An answered call for aid? Cannabinoid clinical framework for the opioid epidemic.

BACKGROUND: The opioid crisis continues in full force, as physicians and caregivers are desperate for resources to help patients with opioid use and chronic pain disorders find safer and more accessible non-opioid tools. MAIN BODY: The purpose of this article is to review the current state of the opioid epidemic; the shifting picture of cannabinoids; and the research, policy, and current events that make opioid risk reduction an urgent public health challenge. The provided table contains an evidence-based clinical framework for the utilization of cannabinoids to treat patients with chronic pain who are dependent on opioids, seeking alternatives to opioids, and tapering opioids. CONCLUSION: Based on a comprehensive review of the literature and epidemiological evidence to date, cannabinoids stand to be one of the most interesting, safe, and accessible tools available to attenuate the devastation resulting from the misuse and abuse of opioid narcotics. Considering the urgency of the opioid epidemic and broadening of cannabinoid accessibility amidst absent prescribing guidelines, the authors recommend use of this clinical framework in the contexts of both clinical research continuity and patient care.

Low sodium diet corrects the defect in lymphocyte beta-adrenergic responsiveness in hypertensive subjects.

To determine the role of dietary sodium intake in the reduction in beta-adrenergic sensitivity in hypertension, lymphocyte beta-receptors from 8 borderline hypertensive and 16 normotensive subjects were studied after 5 d on a high sodium diet (400 meq/d) and also following a low sodium diet (10 meq/d). During the high sodium diet, lymphocyte beta-receptor-stimulated adenylate cyclase activity, expressed as the relative increase over basal levels stimulated by the beta-agonist isoproterenol, was significantly (P less than 0.025) decreased in hypertensive (24 +/- 5%, mean +/- SE) compared with normotensive (42 +/- 4%) subjects. Neither beta-receptor density nor the proportion of nonsequestered beta-receptors differed between groups. A low sodium diet significantly increased beta-receptor-stimulated adenylate cyclase activity in hypertensives (low sodium, 51 +/- 7%; high sodium, 24 +/- 5%, P less than 0.025) to a level not different than that of normotensives (46 +/- 5%). Thus, reduced lymphocyte beta-receptor responsiveness in hypertensive subjects is not due to beta-receptor sequestration and is corrected on a low sodium diet. Dietary sodium may be an important factor in the beta-receptor defect in early hypertension.

Urinary kallikrein response to acute saline or water loads in hypertensive and normal humans.

Urinary kallikrein excretion during acute water or saline loading was studied in normal and hypertensive humans after chronic Na+ depletion and Na+ loading to answer the following questions. 1. Is urinary kallikrein a natriuretic or diuretic substance? 2. During acute water or saline loading, does the underlying Na+ balance influence (a) the urinary kallikrein response? or (b) the relationship between urinary kallikrein and renal Na+ or water handling? 1) Urinary kallikrein did not change during a 1.2 liter water load given to nine white hypertensive and five white normal men. Urinary kallikrein was significantly decreased, however, in five white hypertensive and five white normal subjects during and after 1 hour of isotonic saline infusion (30 ml/kg). In sodium-depleted hypertensive patients kallikrein excretion was decreased from 19.8 to 9.5 mEU /min, and in Na+-depleted normal subjects it was decreased from 15.7 to 12.6 mEU /min (p = 0.003). The response in hypertensive patients was not different from normal subjects. In all Na+-loaded subjects, kallikrein excretion was also significantly decreased during isotonic saline infusion (p = 0.01). Urinary kallikrein did not change in three other subjects given hypertonic saline. 2(a) The underlying state of Na+ balance influenced the baseline level of kallikrein excretion, but not the directional decline in kallikrein during isotonic saline. (b) In Na+-restricted hypertensives given isotonic saline, urinary kallikrein was inversely related to the fractional excretion of Na+ (r = -0.54, p less than 0.01) and the tubular reabsorption of H2O (TcH2O/GFR; r = -0.50, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal urinary kallikrein in hypertension is not related to aldosterone or plasma renin activity.

