Opioid Withdrawal Scores Research Articles

Machine Learning-Driven Analysis of Individualized Treatment Effects Comparing Buprenorphine and Naltrexone in Opioid Use Disorder Relapse Prevention.

A trial comparing extended-release naltrexone and sublingual buprenorphine-naloxone demonstrated higher relapse rates in individuals randomized to extended-release naltrexone. The effectiveness of treatment might vary based on patient characteristics. We hypothesized that causal machine learning would identify individualized treatment effects for each medication. This is a secondary analysis of a multicenter randomized trial that compared the effectiveness of extended-release naltrexone versus buprenorphine-naloxone for preventing relapse of opioid misuse. Three machine learning models were derived using all trial participants with 50% randomly selected for training (n = 285) and the remaining 50% for validation. Individualized treatment effect was measured by the Qini value and c-for-benefit, with the absence of relapse denoting treatment success. Patients were grouped into quartiles by predicted individualized treatment effect to examine differences in characteristics and the observed treatment effects. The best-performing model had a Qini value of 4.45 (95% confidence interval, 1.02-7.83) and a c-for-benefit of 0.63 (95% confidence interval, 0.53-0.68). The quartile most likely to benefit from buprenorphine-naloxone had a 35% absolute benefit from this treatment, and at study entry, they had a high median opioid withdrawal score ( P < 0.001), used cocaine on more days over the prior 30 days than other quartiles ( P < 0.001), and had highest proportions with alcohol and cocaine use disorder ( P ≤ 0.02). Quartile 4 individuals were predicted to be most likely to benefit from extended-release naltrexone, with the greatest proportion having heroin drug preference ( P = 0.02) and all experiencing homelessness ( P < 0.001). Causal machine learning identified differing individualized treatment effects between medications based on characteristics associated with preventing relapse.

Rapid Initiation of Injection Naltrexone for Opioid Use Disorder

Injectable extended-release (XR)-naltrexone is an effective treatment option for opioid use disorder (OUD), but the need to withdraw patients from opioid treatment prior to initiation is a barrier to implementation. To compare the effectiveness of the standard procedure (SP) with the rapid procedure (RP) for XR-naltrexone initiation. The Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone study was an optimized stepped-wedge cluster randomized trial conducted at 6 community-based inpatient addiction treatment units. Units using the SP were randomly assigned at 14-week intervals to implement the RP. Participants admitted with OUD received the procedure the unit was delivering at the time of their admission. Participant recruitment took place between March 16, 2021, and July 18, 2022. The last visit was September 21, 2022. Standard procedure, based on the XR-naltrexone package insert (approximately 5-day buprenorphine taper followed by a 7- to 10-day opioid-free period and RP, defined as 1 day of buprenorphine at minimum necessary dose, 1 opioid-free day, and ascending low doses of oral naltrexone and adjunctive medications (eg, clonidine, clonazepam, antiemetics) for opioid withdrawal. Receipt of XR-naltrexone injection prior to inpatient discharge (primary outcome). Secondary outcomes included opioid withdrawal scores and targeted safety events and serious adverse events. All analyses were intention-to-treat. A total of 415 participants with OUD were enrolled (mean [SD] age, 33.6 [8.48] years; 205 [49.4%] identified sex as male); 54 [13.0%] individuals identified as Black, 91 [21.9%] as Hispanic, 290 [69.9%] as White, and 22 [5.3%] as multiracial. Rates of successful initiation of XR-naltrexone among the RP group (141 of 225 [62.7%]) were noninferior to those of the SP group (68 of 190 [35.8%]) (odds ratio [OR], 3.60; 95% CI, 2.12-6.10). Withdrawal did not differ significantly between conditions (proportion of days with a moderate or greater maximum Clinical Opiate Withdrawal Scale score (>12) for RP vs SP: OR, 1.25; 95% CI, 0.62-2.50). Targeted safety events (RP: 12 [5.3%]; SP: 4 [2.1%]) and serious adverse events (RP: 15 [6.7%]; SP: 3 [1.6%]) were infrequent but occurred more often with RP than SP. In this trial, the RP of XR-naltrexone initiation was noninferior to the standard approach and saved time, although it required more intensive medical management and safety monitoring. The results of this trial suggest that rapid initiation could make XR-naltrexone a more viable treatment for patients with OUD. ClinicalTrials.gov Identifier: NCT04762537.

