Craving in Opioid Use Disorder: From Neurobiology to Clinical Practice.

Opioid use disorder (OUD) is a major public health issue that has reached epidemic levels in some parts of the world. It is a chronic and complex neurobiological disease associated with frequent relapse to drug taking. Craving, defined as an overwhelmingly strong desire or need to use a drug, is a central component of OUD and other substance use disorders. In this review, we describe the neurobiological and neuroendocrine pathways that underpin craving in OUD and also focus on the importance of assessing and treating craving in clinical practice. Craving is strongly associated with patients returning to opioid misuse and is therefore an important treatment target to reduce the risk of relapse and improve patients' quality of life. Opioid agonist therapies (OAT), such as buprenorphine and methadone, can significantly reduce craving and relapse risk, and it is essential that patients are treated optimally with these therapies. There is also evidence to support the benefits of non-pharmacological approaches, such as cognitive behavioral therapy and mindfulness-based interventions, as supplementary treatments to opioid agonist therapies. However, despite the positive impact of these treatments on craving, many OUD patients continue to suffer with negative affect and dysphoria. There is a clear need for further studies to progress our understanding of the neurobiological basis of craving and addiction and to identify novel therapeutic strategies as well as to optimize the use of existing treatments to improve outcomes for the growing numbers of patients affected by OUD.

Standards for opioid use disorder care: An assessment of Nordic approaches.

AIMS: Outcomes in opioid use disorder (OUD) in Nordic countries have improved with integrated treatment and harm-reduction programmes. Approaches and the standard of care are different across the region. Evidence of treatment needs and current approaches are defined from evidence to inform development of a common standard. METHOD: Evidence of population sizes and treatment approach collected. Common standards for care (harm reduction, pharmacotherapy, psychology/social therapy) defined for each country. RESULTS: Evidence defines number in treatment; potential population needing treatment not defined for all countries. Populations sizes, treatment access (ratio in treatment programme compared to total country population) defined: Sweden 4,000 in OUD care (access ratio 40); Finland 3,000 (55); Norway 8,000 (154); Denmark 7,500 (132). Approach to treatment similar: integrated treatment programmes standard. Care provided by specialists in outpatient clinics/primary care; secondary care/inpatient services are available. Harm reduction is limited in Sweden but available and more accessible elsewhere. Treatment entry criteria: access relatively unlimited in Norway and Denmark, more limited in Finland and Sweden. Standards of care defined: easy access to high-quality services, individual planning, care not limited by time, management of relapse, education for patients, continuous engagement, holistic approach including management of comorbidities, needle equipment programmes without limit, treatment in prisons as community. CONCLUSION: There are opportunities to improve OUD care in the Nordics. Policy makers and clinicians can advance OUD care and share common success factors. Collaborative work across the Nordic countries is valuable. Further research in clinical practice development can yield important results for the benefit of patients with OUD.

Principles for managing OUD related to chronic pain in the Nordic countries based on a structured assessment of current practice.

BACKGROUND: Long-term use of opioid analgesics (OA) for chronic pain may result in opioid use disorder (OUD). This is associated with adverse outcomes for individuals, families and society. Treatment needs of people with OUD related to chronic pain are different compared to dependence related to use, and also injection, of illicit opioids. In Nordic countries, day-to-day practical advice to assist clinical decision-making is insufficient. AIM: To develop principles based on expert clinical insights for treatment of OUD related to the long-term use of OA in the context of chronic pain. METHODS: Current status including an assessment of barriers to effective treatment in Finland, Denmark, Iceland, Norway, Sweden was defined using a patient pathway model. Evidence to describe best practice was identified from published literature, clinical guidelines and expert recommendations from practice experience. RESULTS: Availability of national treatment guidelines for OUD related to chronic pain is limited across the Nordics. Important barriers to effective care identified: patients unlikely to present for help, healthcare system set up limits success, diagnosis tools not used, referral pathways unclear and treatment choices not elucidated. Principles include the development of a specific treatment pathway, awareness/ education programs for teams in primary care, guidance on use of diagnostic tools and a flexible treatment plan to encourage best practice in referral, treatment assessment, choice and ongoing management via an integrated care pathway. Healthcare systems and registries in Nordic countries offer an opportunity to further research and identify population risks and solutions. CONCLUSIONS: There is an opportunity to improve outcomes for patients with OUD related to chronic pain by developing and introducing care pathways tailored to specific needs of the population.

Treatment for chronic hepatitis C in a cohort of opiate substitution therapy recipients in three Swedish cities - completion rates and efficacy.

