Clive H. Wilder-Smith

Cortical effects of anticipation and endogenous modulation of visceral pain assessed by functional brain MRI in irritable bowel syndrome patients and healthy controls

&NA; Visceral pain processing is abnormal in a majority of irritable bowel syndrome (IBS) patients. Aberrant endogenous nociceptive modulation and anticipation are possible underlying mechanisms investigated in the current study. Twelve IBS patients and 12 matched healthy controls underwent brain fMRI scanning during the following randomised stimuli: sham and painful rectal distensions by barostat without and with simultaneous activation of endogenous descending nociceptive inhibition using ice water immersion of the foot for heterotopic stimulation. Heterotopic stimulation decreased rectal pain scores from 3.7 ± 0.2 to 3.1 ± 0.3 (mean ± SE, scale 0–5) in controls (p < 0.01), but not significantly in IBS. Controls differed from IBS patients in showing significantly greater activation bilaterally in the anterior insula, SII and putamen during rectal stimulation alone compared to rectal plus heterotopic stimulation. Greater activation during rectal plus heterotopic versus rectal stimulation was seen bilaterally in SI and the right superior temporal gyrus in controls and in the right inferior lobule and bilaterally in the superior temporal gyrus in IBS. Rectal pain scores were similarly low during sham stimulation in both groups, but brain activation patterns differed. In conclusion, IBS patients showed dysfunctional endogenous inhibition of pain and concomitant aberrant activation of brain areas involved in pain processing and integration. Anticipation of rectal pain was associated with different brain activation patterns in IBS involving multiple interoceptive, homeostatic, associative and emotional areas, even though pain scores were similar during sham distension. The aberrant activation of endogenous pain inhibition appears to involve circuitry relating to anticipation as well as pain processing itself.

Do continuous infusions of omeprazole and ranitidine retain their effect with prolonged dosing

BACKGROUND/AIMS Prolonged infusions of H2-antagonists are commonly used in intensive care units, although little is known about their antisecretory efficacy beyond the initial 24 hours of dosing. The aim of this study was to assess the antisecretory effects of infusions of ranitidine and omeprazole for a period of 72 hours. METHODS Twelve healthy volunteers received individually titrated 72-hour intravenous infusions of omeprazole, ranitidine, or placebo in a double-blind, crossover study. Gastric pH and dosing requirements were compared. RESULTS The median percentage of time with pH > 4 (interquartile range) was 93% (88%-95%) on day 1 and 96% (94%-99%) on day 3 with omeprazole and 67% (56%-78%) and 43% (31%-51%), respectively, with ranitidine (both P < 0.001 vs. omeprazole). The mean doses (+/- SD) required on days 1 and 3 for omeprazole were 235.8 +/- 44 mg and 134.0 +/- 37 mg (P < 0.0001), and ranitidine doses were 502.5 +/- 76 mg and 541.8 +/- 25 mg, respectively (P = 0.05). CONCLUSIONS Omeprazole infusions consistently maintained gastric pH above 4 over a period of 72 hours with progressively lower doses. Significant tolerance to the antisecretory effect of ranitidine infusion developed in 72 hours, which was not overcome despite individually titrated doses of more than 500 mg/24 hours. Consequently, application of pharmacodynamic results of single-day H2-blocker and proton-pump inhibitor studies to prolonged infusion trials for stress ulcer-related bleeding is inappropriate.

Effect of Tramadol and Morphine on Pain and Gastrointestinal Motor Function in Patients with Chronic Pancreatitis

Tramadol and morphine were compared fortreatment of severe chronic pancreatitis pain and theirinteraction with gut motor function. Oral tramadol ormorphine doses were titrated double-blinded andrandomized for five days in 25 patients and pain, sideeffects, bowel function, orocecal and colonic transit,anal resting pressure, and rectal distension thresholdswere measured. Pain intensities (mean ± SD, 0 = none, 100 = unbearable) before treatment andon day 4 were 75 ± 19 and 8 ± 13 withtramadol (P < 0.001), and 65 ± 21 and 5± 6 with morphine (P < 0.001). On day 4, 67%of patients with tramadol and 20% with morphine rated their analgesia asexcellent (P < 0.001) with mean respective doses of840 mg (range: 80-1920) and 238 mg (20-1125). Orocecaltransit was unchanged after five days of tramadol, but increased with morphine (P < 0.05). Morepatients had prolonged colonic transit times withmorphine by day 5 (P < 0.05). Rectal distensionthreshold pressures increased only with tramadol (P < 0.01). It is concluded tramadol and morphineare potent analgesics in severe chronic pancreatitispain when individually titrated. Tramadol interferedsignificantly less with gastrointestinal function and was more often rated as an excellent analgesicthan morphine.

