Methadone: You Don’t Prescribe it? You Still Need to Know About it. Karen Triandafyllis, NP Opiate 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:

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 and ask for the NP on call

Methadone-Drug Interactions: HIV medications DrugEffects 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 DrugEffects BenzodiazepinesAdditive CNS depression MAOIsContraindicated 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 ↑ : fluoxetine Mild Methadone ↑ : paroxetine, venlafaxine QTc: fluoxetine, sertraline, venlafaxine Antipsychotics (haloperidol, quetiapine, ziprasidone) QTc prolongation Quetiapine: ↑ Methadone levels CarbamazepineStrong CYP3A4 induction, opioid withdrawal common

Methadone-Drug Interactions: Other medications DrugEffects BarbituatesParticularly phenobarbital, sharp ↓ in Methadone levels and opioid withdrawal Phenytoin and CarbamazepineSharp ↓ in Methadone levels RifampinSevere opioid withdrawal Fluconazole (possible other azoles) ↑ Methadone levels Macrolides (Erythromycin, Clarithromycin) ↑ Methadone levels St. John’s WortSignificant ↓ in Methadone levels (47% in one study) Grapefruit juice ↑ Methadone levels OmeprazoleMay inhibit Methadone absorption CimetidineCYP450 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 or call at 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 and ask for the NP on call

Questions?