Buprenorphine

 Risk Factor: CM
 Class: CENTRAL NERVOUS SYSTEM DRUGS / Narcotic Agonist-Antagonist Analgesics

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

Buprenorphine, an analgesic that possesses both narcotic agonist and antagonist activity, is approximately 33 times more potent than morphine (0.3 mg buprenorphine is equivalent to 10 mg morphine in analgesic and respiratory depressant effects). Although a sublingual formulation is available in other countries, only parenteral buprenorphine has been approved for general use in the United States. The human adult dose is 0.30.6 mg IM or IV repeated up to every 6 hours (0.017 0.034 mg/kg/day for a 70-kg person).

Buprenorphine is currently under investigation as an alternative to methadone maintenance treatment of narcotic dependence (1,2 and 3). The drug has also been studied as an alternative to cocaine, but it is apparently not effective for this use (2). Although these trials have not yet included pregnant women, the advantages of buprenorphine over methadone during gestation may include less respiratory depression at high doses, less toxicity from overdose, less severe withdrawal after abrupt discontinuance of the drug, and potentially less abuse liability (1,2). Of inter est, however, abuse of buprenorphine, often concurrently with opiates, has been reported outside of the United States (4,5). One of these latter citations reported frequent abuse of buprenorphine by pregnant women but provided no outcome data (4).

Reproduction studies in rats and rabbits have been conducted (6,7,8,9,10,11 and 12). No fetal adverse effects were observed in rats and rabbits when their mothers were administered doses up to 5 mg/kg IM during organogenesis (6). Shepard cited a study in which fetal growth retardation, but not congenital defects, was observed in rats exposed to maternal doses of >0.055 mg/kg/day (about 3300 times the recommended human dose [RHD]) given after implantation through delivery (7). Rat fetuses exposed to 5 mg/kg/day in the last week of pregnancy had a reduced survival rate after delivery (7). As reported by the manufacturer, no major congenital malformations were observed in rats given doses of 101000 times (SC or IM) or 160 times (IV) the RHD, but significant increases in postimplantation losses and early fetal deaths were noted with IM doses of 10 and 100 times the RHD (8). A slight increase in postimplantation losses was also observed with IV doses of 40 and 160 times the RHD. In rabbits, IM doses produced a dose-related increase in extra rib formation that was statistically significant at 1000 times the RHD (8). Rats pups exposed in utero throughout gestation to maternal doses of buprenorphine, 1 and 2 mg/kg/day SC, had reduced survival. Minimal effects were observed on the endogenous opioid system, however, as determined by a comparison of the brain enkephalin levels of buprenorphine-exposed pups to those in methadone-exposed pups (9).

In a study involving pregnant rats, buprenorphine was administered by a continuous infusion in doses of 0.3, 1.0, and 3.0 mg/kg/day from day 8 of gestation through parturition (10). At these doses, no evidence of significant maternal toxicity was observed, nor were there any significant effects on the offspring in terms of morbidity and mortality, birth weight, and postnatal growth (up to 60 days) (10). In a second publication by these researchers, using the same drug-administration technique and animal type described above, no disruption in the rest-activity cycle was observed in the exposed offspring at 22 and 30 days of age (11).

The long-term effects on sexual differentiation in rats exposed in utero to maternal injections of buprenorphine, 0.3 or 0.6 mg/kg every 48 hours from day 6 to day 20 of gestation, were described in a study published in 1997 (12). Compared with controls and the lower dose group, spontaneous parental behavior (at 2328 days of age) and the expected sex difference in the consumption of a 0.25% saccharin solution (at 4255 days of age) were impaired in the 0.6-mg/kg-exposed offspring. The authors concluded that the higher dose of buprenorphine produced long-term adverse effects on behavior (12).

As suggested by the relatively low molecular weight of its hydrochloride salt (about 504), buprenorphine crosses the placenta to the fetus. In a 1997 case report, a 24-year-old woman was treated with buprenorphine 4 mg/day for heroin addiction, starting in the 4th month of pregnancy (13). Frequent tests during the remainder of the pregnancy and at delivery confirmed her rapid withdrawal from heroin. Except for buprenorphine, all tests were negative for opiates, cocaine, cannabis, and amphetamines. An apparently normal female infant (birth weight not specified) was delivered at 39 weeks' gestation. Apgar scores were 10 and 10 at 1 and 10 minutes, respectively. High levels of buprenorphine and its metabolite were measured in the newborn approximately 20 hours after birth. Maternal trough serum concentrations of buprenorphine and the metabolite, norbuprenorphine, obtained a few days before delivery were 0.3 and 2.3 ng/mL, respectively. Parent drug and metabolite concentrations in the meconium were 107 and 295 ng/g, respectively. Levels of drug and metabolite were, respectively, 1.9 and 1.7 ng/mL and in the newborn's serum and 36.8 and 61.1 ng/mL in the newborn's urine. The estimated cord:maternal serum ratio was 6.3, whereas the ratio for the metabolite was 0.7. A weak withdrawal syndrome was observed at 48 hours of age with an adapted Finnegan score (used to evaluate the intensity of withdrawal syndromes; range 040) of 12 (13). Symptoms, which resolved without therapy, consisted of agitation, sleep disturbance, tremor, yawning, noisy breathing, and a slight fever (13). The Finnegan score fell to 8 at 3 days of age and was normal by 6 days of age.

