Side Effects of Dolophine (methadone)

Dolophine (methadone) is a strong, synthetic (man-made) narcotic that acts on the central nervous system (brain) in a manner similar to other narcotics used to manage narcotic addiction and for moderate to severe pain when non-narcotic pain medications have failed. 

Dolophine is very addicting and causes significant sedation and respiratory depression.

Drug interactions of Dolophine include drugs that slow brain function, such as alcohol and barbiturates, because the combination can increase the effects of these drugs.

Because Dolophine causes constipation, taking antidiarrheal medications along with Dolophine can result in severe constipation. Drugs that block narcotic (opioid) receptors including pentazocine, nalbuphine, naloxone, butorphanol, and buprenorphine can lead to withdrawal symptoms.

Rifampin, barbiturates, carbamazepine, phenytoin, primidone, and St. John's wort preparations can increase the liver's ability to metabolize (eliminate) Dolophine and reduce its blood concentration which could result in withdrawal side effects, while drugs such as erythromycin, clarithromycin, ketoconazole, and itraconazole can decrease the liver's ability to metabolize Dolophine thereby increase the side effects of this drug. 

Anti-retroviral agents including abacavir, amprenavir, efavirenz, nelfinavir, nevirapine, ritonavir, and lopinavir/ritonavir have been shown to decreased the blood levels of Dolophine making it necessary to adjust the dose of methadone to prevent narcotic withdrawal effects.

Some drugs that slow the heart rate for example, dofetilide, procainamide, quinidine, and sotalol, as well as laxatives and diuretics that cause low magnesium or low potassium in the body, for example, furosemide, can cause rare serious and fatal irregular heartbeats.

Safe use of Dolophine during pregnancy has not been established. Dolophine has been shown to cross the placenta, and it is found in cord blood, amniotic fluid and in newborn urine. Children born to mothers who were taking Dolophine for a prolonged period may exhibit respiratory depression or withdrawal symptoms.

Dolophine enters breast milk, and this can cause sedation and respiratory depression in a breastfeeding infant. The benefit to the mother of taking Dolophine while breastfeeding should be weighed against the risks to the infant.

What are the common side effects of Dolophine?

Common side effects of Dolophine include

• constipation,
• stomach upset,
• nausea,
• shallow breathing,
• hallucinations,
• confusion,
• chest pain,
• dizziness,
• drowsiness,
• fainting,
• fast or pounding heartbeat,
• trouble breathing,
• lightheadedness,
• fainting,
• flushing,
• rash, and
• itching.

What are the serious side effects of Dolophine?

Serious side effects of Dolophine include

• irregular heartbeat,
• anxiety,
• tremors, and
• seizures.

CNS Depressants

• The concomitant use of Dolophine with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients receiving CNS depressants and Dolophine for signs of respiratory depression, sedation and hypotension.
• When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced [Warnings and Precautions (5.5)].
• Deaths have been reported when methadone has been abused in conjunction with benzodiazepines.

Drugs Affecting Cytochrome P450 Is oenzymes

• Methadone undergoes hepatic N-demethylation by cytochrome P450 (CYP) isoforms, principally CYP3A4, CYP2B6, CYP2C19, and to a lesser extent by CYP2C9 and CYP2D6.
• Inhibitors of CYP3A4 and 2C9: Because the CYP3A4 isoenzyme plays a major role in the metabolism of methadone, drugs that inhibit CYP3A4 activity may cause decreased clearance of methadone which could lead to an increase in methadone plasma concentrations and result in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of CYP 2C9 and 3A4 inhibitors. If co-administration with Dolophine is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved.
• Inducers of CYP3A4: CYP450 3A4 inducers may induce the metabolism of methadone and, therefore, may cause increased clearance of the drug which could lead to a decrease in methadone plasma concentrations, lack of efficacy or, possibly, development of a withdrawal syndrome in a patient who had developed physical dependence to methadone. If co-administration with Dolophine is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved.
• After stopping the treatment of a CYP3A4 inducer, as the effects of the inducer decline, methadone plasma concentration will increase which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. If co-administration or discontinuation of a CYP3A4 inducer with Dolophine is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved.
• Paradoxical Effects of Antiretroviral Agents on Dolophine: Concurrent use of certain antiretroviral agents with CYP3A4 inhibitory activity, alone and in combination, such as abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir, saquinavir+ritonavir, and tipranvir+ritonavir, has resulted in increased clearance or decreased plasma levels of methadone. This may result in reduced efficacy of Dolophine and could precipitate a withdrawal syndrome. Monitor methadone-maintained patients receiving any of these anti-retroviral therapies closely for evidence of withdrawal effects and adjust the methadone dose accordingly.
• Effects of Dolophine on Antiretroviral Agents: Didanosine and Stavudine: Experimental evidence demonstrated that methadone decreased the area under the concentration-time curve (AUC) and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered.
• Zidovudine: Experimental evidence demonstrated that methadone increased the AUC of zidovudine, which could result in toxic effects.

Potentially Arrhythmogenic Agents

• Monitor patients closely for cardiac conduction changes when any drug known to have the potential to prolong the QT interval is prescribed in conjunction with methadone. Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents such as class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers.
• Similarly, monitor patients closely when prescribing methadone concomitantly with drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia) that may prolong the QT interval, including diuretics, laxatives, and, in rare cases, mineralocorticoid hormones.

