Ciprofloxacin, given to a patient successfully treated with methadone for more than 6 years, caused profound sedation, confusion, and respiratory depression. We suggest that this was caused by ...ciprofloxacin inhibition of CYP1A2 and CYP3A4 activity, two of the cytochrome p450 isozymes involved in the metabolism of methadone.
Our aim was to study local synovial metabolism, inflammation, and subjective pain scoring after intra-articular injection of morphine, ketorolac, or placebo in knee arthroscopy.
Sixty patients ...undergoing knee arthroscopy were randomized into 3 groups receiving morphine, ketorolac, or placebo before surgery. Microdialysis of the synovial membrane was performed in 10 patients in each group 4 hrs postoperatively. Lactate, glucose, glycerol, glutamate, and prostaglandin E2 (PGE2) were monitored regarding biochemical compounds and visual analog scale regarding perceived postoperative pain.
Ketorolac effectively attenuated postoperative PGE2 levels. Glycerol increased over time in the ketorolac group. Glutamate showed a decrease over time in both the morphine and ketorolac groups. Differences in PGE2 in the reference tissue indicated a systemic effect of ketorolac. There were no effects on subjective pain scoring (visual analog scale).
To our knowledge, this is the first study on the local metabolic and inflammatory effect of intra-articularly administered morphine or ketorolac. For the first time, glutamate was studied in synovial tissue, and our results suggest that local release of glutamate may be important for nociception and inflammation. The effects of ketorolac on PGE2 implicates a local effect on inflammation and possibly, also nociception, but it should be remembered that 60 mg of ketorolac given intra-articularly also has a systemic effect. Release of glycerol after administration of ketorolac may indicate a toxicity of nonsteroidal anti-inflammatory drugs that must be further evaluated.
The outcome of treatment for patients with chronic pancreatitis may be improved by multidisciplinary management.
To study patients with chronic pancreatitis, especially regarding alcohol use, within ...a multi disciplinary program.
Prospective assessment at baseline and follow-up of alcohol use disorders using DSM-IV criteria, AUDIT score, interview-based quantification of alcohol intake and the biomarker for alcohol use s-CDT in patients referred because of chronic pancreatitis together with retrospective classification with the M-ANNHEIM risk factor analysis and severity scoring for chronic pancreatitis.
Sixty patients (95%) of 63 consecutively included patients were classified as having chronic pancreatitis. Forty-four of these (73%) were available for follow-up evaluation, which took place after a minimum of 1 year (median 3 years). Alcohol consumption decreased at follow-up and no patients had ongoing alcohol dependence (P<0.001) as compared to 10 (23%) at initial evaluation. Patients with harmful alcohol use (AUDIT score ≥8 points) and pathological s-CDT had a reduction in both parameters (P=0.004 and P=0.060, respectively). Pain score according to M-ANNHEIM was unchanged, whereas use of analgesics decreased (P=0.005).
This feasibility study of patients with chronic pancreatitis demonstrated that multidisciplinary management seems to give a positive and sustainable effect on alcohol abuse and may be a useful concept for optimal classification, selection and treatment of patients with chronic pancreatitis.