Escalation of Opioid Withdrawal Frequency and Subsequent AMA Rates in Hospitalized Patients From 2017 to 2020.

To measure trends for the emergence of opioid withdrawal (OW) and leaving against medical advice (AMA) among hospitalized patients. Retrospective time-series of hospitalized patients with OW, defined by a Clinical Opioid Withdrawal score &gt;8, using electronic health record data at a tertiary health system and of patients with a discharge status of AMA from January 1, 2017 to December 31, 2020. The average number of monthly hospitalizations with OW showed a year-to-year increment of 15% in 2018, 21% in 2019, and 34% from 2019 to 2020, whereas the total monthly hospitalizations remained stable. The segmented regression analysis showed that the upward trend in hospitalizations with OW became significant after January 2019 (slope: 1.14, 95% confidence interval [CI]: 0.70, 1.57). After August 2019, Fentanyl was added to the hospital urine drug testing panel and was identified in most OW patients. The monthly proportion of patients who left AMA was significantly higher among the OW patients than among all other admitted patients. There was a significant increase of 0.39 (95% CI: 0.29-0.49, P &lt; 0.001) per month in %AMA among patients with OW. The estimated difference in %AMA among OW patients versus all other patients was 7.25 (95% CI: 5.12-9.38) in January 2017, and 16.92 (95% CI: 14.60-19.24) in December 2020. The number of hospitalized patients either presenting with or developing OW increased between 2017 and 2020 with a significant rise occurring after January 2019. The percentage of patients who left AMA among those who developed OW steadily worsened during the entire study period.

685. Evaluating the Role of Medication-assisted Treatment (MAT) in the Management of Infectious Endocarditis in People Who Inject Drugs (PWID)

Abstract Background An estimated 1.29-2.59 million people practice intravenous drug use (IVDU) in the United States making it a growing risk factor for infective endocarditis (IE). In people who inject drugs (PWID), IE accounts for 5-10% of total yearly deaths. IE often requires weeks of intravenous therapy with extensive medical follow-up. The purpose of this study was to evaluate if medication-assisted treatment (MAT) increased treatment retention and survival to optimize addiction assistance and IE treatment efforts. Methods A single-center, retrospective chart review was approved for patients admitted with an ICD-10 code of IE. A multidisciplinary group was created in April, 2019 aimed to improve endocarditis patient outcomes, formed of complex case coordination, infectious disease, cardiology, and pharmacy pain management service members. The historical period was January 1, 2018-March 31, 2019 and the IE pathway (IEP) group was April 1, 2019-June 30, 2020. Patients were excluded if there was no documentation of IVDU (Figure 1). The primary outcome was successful endocarditis therapy, defined per study protocol. Secondary outcomes include: against medical advice (AMA) departures, discharge naloxone prescriptions, clinical opioid withdrawal score (COWS) and patient reported pain. Figure 1. Study Population Methods for study population inclusion and exclusion Results A total of 419 IE patients were evaluated with 166 patients meeting inclusion criteria. The primary outcome was achieved in 51.2% of historical group and 48.8% of the IEP group (p=0.302). AMA departures and inpatient mortality were similar between the two groups. There was increased presence of the pharmacy pain management service with decreased time to consult in the IEP group (Figure 2). Last documented COWS were increased in the IEP group (p=0.002), while last reported patient pain scores decreased (p=0.030). More patients were started on MAT and discharged with naloxone in the IEP group (Table 3). Readmission was found to be higher in the IEP group (p=0.046). Post hoc analysis evaluating outcomes for patients seen by the endocarditis pathway team were similar between the two groups (Table 4). Figure 2. Secondary Outcome (Consult Services) The secondary outcomes of the study population are described comparing the presence and time to various consult services. **P-value indicates statistical significance. Abbreviations: n, number; ID, infectious disease; CT, cardiothoracic Table 3. Secondary Outcomes Table 4. Post Hoc Analysis Conclusion The multidisciplinary group was effective helping to guide the inpatient care of PWID and improve symptom management, but this did not translate to increased successful IE therapy or fewer readmissions. Disclosures All Authors: No reported disclosures

