8/16/2015 1 understanding the medical issues of methadone patients karen miotto, m.d. semel...
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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?
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
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
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/