OBJECTIVES: Opiate substitution treatment (OST) programs could provide opportunities for management of comorbidities, such as hepatitis C virus (HCV) infection, in people who inject drugs. We aimed to prospectively evaluate the real-life feasibility of interferon/ribavirin-based HCV treatment in OST recipients, with a special focus on psychiatric status and health-related quality of life. METHODS: Patients from a cohort of OST recipients from three cities in Sweden were selected for HCV treatment on the basis of structured investigation for HCV-related liver disease. Therapy was delivered in collaboration between infectious disease and OST clinics, with monitoring for completion and adherence, treatment response, adverse events, health-related quality of life (HRQoL) (SF-36) and signs of depression (MADRS-S), or relapse into drug abuse. The primary endpoint was completion of prescribed treatment; the secondary endpoints were sustained virological response (SVR), adherence, and incidence of depression. RESULTS: Among 69 patients with an indication for antiviral therapy, 41 initiated treatment; 34/41 (83%) completed treatment and 19/41 (46%) achieved SVR. Adequate adherence was observed in 29/41 patients (71%). Two serious adverse events occurred, including one death because of liver failure. Baseline scores for self-assessed health were low, with a significant reduction during treatment. Seventy-one percent of patients (29/41) fulfilled the criteria for clinically significant depression at some time point during treatment. Baseline scores for HRQoL/MADRS-S were associated with treatment completion, SVR, and depression during treatment. CONCLUSION: Despite the low HRQoL and the high occurrence of depression, HCV treatment was feasible and showed satisfactory rates of completion in this cohort of unselected OST recipients.

Chronic hepatitis C in Swedish subjects receiving opiate substitution therapy--factors associated with advanced fibrosis.

BACKGROUND: Opiate substitution therapy (OST) reduces the risk of death from directly drug-related causes in heroin users, allowing other chronic health problems to emerge. People who inject drugs (PWID) are exposed to hepatitis C virus (HCV), with an associated risk of chronic liver disease. We investigated HCV prevalence and liver-related morbidity in a cohort of OST recipients, and analyzed factors associated with significant hepatic fibrosis. METHODS: All patients registered on 1 April 2008 in 4 clinics providing OST in the 3 largest cities in Sweden were eligible for inclusion. HCV viremic subjects were evaluated for fibrosis stage by liver biopsy, transient elastometry (TE), and/or a biochemical fibrosis index (Göteborg University Cirrhosis Index; GUCI). Factors associated with severity of fibrosis were determined by logistic regression analysis. RESULTS: Out of 524 eligible patients, 277 consented to enrolment. Two hundred and thirty-six subjects (88%) were anti-HCV-positive, and 162 of these were viremic (69%). Significant liver fibrosis (defined as Ishak stages F3-F6, TE value ≥ 8.85 kPa, or GUCI > 0.33) was found in 69 out of 103 (67%) tested viremic patients, and was associated with alcohol intake (p = 0.03), higher body mass index (BMI; p = 0.04), and the presence of anti-HBc antibodies (indicating exposure to hepatitis B virus (HBV); p = 0.02). CONCLUSIONS: Significant liver fibrosis was detected in two-thirds of HCV viremic OST recipients in this cohort, and was associated with alcohol use, high BMI, and exposure to HBV. These findings indicate that the management of HCV and associated risk factors should be emphasized in Swedish OST programs.

Buprenorphine and methadone treatment of opiate dependence during pregnancy: comparison of fetal growth and neonatal outcomes in two consecutive case series.

AIM: To compare the effects of fetal buprenorphine and methadone exposure during maintenance treatment of pregnant heroin dependent subjects. DESIGN AND SETTING: A population based comparison of consecutive, prospectively followed buprenorphine-exposed pregnancies in Stockholm County, Sweden, to retrospectively analyzed consecutive methadone-exposed pregnancies. PARTICIPANTS: All 47 pregnancies in 39 women with opiate dependence and buprenorphine maintenance treatment 2001-2006, and all 35 methadone-exposed pregnancies (26 women) 1982-2006 in Stockholm County. MEASUREMENTS: Intrauterine growth, birth outcome, malformations, neonatal adaptation, withdrawal syndrome and infant mortality. FINDINGS: Buprenorphine-exposed pregnancies resulted in 47 uneventful live births (2 twin pairs), 1 stillbirth (for which no explanation was found) and 1 miscarriage. The birth weight of the infants was normal. Neonatal abstinence syndrome (NAS) occurred in 19 cases (40.4%), the majority mild in nature and only 7 (14.9%) needing withdrawal treatment. Compared to 35 infants born after intrauterine methadone exposure at the same hospital since 1982 (77.8% of them exhibiting NAS and 52.8% needing withdrawal treatment), there were significant advantages with buprenorphine treatment: birth weight was higher, due to longer gestation. Incidence of NAS of any intensity, as well as incidence of NAS that required pharmacological treatment was lower, while length of hospital stay was shorter. When buprenorphine treatment started pre-conception, NAS at any level was significantly less frequent than in subjects with post-conception initiated treatment (7/27, 26%; 12/20, 60%, respectively). CONCLUSIONS: Data from this non-randomized comparison suggest that buprenorphine may offer advantages for treatment of opiate dependence during pregnancy.

