Methadone:You Don’t Prescribe it?

You Still Need to Know About it.

Karen Triandafyllis, NPOpiate Treatment Outpatient Program

San Francisco General Hospital

April 22, 2010

Methadone has many interactions with both prescribed medications and substances of abuse

These interactions, in turn, can significantly impact patient outcomes Medical Psychiatric Substance Abuse

Case Study #1 48-year old male with Opioid and Cocaine

Dependence, HIV, Hep C+, and Depressive disorder

On Methadone 70mg daily, no illicit opioid use x 6 mos, continues to use crack cocaine 3-4x/wk

On Sertraline 100mg qbedtime for depression PCP wants to start pt on HIV meds. Some

concerns re possible adherence, but thinks stable enough. Prescribes Atripla 1 tab daily

Pt misses initial f/u appt with PCP, returns 4 wks later. States he relapsed on heroin and has been off all his medications, except for Methadone, for the past 2 wks

What do you do to help him?

Case Study #2 35-year old female with Opioid and

Methamphetamine Dependence, Hep C+, HTN, OCD and Anxiety d/o NOS

On Methadone 50mg daily and HCTZ 25mg daily Enters residential tx, does well, stops using

any illicit drugs, engages in psychiatric care and is started on Fluvoxamine 100mg daily and Clonazepam 0.5mg BID

You receive a call from her program stating that she has been nodding off in groups and they are concerned she is abusing her benzos

What can you do to help her?

Methadone Pharmacology Opiate agonist High systemic bioavailability (90%) Peak plasma levels at 2-4 hours Long T ½ allows convenient dosing, but

T ½ is quite variable Relatively lipid soluble Duration of analgesia << expected with

T ½

Methadone Pharmacology (cont’d) Stored and accumulates in tissues (esp.

liver) which extend the apparent T ½ 90% protein bound (not eliminated by

dialysis) Biotransformation by P450 (3A4 and

2D6 mainly) Cleared by GI tract in patients with

significant renal disease

Methadone Safety: Black Box Warnings

QTc Prolongation and Torsade 2009 Clinical Guidelines for QTc Interval Screening in Methadone

Treatment: Consensus Recommendations Disclosure: Clinicians should inform patients of arrhythmia risk when

they prescribe methadone. Clinical History: Clinicians should ask patients about any history of

structural heart disease, arrhythmia, and syncope. Screening: Obtain a pretreatment electrocardiogram for all patients

to measure the QTc interval and then a follow-up electrocardiogram within 30 days and annually. Additional electrocardiography is recommended if the methadone dosage exceeds 100 mg/d or if patients have unexplained syncope or seizures.

Risk Stratification: If the QTc interval is greater than 450 ms but less than 500 ms, discuss potential risks and benefits with patients and monitor them more frequently. If the QTc interval exceeds 500 ms, consider discontinuing or reducing the methadone dose; eliminating contributing factors, such as drugs that promote hypokalemia; or using an alternative therapy.

Drug Interactions: Clinicians should be aware of interactions between methadone and other drugs that possess QT interval–prolonging properties or slow the elimination of methadone.

Krantz et al (2009). Ann Intern Med. 2009;150:387-395.

QTc Prolongation and Torsade (cont’d) Major risk factors include

Electrolyte abnormalities (hypomagnesemia, hypokalemia, hypocalcemia)

Hepatic dysfunction Other QT prolonging medications

Methadone-Drug Interactions CYP inhibitors

Slow Methadone metabolism, raise serum methadone levels, extend duration of its effects, possible cause Methadone-related toxicity (e.g., oversedation, respiratory depression, prolonged QTc)

Overmedication reactions develop within a few days after concurrent drug administration

CYP inducers Accelerate Methadone breakdown, abbreviate duration of Methadone effects, lower

serum methadone levels, possibly precipitate withdrawal May take a week or much longer to emerge, producing withdrawal sx

Not all interactions are related to altered drug metabolism Additive effects of Methadone with other CNS depressants, for example, causing

hypotension, sedation, respiratory depression or coma Other QTc prolonging medications

Methadone can also increase or decrease some concomitant drug levels, leading to toxicity or lack of efficacy

