Subjective Opioid Withdrawal Scale Research Articles

Kratom addiction per DSM-5 SUD criteria, and kratom physical dependence: Insights from dosing amount versus frequency

BackgroundKratom products are widely used in the United States, with inadequate understanding of how dosing amounts/frequencies relate to outcomes. MethodsBetween July-November 2022, we enrolled 395 active US adult kratom consumers into a remote study with a baseline survey. We examined self-reported typical dose amounts and frequencies across people and product types, and their associations with outcomes: multiple regression was used to examine whether amounts and frequencies (doses/day) were associated with acute effects, withdrawal symptoms, scores on the Subjective Opioid Withdrawal Scale (SOWS), and addiction (operationalized as DSM-5-based symptoms of kratom-use disorder, KUD). ResultsParticipants were 54.9% male, aged 38.1 on average, and 81.3% White. Mean length of kratom use was 5.7 years. Most (95.9%) reported regularly using whole-leaf kratom products; 16 (4.1%) reported regular extract use. SOWS scores were mild to moderate on average (13.5, SD 11.9). KUD symptom counts were mostly in the mild/moderate range (80.7%). Withdrawal and KUD symptoms were more closely associated with dose frequency than dose amount. Men reported more acute effects, withdrawal symptoms with cessation, and KUD symptoms than women. ConclusionsGreater dose amount and frequency were systematically related to the number of withdrawal symptoms upon cessation and to KUD symptoms; the relationship was stronger for dose frequency than amount. Men may have more acute effects and more withdrawal and KUD symptoms than women. Although kratom may be used nonproblematically by some consumers, physical dependence (tolerance, withdrawal, or use to avoid withdrawal) and KUD become more likely with increasing dose frequency.

Responses to a "Typical" Morning Dose of Kratom in People Who Use Kratom Regularly: A Direct-Observation Study.

Use of kratom has outpaced systematic study of its effects, with most studies reliant on retrospective self-report. We aimed to assess acute effects following kratom use in adults who use regularly, and quantify alkaloids in the products, urine, and plasma. Between July and November 2022, 10 adults came to our clinic and orally self-administered their typical kratom dose; blinding procedures were not used. Physiological measures included blood pressure, respiratory rate, heart rate, pulse oximetry, temperature, and pupil diameter. Subjective outcomes included Subjective Opioid Withdrawal Scale, Addiction Research Center Inventory, and Drug Effects Questionnaire. Psychomotor performance was also assessed. Participants were 6 men and 4 women, mean age 41.2 years. Nine were non-Hispanic White; 1 was biracial. They had used kratom for 6.6 years (SD, 3.8 years) on average (2.0-14.1). Sessions were 190.89 minutes on average (SD, 15.10 minutes). Mean session dose was 5.16 g (median, 4.38 g; range, 1.1-10.9 g) leaf powder. Relative to baseline, physiological changes were minor. However, pupil diameter decreased (right, b = -0.70, P < 0.01; left, b = -0.73, P < 0.01) 40-80 minutes postdose and remained below baseline >160 minutes. Subjective Opioid Withdrawal Scale pre-dosing was mild (5.5 ± 3.3) and decreased postdose (b = [-4.0, -2.9], P < 0.01). Drug Effects Questionnaire "feeling effects" increased to 40/100 (SD, 30.5) within 40 minutes and remained above baseline 80 to 120 minutes (b = 19.0, P = 0.04), peaking at 72.7/100; 6 participants rated euphoria as mild on the Addiction Research Center Inventory Morphine-Benzedrine-scale. Psychomotor performance did not reliably improve or deteriorate postdosing. Among regular consumers, we found few clinically significant differences pre- and post-kratom dosing. Alkaloidal contents in products were within expected ranges.

