Substance dependence-incorporates physiological, psychological and behavioural elements. If a patient exhibits either tolerance or withdrawal, they may be specified as having physiological dependence. The dependence syndrome is diagnosed if threee or more of the following have been present together at some time during the past year: - Strong desire or compulsion to take substance. - Difficulty in controlling substance taking behaviour - Physiological withdrawal state when substance use has reduced or ceased. - Signs of tolerance. - Neglect of other interest and activities. - Persistence with substance use despite clear awareness of harmful consequences. Buprenorphine- opioid partial agonist. May result in withdrawal symptoms when administered, therefore patients should be encouraged to reduce their daily opioid intake before starting therapy. Used in moderate opioid dependency. Naltrexone- Opioid antagonist. Blocks action of opioids. Precipitates withdrawal symptoms in opioid dependent individuals. Eurphoric action of opioid antagonists is blocked. Given to former addicts to prevent relapse. Lofexidine- Used to alleiviate symptoms in individuals whose opioid use is well controlled and who are undergoing opioid withdrawal. Alpha adrenergic agonist, acts centrally to reduce sympathetic tone. Dosing methadone: 10-40mg daily initially. Increased by up to 10mg daily. Usual dose range 60-120mg. PRICE- 60ml 87p. Nalorex 28 tabs £23.72 (combined withnaltrexone)
Bristol specialist drugs service, stokes croft. “I can’t believe they’re giving this pregnant women methadone- surely it’s harming the baby!” “ How do they know she’s telling the truth? If she wasn’t sick, surely she’s receiving really high levels of methadone”
Heroin users get pregnant - In the EU and Norway, between 1.3 and 1.5 million problem heroin users at present. (EMCDDA, 2009) - Statistics likely to be an underestimation, as difficult to collect data - 4.4% prevalence in Iran. UNODC= united nations office of drugs and crime (ref 367) EMCDDA = European monitoring centre for drugs and drug addiction Not uncommon, despite: Heroin use causes: Amenorrhoea and other menstrual abnormalities. Suppression of ovulation Couldn’t find any studies to do with menstrual abnormalities since 1960s- was one Santen, 1975 to do with ovulation though. Ostrea and Knapp- study carried out in Detroit, 58 women samping meconium and hair. (not the best of studies..) TRAINSPOTTING Awareness: Lots of stigma associated with methadone use. Assumption that methadone use in pregnant women is ‘un-ethical’ as may harm the baby. Methadone use in pregnancy advantageous over the alternatives. Pregnancy provides a unique opportunity to bring dependent women into medical, obstetric and drug treatment. Methadone administration in a stable environment reduces maternal and foetal morbidity and mortality, and promotes foetal stability and growth. American group (stein et al, 1999) big review of lots of data- show that methadone maintenance provides an invaluable opportunity to improve the outcomes of these pregnancies Offers opiate addicted women a chance to improve their lives, and lives of their families. Drug dependent, pregnant women on the streets? Prostitution for heroin money whilst pregnant? Many women might not have had contact with medical services before- pregnancy forces them to, and has to be regular contact so constant monitoring. A problem a lot of the time is that heroin addicts don’t come into contact with the medical services regularly enough to be monitored, and if they do come in they don’t provide contact details, and may not come back. Methadone administration superior to using IV heroin on the streets- could have been cut with substances that could be harmful to the baby, pick up BBVs that infect the baby (HIV?) Group in New York have done lots of work into pregnancy and methadone use, and see it as an invaluble opportunity to help women get off opiod dependency. Life threatening? Mortality of neonates from opioid-dependent mothers is relatively low, however greatly increased risk of Sudden Infant Death syndrome. Also, risk of BBVs if mothers have been injecting heroin. Awareness of these issues is essential for obstetricians and midwives, so they know how to care for the neonates.
The plasma concentration of methadone decreases, despite an unchanged dose of methadone. The decreased plasma conc. May also be due to: Increased volume of distribution Decreased plasma protein binding Decreased oral absorption. EDDP=2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine Hepatic cytochrome: P4503A4 (CYP3A4) EDMP= 2-ethyl-5-methy-3,3-diphenyl-pyrroline (produced by intestine) Microsomal enzymes, CYP-2D6, -1A2, -2B6, -2C9, and -microsomal enzymes, CYP-2D6, -1A2, -2B6, -2C9, and - 2C19
METHADONE AND PLACENTA The placenta also acts as a filter. The placenta permeability to methadone is variable. Methadone may also be retained by the placenta, although this doesn’t affect its viability or function. Methadone can also be altered by the placenta. Aromatase CYP19 Not that many studies have been done on how much actually reaches the foetus. Studies suggest extensive materno-foetal transfer, with significant levels in the cord blood. However, placental inactivation is significantly less than maternal liver or intestinal inactivation. Therefore the amount of methadone transferred to the foetus is regulated, but variable, and it is very difficult to select an appropriate methadone dose.
