J Pharmacol Exp Ther. 1993 Oct;267(1):331-40.
Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol.

Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL, Jacoby HI, Selve N.

R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania.

The explanation for the co-existence of opioid and nonopioid components of tramadol-induced antinociception appears to be related to the different, but complementary and interactive, pharmacologies of its enantiomers. The (+) enantiomer had Ki values of only 1.33, 62.4 and 54.0 microM at mu, delta and kappa receptors, respectively. The (-) enantiomer had even lower affinity at the mu and delta sites (Ki = 24.8, 213 and 53.5 microM, respectively. The (+) enantiomer was the most potent inhibitor of serotonin uptake (Ki = 0.53 microM) and the (-) enantiomer was the most potent inhibitor of norepinephrine uptake (Ki = 0.43 microM). Basal serotonin release was preferentially enhanced by the (+) enantiomer and stimulation-evoked norepinephrine release was preferentially enhanced by the (-) enantiomer. The (+) and (-) enantiomers each independently produced centrally mediated antinociception in the acetylcholine-induced abdominal constriction test (ED50 = 14.1 and 35.0 micrograms i.t., respectively). Racemic tramadol was significantly more potent (P < .05) than the theoretical additive effect of the enantiomers (antinociceptive synergy). Synergy was also demonstrated (P < .1) in the mouse 55 degrees C hot-plate test (i.p. route) and (P < .05) the rat Randall-Selitto yeast-induced inflammatory nociception model (i.v. and i.p. routes). Critically, the enantiomers interacted less than synergistically in two side-effects of inhibition of colonic propulsive motility and impairment of rotarod performance. The racemate and the (+) enantiomer were active in a chronic (arthritic) inflammatory pain model. Taken together, these findings provide a rational explanation for the coexistence of dual components to tramadol-induced antinociception and might form the basis for understanding its clinical profile.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8229760&dopt=Abstract tramadol Ultram




Yao Xue Xue Bao. 1993;28(5):379-83.
[Analysis of tramadol and its metabolites in human urine]

[Article in Chinese]

Xu YX, Xu YQ, Zhang CJ, Shen L.

China Doping Control Center, National Research Institute of Sports Medicine, Beijing.

A GC-MS method for the analysis of tramadol and its four metabolites in human urine is described. The urine samples were acid hydrolyzed with hydrochloric acid, cleaned with diethyl ether and extracted with dichloromethane-isopropanol (9:1). After derivatization, the solution was analyzed with GC-MSD. Tramadol and its 4 metabolites were detected in urine samples 2-40 hours after oral administration. The recovery of tramadol was 85.2% +/- 5.4 (n = 3), the detection limit was down to 12.5 pg. The derivatization methods was discussed.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8237385&dopt=Abstract tramadol Ultram




Arch Pharm (Weinheim). 1993 Sep;326(9):513-8.
[Synthesis and CNS-activity of spirocyclic pethidine and prodine analogs]

[Article in German]

Wunsch B, Hofner G, Bauschke G.

Institut fur Pharmazie und Lebensmittelchemie, Universitat Munchen.

The bromoacetals 5a and 5b react with n-butyllithium and the piperidone 7 to yield the hydroxyacetals 8b and 8c, respectively. Cyclization of 8b and 8c followed by acid hydrolysis affords the spirocyclic hemiacetals 10b and 10c which are oxidized by PCC to give the spirocyclic prodine analogues 4b and 4c. The corresponding spirocyclic pethidine derivative 2 is prepared by alkylation of the 2-benzopyran-3-one 16 with N-Lost (17). In the mouse writhing test the spiropethidine 2 is not analgesic active up to a dose of 20 mg/kg body weight (bw). In the spirocyclic prodine series the methylated lactone 4c is the most active analgesic with an ED50-value (ED50 = 9.2 mg/kg bw) in the range of the ED50-value of tramadol.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8239944&dopt=Abstract tramadol Ultram




Chirurg. 1993 Oct;64(10):802-8.
[Patient-controlled analgesia (PCA) for postoperative pain relief. A prospective observational study for evaluating the technology in a ward routine]

[Article in German]

Ure BM, Neugebauer E, Ullmann K, Driever R, Troidl H.

Chirurgische Klinik, II. Lehrstuhls fur Chirurgie, Universitat Koln.

Patient-controlled analgesia (PCA) is rarely used on surgical wards despite described advantages of this method as compared to conventional techniques. Uncertainties in patient selection and insufficient evaluation of this technique may explain these circumstances. The aim of our study was to evaluate PCA on general surgery and traumatology wards by means of standardized criteria for technology assessment (i.e. safety, practicability, benefit for patients and medical staff) and the efficacy of pain relief. In a prospective study we investigated 120 patients. In phase I, we performed analgesic therapy with tramadol/metamizol (50 ASA status I-IV patients). In phase II, piritramid had been applied to 70 ASA status I-II patients after an intermediate analysis of phase I. In 7% of the patients technical problems led to an early interruption even at the end of the study period. There were, however, no incidents which caused vital problems for the patients. A mean postoperative pain level of 55 visual analogue scale points (0-100 point scale) was achieved with tramadol/metamizol. PCA was stopped in 16% of the patients due to the occurrence of nausea or vomiting and in two patients due to insufficient pain relief. The use of piritramid in phase II led to lower pain levels and no interruptions of PCA because of ineffectivity or nausea/vomiting.(ABSTRACT TRUNCATED AT 250 WORDS)

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8269745&dopt=Abstract tramadol Ultram




Life Sci. 1996;58(2):PL 23-8.
Testing for synergism over a range of fixed ratio drug combinations: replacing the isobologram.

Tallarida RJ, Raffa RB.

Department of Pharmacology, Temple University School of Medicine, Philadelphia PA 19140-5104, USA.

An isobologram is a Cartesian plot of pairs of doses that, in combination, yield a specified level of effect. It is a convenient and presently popular way of graphically displaying results of drug-combination and similar studies, because paired values of experimental points that fall below or above the line connecting the axial points (usually ED50 values) denote supra- and sub-additive combinations, respectively. However, an isobologram does not fulfill the criteria for standard least squares regression analysis. It is thus less useful for addressing questions related to the range of combination ratios over which synergy occurs. We describe herein a substitute for the isobologram in which log(total-dose) is plotted against the proportion of a component in a combination. One advantage is that a nonlinear curve-fitting procedure and determination of the confidence interval of a single parameter allow the determination of departure from additivity over a range of fixed proportion mixtures. An example is given of the combination of two analgesics (acetaminophen and tramadol hydrochloride). Another advantage of the new method is the reduction of animal use.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8606615&dopt=Abstract tramadol Ultram