Novel treatment of opioid use disorder using ibogaine and iboga in two adults

AbstractIbogaine is a naturally occurring psychedelic medicine with anti-addictive properties. While research on ibogaine is limited, several observational studies have shown ibogaine can mitigate opioid withdrawal, as seen with reductions in clinical and subjective opioid withdrawal scores and reduced drug use severity (Noller, Frampton, &amp; Yazar-Klosinski, 2018; Brown &amp; Alper 2018). Furthermore, the psychoactive experience may help individuals to realign their values, purpose and sense of connection, as seen with post treatment reductions in depression scores (Noller et al., 2018; Mash et al., 2000).Case seriesThis case series describes two cases of individuals accessing ibogaine through private unregulated clinics in the Vancouver area to treat their opioid use disorder.ConclusionsIn case 1, the client achieved total abstinence from all opioids within 5–6 days of starting ibogaine treatment, did not experience any opioid withdrawal symptoms after ibogaine treatment and maintained abstinence from opioids for 3 years. In case 2, the patient took ibogaine/iboga in multiple treatments over a short period of time (&lt;4 months). The patient stopped all non-medical opioids after the first iboga treatment and then used ibogaine to aid with further dose reductions of her opioid agonist therapy (OAT) and has maintained abstinence from opioids for 2 years. Ibogaine offers a unique and novel therapeutic approach to treating opioid use disorder. Further studies are needed to establish the safety, risks and potential role for ibogaine as a mainstream, evidence-based addiction treatment.

Buprenorphine therapy in the setting of induced opioid withdrawal from oral naltrexone: a case report

BackgroundPatients with opioid use disorder (OUD) frequently present to the emergency department for acute treatment of overdose and withdrawal.Case presentationA 29-year-old male presented to the emergency room after intravenous heroin use followed by accidental ingestion of naltrexone. He was treated with buprenorphine with significant improvement in his Clinical Opioid Withdrawal Score, from moderately severe to mild withdrawal symptoms within a few hours.ConclusionBuprenorphine and minimal supportive care can be used to treat acute withdrawal precipitated by oral naltrexone in patients with OUD.

Assessment and treatment of the withdrawal syndrome in paediatric intensive care units: Systematic review.

Sedoanalgesia secondary iatrogenic withdrawal syndrome (IWS) in paediatric intensive units is frequent and its assessment is complex. Therapies are heterogeneous, and there is currently no gold standard method for diagnosis. In addition, the assessment scales validated in children are scarce. This paper aims to identify and describe both the paediatric diagnostic and assessment tools for the IWS and the treatments for the IWS in critically ill paediatric patients. A systematic review was conducted according to the PRISMA guidelines. This review included descriptive and observational studies published since 2000 that analyzed paediatric scales for the evaluation of the iatrogenic withdrawal syndrome and its treatments. The eligibility criteria included neonates, newborns, infants, pre-schoolers, and adolescents, up to age 18, who were admitted to the paediatric intensive care units with continuous infusion of hypnotics and/or opioid analgesics, and who presented signs or symptoms of deprivation related to withdrawal and prolonged infusion of sedoanalgesia. Three assessment scales were identified: Withdrawal Assessment Tool-1, Sophia Observation Withdrawal Symptoms, and Opioid and Benzodiazepine Withdrawal Score. Dexmedetomidine, methadone and clonidine were revealed as options for the treatment and prevention of the iatrogenic withdrawal syndrome. Finally, the use of phenobarbital suppressed symptoms of deprivation that are resistant to other drugs. The reviewed scales facilitate the assessment of the iatrogenic withdrawal syndrome and have a high diagnostic quality. However, its clinical use is very rare. The treatments identified in this review prevent and effectively treat this syndrome. The use of validated iatrogenic withdrawal syndrome assessment scales in paediatrics clinical practice facilitates assessment, have a high diagnostic quality, and should be encouraged, also ensuring nurses' training in their usage.

Outpatient transition to extended-release injectable naltrexone for patients with opioid use disorder: A phase 3 randomized trial

