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The article discusses the challenges and opportunities related to contemporary opioid use. New techniques in drug delivery have augmented traditional routes of opioids administration to enhance patients' relief of pain. It is considered that the most worrisome opioid adverse effect has been respiratory depression. The challenges and opportunities associated with opioid use have led in the introduction of new drugs and techniques for established indications.

Abstract: Background: Methadone plasma concentrations are decreased by nelfinavir. Methadone clearance and the drug interactions have been attributed to CYP3A4, but actual mechanisms of methadone clearance and the nelfinavir interaction are unknown. We assessed nelfinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A4/5 activity, and intestinal P-glycoprotein transport activity. CYP3A4/5 and transporters were assessed using alfentanil and fexofenadine, respectively. Methods: Twelve healthy HIV-negative volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral methadone. This was repeated after nelfinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by pupil diameter change (miosis). Results: Nelfinavir decreased intravenous and oral methadone plasma concentrations 40–50%. Systemic clearance, hepatic clearance, and hepatic extraction all increased 1.6- and 2-fold, respectively, for R- and S-methadone; apparent oral clearance increased 1.7- and 1.9-fold. Nelfinavir stereoselectively increased (S>R) methadone metabolism and metabolite formation clearance, and methadone renal clearance. Methadone bioavailability and P-glycoprotein activity were minimally affected. Nelfinavir decreased alfentanil systemic and apparent oral clearances 50 and 76%, respectively. Nelfinavir appeared to shift the methadone plasma concentration–effect (miosis) curve leftward and upward. Conclusions: Nelfinavir induced methadone clearance by increasing renal clearance, and more so by stereoselectively increasing hepatic metabolism, extraction and clearance. Induction occurred despite 50% inhibition of hepatic CYP3A4/5 activity and more than 75% inhibition of first-pass CYP3A4/5 activity, suggesting little or no role for CYP3A in clinical methadone disposition. Nelfinavir may alter methadone pharmacodynamics, increasing clinical effects. [Copyright &y& Elsevier]

The author reflects on mutations in a molecule and the virtues of antagonism in clinical trials. He notes that drug development evolved through eras of natural product use, serendipitous discovery, national drug design and drug discovery. He found the discovery and development stories of methyl-naltrexone and alvimopan fascinating and provide an interesting perspective on modern drug development.

Morphine and hydromorphone have differing onsets, magnitudes, and durations of effects and side-effects. Differences between opioids in their interindividual variabilities in pharmacokinetics and pharmacodynamics might influence rational drug selection. Crossover drug studies can provide more informative interindividual variability data than parallel group studies. Using data from a crossover study of i.v. morphine and hydromorphone in healthy volunteers, we tested the hypothesis that morphine and hydromorphone differ in their interindividual pharmacokinetic variability. Arterial opioid and metabolite concentrations from a randomised crossover study in 51 volunteers receiving a 2-h infusion of hydromorphone (0.05 or 0.1 mg kg−1 i.v.) or morphine (total 0.1 or 0.2 mg kg−1 i.v.) 1–2 weeks apart were evaluated with a three-compartmental model for parent opioid and incorporating glucuronides using population modelling (NONMEM). The primary outcome was interindividual variability in pharmacokinetics, based on the coefficient of variation (%CV) of individual model parameters, calculated as √[exp(ω2)–1]×100 where ω2 is the interindividual variability. Data were analysed per drug and in a combined morphine–hydromorphone model. Both analyses indicate that interindividual variabilities for hydromorphone and morphine were comparable with %CV ranging from 9% to 31% for structural model parameters (combined analysis). Similarly, additive and relative residual errors had comparable variabilities, 20–40% and 72–87%, respectively, for morphine and hydromorphone (combined analysis). Morphine and hydromorphone did not differ in a statistically significant or clinically meaningful manner in their interindividual pharmacokinetic variability. Interindividual pharmacokinetic variability does not appear a meaningful consideration in the choice between these two opioids. [ABSTRACT FROM AUTHOR]

