5 mg oxycodone + 5 mg dronabinol = 37.4 [± 11.3]). CONCLUSIONS: This study indicates that dronabinol did not enhance the analgesic effects of oxycodone and increased abuse- and impairment-related subjective effects. These data suggest that dronabinol may not be an effective or appropriate opioid adjuvant; it could potentially increase opioid dose requirements, while increasing psychoactive opioid effects.
Assuntos
Analgesia/métodos , Analgesia/psicologia , Analgésicos Opioides/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Medição da Dor/efeitos dos fármacos , Medição da Dor/psicologia , Adolescente , Adulto , Analgésicos Opioides/uso terapêutico , Agonistas de Receptores de Canabinoides/uso terapêutico , Estudos Cross-Over , Autoavaliação Diagnóstica , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Dor/tratamento farmacológico , Dor/psicologia , Medição da Dor/métodos , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Adulto JovemRESUMO
Abuse of prescription opioids has risen precipitously in the United States. Few controlled comparisons of the abuse liability of the most commonly abused opioids have been conducted. This outpatient study employed a double-blind, randomized, within-subject, placebo-controlled design to examine the relative abuse potential and potency of oral oxycodone (10, 20 and 40 mg), hydrocodone (15, 30 and 45 mg), hydromorphone (10, 17.5 and 25mg) and placebo. Healthy adult volunteers (n=9) with sporadic prescription opioid abuse participated in 11 experimental sessions (6.5h in duration) conducted in a hospital setting. All three opioids produced a typical mu opioid agonist profile of subjective (increased ratings of liking, good effects, high and opiate symptoms), observer-rated, and physiological effects (miosis, modest respiratory depression, exophoria and decrements in visual threshold discrimination) that were generally dose-related. Valid relative potency assays revealed that oxycodone was roughly equipotent to or slightly more potent than hydrocodone. Hydromorphone was only modestly more potent (less than two-fold) than either hydrocodone or oxycodone, which is inconsistent with prior estimates arising from analgesic studies. These data suggest that the abuse liability profile and relative potency of these three commonly used opioids do not differ substantially from one another and suggest that analgesic potencies may not accurately reflect relative differences in abuse liability of prescription opioids.
Assuntos
Analgésicos Opioides , Hidrocodona , Hidromorfona , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Transtornos Relacionados ao Uso de Opioides/psicologia , Oxicodona , Medicamentos sob Prescrição , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Euforia/efeitos dos fármacos , Humanos , Miose/induzido quimicamente , Músculos Oculomotores/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Pupila/efeitos dos fármacosRESUMO
BACKGROUND: Levomethadyl acetate, methadone hydrochloride, and buprenorphine hydrochloride are equally effective treatments for opioid dependence. Each blocks the human ether-a-go-go-related gene (hERG)-associated channel in vitro and represents a risk for QT prolongation. To compare the effects of 3 known hERG-associated channel blockers on the corrected QT (QTc), we conducted a randomized, controlled trial of opioid-addicted subjects. METHODS: We analyzed 12-lead electrocardiograms collected at baseline and every 4 weeks from 165 opioid-addicted participants in a 17-week randomized double-blind clinical trial of equally effective doses of levomethadyl, methadone, and buprenorphine at a major referral center. Analyses were limited to the 154 patients with a normal baseline QTc = (QT/ radical R-R) who had at least 1 subsequent in-treatment electrocardiogram. Patients were randomized to receive treatment with levomethadyl, methadone, or buprenorphine (hereinafter, levomethadyl, methadone, and buprenorphine groups, respectively). The prespecified end points were a QTc greater than 470 milliseconds in men (or >490 milliseconds in women), or an increase from baseline in QTc greater than 60 milliseconds. RESULTS: Baseline QTc was similar in the 3 groups. The levomethadyl and methadone groups were significantly more likely to manifest a QTc greater than 470 or 490 milliseconds (28% for the levomethadyl group vs 23% for the methadone group vs 0% for the buprenorphine group; P < .001) or an increase from baseline in QTc greater than 60 milliseconds (21% of the levomethadyl group [odds ratio, 15.8; 95% confidence interval, 3.7-67.1] and 12% of the methadone group [odds ratio, 8.4; 95% confidence interval, 1.9-36.4]) compared with the buprenorphine group (2% of subjects; P < .001). In subjects whose dosage of levomethadyl or methadone remained fixed over at least 8 weeks, the QTc continued to increase progressively over time (P = .08 for the levomethadyl group, P = .01 for the methadone group). CONCLUSION: Buprenorphine is associated with less QTc prolongation than levomethadyl or methadone and may be a safe alternative.