BackgroundInjectable extended-release naltrexone (XR-NTX), approved to prevent relapse to opioid dependence, requires initial abstinence. This multisite outpatient clinical trial examined the efficacy and safety of low-dose oral naltrexone (NTX), combined with a brief buprenorphine (BUP) taper and standing ancillary medications, for detoxification and induction onto XR-NTX. MethodsPatients (N = 378) were randomized, stratified by primary short-acting opioid-of-use, to one of three regimens: NTX + BUP; NTX + placebo BUP (PBO-B); placebo NTX (PBO-N) + PBO-B. Patients received 7 days of ascending NTX or placebo, concurrent with a 3-day BUP or placebo taper, and ancillary medications in an outpatient setting. Daily psychoeducational counseling was provided. On Day 8, patients passing a naloxone challenge received XR-NTX. ResultsRates of transition to XR-NTX were comparable across groups: NTX/BUP (46.0%) vs. NTX/PBO-B (40.5%) vs. PBO-N/PBO-B (46.0%). Thus, the study did not meet its primary endpoint. Adverse events, reported by 32.5% of all patients, were mild to moderate in severity and consistent with opioid withdrawal. A first, second, and third XR-NTX injection was received by 44.4%, 29.9%, and 22.5% of patients, respectively. Compared with the PBO-N/PBO-B group, the NTX/BUP group demonstrated higher opioid abstinence during the transition and lower post-XR-NTX subjective opioid withdrawal scores. ConclusionsA 7-day detoxification protocol with NTX alone or NTX + BUP provided similar rates of induction to XR-NTX as placebo. For those inducted onto XR-NTX, management of opioid withdrawal symptoms prior to induction was achieved in a structured outpatient setting using a well-tolerated, fixed-dose ancillary medication regimen common to all three groups.

Ondansetron Does Not Reduce Withdrawal in Patients With Physical Dependence on Chronic Opioid Therapy.

Individuals taking opioids for an extended period of time may become physically dependent, and will therefore experience opioid withdrawal should they stop taking the medication. Previous work in animal and human models has shown that the serotonin (5-HT3) receptor may be implicated in opioid withdrawal. In this study, we investigated if ondansetron, a 5-HT3-receptor antagonist, could reduce the symptoms of opioid withdrawal after chronic opioid exposure in humans. In this double-blinded, randomized, crossover study, 33 chronic back pain patients (N = 33) were titrated onto sustained-release oral morphine for 30 days. After titration, participants attended 2 study sessions, 1 week apart, in which opioid withdrawal was induced with intravenous naloxone, with or without 8 mg intravenous ondansetron pretreatment. Opioid withdrawal symptoms were assessed by a blinded research assistant (objective opioid withdrawal score [OOWS]) and by the research participant (subjective opioid withdrawal score [SOWS]). Clinically significant signs of withdrawal were observed during both the ondansetron (ΔOOWS = 3.58 ± 2.22, P < 0.0001; ΔSOWS = 12.48 ± 11.18, P < 0.0001) and placebo sessions (ΔOOWS = 3.55 ± 2.39, P < 0.0001; ΔSOWS = 12.21 ± 10.72, P < 0.0001), but no significant differences were seen between the treatment sessions in either the OOWS or SOWS scores. We hypothesized that ondansetron would reduce opioid withdrawal symptoms in human subjects, but found no difference in withdrawal severity between ondansetron and placebo sessions. These findings suggest that more investigation may be necessary to determine if 5-HT3-receptor antagonists are suitable treatment options for opioid withdrawal.

Ondansetron does not prevent physical dependence in patients taking opioid medications chronically for pain control

ObjectivesIn this study, we investigated the co-administration of ondansetron with morphine, and whether it could prevent the development of physical dependence in patients taking opioids for the treatment of chronic pain. MethodsA total of 48 chronic back pain patients (N = 48) participated in this double-blinded, placebo-controlled, randomized study. Patients were titrated onto sustained-release oral morphine and randomized to take 8 mg ondansetron or placebo three times daily concurrently with morphine during the 30-day titration. Following titration, patients underwent Naloxone induced opioid withdrawal. Opioid withdrawal signs and symptoms were then assessed by a blinded research assistant (objective opioid withdrawal score: OOWS) and by the research participant (subjective opioid withdrawal score: SOWS). ResultsWe observed clinically significant signs of naloxone-precipitated opioid withdrawal in all participants (ΔOOWS = 4.3 ± 2.4, p < 0.0001; ΔSOWS = 14.1 ± 11.7, p < 0.0001), however no significant differences in withdrawal scores were detected between treatment groups. ConclusionWe hypothesized that ondansetron would prevent the development of physical dependence in human subjects when co-administered with opioids, but found no difference in naloxone-precipitated opioid withdrawal scores between ondansetron and placebo treatment groups. These results suggest that further studies are needed to determine if 5HT3 receptor antagonists are useful in preventing opioid physical dependence.

