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REVIEW ARTICLE

Clin Pharmacokinet 2005; 44 (7): 661-680 0312-5963/05/0007-0661/$34.95/0 2005 Adis Data Information BV. All rights reserved.

Buprenorphine
Clinical Pharmacokinetics in the Treatment of Opioid Dependence
Alexander Elkader and Beth Sproule
Centre for Addiction and Mental Health, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661 1. Buprenorphine Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663 1.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663 1.2 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671 1.3 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671 1.4 Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672 2. Buprenorphine-Naloxone Combination Product Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673 3. Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673 3.1 Renal Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673 3.2 Liver Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673 3.3 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674 4. Cytochrome P450 (CYP) 3A4 and Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674 4.1 HIV Protease Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675 4.2 Ketoconazole and Imidazole Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675 4.3 Selective Serotonin Reuptake Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675 4.4 Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675 4.5 CYP3A4 Inducers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676 5. Pharmacokinetic-Pharmacodynamic Link for Buprenorphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677

Abstract

Buprenorphine is a semi-synthetic opioid derived from thebaine, a naturally occurring alkaloid of the opium poppy, Papaver somniferum. The pharmacology of buprenorphine is unique in that it is a partial agonist at the opioid receptor. Buprenorphine undergoes extensive first-pass metabolism and therefore has very low oral bioavailability; however, its bioavailability sublingually is extensive enough to make this a feasible route of administration for the treatment of opioid dependence. The mean time to maximum plasma concentration following sublingual administration is variable, ranging from 40 minutes to 3.5 hours. Buprenorphine has a large volume of distribution and is highly protein bound (96%). It is extensively metabolised by N-dealkylation to norbuprenorphine primarily through cytochrome P450 (CYP) 3A4. The terminal elimination half-life of buprenorphine is long and there is considerable variation in reported values (mean values ranging from 3 to 44 hours). Most of a dose of buprenorphine is eliminated in the faeces, with approximately 1030% excreted in urine. Naloxone has been added to a sublingual formulation of buprenorphine to reduce the abuse liability of the product. The presence of naloxone does not appear to influence the pharmacokinetics of buprenorphine. Buprenorphine crosses the placenta during pregnan-

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cy and also crosses into breast milk. Buprenorphine dosage does not need to be significantly adjusted in patients with renal impairment; however, since CYP3A activity may be decreased in patients with severe chronic liver disease, it is possible that the metabolism of buprenorphine will be altered in these patients. Although there is limited evidence in the literature to date, drugs that are known to inhibit or induce CYP3A4 have the potential to diminish or enhance buprenorphine N-dealkylation. It appears that the interaction between buprenorphine and benzodiazepines is more likely to be a pharmacodynamic (additive or synergistic) than a pharmacokinetic interaction. The relationship between buprenorphine plasma concentration and response in the treatment of opioid dependence has not been well studied. The pharmacokinetic and pharmacodynamic properties of buprenorphine allow it to be a feasible option for substitution therapy in the treatment of opioid dependence.

Buprenorphine is a semi-synthetic opioid derived from thebaine, a naturally occurring alkaloid of the opium poppy, Papaver somniferum. Buprenorphine is used clinically as an analgesic and as substitution therapy for opioid dependence. This review focuses on the pharmacokinetics of buprenorphine as they relate to its use in the treatment of opioid dependence. Both opioid receptor agonists (e.g. methadone and levacetylmethadol [LAAM; levo--acetylmethadol]) and antagonists (e.g. naltrexone) have been used in the treatment of opioid dependence. The pharmacology of buprenorphine is unique in that it is a partial agonist at the opioid receptor.[1,2] Its opioid receptor agonist properties produce clinical effects similar to methadone, including analgesia, sedation, euphoria and respiratory depression. However, as a partial agonist, buprenorphine has maximal opioid effects lower than those of full agonists, providing a wider safety margin.[3] For example, in France, where buprenorphine has been available for several years, a retrospective evaluation of sudden deaths that were attributed to the misuse of buprenorphine or methadone estimated a 3-fold higher yearly death rate associated with methadone than with buprenorphine despite the fewer restrictions on buprenorphine prescribing.[4] A potential contributing factor to the increased safety profile of buprenorphine compared with methadone and LAAM could be the apparent lower risk of QT interval prolongation and cardiac toxicity.[5]
2005 Adis Data Information BV. All rights reserved.

Buprenorphine has a long receptor fixation halflife of 40 minutes (compared with milliseconds for morphine),[2] which probably contributes to its prolonged duration of action. This allows for the effective use of less than daily dose administration,[6,7] similar to LAAM or naltrexone but unlike methadone. As a partial opioid receptor agonist with a long duration of action, buprenorphine may also have the advantage of being associated with a delayed and less severe withdrawal syndrome compared with other opioids.[8,9] Several studies have demonstrated the efficacy of sublingually administered buprenorphine as substitution therapy in the treatment of opioid dependence.[7,10-15] Initial clinical trials used a sublingual alcohol (ethanol) solution of buprenorphine, whereas subsequent trials have used a sublingual tablet that is now available on the market in several countries. A disadvantage buprenorphine shares with other opioid receptor agonists is a potential for abuse. To reduce this risk, buprenorphine is also marketed as a combination sublingual tablet containing both buprenorphine and naloxone in a ratio of 4 : 1. The rationale is that when taken as intended, appreciable amounts of naloxone are not absorbed; however, if the tablets are crushed and injected, naloxone will exert its opioid receptor antagonist properties. There is some experimental research support for this rationale: opioid-dependent individuals using the combination product sublingually did not exhibit withdrawal symptoms;[16,17] buprenorphine and naloxone administered in combination
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Buprenorphine Pharmacokinetics

