Intervention: Methadone
Trial phase: Phase 4
ATC code: N02AC52 | N07BC02
SMILES: CCC(=O)C(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 520
Group description: For the MET group, all participants will receive a maximum of 30 mg for the first dose and a maximum of 40 mg on Day 1. It is recommended that participants receive a dose on day 2 that is 10 mg higher than their total day 1 dose, and a dose on day 3 that is 10 mg higher than their total day 2 dose, unless, in the clinical judgment of the physician, a slower induction is needed. Doses will be adjusted on Day 4 and thereafter according to clinical impression and depending upon the participant's clinical need with no specific upper limit. Investigators are encouraged to dose adequately to decrease craving and to obtain negative urine toxicology specimens.
Eligibility criteria:
Inclusion Criteria:

Were age 18 years or older,
Met DSM-IV-TR criteria for opioid dependence,
Were in good general health, or, in case of a medical/psychiatric condition requiring ongoing treatment, were under the care of a physician willing to continue participant's medical management and cooperate with study physicians,

For female participants, use of one of the following acceptable methods of birth control:

oral contraceptives
barrier (diaphragm or condom) with spermicide
IUD
intrauterine progesterone contraceptive system
levonorgestrel implant
medroxyprogesterone acetate contraceptive injection
contraceptive transdermal patch
hormonal vaginal contraceptive ring
surgical sterilization
complete abstinence from sexual intercourse
Able to read and verbalize understanding of the study and voluntarily sign study informed consent form.

Exclusion Criteria:

ALT or AST values > 5 times the upper limit of normal as per testing laboratory range criteria,
ALP values >3 times the upper limit of normal per testing laboratory criteria,
Any documented past or present history of ascites, presence of esophageal or gastric varices, hepatic encephalopathy or other signs of significant liver disease as indicated by a Model for Endstage Liver Disease score (Kamath et al., 2001) of ≥11,
Total bilirubin > 2.0 mg/dl (participants with documented Gilbert's syndrome were not excluded based on this criterion),
Prothrombin time more than 3 seconds prolonged,
Albumin level less than 2.5 g/dl,

Any cardiopathy or risk factor listed below without evidence of a normal ECG* with report performed within 6 months prior to first study medication dose,

Congestive heart failure
Left ventricular hypertrophy
Bradycardia
Hereditary QT prolongation
Uncorrected electrolyte imbalance
Concomitant medications that are known to have a risk of QT interval prolongation; refer to Appendix D for a list of medications.

Note: The list was not all-inclusive.

*An ECG was abnormal if one or more of the following occurred:

Significant ST segment abnormalities:

ST segment elevations in two or more continuous leads of > 0.1 mV
ST segment depression of greater than 1 mm that are flat or down-sloping at 80 msec after the J point ST segment abnormalities identified as "non-specific" are acceptable. If a potential participant's ECG indicated ST segment elevations or depression consistent with ischemia, the physician obtained a medical history of cardiac symptoms and referred the participant for evaluation.

Conduction abnormalities:

Mobitz II 2nd degree or 3rd degree heart block
Atrial fibrillation, atrial flutter, or any non-sinus tachyarrhythmia
Three or more consecutive ectopic ventricular complexes at a rate of > 100 per minute.
QTc greater than 450 msec in men and 480 msec in women

Repolarization abnormalities:

• Acute medical condition that would make participation, in the opinion of the study physician, medically hazardous (e.g., unstable pancreatic, cardiovascular or renal disease, significant anemia)

Known allergy or sensitivity to BUP, naloxone or MET or to any of the inactive ingredients in the study medications (including lactose, mannitol, cornstarch, povidone K30, citric acid, sodium citrate, FD&C Yellow No.6 color, magnesium stearate, Acesulfame K sweetener)
Known diagnosis of acute psychosis, severe depression or imminent suicide risk as determined via clinical interview by study physician or surrogates
DSM-IV diagnosis of dependence on alcohol requiring immediate medical attention.
DSM-IV diagnosis of dependence on benzodiazepines requiring immediate medical attention
DSM-IV diagnosis of dependence on other depressants, or stimulants requiring immediate medical attention
Participation in an investigational drug study within the past 30 days
Treatment with MET, BUP/NX, or BUP for more than 15 of the past 30 days (illicit use of these medications is allowed)
Pending legal action that could prohibit study participation
Unable or unwilling to comply with study requirements
Unable or unwilling to remain in the local area for duration of treatment
Poor venous access such that venipuncture could not be accomplished from a vein in an extremity during eligibility
Pregnant or lactating (females only)