Tramadol is an opioid analgesic medicine used in the management of pain resistant or non-responsive to other modalities of treatment. The immediate-release tramadol is used for acute pain as and when necessary. The extended-release tramadol is used for long term round-the-clock management of pain. Tramadol has addictive properties and should be used when other pain medicines are not effective, not tolerated or are contraindicated. Tramadol has one-tenth the potency of Morphine and is practically equally potent as codeine and pethidine!

Off-label uses of tramadol include:

• Management of Restless legs syndrome resistant to first-line therapy
• Treatment of premature ejaculation

Tramadol Dose in Adults

For the management of moderate to severe pain:

• Tramadol should be used as an adjunct to other modalities of pain.
• Combination therapy with other analgesic and with different mechanisms improves the efficacy of tramadol.
• Furthermore, prior to initiating opioid therapy, the dose of other analgesics should be increased to a maximum.

Tramadol for acute severe pain:

• Initiate therapy with the lowest possible dose and for a minimum possible duration.
• Tramadol may be prescribed for three to five days.
• The total duration of therapy should not exceed seven days.
• Long-acting or extended-release tablets should not be used for acute pain especially in treatment-naive patients.

Immediate-release tablets:

• 50 mg every four to six hours as needed.
• The dose may be increased to 100 mg every six hours if needed. (The maximum dose is 400 mg per day)

Tramadol for chronic pain:

• Tramadol, like other opioids, is not the preferred analgesic for the management of chronic pain as benefits may outweigh risks.
• Patients who experience a clinically meaningful response to opioid analgesics like tramadol may be continued with the drug. The use of tramadol in cancer patients is debatable.

Tramadol-naive patients not currently on immediate-release tablets.

• The daily dose should not exceed 300 mg per day which is equivalent to 50 mg of morphine.
• Patients should be started with the immediate-release tablets in a dose of 30 to 50 mg every 4 to 6 hours. Patients who have persistent pain despite on immediate-release tramadol for one week may be advised the extended-release tablets.
• The extended-release tramadol should be started as 100 mg tablets and incrementally increase by 100 mg every 5 to 7 days to a maximum of 300 mg per day.
• Patients who are using immediate-release tablets for more than one week may be started on the extended-release tablets in a dose equivalent to the total dose of immediate-release tablets per day.

Dose in premature ejaculation:

• 25 to 50 mg one to three hours prior to intercourse.
• Tramadol should be used for premature ejaculation who have failed to respond to other therapies like topical anesthetics and SSRIs.

Refractory Restless legs syndrome:

• Patients who fail to respond to first-line therapy and have severe symptoms refractory to other modalities may be tried tramadol. (Note: some patients may note worsening of symptoms when started on tramadol).
• Dose: 50 mg once daily at bed-time (titrate to the lowest possible dose)
• The extended-release formulation may be more effective in patients who have been using the immediate-release formulation for more than 7 days.

Tramadol Dose in Childrens

• Children less than 12 years of age should avoid its use especially obese children, children with severe lung diseases, obstructive sleep apnea and those undergoing tonsillectomy or adenoidectomy.
• Childen 12 to 16 years of age: 1-2 mg/kg/dose every 4 to 6 hours to a maximum dose of 8 mg/kg/day (or 400 mg per day). Patients aged 18 years or more, requiring long term round the clock management of pain may be given the extended-release formulation similar to adults. Tramadol should be used in extreme caution in geriatric patients. If it is used, the immediate-release formulation should be used instead of the extended-release tramadol.

Pregnancy Risk Factor: C

• Tramadol crosses into the placenta, which can lead to unfavorable pregnancy outcomes. 
• Opioid use by mothers can lead to preterm births, stillbirth, poor fetal growth and birth defects.
• Neonatal withdrawal symptoms may develop from long-term tramadol usage during pregnancy. 
• For pain relief during pregnancy, you may also need to take other analgesic medications.

Tramadol in Breast-feeding:

• Tramadol and its activemetabolite are both absorbed into breast milk. 
• Tramadol's active metabolite has a higher potency than tramadol. 
• Breastfeeding is not recommended for tramadol. 
• It is important to monitor infants for withdrawal symptoms and toxicity.  

Hoe to Discontinue Tramadol?

