Spinal antinociceptive synergism between morphine and clonidine persists in mice made acutely or chronically tolerant to morphine.
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Morphine (Mor) tolerance has been attributed to a reduction of opioid-adrenergic antinociceptive synergy at the spinal level. The present experiments tested the interaction of intrathecally (i.t.) administered Mor-clonidine (Clon) combinations in mice made acutely or chronically tolerant to Mor. ICR mice were pretreated with Mor either acutely (40 nmol i.t., 8 h; 100 mg/kg s.c., 4 h) or chronically (3 mg/kg s.c. every 6 h days 1 and 2; 5 mg/kg s.c. every 6 h days 3 and 4). Antinociception was detected via the hot water (52.5 degrees C) tail-flick test. After the tail-flick latencies returned to baseline levels, dose-response curves were generated to Mor, Clon, and Mor-Clon combinations in tolerant and control mice. Development of tolerance was confirmed by significant rightward shifts of the Mor dose-response curves in tolerant mice compared with controls. Isobolographic analysis was conducted; the experimental combined ED50 values were compared statistically against their respective theoretical additive ED50 values. In all Mor-pretreated groups, the combination of Mor and Clon resulted in significant leftward shifts in the dose-response curves compared with those of each agonist administered separately. In all tolerant and control groups, the combination of Mor and Clon produced an ED50 value significantly less than the corresponding theoretical additive ED50 value. Mor and Clon synergized in Mor-tolerant as well as in control mice. Spinally administered adrenergic/opioid synergistic combinations may be effective therapeutic strategies to manage pain in patients apparently tolerant to the analgesic effects of Mor. (+info)
Characterization of the analgesic and anti-inflammatory activities of ketorolac and its enantiomers in the rat.
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The marked analgesic efficacy of ketorolac in humans, relative to other nonsteroidal anti-inflammatory drugs (NSAIDs), has lead to speculation as to whether additional non-NSAID mechanism(s) contribute to its analgesic actions. To evaluate this possibility, we characterized (R,S)-ketorolac's pharmacological properties in vivo and in vitro using the nonselective cyclooxygenase (COX) inhibitors [indomethacin (INDO) and diclofenac sodium (DS)] as well as the selective COX-2 inhibitor, celecoxib, as references. The potency of racemic (R,S)-ketorolac was similar in tests of acetic acid-induced writhing, carrageenan-induced paw hyperalgesia, and carrageenan-induced edema formation in rats; ID50 values = 0.24, 0. 29, and 0.08 mg/kg, respectively. (R,S)-ketorolac's actions were stereospecific, with (S)-ketorolac possessing the biological activity of the racemate in the above tests. The analgesic potencies for (R,S)-, (S)-, and (R)-ketorolac, INDO, and DS were highly correlated with their anti-inflammatory potencies, suggesting a common mechanism. (R,S)-ketorolac was significantly more potent than INDO or DS in vivo. Neither difference in relative potency of COX inhibition for (R,S)-ketorolac over INDO and DS nor activity of (S)-ketorolac at a number of other enzymes, channels, or receptors could account for the differences in observed potency. The distribution coefficient for (R,S)-ketorolac was approximately 30-fold less than for DS or INDO, indicating that (R,S)-ketorolac is much less lipophilic than these NSAIDs. Therefore, the physicochemical and pharmacokinetics properties of (R,S)-ketorolac may optimize the concentrations of (S)-ketorolac at its biological target(s), resulting in greater efficacy and potency in vivo. (+info)
Cannabinoid suppression of noxious heat-evoked activity in wide dynamic range neurons in the lumbar dorsal horn of the rat.
