Over the past ten years, there has been a consistent increase in opioid use, which has resulted in an increase in enrolment in methadone maintenance therapy [MMT]. With retention in MMT being a key factor, in order to understand the process of retention, it is important to gain an understanding of individual perceptions and experiences. No research in Ottawa, Ontario has addressed the perspective of MMT from people enrolled in MMT; therefore, nursing based research was undertaken. The objective was to understand the process and experiences associated with MMT from the perspective of persons who are enrolled in treatment. Twelve participants were engaged in semi-structured interviews. These participants described that, although MMT can positively affect the people who use such a treatment option, it continues to have a negative impact that repeatedly affects MMT initiation and delivery. The theoretical framework of Hardt and Negri’s “Triple Imperative of Empire” was used to analyze the research participants’ interviews within the current MMT program, to help develop a more inclusive healthcare service that addressed the current barriers hindering access and retention in treatment. The integration of this framework can help engage persons in treatment, tailor treatment to patient specific needs, and as a result increase access and retention in MMT programs.

Background: The consequences of continued opioid abuse among patients treated with opioid substitution therapy (OST) are serious and can result in abnormal cardiovascular function, overdose, and mortality. Conflicting evidence exists that both implicates and refutes the role of chronic non-cancer pain (CNCP) as a major risk factor for continued opioid abuse within the addiction treatment setting. This thesis aims to 1) evaluate the impact of chronic pain on the treatment outcomes of patients with opioid addiction receiving OST, 2) determine whether a clinical or inflammatory profile exists to distinguish pain in this population, 3) explore the sources of heterogeneity in previous studies examining this question, 4) determine the best therapy for patients with chronic pain, and 5) evaluate the most effective treatment for opioid addiction. We anticipate chronic pain to be an important predictor of continued opioid abuse such that patients with comorbid pain will require careful consideration when managed on OST. Methods: We systematically reviewed the literature to determine the impact of pain in opioid addiction patients receiving methadone maintenance treatment (MMT). We determined the clinical and inflammatory profile of MMT patients using data from the Genetics of Opioid Addiction (GENOA) research collaborative between the Canadian Addiction Treatment Centres (CATC) and the Population Genomic Program. GENOA is a prospective cohort study aimed to determine the genetic, biological, and psychosocial determinants of treatment prognosis for opioid addiction patients receiving MMT. GENOA recruits patients ≥ 18 years of age meeting the DSM-IV criteria for opioid dependence. All GENOA participants are receiving MMT for the management of opioid addiction. Baseline data from the GENOA pilot study (n=235) were used to evaluate the impact of pain on illict opioid use behaviour and determine the clinical and inflammatory profile of patients with comorbid pain. We explored sources of heterogeneity in previous studies using data from the full-phase GENOA study (n=444), examining the prognostic value of different pain measures for predicting illicit opioid use. We then performed a multiple treatment comparison of all opioid substitution and antagonist therapies in efforts to determine the best intervention for improving treatment outcomes for patients with comorbid pain. We lastly determined the most effective treatment for opioid addiction by performing a network meta-analysis using data from a systematic review of opioid maintenance therapy trials. Results: Our initial systematic review confirmed a lack of consensus in the literature, whereby some studies suggest pain increases risk for illicit opioid use and other studies suggest pain has no effect on substance use behaviour. Findings from the analysis of GENOA pilot data confirmed chronic pain to be an important predictor of sustained opioid abuse and also showed patients with pain to have elevated Interferon-Gamma. Using data from the GENOA prospective cohort study we determined the Brief Pain Inventory (a commonly used pain measurement in pervious studies) to be highly sensitive with poor prognostic value. Our final reviews propose 1) there is limited evidence to suggest any OST is superior for managing patients with comorbid pain, and 2) heroin and high-dose methadone are the most effective treatments for improving treatment retention. The final systematic review and network meta-analysis in this thesis also highlights a major problem in the treatment of opioid use disorders, primarily the lack of consensus as to what outcomes matter for determining success in patients with addiction. Conclusion: Patients with comorbid pain and addiction are at high-risk for continued opioid abuse and should be managed closely by clinicians administering OST. Contention in the previous literature likely resulted from the use of pain measurements with poor prognostic value. No OST demonstrated superiority for managing patients with chronic pain. While our findings indicate heroin is the most effective treatment across multiple endpoints, we use this thesis to provide readers with 1) a sense of the feasibility issues associated with heroin administration, 2) a summary of the limitations of this evidence base, and 3) recommendations for how to improve the addiction trials’ design for future research. / Thesis / Doctor of Philosophy (PhD)

