Understanding the Medical Issues of Methadone Patients

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Understanding the Medical Issues of Methadone
Patients Karen Miotto, M.D. Semel Institute for
Neuroscience and Human Behavior David Geffen
School of Medicine University of California at
Los Angeles kmiotto_at_mednet.ucla.edu 310
206-2782
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Areas of Discussion

• Increase in methadone use for pain
• Pain patients on methadone may be treated by
  doctors with less than optimal training in
  pain/addiction
• Nature of medical concerns associated with
  methadone
• Safety concerns
• Induction
• Drug interaction
• Cardiac concerns
• Increase in methadone death increase stigma

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Methadone
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
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Methadone Distribution2000 2007
GRAMS PER 100K POPULATION
Includes NTPs
01/01/2007 03/31/2007
Source ARCOS Date Prepared 07/19/2007
Drug Enforcement Administration, Office of
Enforcement Operations, Pharmaceutical
Investigations Section, Targeting and Analysis
Unit
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Sales data Total extended units of methadone
sold to retail and non-retail channels of
distribution, Years 2002 2006, IMS Health, IMS
National Sales PerspectivesTM
IMS Health, IMS National Sales Perspectives,
Years 2002 - 2006, Extracted July 2007.

• Overall sales of methadone have increased by 89
  between year 2002 and 2006
• Sales in retail channels have doubled since 2002,
  whereas only 59 increase in the non-retail sector

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Total PrescriptionsSelected Narcotic
AnalgesicsSource IMS Health Prescription Audit
Millions of Prescriptions
Note In 2006, there were about 35-fold more
hydrocodone prescriptions and 10-fold more
oxycodone prescriptions compared to methadone
prescriptions.
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Trends In Emergency Department
Mentions2004-2005
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Methadone deaths by underlying mechanism and
intent 1999-2004
Source NCHS, data from the National Vital
Statistics System
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Relative Abuse Potential?

• 3-year retrospective
• Free-standing pain clinic
• Patients discharged for opioid misuse vs. 200
  random patients receiving opioid therapy
• Multisourcing
• toxicology discrepancies
• repeated escalation , etc.
• Relative misuse potential
• Drug frequency in the discharged
  patients/frequency in active patients
• Problem
• True misuse potential would require prospective
  study with random assignment

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Methadone Death

• Overdose, overmedication or drug-drug interaction?

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Methadone

• And Pain

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Chronic Pain Patients in Methadone Clinics Types
of Pain

• Low back pain (42.8)
• Lower extremity pain (23.7)
• Total body pain (13.2)
• Headaches (9.2)
• Upper extremity pain (5.3)
• Chest abdominal pain (3.9)
• Neck pain (2.6)
• 65 have a second pain site

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Methadone-maintenance Patients with Pain vs Those
Without Pain

• More medical illness
• More psychiatric illness
• More prescribed medications
• More non-prescribed medications
• Average pain duration more than 10 years
• Average intensity gt 5 on a 1-10 scale

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Methadone-maintained Patients vs Other Pain
Patients Mysteries

• Methadone-maintained patients are hypersensitive
  to pain, especially to cold pressor pain.
• Methadone-maintained patients are very tolerant
  to methadone morphine analgesia

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Why is methadone a good pain medicine?

• Efficacy
• Long half life ? Long duration effect
• Useful in managing chronic pain
• Convenient dosing schedule
• Good oral bioavailability
• Methadone a common choice of drug for pain that
  does not respond to weaker agonists
• Low cost
• Methadone is synthetic and easily manufactured
  it is also 1/10 the cost of other opioids. It is
  particularly cost-saving for cancer patients who
  require high-dose opioids.

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Pharmacology

• Methadone is
• Mu receptor agonist
• NMDA-antagonist (n-Methyl-d-Aspartate)
• glutamate and aspartate are released in response
  to pain
• bind to NMDA receptor and cause changes in CNS
• may underlie chronic pain and neuropathic pain
• hyperalgesia exagerated pain response
• wind-up increase of nerve firing to point where
  it fires spontaneously

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

• Some methadone conversion tables are
• at least problematic
• some are incorrect
• (recommending too high initial methadone doses)
• This contributes to confusion and dosing error!
• Pain treatment providers should call Pain
  Resource for dosing guidelines
• -Dolophine
• Solution
• IV methadone
• Tablets

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Ripamonti Method

• Determine 24-hour oral morphine equivalent dose
• For 24-hour morphine dose of
• 0-90 mg Use 41 morphinemethadone
• 90-300 mg Use 81 morphinemethadone
• 300 mg Use 121 morphinemethadone
• Generally use another opioid for breakthrough
  pain
• Ripamonti, et al., 1998

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Ayonrinde Method

• For 24-hour morphine dose of
• lt100mg Use 31 morphinemethadone
• 101-300 mg Use 51 morphinemethadone
• 301-600 mg Use 101 morphinemethadone
• 601-800 mg Use 121 morphinemethadone
• 801-1000 mg Use 151 morphinemethadone
• gt1000 mg Use 201 morphinemethadone
• Gazelle, G and Fine, P. Methadone for pain 75,
  Journal of Palliative Medicine, vol.7(2), 2004

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Absorption - Methadone

• Detected at 30 min. following oral dosing
• Peak plasma levels occur at 2-4 hours
• Large amounts stored in liver and other tissues
  for later release into circulation to maintain
  steady-state (Reservoir Effect)
• Protein binding extensive, up to 90 of
  therapeutic dose
• Highly lipophillic, parenteral doses readily
  cross blood-brain barrier

