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PubMed2000

[Non-opioid analgesics--irreplaceable in cancer pain therapy?

Sufficient therapy of pain is essential for the treatment of tumor patients. World Health Organisation (WHO)-guidelines recommend a combination of opioids with non-opioid-analgesics (NOA) for patients with medium to strong pain. Cancer pain is often a combination of pain caused by the tumor itself, tumor associated and pain caused by therapy. Various substances act by different mechanisms and therefore combinations may demonstrate superior effects. Opioids ("central analgesics") inhibit neuronal transduction within the spinal cord, enhance inhibiting function of midbrain nuclei on ascending pain transduction and influence pain perception via modulation of the limbic system. NOAs ("peripheral analgesics") inhibit cyclooxygenase hindering activation of the peripheral nociceptor-system. There are 2 different classes of NOAs: 1) non-acidic, antipyretic analgesics like pyrazolones (metamizol) and anilin-derivates (paracetamol) and 2) non-steroidal antirheumatics (NSAR) like salicylates (acetylsalicylic acid), derivates of propionic acid (ibuprofen, naproxen), acetate acid (indomethacin, diclofenac), enolic acid (piroxicam, meloxicam) and anthranil acid (mefenamin). Adjuvant therapy is necessary to control common NSAR-side-effects like dyspepsia, ulcer and gastrointestinal bleeding. Due to its exceptional analgesic, antipyretic and spasmolytic properties, metamizol is an essential substance in tumor therapy. As agranulocytosis-incidence of 1:1,000,000 is low, good gastrointestinal and renal tolerance makes metamizol an excellent alternative to NSAR. There is scientific evidence that adequate combinations of non-opioids, opioids and adjuvant drugs, considering adverse side effects, were effective and safe in the treatment of cancer pain.

Analgesia↗
PubMed1989

Analgesic use and chronic renal disease.

To examine the use of analgesics as a cause of chronic renal disease, we performed a multicenter case-control study of 554 adults with newly diagnosed kidney disease (serum creatinine, greater than or equal to 130 mumol per liter [1.5 mg per deciliter]) and 516 matched control subjects selected randomly from the same area of North Carolina. Histories of use of analgesics (phenacetin, acetaminophen, and aspirin) were obtained by telephone interview with the patients or their proxies. Daily users of analgesics had significantly more renal disease than infrequent users (odds ratio, 2.79; 95 percent confidence interval, 1.85 to 4.21). The risk of renal disease was highest in daily users of phenacetin (odds ratio, 5.11; confidence interval, 1.76 to 14.9, after adjustment for the effects of other analgesics). The risk of renal disease was also increased in daily users of acetaminophen; after adjustment for the use of aspirin and phenacetin, the odds ratio was 3.21 (confidence interval, 1.05 to 9.80). There was no increased risk in daily aspirin users (adjusted odds ratio, 1.32; confidence interval, 0.69 to 2.51). The risks with daily use of either phenacetin or acetaminophen changed little after adjustment for diabetes, hypertension, and the indication for analgesic use. We conclude that the long-term, regular use of phenacetin may increase the risk of chronic renal disease. The long-term, daily use of acetaminophen, the major metabolite of phenacetin, is associated independently with an increased risk of chronic renal disease. We could find no increased risk in daily users of aspirin.

Acetaminophen↗
PubMed2006

Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin.

Neuropathic pain is a debilitating condition affecting millions of people around the world and is defined as pain that follows a lesion or dysfunction of the nervous system. This type of pain is difficult to treat, but the novel compounds pregabalin (Lyrica) and gabapentin (Neurontin) have proven clinical efficacy. Unlike traditional analgesics such as nonsteroidal antiinflammatory drugs or narcotics, these agents have no frank antiinflammatory actions and no effect on physiological pain. Although extensive preclinical studies have led to a number of suggestions, until recently their mechanism of action has not been clearly defined. Here, we describe studies on the analgesic effects of pregabalin in a mutant mouse containing a single-point mutation within the gene encoding a specific auxiliary subunit protein (alpha2-delta-1) of voltage-dependent calcium channels. The mice demonstrate normal pain phenotypes and typical responses to other analgesic drugs. We show that the mutation leads to a significant reduction in the binding affinity of pregabalin in the brain and spinal cord and the loss of its analgesic efficacy. These studies show conclusively that the analgesic actions of pregabalin are mediated through the alpha2-delta-1 subunit of voltage-gated calcium channels and establish this subunit as a therapeutic target for pain control.

