Five easy pieces on evidence-based medicine.
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Evidence-Based Medicine↗
Biomedical subjects
E Kalso
Publications and source records attributed to E Kalso.
Five easy pieces on evidence-based medicine (2).
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Double-Blind Method↗
Effects of radolmidine, a novel alpha2 -adrenergic agonist compared with dexmedetomidine in different pain models in the rat.
BACKGROUND: Intrathecally administered alpha2-adrenoceptor agonists produce effective antinociception, but sedation is an important adverse effect. Radolmidine is a novel alpha2-adrenoceptor agonist with a different pharmacokinetic profile compared with the well-researched dexmedetomidine. This study determined the antinociceptive and sedative effects of radolmidine in different models of acute and chronic pain. Dexmedetomidine and saline served as controls. METHODS: Male Sprague-Dawley rats were studied in acute pain (tail flick), carrageenan inflammation, and the spinal nerve ligation model of neuropathic pain. Mechanical allodynia was assessed with von Frey filaments, cold allodynia with the acetone test, and thermal hyperalgesia with the paw flick test. Locomotor activity-vigilance was assessed in a dark field. Dexmedetomidine and radolmidine were administered intrathecally in doses of 0.25 microg, 2.5 microg, 5 microg, and 10 microg. RESULTS: In the tail flick test, radolmidine showed a dose-dependent antinociceptive effect, being equipotent compared with dexmedetomidine. In carrageenan inflammation, intrathecal doses of 2.5 microg or 5 microg of dexmedetomidine/radolmidine produced significant antinociception compared with saline (P < 0.01). The two drugs were equianalgesic. In the neuropathic pain model, an intrathecal dose of 5 microg dexmedetomidine-radolmidine had a significant antiallodynic effect compared with saline (P < 0.01). The two drugs were equipotent. Intrathecal administration of both dexmedetomidine and radolmidine dose dependently decreased spontaneous locomotor acitivity-vigilance, but this effect was significantly smaller after intrathecal administration of radolmidine than after intrathecal dexmedetomidine. CONCLUSIONS: Radolmidine and dexmedetomidine had equipotent antinociceptive effects in all tests studied. However, radolmidine caused significantly less sedation than dexmedetomidine, probably because of a different pharmacokinetic profile.
Adrenergic alpha-Agonists↗
Neuropeptide FF and modulation of pain.
Neuropeptide FF (NPFF) and the related longer peptide neuropeptide AF (NPAF) derive from a single gene in several mammalian species. The gene product is expressed mainly in the CNS, where the posterior pituitary and dorsal spinal cord contain the highest concentrations. Evidence from biochemical and immunohistochemical studies combined with in situ hybridization using NPFF gene-specific probes suggest that all NPFF-like peptides may not derive from the characterized NPFF gene, but that other genes can exist which give rise to related peptides. Intraventricular NPFF exerts antiopioid effects, but intrathecal NPFF potentiates the analgesic effects of morphine. NPFF mRNA expression is upregulated in the dorsal horn of the spinal cord after carrageenan-induced inflammation in the hind paw of the rat, but not in the neuropathic pain model induced by ligation of the spinal roots. NPFF produces a submodality-selective potentiation of the antinociceptive effect induced by brain stem stimulation in the spinal cord during inflammation, and this effect is independent of naloxone-sensitive opioid receptors. In neuropathic animals, NPFF injected into the periaqueductal grey produces a significant attenuation of tactile allodynia, which is not modulated by naloxone. NPFF thus modulates pain sensation and morphine analgesia under normal and pathological conditions through both spinal and brain mechanisms.
Animals↗
Endogenous noradrenergic tone controls symptoms of allodynia in the spinal nerve ligation model of neuropathic pain.
Endogenous inhibitory controls were studied in the spinal nerve ligation model of neuropathic pain. Atipamezole, a selective alpha2-adrenoceptor antagonist, produced both mechanical and cold allodynia in those rats which had not developed clear neuropathic symptoms. The same doses (50 microg i.t. or 1 mg/kg s.c.) did not increase the severity of symptoms in rats which had developed them. The opioid receptor antagonist naloxone (20 microg i.t. or 1 mg/kg s.c.) had no effect on the neuropathic symptoms. These results indicate that mechanical and cold allodynia are under endogenous noradrenergic rather than opioidergic control in this model of neuropathic pain.
Adrenergic alpha-Antagonists↗
Effects of (1DMe)NPYF, a synthetic neuropeptide FF analogue, in different pain models.