Neuromodulation with percutaneous electrical nerve field stimulation is associated with reduction in signs and symptoms of opioid withdrawal: a multisite, retrospective assessment

ABSTRACTBackground: Finding an effective, non-pharmacological approach to treat opioid withdrawal could remove some of the barriers associated with pharmacotherapy. The BRIDGE® is a noninvasive, percutaneous electrical nerve field stimulator developed to target pain. Objectives: This pilot study aimed to determine (1) the effects of the BRIDGE on withdrawal scores during the induction phase of opioid withdrawal therapy, (2) the percentage of subjects who successfully transitioned to medication assisted therapy (MAT). Methods: Adult patients treated with the BRIDGE during medically supervised withdrawal were included in this open label, uncontrolled, and retrospective study. The clinical opioid withdrawal scale (COWS) scores were prospectively recorded at different intervals (20, 30, and 60 min) and analyzed retrospectively. A subset of patients had scores recorded 5-days post-BRIDGE. Those who returned to the clinic and received their first dose of maintenance medication were considered to be successfully transitioned. Results: In this cohort (n=73), 65% were male. The mean COWS score prior to BRIDGE placement was 20.1 (±6.1). Twenty minutes after BRIDGE placement, the mean score was reduced to 7.5 (±5.9) (62.7% reduction, p<0.001). The scores further decreased after 30 minutes 4.0 (±4.4) and 60 minutes 3.1 (±3.4) (84.6% reduction, p<0.001). No rescue medications were administered during this period. The mean withdrawal score on day 5 was 0.6 (97.1% reduction, p<0.001) (n=33). Overall, 64/73 patients (88.8%) successfully transitioned to MAT. Conclusions: Neurostimulation with the BRIDGE is associated with a reduction in opioid withdrawal scores. This effect persisted during the induction period and allowed for effective transition to MAT.

Palonosetron and hydroxyzine pre-treatment reduces the objective signs of experimentally-induced acute opioid withdrawal in humans: a double-blinded, randomized, placebo-controlled crossover study

ABSTRACTBackground: Treatments for reducing opioid withdrawal are limited and prone to problematic side effects. Laboratory studies, clinical observations, and limited human trial data suggest 5-HT3-receptor antagonists and antihistamines may be effective. Objectives: This double-blind, crossover, placebo-controlled study employing an acute physical dependence model evaluated whether (i) treatment with a 5-HT3-receptor antagonist (palonosetron) would reduce opioid withdrawal symptoms, and (ii) co-administration of an antihistamine (hydroxyzine) would enhance any treatment effect. Methods: At timepoint T = 0, healthy (non-opioid dependent, non-substance abuser) male volunteers (N = 10) were pre-treated with either a) placebo, b) palonosetron IV (0.75 mg), or c) palonosetron IV (0.75 mg) and hydroxyzine PO (100 mg) in a crossover study design. This was followed at T = 30 by intravenous morphine (10 mg/70kg). At T = 165, 10 mg/70kg naloxone IV was given to precipitate opioid withdrawal. The objective opioid withdrawal score (OOWS) and subjective opioid withdrawal score (SOWS) were determined 5 and 15 minutes after naloxone administration (T = 170, 180, respectively). Baseline measurements were recorded at T = −30 and T = −15. Results: Comparison of average baseline OOWS scores with OOWS scores obtained 15 minutes after naloxone was significant (p = 0.0001). Scores from 15 minutes post-naloxone infusion showed significant differences in OOWS scores between treatment groups: placebo, 3.7 ± 2.4; palonosetron, 1.5 ± 0.97; and palonosetron with hydroxyzine, 0.2 ± 0.1333. Conclusions: Pretreatment with palonosetron significantly reduced many signs of experimentally-induced opioid withdrawal. Co-administration with hydroxyzine further reduced opioid withdrawal severity. These results suggest that 5-HT3 receptor antagonists, alone or in combination with an antihistamine, may be useful in the treatment of opioid withdrawal.

Efficacy and safety of naloxegol in patients with opioid-induced constipation and laxative-inadequate response.