Assuntos
Analgésicos Opioides/administração & dosagem , Buprenorfina/administração & dosagem , Eletrocardiografia/efeitos dos fármacos , Metadona/administração & dosagem , Acetato de Metadil/administração & dosagem , Transtornos Relacionados ao Uso de Opioides/reabilitação , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
OBJECTIVE: To conduct a pilot needs assessment of underlying substance use disorders (SUD), motivation for SUD treatment, and willingness to enter residential SUD treatment in hospitalized adults who inject drugs with complex infections requiring intravenous (IV) antibiotics, and to assess the presence of in-hospital illicit substance use. PATIENTS AND METHODS: From March 8, 2016 through August 25, 2016 hospitalized, English-speaking, adult patients not currently in SUD treatment with a history of injection drug use and a current infection requiring treatment with IV antibiotics, were prospectively enrolled. Participants were followed weekly during the hospitalization and for 60â¯days after discharge via interview and medical record review. RESULTS: Of the 42 participants, 8 (19.0%) accepted discharge to residential SUD treatment, 16 (38.0%) completed at least one follow-up research visit after hospital discharge, and 3 (7.1%) died during the 5-month study period. The majority (33; 78%) were hospitalized with endocarditis, and 37 (88.0%) had an opioid use disorder (DSM-5). Mean days of self-reported IV opioid use in the 30â¯days before hospitalization compared to 30â¯days after discharge decreased significantly (16.5 to 1.5, Pâ¯=â¯.001) despite not receiving SUD treatment. Illicit in-hospital drug use was identified in 17 (40.5%) participants, with opioids most commonly detected. CONCLUSION: Hospitalization is a 'reachable moment' and critical opportunity to initiate evidence-based treatment for opioid use disorder. The ongoing in-hospital illicit drug use and high short-term mortality observed in this study contribute to the mandate to expand access to effective pharmacotherapy for opioid use disorder and integrate it into health care settings.
Assuntos
Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Tratamento Domiciliar/estatística & dados numéricos , Abuso de Substâncias por Via Intravenosa/reabilitação , Transtornos Relacionados ao Uso de Substâncias/reabilitação , Adulto , Antibacterianos/administração & dosagem , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Drogas Ilícitas , Infecções/epidemiologia , Infecções/etiologia , Masculino , Pessoa de Meia-Idade , Motivação , Avaliação das Necessidades , Transtornos Relacionados ao Uso de Opioides/complicações , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Alta do Paciente , Projetos Piloto , Estudos Prospectivos , Índice de Gravidade de Doença , Abuso de Substâncias por Via Intravenosa/complicações , Transtornos Relacionados ao Uso de Substâncias/complicações , Adulto JovemRESUMO
OBJECTIVE: In preclinical studies, lobeline inhibited hyperactivity induced by nicotine and amphetamine, and improved performance and learning in studies utilizing radial-arm maze and spatial-discrimination water maze. This laboratory proof-of-concept study investigated lobeline as a treatment for ADHD symptoms in adults (31.11 ± 7.08 years). METHOD: Using cognitive tasks and self-report measures, the effects of lobeline (0, 7.5, 15, or 30 mg, s.l.) and methylphenidate (0, 15, or 30 mg, p.o.) were assessed in nine volunteers with ADHD. RESULTS: Evidence suggested that lobeline could modestly improve working memory in adults with ADHD, but no significant improvement in attention was observed. Lobeline administration was associated with mild adverse side effects (nausea). CONCLUSION: Further investigation of lobeline on working memory may be warranted.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/administração & dosagem , Cognição/efeitos dos fármacos , Comportamento Impulsivo/efeitos dos fármacos , Lobelina/administração & dosagem , Memória de Curto Prazo/efeitos dos fármacos , Metilfenidato/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Adulto , Atenção/efeitos dos fármacos , Atenção/fisiologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Lobelina/uso terapêutico , Masculino , Metilfenidato/uso terapêutico , Agonistas Nicotínicos/uso terapêutico , Resultado do TratamentoRESUMO
