Asbjørn Mohr Drewes

Incidence of Adenocarcinoma among Patients with Barrett's Esophagus

BACKGROUND Accurate population-based data are needed on the incidence of esophageal adenocarcinoma and high-grade dysplasia among patients with Barretts esophagus. METHODS We conducted a nationwide, population-based, cohort study involving all patients with Barretts esophagus in Denmark during the period from 1992 through 2009, using data from the Danish Pathology Registry and the Danish Cancer Registry. We determined the incidence rates (numbers of cases per 1000 person-years) of adenocarcinoma and high-grade dysplasia. As a measure of relative risk, standardized incidence ratios were calculated with the use of national cancer rates in Denmark during the study period. RESULTS We identified 11,028 patients with Barretts esophagus and analyzed their data for a median of 5.2 years. Within the first year after the index endoscopy, 131 new cases of adenocarcinoma were diagnosed. During subsequent years, 66 new adenocarcinomas were detected, yielding an incidence rate for adenocarcinoma of 1.2 cases per 1000 person-years (95% confidence interval [CI], 0.9 to 1.5). As compared with the risk in the general population, the relative risk of adenocarcinoma among patients with Barretts esophagus was 11.3 (95% CI, 8.8 to 14.4). The annual risk of esophageal adenocarcinoma was 0.12% (95% CI, 0.09 to 0.15). Detection of low-grade dysplasia on the index endoscopy was associated with an incidence rate for adenocarcinoma of 5.1 cases per 1000 person-years. In contrast, the incidence rate among patients without dysplasia was 1.0 case per 1000 person-years. Risk estimates for patients with high-grade dysplasia were slightly higher. CONCLUSIONS Barretts esophagus is a strong risk factor for esophageal adenocarcinoma, but the absolute annual risk, 0.12%, is much lower than the assumed risk of 0.5%, which is the basis for current surveillance guidelines. Data from the current study call into question the rationale for ongoing surveillance in patients who have Barretts esophagus without dysplasia. (Funded by the Clinical Institute, University of Aarhus, Aarhus, Denmark.).

McGill Pain Questionnaire translated into Danish: experimental and clinical findings

Objective:To develop a methodology for translating the McGill Pain Questionaire (MPQ) into a Danish version, and to make comparisons to studies of patients speaking other languages. Design:Finding suitable Danish adjectives using the same methodology as that in the original MPQ. Comparison of Danish descriptors to the words in the English version of MPQ. Survey in healthy subjects and patients with rheumatoid arthritis (RA) and fibromyalgia (F). Setting:The general public and hospital outpatients. Patients:A random sample of 186 healthy volunteers, 20 patients with rheumatoid arthritis and 41 patients with fibromyalgia. Main Outcome Measures:Danish words translated as closely as possible to the descriptors in the original McGill Pain Questionnarire. A pain-assessment instrument making international pain description possible. Results:A Danish version of the McGill Pain Questionnaire was developed with scale values of Danish descriptors not differing more than 5xSEM from the ‘patient’ words in the English version.The subdivision into classes and subclasses was respected. In the reliability experiment, the same rank values were found in 85% of subclasses. In a study using two experimental pain stimulus intensities, seven of 10 subjects obtained higher MPQ scores following the high-intensity stimulus. In the clinical study, the pain profiles of patients with RA and F in English, Italian, and Danish patients were almost the same. Conclusion:The present methodology of translating the McGill Pain Questionnaire permits comparison of studies from English-speaking and non-English-speaking populations, thus facilitating international research exchange.

