Tramadol in pediatrics

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Tramadol has been marketed since September 2004 for children from the age of three in the form of oral drops (Contramal drops and Topalgic drops). The indication for tramadol is the management of moderate to severe pain. Tramadol is authorized in children over one year of age in many countries. In France, it has been available for 7 years for adults and in Europe for 27 years. Millions of adult patients have already been treated with this analgesic. Numerous studies have evaluated the place of tramadol in different situations in adults, particularly in chronic rheumatological pain and neuropathic pain.

Action mechanism

Tramadol has two modes of action: opioid action and mono-aminergic action. It is a -receptor agonist with a weak affinity, ten times less than that of codeine, sixty times less than dextropropoxyphene and six hundred times less than that of morphine. Yet the ratio of equi-analgesia to morphine is 1/10 intravenously and 1/6 orally.

Indeed, tramadol inhibits the reuptake of serotonin and norepinephrine, and increases the presynaptic release of serotonin at the level of the descending inhibitory pathways of pain. This effect of tramadol modulates the response to a painful ascending nociceptive stimulus by enhancing the action of the descending inhibitory pathways of pain and thereby decreasing pain perception. This action is probably responsible for most of the analgesic effect and in some countries tramadol is not classified as opioids.

Pharmacokinetics and metabolism

Oral absorption of tramadol is excellent. Its bioavailability is 70% after the first dose and reaches more than 90% after 36 hours of treatment. The analgesic effect appears approximately 25 to 30 minutes after the setting and the maximum concentration is observed at H2. Its duration of action is 4 to 6 hours, and its elimination half-life is 5 to 7 hours. Like other opiates, tramadol has a hepatic metabolism that uses cytochrome pathways, leading to the production of many metabolites, only one of which is active. Elimination is renal, mainly in metabolized form.

Dosage

The unit dose is 1 to 2 mg / kg every 6 hours, not exceeding 8 mg / kg / 24 hours and with a maximum dosage of 400 mg / day even if the weight of the child is greater than 50 kg. One drop of tramadol solution contains 2.5 mg of active ingredient. In case of non-acute pain, it is advisable to start the treatment at low dose in the evening, in order to limit the classic adverse effects such as nausea.

Efficiency studies

Many studies have been conducted in children in single or repeated doses (> 2000 patients), especially during the perioperative period, most often IV or IM but also orally. Some studies have also used tramadol epidurally or rectally. Numerous studies have been conducted in adults, mainly in the postoperative context but also in chronic low back pain, osteo-articular and musculoskeletal pain, and diabetic or post-herpetic neuropathies. Efficacy is widely demonstrated in adults, so it no longer needs to be demonstrated in children. Studies in children have tested tolerance and dosage: here are some of those conducted in children with oral tramadol.