The antinociceptive effects of intrathecal (IT) (1DMe)NPYF were studied in adult Sprague-Dawley rats. (1DMe)NPYF produced dose-dependent antinociception that was reduced by subcutaneous injection of naloxone. (1DMe)NPYF (0.5 nmol) also potentiated the antinociceptive effects of intrathecal morphine 7.8 nmol. This suggests that the antinociceptive effects of (1DMe)NPYF are partially mediated by opioid receptor activation. In carrageenan inflammation, 5-10 nmol of (1DMe)NPYF was effective against both thermal hyperalgesia and mechanical allodynia. In the neuropathic pain model, the lowest dose tested (0.5 nmol) showed antiallodynic effects against cold allodynia. The results suggest a potential role for (1DMe)NPYF in the treatment of pain including neuropathic pain.
Amino Acid Sequence↗
Pain related undergraduate teaching in medical faculties in Finland.
The present questionnaire study was conducted to examine how teachers in all Finnish medical faculties have included pain teaching in their courses for undergraduate medical students. The study was planned to compare the existing education in Finland with the IASP curriculum on pain for medical schools. In 1991 and 1995 the questionnaire was sent to a total of 135 and 130 university teachers, respectively. The teachers were asked about the quantity and quality of their pain teaching. Teachers' attitudes on pain related teaching were also examined. A Finnish translation of the IASP curriculum was provided, and university teachers were asked to evaluate it and compare it with their current teaching. The educational programs of all universities were also analyzed. After completion of these surveys, representatives of teachers responsible for teaching of pain, and of medical students from all Finnish medical faculties were invited to a meeting to discuss methods for improving and developing education. Completed questionnaires were received from 107 university teachers (78%) in 1991 and from 74 (60%) in 1995. No printed curricula for pain education were found in any university and in all universities pain teaching was provided in an inconsistent way. There were differences, yet statistically non-significant, between the faculties in the pain teaching. No major differences were observed between the two questionnaires. A serious lack of teaching in psychology of pain was a general finding. University teachers were found to have positive attitudes towards developing their teaching of pain. The IASP curriculum has not been fully followed but was considered a valuable tool in planning the educational programs. The curriculum should be distributed directly to the governmental bodies of the universities, since individual university teachers are not necessarily familiar with it. Local associations may have an important role in this distribution as we have shown. This report shows the necessity of changing the attitudes of university teachers providing concrete teaching programs for pain. A multimedia package of pain containing references, video tapes and cd-discs produced by a workshop of IASP would certainly be welcome.
Curriculum↗
Behavioural measures of depression and anxiety in rats with spinal nerve ligation-induced neuropathy.
The behaviour of rats with spinal nerve ligation-induced neuropathic pain was studied using tests developed to measure depression and anxiety. Adult male Sprague-Dawley rats were tested with the open field test, elevated plus maze, two compartment test and forced swimming test. Spontaneous motility was measured in a photocell observation box. Mechanical sensitivity was tested with von Frey hairs and cold sensitivity with the acetone drop test. The L5-6 spinal nerves were ligated or a sham operation was performed and the rats were followed for 2 weeks before the same set of tests were repeated. Most of the neuropathy operated rats had mechanical and cold allodynia. With post-injury there was a significant decrease in the activity in the open field test and motility box tests, when compared with the pre-injury results. In the elevated plus maze test there was a significant reduction in the motility, but there was no change in the time spent in the closed wings. In the two compartment test there were no significant differences between the pre- and post-injury results. There were no differences between the rats with spinal nerve ligation injury and the sham operated rats in any of the tests. The results were also comparable when rats that developed a high degree of neuropathy were compared with the rats with low degree of neuropathy and the sham operated group. In conclusion, spinal nerve ligation injury of the spinal nerves L5-6 induces mechanical and cold allodynia, but it does not seem to produce general suffering or measurable anxiety to the animals. Furthermore, tests for anxiety and depression were not able to predict which animals were vulnerable to express symptoms of neuropathic pain after nerve injury.
Animals↗
Chronic pain after thoracic surgery: a follow-up study.
BACKGROUND: The incidence of long-term post-thoracotomy pain is reported to be up to 67%. A relationship between the severity of acute postoperative pain and the development of chronic post-thoracotomy pain has been suggested. METHODS: Patients scheduled for elective thoracotomy were interviewed before and one week after surgery to find out if they had pain before surgery and how much pain they experienced postoperatively. The amount of analgesics the patients were given were registered during the first 5 postoperative days. The patients were interviewed by letter 3, 6 and 12 months after surgery to find out if they still had pain due to surgery and to what extent this pain interfered with their daily activities. RESULTS: One hundred and ten patients entered the study. Information about the complete study period was obtained from 67 patients. The incidence of chronic post-thoracotomy pain was 80% at 3 months, 75% at 6 months and 61% one year after surgery. The incidence of severe pain was 3-5%. Chronic post-thoracotomy pain interfered with the patient's normal daily life in more than half of the patients. High consumption of analgesics during the first postoperative week was associated with a higher risk of chronic post-thoracotomy pain. CONCLUSION: A significant proportion of patients undergoing thoracotomies will suffer from chronic pain. Surgeons and anaesthetists should be aware of this fact and they should look for effective means of preventing and treating this pain syndrome.