The relationships between urinary kallikrein (Ukal), and plasma renin activity (PRA), urinary aldosterone (Ualdo), Na+ balance, SK+, and renal function were studied in essential hypertensives (EHT) and normals. Ukal was measured by a radiochemical esterolytic assay. We studied 18 white patients with EHT (15 men, 3 women) ages 31.6 to +/- 2.1 (SEM) yrs, BP 138 +/- 2/95 +/- 2 mm Hg. and 12 white normals (NLS) (7 men, 5 women) ages 30.2 +/- 2.3 yrs, BP 112 +/- 4/71 +/- 2 mm Hg. All received a 5-day diet of 400 mEq Na+, 80 mEq K+/day, and 5 days of 10 mEq Na+, 80 mEq K+/day. All achieved Na+ balance by Day 5. On Day 5 of the low Na+ diet, 24 hr. Ukal in EHT was 15.8 +/- 2.4 (esterase units/24 hr) vs NLS, 17.0 +/- 2.8 PRA was the same in EHT and NLS, but Ualdo was higher in NLS. (Day 5, low Na+, EHT, Ualdo = 29.4 +/0 3.3 microgram/24h. vs NLS 41.8 +/- 4.7, p less than 0.02). Analysis of individuals showed that all NLS increased Ukal after salt restriction, while 3 EHT decreased Ukal after salt restriction. This abnormal response in EHT was not related to abnormalities in Ualdo, PRA, Na+ balance, SK+, or creatinine clearance. In 3 EHT with low-renin EHT, the Ukal response was normal. In two of four patients with primary aldosteronism, Ukal was normal despite increased Ualdo. The Ukal response to salt restriction is abnormal in some EHT, unrelated to Ualdo or PRA, suggesting either a primary defect in Ukal and/or the presence of other factors modulating Ukal in EHT.

Dietary salt produces abnormal renal vasoconstrictor responses to upright posture in borderline hypertensive subjects.

We studied the effect of high and low NaCl diets in normotensive and borderline hypertensive subjects to determine if a high NaCl diet produces abnormal renal vasoconstriction during the stress of upright posture in borderline hypertensive subjects. We studied 13 normotensive young men with diastolic blood pressures below 85 mm Hg and nine borderline hypertensive young men defined by diastolic blood pressures intermittently above 90 mm Hg. The subjects achieved comparable sodium balance during 6 days of low NaCl (10 mEq Na, 40 mEq Cl, 100 mEq K) and high NaCl (400 mEq Na, 400 mEq Cl, 100 mEq K) diets. In the normotensive subjects, standing for 30 minutes resulted in a tendency for diastolic blood pressure to fall during both diets. In contrast, during standing borderline hypertensive subjects showed no change in diastolic blood pressure during the low salt diet and a tendency for diastolic blood pressure to increase after the high salt diet. Standing reduced renal plasma flow in both groups during both diets. However, only during the high NaCl diet did the absolute decrease and percent decrease in renal plasma flow during standing differ significantly (p less than 0.05 and p less than 0.01, respectively) between the borderline hypertensive (-151 +/- 24 ml/min/1.73m2; -29 +/- 4%) and normotensive subjects (-79 +/- 17 ml/min/1.73m2; -15 +/- 3%). The resultant increase in the renal vascular resistance index with standing did not differ between the two groups during the low NaCl diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Elevated sympathetic nerve activity in borderline hypertensive humans. Evidence from direct intraneural recordings.

Reports of elevated plasma catecholamine levels and augmented responses to autonomic blockade suggest increased sympathetic tone in borderline hypertension. It is not known if this reflects greater sympathetic neural outflow. We directly recorded muscle sympathetic nerve activity (microneurography) in 15 normotensive and 12 borderline hypertensive age-matched men to determine whether borderline hypertensive individuals have elevated sympathetic nerve activity. Supine heart rate, blood pressure, plasma norepinephrine, and efferent muscle sympathetic nerve activity (peroneal nerve) were measured after 6 days of both low and high dietary sodium intake (10 and 400 meq sodium/24 hr). Sympathetic nerve activity was elevated significantly in borderline hypertensive individuals on both low (37 +/- 1 in borderline hypertensive individuals vs. 29 +/- 1 bursts/min in normotensive individuals; p less than 0.01) and high (25 + 1 in borderline hypertensive individuals vs. 16 +/- 1 bursts/min in normotensive individuals; p less than 0.01) sodium diets. The borderline hypertensive group had higher systolic (p less than 0.01) and diastolic (p less than 0.05) blood pressures independent of sodium intake. Across both groups, high sodium intake reduced muscle sympathetic nerve activity (p less than 0.001), plasma norepinephrine (p less than 0.001), diastolic blood pressure (p less than 0.02), heart rate (p less than 0.002), and increased weight (p less than 0.005). A significant (p less than 0.05) group-by-diet interaction was observed for plasma norepinephrine levels. Specifically, compared with the normotensive group, plasma norepinephrine levels in the borderline hypertensive group tended to be higher on low sodium diet (p = 0.08) and lower on high sodium diet (p = 0.23).(ABSTRACT TRUNCATED AT 250 WORDS)

Fludrocortisone suppression of sympathetic nervous activity.

