Pharmacokinetic and neuroimmune pharmacogenetic impacts on slow-release morphine cancer pain control and adverse effects.

The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. Morphine-3-glucuronide concentrations (standardised to 11 h post-dose) were higher in patients without pain control (median (interquartile range) 1.2 (0.7-2.3) versus 1.0 (0.5-1.9) µM, P = 0.006), whereas morphine concentrations were higher in patients with cognitive dysfunction (40 (20-81) versus 29 (14-60) nM, P = 0.02). TLR2 rs3804100 variant carriers had reduced odds (adjusted odds ratio (95% confidence interval) 0.42 (0.22-0.82), P = 0.01) of opioid adverse events. IL2 rs2069762 G/G (0.20 (0.06-0.52)), BDNF rs6265 A/A (0.15 (0.02-0.63)) and IL6R rs8192284 carrier (0.55 (0.34-0.90)) genotypes had decreased, and IL6 rs10499563 C/C increased (3.3 (1.2-9.3)), odds of sickness response (P ≤ 0.02). The study has limitations in heterogeneity in doses, sampling times and diagnoses but still suggests that pharmacokinetics and immune genetics co-contribute to morphine pain control and adverse effects in cancer patients.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

BACKGROUND: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed. AIMS: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au. METHOD: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4. RESULTS: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. CONCLUSIONS: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.

The incidence, impact, and risk factors for moderate to severe persistent pain after breast cancer surgery: a prospective cohort study.

BACKGROUND: Few Australasian studies have evaluated persistent pain after breast cancer surgery. OBJECTIVE: To evaluate the incidence, impact, and risk factors of moderate to severe persistent pain after breast cancer surgery in a New Zealand cohort. DESIGN: Prospective cohort study. METHODS: Consented patients were reviewed at 3 timepoints (preoperative, 2 weeks and 6 months postoperative). Pain incidence and interference, psychological distress and upper limb disability were assessed perioperatively. Clinical, demographic, psychological, cancer treatment-related variables, quantitative sensory testing, and patient genotype (COMT, OPRM1, GCH1, ESR1, and KCNJ6) were assessed as risk factors using multiple logistic regression. RESULTS: Of the 173 patients recruited, 140 completed the 6-month follow-up. Overall, 15.0% (n = 21, 95% CI: 9.5%-22.0%) of patients reported moderate to severe persistent pain after breast cancer surgery with 42.9% (n = 9, 95% CI: 21.9%-66.0%) reporting likely neuropathic pain. Pain interference, upper limb dysfunction and psychological distress were significantly higher in patients with moderate to severe pain (P < .004). Moderate to severe preoperative pain (OR= 3.60, 95% CI: 1.13-11.44, P = .03), COMT rs6269 GA genotype (OR = 5.03, 95% CI: 1.49-17.04, P = .009) and psychological distress at postoperative day 14 (OR= 1.08, 95% CI: 1.02-1.16, P = .02) were identified as risk factors. Total intravenous anesthesia (OR= 0.31, 95% CI: 0.10 - 0.99, P = .048) was identified as protective. CONCLUSION: The incidence of moderate to severe persistent pain after breast cancer surgery is high with associated pain interference, physical disability, and psychological distress. Important modifiable risk factors were identified to reduce this important condition.

A systematic literature review and meta-analysis of the effect of psilocybin and methylenedioxymethamphetamine on mental, behavioural or developmental disorders.