Experimental Pain in Gastroenterology. A Reappraisal of Human Studies

Abdominal pain is of frequent occurrence, even in the normal population (1), and pain is probably the most prevalent symptom in the gastroenterology clinic. Consequently, characterization of gut pain is one of the most important issues in the diagnosis and assessment of organ dysfunction, and research leading to a better insight into pain mechanisms in the gastrointestinal (GI) tract will improve the treatment of patients (2). In clinical work, characterization of pain is confounded by many other symptoms caused by the diseases, such as complaints relating to psychological, cognitive and social aspects of the illness. Moreover, many diseases are typically associated with systemic reactions such as fever and general malaise, which can be difficult to distinguish from the symptoms relating to pain. Finally, the patients are typically treated with different therapeutic interventions that may cause sedation and changes in gut motor function. All such confounders can influence the perception of pain, making its assessment in clinical studies difficult. A possible way to overcome this problem is to use experimental models, where the investigator can control the pain ‘input’ e.g., the nature, localization, intensity, frequency and duration of the stimulus, and provide reproducible measures of the ‘output’ e.g., the psychophysical, behavioural or the neurophysiological response (3, 4). Experimental models have been used in different animal species, where the investigators can study the neuronal activity in anaesthetized or spinalized animals directly, with invasive techniques or with assessment of behaviour (for review, see (5)). The neurobiology of the pain system differs, however, between the species, and this limits the interpolation of findings from animal studies to man. Moreover, pain is the net effect of complex multidimensional mechanisms that involve most parts of the central nervous system. Therefore, although nociceptive reflexes or electrophysiological recordings from selected pathways in the animal nervous system are important in basic research, the central pain mechanisms and associated complex reactions are typically suppressed, and animal experiments can only to some degree reflect the experience of clinical pain in humans. Consequently, the interest in human experimental pain studies has increased rapidly during the last decade (6), and also in gastroenterology the focus has been on developing methods for experimental induction and assessment of human pain.

A comparative study of oxycodone and morphine in a multi-modal, tissue-differentiated experimental pain model.

Abstract Visceral pain can be difficult to treat with classical &mgr;‐opioid agonists and it has been suggested to use opioids with distinct pharmacological profiles. In animal experiments, oxycodone has shown different effects compared to morphine, and clinical observations have shown that oxycodone may occasionally be superior to, e.g., morphine in the treatment of visceral pain. In the current study, we randomised 24 healthy subjects to treatment with either morphine (30 mg), oxycodone (15 mg) or placebo in a crossover study. The experimental pain model involved multi‐modal (mechanical, thermal and electrical) pain tests in the skin, muscles and viscera. The pain tests were carried out at baseline and 30, 60 and 90 min after oral administration of the drugs. The model showed effect of the two opioids compared to placebo on all stimulus modalities in all three types of tissues (all P values <0.001). Both opioids attenuated the sensory response mainly to painful stimulations. Morphine and oxycodone were equipotent in pain modulation of the skin and muscles, but oxycodone had superior analgesic effect to both morphine and placebo on the mechanical (P < 0.001) and thermal (P < 0.001) stimulations of the oesophagus. In conclusion, the multi‐modal and tissue‐differentiated pain model could link findings from animal experiments to clinical findings. A different pharmacological profile of oxycodone compared to that of morphine was shown, and thus oxycodone may be a useful alternative to morphine in the treatment of visceral pain syndromes.

Experimental human muscle pain and muscular hyperalgesia induced by combinations of serotonin and bradykinin.

