Tramadol Hydrochloride

Registered South African indications:

• Management of moderate to moderately severe pain

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Patients suffering from acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic medicines
• Administration to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal
• Patients with epilepsy not adequately controlled by treatment
• Use in narcotic withdrawal treatment
• Pregnancy
• Breastfeeding
• All children younger than 12 years of age
• Patients with respiratory depression especially in the presence of cyanosis and excessive bronchial secretions
• Patients with increased intracranial pressure or central nervous depression due to head injury or cerebral disease

South African recommendations

Caution in the following patient groups

• Renal impairment
• Severe hepatic impairment
• Elderly
• Opioid-dependent patients
• Patients with head injury
• A reduced level of consciousness of uncertain origin
• Disorders of the respiratory centre or function
• Patients prone to convulsive disorders or in shock

Tolerance, dependence and withdrawal

• At therapeutic doses, tramadol has the potential to cause withdrawal symptoms. Cases of dependence and abuse have been reported. Because of this potential, the clinical need for continued analgesic treatment should be reviewed regularly
• Tolerance, psychic and physical dependence (of the morphine-type) may develop, especially after long-term use
• When a patient no longer requires therapy, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal
• Tramadol is not a suitable substitute for opioid-dependent patients and does not suppress morphine withdrawal symptoms

Drowsiness and CNS depressants

• Tramadol 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
• Concomitant use with sedating medicines such as benzodiazepines may result in respiratory depression, sedation, coma, and death. If concomitant prescribing is the only option, the lowest effective dose should be used for the shortest possible duration, and patients should be monitored closely for signs and symptoms of respiratory depression and sedation

CYP2D6 metabolism

• If a patient has a deficiency or is completely lacking the liver enzyme CYP2D6, an adequate analgesic effect may not be obtained. However, if a patient is an ultra-rapid metaboliser, there is a risk of developing side effects of opioid toxicity, including life-threatening respiratory depression, even at commonly prescribed doses

Minor pain

• Tramadol should not be used in the treatment of minor pain

Children

• Tramadol Injection Pharma-Q is not suitable for children under the age of 12 years. There have been reports that tramadol given post-operatively to children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea led to life-threatening adverse events. Children with compromised respiratory function have factors which may worsen symptoms of opioid toxicity

Other precautions

• Convulsions have been reported at therapeutic doses, and the risk may be increased at doses exceeding the usual upper daily dose limit (400 mg)
• Patients with a history of epilepsy or those susceptible to seizures should only be treated if there are compelling reasons. The risk of convulsions may increase in patients receiving tramadol and concomitant medicines that can lower the seizure threshold
• The risk of seizures may also be increased in patients with a recognised risk for seizures, such as drug and alcohol withdrawal, intracranial infections, head trauma, metabolic disorders, and naloxone treatment with tramadol overdose

Respiratory depression

• Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant medicines are being administered, or if the recommended dosage is significantly exceeded. At therapeutic doses, respiratory depression has infrequently been reported

Anaesthesia

• The use of tramadol during potentially very light planes of general anaesthesia should be avoided as it was reported to enhance intra-operative recall. However, its use may be considered intra-operatively in the same way as other analgesic agents, provided continuous, potent anaesthetic agent is followed

Effects on ability to drive and use machines

• Tramadol may cause somnolence and dizziness and these effects may be potentiated by alcohol and other CNS depressants
• Ambulant patients should be warned not to drive or operate machinery if affected. Tramadol can impair cognitive function and can affect a patient's ability to drive safely

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Management of moderate to moderately severe pain
- Postoperative pain

• IV/IM/SC: Initial: 100mg bolus; During the 90min following the initial bolus, further doses of 50mg may be given every 30min, up to a total dose of 250mg including the initial bolus; Subsequent doses: 50mg or 100mg, 4 - 6hrly; Max: 250mg in first 90min postoperative; Max: 400mg/24hrs

- For less severe pain

• IV/IM/SC: Admin. 50mg or 100mg, 4- 6hrly

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The dosage should be adjusted to the intensity of pain and the individual's response to the analgesic action of tramadol

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Tramadol should not be used to treat minor pain

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If concomitant prescribing of tramadol and sedating medicines (such as benzodiazepines or related substances) is the only option, the lowest effective dose of tramadol should be used, and duration of concomitant treatment should be as short as possible

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Method of administration
Tramadol injection is for parenteral injection either intramuscularly, by slow intravenous injection or diluted in solution for administration by infusion or patient controlled analgesia
 Intravenous injection must be given slowly over 2-3 minutes. May also be diluted in solution for infusion and infused
For instructions for use and handling of the medicine before administration, refer to the product specific information

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Management of moderate to moderately severe pain

Younger than 12 years

• Contraindicated

Older than 12 years

• See adult dosage

Pregnancy

South African recommendations

• Contraindicated
• Tramadol injection is contraindicated in pregnancy
• Animal studies with tramadol have revealed effects on organ development, ossification and neonatal mortality
• Tramadol crosses the placenta. Chronic use during pregnancy may lead to neonatal withdrawal symptoms

Breastfeeding

South African recommendations

• Contraindicated
• Approximately 0,1 % of the maternal dose of tramadol is excreted in breast milk
• Tramadol should not be administered during breastfeeding or alternatively, breastfeeding should be discontinued during treatment with tramadol
• After a single administration of tramadol injection however, it is not usually necessary to interrupt breastfeeding

