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Drug and Alcohol Dependence Sep 2019Understanding mechanisms of physiological opioid withdrawal symptoms can inform treatment strategies. This secondary analysis evaluated the association between mydriasis...
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.
Topics: Adult; Analgesics, Opioid; Female; Humans; Male; Morphine; Naloxone; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Pupil; Substance Withdrawal Syndrome
PubMed: 31336328
DOI: 10.1016/j.drugalcdep.2019.05.010 -
Substance Abuse Treatment, Prevention,... Mar 2015Buprenorphine is under-utilized in treating opioid addiction. Payers and providers both have substantial influence over the adoption and use of this medication to...
BACKGROUND
Buprenorphine is under-utilized in treating opioid addiction. Payers and providers both have substantial influence over the adoption and use of this medication to enhance recovery. Their views could provide insights into the barriers and facilitators in buprenorphine adoption.
METHODS
We conducted individual interviews with 18 Ohio county Alcohol, Drug Addiction, and Mental Health Services (ADAMHS) Boards (payers) and 36 addiction treatment centers (providers) to examine barriers and facilitators to buprenorphine use. Transcripts were reviewed, coded, and qualitatively analyzed. First, we examined reasons that county boards supported buprenorphine use. A second analysis compared county boards and addiction treatment providers on perceived barriers and facilitators to buprenorphine use. The final analysis compared county boards with low and high use of buprenorphine to determine how facilitators and barriers differed between those settings.
RESULTS
County boards (payers) promoted buprenorphine use to improve clinical care, reduce opioid overdose deaths, and prepare providers for participation in integrated models of health care delivery with primary care clinics and hospitals. Providers and payers shared many of the same perceptions of facilitators and barriers to buprenorphine use. Common facilitators identified were knowledge of buprenorphine benefits, funds allocated to purchase buprenorphine, and support from the criminal justice system. Common barriers were negative attitudes toward use of agonist pharmacotherapy, payment environment, and physician prescribing capacity. County boards with low buprenorphine use rates cited negative attitudes toward use of agonist medication as a primary barrier. County boards with high rates of buprenorphine use dedicated funds to purchase buprenorphine in spite of concerns about limited physician prescribing capacity.
CONCLUSIONS
This qualitative analysis found that attitudes toward use of medication and medication funding environment play important roles in an organization's decision to begin buprenorphine use and that physician availability influences an organization's ability to expand buprenorphine use over time. Additional education, reimbursement support, and policy changes are needed to support buprenorphine adoption and use, along with a greater understanding of the roles payers, providers, and regulators play in the adoption of targeted practices.
Topics: Attitude of Health Personnel; Buprenorphine; Health Care Costs; Health Knowledge, Attitudes, Practice; Health Services Accessibility; Humans; Narcotic Antagonists; Ohio; Opiate Substitution Treatment; Opioid-Related Disorders
PubMed: 25884206
DOI: 10.1186/s13011-015-0009-2 -
Clinical Pharmacology and Therapeutics Jan 2004Buprenorphine is a partial mu-opiate agonist and kappa-opiate antagonist with established efficacy in the treatment of opiate dependence. Its efficacy for cocaine... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Buprenorphine is a partial mu-opiate agonist and kappa-opiate antagonist with established efficacy in the treatment of opiate dependence. Its efficacy for cocaine dependence is uncertain. This study evaluated buprenorphine for the treatment of concomitant cocaine and opiate dependence.
METHODS
Two hundred outpatients currently dependent on both cocaine and opiates were randomly assigned to double-blind groups receiving a sublingual solution of buprenorphine (2, 8, or 16 mg daily, or 16 mg on alternate days, or placebo), plus weekly individual drug abuse counseling, for 13 weeks. The chief outcome measures were urine concentrations of opiate and cocaine metabolites (quantitative) and proportion of urine samples positive for opiates or cocaine (qualitative). Group differences were assessed by use of mixed regression modeling.
RESULTS
The target dose of buprenorphine was achieved in 179 subjects. Subjects receiving 8 or 16 mg buprenorphine daily showed statistically significant decreases in urine morphine levels (P =.0135 for 8 mg and P <.001 for 16 mg) or benzoylecgonine concentrations (P =.0277 for 8 mg and P =.006 for 16 mg) during the maintenance phase of the study. For the 16-mg group, mean benzoylecgonine concentrations fell from 3715 ng/mL during baseline to 186 ng/mL during the withdrawal phase; mean morphine concentrations fell from 3311 ng/mL during baseline to 263 ng/mL during withdrawal. For the 8-mg group, mean benzoylecgonine concentrations fell from 6761 ng/mL during baseline to 676 ng/mL during withdrawal; mean morphine concentrations fell from 3890 ng/mL during baseline to 661 ng/mL during withdrawal. Qualitative urinalysis showed a similar pattern of results. Subjects receiving the highest dose showed concomitant decreases in both urine morphine and benzoylecgonine concentrations. There were no significant group differences in treatment retention or adverse events.
