Jacob Juel

Pain severity reduces life quality in chronic pancreatitis: Implications for design of future outcome trials

BACKGROUND/OBJECTIVES Chronic pancreatitis (CP) is a disabling disease characterised by abdominal pain, and various pancreatic and extra-pancreatic complications. We investigated the interactions between pain characteristics (i.e. pain severity and its pattern in time), complications, and quality of life (QOL) in patients with CP. METHODS This was a cross-sectional study of 106 patients with CP conducted at two North European tertiary medical centres. Detailed information on clinical patient characteristics was obtained from interviews and through review of the individual patient records. Pain severity scores and pain pattern time profiles were extracted from the modified brief pain inventory short form and correlated to QOL as assessed by the EORTC QLQ-C30 questionnaire. Interactions with exocrine and endocrine pancreatic insufficiency, as well as pancreatic and extra-pancreatic complications were analysed using regression models. RESULTS Pain was the most prominent symptom in our cohort and its severity was significantly correlated with EORTC global health status (r = -0.46; P < 0.001) and most functional and symptom subscales. In contrast the patterns of pain in time were not associated with any of the life quality subscales. When controlling for interactions from exocrine and endocrine pancreatic insufficiency no effect modifications were evident (P = 0.72 and P = 0.85 respectively), while the presence of pancreatic and extra-pancreatic complications was associated with an almost 15% decrease in life quality (P = 0.004). CONCLUSIONS Pain severity and disease related complications significantly reduce life quality in patients with CP. This information is important in order to design more accurate and clinical meaningful endpoints in future outcome trials.

Pharmacological pain management in chronic pancreatitis

Intense abdominal pain is a prominent feature of chronic pancreatitis and its treatment remains a major clinical challenge. Basic studies of pancreatic nerves and experimental human pain research have provided evidence that pain processing is abnormal in these patients and in many cases resembles that seen in neuropathic and chronic pain disorders. An important ultimate outcome of such aberrant pain processing is that once the disease has advanced and the pathophysiological processes are firmly established, the generation of pain can become self-perpetuating and independent of the initial peripheral nociceptive drive. Consequently, the management of pain by traditional methods based on nociceptive deafferentation (e.g., surgery and visceral nerve blockade) becomes difficult and often ineffective. This novel and improved understanding of pain aetiology requires a paradigm shift in pain management of chronic pancreatitis. Modern mechanism based pain treatments taking into account altered pain processing are likely to increasingly replace invasive therapies targeting the nociceptive source, which should be reserved for special and carefully selected cases. In this review, we offer an overview of the current available pharmacological options for pain management in chronic pancreatitis. In addition, future options for pain management are discussed with special emphasis on personalized pain medicine and multidisciplinarity.

Unrecognised myocardial infarction in patients with schizophrenia.

Objective Schizophrenia is associated with a reduction of the lifespan by 20 years, with type II diabetes and cardiovascular disease contributing the most to the increased mortality. Unrecognised or silent myocardial infarction (MI) occurs in ~30% of the population, but the rates of unrecognised MI in patients with schizophrenia have only been sparsely investigated. Method Electrocardiograms (ECG) from three psychiatric hospitals in Denmark were manually interpreted for signs of previous MI. Subsequently, ECGs were linked to the National Patient Registry in order to determine whether patients had a diagnosis consistent with previous MI. Results A total of 937 ECGs were interpreted, 538 men (57.4%) and 399 women (42.6%). Mean age at the time of ECG acquisition was 40.6 years (95% CI: 39.7–41.5, range: 15.9–94.6). We identified 32 patients with positive ECG signs of MIs. Only two of these patients had a diagnosis of MI in the National Patient Registry. An additional number of eight patients had a diagnosis of MI in the Danish National Patient Registry, but with no ECG signs of previous MI. This means that 30 out of 40 (75%) MIs were unrecognised. Only increasing age was associated with unrecognised MI in a stepwise multiple logistic regression model compared with patients with no history of MI, OR: 1.03 per year of age, 95% CI: 1.00–1.06, p=0.021. Conclusion Unrecognised MI is common among patients with schizophrenia and may contribute to the increased mortality found in this patient group.

