Neural mechanisms mediating positive and negative treatment expectations in visceral pain: A functional magnetic resonance imaging study on placebo and nocebo effects in healthy volunteers

To elucidate placebo and nocebo effects in visceral pain, we conducted a functional magnetic resonance imaging (fMRI) study to analyze effects of positive and negative treatment expectations in a rectal pain model. In 36 healthy volunteers, painful rectal distensions were delivered after intravenous application of an inert substance combined with either positive instructions of pain relief (placebo group) or negative instructions of pain increase (nocebo group), each compared to neutral instructions. Neural activation during cued-pain anticipation and pain was analyzed along with expected and perceived pain intensity. Expected and perceived pain intensity were significantly increased in the nocebo group and significantly decreased in the placebo group. In the placebo group, positive expectations significantly reduced activation of the somatosensory cortex during anticipation and of the insula, somatosensory cortex, and amygdala during pain delivery when compared to neutral expectations. Within the nocebo group, negative expectations led to significantly increased insula activation during painful stimulation. Direct group contrasts during expectation modulation revealed significantly increased distension-induced activation within the somatosensory cortex in the nocebo group. In conclusion, the experience and neural processing of visceral pain can be increased or decreased by drug-specific expectations. This first brain imaging study on nocebo effects in visceral pain has implications for the pathophysiology and treatment of patients with chronic abdominal complaints such as irritable bowel syndrome.     

Enhanced Absorption of Insulin Aspart as the Result of a Dispersed Injection Strategy Tested in a Randomized Trial in Type 1 Diabetic Patients

OBJECTIVE

We investigated the impact of two different injection strategies on the pharmacokinetics and pharmacodynamics of insulin aspart in vivo in an open-label, two-period crossover study and verified changes in the surface-to-volume ratio ex vivo.

RESEARCH DESIGN AND METHODS

Before the clinical trial, insulin aspart was injected ex vivo into explanted human abdominal skin flaps. The surface-to-volume ratio of the subcutaneous insulin depot was assessed by microfocus computed tomography that compared 1 bolus of 18 IU with 9 dispersed boluses of 2 IU. These two injection strategies were then tested in vivo, in 12 C-peptide–negative type 1 diabetic patients in a euglycemic glucose clamp (glucose target 5.5 ± 1.1 mmol/L) for 8 h after the first insulin administration.

RESULTS

The ex vivo experiment showed a 1.8-fold higher mean surface-to-volume ratio for the dispersed injection strategy. The maximum glucose infusion rates (GIR) were similar for the two strategies (10 ± 4 vs. 9 ± 4; P = 0.5); however, times to reach maximum GIR and 50% and 10% of the maximum GIR were significantly reduced by using the 9 × 2 IU strategy (68 ± 33 vs. 127 ± 93 min; P = 0.01; 38 ± 9 vs. 49 ± 16 min; P < 0.01; 23 ± 6 vs. 30 ± 10 min; P < 0.05). For 9 × 2 IU, the area under the GIR curve was greater during the first 60 min (219 ± 89 vs. 137 ± 75; P < 0.01) and halved until maximum GIR (242 ± 183 vs. 501 ± 396; P < 0.01); however, it was similar across the whole study period (1,361 ± 469 vs. 1,565 ± 527; P = 0.08).

CONCLUSIONS

A dispersed insulin injection strategy enhanced the effect of a fast-acting insulin analog. The increased surface-to-volume ratio of the subcutaneous insulin depot can facilitate insulin absorption into the vascular system.Fast-acting insulin analogs have been developed to avoid postprandial glucose peaks (1,2). Some studies suggest that postprandial hyperglycemia can contribute to elevated levels of hemoglobin A_1c (3,4) and lead to the development of short- and long-term diabetes complications (5,6). Although currently available fast-acting insulin analogs have been designed for a better match with meal-induced glucose excursions, insulin absorption and insulin action still lag behind (7,8). Even bolus administration of fast-acting insulin analogs immediately before meals does not completely avoid postprandial glucose peaks. Modern fast-acting insulin analogs still only insufficiently mimic physiological insulin profiles; however, their effect could be further improved by accelerating insulin absorption from the injection site into the vascular system.Accelerated insulin absorption in response to an increased blood flow has been described for heated injection sites (9) or coadministered adjuvants such as hyaluronidase (10–12) but also for a larger distribution of the subcutaneous insulin depot achieved with a modified injection strategy. Human insulin absorption has been tested with a “sprinkler needle” that has 14 holes in its walls and a sealed tip, thus dispersing the insulin bolus at the injection site. With the sprinkler needle, insulin was absorbed more rapidly and glucose levels were less raised relative to a regular injection needle (13). A dispersed insulin bolus should have an increased surface-to-volume ratio and could further contribute to even faster insulin absorption of modern already fast-acting insulin analogs.The aim of our study was to test whether the absorption rate of a fast-acting insulin analog (insulin aspart) could be further accelerated through the dispersion of a single predefined insulin bolus into nine separate insulin injections. We compared the two different injection strategies ex vivo by using microfocus computed tomography (micro-CT) to assess the increase in the surface-to-volume ratio and in vivo by assessing the pharmacokinetic and pharmacodynamic response in a clinical trial.     