The effect of epidural buprenorphine combined with bupivacaine has been compared with epidural combinations of bupivacaine and morphine, fentanyl, sufentanil, and oxymorphone for analgesia during and after cesarean section (14,15,16 and 17). The analgesic effects of the narcotic agents were similar, but buprenorphine caused a significant increase in maternal vomiting (14,15 and 16). No adverse neonatal effects were observed in the two studies that used buprenorphine before delivery (14,17).

The use of sublingual buprenorphine for labor pain in 34 primigravida women was described in a 1992 report (18). Each patient received a single 6-g/kg dose during the first stage of labor. No effects were observed on the progression of labor and none of the women had nausea or vomiting. Similarly, no changes in fetal heart rate (range 138150 beats/minute) were observed. Buprenorphine produced no neonatal depression as evidenced by the average Apgar scores (range not specified) at 1 and 5 minutes of 9.71 and 9.94, respectively.

In summary, buprenorphine is a potent narcotic agonist and antagonist that has been used during human pregnancy for analgesia immediately prior to delivery in a small number of cases. Only one pregnancy case has been located in which the drug was given as a narcotic substitute for heroin dependency. Neonatal withdrawal was observed, but the symptoms were less than that expected with methadone. Animal studies have demonstrated dose-related maternal, embryo, and fetal toxicity and dose-related behavioral changes in offspring, but no congenital malformations. Although the lack of congenital anomalies is reassuring, the behavioral changes in animals combined with the absence of published early human pregnancy experience prevent an assessment of the risk this drug presents to the embryo or fetus. Because there is substantially more published human pregnancy experience for other narcotic analgesics, they are preferred to buprenorphine, especially during early gestation. Buprenorphine may have a role as substitution therapy for maternal heroin addiction, but additional reports are needed to define its pregnancy safety profile before this use can be recommended.

Breast Feeding Summary

Buprenorphine is excreted into human milk. In a 1997 case report (see above), a 24-year-old former heroin addict on buprenorphine maintenance therapy (4 mg/day) gave birth to an apparently normal female infant at 39 weeks' gestation (13). She continued taking buprenorphine while nursing her infant. At 4 weeks of age, buprenorphine and its metabolite, norbuprenorphine, were determined in her milk at each feeding over a 24-hour period. The volume of milk drunk was estimated by weighing the infant before and after the feedings. Although the specific milk concentrations were not provided, the authors estimated that the total doses of drug and metabolite ingested by the infant over the 24-hour period were 3.28 and 0.33 g, respectively. No withdrawal symptoms in the infant were observed when lactation was abruptly interrupted at 8 weeks of age.

A study published in 1997 described the effects of continuous extradural bupivacaine and buprenorphine on analgesia and breast feeding in 20 healthy women who had undergone a cesarean section at term (19). The study group (N=10) received a 5-mL bolus of bupivacaine 0.25% with 200 mg of buprenorphine extradurally at cord clamping, followed by a continuous extradural infusion of bupivacaine (0.25%) and buprenorphine (12 mg/mL) infused at 0.7 mL/hour for 3 days. The control group (N=10) received the same bolus and continuous infusion, but without the buprenorphine. There were no significant differences in visual analogue pain scores between the groups at 2 hours, 1 day, and 2 days, but the controls received significantly more supplemental diclofenac (a nonsteroidal antiinflammatory agent) during the 2-day period (mean 25 mg vs. 5 mg, p<0.05). The weight of breast milk ingested at each feeding was estimated by weighing the infant before and after each feeding. Compared with the control group, the buprenorphine group ingested significantly less milk each day (starting at day 3), and the infant's daily weight as a percentage of birth weight was significantly less starting at day 7. In both effects, the significant differences continued up to 11 days, near the time of discharge from the hospital. The investigators speculated that the differences between the two groups might be due to central nervous system depression in the mother and infant. Although one author thought the stress of the prolonged hospital stay may have depressed the breast feeding (20), the investigators responded that long hospital stays are normal in Japan and, if stress is a factor, would have affected both groups similarly (19).

