Buprenorphine

Drug Levels and Effects:




Summary of Use during Lactation:


Because of the low levels of buprenorphine in breastmilk, its poor oral bioavailability in infants, and the low drug concentrations found in the serum and urine of breastfed infants, its use is acceptable in nursing mothers.[1][2] Monitor the infant for drowsiness, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants. Although unlikely, if the baby shows signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness, a physician should be contacted immediately. Observe infants for withdrawal signs if breastfeeding is stopped abruptly. The breastfeeding rate among mothers taking buprenorphine for opiate addiction may be lower than in other mothers.


Drug Levels:


Buprenorphinehas poor oral bioavailability and is usually given by the sublingual or parenteral route. Sublingual bioavailability is 30 to 40% in adults and peak levels in blood occur 60 to 90 minutes after a dose.Buprenorphineis metabolized to the active metabolite, norbuprenorphine. Further metabolism is by glucuronidation.

Maternal Levels.

A breastfeeding mother taking oral buprenorphine maintenance 4 mg daily during pregnancy and lactation had milk samples collected 6 times over the course of a day at 4 weeks postpartum. Milk levels and milk volumes ingested by the infant were measured, but not reported. The authors estimated that the total dose ingested by the infant over 1 day was 3.28 mcg of buprenorphine and 0.33 mcg of norbuprenophine.[3] Assuming an infant weight of 4 kg, the infant dosage in this study is equivalent to about 1.4% of the maternal weight-adjusted dosage.

Four mothers who were 4 days postpartum and taking 0.4, 2, 4 or 6 mg of oral buprenorphine maintenance once daily during pregnancy and lactation had their milk collected 2, 4, 6 and 12 hours after a dose. Peak milk levels occurred 2 hours after the dose in the mothers taking 2 and 4 mg and 4 hours after the dose in the mother taking 6 mg daily. Peak levels were 0.8, 7.8 and 5.8 mcg/L, respectively. Milk levels of buprenorphine and norbuprenorphine were undetectable (lower limit of the assay not given) in the mother taking buprenorphine 0.4 mg daily. Average milk levels in the mothers taking 2, 4 and 6 mg were 0.4, 3.5, and 4.4 mcg/L of buprenorphine and 0.57, 0.45, and 1.15 mcg/L of norbuprenorphine, respectively.[4][5] Based on the average milk levels reported, an exclusively breastfed infant would receive less than 1% of the maternal weight-adjusted dosage. Dosages were on the low end of the usual dosage range for treatment of opiate withdrawal. Furthermore, the authors reported that the mothers' doses were given orally. The oral route is known to have poor bioavailability. The combination of low dose and oral route may have contributed to the low milk levels.

One woman who was receiving daily buprenorphine (dosage and route not stated) for narcotic abstinence had milk levels of 520, 720 and 230 mcg/L on days 3, 6 and 9 postpartum (time of sample not stated).[6]

One woman who was 8 days postpartum had been receiving buprenorphine 8 mg sublingually for narcotic abstinence for 7 months. Ten random milk samples were collected over 4 days. The highest milk levels of buprenorphine and norbuprenorphine were 14.7 and 6.3 mcg/L.[7] Using the peak milk level data, the estimated maximum intake of an exclusively breastfed infant would be 2.4% of the maternal weight-adjusted dosage of buprenorphine and norbuprenorphine, but not including the contribution of any glucuronide metabolite.

Six women receiving a median daily dose of 0.29 mg/kg of buprenorphine for opiate abstinence were studied during the first 5 to 8 days postpartum. Hindmilk samples were obtained 6 to 8 times over a 24-hour period. Breastmilk contained estimated median infant doses of 0.42 mcg/kg of buprenorphine and 0.33 mcg/kg of norbuprenorphine daily, which are equivalent to 0.2% and 0.12% of the maternal weight-adjusted dosage. The range of buprenorphine plus norbuprenorphine was 0.18% to 0.77% of the maternal weight-adjusted dosage. Milk from the nursing mother of a 9-month-old infant receiving 0.32 mg/kg of buprenorphine had concentrations of the drug and metabolite similar to those of the other women.[8]

Seven infant who averaged 1.12 months postpartum (range 0.58 to 1.85 months)and taking buprenorphine for opiate substitution during pregnancy and lactation collected foremilk and hindmilk samples with each feeding for 24 hours. The average maternal dosage was 9.3 mg daily and the median was 7 mg daily (range 2.4 to 24 mg daily). The average buprenorphine concentration in milk was 3.65 mcg/L and the average norbuprenorphine concentration was 1.94 mcg/L. These corresponded to daily dosages of 0.55 and 0.29 mcg/kg, respectively and weight-adjusted dosages of 0.38% and 0.18% of the maternal dosage, respectively.[9]

Infant Levels.