• Abrupt withdrawal of chronic tramadol use, like other opioids, may lead to withdrawal symptoms.
• Henceforth, it should be tapered off very slowly. An optimal tapering regimen has not been established, however, most authorities recommend reducing the dose by 10% every week.
• Patients who have been using tramadol for a much longer duration may taper the drug even much slower to reduce the chances of opioid withdrawal.
• If, while tapering the dose, the patient experiences withdrawal symptoms, consider:
  • Slowing the tapering regimen
  • Decrease the amount of dose reduction
  • Restart the patient on the previous dose and restart tapering when the patient is ready
  • Administer an alpha 2 agonist like clonidine to blunt withdrawal symptoms
  • Consider adding a non-opioid analgesic for pain.

Tramadol Dose in Renal Disease:

CrCl > 30 ml/min: No dose adjustment is necessary

• CrCl < 30 ml/min and those on dialysis:
  • Immediate-release tablets: increase the interval between doses to twelve hours (maximum dose: 200 mg per day)
  • Extended-release formulation:
• CrCl > 30 ml/min: No dose adjustment is necessary
• CrCl < 30 ml/min and those on dialysis: Avoid its use

Tramadol Dose in Liver Disease:

• No dose adjustment has been provided in the manufacturer’s labeling.
• In patients with cirrhosis, the recommended dose is 50 mg given twelve hours apart.
• For the extended-release tablets, the manufacturer has not provided any dose adjustment, however, it should be used with caution.
• In patients with child class C, avoid its use.

How to Administer Tramadol?

• Administer immediate-release tramadol without regards to meals.
• The extended-release drug should be swallowed as a whole (it should not be crushed, chewed, cut or dissolved and should be taken the same time each day. 

Most common side effects:

• Central Nervous system:
  • Dizziness, vertigo, headache, and drowsiness and skeletal weakness
• Gastrointestinal:
  • nausea, vomiting, constipation, dyspepsia, and dry mouth

Less common side effects:

• Cardiovascular:
  • Flushing, chest pain, hypertension, vasodilation, peripheral edema, and orthostatic hypotension
• Central nervous system:
  • anxiety, apathy, ataxia, chills, confusion, depression, temperature changes, hypoesthesias, lethargy, nervousness, pain, paraesthesia, restlessness, rigors, agitation, euphoria, hypertonia, malaise, sleep disorders, insomnia, and withdrawal syndromes. Abnormal dreams, amnesia, disorientation, hallucinations and cognitive dysfunction.
• Skin:
  • sweating, dermatitis, rash, pruritis
• Endocrine & metabolic:
  • hot flashes, hyperglycemia, weight loss
• Gastrointestinal:
  • diarrhea, anorexia, abdominal pain, sore throat, flatulence, and gastroenteritis
• Genitourinary:
  • Pelvic pain, menopausal symptoms, urinary frequency, urgency, hesitation, and dribbling
• Infections:
  • viral influenza
• Neuromuscular and skeletal:
  • increased creatinine kinase
• Eye:
  • blurred vision, miosis, and visual disturbances
• Respiratory:
  • bronchitis, cough, nasal congestion, pharyngitis, rhinitis, and upper respiratory tract symptoms

Contraindications to tramadol include:

• Allergy or sensitivity to tramadol and other opioids
• Children younger than 12 years old
• Children under 18 years old who have had tonsils or adenoids removed.
• Respiratory depression
• Acute severe asthma
• Intestinal obstruction
• Use Mao inhibitors in conjunction
• Hepatic and renal impairments severe
• Hypercapnia, seizures and increased intracranial pressure are all possible
• Intoxication from other sedative drugs can lead to acute intoxication
• Pregnancy, breastfeeding, and labor.

Precautions and warnings

• Severe anaphylactic reactions including hives, pruritis, Steven Johnson syndrome and TEN have occurred
• CNS depression and impairments of mental abilities. It is important to advise patients not to operate or drive heavy machinery.
• Hypoglycemia may occur, particularly in the first month.
• Hypotension can occur in patients with heart disease and those with low blood volume.
• Respiratory depression can be life-threatening and severe.
• Patients taking SSRIs or SNRIs, TCAs, MAO inhibitors, and TCAs may experience seizures.
• Concomitant use serotonergic drugs may cause serotonin syndrome
• You should use it with caution under the following conditions:
  • Acute abdominal conditions
  • Insufficiency of the adrenals
  • Biliary tract Disease
  • CNS depression and coma
  • Delirium tremens
  • Head trauma
  • Hepatic impairment and renal impairment
  • Obesity
  • Prostatic hyperplasia
  • Psychosis
  • Respiratory disease
  • Obstructive sleep apnea
  • Thyroid dysfunction, and
  • Suicidal tendencies in those with suicidal tendencie