This study examined the effects of prenatal exposure to methadone on clinical and neurobehavioural outcomes of infants between 40 and 42 weeks gestation. The aims of this study were: (a) to describe clinical and neurobehavioural outcomes of infants exposed to methadone during pregnancy, (b) to examine the effects of maternal methadone dose during pregnancy on infant clinical and neurobehavioural measures, and (c) to examine the extent to which associations between exposure to methadone during pregnancy and infant outcomes persisted after statistical control for a range of confounding variables. Two groups of study infants were recruited. These consisted of 51 consecutively recruited infants born to mothers maintained on methadone during their pregnancy and 42 randomly identified non-methadone exposed comparison infants. Prior to her child's birth, each pregnant woman completed a comprehensive maternal interview. At birth and during the infant's hospital stay a broad perinatal data-base was collected. At 42 weeks gestation infants underwent a neurobehavioural assessment including the NICU Network Neurobehavioural Scale (NNNS; Lester & Tronick, 2004) and infant cry analysis. Study results showed significant differences across several clinical and neurobehavioural measures. Infants exposed to methadone in utero were found to be significantly lighter, have smaller head circumferences, and spend longer in hospital. Neurobehaviourally, they were significantly less well regulated, less attentive, more easily aroused, more excitable, and more hypertonic. In addition, they exhibited less motor maturity, displayed more stress abstinence symptomatology, and required more support from the assessor in order to remain in an appropriate state. Concurrent analysis of infant cry characteristics revealed no significant differences between the fundamental frequencies or the melody contours of the two groups. However, infants prenatally exposed to methadone did display higher levels of frequency perturbation in their cries, as evidenced by analysis of their jitter factor and percentage of directional jitter. Analysis of the effects of maternal dose during pregnancy suggested that maternal dose levels above 60mg/day were general indicative of poorer infant outcomes than those below 60mg/day, with significant linear trends occurring across a number of measures. The extent to which associations between methadone exposure during pregnancy and infant outcomes reflected either a) the direct effects of methadone exposure and/or b) the effects of confounding factors correlated with maternal methadone use was examined using regression analysis. The results of this analysis for infant clinical outcomes showed confounding variables attenuated the effects of methadone exposure on infant birth length and, to some degree, infant head circumference. In contrast, associations between methadone exposure during pregnancy and most neurobehavioural outcomes remained significant, suggesting that maternal methadone use during pregnancy is an important, independent predictor of infant neurobehavioural functioning. These findings support the view that prenatal exposure to methadone has at least short term impacts on the infant's central nervous system (CNS) development. Important implications of possible vulnerabilities faced by these infants and their families are discussed.

A preliminary investigation of the extent to which supportive services contribute to the effectiveness of a methadone treatment program was conducted.

by Yiu-kuen Kam. / Bibliography: leaves 108-118 / Thesis (M.Phil.) -- Chinese University of Hong Kong, 1983

Opioid replacement therapy with methadone or buprenorphine has been recommended for managing opioid dependence during pregnancy. Although opioid replacement therapy decreases harmful consequences from maternal illicit drug seeking behaviors, the effects of methadone and buprenorphine on neurogenesis and myelination in the developing fetus have not been thoroughly reviewed. Methadone and buprenorphine may alter newborn neurobehavioral functions by impairing neurogenesis and changing the developmental pattern of myelination. This review found that therapeutic doses of methadone and buprenorphine disturb both neurogenesis and myelination in rodents. Methadone and buprenorphine may alter newborn neurobehavioral functions by impairing neurogenesis and changing the developmental pattern of myelination. However, further studies are required to bridge the gap in the understanding between changes in neural development and abnormalities in neurobehavioral functions in the newborn.

Methadone is the foremost, long-standing pharmacological treatment for opioid addiction. It has been shown to have considerable cost benefit to the community and to decrease mortality. Despite methadone's decades-long use, much is still unknown regarding its clinical pharmacology, particularly during the induction phase of Methadone Maintenance Treatment (MMT). Contrary to previous reports, I found systemic methadone clearance does not increase significantly between induction and steady state phases of MMT, and did not approach the previously reported 3-fold increase. Clinical dose prescription based on the premise of metabolism auto-induction could increase risk of respiratory depression. Significant differences between R- and S-methadone pharmacokinetics showed the importance of stereoselective measurement in a clinical situation and significant plasma concentration-effect relationships demonstrated their potential influence on induction pharmacodynamics. Small increases in CYP3A4 activity as measured by the Erythromycin Breath Test from Day 1 to Day 40 of MMT were not correlated with changes in methadone clearance. CYP3A4 activities were informative but would be insufficient for use as a sole predictor of methadone clearance during MMT. Clinically significant respiratory depression occurred in 20% of subjects, at times of peak plasma R-methadone concentrations, after reports of withdrawal symptoms at pre-dose sampling times, and irrespective of illicit opioid use. Utilisation of both respiratory rate and blood oxygen saturation measurements provided a good indication of respiratory risk for individuals. Although prior opioid use was a strong predictor of continued use during MMT, adoption of a new equation ("abc") and comprehensive documentation of each individual's MMT may increase prediction of MMT success. Even in light of recent advances in opioid substitution therapies, MMT's advantages ensure it is still at the forefront of addiction treatment. Careful choice of methodology enabled narrowing of this investigation to those factors most relevant in methadone pharmacology and most responsible for MMT success or failure, and therefore extending previous knowledge of this area. Such data might be utilised to develop a clinically applicable model for MMT, and help provide clients with a safe and uncomplicated transition from heroin use to methadone induction in the future. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1269301 / Thesis (Ph.D.) -- School of Medical Sciences, 2007

Bibliography: leaves 302-359. / xxvi, 392 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Psychology, 2000?