Assessing the Recovery Process after a Vaso Occlusive Crisis

Introduction: Adults with sickle cell disease (SCD) suffer from vaso-occlusive pain episodes (VOEs) for which they often receive care in infusion clinics (ICs). Typically, 80% of patients treated for VOE are discharged home but it is not clear how long it takes to recover to baseline functioning after an acute visit.1 Recent clinical trials have struggled to identify practical and useful outcomes for novel therapies that decrease the length of VOE or pain during hospitalization. As many patients with VOE are seen and treated in an IC and discharged home, identifying potential endpoints for novel therapies in this site of care are needed. The purpose of this study was to measure time to recovery for two weeks post an IC visit for management of VOE and to identify patient characteristics that predict a return visit for pain management within that time period. Methods: A convenience sample of adults with SCD (≥18YO) were consented to and enrolled into this IRB-approved study during a visit to the IC for VOE. Medical records of all subjects were reviewed to collect data on the number of acute visits, hospitalizations, use of disease-modifying therapies, use of pain medications, baseline laboratory data, and comorbidities. Data was collected on the date VOE pain started, pain scores before and after treatment, and analgesic management. Baseline surveys were collected on the day of the visit and patients were sent follow-up surveys after discharge electronically through REDCap on post-discharge days 2,4,6,8,10,12,14. Participants were asked to rate their pain on a 0-10 Visual Analog Scale. The PROMIS pain interference and Fatigue scales were used to assess pain impact and the Subjective Opioid Withdrawal Scale (SOWS) was used to assess for signs of opioid withdrawal. Return to baseline functioning was estimated by asking participants at each contact post-visit to rate their current level of functioning in activities of daily living on a scale of 0-100, with 100 being their baseline level of function. A similar scale was used to measure the resolution of pain, with the anchor being "back to your usual, non-crisis, level of daily pain." Subjects were encouraged to complete surveys through text message reminders and were compensated with a fifty-dollar gift card if all surveys were completed. Cox proportional hazards modeling was used to examine predictors of time to a return acute care visit within 14 days of the index visit. Results: Table 1 shows the characteristics of the 48 patients enrolled in the study. Despite multiple text/email reminders, few patients completed all the surveys (8/48). Thirty-two out of 48 people completed initial surveys. Of the 17 patients who completed a day 2 or later SOWS score 7 had moderate or severe withdrawal symptoms and of those 3 had a return visit within 14 days while 5/10 of those with mild scores had a return visit. Nineteen out of 48 patients returned for treatment within 14 days. Controlling for pain at discharge, sex, and genotype only the number of acute visits in the six months prior to the index visit was associated with a return visit in 14 days (HR 1.31, 95% CI: 1.13 1.53). The figure shows the probability of a return visit over time by genotype. The median number of visits the entire cohort had in the six months prior to the index visit was 4.5 (IQR: 2,10) however, in those patients that returned for treatment within 14 days the median number of visits in the last six months was 8 (IQR: 5,11). Conclusions: In this study of patients' experience post an acute visit for pain management at an IC, we identified that the number of acute visits in the six months prior to the index visit predicted a return visit within 14 days. It was challenging for patients to complete surveys after their acute visits suggesting that this was not a feasible way to collect these important patient-reported outcomes. With almost 40% of patients returning for an acute care visit within 14 days, decreasing the percentage of patients with return visits may be a potential outcome for trials of novel therapies to treat VOE in the IC setting. 1. Lanzkron S, Carroll CP, Hill P, David M, Paul N, Haywood C, Jr. Impact of a dedicated infusion clinic for acute management of adults with sickle cell pain crisis. Am J Hematol. 2015;90(5):376-380. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Thirty-day Treatment Continuation After Audio-only Buprenorphine Telehealth Initiation.

Before the coronavirus disease 2019 pandemic, federal law required in-person evaluation before buprenorphine initiation. Regulatory changes during the pandemic allow for buprenorphine initiation by audio-only or audiovisual telehealth. Little is known about treatment engagement after buprenorphine initiation conducted via audio-only telehealth. A retrospective cohort study of 94 individuals who received initial treatment through an audio-only encounter between April 2020 and February 2021 was performed. Participant demographics, substance use history, withdrawal symptoms, 30-day treatment engagement, and adverse outcomes were determined by an electronic chart and REDcap database review. Subsequent buprenorphine prescriptions filled within 30 days of the initial encounter were tracked through the Rhode Island Prescription Drug Monitoring Program. Buprenorphine was prescribed for 94 individuals. Most (92 of 94 [97.9%]) filled their prescription within 30 days. Most had previously taken buprenorphine, including prescribed (42 of 92 [45.7%]) and nonprescribed (58 of 92 [63.0%]). Two thirds were in opioid withdrawal at the time of the call (61 of 92 [66.3%]) with a mean Subjective Opioid Withdrawal Scale of 26.8 (range, 4-57). Four individuals experienced precipitated withdrawal (4 of 94 [4.3%]), and 2 reported persistent withdrawal at their follow-up visit (2 of 94 [2.1%]). More than 70% filled a subsequent prescription for buprenorphine within 30 days of the end of their hotline prescription (65 of 92 [70.7%]), on average of 5.88 days (range, 0-28) after completion of their telehealth prescription. Expanding telehealth-delivered buprenorphine care has the potential to address treatment gaps and facilitate delivery of on-demand services during peak motivation. This evaluation of audio-only buprenorphine initiation found high rates of unobserved buprenorphine initiation and treatment continuation with low rates of complications.

Worsening sleep quality across the lifespan and persistent sleep disturbances in persons with opioid use disorder.