Fludrocortisone depressed plasma norepinephrine in normal subjects but to a lesser degree than it depressed renin activity or urinary aldosterone excretion. Sympathetic nervous reactivity (defined as upright/supine plasma norepinephrine) was decreased more than supine plasma norepinephrine. Pretreatment supine plasma norepinephrine (but not plasma renin activity or aldosterone excretion) correlated with blood pressure changes during fludrocortisone dosing, which suggests participation of the sympathetic nervous system in the blood pressure elevations reported during exogenous steroid administration or primary aldosteronism. Suppression of sympathetic nervous activity and reactivity by fludrocortisone tends to explain its limited usefulness in patients with autonomic dysfunction and postural hypotension.

Renal clearances of oxypurinol and inulin on an isocaloric, low-protein diet.

In previous studies a low-calorie, low-protein diet caused a sustained reduction in both oxypurinol and uric acid renal clearances (CLR). With the hypothesis that the decrease in CLR was due to the low-protein and not the low-caloric content of the diet, we studied the CLR of oxypurinol, uric acid, creatinine, and inulin in normal subjects during isocaloric (2600 calories per 70 kg per day), normal-protein (150 gm per day), and low-protein (19 gm per day) diets. There were three major findings: (1) the CLR of oxypurinol declined from 26.6 +/- 1.8 ml/min on the normal-protein diet to 13.5 +/- 1.4 ml/min on the isocaloric low-protein diet (p less than 0.05); (2) the CLR of inulin and creatinine fell 14% and 20%, respectively, on the low-protein diet compared with the normal-protein diet (both p less than 0.05); and (3) there was a diurnal variation in the CLR of oxypurinol. We conclude that the decreased CLR of oxypurinol was the result of the reduced protein content of the diet and the CLR of both inulin and creatinine were decreased on the low-protein diet.

Phosphorus metabolism in potassium-deficient rats.

Hypophosphatemia as a consequence of potassium deficiency has been reported sporadically. Most cases have been complicated by other factors which might lead to decreased serum phosphorus levels. Therefore, the serum phosphorus in this study was measured in Sprague-Dawley rats with nutritionally induced potassium deficiency. Severe potassium depletion was manifested by hypokalemia (2.4 mEq/liter versus 3.9 mEq/liter in controls) and decreased muscle potassium content. Statistically significant hypophosphatemia did not develop, although decreased muscle phosphorus content was observed. Therefore, hypophosphatemia is not a regular accompaniment of severe potassium deficiency in the rat.

Predicting change in depression following renal transplantation: effect of patient coping preferences.

Improvement in patient quality of life is a central goal of renal transplantation. This study examined the hypothesis that change in depression following transplantation would vary as a function of patient coping preferences. Sixty patients were assessed with the Krantz Health Opinion Survey and the Beck Depression Inventory while on the waiting list for a cadaveric renal transplant. Patients were reassessed approximately 12 months later. Among the 33 patients receiving a transplant during the follow-up period, those with a high preference for health-related information exhibited a substantial reduction in depression. In contrast, patients low in preference for information showed a slight increase in depression. Among the 27 patients who were not transplanted during the follow-up period, preference for information had no effect on depression. Patient differences in preference for behavioral involvement did not exert a significant effect on depression.

Monitoring attentional style and medical regimen adherence in hemodialysis patients.

Previous research involving individuals facing chronic health problems suggests that an attentional style characterized by pronounced monitoring of threat-relevant information is associated with poorer behavioral and emotional adjustment. This study examined the hypothesis that a pronounced monitoring style would be associated with poorer medical regimen adherence in a sample of 51 chronic hemodialysis patients. Hierarchical regression analyses (controlling for demographic factors and trait anxiety) revealed that "high monitors" exhibited higher interdialysis weight gains and higher serum K values reflecting poorer adherence to fluid-intake and dietary restrictions. However, monitoring was not associated with a measure of medication adherence. Partial support was found for a model suggesting that a lack of perceived control is responsible for the relationship between higher monitoring and poorer adherence.

Body consciousness, illness-related impairment, and patient adherence in hemodialysis.