Much of the burden of depressive illness is due to relapses that occur after treatment into remission. Prediction of an individual's imminent depressive relapse could lead to just-in-time interventions to prevent relapse, reducing depression's substantial burden of disability, costs, and suicide risk. Increasingly strong relationships in the form of autocorrelations between depressive symptoms, a signal of a phenomenon described as critical slowing down (CSD), have been proposed as a means of predicting relapse. In the current study, four participants in remission from depression, one of whom relapsed, responded to daily smartphone surveys with depression symptoms. We used p-technique factor analysis to identify depression factors from over 100 survey responses. We then tested for the presence of CSD using time-varying vector autoregression and detrended fluctuation analysis. We found evidence that CSD provided an early warning sign for depression in the participant who relapsed, but we also detected false positive indications of CSD in participants who did not relapse. Results from time-varying vector autoregression and detrended fluctuation analysis were not in agreement. Limitations include use of secondary data and a small number of participants with daily responding to a subset of depression symptoms. CSD provides a compelling framework for predicting depressive relapse and future research should focus on improving detection of early warning signs reliably. Improving early detection methods for depression is clinically significant, as it would allow for the development of just-in-time interventions. • High relapse rates even after successful treatment increase burden of depression. • Critical slowing down (CSD) is a phenomenon that may precede relapse. • We evaluated evidence for CSD in one patient who relapsed and three who did not. • We found evidence for CSD in patient who relapsed but false positives in others. • Implications for future research on CSD in depression are discussed. [ABSTRACT FROM AUTHOR]

Opioid administration to patients with obstructive sleep apnoea (OSA) is controversial because they are believed to be more sensitive to opioids. However, objective data on opioid effects in OSA are lacking. We tested the hypothesis that subjects with untreated OSA have increased sensitivity to opioids compared with subjects without OSA, or with OSA treated with continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BIPAP). This was a single-centre, prospective cohort study in subjects without OSA (n =20), with untreated OSA (n =33), or with treated OSA (n =21). OSA diagnosis was verified using type III (in-home) polysomnography. Subjects received a stepped-dose remifentanil infusion (target effect-site concentrations of 0.5, 1, 2, 3, 4 ng ml−1). Primary outcome was miosis (pupil area fractional change), the most sensitive opioid effect. Secondary outcomes were ventilatory rate, end-expired CO 2 , sedation, and thermal analgesia. There were no differences in miosis between untreated OSA subjects (mean=0.51, 95% confidence interval [CI] 0.41–0.61) and subjects without OSA (mean=0.49, 95% CI 0.36–0.62) (mean difference=0.02, 95% CI −0.18 to 0.22); between treated OSA subjects (mean=0.56, 95% CI 0.43–0.68) and subjects without OSA (difference=0.07, 95% CI −0.16 to 0.29); or between untreated OSA and treated OSA (difference=−0.05, 95% CI −0.25 to 0.16). There were no significant differences between subjects without OSA, untreated OSA, and treated OSA in ventilatory rate, end-expired CO 2 , sedation, or thermal analgesia responses to remifentanil. There was no relationship between OSA severity and magnitude of opioid effects. Neither obstructive sleep apnoea nor obstructive sleep apnoea treatment affected sensitivity to the miotic, sedative, analgesic, or respiratory depressant effects of the opioid remifentanil in awake adults. These results challenge conventional notions of opioid effects in obstructive sleep apnoea. NCT02898792 (clinicaltrials.gov). [ABSTRACT FROM AUTHOR]

