Maintenance agonist treatments for opiate-dependent pregnant women.

BACKGROUND: The prevalence of opiate use among pregnant women can range from 1% to 2% to as high as 21%. Just in the United States alone, among pregnant women with hospital delivery, a fourfold increase in opioid use is reported from 1999 to 2014 (Haight 2018). Heroin crosses the placenta, and pregnant, opiate-dependent women experience a six-fold increase in maternal obstetric complications such as low birth weight, toxaemia, third trimester bleeding, malpresentation, puerperal morbidity, fetal distress and meconium aspiration. Neonatal complications include narcotic withdrawal, postnatal growth deficiency, microcephaly, neuro-behavioural problems, increased neonatal mortality and a 74-fold increase in sudden infant death syndrome. This is an updated version of the original Cochrane Review first published in 2008 and last updated in 2013. OBJECTIVES: To assess the effectiveness of any maintenance treatment alone or in combination with a psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions alone for child health status, neonatal mortality, retaining pregnant women in treatment, and reducing the use of substances. SEARCH METHODS: We updated our searches of the following databases to February 2020: the Cochrane Drugs and Alcohol Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and Web of Science. We also searched two trials registers and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA: Randomised controlled trials which assessed the efficacy of any pharmacological maintenance treatment for opiate-dependent pregnant women. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: We found four trials with 271 pregnant women. Three compared methadone with buprenorphine and one methadone with oral slow-release morphine. Three out of four studies had adequate allocation concealment and were double-blind. The major flaw in the included studies was attrition bias: three out of four had a high dropout rate (30% to 40%), and this was unbalanced between groups. Methadone versus buprenorphine: There was probably no evidence of a difference in the dropout rate from treatment (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.37 to 1.20, three studies, 223 participants, moderate-quality evidence). There may be no evidence of a difference in the use of primary substances between methadone and buprenorphine (RR 1.81, 95% CI 0.70 to 4.68, two studies, 151 participants, low-quality evidence). Birth weight may be higher in the buprenorphine group in the two trials that reported data MD;-530.00 g, 95%CI -662.78 to -397.22 (one study, 19 particpants) and MD: -215.00 g, 95%CI -238.93 to -191.07 (one study, 131 participants) although the results could not be pooled due to very high heterogeneity (very low-quality of evidence). The third study reported that there was no evidence of a difference. We found there may be no evidence of a difference in the APGAR score (MD: 0.00, 95% CI -0.03 to 0.03, two studies,163 participants, low-quality evidence). Many measures were used in the studies to assess neonatal abstinence syndrome. The number of newborns treated for neonatal abstinence syndrome, which is the most critical outcome, may not differ between groups (RR 1.19, 95% CI 0.87 to1.63, three studies, 166 participants, low-quality evidence). Only one study which compared methadone with buprenorphine reported side effects. We found there may be no evidence of a difference in the number of mothers with serious adverse events (AEs) (RR 1.69, 95% CI 0.75 to 3.83, 175 participants, low-quality evidence) and we found there may be no difference in the numbers of newborns with serious AEs (RR 4.77, 95% CI 0.59, 38.49,131 participants, low-quality evidence). Methadone versus slow-release morphine: There were no dropouts in either treatment group. Oral slow-release morphine may be superior to methadone for abstinence from heroin use during pregnancy (RR 2.40, 95% CI 1.00 to 5.77, one study, 48 participants, low-quality evidence). In the comparison between methadone and slow-release morphine, no side effects were reported for the mother. In contrast, one child in the methadone group had central apnoea, and one child in the morphine group had obstructive apnoea (low-quality evidence). AUTHORS' CONCLUSIONS: Methadone and buprenorphine may be similar in efficacy and safety for the treatment of opioid-dependent pregnant women and their babies. There is not enough evidence to make conclusions for the comparison between methadone and slow-release morphine. Overall, the body of evidence is too small to make firm conclusions about the equivalence of the treatments compared. There is still a need for randomised controlled trials of adequate sample size comparing different maintenance treatments.