Recent theory and evidence suggests that bodily self-focusing tendencies (e.g. private body consciousness) may be associated with medical regimen adherence among chronically ill patients. The present study examined the joint effects of private body consciousness and degree of illness-related physical impairment on treatment regimen adherence in a sample of 52 hemodialysis patients. It was predicted that the effect of PBC on adherence would vary as a function of patients' level of illness-related physical impairment. For patients experiencing more severe impairment, higher PBC scores were associated with poorer adherence to the prescribed medication and dietary regimen. In contrast, for patients experiencing a relatively low degree of disease-related physical impairment, higher private body consciousness was associated with more favorable adherence. Results are discussed in terms of self-focused attention and behavioral self-regulation theories. Implications for future research and clinical intervention are also discussed.

Coping with treatment-related stress: effects on patient adherence in hemodialysis.

With a modified version of the Ways of Coping Checklist, the relation of coping to adherence among 57 hemodialysis patients was examined. The association of a particular type of coping to adherence was predicted to depend on the specific type of stressful encounter being considered. As predicted, coping efforts involving planful problem solving were associated with more favorable adherence when used in response to stressors involving a relatively controllable aspect of the hemodialysis context. For less controllable stressors, coping efforts involving emotional self-control were associated with more favorable adherence. The seeking of informational support in response to an uncontrollable encounter was associated with poorer fluid-intake adherence. Confrontive coping was associated with poorer adherence for both high- and low-control situations.

The effects of therapy for mild hypertension on circulating level of dopamine beta-hydroxylase.

Circulating dopamine beta-hydroxylase levels and norepinephrine excretion were measured in 76 mild hypertensive patients. Levels of dopamine beta-hydroxylase, norepinephrine excretion and blood pressure were obtained both before and after the initiation of therapy. Data from 20 patients exhibiting a diastolic blood pressure decrease of 10 mmHg or more were compared with data from 10 normotensive individuals. Changes in dopamine beta-hydroxylase levels were similar for the two groups and were not related to blood pressure changes. Intra-individual variation was small in both groups. There were no detectable functional relationships between diastolic pressure and urinary norepinephrine, norepinephrine and dopamine beta-hydroxylase or dopamine beta-hydroxylase and diastolic pressure. It dose not seem likely that dopamine beta-hydroxylase levels can replace urinary catecholamines as a commonly used index of sympathetic activity.

The short-term course of renal function in malignant hypertensives with renal insufficiency.

Vigorous antihypertensive therapy in patients with malignant hypertension and renal insufficiency was evaluated to (a) predict which patients would show short-term improvement in renal function and which would require dialysis and (b) establish a time-frame for the improvement. Twenty-one patients were discharged at 32 +/- 4 days with improved or stable renal function (compared to admission) and another 21 patients had worse renal function at 42 +/- 7 days. Admission blood pressure and blood pressure control were the same in the two groups. If admission serum creatinine (Scr) was 1.4-4.4 mg/dl, 68% of the patients were discharged with stable or improved Scr and dialysis was not required. If Scr was 4.5-6.9 mg/dl, 1/4 required dialysis; if 7-9.9 mg/dl, 1/2 required dialysis; if greater than 10 mg/dl, 3/4 required dialysis. Seven of 8 patients admitted with congestive heart failure required dialysis. In 10% of patients (n = 5) renal function immediately stabilized. In 30% (n - 13) renal function progressively deteriorated. In 60% (n = 24) renal function transiently deteriorated and then improved. In 22 of the 24, Scr peaked by 2 weeks and then declined. Malignant hypertensives with renal insufficiency who will potentially show improvement in renal function can be identified after two weeks of vigorous antihypertensive therapy. Four of the total group (n = 42) died during hospitalization and an additional 9 patients died by 1 year follow-up. The overall 1 year survival was 69%.

Nephrology rounds, University of Iowa Hospitals: renal tubular acidosis.