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parenterally to non-physically dependent individuals attenuated (but did not block) the subjective effects of buprenorphine;[18,19] and the combination administered parenterally to physically dependent opioid users precipitated withdrawal symptoms.[17,20-24] The fact that naloxone did not completely block buprenorphine subjective effects[16,17] is probably explained by the relatively high affinity of buprenorphine for the opioid receptor. The other important clinical implication is that in the case of buprenorphine overdose, naloxone may not be effective at reversing respiratory depression.[25] 1. Buprenorphine Pharmacokinetics One challenge in the study of buprenorphine pharmacokinetics has been in the availability of appropriate assays to quantify buprenorphine concentrations. Buprenorphine is 2540 times more potent than morphine;[26] therefore, acute doses and resulting buprenorphine plasma concentrations are very low, often falling below 1 ng/mL. A radioimmunoassay (RIA) was used in the earlier pharmacokinetic studies;[27] however, it has been shown that this assay may be incapable of distinguishing between buprenorphine and its metabolite, norbuprenorphine.[28] When this was all that was available, it was accepted for use in single-dose studies, since metabolite contributions in this setting may be less than with multiple-dose studies. Newer assays involving mass spectrometry or tandem mass spectrometry, usually coupled to a gas chromatograph or liquid chromatograph, are very specific and are capable of quantifying very low plasma levels (<1.0 ng/mL).[29-31] Therefore, buprenorphine pharmacokinetics have been studied with different assaying techniques over the years, which is likely to have contributed to the variable results obtained and reported in this review.
1.1 Absorption

Buprenorphine undergoes extensive first-pass metabolism and therefore has very low oral bioavailability.[2] Absorption of buprenorphine transdermally is also limited,[32] although a new transdermal matrix patch has been developed for use in patients with pain.[33] The bioavailability of buprenorphine sublingually is extensive enough to make
2005 Adis Data Information BV. All rights reserved.

this a feasible route of administration for the treatment of opioid dependence. Studies utilising specific assays have reported buprenorphine sublingual solutions mean bioavailability of 2851% (table I).[34,35] The plasma bioavailability of the sublingual tablet has been estimated as 4963% that of the sublingual solution (table I).[36,37] However, the clinical significance of these differences in bioavailability may be limited, based on recent investigations that reported similar opioid-receptor binding changes in subjects (n = 3) taking buprenorphine sublingual liquid (2 and 16mg) compared with subjects (n = 5) taking buprenorphine sublingual tablets (2 and 16mg).[38,39] A number of factors could possibly influence sublingual absorption and bioavailability. At physiological pH, opioids can exist in ionised and nonionised forms. By increasing the pH of the oral environment, more of the drug would be in the nonionised form, therefore potentially enhancing absorption. In a study of the sublingual absorption of selected opioids, it was found that methadone absorption increased from 34% at a saliva pH of 6.5 to 75% at pH 8.5. A similar test could not be done with buprenorphine because of the difficulty of dissolving it in basic pH.[47] One study found a significant but low correlation, suggesting that as saliva pH increased, the recovery of buprenorphine in saliva decreased (r = 0.33; p = 0.05), indicating increased absorption.[35] In contrast, in another study the same group found no significant correlation between saliva pH and buprenorphine area under the plasma concentration-time curve (AUC) [r = 0.33; p = 0.52].[36] Likewise, the length of time the dose is held under the tongue seems to have minimal effect on the absorption of buprenorphine, as demonstrated by the bioequivalence of 3- and 5-minute sublingual solution holds,[35] and the similar absorbed fractions after 2.5- and 10-minute sublingual solution holds, under controlled study conditions.[47] It is not known if this is the case for the sublingual tablets. Of course, very short hold times would be likely to reduce the amount absorbed, which may be of concern in some patients who are unwilling to wait for complete tablet dissolution. Although this demonstrates that buprenorphine is rapidly absorbed into the oral mucosa, absorption into the systemic circulation is slower. The mean
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Table I. Summary of studies determining pharmacokinetic parameters of buprenorphinea Study Kuhlman et al.[34] Subjects Nondependent heroin users F (%) Buccal 4mg, single dose, 27.8 8.9 SEM plastic strip; buccal [4.142.7]b hold for 10 min n=4 Route Dosing conditions tmax (h) 0.81 0.17 SEM [0.331.50] NBUP: 1.29 0.19 SEM [0.752.00] n=4 Cmax (ng/mL) 1.98 0.55 SEM [0.253.90] NBUP: 0.50 0.20 SEM [0.031.26] n=6 3.31 0.81 SEM [1.937.20] NBUP: 0.41 0.08 [0.160.64] n=6 NA Vss (L) Vd/F: 5598 990 [34899224] n=5 CL (mL/min) CL/F: 11 865 7508 [219041 400] n=5 t1/2 Assay (h) 19.01 8.44 SEM NCI-MS/MS [1.3248.63] NBUP: 73.63 23.72 SEM [13.42143.1] PST: 96h n=5 27.72 6.08 SEM [5.2149.09] NBUP: 83.0 33.2 SEM [9.7216.3] PST: 96h n=6 3.21 1.25 [1.628.18] PST: 96h n=5 NA NCI-MS/MS

