Phase III randomised clinical trials provide the highest level of evidence to support the superior effectiveness of a new drug or therapy. The main practical problems encountered in the initiation, design, conduct and completion of both investigator-initiated and sponsor-initiated phase III clinical drug trials will be reviewed. METHODS: A Medline search of clinical drug trials conducted in Singapore as well as journal articles highlighting important methodological considerations and practical problems encountered in phase III clinical trials was performed. RESULTS: Several phase III randomised clinical trials have been conducted in Singapore which include the investigation of interventions that include Tramadol ( Generic Ultram ), estradiol patch and colloidal bismuth subcitrate. The main problems encountered in phase III clinical drug trials include difficulties with recruitment of subjects for the study, proper filing of case report forms, special problems in children and the elderly, adequate compensation for adverse events and the adequate archival of documents of the completion of trials. In investigator-initiated trials, careful attention should be given to identifying a suitable study question, choice of study design, sample size calculations and data analysis. In sponsor-initiated trials, a good working relationship with the sponsor is essential and publication terms should be spelt from the onset of the trial. CONCLUSIONS: Well-planned clinical trials led by a team of competent investigators are essential for the conduct of rigorous sponsor-initiated and investigator-initiated clinical trials.

Switching opioids to transdermal fentanyl in a clinical setting

INTRODUCTION: The use of transdermal fentanyl is gaining in importance in the management of cancer pain. We describe the reasons for switching opioid medication to transdermal fentanyl in a pain management unit. METHODS: Case records of patients treated with transdermal fentanyl in our pain clinic were evaluated retrospectively. Conversion ratios were calculated from the opioid dosage before and after conversion. Pain intensities were assessed on a numeric rating scale (NRS 0: no pain, 10: worst pain imaginable). RESULTS: From October 1995 to December 1997 101 patients received transdermal fentanyl. Thirty-six patients had been treated with transdermal fentanyl before admission to our pain clinic, and relevant information was missing for one patient, so 64 patients were evaluated. Opioid therapy was switched to transdermal fentanyl during in-patient treatment for 53 patients and during out-patient treatment for 11 patients. Before conversion patients were treated with slow-release morphine (48%), immediate-release morphine (17%), buprenorphine (11%), Tramadol ( Generic Ultram ) (11%), levomethadone (5%), tilidine/naloxone (5%) and piritramid (3%). Reasons for opioid rotation were inadequate pain relief ( 33%), the patients' wish to reduce oral medication (20%), gastrointestinal side effects such as nausea (31%), vomiting (13%) and constipation (19%), dysphagia (27%) or others. Reduction of side effects was reported by 10 of 19 patients. In 12 of 21 patients, in whom the medication was switched because of inadequate pain relief, a reduction in pain intensity was reported. DISCUSSION: Conversion to transdermal therapy may readjust the balance between opioid analgesia and side effects. The opioid switch resulted in more pain relief or fewer side effects in half of the patients. A proposed equianalgesic conversion ratio between 70:1 and 100:1 from oral slow-release morphine to transdermal fentanyl can be confirmed by our data. Conversion rates from other opioids to transdermal fentanyl are suggested.

Tramadol ( Generic Ultram ), M1 metabolite and enantiomer affinities for cloned human opioid receptors expressed in transfected HN9.10 neuroblastoma cells.

Tramadol ( Generic Ultram ) hydrochloride is a centrally acting synthetic analgesic in widespread clinical use. Despite different degrees of opioid-like characteristics in preclinical tests, it is characterized by lack of full naloxone reversibility or naloxone-precipitated withdrawal in humans. To investigate this apparent discrepancy, the present study measured the affinity of Tramadol ( Generic Ultram ) (and its enantiomers) and an active O-desmethyl metabolite (M1) (and its enantiomers) to cloned human opioid receptors of the mu, delta and kappa type stably expressed in HN9.10 neuroblastoma cells. At mu sites, the Ki values for Tramadol ( Generic Ultram ), its (+) and (-) enantiomers, M1, and its (+) and (-) enantiomers were 17000, 15700, 28800, 3190, 153 and 9680 nM, respectively, compared to 7.1 nM for morphine. These results are consistent with the suggestion of a non-opioid contribution to the clinical profile of Tramadol ( Generic Ultram ).

Based on the recent finding that Tramadol ( Generic Ultram ) (TRAM) produces conditioned place preference (CPP) and dopamine release in the nucleus accumbens, it was suggested that the abuse liability of TRAM may be greater than hitherto assumed. We re-evaluated the effects of TRAM in CPP and behavioral sensitization, in comparison with morphine (MOR) and meptazinol (MEPT), an opioid drug with minimal abuse potential. While MOR produced CPP and very strong locomotor sensitization, TRAM and MEPT produced only CPP. It has been suggested that sensitization plays an important role in the development of addiction, hence our results suggest that the abuse potential of TRAM might resemble more that of MEPT than that of MOR, and they are consistent with the clinical picture, in that although TRAM is not completely devoid of positively reinforcing effects, reports on abuse are rare. The low propensity to induce addiction may be related to the lack of changes in the brain circuitry mediating reward and motivation, as evidenced by the lack of sensitization. Copyright 2002 Elsevier Science Ireland Ltd.

Withdrawal syndrome and dependence: Tramadol ( Generic Ultram ) too.

(1) Tramadol ( Generic Ultram ) carries a risk of dependence and abuse, even in patients with no history of drug abuse. (2) Abrupt withdrawal of treatment with Tramadol ( Generic Ultram ), even at the recommended dose, can induce withdrawal symptoms. (3) In practice, patients must be advised to stop their treatment gradually, especially after lengthy treatment periods. Prescription renewals are a good opportunity to re-assess the need for Tramadol ( Generic Ultram ). Use of this opioid analgesic should not be trivialised.

Influence of complex solubility on formulations based on lambda carrageenan and basic drugs.

We have used the sucrose gap method to measure the effects of drugs on the electrophysiological properties of rat sciatic nerves. The results showed that 4-aminopyridine produced a slight conduction block, prolonged the duration of action potential, enhanced the hyperpolarizing afterpotential, and elicited a hump that followed the action potential. In the presence of 4-aminopyridine, the impulse-blocking activity of lidocaine and Tramadol ( Generic Ultram ) was enhanced. Both lidocaine and Tramadol ( Generic Ultram ) effectively depressed the delayed depolarization generated by 4-aminopyridine. While Tramadol ( Generic Ultram ) decreased the activity-evoked hyperpolarizing afterpotentials, lidocaine completely removed them. These findings indicate that lidocaine may be more effective in blocking the Na(+) channels than Tramadol ( Generic Ultram ). Tramadol ( Generic Ultram ) may be more effective on the delayed rectifier K(+) channels than lidocaine. Copyright 2003 S. Karger AG, Basel