A common clinical problem with opioid analgesics is the loss of analgesic efficacy after repeated dosing; when this occurs, it is not clear what principles should guide providing effective analgesia among opioid-dependent individuals. This within-subject inpatient study aimed to determine if physically dependent opioid abusers (n = 11) experience changes in oxycodone-induced analgesia during 2 oxycodone maintenance (30 mg orally 4 times per day) phases: initial stabilization (days 1-3) and after 6 weeks of chronic dosing. Six sessions (3 each phase), measured threshold, tolerance, and pain ratings for a Pressure Pain Test and Cold Pressor Test after a single double-blind dose of oxycodone 30 mg (initial stabilization) and 0, 30, and 60 mg (chronic dosing) given in place of a scheduled maintenance dose. Physiologic and opioid agonist effects were assessed during chronic dosing sessions. There was no analgesic response to oxycodone 30 mg. Oxycodone (60 mg) produced a 25% increase in peak Cold Pressor Test threshold compared with placebo, and significantly increased expired breath CO2, miosis, and ratings of abuse liability measures. These data suggest that more than twice the acute oxycodone maintenance dose is needed to produce robust acute analgesia, although adverse effects (eg, respiratory depression and abuse signals) may occur with lower doses. PERSPECTIVE: To understand sensitivity to opioid analgesia in opioid-dependent individuals, this article describes experimental pain, subjective and physiological responses during stabilization and after 6 weeks of oxycodone maintenance. Oxycodone produced euphoric effects and miosis with limited evidence of analgesia.
Assuntos
Analgesia , Analgésicos Opioides/farmacologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Oxicodona/farmacologia , Dor/tratamento farmacológico , Adulto , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Oxicodona/administração & dosagem , Oxicodona/efeitos adversosRESUMO
BACKGROUND: Opioid overdose (OD) has become a significant public health problem in need of effective interventions. The majority of existing educational interventions target provision of naloxone and are conducted in-person; these elements present logistical barriers that may limit wide-spread implementation. This study developed and evaluated an easily disseminated opioid OD educational intervention and compared computerized versus pamphlet delivery METHODS: Participants (N=76) undergoing opioid detoxification were randomly assigned to receive OD education via a Pamphlet (N=25), Computer (N=24), or Computer+Mastery (N=27) with identical content for all delivery modalities. Primary outcomes were changes from pre- to post-intervention in knowledge of opioid effects, opioid OD symptoms, and recommended opioid OD responses, as well as intervention acceptability. Also assessed at 1 and 3-month follow-ups were retention of knowledge and change in reported OD risk behaviors. RESULTS: Knowledge increased following all three intervention-delivery modalities with few between-group differences observed in knowledge gain or acceptability ratings. Largest gains were in the domain of opioid OD response (from 41.8% to 73.8% mean correct responses; p<0.001). Knowledge was well sustained at the 1 and 3-month follow-ups among completers, where a significant reduction was seen in the critical behavioral risk factor of using opioids while alone. CONCLUSION: Opioid overdose education delivered by computer or written pamphlet produced sustained increases in knowledge and reduction in a key behavioral risk factor. RESULTS: Results support further evaluation of this educational intervention that can be used alone or to complement naloxone-training programs.
