The effects of tramadol and its metabolite on glycine, gamma-aminobutyric acidA, and N-methyl-D-aspartate receptors expressed in Xenopus oocytes

We assessed the effects of tramadol, a centrally acting analgesic, and its major metabolite, on neurotransmitter-gated ion channels. Tramadol binds to mu-opioid receptors with low affinity and inhibits reuptake of monoamines in the central nervous system. These actions are believed to primarily contribute to its antinociceptive effects. However, little is known about other sites of tramadols action. We tested the effects of tramadol and its M1 metabolite (0.1-100 microM) on human recombinant neurotransmitter-gated ion channels, including glycine, gamma-aminobutyric acid(A) (GABA(A)), and N-methyl-D-aspartate (NMDA) receptors, expressed in Xenopus oocytes. Tramadol and M1 metabolite did not have any effects on glycine receptors. GABA(A) receptors were significantly inhibited only at large concentrations (100 microM). NMDA receptors were inhibited in a concentration-dependent manner. Tramadol and M1 metabolite inhibited the glutamate-concentration response curve without changing the half-maximal effective concentration or the Hill coefficient, indicating a noncompetitive inhibition. This study suggests that glycine receptors do not provide the antinociceptive effect of tramadol and that the inhibition of GABA(A) receptors at large concentration might correlate with convulsions. The inhibitory effect on NMDA receptors may contribute to the antinociceptive effect of tramadol at relatively large concentrations.

Side effects of tramadol: 12 years of experience in the Netherlands

Tramadol is a synthetic opioid that has been available in the Netherlands since 1992 and is usually used as a centrally-acting analgesic when paracetamol or an NSAID provides insufficient relief. In the period 1 January 1992--30 November 2003, the Netherlands Pharmacovigilance Centre Lareb received 299 reports concerning 522 adverse drug reactions associated with the use of tramadol. Some of the frequently reported side effects with a high reporting odds ratio were nausea, constipation and withdrawal symptoms. These side effects are very similar to those of the other opioids due to the affinity of tramadol for the micro-opioid receptor. Because tramadol is often not recognised as an opioid, it is important that such opiate effects be recognised as an adverse drug reaction on time.

Tramadol produces outward currents by activating mu-opioid receptors in adult rat substantia gelatinosa neurones

An action of a tramadol metabolite, mono-O-dimethyl-tramadol (M1), on substantia gelatinosa (SG) neurones in adult rat spinal cord slices was examined by using the whole-cell patch-clamp technique.In 41% of the neurones examined, superfusing M1 produced an outward current at -70 mV; this response reversed at a potential close to the equilibrium potential for K(+). M1 current hardly declined and persisted for >30 min after its washout.M1 current correlated in amplitude with current produced by mu-opioid receptor agonist DAMGO in the same neurone, and largely reduced in amplitude in the presence of mu-opioid receptor antagonist CTAP but not alpha2-adrenoceptor antagonist yohimbine. In a neurone where M1 had no effect on holding currents, noradrenaline produced an outward current at -70 mV.The amplitude of the M1 response, relative to that of the DAMGO response, exhibited an EC(50) value of 300 muM.We conclude that M1 produces a persistent hyperpolarization by activating mu-opioid receptors in adult rat SG neurones. This could contribute to at least a part of pain alleviation produced by tramadol.British Journal of Pharmacology (2005) 145, 602-607. doi:10.1038/sj.bjp.0706225 Published online 18 April 2005.

A comparison of 0.2 and 0.5 mg intrathecal morphine for postoperative analgesia after total knee replacement.

