RCT Comparing Methadone and Buprenorphine in Pregnant Women

• ClinicalTrials.gov Identifier: NCT00271219
• Recruitment Status: Completed
• First Posted: December 30, 2005
• Results First Posted: August 5, 2015
• Last Update Posted: August 5, 2015
• Sponsor: Johns Hopkins University
• Collaborator: National Institute on Drug Abuse (NIDA)
• Information provided by (Responsible Party): Hendree E. Jones, Johns Hopkins University

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Opioid Related Disorders; Pregnancy; Opioid Dependence
• Interventions: Drug: Methadone; Drug: Buprenorphine
• Enrollment: 175

Participant Flow

Recruitment Details	1074 Patients were screened for eligibility. 175 underwent randomization. 86 were assigned to receive buprenorphine. 58 of the patients assigned to buprenorphine completed the study. 89 were assigned to receive methadone. 73 of the patients assigned to methadone completed the study.
Pre-assignment Details	Of the 1074 screened: 243 did not give consent. 656 were excluded for a variety of reasons ranging from an estimated gestation age outside the range, to impending legal issues, to multiple-fetus pregnancy.

Arm/Group Title	Methadone	Buprenorphine
Arm/Group Description	Methadone Methadone : daily oral dosing 20-140 mg	Buprenorphine Buprenorphine : sl daily 2-32 mg
Period Title: Overall Study
Started	89	86
Completed	73	58
Not Completed	16	28

Baseline Characteristics

Arm/Group Title		Methadone	Buprenorphine	Total
Arm/Group Description		Methadone Methadone : daily oral dosing 20-140 mg	Buprenorphine Buprenorphine : sl daily 2-32 mg	Total of all reporting groups
Overall Number of Baseline Participants		73	58	131
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	73 participants	58 participants	131 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	73 100.0%	58 100.0%	131 100.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	73 participants	58 participants	131 participants
		27.7 (0.7)	25.3 (0.7)	26.5 (0.7)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	73 participants	58 participants	131 participants
	Female	73 100.0%	58 100.0%	131 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	73 participants	58 participants	131 participants
United States		54	40	94
Austria		19	18	37

Outcome Measures

1. Primary Outcome

Title	Child's Head Circumference Measurement (Measured at Birth)
Description	[Not Specified]
Time Frame	birth

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A Methadone	B Buprenorphine
Arm/Group Description:	Methadone Methadone : daily oral dosing 20-140 mg	Buprenorphine Buprenorphine : sl daily 2-32 mg
Overall Number of Participants Analyzed	73	58
Mean (95% Confidence Interval); Unit of Measure: cm
	33.0; (32.7 to 33.3)	33.8; (33.5 to 34.1)

2. Primary Outcome

Title	Child's Length of Hospital Stay
Description	[Not Specified]
Time Frame	delivery until hospital discharge (min=2 days, max=79 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A Methadone	B Buprenorphine
Arm/Group Description:	Methadone Methadone : daily oral dosing 20-140 mg	Buprenorphine Buprenorphine : sl daily 2-32 mg
Overall Number of Participants Analyzed	73	58
Mean (95% Confidence Interval); Unit of Measure: days
	17.5; (16 to 19)	10.0; (8.8 to 11.2)

3. Primary Outcome

Title	Number of Children Requiring Treatment for Neonatal Abstinence Signs (NAS)
Description	Neonatal abstinence syndrome (NAS) characterized by hyperirritability of the central nervous system and dysfunction in the autonomic nervous system, gastrointestinal tract, and respiratory system.11 When left untreated, NAS can result in serious illness (e.g., diarrhea, feeding difficulties, weight loss, and seizures) and death.
Time Frame	From birth until hospital discharge (min=4 days, max=10, depending on site)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A Methadone	B Buprenorphine
Arm/Group Description:	Methadone Methadone : daily oral dosing 20-140 mg	Buprenorphine Buprenorphine : sl daily 2-32 mg
Overall Number of Participants Analyzed	73	58
Measure Type: Number; Unit of Measure: participants
	41	27

4. Primary Outcome

Title	Child's Peak Daily Total NAS Score
Description	NAS was measured with the MOTHER NAS scale, which includes 28 items, 19 of which are used for scoring and medication decisions. Scores can range from 0 to 42, with higher scores indicating more severe withdrawal.
Time Frame	minimum twice daily from birth until NAS no longer measured (min=10 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A Methadone	B Buprenorphine
Arm/Group Description:	Methadone Methadone : daily oral dosing 20-140 mg	Buprenorphine Buprenorphine : sl daily 2-32 mg
Overall Number of Participants Analyzed	73	58
Mean (95% Confidence Interval); Unit of Measure: Score on the scale
	12.8; (12.2 to 13.4)	11.0; (10.4 to 11.6)

