Methadone
History
Methadone is a synthetic narcotic developed more than 50
years ago. The circumstances surrounding its development have been, and perhaps
still are, associated with an interesting myth. Methadone was said to have been
developed in response to an order by Hitler to develop an alternative to
morphine, which was in short supply at the end of World War II. The trade name Dolophine was said to have been derived from Hitler’s
first name Adolph. The truth is that methadone was discovered at I.G. Farbendustrie at Hoechst-am-Main in
By
1950, oral methadone was established at U.S. Public Health Service hospitals as
a treatment for the opioid abstinence syndrome, though realization of its
distinct pharmacokinetic properties would not occur until the mid-1960s. In
response to a growing epidemic of heroin addiction, the New York City Health
Research Council awarded a grant for methadone research to Vincent Dole, MD. It
was he and his colleagues who determined that patients required only one daily
dose of methadone to prevent opioid craving and symptoms of withdrawal. This
early research, done in just two subjects, not only gave insight into the
pharmacokinetics of methadone, but also demonstrated its value in enabling
heroin abstinence. The enthusiasm for this early success was tempered somewhat
by an inability to withdraw these patients from methadone. The study expanded
to include 22 patients whose similar success was enthusiastically received by
the media, which heralded methadone as a “medical breakthrough.”
Following this, there was tremendous expansion of methadone maintenance
treatment programs, and by 1971 an estimated 25,000 patients were enrolled. In
response to growing criticism that these programs were simply substituting one
narcotic for another, strict regulations were enacted in 1973. As part of these
regulations, a closed system was established that required separate
registrations for each doctor or pharmacy to prescribe or dispense methadone,
regardless of indication. These requirements slowed the growth of methadone
maintenance programs tremendously. In 1976, the American Pharmaceutical
Association successfully sued for the right of pharmacies to dispense methadone
as an analgesic. The closed-system regulatory restrictions continue for
methadone dispensed for narcotic withdrawal.
“John F Kennedy, celebrated
for bringing youthful vigor to the White House, spent his presidency in
constant pain, relying on a daily cocktail of painkillers, anti-anxiety drugs
and other treatments to combat a life-threatening hormonal condition, back
problems and intestinal trouble, newly released medical information
shows… Stimulants, barbiturates, methadone and thyroid hormones
also helped Kennedy to maintain an energetic exterior,
despite being in so much pain that he could not put a sock on to his left foot
by himself.” - Monday November
18, 2002. In “Kennedy
lived on cocktail of drugs”
by Oliver
Burkeman in
“The
president had so much pain from three fractured vertebrae from osteoporosis
that he could not put a sock or shoe on his left foot unaided, the records
reveal. He sometimes reported waking before dawn with severe abdominal cramps.
In August 1961, the records show, Mrs. Kennedy rushed in from another room when
he screamed in pain as the White House physician, Dr. Janet G. Travell, injected procaine deep into his back muscles to
numb them.” - November 17, 2002. In “J.F.K. File, Hidden
Illness, Pain and Pills” by
Why Methadone?
At times, pain relief in palliative care can be quite challenging. Despite
standard treatment with opioids, uncontrolled pain situations occur. These have
been variously termed: ‘opioid-non-responsive pain’, ‘opioid-resistant
pain’ or ‘opioid-poorly responsive pain’. More recently
‘paradoxical or overwhelming pain syndrome’ has been defined as
pain which ceases to be relieved or may actually be worsened by increases in
opioids. The phenomenon of hyperalgesia has been the impetus to a number of
studies and hypotheses trying to explain its etiology and finding better ways
to control the pain. In recent years, animal studies have attributed the
mechanisms of hyperalgesia to a cascade of changes (wind-up phenomenon) at the
synapse of the nociceptive neurons; changes where the excitatory amino acid
N-methyl-D-aspartate (NMDA) seems to play a major
role. Antagonizing this receptor reverses a hyperalgesic
state as well as morphine tolerance. These developments have led pain control
clinicians to consider the use of NMDA antagonist agents. Methadone, apart from
being a strong “?” agonist (opioid), also antagonizes the NMDA
receptor. Unlike morphine, methadone has no known active metabolites to create
toxicity with increasing dosages. It is also a very inexpensive medication. As
interest has rekindled for its use in difficult pain management situations,
protocols and guidelines have been developed for safe administration.