OBJECTIVES: There is an increasing interest in combining psilocybin or methylenedioxymethamphetamine with psychological support in treating psychiatric disorders. Although there have been several recent systematic reviews, study and participant numbers have been limited, and the field is rapidly evolving with the publication of more studies. We therefore conducted a systematic review of PubMed, MEDLINE, PsycINFO, the Cochrane Central Register of Controlled Trials, Embase, and CINAHL for randomised controlled trials of methylenedioxymethamphetamine and psilocybin with either inactive or active controls. METHODS: Outcomes were psychiatric symptoms measured by standardised, validated and internationally recognised instruments at least 2 weeks following drug administration, Quality was independently assessed using the Cochrane risk of bias assessment tool and Grading of Recommendations Assessment, Development and Evaluation framework. RESULTS: There were eight studies on methylenedioxymethamphetamine and six on psilocybin. Diagnoses included post-traumatic stress disorder, long-standing/treatment-resistant depression, obsessive-compulsive disorder, social anxiety in adults with autism, and anxiety or depression in life-threatening disease. The most information and strongest association was for the change in methylenedioxymethamphetamine scores compared to active controls in post-traumatic stress disorder (k = 4; standardised mean difference = -0.86; 95% confidence interval = [-1.23, -0.50]; p < 0.0001). There were also small benefits for social anxiety in adults with autism. Psilocybin was superior to wait-list but not niacin (active control) in life-threatening disease anxiety or depression. It was equally as effective as escitalopram in long-standing depression for the primary study outcome and superior for most of the secondary outcomes in analyses uncorrected for multiple comparisons. Both agents were well tolerated in supervised trials. Trial quality varied with only small proportions of potential participants included in the randomised phase. Overall certainty of evidence was low or very low using the Grading of Recommendations Assessment, Development and Evaluation framework. CONCLUSION: Methylenedioxymethamphetamine and psilocybin may show promise in highly selected populations when administered in closely supervised settings and with intensive support.

Trajectories of Pain and Function Outcomes up to 5 to 8 Years Following Total Knee Arthroplasty.

BACKGROUND: There appears to be substantial variability in outcomes > 2 years following total knee arthroplasty (TKA) that is masked by whole group analyses. The goal of the study was to identify trajectories of pain and function outcomes up to 5 to 8 years post-TKA and to identify baseline factors that are associated with different trajectories of recovery. METHODS: Baseline, 6-month, and 12-month pain and function data were collected in a previous study investigating predictors of outcome following primary TKA (n = 286), along with a variety of baseline predictor variables. The present study obtained pain and function data at 5 to 8 years following TKA in the same cohort (n = 201). Latent class linear mixed models were used to identify different classes of pain and functional trajectories over time. The extent to which differences across latent classes were explained by baseline predictor variables was determined. RESULTS: Three classes of pain and two classes of function trajectory were identified. While most patients (84% to 93%) followed a trajectory that showed an initial rapid gain following surgery that was sustained through 5 to 8 years, both pain and function included at least one trajectory class that showed a meaningful change after 12 months. No predictor variables were significantly associated with either the pain or function classes. CONCLUSIONS: Most patients follow a traditional trajectory of recovery in knee pain and function over 5 to 8 years. However, alternative trajectories are observed in an important minority of patients such that knee pain and function at 12 months after surgery does not always reflect outcomes at 5 to 8 years.

Toll-like receptors change morphine-induced antinociception, tolerance and dependence: Studies using male and female TLR and signalling gene KO mice.

Toll-like receptors (TLR) have been proposed as a site of action that alters opioid pharmacodynamics. However, a comprehensive assessment of acute opioid antinociception, tolerance and withdrawal behaviours in genetic null mutant strains with altered innate immune signalling has not been performed. Nor has the impact of genetic deletion of TLR2/4 on high-affinity opioid receptor binding. Here we show that diminished TLR signalling potentiates acute morphine antinociception equally in male and female mice. However, only male TIR8 null mutant mice showed reduced morphine analgesia. Analgesic tolerance was prevented in TLR2 and TLR4 null mutants, but not MyD88 animals. Withdrawal behaviours were only protected in TLR2-/- mice. In silico docking simulations revealed opioid ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. There was no binding of [3H](-)-naloxone or [3H]diprenorphine to TLR4 in the concentrations explored. These data confirm that opioids have high efficacy activity at innate immune pattern recognition binding sites but do not bind to TLR4 and identify critical pathway and sex-specific effects of the complex innate immune signalling contributions to opioid pharmacodynamics. These data further support the behavioural importance of the TLR-opioid interaction but fail to demonstrate direct evidence for high-affinity binding of the TLR4 signalling complex to ligands.

The Role of Pharmacogenomics in Opioid Prescribing.