  • The efficacy of oral tramadol has been evaluated in dental surgery. Sixty children aged 3 to 8 years, requiring multiple dental extractions (more than 6) under general anesthesia, received a single oral dose of tramadol at a dose of 1.5 mg / kg or placebo preoperatively.
  • The evaluation of the pain was performed within 2 hours after the surgical procedure using the Oucher face scale. Pain scores were significantly lower in the tramadol group. Only 19% of children who received tramadol compared to 83% of children who received placebo had recourse to paracetamol.The efficacy of tramadol was compared with that of paracetamol after tonsillectomy.
  • Fifty children aged 2-9 years were randomized into two groups. The tramadol group received an oral dose of 2.5 mg / kg / 8 h for three days after intraoperative intravenous bolus administration. The paracetamol group received a rectal administration of 15 mg / kg / 6 h after intraoperative intravenous bolus administration. The pain was assessed by a CHEOPS scale in the post-interventional surveillance room and then by hetero-evaluation using a simple five-level verbal scale. The tramadol group has showed significantly lower pain scores than the paracetamol group. The tramadol group less often required the use of additional analgesia with diclofenac (24 versus 60% in the paracetamol group, p<0.05). These two studies provide little useful data because the result was predictable. A randomized, double-blind study evaluated the efficacy and safety of two oral doses of tramadol (2 versus 1 mg / kg).
  • Eighty-one children between the ages of 7 and 16 received one of two post-operative doses of tramadol in combination with a PCA morphine. The effectiveness of the treatment was assessed by the scale of faces and the need for recourse treatment. Administration of the highest dose of tramadol resulted in a significant decrease in pain scores and in the number of additional treatments. The adverse effects were comparable. Several open studies have evaluated the efficacy and safety of oral tramadol in children. One study included 113 children aged 6 to 16, suffering from various medical or postoperative pain conditions.
  • Patients received tramadol in repeated doses for 7 to 30 days (mean 14 days). The average dose received by each child was relatively low, of the order of 3 mg / kg / day. Efficacy was rated as excellent by 70% of caregivers and parents. The efficacy of tramadol was therefore confirmed in children. Unfortunately, there are no studies comparing the efficacy and safety of oral tramadol and codeine.IndicationsThe current indications for tramadol in pediatrics are the treatment of pain not relieved by a Tier 1 analgesic and does not require a level 3 analgesic. It is useful for acute pain and chronic pain. It could also have a preventive interest for punctual painful acts such as dressings. It has a potential interest for neuropathic pain or mixed pain (cancer, polyhandicap …). Side effectsThe frequency of side effects is variable. The most common are nausea and vomiting, which have been studied mainly during the postoperative period (3 to 40% or more, which is usual postoperatively, even outside the administration of opioids); the vomiting rate in children after tramadol administration outside the postoperative period is not known. Dizziness, pseudo-drunkenness and drowsiness are possible. In adults, these side effects are as common as those observed with codeine, and are less important with the delayed form. The other effects of opioids are rare because of the low affinity for  receptors. The risk of constipation is low, or even zero. No respiratory depression is observed at therapeutic doses. Rare cases of convulsions are reported, especially in epileptics. There is no euphoric effect. Finally, tramadol does not seem to have any addictive power. This has been well studied in adults: patients do not develop palatability or dependence for this product, tramadol is not sought after or appreciated by drug addicts and during long-term treatment, it does not occur. withdrawal syndrome.

Surdosage

The manifestations observed in case of accidental or voluntary overdose are sedation, respiratory depression, convulsions or even collapse. Naloxone is effective on the side effects of opioid type. Other symptoms warrant symptomatic treatment. The bottle has a safety cap, drops drop slowly one by one when it is spilled and have a pronounced taste of mint, which reduces the risk of intoxication. ContraindicationsThe main contraindications to tramadol are severe renal insufficiency, severe hepatic insufficiency, hypersensitivity to tramadol and uncontrolled epilepsy.

Some chronic pain such as headache, migraines, recurrent abdominal pain, and Somatoform disorders are not indications of Tier 2 analgesics and therefore are not indications of tramadol.Administration of tramadol in children with progressive central neurological disorders or progressive respiratory disorders requires precautions, such as: for another morphine in these patients. In case of renal insufficiency or hepatic insufficiency, the dosage must be adapted (reduction and spacing of the doses) .Presentations Tramadol is available in four galenic forms. The oral form oral drops can be used in children from three years of age, the immediate-release tablet in children over fifteen, the extended-release tablet in children over 12 years, and the tablet associated with paracetamol in children over 12 years old.

Tramadol can be combined with all other analgesics except morphine. It may be associated with paracetamol, nonsteroidal anti-inflammatory drugs, local or locoregional anesthetics, nitrous oxide, and neuropathic pain treatments, with caution, however, for monoaminergic treatments (tricyclic antidepressants). Tramadol will soon also be approved IV in children.In conclusion, tramadol is an effective analgesic on a wide range of pain. Its side effects profile is well known, with the disadvantage (yet to be evaluated accurately), nausea or vomiting. It has advantages over other opioids: little constipation, little respiratory depression, and especially a very low risk of abuse or dependence on therapeutic doses, even over the long term. The dosage can be adapted to the intensity of the pain and the adverse effects.