Breast cancer is the most frequent type of cancer and the second leading cause of cancer-related mortality in women. Mastectomies remain a key component of the treatment of non-metastatic breast cancer, and strategies to treat acute postoperative pain, a complication affecting nearly all patients undergoing surgery, continues to be an important clinical challenge. This study aimed to determine the impact of intraoperative methadone administration compared to conventional short-acting opioids on pain-related perioperative outcomes in women undergoing a mastectomy. This single-center retrospective study included adult women undergoing total mastectomy. The primary outcome of this study was postoperative pain intensity on day 1 after surgery. Secondary outcomes included perioperative opioid consumption, perioperative non-opioid analgesics use, duration of surgery and anesthesia, time to extubation, pain intensity in the postanesthesia care unit (PACU), anti-emetic use in PACU, and length of stay in hospital. We used the propensity score-based nearest matching with a 1:3 ratio to balance the patient baseline characteristics. 133 patients received methadone, and 2192 patients were treated with short-acting opioids. The analysis demonstrated that methadone was associated with significantly lower intraoperative and postoperative opioid consumption as measured by oral morphine equivalents and lower average pain intensity scores in the postanesthesia care unit. Moreover, methadone was also shown to reduce the use of non-opioid analgesia during surgery. Our study suggests that the unique pharmacological properties of methadone, including a short onset of action when given intravenously, long-acting pharmacokinetics, and multimodal effects, are associated with better acute pain management after a total mastectomy. • Methadone was associated with significantly less perioperative opioid consumption than short-acting opioids. • Methadone was associated with less use of non-opioid analgesia. • Methadone was associated with lower average pain intensity scores. [ABSTRACT FROM AUTHOR]

Abstract: A fast, sensitive and selective liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the determination of alfentanil and midazolam in human plasma has been developed and validated. Alfentanil and midazolam were extracted from plasma using a mixed-mode cation exchange solid phase extraction method, with recoveries of both compounds greater than 80% at 3 different concentrations (1, 10 and 100ng/ml). Compounds were analyzed on a C18 column with a water and methanol mobile phase gradient with acetic acid as an additive, at a flow rate of 0.3ml/min. The working assay range was linear from 0.25 to 100ng/ml for each compound. The signal to noise ratio was 80 and 40 for alfentanil and midazolam, respectively, at the lowest concentration calibration standard, with less than 10% matrix suppression by human plasma at this concentration. Alfentanil and midazolam were stable in human plasma during storage at −80°C, processing, and analysis. The procedure was validated and applied to the analysis of plasma samples from healthy human subjects administered oral and intravenous alfentanil and midazolam. [Copyright &y& Elsevier]

Drug interactions involving methadone and/or HIV antiretrovirals can be problematic. Mechanisms whereby antiretrovirals induce clinical methadone clearance are poorly understood. Methadone is N -demethylated to 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) by CYP2B6 and CYP3A4 in vitro , but by CYP2B6 in vivo. This investigation evaluated human hepatocytes as a model for methadone induction, and tested the hypothesis that methadone and EDDP are substrates for human drug transporters. Human hepatocyte induction by several antiretrovirals of methadone N -demethylation, and CYP2B6 and CYP3A4 transcription, protein expression and catalytic activity, and pregnane X receptor (PXR) activation were evaluated. Methadone and EDDP uptake and efflux by overexpressed transporters were also determined. Methadone N -demethylation was generally not significantly increased by the antiretrovirals. CYP2B6 mRNA and activity (bupropion N -demethylation) were induced by several antiretrovirals, as were CYP3A4 mRNA and protein expression, but only indinavir increased CYP3A activity (alfentanil dealkylation). CYP upregulation appeared related to PXR activation. Methadone was not a substrate for uptake (OCT1, OCT2, OCT3, OATP1A2, OATP1B1, OATP1B3, OATP2B1) or efflux (P-gp, BCRP) transporters. EDDP was a good substrate for P-gp, BCRP, OCT1, OCT3, OATP1A2, and OATP1B1. OATP1A2- and OCT3-mediated EDDP uptake, and BCRP-mediated EDDP efflux transport, was inhibited by several antiretrovirals. Results show that hepatocyte methadone N -demethylation resembles expressed and liver microsomal metabolism more than clinical metabolism. Compared with clinical studies, hepatocytes underreport induction of methadone metabolism by HIV drugs. Hepatocytes are not a good predictive model for clinical antiretroviral induction of methadone metabolism and not a substitute for clinical studies. EDDP is a transporter substrate, and is susceptible to transporter-mediated interactions. [ABSTRACT FROM AUTHOR]