OPINION STATEMENT: Pharmacogenomics is increasingly important to guide objective, safe, and effective individualised prescribing. Personalised prescribing has revolutionised treatments in the past decade, allowing clinicians to maximise drug efficacy and minimise adverse effects based on a person's genetic profile. Opioids, the gold standard for cancer pain relief, are among the commonest medications prescribed in palliative care practice. This narrative review examines the literature surrounding opioid pharmacogenomics and its applicability to the palliative care cancer population. There is currently limited intersection between the fields of palliative care and pharmacogenomics, but growing evidence presents a need to build linkages between the two disciplines. Pharmacogenomic evidence guiding opioid prescribing is currently available for codeine and tramadol, which relates to CYP2D6 gene variants. However, these medications are prescribed less commonly for pain in palliative care. Research is accelerating with other opioids, where oxycodone (CYP2D6) and methadone (CYP2B6, ABCB1) already have moderate evidence of an association in terms of drug metabolism and downstream analgesic response and side effects. OPRM1 and COMT are receiving increasing attention and have implications for all opioids, with changes in opioid dosage requirements observed but they have not yet been studied widely enough to be considered clinically actionable. Current evidence indicates that incorporation of pharmacogenomic testing into opioid prescribing practice should focus on the CYP2D6 gene and its actionable variants. Although opioid pharmacogenomic tests are not widely used in clinical practice, the progressively reducing costs and rapid turnover means greater accessibility and affordability to patients, and thus, clinicians will be increasingly asked to provide guidance in this area. The upsurge in pharmacogenomic research will likely discover more actionable gene variants to expand international guidelines to impact opioid prescribing. This rapidly expanding area requires consideration and monitoring by clinicians in order for key findings with clinical implications to be accessible, meaningfully interpretable and communicated.

The effect of acute morphine on sleep in male patients suffering from sleep apnea: Is there a genetic effect? An RCT Study.

Questionnaire-based studies have suggested genetic differences in sleep symptoms in chronic opioid users. The present study aims to investigate if there is a genetic effect on sleep architecture and quantitative electroencephalogram (EEG) in response to acute morphine. Under a randomized, double-blind, placebo-controlled, crossover design, 68 men with obstructive sleep apnea undertook two overnight polysomnographic studies conducted at least 1 week apart. Each night they received either 40 mg of controlled-release morphine or placebo. Sleep architecture and quantitative EEG were compared between conditions. Blood was sampled before sleep and on the next morning for genotyping and pharmacokinetic analyses. We analysed three candidate genes (OPRM1 [rs1799971, 118 A > G], ABCB1[rs1045642, 3435 C > T] and HTR3B [rs7103572 C > T]). We found that morphine decreased slow wave sleep and rapid eye movement sleep and increased stage 2 sleep. Those effects were less in subjects with HTR3B CT/TT than in those with CC genotype. Similarly, sleep onset latency was shortened in the ABCB1 CC subgroup compared with the CT/TT subgroup. Total sleep time was significantly increased in ABCB1 CC but not in CT/TT subjects. Sleep apnea and plasma morphine and metabolite concentration were not confounding factors for these genetic differences in sleep. With morphine, patients had significantly more active/unstable EEG (lower delta/alpha ratio) during sleep. No genetic effects on quantitative EEG were detected. In summary, we identified two genes (HTR3B and ABCB1) with significant variation in the sleep architecture response to morphine. Morphine caused a more active/unstable EEG during sleep. Our findings may have relevance for a personalized medicine approach to targeted morphine therapy.

Tacrolimus dose, blood concentrations and acute nephrotoxicity, but not CYP3A5/ABCB1 genetics, are associated with allograft tacrolimus concentrations in renal transplant recipients.