Individuals with opioid use disorder (OUD) may experience worsening sleep quality over time, and a subset of individuals may have sleep disturbances that precede opioid use and do not resolve following abstinence. The purpose of the present study was to (1) collect retrospective reports of sleep across the lifespan and (2) identify characteristics associated with persistent sleep disturbance and changes in sleep quality in persons with OUD. Adults with OUD (n = 154) completed a cross-sectional study assessing current and past sleep disturbance, opioid use history, and chronic pain. Repeated-measures analysis of variance was used to examine changes in retrospectively reported sleep quality, and whether changes varied by screening positive for insomnia and/or chronic pain. Multivariate linear regression analyses were used to identify additional correlates of persistent sleep disturbance. Participants reported that their sleep quality declined over their lifespan. Changes in reported sleep over time varied based on whether the individual screened positive for co-occurring insomnia and/or chronic pain. In regression analyses, female sex (β = 0.16, P = .042), a greater number of treatment episodes (β = 0.20, P = .024), and positive screens for chronic pain (β = 0.19, P = .018) and insomnia (β=0.22, P = .013) were associated with self-reported persistent sleep disturbance. Only a portion of participants who screened positive for sleep disorders had received a formal diagnosis. OUD treatment providers should routinely screen for co-occurring sleep disturbance and chronic pain. Interventions that treat co-occurring OUD, sleep disturbance, and chronic pain are needed. Ellis JD, Mayo JL, Gamaldo CE, Finan PH, Huhn AS. Worsening sleep quality across the lifespan and persistent sleep disturbances in persons with opioid use disorder. J Clin Sleep Med. 2022;18(2):587-595.

Subjective symptoms and serum methadone concentrations: what should guide dose adjustments in methadone maintenance treatment? A naturalistic cohort study from Norway

BackgroundThere is little evidence-based guidance on how to optimize methadone dosages among patients with opioid addiction undergoing methadone maintenance treatment (MMT). This study aims to investigate whether self-perceived opioid withdrawal symptoms, adverse effects, and self-reported substance use in patients on MMT are related to serum methadone concentrations and the role that these variables could play in clinical decisions on dose adjustments.MethodsThis naturalistic prospective cohort study included clinical and laboratory measurements from 83 patients undergoing MMT in outpatient clinics in Bergen, Norway, from May 2017 to January 2020. Information on age, gender, methadone daily doses and serum concentrations, subjective opioid withdrawal symptoms using 16 items Subjective Opioid Withdrawal Scale (SOWS) questionnaire, self-reported adverse effects, and substance use was obtained. Linear mixed modelling was used for analyzing the data.ResultsThe mean age of the participants was 45 years, and 33% were women. Almost half reported mild to moderate subjective opioid withdrawal symptoms, and all had experienced at least one subjective adverse effect. The use of at least one substance was reported by 88% of the participants. Serum concentration-to-dose ratios were lower among those who had reported subjective opioid withdrawal symptoms (p) = 0.039). The total SOWS score (p < 0.001); the specific subjective withdrawal symptoms of anxiety (p = 0.004), bone and muscle aches (p = 0.003), restlessness (p = 0.017), and (slightly) shaking (p = 0.046), also use of heroin (p = 0.015) and alcohol (p = 0.011) were associated with lower methadone concentrations. Cannabis use was slightly related to higher methadone concentrations (p = 0.049).ConclusionsThe findings suggest that the patient’s self-perceived symptoms and current clinical condition are related to the serum concentrations of methadone. This interpretation supports dose adjustments based on patient-reported symptoms. In some aberrant cases, measurement of serum concentrations together with other individual assessments may be considered to support the clinical decision.

The Chinese version of obsessive compulsive drug use scale: validation in outpatient methadone maintenance treatment program

BackgroundThe Obsessive Compulsive Drug Use Scale (OCDUS) measures the overall craving level within a period from a multidimensional perspective. However, no studies have addressed the validity of the new OCDUS factor structure, presented in 2016, in China. Additionally, there is lack of evidence on the interaction among risk factors for relapse. We aimed to assess the psychometric properties of the scores of the Chinese version of the OCDUS in patients with heroin dependence receiving methadone maintenance treatment (MMT). Further, we aimed to assess the correlations of the OCDUS scores with withdrawal symptoms, depression, anxiety, and nicotine dependence.MethodsWe enrolled 113 adults (age 32–64 years) and administered them with the OCDUS, Subjective Opioid Withdrawal Scale (SOWS), Beck Depression Inventory-II (BDI-II), State-Trait Anxiety Inventory (STAI), and Fagerstrom Test for Nicotine Dependence (FTND).ResultsExploratory factor analysis identified a 3-dimensional component that included “Frequency of craving,” “Inference of heroin,” and “Control of heroin.” These factors showed acceptable internal consistency, adequate item-total correlations, and significant item-subscale correlations. There was no correlation between the OCUDS scores and age, education, duration of receiving MMT, and MMT dosages. However, there was a significant correlation between the OCDUS total scores and the SOWS, STAI, BDI-II, and FTND scores. The scores of all the subscales were associated with the SOWS scores; further, the scores of the first two subscales were associated with BDI-II scores while only the scores of the first subscale were associated with the FTND scores.ConclusionsOur findings support the reliability and structure validity of the OCDUS scores. Heroin craving, withdrawal symptoms, negative emotions, and nicotine dependence, which are considered as risk factors for heroin relapse, might interact with each other. There is a need for further studies on the underlying mechanism of these clinical phenomena.

