      Document 0224
 DOCN  DRG0224
 UNIQUE IDENTIFIER        DRG-0023
 NAME OF SUBSTANCE        Methadone hydrochloride [USAN 1995]
 REGISTRY NUMBER          1095-90-5
 STANDARD CHEMICAL NAME   6-(Dimethylamino)-4,4-diphenyl-3-heptanone
                          hydrochloride [USAN 1995]
 SYNONYMS                 1,1-Diphenyl-1-(2-dimethylaminopropyl)-2-buta-
                          none hydrochloride [Merck Index 1989]
 SYNONYMS                 4,-4-Diphenyl-6-dimethylamino-3-heptanone
                          hydrochloride [Merck Index 1989]
 SYNONYMS                 6-Dimethylamino-4,4-diphenyl-3-heptanone
                          hydrochloride [USAN 1993]
 SYNONYMS                 Adanon hydrochloride [USAN 1995]
 SYNONYMS                 Algidon [Merck Index 1989]
 SYNONYMS                 Algolysin [Merck Index 1989]
 SYNONYMS                 Amidon hydrochloride [Merck Index 1989]
 SYNONYMS                 Butalgin [Merck Index 1989]
 SYNONYMS                 Depridol [Merck Index 1989]
 SYNONYMS                 Diaminon hydrochloride [Merck Index 1989]
 SYNONYMS                 Fenadone [Merck Index 1989]
 SYNONYMS                 Heptadon hydrochloride [Merck Index 1989]
 SYNONYMS                 Ketalgin hydrochloride [Merck Index 1989]
 SYNONYMS                 Mecodin [Merck Index 1989]
 SYNONYMS                 Mephenon [Merck Index 1989]
 SYNONYMS                 Miadone [Merck Index 1989]
 SYNONYMS                 Meheptan [Merck Index 1989]
 SYNONYMS                 Phenadone hydrochloride [Merck Index 1989]
 SYNONYMS                 Physeptone hydrochloride [Merck Index 1989]
 SYNONYMS                 Tussal [Merck Index 1989]
 SYNONYMS                 Levadone [Merck Index 1989]
 SYNONYMS                 Levothyl [Merck Index 1989]
 SYNONYMS                 L-Polamidon [Merck Index 1989]
 SYNONYMS                 Dolophine hydrochloride [USAN 1995]
 SYNONYMS                 Methadose [USAN 1995]
 SYNONYMS                 Heptanon [Merck Index 1989]
 PROTOCOL ID NUMBERS      NIAID ACTG 055
 PROTOCOL ID NUMBERS      NIAID ACTG 363
 PROTOCOL ID NUMBERS      NIAID CPCRA 030
 SECONDARY SOURCE ID      AN-148 [Merck Index 1989]
 SECONDARY SOURCE ID      Hoechst 10820 [Merck Index 1989]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: An opioid agonist analgesic,
                          which like morphine, exerts its activity by
                          binding to the stereospecific receptors in
                          the central nervous system. A 10 mg
                          intramuscular dose or 20 mg oral dose is
                          equivalent to 10 mg of intramuscular
                          morphine. Protein binding is high. Half-life
                          is 15-25 hours. The onset of action is 10-20
                          minutes (IM), 30-60 minutes (oral). The
                          duration of action is 4-5 hours (IM), 3-4
                          hours (IV), 4-6 hours (oral). This duration
                          may increase with chronic use. Excretion is
                          primarily via the kidneys. [USP DI 1995]
 DISEASES STUDIED/TREATED Management of narcotic abuse [NIAID ACTG 055]
 CLASSIFICATION CODE      Narcotic analgesic [USAN 1995]
 CLASSIFICATION CODE      Detoxification maintenance [PDR 1995]
 OTHER MAJOR USES         Used in detoxification and maintenance
                          treatment of narcotic addiction to heroin and
                          other morphine-like drugs; used for treatment
                          of severe pain, as a suppressant to permit
                          detoxification, and in maintenance therapy to
                          discourage addicts from returning to illicit
                          use of other opioid drugs [PDR 1995]
 SUBSTANCE INTERACTIONS   Patients who are on a methadone maintenance
                          program (or who are addicted to heroin) may
                          experience withdrawal symptoms when given
                          pentazocine; concurrent administration of
                          rifampin (an antituberculosis agent) may
                          reduce the blood concentration of methadone
                          (possibly through the enhancement of
                          microsomal drug metabolized enzymes)
                          sufficient to produce withdrawal symptoms.