This study examined the effects of prenatal exposure to methadone on clinical and neurobehavioural outcomes of infants between 40 and 42 weeks gestation. The aims of this study were: (a) to describe clinical and neurobehavioural outcomes of infants exposed to methadone during pregnancy, (b) to examine the effects of maternal methadone dose during pregnancy on infant clinical and neurobehavioural measures, and (c) to examine the extent to which associations between exposure to methadone during pregnancy and infant outcomes persisted after statistical control for a range of confounding variables. Two groups of study infants were recruited. These consisted of 51 consecutively recruited infants born to mothers maintained on methadone during their pregnancy and 42 randomly identified non-methadone exposed comparison infants. Prior to her child's birth, each pregnant woman completed a comprehensive maternal interview. At birth and during the infant's hospital stay a broad perinatal data-base was collected. At 42 weeks gestation infants underwent a neurobehavioural assessment including the NICU Network Neurobehavioural Scale (NNNS; Lester & Tronick, 2004) and infant cry analysis. Study results showed significant differences across several clinical and neurobehavioural measures. Infants exposed to methadone in utero were found to be significantly lighter, have smaller head circumferences, and spend longer in hospital. Neurobehaviourally, they were significantly less well regulated, less attentive, more easily aroused, more excitable, and more hypertonic. In addition, they exhibited less motor maturity, displayed more stress abstinence symptomatology, and required more support from the assessor in order to remain in an appropriate state. Concurrent analysis of infant cry characteristics revealed no significant differences between the fundamental frequencies or the melody contours of the two groups. However, infants prenatally exposed to methadone did display higher levels of frequency perturbation in their cries, as evidenced by analysis of their jitter factor and percentage of directional jitter. Analysis of the effects of maternal dose during pregnancy suggested that maternal dose levels above 60mg/day were general indicative of poorer infant outcomes than those below 60mg/day, with significant linear trends occurring across a number of measures. The extent to which associations between methadone exposure during pregnancy and infant outcomes reflected either a) the direct effects of methadone exposure and/or b) the effects of confounding factors correlated with maternal methadone use was examined using regression analysis. The results of this analysis for infant clinical outcomes showed confounding variables attenuated the effects of methadone exposure on infant birth length and, to some degree, infant head circumference. In contrast, associations between methadone exposure during pregnancy and most neurobehavioural outcomes remained significant, suggesting that maternal methadone use during pregnancy is an important, independent predictor of infant neurobehavioural functioning. These findings support the view that prenatal exposure to methadone has at least short term impacts on the infant's central nervous system (CNS) development. Important implications of possible vulnerabilities faced by these infants and their families are discussed.

Indiana University-Purdue University Indianapolis (IUPUI) / The opioid crisis has resulted in an unprecedented number of neonates born with prenatal opioid exposure; however, the long-term effects of opioid exposure on offspring behavior and neurodevelopment remain relatively unknown. I developed a translational mouse model of prenatal methadone exposure (PME) that resembles the typical pattern of opioid use by pregnant women who first use oxycodone then switch to methadone maintenance pharmacotherapy, and subsequently become pregnant while maintained on methadone. PME produced substantial impairments in offspring growth, sensorimotor milestone acquisition, and activity in an open field. Furthermore, these behavioral alterations were associated with significant disruptions in the primary motor cortex (M1). Notably, layer 5 pyramidal neurons of the M1 displayed significantly increased voltage sag which is primarily mediated by HCN1 channels. Interestingly, the α2-adrenergic receptor, a known modulator of HCN1 channels, displayed significantly increased expression in the M1 of PME animals. The locomotor activity in an open field was significantly reduced following in vivo pharmacological activation of the α2-adrenergic receptor with clonidine in PME offspring suggesting this may be therapeutic target for the hyperactivity associated with prenatal exposure to opioids. Previous work has also described an association between prenatal opioid exposure and alterations in opioid reward-related behavior; however, the effect of PME on alcohol reward remains undetermined. Given the widespread accessibility and usage, alcohol represents the most likely addictive substance the growing population of opioid exposed neonates will encounter as they age. I discovered that PME disrupts conditioned preference for alcohol, enhances the locomotor stimulating effects of alcohol, and increases alcohol consumption in a sex-dependent manner. This alcohol-reward phenotype in PME offspring was associated with altered excitatory neurotransmission and disrupted cannabinoid-mediated long-term depression (CB-LTD) in the dorsolateral striatum, an important substrate involved in compulsive drug use. Further work is required to determine the specific inputs at which CB-LTD is disrupted and if restoring this form of plasticity in PME animals prevents the enhanced alcohol addiction phenotype. / 2023-03-02