Because buprenorphine is excreted into milk and because depression of the nursing infant resulting in lower weight gain is a possibility, mothers receiving buprenorphine should probably not breast-feed. If breast feeding is undertaken, the mother should be advised of the potential risk to her infant.

References

1. Vocci F, Chiang CN, Cummings L, Hawks R. Overview: medications development for the treatment of drug abuse. NIDA Res Monogr 1995;149:415.
2. Schottenfeld RS. Clinical trials of pharmacologic treatments in pregnant women - methodologic considerations. NIDA Res Monogr 1995;149:20123.
3. O'Connor PG, Oliveto AH, Shi JM, Triffleman EG, Carroll KM, Kosten TR, Rounsaville BJ, Pakes JA, Schottenfeld RS. A randomized trial of buprenorphine maintenance for heroin dependence in a primary care clinic for substance users versus a methadone clinic. Am J Med 1998;105:1005.
4. Stewart MJ. Effect of scheduling of buprenorphine (Temgesic) on drug abuse patterns in Glasgow. BMJ 1991;302:969.
5. Strang J. Abuse of buprenorphine (Temgesic) by snorting. BMJ 1991;302:969.
6. Heel RC, Brogden RN, Speight TM, Avery GS. Buprenorphine: a review of its pharmacological properties and therapeutic efficacy. Drugs 1979;17:81110.
7. Mori N, Sakanoue M, Kamata S, Takeuchi M, Shimpo K, Tamagawa M. Toxicological studies of buprenorphine teratogenicity, perinatal and postnatal studies in the rat. Iyaku Kenkyu 1982;13:50944. As cited in Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD:Johns Hopkins University Press, 1995:589.
8. Product information. Buprenex. Reckitt & Colman Pharmaceuticals, 1998.
9. Tiong GK, Olley JE. Effects of exposure in utero to methadone and buprenorphine on enkephalin levels in the developing rat brain. Neurosci Lett 1988;93:1016.
10. Hutchings DE, Zmitrovich AC, Hamowy AS, Liu P-YR. Prenatal administration of buprenorphine using the osmotic minipump: a preliminary study of maternal and offspring toxicity and growth in the rat. Neurotoxicol Teratol 1995;17:41923.
11. Hutchings DE, Hamowy AS, Williams EM, Zmitrovich AC. Prenatal administration of buprenorphine in the rat: effects on the rest-activity cycle at 22 and 30 days of age. Pharmacol Biochem Behav 1996;55:60713.
12. Barron S, Chung VM. Prenatal buprenorphine exposure and sexually dimorphic nonreproductive behaviors in rats. Pharmacol Biochem Behav 1997;58:33743.
13. Marquet P, Chevrel J, Lavignasse P, Merle L, Lachatre G. Buprenorphine withdrawal syndrome in a newborn. Clin Pharmacol Ther 1997;62:56971.
14. Celleno D, Costantino P, Emanuelli M, Capogna G, Muratori F, Sebastiani M, Cipriani G. Epidural analgesia during and after cesarean delivery. Comparison of five opioids. Reg Anesth 1991;16:79 83.
15. Cohen S, Amar D, Pantuck CB, Pantuck EJ, Weissman AM, Landa S, Singer N. Epidural patient-controlled analgesia after cesarean section: buprenorphine-0.015% bupivacaine with epinephrine versus fentanyl-0.015% bupivacaine with and without epinephrine. Anesth Analg 1992;74:22630.
16. Cohen S, Amar D, Pantuck CB, Pantuck EJ, Weissman AB. Adverse effects of epidural 0.03% bupivacaine during analgesia after cesarean section. Anesth Analg 1992;75:7536.
17. Lehmann KA, Stern S, Breuker KH. Obstetrical peridural anesthesia with bupivacaine and buprenorphine. A randomized double-blind study in comparison with untreated controls. Anaesthesist 1992;41:41422.
18. Roy S, Basu RK. Role of sublingual administration of tablet buprenorphine hydrochloride on relief of labour pain. J Indian Med Assoc 1992;90:1513.
19. Hirose M, Hosokawa T, Tanaka Y. Extradural buprenorphine suppresses breast feeding after caesarean section. Br J Anaesth 1997;79:1201.
20. Celebioglu B. Extradural buprenorphine and breast feeding after caesarean section. Br J Anaesth 1998;80:271.
    
    

Questions and Answers

What are the differences between buprenorphine and methadone?, I have read some things that say that buprenorphine is now the medication of choice among many individuals suffering from opioid addiction. I was just wondering about the advantages of using buprenorphine as compared to methadone.

Though buprenorphine and methadone are both utilized for long-terma and short term opioid maintencance therapy, each one has its advantages as well as disadvantages.