Postamputation pain and sensory changes in treatment-naive patients: characteristics and responses to treatment with tramadol, amitriptyline, and placebo.

Background:Pain after amputation is common but difficult to treat, and few controlled treatment studies exist. Methods:In the current study, 94 treatment-naive posttraumatic limb amputees with phantom pain (intensity: mean visual analog scale score [0–100], 40 [95% confidence interval, 38–41]) were randomly assigned to receive individually titrated doses of tramadol, placebo (double-blind comparison), or amitriptyline (open comparison) for 1 month. Nonresponders were crossed over to the alternative active treatment. Results:After 1 month, phantom pain intensity was 1 (0–2) in the 48 tramadol responders (mean dose, 448 mg [95% confidence interval, 391–505 mg]), 0 (0–0) in the 40 amitriptyline responders (55 [50–59] mg), and 0 (0–0) in the 2 placebo responders, with similar effects on stump pain. Cytochrome P-450 2D6 slow metabolizers derived greater analgesia from tramadol and less from amitriptyline compared with fast metabolizers in the first treatment week (P < 0.01). Electrical pain thresholds increased and pain during suprathreshold stimulation decreased markedly on the stump and, to a lesser extent, on the contralateral limb after 1 month of treatment with amitriptyline or tramadol. Adverse effects were minor in all groups, but more common with tramadol. Conclusions:In treatment-naive patients, both amitriptyline and tramadol provided excellent and stable phantom limb and stump pain control with no major adverse events. Both drugs demonstrated consistent and large antinociceptive effects on both the stump and the intact limbs.

Postoperative sensitization and pain after cesarean delivery and the effects of single IM doses of tramadol and diclofenac alone and in combination

Combining different analgesic mechanisms can reduce postoperative pain. We investigated postoperative pain and sensory sensitization in a double-blinded, placebo-controlled, randomized, single-dose comparison of the monoaminergic and &mgr;-opioid agonist tramadol, 100 mg, and diclofenac 75 mg given IM in combination or alone in 120 patients who had elective cesarean delivery. The time to first postoperative demand for rescue analgesia, pain, tramadol pharmacokinetics, and electrical sensory thresholds at or distant from the incision were studied. The median time to first rescue (interquartile range) was 197 min (70–1000 min) with tramadol plus diclofenac, 48 min (25–90 min) with tramadol plus placebo, 113 min (35–270 min) with diclofenac plus placebo, and 55 min (30–100 min) with double placebo (tramadol plus diclofenac versus all other groups, P < 0.05). Pain intensity decreased markedly over time in all groups, and time and drug effects were significant (analysis of variance; P < 0.00001). Side effects were similarly minimal with all treatments. Pain thresholds at or distant from the incision increased significantly after surgery only with tramadol plus diclofenac. Preoperative sensory thresholds correlated with postoperative sensory changes (r > 0.53; P < 0.0001). The pharmacokinetics of tramadol and O-desmethyltramadol were unchanged by diclofenac. The combination of tramadol and diclofenac resulted in improved analgesia compared with monotherapy. Only the analgesic combination prevented both primary and secondary hyperalgesia. Preoperative sensory thresholds may allow prediction of postoperative sensitization.

Quantification of dental erosions in patients with GERD using optical coherence tomography before and after double-blind, randomized treatment with esomeprazole or placebo.

OBJECTIVES:Dental erosion, the chemical dissolution of enamel without bacterial involvement, is a rarely reported manifestation of gastroesophageal reflux disease (GERD), as well as of recurrent vomiting and dietary habits. It leads to loss of tooth substance, hypersensitivity, functional impairment, and even tooth fracture. To date, dental erosions have been assessed using only very basic visual methods, and no evidence-based guidelines or studies exist regarding the prevention or treatment of GERD-related dental erosions.METHODS:In this randomized, double-blind study, we used optical coherence tomography (OCT) to quantify dental tissue demineralization and enamel loss before and after 3 weeks of acid-suppressive treatment with esomeprazole 20 mg b.i.d. or placebo in 30 patients presenting to the Berne University Dental Clinic with advanced dental erosions and abnormal acid exposure by 24-h esophageal pH manometry (defined as >4% of the 24-h period with pH<4). Enamel thickness, reflectivity, and absorbance as measures of demineralization were quantified by OCT before and after therapy at identical localizations on teeth with most severe visible erosions as well as several other predefined changes in teeth.RESULTS:The mean±s.e.m. decrease of enamel thickness of all teeth before and after treatment at the site of maximum exposure was 7.2±0.16 ▴m with esomeprazole and 15.25±0.17▴m with placebo (P=0.013), representing a loss of 0.3% and 0.8% of the total enamel thickness, respectively. The change in optical reflectivity to a depth of 25 ▴m after treatment was−1.122 ±0.769 dB with esomeprazole and +2.059±0.534 dB with placebo (P 0.012), with increased reflectivity signifying demineralization.CONCLUSIONS:OCT non-invasively detected and quantified significantly diminished progression of dental tissue demineralization and enamel loss after only 3 weeks of treatment with esomeprazole 20 mg b.i.d. vs. placebo. This suggests that esomeprazole may be useful in counteracting progression of GERD-related dental erosions. Further validation of preventative treatment regimens using this sensitive detection method is required, including longer follow-up and correlation with quantitative reflux measures.