The optimal dose of intrathecal morphine for postoperative analgesia after major surgery is a matter of debate, with some uncertainty concerning the therapeutic potential and safety of intrathecal morphine in the dose range 0.3-1.0 mg. This randomised double-blind study compared the efficacy and side-effect profile of 0.2 mg and 0.5 mg intrathecal morphine in 70 patients undergoing knee replacement surgery. The primary endpoint was the number of patients requiring rescue analgesia (tramadol) during the first 24 h postoperatively. Secondary endpoints included consumption of tramadol and the incidence of adverse effects. Fewer patients in the 0.5-mg group required rescue analgesia in the first 24 h than in the 0.2-mg group (16 (48%) vs 28 (85%), respectively; p = 0.003). Median (IQR [range]) tramadol consumption was lower in the 0.5-mg group than in the 0.2-mg group (0 (0-100 [0-350]) mg vs 100 (50-100 [0-350]) mg, respectively; p = 0.02). The incidence of adverse effects was similar in both groups. This study has demonstrated that 0.5 mg intrathecal morphine produces better analgesia than 0.2 mg after knee replacement without any increase in side-effects.

The influence of psychotropic drugs on cerebral cell death: female neurovulnerability to antipsychotics

Tissue transglutaminase (tTG) is a marker for apoptosis, and its protein level is known to be increased in post-mortem Alzheimers and Huntingtons disease brains. tTG is increased in the cerebrospinal fluid of patients with Alzheimers disease. However, the influence of psychotropic medication on acute cell death has not been studied so far in vivo, although some experiments performed in vitro suggest that antipsychotic drugs are neurotoxic. The protein level of tTG was examined in the cerebrospinal fluid obtained from 29 patients under neuroleptic medication in the last 24 h before lumbar puncture (eight patients diagnosed with Alzheimers disease and 21 patients with other neurological diseases), and compared with those from 55 patients without antipsychotic medication (25 Alzheimers patients and 30 others). In addition, the influence of several other psychotropic drugs on apoptosis was analysed. A significant influence (P<0.01) of antipsychotic drugs for both the Alzheimers and the non-Alzheimers group was found with respect to tTG protein levels in cerebrospinal fluid. By contrast to the male subgroups, the female groups showed a strong influence of neuroleptics on cerebral cell death. Surprisingly, atypical antipsychotics did not differ from typical neuroleptics in neurotoxicity. By contrast, no influence of antidepressants, cholinesterase-inhibitors, nootropics, tranquilizers and tramadol on cerebral cell death was found. The results suggest that typical and atypical antipsychotic drugs may induce cerebral cell death, especially in female patients. Subjects with Alzheimers disease might be even more vulnerable to any antipsychotic. Therefore, subsequent research should aim to identify atypical neuroleptics without neurotoxicity. A limit on the use of first- and second-generation antipsychotics in elderly patients is proposed. Finally, the possible connection between the observed increased cerebral cell death and tardive dyskinesia, the most threatening side-effect in antipsychotic therapy, is discussed.

Long-term tolerability of tramadol LP, a new once-daily formulation, in patients with osteoarthritis or low back pain

INTRODUCTION: Tramadol hydrochloride is a centrally acting analgesic, which possesses opioid agonist properties and activates monoaminergic spinal inhibition of pain. An oral, once a day, sustained release formulation of tramadol is thought to be advantageous compared with immediate release preparations as it prevents plasma peaks associated with increased side-effects of the drug. It may also improve compliance. The purpose of the study was to assess the long-term safety of a new sustained-release formulation of tramadol (tramadol LP) in patients with knee or hip osteoarthritis and in patients with refractory low back pain. STUDY DESIGN: The design was a phase III, open, multicentre, international, tolerability study with tramadol LP at a dose titrated by the patient between 100 and 400 mg once daily, according to the intensity of pain. The treatment was administered for a continuous period of 4 weeks followed by an intermittent intake of 5 months in 204 patients. The safety criteria for evaluation were recording of adverse events, laboratory tests, electrocardiogram, radiography, global tolerability assessed by the patient and the investigators. RESULTS: Long-term use of tramadol LP was reasonably well tolerated. Most of the reported adverse events were expected and occurred within the first month of treatment. Roughly half of the patients (49%) reported adverse events, of which 66% were related to treatment. Gastrointestinal events (nausea and vomiting) were the most frequent. Serious adverse events were reported in 6.4% of patients, from which only two cases were related to treatment. There was no sign of tolerance development and the percentage of patients presenting withdrawal symptoms after the end of treatment was low (6%). CONCLUSION: Long-term treatment with tramadol LP once daily is generally safe in patients with osteoarthritis or refractory low back pain.

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