Warnings: At therapeutic doses, Tramadol hydrochloride has the potential to cause withdrawal symptoms. Rarely cases of dependence and abuse have been reported.
At therapeutic doses withdrawal symptoms have been reported at a reporting frequency of 1 in 8,000. Reports of dependence and abuse have been less frequent. Because of this potential, the clinical need for continued analgesic treatment should be reviewed regularly.
In patients with a tendency to drug abuse or dependence, treatment should be for short periods and under strict medical supervision.
Tramadol hydrochloride is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, Tramadol hydrochloride cannot suppress morphine withdrawal symptoms.
Paediatric population: The safety and efficacy of Tramadol has not been studied in the paediatric population. Therefore, use of Tramox is not recommended in patients under 12 years of age.
Respiratory depression: Administer Tramox cautiously in patients at risk for respiratory depression, including patients with substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression, as in these patients, even therapeutic doses of Tramox may decrease respiratory drive to the point of apnea. In these patients, alternative non-opioid analgesics should be considered. When large doses of tramadol are administered with anaesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures.
Cytochromes P450 (CYP) 2D6 Ultra-Rapid Metabolism: Some individuals may be CYP2D6 ultra-rapid metabolisers. These individuals convert tramadol more rapidly than other people into its more potent opioid metabolites O-desmethyltramadol (M1). This rapid conversion could result in higher than expected opioid-like side effects including lifethreatening respiratory depression. The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese, Japanese and Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16-28% in North African, Ethiopians and Arabs. Data are not available for other ethnic groups.
Precautions: Tramadol hydrochloride should be used with caution in patients with head injury, increased intracranial pressure, severe impairment of hepatic and renal function and in patients prone to convulsive disorders or in shock.
Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit. Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling reasons. The risk of convulsions may increase in patients taking tramadol and concomitant medication that can lower the seizure threshold (see 'Interactions').
Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being administered, as the possibility of respiratory depression cannot be excluded in these situations. At therapeutic doses, respiratory depression has infrequently been reported.
Tramadol hydrochloride may cause drowsiness and this effect may be potentiated by alcohol and other CNS depressants. Ambulant patients should be warned not to drive or operate machinery if affected.
Risks from Concomitant Use with Benzodiazepines: Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Tramox with benzodiazepines. Observational studies have demonstrated that concomitant use of opioids and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
If the decision is made to newly prescribe a benzodiazepine and an opioid together, prescribe the lowest effective dosages and minimum durations of concomitant use.
If the decision is made to prescribe a benzodiazepine in a patient already receiving an opioid, prescribe a lower initial dose of the benzodiazepine than indicated in the absence of an opioid, and titrate based on clinical response.
If the decision is made to prescribe an opioid in a patient already taking a benzodiazepine, prescribe a lower initial dose of the opioid, and titrate based on clinical response.
Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when Tramox is used with benzodiazepines. Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of benzodiazepines (See Interactions).
Serotonin Syndrome with Concomitant Use of Serotonergic Drugs: Cases of serotonin syndrome, a potentially lifethreatening condition, have been reported during concurrent use of Tramox with serotonergic drugs (See Interactions). This may occur within the recommended dosage range. Serotonin syndrome symptoms may include mental-status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea) and can be fatal (See Interactions). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue Tramox if serotonin syndrome is suspected.
Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, decreased appetite, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement dosing of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
Sexual Function/Reproduction: Long term use of opioids may be associated with decreased sex hormone levels and symptoms such as low libido, erectile dysfunction, or infertility (See Postmarketing Experience under Side Effects).