Assuntos
Analgésicos Opioides/efeitos adversos , Instrução por Computador , Overdose de Drogas/prevenção & controle , Naloxona/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/reabilitação , Educação de Pacientes como Assunto/métodos , Adulto , Overdose de Drogas/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Entorpecentes/uso terapêutico , FolhetosRESUMO
Importance: Buprenorphine is an efficacious, widely used treatment for opioid use disorder (OUD). Daily oral transmucosal formulations can be associated with misuse, diversion, and nonadherence; these limitations may be obviated by a sustained release formulation. Objective: To evaluate the ability of a novel, weekly, subcutaneous buprenorphine depot formulation, CAM2038, to block euphorigenic opioid effects and suppress opioid withdrawal in non-treatment-seeking individuals with OUD. Design, Setting, and Participants: This multisite, double-blind, randomized within-patient study was conducted at 3 controlled inpatient research facilities. It involved 47 adults with DSM-V moderate-to-severe OUD. The study was conducted from October 12, 2015 (first patient enrolled), to April 21, 2016 (last patient visit). Interventions: A total of five 3-day test sessions evaluated the response to hydromorphone (0, 6, and 18 mg intramuscular in random order; 1 dose/session/day). After the first 3-day session (ie, qualification phase), participants were randomized to either CAM2038 weekly at 24 mg (n = 22) or 32 mg (n = 25); the assigned CAM2038 dose was given twice, 1 week apart (day 0 and 7). Four sets of sessions were conducted after randomization (days 1-3, 4-6, 8-10, and 11-13). Main Outcomes and Measures: The primary end point was maximum rating on the visual analog scale for drug liking. Secondary end points included other visual analog scale (eg, high and desire to use), opioid withdrawal scales, and physiological and pharmacokinetic outcomes. Results: A total of 46 of 47 randomized participants (mean [SD] age, 35.5 [9] years; 76% male [n = 35]) completed the study. Both weekly CAM2038 doses produced immediate and sustained blockade of hydromorphone effects (liking maximum effect, CAM2038, 24 mg: effect size, 0.813; P < .001, and CAM2038, 32 mg: effect size, 0.753; P < .001) and suppression of withdrawal (Clinical Opiate Withdrawal Scale, CAM2038, 24 mg: effect size, 0.617; P < .001, and CAM2038, 32 mg: effect size, 0.751; P < .001). CAM2038 produces a rapid initial rise of buprenorphine in plasma with maximum concentration around 24 hours, with an apparent half-life of 4 to 5 days and approximately 50% accumulation of trough concentration from first to second dose (trough concentration = 0.822 and 1.23 ng/mL for weeks 1 and 2, respectively, with 24 mg; trough concentration = 0.993 and 1.47 ng/mL for weeks 1 and 2, respectively, with 32 mg). Conclusions and Relevance: CAM2038 weekly, 24 and 32 mg, was safely tolerated and produced immediate and sustained opioid blockade and withdrawal suppression. The results support the use of this depot formulation for treatment initiation and stabilization of patients with OUD, with the further benefit of obviating the risk for misuse and diversion of daily buprenorphine while retaining its therapeutic benefits. Trial Registration: Clinicaltrials.gov Identifier: NCT02611752.
Assuntos
Buprenorfina/uso terapêutico , Hidromorfona/antagonistas & inibidores , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Adolescente , Adulto , Analgésicos Opioides/antagonistas & inibidores , Buprenorfina/efeitos adversos , Buprenorfina/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Entorpecentes/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The cannabinoid (CB) system is a rational novel target for treating opioid dependence, a significant public health problem around the world. This proof-of-concept study examined the potential efficacy of a CB1 receptor partial agonist, dronabinol, in relieving signs and symptoms of opioid withdrawal. METHODS: Twelve opioid dependent adults participated in this 5-week, inpatient, double-blind, randomized, placebo-controlled study. Volunteers were maintained on double-blind oxycodone (30mg oral, four times/day) and participated in a training session followed by 7 experimental sessions, each testing a single oral test dose (placebo, oxycodone 30 and 60mg, dronabinol 5, 10, 20, and 30mg [decreased from 40mg]). Placebo was substituted for oxycodone maintenance doses for 21h before each session in order to produce measurable opioid withdrawal. Outcomes included observer- and participant-ratings of opioid agonist, opioid withdrawal and psychomotor/cognitive performance. RESULTS: Oxycodone produced prototypic opioid agonist effects (i.e. suppressing withdrawal and increasing subjective effects indicative of abuse liability). Dronabinol 5 and 10mg produced effects most similar to placebo, while the 20 and 30mg doses produced modest signals of withdrawal suppression that were accompanied by dose-related increases in high, sedation, bad effects, feelings of heart racing, and tachycardia. Dronabinol was not liked more than placebo, showed some impairment in cognitive performance, and was identified as marijuana with increasing dose. CONCLUSION: CB1 receptor activation is a reasonable strategy to pursue for the treatment of opioid withdrawal; however, dronabinol is not a likely candidate given its modest withdrawal suppression effects of limited duration and previously reported tachycardia during opioid withdrawal.