Fertility

South African recommendations

• Post marketing surveillance does not suggest an effect of tramadol on fertility. Animal studies did not show an effect of tramadol on fertility

South African recommendations

• CrCl ≥ 30ml/min: Caution; no dose adjustment recommended
  The elimination of tramadol may be prolonged. It is recommended that the usual initial dosage be used
• CrCl < 30ml/min: Caution; dose adjustment recommended
  Dosage interval should be increased to 12 hours
  As tramadol is removed very slowly by haemodialysis or haemofiltration, post-dialysis administration to maintain analgesia is not usually necessary

South African recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; dose adjustment recommended
  The elimination of tramadol may be prolonged. The usual initial dosage should be used but in severe hepatic impairment the dosage interval should be increased to 12 hours

South African recommendations

• ≥ 75 years: Caution; dose adjustment recommended
  The usual dosages may be used except in patients 75 years of age and over where a downward adjustment of the dose and/or prolongation of the interval between doses are recommended

Immune System Disorders

Less frequent

• Allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema)
• Anaphylaxis

Metabolism and Nutrition Disorders

Less frequent

• Changes in appetite

Frequency not known

• Hypoglycaemia

Psychiatric Disorders

Less frequent

• Hallucinations
• Confusion
• Sleep disturbance
• Delirium
• Anxiety
• Nightmares
• Changes in mood (usually elation, occasionally dysphoria)
• Changes in activity (usually suppression, occasionally increase)
• Changes in cognitive and sensorial capacity (e.g. decision behaviour, perception disorders)
• Dependence may occur

Nervous System Disorders

Frequent

• Dizziness
• Headache
• Somnolence

Less frequent

• Changes in appetite
• Paraesthesia
• Tremor
• Epileptiform convulsions
• Involuntary muscle contractions
• Abnormal coordination
• Syncope
• Speech disorders

Eye Disorders

Less frequent

• Blurred vision
• Miosis
• Mydriasis

Cardiovascular System Disorders 

Less frequent

• Cardiovascular regulation
  • Palpitation
  • Tachycardia
  • Postural hypotension or cardiovascular collapse
• Bradycardia

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Respiratory depression
• Dyspnoea

Gastrointestinal Disorders

Frequent

• Nausea
• Vomiting
• Constipation
• Dry mouth

Less frequent

• Retching
• Gastrointestinal irritation (a feeling of pressure in the stomach, bloating)
• Diarrhoea

Hepatobiliary Disorders

Less frequent

• Increase in liver enzyme values

Skin and Subcutaneous Tissue Disorders

Frequent

• Sweating

Less frequent

• Dermal reactions (e.g. pruritus, rash, urticaria)

Musculoskeletal and Connective Tissue Disorders

Less frequent

• Muscular weakness

Renal and Urinary Disorders

Less frequent

• Micturition disorders (difficulty in passing urine, dysuria and urinary retention)

General Disorders  and Administrative Site Conditions

Frequent

• Fatigue

Investigations

Less frequent

• Increase in blood pressure

• Monoamine oxidase inhibitors or within two weeks of their use
• Sedating agents
• Benzodiazepines
• Centrally acting medicines
• Selective serotonin reuptake inhibitors
• Serotonin-norepinephrine reuptake inhibitors
• Tricyclic antidepressants
• Antipsychotics 
• Seizure threshold lowering medicines
• Bupropion
• Mirtazapine
• Tetrahydrocannabinol
• Lithium
• Serotonergic medicines
• Coumarin anticoagulants
• Carbamazepine
• Ketoconazole
• Erythromycin
• Ondansetron

Other interactions

• Alcohol

None routine. Specific cases may require

• Signs and symptoms of respiratory depression and sedation

Tramadol is a centrally acting analgesic with binding to specific opioid receptors. It is a non-selective, pure agonist at mu (μ), delta (8) and kappa (k) opioid receptors with a higher affinity for the μ receptor. Other mechanisms, which may contribute to its analgesic effect, are inhibition of neuronal re-uptake of noradrenaline and serotonin. Tramadol does not promote the release of histamine.

Capsule 50mg

• Austell Tramadol (Austell)
• Domadol (Unichem)
• Dolotram (Ranbaxy)
• Tramal (Janssen) originator
• Tramahexal (Sandoz)
• Tramaspen (Pharmacare)
• Tramazac (Zydus)

Tablet 50mg

• Tramagesic flashtabs (Adcock)

Slow-release tablet 100mg

• Tramal SR (Janssen) originator
• Tramahexal SR (Sandoz)
• Tramazac SR (Zydus)

Slow-release tablet 150mg

• Tramal SR (Janssen) originator
• Tramazac SR (Zydus)
• Tramahexal SR (Sandoz)

Slow-release tablet 200mg

• Tramal SR (Janssen) originator
• Tramahexal SR (Sandoz)
• Tramazac SR (Zydus)

Injection (per ml) 50mg 

• Dolotram (Ranbaxy) originator
• Domadol (Unichem)
• Nobligan (Janssen) originator
• Tramal (Janssen) originator
• Tramahexal (Sandoz)
• Tramaspen (Pharmacare)
• Tramazac (Zydus) (NON EML)

COMBINATION PREPARATIONS

Paracetamol/ Tramadol 

Tablet 325mg/37,5mg

• Tramazac Co (Zydus)
• Tramacet (Janssen) originator
• Tramahexal Co (Sandoz/Zydus)
• Ultracet (Janssen) originator