Pharmacol Biochem Behav. 2005 Jan;80(1):69-75. Epub 2004 Dec 10.

Involvement of potassium channels and nitric oxide in tramadol antinociception.

Yalcin I, Aksu F.

Department of Pharmacology, Faculty of Medicine, Cukurova University, TR-01330, Balcali, Adana, Turkey.

It has been considered that tramadol, a centrally acting analgesic, shows its effect via opiatergic, noradrenergic, and serotonergic systems. It has a low affinity for opioid receptors, and its effect can be partly blocked by naloxone. Since the noradrenergic and serotonergic mechanisms are still unknown, other systems which are associated with pain and analgesia may have a role on the antinociceptive effect of tramadol. The aim of this study was to evaluate the effects of K(+) channels and nitrergic systems on the antinociceptive action of tramadol. The antinociceptive effects of tramadol were determined in mice by the hot plate test. To examine the effects of K(+) channels and the nitrergic system nonspecific voltage-dependent K(+) channel blockers 4-aminopyridine (4-AP) and tetraethylammonium (TEA), nitric oxide (NO) precursor l-arginine, and the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) were used. Our results indicated that 4-AP, TEA, and l-arginine reduced the antinociceptive effect of tramadol. However, l-NAME augmented the antinociceptive effect of tramadol. The reduction of the effects of tramadol by l-arginine was reversed by l-NAME. The results of our study suggest that nonspecific voltage-dependent K(+) channels and nitrergic system have a role on the antinociceptive effect of tramadol in mice hot plate test.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15652382




Anesth Analg. 2004 Nov;99(5):1461-4

The postoperative analgesic effect of tramadol when used as subcutaneous local anesthetic.

Altunkaya H, Ozer Y, Kargi E, Ozkocak I, Hosnuter M, Demirel CB, Babuccu O.

Department of Anesthesiology, Zonguldak Karaelmas University, School of Medicine, Ev-Ko Konutlari F-66 No: 8, 67600 Kozlu/Zonguldak, Turkey.

Recently, it has been shown that tramadol was an effective local anesthetic in minor surgery. In this study, its efficacy for relieving postoperative pain was evaluated. Forty patients undergoing minor surgery (lipoma excision and scar revision) under local anesthesia were included. The patients were randomly allocated into two groups: In group T (n = 20), 2 mg/kg tramadol, and in group L (n = 20), 1 mg/kg lidocaine were given subcutaneously. In both groups, the injection volume was 5 mL containing 1/200,000 adrenalin. The degree of the erythema, burning sensation, and pain at the injection site were recorded. Incision response, which is a degree of the pain sensation during incision, was recorded and graded with the visual analog scale (VAS) 0-10. After incision, VAS values were recorded at 15-min intervals. When the VAS score of the pain during surgery exceeded 4, an additional 0.5 mg/kg of the study drug was injected and this dosage was added to the total amount. Patients were discharged on the same day. Subjects with VAS > or =4 were advised to take paracetamol as needed. No side effects were recorded in either group except for 1 patient complaining of nausea in group T at the 30th min of operation. After 24 h, patients were called and the time of first analgesic use and total analgesic dose taken during the postoperative period were recorded. During the 24 postoperative hours, 18 of 20 (90%) subjects did not need any type of analgesia in group T, whereas this number was 10 (50%) in group L (P < 0.05). The time span before taking first analgesic medication was longer (4.9 +/- 0.3 h) in group T than that of group L (4.4 +/- 0.7 h) (P < 0.05). We propose that tramadol can be used as an alternative drug to lidocaine for minor surgeries because of its ability to decrease the demand for postoperative analgesia.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15502049




J Clin Pharm Ther. 2004 Oct;29(5):455-63.

Population pharmacokinetic modelling of tramadol with application of the NPEM algorithms.

Gan SH, Ismail R, Wan Adnan WA, Zulmi W, Jelliffe RW.