In the present study, we assessed the muscle pain and possible development of muscular hyperalgesia to mechanical stimuli after two subsequent intramuscular infusions of serotonin (5-HT) and bradykinin (BKN). The pain intensity after the infusions was continuously scored on a visual analogue scale (VAS). The subjects drew the distribution of the pain areas on a map. Pressure pain thresholds (PPTs) and suprapressure pain thresholds (SPPTs) stimulations as 150% of the pre-infusion PPTs were assessed with a pressure algometer at the injection site (10 cm below the patella), at the ankle, and at the contralateral leg and ankle. Skin sensibility was assessed with a Von Frey hair at the same sites. This was done before and after an infusion into the tibialis anterior (TA) muscle on the right leg in ten volunteers. The first infusion in each combination was either serotonin (20 nmol) or isotonic saline (NaCl 0.9%). The second infusion was bradykinin (5 or 10 nmol) or isotonic saline. The two infusions were given over 20 s and separated by 3 min. The isotonic saline followed by BKN did not induce muscle pain or muscular hyperalgesia. However, the combination of 5-HT and BKN (10 nmol) produced: (1) significantly higher VAS scores (P < 0.05) compared with all other combinations; (2) significantly longer pain offset (P < 0.05) compared with the combinations of isotonic saline and BKN; (3) significantly lower PPTs at 5, 20, and 40 min post-infusion (P < 0.05) compared with baseline PPT and PPTs after all other combinations. Cutaneous sensibility to mechanical stimuli and SPPTs were not affected by any of the combinations. The combinations of serotonin and bradykinin produce experimental muscle pain and muscular hyperalgesia to mechanical stimuli. Pre-treatment with serotonin may enhance the effect of bradykinin in the generation of muscle pain and muscular hyperalgesia in humans.

Referred pain as an indicator for neural plasticity

Publisher Summary Pain originating from deep somatic structures and viscera represents a major part of patients pain complaints. The chapter discusses the possible mechanisms underlying referred pain from muscles and viscera. Referred pain has been known and has been used extensively as a diagnostic tool in the clinic. Several theories regarding appearance of referred pain have been suggested, and basically, they state that nociceptive dorsal horn neurons receive convergent inputs from various tissues. In clinical practice, classical signs of viscerally referred pain are (1) the radiating pain in arms, particularly the left arm during angina pectoris, (2) McBurneys sign indicative of appendicitis, (3) superficial abdominal pain from gastric ulcers (4) the pain of cholecystitis, which may radiate to the interscapular area, right scapula, shoulder, or back, and (5) pain from renal and urethral stones referred to the lower back. Referred muscle pain is manifested in somatic structures whereas visceral pain manifests in somatic as well as visceral structures. These manifestations are of significantly clinical importance for the diagnosis of pain pathologies.

Increase in incidence and prevalence of inflammatory bowel disease in northern Denmark: A population-based study, 1978-2002

Objectives Although incidence rates of inflammatory bowel disease have been reported worldwide, few long-term population-based studies with current time-trend analyses exist. We therefore examined time trends in the incidence rate of inflammatory bowel disease in a 25-year study period, and estimated the prevalence in 2002. All patients diagnosed between 1978 and 2002 were included as incident cases (n=2326) and all patients living in North Jutland County on 31 December 2002 were used to estimate prevalent cases (n=2205). Methods Medical records of all patients diagnosed with ulcerative colitis and Crohns disease in the North Jutland County Hospital Discharge Registry were reviewed to examine if the diagnostic criteria were fulfilled. Age-specific and gender-specific standardized incidence rates were calculated. Results For ulcerative colitis, incidence rates in women increased from 8.3 (95% confidence interval (CI): 6.7–9.9) in 1978–1982 to 17.0 (95% CI: 14.7–19.3) per 100 000 person-years in 1998–2002. The corresponding figures for men were 7.7 (95% CI: 6.1–9.3) and 16.7 (95% CI: 14.4–18.8) per 100 000 person-years. For Crohns disease, the incidence rates in women increased from 4.1 (95% CI: 3.0–5.2) in 1978–1982 to 10.7 (95% CI: 8.8–12.5) per 100 000 person-years in 1998–2002. The corresponding figures for men were 3.2 (95% CI: 2.1–4.2) and 8.5 (95% CI: 6.9–10.2) per 100 000 person-years. The prevalence of ulcerative colitis and Crohns disease was 294 and 151 per 100 000 inhabitants, respectively. Conclusions A marked and parallel increase was seen in both ulcerative colitis and Crohns disease in both genders during the last 25 years, with a corresponding high prevalence of both diseases.

