Non-Prescribed Substance Use during the First Month of Treatment by People Receiving Depot Buprenorphine for Opioid Use Disorder.

Background: Non-prescribed substance use (NPSU) during the treatment of opioid use disorder (OUD) is a recognized phenomenon. The use of non-prescribed substances is associated with discontinuing treatment and drop-out can occur within the early weeks of treatment, before benefit from treatment occurs. Recent developments in treatment include long-acting, slow-release depot buprenorphine injections. This article focuses on NPSU during the first month of treatment with depot buprenorphine, addressing the frequency with which it occurs, the substances used, and reasons for use. Methods: 70 semi-structured interviews (held at three time-points) were conducted with 26 patients initiating depot buprenorphine as part of a longitudinal qualitative study. Analysis prioritized content and framework analyses. Findings: 17/26 participants self-reported NPSU at various times during the first month of treatment. NPSU typically involved heroin, crack-cocaine and some use of benzodiazepines and/or cannabis. Participants' reasons for heroin use were connected to their subjective accounts of opioid withdrawal symptoms, the management of pain, and experimentation (to test the blockade effect of buprenorphine). Frequency of heroin use was typically episodic rather than sustained. Participants associated crack-cocaine use with stimulant-craving and social connections, and considered their use of this substance to be difficult to manage. Conclusions: Patients' initial engagement with treatment for OUD is rarely examined in qualitative research. This study highlights how NPSU amongst patients receiving new forms of such treatment continues to be a challenge. As such, shared decision-making (between providers and patients) regarding treatment goals and NPSU should be central to the delivery of depot buprenorphine treatment programmes.

Association of medication-assisted treatment and short acting opioids with newborn head circumference and birth weight.

OBJECTIVE: We compared the association of methadone, buprenorphine, and short-acting opioid exposure with newborn head circumference (HC) and birth weight (BW), and evaluated gestational age (GA) as a mediator. STUDY DESIGN: We included newborns born 2013-2018 identified by neonatal abstinence syndrome diagnosis code (N = 572) and birthday-matched unexposed controls (N = 571). Linear regressions of opioid exposure with HC and BW controlled for tobacco, marijuana, cocaine, gabapentin, cesarean section, Medicaid, and newborn sex, with mediation analysis by GA. RESULT: Methadone was associated with 0.81 cm lower HC (95% CI = -1.22, -0.40) and 0.23 kg lower BW (95% CI = -0.35, -0.10) with approximately 24% and 41% mediated by GA, respectively. Buprenorphine and short acting opioids were not associated with HC or BW. CONCLUSION: Methadone exposed newborns have smaller HC and lower BW not fully attributable to younger GA, suggesting a direct effect of methadone on intrauterine growth. Exploration of potential developmental consequences of this is urgently needed.

Successful buprenorphine transition while overlapping with a full opioid agonist to treat chronic pain: a case report.

Buprenorphine is a partial mu opioid agonist that has been increasingly utilized to treat patients with chronic pain and opioid use disorder (OUD). The drug has proven to provide significant chronic pain relief at low doses ranging from 75 to 1800 mcg. The conventional buprenorphine transitional process delays its introduction until patients begin withdrawal. However, this process can pose a barrier to both patients and providers due to some patients' inability to tolerate traditional prerequisite withdrawal. To our knowledge, this is a rare reported case to describe a transitional process utilizing buccal buprenorphine in which a patient with chronic pain simultaneously tapered completely off an extended-release (ER) full opioid agonist and uptitrated buprenorphine. The patient was weaned from oxycodone ER 30 mg every 12 h and oxycodone/acetaminophen 10/325 mg 3x/day for breakthrough pain utilizing an unconventional approach. Tapering down to oxycodone ER 20 mg 2x/day for the first 2 weeks was successful. However, reducing to oxycodone ER 10 mg 2x/day for the following 2 weeks presented adherence difficulty and increased breakthrough pain. At this time, buccal buprenorphine was added at 300 mcg daily for 3 days. From days 4 to 6, buprenorphine was increased to 300 mcg 2x/day and oxycodone ER decreased to 10 mg daily. Six days later, oxycodone ER was discontinued and oxycodone/acetaminophen continued as needed. The patient exhibited no signs of withdrawal and adequate relief of symptoms through this tapering process. At the 1-month follow-up, the patient was doing well and was being treated solely with buprenorphine and oxycodone/acetaminophen to control her breakthrough pain. After 5 months, buprenorphine was increased to 600 mcg 2x/day and her oxycodone/acetaminophen decreased to 5/325 mg 3x/day as needed. From the start of the patient's taper to her current transition, the patient reduced her morphine milligram equivalent (MME) dosage from 135 MME to 22.5 MME. The Clinical Opioid Withdrawal Scale (COWS), which measures the severity of a patient's opioid withdrawal symptoms, was consistently less than 5. This buprenorphine schedule demonstrated a successful tapering approach for this patient because she had reported improved quality of life and function. A patient-centered osteopathic treatment approach was utilized when the patient presented with mid-taper adherence difficulty. Transitioning patients from full to partial opioid agonists could become an important practice standard for patient safety not only for formal pain management practices but also in primary care, family practice, and even geriatric offices.

