Jan Hasselström

Morphine pharmacokinetics and metabolism in humans : enterohepatic cycling and relative contribution of metabolites to active opioid concentrations

SummaryMorphine, morphine-6-glucuronide (M6G), morphine-3-glucuronide (M3G) and normorphine were analysed with high performance liquid chromatography in plasma and urine, collected over 72h after administration of single intravenous 5mg and oral 20mg doses of morphine to 7 healthy volunteers. Systemic plasma clearance of morphine was on average 21.1 ± 3.4 ml/min/kg (1.27 ± 0.20 L/h/kg), volume of distribution was 2.9 ± 0.8 L/kg and oral bioavailability was 29.2 ± 7.2%. Clearance of morphine to form M3G and M6G comprised 57.3% and 10.4%, respectively, and renal clearance comprised 10.9% of total systemic plasma clearance; hence, more than one-fifth of a dose (20.8%) remained as unidentified residual clearance. On the basis of the area under the plasma concentration-time curves determined after oral and intravenous administration, the ratios of M6G: morphine were 3.6 ± 1.2 and 0.7 ± 0.3, respectively. The corresponding figures for M3G: morphine were 29.9 ± 6.8 and 7.7 ± 1.4. Differences in metabolic ratios between the parenteral and oral routes could be attributed solely to differences in morphine concentrations as evidenced both by plasma concentrations and amounts excreted in urine. An oral: parenteral potency ratio of 1: 3 may, thus, be due to differences in circulating amounts of morphine since the proportions of an administered dose found as M6G and M3G after administration by both routes were equal.A major finding was a slowly declining terminal phase of morphine and metabolites that was evident both in plasma and in urinary excretion versus time curves, where the half-lives of morphine, M3G and M6G were 15.1 ± 6.5h, 11.2 ± 2.7h and 12.9 ± 4.5h, respectively. The terminal half-life of normorphine was 23.9 ± 10.1 h after oral administration. Comparison of oral with intravenous excretion curves showed that a greater part of morphine and metabolites were excreted during the slowly declining phase after the oral dose than the intravenous dose, which is highly suggestive of enterohepatic cycling. The renal clearance of M6G and morphine was seen to exceed creatinine clearance, possibly due to an active secretion process.

Prevalence of pain in general practice

OBJECTIVE The aim of this study is to estimate the prevalence and diagnostic pattern of pain at the primary care level during one year in a group practice. This practice serves the patients of a geographically defined area with approximately 14,000 inhabitants.

Risk scoring and thromboprophylactic treatment of patients with atrial fibrillation with and without access to primary healthcare data: Experience from the Stockholm health care system

BACKGROUND Earlier validation studies of risk scoring by CHA2DS2VASc for assessments of appropriateness of warfarin treatment in patients with atrial fibrillation have been performed solely with diagnoses recorded in hospital based care, even though many patients to a large extent are managed in primary care. METHODS Cross-sectional registry study of all 43 353 patients with a diagnosis of non-valvular atrial fibrillation recorded in inpatient care, specialist ambulatory care or primary care in the Stockholm County during 2006-2010. RESULTS The mean CHA2DS2VASc score was 3.82 (4.67 for women and 3.14 for men). 64% of the entire cohort of patients with atrial fibrillation had the diagnosis in primary care (12% only there). The mean CHA2DS2VASc score of patients with a diagnosis only in inpatient care or specialist ambulatory care increased from 3.63 to 3.83 when comorbidities registered in primary care were added. In 2010 warfarin prescriptions were claimed by 47.2%, and ASA by 41.6% of the entire cohort. 34% of patients with CHA2DS2VASc=1 and 20% with CHA2DS2VASc=0 had warfarin treatment. ASA was more frequently used instead of warfarin among women and elderly patients. CONCLUSIONS Registry CHA2DS2VASc scores were underestimated without co-morbidity data from primary care. Many individuals with scores 0 and 1 were treated with warfarin, despite poor documentation of clinical benefit. In contrast, warfarin appears to be underused and ASA overused among high risk atrial fibrillation patients. Lack of diagnoses from primary care underestimated CHA2DS2VASc scores and may thereby have overestimated treatment benefits in low-risk patients in earlier studies.

