Fig. 14.1
Molecular structure of methadone
Methadone’s activity at opioid sub-receptors is unique. Like morphine, methadone has agonist affinity for both the mu and delta opioid receptors. However, in animal studies, methadone has proportionately less mu receptor binding than morphine which may explain its more tolerable side effect profile. It is theorized that when compared to morphine which sensitizes the mu receptor, methadone’s pharmacology may desensitize the mu receptor. This, coupled with affinity for the delta mu receptor, may lead some to use methadone to prevent dependence and tolerance. In comparison to other opioids, methadone has action on the serotoninergic and NMDA receptors. Animal and in vitro studies of the NMDA receptor suggest its possible role in neuropathic pain, as well as in tolerance and dependence of opioids. Theoretically, methadone’s NMDA antagonist properties may make it better suited than other opioids for neuropathic pain syndromes. How the reuptake inhibition of serotonin and norepinephrine impacts its analgesic effects is currently unclear. Norepinephrine reuptake inhibition has specifically been a target for analgesic drug design in recent years. A medication with a broad ensemble of receptor affinities may have many medical uses. However, rising concerns about potential adverse effects may substantially temper such views.
Methadone has a basic pH and is available as a racemic mixture of enantiomers with different pharmacokinetic properties. The enantiomers, S-methadone (d-isomer) and R-methadone (l-isomer), can be reconstituted from a powder form into oral, rectal, intramuscular, and parenteral formulations. R-methadone acts largely at the mu opioid receptor site, while S-methadone antagonizes the NMDA receptor and inhibits the reuptake of 5-hydroxytryptamine (serotonin) and norepinephrine. The R isomer is thought to be less cardiotoxic compared to the racemic mixture. The potency of the R enantiomer at the mu opioid receptor is also greater than the S enantiomer.
Methadone has unique pharmacokinetic properties within the opioid class. The drug’s high lipophilicity causes it to be stored in fat and released slowly into the plasma to reach a steady state. Elderly people who have higher body fat content may accumulate higher methadone doses and need less frequent dosing. In addition, methadone has a large volume of distribution, ranging from 1.71 to 5.34 l/kg in chronic pain patients and even higher in those with opioid addiction. Methadone is 80 to 90 % protein bound which has repercussions for its duration of action and circulating blood levels. The main binding protein is alpha-1-acid glycoprotein (AAG), an acute phase reactant whose levels can differ in disease states [1]. This fluctuation can predispose to serious variability of circulating methadone levels.
The oral bioavailability of methadone is high, ranging from 40 to 99 %, but is dependent on intestinal transporters. For the oral formulation, time to peak concentration is 2.5 to 4 hours, with a terminal half-life between 24 to 60 hours. The half-life is related to the chronicity of administration with the lower range in chronic methadone therapy versus the upper range in acute dosing. Oral absorption further depends on gastric pH and motility. Rectal bioavailability is similar to parenteral bioavailability with a quick onset of action within 15 to 45 minutes. Methadone, given rectally, is rapidly absorbed through mucosa and has duration of action of up to 10 h. Methadone’s plasma concentrations by the intramuscular route will depend on the site of the injection. For example, when compared to administration in the gluteal region, the deltoid muscle offers an increase in peak plasma concentration and improved pain control. Methadone may be used subcutaneously or absorbed through the buccal mucosa due to high lipid solubility.
Methadone’s metabolism is largely dependent on the hepatic metabolism. It undergoes N-demethylation in the liver by the P450 CYP enzymes to 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium (EDDP). The main metabolizers are thought to be CYP3A4, CYP2B6, and CYP2C19, while the CYP2B6 enzyme primarily generates EDDP. Other lesser CYP enzymes have varying roles in methadone’s metabolism, but of note, certain enzymes may preferentially metabolize the S versus the R enantiomer. Further complicating metabolism is the fact that the type I CYP enzyme system exhibits genetic and ethnic variability in expression, which affects methadone’s duration of action between individuals and groups. CYP3A4 is itself unique in being an autoinducible enzyme which brings about methadone’s own metabolism over time.