Treatment options for patients with opioid-induced constipation (OIC) and inadequate response to laxatives (LIR) are few. Assess the efficacy and safety of orally administered naloxegol in patients with prospectively confirmed OIC and LIR. We analyzed pooled data from two identical randomized, double-blind, placebo-controlled, Phase 3 trials of naloxegol in patients with non-cancer pain, OIC and LIR in which naloxegol (12.5 mg, n = 240; 25 mg, n = 241) or placebo (n = 239) were administered daily. We assessed the response rates, time to first post-dose laxation, spontaneous bowel movements (SBMs), OIC symptoms and patient-reported outcomes over 12 weeks. OIC response rates for the naloxegol 25-mg (p < 0.001) and the 12.5-mg (p = 0.005) LIR dose groups were higher than placebo. Median times to first post-dose SBM were 7.6, 19.2 and 41.1 hours for the naloxegol 25 mg, naloxegol 12.5 mg and placebo groups, respectively. Other SBM measures, daily symptoms of OIC, and both the Patient Assessment of Constipation - Symptoms and Patient Assessment of Constipation-Quality of Life scores improved from baseline with naloxegol treatment. Changes from baseline in opioid dose, pain scores and opioid withdrawal scores were similar among treatment groups. Naloxegol was efficacious, generally safe and well tolerated in the patients with OIC and LIR, while preserving opioid analgesia. ClinicalTrials.gov identifiers: NCT01309841; NCT01323790.

No evidence for reduction of opioid-withdrawal symptoms by cannabis smoking during a methadone dose taper.

To support medication development with cannabinoids, smoked cannabis has been said to alleviate symptoms of opioid withdrawal. We evaluated that hypothesis. We analyzed data from the methadone-taper phase of a clinical trial we had conducted. Participants were 116 outpatient heroin and cocaine users (of whom 46 were also cannabis users) who stayed for the 10-week taper. Main outcome measures were weekly urine screens for cannabinoids, plus every-two-week assessments of opioid-withdrawal symptoms. Opioid-withdrawal scores did not differ overall between users and nonusers of cannabis. In a lagged analysis in the 46 users, there was a slight (not statistically significant) indication that weeks of higher opiate-withdrawal symptoms preceded weeks of cannabis use (effect-size r = .20, 95% CI -.10 to .46, p = .52). Even if this finding is taken to suggest self-medication with cannabis, a lagged analysis in the other temporal direction showed no indication that cannabis use predicted lower opiate-withdrawal symptoms the next week (effect-size r = .01, 95% CI -.28 to .30, p = .69). These findings persisted in sensitivity analyses controlling for each of 17 potential confounds. With our findings, the clinical evidence for smoked cannabis as a reducer of opioid-withdrawal symptoms moves slightly further from "inconclusive" or "mixed" and closer to negative, at least in the context of a methadone dose taper like the one used here. This finding may remove one rationale for medication development using cannabinoids to treat opioid withdrawal, but leaves other rationales intact.

Opioid withdrawal signs and symptoms in children: Frequency and determinants

ObjectivesThe purpose of this study was to, in a pediatric population, describe the frequency of opioid withdrawal signs and symptoms and to identify factors associated with these opioid withdrawal signs and symptoms. BackgroundOpioids are used routinely in the pediatric intensive care population for analgesia, sedation, blunting of physiologic responses to stress, and safety. In children, physical dependence may occur in as little as 2–3 days of continuous opioid therapy. Once the child no longer needs the opioid, the medications are reduced over time. MethodsA prospective, descriptive study was conducted. The sample of 26 was drawn from all patients, ages 2 weeks to 21 years admitted to the Children's Hospital of Richmond pediatric intensive care unit (PICU) and who have received continuous infusion or scheduled opioids for at least 5 days. Data collected included: opioid withdrawal score (WAT-1), opioid taper rate (total dose of opioid per day in morphine equivalents per kilogram [MEK]), pretaper peak MEK, pretaper cumulative MEK, number of days of opioid exposure prior to taper, and age. ResultsOut of 26 enrolled participants, only 9 (45%) had opioid withdrawal on any given day. In addition, there was limited variability in WAT-1 scores. The most common symptoms notes were diarrhea, vomit, sweat, and fever. ConclusionsFor optimal opioid withdrawal assessments, clinicians should use a validated instrument such as the WAT-1 to measure for signs and symptoms of opioid withdrawal. Further research is indicated to examine risk factors for opioid withdrawal in children.

