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.

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.

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.

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.

Medications development for opioid abuse.

Here we describe methods for preclinical evaluation of candidate medications to treat opioid abuse and dependence. Our perspective is founded on the propositions that (1) drug self-administration procedures provide the most direct method for assessment of medication effects, (2) procedures that assess choice between opioid and nondrug reinforcers are especially useful, and (3) the states of opioid dependence and withdrawal profoundly influence both opioid reinforcement and the effects of candidate medications. Effects of opioid medications 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, and (2) continued development of nonopioids such as inhibitors of endocannabinoid catabolic enzymes or inhibitors of opioid-induced glial activation.

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.

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.

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.

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.

3D-QSAR studies of orvinol analogs as kappa-opioid agonists.

Orvinols are potent analgesics that target opioid receptors. However, their analgesic mechanism remains unclear and no significant preference for subtype opioid receptor has been achieved. In order to find new orvinols that target the kappa-receptor, comparative 3D-QSAR studies were performed on 26 orvinol analogs using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The best predictions for the kappa-receptor were obtained with the CoMFA standard model (q2 = 0.686, r2 = 0.947) and CoMSIA model combined steric, electrostatic, hydrophobic, and hydrogen bond donor/acceptor fields (q2 = 0.678, r2 = 0.914). The models built were further validated by a test set made up of seven compounds, leading to predictive r2 values of 0.672 for CoMFA and 0.593 for CoMSIA. The study could be helpful for designing and prepare new category kappa-agonists from orvinols.

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.

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.

Males and females differ in response to opioid agonist medications.

Few clinical trials include sex as a factor. This analysis explored within-sex differences in response to opioid agonist medications. Males and females randomly assigned to buprenorphine, LAAM, or methadone were compared on opioid use and retention in treatment. Females receiving buprenorphine had less objective drug use than females receiving methadone, while males receiving LAAM had less objective drug use than males receiving buprenorphine. Retention in treatment was longer for both sexes receiving methadone versus LAAM. Within-subject change results indicate that all three medications benefit both sexes. Clinical trials should be designed to examine the impact of sex on outcomes.

Estudio sobre la respuesta de estrés, hemodinámica e inmunológica de dos técnicas anestésicas (inhalatoria e intravenosa) en colecistectomías videolaparoscópicas / Stress, hemodynamic and immunological responses to inhaled and intravenous anesthetic techniques for video-assisted laparoscopic cholecystectomy

OBJETIVO: Dados los efectos inmunomodulatorios de la anestesia y la cirugía, se compararon dos regímenes anestésicos en uso clínico, evaluando la respuesta hemodinámica, de estrés e inmunológica en pacientes de colecistectomía laparoscópica (CVL). PACIENTES Y MÉTODOS: Estudio clínico prospectivo randomizado en pacientes ASA I de CVL electivas. Los pacientes fueron asignados al azar al grupo Inhalatorio (13 pacientes anestesiados con propofol-fentanilo-isoflurano) o al grupo TIVA (14 pacientes, recibieron anestesia con propofol-remifentanilo). Se administró vecuronio en ambos grupos como relajante neuromuscular. La evaluación incluyó variables hemodinámicas, niveles de cortisol, prolactina e interleucina-6, así como recuentos leucocitarios y linfocitarios, que fueron registrados antes de la cirugía, intraoperatorio (1 hora después del comienzo de la anestesia) y en el postoperatorio (24 horas y 7 días). RESULTADOS: En ambos grupos se verificó buen control hemodinámico. En cada grupo, en los diferentes momentos anestésico quirúrgicos se produjeron cambios significativos con respecto a los valores basales en cortisol, prolactina y marcadores de la respuesta inmune-inflamatoria. Los pacientes que recibieron TIVA no modificaron sus niveles de cortisol a lo largo del estudio. Al comparar entre las dos técnicas anestésicas se observó en TIVAmenores niveles de cortisol (207 ± 100 ng/ml), y niveles más altos de neutrófilos (75 ± 12,5%) y linfocitos TCD4 (53 ± 11,6%) que en el grupo inhalatorio: cortisol 293 ± 97 ng/ml, p<0,05; neutrófilos 62 ± 20%, p<0,05 y LTCD4 42 ± 17,6%, p<0,001. CONCLUSIONES: Si bien ambas técnicas brindaron estabilidad hemodinámica, la técnica intravenosa (propofol-remifentanilo) mostró menor respuesta de cortisol y sería de elección en pacientes con compromiso de la respuesta inmunológica