Buprenorphine has a longer duration of action which can allow dosing to be done every two days, as opposed to methadone wherein daily dosing is required. Buprenorphine may also have a lower dependence-liability compared to methadone. Also, buprenorphine treatment may last from several months to a few years. Methadone treatment, however, is often indefinite and becomes a life-long regimen. Buprenorphine also has less severe effects of withdrawal when compared to methadone, which makes it easier for the patient to discontinue use.

I hope that satisfied your curiosity! :)

Are there any drug rehabs in Mertztown, Pennsylvania that administer buprenorphine?, I would like to know a lot of information about buprenorphine. I have already searched the Internet for information but I have found some sources to be contradicting when it comes to the info that they provide. This is why I would like to find the people themselves who are familiar with this kind of medication.

The links below will get to help you out in finding drug rehabs. Just inquire and ask them if they do administer buprenorphine. You can also call this helpline: 800-559-9503. They might know answers to your questions. You can also contact your local health services administration and ask around for information. Good luck!

I want to find drug rehabs in Lotus, California, that administer buprenorphine. How?, I have heard that buprenorphine is a more appealing treatment option than methadone. I would like to research more information about this, thus the desire to find drug rehabs that administer it.

From what I have read about buprenorphine, it does seem to be a more appealing treatment option than methadone, though it also has a lot of side effects. I'm sure your research will yield more details, though. You can use the following links to find drug rehabs. You can also call your local health services department for more information. :)

How long after using suboxone (buprenorphine) will ultram (tramadol) be effective?, I take 2mg of suboxone/day; how long must i go without taking suboxone (buprenorphine) before Ultram (tramadol) will be effective and how effective will the tramadol be in comparison to if suboxone had never been used?

I know a girl that takes suboxone and she says that you have no pain or no cravings for pain meds.
You are not suppose to mix suboxone with anything without asking your doctor cause it can cause you to go into being so sick.

Follow the link: http://www.suboxone.com

I would like to find drug rehabs in Avenel, New Jersey that administer buprenorphine. Any suggestions?, I would like to know more information regarding buprenorphine use and I want to speak to the people who are used to administering this drug.

I have read somewhere that buprenorphine's a lot more appealing than methadone when it comes to the treatment of opiate addiction. Anyway, in order for you to find drug rehabilitation centers that administer buprenorphine, just use the links below. I do hope that you get the information you need. Good luck!

is it easier to overdose on methadone alone than to overdose on buprenorphine?, Is it easier to overdose on methadone alone than to overdose on buprenorphine.

i dont think that you shld overdose on either, so im not going to give you advise on which one is easier to overdose on

Instead of Methadone I am going on buprenorphine?, I have been hooked on percs, oxy's and codiene. Instead of the methadone program my shrink is putting me on buprenorphine. Has anyone done this route to get off opiates? If so please tell me about your experience with this drug.

suboxone is the real deal-forget all that crap you've been taking -I used to take all that too-this stuff has worked wonders for me and i will soon be going off it also .

How long does Suboxon stay in your system for a drug test? A Buprenorphine drug test?, I need to know ASAP how long Suboxone is in your system, i am going to jail on a work release program and they DO test for it. They have had to many problems with people on it and them not catching them. So they ordered test for Buprenorphine. So is it like regular opiates? 3 days? get back to me asap please! thanks

Buprenorphine and its metabolites can be detected for 96 hours.

Does anyone here have any information on buprenorphine as a substance abuse treatment?, I have read some stuff that claim that methadone can be addictive as well. Of course, if the intake is facilitated properly, the chances that one will overdose is slim. But I have recently heard about buprenorphine and I was just wondering about whether this is better than methadone when it comes to the treatment of substance abuse.

It has been stated by the Behavioral Pharmacology Research Unit at The Johns Hopkins University School of Medicine in Baltimore, that just a single injection of buprenorphine is able to block the effects of heroin and relieve heroin craving and withdrawal symptoms for up to 6 weeks. Tests also showed that the formulation of buprenorphine appeared to be safe and well-tolerated, with no side effects or signs of respiratory depression or opioid intoxication. In addition, patients also did not need additional medication for relief from withdrawal. All in all, buprenorphine seems to be an appealing and effective treatment option for heroin and other opioid addicts.

Is there an addiction treatment center in Hockessin, Delaware that uses buprenorphine for the patients?, I have heard from a friend of mine (who is located at another state) that buprenorphine is better than methadone, and that it is administered in less dosages, but that the effects last a long time. I want to know if there is someone here who can point me to a center wherein they use buprenorphine for medication.

I have included in the links below a buprenorphine physician locator. I hope that helps. There's also a list of the available treatment centers in your area, so maybe you could call a few and ask. Before you choose one, though, make sure to check with the doctor first if it would really be good to get buprenorphine treatment.