Opioid-induced constipation: rationale for the role of norbuprenorphine in buprenorphine-treated individuals

Figures & data

Table 1 Secondary symptoms and complications of unmanaged constipation

Incomplete evacuation	Hemorrhoids
Abdominal distension	Rectal pain and burning
Bloating	Fecal impaction
Anorexia	Bowel obstruction or rupture
Nausea/vomiting	Interference with drug administration and absorption

Note: Data from studies.^17,20,21

Table 2 Gastrointestinal adverse events (%) after 4 weeks of treatment with the sublingual tablet formulations of buprenorphine–naloxone (16/4 mg) or buprenorphine (16 mg)

Event	Treatment (%)			P-valuea
	Buprenorphine (n=103)	SLBN (n=107)	Placebo (n=107)
Nausea	14	15	11	0.73
Constipation	8	12	3	0.03
Abdominal pain	12	11	7	0.37
Vomiting	8	8	5	0.66
Diarrhea	5	4	15	0.005

Notes:

a For the overall comparison across the three groups. From N Engl J Med, Fudala PJ, Bridge TP, Herbert S, et al; Buprenorphine/Naloxone Collaborative Study Group, Office-based treatment of opiate addiction with a sublingual tablet formulation of buprenorphine and naloxone, 349, 949–958.⁵ Copyright © 2003 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Abbreviation: SLBN, buprenorphine–naloxone sublingual tablet.

Figure 1 Constipation* at baseline and at week 12 in patients converted from SLBN to BBN (N=186).

Notes: *As reported on a BN-related symptom checklist; 95% confidence intervals on 68% risk reduction are 60%–77%. Reprinted from Clin Ther, 37, Sullivan JG, Webster L, Novel buccal film formulation of buprenorphine-naloxone for the maintenance treatment of opioid dependence: a 12-week conversion study, 1064–1075,³⁴ Copyright © 2015, with permission from Elsevier.
Abbreviations: BBN, buccal buprenorphine-naloxone film; ET, early termination; SLBN, sublingual buprenorphine-naloxone tablets or films.

Table 3 Systemic exposure of 4.2/0.7 mg BBN film and 8/2 mg SLBN tablet (N=80)

PK parameter	Geometric mean		Geometric mean ratio (%)	90% CI of the geometric ratio
	BBN 4.2/0.7 mg	SLBN 8/2 mg	BBN/SLBN	Lower	Upper
Buprenorphine
ln (Cmax)	3.15	2.89	109.07	100.49	118.39
ln (AUClast)	24.21	25.40	95.35	88.92	102.24
ln (AUCinf)	25.57	27.03	94.62	88.48	101.19
Norbuprenorphine
ln (Cmax)	0.46	1.16	39.54	36.35	43.02
ln (AUClast)	16.18	33.70	48.00	43.86	52.52
ln (AUCinf)	18.81	36.41	51.64	48.20	55.33
Naloxone
ln (Cmax)	117.57	161.37	72.86	65.94	80.51
ln (AUClast)	298.14	442.28	67.41	61.98	73.31
ln (AUCinf)	304.39	458.95	66.32	61.14	71.94

Note: Data from Vasisht et al.³⁵

Abbreviations: BBN, buccal buprenorphine-naloxone film; CI, confidence interval; SLBN, sublingual buprenorphine-naloxone tablets or films; PK, pharmacokinetic; C_max, maximum plasma concentration; AUC, area under the plasma concentration-time curve; AUC_last, AUC from time 0 to the last measurable concentration; AUC_inf, AUC extrapolated to infinity.

Table 4 Predicted buprenorphine and norbuprenorphine exposure with SLBN tablets and BBN films: daily dosing and steady-state conditions

	Daily (AUC0–24) ng × h/mL		Steady-state (AUC) ng × h/mL
	Norbuprenorphine	Buprenorphine	Norbuprenorphine	Buprenorphine
BBN (n=65)	15	37.8	37.1	51.9
SLBN (n=68)	29.6	40.8	71.3	54.3

Abbreviations: AUC, area under the plasma concentration-time curve; BBN, buccal buprenorphine-naloxone film; SLBN, sublingual buprenorphine-naloxone tablet.

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