CONCLUSIONS
A sublingual buprenorphine solution at 16 mg daily is well tolerated and effective in reducing concomitant opiate and cocaine use. The therapeutic effect on cocaine use appears independent of that on opiate use.
Topics: Administration, Sublingual; Adult; Buprenorphine; Cocaine-Related Disorders; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Narcotic Antagonists; Opioid-Related Disorders; Patient Compliance; Treatment Outcome
PubMed: 14749690
DOI: 10.1016/j.clpt.2003.09.004 -
Addiction (Abingdon, England) Nov 2017In a recent randomized trial, patients with opioid dependence receiving brief intervention, emergency department (ED)-initiated buprenorphine and ongoing follow-up in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
In a recent randomized trial, patients with opioid dependence receiving brief intervention, emergency department (ED)-initiated buprenorphine and ongoing follow-up in primary care with buprenorphine (buprenorphine) were twice as likely to be engaged in addiction treatment compared with referral to community-based treatment (referral) or brief intervention and referral (brief intervention). Our aim was to evaluate the relative cost-effectiveness of these three methods of intervening on opioid dependence in the ED.
DESIGN
Measured health-care use was converted to dollar values. We considered a health-care system perspective and constructed cost-effectiveness acceptability curves that indicate the probability each treatment is cost-effective under different thresholds of willingness-to-pay for outcomes studied.
SETTING
An urban ED in the United States.
PARTICIPANTS
Opioid-dependent patients aged 18 years or older.
MEASUREMENTS
Self-reported 30-day assessment data were used to construct cost-effectiveness acceptability curves for patient engagement in formal addiction treatment at 30 days and the number of days illicit opioid-free in the past week.
FINDINGS
Considering only health-care system costs, cost-effectiveness acceptability curves indicate that at all positive willingness-to-pay values, ED-initiated buprenorphine treatment was more cost-effective than brief intervention or referral. For example, at a willingness-to-pay threshold of $1000 for 30-day treatment engagement, we are 79% certain ED-initiated buprenorphine is most cost-effective compared with other studied treatments. Similar results were found for days illicit opioid-free in the past week. Results were robust to secondary analyses that included patients with missing cost data, included crime and patient time costs in the numerator, and to changes in unit price estimates.
CONCLUSION
In the United States, emergency department-initiated buprenorphine intervention for patients with opioid dependence provides high value compared with referral to community-based treatment or combined brief intervention and referral.
Topics: Aftercare; Analgesics, Opioid; Buprenorphine; Cost-Benefit Analysis; Emergency Service, Hospital; Health Services; Humans; Opiate Substitution Treatment; Opioid-Related Disorders; Patient Participation; Primary Health Care; Referral and Consultation; United States
PubMed: 28815789
DOI: 10.1111/add.13900 -
Molecules (Basel, Switzerland) Feb 2022In our continuing effort to develop effective anti-heroin vaccines as potential medications for the treatment of opioid use disorder, herein we present the design and...
In our continuing effort to develop effective anti-heroin vaccines as potential medications for the treatment of opioid use disorder, herein we present the design and synthesis of the haptens: 1-AmidoMorHap (), 1-AmidoMorHap epimer (), 1 Amido-DihydroMorHap (), and 1 Amido-DihydroMorHap epimer (). This is the first report of hydrolytically stable haptenic surrogates of heroin with the attachment site at the C1 position in the 4,5-epoxymorophinan nucleus. We prepared respective tetanus toxoid (TT)-hapten conjugates as heroin vaccine immunogens and evaluated their efficacy in vivo. We showed that all TT-hapten conjugates induced high antibody endpoint titers against the targets but only haptens and can induce protective effects against heroin in vivo. The epimeric analogues of these haptens, and , failed to protect mice from the effects of heroin. We also showed that the in vivo efficacy is consistent with the results of the in vitro drug sequestration assay. Attachment of the linker at the C1 position induced antibodies with weak binding to the target drugs. Only TT- and TT- yielded antibodies that bound heroin and 6-acetyl morphine. None of the TT-hapten conjugates induced antibodies that cross-reacted with morphine, methadone, naloxone, or naltrexone, and only TT- interacted weakly with buprenorphine, and that subtle structural difference, especially at the C6 position, can vastly alter the specificity of the induced antibodies. This study is an important contribution in the field of vaccine development against small-molecule targets, providing proof that the chirality at C6 in these epoxymorphinans is a vital key to their effectiveness.
