Prog Neuropsychopharmacol Biol Psychiatry. 2004 Jul;28(4):641-9.

Isobolographic analysis of interaction between cyclooxygenase inhibitors and tramadol in acetic acid-induced writhing in mice.

Satyanarayana PS, Jain NK, Singh A, Kulkarni SK.

Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014, India.

Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are the most commonly used analgesics in the management of acute and chronic pain. Combined use of NSAIDs and opioids has been indicated for achieving better analgesia with reduced side effects. The present study was aimed at evaluating the combination of different NSAIDs, which inhibit cyclooxygenase (COX) enzymes and tramadol against acetic acid-induced writhing in mice. The expected beneficial effect of combination regimen was analyzed by isobolographic analysis. The oral and intrathecally administered tramadol, a mu-opioid and naproxen, a nonselective COX inhibitor produced dose-dependent antinociception, however, rofecoxib, a selective COX-2 inhibitor lacked analgesic efficacy in writhing test. Isobolographic analysis showed synergistic or supra-additive interactions for the combinations of naproxen and tramadol after oral and intrathecal administration. However, similar interaction was not observed when tramadol was combined with rofecoxib. Pretreatment with naloxone partially reversed the antinociceptive effect of tramadol per se and its combination with naproxen without modifying the per se effect of NSAID. The results demonstrated marked synergistic interaction between naproxen and tramadol and such interaction involved opioid as well as non-opioid mechanisms of tramadol and inhibition of COX-1 but not COX-2 by naproxen.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15276689




Brain Res. 2004 Aug 6;1016(2):263-7.

Effects of tramadol on alpha2-adrenergic receptors in the rat brain.

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

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

In recent years, it has been postulated that tramadol, used mainly for the treatment of moderate to severe pain, might display a potential as an antidepressant drug. The present study investigated the effects of acute and repeated tramadol administration on the binding of [3H]RX 821002, a selective alpha2-adrenergic receptor ligand, in the rat brain. Male Wistar rats were used. Tramadol (20 mg/kg, i.p.) administered acutely (single dose), at 24 h after dosing, induced a significant decrease in the alpha2-adrenergic receptors in all brain regions studied. The most pronounced effects were observed in all subregions of the olfactory system, nucleus accumbens and septum, thalamus, hypothalamus, amygdala, and cerebral cortex. Repeated treatment with tramadol (20 mg/kg, i.p., once daily for 21 days) also induced statistically significant downregulation of [3H]RX 821002 binding sites in the rat brain. However, the effect--although statistically significant--was less pronounced than in the group treated acutely with the drug. Since drugs such as mianserin and mirtazapine are potent antagonists of central alpha2-adrenergic receptors and are effective antidepressants, it is tempting to suggest that, in addition to other alterations induced by tramadol, downregulation of these receptors may represent a potential antidepressant efficacy. On the other hand, one should be careful to avoid the treatment of chronic pain with tramadol in patients already receiving antidepressant drugs. Tramadol-induced downregulation of alpha2-adrenergic receptors--when combined with ongoing antidepressant therapy with drugs, which themselves inhibit serotonin reuptake or are antagonists of alpha2-adrenergic receptors--might cause threatening complications.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15246863




J Pain Symptom Manage. 2004 Jul;28(1):59-71.

Efficacy and safety of extended-release, once-daily tramadol in chronic pain: a randomized 12-week clinical trial in osteoarthritis of the knee.

Babul N, Noveck R, Chipman H, Roth SH, Gana T, Albert K.

TheraQuest, Blue Bell, Pennsylvania 19422, USA.

The efficacy and safety of a once-daily extended-release formulation of tramadol hydrochloride (tramadol ER) was evaluated in patients with moderate to severe chronic pain of osteoarthritis (OA). This was a randomized, double-blind, placebo-controlled, parallel-group, 12-week study. Eligible patients with radiographically confirmed OA of the knee meeting the American College of Rheumatology diagnostic criteria, defined by knee pain and presence of osteophytes, plus at least age >50 years, morning stiffness <30 minutes in duration, and/or crepitus, entered a 2-7 day washout period during which all analgesics were discontinued. When pain at the index knee joint reached > or =40 mm (0-100 mm VAS), patients were randomized to tramadol ER or placebo. Tramadol ER was initiated at 100 mg QD and increased to 200 mg QD by the end of 1 week of treatment. After the first week, further increases to tramadol ER 300 mg or 400 mg QD were allowed. Outcome measures included Arthritis Pain Intensity Visual Analogue Scale (VAS), Western Ontario and McMaster Universities Arthritis Scale (WOMAC) Pain, Stiffness, Physical Function VAS subscales, Patient and Physician Global Assessment of Therapy, Sleep, dropouts due to insufficient therapeutic effect, and adverse events. Two hundred forty-six patients were randomized (tramadol ER 124, placebo 122). There were no baseline differences between the two treatments. The mean age was 61 years, mean duration of OA 12.9 years, and the mean tramadol ER dose was 276 mg QD. All efficacy outcome measures favored tramadol ER over placebo. On the primary outcome variable of average change from baseline in Arthritis Pain Intensity VAS over 12 weeks, tramadol ER was superior to placebo (least squares mean change from baseline: 30.4 mm vs. 17.7 mm, P < 0.001). Significant differences from placebo were evident at week 1, the first post-treatment visit. Similarly, outcomes on the WOMAC Pain, Stiffness and Physical Function subscales, the WOMAC Composite Scale, dropouts due to insufficient therapeutic effect, Patient and Physician Global Assessment of Therapy, and Sleep were all significantly better with tramadol ER than placebo (P < 0.001 to < 0.05). Treatment with tramadol ER results in statistically significant and clinically important and sustained improvements in pain, stiffness, physical function, global status, and sleep in patients with chronic pain. A once-a-day formulation of tramadol has the potential to provide patients increased control over the management of their pain, fewer interruptions in sleep and improved compliance.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15223085