Characterisation of non-warfarin-associated bleeding events reported to the Norwegian spontaneous reporting system

Objective

The aim of the study was to analyse non-warfarin-associated bleeding adverse drug events reported to the Norwegian spontaneous reporting system, with characterisation of the bleeding locations, outcome and drug interactions. In addition, concordance in assessments between reporters and evaluators, trend shifts in reporting, and detection of potentially new adverse drug interaction signals were studied.

Methods

Data on bleeding events reported between 1 January 2003 and 31 December 2005 were retrieved from the Norwegian spontaneous reporting system database.

Results

Of 327 case reports of non-warfarin-associated bleeding events, 270 reports (82.6 %) were characterised as serious and 69 (21.1 %) had a fatal outcome. One hundred and eighty-seven bleeds (57.5 %) were gastrointestinal, 57 (17.4 %) were cerebral, and 81 (24.8 %) were from other bleeding sites. The bleeding sites differed with respect to the patient's age, drug use, diagnoses and outcomes. Of drugs associated with bleeding, nonsteroidal anti-inflammatory drugs (NSAIDs)/COX-2 inhibitors (145 reports) and acetylsalicylic acid (128 reports) were most frequently used. Only fibrinolytics were associated with increased mortality. There was a 67.4 % correlation between reporters and evaluators in assessment of drugs associated with bleeding (P?<?0.001), with considerable variation in concordance between drug groups.

Conclusion

Non-warfarin-associated bleeding events are associated with substantial mortality. Old age, cerebral bleeds, number of drugs used, and use of fibrinolytics are all independently associated with increased mortality. The recognition of the bleeding risk of commonly used drugs such as acetylsalicylic acid and heparins may be insufficient among prescribers.     

La gestione del lavoratore portatore di disabilità psichica

«Mental disability management within occupational health surveillance».Introduction:The management of workers with mental disability is a current topic of great interest. The aim of the article is to report the experience of managing cases of employees with mental disabilities in an Italian university hospital and to describe the preventive measures adopted and the therapeutic programs carried out.Methods:A group of 100 workers suffering from psychiatric disorders has been included in a medical surveillance program lasting at least 6 months. The workers were followed up within a protocol that included psychiatric visits, psychotherapeutic interventions, visits by the occupational physician and medico-legal evaluations. Evaluation scales of disease severity and treatment efficacy (CGI) and overall functioning (GAF) were administered at the baseline and after 6 months of follow-up.Results:The sample was mainly composed of nurses (44%) and nursing assistants (24%) and the most commonly diagnosed disorders were mood and anxiety disorders. Participation in the medical surveillance program with the implementation of specific therapeutic strategies and organizational interventions resulted in a statistically significant reduction in the severity of the disease and an improvement in overall functioning and made it possible to keep the job and place of work in almost all cases.Discussion:The results of this experience allow us to affirm that the integration of skills is a valid tool both for the multidisciplinary diagnostic assessment and for the monitoring and management of workers with mental disability under periodic health surveillance.Key words: Psychic disability, health surveillance, occupational medicine, mental disorders     

Psychosocial consequences of potential overdiagnosis in prostate cancer a qualitative interview study

Background Prostate cancer is a frequently diagnosed cancer and made up 6% of male cancer deaths globally in 2008. Its incidence varies more than 25-fold worldwide, which is primarily attributed to the implementation of the prostate-specific antigen (PSA) test in developed countries. To reduce harm of overdiagnosis, most international guidelines recommend surveillance programmes. However, this approach can entail negative psychosocial consequences from being under surveillance for an (over)diagnosed prostate cancer.Aim To explore men’s feelings and experiences in a surveillance programme.Design and setting Qualitative study with Danish men diagnosed with asymptomatic prostate cancer Gleason score ≤ 6, who are in a surveillance programmeMethods 12 semi-structured, individual interviews were conducted and analysed with systematic text condensation and selected theories.Results Most informants reported that they were astonished at the time of diagnosis. They were aware of the small likelihood of dying from cancer, but in some cases, the uncertainty created ambivalence between knowing and not knowing. The men expressed their risk awareness in different ways: a realization that life does not last forever, uncertainty towards the future, a feeling of powerlessness, and a need for control.Conclusions The men in this study had substantial psychosocial consequences from being labelled with a cancer diagnosis. Bearing these men’s high risk of overdiagnosis in mind, it is important to discuss whether the harms of this diagnosis outweigh the benefits. The psychosocial consequences of being in a prostate cancer surveillance programme should be explored further.

KEY POINTS

• Current awareness: The number of men living with an asymptomatic prostate cancer has increased the last 20 years after the implementation of the PSA test.
• Main Statements: Men living with an asymptomatic, low-risk prostate cancer experience negative psychocosial consequences
• GPs should consider the possible negative psychosocial consequences in their decision-making of measuring the PSA level

     

Baseline Prostate-specific Antigen Level in Midlife and Aggressive Prostate Cancer in Black Men

Background

Prostate-specific antigen (PSA) measurement in midlife predicts long-term prostate cancer (PCa) mortality among white men.