References: Gannon, C. The Use of Methadone in the Care of the Dying. Euro. J. Pal. Care 1997; 4(5):152-8. Ripamonti C., Zecca E., Bruera E. An Update of the Clinical Use of Methadone for Cancer Pain. Pain 1997; 70:109-115.
Methadone and pain control
Methadone is indicated for relief of severe pain. Methadone’s high bioavailability (79 ± 11.7%) and long half-life (30.4 ± 16.3 h) make it an ideal drug for outpatient maintenance. While these characteristics also would seem to make it an ideal analgesic for chronic pain, tremendous interpatient pharmacokinetic variability. The above difficulties, combined with the fact it is not a patent drug and therefore is not marketed to prescribers, have prevented methadone from being widely used as an analgesic.
When employed by experienced practitioners, in appropriate clinical circumstances, methadone does have several distinct advantages compared with other opioids. First, methadone has no active metabolites. Much of the toxicity associated with other opioids (e.g., morphine, hydromorphone, meperidine, and fentanyl) is the result of metabolite accumulation. Methadone would therefore be a logical choice for the patient experiencing, or at risk for, toxicity associated with metabolite accumulation. Second, because of incomplete cross-tolerance, methadone is an appropriate alternative when intolerable side effects to another opioid have limited further dose escalation. Third, methadone is very inexpensive. Fourth, methadone’s long duration of analgesia with chronic use allows less frequent dosing than with other opioids. Extended-release opioid products are available, but they are costly. Finally, methadone is highly lipophilic, making it amenable to many routes of administration. While the oral and intramuscular routes are approved by the Food and Drug Administration, the epidural, intrathecal, intravenous, rectal, subcutaneous, and sublingual routes have all been studied (Fainsinger, Schoeller,
Consideration of methadone’s unique characteristics makes it a logical choice for controlling malignant and nonmalignant chronic pain. The lack of understanding regarding methadone’s pharmacokinetics and relative potency confers second-line status to this agent. However, for the experienced clinician, methadone is an extremely valuable tool for patients who have responded adversely or inadequately to other treatments.
Chronic analgesic dosing schedule
It is well established that methadone given every 24 hours is sufficient to suppress opioid withdrawal. There is, however, no clear consensus on the appropriate interval for analgesic dosing. The recommended dosing intervals range from 3 to 24 hours. The duration of analgesia following a single dose of methadone has been shown to be 4 to 6 hours. The brevity of analgesic effect relative to the long half-life of methadone is a result of the drug’s rapid absorption-distribution phase. With repeated dosing, methadone accumulates in the tissues, and the plasma concentration is sustained by this peripheral reservoir. It would seem reasonable to start with an 8-hour interval and adjust according to patient response and signs of toxicity.
The appropriate analgesic dose of methadone
Many factors must be considered when dosing methadone, including severity of pain, route of administration, and history of previous opioid use. Regardless of whether methadone is being initiated in an opioid-naïve patient or in a patient with a significant history of opioid use, the key to establishing an effective regimen that minimizes adverse effects is careful individualization. For methadone, one size definitely does not fit all. Methadone shares all of the common toxicities associated with other opioid agonists. Patients over 65 years of age have reduced methadone clearance and need cautious dosing and supervision. Methadone, when dosed properly, is a valuable addition for clinicians treating severe cancer pain, cancer pain with a neuropathic component, pain that is poorly responsive to other opioids, or when finances dictate a change based on other high-dose therapies.
Methadone Rediscovered
Methadone is a potent synthetic opioid agonist that has been available for over 50 years. Methadone has been somewhat stigmatized by the medical and lay public as the “heroin addict’s drug”, but it is a very useful, cost-effective agent for treating chronic pain and cancer pain that is non-responsive or refractory to high doses of other opioid agonists (morphine, hydromorphone, oxycodone, fentanyl) due to tolerance or disease progression. Methadone is also useful for the treatment of severe neuropathic pain requiring high-dose opioid therapy where the addition of tricyclic antidepressants and anticonvulsants has been ineffective. It also has a role when high doses of other opioids produce significant financial impact to the patient or the patient experiences intolerable adverse effects from other opioids.