Activities of Daily Living↗
Chronic post-treatment symptoms in patients with breast cancer operated in different surgical units.
AIMS: This study was designed to find out whether women operated in high volume surgical units have less chronic symptoms than women operated in smaller volume units. METHODS: A questionnaire was sent to 265 consecutive women treated at the Department of Oncology, Helsinki University Central Hospital, from January to June 1996. Of the patients, 129 were operated in hospitals experienced in breast cancer surgery (high volume units = HVU) and 92 patients in district hospitals with less experience in breast surgery (low volume units = LVU). RESULTS: Chronic symptoms were less common in HVU than in LVU: chronic pain (56 vs. 43%, P<0.05) or strange sensations (45 vs. 26%, P<0.01) in the ipsilateral arm or phantom sensations in the removed breast (66 vs. 26%, P<0.001). The risk factors included in the multivariate model for chronic pain in the breast area were: intensity of acute post-operative pain, radiotherapy and depression and for the chronic arm pain: low volume unit and depression. CONCLUSIONS: More careful surgical technique seems to reduce the risk of chronic pain following treatment of breast cancer. Chronic pain is associated with more intense post-operative pain and depression.
Adult↗
I.v. diclofenac and ketorolac for pain after thoracoscopic surgery.
We studied intensity of pain, cumulative morphine consumption, ventilatory and renal function, and haemostasis in patients undergoing video-assisted thoracoscopic surgery and receiving a 2-day i.v. infusion of diclofenac, ketorolac or saline. Plasma concentrations of the two NSAID were also measured. The study was randomized, double-blind and placebo-controlled, with 10 patients in each group. Patients experienced mainly moderate pain. Mean consumption of i.v. morphine during the first day after operation was 57 (SEM 11) mg in the placebo group. Diclofenac and ketorolac were equally effective in reducing total morphine consumption (61% and 52%, respectively). Adverse events were similar and minor. Greater variability in plasma concentrations of ketorolac were detected compared with diclofenac.
Adolescent↗
Systemic physostigmine shows antiallodynic effects in neuropathic rats.
UNLABELLED: The aim of this study was to examine the antiallodynic and antinociceptive effects of subcutaneously administered physostigmine (50, 100, 200 micrograms/kg), compared with morphine (2.5, 5, 10 mg/kg) and NaCl after spinal nerve ligation in rats. The following stimuli were used: acetone (cold allodynia), von Frey hairs (mechanical allodynia), and paw flick test (thermal nociception). Motility boxes were used to investigate the effects of the drugs on motor performance. Physostigmine attenuated both mechanical and cold allodynia dose-dependently but had no effect on the paw flick test. The effect was antagonized by atropine (muscarinic receptor antagonist) but not by mecamylamine (nicotinic receptor antagonist) or naloxone (opioid receptor antagonist). Morphine produced dose-dependent antiallodynic and antinociceptive effects. In the antiallodynic doses, morphine caused severe rigidity. Physostigmine 200 micrograms/kg impaired locomotor activity, but no rigidity was observed. IMPLICATIONS: Physostigmine has different effects on allodynia and nociception, which suggests that different cholinergic (muscarinic) mechanisms may be involved in neuropathic and nociceptive pain.
Analgesics↗
Gene for pain modulatory neuropeptide NPFF: induction in spinal cord by noxious stimuli.
Neuropeptides FF (NPFF), AF (NPAF), and SF (NPSF) are homologous amidated peptides that were originally identified on the basis of similarity to the molluscan neuropeptide FMRF-amide. They have been hypothesized to have wide-ranging functions in the mammalian central nervous system, including pain modulation, opiate function, cardiovascular regulation, and neuroendocrine function. We have cloned the NPFF gene from human, bovine, rat, and mouse, and show that the precursor mRNA encodes for all three of the biochemically identified peptides (NPFF, NPAF, and NPSF). We demonstrate that NPFF precursor mRNA expression by Northern analysis and map sites of expression by in situ hybridization. We confirm the validity of the in situ hybridization by showing that its distribution in the brain and spinal cord matches the distribution of NPFF and NPSF immunoreactivity. We go on to show that the mRNA levels (as measured by in situ hybridization) in the spinal cord can be up-regulated by a model for inflammatory pain (carrageenan injection), but not by a model for neuropathic pain (lumbar nerve ligation). Our results confirm the evolutionary conservation of NPFF, NPAF, and NPSF neuropeptide expression in mammalian brain. They also provide a context for the interpretation of the pain-sensitizing effects of injections of these peptides that have been previously reported. Our results support a model for the role of these peptides in pain regulation at the level of the spinal cord.