                          Therapeutic doses of meperidine have
                          precipitated severe reactions in patients
                          concurrently receiving monoamine oxidase
                          inhibitors or in patients who have received
                          such agents within 14 days - similar
                          reactions have not yet been reported with
                          methadone, but if methadone is used for such
                          patients, a sensitivity test should be
                          performed using small incremental doses of
                          methadone over the period of several hours
                          while monitoring the patient's condition and
                          vital signs. Methadone should be used with
                          caution and in reduced dosage in patients
                          concurrently receiving other narcotic
                          analgesics, general anesthetics,
                          phenothiazines, other tranquilizers,
                          sedative-hypnotics, tricyclic
                          antidepressants, and other central nervous
                          system depressants (including alcohol), since
                          respiratory depression, hypotension, and
                          profound sedation or coma may result.
                          Coadministration of methadone with
                          phenothiazines or certain anesthetics may
                          cause severe hypotension. Methadone overdose
                          has been treated by repeated intravenous
                          administration of Naloxone, the drug of
                          choice to reverse signs of such intoxication.
                          Methadone metabolism and disposition also is
                          altered by the antituberculosis agent
                          rifampin (in humans); there is no evidence
                          that methadone alters its own metabolism or
                          that of other drugs in humans. A number of
                          adverse drug interactions with methadone have
                          been reported. [PDR 1995]
 ADVERSE EFFECTS          Major hazards of methadone include potential
                          for respiratory depression, circulatory
                          depression, respiratory arrest, shock, and
                          cardiac arrest.  Most frequently observed
                          adverse reactions include lightheadedness,
                          dizziness, sedation, nausea, vomiting, and
                          sweating, especially in ambulatory patients
                          who lie down. Other adverse reactions include
                          the following: central nervous system
                          (euphoria, dysphoria, weakness, headache,
                          insomnia, agitation, disorientation, visual
                          disturbances); gastrointestinal (dry mouth,
                          anorexia, constipation, biliary tract spasm);
                          cardiovascular (flushing of the face,
                          bradycardia, palpitation, faintness,
                          syncope); genitourinary (urinary retention or
                          hesitancy, antidiuretic effect, reduced
                          libido and/or potency); allergic (pruritus,
                          urticaria, other skin rashes, edema,
                          hemorrhagic urticaria (rarely)); and
                          hematologic (reversible thrombocytopenia
                          (narcotic addiction with chronic hepatitis)).
                           May cause exaggerated elevation of
                          cerebrospinal-fluid pressure (in patients
                          having increased intracranial pressure),
                          apnea (in patients with asthma and other
                          respiratory conditions), severe hypotension,
                          and impairment of mental and/or physical
                          abilities (ambulatory patients). Methadone
                          can produce drug dependence of the morphine
                          type, and therefore has the potential for
                          being abused, causing psychic and physical
                          dependence and tolerance. [PDR 1989] The more
                          frequent side effects include constipation,
                          dizziness, drowsiness, increased sweating or
                          flushing of the face, and nausea or vomiting.
                          [PDR 1995]
 CONTRAINDICATIONS        Contraindicated in patients with
                          hypersensitivity to methadone. Should be used
                          with caution and in reduced dosage in the
                          elderly or debilitated, and in patients with
                          severe impairment of hepatic/renal function,
                          hypothyroidism, Addison's disease, prostatic
                          hypertrophy, or urethral stricture.
                          Contraindicated for obstetrical analgesia,
                          since its long duration of action increases
                          the risk of neonatal respiratory depression.