Mood and neuroendocrine response to a chemical stressor, metyrapone, in buprenorphine-maintained heroin dependence.

BACKGROUND: Heroin dependence is associated with a hyperactive hypothalamic-pituitary-adrenal (HPA) axis, proposed as a biological correlate of craving. Maintenance treatment with methadone normalizes HPA axis activity. Here, we examined HPA axis activity under maintenance treatment with the increasingly utilized partial opiate agonist buprenorphine. METHODS: Responses to a metyrapone challenge were compared in 20 buprenorphine-maintained heroin addicts and 20 healthy volunteers (10 received a single 50 mg naltrexone dose [NTX+] and 10 received no naltrexone [NTX-]). Patients were 16 male subjects and 4 female subjects, aged 30 to 38 years, heroin-dependent and relapse-free under buprenorphine maintenance (BUP) for a minimum of 6 months. Healthy volunteers were 9 male subjects and 11 female subjects, aged 36 to 49 years, with no history of dependence. Serial measures were obtained of plasma adrenocorticotropic hormone (ACTH) and cortisol and Profile of Mood States (POMS) ratings over time. Subjects were genotyped for the OPRM1 118A/G polymorphism. RESULTS: Buprenorphine maintenance showed a dampened HPA axis response to metyrapone, with OPRM1 118G carriers showing a significantly attenuated response compared with 118A carriers. The response of the NTX+ group was markedly increased. In contrast, negative affect was elevated in the BUP group but did not differ between NTX- and NTX+. Buprenorphine maintenance and NTX- groups did not differ in positive affect, whereas the NTX+ group was lower. CONCLUSIONS: In contrast to exaggerated HPA axis responsiveness reported in untreated heroin dependence, response to metyrapone was subnormal in heroin addicts maintained on buprenorphine. Despite this, increased measures of negative affect were seen in this group. This implies a dissociation of HPA axis responsiveness and affect in heroin dependence.

A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial.

OBJECTIVE: Both methadone and buprenorphine are effective therapy for heroin dependence. Efficacy is best documented for methadone maintenance therapy, but safety concerns limit its use. Buprenorphine offers lower overdose risk and improved access, but efficacy may be lower. The authors compared adaptive, buprenorphine-based stepped care to optimal methadone maintenance treatment. METHOD: This randomized controlled trial was undertaken 2004-2006. It consisted of a 24-day uniform double-blind induction phase followed by single-blind flexible dosing based on structured clinical criteria, for a total of 6 months. Ninety-six self-referred subjects with heroin dependence were randomly assigned to methadone or to stepped treatment initiated with buprenorphine/naloxone and escalated to methadone if needed. All subjects received intensive behavioral treatment. Primary outcome was retention in treatment. Secondary outcomes were completer analyses of problem severity (Addiction Severity Index) and proportion of urine samples free of illicit drugs. RESULTS: Overall, 6-month retention was 78%. Stepped treatment and methadone maintenance therapy outcomes were virtually identical. Among completers of stepped therapy, 46% remained on buprenorphine/naloxone. Proportion of urine samples free of illicit opiates increased over time and ultimately reached approximately 80% in both arms. Problem severity decreased significantly and uniformly in both arms. CONCLUSIONS: A stepped treatment of heroin dependence as described here appears equally efficacious compared to optimally delivered methadone maintenance therapy. Together with prior data on the advantageous safety of buprenorphine, this suggests that broad implementation of strategies using buprenorphine as first-line treatment should be considered.

1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial.

BACKGROUND: The partial opiate-receptor agonist buprenorphine has been suggested for treatment of heroin dependence, but there are few long-term and placebo-controlled studies of its effectiveness. We aimed to assess the 1-year efficacy of buprenorphine in combination with intensive psychosocial therapy for treatment of heroin dependence. METHODS: 40 individuals aged older than 20 years, who met DSM-IV criteria for opiate dependence for at least 1 year, but did not fulfil Swedish legal criteria for methadone maintenance treatment were randomly allocated either to daily buprenorphine (fixed dose 16 mg sublingually for 12 months; supervised daily administration for a least 6 months, possible take-home doses thereafter) or a tapered 6 day regimen of buprenorphine, thereafter followed by placebo. All patients participated in cognitive-behavioural group therapy to prevent relapse, received weekly individual counselling sessions, and submitted thrice weekly supervised urine samples for analysis to detect illicit drug use. Our primary endpoint was 1-year retention in treatment and analysis was by intention to treat. FINDINGS: 1-year retention in treatment was 75% and 0% in the buprenorphine and placebo groups, respectively (p=0.0001; risk ratio 58.7 [95% CI 7.4-467.4]). Urine screens were about 75% negative for illicit opiates, central stimulants, cannabinoids, and benzodiazepines in the patients remaining in treatment. INTERPRETATION: The combination of buprenorphine and intensive psychosocial treatment is safe and highly efficacious, and should be added to the treatment options available for individuals who are dependent on heroin.