Hagopian 1996- measured the head circumference of neonates and foetal growth- study included 172 babies over 2 years. Showed higher doses correlated with increased growth VS the control of heroin dependent mothers. American study done in Chicago. Lam et al 1992- study involved 52 women in hong kong who had abused narcotics. Showed that the perinatal mortality rate was 2.5 times higher than in the control group. Antepartum haemorrhage, venereal disease, miscarriage.
The graph is based on data taken from Stein et al. paper ‘The methadone maintained pregnancy’. The Data shows that the greatest percentage of underweight neonates is seen in heroin exposed infants, then in those methadone exposed, then in those drug free. This emphasises that methadone treatment is still harmful, but is preferential when compared to using heroin. Data based on mean figures for studies done with: heroin- 730 neonates Methadone- 845 neonates Drug-free- 4219 neonates
Subdivided into NAS caused by drug abuse, and NAS caused by opioid treatment or fentanyl in the mother. Characterised by high pitched crying, hyperactive reflexes, tremors hypertonicity, convulsions, frantic suckling fists, diarrhoea, dehydration etc etc.
Strabismus is when the eyes aren’t properly aligned. Lots of studies done in 1980s and early 1990s into this long term effects. Are the behavioural effects psychosocial?
Management plans The best management isn’t necessarily the most obvious. - Stop taking drugs all together! - Reduced dose of methadone? - Relapse? Lose contact with services? - Long term consequences could be much more detrimental -Upholds the policy of ‘harm minimisation’ 2) Lying patients Even if the patient is lying, they have autonomy and the right to decide what they lie about: - Related to CASE STUDY - Not up to clinician to judge whether lying or not - Ethically, if the patient has capacity they have the right to decide whether they have more or not, and they will suffer the consequences if they have been lying. 3) Ethical issues Treating pregnant women with methadone seems unethical. Actually, often in both baby and mothers best interest 4) Clinical experience - Seeing patients at dispensing unit made researching the ssc more interesting, enjoyable, and made things ‘stick in my head’ a lot better 5) Collecting evidence Especially in this topic, as most of the papers were quire old Not basing evidence on one study essential (lots of papers were contradictory and when looked at in more detail were dubious) Better critical analysis of data in future iSSC
Methadone Use and Pregnancy
What is methadone?
Why this topic is important
How does methadone act differently in pregnancy?
What I’ve gained from this iSSC
Further information & References
An opioid agonist.
Substituted for opioids eg. diamorphine , preventing the onset of withdrawal symptoms in opioid
Addictive- so should only be prescribed to the physically dependent on opioids.
Administered in a single daily dose, usually methadone oral solution( 1mg/mL).
Dose is adjusted according to the degree of dependence.
The NICE guidlines:
Oral methadone and buprenorphine are recommended for maintenance therapy in the
management of opioid dependence. Patients should be committed to a supportive care
programme including a flexible dosing regimen administered under supervision for at least 3
months until compliance is assured. Selection of methadone or buprenorphine should be made
on a case-by-case basis, but methadone should be prescribed if both drugs are equally suitable.
Other drugs used for opioid dependency include:
• X smoked ~£10 (1 bag) heroin per day for the past 10 years.
• X is 7 months pregnant.
• Since X found out she was pregnant, she has been coming to the clinic for
methadone maintenance treatment.
• She receives 70mls/day.
• On this particular day, X went home immediately after coming to the dispensing
unit for her daily methadone. She was sick, approximately 10 minutes after
leaving the clinic.
• X came back and asked the doctor for some more methadone.
• It was agreed she would receive another 40mls.
Because heroin users can become pregnant
• The global average of heroin use prevalence was 0.3% 2003-2004 (Iran
4.4%) (UNODC, 2005)
• 80-90% IV heroin users are of reproductive age.
• Pregnancy isn’t uncommon (Gaulden, 1964).
• 1/3 patients at a high risk clinic were positive for opiod use at some stage in
their pregnancy (Ostrea, Knapp 2001)
Because awareness of methadone use in pregnancy should be
• Methadone use in pregnancy is advantageous over the alternatives ie.
Pregnant, opioid dependent women on the streets.
Care for infants of opioid-dependent mothers could be life-saving.
• Risk of SIDS and BBVs
Methadone acts differently during pregnany
• Should be taken into consideration by clinicans when dosing
As pregnancy progresses, methadone metabolism is enhanced resulting in
Half life reduced from 24hrs to 8-20hrs. (Swift & Dudley, 1989)
During the 3rd
trimester, and oral methadone dose of 50-150mg is required to
achieve a level of 240ng/ml in the maternal circulation.
