8/16/2015 1 Understanding the Medical Issues of Methadone Patients Karen Miotto, M.D. Semel Institute for Neuroscience and Human Behavior David Geffen.

04/19/23 1

Understanding the Medical Issues of Methadone

Patients

Karen Miotto, M.D.Karen Miotto, M.D.Semel Institute for Neuroscience and Human Semel Institute for Neuroscience and Human

BehaviorBehaviorDavid Geffen School of MedicineDavid Geffen School of Medicine

University of California at Los AngelesUniversity of California at Los [email protected]

310 206-2782310 206-2782

Areas of DiscussionAreas of Discussion Increase in methadone use for painIncrease in methadone use for pain Pain patients on methadone may be Pain patients on methadone may be

treated by doctors with less than optimal treated by doctors with less than optimal training in pain/addictiontraining in pain/addiction

Nature of medical concerns associated Nature of medical concerns associated with methadonewith methadone

Safety concernsSafety concerns InductionInduction Drug interactionDrug interaction Cardiac concernsCardiac concerns Increase in methadone death increase Increase in methadone death increase

stigmastigma

MethadoneMethadone

Synthetic opioid, structure very different from other opioid

methadone codeine morphine

Philip Peng MBBS FRCPC Director, Anesthesia Chronic Pain Program, University Health Network, Wasser Pain Management Center, Mount Sinai Hospital

0

200

400

600

800

1,000

1,200

1,400

MethadoneMethadone Distribution* Distribution*2000 – 2007** 2000 – 2007**

GR

AM

S P

ER

100

K P

OP

UL

AT

ION

* Includes NTPs

Source: ARCOS Date Prepared: 07/19/2007Drug Enforcement Administration, Office of Enforcement Operations, Pharmaceutical Investigations Section, Targeting and Analysis Unit

** 01/01/2007 – 03/31/2007

Sales data: Total extended units of methadone sold to Sales data: Total extended units of methadone sold to retail and non-retail channels of distribution, Years retail and non-retail channels of distribution, Years

2002 – 2006, IMS Health, IMS National Sales 2002 – 2006, IMS Health, IMS National Sales PerspectivesPerspectivesTMTM

76.8%75.5%75.4%75.0%

72.4%

23.2%24.5%

24.6%25.0%

27.7%

0

100

200

300

400

500

600

700

800

2002 2003 2004 2005 2006Years

Ext

end

ed U

nit

s (m

illio

ns)

Non-Retail

Retail

Overall sales of methadone have increased by 89% Overall sales of methadone have increased by 89% between year 2002 and 2006between year 2002 and 2006

Sales in retail channels have doubled since 2002, Sales in retail channels have doubled since 2002, whereas only 59% increase in the non-retail sectorwhereas only 59% increase in the non-retail sector

5

IMS Health, IMS National Sales Perspectives™, Years 2002 - 2006, Extracted July 2007.

Total PrescriptionsTotal PrescriptionsSelected Narcotic AnalgesicsSelected Narcotic Analgesics

Source: IMS Health Prescription AuditSource: IMS Health Prescription Audit

0

20

40

60

80

100

120

140

2002 2003 2004 2005 2006

hydrocodone

oxycodone

methadone

Note: In 2006, there were about 35-fold more hydrocodone prescriptions and 10-fold more oxycodone prescriptions compared to methadone prescriptions.

Mil

lion

s of

P

resc

rip

tion

s

Trends In Emergency Department Trends In Emergency Department MentionsMentions

2004-20052004-2005

0 100,000 200,000

2004

2005

Heroin Rx Opioids

SOURCE: SAMHSA Drug Abuse Warning Network, 2007

Methadone deaths by Methadone deaths by underlying mechanism and underlying mechanism and

intent: 1999-2004intent: 1999-2004

1

10

100

1,000

10,000

1999 2000 2001 2002 2003 2004

Nu

mb

er

of

de

ath

s

Unintentional poisoning

Undetermined intent by poisoning

Suicide by poisoning

Non-injury deaths

Homicide by poisoning

Oher injury deaths

Lois FingerhutSource: NCHS, data from the National Vital Statistics System

Relative Abuse Potential?Relative Abuse Potential? 3-year retrospective 3-year retrospective Free-standing pain clinic Free-standing pain clinic Patients discharged for opioid Patients discharged for opioid

misuse vs. 200 random patients misuse vs. 200 random patients receiving opioid therapy receiving opioid therapy MultisourcingMultisourcing toxicology discrepanciestoxicology discrepancies repeated escalation , etc.repeated escalation , etc.