The P450 system can be affected by induction or inhibition by a variety of substrates that are common and medically important. For example, various medications in the treatment of HIV such as ritonavir may prolong methadone action by inhibition of the CYP3A4 and CYP2B6 systems. Many antiepileptic, antibiotic, and antidepressant medications taken concomitantly can influence methadone levels by either inhibition or induction of enzymes. Drug-drug interactions with methadone may make management of complex patients on polypharmacy regimens challenging. In addition, pregnancy does not relate to a state of high gastric pH, elevated AAG; and urine pH < 6.0 can cause methadone to be metabolized faster or decrease its levels. Opioid transporters in the blood-brain barrier also regulate the access of methadone to sites of action. These variables make predicting methadone metabolism and subsequent blood plasma levels difficult.
Methadone use in pregnancy is not uncommon as it has long been recommended for substance abuse treatment and withdrawal prevention. Parturients have a decrease in half-life and an increase in clearance of methadone. Fetuses born to mothers on chronic methadone therapy should be assessed for respiratory depression even though placental transfer and breast milk exposure are thought to be low. Fetal abstinence syndrome has been described in newborns of mothers who were on methadone maintenance therapy. Infant mortality is higher in babies exposed to methadone in utero than for the general parturient population [2]. Methadone has been shown to prolong the QTc interval in human newborns. In addition, the use of opioids in early stages of pregnancy has been linked to birth defects of the cardiovascular system [3].
Methadone is often used in patients with complex medical problems for whom it seems to have certain advantages. The lack of active metabolites is one aspect of methadone’s pharmacology that may make it beneficial in some frail patients. Use of methadone in liver disease has been described sparingly. Theoretically, methadone can accumulate in disease states that alter metabolism by the hepatic cytochrome P450 system. Patients in methadone maintenance treatment programs often have a history of intravenous drug use and subsequent chronic hepatitis. Regardless, methadone has been successfully used in patients with chronic hepatitis and cirrhosis.
Elimination of methadone is biphasic, following both an alpha (8 to 12 h) and beta (30 to 60 h) phase (Fig. 14.2). The alpha phase typically corresponds to the analgesic period that is far shorter than the terminal half-life. This alpha phase correlates with the analgesic phase and serves as the rational for 3–4 times a day dosing in chronic pain. The long beta phase prevents withdrawal symptoms but provides for little analgesia. This slow clearance allows for once a day dosing in maintenance therapy programs but dictates careful upward titration [4]. The use of methadone as a breakthrough medication is limited due to the long elimination phase and terminal half-life. Methadone taken in repetitive doses to achieve euphoric effects will often cause accumulation of the drug resulting in subsequent adverse events due to long-lasting pharmacokinetics.
Fig. 14.2
Elimination curve for methadone depicting alpha (8 to 12 h) and beta phase (30 to 60 h)
Methadone elimination is largely fecal with some contribution from the renal system. For this reason, it is largely safe for use in renal failure and is insignificantly dialyzed due to high lipid solubility. Patients with renal failure will excrete a vast majority of methadone in the feces. Acidic urine, with a pH < 6, causes more excretion of the unionized total methadone dose. While medications that may alkanize the urine allow methadone to accumulate. Methadone, however, has no neurotoxic metabolites that may accumulate in kidney disease as compared to morphine. This theoretically makes methadone a more tolerable medication in patients with a low glomerular filtration rate.
Clinical Issues
Side effects of methadone are not unlike those of shorter-acting opioids. There is still a serious risk of respiratory depression, sedation, constipation, and pruritis. Many studies attest to methadone having a comparable rate of side effects when compared to morphine. But unique to methadone is the tendency to prolong the QT interval corrected (QTc) for heart rate and predisposition to tachyarrhythmias such as ventricular fibrillation and torsades de pointes. Arrhythmias were originally described in the methadone maintenance population who were presenting with sudden death within weeks of starting the program or after dose escalation. Structural heart disease is often not found among these decedents. The mechanism is thought to be blockade of the cardiac ether-a-go-go-related gene (hERG) coding potassium channel that prevents repolarization during phase III of the cardiac action potential. This channel is the delayed rectifier potassium ion (Ikr) whose blockade causes bradycardia and predisposes to torsades [5]. Methadone, like other opioids, is a negative chronotrope which further slows the heart rate. Several risk factors have been identified for prolongation of the QTc in methadone patients including high dose, concomitant use of other QTc prolonging medications, antidepressants, antibiotics, electrolyte disturbances, congenital long QTc syndrome, structural heart disease, liver or renal disease, and alcohol and benzodiazepine use. Chronic pain patients may be on a variety of medicines that are otherwise potentially cardiotoxic such as tricyclic antidepressants, which theoretically may offer additive toxicity.
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