Amino Acid Sequence↗
PubMed2005

An investigation of the analgesic and anti-inflammatory effects of Nigella sativa seed polyphenols.

Extracts obtained from the seeds of Nigella sativa are used as a spice or remedy for the treatment of various inflammatory diseases. The purpose of this study was to examine the analgesic and anti-inflammatory effects of its polyphenols. N. sativa seed polyphenols were prepared, and analgesic and anti-inflammatory effects were studied in mice and rats using the acetic acid-induced writhing, formalin, light tail flick, carrageenan-induced paw edema, and croton oil-induced ear edema tests. In the acetic acid-induced writhing test, oral administration of N. sativa polyphenols (NSP) decreased the number of abdominal constrictions. Both oral and intraperitoneal administration of NSP significantly suppressed in a dose-dependent manner the nociceptive response in the early and late phases of the formalin test, and the effect on the late phase was more pronounced. Pretreatment with naloxone failed to reverse the analgesic activity of NSP in this test. NSP did not produce a significant analgesia in the light tail flick test in mice. Oral administration of NSP did not produce a significant reduction in carrageenan-induced paw edema. However, when injected intraperitoneally, NSP inhibited paw edema in a dosedependent manner. NSP when applied topically failed to reduce croton oil-induced ear edema. These results suggest that NSP have analgesic and anti-inflammatory effects. The lack of analgesic effect of NSP in the light tail flick test and also the failure of naloxone to reverse the analgesia in the formalin test reveal that mechanisms other than stimulation of opioid receptors are involved.

Acetic Acid↗
PubMed1996

Psychophysical and electrophysiological responses to experimental pain may be influenced by sedation: comparison of the effects of a hypnotic (propofol) and an analgesic (alfentanil).

Sedation may influence the responses of some experimental pain models used to test analgesic efficacy. In this study we compared the effects of a sedative (propofol) and analgesic (alfentanil) on: nociceptive reflex to single and repeated electrical stimulations; mechanical pressure pain; and evoked potentials elicited by nociceptive (electrical and laser) and non-nociceptive (acoustical) stimulation. We studied 12 healthy volunteers with two subanaesthetic concentrations of propofol and two analgesic concentrations of alfentanil. Both propofol and alfentanil increased the threshold for nociceptive reflex to single electrical stimulations, but only alfentanil increased the threshold for nociceptive reflex to repeated electrical stimulations. The pressure pain tolerance thresholds were increased significantly by alfentanil, whereas propofol significantly decreased the thresholds (hyperalgesia). Propofol and alfentanil induced similar reductions in the amplitudes of the evoked potentials elicited by nociceptive (electrical and laser) and non-nociceptive (acoustical) stimulation, whereas only alfentanil reduced the perceived pain to nociceptive stimulations. We have shown that sedation can influence both the psychophysical and electrophysiological responses of some experimental pain tests used to measure analgesic efficacy, and that propofol in subhypnotic doses, has no analgesic effect on painful electrical and heat stimulations, but has a hyperalgesic effect on mechanical pressure pain.

Adult↗
PubMed2006

The analgesic effect of lornoxicam when added to lidocaine for intravenous regional anaesthesia.