Department of Pharmacology, School of Medical Science, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

BACKGROUND AND OBJECTIVE: Although the kinetic behaviour of tramadol has been described, the present study is the first to our knowledge, to report specifically on the population pharmacokinetic modelling of tramadol hydrochloride. METHODS: The parametric Iterative Two-stage Bayesian Population Model (IT2B) program followed by the Non-parametric Expectation Maximization Population Model (NPEM2) program was used to determine population pharmacokinetic parameter values of tramadol in 138 postoperative orthopaedic Malaysian patients. All patients had received a 100 mg intravenous dose of tramadol, infused over 2-3 min, as their first postoperative analgesic. Blood was sampled at 0 min and subsequently at 15, 30 min, 1, 2, 4, 8, 16, 20 and 24 h for serum tramadol high-performance liquid chromatography analysis. RESULTS AND DISCUSSION: The one-compartmental model pharmacokinetic parameters--volume of distribution (Vd), elimination rate constant (kel) and the total clearance rates (ClT)--found were: mean Vd = 167.6 +/- 63.84 L; median Vd = 161.48 L; mean kel = 0.1241 +/- 0.056 h(-1); median kel = 0.1138 h(-1); ClT = 19.57 +/- 9.51 L/h; median ClT =18.12 L/h. The interindividual coefficient of variation of ClT (48.56%) was higher than that of Vd (38.09%), indicating the presence of other possible influencing factors on tramadol's ClT such as CYP2D6 polymorphism, gender and age. Overall, NPEM2 suggested more diversity in the population than did IT2B.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15482390




Eur J Pharmacol. 2004 Oct 6;501(1-3):103-10.

Long-term exposure of rats to tramadol alters brain dopamine and alpha(1)-adrenoceptor function that may be related to antidepressant potency.

Faron-Gorecka A, Kusmider M, Inan SY, Siwanowicz J, Piwowarczyk T, Dziedzicka-Wasylewska M.

Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.

The aim of the present study was to determine whether tramadol, which has a potential antidepressant efficacy, evokes, when administered repeatedly, changes similar to the alterations induced by conventional antidepressant drugs. Repeated administration of tramadol (20 mg/kg i.p. for 21 days) enhanced the d-amphetamine-induced locomotor hyperactivity and increased the density of alpha(1)-adrenoceptors in the rat brain cortex, as measured by saturation analysis of [(3)H]prazosin binding. Autoradiographic analysis of [(3)H]7-OH-DPAT and [(3)H]raclopride binding revealed a significant up-regulation of dopamine D2 and D3 receptors in the rat nucleus accumbens upon repeated treatment with tramadol. All the above-mentioned effects induced by repeated administration of tramadol resemble the effects induced by conventional antidepressants. However, tramadol when administered repeatedly did not increase the levels of mRNA encoding for brain-derived neurotrophic factor (BDNF) and its receptor, TrkB. This is what differs tramadol from conventional antidepressants, since neurotrophic effects of these drugs have recently been postulated.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15464068




J Forensic Sci. 2004 Sep;49(5):1101-5.

Tramadol (Ultram) concentrations in death investigation and impaired driving cases and their significance.

Clarkson JE, Lacy JM, Fligner CL, Thiersch N, Howard J, Harruff RC, Logan BK.

Washington State Toxicology Laboratory, Forensic Laboratory Services Bureau, Washington State Patrol, 2203 Airport Way South, Seattle, WA 98134, USA.

We reviewed a series of 66 deaths in Washington State between 1995-2000 in which tramadol (Ultram and Ultracet, Ortho-McNeil) was detected in the decedent's blood, in order to assess the role tramadol was determined to have played. Additionally, we reviewed a series of 83 impaired driving cases in which tramadol was detected in order to establish a non-lethal blood tramadol concentration reference range. In both populations, tramadol was consistently found together with other analgesic, muscle relaxant, and CNS depressant drugs. Death was rarely attributable to tramadol alone. However, tramadol may be a significant contributor to lethal intoxication when taken in excess with other drugs, via the potential interaction with serotonergic antidepressant medications, as well as the potential for increased CNS depression. Although the incidence of tramadol detection has increased consistently over the last eight years, there is no evidence of a corresponding increase in the number of cases in which death was attributed solely to tramadol. Blood drug concentrations in many deaths exceeded the therapeutic serum range of 0.28-0.61 mg/L; however, the concentrations overlapped almost completely with the range identified in living subjects arrested for impaired driving. These findings suggest caution in the interpretation of blood tramadol concentrations outside of the recognized therapeutic range. It also suggests that the drug, even when used in moderate excess, is not a principle cause of death in suicidal or accidental deaths.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15461118