Assuntos
Analgésicos não Narcóticos/uso terapêutico , Dronabinol/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/reabilitação , Síndrome de Abstinência a Substâncias/reabilitação , Administração Oral , Adulto , Analgésicos não Narcóticos/efeitos adversos , Analgésicos Opioides , Relação Dose-Resposta a Droga , Método Duplo-Cego , Dronabinol/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tratamento de Substituição de Opiáceos , Oxicodona/uso terapêutico , Receptor CB1 de Canabinoide/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Adulto JovemRESUMO
BACKGROUND: Buprenorphine can be abused by the intranasal route. This study sought to examine the relative abuse liability and reinforcing efficacy of intranasal buprenorphine compared to intranasal buprenorphine/naloxone in opioid-dependent individuals. METHODS: Eleven healthy male and female volunteers physically dependent on short-acting opioids resided as inpatients during participation in this double blind, within subject, placebo-controlled study. Participants were maintained on oxycodone (30 mg/q.i.d., p.o.) throughout the 6-week study. Eight pairs of experimental sessions were conducted at ≥48 h intervals to examine the pharmacodynamic profile (Sample) and reinforcing efficacy (Self-administration the following day) of intranasal placebo, oxycodone (60 mg), buprenorphine (2, 8 & 16 mg) and buprenorphine/naloxone (2/0.5, 8/2 & 16/4 mg). Subjective, observer-rated and physiological measures were collected to assess the magnitude of opioid agonist and antagonist effects. A progressive ratio self-administration procedure assessed choices for drug versus money. RESULTS: All active doses produced opioid agonist-like effects (e.g., increased ratings of "liking," and miosis) compared to placebo. The effects of buprenorphine and buprenorphine/naloxone were not reliably dose-dependent. Intranasal buprenorphine/naloxone elicited modest and transient opioid withdrawal-like effects in the first hour post-drug administration, while simultaneously blunting or blocking the early onset of agonist effects seen with buprenorphine alone. All active doses of buprenorphine were self-administered more than placebo, but buprenorphine/naloxone doses were not. CONCLUSIONS: These data confirm that intranasal buprenorphine/naloxone has deterrent properties related to transient withdrawal effects that likely decrease its desirability for misuse compared to buprenorphine in opioid-dependent individuals maintained on short-acting opioids.
Assuntos
Combinação Buprenorfina e Naloxona/farmacologia , Buprenorfina/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Administração Intranasal , Adolescente , Adulto , Analgésicos Opioides , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Entorpecentes , Tratamento de Substituição de Opiáceos/métodos , Oxicodona/farmacologia , Reforço Psicológico , Autoadministração , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Adulto JovemRESUMO
Cannabidiol (CBD), a constituent of cannabis with few psychoactive effects, has been reported in some studies to attenuate certain aspects of Δ(9)-tetrahydrocannabinol (THC) intoxication. However, most studies have tested only one dose of CBD in combination with one dose of oral THC, making it difficult to assess the nature of this interaction. Further, the effect of oral CBD on smoked cannabis administration is unknown. The objective of this multi-site, randomized, double-blind, within-subject laboratory study was to assess the influence of CBD (0, 200, 400, 800 mg, p.o.) pretreatment on the reinforcing, subjective, cognitive, and physiological effects of smoked cannabis (0.01 (inactive), 5.30-5.80% THC). Non-treatment-seeking, healthy cannabis smokers (n=31; 17M, 14 F) completed eight outpatient sessions. CBD was administered 90 min prior to cannabis administration. The behavioral and cardiovascular effects of cannabis were measured at baseline and repeatedly throughout the session. A subset of participants (n=8) completed an additional session to measure plasma CBD concentrations after administration of the highest CBD dose (800 mg). Under placebo CBD conditions, active cannabis (1) was self-administered by significantly more participants than placebo cannabis and (2) produced significant, time-dependent increases in ratings of 'High', 'Good Effect', ratings of the cannabis cigarette (eg, strength, liking), and heart rate relative to inactive cannabis. CBD, which alone produced no significant psychoactive or cardiovascular effects, did not significantly alter any of these outcomes. Cannabis self-administration, subjective effects, and cannabis ratings did not vary as a function of CBD dose relative to placebo capsules. These findings suggest that oral CBD does not reduce the reinforcing, physiological, or positive subjective effects of smoked cannabis.