The role of the opioid system in decision making and cognitive control: A review.

The opioid system regulates affective processing, including pain, pleasure, and reward. Restricting the role of this system to hedonic modulation may be an underestimation, however. Opioid receptors are distributed widely in the human brain, including the more "cognitive" regions in the frontal and parietal lobes. Nonhuman animal research points to opioid modulation of cognitive and decision-making processes. We review emerging evidence on whether acute opioid drug modulation in healthy humans can influence cognitive function, such as how we choose between actions of different values and how we control our behavior in the face of distracting information. Specifically, we review studies employing opioid agonists or antagonists together with experimental paradigms of reward-based decision making, impulsivity, executive functioning, attention, inhibition, and effort. Although this field is still in its infancy, the emerging picture suggests that the mu-opioid system can influence higher-level cognitive function via modulation of valuation, motivation, and control circuits dense in mu-opioid receptors, including orbitofrontal cortex, basal ganglia, amygdalae, anterior cingulate cortex, and prefrontal cortex. The framework that we put forward proposes that opioids influence decision making and cognitive control by increasing the subjective value of reward and reducing aversive arousal. We highlight potential mechanisms that might underlie the effects of mu-opioid signaling on decision making and cognitive control and provide directions for future research.

Maintenance agonist treatments for opiate-dependent pregnant women.

BACKGROUND: The prevalence of opiate use among pregnant women can range from 1% to 2% to as high as 21%. Heroin crosses the placenta and pregnant, opiate-dependent women experience a six-fold increase in maternal obstetric complications such as low birth weight, toxaemia, third trimester bleeding, malpresentation, puerperal morbidity, fetal distress and meconium aspiration. Neonatal complications include narcotic withdrawal, postnatal growth deficiency, microcephaly, neuro-behavioural problems, increased neonatal mortality and a 74-fold increase in sudden infant death syndrome. OBJECTIVES: To assess the effectiveness of any maintenance treatment alone or in combination with psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions for child health status, neonatal mortality, retaining pregnant women in treatment and reducing the use of substances. SEARCH METHODS: We searched the Cochrane Drugs and Alcohol Group Trials Register (September 2013), PubMed (1966 to September 2013), CINAHL (1982 to September 2013), reference lists of relevant papers, sources of ongoing trials, conference proceedings and national focal points for drug research. We contacted authors of included studies and experts in the field. SELECTION CRITERIA: Randomised controlled trials assessing the efficacy of any maintenance pharmacological treatment for opiate-dependent pregnant women. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We found four trials with 271 pregnant women. Three compared methadone with buprenorphine and one methadone with oral slow-release morphine. Three out of four studies had adequate allocation concealment and were double-blind. The major flaw in the included studies was attrition bias: three out of four had a high drop-out rate (30% to 40%) and this was unbalanced between groups.Methadone versus buprenorphine: the drop-out rate from treatment was lower in the methadone group (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.41 to 1.01, three studies, 223 participants). There was no statistically significant difference in the use of primary substance between methadone and buprenorphine (RR 1.81, 95% CI 0.70 to 4.69, two studies, 151 participants). For both, we judged the quality of evidence as low. Birth weight was higher in the buprenorphine group in the two trials that could be pooled (mean difference (MD) -365.45 g (95% CI -673.84 to -57.07), two studies, 150 participants). The third study reported that there was no statistically significant difference. For APGAR score neither of the studies which compared methadone with buprenorphine found a significant difference. For both, we judged the quality of evidence as low. Many measures were used in the studies to assess neonatal abstinence syndrome. The number of newborns treated for neonatal abstinence syndrome, which is the most critical outcome, did not differ significantly between groups. We judged the quality of evidence as very low.Methadone versus slow-release morphine: there was no drop-out in either treatment group. Oral slow-release morphine seemed superior to methadone for abstinence from heroin use during pregnancy (RR 2.40, 95% CI 1.00 to 5.77, one study, 48 participants). We judged the quality of evidence as moderate.Only one study which compared methadone with buprenorphine reported side effects. For the mother there was no statistically significant difference; for the newborns in the buprenorphine group there were significantly fewer serious side effects.In the comparison between methadone and slow-release morphine no side effects were reported for the mother, whereas one child in the methadone group had central apnoea and one child in the morphine group had obstructive apnoea. AUTHORS' CONCLUSIONS: We did not find sufficient significant differences between methadone and buprenorphine or slow-release morphineto allow us to conclude that one treatment is superior to another for all relevant outcomes. While methadone seems superior in terms of retaining patients in treatment, buprenorphine seems to lead to less severe neonatal abstinence syndrome. Additionally, even though a multi-centre, international trial with 175 pregnant women has recently been completed and its results published and included in this review, the body of evidence is still too small to draw firm conclusions about the equivalence of the treatments compared. There is still a need for randomised controlled trials of adequate sample size comparing different maintenance treatments.