Nondependent heroin users

SL

4mg, single 51.4 13.2 SEM 0.71 0.08 SEM [0.501.00] solution dose [12.892.9]b SL hold for 10 min n = 5 NBUP: 3.63 0.98 [0.757.00] n=5 1.2mg, single IV infusion dose (over 1 min) 0.4mg, single tablet dose given 3h after a 0.3mg IV dose 0.8mg, single tablet dose given 3h after a 0.3mg IV dose 0.3mg, single IV dose intraoperatively 2mg, single solution dose SL hold for 3 min 2mg, single solution dose SL hold for 5 min 1mg, single IV infusion dose (over 30 min) NA NA

Vd/F: 6750 1212 [320310376] n=5

CL/F: 3507 857 [18757217] n=6

Nondependent heroin users Bullingham Postoperative et al.[40]

IV

334.9 116.2 1280 218 [124.6770.8] [9601922]; n=5 n=5 NA NA

NCI-MS/MS

SL

55.7 6.0 SEM [43.677.8]c n=5

3.5 0.67 SEM [26]c n=5

0.43 0.06 SEMc n=5 0.85 0.32 SEMc n=5 NA

RIA

Postoperative

SL

54.1 12.7 SEM 3.2 0.82 SEM [1.56]c [15.794.4]c n=5 n=5 NA NA

NA

NA

NA

RIA

Operative/ postoperative

IV

NA

NA

5.18 0.55 SEM [3.886.39]d PST: 13h n=5 NA

RIA

Mendelson Healthy volunteer et al.[35] Healthy volunteer Healthy volunteer

SL

28 10 [2836]e n=6 29 10 [2933]e n=6 NA

NA

1.60 0.66 n=6 1.72 0.87 n=6 NA

NA

NA

GC-ECD

SL

NA

NA

NA

NA

GC-ECD

IV

NA

NA

1041 363 n=6

16.2 20.1f PST: 24h n=6

GC-ECD

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2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (7)

Buprenorphine Pharmacokinetics

Table I. Contd Study Subjects Route Dosing conditions SL 0.4mg, single tablet dose given 3h after a 0.3mg IV dose F (%) 31g n = 10 tmax (h) NA Cmax (ng/mL) NA Vss (L) NA CL (mL/min) NA t1/2 (h) NA Assay RIA

Bullingham Postoperative et al.[41]

Harris et al.[16]

Opioiddependent

SL

8mg, solution dose ~40h after stabilisation n=9 (at least 7 days) on buprenorphine 8mg 8mg, solution dose ~40h in combination with n = 9 naloxone 4mg, after stabilisation (at least 7 days) on buprenorphine 8mg 8mg, solution dose ~40h in combination with n = 9 naloxone 8mg, after stabilisation (at least 7 days) on buprenorphine 8mg 4mg, in combination with naloxone 4.0mg NA

1.00 0.31 NBUP: 1.91 1.13 n=9 1.47 0.48 NBUP: 3.29 2.67 n=9

9.40 4.13 NBUP: 2.49 1.06 n=9 8.32 3.74 NBUP: 2.33 1.08 n=9

NA

NA

19.8 8.2 PST: 24h n=9 23.2 9.3 PST: 24h n=9

LC-MS/MS

Opioiddependent

SL

NA

NA

LC-MS/MS

Opioiddependent

SL

1.45 0.52 NBUP: 5.08 7.20 n=9

7.76 2.64 NBUP: 2.88 2.25 n=9

NA

NA

21.8 11.2 PST: 24h n=9

LC-MS/MS

Opioiddependent

IV

NA

NA

NA

NA

32.1 12.0 NBUP: 34.6 16.4 PST: 144h n=9 NA

LC-MS/MS

Nath et al.[36]

Nondependent opioid users Nondependent opioid users

SL

7.7mg solution, single dose SL hold for 5 min 8mg, single tablet dose SL hold for 5 min

Frel: 49 25% tablet to solutioni n=6 Frel: 49 25% tablet to solutioni n=6

1.2 0.3 n=6 0.9 0.3 n=6

7.1 2.8 n=6 2.9 0.5 n=6

NA

NA

Capillary GC-ECD

SL

NA

NA

NA

Capillary GC-ECD

Schuh and OpioidJohanson[37] dependent

SL

2mg, solution dose Frel: 63% tablet Maintained on dose to solution for at least 7 days n = 14 SL hold for at least 5 min

2 n = 14

2.04 n = 14

NA

NA

NA

LC-MS/MS

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Table I. Contd Study Subjects Opioiddependent Route Dosing conditions SL F (%) 4mg, solution dose Frel: 63% tablet Maintained on dose to solution for at least 7 days n = 14 SL hold for at least 5 min 8mg, solution or Frel: 63% tablet tablet dose to solution Maintained on dose n = 14 for at least 7 days SL hold for at least 5 min 2 mg/day, tablet dose for 14 days (during a down taper) NA tmax (h) 2 n = 14 Cmax (ng/mL) 2.74 n = 14 Vss (L) NA CL (mL/min) NA t1/2 (h) NA Assay LC-MS/MS

Opioiddependent

SL

2 n = 14

5.83 NA (solution dose), 3.02 (tablet dose) n = 14 0.3 0.1 SEM NBUP: 0.7 0.2 SEM n=5 6.3 0.9 SEM NBUP: 5.4 1.3 SEM n=5 13.2 4.2 SEM NBUP: 14.2 2.9 SEM n=5 NA NA