Pharmacologic Treatment of Opioid Use Disorder: a Review of Pharmacotherapy, Adjuncts, and Toxicity.

Opioid use disorder continues to be a significant source of morbidity and mortality in the USA and the world. Pharmacologic treatment with methadone and buprenorphine has been shown to be effective at retaining people in treatment programs, decreasing illicit opioid use, decreasing rates of hepatitis B, and reducing all cause and overdose mortality. Unfortunately, barriers exist in accessing these lifesaving medications: users wishing to start buprenorphine therapy require a waivered provider to prescribe the medication, while some states have no methadone clinics. As such, users looking to wean themselves from opioids or treat their opioid dependence will turn to alternative agents. These agents include using prescription medications, like clonidine or gabapentin, off-label, or over the counter drugs, like loperamide, in supratherapeutic doses. This review provides information on the pharmacology and the toxic effects of pharmacologic agents that are used to treat opioid use disorder. The xenobiotics reviewed in depth include buprenorphine, clonidine, kratom, loperamide, and methadone, with additional information provided on lofexidine, akuamma seeds, kava, and gabapentin.

Pharmacological therapies for management of opium withdrawal.

BACKGROUND: Pharmacologic therapies for management of heroin withdrawal have been studied and reviewed widely. Opium dependence is generally associated with less severe dependence and milder withdrawal symptoms than heroin. The evidence on withdrawal management of heroin might therefore not be exactly applicable for opium. OBJECTIVES: To assess the effectiveness and safety of various pharmacologic therapies for the management of the acute phase of opium withdrawal. SEARCH METHODS: We searched the following sources up to September 2017: CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, regional and national databases (IMEMR, Iranmedex, and IranPsych), main electronic sources of ongoing trials, and reference lists of all relevant papers. In addition, we contacted known investigators to obtain missing data or incomplete trials. SELECTION CRITERIA: Controlled clinical trials and randomised controlled trials on pharmacological therapies, compared with no intervention, placebo, other pharmacologic treatments, different doses of the same drug, and psychosocial intervention, to manage acute withdrawal from opium in a maximum duration of 30 days. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 13 trials involving 1096 participants. No pooled analysis was possible. Studies were carried out in three countries, Iran, India, and Thailand, in outpatient and inpatient settings. The quality of the evidence was generally very low.When the mean of withdrawal symptoms was provided for several days, we mainly focused on day 3. The reason for this was that the highest severity of opium withdrawal is in the second to fourth day.Comparing different pharmacological treatments with each other, clonidine was twice as good as methadone for completion of treatment (risk ratio (RR) 2.01, 95% confidence interval (CI) 1.69 to 2.38; 361 participants, 1 study, low-quality evidence). All the other results showed no differences between the considered drugs: baclofen versus clonidine (RR 1.06, 95% CI 0.63 to 1.80; 66 participants, 1 study, very low-quality evidence); clonidine versus clonidine plus amantadine (RR 1.03, 95% CI 0.86 to 1.24; 69 participants, 1 study); clonidine versus buprenorphine in an inpatient setting (RR 1.04, 95% CI 0.90 to 1.20; 1 study, 35 participants, very low-quality evidence); methadone versus tramadol (RR 0.95, 95% CI 0.65 to 1.37; 1 study, 72 participants, very low-quality evidence); methadone versus methadone plus gabapentin (RR 1.17, 95% CI 0.96 to 1.43; 1 study, 40 participants, low-quality evidence), and tincture of opium versus methadone (1 study, 74 participants, low-quality evidence).Comparing different pharmacological treatments with each other, adding amantadine to clonidine decreased withdrawal scores rated at day 3 (mean difference (MD) -3.56, 95% CI -5.97 to -1.15; 1 study, 60 participants, very low-quality evidence). Comparing clonidine with buprenorphine in an inpatient setting, we