J Pharmacol Exp Ther. 2003 May;305(2):710-8. Epub 2003 Feb 11.
Pharmacokinetic/pharmacodynamic modeling of the antinociceptive effects of (+)-tramadol in the rat: role of cytochrome P450 2D activity.

Garrido MJ, Sayar O, Segura C, Rapado J, Dios-Vieitez MC, Renedo MJ, Troconiz IF.

Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona 31080, Spain.

In this study the role of cytochrome P450 2D (CYP2D) in the pharmacokinetic/pharmacodynamic relationship of (+)-tramadol [(+)-T] has been explored in rats. Male Wistar rats were infused with (+)-T in the absence of and during pretreatment with a reversible CYP2D inhibitor quinine (Q), determining plasma concentrations of Q, (+)-T, and (+)-O-demethyltramadol [(+)-M1], and measuring antinociception. Pharmacokinetics of (+)-M1, but not (+)-T, was affected by Q pretreatment: early after the start of (+)-T infusion, levels of (+)-M1 were significantly lower (P < 0.05). However, at later times during Q infusion those levels increased continuously, exceeding the values found in animals that did not receive the inhibitor. These results suggest that CYP2D is involved in the formation and elimination of (+)-M1. In fact, results from another experiment where (+)-M1 was given in the presence and in absence of Q showed that (+)-M1 elimination clearance (CL(ME0)) was significantly lower (P < 0.05) in animals receiving Q. Inhibition of both (+)-M1 formation clearance (CL(M10)) and CL(ME0) were modeled by an inhibitory E(MAX) model, and the estimates (relative standard error) of the maximum degree of inhibition (E(MAX)) and IC(50), plasma concentration of Q eliciting half of E(MAX) for CL(M10) and CL(ME0), were 0.94 (0.04), 97 (0.51) ng/ml, and 48 (0.42) ng/ml, respectively. The modeling of the time course of antinociception showed that the contribution of (+)-T was negligible and (+)-M1 was responsible for the observed effects, which depend linearly on (+)-M1 effect site concentrations. Therefore, the CYP2D activity is a major determinant of the antinociception elicited after (+)-T administration.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12606644&dopt=Abstract tramadol Ultram




Drug Alcohol Depend. 2003 Apr 1;69(3):233-41.
Physical dependence on Ultram (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur.

Senay EC, Adams EH, Geller A, Inciardi JA, Munoz A, Schnoll SH, Woody GE, Cicero TJ.

Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA.

In 1994, the Drug Abuse Advisory Committee (DAAC) of the Food and Drug Administration (FDA) concluded that Ultram (tramadol hydrochloride) could be marketed as an analgesic drug without scheduling under the Controlled Substances Act based upon extensive pre-clinical, clinical and European epidemiological data. However, to guard against unexpectedly high levels of abuse in the United States, the DAAC recommended that an independent steering committee (ISC) be appointed to proactively monitor abuse/dependence. In the event that high rates of abuse were found, this ISC was given the authority to immediately recommend to the FDA that Ultram be scheduled. In the course of the surveillance project, the ISC received reports of withdrawal following abrupt discontinuation of Ultram and in some instances, following dose reductions. In most cases, the withdrawal symptoms consisted of classical opioid withdrawal, but in some cases were accompanied by withdrawal symptoms not normally observed in opiate withdrawal, such as hallucinations, paranoia, extreme anxiety, panic attacks, confusion and unusual sensory experiences such as numbness and tingling in one or more extremities. Withdrawal symptoms of either type were one of the more prevalent adverse events associated with chronic Ultram use, comprising nearly 40% of all adverse events reported with Ultram. Most of these consisted of typical opiate withdrawal symptoms, but 1 in 8 cases presented as atypical. These results indicate that physicians and other healthcare professionals need to be aware of the potential of Ultram to induce withdrawal of the classical opioid type, and that atypical withdrawal may also occur.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12633909&dopt=Abstract tramadol Ultram

post.rwth-aachen.de

The objective of the study was to elucidate thermal based ablation techniques for local tumor control. Seven lesions of renal cell carcinoma (2 renal, 1 adrenal, 2 muscle, 1 hepatic, 1 bone) were treated under local (n=2) or general (n=6) anaesthesia with percutaneous cryoablation (CRA): CryoHit device or radiofrequency (RF) ablation (RFA): RF 3000). Treatment was palliative in 4 patients with progression after systemic therapies, and with curative intention in one organ confined tumor (patient with active HCV and HIV infection). Mean power for RFA was 165 watts. Duration of treatments was 10-91 min. No bleeding or urinary leakage was observed; no drainage or indwelling catheters necessary. Pain relief was sufficiently achieved by tramadol and novaminesulfon. Inpatient period on average was 4.25 days. CRA led to complete tumor destruction (CTD) of an adrenal mass (time to progression, 15+ months) and partial tumor destruction (PTD) of a lumbar lesion (19 months); RFA resulted in CTD of 3 lesions (liver, 9+ months; kidney, 1+, 13+ months) and PTD in 2 lesions (muscle and bone, 3 months). In conclusion, it was found that CRA and RFA are safe and effective methods to destroy metastatic RCC. Such minimal invasive techniques are favorable for palliative treatment (low performance status, surgical preconditions) and in conjunction with immunochemotherapy; A decreased risk of bleeding, the shorter duration of hospitalization and a faster recovery of the patient encourage minimal invasive percutaneous thermal based therapies due to life-quality and economic aspects. Treatment of primary renal cell carcinoma is currently under investigation.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12684654&dopt=Abstract tramadol Ultram




Eur J Pain. 2003;7(3):219-24.
Patient reporting of adverse drug reactions: useful information for pain management?

Jarernsiripornkul N, Krska J, Richards RM, Capps PA.

Department of Clinical Pharmacy, Khon Kaen University, Thailand.

BACKGROUND: Patients' perceptions of adverse effects caused by the medicines they are prescribed may influence how they use these medicines. Little is known about patients' perceptions of the adverse effects of specific drugs in everyday use and whether these differ from those identified by clinical trials and standard post-marketing surveillance methods. AIM: To compare reports of perceived adverse drug reactions (ADRs) obtained directly from patients taking tramadol to those found in clinical trials and two methods of post-marketing surveillance. METHOD: Postal questionnaire distributed to 1048 patients who had a prescription for tramadol dispensed over a 3-month period. RESULTS: Most (84%) of the 344 respondents reported at least one symptom perceived as an ADR to tramadol. Dry mouth, light-headedness and constipation were most commonly reported. Almost half (48%) rated their most bothersome symptom as at least moderate and 43% claimed to have reported symptoms to their doctor. Perceived problems had led 38 respondents to stop taking tramadol. The 10 most frequently reported symptoms were all previously reported ADRs to tramadol. Although relatively minor, all 10 also appeared in reports to the UK Committee on the Safety of Medicines (CSM) and in prescription event monitoring. For many symptoms, the estimated range of frequency was in line with published reports, but considerably higher than that of post-marketing surveillance methods. CONCLUSIONS: Symptoms were reported by the majority of respondents and for many symptoms the frequency was high. Many patients did not report symptoms they perceived to be adverse effects to their doctor. The results indicate that patient perceptions of potential ADRs are relevant and should be an integral part of a pain management strategy.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12725844&dopt=Abstract tramadol Ultram

yamanouchi.co.jp

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 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.

Tramadol reference source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12730275&dopt=Abstract tramadol Ultram