                          [USP DI 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Methadone hydrochloride is
                          a synthetic diphenylheptane derivative with
                          opioid analgesic activity [AHFS Drug
                          Information 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C21H28ClNO (hydrochloride)
                          [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 345.91 (hydrochloride)
                          [USAN 1995]
 CHEMICAL/PHYSICAL DATA   PERCENT ELEMENTAL COMPOSITION
                          (hydrochloride): C72.91%; H8.16%; Cl10.25%;
                          N4.05%; O4.63% [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   MELTING POINT: 235 C (dl-form); 241 C
                          (l-Form); 78 C (free base) [USAN 1990]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: (of hydrochloride) (g/100 ml):
                          Water (12), alcohol (8), isopropanol (2.4);
                          practically insoluble in ether, glycerol; the
                          free base is precipitated from aqueous
                          solution above pH 6 [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   STABILITY: (of hydrochloride) Aqueous
                          solutions of the hydrochloride can be
                          autoclaved at 120 C for 1 hour without loss
                          of potency [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   DRUG PHYSICAL COMMENT: Acidity of 1 percent
                          aqueous solution of Methadone Hydrochloride:
                          pH 4.5-5.6 [USAN 1990]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: Colorless crystals or
                          white, crystalline powder [AHFS Drug
                          Information 1995]
 CHEMICAL/PHYSICAL DATA   ELEMENTAL COMPOSITION: (hydrochloride)
                          C72.91%, H8.16%, N4.05%, 04.63%, CL10.25%
                          [Merck Index 1989]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Oral solutions (5 or 10 mg/5
                          ml), concentrated solutions for dilution (10
                          mg/ml), and disperible tablets (40 mg) and
                          regular tablets (5 mg and 10 mg). [USP DI
                          1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral; intramuscular or
                          subcutaneous injection. Oral formulations can
                          be dissolved in water or fruit juice. [PDR
                          1995]
 SUBSTANCE DELIVERY DATA  STORAGE INSTRUCTIONS: Store solutions between
                          15 C and 30 C, in a tight container protected
                          from light and freezing. [USP DI 1995]
 SUBSTANCE DELIVERY DATA  STORAGE INSTRUCTIONS: Store regular tablets
                          below 40 C, preferably between 15 C and 30 C,
                          in a well closed container. Store disperible
                          tablets between 15 C and 30 C in a well
                          closed container.
 SUBSTANCE DELIVERY DATA  STORAGE INSTRUCTIONS: Store injections below
                          40 C, preferably between 15 C and 30 C, in a
                          light resistant container. [USP DI 1995]
 MANUFACTURERS            Eli Lilly
 REFERENCES               Nurco DN, Primm BJ, Lerner M, Stephenson P,
                          Brown LS, Ajuluchukwu DC. Changes in
                          locus-of-control attitudes about drug misuse
                          in a self-help group in a methadone
                          maintenance clinic. Int J Addict 1995
                          May;30(6):765-78.
 REFERENCES               Wall TL, Sorensen JL, Batki SL, Delucchi KL,
                          London JA, Chesney MA. Adherence to
                          zidovudine (AZT) among HIV-infected methadone
                          patients: a pilot study of supervised therapy
                          and dispensing compared to usual care. Drug
                          Alcohol Depend. 1995 Mar;37(3):261-9.
 REFERENCES               Dansereau DF, Joe GW, Simpson DD. Attention
                          difficulties and the effectiveness of a
                          visual representation strategy for counseling
                          drug-addicted clients. Int J Addict. 1995
                          Mar;30(4):371-86.
 REFERENCES               Levinson I, Galynker II, Rosenthal RN.
                          Methadone withdrawal psychosis. J Clin
                          Psychiatry. 1995 Feb;56(2):73-6.
 REFERENCES               Moolchan ET, Hoffman JA. Phases of treatment:
                          a practical approach to methadone maintenance
                          treatment. Int J Addict. 1994
                          Jan;29(2):135-60.
 REFERENCES               De Leon G, Staines GL, Perlis TE, Sacks S,
                          McKendrick K, Hilton R, Brady R. Therapeutic
                          community  methods in methadone maintenance
                          (Passages): an open clinical trial. Drug
                          Alcohol Depend. 1995 Jan;37(1):45-57.
 REFERENCES               Hasson AL, Grella CE, Rawson R, Anglin MD.
                          Case management within a methadone
                          maintenance program. A research demonstration
                          project for HIV risk reduction. J Case Manag.
                          1994 Winter;3(4):167-72.
 REFERENCES               Grella CE, Anglin MD, Wugalter SE, Rawson R,
                          Hasson A. Reasons for discharge from
                          methadone maintenance for addicts at high
                          risk of HIV infection or transmission. J
                          Psychoactive Drugs. 1994
                          Apr-Jun;26(2):223-32.
 REFERENCES               Ness R, Handelsman L, Aronson MJ, Hershkowitz
                          A, Kanof PD. The acute effects of a rapid
                          medical detoxification upon dysphoria and
                          other psychopathology experienced by heroin
                          abusers. J Nerv Ment Dis. 1994
                          Jun;182(6):353-9.
 REFERENCES               Bertschy G, Baumann P, Eap CB, Baettig D.
                          Probable metabolic interaction between
                          methadone and fluvoxamine in addict patients.
                          Ther Drug Monit. 1994 Feb;16(1):42-5.
 ENTRY MONTH              8906
 LAST REVISION DATE       960502
 

SOURCE: National Library of Medicine, Bethesda, MD.  Distributed by AEGIS.