found no difference in withdrawal symptoms rated by a physician (MD -1.40, 95% CI -2.93 to 0.13; 1 study, 34 participants, very low-quality evidence), and results in favour of buprenorpine when rated by participants (MD -11.80, 95% CI -15.56 to -8.04). Buprenorphine was superior to clonidine in controlling severe withdrawal symptoms in an outpatient setting (RR 0.35, 95% CI 0.19 to 0.64; 1 study, 76 participants). We found no difference in the comparison of methadone versus tramadol (MD 0.04, 95% CI -2.68 to 2.76; 1 study, 72 participants) and in the comparison of methadone versus methadone plus gabapentin (MD -2.20, 95% CI -6.72 to 2.32; 1 study, 40 participants).Comparing clonidine versus buprenorphine in an outpatient setting, more adverse effects were reported in the clonidine group (1 study, 76 participants). Higher numbers of participants in the clonidine group experienced hypotension at days 5 to 8, headache at days 1 to 8, sedation at days 5 to 8, dizziness and dry mouth at days 1 to 10, and nausea at days 1 to 9. Sweating was reported in a significantly higher number of participants in the buprenorphine group at days 1 to 10. We found no difference between groups for all the other comparisons considering this outcome.Comparing different dosages of the same pharmacological detoxification treatment, a high dose of clonidine (1 to 1.2 mg/day) did not differ from a low dose of clonidine (0.5 to 0.6 mg/day) in completion of treatment in an inpatient setting (RR 1.00, 95% CI 0.84 to 1.19; 1 study, 68 participants), however a higher number of participants with hypotension was reported in the high-dose group (RR 3.25, 95% CI 1.77 to 5.98). Gradual reduction of methadone was associated with more adverse effects than abrupt withdrawal of methadone (RR 2.25, 95% CI 1.02 to 4.94; 1 study, 20 participants, very low-quality evidence). AUTHORS' CONCLUSIONS: Results did not support using any specific pharmacological approach for the management of opium withdrawal due to generally very low-quality evidence and small or no differences between treatments. However, it seems that opium withdrawal symptoms are significant, especially at days 2 to 4 after discontinuation of opium. All of the assessed medications might be useful in alleviating symptoms. Those who receive clonidine might experience hypotension.

Constipation and other common symptoms reported by women and men in methadone and buprenorphine maintenance treatment.

BACKGROUND: Opioid substitution treatment (OST) is often continued long-term and, therefore, opioid-associated symptoms are of interest. Symptoms associated with methadone maintenance treatment (MMT) in men are well described, but there are fewer reports concerning symptoms associated with buprenorphine maintenance treatment (BMT) and very few reports among women. METHOD: Recipients of BMT (n=113) and MMT (n=184), non-opioid users (n=105) and opioid users not receiving OST (n=87) completed the Patient Assessment of Constipation (PAC-SYM) and a general symptom checklist. Multivariate analysis included other potential moderators of opioid-associated symptoms. FINDINGS: Opioid users reported a higher frequency and severity of symptoms than non-opioid users. Constipation, dry mouth, decreased appetite, sweating and fatigue were highly prevalent in the previous 30days (51-80%). Nausea, itchy skin, trouble urinating, menstrual problems, lightheadedness, blurred vision, heart racing were also common (30-50%). Non-OST opioid users had significantly higher frequency and severity than OST recipients of nausea, vomiting, diarrhoea, decreased appetite, sweating and itchy skin. Sweating was significantly more common in MMT than BMT. Constipation scores were higher in women, otherwise most sex differences were small. Higher PAC-SYM scores were associated with vomiting (OR=1.04) and sweating (OR=1.06). Cannabis use was associated with vomiting (OR=2.19). Constipation (OR=1.07), insomnia (OR=2.5) and depression (OR=2.82) were associated with fatigue. CONCLUSION: Men and women receiving OST report similarly high rates of somatic symptoms, though less than opioid users not receiving OST. There were few differences between BMT and MMT. Buprenorphine might be preferred where sweating is problematic. Several modifiable factors were identified.

