Pharmacological mechanisms of action of flupirtine: a novel, centrally acting, nonopioid analgesic evaluated by its discriminative effects in the rat.

Rats were trained to discriminate the novel analgesic flupirtine (10.0 mg/kg i.p., 10 min) from no drug under a two-choice fixed-ratio 5 shock-termination schedule. Flupirtine yielded a dose-response curve with an ED50 of 3.87 mg/kg. The opioid analgesics pentazocine, codeine and Tramadol ( Generic Ultram ) failed to produce flupirtine appropriate responding. The opioid antagonist naltrexone did not antagonize the discriminative effects of flupirtine. The mixed alpha-1/alpha-2 adrenergic agonist clonidine and the highly specific alpha-2 adrenergic agonist UK-14304, both partially and dose-dependently produced flupirtine appropriate responding. The mixed alpha-1/alpha-2 antagonist yohimbine and the highly specific alpha-2 antagonists idazoxan and L-654,284 all partially and dose-dependently antagonized flupirtine appropriate responding. Neither of the alpha-1 agonists phenylephrine or ST 587 produced flupirtine appropriate responding, nor did the alpha-1 antagonist prazosin antagonize flupirtine responding. It is concluded that the discriminative effects of flupirtine are neither of opioid nor of alpha-1 adrenergic type, but are primarily mediated through alpha-2 adrenergic mechanisms.

How we use opioid drugs on patients with neoplasms

Tramadol ( Generic Ultram ) is a centrally acting analgesic drug with a dual mechanism of action: binding to mu-opioid receptors and potentiation of the monoaminergic systems. In this study, we evaluated the effects of the acute and chronic administration of Tramadol ( Generic Ultram ) on nociceptive thresholds (by the hot-plate test) and on immune responses (by measuring Concanavalin A-induced splenocyte proliferation, IL-2 production and natural killer activity) in the mouse. After acute subcutaneous administration, Tramadol ( Generic Ultram ) induced antinociception starting from a dose of 20 mg/kg, whereas it significantly enhanced natural killer activity and IL-2 production at doses as low as 1 mg/kg and splenocyte proliferation starting from a dose of 10 mg/kg. After the chronic administration, the antinociceptive effect of the drug was still present, whereas the immune modifications disappeared. Thus, the pharmacological profile of Tramadol ( Generic Ultram ) is totally different from that of other drugs which bind mu-opioid receptors. Our results suggest that Tramadol ( Generic Ultram ) could be a good choice for the treatment of pain in patients where immunosuppression may be particularly contraindicated.

Patient reporting of adverse drug reactions: useful information for pain management?

The complete Freund's adjuvant (CFA)-induced arthritic rat model has extensively served as a laboratory model in the study of arthritic pain. However, the time courses of allodynia and hyperalgesia and the efficacies of different analgesics have not fully been analyzed in this model. Mechanical allodynia, thermal and joint hyperalgesia, and other disease development parameters (body weight, mobility, paw volume, and joint stiffness) were measured on postinoculation days (PIDs) 0 to 28 in rats. Acute analgesic efficacies of drugs were evaluated on PID 9 when degrees of allodynia, hyperalgesia, and joint stiffness in the ipsilateral paw reached almost the maximum, although those in the contralateral paw changed only slightly. In the ipsilateral paw, thermal hyperalgesia reached the maximum on PID 1, whereas mechanical allodynia and joint hyperalgesia progressively developed during the first 7 or 8 days, being tuned in to arthritis development. In the contralateral paw, thermal hyperalgesia never occurred, whereas mechanical allodynia and joint hyperalgesia developed after PID 11. Morphine and Tramadol ( Generic Ultram ) had full efficacies for all the pain parameters tested at sedation-inducing doses. Indomethacin and diclofenac significantly but partially improved thermal and joint hyperalgesia. Amitriptyline significantly reduced thermal and joint hyperalgesia only at sedation-inducing dose. Acetaminophen, carbamazepine, and gabapentin had, at the most, very small efficacies. In conclusion, the present study provided integrated information about the time course of pain and other disease development parameters in the CFA-induced arthritic rats, and clarified acute efficacies of different categories of analgesics for the allodynia and hyperalgesia.