AIMS: Long-term use of the immunosuppressant tacrolimus is limited by nephrotoxicity. Following renal transplantation, the risk of nephrotoxicity may be determined more by allograft than by blood tacrolimus concentrations, and thus may be affected by donor CYP3A5 and ABCB1 genetics. Little is known regarding factors that determine tacrolimus intrarenal exposure. METHODS: This study investigated the relationship between trough blood (C0Blood ) and allograft (CGraft ) tacrolimus concentrations and tacrolimus dose, haematocrit, genetics, acute nephrotoxicity, rejection status, delayed graft function, and time post-transplant. C0Blood and CGraft were quantified in 132 renal transplant recipients together with recipient and donor CYP3A5 (rs776746) and ABCB1 3435 (rs1045642) genotypes. RESULTS: C0Blood ranged from 2.6 to 52.3 ng/mL and CGraft from 33 to 828 pg/mg tissue. Adjusting for dose, recipients who were CYP3A5 expressors had lower C0Blood compared to nonexpressors, whilst delayed graft function was associated with higher C0Blood . Linear regression showed that the significant predictors of CGraft were C0Blood (point-wise P = 7 × 10-10 ), dose (P = .004) acute nephrotoxicity (P = .002) and an interaction between C0Blood and acute tacrolimus nephrotoxicity (P = .0002), with an adjusted r2  = 0.35 and no contribution from donor or recipient CYP3A5 or ABCB1 genotype. The association between CGraft and acute nephrotoxicity depended on one very high CGraft (828 pg/mg tissue). CONCLUSIONS: Recipient and donor CYP3A5 and ABCB1 3435C>T genotypes are not determinants of allograft tacrolimus exposure in kidney transplant recipients. However, tacrolimus dose and C0Blood were significant predictors of CGraft , and the relationship between C0Blood and CGraft appeared to differ in the presence or absence of acute nephrotoxicity.

Innate Immune and Neuronal Genetic Markers Are Highly Predictive of Postoperative Pain and Morphine Patient-Controlled Analgesia Requirements in Indian but Not Chinese or Malay Hysterectomy Patients.

OBJECTIVE: Pain severity and opioid requirements in the postoperative period show substantial and clinically significant inter-patient variation due mainly to factors such as age, surgery type, and duration. Genetic factors have not been adequately assessed except for the neuronal OPRM1 rs1799971 and COMT rs4680, whereas the contribution of innate immune signaling pathway genetics has seldom been investigated. SETTING: Hospital surgical ward. SUBJECTS: Women (107 Indian, 184 Malay, and 750 Han Chinese) undergoing total hysterectomy surgery. METHODS: Morphine consumption, preoperative pain, and postoperative pain were evaluated in relation to genetic variability comprising 19 single-nucleotide polymorphisms (SNPs) in 14 genes involved in glial activation, inflammatory signaling, and neuronal regulation, plus OPRM1 (1 SNP) and COMT (3 SNPs). RESULTS: Pre- and postoperative pain and age were associated with increased and decreased morphine consumption, respectively. In Chinese patients, only 8% of the variability in consumption could be explained by these nongenetic and genetic (BDNF, IL1B, IL6R, CRP, OPRM1, COMT, MYD88) factors. However, in Indian patients, 41% of morphine consumption variability could be explained by age (explaining <3%) and variants in OPRM1 rs1799971, CRP rs2794521, TLR4 rs4986790, IL2 rs2069762, COMT rs4818, TGFB1 rs1800469, and IL6R rs8192284 without controlling for postoperative pain. CONCLUSIONS: This is the highest known value reported for genetic contributions (38%) to morphine use in the acute postoperative pain setting. Our findings highlight the need to incorporate both genetic and nongenetic factors and consider ethnicity-dependent and nonadditive genotypic models in the assessment of factors that contribute to variability in opioid use.

Effect of tacrolimus dispositional genetics on acute rejection in the first 2 weeks and estimated glomerular filtration rate in the first 3 months following kidney transplantation.

