A weak opioid agoniist.

Routes include oral, IV, IM, rectal, sublingual, buccal, and intranasal.

Has bioavailability of 68-72% and protein binding of 20%.

Metabolism by hepatic demethylation and glucuronidation, with half-life of 5.5�7 hours.

Excretion is renal.

Marketed as Ultram.

A centrally acting opioid analgesic used to treat moderate to moderately severe pain.

A weak mu-opioid receptor agonist, a serotonin releaser and a reuptake inhibitor of norepinephrine.


Tramadol, a mu opioid receptor agonist and weak serotonin and norepinephrine reuptake inhibitor, may be considered in very limited contexts in which NSAIDs are contraindicated or ineffective and the pain is severe. 

Binds to the mu-receptor with 6000 times less affinity than morphine.

Blocks norepinephrine reuptake and serotonin, which offers limited analgesia supporting that it is a weaker opioid.

Metabolized to O-desmethyltramadol, a significantly more potent ?-opioid agonist.

The analgesic action believed to work through modulation of serotonin and norepinephrine in addition to its relatively weak ?-opioid receptor agonism.

Used similarly to codeine, to treat moderate to severe pain.

Molecularly similar to venlafaxine (Effexor), with similar SNRI effects, with antinociceptive effects.

Provided as 50 mg immediate-release tablets, 50 mg orally disintegrating tablets,

100 mg, 200 mg, and 300 mg extended-release tablets, 100 mg, 150 mg, 200 mg, and 300 mg extended-release capsules.

Available in conjunction with APAP as Ultracet or Tramacet

A meta-analysis showed no statistical significance association of tramadol versus NSAIDs for pain relief among patients with osteoarthritis, but tramadol was associated with more opioid related adverse effects.

Among patient’s age 50 years and older with osteoarthritis, initial tramadol was associated with a significantly higher risk of mortality over one year of follow up compared with commonly prescribed NSAIDS (Zeng O).

Preservative-free solutions for injection by the various spinal routes such as epidural, intrathecal, and caudal, are available.

Available in liquid form with and without alcohol for oral and sub-lingual administration.

Can be used as topical gel, creams, and solutions for nerve pain.

Available as a rectal foam, retention enema, and a skin plaster.

Probability of adverse effects: any adverse effect 71%, drowsiness 17%, nausea 17%, dizziness15%, constipation 11%, headache 11%, vomiting 7%, diarrhea 6%, dry mouth 5%, and fatigue 5%.

Drowsiness is less of an issue than for other opioids.

If weaned off too quickly withdrawal symptoms including tremors, muscle contracture, anxiety, electrical shock, and thrashing in bed have been reported.

Due to its interaction with 5HT it can produce delayed ejaculation, and other sexual dysfunctions,

Respiratory depression is not clinically significant in usual doses.

Decreases the seizure threshold, especially when combined with SSRIs, and tricyclic antidepressants.

Use contraindicated in patients with uncontrolled seizures.

Most often causes tonic-clonic seizures.

When taken with SSRIs, increases the risk of serotonin toxicity.

Risk of seizure is highest among those aged 25-54 years, those prolonged use, and those with alcohol abuse, stroke, or head injury.

Constipation can be a severe complication.

Long-term use of high doses of medication may be associated with physical dependence and a withdrawal syndrome.

Causes typical opiate-like withdrawal symptoms as well as atypical withdrawal symptoms including seizures.

The atypical withdrawal symptoms are probably related to the drugs effect on serotonin and norepinephrine re-uptake, and include: anxiety, depression, mood swings, aggressiveness, electric-shock-like sensations, paresthesias, sweating, palpitations, restless legs syndrome, sneezing, insomnia, nightmares, tremors, and headache.

Withdrawal symptoms start 12-20 hours after the last dose, and lasts longer than that of other opioids.

Withdrawal symptoms can last seven days or more, as opposed to typically three or four days for other codeine analogues.

It is recommended that patients physically dependent on pain killers take their medication regularly to prevent onset of withdrawal symptoms and this is particularly relevant to tramadol because of its SSRI and SNRI properties, and, when the time comes to

Discontinuing tramadol should be done gradually to prevent withdrawal symptoms.

Generally considered to have a relatively low dependence liability

Not currently scheduled as a controlled substance.

Causes a higher incidence of nausea, dizziness, loss of appetite compared with opiates, so fewer patients choose to abuse tramadol compared to hydrocodone,

Significant doses may cause insomnia.

The analgesic effect is not fully antagonised by the ?-opioid receptor antagonist naloxone.

Marketed as a racemic mixture of enantiomers with a weak affinity for the ?-opioid receptor at approximately 1/6000th that of morphine.

The serotonergic-modulating properties of tramadol give it the potential to interact with other serotonergic agents, and there is an increased risk of serotonin toxicity when taken in combination with selective serotonin reuptake inhibitors.

SSRIs potentiate the effect of 5-HT but also inhibits tramadol metabolism.

Has inhibitory actions on the 5-HT2C receptor.

Analgesic profile supports use in the treatment of intermediate pain, especially of chronic nature.

It is slightly less effective for acute pain than hydrocodone, but more effective than codeine.

Its potential for misuse relatively low among intermediate strength analgesics.

The primary active metabolite, O-desmethyltramadol, is a considerably more potent ?-opioid receptor agonist than tramadol itself, thus, tramadol is in part a prodrug to O-desmethyltramadol.

O-desmethyltramadol is a norepinephrine reuptake inhibitor, 5-HT2C receptor antagonist, and M1 and M3 muscarinic acetylcholine receptor antagonist.

Tapentadol is the closest chemical relative of tramadol in clinical use.

Undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2B6, CYP2D6 and CYP3A4, being demethylated to five different metabolites.

O-desmethyltramadol is the most significant metabolite with 200 times the ?-affinity of tramadol

O-desmethyltramadolnd has an elimination half-life of nine hours, compared with six hours for tramadol itself.

In the 6% of the population with increased CYP2D6 activity resulting in increased metabolism there is an increased analgesic effect.

Patients with decreased CYP2D6 activity will experience less analgesia.

Reduced doses may be used in renal and hepatic impairment.

A new prescription dispensation of tramadol, compared with codeine, was significantly associated with a higher risk of all-cause mortality, cardiovascular events and fractures, but no significant difference in the risk of constipation, delirium, falls, opioid abuse/dependence, or sleep disorders.

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