Mixed Agonist/Antagonist And Partial Agonist Opioid Analgesics

• Mixed agonist/antagonist (i.e., pentazocine, nalbuphine and butorphanol) and partial agonist (buprenorphine) analgesics may reduce the analgesic effect of Dolophine or precipitate withdrawal symptoms. Avoid the use of mixed agonist/antagonist and partial agonist analgesics in patients receiving Dolophine.

Antidepressants

• 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. However, if the use of methadone is necessary in such patients, a sensitivity test should be performed in which repeated small, incremental doses of methadone are administered over the course of several hours while the patient's condition and vital signs are carefully observed.
• Desipramine: Blood levels of desipramine have increased with concurrent methadone administration.

Anticholinergics

• Anticholinergics or other drugs with anticholinergic activity when used concurrently with opioids may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when Dolophine is used concurrently with anticholinergic drugs.

Laboratory Test Interactions

• False positive urine drug screens for methadone have been reported for several drugs including diphenhydramine, doxylamine, clomipramine, chlorpromazine, thioridazine, quetiapine, and verapamil.

Drug Abuse And Dependence

Controlled Substance

• Methadone is a mu-agonist opioid with an abuse liability similar to other opioid agonists and is a Schedule II controlled substance. Methadone can be abused and is subject to misuse, addiction, and criminal diversion.

Abuse

• All patients treated with opioids for pain management require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
• Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the counter drug to get “high”, or the use of steroids for performance enhancement and muscle build up.
• Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
• “Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of lost prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.
• Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.
• Dolophine, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record- keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state law, is strongly advised.
• Risks Specific To Abuse Of Dolophine
• Abuse of Dolophine poses a risk of overdose and death. This risk is increased with concurrent abuse of methadone and alcohol or other substances. Dolophine is for oral use only and must not be injected. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
• Proper assessment and selection of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

• Dependence

• Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
• Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
• Dolophine should not be abruptly discontinued. If Dolophine is abruptly discontinued in a physically dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.
•  Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms.

The following serious adverse reactions are discussed elsewhere in the labeling:

• Addiction, Abuse, and Misuse
• Life Threatening Respiratory Depression
• QT Prolongation
• Neonatal Opioid Withdrawal Syndrome
• Interactions with Other CNS Depressants
• Hypotensive Effect
• Gastrointestinal Effects
• Seizures

The major hazards of methadone are respiratory depression and, to a lesser degree, systemic hypotension. Respiratory arrest, shock, cardiac arrest, and death 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 pain. In such individuals, lower doses are advisable.

Other adverse reactions include the following:

Body as a Whole: asthenia (weakness), edema, headache

Cardiovascular: arrhythmias, bigeminal rhythms, bradycardia, cardiomyopathy, ECG abnormalities, extrasystoles, flushing, heart failure, hypotension, palpitations, phlebitis, QT interval prolongation, syncope, T-wave inversion, tachycardia, torsades de pointes, ventricular fibrillation, ventricular tachycardia

Central Nervous System: agitation, confusion, disorientation, dysphoria, euphoria, insomnia, hallucinations, seizures, visual disturbances

Endocrine: hypogonadism

Gastrointestinal: abdominal pain, anorexia, biliary tract spasm, constipation, dry mouth, glossitis

Hematologic: reversible thrombocytopenia has been described in opioid addicts with chronic hepatitis

Metabolic: hypokalemia, hypomagnesemia, weight gain

Renal: antidiuretic effect, urinary retention or hesitancy

Reproductive: amenorrhea, reduced libido and/or potency, reduced ejaculate volume, reduced seminal vesicle and prostate secretions, decreased sperm motility, abnormalities in sperm morphology

Respiratory: pulmonary edema, respiratory depression

Skin and Subcutaneous Tissue: pruritus, urticaria, other skin rashes, and rarely, hemorrhagic urticaria

Hypersensitivity: Anaphylaxis has been reported with ingredients contained in Dolophine. Advise patients how to recognize such a reaction and when to seek medical attention.

Maintenance on a Stabilized Dose: During prolonged administration of methadone, as in a methadone maintenance treatment program, constipation and sweating often persist and hypogonadism, decreased serum testosterone and reproductive effects are thought to be related to chronic opioid use.

Dolophine for the Detoxification and Maintenance Treatment of Opioid Dependence: During the induction phase of methadone maintenance treatment, patients are being withdrawn from illicit opioids and may have opioid withdrawal symptoms.

Monitor patients for signs and symptoms including:

• lacrimation,
• rhinorrhea,
• sneezing,
• yawning,
• excessive perspiration,
•  goose-flesh,
• fever,
• chilling alternating with flushing,
• restlessness,
• irritability,
• weakness,
• anxiety,
• depression,
• dilated pupils,
• tremors,
• tachycardia,
• abdominal cramps,
• body aches,
• involuntary twitching and kicking movements,
•  anorexia,
• nausea,
• vomiting,
• diarrhea,
•  intestinal spasms, and
• weight loss and
• consider dose adjustment as indicated.