Can Treatment for Substance Use Disorder Prescribe the same Substance as that Used? The Case of Injectable Opioid Agonist Treatment.

This article examines injectable Opioid Agonist Treatment (iOAT), in which patients suffering from long-term, treatment refractory opioid use disorder (OUD) are prescribed injectable diacetylmorphine, the active ingredient of heroin. While iOAT is part of the continuum of care for OUD in some European countries and in some parts of Canada, it is not an available treatment in the United States. We suggest that one reason for this situation is the belief that a genuine treatment for substance use disorder cannot prescribe the same substance as that used. We examine possible rationales for this belief by considering four combinations of views on the constitutive causal basis of substance use disorders and the definition of effective treatment. We show that all but one combination counts iOAT as a genuine treatment and that there are good reasons to reject the one that does not. Specifically, we claim that medical interventions, such as iOAT, that significantly reduce the severity of a disorder deserve to be categorized as effective treatments and regarded as such in practice.

Medications Development for Treatment of Opioid Use Disorder.

This review describes methods for preclinical evaluation of candidate medications to treat opioid use disorder (OUD). The review is founded on the propositions that (1) drug self-administration procedures provide the most direct method for assessment of medication effectiveness, (2) procedures that assess choice between opioid and nondrug reinforcers are especially useful, and (3) states of opioid dependence and withdrawal profoundly influence both opioid reinforcement and effects of candidate medications. Effects of opioid medications and vaccines on opioid choice in nondependent and opioid-dependent subjects are reviewed. Various nonopioid medications have also been examined, but none yet have been identified that safely and reliably reduce opioid choice. Future research will focus on (1) strategies for increasing safety and/or effectiveness of opioid medications (e.g., G-protein-biased µ-opioid agonists), and (2) continued development of nonopioid medications (e.g., clonidine) that might serve as adjunctive agents to current opioid medications.

Pharmacological treatment for depression during opioid agonist treatment for opioid dependence.

