1.  Jack McCarthy, M.D., FASM, ABPN  Bi-Valley Medical Clinic  Sacramento

2.  1. Conceiving while in an opiate dependent state, licit or illicit, is a complication of pregnancy  2. Opiate withdrawal causes uterine irritability. Early in gestation this risks miscarriage, later in pregnancy the risk is premature labor and fetal distress.  3. In 2 nd and 3 rd trimesters, when enough brain opiate receptors have developed, fetal dependence occurs and the fetus can experience withdrawal.  4: All women on maintenance for addiction or chronic pain need to be informed of this complication if they conceive.

3.  1. The baby doesn’t have withdrawal just at birth. It can go thru withdrawal in the womb. When the mother’s level of opiate falls below a critical point, so does the baby’s.  2. Withdrawal is a hyper-adrenergic, hyper- motoric state (kicking), complicated by umbilical artery hypotension (low oxygen), and can result in fetal death.  3. Fetal withdrawal is treated by increasing the mother’s methadone dose.

4.  1. Methadone can be used to do a slow taper during pregnancy. The ultimate decision about maintenance or taper clearly resides with the mother.  2. Withdrawal stresses the fetus during the most critical period of development. Endorphins play a critical role in brain development.  3. Withdrawal leads to relapses  4. Tapers often need to be reversed

5.  1. It is often very difficult to keep a pregnant mother out of withdrawal without repeated dose increases and often very high doses.  2. Increases in the metabolism of methadone in pregnancy can be quite dramatic. Serum levels can be falling as the dose is increasing!  3. The fetus is only exposed to maternal serum levels, not to maternal dose!  4. Serum levels can rise dramatically post- partum. Watch for over sedation!!  5. Use repeated trough serum levels to monitor maternal metabolism both pre and post partum. I

6.  Patient started on 30mg in late first trimester and required repeated dose increases all thru pregnancy  Serum levels vs dose:  5/24 on 150mg (75/75), serum 100ng  6/24 on 200mg (100/100), serum 130ng  8/5 on 250mg (80/85/85), serum ‘none detected’  Delivered baby on 8/11 on 260mg. Baby had minimal withdrawal and no need for meds and went home in 3 days with mom.  Post-partum: 8/17 on 240mg (80/80/80), serum 320ng.

7.  After induction needed repeated dose increases to stabilize  Serum level during pregnancy ◦ 6/16/10, dose 130mg (65/65), serum 440ng  Delivered 6/28/10 on 140mg (70/70)  Post-Partum Dose 8/2/10 140mg (70/70) serum level 990ng Dose 8/17/10 on 120mg (60/60) serum 880ng

8.  Individualize dose based on maternal symptoms of withdrawal, no arbitrary limits.  Split dose all patients, BID, at times TID  Use serum levels to monitor maternal methadone metabolism and fetal exposure  Get post-partum serum levels 1-2 weeks after delivery and monitor closely

9.  N=17 delivered  Conceived on pills 8, heroin 5, methadone 4  Average dose 145mg  Average serum pregnant 288ng  In recovery at delivery 15/17 (88%)  Baby treated with meds 4/17 (23%)  Nursed 10/17 (59%)  Gestational age 38.5 weeks

10.  1. Keep the fetus out of opiate withdrawal, if the mom’s in withdrawal, then so is the fetus  2. Keep the mother out of withdrawal, watch for the timing of symptoms.  3. Recovery  4. Educate the patient about methadone and pregnancy. Education is best done in groups  5. NO NUBAIN in labor!!

11.  1. Rapid metabolism? Get serum level  2. Stress: situational abstinence syndrome?  3. Other medications like dilantin, phenobarbitol, rifampin (enzyme inducers) that accelerate metabolism?  4. Other conditions that mimic withdrawal like anxiety, bi-polar disorder, flu syndromes, the effects of pain?  Other drugs like alcohol (an enzyme inducer), or stimulants

12.  The QT interval is the time between the Q and T points on an EKG  The QTc is a calculation based on differences in heart rate  The normal QTc is up to 440-450msec (<1/2 sec).  Methadone has some modest potential to prolong the QT interval in some patients. Higher doses (or higher serum levels) may the increase risk.