BACKGROUND: The aim of the study was to evaluate the effect of lornoxicam (L) on sensory and motor block onset time, tourniquet pain, and postoperative analgesia, when added to lidocaine in intravenous regional anaesthesia (IVRA). METHODS: Forty-five patients undergoing hand surgery were randomly and blindly divided into three groups as to receive either i.v. saline and IVRA with lidocaine 0.5% (Control group, n=15), i.v. saline and IVRA lidocaine 0.5% with lornoxicam (L-IVRA group, n=15), or intravenous lornoxicam and IVRA lidocaine 0.5% (L-IV group, n=15). Sensory and motor blocks onset time, and tourniquet pain was measured after tourniquet application at 5, 10, 20, and 30 min, and analgesic use were recorded during operation. After the tourniquet deflation, at 1, 30 min, and 2, 4 h, visual analogue scales score, the time to first analgesic requirement, total analgesic consumption in first 24 h, and side effects were noted. RESULTS: Sensory and motor block onset times were shorter and the recovery time prolonged in the Group L-IVRA compared with the other group (P=0.001). A decreased tourniquet pain, a prolonged time first analgesic requirement [229 (85) min vs 28 (20) and 95 (24) min, P=0.0038) and less postoperative analgesic requirements during 24 h were found in Group L-IVRA compared with the other groups (P<0.05). CONCLUSIONS: The addition of lornoxicam to lidocaine for intravenous regional anaesthesia shortens the onset of sensory and motor block, decreases tourniquet pain and improves postoperative analgesia without causing any side effect.

Adult↗
PubMedDate not supplied

Fever associated with repeated intramuscular injections of analgesics.

Five patients who developed a fever of undetermined origin during hospitalization are discussed. No infection was found in any of these patients. Occurrence of fever was temporally related to intramuscular (im) analgesic injections. In four cases damage of subcutaneous tissue was evident, and in two cases gallium scans showed uptake of gallium at injection sites. All five patients had received hydroxyzine either alone or in combination with other im analgesics. In addition, a retrospective chart survey of patients hospitalized for back pain who had received more than 30 im analgesic injections was carried out. Ten of 29 patients had fever lasting one to 15 days that could not be explained by the presence of obvious infection or inflammation or by the use of a nonanalgesic drug. In the chart survey it was found that febrile patients had been hospitalized significantly longer and had received more injections of all types and more injections of combinations of analgesics per patient than had afebrile patients. Thus, repeated im injections of analgesics may be associated with fever, with or without signs of tissue injury. Particular care should be taken in deciding whether im administration of hydroxyzine is necessary. Injection sites should be carefully monitored.

Analgesics↗
PubMed2003

Analgesic-associated nephropathy in the West of Scotland: a 12-year observational study.

BACKGROUND: Analgesic-associated nephropathy (AAN) is an important and preventable cause of chronic renal failure (CRF). Although its incidence is falling in some countries, others are witnessing an increase in the number of new cases. METHODS: The aim of this study was to evaluate the natural history of AAN, determine the correlates of the rate of decline in renal function and examine factors conferring an increased risk of death or dialysis in such patients. A prospective observational cohort study of all patients with AAN attending a single-centre was conducted. RESULTS: Seventy-eight patients (25 male), with at least 24 months of follow-up for analysis, were diagnosed as having AAN over the 10-year period 1989-1999. During follow up, the mean (+/-SD) rate of change in estimated creatinine clearance (ECC) was -1.2 ml/min/year (+/-5.28). By multiple linear regression three variables were found to independently predict the rate of deterioration in ECC; continuing analgesic use (P < 0.001), degree of proteinuria at presentation (P = 0.002) and male sex (P = 0.03). A Cox's model revealed a 6-fold increase in the hazard of reaching the combined end-point of death or dialysis in those patients with AAN who continue to use analgesics. This was independent of the other two significant risk factors of pre-existing vascular disease (HR 3.93, 1.36-11.29) and ECC at presentation (HR 0.95, 0.91-0.98 per ml/min). CONCLUSIONS: In patients with CRF due to AAN ongoing analgesic use, male gender and increasing proteinuria predict a more rapid decline in renal function. Patients who continue analgesics, those with pre-existing vascular disease and those with more advanced renal impairment at presentation, are at a significantly increased risk of reaching the combined end-point of death or end-stage renal failure requiring dialysis. The design of this study, however, leaves it open to the criticism that selection bias may account for some of its effects, and as with all work on AAN the possible confounding issue of reverse causality is difficult to dismiss.