Topics: Heroin
PubMed: 35268659
DOI: 10.3390/molecules27051553 -
Therapeutic Drug Monitoring Apr 2010Buprenorphine is approved as pharmacotherapy for opioid dependence in nonpregnant patients in multiple countries and is currently under investigation for pregnant women... (Comparative Study)
Comparative Study Randomized Controlled Trial
Buprenorphine is approved as pharmacotherapy for opioid dependence in nonpregnant patients in multiple countries and is currently under investigation for pregnant women in the United States and Europe. This research evaluates the disposition of buprenorphine, opiates, cocaine, and metabolites in five term placentas from a US cohort. Placenta and matched meconium concentrations were compared, and relationships among maternal buprenorphine dose, placenta concentrations, and neonatal outcomes after controlled administration during gestation were investigated. Buprenorphine and/or metabolites were detected in all placenta specimens and were uniformly distributed across this tissue (coefficient of variation less than 27.5%, four locations), except for buprenorphine in three placentas. In two of these, buprenorphine was not detected in some locations and in the third placenta was totally absent. Median (range) concentrations were 1.6 ng/g buprenorphine (not detected to 3.2), 14.9 ng/g norbuprenorphine (6.2-24.2), 3 ng/g buprenorphine-glucuronide (1.3-5.0), and 14.7 ng/g norbuprenorphine-glucuronide (11.4-25.8). Placenta is a potential alternative matrix for detecting in utero buprenorphine exposure, but at lower concentrations (15- to 70-fold) than in meconium. Statistically significant correlations were observed for mean maternal daily dose from enrollment to delivery and placenta buprenorphine-glucuronide concentration and for norbuprenorphine-glucuronide concentrations and time to neonatal abstinence syndrome onset and duration, for norbuprenorphine/norbuprenorphine-glucuronide ratio and maximum neonatal abstinence syndrome score, and newborn length. Analysis of buprenorphine and metabolites in this alternative matrix, an abundant waste product available at the time of delivery, may be valuable for prediction of neonatal outcomes for clinicians treating newborns of buprenorphine-exposed women.
Topics: Adult; Buprenorphine; Cohort Studies; Female; Humans; Infant, Newborn; Male; Maternal-Fetal Exchange; Opioid-Related Disorders; Placenta; Pregnancy; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Treatment Outcome; Young Adult
PubMed: 20216119
DOI: 10.1097/FTD.0b013e3181d0bd68 -
JAMA Psychiatry Dec 2013Although abuse of prescription opioids (POs) is a significant public health problem, few experimental studies have investigated the treatment needs of this growing... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Although abuse of prescription opioids (POs) is a significant public health problem, few experimental studies have investigated the treatment needs of this growing population.
OBJECTIVE
To evaluate, following brief stabilization with a combination of buprenorphine hydrochloride and naloxone hydrochloride dihydrate, the relative efficacy of 1-, 2-, and 4-week buprenorphine tapering regimens and subsequent naltrexone hydrochloride therapy in PO-dependent outpatients.
DESIGN, SETTING, AND PARTICIPANTS
A double-blind, 12-week randomized clinical trial was conducted in an outpatient research clinic. Following a brief period of buprenorphine stabilization, 70 PO-dependent adults were randomized to receive 1-, 2-, or 4-week tapers followed by naltrexone therapy.
INTERVENTION
During phase 1 (weeks 1-5 after randomization), participants visited the clinic daily; during phase 2 (weeks 6-12), visits were reduced to thrice weekly. Participants received behavioral therapy and urine toxicology testing throughout the trial.
MAIN OUTCOMES AND MEASURES
The percentage of participants negative for illicit opioid use, retention, naltrexone ingestion, and favorable treatment response (ie, retained in treatment, opioid abstinent, and receiving naltrexone at the end of the study).
RESULTS
Opioid abstinence at the end of phase 1 was greater in the 4-week compared with the 2- and 1-week taper conditions (P = .02), with 63% (n = 14), 29% (n = 7), and 29% (n = 7) of participants abstinent in the 4-, 2-, and 1-week conditions, respectively. Abstinence at the end of phase 2 was also greater in the 4-week compared with the 2- and 1-week conditions (P = .03), with 50% (n = 11), 16% (n = 4), and 20% (n = 5) of participants abstinent in the 4-, 2-, and 1-week conditions, respectively. There were more treatment responders in the 4-week condition (P = .03), with 50% (n = 11), 17% (n = 4), and 21% (n = 5) of participants in the 4-, 2-, and 1-week groups considered responders at the end of treatment, respectively. Retention and naltrexone ingestion also were superior in the 4-week vs briefer tapers (both P = .04). Experimental condition (ie, taper duration) was the strongest predictor of treatment response, followed by buprenorphine stabilization dose.
CONCLUSIONS AND RELEVANCE
This study represents a rigorous experimental evaluation of outpatient buprenorphine stabilization, brief taper, and naltrexone maintenance for treatment of PO dependence. Results suggest that a meaningful subset of PO-dependent outpatients may respond positively to a 4-week taper plus naltrexone maintenance intervention.