““Relative misuse potential”Relative misuse potential” Drug frequency in the Drug frequency in the

discharged discharged patients/frequency in active patients/frequency in active patients patients

ProblemProblem True misuse potential would True misuse potential would

require prospective study require prospective study with random assignmentwith random assignment

10

0 1 2 3 4 5

Stadol

Propoxyphene

Hydrocodone

Codeine/APAP

Oxycodone

Oxycontin

MS Contin

Duragesic

Methadone

Methadone DeathMethadone Death

Overdose, overmedication or Overdose, overmedication or drug-drug interaction?drug-drug interaction?

MethadoneMethadone

And PainAnd Pain

Chronic Pain Patients in Chronic Pain Patients in Methadone Clinics: Methadone Clinics:

Types of PainTypes of Pain Low back pain (42.8%)Low back pain (42.8%) Lower extremity pain (23.7%)Lower extremity pain (23.7%) Total body pain (13.2%)Total body pain (13.2%) Headaches (9.2%)Headaches (9.2%) Upper extremity pain (5.3%)Upper extremity pain (5.3%) Chest & abdominal pain (3.9%)Chest & abdominal pain (3.9%) Neck pain (2.6%)Neck pain (2.6%) * 65% have a second pain site* 65% have a second pain site

04/19/23 15

Methadone-maintenance Methadone-maintenance Patients with Patients with PainPain vs vs ThoseThose Without Pain Without Pain

More medical illnessMore medical illness More psychiatric illnessMore psychiatric illness More prescribed medicationsMore prescribed medications More non-prescribed medications More non-prescribed medications

*Average pain duration more than 10 years*Average pain duration more than 10 years Average intensity > 5 on a 1-10 scaleAverage intensity > 5 on a 1-10 scale

04/19/23 16

Methadone-maintained Methadone-maintained Patients vs Patients vs

Other Pain Patients: Other Pain Patients: MysteriesMysteries

Methadone-maintained patients are Methadone-maintained patients are hypersensitive to pain, especially to hypersensitive to pain, especially to cold pressor pain. cold pressor pain.

Methadone-maintained patients are Methadone-maintained patients are very tolerant to methadone & very tolerant to methadone & morphine analgesiamorphine analgesia

04/19/23 17

Why is methadone a good Why is methadone a good pain medicine?pain medicine?

EfficacyEfficacy Long half life Long half life Long duration effect Long duration effect

• Useful in managing chronic painUseful in managing chronic pain Convenient dosing scheduleConvenient dosing schedule Good oral bioavailability Good oral bioavailability

• Methadone a common choice of drug for pain Methadone a common choice of drug for pain that does not respond to weaker agoniststhat does not respond to weaker agonists

Low costLow cost Methadone is synthetic and easily Methadone is synthetic and easily

manufactured; it is also 1/10 the cost of other manufactured; it is also 1/10 the cost of other opioids. It is particularly cost-saving for cancer opioids. It is particularly cost-saving for cancer patients who require high-dose opioids.patients who require high-dose opioids.

PharmacologyPharmacology Methadone is:Methadone is:

Mu receptor agonistMu receptor agonist NMDA-antagonist (n-Methyl-d-Aspartate)NMDA-antagonist (n-Methyl-d-Aspartate)

glutamate and aspartate are released in glutamate and aspartate are released in response to painresponse to pain

bind to NMDA receptor and cause changes in bind to NMDA receptor and cause changes in CNSCNS

may underlie chronic pain and neuropathic painmay underlie chronic pain and neuropathic pain hyperalgesia: exagerated pain responsehyperalgesia: exagerated pain response wind-up: increase of nerve firing to point wind-up: increase of nerve firing to point

where it fires spontaneouslywhere it fires spontaneously

Joel S. Policzer, M.D. Methadone:Pharmacology and Usage Guidelines National Medical Director Vitas Healthcare

Dosing MethadoneDosing Methadone Some methadone conversion tables are:Some methadone conversion tables are:

at least problematicat least problematic; ; some are some are incorrectincorrect

(recommending (recommending too hightoo high initial methadone doses) initial methadone doses)

This contributes to confusion and dosing error! This contributes to confusion and dosing error!

