Gabapentinoids: a therapeutic review.

The Australian Therapeutic Goods Administration's approved indications for prescription of gabapentinoids are refractory focal epilepsy and neuropathic pain. Use of gabapentinoids outside of the approved indications is common, but evidence for this is limited, especially for chronic nonspecific back pain and nonradicular leg pain. Some effects of gabapentinoids encourage their nonmedical use (e.g. euphoria, sedation, disinhibition). Widespread nonmedical use has increased the incidence of accidental and deliberate poisonings. Dependence may develop with chronic use of gabapentinoids and abrupt cessation may induce withdrawal symptoms. If the indication for continued use is unclear, gradual dose tapering as a means of deprescribing is recommended. Clinicians should consider the indication, patient characteristics and harm-benefit profile when prescribing gabapentinoids. Some people, such as those with kidney disease, have an increased risk of harm when using these drugs.

Transdermal Magnesium for the Treatment of Peripheral Neuropathy in Chronic Kidney Disease: A Single-Arm, Open-Label Pilot Study.

Introduction: Peripheral neuropathy is common in chronic kidney disease (CKD) and may be multifactorial in origin, resulting from uremia, hyperkalemia, and diabetes. Previous studies have suggested that magnesium plays a crucial role in chronic pain. Studies evaluating magnesium in neuropathy have demonstrated mixed results. Aims: To provide preliminary data on the effectiveness of transdermal magnesium in treating peripheral neuropathy related to CKD. Methods: Twenty participants with advanced CKD were enrolled from a major teaching hospital clinic in Sydney, Australia. Each participant was provided with a spray bottle containing magnesium chloride and instructed to apply five sprays to each limb affected by neuropathy daily for 12 weeks. Participants completed the Neuropathy Total Symptom Score-6 (NTSS-6) every 4 weeks during follow-up. Serum magnesium concentrations were measured at 4-week intervals. Results: Twenty participants were recruited, of which 14 completed the 12-week follow-up period. Mean age was 78.90 years, 80.00% were female and mean estimated glomerular filtration rate was 9.78 mL/min/1.73 m2. With intention to treat analysis (mean [95% confidence interval]), NTSS-6 was significantly reduced at weeks 8 (4.04 [2.43-5.65]) and 12 (4.26 [2.47-6.05]), compared with baseline (6.92 [5.29-8.55]), p < 0.05. Serum magnesium concentration did not change significantly during the study. Conclusion: This pilot study suggests that transdermal magnesium may be beneficial in reducing frequency and severity of peripheral neuropathic symptoms in patients with advanced CKD. Trial Registration: australianclinicaltrials.gov.au. Identifier: ACTRN12621000841875. Date first registered January 7, 2021.

Evaluation of adherence monitoring in buprenorphine treatment: A pilot study using timed drug assays to determine accuracy of testing.

AIMS: Buprenorphine is effective at reducing relapse to opioid misuse, morbidity and mortality in opioid-dependent patients. Urine drug screening (UDS) to assess adherence is used routinely in opioid agonist treatment (OAT). The primary aim of this study was to determine factors which may be associated with a negative qualitative urine drug screen for buprenorphine in OAT patients. METHODS: This prospective pilot study was conducted at a tertiary addiction medicine centre. Twenty participants on stable treatment underwent supervised administration of sublingual buprenorphine. Matched urine and blood samples were collected prior to and 2, 4 and 6 hours after buprenorphine administration. Qualitative urine drug screen results were obtained using gas chromatography-mass spectrometry (GC-MS), while quantitative blood and urine results were obtained using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: Qualitative urine assay yielded a negative result for buprenorphine in 57% of tested samples. The median concentration of urinary buprenorphine was 167 mcg/L (range: 2-1730 mcg/L). Thirty percent of all blood samples did not detect buprenorphine (range 0-18 mcg/L). Positive qualitative urine drug screen results were associated with higher urine (343 mcg/L compared with 75 mcg/L; P < .05) and blood (4 mcg/L compared with 2 mcg/L; P < .05) buprenorphine concentrations. Median urine concentrations of buprenorphine were highest at 2 hours and were higher in participants receiving CYP3A4 inhibitors. CONCLUSION: Interpretation of qualitative urine drug screens to assess adherence in OAT is complex. Poor adherence with treatment cannot be assumed in patients returning a negative qualitative GC-MS urine drug screen.