Assuntos
Canabidiol/administração & dosagem , Dronabinol/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Fumar Maconha , Reforço Psicológico , Administração Oral , Adolescente , Adulto , Afeto/efeitos dos fármacos , Canabidiol/sangue , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Autoadministração , Adulto JovemRESUMO
Internet-based group contingencies have been shown to promote brief periods of abstinence from cigarette smoking. Under a group contingency, small teams of smokers must collectively meet abstinence goals to receive monetary consequences. The present study investigated 2 arrangements, 1 in which all team members had to meet group treatment goals to receive monetary consequences (full group), and 1 in which team members had to meet some group goals and some individual goals to receive these consequences (mixed group). MoÌ tiv8 Systems, an Internet-based remote monitoring platform, was used to collect video-recorded breath carbon monoxide (CO) samples. All team members could communicate with each other via an online discussion forum. During baseline conditions, only 3.3% of CO samples were negative for smoking, which suggests that self-monitoring and access to the online discussion forum were insufficient to initiate abstinence. When the group contingencies were instituted 41.3% of CO samples were negative. There were no statistically significant differences between the 2 arrangements in the percentage of negative CO samples or point prevalence at the end of treatment or at the 3-month follow-up. Participants posted an average of 25 comments on the discussion forum, most of which were rated as positive by independent observers. The mean cost of vouchers per participant was lower in the full group ($33) relative to the mixed group ($190). The present results replicate and extend previous findings on group contingencies to promote abstinence and social support.
Assuntos
Terapia Comportamental/métodos , Internet , Abandono do Hábito de Fumar/métodos , Fumar/psicologia , Fumar/terapia , Adolescente , Adulto , Distribuição de Qui-Quadrado , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Fatores de Tempo , Adulto JovemRESUMO
Effective strategies to monitor pharmacotherapy adherence are necessary, and sensitive biological markers are lacking. This study examined a subtherapeutic dose of quinine as a potential adherence tracer. Primary aims included examination of the plasma and urinary pharmacokinetic profile of once-daily quinine; secondary aims assessed pharmacokinetic/pharmacodynamic interactions with oxycodone (a CYP3A and CYP2D substrate). Healthy, nondependent opioid users (n = 9) were enrolled in this within-subject, double-blind, placebo-controlled inpatient study. Participants received the following oral doses: day 1, oxycodone (30 mg); days 2-4, quinine (80 mg); day 5, quinine and oxycodone (2 hours postquinine). Blood and 24-hour urine samples were collected throughout the study, and pharmacodynamic outcomes were assessed during experimental sessions (days 1, 4, 5). Quinine displayed a plasma Tmax â¼2 hours and t1/2 â¼10 hours. Oxycodone and noroxycodone parameters (Tmax , Cmax , t1/2 ) were similar with or without quinine present, although drug exposure (AUC) was slightly greater when combined with quinine. No pharmacodynamic interactions were detected, and doses were safely tolerated. During washout, quinine urinary concentrations steadily declined (elimination t1/2 â¼16 hours), with a 94% decrease observed 72 hours postdose. Overall, low-dose quinine appears to be a good candidate for a medication additive to monitor adherence for detection of missed medication.