Important Drug Interactions:​​​​​​​

• Use of benzodiazepines concurrently (US Boxed Warning): Combination of tramadol and benzodiazepines can cause severe respiratory depression
• CYP 450 interactions

Boxed warnings:

• Tramadol can be addictive. 
• Tramadol should not be used in cases of refractory conditions where the benefits outweigh any potential harm.
• Tramadol can cause serious and life-threatening respiratory depression. 
• Patients with chronic lung diseases or patients taking benzodiazepines should be closely monitored for signs of respiratory depression.
• Even one tablet of tramadol accidentally swallowed by children can cause fatal respiratory depression.
• Tramadol administration may cause severe respiratory depression in children who have had tonsillectomy, adenoidectomy, or rapid metabolizers.
• Neonatal withdrawal syndrome may result from prolonged tramadol use during pregnancy.
• Combining alcohol with benzodiazepines can lead to severe respiratory depression and coma

Monitoring Parameters:

• Patients should be monitored for physical dependence.
• Patients symptoms of pain should be monitored and the dose adjusted.
• Patients should also be monitored for respiratory depression, suicidal ideation, hypogonadism, and hypoadrenalism.
• Risks and benefits of chronic tramadol use should be monitored frequently.

Mechanism of action of tramadol:

• Tramadol, and its active metabolite, block the u receptors that are responsible for sensing sensory afferent pathways. It also blocks the serotonin reuptake descending inhibitory pathway.

The onset of action: within one hour of the immediate release pathway.

Metabolism: is via the liver

Bioavailability of immediate-release tablets & extended-release tablets is 75% and 85% respectively.

Half-life elimination: Immediate-release tablets: 6 hours Extended-release tablets: 8 - 10 hours

Time to peak plasma levels:  Immediate-release tablets: 2 hours Extended-release tablets: 4 - 12 hours

Excretion is via Urine (30% unchanged drug & 60% as metabolites)  

International Brands of Tramadol:

• Adamon
• Adolonta
• Amanda
• Analab
• Betram
• Biodalgic
• Bongesic
• Calmador
• Calmol
• Contramal
• Contramal LP
• Dolodol
• Dolonil
• Dolotral
• Dolpaz
• Dolzam
• Domadol
• Dromadol
• Durodor Retard
• Durotram XR
• E-Dol
• Eufindol
• Kontram XL SR
• Koridol
• Lucidol
• Lumidol
• Mabron
• Mabron SR
• Mandolgin
• Monoalgic LP
• Monotramal LP
• Newtram
• Noax
• Nobligan
• Nobligan Retard
• Nomal
• Onetram
• Orasic
• Paxilfar
• Pengesic
• Pengesic SR
• Pengesic SR 100
• Potendol SR
• Predxal
• Radol
• Ramado Retard
• Rivadol
• Romadol
• Sefmal
• Seminac
• Seminac Continus
• Sensitram
• Syndol
• Tadol
• Takadol
• Tamolan
• Topalgic
• Trabilin
• Tradmin
• Tradol
• Tradol-Puren
• Tradolan
• Tradonal
• Tradorec XL
• Tralgit SR
• Trama Inj
• Tramada
• Tramadex
• Tramadol Slovakofarma
• Tramadolor
• Tramagetic
• Tramagit
• Tramahexal
• Tramake
• Tramal
• Tramal Long
• Tramal Retard
• Tramal SR
• Tramalgin
• Tramazac
• Tramaze
• Tramcontin
• Tramed
• Tramedo
• Tramedo SR
• Tramica
• Tramol
• Tramundin Retard
• Tramundin retard
• Trasic
• Trasik
• TRD-Contin
• Trexol
• Tridol
• Trol
• Ultradol
• Unitral
• Vesnon-V
• Zamadol
• Zamudol
• Zodol
• Zudol
• Zydol
• Zydol SR
• Zydol XL
• Zytram BD
• Zytram XL
• Zytram XL SR

Tramadol Brands in Pakistan: