Tramal

/ Tec-O-Pharm

The dose of Tramal should be adjusted to the intensity of the pain and the sensitivity of the individual patient. Unless otherwise prescribed, Tramal should be administered as follows:
Adults and adolescents above the age of 14 years: Capsules, Drops, Suppositories- 50-100mg tramadol hydrochloride 4-6 hourly Retard Tablets- The usual initial dose is 50- 100 mg twice daily, morning and evening. If pain relief is insufficient, the dose may be titrated upwards to 150 or 200 mg tramadol twice daily. The lowest analgesically effective dose should be generally selected. Daily doses of 400 mg active substance should not be exceeded except in special clinical circumstances.
Elderly patients: A dose adjustment is not usually necessary in elderly patients (up to 75 years) without clinically manifest hepatic or renal insufficiency. In elderly patients (over 75 years) the elimination may be prolonged. Therefore, if necessary, the dosage interval is to be extended according to the patients requirements.
Patients with renal insufficiency/dialysis and hepatic insufficiency: In patients with renal and/or hepatic insufficiency the elimination of tramadol is delayed. In these patients the prolongation of the dosage interval should be carefully considered according to the patients requirements. In cases of severe renal and/or severe hepatic insufficiency Tramadol retard tablets are not recommended.
Children Over 14 years: Dosage as for adults. Not recommended for children under 14 years.
Method of administration: Tramal capsules and Tramal retard are to be taken whole, not divided or chewed, with sufficient liquid, with or without food. Tramal oral drops are to be taken with a little liquid or on sugar, with or without food Tramal suppositories are to be inserted into the rectums, preferably after defecation.
Duration of administration: Tramdol should under no circumstances be administered for longer that absolutely necessary. If long-term treatment with tramadol is necessary in view of the nature and severity of the illness, then careful and regular monitoring should be carried out (if necessary with breaks in treatment) to establish whether and to what extent further treatment is necessary.

Treatment of moderate to severe pain.

In hypersensitivity to tramadol or any of the excipients. In acute intoxication with alcohol, hypnotics, analgesics, opioids or other psychotropic medicinal products. In patients who are receiving monoamine oxidase inhibitors or within 2 weeks (14 days) of their withdrawal.
In patients with epilepsy not adequately controlled by treatment. For use in narcotic withdrawal treatment.

Tramadol may only be used with particular caution in opioid-dependent patients, patients with head injury, shock, a reduced level of consciousness of uncertain origin, disorders of the respiratory center or function, increased intracranial pressure.
In patients sensitive to opiates tramadol should only be used with caution.
Concomitant use of tramadol and sedating medicinal products such as benzodiazepines or related substances or, may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedating medicinal products should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe tramadol concomitantly with sedating medicinal products, the lowest effective dose of tramadol should be used, and the duration of the concomitant treatment should be as short as possible.
The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms.
Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being administered, or if the recommended dosage is significantly exceeded as the possibility of respiratory depression cannot be excluded in these situations.
Sleep-related breathing disorders
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
Convulsions
Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol exceed the recommended upper daily dose limit (400 mg). In addition, tramadol may increase the seizure risk in patients taking other medicinal products that lowers the seizure threshold. Patients with epilepsy or those susceptible to seizures should be only treated with tramadol if there are compelling circumstances.
Serotonin syndrome
Serotonin syndrome, a potentially life-threatening condition, has been reported in patients receiving tramadol in combination with other serotonergic agents or tramadol alone. If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose escalations. Symptoms of serotonin syndrome may include mental status changes, autonomic instability, neuromuscular abnormalities and/or gastrointestinal symptoms. Serotonin syndrome is likely when one of the following is observed:
Spontaneous clonus, Inducible or ocular clonus with agitation or diaphoresis, Tremor and hyperreflexia, Hypertonia and body temperature > 38 °C and inducible or ocular clonus.
If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms. Withdrawal of the serotonergic drugs usually brings about a rapid improvement.
Tolerance and opioid use disorder (abuse and dependence)
Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop upon repeated administration of opioids such as Tramadol.
Repeated use of Tramadol can lead to opioid use disorder (OUD). A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse of Tramadol may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders). Before initiating treatment with Tramal Retard and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient. Before and during treatment the patient should also be informed about the risks and signs of OUD. If these signs occur, patients should be advised to contact their physician. Patients will require monitoring for signs of drug-seeking behaviour (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.
Drug withdrawal syndrome
Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with tramadol.
Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimize symptoms of withdrawal. Tapering from a high dose may take weeks to months.
The opioid drug withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.
If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.
Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.
Hyperalgesia
Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain.
This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.
CYP2D6 metabolism
Tramadol is metabolised by the liver enzyme CYP2D6. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect may not be obtained. However, if the patient is an ultra-rapid metaboliser there is a risk of developing side effects of opioid toxicity even at commonly prescribed doses.
General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life threatening and very rarely fatal.
Post-operative use in children
There have been reports in the published literature that tramadol given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life threatening adverse events. Extreme caution should be exercised when tramadol is administered to children for post-operative pain relief and should be accompanied by close monitoring for symptoms of opioid toxicity including respiratory depression.
Children with compromised respiratory function
Tramadol is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of opioid toxicity.
Adrenal insufficiency
Opioid analgesics may occasionally cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of acute or chronic adrenal insufficiency may include e.g. severe abdominal pain, nausea and vomiting, low blood pressure, extreme fatigue, decreased appetite, and weight loss.
For full details see prescribing information.

Nervous system disorders: very common: dizziness common: headache, somnolence.
Skin and subcutaneous disorders: common: sweating.
Hepatobiliary disorders: In a few isolated cases an increase in liver enzyme values has been reported in a temporal connection with the therapeutic use of tramadol.
General disorders: common: fatigue.
For full details see prescribing information.

MAO Inhhibitors
Tramadol should not be combined with MAO inhibitors. In patients treated with MAO inhibitors in the 14 days prior to the use of the opioid pethidine, life-threatening interactions on the central nervous system, respiratory and cardiovascular function have been observed. The same interactions with MAO inhibitors cannot be ruled out during treatment with Tramadol.
CNS depressant
Concomitant administration of tramadol with other centrally depressant medicinal products including alcohol may potentiate the CNS effects.
The concomitant use of opioids with sedating medicinal products such as benzodiazepines or related substances or gabapentinoids (gabapentin and pregabalin) increases the risk of sedation, respiratory depression, coma or death because of additive CNS depressant effect.
The results of pharmacokinetic studies have so far shown that on the concomitant or previous administration of cimetidine (enzyme inhibitor) clinically relevant interactions are unlikely to occur. Simultaneous or previous administration of carbamazepine (enzyme inducer) may reduce the analgesic effect and shorten the duration of action.
Tramadol can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other seizure threshold-lowering medicinal product (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions.
Serotonin Syndrome
Concomitant therapeutic use of tramadol and serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors, tricyclic antidepressants and mirtazapine may cause serotonin syndrome, a potentially life-threatening condition.
Caution should be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to reports of increased INR with major bleeding and ecchymoses in some patients.
CYP3A4 Inhhibitors
Other active substances known to inhibit CYP3A4, such as ketoconazole and erythromycin, might inhibit the metabolism of tramadol (N-demethylation) probably also the metabolism of the active O-demethylated metabolite. The clinical importance of such an interaction has not been studied
Ondansetron
In a limited number of studies the pre- or postoperative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirement of tramadol in patients with postoperative pain.
For full details see prescribing information.

Pregnancy: Tramal should not be used in pregnancy as there is inadequate evidence available to assess the safety of tramadol in pregnant women. Animal studies with tramadol revealed at very high doses effect on organ development, ossification and neonatal mortality. Tramadol crosses the placenta. Tramadol administered before or during birth does not affect uterine contractility. In neonates it may induce changes in the respiratory rate which are usually not clinically relevant. Chronic use during pregnancy may lead to neonatal withdrawal symptoms.
Lactation: Tramal is not recommended during breast feeding as tramadol and its metabolites have been detected in breast milk. An infant could ingest 0.1% of the dose administered to the mother. After a single administration of tramadol it is not usually necessary to interrupt breast-feeding.

Symptoms: In principle, on intoxication with tramadol symptoms similar to those of other centrally acting analgesics (opioids) are to be expected. These include in particular miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest.
Treatment: The general emergency measures apply. Keep open the respiratory tract (aspiration), maintain respiration and circulation depending on the symptoms. The antidote for respiratory depression is naloxone. In animal experiments naloxone had no effect on convulsions. In such cases diazepam should be given intravenously. In case of intoxication orally, gastrointestinal decontamination with activated charcoal or by gastric lavage is only recommended within 2 hours after tramadol intake. Gastrointestinal decontamination at a later time point may be useful in case of intoxication with exceptionally large quantities or prolonged-release formulations. Tramadol is minimally eliminated from the serum by haemodialysis or haemo-filtration. Therefore treatment of acute intoxication with Tramadol with haemodialysis or haemofiltration alone is not suitable for detoxification.