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The effects of cannabinoid agonists on noxious heat-evoked firing of 62 spinal wide dynamic range (WDR) neurons were examined in urethan-anesthetized rats (1 cell/animal). Noxious thermal stimulation was applied with a Peltier device to the receptive fields in the ipsilateral hindpaw of isolated WDR neurons. To assess the site of action, cannabinoids were administered systemically in intact and spinally transected rats and intraventricularly. Both the aminoalkylindole cannabinoid WIN55,212-2 (125 microg/kg iv) and the bicyclic cannabinoid CP55,940 (125 microg/kg iv) suppressed noxious heat-evoked activity. Responses evoked by mild pressure in nonnociceptive neurons were not altered by CP55,940 (125 microg/kg iv), consistent with previous observations with another cannabinoid agonist, WIN55,212-2. The cannabinoid induced-suppression of noxious heat-evoked activity was blocked by pretreatment with SR141716A (1 mg/kg iv), a competitive antagonist for central cannabinoid CB1 receptors. By contrast, intravenous administration of either vehicle or the receptor-inactive enantiomer WIN55,212-3 (125 microg/kg) failed to alter noxious heat-evoked activity. The suppression of noxious heat-evoked activity induced by WIN55,212-2 in the lumbar dorsal horn of intact animals was markedly attenuated in spinal rats. Moreover, intraventricular administration of WIN55,212-2 suppressed noxious heat-evoked activity in spinal WDR neurons. By contrast, both vehicle and enantiomer were inactive. These findings suggest that cannabinoids selectively modulate the activity of nociceptive neurons in the spinal dorsal horn by actions at CB1 receptors. This modulation represents a suppression of pain neurotransmission because the inhibitory effects are selective for pain-sensitive neurons and are observed with different modalities of noxious stimulation. The data also provide converging lines of evidence for a role for descending antinociceptive mechanisms in cannabinoid modulation of spinal nociceptive processing. (+info)
Pharmacological studies on root bark of mulberry tree (Morus alba L.)
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Pharmacological studies were done on the root bark of mulberry tree and pharmacological effects were compared with the clinical effects of "Sohakuhi" in Chinese medicine. n-Butanol- and water-soluble fractions of mulberry root had similar effects except for those on the cadiovascular system. Both fractions showed cathartic, analgesic, diuretic, antitussive, antiedema, sedative, anticonvulsant, and hypotensive actions in mice, rats, guinea pigs and dogs. There appears to be a correlation between the experimental pharmacological results and the clinical applications of mulberry root found in the literature on Chinese medicine. (+info)
Incidence of analgesic nephropathy in Berlin since 1983.
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BACKGROUND: Phenacetin was removed from the German market in 1986 and was replaced mainly in analgesic compounds by acetaminophen. Our objective was to examine the effect of this measure on the incidence of analgesic nephropathy in light of the changes in other end-stage renal diseases. METHODS: We therefore compared the proportion of renal diseases in all patients starting dialysis treatment during three 18-month periods: 4/1982-9/1983 (n=57); 1/1991-6/1992 (n=81); and 10/1995-3/1997 (n=76). RESULTS: On the one hand, the proportion of end-stage analgesic nephropathy decreased significantly from 30% in 1981-1982 to 21% in 1991-1992 and 12% in 1995-1997 (P=0.01). On the other hand, type II diabetes increased significantly from 7% to 22% (P=0.01) and 29%, (P=0.001). Using the chi2 distribution test to analyze the frequencies of seven diseases at three different time intervals, however, showed that the changes in renal-disease proportions between 1982-1983, 1991-1992 and 1995-1997 were not significantly independent. There was a significant median age increase from 52 years (CI0.95 44-58) in 1982-1983 to 63 (CI0.95 55-67) in 1991-1992 and 63 (CI0.95 60-66) in 1995-1997 (P=0.003) for all patients starting dialysis but not for those with analgesic nephropathy [59 (55-71) vs 64 (53-67) and 61 (50-72); n.s.]. CONCLUSION: The decrease of end-stage analgesic nephropathy since 1983 may be partially due to the removal of phenacetin from the German market in 1986. However, considering the general increase in numbers of dialysis patients, their higher age and the increased incidence of type II diabetes, the decrease in analgesic nephropathy is not a statistically significant independent variable. Altered admittance policies for dialysis treatment have yielded a new pattern of renal-disease proportion which interferes with changes in the incidence of analgesic nephropathy. (+info)
Prevalence and treatment of pain in older adults in nursing homes and other long-term care institutions: a systematic review.
