Pain management in older adults.

The L-type calcium channel antagonists have been, and continue to be, a very successful group of therapeutic agents targeted at cardiovascular disorders, notably angina and hypertension. The discovery that the voltage-gated calcium channels are a large and widely distributed family with important roles in both the peripheral and central nervous systems has initiated a major search for drugs active at other calcium channel types directed at disorders of the central nervous system, including pain, epilepsy, and stroke. These efforts have not been therapeutically successful thus far, and small molecule equivalents of the L-type blockers nifedipine, diltiazem, and verapamil directed at non-L-type channels have not been found. The underlying reasons for this are discussed together with suggestions for new directions, including fertility control, oxygen-sensitive channels, and calcium channel activators.

Drug targets in the voltage-gated calcium channel family: why some are and some are not.

Chronic kidney disease (CKD) affects both brain structure and function. Patients with CKD have a higher risk of both ischemic and hemorrhagic strokes. Age, prior disease history, hypertension, diabetes, atrial fibrillation, smoking, diet, obesity, and sedimentary lifestyle are most common risk factors. Renal-specific pathophysiologic derangements, such as oxidative stress, chronic inflammation, endothelial dysfunction, vascular calcification, anemia, gut dysbiosis, and uremic toxins are important mediators. Dialysis initiation constitutes the highest stroke risk period. CKD significantly worsens stroke outcomes. It is essential to understand the risks and benefits of established stroke therapeutics in patients with CKD, especially in those on dialysis. Subclinical cerebrovascular disease, such as of silent brain infarction, white matter lesions, cerebral microbleeds, and cerebral atrophy are more prevalent with declining renal function. This may lead to functional brain damage manifesting as cognitive impairment. Cognitive dysfunction has been linked to poor compliance with medications, and is associated with greater morbidity and mortality. Thus, understanding the interaction between renal impairment and brain is important in to minimize the risk of neurologic injury in patients with CKD. This article reviews the link between chronic kidney disease and brain abnormalities associated with CKD in detail.

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Cerebrovascular Disease and Cognition in Chronic Kidney Disease Patients.

In patients suffering from moderate-to-severe chronic kidney disease (CKD) or end-stage renal disease (ESRD), subjected to hemodialysis (HD), pain is very common, but often underestimated. Opioids are still the mainstay of severe chronic pain management; however, their prescription in CKD and HD patients is still significantly low and pain is often under-treated. Altered pharmacokinetics and the lack of clinical trials on the use of opioids in patients with renal impairment increase physicians' concerns in this specific population. This narrative review focused on the correct and safe use of opioids in patients with CKD and HD. Morphine and codeine are not recommended, because the accumulation of their metabolites may cause neurotoxic symptoms. Oxycodone and hydromorphone can be safely used, but adequate dosage adjustments are required in CKD. In dialyzed patients, these opioids should be considered as second-line agents and patients should be carefully monitored. According to different studies, buprenorphine and fentanyl could be considered first-line opioids in the management of pain in CKD; however, fentanyl is not appropriate in patients undergoing HD. Tapentadol does not need dosage adjustment in mild-to-moderate renal impairment conditions; however, no data are available on its use in ESRD. Opioid-related side effects may be exacerbated by common comorbidities in CKD patients. Opioid-induced constipation can be managed with peripherally-acting-μ-opioid-receptor-antagonists (PAMORA). Unlike the other PAMORA, naldemedine does not require any dose adjustment in CKD and HD patients. Accurate pain diagnosis, opioid titration and tailoring are mandatory to minimize the risks and to improve the outcome of the analgesic therapy.

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Safe Use of Opioids in Chronic Kidney Disease and Hemodialysis Patients: Tips and Tricks for Non-Pain Specialists.

Management of arterial hypertension in patients with chronic kidney disease (CKD) remains a major challenge due to its high prevalence and associations with cardiovascular disease (CVD) and CKD progression. Several clinical trials and meta-analyses have demonstrated that aggressive treatment of hypertension in patients with and without CKD lowers the risk of CVD and all-cause mortality, nevertheless the effects of blood pressure (BP) lowering in terms of renal protection or harm remain controversial. Both home and ambulatory BP estimation have shown that patients with CKD display abnormal BP patterns outside of the office and further investigation is required, so as to compare the association of ambulatory versus office BP measurements with hard outcomes and adjust treatment strategies accordingly. Although renin-angiotensin system blockade appears to be beneficial in patients with advanced CKD, especially in the setting of proteinuria, discontinuation of renin-angiotensin system inhibition should be considered in the setting of frequent episodes of acute kidney injury or hypotension while awaiting the results of ongoing trials. In light of the new evidence in favor of renal denervation in arterial hypertension, the indications and benefits of its application in individuals with CKD need to be clarified by future studies. Moreover, the clinical utility of the novel players in the pathophysiology of arterial hypertension and CKD, such as microRNAs and the gut microbiota, either as markers of disease or as therapeutic targets, remains a subject of intensive research.