Methadone is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and mu-receptor agonist. NMDA – receptor activation results in central sensitization, which is implicated in hyperalgesia, allodynia, and opioid tolerance. Blocking the NMDA receptors may reduce tolerance to opioids and improve neuropathic pain control, thus the current interest in methadone therapy for chronic pain syndromes.
Recent clinical data suggest that chronic pain due to nerve or soft tissue injury may result in the sensitization of the central nervous system, mediated in part by the excitatory amino acids, glutamate and aspartate. Only a handful of N-methyl-D-aspartate antagonists are clinically available. These include ketamine, dextromethorphan, memantine, and amantadine, as well as three clinically used opioids (methadone, dextropropoxyphene, and ketobemidone). NMDA-receptor antagonists may be effective in the treatment of some types of chronic pain.
Research over the past decade demonstrating that NMDA receptor antagonists have the ability to inhibit opiate tolerance, sensitization and physical dependence has led to the suggestion that NMDA receptors may have a critical role in opiate-induced neural and behavioral plasticity
Pharmacology
Interaction with Other Central-Nervous-System Depressants
Methadone should be used with caution and in reduced dosage in patients who are concurrently receiving other narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics, tricyclic antidepressants, and other CNS depressants (including alcohol). Respiratory depression, hypotension, and profound sedation or coma may result.
Anxiety
Since methadone, as used by tolerant subjects at a constant maintenance dosage, is not a tranquilizer, patients who are maintained on this drug will react to life problems and stresses with the same symptoms of anxiety as do other individuals. The physician should not confuse such symptoms with those of narcotic abstinence and should not attempt to treat anxiety by increasing the dosage of methadone. The action of methadone in maintenance treatment is limited to the control of narcotic symptoms and is ineffective for relief of general anxiety.
Asthma and Other Respiratory Conditions
Methadone should be used with caution in patients having an acute asthmatic attack, in those with chronic obstructive pulmonary disease or cor pulmonale, and in individuals with a substantially decreased respiratory reserve, preexisting respiratory depression, hypoxia, or hypercapnia. In such patients, even usual therapeutic doses of narcotics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.
Hypotensive Effect
The administration of methadone may result in severe hypotension in an individual whose ability to maintain his blood pressure has already been compromised by a depleted blood volume or concurrent administration of such drugs as the phenothiazines or certain anesthetics.
Use in Ambulatory Patients
Methadone may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly.
Methadone, like other narcotics, may produce orthostatic hypotension in ambulatory patients.
Use in Pregnancy
Safe use in pregnancy has not been established in relation to possible adverse effects on fetal development. Therefore, methadone should not be used in pregnant women unless, in the judgment of the physician, the potential benefits outweigh the possible hazards.
Methadone is not recommended for obstetric analgesia because its long duration of action increases the probability of respiratory depression in the newborn.
PRECAUTIONS
Acute Abdominal Conditions
The administration of methadone or other narcotics may obscure the diagnosis or clinical course in patients with acute abdominal conditions.
Special-Risk Patients
Methadone should be given with caution and the initial dose should be reduced in certain patients, such as the elderly or debilitated and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, prostatic hypertrophy, or urethral stricture.
Methadone and
Sudden Death
Methadone prolongs the QT-interval
and is mainly metabolized by the isoenzyme CYP3A4 of
the hepatic cytochrome-P450-system, which is used by numerous other
QT-prolonging agents. Its most severe side effect is the development of
life-threatening “Torsades de pointes”
ventricular arrhythmia (Ventricular Tachycardia) in the setting of a prolonged
QT-interval. The ventricular rate can
range from 150 beats per minute (bpm)
to 250 bpm. In the United States, 300,000
sudden cardiac deaths occur per year. The highest frequency is in patients aged
35-50 years. No physical findings are typical of torsade de pointes (TDP). The electrolyte
disturbances that have been reported to precipitate torsade
include hypokalemia and hypomagnesemia.
Predisposed patients include those with cirrhosis or hypothyroidism. Concomitant abuse of cocaine increases the risk for
developing this major complication of methadone therapy. Before subjecting
patients on methadone to other drugs, the QT-interval should be determined and
it should be ascertained whether the new agent has the property to prolong the
QT-interval.
ADVERSE REACTIONS
THE MAJOR HAZARDS OF METHADONE AS OF OTHER NARCOTIC ANALGESICS, ARE RESPIRATORY DEPRESSION AND TO A LESSER DEGREE, CIRCULATORY DEPRESSION. RESPIRATORY ARREST SHOCK, AND CARDIAC ARREST HAVE OCCURRED.