NA

NA

LC-MS/MS

Greenwald Heroindependent et al.[38]

SL

0.9 0.1 SEM NBUP: 1.6 0.4 SEM n=5

NA

NA

LC-MS/MS

Heroindependent

SL

16 mg/day, tablet dose for 12 days (during a down taper)

NA

1.2 0.2 SEM NBUP: 1.4 0.4 SEM n=5

NA

NA

NA

LC-MS/MS

Heroindependent

SL

32 mg/day, tablet dose for 12 days (beginning of a down taper)

NA

1.2 0.2 SEM NBUP: 1.6 0.2 SEM n=5

NA

NA

NA

LC-MS/MS

Bullingham Postoperative et al.[42] Operative

IM

0.3mg, single IM dose 3h after 0.3mg IV dose 0.3mg, single IV infusion dose (over 1 min) intraoperatively 0.3mg, single IV dose 3h after 0.3mg IV dose

NA

NA

148.1 51.3j n = 10 97.3 7.66k n = 24

992.7 70.3j n = 10 901.3 39.7k n = 24

2.31 0.70 SEM PST: 3h n = 10 2.33 0.24 SEM PST: 3h n = 24 3.06 0.62 SEM PST: 3h n = 11

RIA

IV

NA

NA

NA

RIA

Postoperative

IV

NA

NA

NA

187.9 35.26l 1275 88.9l n = 11 n = 11

RIA

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2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (7)

Buprenorphine Pharmacokinetics

Table I. Contd Study Kuhlman et al.[43] Subjects Opioiddependent Route Dosing conditions SL 8mg, solution dose, steady-state, daily administration F (%) NA tmax (h) NA Cmax (ng/mL) NA Vss (L) NA CL (mL/min) NA t1/2 (h) 40.65 8.29 SEM [23.8662.50]m NBUP: 73.30 28.07 SEM [24.92176.04] PST: 19 days following last dose n=5 43.61 9.00 SEM [28.6868.77]m n=4 NBUP: 40.15 5.82 SEM [22.4056.96] n=6 PST: 19 days following last dose NA Assay NCI-MS/MS

Opioiddependent

SL

8mg, solution NA dose, steady-state, alternate-day administration

NA

NA

NA

NA

NCI-MS/MS

Strain et al.[44]

Opioiddependent

SL

8mg, solution dose, maintained for 1wk

NA

1.10 0.13 SEM [0.501.50] NBUP: 1.80 0.49 SEM [0.506.00] n = 10

Opioiddependent

SL

8mg, solution dose, maintained for 2wk

NA

1.25 0.11 SEM [1.002.00] NBUP: 1.85 0.23 SEM [1.003.00] n = 10

Opioiddependent

SL

8mg, tablet dose, NA maintained for 1wk

1.00 0.13 SEM [0.501.50] NBUP: 1.65 0.20 SEM [1.003.00] n = 10

3.42 0.37 SEM [1.625.07] NBUP: 2.16 0.48 SEM [0.885.88] n = 10 2.73 0.29 SEM [1.064.30] NBUP: 1.69 0.24 SEM [0.733.06] n = 10 2.13 0.31 SEM [0.983.99] NBUP: 1.63 0.25 SEM [0.603.20] n = 10

NA

NA

LC-MS/MS

NA

NA

NA

LC-MS/MS

NA

NA

NA

LC-MS/MS

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Table I. Contd Study Subjects Opioiddependent Route Dosing conditions SL 8mg, tablet dose, maintained for 2wk F (%) NA tmax (h) 1.15 0.08 SEM [1.001.50] NBUP: 1.55 0.20 SEM [1.003.00] n = 10 Cmax (ng/mL) 2.01 0.25 SEM [0.833.37] NBUP: 1.77 0.25 SEM [0.673.18] n = 10 2.80 0.33 SEM [1.815.41] NBUP: 2.26 0.42 SEM [0.924.89] n = 10 2.55 0.32 SEM [0.514.50] NBUP: 2.05 0.37 SEM [0.724.79] n = 10 3.56 1.51 NBUP: 0.33 0.17 n = 12 5.83 2.77 NBUP: 0.88 0.34 n = 12 8.37 2.86 NBUP: 1.24 0.87 n = 12 Vss (L) NA CL (mL/min) NA t1/2 (h) NA Assay LC-MS/MS

Opioiddependent

SL

8mg, tablet dose NA (combination product with 2mg naloxone), maintained for 1wk

1.10 0.18 SEM [0.502.00] NBUP: 1.50 0.15 SEM [1.002.00] n = 10

NA

NA

NA

LC-MS/MS

Opioiddependent

SL

8mg, tablet dose (combination product with 2mg naloxone), maintained for 2wk

NA

1.30 0.23 SEM [0.503.00] NBUP: 1.75 0.50 SEM [0.506.00] n = 10

NA

NA

NA

LC-MS/MS

Harris et al.[45]

Nondependent opioid users Nondependent opioid users Nondependent opioid users Nondependent opioid users

SL

4mg, single solution dose

NA

1.09 0.40 NBUP: 3.29 8.27 n = 12 1.16 0.54 NBUP: 2.96 3.06 n = 12 1.17 0.40 NBUP: 2.75 2.65 n = 12 1.00 0.34 NBUP: 3.23 4.93 n = 12