Newborn birth-weight of pregnant women on methadone or buprenorphine maintenance treatment: A national contingency management approach trial.

BACKGROUND AND OBJECTIVES: Methadone maintenance treatment (MMT) is the gold standard for pregnant women with opioid use disorders. Still, low birth-weights were reported, in particular of mothers who became pregnant before admission to MMT. We studied whether an escalating incentive contingency-management approach may contribute to better newborn birth-weights. METHODS: A nationwide controlled randomized trial among all Israeli methadone/buprenorphine maintenance treatment (MBMT), newly or already in treatment pregnant women was performed. A modified contingency-management protocol with coupons of escalating value depending upon reduction of drug use, cigarette smoking, and alcohol consumption was compared to standard care arm. Drugs in urine, smoking (Fagerstrom score), alcohol use, and depression were monitored. RESULTS: Thirty-five women had 46 pregnancies. In their first pregnancy, 19 from the contingency-management and 16 from the standard care arms were studied. Contingency-management group as compared to the standard care arm included more newly admitted women (36.8% vs. 6.3%, p = .05), with benzodiazepine and cannabis onset at a younger age, and higher proportion of any drug abuse while pregnant (100% vs. 68.8%, p = .01). Fifteen of the contingency-management and 14 of the control arm gave birth (78.9% vs. 87.5%, p = .3) with similar proportions of normal (>2,500 g) birth-weight (71.4% vs. 61.5%, p = .8). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Newborns' birth-weight was comparable among the two study arms indicating no contribution of the contingency-management approach. Small sample and baseline differences between arms might have influenced results. Intensive intervention should be evaluated on a larger scale of participants. (Am J Addict 2017;26:167-175).

Enteral Docosahexaenoic Acid Reduces Analgesic Administration in Neonates Undergoing Cardiovascular Surgery.

BACKGROUND: Neonates undergoing surgery require analgesic medication to ameliorate acute pain. These medications produce negative side effects. Docosahexaenoic acid (DHA) has an antinociceptive effect in animals, but this has not been evaluated in human neonates. We evaluated the DHA effect on cumulative dose and duration of analgesics administered to neonates undergoing cardiovascular surgery. METHODS: A secondary analysis was performed with data from a clinical trial, in which enteral DHA was administered perioperatively compared with sunflower oil (SO). Present study assessed the antinociceptive effect of DHA by measuring the cumulative dose and duration of analgesics administered during postoperative stay in a neonatal intensive care unit. Multivariate linear regression models were performed. RESULTS: Seventeen neonates received DHA and 18 received SO in the control group. Compared with the control group, the DHA group received lower cumulative dose (14.6 ± 2.2 vs. 25.2 ± 4.8 µg/kg, p = 0.029) and shorter duration of buprenorphine (2 days (1-8) vs. 4.5 days (1-12); p = 0.053). After adjusting for confounders, the DHA group received significantly lesser buprenorphine (ß = -27 µg/kg, p = 0.028; R2 model = 0.90) for shorter duration (ß = -9 days, p = 0.003; R2 model = 0.94). No differences in fentanyl or ketorolac were detected. CONCLUSIONS: Buprenorphine administration was reduced in neonates who received DHA, suggesting that DHA likely has analgesic effects.

The safety of high-dose buprenorphine administered subcutaneously in cats.