5. Primary Outcome

Title	Total Amount of Morphine Sulfate That a Neonate Receives to Treat NAS
Description	Total amount in mg
Time Frame	Start of NAS treatment until discontinuation of NAS treatment (min=0 days, max=76 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	A Methadone	B Buprenorphine
Arm/Group Description:	Methadone Methadone : daily oral dosing 20-140 mg	Buprenorphine Buprenorphine : sl daily 2-32 mg
Overall Number of Participants Analyzed	73	58
Mean (95% Confidence Interval); Unit of Measure: mg
	10.4; (7.8 to 13)	1.1; (0.4 to 1.8)

6. Secondary Outcome

Title	Mother's Self-report of Drug Use (Measured Monthly by Time Line Follow Back)
Description	[Not Specified]
Time Frame	monthly from study entry until discontinuation or delivery (min=29 days, max=239 days)

Outcome Measure Data

Analysis Population Description

frequency of use during the course of the study was too low to estimate the parameter with sufficient accuracy

Arm/Group Title	A Methadone	B Buprenorphine
Arm/Group Description:	Methadone Methadone : daily oral dosing 20-140 mg	Buprenorphine Buprenorphine : sl daily 2-32 mg
Overall Number of Participants Analyzed	89	86
Measure Type: Number; Unit of Measure: percentage of drug use
	NA [1]	NA [1]

[1]

frequency of use during the course of the study was too low to estimate the parameter with sufficient accuracy

7. Secondary Outcome

Title	Mother's HIV Risk Behaviors (Measured Monthly by Risk Behavior Assessment)
Description	[Not Specified]
Time Frame	monthly from study entry until discontinuation or delivery (min=29 days, max=239 days)

Outcome Measure Data

Analysis Population Description

frequency of occurrence too low to be estimated with accuracy

Arm/Group Title	A Methadone	B Buprenorphine
Arm/Group Description:	Methadone Methadone : daily oral dosing 20-140 mg	Buprenorphine Buprenorphine : sl daily 2-32 mg
Overall Number of Participants Analyzed	89	86
Measure Type: Number; Unit of Measure: percentage of HIV risk behaviors
	NA [1]	NA [1]

[1]

frequency of occurrence too low to be estimated with accuracy

8. Secondary Outcome

Title	Mother's Measures of Dose Adequacy and Acceptance Over Time (Measured Weekly by Dose Adequacy Measure)
Description	Pregnant women maintained on an opioid agonist medication may require upward adjustment to their medication during the course of pregnant. The Dose Adequacy Measure represented a recordation of dosing adjustments during the course of the study.
Time Frame	from study entry until discontinuation or delivery (min=29 days, max=239 days)

Outcome Measure Data

Analysis Population Description

intra-subject variability in dosing (typically 1 dose) over course of the trial was too small to estimate the parameter of interest with sufficient accuracy

Arm/Group Title	A Methadone	B Buprenorphine
Arm/Group Description:	Methadone Methadone : daily oral dosing 20-140 mg	Buprenorphine Buprenorphine : sl daily 2-32 mg
Overall Number of Participants Analyzed	89	86
Measure Type: Number; Unit of Measure: dose increase per trimester
	NA [1]	NA [1]

[1]

intra-subject variability in dosing (typically 1 dose) over course of the trial was too small to estimate the parameter of interest with sufficient accuracy

9. Secondary Outcome

Title	Mother's Psychosocial Functioning at Delivery as Measured by the Addiction Severity Index Psychosocial Index Score
Description	The Addiction Severity Index is a structured clinical interview that assesses problem severity in 7 areas of functioning: alcohol use, drug use, medical, legal, employment, psychosocial, and psychiatric status. Each area of functioning yields a composite scale score between 0 and 1, with higher scores indicating greater problem severity in that area. Only the psychosocial index was examined in this study.
Time Frame	at delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Methadone	Buprenorphine
Arm/Group Description:	Methadone Methadone : daily oral dosing 20-140 mg	Buprenorphine Buprenorphine : sl daily 2-32 mg
Overall Number of Participants Analyzed	89	86
Mean (95% Confidence Interval); Unit of Measure: Score on the scale
	.014; (-.134 to .166)	.088; (-.027 to .203)