Efficacy And Safety Of Controlled-Release Oxycodone For The Management Of Moderate-To-Severe Chronic Non-Cancer Pain In Japanese Patients: Results From An Open-Label Study.

PurposeTo assess the efficacy and safety of S-8117, an oral, controlled-release formulation of oxycodone hydrochloride, in Japanese patients with chronic non-cancer pain (CNCP).Patients and methodsIn this multicenter, non-randomized, open-label, 2-part (part 1, dose-titration followed by maintenance period; part 2, long-term administration period) study at 38 centers in Japan (2013–2015), adult patients with CNCP for ≥12 weeks were administered S-8117. The primary endpoint was proportion of patients with successful maintenance of pain control in part 1 and long-term safety in part 2. Secondary endpoints included time to inadequate analgesia, rate of transition to the maintenance period, and discontinuation due to inadequate analgesia/adverse events (AEs), Brief Pain Inventory (BPI) pain severity, BPI pain interference, 36-item Short Form Health Survey (SF-36) score, and Western Ontario and McMaster Universities (WOMAC) index, Subjective Opioid Withdrawal Scale (SOWS), Clinical Opioid Withdrawal Scale (COWS), Dependency-2-A (D-2-A), and Dependency-2-B (D-2-B) questionnaires.ResultsOf 130 patients (mean age, 63.6 years; women, 62.3%) in the dose-titration period, 95 entered the maintenance period; 60 of 83 who entered the long-term administration period completed it. The proportion of patients (95% confidence interval) with successful maintenance of pain control, transition to maintenance period, and discontinuation due to inadequate analgesia/AEs was 78.9% (69.4–86.6), 73.1% (64.6–80.5), and 21.1% (13.4–30.6), respectively. Time to inadequate analgesia could not be estimated. Changes from baseline in BPI, SF-36, and WOMAC index scores suggested improvements in pain relief and quality of life. Based on the SOWS, COWS, D-2-A and D-2-B questionnaires, no patient developed clinically relevant withdrawal syndrome or was ascertained to have developed drug dependence. Overall, the incidence of treatment-emergent AEs (TEAEs) was 93.8%; most common TEAEs were constipation (49.2%), nausea (42.3%), nasopharyngitis (34.6%), and somnolence (32.3%).ConclusionThese results demonstrate the efficacy and safety of S-8117 in Japanese patients with CNCP.

Intensity of Withdrawal Symptoms During Opioid Taper in Patients with Chronic Pain-Individualized or Fixed Starting Dosage?

Controlled opioid withdrawal is recommended for patients with chronic noncancer pain (CNCP) with insufficient pain reduction or intolerable side effects while on opioid treatment. Few studies have investigated the management of opioid withdrawal (OW). Most common are protocols with an individualized starting dosage (ISD), calculated from the last opioid intake. After two cases of overdose, we introduced a novel withdrawal protocol using a low fixed starting dosage (FSD) for safety reasons. The present study compares the intensity of withdrawal symptoms using the Subjective Opioid Withdrawal Scale (SOWS) and incidences of serious adverse events (SAE) and dropouts in each taper schedule in 195 CNCP patients with OW in an inpatient facility. Two protocols were compared: FSD (2014-2016): N = 68, starting dose: 90 mg morphine/d; and ISD (2010-2014): N = 127, starting dose: 70% of the patient's daily morphine equivalent dose (MED). Outcome criteria: primary: mean daily SOWS score during the first 10 days (16 questions, daily score 0-64); secondary: change in pain intensity on a numeric rating scale (0-10), rate of dropouts and SAEs. Statistics: Student test, Mann-Whitney U test, chi-square test, analysis of variance, P < 0.05. The mean daily SOWS score was lower in the FSD group (14.9 ± 9.4 vs 16.1 ± 10, P < 0.05) due to a lower rate of high-intensity withdrawal symptoms (12.4% vs 17.6%, P < 0.01), particularly in patients on >180 mg MED (9.7% vs 18.4%, P < 0.01). Pain intensity decreased after withdrawal, and the incidence of SAEs and dropouts was low in both groups. The FSD protocol provides a lesser burden of withdrawal symptoms and equal patient safety. It can be recommended for OW in CNCP patients.

Safety of oral methylnaltrexone for opioid-induced constipation in patients with chronic noncancer pain.