Remifentanil-Induced Tolerance, Withdrawal or Hyperalgesia in Infants: A Randomized Controlled Trial. RAPIP Trial: Remifentanil-Based Analgesia and Sedation of Paediatric Intensive Care Patients

Background: Short-acting opioids like remifentanil are suspected of an increased risk for tolerance, withdrawal and opioid-induced hyperalgesia (OIH). These potential adverse effects have never been investigated in neonates. Objectives: To compare remifentanil and fentanyl concerning the incidence of tolerance, withdrawal and OIH. Methods: 23 mechanically ventilated infants received up to 96 h either a remifentanil- or fentanyl-based analgesia and sedation regimen with low-dose midazolam. We compared the required opioid doses and the number of opioid dose adjustments. Following extubation, withdrawal symptoms were assessed by a modification of the Finnegan score. OIH was evaluated by the CHIPPS scale and by testing the threshold of the flexion withdrawal reflex with calibrated von Frey filaments. Results: Remifentanil had to be increased by 24% and fentanyl by 47% to keep the infants adequately sedated during mechanical ventilation. Following extubation, infants revealed no pronounced opioid withdrawal and low average Finnegan scores in both groups. Only 1 infant of the fentanyl group and 1 infant of the remifentanil group required methadone for treatment of withdrawal symptoms. Infants also revealed no signs of OIH and low CHIPPS scores in both groups. The median threshold of the flexion withdrawal reflex was 4.5 g (IQR = 2.3) in the fentanyl group and 2.7 g (IQR = 3.3) in the remifentanil group (p = 0.312), which is within the physiologic range of healthy infants. Conclusions: Remifentanil does not seem to be associated with an increased risk for tolerance, withdrawal or OIH.

Short-term safety of buprenorphine/naloxone in HIV-seronegative opioid-dependent Chinese and Thai drug injectors enrolled in HIV Prevention Trials Network 058

BackgroundBuprenorphine/naloxone (BUP/NX) is not licenced for use in China or Thailand and there was little clinical experience with this drug combination in these countries at the inception of HIV Prevention Trial Network (HPTN) 058, a randomized trial comparing risk reduction counselling combined with either short-term or long-term medication assisted treatment with BUP/NX to prevent HIV infection and death amongst opioid-dependent injectors. MethodsWe conducted a safety phase that included the first 50 subjects enrolled at each of the three initial study sites (N=150). Clinical and laboratory assessments were conducted at baseline and weekly for the first 4 weeks. Changes in laboratory parameters were estimated with random effects models. ResultsBUP/NX was well tolerated by study subjects and opioid withdrawal scores decreased substantially during the 3-day induction. Two participants experienced grade 3 clinical adverse events, which were categorized as probably not related to the study drug. Grade 2 or 3 increases in alanine aminotransferase (ALT) occurred in 25 (17%) subjects. The magnitude of ALT increase over 4-week follow-up was strongly associated with baseline ALT elevation. ConclusionsIn Chinese and Thai opioid-dependent injectors, we found BUP/NX to be effective in reducing opioid withdrawal symptoms and safe during short-term use. ALT increases were observed over 4-week-follow-up, which are consistent with reports from Western populations. Long-term safety and efficacy evaluations are indicated.

Methadone-Nicotine Interactions in Methadone Maintenance Treatment Patients

Smoking is highly prevalent (85%-98%) in methadone maintenance treatment (MMT) patients. Methadone has been shown to increase cigarette smoking in a dose-dependent manner, whereas smoking/nicotine has been shown to increase methadone self-administration and reinforcing properties. The objective of this study was to evaluate methadone-nicotine interactions in MMT patients during trough and peak methadone effect conditions. Subjective effects of nicotine (administered by cigarette smoking, 4 mg of nicotine gum and placebo gum) and methadone and their combination were assessed in 40 regularly smoking, stabilized MMT patients using a randomized, placebo-controlled, within-subject study design. Subjects responded to a battery of subjective assessments before and after nicotine administration both before methadone administration (cycles 1 and 2) and 3 hours after methadone administration (cycles 3 and 4). There was a main effect of methadone on the decrease of opioid withdrawal scores (P < 0.001), and cigarette smoking enhanced this effect (day x methadone interaction, P = 0.031). Both nicotine and methadone had main effects on the decrease of nicotine withdrawal scores (P < 0.001 and P = 0.001, respectively); this was associated with the cigarette day (day x nicotine interaction, P = 0.003, and day x methadone interaction, P = 0.004). Nicotine plasma levels were highest on the cigarette smoking day (P < 0.001). Methadone and nicotine shared main effects on the increase of ratings of euphoria and drug liking and on the decrease of restlessness, irritability, and depression. The overall results may help to explain high smoking rates in the MMT population and may account for reports of increased positive effects of methadone when the drugs are taken together.