13.  A very prolonged QT interval, more than 500msec (>1/2 sec) can lead to a fatal arrhythmia called Toursades de Pointe  This means “twisting of the point” or a twisting of the EKG complex…a distortion of the normal electrical activity of the heart such that the heart can beat ineffectively or stop. This can self-correct.  Many drugs prolong QT and the effects can be additive if multiple drugs are involved. The list of causes is very long and include heart and liver diseases.  Since methadone can prolong the QT, adding another drug that prolongs QT can increase risk

14. The risk of fatal arrhythmia is unknown. But it is vary rare.  QT prolongation does occur but it can come and go. And may have no relationship to methadone.  There are problems with the accuracy of the measurement, both by cardiologists and by machines.  There is no consensus on whether, when, or if to screen with EKGs

15. Unexplained falling down or fainting Palpitations BUT, there may be no symptoms Some people have a congenital (inherited) QT problem, and they may have a family history of sudden death There is no way to diagnose someone who dies of this kind of heart rhythm disturbance unless they are hooked to an EKG machine. Was it an overdose? Or was it cardiac?

16.  We indentify known risks and get EKGs ‘for cause’.  The major known risk is heart disease.  If you hear that the patient has any heart problems or palpitations, or is on any heart medication (not blood pressure meds), alert the medical staff.  Fainting could be an arrhythmia and must be reported to the medical staff.

17.  We will get EKGs on anyone going over 140mg or those already over 140mg who are requesting a dose increase  Anyone with a high serum methadone level over 500ng

18.  Possibly hundreds, but some more than others  The most serious risks are with heart drugs called anti-arrhythmia medications. So any cardiac (heart) medication is suspect.  Cocaine prolongs the QT  Antibiotics: Bactrim, Erythromycin and Clarithromycin  Old antipsychotics: haldol, mellaril, thorazine  Anti-fungals used in HIV care

19.  More EKGs  More monitoring of other meds  More worrying!  Thank you for worrying!

20.  Methadone is a long acting mu opiate receptor full agonist, but, beyond this well know action, methadone has a number of other receptor actions with significant psychiatric effects: ◦ 1. NMDA antagonism reduces development of tolerance and blocks glutamate, the major excitatory neurotransmitter of the brain, producing anti-anxiety and calming effects ◦ 2. SSRI properties giving anti-anxiety and anti- depressant effects ◦ 3. MAOI action further augments anti-depressant effects.

21.  Most patients with Hep C have functional livers and do not have signs and symptoms of liver failure. They don’t need any changes in their methadone doses.  Some patients will progress to liver failure and can develop encephalopathy (a toxic brain state characterized by reduced consciousness and confusion). These patients often need methadone doses reduced and serum levels monitored.

22.  Terminator budget Pledges to destroy drug treatment in California!!!  “No man in history has ever Done More For Cartel Profits. California Billions go to Cartels!! ( Drug Trade Times, May 2010)  Republican Party goes big into Drug trade! Long term collaboration Pledged!  Prison industry stocks soar!!!  Drug lords stage major celebration : “Were So Happy We Can Hardly Count”

23. When coffee first came to Europe there were reports of psychoses. Tolerance is why we don’t see this anymore. Caffeine hits the adenosine receptor and releases dopamine. It has well documented physical dependence and withdrawal We addict our children to this drug! And we don’t feel guilty!

24.  Starbucks drip 260mg  Brewed tea 40mg  Coke Classic 47mg  WIRED X505 (energy drink) 505mg  Bud Extra Beer 80mg  Excedrin 65mg  Diet: Swarm Extreme 300mg  Metabolife Ultra 150mg

25.  Increases BP  Increase anxiety, panic attacks  Decreased fertility, decreased fetal growth, increased spontaneous abortion

26.  Restlessness, nervousness, excitement  Insomnia (caffeine induced sleep disorder)  Rambling thought and speech  Increased heart rate or arrhythmia  Periods of inexhaustibility  Increased anxiety, caffeine blocks anti- anxiety effects of benzos

27.  Headache  Dysphoric mood, irritability  Difficulty concentrating  Fatigue/drowsiness  Flu-like symptoms: nausea, muscle pain/stiffness

28.  12-24 hrs after last fix  Peak symptoms 20-50 hrs  Durations 2-9 days, maybe up to 3 weeks  30% of caffeine users meet criteria for dependence  50mg a day relieves withdrawal symptoms  Coffee, tobacco, and alcohol cohabitate!!

29.  Ever tried  Ever failed  No matter  Try again  Fail again  Fail better  Samuel Beckett: Worstwood Ho Recovery Recovery