We have discussed two patients who had renal tubular acidosis complicated by hypokalemia. The first patient had a distal acidifying defect. Circumstantial evidence has been presented suggesting that exposure to toluene-diisocyanate or toluene-diamine played a role in the pathogenesis. The acidosis and the hypokalemia of this patient were easily corrected by the administration of small amounts of sodium bicarbonate without potassium supplementation. The second patient had an interstitial nephritis of unknown etiology and presented with moderate renal insufficiency, renal tubular acidosis, and proximal as well as distal acidifying defects. The proximal tubular dysfunction was associated with general aminoaciduria and glucosuria. This patient required large quantities of both alkali and potassium to correct the electrolyte abnormalities. The mechanisms of potassium wasting in proximal and distal renal tubular acidosis are reviewed. A classification is presented of cellular defects that may underlie the different renal acidifying defects. Attempts to distinguish between pump and permeability defects from urinary pCO2 levels must take into account the simultaneous HCO-3 concentration, since large pCO2 elevations require the presence of ample HCO-3 in the urine. Permeability defects may impair urinary acidification by either abnormal back flux of H+ out of the lumen or increased influx of HCO-3 into the lumen. In studies of acidification in vitro, amphotericin B causes increased H+ permeability and has little effect on HCO-3 permeability. Toluene-diamine causes a marked permeability defect which is reversible, but remains to be defined in terms of the ion species, HCO-3 or H+, affected. At times, hyperchloremic acidosis is caused by distal defects in net acid excretion that occur without impairment of the H+ gradient. In certain patients with hypoaldosteronism, for example, distal H+ secretion may be reduced without change in the force of the H+ pump.

Renal and hemodynamic effects of atrial natriuretic peptide in patients with cirrhosis.

The effects of anaritide, a 25-amino-acid synthetic analogue of ANP, were evaluated in 28 patients with cirrhosis complicated by ascites and/or edema. Each patient received two doses of the agent, as well as an infusion of placebo. Six different doses were tested ranging from 0.015-0.300 microgram/kg/min. The infusions lasted for 2 hours and were flanked by both baseline and recovery periods. There was a significant effect of placebo on urinary sodium and chloride excretion rates but no effect on urine flow rate. In response to anaritide, the urine flow rate increased at 0.03, 0.06, 0.075, and 0.100 microgram/kg/min. The sodium and chloride excretion rates increased at all doses except the highest dose. There was no definite effect of anaritide on urinary potassium, calcium, and phosphate excretion rates. There was also no significant effect on creatinine clearance. The mean arterial pressure decreased in response to the 0.060, 0.075, and 0.100 microgram/kg/min doses. In addition, five of the patients receiving the highest dose (0.300 microgram/kg/min) had decreases in their systolic pressures to 90 mm Hg or less. In conclusion, anaritide is natriuretic and diuretic in patients with cirrhosis complicated by ascites and/or edema. Its effect, however, on arterial pressure may limit its therapeutic potential in this patient population.

Multidimensional chirp algorithms for computing Fourier transforms.

Continuous versions of the multidimensional chirp algorithms compute the function G(y)=F(My), where F(y) is the Fourier transform of a function f(x) of a vector variable x and M is an invertible matrix. Discrete versions of the algorithms compute values of F over the lattice L(2)=ML(1 ) from values of f over a lattice L(1), where L(2) need not contain the lattice reciprocal to L(1). If M is symmetric, the algorithms are multidimensional versions of the Bluestein chirp algorithm, which employs two pointwise multiplication operations (PMOs) and one convolution operation (CO). The discrete version may be efficiently implemented using fast algorithms to compute the convolutions. If M is not symmetric, three modifications are required. First, the Fourier transform is factored as the product of two Fresnel transforms. Second, the matrix M is factored as M=AB, where A and B are symmetric matrices. Third, the Fresnel transforms are modified by the matrices A and B and each modified transform is factored into a product of two PMOs and one CO.

Long term follow-up of prophylactic caval clipping.

120 high risk patients who underwent prophylactic inferior vena cava clipping were retrospectively evaluated to determine the incidence of post clipping leg swelling and pulmonary embolism. Each one of those patients had at least two criteria for the clipping. These criteria of high risk factors were precisely identified. There were two patients who had postoperative pulmonary embolism but none of them was fatal, i.e. less than two per cent. Two patients developed severe leg swelling (less than two per cent) and six had mild leg swelling (less than six per cent). Prophylactic inferior vena cava clipping is a safe and effective mean to prevent post-operative pulmonary embolism.

Local and systemic effects of orally applied sodium salts.

This study determines whether the oral application of a baking soda-3% hydrogen peroxide dentifrice and a nearly saturated sodium chloride mouthwash, as a home care method for treating periodontal disease, creates a sodium burden for human subjects. The dietary intake and urinary excretion of sodium and potassium were monitored in participating subjects. Urinary sodium did not increase in subjects using the method. Desquamative gingival lesions, however, were seen in all treated subjects. Further study is needed to determine safe salt concentrations for this home care regimen.