BACKGROUND: CYP3A4/5 and P-glycoprotein (P-gp, ABCB1) affect tacrolimus (TAC) exposure in T cells and kidney cells. Genetic variability of these genes has been widely studied for effects on acute rejection and kidney function after transplantation, but findings remain contradictory. In addition, cytochrome P450 reductase (POR) is important for CYP3A4/5 activity, and the pregnane X receptor (NR1I2) regulates CYP3A4/5 and P-gp expression. However, the relationship between POR and NR1I2 genetics and acute rejection and kidney function has not been extensively investigated. OBJECTIVE: The aim of this study was to investigate the effect of ABCB1 (61A>G, 1199G>A, 1236C>T, 2677G>T, 3435C>T), CYP3A4*22, CYP3A5*3, NR1I2 (8055C>T, 63396C>T) and POR*28 genotypes/haplotypes on acute rejection and kidney function in the first 3 months after transplant. PARTICIPANTS AND METHODS: The study included 165 kidney transplant recipients, who received TAC, mycophenolate and prednisolone, and 129 donors. TAC dose was adjusted to target trough blood concentrations of 8-15 ng/ml by therapeutic drug monitoring. Recipient and donor genotype/haplotype differences in acute rejection incidence within the first 2 weeks after transplant were assessed by logistic regression, adjusting for induction therapy, human leucocyte antigen mismatches, kidney transplant number, peak panel-reactive antibodies and donor type. Recipient and donor genotype/haplotype differences in estimated glomerular filtration rate in the first 3 months after transplant were assessed by linear mixed effects analysis, adjusting for acute rejection, delayed graft function and donor type. RESULTS: No genetic factors significantly affected acute rejection or estimated glomerular filtration rate after correction for multiple comparisons (P>0.004). CONCLUSION: Recipient and donor dispositional genetics had no significant effect on short-term clinical outcomes in kidney transplant patients receiving TAC therapeutic drug monitoring.

The effect of acute morphine on obstructive sleep apnoea: a randomised double-blind placebo-controlled crossover trial.

OBJECTIVE: Anaesthesiology guidelines suggest that opioids worsen obstructive sleep apnoea (OSA) despite no randomised controlled trial evidence. We therefore conducted a randomised controlled trial to evaluate the effects of a common clinical dose of morphine on OSA, and to identify clinical phenotype and genotype vulnerability to opioid-respiratory depression. METHODS: Under a double-blind, randomised, crossover design, 60 male patients with OSA attended two visits to the hospital sleep laboratory, at least 1 week apart. Either 40 mg controlled-release oral morphine or placebo was administered. Awake ventilatory chemoreflex tests were performed post dose and prior to overnight polysomnography monitoring. Blood was sampled before sleep and the next morning for toxicology and genotype analyses. Sleep time with oxygen saturation (SpO2) <90% (T90) was the primary outcome. RESULTS: Despite a large inter-individual variability, 40 mg morphine did not worsen T90 and apnoea-hypopnoea index, and only decreased the SpO2 nadir by 1.3%. In patients with severe OSA, a lower baseline CO2ventilatory response threshold correlated with the worsening of T90, apnoea-hypopnoea index and oxygen desaturation index with morphine use. Patients with OSA and the A118G OPRM1 polymorphism of A/A and A/G had a significantly different morphine effect on awake ventilatory chemosensitivity and T90 during sleep. CONCLUSIONS: 40 mg oral controlled-release morphine did not worsen OSA in men, challenging traditional thinking that OSA will be worsened by opioids. Individual opioid response in patients with OSA may relate to baseline CO2 response threshold and OPRM1 genotype. Our study findings may pave the way for a precision medicine approach to avoid opioid-related risks. TRIAL REGISTRATION NUMBER: The Australian and New Zealand Clinical Trial Registry, ACTRN12613000858796.

Conference report: pharmacogenomics in special populations at WCP2018.

The 18th World Congress of Basic and Clinical Pharmacology (WCP2018), coordinated by IUPHAR and hosted by the Japanese Pharmacological Society and the Japanese Society of Clinical Pharmacology and Therapeutics, was held in July 2018 at the Kyoto International Conference Center, in Kyoto, Japan. Having as its main theme 'Pharmacology for the Future: Science, Drug Development and Therapeutics', WCP2018 was attended by over 4500 delegates, representing 78 countries. The present report is an overview of a symposium at WCP2018, entitled Pharmacogenomics in Special Populations, organized by IUPHAR´s Pharmacogenetics/Genomics (PGx) section. The PGx section congregates distinguished scientists from different continents, covering expertise from basic research, to clinical implementation and ethical aspects of PGx, and one of its major activities is the coordination of symposia and workshops to foster exchange of PGx knowledge (https://iuphar.org/sections-subcoms/pharmacogenetics-genomics/). The symposium attracted a large audience to listen to presentations covering various areas of research and clinical adoption of PGx in Oceania, Africa, Latin America and Asia.