Paediatr Anaesth. 2004 Jul;14(7):568-73.

Analgesia for adenotonsillectomy in children: a comparison of morphine, ketamine and tramadol.

Umuroglu T, Eti Z, Ciftci H, Yilmaz Gogus F.

Department of Anaesthesiology and Reanimation, Medical Faculty of Marmara University, Istanbul, Turkey.

BACKGROUND: Establishment of good analgesia is of major concern in the postoperative period following adenotonsillectomy. The aim of this study was to compare the effects of ketamine, morphine and tramadol on postoperative pain after adenotonsillectomy in children. METHODS: Sixty children (age 5-12 years) scheduled for adenotonsillectomy were randomized into four groups to receive intravenously (i.v.) either 0.5 mg.kg(-1) ketamine hydrochloride (K), 0.1 mg x kg(-1) morphine hydrochloride (M), 1.5 mg x kg(-1) tramadol hydrochloride (T) or normal saline (S) in a volume of 4 ml during induction. After tracheal intubation 10 microg x kg(-1).min(-1) ketamine hydrochloride in group K and 0.6 ml x kg(-1) x h(-1) saline i.v. in groups M, K and S were infused peroperatively. Postoperative analgesic requirements and side-effects were recorded. Pain was assessed by the Numeric Rating Scale (NRS) and the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) scores. RESULTS: Heart rate increased significantly peroperatively only in group K. NRS at first and fifth minute in group M and at first minute in group T and K and CHEOPS score at first, fifth, 15th and 60th min in group M were found to be significantly lower than in the control group. The time to first analgesic requirement was significantly longer in group M compared with ketamine and the control group. Six children in group M, nine in group T, 11 in group K and 15 in group S needed additional analgesics. CONCLUSIONS: Morphine hydrochloride 0.1 mg x kg(-1) i.v. administered during induction of anaesthesia provides efficient pain relief in children undergoing adenotonsillectomy.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15200654




Support Care Cancer. 2005 Jan 12

Randomized double-blind, double-dummy crossover clinical trial of oral tramadol versus rectal tramadol administration in opioid-naive cancer patients with pain.

Mercadante S, Arcuri E, Fusco F, Tirelli W, Villari P, Bussolino C, Campa T, De Conno F, Ripamonti C.

Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, Via San Lorenzo 312, 90146, Palermo, Italy

Tramadol is commonly used as second step drug of the analgesic ladder. In circumstances where the oral route is unavailable, rectal administration of opioids might be a simple alternative. The aim of this study was to compare the analgesic activity and tolerability of tramadol by oral and rectal administration in a double-blind, double-dummy crossover trial. The study included 60 cancer patients with cancer pain no longer responsive to non-opioid drugs. Each patient initially received oral tramadol 50 mg (drops), followed by tramadol sustained release 100 mg orally, and placebo rectally, or tramadol 100 mg rectally and placebo orally, twice a day, in a randomized sequence, on each of 3 days. Patients were allowed to take 50 mg of oral tramadol by drops as needed (four doses per day, to a maximum of 400 mg/day, including the basal dose given by the oral or rectal route). Pain intensity and relief and symptom scores were recorded every day and at the end of each phase of the crossover. The mean age of the patients was 66.1 years (SD 13.5 years); 36 were female, and 44 completed both periods. Patients dropped out due to adverse effects (15 patients) and refusal (1 patient). No differences in the use of rescue dose of oral tramadol were observed between the groups. No differences in pain intensity and relief scores, or in other symptoms between the two treatments were observed. No differences in treatment efficacy as judged by the clinician (P=0.73), in patient compliance (P=0.35), or in patient satisfaction regarding treatment (P<0.35) were found. No differences in adverse effects were found between the two treatments (25.5%, 13 patients, and 20.4%, 11 patients, with oral and rectal treatment, respectively). The proportion of preferences favored oral administration for both physicians (P=0.0002) and patients (P=0.002). Rectal administration of tramadol appears a reliable, noninvasive alternative method of pain control for patients no longer responsive to non-opioid analgesics, unable to take oral tramadol.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15645186