Hypertension in Chronic Kidney Disease: Novel Insights

Pathophysiological Mechanisms in Cardiorenal Syndrome.

Background: Chronic noncancer pain is pervasive throughout the general patient population, transcending all chronic disease states. Patients with end-stage renal disease (ESRD) present a complicated population for which medication management requires careful consideration of the pathogenesis of ESRD and intimate knowledge of pharmacology. The origin of pain must also guide treatment options. As such, the presentation of neuropathic pain in ESRD can present a challenging case. The authors aim to provide a review of available classes of medications and considerations for the treatment of neuropathic pain in ESRD. Summary: In this narrative review, the authors discuss important strategies and considerations for the treatment of neuropathic pain in ESRD, including the pathogenesis of neuropathic pain, physiological changes for consideration in ESRD patients, and disease-specific consideration for medication selection. Pharmacotherapeutic classes discussed include: anticonvulsants, antiarrhythmics, antidepressants, topicals, and opioids. Key Message: Pain management in ESRD patients requires careful assessment of drug-specific properties, accumulation, metabolism (presence of active/toxic metabolites), extraction by dialysis, and presence of drug – drug interactions. In the absence of pharmacokinetic data in ESRD patients, therapeutic window and potential risks should be factored in the decision making along with continued monitoring throughout therapy.

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Pharmacotherapeutic Management of Neuropathic Pain in End-Stage Renal Disease.

Hypertension is an important contributor to progression of nondiabetic chronic kidney disease (CKD). Compelling observational evidence indicates that the divergence of blood pressure (BP) away from an ideal range in either direction is associated with a progressive rise in the risk of mortality and cardiovascular and renal disease progression. To date, various clinical trials and meta-analyses examining strict versus less intensive BP control in nondiabetic CKD have not conclusively demonstrated a renal advantage of one BP-lowering approach over another, except in certain subgroups such as proteinuric patients where evidence is circumstantial. As recent data have come to light suggesting that intensive BP control yields superior survival and cardiovascular outcomes in patients at high risk for cardiovascular disease, interest in the prospect of whether such benefit extends to individuals with CKD has surged. This review is a comprehensive analysis of antihypertensive literature in nondiabetic renal disease, with a particular emphasis on BP target.

Antihypertensive therapy in nondiabetic chronic kidney disease: a review and update.

The ideal blood pressure (BP) target for renoprotection is uncertain in patients with non-diabetic chronic kidney disease (CKD), especially considering the influence exerted by pre-existing proteinuria In this pooled analysis of landmark trials, we coalesced individual data from 5001 such subjects randomized to intensive versus standard BP targets We employed multivariable regression to evaluate the relationship between follow-up systolic blood pressure (SBP) and diastolic blood pressure (DBP) on CKD progression (defined as glomerular filtration rate decline by 50% or end-stage renal disease), focusing on the potential for effect modification by baseline proteinuria or albuminuria The median follow-up was 32 years We found that SBP rather than DBP was the primary predictor of renal outcomes The optimal SBP target was 110–129 mm Hg We observed a strong interaction between SBP and proteinuria such that lower SBP ranges were significantly linked with progressively lower CKD risk in grade A3 albuminuria or ≥05–1 g/day proteinuria (relative to SBP 110–119 mm Hg, the adjusted HR for SBP 120–129 mm Hg, 130–139 mm Hg, and 140–149 mm Hg was 15, 23, and 33, respectively; all p 005), while in grade A1 albuminuria or proteinuria 01) We conclude that in non-diabetic CKD, stricter BP targets

https://jim.bmj.com/content/jim/early/2021/02/04/jim-2020-001702.full.pdf

Roy O. Mathew

Papers

Pathophysiological Mechanisms in Cardiorenal Syndrome.

Pharmacotherapeutic Management of Neuropathic Pain in End-Stage Renal Disease.

Antihypertensive therapy in nondiabetic chronic kidney disease: a review and update.

Effect of intensive blood pressure on the progression of non-diabetic chronic kidney disease at varying degrees of proteinuria.