Pain treatment providers should call Pain Resource for Pain treatment providers should call Pain Resource for dosing guidelinesdosing guidelines

-Dolophine-Dolophine

SolutionSolution

IV methadoneIV methadone

TabletsTablets

Ripamonti MethodRipamonti Method

Determine 24-hour oral morphine equivalent doseDetermine 24-hour oral morphine equivalent dose

For 24-hour morphine dose of:For 24-hour morphine dose of:

0-90 mg 0-90 mg Use 4:1 Use 4:1 morphine:methadonemorphine:methadone

90-300 mg 90-300 mg Use 8:1 Use 8:1 morphine:methadonemorphine:methadone

300+ mg 300+ mg Use 12:1 Use 12:1 morphine:methadonemorphine:methadone

Generally use another opioid for breakthrough Generally use another opioid for breakthrough painpain

Ripamonti, et al., 1998Ripamonti, et al., 1998

Ayonrinde MethodAyonrinde Method

For 24-hour morphine dose of:For 24-hour morphine dose of: <100mg <100mg Use 3:1 morphine:methadoneUse 3:1 morphine:methadone 101-300 mg 101-300 mg Use 5:1 morphine:methadoneUse 5:1 morphine:methadone 301-600 mg 301-600 mg Use 10:1 morphine:methadoneUse 10:1 morphine:methadone 601-800 mg 601-800 mg Use 12:1 morphine:methadoneUse 12:1 morphine:methadone 801-1000 mg801-1000 mg Use 15:1 morphine:methadoneUse 15:1 morphine:methadone >1000 mg >1000 mg Use 20:1 morphine:methadoneUse 20:1 morphine:methadone

Gazelle, G and Fine, P. Methadone for pain: #75, Gazelle, G and Fine, P. Methadone for pain: #75, Journal of Palliative Medicine, Journal of Palliative Medicine, vol.7(2), 2004vol.7(2), 2004

Absorption - Absorption - MethadoneMethadone

Detected at 30 min. following oral dosingDetected at 30 min. following oral dosing Peak plasma levels occur at 2-4 hoursPeak plasma levels occur at 2-4 hours Large amounts stored in liver and other Large amounts stored in liver and other

tissues for later release into circulation to tissues for later release into circulation to maintain steady-state (Reservoir Effect)maintain steady-state (Reservoir Effect)

Protein binding extensive, up to 90% of Protein binding extensive, up to 90% of therapeutic dosetherapeutic dose

Highly lipophillic, parenteral doses readily Highly lipophillic, parenteral doses readily cross blood-brain barriercross blood-brain barrier

Opioid Agonist Treatment of Addiction - Payte - 1998

Source: Goodman & Gilman, Kreek, and others

““All substances are poison. All substances are poison. The right dose The right dose differentiates a poison and differentiates a poison and a remedy”a remedy”

Paracelsus, 1493-1541 ADParacelsus, 1493-1541 AD

04/19/23 26Edwin Salsitz, M.D.

Methadone Single Dose Methadone Single Dose KineticsKinetics

Nilsson MI, et al. Acta anaesth. scand 1982, Suppl 74Nilsson MI, et al. Acta anaesth. scand 1982, Suppl 7427

5 10 15 20

T½ 5-6 hrs

T½ 20-40 hrsPAIN

ANALGESIA

INTOXICATON

Steady State: The point at which during each interdose Steady State: The point at which during each interdose interval the rise and fall of drug concentration for the interval the rise and fall of drug concentration for the

interdose interval is interdose interval is identical for each doseidentical for each dose

0

50

100

150

200

250

300

350

400

450

1 2 3 4 5 6 7 8

ng/ml

Days/Half-Lives – Methadone half-life= 24-36 hoursDose constant at 30 mg daily. Interdose interval = 24 hrs (trough to

trough)Peak levels increase daily for 5-6 days with NO increase in dose!28Colonial Management Group, LP -- J. Thomas Payte, MD

29

The 3 most important questions The 3 most important questions for methadone for methadone titrationtitration are: are:

1.1. What are you like before your first dose in the What are you like before your first dose in the AM? (Trough Level) - Is there an “opioid debt”?AM? (Trough Level) - Is there an “opioid debt”?