Aged↗
PubMed1999

A comparison of the analgesic efficacy of 0.25% levobupivacaine combined with 0.005% morphine, 0.25% levobupivacaine alone, or 0.005% morphine alone for the management of postoperative pain in patients undergoing major abdominal surgery.

UNLABELLED: We compared the relative efficacy of the combination of the single-isomer local anesthetic levobupivacaine and the opioid analgesic morphine versus both drugs alone for postoperative epidural analgesia after major abdominal surgical procedures. Thoracic epidural anesthesia was produced and maintained with levobupivacaine 0.75% in combination with general inhaled anesthesia without opioids. Patients were randomized to one of three postoperative treatment groups: 1) a combination of levobupivacaine 0.25% and morphine 0.005%; 2) levobupivacaine 0.25%; or 3) morphine 0.005%. Postoperatively, all epidural infusions were commenced at a rate of 4 mL/h. Patients could receive a 4 mL-bolus dose and an increase in the epidural infusion rate by 2 mL/h on request for supplemental analgesia. Patients were also allowed ketorolac as a supplemental analgesic at any time after the first analgesic request. Patients in the combination group had longer times to request for supplemental analgesia as compared with the levobupivacaine only group (P < 0.05) and a trend toward longer time to request as compared with the morphine only group (P = 0.066). Patients in the combination group had lower visual analog scale pain scores at rest and activity at 4 and 8 h and fewer requests for supplemental ketorolac (P < 0.05). In conclusion, this study demonstrates a significant improvement in postoperative analgesic efficacy with the combination of levobupivacaine and morphine for continuous epidural analgesia after major abdominal surgical procedures. IMPLICATIONS: A significant improvement in postoperative analgesic efficacy is demonstrated with the thoracic epidural administration of the combination of the single-isomer local anesthetic levobupivacaine 0.25% and morphine 0.005% in patients after major abdominal surgical procedures as compared with either drug used alone.

Abdomen↗
PubMed2002

Analgesic effects of rofecoxib in ear-nose-throat surgery.

UNLABELLED: In this study we evaluated the analgesic efficacy and the opioid-sparing effect of rofecoxib in ear-nose-throat surgery patients. Patients undergoing nasal septal or sinus surgery were randomized to receive either oral placebo or rofecoxib 50 mg 1 h before surgery. All patients received propofol 0.8 mg/kg, fentanyl 1 microg/kg, and local anesthesia at the operative site. Sedation was maintained by a continuous infusion of propofol adjusted to maintain sedation at a 2-3 level on the Ramsey scale. Additional fentanyl 0.5-1 microg/kg was administered at the patient's request or if the verbal rating scale score was >4. Patient sedation and pain scores were obtained at 5, 15, 30 45, and 60 min during surgery and 30 min and 2, 4, 6, 12, and 24 h after completion of the procedure. During the postoperative period, diclofenac 75 mg IM was administered for analgesia at the patient's request or if the visual analog scale (VAS) rating for pain was more than 4. VAS pain scores, intraoperative fentanyl, and postoperative diclofenac requirements were significantly smaller in the rofecoxib group compared with the placebo group (P < 0.001). The times to first analgesic request were also significantly less in the rofecoxib group. We conclude that the preoperative administration of oral rofecoxib provided a significant analgesic benefit and decreased the need for opioids in patients undergoing nasal septal and nasal sinus surgery. IMPLICATIONS: The aim of this study was to evaluate the analgesic efficacy and opioid-sparing effect of rofecoxib, a new selective cyclooxygenase-2 inhibitor drug, in ear-nose-throat surgery patients. Preoperative administration of oral rofecoxib provided a significant analgesic benefit and decreased the need for opioids in patients undergoing nasal septal and nasal sinus surgery.