PurposeOral methylnaltrexone was shown to be effective in treating opioid-induced constipation (OIC) in patients with chronic noncancer pain in a Phase III randomized controlled trial. This report provides a detailed safety analysis from that study.MethodsAdults (n=803) with chronic noncancer pain for ≥2 months and confirmed OIC while receiving opioid doses ≥50 mg morphine equivalent per day for ≥14 days were randomized 1:1:1:1 to oral methylnaltrexone (150, 300, or 450 mg) or placebo once daily for 4 weeks, followed by as-needed use for 8 weeks. Safety was evaluated by examining treatment-emergent adverse events (TEAEs), clinical laboratory parameters, vital signs, electrocardiography, rescue-laxative and opioid use, Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS), and pain-intensity scores.ResultsTEAEs occurred at a similar incidence in the methylnaltrexone groups (59.0%) and placebo group (63.0%). The most common TEAEs with methylnaltrexone were abdominal pain (8.0% vs 8.5% with placebo), nausea (6.8% vs 9.0%), and diarrhea (6.0% vs 3.5%). Cardiac-related TEAEs occurred in 1.8% and 1.0% of patients, respectively, and no major adverse cardiovascular events were reported. No patient had a cluster of TEAEs associated with opioid withdrawal after excluding gastrointestinal TEAEs. Changes in laboratory parameters, vital signs, and electrocardiography were generally small and similar across treatment groups. Rescue-laxative use was more common with placebo than methylnaltrexone 450 mg (6.20% vs 4.27% of study days, P=0.024). Changes in opioid dose, OOWS and SOWS scores, and pain-intensity scores during treatment were minimal.ConclusionOral methylnaltrexone had a safety profile comparable with placebo in the treatment of OIC in patients with chronic noncancer pain, with no evidence of cardiac toxicity or opioid withdrawal.

Changes in Withdrawal and Craving Scores in Participants Undergoing Opioid Detoxification Utilizing Ibogaine

ABSTRACTOpioid use disorder (OUD) is currently an epidemic in the United States (US) and ibogaine is reported to have the ability to interrupt opioid addiction by simultaneously mitigating withdrawal and craving symptoms. This study examined opioid withdrawal and drug craving scores in 50 participants with OUD undergoing a week-long detoxification treatment protocol with ibogaine. The Addiction Severity Index (ASI) was used for baseline characterization of participants’ OUD. Clinical Opioid Withdrawal Scale (COWS), Subjective Opioid Withdrawal Scale (SOWS), and Brief Substance Craving Scale (BSCS) scores were collected at 48 and 24 hours prior to ibogaine administration, as well as 24 and 48 hours after ibogaine administration. At 48 hours following ibogaine administration, withdrawal and craving scores were significantly lowered in comparison to baseline: 78% of patients did not exhibit objective clinical signs of opioid withdrawal, 79% reported minimal cravings for opioids, and 68% reported subjective withdrawal symptoms in the mild range. Ibogaine appears to facilitate opioid detoxification by reducing opioid withdrawal and craving in participants with OUD. These results warrant further research using rigorous controlled trials.

Prediction of withdrawal symptoms during opioid detoxification

The severity of self-reported withdrawal symptoms varies during detoxification of opioid-dependent patients. The aim of this study is to identify subgroups of withdrawal symptoms within the detoxification trajectory and to predict the severity of withdrawal symptoms on the basis of drug-related and sociodemographic characteristics. A prospective study carried out in an in-patient setting in four addiction treatment centres in the Netherlands. Two hundred opioid-dependent patients who participated in a randomized controlled trial and completed more than 75 percent of the administrations of the subjective opioid withdrawal scales during rapid detoxification. Main outcome measure was the severity of opioid withdrawal as measured by the subjective opioid withdrawal scale during detoxification (18 measurements). Predictor baseline data were obtained on sociodemographic background, severity of addiction, psychopathology, personality disorder, and craving. Those variables found to be statistically significant in univariate analyses were entered into multivariate regression models to predict the severity of subjective withdrawal. No distinct subgroups could be identified despite substantial individual variability throughout the detoxification trajectory. The multiple regression results showed only four variables to predict the severity of withdrawal symptoms: baseline withdrawal symptoms, intravenous heroin use in the last 30 days, anxiety, and cluster C personality disorder. The variance explained by these sociodemographic variables was low while the largest amount of variance was explained by baseline withdrawal symptoms (27percent). The results of the present study provide evidence that the severity of withdrawal symptoms during detoxification treatment is moderately predicted by the baseline severity of their withdrawal symptoms and not by drug- and patient-related characteristics.

Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes

ABSTRACTBackground: Ibogaine is a monoterpene indole alkaloid used in medical and nonmedical settings for the treatment of opioid use disorder. Its mechanism of action is apparently novel. There are no published prospective studies of drug use outcomes with ibogaine. Objectives: To study outcomes following opioid detoxification with ibogaine. Methods: In this observational study, 30 subjects with DSM-IV Opioid Dependence (25 males, 5 females) received a mean total dose of 1,540 ± 920 mg ibogaine HCl. Subjects used oxycodone (n = 21; 70%) and/or heroin (n = 18; 60%) in respective amounts of 250 ± 180 mg/day and 1.3 ± 0.94 g/day, and averaged 3.1 ± 2.6 previous episodes of treatment for opioid dependence. Detoxification and follow-up outcomes at 1, 3, 6, 9, and 12 months were evaluated utilizing the Subjective Opioid Withdrawal Scale (SOWS) and Addiction Severity Index Composite (ASIC) scores, respectively. Results: SOWS scores decreased from 31.0 ± 11.6 pretreatment to 14.0 ± 9.8 at 76.5 ± 30 hours posttreatment (t = 7.07, df = 26, p < 0.001). At 1-month posttreatment follow-up, 15 subjects (50%) reported no opioid use during the previous 30 days. ASIC Drug Use and Legal and Family/Social Status scores were improved relative to pretreatment baseline at all posttreatment time points (p < .001). Improvement in Drug Use scores was maximal at 1 month, and subsequently sustained from 3 to 12 months at levels that did not reach equivalence to the effect at 1 month. Conclusion: Ibogaine was associated with substantive effects on opioid withdrawal symptoms and drug use in subjects for whom other treatments had been unsuccessful, and may provide a useful prototype for discovery and development of innovative pharmacotherapy of addiction.

Ibogaine treatment outcomes for opioid dependence from a twelve-month follow-up observational study

ABSTRACTBackground: The psychoactive indole alkaloid ibogaine has been associated with encouraging treatment outcomes for opioid dependence. The legal status of ibogaine in New Zealand provides a unique opportunity to evaluate durability of treatment outcomes. Objective: To examine longitudinal treatment effects over a 12-month period among individuals receiving legal ibogaine treatment for opioid dependence. Method: This observational study measured addiction severity as the primary outcome in 14 participants (50% female) over 12 months post-treatment using the Addiction Severity Index-Lite (ASI-Lite) following a single ibogaine treatment by either of two treatment providers. Secondary effects on depression were assessed via the Beck Depression Inventory-II (BDI-II). The Subjective Opioid Withdrawal Scale (SOWS) was collected before and immediately after treatment to measure opioid withdrawal symptoms. Results: Nonparametric comparisons via Friedman Test between baseline and 12-month follow-up for participants completing all interviews (n = 8) showed a significant reduction for the ASI-Lite drug use (p = 0.002) composite score. Reductions in BDI-II scores from baseline to 12-month follow-up were also significant (p < 0.001). Significant reductions in SOWS scores for all participants (n = 14) were also observed acutely after treatment (p = 0.015). Patients with partial data (n = 4) also showed reductions in ASI-Lite drug use scores and family/social status problems. One patient enrolled in the study died during treatment.Conclusion: A single ibogaine treatment reduced opioid withdrawal symptoms and achieved opioid cessation or sustained reduced use in dependent individuals as measured over 12 months. Ibogaine’s legal availability in New Zealand may offer improved outcomes where legislation supports treatment providers to work closely with other health professionals.

Abuse deterrence testing: A dose ratio escalation study examining naloxone coadministered with intravenous hydromorphone in non-treatment-seeking, opioid-dependent drug users.

To assess the reduction in intravenous (IV) abuse potential of hydromorphone from different dose ratio combinations with naloxone in opioid-dependent drug users. Randomized, blinded, dose ratio escalation study. Single center. Following conversion to a stable IV dose of hydromorphone, 12 non-treatment-seeking, opioid-dependent subjects were randomly assigned and received at least one dose of study drug; seven subjects received all five study treatments. Five subjects withdrew early from the treatment phase: adverse events (2) and participant decision (3). Participants underwent a dose-selection phase to stabilize on an individualized hydromorphone dose. Stable subjects were dosed intravenously on 5 consecutive days. The dose received was one of five hydromorphone/naloxone dose ratios that included the combination of hydromorphone and placebo naloxone. Hydromorphone/naloxone treatment always involved increasing dose ratios of naloxone (8:1, 6:1, 4:1, and 2:1) with the hydromorphone-placebo naloxone treatment randomly assigned within the sequence of dose ratios. Drug Liking visual analog scale (VAS), Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS). Hydromorphone/naloxone placebo produced subjective effects typical of opioid administration, while hydromorphone/naloxone dose ratios were associated with significant increases in SOWS and OOWS scores (p < 0.05). Compared with hydromoprophone/naloxone placebo, naloxone reduced the effects of hydromorphone on most measures, including Drug Liking VAS, the antagonism was greatest for the 4:1 and 2:1 ratios. This study was an ethical investigation of the abuse deterrence potential of four hydromorphone/naloxone dose ratios. The IV coadministration of commercially available IV solutions of hydromorphone and naloxone in 4:1 and 2:1 ratios had statistically greater reductions of abuse-related opioid effects and triggers of withdrawal symptoms and there was a convergence of subjective and objective pharmacodynamic results and safety findings. An oral modified-release product, developed with a 2:1 hydromorphone/naloxone ratio, may have important public health benefits by reducing high-risk, IV abuse of prescription opioids, while providing pain relief when ingested orally and used in accordance with the Product Monograph.