The safety of a proprietary formulation of buprenorphine hydrochloride administered subcutaneously (SC) to young cats was investigated in a blinded, randomized study. Four cohorts of eight cats aged approximately 4 months were administered saline, 0.24, 0.72 or 1.20 mg/kg/day buprenorphine SC for nine consecutive days, representing 0×, 1×, 3× and 5× of the intended dose. Cats were monitored daily for evidence of clinical reactions, food and water intake and adverse events (AEs). Physical examinations, clinical pathology, vital signs and electrocardiograms (ECGs) were evaluated at protocol-specified time points. Complete necropsy and histopathologic examinations were performed following humane euthanasia. Four buprenorphine-treated cats experienced AEs during the study, two unrelated and two related to study drug administration. The two cats with AEs considered related to drug administration had clinical signs of hyperactivity, difficulty in handling, disorientation, agitation and dilated pupils in one 0.24 mg/kg/day cat and one 0.72 mg/kg/day cat. All of these clinical signs were observed simultaneously. There were no drug-related effects on survival, injection response, injection site inspections, body weight, food or water consumption, bleeding time, urinalysis, respiration rate, heart rate, ECGs, blood pressures, body temperatures, macroscopic examinations or organ weights. Once daily buprenorphine s.c. injections at doses of 0.24, 0.72 and 1.20 mg/kg/day for 9 consecutive days were well tolerated in young domestic cats.

In vivo profiling of seven common opioids for antinociception, constipation and respiratory depression: no two opioids have the same profile.

BACKGROUND AND PURPOSE: For patients experiencing inadequate analgesia and intolerable opioid-related side effects on one strong opioid analgesic, pain relief with acceptable tolerability is often achieved by rotation to a second strong opioid. These observations suggest subtle pharmacodynamic differences between opioids in vivo. This study in rats was designed to assess differences between opioids in their in vivo profiles. EXPERIMENTAL APPROACH: Male Sprague Dawley rats were given single i.c.v. bolus doses of morphine, morphine-6-glucuronide (M6G), fentanyl, oxycodone, buprenorphine, DPDPE ([D-penicillamine(2,5) ]-enkephalin) or U69,593. Antinociception, constipation and respiratory depression were assessed using the warm water tail-flick test, the castor oil-induced diarrhoea test and whole body plethysmography respectively. KEY RESULTS: These opioid agonists produced dose-dependent antinociception, constipation and respiratory depression. For antinociception, morphine, fentanyl and oxycodone were full agonists, buprenorphine and M6G were partial agonists, whereas DPDPE and U69,593 had low potency. For constipation, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, morphine produced a bell-shaped dose-response curve, whereas DPDPE and U69,593 were inactive. For respiratory depression, morphine, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, whereas DPDPE and U69,593 were inactive. The respiratory depressant effects of fentanyl and oxycodone were of short duration, whereas morphine, M6G and buprenorphine evoked prolonged respiratory depression. CONCLUSION AND IMPLICATIONS: For the seven opioids we assessed, no two had the same profile for evoking antinociception, constipation and respiratory depression, suggesting that these effects are differentially regulated. Our findings may explain the clinical success of 'opioid rotation'. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Buprenorphine in the workers' compensation setting.

Buprenorphine is approved by the Food and Drug Administration for the treatment of chronic pain in low-dose transdermal patch formulations and for the treatment of addiction in high-dose sublingual tablets and films. Clinicians often prescribe these high-dose preparations "off label" for pain management. In the workers' compensation setting, it is particularly important to consider factors such as a) if the injured person has, and is being treated for co-occurring addiction as well as pain; b) if alternative therapies, including opioid withdrawal, were considered prior to initiating buprenorphine treatment; and c) the anticipated duration of treatment. This article reviews buprenorphine's approved indications, formulations, pharmacology, clinical efficacy, and special considerations in the workers' compensation setting.

Maternal stress and behavioral adaptation in methadone- or buprenorphine-exposed toddlers.

The current study examined the relationship between early interaction, parenting stress, maternal psychological distress symptoms, and behavior problems and health-related quality of life among children born to mothers in opioid maintenance treatment (OMT) in Norway during the period 2005-2007 (N = 36). This group was compared with a normative sample of mothers without substance abuse problems and their children (N = 36). There were significant group differences (p < .01) in perceived child problems in toddlerhood. In a regression model, mothers' self-reported psychological distress symptoms in terms of depression and anxiety symptoms significantly predicted child behavior problems (p < .01) and health-related quality of life (p < .01) rather than parenting stress. No significant, unique effect of exposure was found after controlling for other factors that could influence developmental outcomes. These findings add to the growing evidence on the importance of maternal psychological well-being for child development, and underscore the need to address opioid-maintained women's personal maladjustment and the constellation of stress experienced by mothers in recovery.