Adult↗
PubMed1984

Ventilatory and analgesic effects of dezocine in humans.

The respiratory depressant and analgesic effects of intravenous dezocine were evaluated in six healthy volunteers. Single 0.15 mg/kg doses were compared with identical amounts of morphine, and the two drugs were given in combination. Five successive 0.15 mg/kg doses of dezocine also were given to identify dose-effect relationships. Respiratory center sensitivity was monitored by carbon dioxide (CO2) rebreathing and mouth occlusion pressure (P0.1) measurement, while analgesia to experimental pain was tested with submaximal tourniquet ischemia. Single 0.15 mg/kg doses of dezocine produced significantly more tolerance to experimental pain and greater respiratory depression than a comparable dose of morphine in the first hour, but effects of both drugs were similar thereafter. Multiple doses of dezocine progressively increased pain tolerance from 46 +/- 14% above control with the first dose to 70 +/- 18% above control with the second dose (cumulative total 0.30 mg/kg). Additional dezocine doses did not result in significantly more analgesia. Depression of CO2 sensitivity followed a similar pattern. Morphine 0.15 mg/kg, when given to subjects who had received a prior dose of dezocine, produced no additional effect beyond that observed with dezocine. With the reverse sequence, dezocine increased the respiratory depression of morphine but also produced a dramatic increment in analgesia, which suggested an additive action. Dezocine is therefore an effective analgesic with morphine-like effects. In human subjects it appears to be a slightly more potent analgesic than morphine in identical clinical doses (0.15 mg/kg). Dezocine is similar to other agonist-antagonist analgesics in that it exhibits a ceiling effect for respiratory depression that parallels its analgesic activity.

Adult↗
PubMed1996

Preemptive analgesic effects of steroid anesthesia with alphaxalone in the rat formalin test. Evidence for differential GABA(A) Receptor modulation in persistent nociception.

BACKGROUND: The role of preemptive treatment with volatile and intravenous anesthetics has been examined in previous studies using the rat formalin test. Evidence describing analgesic properties of the gamma-amino butyric acid-ergic (GABAergic) steroid anesthetics, such as alphaxalone, suggest that they may suppress the development of central sensitization to pain. This study examined the preemptive effects of phaxalone in comparison with other GABAergic anesthetics, propofol and pentobarbital. METHODS: The pain behavior of rats was evaluated (using the previously validated weighted scores method of behavioral rating) 15-60 min after subcutaneous hind paw injection of 50 microg 1.5% formalin. In each trial, anesthetics and their respective vehicles were administered by tail-vein injection either 0.5-10 min before or 5 min after, formalin injection. When analgesic effects were observed with any of these agents, further studies were conducted with a GABA(A) receptor antagonist in an attempt to confirm a specific receptor-mediated action of the agent. RESULTS: Alphaxalone pretreatment produced transient analgesia in the early part of phase 2, which was not observed in rats posttreated with alphaxalone. The analgesic effect of alphaxalone was antagonized by picrotoxin, as well. Neither pentobarbital nor propofol showed any analgesic effects at the doses used in our study. CONCLUSIONS: Whereas alphaxalone was shown to produce preemptive analgesia through its action at the GABA(A) receptor, pentobarbital and propofol, which also are known to act at this site, showed no analgesic effects. The diversity of receptor subtypes and functional complexity of GABA(A) receptors is such that steroid anesthetics may have effects that are different from other GABAergic agents. Further research into the role of progesterone metabolites and steroid anesthetics in the prevention of central sensitization may have clinical implications for the treatment of acute or chronic pain.

Analgesics↗
PubMed1997

Epidural clonidine used as the sole analgesic agent during and after abdominal surgery. A dose-response study.