BACKGROUND: Lifetime prevalence of depression in subjects with opioid dependence is higher than in the general population (44-54% versus 16%) and represents a risk factor for morbidity and mortality. For patients on opioid agonist treatment, current prevalence rates of depression ranges between 10 and 30%, influencing negatively the outcome of the treatment. OBJECTIVES: To evaluate the efficacy and the acceptability of antidepressants for the treatment of depressed opioid dependents treated with opioid agonists. SEARCH STRATEGY: We searched Pubmed, EMBASE, CINAHL (to October 2009), CENTRAL (The Cochrane Library Cochrane Drug and Alcohol Group Specialised Register, issue 4, 2009), main electronic sources of ongoing trials, specific trial databases and reference lists of all relevant papers. SELECTION CRITERIA: Randomised and controlled clinical trials examining the efficacy of any antidepressant medication to treat depressed opioid dependents in treatment with opioid agonists. DATA COLLECTION AND ANALYSIS: Two authors independently screened and extracted data from studies. MAIN RESULTS: Seven studies, 482 participants, met the inclusion criteria.- Comparing antidepressant with placebo, no statistically significant results for dropouts. Selecting studies with low risk of bias, 325 participants, results favour placebo, RR 1.40 (Cl 95% 1.00 to 1.96). For severity of depression, results from two studies, 183 participants, favour antidepressants utilising Clinical Global Impression Scale RR 1.92 (CI 95% 1.26 to 2.94), while another study, 95 participants, utilising the Hamilton Depression Rating Scale, did not find a statistically significant difference RR 0.96 (CI 95% 0.54 to 1.71). For adverse events, result favour placebo, four studies, 311 participants, RR 2.90 (Cl 95% 1.23 to 6.86). For drug use, three studies, 211 participants, it was not possible to pool data because outcomes' measures were not comparable. Looking at singular studies, no statistically significant difference was seen.- Comparing different classes of antidepressants, the results favour tricyclics for severity of depression, two studies, 183 participants, RR 1.92 (Cl 95% 1.26 to 2.94) and favour placebo for adverse events, two studies, 172 participants, RR 3.11 (Cl 95% 1.06 to 9.12). AUTHORS' CONCLUSIONS: There is low evidence, at the present, supporting the clinical use of antidepressants for the treatment of depressed opioid addicts in treatment with opioid agonists. There is a need of larger randomised studies investigating relevant outcomes, safety issues and reporting data to allow comparison of results.

Maintenance agonist treatments for opiate dependent pregnant women.

BACKGROUND: The prevalence of opiate use among pregnant women ranges from 1% to 2% to as much as 21%. Heroin crosses the placenta and pregnant opiate dependent women experience a six fold increase in maternal obstetric complications such as low birth weight, toxaemia, 3rd trimester bleeding, malpresentation, puerperal morbidity, fetal distress and meconium aspiration. Neonatal complications include narcotic withdrawal, postnatal growth deficiency, microcephaly, neurobehavioral problems, increased neonatal mortality and a 74-fold increase in sudden infant death syndrome. OBJECTIVES: To assess the effectiveness of any maintenance treatment alone or in combination with psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions on child health status, neonatal mortality, retaining pregnant women in treatment, and reducing use of substances SEARCH STRATEGY: We searched Cochrane Drugs and Alcohol Group' Register of Trials (June 2007), PubMed (1966 - June 2007), CINAHL (1982- June 2007), reference lists of relevant papers, sources of ongoing trials, conference proceedings, National focal points for drug research. Authors of included studies and experts in the field were contacted. SELECTION CRITERIA: Randomised controlled trials enrolling opiate dependent pregnant women DATA COLLECTION AND ANALYSIS: The authors assessed independently the studies for inclusion and methodological quality. Doubts were solved by discussion. MAIN RESULTS: We found three trials with 96 pregnant women. Two compared methadone with buprenorphine and one methadone with oral slow morphine. For the women there was no difference in drop out rate RR 1.00 (95% CI 0.41 to 2.44) and use of primary substance RR 2.50 (95% CI 0.11 to 54.87) between methadone and buprenorphine, whereas oral slow morphine seemed superior to methadone in abstaining women from the use of heroin RR 2.40 (95% CI 1.00 to 5.77)For the newborns in one trial buprenorphine performed better than methadone for birth weight WMD -530 gr (95% CI -662 to -397), this result is not confirmed in the other trial. For the APGAR score both studies didn't find significant difference . No differences for NAS measures used. Comparing methadone with oral slow morphine no differences for birth weight and mean duration of NAS. The APGAR score wasn't considered. AUTHORS' CONCLUSIONS: We didn't find any significant difference between the drugs compared both for mother and for child outcomes; the trials retrieved were too few and the sample size too small to make firm conclusion about the superiority of one treatment over another. There is an urgent need of big randomized controlled trials.

Methadone: dental risks and preventive action.