Human Experimental Pain Models for Assessing the Therapeutic Efficacy of Analgesic Drugs

Pain models in animals have shown low predictivity for analgesic efficacy in humans, and clinical studies are often very confounded, blurring the evaluation. Human experimental pain models may therefore help to evaluate mechanisms and effect of analgesics and bridge findings from basic studies to the clinic. The present review outlines the concept and limitations of human experimental pain models and addresses analgesic efficacy in healthy volunteers and patients. Experimental models to evoke pain and hyperalgesia are available for most tissues. In healthy volunteers, the effect of acetaminophen is difficult to detect unless neurophysiological methods are used, whereas the effect of nonsteroidal anti-inflammatory drugs could be detected in most models. Anticonvulsants and antidepressants are sensitive in several models, particularly in models inducing hyperalgesia. For opioids, tonic pain with high intensity is attenuated more than short-lasting pain and nonpainful sensations. Fewer studies were performed in patients. In general, the sensitivity to analgesics is better in patients than in healthy volunteers, but the lower number of studies may bias the results. Experimental models have variable reliability, and validity shall be interpreted with caution. Models including deep, tonic pain and hyperalgesia are better to predict the effects of analgesics. Assessment with neurophysiologic methods and imaging is valuable as a supplement to psychophysical methods and can increase sensitivity. The models need to be designed with careful consideration of pharmacological mechanisms and pharmacokinetics of analgesics. Knowledge obtained from this review can help design experimental pain studies for new compounds entering phase I and II clinical trials.

Subcutaneous Botulinum toxin type A reduces capsaicin-induced trigeminal pain and vasomotor reactions in human skin.

Abstract The present human study aimed at investigating the effect of subcutaneous administration of Botulinum toxin type A (BoNT/A) on capsaicin‐induced trigeminal pain, neurogenic inflammation and experimentally induced cutaneous pain modalities. Fourteen healthy males (26.3 ± 2.6 years) were included in this double‐blind and placebo‐controlled trial. The subjects received subcutaneous BoNT/A (22.5 U) and isotonic saline in the mirror sides of their forehead. Pain and neurogenic inflammation was induced by four intradermal injections of capsaicin (100 μg/μL) (before, and days 1, 3 and 7 after treatments). The capsaicin‐induced pain intensity, pain area, the area of secondary hyperalgesia, the area of visible flare and vasomotor reactions were recorded together with cutaneous heat, electrical and pressure pain thresholds. BoNT/A reduced the capsaicin‐induced trigeminal pain intensity compared to saline (F = 37.9, P < 0.001). The perceived pain area was smaller for the BoNT/A‐treated side compared to saline (F = 7.8, P < 0.05). BoNT/A reduced the capsaicin‐induced secondary hyperalgesia (F = 5.3, P < 0.05) and flare area (F = 10.3, P < 0.01) compared to saline. BoNT/A reduced blood flow (F1,26 = 109.5, P < 0.001) and skin temperature (F1,26 = 63.1, P < 0.001) at the capsaicin injection sites compared to saline and its suppressive effect was maximal at days 3 and 7 (P < 0.05, post hoc test). BoNT/A elevated cutaneous heat pain thresholds (F = 17.1, P < 0.001) compared to saline; however, no alteration was recorded for electrical or pressure pain thresholds (P > 0.05). Findings from the present study suggest that BoNT/A appears to preferentially target Cfibers and probably TRPV1‐receptors, block neurotransmitter release and subsequently reduce pain, neurogenic inflammation and cutaneous heat pain threshold.

Multi-modal induction and assessment of allodynia and hyperalgesia in the human oesophagus

Background and aims. Experimental pain models based on single stimuli have to some degree limited visceral pain studies in humans. Hence, the aim of this study was to investigate the effect of multi‐modal visceral pain stimuli of the oesophagus in healthy subjects before and after induction of visceral hyperalgesia. We used a multi‐modal psychophysical assessment regime and a neurophysiological method (nociceptive reflex) for the characterisation of the experimentally induced hyperalgesia.