BACKGROUND: Many studies have shown the beneficial effect of epidural clonidine in postoperative pain management. In these studies, the patients received local anesthetics, opioids, or both in combination with clonidine. Due to the interactive potentiation of those drugs, the importance of the intrinsic analgesic properties of the alpha 2-adrenoceptor agonist is difficult to establish. The authors investigated the analgesic potency of epidural clonidine when used as the sole analgesic agent during and after major abdominal surgery. METHODS: Fifty young adult patients undergoing intestinal surgery under general anesthesia with propofol were studied. At induction, the patients received epidurally either an initial dose of 2 micrograms/kg clonidine followed by an infusion of 0.5 microgram.kg-1.h-1 (group 1, n = 10) or 4 micrograms/kg followed by 1 microgram.kg-1.h-1 (group 2, n = 20) or 8 micrograms.kg-1.h-1 followed by an infusion of 2 micrograms.kg-1.h-1 (group 3, n = 20). During the operation, increases in arterial blood pressure or heart rate that did not respond to a propofol bolus (0.5 mg/kg) were treated with a bolus of intravenous lidocaine (1 mg/kg). Three successive injections were allowed. When baseline values were not restored, opioids were added and the patient was removed from the study. After operation, the clonidine infusions were maintained for 12 h. During this period and at every 30 min, sedation scores and visual analog scale values at rest and at cough were noted. In case of subjective scores up to 5 cm at rest or up to 8 cm at cough, the patients were given access to a patient-controlled analgesia device that delivered epidural bupivacaine. The end point of the study was reached once the patient activated the analgesic delivery button. RESULTS: During surgery, 60% of patients in group 1 compared with 33% of patients in group 2 and only 5% of patients in group 3 were removed from the study protocol because of inadequate anesthesia (P < 0.05). After operation, epidural clonidine provided complete analgesia lasting 30 +/- 21 min in group 1 compared with 251 +/- 237 min in group 2 or 369 +/- 256 min in group 3 (P < 0.05 for group 1 vs. groups 2 and 3 and group 2 vs. group 3). CONCLUSIONS: Epidural clonidine used as the sole analgesic agent provided dose-dependent control of the hemodynamic changes associated with surgical stimulation. It also produced dose-dependent postoperative analgesia without major side effects.

Adult↗
PubMed2001

Minimum analgesic dose of epidural sufentanil for first-stage labor analgesia: a comparison between spontaneous and prostaglandin-induced labors in nulliparous women.

BACKGROUND: The aim of this prospective, double-blind, sequential allocation study was to compare the effects of spontaneous and prostaglandin-induced labor on the minimum analgesic dose of epidural sufentanil in the first stage of labor. METHODS: Seventy healthy, nulliparous women, at more than 37 weeks' gestation with cervical dilatation from 2 to 4 cm, requesting epidural pain relief in labor were enrolled. The subjects were assigned to two different groups according to whether labor was spontaneous or induced with dinoprostone 0.5 mg. Parturients received 10 ml of the study solution through a lumbar epidural catheter. The initial dose was sufentanil 25 microg, and subsequent doses were determined by the response of the previous patient in the same group using up-down sequential allocation. The analgesic effectiveness was assessed using 100-mm visual analog pain scores. The up-down sequences were analyzed using the method of independent paired reversals and probit regression. RESULTS: The minimum analgesic dose of sufentanil in spontaneous labor was 22.2 microg (95% CI: 19.6, 22.8) and 27.3 microg (95% CI: 23.8, 30.9) in induced labor. The minimum analgesic dose of sufentanil in induced labor was significantly greater (P = 0.0014) than that in spontaneous labor (95% CI difference: 2.9, 9.3) by a factor of 1.3 (95% CI: 1.1, 1.5). CONCLUSION: Prostaglandin induction of labor produces a significantly greater analgesic requirement than does spontaneous labor.

Adult↗
PubMed2003

Spinal nitric oxide contributes to the analgesic effect of intrathecal [d-pen2,d-pen5]-enkephalin in normal and diabetic rats.