Administration of tramadol or ibuprofen increases the INR level in patients on warfarin

Case report Anticoagulation with the vitamin-K antagonist warfarin is widely used in cardiology to reduce the risk of thromboembolism in cardiac arrhythmias such as atrial fibrillation. The target international normalized ratio (INR) level should often be kept in the interval of 2.0-3.0, in order to diminish the risk of thromboembolism and decrease the risk of adverse effects such as hemorrhage. Monitoring of the INR is necessary [1]. A 74-year-old man was admitted to hospital with recurrence of atrial fibrillation. The patient had been suffering from paroxysmal atrial fibrillation for 5 years and was treated with warfarin. At the time of admission, the patient presented with the feeling of irregular heart rhythm, palpitations, shortness of breath, mild chest pain and with an ECG showing atrial fibrillation. The patient was biochemically screened. This included renal function parameters, electrolytes and thyroid-stimulating hormone. Because of chest pain, troponin Tand CK-MB were included. We found no bleeding of either the skin or the mucosa by physical examination. Finally, INR status was evaluated. The initial blood sample showed an increased INR of 5.8, otherwise the biochemical analysis was normal. Due to the increased INR, the warfarin treatment was immediately paused. We treated the atrial fibrillation of the patient successfully with direct current cardioversion. During the hospitalization, the patient’s preceding INRvalues and his medication was reviewed. We found that the elevation in INR-value was coincident with the prescription of tramadol, which was prescribed due to pain in the back. The patient’s INR-values were monitored on a regular basis. The patient was on 50 mg tramadol three times a day, for four days. He stopped the treatment due to reduced pain in the back. At this time, the INR was 5.3. The previous records of the INR showed that the patient had had steady INR-values in the interval 2.1–2.6 for more than 9 months. After the discontinuation of tramadol, the patient was treated with ibuprofen starting the next day. The dose was 400 mg three times a day until being hospitalized. During this approxmately one month period, the patient’s INR was measured on three occasions, the values being 4.4, 3.9 and 5.7. (Fig. 1). No other drugs were prescribed and no changes in the medication took place during this time. The patient received no potential inhibitors of cytochrome P450 2D6. We checked the Danish Prescription Database to confirm the data. The patient denies any use of over-the-counter drugs during this period. The pause with warfarin treatment and the discontinuation of NSAID treatment normalized the INR values within two days, and the patient was discharged in a good state of health, with sinus rhythm and with a nearly normalized INR value. The patient continued anticoagulation with the same dosage of warfarin as before admission, with periodic INR monitoring at his general practitioner. Reports of interaction between tramadol and warfarin are sparse. The PubMed database contains only a few reports regarding tramadol and warfarin interaction, while the interaction between the NSAID and warfarin is better elucidated. The NSAIDs inhibit platelet aggregation reversibley; the evidence is not substantial for ibuprofen itself, but for all inhibitors of the cyclooxygenase as a class, it is well documented [2–4]. The demonstrated interaction may indicate a pharmacokinetic interaction between warfarin and ibuprofen, leading to inhibition of the metabolism of warfarin. Both warfarin and ibuprofen are metabolized by cytochrome

The Clopidogrel-PPI Interaction: An Updated Mini-Review

Proton pump inhibitors (PPIs) are recommended in patients with prior upper gastrointestinal bleeding and considered appropriate in patients with multiple other risk factors who require dual antiplatelet treatment (DAPT). During the past few years, however, concerns have been raised about the potential for PPIs, especially omeprazole, to decrease the efficacy of clopidogrel, and both the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have issued warnings regarding the concomitant use of these medications. A review of the literature revealed that the pharmacodynamic studies support an interaction, whereas the clinical evidence, which is mainly based on nonrandomized, observational studies and secondary analyses of randomized trials, is conflicting. We conclude that PPIs should be prescribed together with DAPT for patients in whom they are recommended according to the guidelines and for patients with other indications. With respect to omeprazole, current evidence does not allow clear recommendations to be provided.

A New Method for Sham-Controlled Acupuncture in Experimental Visceral Pain – a Randomized, Single-Blinded Study

Acupuncture is increasingly used as an alternative to medical therapy for various pain conditions. To study the effect of acupuncture in experimental and clinical studies, a control condition with sham acupuncture is needed. However, as such models have not been established in assessment of acupunctures effect against visceral pain, this study aimed to validate a new method for blinded sham acupuncture in experimental rectal pain.