Adenosine and adenosine analogs decrease pain-like behavior in animal models of both acute nociceptive and neuropathic pain via adenosine receptor activation at spinal and/or supraspinal levels. This ...open study is the first in a series of intrathecal (IT) adenosine administration studied for the evaluation of efficacy and side effects in 14 patients. All had chronic neuropathic pain with tactile hyperalgesia and/or allodynia primarily of traumatic origin. The effects of IT adenosine (500 micro signg n = 9 or 1000 micro signg n = 5) were evaluated. Approximate areas of tactile pain were mapped. Spontaneous and evoked pain (visual analog scale score 0-100) and tactile pain thresholds were assessed before and 60 min after injection. The injection caused transient pain (<60 min) in the lumbar region in five patients. There were no other side effects. Spontaneous and evoked pain was reduced (median score from 65 to 24 P<0.01 and from 71 to 12 P<0.01, respectively) in parallel with increased tactile pain thresholds in allodynic areas. Areas of tactile hyperalgesia/allodynia were reduced (median reduction 90%; P<0.001). Twelve patients experienced pain relief (median 24 h). We conclude that IT adenosine transiently causes lumbar pain in a subgroup of patients and may reduce various aspects of chronic neuropathic pain. ImplicationsThis is the first series of patients with chronic neuropathic pain in which tolerability to spinal adenosine administration has been evaluated. A subset of patients reported transient low back pain as the only side effect. Spontaneous and evoked pain intensity decreased in most patients, an effect lasting for a median of 24 h.(Anesth Analg 1999;89:136-42)
Musculoskeletal pain is a major clinical problem. By using various experimental models in humans, the understanding of the basic mechanisms behind muscle pain can increase, thereby giving hope for ...new and optimized treatment. Opioids are increasingly often used to treat muscle pain. There are, however, a limited number of previous studies on opioids and muscle pain, most of them using a relative low, single dose. Therefore, we wanted to further study the effect of two rather high doses of alfentanil (25 and 75
ng/ml) and morphine (0.14 and 0.28
mg/kg) in human volunteers. The study consisted of two parallel studies with morphine and alfentanil, respectively, and was conducted as randomized, double-blinded, placebo-controlled, 3-way cross-over. We used intramuscular infusion of hypertonic saline and intramuscular electrical stimulation to induce experimental pain. Visual analog scale (VAS)-score, intramuscular electrical pain thresholds and pain area (local and referred) were measured.
Both alfentanil and morphine at their highest doses induced a 6 to 7-fold increase in pain thresholds to single and repetitive (5 stimulations, 2
Hz) electrical stimulation. Alfentanil and morphine also reduced VAS score about 4 to 5-fold during suprathreshold electric stimulation and during infusion of hypertonic saline. None of the drugs decreased referred pain. There were no apparent differences between the drugs, in terms of effect or adverse reactions.
In conclusion, this is the first study to compare two high doses of alfentanil and morphine on experimental muscle pain in humans. Both alfentanil and morphine reduced experimental muscle pain. There were no indications of any true pharmacodynamic differences between the two drugs.
Burrowing, an ethologically relevant rodent behaviour, has been proposed as a novel outcome measure to assess the global impact of pain in rats. In a prospective multicentre study using male rats ...(Wistar, Sprague-Dawley), replication of suppressed burrowing behaviour in the complete Freund adjuvant (CFA)-induced model of inflammatory pain (unilateral, 1 mg/mL in 100 µL) was evaluated in 11 studies across 8 centres. Following a standard protocol, data from participating centres were collected centrally and analysed with a restricted maximum likelihood-based mixed model for repeated measures. The total population (TP-all animals allocated to treatment; n = 249) and a selected population (SP-TP animals burrowing over 500 g at baseline; n = 200) were analysed separately, assessing the effect of excluding "poor" burrowers. Mean baseline burrowing across studies was 1113 g (95% confidence interval: 1041-1185 g) for TP and 1329 g (1271-1387 g) for SP. Burrowing was significantly suppressed in the majority of studies 24 hours (7 studies/population) and 48 hours (7 TP, 6 SP) after CFA injections. Across all centres, significantly suppressed burrowing peaked 24 hours after CFA injections, with a burrowing deficit of -374 g (-479 to -269 g) for TP and -498 g (-609 to -386 g) for SP. This unique multicentre approach first provided high-quality evidence evaluating suppressed burrowing as robust and reproducible, supporting its use as tool to infer the global effect of pain on rodents. Second, our approach provided important informative value for the use of multicentre studies in the future.
