**3.2. Dual or multimechanism opioids**

Methadone is a synthetic opioid with potent analgesic effects. Although it is commonly asso‐ ciated with treatment of opioid addiction, its unique pharmacokinetics and pharmacodynam‐ ics make it a valuable option in the management of chronic pain.

Methadone has various mechanisms of action. As well as acting through binding to μ and δ opioid receptors centrally and in the periphery, it also acts inhibiting serotonin and noradren‐ alin reuptake and as a noncompetitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist. These multiple action mechanisms give it advantages over other opioids. NMDA antagonism is also believed to attenuate tolerance [12–16]. These combined mechanisms are the cause of its efficacy in chronic and neuropathic pain [17].

The available methadone hydrochloride on the market is a racemic mixture of two stereoisomers: (R)‐ and (S)‐methadone. Both enantiomers are responsible for its analgesic effect: the (R)‐enantio‐ mer exerting most of its opioid effect and acting as a NMDA antagonist and the (S)‐methadone having NMDA receptor antagonism and inhibiting serotonin and noradrenalin reuptake [18–20].

Taken orally and at steady state methadone is subjected to first‐pass effect. It has a variable bioavailability (41–95%) and 60–90% is bound to plasma proteins, mainly to alpha‐1acid gly‐ coprotein (AGP) due to its basic properties. AGP is one of the major acute phase proteins in humans, rats, mice and other species so its serum concentration increases in response to systemic tissue injury, inflammation or infection [21]. As pain and inflammation are nearly always associated with each other, a higher protein binding could be found in patients with chronic pain in comparison with healthy volunteers [22].

Methadone is extensively metabolized in the liver by the enzymes of the P450 cytochrome system (CYP3A4, CYP2B6, CYP2D6, CYP2C19 and other enzymes to a lesser extent) and in the gastrointestinal tract by CYP3A4. CYP3A4 content is much higher in the intestine than in the liver [23]. Methadone is also a substrate of P‐glycoprotein (P‐gp) [24], efflux transporter, which is expressed in several eliminating tissues (intestine, liver and kidneys) [25]. Due to the induction of its own metabolism (CYP3A4 and/or P‐glycoprotein induction), reported by some authors, elimination half‐life is longer after the first dose (36.7 h) [26] than during maintenance treatment [27, 28].

According to previous studies carried out by our group in other drugs [29], methadone must induce both CYP3A4 and P‐glycoprotein for explaining the nonlinearity in drug response when daily dose is changed as it is shown in **Figure 1** with patients whose blood concentra‐ tions were analyzed in our therapeutic drug service.

Hence, a nonlinear relationship between steady state methadone plasma concentrations and methadone daily dose could be explained by induction of both the enzyme and the transporter, reducing its bioavailability and increasing its clearance. The hypothesis of efflux transporter induction is reinforced by the fact that patients treated chronically with metha‐ done, developed higher saliva/plasma drug concentration ratio [30], probably due to the transporter overexpression at the luminal membrane of the acini cells and those surrounding the salivary ducts [31].

**Figure 1.** Predose plasma concentration of methadone (ng/mL) versus methadone daily dose (mg/kg).

**3.2. Dual or multimechanism opioids**

36 Pain Relief - From Analgesics to Alternative Therapies

its efficacy in chronic and neuropathic pain [17].

chronic pain in comparison with healthy volunteers [22].

tions were analyzed in our therapeutic drug service.

maintenance treatment [27, 28].

the salivary ducts [31].

Methadone is a synthetic opioid with potent analgesic effects. Although it is commonly asso‐ ciated with treatment of opioid addiction, its unique pharmacokinetics and pharmacodynam‐

Methadone has various mechanisms of action. As well as acting through binding to μ and δ opioid receptors centrally and in the periphery, it also acts inhibiting serotonin and noradren‐ alin reuptake and as a noncompetitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist. These multiple action mechanisms give it advantages over other opioids. NMDA antagonism is also believed to attenuate tolerance [12–16]. These combined mechanisms are the cause of

The available methadone hydrochloride on the market is a racemic mixture of two stereoisomers: (R)‐ and (S)‐methadone. Both enantiomers are responsible for its analgesic effect: the (R)‐enantio‐ mer exerting most of its opioid effect and acting as a NMDA antagonist and the (S)‐methadone having NMDA receptor antagonism and inhibiting serotonin and noradrenalin reuptake [18–20].