Adverse Events

Time Frame	Entire course of the study, from baseline to end of study period (min=26 days, max=239 days)
Adverse Event Reporting Description	weekly assessment by self-report and clinician review with patient
Arm/Group Title	Methadone: Mothers	Buprenorphine: Mothers	Methadone: Neonates	Buprenorphine: Neonates
Arm/Group Description	Methadone Methadone : daily oral dosing 20-140 mg	Buprenorphine Buprenorphine : sl daily 2-32 mg	Neonates born to mothers maintained on methadone	Neonates born to mothers maintained on buprenorphine
All-Cause Mortality
	Methadone: Mothers	Buprenorphine: Mothers	Methadone: Neonates	Buprenorphine: Neonates
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--	--/--
Serious Adverse Events
	Methadone: Mothers	Buprenorphine: Mothers	Methadone: Neonates	Buprenorphine: Neonates
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	14/89 (15.73%)	8/86 (9.30%)	6/73 (8.22%)	1/58 (1.72%)
Cardiac disorders
cardiovascular † 1	1/89 (1.12%)	0/86 (0.00%)	2/73 (2.74%)	1/58 (1.72%)
Gastrointestinal disorders
gastrointestinal † 1	1/89 (1.12%)	1/86 (1.16%)	0/73 (0.00%)	1/58 (1.72%)
General disorders
other † 1	0/89 (0.00%)	1/86 (1.16%)	1/73 (1.37%)	1/58 (1.72%)
Infections and infestations
sexually transmitted diseases † 1	1/89 (1.12%)	0/86 (0.00%)	0/73 (0.00%)	0/58 (0.00%)
Musculoskeletal and connective tissue disorders
musculoskeletal † 1	0/89 (0.00%)	0/86 (0.00%)	0/73 (0.00%)	1/58 (1.72%)
Nervous system disorders
neurological † 1	0/89 (0.00%)	0/86 (0.00%)	0/73 (0.00%)	1/58 (1.72%)
sleep disturbances † 1 [1]	0/89 (0.00%)	1/86 (1.16%)	0/0	0/0
Pregnancy, puerperium and perinatal conditions
Abnormal fetal health † 1 [1]	3/89 (3.37%)	0/86 (0.00%)	0/0	0/0
obstetrical † 1	6/89 (6.74%)	2/86 (2.33%)	1/73 (1.37%)	1/58 (1.72%)
Psychiatric disorders
Illicit drug use † 1 [1]	1/89 (1.12%)	1/86 (1.16%)	0/0	0/0
psychological † 1 [1]	1/89 (1.12%)	0/86 (0.00%)	0/0	0/0
Renal and urinary disorders
genitourinary † 1	0/89 (0.00%)	1/86 (1.16%)	0/73 (0.00%)	1/58 (1.72%)
Respiratory, thoracic and mediastinal disorders
respiratory † 1	1/89 (1.12%)	0/86 (0.00%)	2/73 (2.74%)	0/58 (0.00%)
Skin and subcutaneous tissue disorders
skin conditions † 1	0/89 (0.00%)	1/86 (1.16%)	0/73 (0.00%)	0/58 (0.00%)
Social circumstances
psychosocial † 1 [1]	1/89 (1.12%)	0/86 (0.00%)	0/0	0/0
Surgical and medical procedures
postsurgical † 1	0/89 (0.00%)	0/86 (0.00%)	0/73 (0.00%)	1/58 (1.72%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (10.0); [1] Mothers only
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Methadone: Mothers	Buprenorphine: Mothers	Methadone: Neonates	Buprenorphine: Neonates
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	83/89 (93.26%)	66/86 (76.74%)	34/73 (46.58%)	29/58 (50.00%)
Blood and lymphatic system disorders
blood-borne disorders † 1	5/89 (5.62%)	1/86 (1.16%)	0/73 (0.00%)	1/58 (1.72%)
hematopoietic or lymphatic symptoms † 1	14/89 (15.73%)	15/86 (17.44%)	17/73 (23.29%)	14/58 (24.14%)
Cardiac disorders
cardiovascular † 1	29/89 (32.58%)	14/86 (16.28%)	8/73 (10.96%)	4/58 (6.90%)
Ear and labyrinth disorders
eye, ear, nose, or throat problems † 1	12/89 (13.48%)	15/86 (17.44%)	1/73 (1.37%)	1/58 (1.72%)
Endocrine disorders
endocrinologic † 1	5/89 (5.62%)	3/86 (3.49%)	1/73 (1.37%)	1/58 (1.72%)
Gastrointestinal disorders
abnormal appetite † 1	2/89 (2.25%)	0/86 (0.00%)	4/73 (5.48%)	1/58 (1.72%)
gastrointestinal † 1	60/89 (67.42%)	47/86 (54.65%)	5/73 (6.85%)	4/58 (6.90%)
General disorders
abnormal laboratory values † 1	10/89 (11.24%)	8/86 (9.30%)	0/73 (0.00%)	0/58 (0.00%)
fever † 1	3/89 (3.37%)	2/86 (2.33%)	0/73 (0.00%)	0/58 (0.00%)
dental problems † 1	22/89 (24.72%)	15/86 (17.44%)	1/73 (1.37%)	2/58 (3.45%)
other AE † 1	4/89 (4.49%)	3/86 (3.49%)	2/73 (2.74%)	3/58 (5.17%)
Infections and infestations
sexually transmitted diseases † 1	8/89 (8.99%)	8/86 (9.30%)	1/73 (1.37%)	1/58 (1.72%)
Musculoskeletal and connective tissue disorders
musculoskeletal † 1	38/89 (42.70%)	28/86 (32.56%)	3/73 (4.11%)	1/58 (1.72%)
Nervous system disorders
neuromuscular † 1	33/89 (37.08%)	29/86 (33.72%)	0/73 (0.00%)	0/58 (0.00%)
neurological † 1	16/89 (17.98%)	12/86 (13.95%)	0/73 (0.00%)	0/58 (0.00%)
sleep disturbances † 1 [1]	24/89 (26.97%)	20/86 (23.26%)	0/0	0/0
somatic † 1 [1]	19/89 (21.35%)	9/86 (10.47%)	0/0	0/0
Pregnancy, puerperium and perinatal conditions
Abnormal fetal health † 1 [1]	6/89 (6.74%)	4/86 (4.65%)	0/0	0/0
obstetrical † 1	29/89 (32.58%)	23/86 (26.74%)	3/73 (4.11%)	4/58 (6.90%)
Psychiatric disorders
Illicit drug use † 1	10/89 (11.24%)	8/86 (9.30%)	3/73 (4.11%)	5/58 (8.62%)
psychological † 1 [1]	24/89 (26.97%)	21/86 (24.42%)	0/0	0/0
Renal and urinary disorders
genitourinary † 1	23/89 (25.84%)	16/86 (18.60%)	1/73 (1.37%)	0/58 (0.00%)
Respiratory, thoracic and mediastinal disorders
respiratory † 1	29/89 (32.58%)	31/86 (36.05%)	14/73 (19.18%)	12/58 (20.69%)
Skin and subcutaneous tissue disorders
skin conditions † 1	16/89 (17.98%)	12/86 (13.95%)	7/73 (9.59%)	2/58 (3.45%)
Social circumstances
psychosocial † 1 [1]	4/89 (4.49%)	5/86 (5.81%)	0/0	0/0
Surgical and medical procedures
postsurgical † 1	16/89 (17.98%)	8/86 (9.30%)	3/73 (4.11%)	0/58 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (10.0); [1] Mothers only