Source Goodman Gilman, Kreek, and others
Opioid Agonist Treatment of Addiction - Payte -
1998
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• All substances are poison. The right dose
  differentiates a poison and a remedy
• Paracelsus, 1493-1541 AD

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Methadone Single Dose Kinetics
INTOXICATON
T½ 5-6 hrs
ANALGESIA
T½ 20-40 hrs
PAIN
5
10
15
20

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

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Steady State The point at which during each
interdose interval the rise and fall of drug
concentration for the interdose interval is
identical for each dose
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!
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Colonial Management Group, LP -- J. Thomas
Payte, MD
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The 3 most important questions for methadone
titration are

• What are you like before your first dose in the
  AM? (Trough Level) - Is there an opioid debt?
• What are you like 1/2hr after the first dose?
  (Onset) Symptom improvement with first dose is
  most likely withdrawal mediated, i.e., inadequate
  24hr total dose
• 3. What are you like 2-4 hours after the first
  dose of the morning? (Peak) - Symptoms that are
  gone by 3 or 4 hrs are almost certainly
  withdrawal mediated

DL Gourlay MD, FRCP, FASAM
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CYP in Methadone Metabolism

• The most important enzymes in methadone
  metabolism are CYP3A4 and CYP2B6. Secondarily
  CYP2D6 appears to have a role, and CYP1A2 may
  possibly be involved.

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Potential Inhibitors of CYP3A4-Mediated
Metabolism may ?methadone level

• Selective Serotonin Reuptake Inhibitors (SSRI)
• Sertraline(zoloft), fluoxetine(prozac),
  paroxetine(seroxate)
• Serotonin Norepinephrine Reuptake
  Inhibitors(SNRI)
• venlafaxine, nefazodone
• Broad-spectrum antifungals and antibacterials
• clotrimazole, fluconazole, fluoroquinolone,
  macrolides, etc.
• HIV drugs ritonavir
• NNRTI zidovudine will decreased by methadone
• Hormones (progesterone, ethinylestradiol,
  dexamethasone)
• Calcium channel antagonists (nifedipine,
  verapamil, diltiazem)
• Miscellaneous (quinidine, midazolam, cyclosporin,
  vinblastine, bromocriptine, cimetidine,
  omeprazole, allopurinol, etc.)

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Potential Inducers of CYP3A4-Mediated Metabolism
may?methadone level

• Some antiepileptics
• phenobarbital, phenytoin, primidone,
  carbemazepine, but not valproate or
  benzodiazepines
• Glucocorticoids
• Antituberculosis drugs rifampin, rifabutin
• HIV drugs
• NNRTI (efavirenz, nevirapine)
• PI (kaletra, nelfinavir)

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Methadone Interactions

• Potential serotonin syndrome with SSRIs, tramadol
• Grapefruit inhibits methadone metabolism
• Smoking induces CYP1A2, and ? methadone levels

• http//atforum.com/SiteRoot/pages/addiction_resour
  ces/ P45020Drug20Interactions.PDF

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Urinary pH Disposition of Methadone
Source Nilsson et al., 1982
Opioid Agonist Treatment of Addiction - Payte -
1998
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Other Mechanisms of Drug Interaction

• ?1-acid glycoprotein
• Circulating level ? with stress, addiction,
  cancer and drugs such as amitriptylline
• Pharmacodynamics interaction

benzodiazepine
Excitatory NMDA
Inhibitory GABA
Respiration rhythm
methadone
Philip Peng MBBS FRCPC Director, Anesthesia
Chronic Pain Program, University Health Network,
Wasser Pain Management Center, Mount Sinai
Hospital
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Methadone Deaths 3 Ways

• Finding of the 2003 National Assessment
• Accumulation during induction for pain or
  addiction
• Clinicians overestimate tolerance, or
• Patient combines other CNS depressants with
  methadone
• Misuse / Abuse / Bingeing on diverted methadone
• High doses or non-tolerant
• Synergistic effects with other depressants
• Poison cocktail resulting from the intake of
  multiple psychotropic drugs
• Alcohol, benzodiazepines, other opioids.
• Methadone seldom is the sole cause of death

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MEDICATION/PSYCHOSOCIAL
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Methadone Side Effects

• Minimal sedation once tolerance achieved
• Constipation
• Increased Appetite/Weight Gain
• Lowered Libido May decrease gonadal hormone
  levels
• Exhaustively studied in all organ systems with no
  evidence of chronic harm

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QTc Prolongation

• Methadone Warnings
• In November 2006, the US Food and Drug
• Administration (FDA) issued a Public Health
  Advisory
• "Methadone use for pain control
• may result in death and life-threatening
• changes in breathing and heartbeat.

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To EKG or not to EKG?

• Risk Factors for Prolonged QTc
• advanced age
• female gender
• electrolyte abnormalities e.g. hypokalaemia or
  severe hypomagnesaemia
• bradycardia
• heart disease (e.g. heart failure or ischaemia)
• congenital long QT syndrome or pre-existing QT
  prolongation
• concomitant use of other QT prolonging medicines
  (e.g. tricyclic antidepressants, some
  antipsychotics and antibiotics- see
  www.torsades.org/medical-pros/drug-lists/drug-list
  s.htm for a more comprehensive listing)
• concomitant use of medicines that inhibit the
  metabolism of methadone (e.g. fluconazole and
  some SSRI antidepressants).

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HARMDHelping America Reduce Methadone Deaths

• Helping America Reduce Methadone Deaths
• http//www.harmd.org/

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