Management of Renal Angiomyolipomas in Tuberous Sclerosis Complex: A Case Report and Literature Review.

We report a case of misdiagnosed tuberous sclerosis complex (TSC) in a patient without TSC gene variant presenting with bilateral renal angiomyolipomas and seizures in the context of strong family history of polycystic kidney disease. Clinical diagnosis of tuberous sclerosis complex was made and treatment with everolimus reduced size of renal angiomyolipomas. In this case, report we discuss the association between tuberous sclerosis complex and polycystic kidney disease and novel treatment for TSC.

Dialysis Disequilibrium: Is Acidosis More Important than Urea?

Dialysis disequilibrium syndrome is a severe complication associated with dialysis treatment. Manifestations may range from mild such as headache to severe such as seizures and coma. Risk factors for development include initial dialysis treatment, uraemia, metabolic acidosis, and extremes of age. We report a case of dialysis disequilibrium in a patient with a failing kidney transplant secondary to the recurrence of IgA nephropathy. Disturbance in cognition and neurologic functioning occurred six hours after the completion of initiation of intermittent haemodialysis. During two sessions of intermittent haemodialysis of 3 and 4 hours, urea was reduced by 21.9 and 17.2 mmol/L and measured serum osmolality was reduced by 25 and 14 mOsm/kg, respectively. Subsequent admission to the intensive care unit and initiation of continuous renal replacement therapy for 48 hours resulted in complete resolution of symptoms. In this case report, we discuss atypical clinical and radiologic features of dialysis disequilibrium occurring with modest reductions in urea and serum osmolality.

Buprenorphine not detected on urine drug screening in supervised treatment.

INTRODUCTION: Urine drug screens (UDS) assist in clinical planning and assessment of adherence in opioid agonist treatment (OAT). Urine drug screens may also be used in criminal justice and child protection settings. Buprenorphine (BPN) UDS testing is complex. Immunoassay often does not detect BPN and gas chromatography-mass spectrometry (GC-MS) is needed. A limited understanding of testing can negatively influence UDS interpretation and clinical decision making. OBJECTIVES: The primary aim was to determine detection rates of BPN in UDS in participants on BPN or buprenorphine/naloxone (BNX) treatment. The secondary aim was to identify if comorbidities, sex, co-prescribed medications, or dosing site and observation were associated with BPN detection. SETTING: Public outpatient clinic in a specialist addiction treatment service. DESIGN/PARTICIPANTS: In this retrospective observational study, records of clients on supervised BPN/BNX treatment between September 2017 and 2018 were reviewed. MEASURES: Data extracted included UDS results, age, sex, indication for BPN, frequency of observed doses, dose of BPN, dosing site, comorbid medical conditions, and medications. RESULTS: One hundred and sixty-one medical records were reviewed. Ninety-seven (60 percent) underwent screening urine immunoassay. Of these 97, 51 (53 percent) had further GC-MS testing for BPN of which 22 (43 percent) did not detect BPN despite directly observed OAT. Co-prescription of medications known to interact with cytochrome P450 3A4 was associated with nondetection of BPN (p < 0.05). No significant association between median dose, dosing site, and observed dosing and BPN detection was identified. CONCLUSION: Urine drug testing for BPN is complex. Failure to detect BPN does not betoken nonadherence to treatment and is associated with co-prescription of drugs interacting with cytochrome P450 3A4.

Data Challenges in Addressing Chronic Kidney Disease in Low- and Lower-Middle-Income Countries.