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Dr. Hendree Jones
• Organization: Departments of Psychiatry and Behavioral Sciences and Obstetrics and Gynecology, Johns Hopkins University School of Medicine
• Phone: 919-485-2664
• EMail: hjones18@jhmi.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O'Grady KE, Selby P, Martin PR. Nonserious adverse events in randomized trials with opioid-dependent pregnant women: direct versus indirect measurement. Am J Addict. 2012 Nov;21 Suppl 1:S1-4. doi: 10.1111/j.1521-0391.2012.00289.x.

Holbrook AM, Jones HE, Heil SH, Martin PR, Stine SM, Fischer G, Coyle MG, Kaltenbach K. Induction of pregnant women onto opioid-agonist maintenance medication: an analysis of withdrawal symptoms and study retention. Drug Alcohol Depend. 2013 Sep 1;132(1-2):329-34. doi: 10.1016/j.drugalcdep.2013.02.031. Epub 2013 Mar 21.

Jones HE, Heil SH, Tuten M, Chisolm MS, Foster JM, O'Grady KE, Kaltenbach K. Cigarette smoking in opioid-dependent pregnant women: neonatal and maternal outcomes. Drug Alcohol Depend. 2013 Aug 1;131(3):271-7. doi: 10.1016/j.drugalcdep.2012.11.019. Epub 2012 Dec 29.