Ritonavir, an HIV protease inhibitor, is successfully used for the prevention and treatment of HIV infections. Ritonavir pharmacokinetics are complicated by inhibition, induction and pharmacogenetics of cytochrome P450 (CYP) enzymes mediating its clearance. This investigation revealed that CYP2J2, along with CYP3A4/5 and CYP2D6, efficiently metabolizes ritonavir, and to a CYP2J2-specific (minor) metabolite. Chemical inhibition of ritonavir metabolism, clearance, KI/kinact and abundance of CYP2J2 in liver microsomes were evaluated and then applied to an in vitro-in vivo static scaling model to estimate the contribution of each isozyme, as a function of CYP abundance, activity, and genotype. Disposition of the CYP2J2-specific metabolite was also evaluated in vivo. In plasma, metabolite abundance was well above previously reported levels with circulating concentrations measured at 2μM for the main hydroxylisopropyl metabolite. Ritonavir and metabolite plasma profiles were simulated using Simcyp®. A modest (2-6%) contribution of CYP2J2 to ritonavir clearance is predicted which increases to more than 20% in subjects carrying CYP2D6 poor metabolizer polymorphisms and CYP3A4 irreversible inhibition. These results indicate that minor drug metabolizing enzymes could become quantitatively important in RTV clearance if main metabolic pathways are impeded. [ABSTRACT FROM AUTHOR]

Long-acting opioid agonists methadone and l -α-acetylmethadol (LAAM) prevent withdrawal in opioid-dependent persons. Attempts to synthesize [ 11 C]-methadone for PET evaluation of brain disposition were unsuccessful. Owing, however, to structural and pharmacologic similarities, we aimed to develop [ 11 C] LAAM as a PET ligand to probe the brain exposure of long-lasting opioids in humans. This manuscript describes [ 11 C] LAAM synthesis and its biodistribution in mice. The radiochemical synthetic strategy afforded high radiochemical yield, purity and specific activity, thereby making the synthesis adaptable to automated modules. [ABSTRACT FROM AUTHOR]

Abstract: To meet a multiple-dose clinical evaluation of the P-gp modulation of [11C]morphine delivery into the human brain, radiosynthesis of [11C]morphine was accomplished on an automated system by N-methylation of normorphine with [11C]CH3I. A methodology employing optimized solid phase extraction of the HPLC eluent was developed. Radiosynthesis took 45min with a radiochemical yield ranging from 45% to 50% and specific activity ranging from 20 to 26Ci/μmol (decay corrected to end-of-bombardment); radiochemical and chemical purities were >95% (n=28). [ABSTRACT FROM AUTHOR]

OBJECTIVE: To test the hypothesis that increased tumor expression of proteins such as aquaporin-1 (AQP1) and adipophilin (ADFP) in patients with renal cancer would result in increased urine AQP1 and ADFP excretion. PATIENTS AND METHODS: Prenephrectomy and postnephrectomy (pseudocontrol) urine samples were collected from 42 patients with an incidental radiographically discovered renal mass and presurgical presumptive diagnosis of kidney cancer from July 8, 2008, through March 10, 2009. Also enrolled were 15 control patients who underwent nonrenal surgery and 19 healthy volunteers. Urine AQP1 and ADFP concentrations normalized to urine creatinine were determined by sensitive and specific Western blot assays. RESULTS: Mean ± SD preexcision urine AQPI and ADFP concentrations (76±29 and 117±74 arbitrary units, respectively) in patients with a pathologic diagnosis of clear ceil (n=22) or papillary (n=10) cancer were significantly greater than in patients with renal cancer of nonproximal tubule origin, control surgical patients, and healthy volunteers (combined values of 0.1±0.1 and 1.0±1.6 arbitrary units, respectively; n=44; P<.001). The AQPI and ADFP concentrations decreased 88% to 97% in the 25 patients with clear cell or papillary cancer who provided postnephrectomy follow-up urine samples. in patients with clear cell and papillary carcinoma, a linear correlation (Spearman) was found between tumor size and preexclsion urine AQPI or ADFP concentration (r=0.82 and 0.76, respectively; P<.001 for each). CONCLUSION: Urine AQPI and ADFP concentrations appear to be sensitive and specific biomarkers of kidney cancers of proximal tubule origin. These biomarkers may be useful to diagnose an Imaged renal mass and screen for kidney cancer at an early stage. [ABSTRACT FROM AUTHOR]