The burden of chronic kidney disease (CKD) is growing globally, particularly in low- and lower-middle-income countries (LLMICs) where access to treatment is poor and the largest increases in disease burden will occur. The individual and societal costs of kidney disease are well recognized, especially in developed health care systems where treatments for the advanced stages of CKD are more readily available. The consequences of CKD are potentially more catastrophic in developing health care systems where such resources are often lacking. Central to addressing this challenge is the availability of data to understand disease burden and ensure that investments in treatments and health resources are effective at a local level. Use of routinely collected administrative data is helpful in this regard, however, the barriers to developing a more systematic focus on data collection should not be underestimated. This article reviews the current tools that have been used to measure the burden of CKD and considers limitations regarding their use in LLMICs. A review of the literature investigating the use of registries, disease specific databases and administrative data to identify populations with CKD in LLMICs, which indicate these to be underused resources, is included. Suggestions regarding the potential use of administrative data for measuring CKD burden in LLMICs are explored.

Acute interstitial nephritis and nephrogenic diabetes insipidus following treatment with sulfamethoxazole-trimethoprim and temozolomide.

We report a case of acute interstitial nephritis with associated nephrogenic diabetes insipidus in a patient treated with temozolomide and sulfamethoxazole-trimethoprim for glioblastoma multiforme. Kidney biopsy demonstrated focal tubulointerstitial change with tubular dilatation, epithelial change and interstitial inflammation. The patient's kidney function improved with cessation of sulfamethoxazole-trimethoprim and treatment with hydrochlorothiazide for nephrogenic diabetes insipidus. Recommencement of temozolomide did not result in further deterioration in kidney function. In this case report, we discuss the novel association between sulfamethoxazole-trimethoprim-induced acute interstitial nephritis and nephrogenic diabetes insipidus, and suggest possible mechanisms involved.

Management of proteinuria: blockade of the renin-angiotensin-aldosterone system.

Proteinuria, in particular albuminuria, is a potentially significant modifiable risk factor for cardiovascular disease and the progression of kidney disease. Current treatment guidelines for albuminuria recommend a single renin­angiotensin­aldosterone inhibitor. This can be an ACE inhibitor or an angiotensin receptor antagonist. The routine use of combined renin­angiotensin­aldosterone inhibition for albuminuria is not supported by current evidence. Combination therapy is associated with higher rates of adverse events such as hyperkalaemia and progressive renal impairment.

Antiemetic drugs: what to prescribe and when.

Nausea and vomiting are common symptoms with many possible causes, including the adverse effects of drugs. If a drug is indicated, the cause guides the choice of antiemetic drug The main antiemetic classes include antagonists of the serotonin, dopamine, histamine, muscarinic and neurokinin systems, corticosteroids and benzodiazepines. Some antiemetics appear more effective for specific indications Serotonin and neurokinin antagonists, such as ondansetron and aprepitant, are highly effective in treating chemotherapy-induced nausea and vomiting. Metoclopramide and antihistamines are first-line options for nausea and vomiting in pregnancy Serotonin antagonists and some dopamine antagonists, such as metoclopramide, can prolong the QT interval on the ECG. Dopamine antagonists can cause extrapyramidal adverse effects, particularly in children

Incomplete responses to the recommended dose of idarucizumab: a systematic review and pharmacokinetic analysis.