Ketoprofen (ketonal): a drug for preventing and treating postoperative pain

An inert matrix to control the release of Tramadol ( Generic Ultram ) HCl was prepared using glyceryl behenate as a matrix-forming agent. The matrices were prepared by either direct compression of a physical mixture of the drug and the matrix-forming agent or by compression of granules prepared by hot fusion of the drug and the matrix-forming agent. The hot fusion method was found to be more effective than compression of physical mixtures in retarding the release of the drug from the matrix. Drug release was adjusted by using release enhancers, such as microcrystalline cellulose and lactose, and the results showed that higher release rates were obtained using lactose. However, the release of the drug was independent of the compression force and the pH of the dissolution medium. This study showed that glyceryl behenate is an appropriate waxy material that can be used as a matrix-forming agent to control the release of a water-soluble drug such as Tramadol ( Generic Ultram ) HCl.

The present study was conducted to characterise the centrally active analgesic drug Tramadol ( Generic Ultram ) hydrochloride [(1RS,2RS)-2-[(dimethyl-amino)-methyl]-1-(3-methoxyphenyl)-cyclohe xanol hydrochloride] and its metabolites M1, M2, M3, M4 and M5 at the cloned human mu-opioid receptor. Membranes from stably transfected Chinese hamster ovary (CHO) cells were used to determine the four parameters of the ligand-receptor interaction: the affinity of (+/-)-Tramadol ( Generic Ultram ) and its metabolites was determined by competitive inhibition of [3H]naloxone binding under high and low salt conditions. The agonist-induced stimulation of [35S]GTPgammaS binding permits the measurement of potency (EC50), efficacy (Emax = maximal stimulation) and relative intrinsic efficacy (effect as a function of receptor occupation). The metabolite (+)-M1 showed the highest affinity (Ki=3.4 nM) to the human mu-opioid receptor, followed by (+/-)-M5 (Ki=100 nM), (-)-M1 (Ki=240 nM) and (+/-)-Tramadol ( Generic Ultram ) (Ki=2.4 microM). The [35S]GTPgammaS binding assay revealed an agonistic activity for the metabolites (+)-M1, (-)-M1 and (+/-)-M5 with the following rank order of intrinsic efficacy: (+)-M1>(+/-)-M5>(-)-M1. The metabolites (+/-)-M2, (+/-)-M3 and (+/-)-M4 displayed only weak affinity (Ki> 10 microM) and had no stimulatory effect on GTPgammaS binding. These data indicate that the metabolite (+)-M1 is responsible for the mu-opioid-derived analgesic effect.
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The pharmacokinetic-pharmacodynamic (pk-pd) characterization of the in vivo antinociceptive interaction between (+)-O-desmethylTramadol ( Generic Ultram ) [(+)-M1] and (-)-O-desmethylTramadol ( Generic Ultram ) [(-)-M1], main metabolites of Tramadol ( Generic Ultram ), was studied in three groups of rats. (+)-M1 and (-)-M1, both with different pd properties, were studied under steady-state and nonsteady-state conditions, depending on the group. Plasma drug concentration and antinociception were simultaneously measured in each animal by using an enantioselective analytical assay and the tail-flick test, respectively. Respiratory depression also was evaluated in another series of experiments according to the same experimental conditions. The pk behavior was similar for both enantiomers and no significant (P >.05) interaction between two compounds was found at this level. However, a significant (P <.01) potentiation in the antinociceptive effect elicited by (+)-M1 was found during and after (-)-M1 administration. The pd model used to describe the time course of the antinociception in the presence of (+)-M1, (-)-M1, or both is based on previous knowledge of the compounds and includes the following: 1) an effect compartment model to account for the opioid effect of (+)-M1, and 2) an indirect response model accounting for the release of noradrenaline (NA) caused by (+)-M1, and the inhibition of the NA reuptake due to the action of (-)-M1. The model predicts a positive contribution to antinociception of the predicted increasing levels of NA. No significant (P >.05) respiratory effects were seen during or after (+)-M1 and (-)-M1 administration.

Relationship between the antitussic and analgesic activity of substances.

The authors studied relationship between the antitussic and analgesic activity of substances. The antitussic effect of codeine, tilidine, Tramadol ( Generic Ultram ) and pentazocine has been studied in nonanesthetized healthy cats. The drugs except tilidine, were administered intraperitoneally in a dose of 10 mg/kg body weight. Tilidine was administered intramuscularly in the same dose. Cough induced in nonanesthetized cats by mechanical irritation of laryngopharyngeal and tracheobronchial areas was evaluated by changes of the lateral tracheal pressure. A significant decrease of the subsequent cough parameters was observed after the application of codeine, tilidine, Tramadol ( Generic Ultram ) and pentazocine. Naloxone given 5 min before the application of the drug has not prevented the cough-suppressing effect due to codeine. Naloxone alone administered in a dose of 1 mg/kg body weight has not significantly influenced the experimentally-induced cough reflex in nonanesthetized cats.