Methadone Hydrochloride and Norepinephrine Bitartrate

• Generic Name: methadone
• Dosage Forms: n.a.
• Other Brand Names: Dolophine, Methadose, Methadose Sugar-Free, Diskets

Used parenterally for the relief of moderate to severe pain that has not responded to nonopiate analgesics.

Used orally for the relief of moderate to severe pain when a continuous, around-the-clock analgesic is needed for an extended period of time. Oral preparations are not indicated for relief of acute (e.g., postoperative) pain, for relief of pain that is mild or is not expected to persist for an extended period of time, or for use on an as-needed (“prn”) basis.

For relief of chronic pain in both opiate-naive patients and in individuals being switched to methadone therapy from other opiate agonists because of inadequate pain relief or adverse effects from the previous drug (opiate rotation).

Clinical studies suggest that efficacy may be similar to that of morphine and other opiates in patients with chronic malignant pain. However, experts generally agree that methadone should be prescribed for chronic pain management only by clinicians knowledgeable about its risks (e.g., QT-interval prolongation) and pharmacokinetics, and should not be the first choice for an extended-release or long-acting opiate analgesic.

Benefits associated with use of methadone for management of chronic pain include the commercial availability of multiple dosage forms of the drug, good oral bioavailability, rapid onset of action, reduced dosing frequency (because of the drug’s long half-life), low cost, and lack of active metabolites.

Disadvantages associated with use include increased potential for accumulation with repeated doses (which may result in toxicity), considerable interindividual variability in pharmacokinetic parameters, potential for drug interactions, challenges associated with dosage titration and with the transfer of patients from therapy with other opiate agonists, and commercial availability and relative ease of use of extended-release preparations of other opiate agonists.

Generally use opiates for management of chronic pain (i.e., pain lasting >3 months or past the time of normal tissue healing ) that is not associated with active cancer treatment, palliative care, or end-of-life care only if other appropriate nonpharmacologic and nonopiate pharmacologic strategies have been ineffective and expected benefits for both pain relief and functional improvement are anticipated to outweigh risks.

If used for chronic pain, opiate analgesics should be part of an integrated approach that also includes appropriate nonpharmacologic modalities (e.g., cognitive-behavioral therapy, relaxation techniques, biofeedback, functional restoration, exercise therapy, certain interventional procedures) and other appropriate pharmacologic therapies (e.g., nonopiate analgesics, analgesic adjuncts such as selected anticonvulsants and antidepressants for certain neuropathic pain conditions).

Available evidence insufficient to determine whether long-term opiate therapy for chronic pain results in sustained pain relief or improvements in function and quality of life or is superior to other pharmacologic or nonpharmacologic treatments. Use is associated with serious risks (e.g., opiate use disorder, overdose). (See Managing Opiate Therapy for Chronic Noncancer Pain under Dosage and Administration.)

Used in detoxification treatment and maintenance treatment as an oral substitute for heroin or other morphine-like drugs to suppress the opiate-agonist abstinence syndrome in patients who are dependent on these drugs.

Success of treatment is dependent on the selection of properly motivated patients and on availability of social, psychologic, vocational, and educational as well as medical supportive services.

Has been used to manage manifestations of opiate abstinence syndrome (i.e., postnatal withdrawal) in neonates exposed to opiates in utero.

Opiates recommended as first-line pharmacologic therapy when environmental and supportive measures (e.g., minimization of external stimuli, maximization of mother-infant contact [e.g., parental “rooming in”], breast-feeding when not contraindicated, swaddling and gentle handling) are inadequate. May add other adjunctive therapy (e.g., clonidine, phenobarbital) if response to opiates is inadequate or add phenobarbital if neonate was exposed to additional substances in utero.

While morphine has been used more extensively than other opiates in the management of neonatal opiate abstinence syndrome, some studies suggest methadone or buprenorphine may be associated with shorter treatment durations and hospital stays. Additional study needed to establish optimal dosage schedules and preferred opiate drugs and to evaluate longer-term (e.g., neurodevelopmental) outcomes.

Use of standardized protocols for identification, evaluation, and treatment recommended; use of protocols improves overall response, including shorter hospital stays and durations of pharmacologic treatment. Some evidence suggests that use of a standardized protocol may be more important than use of a specific opiate agonist (e.g., methadone versus morphine) in improving outcomes.

• Generic Name: norepinephrine
• Dosage Forms: n.a.
• Other Brand Names: Levophed, Levophed Bitartrate

Used as adjunctive therapy to produce vasoconstriction and maintain BP in the management of certain acute hypotensive states (e.g., pheochromocytomectomy, sympathectomy, poliomyelitis, spinal anesthesia, MI, septicemia, blood transfusion, drug reactions).

Pressor therapy is not a substitute for replacement of blood, plasma, fluids, and/or electrolytes. Correct blood volume depletion as fully as possible before administration.

The Surviving Sepsis Campaign International Guidelines for Management of Sepsis and Septic Shock recommend norepinephrine as the vasopressor of choice in adults with septic shock; if adequate BP not achieved, vasopressin or epinephrine may be added. Vasopressin also may be given in conjunction with norepinephrine to reduce dosage requirements of norepinephrine.

Also used to provide vasopressor support in other types of shock (e.g., cardiogenic, hemorrhagic), generally as a temporary measure until underlying cause can be treated.

In patients who are hypotensive from blood volume deficits, manufacturer states to use norepinephrine only as an emergency measure to maintain coronary and cerebral artery perfusion until blood volume replacement therapy can be completed.

Early revascularization is standard of care in patients with cardiogenic shock; individualize use of vasopressors in this setting.

Has been used to treat hypotension during spinal anesthesia; however, other vasopressors with a longer duration (e.g., phenylephrine) more commonly used.

Used adjunctively in the management of cardiac arrest to restore and maintain adequate BP after an effective heartbeat and ventilation have been established by other means.

High-quality CPR and defibrillation are the only proven interventions to increase survival to hospital discharge in ACLS. Other resuscitative efforts, including drug therapy, are considered secondary and should be performed without compromising the quality and timely delivery of chest compressions and defibrillation.

Principal goal of pharmacologic therapy during cardiac arrest is to facilitate the return of spontaneous circulation (ROSC), and epinephrine is the drug of choice for this use. Vasoactive drugs such as norepinephrine may be used for hemodynamic support following resuscitation.