Topics: Adult; Buprenorphine; Cognitive Behavioral Therapy; Combined Modality Therapy; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Naloxone; Naltrexone; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Psychiatric Status Rating Scales; Severity of Illness Index; Time Factors; Treatment Outcome; Young Adult
PubMed: 24153411
DOI: 10.1001/jamapsychiatry.2013.2216 -
Addiction Biology Jan 2020Opioid use disorder (OUD) is a public health crisis. Differences in opioid withdrawal severity that predict treatment outcome could facilitate the process of matching... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Adult; Analgesics; Buprenorphine; Clonidine; Cluster Analysis; Double-Blind Method; Female; Humans; Male; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Opiate Substitution Treatment; Opioid-Related Disorders; Phenotype; Severity of Illness Index; Substance Withdrawal Syndrome; Tramadol; Treatment Outcome
PubMed: 30295400
DOI: 10.1111/adb.12680 -
Bioconjugate Chemistry Apr 2011Norbuprenorphine-3-β-d-glucuronide (nBPN-3-β-d-G, 1) is a major phase II metabolite of buprenorphine, a pharmaceutical used for the treatment of opioid addiction. The...
Norbuprenorphine-3-β-d-glucuronide (nBPN-3-β-d-G, 1) is a major phase II metabolite of buprenorphine, a pharmaceutical used for the treatment of opioid addiction. The pharmacological activity of compound 1 is not clear because investigations have been limited by the lack of chemically pure, well characterized 1 in sufficient quantities for in vitro and in vivo experiments. This work describes two concise, new methods of synthesis of 1, a chemical and an enzyme-assisted synthesis. The chemical synthesis used a strategy based on a combination of Koenig-Knorr coupling and amino-silyl protection. The enzyme-assisted synthesis used dog liver to convert the substrate norbuprenorphine (nBPN, 2) to 1. Both methods provided 1, characterized by (1)H NMR and tandem mass spectrometry, with purity >96%. The fractional yield of the enzyme-assisted synthesis was greater than that of the chemical synthesis (67% vs 5.3%), but due to larger reaction volumes, the chemical synthesis afforded greater amounts of total 1.
Topics: Animals; Biocatalysis; Buprenorphine; Dogs; Glucosephosphate Dehydrogenase; Liver; Molecular Conformation; Stereoisomerism
PubMed: 21434652
DOI: 10.1021/bc100550u -
Journal of Chromatography. B,... Apr 2024Diamorphine, commonly known as heroin, is a semi-synthetic opioid analgesic. In the context of heroin-assisted treatment for opioid-dependent patients, diamorphine is...
Development and validation of an LC-MS/MS method for quantifying diamorphine and its major metabolites 6-monoacetylmorphine, morphine, morphine-3-glucuronide, and morphine-6-glucuronide in human plasma.
Diamorphine, commonly known as heroin, is a semi-synthetic opioid analgesic. In the context of heroin-assisted treatment for opioid-dependent patients, diamorphine is mostly administered intravenously. However, recent attention has shifted towards intranasal administration as a better-tolerated alternative to the intravenous route. Here, we developed and validated a rapid bioanalytical method for the simultaneous quantification of diamorphine and its major metabolites 6-monoacetylmorphine, morphine, morphine-3-glucuronide, and morphine-6-glucuronide in human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A straightforward protein precipitation extraction step was used for sample preparation. Chromatographic analyte separation was achieved using a Kinetex EVO C analytical column and a mobile phase gradient comprising an aqueous solution of ammonium hydrogen carbonate and methanol supplied with formic acid. Employing positive electrospray ionization and scheduled multiple reaction monitoring, we established a quantification range of 1-1,000 ng/mL for all analytes. Our validation results demonstrate a mean intra-assay accuracy of 91-106% and an intra-assay precision (CV) between 2 and 9% for all analytes and over three validation runs. The method exhibits a high extraction recovery (> 87%) and a negligible matrix effect (99-125%). Furthermore, no interferences with endogenous plasma compounds were detected. Lastly, we applied the method to assess the plasma concentrations of an opioid-dependent patient after the intranasal administration of diamorphine in a clinical study. In summary, we have successfully developed a rapid, highly reliable, and straightforward bioanalytical method for quantifying diamorphine and its metabolites in low amounts of clinical plasma samples.
Topics: Humans; Morphine; Heroin; Chromatography, Liquid; Analgesics, Opioid; Tandem Mass Spectrometry; Liquid Chromatography-Mass Spectrometry; Morphine Derivatives; Reproducibility of Results; Chromatography, High Pressure Liquid
PubMed: 38552595
DOI: 10.1016/j.jchromb.2024.124104