Use of conventional, complementary, and alternative treatments for pain among individuals seeking primary care treatment with buprenorphine-naloxone.

UNLABELLED: Previous studies have not examined patterns of pain treatment use among patients seeking office-based buprenorphine-naloxone treatment (BNT) for opioid dependence. OBJECTIVES: To examine, among individuals with pain seeking BNT for opioid dependence, the use of pain treatment modalities, perceived efficacy of prior pain treatment, and interest in pursuing pain treatment while in BNT. METHODS: A total of 244 patients seeking office-based BNT for opioid dependence completed measures of demographics, pain status (ie, "chronic pain (CP)" [pain lasting at least 3 months] vs "some pain (SP)" [pain in the past week not meeting the duration criteria for chronic pain]), pain treatment use, perceived efficacy of prior pain treatment, and interest in receiving pain treatment while in BNT. RESULTS: In comparison with the SP group (N = 87), the CP group (N = 88) was more likely to report past-week medical use of opioid medication (adjusted odds ratio [AOR] = 3.2; 95% CI, 1.2-8.4), lifetime medical use of nonopioid prescribed medication (AOR = 2.2; 95% CI, 1.1-4.7), and lifetime use of prayer (AOR = 2.8; 95% CI, 1.2-6.5) and was less likely to report lifetime use of yoga (AOR = 0.2; 95% CI, 0.1-0.7) to treat pain. Although the 2 pain groups did not differ on levels of perceived efficacy of prior lifetime pain treatments, in comparison with the SP group, the CP group was more likely to report interest in receiving pain treatment while in BNT (P < 0.001). CONCLUSIONS: Individuals with pain seeking BNT for opioid dependence report a wide range of conventional, complementary, and alternative pain-related treatments and are interested (especially those with CP) in receiving pain management services along with BNT.

Neonatal abstinence syndrome after methadone or buprenorphine exposure.

BACKGROUND: Methadone, a full mu-opioid agonist, is the recommended treatment for opioid dependence during pregnancy. However, prenatal exposure to methadone is associated with a neonatal abstinence syndrome (NAS) characterized by central nervous system hyperirritability and autonomic nervous system dysfunction, which often requires medication and extended hospitalization. Buprenorphine, a partial mu-opioid agonist, is an alternative treatment for opioid dependence but has not been extensively studied in pregnancy. METHODS: We conducted a double-blind, double-dummy, flexible-dosing, randomized, controlled study in which buprenorphine and methadone were compared for use in the comprehensive care of 175 pregnant women with opioid dependency at eight international sites. Primary outcomes were the number of neonates requiring treatment for NAS, the peak NAS score, the total amount of morphine needed to treat NAS, the length of the hospital stay for neonates, and neonatal head circumference. RESULTS: Treatment was discontinued by 16 of the 89 women in the methadone group (18%) and 28 of the 86 women in the buprenorphine group (33%). A comparison of the 131 neonates whose mothers were followed to the end of pregnancy according to treatment group (with 58 exposed to buprenorphine and 73 exposed to methadone) showed that the former group required significantly less morphine (mean dose, 1.1 mg vs. 10.4 mg; P<0.0091), had a significantly shorter hospital stay (10.0 days vs. 17.5 days, P<0.0091), and had a significantly shorter duration of treatment for the neonatal abstinence syndrome (4.1 days vs. 9.9 days, P<0.003125) (P values calculated in accordance with prespecified thresholds for significance). There were no significant differences between groups in other primary or secondary outcomes or in the rates of maternal or neonatal adverse events. CONCLUSIONS: These results are consistent with the use of buprenorphine as an acceptable treatment for opioid dependence in pregnant women. (Funded by the National Institute on Drug Abuse; ClinicalTrials.gov number, NCT00271219.).

Predictors of buprenorphine-naloxone dosing in a 12-week treatment trial for opioid-dependent youth: secondary analyses from a NIDA Clinical Trials Network study.