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BACKGROUND: The high prevalence of pain in older adults and its impact in this age group make it a public health issue, yet few studies of pain relief focus on older adults. Residents of long-term care facilities have more cognitive impairment than their community-living counterparts and may have difficulty reporting the presence and severity of pain. This systematic literature review was conducted to determine the prevalence of pain, and the type and effectiveness of interventions that have been used to treat pain in residents of nursing homes. METHODS: Studies were identified by searching MEDLINE (from January 1966 to May 1997), HEALTH (from January 1975 to May 1997), CINAHL (from January 1982 to April 1997), AGELINE (from January 1978 to April 1997) and the Cochrane Library (1997, issue 1) and by performing a manual search of textbooks and reference lists. Studies of any methodological design were included if they estimated the prevalence of pain in nursing homes or other long-term care institutions or evaluated interventions for the treatment of pain in residents. Of the 14 eligible studies, 12 were noncomparative studies, 1 was a comparison study with nonrandomized contemporaneous controls, and 1 was a randomized controlled trial. Information on several factors was extracted from each study, including study design, number of patients and facilities, main outcomes measured, methods used to identify and detect pain, prevalence and types of pain, and interventions used to treat pain. The strength of the evidence provided by each study was also assessed. RESULTS: In the 6 studies with data from self-reporting or chart reviews, the prevalence of pain ranged from 49% to 83%. In the 5 studies with data on analgesic use only, the prevalence of pain ranged from 27% to 44%. Only 3 studies, with just 30 patients in total, evaluated an intervention for the treatment of pain. INTERPRETATION: Despite the high prevalence of pain in residents of nursing homes, there is a lack of studies evaluating interventions to relieve their pain. The authors make recommendations for future studies in this area. (+info)
Evaluation of lidocaine as an analgesic when added to hypertonic saline for sclerotherapy.
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PURPOSE: The efficacy of sclerosing agents for the treatment of telangiectasias and reticular veins is well established. The injection of these agents is often associated with pain, and it is not uncommon for sclerotherapists to include lidocaine with the sclerosants in an attempt to reduce the pain associated with treatment. However, there are concerns that this may reduce the overall efficacy of the treatment because of dilution of the sclerosant. Patient comfort and overall outcome associated with treatment using HS with lidocaine (LIDO) versus that using HS alone was compared. METHODS: Forty-two patients were prospectively entered into the study and randomized blindly to sclerotherapy with 23.4% HS or 19% LIDO. Study subjects and treating physicians were blinded to the injection solution used. Injection sites were chosen for veins ranging in size from 0.1 to 3 mm. Photographs of the area to be treated were taken, and the patients rated their pain. They were then observed at regular intervals for four months, and clinical data was collected. Thirty-five subjects completed the full follow-up period, and photographs of the injected area were taken again. Three investigators blinded to the treatment assignment then evaluated the photographs and scored the treatment efficacy according to a standardized system. RESULTS: In the HS group, 61.9% (13 of 21) patients rated their pain as none or mild, whereas 90.5% (19 of 21) of patients in the LIDO group had no or mild discomfort. This difference is significant, with a P value of.034. There was no difference in the overall efficacy of treatment between the two groups. The groups had similar rates of vein thrombosis and skin necrosis. CONCLUSION: Although lidocaine is often used with sclerosing agents, there are no previous reports in the literature to evaluate its effectiveness in reducing the pain experienced by the patient. In this study, patients receiving LIDO experienced significantly less discomfort at the time of injection than patients who received HS alone. There were no differences in the effectiveness of treatment or in the incidence of complications between the two groups. (+info)
Ketamine-induced peripheral analgesia in rats.
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AIM: To examine whether ketamine may directly act at peripheral nociceptors to produce analgesia. METHODS: Wistar rats were anesthetized with urethane. As a nociceptive flexion reflex (FR), C responses from the posterior biceps semitendinosus (PBST) muscle was evoked by electrical stimulation (2 ms, 80 V, 2-3 pulses, 0.5 Hz) via a pair of stainless steel needles inserted subcutaneously applied to the two toes of ipsilateral hindpw. RESULTS: Subcutaneous injection of ketamine (36 mmol.L-1, 5 microL) into the ipsilateral hindpaw produced an inhibition of C responses. At 9 min after application of ketamine, injection of naloxone (1%, 5 microL) into the same area annulled ketamine-induced inhibition. CONCLUSION: Ketamine as a dissociate anesthetic acts on peripheral nociceptors to produce analgesia, which is related to activity of peripheral opioid receptors. (+info)