The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not suffering severe chronic pain. In such individuals, lower doses are advisable. Some adverse reactions may be alleviated in the ambulatory patient if he lies down.
Other adverse reactions include the following:
Central Nervous System- Euphoria, dysphoria, weakness, headache, restlessness, sedation, seizures, SIADH, tinnitus, tremor, vertigo, withdrawal, asthenia, CNS depression, depression, paresthesias, diaphoresis, dizziness, miosis, physiological dependence, drowsiness, dysgeusia insomnia, agitation, anxiety, disorientation, confusion, coma, xerostomia, blurred vision, and visual disturbances.
Respiratory System- dyspnea, nasal congestion, nasal irritation, pharyngitis, respiratory depression, and rhinitis.
Gastrointestinal- Dry mouth, anorexia, epistaxis, nausea/vomiting , constipation and biliary tract spasm and/or obstruction.
Cardiovascular- Flushing of the face, bradycardia, palpitations, flushing, hypertension, hypotension, sinus tachycardia, sinus bradycardia, orthostatic hypotension , faintness, and syncope.
Genitourinary- Urinary retention or hesitancy, antidiuretic effect, and reduced libido and/or potency.
Allergic- Pruritus, urticaria, other skin rashes, edema, and, rarely, hemorrhagic urticaria.
Hematologic- Reversible thrombocytopenia has been described in a narcotics addict with chronic hepatitis. erythema,
DRUG INTERACTIONS
Interaction with Pentazocine
Patients who are addicted to heroin or who are on the methadone maintenance program may experience withdrawal symptoms when given pentazocine.
Interaction with Rifampin
The concurrent administration of rifampin may possibly reduce the blood concentration of methadone. The mechanism by which rifampin may decrease blood concentrations of methadone is not fully understood although enhanced microsomal drug-metabolized enzymes may influence drug disposition.
Interaction with Monoamine Oxidase (MAO) Inhibitors
Therapeutic doses of meperidine have precipitated severe reactions in patients concurrently receiving monoamine oxidase inhibitors or those who have received such agents within 14 days. Similar reactions thus far have not been reported with methadone; but if the use of methadone is necessary in such patients, a sensitivity test should be performed in which repeated small incremental doses are administered over the course of several hours while the patient's condition and vital signs are under careful observation.
Interaction with Other Central-Nervous-System Depressants
Methadone should be used with caution and in reduced dosage in patients who are concurrently receiving other narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics, tricyclic antidepressants, and other CNS depressants (including alcohol). Respiratory depression, hypotension, and profound sedation or coma may result.
Drugs Which
May Lower Plasma Levels of Methadone or Decrease Methadone Effects
|
Generic Name |
Action/Use |
Brands/Examples |
|
Butabarbital sodium,
|
barbiturate sedatives and/or |
Bitosol Sodium, Mebaral, |
|
carbamazepine |
anticonvulsant for epilepsy and |
Atretol, Tegretol |
|
ethanol |
chronic use |
wine, beer, whiskey, etc. |
|
phenytoin |
control of seizures |
Dilantin |
|
rifampin |
Treatment of pulmonary |
Rifadin, Rifamate, Rifater,
|
|
urinary acidifiers, ascorbic
acid |
keeps calcium soluble, controls |
K-Phos,
Vitamin C (large doses) |
Drugs Which
May Increase Plasma Levels of Methadone or Increase Methadone Effects
|
Generic Name |
Action/Use |
Brands/Examples |
|
amitriptyline |
treatment of depression and
anxiety |
Elavil, Endep,
Entrafon |
|
cimetidine |
H2 receptor antagonist for the
treatment of |
Tagamet |
|
diazepam |
control of anxiety and stress |
Dizac, Vairelease, Valium |
|
ethanol |
acute use |
wine, beer, whiskey, etc. |
|
fluvoxamine |
serotonin reuptake inhibitor for
treatment of |
Luvox |
|
ketoconazole |
anti-fungal agent |
Nizoral Tablets |
|
urinary alkalinizers |
treatment of kidney stones, gout
therapy |
Bicitra, Polycitra |
Charts from A. T. Forum, (1997, Spring), Vol. VI,
#2, p.3.