NA

NA

NA

LC-MS/MS

SL

8mg, single solution dose

NA

NA

NA

NA

LC-MS/MS

SL

16mg, single solution dose

NA

NA

NA

NA

LC-MS/MS

SL

32mg, single solution dose

NA

13.70 4.38 NA NBUP: 2.48 1.74 n = 12

NA

NA

LC-MS/MS

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2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (7)

Buprenorphine Pharmacokinetics

Table I. Contd Study Subjects Nondependent opioid users Route Dosing conditions SL 4mg, single tablet dose (combination product with 1mg naloxone) 8mg, single tablet dose (combination product with 2mg naloxone) F (%) NA tmax (h) 1.06 0.42 NBUP: 4.81 8.00 n=8 1.01 0.36 NBUP: 1.07 0.48 n=8 0.79 0.27 NBUP: 0.98 0.42 n=8 1.04 0.65 NBUP: 1.44 0.86 n=8 Cmax (ng/mL) 1.84 0.72 NBUP: 0.83 0.27 n=8 3.00 1.53 NBUP: 1.48 0.56 n=8 5.95 2.28 NBUP: 3.50 1.39 n=8 5.47 1.27 NBUP: 2.54 1.29 n=8 Vss (L) NA CL (mL/min) NA t1/2 (h) NA Assay LC-MS/MS

Nondependent opioid users

SL

NA

NA

NA

NA

LC-MS/MS

Nondependent opioid users

SL

16mg, single tablet NA dose (combination product with 4mg naloxone) 16mg, single tablet NA dose

NA

NA

NA

LC-MS/MS

Nondependent opioid users

SL

NA

NA

NA

LC-MS/MS

McAleer et al.[46]

Opioid-naive subjects under naltrexone blockade Opioid-naive subjects under naltrexone blockade Opioid-naive subjects under naltrexone blockade Opioid-naive subjects under naltrexone blockade

SL

2mg, single tablet dose

NA

1.50 [1.003.00]n 1.6 0.5 n = 27 n = 27

NA

NA

NA

LC-MS/MS

SL

8mg, single tablet dose

NA

1.02 [0.752.00]n 4.0 1.2 n = 27 n = 27

NA

NA

30.02 11.99 PST = 72h n = 23

LC-MS/MS

SL

12mg, single tablet NA dose

1.00 [0.502.00]n 5.4 1.8 n = 27 n = 27

NA

NA

25.63 7.05 PST = 72h n = 26

LC-MS/MS

SL

16mg, single tablet NA dose

0.75 [0.502.00]n 6.4 2.6 n = 27 n = 27

NA

NA

23.89 6.55 PST = 72h n = 27

LC-MS/MS

Continued next page

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670

Table I. Contd Study Subjects Opioid-naive subjects under naltrexone blockade Opioid-naive subjects under naltrexone blockade Route Dosing conditions SL 8mg, single tablet dose (combination product with 2mg naloxone) formulation A 8mg, single tablet dose (combination product with 2mg naloxone) formulation B F (%) NA tmax (h) 1.00 [0.502.00]n n = 36 Cmax (ng/mL) 3.2 1.3 n = 36 Vss (L) NA CL (mL/min) NA t1/2 (h) 25.51 8.40 PST = 72h n = 35 Assay LC-MS/MS

SL

NA

1.00 [0.502.02]n 3.2 1.2 n = 36 n = 36

NA

NA

26.79 8.17 PST = 72h n = 36

LC-MS/MS

a b c d e f g h i j k l

Values are mean SD [range], unless specified otherwise. Compared to a 1.2mg IV dose. SL profile obtained by adjusting for predicted IV plasma decay. Blood samples taken while the subjects were in surgery. Subjects given 10mg diazepam orally 2h preoperatively. Compared to a 1mg IV dose. Estimate limited by assay sensitivity considerations according to authors. SL profile obtained by adjusting for predicted IV plasma decay. Bioavailability estimate from 0 to 180 min. Compared to 4mg/4mg buprenorphine/naloxone dose. SL tablet dissolution time was 6.6 2.3 min. IM profile obtained by adjusting for IV plasma decay. Subjects given 10mg diazepam orally 24h preoperatively. Blood samples taken while the subjects were in surgery and afterwards to 180 min. Subjects given 10mg diazepam orally 24h preoperatively. Second IV dose profile obtained by adjusting for predicted decay of the first dose. Subjects given 10mg diazepam orally 24h preoperatively.

m Concurrent medications available as necessary 72h after last dose.

Elkader & Sproule

Values are median [range].

CL = plasma clearance; Cmax = maximum plasma concentration; F = absolute bioavailability; Frel = relative bioavailability; GC-ECD = gas chromatography-electron capture detector; IM = intramuscular; IV = intravenous; LC-MS/MS = liquid chromatography-tandem mass spectrometry; n = number of subjects; NA = not available; NBUP = norbuprenorphine; NCI-MS/MS = negative chemical ionization-tandem mass spectrometry; PST = plasma sample time; RIA = radioimmunoassay; SEM = standard error of the mean; SL = sublingual; t1/2 = elimination half-life; tmax = time to reach Cmax; Vd/F = volume of distribution over fraction absorbed; Vss = volume of distribution at steady state;.