OBJECTIVE: Given the immunomodulatory effects of anesthesia and surgery, 2 anesthetic regimens in clinical use were compared to evaluate hemodynamic, stress, and immunologic response in patients undergoing laparoscopic cholecystectomy. PATIENTS AND METHODS: Randomized controlled trial in patients classified ASA I and scheduled for laparoscopic cholecystectomy. Patients were randomly assigned to the inhaled anesthetic group (13 anesthetized with propofol– fentanyl–isoflurane) or the total intravenous anesthesia (TIVA) group (14 patients anesthetized with propofol– remifentanil). Patients in both groups received the muscle relaxant vecuronium. We assessed hemodynamic variables, cortisol levels, prolactin, interleukin 6, white cell and lymphocyte counts before, during (1 hour after induction) and after (24 hours and 7 days) surgery. RESULTS: Hemodynamic variables were stable in both groups. Significant changes in prolactin levels and markers of immune and inflammatory responses between baseline and later measurements occurred in both groups. Patients who received TIVA had no change in cortisol levels at any time during the study. The TIVA group had lower levels of cortisol than did the inhaled anesthesia group (TIVA, 207 [SD, 100] ng/mL; inhaled 293 [97] ng/mL; P<0.05)), higher neutrophil counts (TIVA, 75 [12.5]%; inhaled: 62 [20]%; P<0.05) and higher CD4+ T lymphocyte counts (TIVA, 53 [11.6]%; inhaled: 42 [17.6]%; P<0.001). CONCLUSION: Although both techniques afford hemodynamic stability, lower cortisol levels were observed with the application of TIVA with propofol–remifentanil. That would be the technique of choice for patients with compromised immune response

Cyclic enkephalin analogs containing various para-substituted phenylalanine derivatives in place of Tyr1 are potent opioid agonists.

The cyclic enkephalin analog H-Tyr-c[D-Cys-Gly-Phe(pNO(2))-D-Cys]NH(2) is a highly potent opioid agonist with IC(50)s of 35 pm and 19 pm in the guinea-pig ileum (GPI) and mouse vas deferens (MVD) assays, respectively. The Phe(1)-analog of this peptide showed 370-fold and 6790-fold lower agonist potency in the GPI and MVD assays, respectively, indicating the importance of the Tyr(1) hydroxyl-group in the interaction with mu and delta opioid receptors. In the present study, the effect of various substituents (-NH(2), -NO(2), -CN, -CH(3), -COOH, -COCH(3), -CONH(2)) introduced in the para-position of the Phe(1)-residue of H-Phe-c[D-Cys-Gly-Phe(pNO(2))-D-Cys]NH(2) on the in vitro opioid activity profile was examined. Most analogs showed enhanced mu and delta agonist potencies in the two bioassays, except for the Phe(pCOOH)(1)-analog, which was weakly active, probably as a consequence of the negative charge. The most potent compounds were the Phe(pCOH(3))(1)- and the Phe(pCONH(2))(1)-analogs. The latter compound showed subnanomolar mu and delta agonist potencies and represents the most potent enkephalin analog lacking the Tyr(1) hydroxyl-group reported to date. Taken together, these results indicate that various substituents introduced in the para-position of Phe(1) enhance opioid activity via hydrogen bonding or hydrophobic interactions with the receptor. Comparison with existing structure-activity relationship on phenolic hydroxyl replacements in morphinans indicates that these nonpeptide opiates and some of the cyclic enkephalin analogs described here may have different modes of binding to the receptor.