Also consider potential effects when discontinuing medications

Risks of Reduced Serum Methadone Levels

Potential relapse to illicit opioids

Non-adherence to prescribed medications

Prescribing Medications that Interact with Methadone Use alternative, non-interacting drugs if

possible Adjust concomitant drug as appropriate if

Methadone affects its levels Advise pts in advance of physical symptoms of

overmedication or withdrawal that may occur Encourage pts to let their Methadone Clinic

know about initiation or discontinuation of interacting medications

Inform Methadone Clinic about changes For W93 pts, call 206-8412 and ask for the NP on call

Methadone-Drug Interactions: HIV medications

Drug Effects

Didanosine (ddl) Significant ↓ in ddl concentration

Stavudine (d4T) Significant ↓ in d4T concentration

Zidovudine (AZT) AZT concentration increased 40%

Abacavir (ABC) ↓ Methadone level; ↓ ABC peak concentration

Efavirenz ↓ Methadone level, withdrawal common

Lopinavir+Ritonavir ↓ Methadone level, withdrawal common

Darunavir ↓ Methadone level, withdrawal may occur

Nevirapine ↓ Methadone level, may precipitate withdrawal

Methadone-Drug Interactions: Psychotropic medications

Drug Effects

Benzodiazepines Additive CNS depression

MAOIs Contraindicated due to potential adverse reactions

TCAs (amitriptyline, desipramine, imipramine, nortriptyline)

↑ TCA toxicity (desipramine level doubles), proarrhythmic effects

SSRIs/SNRIs (fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine)

fluvoxamine: Potentially dangerous ↑ in Methadone levels. Moderate Methadone ↑: fluoxetineMild Methadone ↑: paroxetine, venlafaxineQTc: fluoxetine, sertraline, venlafaxine

Antipsychotics (haloperidol, quetiapine, ziprasidone)

QTc prolongationQuetiapine: ↑ Methadone levels

Carbamazepine Strong CYP3A4 induction, opioid withdrawal common

Methadone-Drug Interactions: Other medications

Drug Effects

Barbituates Particularly phenobarbital, sharp ↓ in Methadone levels and opioid withdrawal

Phenytoin and Carbamazepine Sharp ↓ in Methadone levels

Rifampin Severe opioid withdrawal

Fluconazole (possible other azoles)

↑ Methadone levels

Macrolides (Erythromycin, Clarithromycin)

↑ Methadone levels

St. John’s Wort Significant ↓ in Methadone levels (47% in one study)

Grapefruit juice ↑ Methadone levels

Omeprazole May inhibit Methadone absorption

Cimetidine CYP450 enzyme inhibitor

Methadone-Drug Interactions: Substances of Abuse ETOH and Sedatives: additive effects,

risk for overdose

Cocaine: accelerates Methadone elimination

Methamphetamine: not studied in human pharmacokinetics studies

Tobacco: mixed reports, most indicate reduced effectiveness of Methadone

Case Study #1 48-year old male with Opioid and Cocaine

Dependence, HIV, Hep C+, and Depressive disorder

On Methadone 70mg daily, no illicit opioid use x 6 mos, continues to use crack cocaine 3-4x/wk

On Sertraline 100mg qbedtime for depression PCP wants to start pt on HIV meds. Some

concerns re possible adherence, but thinks stable enough. Prescribes Atripla 1 tab daily

Pt misses initial f/u appt with PCP, returns 4 wks later. States he relapsed on heroin and has been off all his medications, except for Methadone, for the past 2 wks

What do you do to help him?

Case Study #2 35-year old female with Opioid and

Methamphetamine Dependence, Hep C+, HTN, OCD and Anxiety d/o NOS

On Methadone 50mg daily and HCTZ 25mg daily Enters residential tx, does well, stops using

any illicit drugs, engages in psychiatric care and is started on Fluvoxamine 100mg daily and Clonazepam 0.5mg BID

You receive a call from her program stating that she has been nodding off in groups and they are concerned she is abusing her benzos

What can you do to help her?

Ward 93 Contact Information Referrals

Referral forms available at most clinics, ED, Wound Clinic, and Urgent Care

Fax referral form to Bryan Jackson at 206-6875 or call at 206-4288

Most pts admitted to 30-day or 90-day detox Direct admission to MMTP for pregnant pts or

Forensic AIDS Program (FAP) pts

To discuss medical concerns and coordinate care, phone 206-8412 and ask for the NP on call

Questions?