BACKGROUND: Spinal nitric oxide (NO) is important for the analgesic actions of morphine and cholinergic agents. Its role in the analgesic effect of delta-opioid receptor agonists is not known. In the present study, the authors determined the role of spinal endogenous NO in the antinociceptive effect of intrathecal [D-Pen2, D-Pen5 ]-enkephalin (DPDPE), a delta-opioid receptor agonist, in normal rats and a rat model of diabetic neuropathic pain. METHODS: Rats were rendered diabetic with streptozotocin (50 mg/kg, intraperitoneal). Intrathecal catheters were implanted in age-matched normal and diabetic rats. Nociceptive thresholds were determined by application of a noxious pressure stimulus to the hind paw. The dose-dependent effect of intrathecal DPDPE was first determined. The role of spinal NO in the analgesic effect of intrathecal DPDPE was then examined through intrathecal treatments with NO synthase inhibitors (NMMA and TRIM) and a specific NO scavenger (carboxy-PTIO). RESULTS: The diabetic rats developed a sustained mechanical hyperalgesia within 3 weeks after streptozotocin injection. Intrathecal DPDPE, 2-20 micro g, dose-dependently increased the withdrawal threshold in response to the noxious pressure in normal and diabetic rats. However, the ED(50) of DPDPE in diabetic rats was about twofold higher than that in normal rats. Intrathecal pretreatment with NMMA, TRIM, or carboxy-PTIO diminished the analgesic effect of DPDPE in both normal and diabetic rats. Furthermore, the inhibitory effect of NMMA on the action of intrathecal DPDPE was reversed by intrathecal l-arginine but not d-arginine. CONCLUSIONS: Intrathecal DPDPE produces an antinociceptive effect in normal rats and a rat model of diabetic neuropathic pain. Spinal endogenous NO contributes importantly to the analgesic action of intrathecal DPDPE in both normal and diabetic neuropathic pain conditions.

Analgesics, Opioid↗
PubMed2004

Dexmedetomidine enhances analgesic action of nitrous oxide: mechanisms of action.

BACKGROUND: Nitrous oxide and dexmedetomidine are thought to mediate analgesia (antinociception in a noncommunicative organism) via alpha 2B- and alpha 2A-adrenergic receptor subtypes within the spinal cord, respectively. Nitrous oxide and dexmedetomidine exert diametrically opposite effects on neuronal activity within the locus ceruleus, a pivotal site for modulation of analgesia. Because of these differences, the authors explored whether the two analgesics in combination would provide satisfactory analgesia. METHODS: The analgesic effects of nitrous oxide and dexmedetomidine given both intraperitoneally and intrathecally were evaluated using the tail-flick latency test in rats. For investigation of the interaction, rats were pretreated with dexmedetomidine, either intraperitoneally or intrathecally, immediately before nitrous oxide exposure such that peak antinociceptive effects of each drug coincided. For assessment of the effect on tolerance, dexmedetomidine was administered as tolerance to nitrous oxide developed. Expression of c-Fos was used to assess neuronal activity in the locus ceruleus. RESULTS: Nitrous oxide and dexmedetomidine increased tail-flick latency with an ED50 (mean +/- SEM) of 55.0 +/- 2.2% atm for nitrous oxide, 27.6 +/- 5.1 for microg/kg intraperitoneal dexmedetomidine, and 2.9 +/- 0.1 microg for intrathecal dexmedetomidine. Combinations of systemically administered dexmedetomidine and nitrous oxide produced an additive analgesic interaction; however, neuraxially administered dexmedetomidine interacted synergistically with nitrous oxide. Tolerance to nitrous oxide was reversed by coadministration of dexmedetomidine. Prazosin, the alpha 1-/alpha 2B-adrenoceptor antagonist, attenuated the analgesic effect of nitrous oxide and prevented dexmedetomidine-induced reversal of tolerance to nitrous oxide. Nitrous oxide-induced increase of neuronal activity in the locus ceruleus was reversed by dexmedetomidine. CONCLUSION: The synergistic analgesic interaction between nitrous oxide and dexmedetomidine within the spinal cord is obscured by a supraspinal antagonism when dexmedetomidine is administered systemically in the pretolerant state. After tolerance to nitrous oxide develops, supraspinal functional antagonism no longer obtains exposing the synergistic action at the level of the spinal cord, which expresses itself as a reversal of the tolerant state. The authors speculate that the addition of dexmedetomidine to nitrous oxide is likely to provide enhanced and more durable analgesia in settings in which nitrous oxide is currently used alone (e.g., labor and dental surgery).