Introduction: Dabigatran, a direct thrombin inhibitor, is 80% renally eliminated and demonstrates multi-compartmental pharmacokinetics. Idarucizumab is a monoclonal antibody that reverses dabigatran-induced anticoagulation and displays single compartment pharmacokinetics, with a smaller volume of distribution and shorter elimination half-life than dabigatran. These differences in pharmacokinetics mean that redistribution of dabigatran from peripheral compartments can occur after idarucizumab has been eliminated, resulting in rebound in the dabigatran plasma concentration and treatment failure. Clinical experience notes failure of a single idarucizumab 5 g dose to fully reverse coagulopathy in certain patients.Aims: To identify factors predisposing to an incomplete response to the standard idarucizumab 5 g dose.Methods: A systematic literature search in PubMed using terms "dabigatran" and "idarucizumab" covering 2015 to October 2019 identified 387 entries. Titles and abstracts were screened initially, followed by full text review and data extraction from 97 eligible articles. Data extracted included clinical information, dabigatran concentrations, coagulation results, idarucizumab dosage and patient outcomes. Pharmacokinetic simulations were conducted using a two-compartment model to predict the likelihood that acute or chronic kidney disease will contribute to an incomplete reversal of dabigatran-induced anticoagulation.Results: Of 240 published cases receiving idarucizumab, 33 reported dabigatran concentration rebound, within a median time of 22 h. From 231 cases reporting idarucizumab dose, 10 received repeated administration due to a rebound in dabigatran concentrations. Baseline dabigatran concentrations >228 ng/mL were more likely to experience a rebound post-idarucizumab to >30 ng/mL (detectable). For baseline dabigatran >488 ng/mL, the concentration rebounded to >75 ng/mL (therapeutic). The impact of kidney dysfunction on the effect of the recommended dose of idarucizumab: Idarucizumab is expected to neutralise a maximum plasma dabigatran concentration of 980 ng/mL, but most likely a lesser amount. Pharmacokinetic modelling suggests, for patients taking dabigatran 150 mg twice daily, an incomplete response to 5 g idarucizumab is predicted after approximately 72 h dosing when GFR less than 30 mL/min (25% of normal), and after 36 h with severely impaired renal function (GFR 6 mL/min; GFR 5% of normal). Acute dabigatran self-poisoning: Idarucizumab has neutralised dabigatran following deliberate self-poisoning with dabigatran in a limited number of cases, even in the absence of bleeding. There are insufficient data regarding the use of idarucizumab as part of standard supportive care in this context. Clinical use of idarucizumab in complex circumstances: The dilute thrombin time can be used to determine the dabigatran concentration, but other more standard coagulation assays are less precise. A normal aPTT largely excludes dabigatran. We suggest performing coagulation assays and dabigatran concentrations every 6 h for a minimum of 36 h after idarucizumab administration to detect a rebound in dabigatran. This is particularly necessary in patients with glomerular filtration rate <30 mL/min or those with a plasma dabigatran concentration exceeding approximately 500 ng/mL. If a rebound in dabigatran is noted, then repeat administration of idarucizumab 5 g can be considered for reversal of recurrent coagulopathy if clinically indicated.Conclusion: The use of idarucizumab for reversal of dabigatran is complex and requires consideration of clinical circumstances and laboratory investigations. Monitoring post-idarucizumab may be required in acute or chronic kidney disease to detect a rebound in dabigatran concentration and the need for additional doses of idarucizumab.

Unique approach to continuing medical education in clinical pharmacology across Australia and New Zealand.

BACKGROUND: Advanced physician training in clinical pharmacology lacks a continuing education programme. There is a need for continuing medical education but how to introduce and develop education remains unclear. AIMS: The primary aim was to develop and implement a peer-led, web-based multiple choice question approach to continuing education in clinical pharmacology training across Australia and New Zealand. Secondary aims included determining, quality, difficulty, utility, relevance, user-friendliness, sustainability and potential to form part of formal clinical pharmacology physician training. METHODS: In February 2018, a survey of clinical pharmacology trainees identified topics for question development. Questions covering requested topics were developed and piloted in PeerWise between March and October 2018. Participants could rate quality and difficulty of questions using categorical rating scales and make free text comments. After questions were piloted, a survey using a 0-10-point Likert scale and yes/no responses assessed utility, relevance, user-friendliness, sustainability and formalisation potential. RESULTS: Twenty-four trainees were invited to participate. Nine (38%) of trainees completed the initial survey, 10 (42%) attempted questions and 7 (29%) completed the end survey. Median scores of 8.00 (IQR 6.50 - 9.00), 7.00 (IQR 6.50 - 7.50) and 8.00 (IQR 6.50 - 8.00) using a 0-10-point Likert scale indicated trainees found this approach useful, relevant and user-friendly. Five (71%) out of seven responding trainees felt this approach was sustainable and could be incorporated as part of formal clinical training. CONCLUSION: This study suggests that peer-led multiple choice questions could form an enduring education modality which could be incorporated into clinical pharmacology training.