Six nursing infants from 5 to 8 days of age whose mothers were taking a median daily dose of 0.29 mg/kg of buprenorphine had one urine sample collected between 4 and 20 hours after the previous maternal dose.Buprenorphinewas undetectable (<187 ng/L) in 3 infants; the other 3 had urine concentrations of about 468 ng/L. Norbuprenorphine urine concentrations ranged from 414 to 1987 ng/L (median 952 ng/L). A seventh 9-month-old breastfed infant whose mother was taking 20 mg (0.32 mg/kg) of buprenorphine daily had serum and urine collected. Serum concentrations of buprenorphine and norbuprenorphine were 234 ng/L and 745 ng/L, respectively, at 2.25 hours after the previous maternal dose. A urine sample obtained 3.5 hours after the previous maternal dose contained <234 ng/l="" and="" 455="" ng/l="" of="" the="" drug="" and="" metabolite,="">


Effects in Breastfed Infants:


Numerous infants have been reported to breastfeed during maternal narcotic abstinence therapy with buprenorphine with no adverse effects,[3][6][10][11][12] one for 6 months.[10] The amounts of buprenorphine in milk may not be sufficient to prevent neonatal withdrawal, and treatment of infant may be required.[5][13]

Despite breastfeeding and relatively high infant serum drug levels, mild buprenorphine withdrawal occurred in the neonate of a mother taking buprenorphine 4 mg daily (route not specified) during pregnancy and postpartum for heroin addiction.[3] This indicates that an insufficient dosage appeared in milk to prevent neonatal abstinence.

Ten women who had undergone cesarean section delivery of term newborns were given extradural buprenorphine 200 mcg followed by 8.4 mcg/hour with an anesthetic for postoperative pain for 3 days postpartum. A control group of 10 other women were given extradural anaesthetic only without buprenorphine . Over 11 days postpartum, newborns of mothers in the buprenorphine group had much lower milk intake and lower weight gain than those in the non- buprenorphine group. The authors suggested that extradural buprenorphine suppressed infant breastfeeding. Infant neurobehavioral assessments were not performed.[14]

Six infants whose mothers were taking buprenorphine during pregnancy and postpartum were breastfed. Four of the infants had signs of opioid abstinence, indicating that the amounts of buprenorphine in breastmilk were inadequate to prevent withdrawal. At 1 month after discharge from the hospital, all infants had normal development and weight gain.[8]

Seven infant who averaged 1.12 months of age (range 0.58 to 1.85 months) were being breastfed by mothers taking buprenorphine for opiate substitution during pregnancy and lactation. Urine screening indicated that 4 mothers had also been using cannabis, 1 was using unprescribed benzodiazepines, and 1 mother was using both cannabis and benzodiazepines. Four of the infants were exclusively breastfed and 3 were mostly breastfed. Infants had no apparent drug-related adverse effects and showed satisfactory developmental progress.[9]

A mother used buprenorphine (dose and indication not stated) during pregnancy. Her infant displayed no signs of neonatal abstinence at birth. The infant was breastfed (extent not stated) until 4 months of age when the mother stopped breastfeeding. Two days later the infant had withdrawal symptoms including frequent yawning, sneezing, pupillary dilation, agitation, sweating, hyperactive Moro reflex, myoclonic jerks, tremors, and insomnia. The infant was given methadone with immediate improvement of her withdrawal symptoms. The infant's withdrawal symptoms were probably caused by abrupt withdrawal of breastfeeding.[15]


Possible Effects on Lactation:


Buprenorphinecan increase serum prolactin.[16] However, the prolactin level in a mother with established lactation may not affect her ability to breastfeed.

In a multicenter prospective study of 246 pregnant women receiving either methadone or buprenorphine for opiate addiction, 153 women were receiving high-dose buprenorphine . Twenty-two percent of women receiving buprenorphine breastfed their infants, which was the same percentage as those receiving methadone.[17]

A case series of opiate-dependent mothers who delivered in a Baby Friendly Hospital found that mothers taking buprenorphine or methadone for opiate addiction were unlikely to breastfeed their infants. Only 45% of the 20 mothers on buprenorphine maintenance initiated breastfeeding. Of all women in the study, 60% discontinued breastfeeding before discharge from the hospital.[18]

In a case series of 23 women maintained on buprenorphine during pregnancy and postpartum, 70% were breastfeeding on discharge from the hospital and 50% were breastfeeding at their 6- to 8-week follow-up appointment (extent of nursing not stated).[19]