Analgesics↗
PubMed2006

Enhancement of morphine analgesic effect with induction of mu-opioid receptor endocytosis in rats.

BACKGROUND: Morphine can desensitize mu-opioid receptor (MOR), but it does not cause internalization of the receptor after binding. Acute desensitization of MOR impairs the efficiency of signaling, whereas the receptor internalization restores the cell responsiveness to the agonists. Thereby, the property of morphine may limit the analgesic effects of this opiate drug. It has been shown that [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO), a potent MOR agonist inducing the internalization, facilitates morphine to internalize MOR, suggesting that MOR agonists with low relative activity versus endocytosis (RAVE) values such as DAMGO can potentiate analgesic effects of morphine through stimulating MOR internalization. The authors examined whether the acute analgesic effect of morphine can be potentiated by low relative activity versus endocytosis agonists DAMGO and fentanyl. METHODS: Rats injected intrathecally with opioids were subjected to a hot plate test for antinociceptive effect. Immunostained spinal dorsal horn was analyzed by confocal microscopy. RESULTS: Fentanyl induced MOR internalization to a lesser extent than DAMGO at equianalgesic doses. Coadministration of fentanyl promoted morphine-induced MOR internalization. The analgesic effect of morphine was greatly potentiated together with decrease in the relative activity versus endocytosis value when MOR internalization was induced by coadministration of a subanalgesic dose of DAMGO or fentanyl. In contrast, the combination of DAMGO and fentanyl increased neither the analgesic effect nor the internalization of MOR. CONCLUSIONS: The results suggest that the coadministration of morphine with MOR-internalizing agonist is clinically applicable to develop successful pain-management regimens to achieve satisfactory analgesia using less morphine.

Analgesics, Opioid↗
PubMedDate not supplied

Analgesics for acute pain: Meeting the United States Food and Drug Administration's requirements for proof of efficacy.

OBJECTIVE: To examine the United States Food and Drug Administration's (FDA) standards for reviews of the scientific basis for efficacy claims for newly approved oral analgesics. METHODS: Comparison of the trial methodologies and results provided by the FDA's medical reviewer in the Summary Bases of Approval (SBA) for the 9 oral acute analgesics approved in the last 10 years: ketorolac, diclofenac potassium, bromfenac, tramadol, hydrocodone/ibuprofen fixed combination, celecoxib, rofecoxib, tramadol/acetaminophen, and valdecoxib. RESULTS: For all 9 new analgesics, studies were conducted in patients with postoperative dental pain and nondental surgical pain. The relief of gynecologic pain was examined for 5 of the new drugs. No studies in other pain models (such as infection, neuropathy, and nonsurgical trauma) supported claims of efficacy for any of the new drugs. The overall designs of the dental and nondental surgical studies, including timing of the single dose of trial drug, timing of evaluations, scales used for evaluations, and the use of both measured and derived outcome variables, were similar across the 8 development programs fully described in SBAs. Other characteristics of the trials, including choice of population for efficacy analyses, methods of carrying forward pain intensity and pain relief scores, and the length of time patients were encouraged to refrain from use of rescue medication differed across the development programs. CONCLUSION: The requirements for approval of new analgesics in the United States encourage the pharmaceutical industry to perform efficacy studies using stylized designs in dental and nondental surgical pain. Studies of the efficacy of new analgesics in other common clinical settings are rarely or never included in development programs.

Acute Disease↗