The objectives of this study were to characterize and compare the metabolic profile of cyclosporine A (CsA) catalyzed by CYP3A4, CYP3A5 and human kidney and liver microsomes, and to evaluate the impact of the CYP3A5 polymorphism on product formation from parent drug and its primary metabolites. Three primary CsA metabolites (AM1, AM9 and AM4N) were produced by heterologously expressed CYP3A4. In contrast, only AM9 was formed by CYP3A5. Substrate inhibition was observed for the formation of AM1 and AM9 by CYP3A4, and for the formation of AM9 by CYP3A5. Microsomes isolated from human kidney produced only AM9 and the rate of product formation (2 and 20μM CsA) was positively associated with the detection of CYP3A5 protein and presence of the CYP3A5*1 allele in 4 of the 20 kidneys tested. A kinetic experiment with the most active CYP3A5*1-positive renal microsomal preparation yielded an apparent Km (15.5μM) similar to that of CYP3A5 (11.3μM). Ketoconazole (200nM) inhibited renal AM9 formation by 22–55% over a CsA concentration range of 2–45μM. Using liver microsomes paired with similar CYP3A4 content and different CYP3A5 genotypes, the formation of AM9 was two-fold higher in CYP3A5*1/*3 livers, compared to CYP3A5*3/*3 livers. AM19 and AM1c9, two of the major secondary metabolites of CsA, were produced by CsA, AM1 and AM1c when incubated with CYP3A4, CYP3A5, kidney microsomes from CYP3A5*1/*3 donors and all liver microsomes. Also, the formation of AM19 and AM1c9 was higher from incubations with liver and kidney microsomes with a CYP3A5*1/*3 genotype, compared to those with a CYP3A5*3/*3 genotype. Together, the data demonstrate that CYP3A5 may contribute to the formation of primary and secondary metabolites of CsA, particularly in kidneys carrying the wild-type CYP3A5*1 allele. [Copyright &y& Elsevier]

Objective: To evaluate the trends in urine aquaporin-1 (AQP1) and perilipin 2 (PLIN2) concentrations in patients with clear cell and papillary renal cell carcinoma (RCC), we determined the relationship between the urine concentration of these biomarkers and tumor size, grade, and stage. Materials and Methods: The biomarker concentrations were determined by sensitive and specific Western blot procedures normalized to the urine creatinine excretion. The analysis included 61 patients undergoing partial or radical nephrectomy for clear cell or papillary RCC and 43 age- and sex-matched control patients. Relationships between urine biomarker concentrations and tumor size, stage, and grade were assessed. Results: Patients with RCC had 35-fold and 9-fold higher median urinary AQP1 and PLIN2 concentrations, respectively, compared with controls. Both tumor markers decreased after tumor resection to concentrations equivalent to those of controls. The sensitivity and specificity were both 100% for AQP1 and 92% and 100%, respectively, for PLIN2. A significant linear correlation was found between the tumor size and the prenephrectomy AQP1 (Spearman coefficient 0.78, P <.001) and PLIN2 (Spearman coefficient 0.69, P <.001) concentrations. A correlation was found for both markers with tumor stage (overall P = .030), when the stage was dependent primarily on the tumor size (stages T1 and T2), but not with stage T3, which reflected extrarenal spread. Neither marker showed a significant correlation with tumor grade. Conclusion: AQP1 and PLIN2 were significantly increased in patients with clear cell and papillary RCC compared with controls. The preoperative urinary concentrations of these markers reflected the tumor size and stage. [Copyright &y& Elsevier]