Postgrad Med J. 1987;63 Suppl 3:19-28.
The antinociceptive activity of flupirtine: a structurally new analgesic.

Nickel B.

Biological Research Pharmacology, Homburg Degussa Pharma Gruppe, Frankfurt, Federal Republic of Germany.

The antinociceptive activity of flupirtine was measured in various test procedures predictive of analgesic activity. In the electrostimulated pain test in mice the oral ED50 for flupirtine was 25.7 mg/kg p.o. Thus, flupirtine was approximately 31.7 times more potent than paracetamol (ED50: 814 mg/kg p.o.) and as potent as pentazocine (ED50: 38.5 mg/kg p.o.). Morphine (ED50: 16.8 mg/kg p.o.) was 1.5 times and buprenorphine (ED50: 2.6 mg/kg p.o.) 9.9 times more potent than flupirtine. In the hot plate test (mice) flupirtine (ED50: 32 mg/kg p.o.) was approximately half as potent as morphine (ED50: 15.5 mg/kg p.o.). The oral and intravenous antinociceptive activity (ED50) of flupirtine in the electrical tooth pulp stimulation test in conscious dogs was 3.5 mg/kg p.o. and 0.7 mg/kg i.v. which was similar to that of pentazocine (ED50: 4.2 mg/kg p.o. and 0.5 mg/kg i.v.). Buprenorphine had, as expected, stronger antinociceptive activity (ED50: 1.0 mg/kg p.o. and 0.04 mg/kg i.v.). Fifteen minutes after oral administration of 40 mg/kg flupirtine, the pain threshold in the electrostimulated pain test was increased by 54%. The maximal antinociceptive effect was observed 30 minutes after dosing. The analgesia lasted at least 75 minutes. Codeine significantly elevated the pain threshold 15 minutes after dosing. Its maximal effect was also reached 30 min after application but the antinociceptive activity wore off earlier than after flupirtine. The intracerebroventricular and intrathecal administration of flupirtine also caused dose dependent antinociceptive activity in dose ranges which, when applied systematically, did not produce analgesia in rats. The antinociceptive activity of flupirtine was not abolished by naloxone whether given orally or by the intraventricular or intrathecal routes. In opiate receptor binding studies flupirtine had no affinity for mu, delta or kappa opiate receptors at the highest concentration used (10(-5) M). Whereas buprenorphine and tramadol showed a striking similarity in the pharmaco-electroencephalogram recorded from different parts of the brain (frontal cortex, thalamus, striatum and the mesencephalic reticular formation) of the freely moving rat, flupirtine was clearly different in action. It produced dose dependent increases in nearly all frequency bands but its effects were different from those of the minor tranquillizer diazepam and the anticonvulsant phenobarbitone. These findings show that the central antinociceptive activity of flupirtine is not based on an opiate mechanism and is not comparable with that of diazepam and phenobarbitone.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2833734&dopt=Abstract tramadol Ultram




Postgrad Med J. 1987;63 Suppl 3:41-3.
Comparative physical dependence studies in rats with flupirtine and opiate receptor stimulating analgesics.

Nickel B, Aledter A.

Biological Research Pharmacology, Homburg Degussa Pharma Gruppe, Frankfurt, Federal Republic of Germany.

In physical dependence studies in rats the principle criterion was loss of body weight after withdrawal of the dependence producing drug. Other typical signs of withdrawal were also observed. In contrast to buprenorphine, codeine and tramadol, flupirtine caused no decrease in body weight and no other withdrawal symptoms. Flupirtine does not produce opiate type physical dependence.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2833735&dopt=Abstract tramadol Ultram




J Pharmacol Exp Ther. 1988 Sep;246(3):1067-74.
Pharmacological mechanisms of action of flupirtine: a novel, centrally acting, nonopioid analgesic evaluated by its discriminative effects in the rat.

Swedberg MD, Shannon HE, Nickel B, Goldberg SR.

Department of Health and Human Services, National Institute on Drug Abuse, Baltimore, Maryland.

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 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.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2901483&dopt=Abstract tramadol Ultram




J Med Assoc Thai. 1988 Jul;71 Suppl 2:65-7.
Amnesic effect of midazolam as premedication in interval laparoscopic sterilization.

Pausawasdi S, Padmasuta K, Tangtrakul S, Chaturachinda K.

PIP: Midazolam, a water soluble bensodiasepine, has proven to induce a sleep pattern and amnesic effect that makes it preferable for use as a premedication for outpatient surgery. Used in addition to the regular anesthesia, Midazolam obviates the ineffectiveness of the analgesic drug. Since 1970, neuroleptic analgesia has been used as a method of outpatient anesthesia. Unfortunately, neuroleptic analgesia has provided inadequate coverage of pain relief causing pain and discomfort to patients. When a sedation and anxiolytic premedication are used, the patient acceptance increases. In a study in Ramathibodi hospital, Bangkok, Thailand effectiveness of midazolam as a premedication drug in laparoscopic interval sterilization, 150 women capable of reproduction and who were schelduled for the operation were studied. All of the women received 15mg midazolam orally either 60 or 90 minutes before the operation. The women were divided into 3 groups of 50 classified by the type of analgesic administered (tramadol or pethidine). Heart and respiratory rates and blood pressure were measured prior to, during, and after the operation. No difference in the rate of amnesia was found among the 3 groups, and a rate of 36% of amnesia was found in the study. Those results were lower than earlier reports, possibly due to circumstances at the hospital such as lack of coordination between administration of the medication and timing of the surgery.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3183558&dopt=Abstract tramadol Ultram




Neuropsychobiology. 1986;16(2-3):163-8.
Radioelectroencephalography (Tele-Stereo-EEG) in the rat as a pharmacological model to differentiate the central action of flupirtine from that of opiates, diazepam and phenobarbital.

Dimpfel W, Spuler M, Nickel B.

Chronic implantation of 4 bipolar concentric electrodes into frontal cortex, thalamus, striatum and reticular formation allowed repeated recordings of field potentials from freely moving rats. After radiotransmission the signals were quantitatively evaluated by spectral power analysis. The power in particular frequency bands changed in the presence of drugs in a characteristic manner and allowed us to describe the central action of analgesics in comparison with diazepam and phenobarbital. Analysis of the data showed that the action of diazepam was mainly confined to alpha 1 and beta 2 frequencies whereas tramadol acted predominantly on the theta and alpha range. Buprenorphine and morphine most consistently influenced the alpha 2 frequencies. Whereas buprenorphine and tramadol (2 opiate drugs) showed a striking similarity to the action of morphine in corresponding brain areas the minor tranquilizer diazepam and the anticonvulsive phenobarbital could clearly be separated from them. Flupirtine, a new analgesic not suspected of an opiate-like action profile, did not resemble any of them and thus could be confirmed to have a different mode of action.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3587575&dopt=Abstract tramadol Ultram