Alternate Drugs to Consider:


(Narcotic Abstinence) Methadone,Naltrexone,(Pain) Acetaminophen,Ibuprofen,Morphine


References:


1. US Department of Health and Human Services. Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction. A treatment improvement protocol: TIP 40. 2004;70.
2. ACOG Committee Opinion No. 524: Opioid abuse, dependence, and addiction in pregnancy. Obstet Gynecol. 2012;119:1070-6. PMID:22525931
3. Marquet P, Chevrel J, Lavignasse P et al.Buprenorphinewithdrawal syndrome in a newborn. Clin Pharmacol Ther. 1997;62:569-71. PMID:9390114
4. Jernite M, Diemunsch P, Kintz P.Buprenorphineexcretion in breast milk. Anesthesiology. 1999;91:A1095. Abstract.
5. Jernite M, Diemunsch P, Kintz P et al. [Passage of buprenorphine into mother's milk]. Ann Fr Anesth Reanim. 1999;18 (Suppl 1):109S. Abstract.
6. Johnson RE, Jones HE, Jasinski DR et al.Buprenorphinetreatment of pregnant opioid--dependent women: maternal and neonatal outcomes. Drug Alcohol Depend. 2001;63:97-103. PMID:11297835
7. Grimm D, Pauly E, Poschl J et al.Buprenorphineand norbuprenorphine concentrations in human breast milk samples determined by liquid chromatography-tandem mass spectrometry. Ther Drug Monit. 2005;27:526-30. PMID:16044112
8. Lindemalm S, Nydert P, Svensson JO et al. Transfer of buprenorphine into breast milk and calculation of infant drug dose. J Hum Lact. 2009;25:199-205. PMID:19136395
9. Ilett KF, Hackett LP, Gower S et al. Estimated dose exposure of the neonate to buprenorphine and its metabolite norbuprenorphine via breastmilk during maternal buprenorphine substitution treatment. Breastfeed Med. 2012;7:269-74. PMID:22011128
10. Schindler SD, Eder H, Ortner R et al. Neonatal outcome following buprenorphine maintenance during conception and throughout pregnancy. Addiction. 2003;98:103-10. PMID:12492761
11. Kayemba-Kay's S, Laclyde JP.Buprenorphinewithdrawal syndrome in newborns: a report of 13 cases. Addiction. 2003;98:1599-604. PMID:14616186
12. Johnson RE, Jones HE, Fischer G. Use of buprenorphine in pregnancy: patient management and effects on the neonate. Drug Alcohol Depend. 2003;70 (2 Suppl):S87-S101. PMID:12738353
13. Loustauneau A, Auriacombe M, Daulouede JP, Tignol J . [Is buprenorphine a potential alternative to methadone for treating pregnant drug users? Inventory of clinical data in the literature]. Ann Med Interne (Paris). 2002;153 (7 Suppl):2S31-6. PMID:12518080
14. Hirose M, Hosokawa T, Tanaka Y. Extradural buprenorphine suppresses breast feeding after cesarean section. Br J Anaesth. 1997;79:120-1. PMID:9301399
15. Elladki H, Thill P.Buprenorphinewithdrawal in an infant after cessation of breastfeeding: A case report and review of the literature. Pharmacotherapy. 2011;31:435e.
16. Saarialho-Kere U, Mattila MJ, Paloheimo M, Seppala T. Psychomotor, respiratory and neuroendocrinological effects of buprenorphine and amitriptyline in healthy volunteers. Eur J Clin Pharmacol. 1987 ;33:139-46. PMID:3691607
17. Lejeune C, Aubisson S, Simmat-Durand L et al. [Withdrawal syndromes of newborns of pregnant drug abusers maintained under methadone or high-dose buprenorphine : 246 cases]. Ann Med Interne (Paris). 2001;152 (Suppl 7):21-7. PMID:11965095
18. Wachman EM, Byun J, Philipp BL. Breastfeeding rates among mothers of infants with neonatal abstinence syndrome. Breastfeed Med. 2010;5:159-64. PMID:20658895
19. O'Connor A, Alto W, Musgrave K et al. Observational study of buprenorphine treatment of opioid-dependent pregnant women in a family medicine residency: reports on maternal and infant outcomes. J Am Board Fam Med. 2011;24:194-201. PMID:21383220



Substance Identification:




Substance Name:

Buprenorphine

CAS Registry Number:

52485-79-7

Drug Class:


  • Analgesics, Opioid

  • Narcotics

  • Narcotic Antagonists


  • Administrative Information:




    LactMed Record Number:


    338


    Last Revision Date:


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