This study aimed to investigate whether granisetron reduces masseter muscle pain and allodynia induced by hypertonic saline. Fifteen healthy women and 15 age-matched healthy men participated in this ...randomized, placebo-controlled, double-blinded study. They first received bilateral injections of hypertonic saline into the masseter muscles (internal control). The evoked pain intensity and the pressure-pain threshold (PPT) were recorded during 30 minutes. Granisetron was then injected on one side and placebo (normal saline) on the contralateral side. Two minutes thereafter, the hypertonic saline injections were repeated. Pain and PPT were again recorded. The first injection of hypertonic saline induced pain of similar intensity, duration, and pain area on both sides, but with larger pain area in the women (P = .017). The PPT did not change significantly. The second injection of hypertonic saline induced considerably less pain (62.5%), of shorter duration (44.1%), and of smaller area (77.4%) on the side pretreated with granisetron (P = .005). The PPT was increased on the granisetron side in the men (P = .002). The results of this study show that local injection of a single dose of granisetron attenuates masseter muscle pain induced by hypertonic saline.
This article presents the changes of hypertonic saline-induced masseter muscle pain characteristics by infusion of granisetron. It appears that the pain-inducing effect in this experimental pain model is partly due to activation of 5-HT3-receptors. Hence, the results indicate that granisetron might offer a new treatment approach for localized myofascial pain.
The histamine H3 receptor represents an appealing central nervous system drug target due to its important role in the neurobiology of cognition and wake-sleep regulation. The therapeutic benefit of ...H3 antagonists/inverse agonists may be hampered by disruption of sleep that has been observed in humans with prolonged high H3 receptor occupancy (H3RO), extending into night-time. AZD5213 is a highly selective H3 antagonist (in vitro inverse agonist) developed to achieve a pharmacokinetic profile permitting circadian fluctuations of H3RO. Its efficacy has been demonstrated in rodent behavioural models of cognition. In human subjects, AZD5213 was safe and well tolerated following repeated doses (1–14 mg/d) and demonstrated a short (∼5 h) half-life. In this PET study H3RO was measured using the radioligand 11CGSK189254 (11CAZ12807110) in seven young male volunteers following single doses of AZD5213 (0.05–30 mg). H3RO was calculated using the Lassen plot method. The plasma concentrations and the affinity constant (Ki,pl 1.14 nmol/l, corresponding to the plasma concentration required to occupy 50% of available receptors) were used to estimate the H3RO time-course. AZD5213 showed dose and concentration dependent H3RO ranging from 16 to 90%. These binding characteristics and the pharmacokinetic profile of AZD5213 indicate that high daytime and low night-time H3RO could be achieved following once daily oral dosing of AZD5213. Fluctuations of H3RO following circadian rhythm of the histamine system may be expected to reduce the risk of sleep disruption while maintaining daytime efficacy. AZD5213 may thus be an optimal compound to evaluate the clinical benefit of selective H3 antagonism in cognitive disorders.
Seven patients diagnosed with erythromelalgia (EM) were investigated by microneurography to record from unmyelinated nerve fibers in the peroneal nerve. Two patients had characterized variants of ...sodium channel Na(v)1.7 (I848T, I228M), whereas no mutations of coding regions of Na(v)s were found in 5 patients with EM. Irrespective of Na(v)1.7 mutations, more than 50% of the silent nociceptors in the patients with EM showed spontaneous activity. In the patient with mutation I848T, all nociceptors, but not sympathetic efferents, displayed enhanced early subnormal conduction in the velocity recovery cycles and the expected late subnormality was reversed to supranormal conduction. The larger hyperpolarizing shift of activation might explain the difference to the I228M mutation. Sympathetic fibers that lack Na(v)1.8 did not show supranormal conduction in the patient carrying the I848T mutation, confirming in human subjects that the presence of Na(v)1.8 crucially modulates conduction in cells expressing EM mutant channels. The characteristic pattern of changes in conduction velocity observed in the patient with the I848T gain-of function mutation in Na(v)1.7 could be explained by axonal depolarization and concomitant inactivation of Na(v)1.7. If this were true, activity-dependent hyperpolarization would reverse inactivation of Na(v)1.7 and account for the supranormal CV. This mechanism might explain normal pain thresholds under resting conditions.
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