The analgesic effect of racemic ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans

Background: Ketamine in sub‐dissociative doses has been shown to have analgesic and phantom‐Limb pain, where conventional treatment has often failed. Chronic ischemic pain due to lower extremity arteriosclerosis obliterans often responds poorly to analgesics, and the pain‐generating mechanisms are not well understood.

Gender differences in antihypertensive drug treatment: results from the Swedish Primary Care Cardiovascular Database (SPCCD)

There are gender differences in antihypertensive treatment. This study aimed to investigate if gender differences in treatment could be explained by comorbidities. In addition, we aimed to study whether blood pressure control is different in women and men, and whether women interrupt treatment more often with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) compared with men.This cohort study within the Swedish Primary Care Cardiovascular Database included 40,825 patients with hypertension attending primary health care from 2007 to 2008. Cardiovascular comorbidities, with the exception of heart failure, were more common in men. Women were more often treated with diuretics, and men with ACEI, as were hypertensive patients with diabetes. Comorbidities could not entirely explain gender differences in antihypertensive treatment in a regression model. Women had higher systolic and lower diastolic blood pressure; this was also true in subgroups with cardiovascular comorbidity. Men more often than women were prescribed ACEIs/ARBs and interrupted treatment. Women and men are treated with different antihypertensive drugs, and this is not fully explained by differences in comorbidities. Women have higher systolic blood pressures, irrespective of comorbidity. Men have interrupted treatment more often with ACEIs/ARBs. These gender differences could affect outcome and warrant further investigation.

Antihypertensive treatment and control in a large primary care population of 21 167 patients.

The efficacy of antihypertensive drug therapy is undisputed, but observational studies show that few patients reach a target blood pressure <140/90 mm Hg. However, there is limited data on the drug prescribing patterns and their effectiveness in real practice. This retrospective observational survey of electronic patient records extracted data from 24 Swedish primary health-care centres, with a combined registered population of 330 000 subjects. We included all patients ⩾30 years with a recorded diagnosis of hypertension who consulted the centres in 2005 or 2006 (n=21 167). Main outcome measures were systolic and diastolic blood pressures, and prescribed antihypertensive drug classes. Only 27% had a blood pressure <140/90 mm Hg. The number of prescribed drugs increased with age, except among the oldest (⩾90 years). Only 29% of patients given monotherapy had a blood pressure <140/90 mm Hg. Women more often received diuretics (52 vs 42%), and less often angiotensin-converting enzyme inhibitors (22 vs 33%) and calcium channel blockers (26 vs 31%) than men. β-Blockers and diuretics were the most common drug classes prescribed, independent of comorbidity. In conclusion, one out of four primary care patients with hypertension reach target blood pressure. More frequent use of drug combinations may improve blood pressure control.

SINGLE-DOSE AND STEADY-STATE KINETICS OF MORPHINE AND ITS METABOLITES IN CANCER PATIENTS : A COMPARISON OF TWO ORAL FORMULATIONS

SummaryThe single-dose and steady state kinetics of morphine given as controlled-release tablets (30 mg every 12 h) and as a solution (15 mg every 6 h) have been compared in 11 cancer patients with chronic pain. The concentrations of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were analyzed by HPLC.There were no significant differences between the tablets and solution in the mean steady state concentrations of morphine, M3G or M6G. The tmax was 3.3 h for the tablets compared to 1.1 h for the solution.After giving the controlled-release tablets every 12 h there was a significantly higher fluctuation index of the morphine concentrations than after the solution. Urinary recovery at steady state was comparable between the two preparations, with averages of 57% and 47%, respectively.Thus, no major differences were found in the pharmacokinetics of morphine and its glucuronidated metabolites after 30 mg morphine as controlled-release tablets every 12 h or 15 mg of morphine solution every 6 h, except for a significantly longer tmax and greater fluctuation in morphine concentrations after the controlled-release tablets.

