Understanding the Medical Issues of Methadone
Download
1 / 43

Understanding the Medical Issues of Methadone Patients Karen Miotto , M.D. Semel Institute for Neuroscience and Human - PowerPoint PPT Presentation


  • 172 Views
  • Uploaded on

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 [email protected] 310 206-2782. Areas of Discussion.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Understanding the Medical Issues of Methadone Patients Karen Miotto , M.D. Semel Institute for Neuroscience and Human' - ramona


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
Slide1 l.jpg

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

[email protected]

310 206-2782


Areas of discussion l.jpg
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


Methadone l.jpg
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


Methadone distribution 2000 2007 l.jpg

Methadone Distribution*2000 – 2007**

GRAMS PER 100K POPULATION

** 01/01/2007 – 03/31/2007

* Includes NTPs

Source: ARCOS

Date Prepared: 07/19/2007

Drug Enforcement Administration, Office of Enforcement Operations, Pharmaceutical Investigations Section, Targeting and Analysis Unit


Slide5 l.jpg

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

  • 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

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


Total prescriptions selected narcotic analgesics source ims health prescription audit l.jpg
Total Prescriptions retail and non-retail channels of distribution, Years 2002 – 2006, IMS Health, IMS National Sales PerspectivesSelected 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.


Trends in emergency department mentions 2004 2005 l.jpg
Trends In Emergency Department Mentions retail and non-retail channels of distribution, Years 2002 – 2006, IMS Health, IMS National Sales Perspectives2004-2005


Methadone deaths by underlying mechanism and intent 1999 2004 l.jpg
Methadone deaths by underlying mechanism and intent: 1999-2004

Lois Fingerhut

Source: NCHS, data from the National Vital Statistics System


Relative abuse potential l.jpg
Relative Abuse Potential? 1999-2004

  • 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


Methadone death l.jpg

Methadone Death 1999-2004

Overdose, overmedication or drug-drug interaction?


Methadone14 l.jpg

Methadone 1999-2004

And Pain


Chronic pain patients in methadone clinics types of pain l.jpg
Chronic Pain Patients in Methadone Clinics: Types of Pain 1999-2004

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


Methadone maintenance patients with pain vs those without pain l.jpg
Methadone-maintenance Patients with 1999-2004Pain 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 > 5 on a 1-10 scale


Methadone maintained patients vs other pain patients mysteries l.jpg
Methadone-maintained Patients vs 1999-2004Other 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


Why is methadone a good pain medicine l.jpg
Why is methadone a good pain medicine? 1999-2004

  • 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.


Pharmacology l.jpg
Pharmacology 1999-2004

  • 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. Methadone:Pharmacology and Usage Guidelines National Medical Director Vitas Healthcare


Dosing methadone l.jpg
Dosing Methadone 1999-2004

  • 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


Ripamonti method l.jpg
Ripamonti Method 1999-2004

Determine 24-hour oral morphine equivalent dose

For 24-hour morphine dose of:

0-90 mg Use 4:1 morphine:methadone

90-300 mg Use 8:1 morphine:methadone

300+ mg Use 12:1 morphine:methadone

Generally use another opioid for breakthrough pain

Ripamonti, et al., 1998


Ayonrinde method l.jpg
Ayonrinde Method 1999-2004

For 24-hour morphine dose of:

<100mg Use 3:1 morphine:methadone

101-300 mg Use 5:1 morphine:methadone

301-600 mg Use 10:1 morphine:methadone

601-800 mg Use 12:1 morphine:methadone

801-1000 mg Use 15:1 morphine:methadone

>1000 mg Use 20:1 morphine:methadone

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


Absorption methadone l.jpg
Absorption - Methadone 1999-2004

Source: Goodman & Gilman, Kreek, and others

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

Opioid Agonist Treatment of Addiction - Payte - 1998


Slide25 l.jpg

1999-2004All substances are poison. The right dose differentiates a poison and a remedy”

Paracelsus, 1493-1541 AD



Methadone single dose kinetics l.jpg
Methadone Single Dose Kinetics 1999-2004

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


Slide28 l.jpg

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!

28

Colonial Management Group, LP -- J. Thomas Payte, MD


The 3 most important questions for methadone titration are l.jpg
The 3 most important questions for methadone interval the rise and fall of drug concentration for the interdose interval is titration are:

DL Gourlay MD, FRCP, FASAM

29

  • 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


Cyp in methadone metabolism l.jpg
CYP in Methadone Metabolism interval the rise and fall of drug concentration for the interdose interval is

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


Potential inhibitors of cyp3a4 mediated metabolism may methadone level l.jpg
Potential Inhibitors of CYP3A4-Mediated Metabolism — may interval the rise and fall of drug concentration for the interdose interval is ↑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.)


Potential inducers of cyp3a4 mediated metabolism may methadone level l.jpg
Potential Inducers of CYP3A4-Mediated Metabolism — interval the rise and fall of drug concentration for the interdose interval is 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)


Methadone interactions l.jpg
Methadone Interactions interval the rise and fall of drug concentration for the interdose interval is

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

Potential serotonin syndrome with SSRIs, tramadol

Grapefruit inhibits methadone metabolism

Smoking induces CYP1A2, and ↓ methadone levels


Urinary ph disposition of methadone l.jpg
Urinary pH Disposition of Methadone interval the rise and fall of drug concentration for the interdose interval is

Source: Nilsson et al., 1982

Opioid Agonist Treatment of Addiction - Payte - 1998


Other mechanisms of drug interaction l.jpg
Other Mechanisms of Drug Interaction interval the rise and fall of drug concentration for the interdose interval is

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

  • 1-acid glycoprotein

    • Circulating level  with stress, addiction, cancer and drugs such as amitriptylline

  • Pharmacodynamics interaction


Methadone deaths 3 ways l.jpg
Methadone Deaths: 3 Ways interval the rise and fall of drug concentration for the interdose interval is

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


Slide38 l.jpg

MEDICATION/PSYCHOSOCIAL interval the rise and fall of drug concentration for the interdose interval is


Methadone side effects l.jpg
Methadone Side Effects interval the rise and fall of drug concentration for the interdose interval is

  • 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


Qtc prolongation l.jpg
QTc interval the rise and fall of drug concentration for the interdose interval is 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.“


To ekg or not to ekg l.jpg
To EKG or not to EKG? interval the rise and fall of drug concentration for the interdose interval is

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-lists.htm for a more comprehensive listing)

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


Harmd helping america reduce methadone deaths l.jpg
HARMD interval the rise and fall of drug concentration for the interdose interval is Helping America Reduce Methadone Deaths

“Helping America Reduce Methadone Deaths”

http://www.harmd.org/


Slide43 l.jpg

Edwin Salsitz, M.D. interval the rise and fall of drug concentration for the interdose interval is


ad