The bioavailability of methadone is normally 40-99%
Low levels of methadone in the maternal circulation may result in withdrawal
Methadone should therefore be dosed carefully during pregnancy
& Microsomal enzymes
Methadone transfer from mother to foetus occurs via the placenta.
The placenta may also act as a filter, retain methadone, and alter the methadone.
The foetus can metabolise methadone in the liver.
Depends on the level of foetal maturation.
Capacity significantly less than in the mother, due to the absence of certain
Methadone has also been identifed in the amniotic fluid, suggesting oral and
cloacal uptake (likely to be a lot less than recieved across the placenta.)
Methadone is also transferred in the breast milk, leading to post-natal exposure
of the infant to methadone.
Inconclusive data about how much transfer actually occurs. Thought to be
variable, and multi-factorial.
MMT has inarguably improved management of pregnancy and neonatal
outcomes in heroin addicts.
High methadone doses in 3rd
trimester result in improved foetal growth
No serious foetal toxicity has been associated with methadone.
Some adverse effects identified, however, this data is inconsistent and there isn’t
an established causal link to methadone use (Lam et al, 1992).
› Higher incidence of prematurity.
› Intrauterine growth retardation
› Increased foetal mortality.
Clinical observations in utero:
› Decreased foetal activity
› Decreased respiration rate
› Decreased heart rate
(in contrast to mothers not on oral methadone)
•Decreased average birth weight
•Decreased head circumference
•Increased morbidity and mortality
•Increased incidence of NAS
(Stein et. al. 1999)
Complex disorder, characterised by behavioural and physiological signs and
symptoms that are very similar, despite very different causative agents.
Acute phase lasts for 7-14 days post-partum
High pitched crying particularly characteristic.
The pathological severity is assessed using the Finnegan scale
Opiate induced growth reductions:
› Decreased postnatal weight gain
› Decreased head circumference
› Decreased height
These effects decrease with age, but may last for up to 5.5 years...
› Behavioural effects (mood, attention, cognitive defects)
Up to the age of 5 years, show cognitive impairment.
Less interactive aged 5
Aged 7, behaviour at school different: Underachieving, aggressive, disruptive.
No difference between effects of heroin and methadone on post-natal outcomes...
How do you know if a patients lying?
Methadone Maintentenance treatment is standard procedure in the UK for
opioid dependent pregnant women.
Methadone is metabolised faster in pregnancy, so higher doses may be required
to acheive the same ‘euphoric’ effect.
Methadone often, but not always, has detrimental effects on the foetus,
neonate, and post-natally.
The detrimental effects methadone has on the foetus is less than the effects of
The use of MMT in pregnant women should be encouraged, and seen as harm
Bristol Specialist Drug Service
59-61 Stokes Croft
Bristol, BS1 3QP
0117 923 2077
The methadone maintained pregnancy
Stein et al. (1999) Clinical Perinatology 26(1):173-83.
The Effects of Maternally Administered Methadone, Buprenorphine and
Naltrexone on Offspring: Review of Human and Animal Data
Farid et al. (2008) Current Neuropharmacology, 6, 125-150
•Ostrea, EM Jr et al., (2001) Estimates of illicit drug use during pregnancy by maternal interview,
hair analysis, and meconium analysis J Pediatr. 138(3):344-8.
•Hadman, A. (2009). Neonatal Abstinence Syndrome. Medscape. Available on the world wide web
< http://emedicine.medscape.com/article/978763-overview > [January 2010]
•Farid et al. (2008)The Effects of Maternally Administered Methadone, Buprenorphine and
Naltrexone on Offspring: Review of Human and Animal Data Current Neuropharmacology, 6, 125-
• Swift, M & Dudley, RM (1989) Altered methadone pharmacokinetics in pregnancy: implications
for dosing J Subst Abuse. 1(4):453-60.
• Hagopian, GS et al. (1996) Neonatal outcome following methadone exposure in utero. J Matern
Fetal Med. 5(6):348-54.
• Lam, SK et al. (1992) Narcotic addiction in pregnancy with adverse maternal and perinatal
outcome. Aust N Z J Obstet Gynaecol. 32(3): 216-21
• Stein, J. Et al. (1999) The Methadone-maintained pregnancy. 26(1):173-83.
• Berghella, V. Et al. (2003) Maternal methadone dose and neonatal withdrawal. Am J Obstet
Gynecol 190 (6): 1806-7
•Gaulden, E.C. et al. (1964) Menstrual abnormalities associated with heroin addiction. Am J
Obstet Gynecol. Sep 15;90:155-60.
• UNODC (2010). UNODC and Illicit drug facts. Available on the world wide web <
http://www.unodc.org/unodc/en/illicit-drugs/index.html?ref=menuside> [January 2010]