INTRODUCTION: The present investigation examines baseline patient characteristics to predict dosing of buprenorphine-naloxone, a promising treatment for opioid addiction in youths. METHODS: This study of 69 opioid-dependent youths is a secondary analysis of data collected during a National Institute on Drug Abuse (NIDA) Clinical Trials Network study. Outpatients aged 15-21 were randomized to a 12-week buprenorphine-naloxone dosing condition (including 4 weeks of taper). Predictors of dosing included sociodemographic characteristics (gender, race, age, and education), substance use (alcohol, cannabis, cocaine, and nicotine use), and clinical characteristics (pain and withdrawal severity). RESULTS: Most (75.4%) reported having either "some" (n=40, 58.0%) or "extreme" (n=12, 17.4%) pain on enrollment. Maximum daily dose of buprenorphine-naloxone (19.7 mg) received by patients reporting "extreme" pain at baseline was significantly higher than the dose received by patients reporting "some" pain (15.0mg) and those without pain (12.8 mg). In the adjusted analysis, only severity of pain and withdrawal significantly predicted dose. During the dosing period, there were no significant differences in opioid use, as measured by urinalysis, by level of pain. CONCLUSION: These data suggest that the presence of pain predicts buprenorphine-naloxone dose levels in opioid-dependent youth, and that patients with pain have comparable opioid use outcomes to those without pain, but require higher buprenorphine-naloxone doses.

[Substitution treatment of drug addicts during pregnancy: consequences for the children?]. / Har legemiddelassistert rehabilitering i svangerskapet konsekvenser for barna?

BACKGROUND: Substitution treatment of opioid-dependent addicts was introduced in Norway in 1998. During the last 10 years, approximately 150 infants have been born to mothers taking part in this programme. MATERIAL AND METHODS: 10 mothers, who took part in the substitution treatment programme, gave birth to 15 infants at Haukeland University Hospital in the period 1999-2005. The infants were observed and monitored at the Department of Pediatrics, Haukeland University Hospital. RESULTS: During pregnancy, six of the infants were only exposed to opiates, i.e methadone or buprenorphine. Eight infants were also exposed to heroine, benzodiazepines or cannabis. As a group, these infants had lower birth weight than the national average. 14 of the 15 children developed neonatal abstinence syndrome (NAS), 10 needed treatment and two children died from sudden infant death syndrome (SIDS). Long-term follow-up showed that six of 13 children had normal psychomotor development, five had various degrees of delayed psychomotor development and two children had symptoms indicating a hyperkinetic disorder. Five children were in foster care. INTERPRETATION: Infants of women included in substitution treatment programmes for drug addicts are at high risk compared to infants of women without such addiction. For the newborn, NAS was a frequent complication. The study also showed that symptoms of hyperkinetic disorder and delayed psychomotor development were common. Children who had been exposed to opiates in combination with additional drugs seemed to have a high risk of delayed development and behaviour disorders. As they get older many were placed in foster care, despite well-coordinated, multidisciplinary treatment for the mother.

Hypogonadism in men receiving methadone and buprenorphine maintenance treatment.

The aim of this study was to determine the prevalence and investigate the aetiology of hypogonadism in men on methadone or buprenorphine maintenance treatment (MMT, BMT). 103 men (mean age 37.6 +/- 7.9) on MMT (n = 84) or BMT (n = 19) were evaluated using hormone assays, body mass index (BMI), serological, biochemical, demographic and substance use measures. Overall 54% of men (methadone 65%; buprenorphine 28%) had total testosterone (TT) <12.0 nm; 34% (methadone 39%; buprenorphine 11%) had TT <8.0 nm. Both methadone- and buprenorphine-treated men had lower free testosterone, luteinising hormone and estradiol than age-matched reference groups. Methadone-treated men had lower TT than buprenorphine-treated men and reference groups. Prolactin did not differ between methadone, buprenorphine groups, and reference groups. Primary testicular failure was an uncommon cause of hypogonadism. Yearly percentage fall in TT by age across the patient group was 2.3%, more than twice that expected normally. There were no associations between TT and opioid dose, cannabis, alcohol and tobacco consumption, or chronic hepatitis C viraemia. On multiple regression higher TT was associated with higher alanine aminotransferase and lower TT with higher BMI. Men on MMT have high prevalence of hypogonadotrophic hypogonadism. The extent of hormonal changes associated with buprenorphine needs to be explored further in larger studies. Men receiving long term opioid replacement treatment, especially methadone treatment, should be screened for hypogonadism. Wide interindividual differences in methadone metabolism and tolerance may in a cross-sectional study obscure a methadone dose relationship to testosterone in individuals. Future studies of hypogonadism in opioid-treated men should examine the potential benefits of dose reduction, choice of opioid medication, weight loss, and androgen replacement.

