Tramadol: an atypical analgesic

Tramadol is opioid analgesic

Tramadol is a painkiller belonging to level 2 of the World Health Organization’s (WHO) scale of treatment for pain. Tramadol therapy should therefore be started after the absence of results with analgesics such as paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs) and before starting morphine or another opioid. Does tramadol (Tramal, Tramadolor-Mepha) have any advantages over other Tier 2 analgesics such as codeine, buprenorphine (Temgesic) or dextropropoxyphene (Depronal)? This article attempts to provide an update on this topic. Methods of Action for Tramadol Tramadol has only a moderate affinity for the m-type opioid receptor. However, among the five metabolites of tramadol, O-demethyl-tramadol (M1 metabolite) has a 700-fold higher affinity for this receptor subtype.

  1. However, this affinity is lower than that of morphine.
  2. The marketed tramadol is in fact a racemic mixture of two stereoisomers, (+) – and (-) – tramadol, which generate different metabolites after hepatic metabolism. An agonist effect at the m-receptor is only observed with a single isomer, (+) – O-demethyl-tramadol.
  3. The formation of the M1 metabolite is provided by the cytochrome P450 2D6,
  4. Of which there is a genetic polymorphism of its expression in the population. About 8% of the Caucasian population has a deficit of expression of this cytochrome, which results in a lower level of the metabolite M1 and a weaker response to the analgesic effect of tramadol, at least when this analgesic is administered per os. The analgesic effect of codeine, which is dependent on its transformation into morphine, is completely absent in poor metabolisers.6 In the laboratory animal, the analgesic effect of tramadol is mainly due to an agonist effect at the level of the receptors. opiates, because it is abolished by antagonists such as naloxone,
  5. Whereas in humans, the effect of 100 mg tramadol is only partially reduced by this antagonist.
  6. An additional, non-opioid, dependent mechanism Monoamines have been mentioned very early.
  7. Tramadol inhibits the reuptake of norepinephrine and serotonin. It therefore has a mechanism of action similar to that of tricyclic antidepressants or venlafaxine (Efexor), which has recently been market.

Antidepressant properties of tramadol have, moreover, been demonstrated in laboratory animals. This particular property seems to participate in the analgesic effect, since  2 -adrenergic receptor antagonists, such as yohimbine, reduce the effect. analgesic effect of tramadol in an experimental model of pain in humans.

The effect of tramadol on serotonin reuptake is mainly due to one of the isomers of the parent molecule, (+) – tramadol, and marginally to metabolite M1.12 (-) – tramadol inhibits norepinephrine reuptake. In addition to the effect of tramadol on the reuptake of monoamines, this substance stimulates the release of norepinephrine and serotonin.

Other pharmacological properties have been demonstrated, such as an anti-inflammatory effect, but it has not been established that this effect is important in humans. Pharmacokinetics Bioavib The orality of tramadol is 70% when it is presented as drops or tablets. Peak plasma is reached only after about 70 minutes, suggesting that oral tramadol is certainly not the drug of choice. choice when it comes to quickly combat a painful condition. Peak plasma levels are delayed in patients> 75 years of age.

The elimination half-life of tramadol is approximately 6 hours, while the half-life of M1 is approximately 7.5 hours; it is prolonged in patients with hepatic insufficiency, in whom the half-life can reach 13 hours for tramadol, and 19 hours for metabolite M1.

However, the literature at our disposal shows little clinical experience with tramadol in hepatic insufficiency. In elderly patients, the elimination of tramadol is delayed and its bioavailability is increased.

The elimination of metabolites and tramadol unchanged (30% of the dose) is mainly performed by the renal route. A case of respiratory depression has been described in a patient treated with tramadol and with renal insufficiency.

The duration of the analgesic effect is 3 to 7 hours during iterative administration.DosesThe doses of tramadol having been the subject Studies are in the range of 50-100 mg every 4-6 hours, with a maximum daily dose of 400 mg. In patients over 75 years of age, the maximum dose is 300 mg daily. In case of renal insufficiency (ClCr).