New Formulation of Sustained Release Naloxone Can Reverse Opioid Induced Constipation Without Compromising the Desired Opioid Effects.

An international double-blind randomized placebo controlled study evaluated the safety and efficacy of four doses of a new sustained release naloxone capsule to treat Opioid Induced Constipation (OIC). Forty patients taking opioids for noncancer related pain, and experiencing OIC, were randomized into 4 cohorts of 10 patients. A multiple ascending dose design was used to evaluate the safety and efficacy of 2.5 mg, 5 mg, 10 mg, and 20 mg naloxone sustained release (NSR) capsules vs placebo. Drug was given once-daily for 3 weeks followed by twice daily (bid) dosing between weeks 4 and 6. The incidence of treatment emergent adverse events was highest in the placebo group. The incidence of adverse events among the four active treatment groups were similar. There were no serious adverse events. The number of severe events was low overall but highest in the placebo group. Significant improvements were seen in Spontaneous Bowel Movements with 5 mg, 10 mg, and 20 mg NSR capsules. Mean change in SBMs from baseline of 2.21 (P = 0.052), 2.37 (P = 0.032); 4.11 (P = 0.0005); 5.19 (<0.0001) was noted with NSR 2.5 mg, 5 mg, 10 mg, and 20 mg, respectively, when taken once daily, compared with 1.38 (P = 0.2) for patients on placebo therapy. No changes in subjective or objective measures of opioid withdrawal as measured by the Subjective Opioid Withdrawal Scale or Clinical Opioid Withdrawal Scale were observed. There was no increase in patient reported pain as measured daily using a visual analogue scale. This Phase II study has shown that using a new sustained release formulation to deliver oral naloxone to the colon allows successful treatment of OIC without comprising the desired opioid effects.

The effects of dronabinol during detoxification and the initiation of treatment with extended release naltrexone

BackgroundEvidence suggests that the cannabinoid system is involved in the maintenance of opioid dependence. We examined whether dronabinol, a cannabinoid receptor type 1 partial agonist, reduces opioid withdrawal and increases retention in treatment with extended release naltrexone (XR-naltrexone). MethodsOpioid dependent participants were randomized to receive dronabinol 30mg/d (n=40) or placebo (n=20), under double-blind conditions, while they underwent inpatient detoxification and naltrexone induction. Before discharge all participants received an injection of XR-naltrexone, with an additional dose given four weeks later. Dronabinol or placebo was given while inpatient and for 5 weeks afterwards. The primary outcomes were the severity of opioid withdrawal, measured with the Subjective Opioid Withdrawal Scale, and retention in treatment at the end of the inpatient phase and at the end of the 8-week trial. ResultsThe severity of opioid withdrawal during inpatient phase was lower in the dronabinol group relative to placebo group (p=0.006). Rates of successful induction onto XR-naltrexone (dronabinol 66%, placebo 55%) and completion of treatment (dronabinol 35%, placebo 35%) were not significantly different. Post hoc analysis showed that the 32% of participants who smoked marijuana regularly during the outpatient phase had significantly lower ratings of insomnia and anxiety and were more likely to complete the 8-week trial. ConclusionDronabinol reduced the severity of opiate withdrawal during acute detoxification but had no effect on rates of XR-naltrexone treatment induction and retention. Participants who elected to smoke marijuana during the trial were more likely to complete treatment regardless of treatment group assignment.

The effects of ibudilast, a glial activation inhibitor, on opioid withdrawal symptoms in opioid-dependent volunteers.