Outbreak of exogenous Cushing's syndrome due to unlicensed medications.

OBJECTIVE: Despite the widespread medical use of glucocorticoids, reports of factitious administration of these hormones have been uncommon. We herein report an outbreak of Cushing's syndrome in Tehran among the addicts using Tamgesic (a brand of Buprenorphine) to help them through the narcotic withdrawal stage, without knowledge of the glucocorticoid content of the black-market drug. DESIGN AND MEASUREMENTS: Case histories of 19 patients with a final diagnosis of iatrogenic Cushing's syndrome were reviewed. Liquid chromatography/mass spectrometry (LC-Mass) method was used to evaluate glucocorticoid existence in the brand. High performance liquid chromatography was used to determine plasma dexamethasone level. RESULTS: No buprenorphine was present in the vials. Each Tamgesic vial contained 0.4 mg of Dexamethasone disodium phosphate; Heroin was also found in them. The duration of injection abuse and the total dexamethasone intake was 4.5 (1-18) months and 2.6 (0.8-8) mg/day, respectively. Median plasma dexamethasone concentration was 5.8 nmol/l, with a range of 5-8.7. Physical findings of the cases were not different from those of the classic endogenous Cushing's syndrome but their serum cortisol and urinary free cortisol were suppressed. Severe life-threatening complications were demonstrated in five cases. CONCLUSION: Surreptitious use of steroids resulting in Cushing's syndrome may be more common in opium addicts; a high degree of suspicion is needed to uncover this disorder. Whenever facing a cushingoid appearance in addicts, the possibility of using black market drugs with corticosteroid contents should be kept in mind.

Erectile dysfunction in men receiving methadone and buprenorphine maintenance treatment.

INTRODUCTION: Use of opiates/opioids is associated with hypoactive sexual desire, erectile and orgasmic dysfunction. AIM: To determine prevalence and investigate etiology of sexual dysfunction in men on methadone or buprenorphine maintenance treatment (MMT, BMT). MAIN OUTCOME MEASURES: International Index of Erectile Function (IIEF), hormone assays, Beck Depression Inventory. METHODS: A total of 103 men (mean age 37.6 +/- 7.9) on MMT (N = 84) or BMT (N = 19) were evaluated using the IIEF, hormone assays, Beck Depression Inventory, body mass index (BMI), demographic, and other substance use measures. RESULTS: Mean total IIEF scores for partnered men were lower for MMT (50.4 +/- 18.2; N = 53) than reference groups (61.4 +/- 16.8; N = 415; P < 0.0001) or BMT (61.4 +/- 7.0; N = 14; P = 0.048). Among partnered men on MMT, 53% had erectile dysfunction (ED) compared with 24% of reference groups; 26% had moderate to severe ED, 12.1% in under 40s and 40.0% among those 40+ years. On multiple regression, depression, older age, and lower total testosterone were associated with lower IIEF and EF domain; on multivariate analysis, there were no significant associations between IIEF or EF and free testosterone, opioid dose, cannabis or other substance use, viral hepatitis, or BMI. Total testosterone accounted for 16% of IIEF and 15% of EF variance. Men without sexual partners had lower Desire and Erection Confidence scores and less recent sexual activity, suggesting potentially higher prevalence of sexual dysfunction in this group. CONCLUSION: Men on MMT, but not BMT, have high prevalence of ED, related to hypogonadism and depression. Practitioners should screen for sexual dysfunction in men receiving opioid replacement treatment. Future studies of sexual dysfunction in opioid-treated men should examine the potential benefits of dose reduction, androgen replacement, treatment of depression, and choice of opioid.