**4.9 Tramadol**

*Pain Management - Practices, Novel Therapies and Bioactives*

Elderly Increased sensitivity to opioid

Hepatic failure Increased sensitivity to

only)

opioids (in severe liver failure

*Factors influencing opioid pharmacokinetics and pharmacodynamics.*

Renal failure Morphine toxicity Accumulation of M6G

**Effect Mechanism**

Infant Prolonged effect Decreased conjugation capacity

Obesity Overdosage Central volume of distribution is not reflected by

actual body weight

elimination half-life

Prolonged effect of infusion Decreased lean body mass with increase adipose

distribution

of 75)

tramadol

compound

Immature renal function

Decreased neuronal cell mass

Synergism if encephalopathic Altered integrity of blood-brain barrier Increased elimination half-life for pethidine and

blood-brain barrier permeability

Increased volume of distribution prolongs

Decreased central volume of distribution

tissue is responsible for an increase in total volume of

Decreased hepatic blood flow (by 40–50% by age

Possible hydrolysis of glucuronides back to parent

Uraemia potentiates CNS depression and increases

**Physiological states**

consciousness with a synergic action from the opioids side and also increase the risk of cardiovascular depression. With anaesthetic use, opioids may decrease the concentration of volatile agents by up to 50% while ensuring amnesia and immobility, with the preservation of hemodynamic stability at low inhaled concentrations (≤1 MAC) [6]. The use of opioids (particularly pethidine and tramadol) with monoamine oxidase inhibitors (MAOI) may lead to serious and potentially fatal consequences as excitatory syndrome (type I) [2, 6]. This is complex syndrome characterised by excitatory phenomena including agitation, fever, rigidity, seizures and coma. This is triggered by the excessive CNS serotonin activity, since both MAOI and pethidine block serotonin reuptake. Rarely also can arise an inhibitory syndrome (type II) characterised by respiratory depression, coma and hypotension, which is the result of MAOI inhibition of hepatic microsomal enzymes leading to a pethidine

A similar excitatory syndrome (serotoninergic) is found during the combination

Morphine has been recommended as the opioid of choice for use in these patients.

Naloxone is an N-allyl derivate of oxymorphone. It is pure opioid antagonist, without an intrinsic pharmacological activity. It has a high affinity for miu opioid receptors but also blocks other receptors. Naloxone reverses the respiratory depression and analgesia of opioids but also precipitates the withdrawal syndrome in opioids addicts. Naloxone could also block the action of endogenous opioids. IV administration of 200–400 mcg of naloxone will reverse the respiratory depression,

of tramadol and serotonin-noradrenaline reuptake inhibitors (SNRIs) [6].

The main opioid antagonist currently used in practice is naloxone.

**250**

accumulation.

**Table 8.**

**4.8 Opioid antagonists**

Tramadol is included in the opioids class of drugs, with unique and complex mode of action, only part of which is mediated through opioid receptors. Tramadol is an analogue of codeine and acts as a weak agonist at all types of opioid receptors, with some preference for the miu receptors. It has 10% of the potency of morphine. Tramadol blocks the reuptake of noradrenaline and 5-HT (serotonin) and facilitate the release of the later. By its effects, influences nociceptive transmission activating the descending inhibitory pathways in the CNS. Therefore, Naloxone only partially reverses the analgesic effects of tramadol. Effects on alfa2-adrenergic, NMDA and benzodiazepine receptors may be due to indirect effects secondary noradrenergic system effects [31].

Tramadol is recommended in the treatment of moderate to severe pain. It is well absorbed when given orally, with a bioavailability of 68% and only 20% protein bound. Tramadol is predominantly metabolised in the liver by demethylation and conjugation, with 90% being excreted in the urine. The elimination half-life is 4–6 hours. His metabolites have longer half-life (up to 9 hours) and 2–4 times greater analgesic potency than tramadol and precautions should be taken in hepatic and renal failure.

Tramadol exhibits small risk for respiratory depression when compared with equianalgesic doses of morphine. Also, cardiovascular effects are minimal. There is a low potency for abuse and physical dependence, but still reported. Tramadol's known side effects include: dizziness, nausea, sedation, dry mouth, sweating and skin rashes.

Concomitant use of MAOIs is contraindicated and co-administration with carbamazepine may decrease the concentration and effect of tramadol.