Relationship between allograft cyclosporin concentrations and P-glycoprotein expression in the 1st month following renal transplantation.

The immunosuppressant cyclosporin is a P-glycoprotein (P-gp) substrate whose impaired function has been associated with an increased risk of cyclosporin-induced nephrotoxicity following renal transplantation. This study investigated the relationship between blood and allograft cyclosporin concentration, and the effect of P-gp expression. Fifty biopsy samples were obtained from 39 renal transplant recipients who received cyclosporin as part of maintenance immunosuppression. Blood cyclosporin concentrations (2 hours postdose) were obtained from clinical records, matching allograft cyclosporin concentrations were measured in frozen biopsy tissue by liquid chromatography-tandem mass spectrometry, and allograft P-gp expression was assessed by immunohistochemistry. Blood and allograft cyclosporin concentrations in the 1st month post-transplantation ranged from 505-2005 µg/L and 0.01-16.7 ng/mg tissue, respectively. Dose was the only significant predictor of allograft cyclosporin concentrations (adjusted R2  = .24, F-statistic = 11.52, P = .0019), with no effect of P-gp expression or blood cyclosporin concentrations. P-gp expression is not the major determinant of allograft cyclosporin concentrations.

High and variable population prevalence of HLA-B*56:02 in indigenous Australians and relation to phenytoin-associated drug reaction with eosinophilia and systemic symptoms.

Phenytoin drug reaction with eosinophilia and systemic symptoms (DRESS) in 3 Aboriginal Australians positive for HLA-B*56:02 has been previously reported. We report the allele frequency of HLA-B*56:02 in 2 South Australian populations, 1 Aboriginal (4.8%, 95% confidence interval 2.4-7.8%) and the other European (0%). We compared the frequency with publicly available information on HLA-B*56:02 status in other Indigenous Australian (n = 4) and European Australian cohorts (n = 1). In the Indigenous Australian cohorts, HLA-B*56:02 allele frequency ranged from 1.3 to 19%. We also describe an additional case of phenytoin DRESS (RegiSCAR DRESS score 7) in an Aboriginal Australian that was associated with HLA-B*56:02 and with CYP2C9*1/*3 genotype. In Aboriginal Australians, phenytoin DRESS appears distinctly linked to HLA-B*56:02 with an allele carriage rate substantially higher than in Europeans, but also with considerable regional variation. Investigations of human leucocyte antigen and other contributing genes and severe adverse drug reactions in understudied non-European populations are required to optimize safe medication use and inform risk mitigation strategies.

Is There a Temporal Relationship Between Trough Whole Blood Tacrolimus Concentration and Acute Rejection in the First 14 Days After Kidney Transplantation?

BACKGROUND: There are inconsistent findings regarding the relationship between trough whole blood tacrolimus concentration (TAC C0) and acute kidney rejection in recipients undergoing TAC therapeutic drug monitoring (TDM). However, studies have not always assessed TAC C0 at the time of rejection or accounted for variability in hematocrit. Therefore, this study aimed to investigate the temporal relationship between TAC C0 and acute rejection, including when accounting for variation in hematocrit. METHODS: For 38 recipients who developed biopsy-proven acute rejection (BPAR) in the first 14 days after kidney transplantation, daily TAC C0 from TDM and hematocrit was collected from case notes. Differences in log10-transformed TAC C0 between the day of BPAR (log Cr), 1 day before BPAR (log Cr-1), and 2 days before BPAR (log Cr-2) and the combined median concentrations for the days preceding these (log Cprior) were examined by repeated-measures analysis of variance with Dunnett post hoc testing. Generalized linear mixed-effects regression (glmer) examined the ability of TAC C0 to predict acute rejection episodes with and without controlling for hematocrit. RESULTS: Log Cr-1 [mean difference (95% confidence interval) = -0.13 (-0.21 to -0.048), post hoc P = 0.002] and log Cr [-0.13 (-0.24 to -0.025), post hoc P = 0.013] were significantly lower than log Cprior. TAC C0 was a significant (P = 0.0078) predictor of rejection episodes (area under the receiver operating characteristic curve = 0.79) only in glmer models accounting for variability in hematocrit. CONCLUSIONS: In recipients who developed BPAR, there was a significant temporal relationship between TAC C0 and BPAR incidence under TAC TDM that may not be detected in cross-sectional studies, especially if variability in hematocrit is not addressed. This supports a TAC C0-rejection relationship, which differs between recipients, and may explain why some recipients do or do not experience rejection within or below the TDM range, respectively. However, studies with larger sample sizes are needed to confirm this finding.

Buprenorphine Maintenance Subjects Are Hyperalgesic and Have No Antinociceptive Response to a Very High Morphine Dose.

Objective: Acute pain management in opioid-dependent persons is complicated because of tolerance and opioid-induced hyperalgesia. Very high doses of morphine are ineffective in overcoming opioid-induced hyperalgesia and providing antinociception to methadone-maintained patients in an experimental setting. Whether the same occurs in buprenorphine-maintained subjects is unknown. Design: Randomized double-blind placebo-controlled. Subjects were tested on two occasions, at least five days apart, once with intravenous morphine and once with intravenous saline. Subjects were tested at about the time of putative trough plasma buprenorphine concentrations. Setting: Ambulatory. Subjects: Twelve buprenorphine-maintained subjects: once daily sublingual dose (range = 2-22 mg); no dose change for 1.5-12 months. Ten healthy controls. Methods: Intravenous morphine bolus and infusions administered over two hours to achieve two separate pseudo-steady-state plasma concentrations one hour apart. Pain tolerance was assessed by application of nociceptive stimuli (cold pressor [seconds] and electrical stimulation [volts]). Ten blood samples were collected for assay of plasma morphine, buprenorphine, and norbuprenorphine concentrations until three hours after the end of the last infusion; pain tolerance and respiration rate were measured to coincide with blood sampling times. Results: Cold pressor responses (seconds): baseline: control 34 ± 6 vs buprenorphine 17 ± 2 (P = 0.009); morphine infusion-end: control 52 ± 11(P = 0.04), buprenorphine 17 ± 2 (P > 0.5); electrical stimulation responses (volts): baseline: control 65 ± 6 vs buprenorphine 53 ± 5 (P = 0.13); infusion-end: control 74 ± 5 (P = 0.007), buprenorphine 53 ± 5 (P > 0.98). Respiratory rate (breaths per minute): baseline: control 17 vs buprenorphine 14 (P = 0.03); infusion-end: control 15 (P = 0.09), buprenorphine 12 (P < 0.01). Infusion-end plasma morphine concentrations (ng/mL): control 23 ± 1, buprenorphine 136 ± 10. Conclusions: Buprenorphine subjects, compared with controls, were hyperalgesic (cold pressor test), did not experience antinociception, despite high plasma morphine concentrations, and experienced respiratory depression. Clinical implications are discussed.

The Prevalence, Impact, and Risk Factors for Persistent Pain After Breast Cancer Surgery in a New Zealand Population.

