outside of the narcotic treatment arena. Coupled with the increase in the use of methadone for pain, questions of its safety have also been on the rise. Although methadone accounts for fewer than 5% of opioid prescriptions, it has been linked to one-third of opioid-related deaths. 147,148 There is a disconnect between the half-life of methadone in the blood and the duration of analgesia that it provides. The plasma half-life ranges from 8 to 60 hours; the duration of methadone analgesia is 6 to 12 hours. In practice, pain relief may end long before the drug is eliminated from the body, leading to redosing and potentially dangerous systemic accumulations. Furthermore, methadone is metabolized by several different enzyme systems, subjecting it to multiple potential drug-drug interactions. The use of methadone is also complicated by its interaction with cigarette smoking, which increases the rate of its metabolism, and alcohol, which can augment its toxicity in addition to increasing the rate of its metabolism. Because of these liabilities, prescribers must exercise great caution when prescribing methadone. 111,148 Although methadone is not commonly employed as a first-line opioid, it could be beneficial in opioid- naïve patients. Because of its slow onset and long duration of effect, it may help avoid some of the reward behaviors common to fast-acting opioids. The American Pain Society and American Academy of Pain Medicine (APS/AAPM) guidelines recommend a starting dose in most opioid-naïve patients of 2.5 mg every 8 hours, with dose increases occurring no more frequently than weekly. 111,148 It is nearly impossible to determine an equivalent dose of methadone based on morphine dosing because the required methadone dose will decrease over time. Therefore, the lowest possible dose titration should be followed in opioid-tolerant patients. Most available narcotic equivalence tables are based on single doses. Because of its potential accumulation, relying on these charts for chronic methadone dosing can result in a substantial overdose that may not become apparent for several days. 111,148 In 2006, the FDA issued an alert warning that methadone can cause serious cardiac conduction disturbances, including QT-interval prolongation and torsades de pointes, a potentially fatal ventricular arrhythmia. It appears that methadone-related corrected QT (QTc) interval prolongation and cardiac arrhythmias can occur at any dose, but are more likely at higher doses, or with concomitant use of drugs that interact with methadone or that themselves prolong QTc. Although uncommon, cardiac arrhythmias that can be induced by methadone are potentially lethal if not detected. Clinicians should assess the cardiac health of patients who are candidates for methadone, paying particular attention to any history of heart disease or arrhythmias. An initial ECG may be advisable prior to starting methadone, particularly if a patient has a specific cardiac disease, or cardiac risk factors, or is taking agents that may interact with methadone. 149
Partial Agonists Partial opioid agonists elicit a partial response at the opioid receptors, resulting in a ceiling effect of analgesia. As a result, partial agonists are considered to have less abuse potential and are less likely to cause overdose because of a reduced ability to cause respiratory depression. Examples of partial agonists include buprenorphine and tramadol. 111,143 Buprenorphine works as a partial agonist at the mu-opioid receptor. Because of this activity, it can be difficult to overdose on buprenorphine alone. Additionally, it can be difficult to overdose and also achieve analgesia when someone taking buprenorphine also takes an opioid agonist. This is seen as a benefit when treating addiction but can pose a challenge when treating acute pain. Since buprenorphine does have agonistic properties, albeit limited, it has some use in the treatment of chronic pain. One formulation, branded as Butrans, is a transdermal patch approved for the use of chronic pain syndromes. 111,143 Buprenorphine is also commonly used as a treatment modality for opioid addiction. Its formulations include Subutex (sublingual) and Suboxone (a sublingual product also containing naloxone). The activity of buprenorphine at the opioid receptors is thought to decrease withdrawal symptoms, decrease drug cravings, as well as have stress-relieving and anxiolytic properties. 111,143 Tramadol is a partial opioid agonist at the mu- opioid receptor and also prevents the reuptake of neurotransmitters serotonin and norepinephrine. Because of the additional neurotransmitter action, tramadol has numerous drug interactions with other medications that affect serotonin, such as selective serotonin reuptake inhibitors (SSRIs). This mechanism is also associated with seizures in overdose situations. 111,143 Opioid Antagonists Opioid antagonists block the opioid receptors and prevent any opioids with agonistic effects from exhibiting their action. They can also displace opioid agonists from their bind with opioid receptors, stopping them from exerting their action. Naloxone and naltrexone are opioid antagonists, commonly used to treat opioid overdose and in the treatment of substance use disorders. 143,150 Choosing an Opioid Prescribers should consider opioid therapy only if the benefits for function and pain are expected to outweigh the potential risks to the patient. If opioids are used, their use should be combined with nonpharmacologic and nonopioid therapy as appropriate to maximize the available treatment options. 118 When starting opioid therapy in an opioid-naïve patient, immediate-release opioids should be used first at the lowest effective dosage before considering long-acting opioids. 118 Short-acting oral opioid agonists typically have a rapid effect (15 to 30 minutes) but may take longer to achieve peak efficacy because of the time required to pass the blood-brain barrier.
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Book Code: CA23CME
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