Clinical use

In acute post-operative pain, tramadol (100 mg suppositories) was compared with paracetamol (1000 mg) and codeine (20 mg) given every 6 hours. Although the analgesic efficacy of the two therapies was identical during the 42 hours following the operation, the frequency of nausea was particularly high in the tramadol group (84%), requiring antiemetic medication in 42% of patients, while only 31% of patients treated with paracetamol / codeine were nauseated, treated in 16% of cases.

In patients undergoing craniotomy, tramadol (50-75 mg im) was also less well tolerated than codeine (60 mg im), while less effective.

A study in patients with abdominal surgery who had PCA (patient-controlled analgesia) pump analgesia morphine, either with tramadol showed similar analgesic efficacy, but the frequency of nausea was higher in the tramadol group.

The use of tramadol peri and postoperatively Recently, a meta-analysis of 3,453 patients evaluating the effectiveness of tramadol postoperatively showed a dose-dependent frequency of nausea in tramadol-treated patients, and a comparable efficacy to that of reference substances.22 In orthopedic surgery, tramadol produced contradictory results. Some studies show that tramadol is much less effective than the paracetamol / codeine combination, while others do not find any difference between the reference treatment and tramadol.

In summary, tramadol is effective for the treatment of postoperative pain and can represent an interesting alternative for patients in whom respiratory depression is to be feared (see below).

Chronic Cancer Pain

Tramadol is used for the treatment of mild to moderate cancer pain. In a non-randomized, non-double blind study, tramadol (mean daily dose of 428 mg) was compared with morphine (mean daily dose of 42 mg). The reduction of pain symptoms was similar in both groups, but the frequency of constipation, neuropsychological symptoms and pruritus was higher in patients receiving morphine (p NeuropathiesThe efficacy of tramadol in diabetic neuropathies was evaluated. recently.

Sixty-six patients received placebo and an equivalent number of tramadol patients four times daily (mean daily dose 210 mg) .A statistically significant effect on pain was observed after two weeks and was maintained during However, this work was criticized because the high frequency of nausea reported in patients treated with tramadol (23% versus 3% on placebo) made the concept of “double blind” questionable. to be maintained when treatment is continued in the long term.

In an article assessing the effectiveness of different drugs for the treatment of neurogenic pain, tramadol appears to be less effective than tricyclic antidepressants.

Rheumatic Pain Tramadol has been compared to dextropropoxyphene in patients with osteoarthritis of the hip and knee. The analgesic efficacy was similar with both types of treatment, but the frequency of adverse effects was higher in the tramadol group than in the dextropropoxyphene group.28 In this indication, tramadol decreases the use of alcohol consumption. NSAIDs.

Adverse effects of tramadolThe side effect profile of tramadol is similar to that of opiates. The most commonly reported effects are nausea, dizziness, lightheadedness, sweating, and dry mouth. The frequency of side effects is extremely variable according to the references mentioned above. In general, the parenteral route seems to be less well tolerated than the oral route. Respiratory depression At the therapeutic dose, tramadol depresses respiration only slightly, in contrast to equi-analgesic doses of pure opiates. does not reduce the ventilatory response to hypoxia.

Nausea, vomitingNausea and vomiting frequently occur in patients treated with tramadol. It is likely that the high frequency of these adverse effects is a consequence of the particular pharmacology of tramadol described above. In fact, in addition to its opioid receptor agonist properties, tramadol inhibits the reuptake of norepinephrine and serotonin, as does venlafaxine, an antidepressant.

Some dosage regimens have been proposed to reduce the occurrence of nausea, such as an increase of 50 mg every three days.

These patterns are naturally difficult to apply in the middle. hospital, where metoclopramide (Primpéran ) will be readily used to reduce the incidence of this adverse effect.ConstipationThe opiates slow down the intestinal transit, without tangible development of tolerance to this undesirable effect. In this context, tramadol has a certain advantage over other opiates. Indeed, when it is administered following a hysterectomy, it slows down the intestinal transit less than morphine.