The Withdrawal Assessment Tool–1 (WAT–1): An assessment instrument for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients*

To develop and test the validity and reliability of the Withdrawal Assessment Tool-1 for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients. Prospective psychometric evaluation. Pediatric critical care nurses assessed eligible at-risk pediatric patients for the presence of 19 withdrawal symptoms and rated the patient's overall withdrawal intensity using a Numeric Rating Scale where zero indicated no withdrawal and 10 indicated worst possible withdrawal. The 19 symptoms were derived from the Opioid and Benzodiazepine Withdrawal Score, the literature and expert opinion. Two pediatric intensive care units in university-affiliated academic children's hospitals. Eighty-three pediatric patients, median age 35 mos (interquartile range: 7 mos-10 yrs), recovering from acute respiratory failure who were being weaned from more than 5 days of continuous infusion or round-the-clock opioid and benzodiazepine administration. Repeated observations during analgesia and sedative weaning. A total of 1040 withdrawal symptom assessments were completed, with a median (interquartile range) of 11 (6-16) per patient over 6.6 (4.8-11) days. Generalized linear modeling was used to analyze each symptom in relation to withdrawal intensity ratings, adjusted for site, subject, and age group. Symptoms with high redundancy or low levels of association with withdrawal intensity ratings were dropped, resulting in an 11-item (12-point) scale. Concurrent validity was indicated by high sensitivity (0.872) and specificity (0.880) for Withdrawal Assessment Tool-1 > 3 predicting Numeric Rating Scale > 4. Construct validity was supported by significant differences in drug exposure, length of treatment and weaning from sedation, length of mechanical ventilation and intensive care unit stay for patients with Withdrawal Assessment Tool-1 scores > 3 compared with those with lower scores. The Withdrawal Assessment Tool-1 shows excellent preliminary psychometric performance when used to assess clinically important withdrawal symptoms in the pediatric intensive care unit setting. Further psychometric evaluation in diverse at-risk groups is needed.

Subjective and physiological responses among racemic‐methadone maintenance patients in relation to relative (S)‐ vs. (R)‐methadone exposure

To investigate the possibility that (S)-methadone influences therapeutic and adverse responses to rac-methadone maintenance treatment, by examining how subjective and physiological responses among rac-methadone maintenance patients vary in relation to relative exposure to (S)- vs. (R)-methadone. Mood states (Profile of Mood States), opioid withdrawal (Methadone Symptoms Checklist), physiological responses (pupil diameter, heart rate, respiration rate, blood pressure), and plasma concentrations (CP) of (R)- and (S)-methadone were measured concurrently 11-12 times over a 24-h interdosing interval in 55 methadone maintenance patients. Average steady-state plasma concentrations (C(av)) and pharmacodynamic responses were calculated using area under the curve (AUC). Linear regression was used to determine whether variability in pharmacodynamic responses was accounted for by (S)-methadone C(av) controlling for (R)-methadone C(av) and rac-methadone dose. Ratios of (S)-:(R)-methadone using AUC(CP) and trough values were correlated with pharmacodynamic responses for all subjects and separately for those with daily rac-methadone doses > or = 100 mg. (S)-methadone C(av) accounted for significant variability in pharmacodynamic responses beyond that accounted for by (R)-methadone C(av) and rac-methadone dose, showing positive associations (partial r) with the intensity of negative mood states such as Tension (0.28), Fatigue (0.31), Confusion (0.32), and opioid withdrawal scores (0.30); an opposite pattern of relationships was evident for (R)-methadone. The plasma (S)-:(R)-methadone AUC(CP) ratio (mean +/- SD 1.05 +/- 0.21, range 0.65-1.51) was not significantly related to pharmacodynamic responses for the subjects as a whole but showed significant positive associations (r) with the intensity of negative mood states such as Total Mood Disturbance (0.61), Tension (0.69), Fatigue (0.65), Confusion (0.64), Depression (0.49) and heart rate (0.59) for the > or = 100-mg dose range. These findings agree with previous evidence that (S)-methadone is associated with a significant and potentially adverse profile of responses distinct from that of (R)-methadone. Individual variability in relative (S)- vs. (R)-methadone exposure may be associated with variability in response to rac-methadone maintenance treatment.