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time to reach maximum plasma concentration (tmax) following sublingual administration is variable, ranging from 40 minutes to 3.5 hours[34,36,37,40] (table I); tmax does not appear to be dependent on the formulation (tablet versus solution).[37] Likewise, dosing conditions do not seem to affect estimates of tmax, although estimates taken after single-dose administrations appear more variable, encompassing the entire range (i.e. 40 minutes to 3.5 hours), whereas multiple-dose estimates range from 1.0 to 2.0 hours. It has been suggested that the delayed systemic absorption is due to the presence of a drug reservoir in the oral mucosa,[34] based on data indicating salivary buprenorphine concentrations were substantially elevated compared with plasma concentrations for 12 hours following acute sublingual administration; whereas they were substantially less than plasma concentrations following an acute intramuscular injection.[48] Maximum plasma concentration (Cmax) values achieved following sublingual administration are associated with coefficients of variation ranging from 31% to 84%[34,36,37,40-42] (table I). The variability in tmax and Cmax may influence the acute effects of buprenorphine in individual patients; however, the relationship between plasma concentrations and effects has not been well studied. It appears that peak subjective effects may occur later than peak physiological effects (e.g. pupillary constriction) and peak plasma concentrations.[3,36,49] In summary, the rapid sublingual absorption at physiological pH of buprenorphine, followed by a delay in the systemic absorption, provides a useful route of administration in the treatment of opioid dependence. Relatively short sublingual hold times are an important practical consideration for longterm administration, and the delayed peak concentrations reduce the intensity of opioid effects that may be experienced.
1.2 Distribution

for bioavailability, although interpretation of these results is limited owing to different dosing, assay and blood sampling conditions among the studies. Buprenorphine is highly protein bound (96%), primarily to - and -globulin.[2,25,50] Buprenorphine appears to readily cross the blood-brain barrier. Following regular maintenance doses, only buprenorphine, and not its metabolites, is found in the brain post-mortem.[2] However, both buprenorphine and norbuprenorphine were found in the brain post-mortem following a large buprenorphine overdose.[51] The investigators speculated that this may be due to overwhelming a transport system such as P-glycoprotein.[51]
1.3 Metabolism

Buprenorphine distribution characteristics appear to be consistent with its high lipophilicity. Buprenorphine has a large volume of distribution that is greater than physiological volumes. It has been estimated to be 188335L following intravenous administration[34,42] (table I). From table I, the apparent volume of distribution appears to be greater following sublingual administration, even after adjusting
2005 Adis Data Information BV. All rights reserved.

Buprenorphine is extensively metabolised by Ndealkylation to norbuprenorphine, and then both undergo glucuronidation.[52] Norbuprenorphine is an active metabolite with an estimated one-fiftieth the analgesic potency of buprenorphine.[53] Therefore, its contribution to the overall therapeutic efficacy of buprenorphine in the treatment of opioid dependence is thought to be low; however, this has not been fully studied.[54] The glucuronide metabolites are considered to be inactive. Buprenorphine N-dealkylation is primarily cytochrome P450 (CYP) 3A4 mediated. This is based on in vitro human liver microsome studies showing high correlations between buprenorphine N-dealkylation activity and other CYP3A-specific metabolic reactions;[55,56] as well as correlations with the total amount of CYP3A immunodetected by a monoclonal anti-human CYP3A4 antibody[55] and the lack of N-dealkylation with other CYP enzymes.[55,56] Buprenorphine is a highly extracted drug, with a hepatic extraction ratio estimated to be close to 1. This estimate has been based on comparing buprenorphine plasma clearance rates with expected hepatic blood flow rates. For example, in an early paper in which buprenorphine was administered intravenously to anaesthetised patients, the average buprenorphine plasma clearance rate was 901.2 39.7 mL/min. Hepatic blood flow estimates under anaesthesia have been estimated in the range of 900[57] to 1300 mL/min,[58] which corresponds to extraction ratios of 0.71 (with a plasma/red cell ratio of bupreClin Pharmacokinet 2005; 44 (7)

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norphine close to unity according to the investigators).[42] The mean buprenorphine plasma clearance rates estimated following intravenous administration to healthy volunteers have ranged from 1042 to 1280 mL/min[34,35] (table I), and hepatic blood flow for healthy individuals has been estimated, for example, as 1450[59] and 1881 mL/min,[58] giving estimated extraction ratios ranging from 0.6 to 0.9, assuming equivalent plasma and blood clearance rates and similar subject bodyweights. The elimination half-life of buprenorphine is long and there is considerable variation in values reported for it (table I). In early studies it was reported that the elimination half-life of buprenorphine was 23 hours, based on intravenous administration, although the plasma sampling was only for 3 hours.[42] In a follow-up study by the same group, plasma samples were collected for 13 hours after intravenous drug administration and the mean elimination half-life was 5.2 hours.[40] A longer elimination half-life estimate (mean 16.2 hours) was obtained in a study that administered buprenorphine intravenously over 30 minutes and took blood samples out to 24 hours.[35] Conversely, a shorter mean elimination half-life (3.2 hours) was determined in a study that analysed samples for 96 hours after intravenous drug administration.[34] In the same study, the mean elimination half-life following sublingual single-dose administration was 27.7 hours and the mean buccal elimination half-life was 19 hours.[34] In a subsequent study by the same group, there was large interindividual variation in the elimination half-life estimates (2469 hours) in nine subjects given buprenorphine sublingually for 36 days, using plasma samples obtained upon discontinuation of buprenorphine.[43] The elimination half-life of norbuprenorphine in these patients had an even wider range (22176 hours).[43] The product monograph states that sublingual buprenorphine has a mean elimination half-life from plasma of 37 hours.[25] The discrepancies in the elimination half-life estimates may be related to assay sensitivities when lower doses of buprenorphine are administered. The final concentrations determined may not adequately reflect the terminal elimination rate. For example, in the previously mentioned study that estimated the elimination half-life as 16 hours after intravenous
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administration of 1mg of buprenorphine, the investigators indicated the estimate was limited by assay sensitivity considerations (0.10.3 ng/mL).[35] In the study that estimated an elimination half-life of 3 hours following intravenous administration of 1.2mg of buprenorphine, the mean buprenorphine concentrations fell below the level of quantification (0.2 ng/mL) at 13 hours.[34] Another influencing factor may be the route of administration. The elimination half-life estimates appear to be longer for sublingually administered buprenorphine than for intravenous administration. Because the elimination half-life reflects the volume of distribution and the clearance of the drug, if the elimination half-life is longer, either the volume of distribution has increased or the clearance has decreased, or both. There is no indication that clearance is altered by the route of administration; however, the volume of distribution does appear to be higher following sublingual administration, as discussed previously (table I). Therefore enhanced sequestration in adipose tissue or a reservoir in the oral mucosa may influence the elimination half-life. Kuhlman et al.[34] have proposed a three-compartment model for buprenorphine pharmacokinetics with a depot absorption component where the rate constant from the depot to the central compartment is slower than the elimination rate constant. In summary, buprenorphine is extensively metabolised and has a long elimination half-life following sublingual administration. Therefore, both the tight binding of buprenorphine to the opioid receptor and its long elimination half-life contribute to the extended duration of action of buprenorphine in the treatment of opioid dependence.
1.4 Elimination