Fructose and lactose intolerance and malabsorption testing: the relationship with symptoms in functional gastrointestinal disorders

The association of fructose and lactose intolerance and malabsorption with the symptoms of different functional gastrointestinal disorders (FGID) remains unclear.

Esomeprazole 20mg Provides More Effective Intragastric Acid Control than Maintenance-Dose Rabeprazole, Lansoprazole or Pantoprazole in Healthy Volunteers

ObjectiveA high proportion of patients with gastro-oesophageal reflux disease experience recurrence of symptoms within a year of initial treatment. The key to preventing relapse is an effective maintenance therapy that maintains intragastric pH >4. This study was conducted to compare the effects on intragastric pH of maintenance doses of four proton pump inhibitors: esomeprazole 20mg, lansoprazole 15mg, rabeprazole 10mg and pantoprazole 20mg.Study participants and methodsThree standardised, randomised, two-way crossover studies were performed in a total of 108 Helicobacter pylori-negative healthy subjects. Intragastric pH was monitored on day 5 of once-daily oral dosing. The percentage of time of a 24-hour period with intragastric pH >4 and 24-hour median pH were measured on day 5.ResultsThe mean percentage of time with intragastric pH >4 on day 5 was significantly longer following esomeprazole 20mg compared with either lansoprazole 15mg (esomeprazole 50.4% vs lansoprazole 43.0%, p = 0.026), rabeprazole 10mg (esomeprazole 59.8% vs rabeprazole 51.7%, p = 0.011) or pantoprazole 20mg (esomeprazole 59.6% vs pantoprazole 39.5%, p < 0.0001).ConclusionsMaintenance dose esomeprazole 20mg provided greater acid control and maintained intragastric pH >4 for a longer period of time than maintenance dose lansoprazole 15mg, rabeprazole 10mg and pantoprazole 20mg in healthy subjects.

Gastrospirillum hominis in Asymptomatic, Healthy Individuals

Gastrospirillum hominis is a spiral-shaped bacterium found in the stomach. It has been implicated as a possible cause of chronic gastritis. We report two cases ofG. hominis colonization observed in a series of 175 healthy, asymptomatic volunteers investigated forHelicobacter pylori. None of the volunteers has symptoms or a history of gastrointestinal disease. Both carriers ofG. hominis had histological signs of chronic, active antral gastritis. Multiple tests forH. pylori were negative. The prevalence of this spiral bacterium in healthy, asymptomatic individuals may be as low as in symptomatic persons.

Esomeprazole 40 mg provides improved intragastric acid control as compared with lansoprazole 30 mg and rabeprazole 20 mg in healthy volunteers.

Aim: To compare the effects of standard-dose esomeprazole with those of standard doses of lansoprazole and rabeprazole on intragastric pH during repeated daily oral dosing in healthy volunteers. Methods: In two standardized, randomized crossover studies, Helicobacter pylori negative healthy volunteers (study A: 19 males, 5 females; study B: 13 males, 10 females) received esomeprazole 40 mg and either lansoprazole 30 mg (study A) or rabeprazole 20 mg (study B) orally once daily in the morning for 5 days. Continuous 24-hour intragastric pH recording was performed on day 5. Results: The intragastric pH was maintained >4 for 65% (95% CI 59.5–71.3) of the 24-hour period with esomeprazole and for 53% of the time (95% CI 47.0–58.9) with lansoprazole in study A (p < 0.001). In study B, the proportion of time with pH >4 was 61% (95% CI 53.6–68.3) with esomeprazole versus 45% (95% CI 37.7–52.5) with rabeprazole (p = 0.005). The 24-hour median pH and the proportion of volunteers with intragastric pH >4 for ≧12 h and ≧16 h were significantly higher with esomeprazole than with either lansoprazole or rabeprazole. Conclusion: Esomeprazole 40 mg provides significantly more effective and more sustained gastric acid control than lansoprazole 30 mg or rabeprazole 20 mg in healthy volunteers.