2.2. What are you like 1/2hr after the first dose? What are you like 1/2hr after the first dose? (Onset) – Symptom improvement with first (Onset) – Symptom improvement with first dose is most likely withdrawal mediated, i.e., dose is most likely withdrawal mediated, i.e., inadequate 24hr total doseinadequate 24hr total dose

3.3. What are you like 2-4 hours after the first What are you like 2-4 hours after the first dose of the morning? (Peak) - Symptoms that dose of the morning? (Peak) - Symptoms that are gone by 3 or 4 hrs are almost certainly are gone by 3 or 4 hrs are almost certainly withdrawal mediatedwithdrawal mediated

DL Gourlay MD, FRCP, FASAM 29

CYP in Methadone CYP in Methadone MetabolismMetabolism

The most important enzymes in The most important enzymes in methadone metabolism are methadone metabolism are CYP3A4CYP3A4 and and CYP2B6CYP2B6. Secondarily CYP2D6 . Secondarily CYP2D6 appears to have a role, and CYP1A2 appears to have a role, and CYP1A2 may possibly be involved.may possibly be involved.

Potential Inhibitors of CYP3A4-Potential Inhibitors of CYP3A4-Mediated Metabolism — may Mediated Metabolism — may

↑↑methadone levelmethadone level Selective Serotonin Reuptake Inhibitors (SSRISelective Serotonin Reuptake Inhibitors (SSRI))

Sertraline(zoloftSertraline(zoloft®®), fluoxetine(prozac), fluoxetine(prozac®®), ), paroxetine(seroxateparoxetine(seroxate®®))

Serotonin Norepinephrine Reuptake Inhibitors(SNRISerotonin Norepinephrine Reuptake Inhibitors(SNRI)) venlafaxine, nefazodonevenlafaxine, nefazodone

Broad-spectrum antifungals and antibacterials Broad-spectrum antifungals and antibacterials clotrimazole, fluconazole, fluoroquinolone, macrolides, clotrimazole, fluconazole, fluoroquinolone, macrolides,

etc.etc. HIV drugs : ritonavirHIV drugs : ritonavir

NNRTI : zidovudine will decreased by methadoneNNRTI : zidovudine will decreased by methadone Hormones Hormones (progesterone, ethinylestradiol, (progesterone, ethinylestradiol,

dexamethasone)dexamethasone) Calcium channel antagonistsCalcium channel antagonists (nifedipine, verapamil, (nifedipine, verapamil,

diltiazem)diltiazem) Miscellaneous (quinidine, midazolam, cyclosporin, Miscellaneous (quinidine, midazolam, cyclosporin,

vinblastine, bromocriptine, cimetidine, omeprazole, vinblastine, bromocriptine, cimetidine, omeprazole, allopurinol, etc.)allopurinol, etc.)

Potential Inducers of CYP3A4-Potential Inducers of CYP3A4-Mediated Metabolism — Mediated Metabolism — maymay↓↓methadone levelmethadone level

Some antiepilepticsSome antiepileptics phenobarbital, phenytoin, primidone, phenobarbital, phenytoin, primidone,

carbemazepine, but not valproate or carbemazepine, but not valproate or benzodiazepinesbenzodiazepines

GlucocorticoidsGlucocorticoids Antituberculosis drugs : rifampin, Antituberculosis drugs : rifampin,

rifabutinrifabutin HIV drugs : HIV drugs :

NNRTI (efavirenz, nevirapine)NNRTI (efavirenz, nevirapine) PI (kaletra, nelfinavir)PI (kaletra, nelfinavir)

Methadone InteractionsMethadone Interactions

Potential serotonin syndrome with Potential serotonin syndrome with SSRIs, tramadolSSRIs, tramadol

Grapefruit inhibits methadone Grapefruit inhibits methadone metabolismmetabolism

Smoking induces CYP1A2, and Smoking induces CYP1A2, and ↓↓ methadone levels methadone levels

33

•http://atforum.com/SiteRoot/pages/addiction_resources/ P450%20Drug%20Interactions.PDF