Anaphylactic shock and cardiac arrest caused by thiamine infusion

Parenteral thiamine has a very high safety profile. The most common adverse effect is local irritation; however, anaphylactic or anaphylactoid reactions may occur, mostly related to intravenous administration. We describe a 44-year-old man, a chronic alcoholic, who was admitted with alcohol intoxication and developed cardiac arrest due to anaphylactic shock following intravenous thiamine infusion. The patient was successfully resuscitated after 15 min and repeated epinephrine administrations. He was discharged in good health after 14 days. This case report emphasises both the importance of recognising the symptoms of anaphylaxis and the fact that facilities for treating anaphylaxis and cardiopulmonary resuscitation should be available when thiamine or for that matter, any drug is given in-hospital.

Study protocol for a randomised, double-blinded, placebo-controlled, clinical trial of S-ketamine for pain treatment in patients with chronic pancreatitis (RESET trial)

Introduction Chronic pancreatitis (CP) is an inflammatory disease that causes irreversible damage to pancreatic tissue. Pain is its most prominent symptom. In the absence of pathology suitable for endoscopic or surgical interventions, pain treatment usually includes opioids. However, opioids often have limited efficacy. Moreover, side effects are common and bothersome. Hence, novel approaches to control pain associated with CP are highly desirable. Sensitisation of the central nervous system is reported to play a key role in pain generation and chronification. Fundamental to the process of central sensitisation is abnormal activation of the N-methyl-d-aspartate receptor, which can be antagonised by S-ketamine. The RESET trial is investigating the analgaesic and antihyperalgesic effect of S-ketamine in patients with CP. Methods and analysis 40 patients with CP will be enrolled. Patients are randomised to receive 8 h of intravenous S-ketamine followed by oral S-ketamine, or matching placebo, for 4 weeks. To improve blinding, 1 mg of midazolam will be added to active and placebo treatment. The primary end point is clinical pain relief as assessed by a daily pain diary. Secondary end points include changes in patient-reported outcome measures, opioid consumption and rates of side effects. The end points are registered through the 4-week medication period and for an additional follow-up period of 8 weeks to investigate long-term effects. In addition, experimental pain measures also serves as secondary end points, and neurophysiological imaging parameters are collected. Furthermore, experimental baseline recordings are compared to recordings from a group of healthy controls to evaluate general aspects of pain processing in CP. Ethics and dissemination The protocol is approved by the North Denmark Region Committee on Health Research Ethics (N-20130040) and the Danish Health and Medicines Authorities (EudraCT number: 2013-003357-17). The results will be disseminated in peer-reviewed journals and at scientific conferences. Trial registration number The study is registered at http://www.clinicaltrialsregister.eu (EudraCT number 2013-003357-17).

Acupuncture for Pain in Chronic Pancreatitis: A Single-Blinded Randomized Crossover Trial

Objectives Many patients with painful chronic pancreatitis (CP) have insufficient effect of treatment, and the prevalence of adverse effects is high. Consequently, alternatives to conventional management are needed. We aimed to study the effect of acupuncture in painful CP. Methods This was a prospective, single-blinded, randomized crossover trial. Fifteen patients with CP were assigned to a session of acupuncture followed by sham stimulation or vice versa. Patients rated clinical pain scores daily on a 0 to 10 visual analogue scale (VAS) and completed the Patient Global Impression of Change. For mechanistic linkage, resting state electroencephalograms were recorded and quantified by spectral power analysis to explore effects on central pain processing. Results Acupuncture, compared with sham stimulation, caused more pain relief (2.0 ± 1.5 VAS vs 0.7 ± 0.8 VAS; P = 0.009). The effect, however, was short, and after 1-week follow-up, there was no difference in clinical pain scores between groups (P = 1.0) or the rating of Patient Global Impression of Change (P = 0.8). Electroencephalogram spectral power distributions between sham and acupuncture were comparable between groups (all P > 0.6). Conclusions The study presents proof-of-concept for the analgesic effect of acupuncture in pancreatic pain. Although the effect was short lasting, the framework may be used to conceptualize future trials of acupuncture in visceral pain.

A case of clear cell sarcoma-A rare malignancy

Highlights • Clear cell sarcomas are rare malignancies of the soft tissue.• Clear cell sarcoma share characteristics with malignant melanoma, but modern techniques are able to distinguish the tumours.• Timely and accurate primary diagnosis is important, as tumour size larger than 5 cm is correlated to a more sinister prognosis.• Surgical treatment is imperative, the role of radiotherapy and chemotherapy remain unknown.• Follow-up in a multidisciplinary setting is recommended.