OBJECTIVE: Few Australasian studies have assessed persistent pain after breast cancer surgery. This study aims to evaluate the prevalence, impact, and risk factors of moderate to severe persistent pain after breast cancer surgery in a New Zealand population. METHODS: Retrospective cross-sectional study of patients who underwent breast cancer surgery between six and 48 months previously. Validated questionnaires were used to assess pain prevalence and impact, psychological distress, and upper limb function. Patients' clinical records were assessed for potential risk factors. RESULTS: Of the 375 patients who were sent questionnaires, 201 were included in the study. More than half of the patients (N = 111, 55%) reported breast surgery related-persistent pain, with 46 (23%) rating the pain as moderate to severe. Neuropathic pain was reported by 21 (46%) patients with moderate to severe pain. Pain interference, upper limb dysfunction, and psychological distress were significantly higher in patients with moderate to severe pain (P < 0.001). Non-European ethnicity (odds ratio [OR] = 5.02, 95% confidence interval [CI] = 2.05-12.25, P < 0.001), reconstruction surgery (OR = 4.10, 95% CI = 1.30-13.00, P = 0.02), and axillary node dissection (OR = 4.33, 95% CI = 1.19-15.73, P < 0.03) were identified as risk factors for moderate to severe pain by multivariate logistic regression analysis. CONCLUSIONS: Moderate to severe persistent pain after breast cancer surgery affects many New Zealand patients, and is associated with impaired daily life activities, physical disability, and psychological distress. Large numbers of patients undergo breast cancer surgery annually. This study emphasizes the importance of identification and management of these patients perioperatively.

Effects of Electroacupuncture on Opioid Consumption in Patients with Chronic Musculoskeletal Pain: A Multicenter Randomized Controlled Trial.

OBJECTIVES: To evaluate the efficacy and safety of electroacupuncture in reducing opioid consumption in patients with chronic musculoskeletal pain. DESIGN: A randomized, participant-assessor-blinded, three-arm trial. SETTING: Participants from three pain clinics and from the public. SUBJECTS: One hundred and eight adults with chronic pain who were taking opioids. METHODS: All participants received pain and medication management education. Participants were randomly allocated to electroacupuncture (N = 48), sham electroacupuncture (N = 29), or education alone (N = 31) to receive relevant treatment for 12 weeks. The last group received electroacupuncture during the three-month follow-up. Analysis of covariance and paired t tested were used. RESULTS: Opioid dosage, that is, the primary outcome measure, was reduced by 20.5% (P < 0.05) and 13.7% (P < 0.01) in the two acupuncture groups and by 4.5% in the education group at the end of the treatment phase, but without any group difference. Intensity of pain of all three groups did not change over time. No group differences were found in dosage of nonopioid analgesics, pain intensity, function, and opioid-related adverse events. During follow-up, the education group had a 47% reduction of opioids after a course of electroacupuncture. Adverse events to electroacupuncture were minor. CONCLUSION: It is safe to reduce opioid medication use in patients with chronic pain. Due to the small sample size, we could not confirm if electroacupuncture offers extra benefit in addition to education. This nondrug therapy could be a promising adjunct to facilitate opioid tapering in patients who are willing to reduce opioids.

Pharmacogenomics in Papua New Guineans: unique profiles and implications for enhancing drug efficacy while improving drug safety.

Papua New Guinea (PNG) can be roughly divided into highland, coastal and island peoples with significant mitochondrial DNA differentiation reflecting early and recent distinct migrations from Africa and East Asia, respectively. Infectious diseases such as tuberculosis, malaria and HIV severely impact on the health of its peoples for which drug therapy is the major treatment and pharmacogenetics has clinical relevance for many of these drugs. Although there is generally little information about known single nucleotide polymorphisms in the population, in some instances, their frequencies have been shown to be higher than anywhere worldwide. For example, CYP2B6*6 is over 50%, and CYP2C19*2 and *3 are over 40 and 25%, respectively. Conversely, CYP2A6*9, 2B6*2, *3, *4 and *18, and 2C8*3 appear to be much lower than in Whites. CYP2D6 known variants are unclear, and for phase II enzymes, only UGT2B7 and UGT1A9 data are available, with variant frequencies either slightly lower than or similar to Whites. Although almost all PNG people tested are rapid acetylators, but which variant(s) define this phenotype is not known. For HLA-B*13:01, HLA-B*35:05 and HLA-C*04:01, the frequencies show some regioselectivity, but the clinical implications with respect to adverse drug reactions are not known. There are minimal phenotype data for the CYPs and nothing is known about drug transporter or receptor genetics. Determination of genetic variants that are rare in Whites or Asians but common in PNG people is a topic of both scientific and clinical importance, and further research needs to be carried out. Optimizing the safety and efficacy of infectious disease drug therapy through pharmacogenetic studies that have translation potential is a priority.