Glial activation is hypothesized to contribute directly to opioid withdrawal. This study investigated the dose-dependent effects of a glial cell modulator, ibudilast, on withdrawal symptoms in opioid-dependent volunteers after abrupt discontinuation of morphine administration. Non-treatment-seeking heroin-dependent volunteers (n = 31) completed the in-patient, double-blind, placebo-controlled, within-subject and between-group study. Volunteers were maintained on morphine (30 mg, QID) for 14 days and placebo (0 mg, QID) for the last 7 days of the 3-week study. Volunteers also received placebo (0 mg, PO, BID) capsules on days 1-7. On days 8-21, volunteers were randomized to receive ibudilast (20 or 40 mg, PO, BID) or placebo capsules. Subjective and clinical ratings of withdrawal symptoms were completed daily using daily using the Subjective Opioid Withdrawal Scale (SOWS) and Clinical Opioid Withdrawal Scale (COWS). Medication side effects were also monitored. Relative to the first 2 weeks, all groups exhibited withdrawal during the third week as assessed by the SOWS and COWS (P ≤ 0.0001). Although overall SOWS scores did not differ between groups, exploratory analyses pooling the two ibudilast groups demonstrated that they had lower ratings of withdrawal symptoms on SOWS items ('anxious,' 'perspiring,' 'restless,' 'stomach cramps') during detoxification relative to the placebo group. Ibudilast was well tolerated; no serious adverse events occurred during the study. Pharmacological modulation of glial activity with ibudilast decreased some subjective ratings of opioid withdrawal symptoms. These exploratory findings are the first to demonstrate the potential clinical utility of glial modulators for treating opioid withdrawal in humans.

Naltrexone-Facilitated Buprenorphine Discontinuation: A Feasibility Trial

RationaleBuprenorphine is an effective and popular treatment for opioid dependence. It remains unclear, however, when or how to transition stable buprenorphine-maintained individuals to complete abstinence. This trial investigates the feasibility of using naltrexone to facilitate buprenorphine discontinuation in stable individuals who had tolerated a taper to 2mg or less but were unable to terminate entirely due to withdrawal-related distress. MethodsThe sample consisted of 6 buprenorphine-maintained individuals in sustained full remission, and who had tolerated a taper but were unable to discontinue altogether. A rapid induction procedure was performed, which included supervised buprenorphine discontinuation, oral naltrexone titration with a starting dose of 6.25mg, and administration of long-acting injectable naltrexone. Participants were followed weekly for 5weeks after the injection, with telephone follow-up occurring at 6months. ResultsThe rapid induction procedure was well tolerated. There was no observed or reported clinical worsening over the course of study participation. Notably, no participants experienced an increase in Subjective Opioid Withdrawal Scale (SOWS) scores after the first oral dose of NTX as compared to day 1 (24hours after last dose of buprenorphine); instead, SOWS scores decreased between days 1 and 7 (p=0.043). All participants were able to discontinue buprenorphine and to remain opioid free during the trial and at follow-up. ConclusionsThis preliminary trial represented for all participants the first successful attempt at buprenorphine discontinuation. Further research is needed to better understand if naltrexone is effective at facilitating buprenorphine discontinuation, as well as the feasibility of a sequential approach (buprenorphine stabilization to naltrexone) for opioid use disorders.

Pharmacokinetic-Pharmacodynamic Modeling of Mood and Withdrawal Symptoms in Relation to Plasma Concentrations of Methadone in Patients Undergoing Methadone Maintenance Treatment

The aims of the present study were to characterize the relationship between plasma racemic methadone and its enantiomers' concentrations with respect to their pharmacodynamic effects and to investigate the influence of potential covariates on the pharmacodynamic parameters in patients on methadone maintenance treatment (MMT). Eighty-eight regular subjects at the Sheffield Care Trust Substance Misuse Services were studied. Samples of blood and urine were collected before the daily dose of methadone. Blood samples were taken up to 5 hours after dose. Total plasma concentrations of (RS)-methadone and total and unbound plasma concentrations of both enantiomers were measured by liquid chromatography-mass spectrometry. The Total Mood Disturbance Score (TMDS), the Objective Opioid Withdrawal Scale (OOWS), and the Subjective Opioid Withdrawal Scale (SOWS) were used as measures of mood and withdrawal. Population pharmacokinetic/pharmacodynamic analysis and subsequent multiple regression analysis were used to determine the factors influencing the pharmacodynamic effects of methadone. Significant decreases (P ≤ 0.04) were observed in the scores for the TMDS, SOWS, and OOWS for 5 hours after methadone dosage. The TMDS had returned to baseline by 10 hours after dose (P = 0.98), at which time the SOWS remained significantly below baseline (P = 0.001). Multiple regression analysis revealed that 33% of the overall variation in unbound (R)-methadone EC50 was explained by 3 variables, namely CYP3A activity (9%), age (16%), and sex (8%). Age also accounted for 8% and 9% of the variation in total (rac)- and (R)-methadone EC50. The present study has confirmed that the duration of mood change in the present study was shorter than the effect of methadone in stabilizing withdrawal symptoms. Thus, it is likely that a once-daily dose of methadone, albeit effective for preventing withdrawal, may not be sufficient to improve mood in some patients. Finally, it was established that CYP3A activity, years of dependent use, sex, and age are major determinants of methadone EC50 with respect to TMDS.