**5. Anticonvulsants**

drugs that impair the metabolism of these drugs (CYP2D6 and CYP3A4 inhibitors) are used concurrently. Symptoms include changes in mental status (e.g., agitation, hallucinations and coma), autonomic instability (e.g., tachycardia, labile blood pressure and hyperthermia), neu‐ romuscular aberrations (e.g., hyperreflexia and incoordination) and/or gastrointestinal symp‐

**Figure 2.** Mean saliva methadone concentration‐time curve after administration of methadone dose with standard error

During platelet activation, serotonin, along with other aggregating factors, becomes a stimu‐ lus for platelet aggregation. A transporter protein is necessary to transport serotonin into the platelet. Methadone, tramadol and SSRIs are antagonists of this transporter, and because platelets do not produce serotonin, they are dependent on plasma uptake of serotonin [34]. It is plausible that these drugs could increase bleeding risks as the blockade of the serotonin transporter could lead to a decreased concentration of serotonin within the platelet [35].

Inhibition of serotonin reuptake has been associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and hyponatremia [36]. SIADH is more likely in

Lastly, both S‐ and R‐form of methadone inhibit the cardiac potassium channel leading to pro‐ longed action potentials that are expressed as long QT intervals resulting in potentially fatal polymorphic ventricular tachycardia: torsades de pointes (TdP). The risk of acquired QT pro‐ longation and TdP is more pronounced in patients receiving more than one QT‐prolonging drug simultaneously (e.g., escitalopram, citalopram, paroxetine, sertraline and venlafaxine) [38].

some populations, including people who are elderly or who take diuretics [37].

toms (e.g., nausea, vomiting and diarrhea).

in eight patients. The arrows represent meals intake.

38 Pain Relief - From Analgesics to Alternative Therapies

Certain anticonvulsants exhibit analgesic action in neuropathic pain. This is on the basis of their ability to reduce neuronal excitability [40]. The most well‐studied agents are gabapentin, pregabalin and carbamazepine; however, there is growing evidence that lamotrigine, topira‐ mate and oxcarbazepine can act as analgesic too [40–42].

Gabapentin and pregabalin were originally developed as a structural analogue of gamma‐ aminobutyric acid (GABA), but do not actually bind to GABA or affect GABA reuptake or metabolism. They bind to the α2‐δ subunit of voltage‐dependent calcium channels and thus may modulate presynaptic release of excitatory neurotransmitters.

Carbamazepine remains the most successful first‐line approach in treatment of trigeminal neuralgia [43, 44]. Its mechanism in stabilizing neuronal excitability is through sodium chan‐ nel blockade.

Carbamazepine is extensively metabolized in the liver and the intestine by the isoenzyme CYP3A4 and is a substrate of multidrug resistance protein (MRP2) [45].

Like methadone, carbamazepine induces both CYP3A4 and P‐glycoprotein explaining, in this way, the nonlinearity in drug response when daily dose is changed. This fact was confirmed by our studies [46].