UNLABELLED: For some time dentists have successfully promoted the benefits of sugar-free medications. There are now over 180 sugar-free medicines manufactured and prescribed. Methadone, used in the rehabilitation of drug-users, is available as a sugar-free preparation; however, the sugar-based version is most often used. This article examines the content of methadone, explains some of the reasons for prescribing patterns and explores how a multi-disciplinary approach can be used to help methadone users with their rehabilitation and minimize risks to oral health. The wider public health and health policy implications of methadone use are discussed and the available literature reviewed. CLINICAL RELEVANCE: Dentists are most likely to encounter patients on methadone as a dental emergency and they need to be aware that methadone users are at greater risk of decay and erosion from methadone sugar syrup, as well as perhaps their lifestyle. For dental practitioners, addressing the oral health needs of methadone users can contribute to their general well-being.

Using nominal group technique among clinical providers to identify barriers and prioritize solutions to scaling up opioid agonist therapies in Ukraine.

BACKGROUND: Opioid agonist therapies (OAT) like methadone and buprenorphine maintenance treatment remain markedly under-scaled in Ukraine despite adequate funding. Clinicians and administrators were assembled as part of an implementation science strategy to scale-up OAT using the Network for Improvement of Addiction Treatment (NIATx) approach. METHODS: Nominal Group Technique (NGT), a key ingredient of the NIATx toolkit, was directed by three trained coaches within a learning collaborative of 18 OAT clinicians and administrators to identify barriers to increase OAT capacity at the regional "oblast" level, develop solutions, and prioritize local change projects. NGT findings were supplemented from detailed notes collected during the NGT discussion. RESULTS: The top three identified barriers included: (1) Strict regulations and inflexible policies dictating distribution and dispensing of OAT; (2) No systematic approach to assessing OAT needs on regional or local level; and (3) Limited funding and financing mechanisms combined with a lack of local/regional control over funding for OAT treatment services. CONCLUSIONS: NGT provides a rapid strategy for individuals at multiple levels to work collaboratively to identify and address structural barriers to OAT scale-up. This technique creates a transparent process to address and prioritize complex issues. Targeting these priorities allowed leaders at the regional and national level to advocate collectively for approaches to minimize obstacles and create policies to improve OAT services.

Lessons learned about implementing research evidence into clinical practice. Experiences from VA QUERI.

The mission of the Veterans Health Administration's (VHA) quality enhancement research initiative (QUERI) is to enhance the quality of VHA health care by implementing clinical research findings into routine care. This paper presents lessons that QUERI investigators have learned through their initial attempts to pursue the QUERI mission. The lessons in this paper represent those that were common across multiple QUERI projects and were mutually agreed on as having substantial impact on the success of implementation. While the lessons are consistent with commonly recognized ingredients of successful implementation efforts, the examples highlight the fact that, even with a thorough knowledge of the literature and thoughtful planning, unexpected circumstances arise during implementation efforts that require flexibility and adaptability. The findings stress the importance of utilizing formative evaluation techniques to identify barriers to successful implementation and strategies to address these barriers.

Predictors of retention in methadone programs: a signal detection analysis.

Retention in Opioid Agonist Therapy (OAT) is associated with reductions in substance use, HIV risk behavior, and criminal activities in opioid dependent patients. To improve the effectiveness of treatment for opioid dependence, it is important to identify predisposing characteristics and provider-related variables that predict retention in OAT. Participants include 258 veterans enrolled in 8 outpatient methadone/l-alpha-acetylmethadol (LAAM) treatment programs. Signal detection analysis was utilized to identify variables predictive of 1-year retention and to identify the optimal cut-offs for significant predictors. Provider-related variables play a vital role in predicting retention in OAT programs, as higher methadone dose (> or =59 mg/day) and greater treatment satisfaction were among the strongest predictors of retention at 1-year follow-up.

mu-Opioid receptors: Ligand-dependent activation of potassium conductance, desensitization, and internalization.

micro-Opioid receptor (MOR) desensitization and endocytosis have been implicated in tolerance and dependence to opioids. The efficiency of each process is known to be agonist dependent; however, it is not known what determines the relative efficiency of various agonists at either process. In the present study, homologous MOR desensitization in locus ceruleus (LC) neurons and MOR internalization in HEK293 cells were examined using a series of agonists. The results show that the rank order of this series of agonists was different when comparing the magnitude of hyperpolarization and the ability to cause desensitization in LC neurons. Endocytosis of MOR was also examined in HEK293 cells using the same agonists. The relative ability to cause endocytosis in HEK293 cells correlated with the degree of desensitization in LC cells. This strong correlation suggests that the two processes are closely linked. The results also suggest that agonist efficacy is not necessarily a predictor of the ability to cause MOR desensitization or endocytosis. Identification and characterization of the biophysical properties of agonists that favor desensitization and internalization of receptors will lead to a better understanding of opioid signaling.

Opioids are non-competitive inhibitors of nitric oxide synthase in T47D human breast cancer cells.

Opioids and nitric oxide (NO) interact functionally in different systems. NO-generating agents decrease the activity of opioid agonists, prevent opioid tolerance, and are used in opioid withdrawal syndromes. There exist, however, few reports indicating a direct interaction of the two systems. T47D human breast cancer cells in culture express opioid receptors, and opioid agonists inhibit their growth, while they release high amounts of the NO-related molecules NO(2-)/NO(3-)to the culture medium. We have used this system to assay a possible direct interaction of opiergic and nitric oxide systems. Our results show that delta- or mu-acting opioid agonists do not modify the release of NO(2-)/NO(3-). In contrast, kappa-acting opioid agonists (ethylketocyclazocine, and alpha(S1)-casomorphine) decrease the release of NO(2-)/NO(3-), in a time- and dose-dependent manner. The general opioid antagonist diprenorphine (10(-6) M) produce a similar NO(2-)/NO(3-)release inhibition, indicating a possible non-opioid-receptor mediated phenomenon. In addition, ethylketocyclazocine, alpha(S1)-casomorphin and diprenorphine directly inhibit NOS activity: agonists, interact with both calcium-dependent and independent NOS-isoforms, while the antagonist diprenorphine modifies only the activity of the calcium-dependent fraction of the enzyme. Analysis of this interaction revealed that opioids modify the dimeric active form of NOS, through binding to the reductase part of the molecule, acting as non-competitive inhibitors of the enzyme. This interaction opens interesting new possibilities for tumor biology and breast cancer therapy.

Rational treatment of addiction.

Treatment of alcohol and drug addictions, which has been neglected medically for a long time, is currently sparked with optimism. Craving for alcohol can be treated with two newly registered drugs: naltrexone and acamprosate. New approaches to symptom relief during detoxification or during maintenance therapies are rationally based on experimental and clinical work. It is now clear that addictive drugs are surrogates of natural substances involved in the 'reward system'.

Buprenorphine retention in primary care.

BACKGROUND: This study assesses the rate and predictors of treatment retention for primary care patients with opioid dependence-prescribed buprenorphine, a long-acting partial opioid agonist. METHODS: Observational cohort study of patients prescribed buprenorphine/naloxone and followed for 6 months in the period after the adoption of buprenophine/naloxone by a primary care practice in Rhode Island. Practice policy precluded patient discharges due to continuing drug use. RESULTS: Patients (n=41) had a mean duration of opioid use of 15.7 years and most had a history of heroin use (63.4%). Thirty-nine percent of patients transferred from methadone maintenance. At 24 weeks, 59% remained in treatment. Nearly half of dropouts occurred in the first 30 days. Participants with opiate-positive toxicologies at week 1 were more likely to drop out of the program (P<.01) and had a significantly shorter retention time (P<.01) on average. Among other drug use and drug treatment variables, employment and addiction counseling during treatment were significantly associated with treatment retention (P=.03). CONCLUSION: Retention rates in a real world, primary care-based buprenorphine maintenance practice reflect those reported in clinical trials. Abstinence during the first week of treatment and receipt of counseling were critical to patient retention.

Decreasing international HIV transmission: the role of expanding access to opioid agonist therapies for injection drug users.

AIMS: To examine the role of expanded access to opioid agonist treatment as a means to decrease international HIV transmission. DESIGN: Review of the English language literature via Medline. MEASUREMENTS: Estimates of prevalence rates for injection drug use, HIV infection and treatment effect sizes for changes in opioid use, opioid injection, needle-sharing, injection-related HIV risk behavior and cost. FINDINGS: An estimated 12.6 million injection drug users internationally accounted for 10% of the 4.2 million new HIV infections in 2003. Ninety-three of the 136 countries (68%) that report injection drug use identify HIV infection related to this behavior. Observational studies of methadone treatment demonstrate decreases in opioid use, opioid injection, needle-sharing and lower rates of HIV prevalence and incidence. The effectiveness of buprenorphine in demonstrating similar findings is expected, although implementations and research are still emerging. The cost-effectiveness of opioid agonist treatment has been established. The barriers to international adoption of opioid agonist treatment, despite the research evidence and international guidelines, are discussed. CONCLUSIONS: Untreated opioid dependence leads to HIV transmission, on an international level. Opioid agonist treatments are associated with reductions in the frequency of opioid use, fewer injections and injection-related HIV risk behaviors and lower rates of HIV prevalence and incidence. Despite international recommendations, treatment for opioid-dependent injection drug users with methadone and buprenorphine is limited. Research, implementation efforts and political strategies to expand access to opioid agonist treatment are needed in order to combat the spread of HIV, especially in the developing world.

New federal initiatives to enhance the medical treatment of opioid dependence.

Opioid dependence is a chronic relapsing medical condition with substantial health and societal complications. Recent federal initiatives are designed to enhance the medical treatment of patients with opioid dependence and will expand the role of internists in the care of these patients. These initiatives include a process for federal exemptions to allow for pharmacologic treatment in office settings, waivers for the use of new medications, and new rules governing the oversight and distribution of opioid agonist medications for maintenance treatment. This perspective describes these initiatives and their implications for internists.

Agonist regulation of the expression of the delta opioid receptor in NG108-15 cells.

Exposure of neuronal cells to the chronic presence of opiates leads to a complex series of biochemical events which reflect the changes that result in tolerance and dependence in animals. To achieve a better understanding of the molecular mechanisms underlying these processes, we have examined the effect of agonist efficacy on the regulation of the delta-opioid receptor mRNA in NG108-15 cells. Incubation with various opiates decreased receptor numbers in the order of their efficacy. Northern blot analysis showed that there are 4 size classes of mRNA coding for the delta-opioid receptor in NG108-15 cells even though only one known protein species is found. Moreover, the amount of each transcript is coordinately decreased by long-term etorphine treatment, but not necessarily to the same extent. The etorphine-induced decrease in receptor mRNA was found to be slow in onset, whereas a much more rapid loss of receptor number was observed. This disparity suggests that the down-regulation induced by etorphine can occur both at the levels of receptor protein modification and receptor gene expression, and that the mechanisms of the two processes may be different.

Cholecystokinin antagonists a new way to improve the analgesia from old analgesics?

Cholecystokinin, originally thought to be confined only to the gastrointestinal tract, is now known to be co-localised in both the gastrointestinal tract and central nervous system. In animal models levels are increased after neural injury and with opioid administration. This peptide acts as an anti-opioid, and as levels increase, the extent of opioid derived antinociception decreases. Co-administration of a CCK antagonist along with an opioid is associated with an improved level of antinociception. Furthermore CCK antagonists may prevent antinociceptive tolerance with opioids and even reverse established tolerance. Human studies have now confirmed the pro-analgesic effect of some CCK antagonists. Human investigation of the effect of CCK antagonists on analgesic tolerance has yet to be performed. This review examines the available evidence that suggests a role for CCK antagonists in human pain management.