Amino Acid Sequence↗
[New opioid preparations in the treatment of pain].
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Administration, Cutaneous↗
Phantom-limb pain.
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Amputation, Surgical↗
Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone.
BACKGROUND: Oxycodone is metabolized in the liver by means of O-demethylation to form oxymorphone in a reaction catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). This enzyme is expressed as 2 phenotypes (extensive and poor metabolizers). Several drugs are metabolized by CYP2D6, and clinically relevant drug interactions may occur. The aim of this study was to evaluate the role of oxymorphone in mediating the opioid effects of oxycodone by means of blocking CYP2D6 with quinidine. METHODS: Ten healthy extensive metabolizers were administered 20 mg controlled-release oxycodone after premedication with placebo or 200 mg quinidine in this randomized, double-blind crossover study. A dose of 100 mg quinidine was administered 6 hours later. Plasma opioid concentrations, subjective pharmacodynamic ratings, and psychomotor function were assessed for 24 hours after drug administration. RESULTS: No oxymorphone was detected at any time after quinidine premedication in 8 of 10 subjects. Plasma oxycodone (difference not significant) and noroxycodone (P < .01) concentrations were greater after quinidine pretreatment. Prevention of the production of oxymorphone by quinidine did not affect the psychomotor or subjective drug effects of oxycodone. No difference in number of adverse effects was observed after the 2 pretreatments. CONCLUSIONS: A significant reduction in plasma oxymorphone levels did not substantially alter the pharmacodynamic effects of oxycodone. Analgesia was not evaluated because pain was not present.
Adult↗
Systemic local-anaesthetic-type drugs in chronic pain: a systematic review.
Basic research indicates that systemic local-anaesthetic-type drugs that block sodium channels are effective in pain due to nerve damage. These drugs were first used as analgesics in the 1950s and they are still commonly used to try to relieve neuropathic pain and incident pain caused by cancer. As they are potentially toxic, these drugs should not be used without proven effectiveness. For these reasons, a systematic review of randomized controlled trials of systemically administered local-anaesthetic-type drugs in chronic pain was performed. Main outcomes were pain relief or pain intensity difference and adverse effects. Twenty-one reports were found, and four publications were excluded. In the remaining 17 studies (450 patients), 10 used intravenous lignocaine, two used intranasal lignocaine, four used oral mexiletine and one used oral tocainide. The best documented effective dose of intravenous lignocaine was 5 mg/kg, and when infused over 30 min it was well tolerated. Intravenous lignocaine was effective in all four studies in non-cancer-related neuropathic pain. In migraine, lignocaine produced an inconsistent effect. Lignocaine was without effect in all three studies in cancer-related pain. Oral mexiletine showed some efficacy in all three studies in pain due to peripheral nerve damage, but lacked effect in the only study in central pain. Only minor dose-related adverse effects were reported in the 85 patients given mexiletine 225-750 mg. Local-anaesthetic-type drugs are effective in pain due to nerve damage, but there is little or no evidence to support their use in cancer-related pain. Copyright 1998 European Federation of Chapters of the International Association for the Study of Pain.
Journal Article↗
Systemic morphine in the prevention of allodynia in the rat spinal nerve ligation model of neuropathic pain.
Peripheral nerve injury may lead to neuropathic pain that has been considered unresponsive to opioids. In animal models of neuropathic pain, there are previous data of both increased and decreased effect of opioids, but only limited information of the long-term effects of opioid treatment on the development of the symptoms of neuropathy. The possibility of preventing the development of signs of neuropathy with either a single pre-injury injection or chronic postinjury administration of morphine was studied in rats with unilateral peripheral neuropathy due to tight ligation of the L5 and L6 spinal nerves. These rats developed both mechanical and cold allodynia, but no thermal hyperalgesia. Neither subcutaneous morphine given as single injection (10 mg/kg) before the nerve injury nor chronic administration starting immediately after surgery using slow-release pellets (one, two or five pellets containing 75 mg of morphine, resulting in a total dose of 75, 150 or 375 mg) prevented the development of either mechanical or cold allodynia. No autotomy, signs of distress, altered social behaviour or morphine withdrawal was seen in any of the rats. The fact that neuropathic pain-like symptoms were not attenuated by any of the treatments studied could indicate that neither premedication nor postoperative pain management with systemic morphine is effective in preventing postoperative neuropathic pain. Copyright 1998 European Federation of Chapters of the International Association for the Study of Pain.
Journal Article↗