McNicholas LF, Holbrook AM, O'Grady KE, Jones HE, Coyle MG, Martin PR, Heil SH, Stine SM, Kaltenbach K. Effect of hepatitis C virus status on liver enzymes in opioid-dependent pregnant women maintained on opioid-agonist medication. Addiction. 2012 Nov;107 Suppl 1(0 1):91-7. doi: 10.1111/j.1360-0443.2012.04043.x.

Holbrook AM, Baxter JK, Jones HE, Heil SH, Coyle MG, Martin PR, Stine SM, Kaltenbach K. Infections and obstetric outcomes in opioid-dependent pregnant women maintained on methadone or buprenorphine. Addiction. 2012 Nov;107 Suppl 1(Suppl 1):83-90. doi: 10.1111/j.1360-0443.2012.04042.x.

Benningfield MM, Dietrich MS, Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O'Grady KE, Fischer G, Martin PR. Opioid dependence during pregnancy: relationships of anxiety and depression symptoms to treatment outcomes. Addiction. 2012 Nov;107 Suppl 1(0 1):74-82. doi: 10.1111/j.1360-0443.2012.04041.x.

Coyle MG, Salisbury AL, Lester BM, Jones HE, Lin H, Graf-Rohrmeister K, Fischer G. Neonatal neurobehavior effects following buprenorphine versus methadone exposure. Addiction. 2012 Nov;107 Suppl 1(0 1):63-73. doi: 10.1111/j.1360-0443.2012.04040.x.

Gaalema DE, Scott TL, Heil SH, Coyle MG, Kaltenbach K, Badger GJ, Arria AM, Stine SM, Martin PR, Jones HE. Differences in the profile of neonatal abstinence syndrome signs in methadone- versus buprenorphine-exposed neonates. Addiction. 2012 Nov;107 Suppl 1(0 1):53-62. doi: 10.1111/j.1360-0443.2012.04039.x.

Kaltenbach K, Holbrook AM, Coyle MG, Heil SH, Salisbury AL, Stine SM, Martin PR, Jones HE. Predicting treatment for neonatal abstinence syndrome in infants born to women maintained on opioid agonist medication. Addiction. 2012 Nov;107 Suppl 1(0 1):45-52. doi: 10.1111/j.1360-0443.2012.04038.x.

Salisbury AL, Coyle MG, O'Grady KE, Heil SH, Martin PR, Stine SM, Kaltenbach K, Weninger M, Jones HE. Fetal assessment before and after dosing with buprenorphine or methadone. Addiction. 2012 Nov;107 Suppl 1(0 1):36-44. doi: 10.1111/j.1360-0443.2012.04037.x.

Jones HE, Fischer G, Heil SH, Kaltenbach K, Martin PR, Coyle MG, Selby P, Stine SM, O'Grady KE, Arria AM. Maternal Opioid Treatment: Human Experimental Research (MOTHER)--approach, issues and lessons learned. Addiction. 2012 Nov;107 Suppl 1(0 1):28-35. doi: 10.1111/j.1360-0443.2012.04036.x.

Jones HE, Heil SH, Baewert A, Arria AM, Kaltenbach K, Martin PR, Coyle MG, Selby P, Stine SM, Fischer G. Buprenorphine treatment of opioid-dependent pregnant women: a comprehensive review. Addiction. 2012 Nov;107 Suppl 1(0 1):5-27. doi: 10.1111/j.1360-0443.2012.04035.x.

Unger A, Jagsch R, Bawert A, Winklbaur B, Rohrmeister K, Martin PR, Coyle M, Fischer G. Are male neonates more vulnerable to neonatal abstinence syndrome than female neonates? Gend Med. 2011 Dec;8(6):355-64. doi: 10.1016/j.genm.2011.10.001. Epub 2011 Nov 15.

Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O'Grady KE, Selby P, Martin PR, Fischer G. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010 Dec 9;363(24):2320-31. doi: 10.1056/NEJMoa1005359.

• Responsible Party: Hendree E. Jones, Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT00271219
• Other Study ID Numbers: R01DA15764-1; R01DA015764 ( U.S. NIH Grant/Contract ); R01DA15764-1; DPMC
• First Submitted: December 28, 2005
• First Posted: December 30, 2005
• Results First Submitted: March 11, 2013
• Results First Posted: August 5, 2015
• Last Update Posted: August 5, 2015