The Swedish Primary Care Cardiovascular Database (SPCCD): 74 751 hypertensive primary care patients.

Abstract Objective. To describe the Swedish Primary Care Cardiovascular Database, SPCCD. Design. Longitudinal data from electronic medical records, linked to national registers. Setting. 48 primary healthcare centres in urban (south-western Stockholm) and rural (Skaraborg) regions in Sweden. Subjects. Patients diagnosed with hypertension 2001–2008. Main outcome measures. Blood pressure (BP) and impact of retrieval of data on BP levels, clinical characteristics, co-morbidity and pharmacological treatment. Results. The SPCCD contains 74 751 individuals, 56% women. Completeness of data ranged from > 99% for drug prescriptions to 34% for smoking habits. BP was recorded in 98% of patients during 2001–2008 and in 63% in 2008. Mean BP based on the last recorded value in 2008 was 142 ± 17/80 ± 13 mmHg. Digit preference in BP measurements differed between the two regions, p < 0.001. Antihypertensive drugs were prescribed in primary healthcare to 88% of the patients in 2008; however, when all prescribers were included 96% purchased their drugs. Cardiovascular co-morbidity and diabetes mellitus were present in 28% and 22%, respectively. Conclusion. This large and representative database shows that there is room for improvement of BP control in Sweden. The SPCCD will provide a rich source for further research of hypertension and its complications.

The effect of codeine on gastrointestinal transit in extensive and poor metabolisers of debrisoquine

AbstractMethods: Codeine (50 mg) was administered to 12 extensive metabolisers (EM) and 12 poor metabolisers (PM) of debrisoquine. The oro-caecal transit time was estimated by the hydrogen breath test. The urinary excretion of codeine and metabolites during a 6-h interval was estimated after simultaneous analysis of codeine, morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), morphine (M), normorphine (NM), norcodeine, norcodeine glucuronide and codeine-6-glucuronide using HPLC. Results: The mean transit times after placebo were 1.3 h in the EM and 1.4 h in the PM. The corresponding figures after ingestion of codeine were 2.2 h and 2.1 h. The differences between the groups were statistically and clinically insignificant. The effect of codeine compared with placebo was significantly different in both groups. As expected, the metabolites of the O-demethylation pathway, M, M6G, M3G and NM were significantly lower in the PM. Interestingly, the recovery of the dose in the form of codeine (>1.7 times) and norcodeine (>2.5 times) was significantly higher in the PM, indicating compensatory metabolism via N-demethylation. Conclusion: In contrast to the analgesic effect, the prolongation of gastrointestinal transit caused by the drug does not depend on the formation of O-demethylated active metabolites M, M6G or NM.

Enantioselective steady-state kinetics of unbound disopyramide and its dealkylated metabolite in man

SummaryDisopyramide is provided as a racemic mixture of R and S enantiomers, which have different pharmacodynamic and pharmacokinetic characteristics. Five volunteers were given racemic disopyramide 100 mg and 200 mg t.d.s. in a cross-over design. Plasma and urine concentrations of disopyramide and its active metabolite monodesisopropyl-disopyramide (MND) were determined at steady state by an enantioselective HPLC method. Unbound drug in plasma was measured after ultrafiltration.There was enantioselective clearance of unbound disopyramide (0.39 l.h−1.kg−1 for R-disopyramide and 0.58 l.h−1.kg−1 for S-disopyramide after 100 mg t.d.s.). The enantioselectivity was due to differences in the metabolism of disopyramide to MND and in further non-renal clearance, and the renal clearance of disopyramide was not enantioselective.The in vivo protein binding of disopyramide, which was saturable for both enantiomers, was also enantioselective. The difference in binding of the two enantiomers was explained by a difference in apparent binding capacity rather than in apparent binding affinity.The renal clearance of S-MND was significantly higher than R-MND (0.29 and 0.19 l.h−1.kg−1, respectively, after 100 mg t.d.s.). The renal clearance of MND also showed a tendency to saturation at higher concentrations.