Urinary pH Disposition of Urinary pH Disposition of MethadoneMethadone

Urinary pH 5.2 7.8

MethadonePlasmaHalf-life

19.5 +/- 3.6hours

42.1 +/- 8.8hours

Opioid Agonist Treatment of Addiction - Payte - 1998

Source: Nilsson et al., 1982

Other Mechanisms of Drug Other Mechanisms of Drug InteractionInteraction

11-acid glycoprotein-acid glycoprotein Circulating level Circulating level with stress, addiction, with stress, addiction,

cancer and drugs such as amitriptyllinecancer and drugs such as amitriptylline

Pharmacodynamics interactionPharmacodynamics interaction

Excitatory: NMDA Inhibitory : GABA

Respiration rhythmmethadone

benzodiazepine

Philip Peng MBBS FRCPC Director, Anesthesia Chronic Pain Program, University Health Network, Wasser Pain Management Center, Mount Sinai Hospital

Methadone Deaths: 3 WaysMethadone Deaths: 3 Ways

Finding of the 2003 National Assessment: Finding of the 2003 National Assessment: Accumulation during inductionAccumulation during induction for pain or addiction for pain or addiction

Clinicians overestimate tolerance, or Clinicians overestimate tolerance, or Patient combines other CNS depressants with Patient combines other CNS depressants with

methadone methadone Misuse / Abuse / Bingeing on diverted Misuse / Abuse / Bingeing on diverted

methadonemethadone High doses or non-tolerant High doses or non-tolerant

Synergistic effects with other depressantsSynergistic effects with other depressants ““Poison cocktail” resulting from the intake of Poison cocktail” resulting from the intake of

multiple psychotropic drugs multiple psychotropic drugs Alcohol, benzodiazepines, other opioids. Alcohol, benzodiazepines, other opioids. Methadone seldom is the sole cause of deathMethadone seldom is the sole cause of death

37

MEDICATION/PSYCHOSOCIAL

Methadone Side EffectsMethadone Side Effects Minimal sedation once tolerance Minimal sedation once tolerance

achievedachieved ConstipationConstipation Increased Appetite/Weight GainIncreased Appetite/Weight Gain Lowered Libido; May decrease Lowered Libido; May decrease

gonadal hormone levelsgonadal hormone levels Exhaustively studied in all organ Exhaustively studied in all organ

systems with no evidence of systems with no evidence of chronic harmchronic harm

QTc ProlongationQTc Prolongation

Methadone WarningsMethadone Warnings

In November 2006, the US Food and In November 2006, the US Food and DrugDrug

Administration (FDA) issued a Public Administration (FDA) issued a Public Health Advisory:Health Advisory:

"Methadone use for pain control"Methadone use for pain control

may result in death and life-threateningmay result in death and life-threatening

changes in breathing and heartbeat.“changes in breathing and heartbeat.“

To EKG or not to EKG?To EKG or not to EKG? Risk Factors for Prolonged QTcRisk Factors for Prolonged QTc advanced age advanced age female gender female gender electrolyte abnormalities e.g. hypokalaemia or severe electrolyte abnormalities e.g. hypokalaemia or severe

hypomagnesaemia hypomagnesaemia bradycardia bradycardia heart disease (e.g. heart failure or ischaemia) heart disease (e.g. heart failure or ischaemia) congenital long QT syndrome or pre-existing QT prolongation congenital long QT syndrome or pre-existing QT prolongation concomitant use of other QT prolonging medicines (e.g. tricyclic concomitant use of other QT prolonging medicines (e.g. tricyclic

antidepressants, some antipsychotics and antibiotics- see antidepressants, some antipsychotics and antibiotics- see www.torsades.org/medical-pros/drug-lists/drug-lists.htm for a for a more comprehensive listing) more comprehensive listing)

concomitant use of medicines that inhibit the metabolism of concomitant use of medicines that inhibit the metabolism of methadone (e.g. fluconazole and some SSRI antidepressants). methadone (e.g. fluconazole and some SSRI antidepressants).

HARMDHARMDHelping America Reduce Helping America Reduce

Methadone DeathsMethadone Deaths

““Helping America Reduce Methadone Helping America Reduce Methadone Deaths”Deaths”

http://www.harmd.org/http://www.harmd.org/

Edwin Salsitz, M.D.