Taken orally and at steady state methadone is subjected to first‐pass effect. It has a variable bioavailability (41–95%) and 60–90% is bound to plasma proteins, mainly to alpha‐1acid gly‐ coprotein (AGP) due to its basic properties. AGP is one of the major acute phase proteins in humans, rats, mice and other species so its serum concentration increases in response to systemic tissue injury, inflammation or infection [21]. As pain and inflammation are nearly always associated with each other, a higher protein binding could be found in patients with

Methadone is extensively metabolized in the liver by the enzymes of the P450 cytochrome system (CYP3A4, CYP2B6, CYP2D6, CYP2C19 and other enzymes to a lesser extent) and in the gastrointestinal tract by CYP3A4. CYP3A4 content is much higher in the intestine than in the liver [23]. Methadone is also a substrate of P‐glycoprotein (P‐gp) [24], efflux transporter, which is expressed in several eliminating tissues (intestine, liver and kidneys) [25]. Due to the induction of its own metabolism (CYP3A4 and/or P‐glycoprotein induction), reported by some authors, elimination half‐life is longer after the first dose (36.7 h) [26] than during

According to previous studies carried out by our group in other drugs [29], methadone must induce both CYP3A4 and P‐glycoprotein for explaining the nonlinearity in drug response when daily dose is changed as it is shown in **Figure 1** with patients whose blood concentra‐

Hence, a nonlinear relationship between steady state methadone plasma concentrations and methadone daily dose could be explained by induction of both the enzyme and the transporter, reducing its bioavailability and increasing its clearance. The hypothesis of efflux transporter induction is reinforced by the fact that patients treated chronically with metha‐ done, developed higher saliva/plasma drug concentration ratio [30], probably due to the transporter overexpression at the luminal membrane of the acini cells and those surrounding

ics make it a valuable option in the management of chronic pain.

Our research group has also identified methadone recirculation process via gastric secre‐ tion and intestinal reabsorption using saliva as biological fluid [32] as it can be observed in **Figure 2**.

A possible explanation for the appearance of these peaks is that, unlike NSAIDs, methadone is a basic drug and may be secreted into the stomach, to a greater extent once a meal was taken, and then reabsorbed from the intestine. Such secretions could be due to both the pH gradient between plasma (pH 7.4) and the gastric juice (pH 1.2), and the increased blood flow rate and gastric fraction of the cardiac output that takes place after food intake. The knowl‐ edge on methadone gastric secretion could have impact in the clinical setting in case of metha‐ done intoxication. The administration of activated charcoal could be a solution as methadone reentries could be interrupted resulting in a more rapid drug elimination rate.

Tramadol has shown another mechanism of action other than acting as an agonist of μ recep‐ tors. Inhibition of noradrenalin (NA) and serotonin (5‐HT) reuptake makes a significant con‐ tribution to the analgesic action of this drug by blocking nociceptive impulses at the spinal level. Tramadol is extensively metabolized in the liver and has one main major metabolite, O‐ desmethyltramadol. Both the parent drug and the metabolite drug contribute to the analgesic effect, but the metabolite has a significantly higher affinity for opioid receptors than tramadol [33]. CYP2D6 is responsible for the metabolite formation, and CYP2D6 gene is highly poly‐ morphic so for poor metabolizers pain relief could be insufficient.

Serotonin syndrome is a potentially life‐threatening syndrome that may occur with the use of tramadol or methadone, especially if other medications such as antidepressants or other

**Figure 2.** Mean saliva methadone concentration‐time curve after administration of methadone dose with standard error in eight patients. The arrows represent meals intake.

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

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

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].