Most of a dose of buprenorphine is eliminated in the faeces, with approximately 1030% of the dose excreted in urine.[50,52,60] In urine, most buprenorphine and norbuprenorphine are in the more polar conjugated forms,[52,61] while in the faeces almost all buprenorphine and norbuprenorphine are in the free forms.[50,52] It is likely that the glucuronidated forms of buprenorphine and norbuprenorphine enter the bile, are secreted into the small intestine and hydrolysed in the intestinal flora, undergo enteroClin Pharmacokinet 2005; 44 (7)

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hepatic recirculation and are finally eliminated in the faeces.[52,60] Although buprenorphine and its metabolites may be excreted in urine for 17 days following use,[52,61] currently available routine toxicology screens for opioids do not detect buprenorphine. 2. Buprenorphine-Naloxone Combination Product Pharmacokinetics Naloxone has been added to a sublingual formulation of buprenorphine to reduce the abuse liability of the product. Sublingual bioavailability of naloxone is only approximately 10% when administered as a solution,[16] which is consistent with an estimated sublingual aqueous solution potency of approximately 10- to 20-fold less than parenteral naloxone.[62] In addition, the elimination half-life of naloxone is quite short (12 hours)[16] compared with that of buprenorphine. The presence of naloxone does not appear to influence the pharmacokinetics of buprenorphine based on a study using sublingual solution formulations. In this study,[16] nine opioid-dependent subjects were stabilised on buprenorphine 8mg for 1 week and then studied following single sublingual doses of buprenorphine alone, buprenorphine with naloxone 4mg and buprenorphine with naloxone 8mg. There were no differences among the three sublingual administrations in the AUC from 0 to 24 hours (AUC24), Cmax and tmax of buprenorphine and norbuprenorphine. In a recent study comparing buprenorphine 8mg sublingual tablets with buprenorphine 8mg combined with 2mg naloxone sublingual tablets, Cmax was higher in the first week with the combination formulation[45] (see table I). 3. Special Populations
3.1 Renal Impairment

the non-renally impaired patients, although buprenorphine concentrations were measured using an immunoassay for only 3 hours after administration. In the other study, 15 patients undergoing surgery were given buprenorphine 0.3mg intravenously and blood samples were measured for 24 hours.[64] The normal renal function group had a mean clearance rate of 650.5 mL/min compared with 987.6 mL/min in the impaired renal function group (p = 0.05) and a mean residence time of 8.5 versus 4.7 hours (p < 0.05). The apparent volume of distribution at steady state and elimination half-life estimates were not significantly different between normal renal function and impaired renal function groups (312.7 vs 200L and 6.6 vs 4 hours). In this report, another 20 surgical patients (8 with renal impairment, 12 with normal renal function) were given buprenorphine by infusion for 29 hours. In this setting, although the buprenorphine concentrations were similar, the plasma concentrations of buprenorphine metabolites were higher in the renally impaired population: 4fold for norbuprenorphine and 15-fold for buprenorphine 3-glucuronide.[64] This is consistent with a predominantly renal route of elimination of the more polar buprenorphine metabolites. Therefore, it appears that buprenorphine dosage may not need to be significantly adjusted in patients with renal impairment. However, the effects of renal impairment have been studied only under short-term dosing conditions and therefore are not necessarily predictive of maintenance dosage in buprenorphine substitution therapy. Under long-term dosing conditions in renally impaired patients, there is the potential for an accumulation of buprenorphine metabolites in plasma. This may not be clinically significant, as norbuprenorphine is only very weakly active and has poor permeation in to the brain, and the glucuronidated metabolites are not considered active.[53]
3.2 Liver Disease

The pharmacokinetics of buprenorphine in renally impaired patients has been evaluated in two studies. In one study,[63] buprenorphine 0.3mg was administered intravenously to five patients with endstage renal failure and ten non-renally impaired postoperative patients. The mean AUC from time zero to infinity (AUC) for the renally impaired patients was not significantly different from that of
2005 Adis Data Information BV. All rights reserved.

No specific pharmacokinetic studies have been conducted in patients with liver disease. As discussed previously, the N-dealkylation of buprenorphine to norbuprenorphine is catalysed by hepatic CYP3A4[55,56] and it has been shown that expression of CYP3A may be significantly decreased in patients with severe chronic liver disease.[65,66]
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Therefore, it is possible that the metabolism of buprenorphine will be altered in these patients and dosage should be adjusted accordingly and closely monitored. In one study, in which patients with hepatitis received buprenorphine for a minimum of 40 days, increases in ALT and dose-dependent increases in AST were noted.[67] Therefore, in patients with hepatitis treated with buprenorphine, monitoring of liver enzyme levels is recommended.
3.3 Pregnancy

In the US and Europe, one-third of all patients entering treatment for opioid dependence are females of childbearing age.[68] The availability of pharmacokinetic data in pregnant women taking buprenorphine is limited. In a case report of a pregnant woman who took buprenorphine 4 mg/day for approximately 5 months, the serum concentration of buprenorphine in the neonate at 20 hours after birth was higher than the mothers serum concentration at trough a few days before the birth (1.9 vs 0.3 ng/mL), although norbuprenorphine serum concentrations were lower (1.7 vs 2.3 ng/mL).[69] Buprenorphine and norbuprenorphine were also present in the neonates urine (36.8 and 61.1 ng/mL) and meconium (107 and 295 ng/g). At 4 weeks of age the amount of buprenorphine consumed via breast milk in this child was determined over one 24-hour period: 3.28g of buprenorphine and 0.33g of norbuprenorphine (the childs weight was not indicated).[69] In another study of three opioid-dependent women maintained on 812 mg/day of buprenorphine for the last few months of pregnancy, trough buprenorphine plasma concentrations were measured before and after delivery. The trough plasma concentrations before delivery (mean 0.36 ng/mL, range 0.120.49 ng/mL) were similar to those after delivery (mean 0.37 ng/mL, range 0.120.79 ng/mL).[70] The infant cord plasma buprenorphine concentrations ranged from 0.10 to 0.14 ng/mL at delivery. In one maternal-infant pair the maternal, cord and infant plasma concentrations were reported as comparable, although the values were not stated. The concentration of buprenorphine in the urine of one infant approximately 3 hours after delivery (1.13 ng/mL) was 8- to 10-fold higher than the
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plasma concentrations.[70] The investigators also reported an increase in the buprenorphine concentration in the meconium of one infant from the first to the third bowel movement (1.3 and 35.4 ng/g). The concentrations of buprenorphine in the breast milk of one woman were similar to her plasma concentrations on day 3 (0.52 and 0.52 ng/mL, respectively) and day 6 (0.72 and 0.64 ng/mL, respectively) postpartum.[70] From these reports it appears that buprenorphine induces a more mild withdrawal syndrome in neonates, when compared with methadone.[68] The higher buprenorphine-to-norbuprenorphine ratio in neonates than adults may be due to immature hepatic function in the neonates. CYP3A7 is the predominant fetal hepatic cytochrome,[71] which may not metabolise buprenorphine. Buprenorphine also freely crosses into breast milk with concentrations that may be similar to those in maternal plasma. However, the oral bioavailability of buprenorphine may be low in infants, since CYP3A4 appears after birth and reaches 3040% of adult activity by the first postnatal month.[71,72] Therefore, exposure to buprenorphine through breast milk may be minimal, which is supported by the clinical observations that the neonatal abstinence syndrome following birth is not suppressed in infants who are breastfed and there have been no reported cases of neonatal abstinence symptoms following cessation of breast feeding.[68] 4. Cytochrome P450 (CYP) 3A4 and Drug Interactions Many drugs are substrates, inhibitors or inducers of CYP3A4; therefore, it is possible that some of these drugs will interact with buprenorphine. In vitro, buprenorphine inhibits CYP3A4 and other CYP enzymes with inhibition constant (Ki) values too high to be clinically significant at concentrations obtained in human tissues.[73,74] However, there is the potential for other drugs to influence the pharmacokinetics of buprenorphine through modulation of CYP3A4. Although there is limited evidence in the literature to date, any drug that is known to inhibit or induce CYP3A4 has the potential to diminish or enhance buprenorphine N-dealkylation. The following sections provide examples and the in vitro or in vivo data available.
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4.1 HIV Protease Inhibitors

The seroprevalence of HIV in illicit opioid or injection drug users is estimated to be 715% in North America and Europe,[75-78] with injection drug users accounting for approximately 4050% of all new cases of HIV infection.[75,78] Several protease inhibitors are also inhibitors of CYP3A4. The in vitro pharmacokinetics of buprenorphine have been studied in the presence and absence of ritonavir, indinavir and saquinavir.[79] In this report ritonavir exhibited very potent competitive inhibition (apparent Ki of 20 nmol/L), leading to the prediction that ritonavir coadministration clinically could result in the complete inhibition of buprenorphine N-dealkylation.[79] Indinavir was determined to be a potent mixed-type inhibitor of buprenorphine N-dealkylation (apparent Ki of 800 nmol/L), with a prediction to inhibit about 85% of buprenorphine N-dealkylation in vivo.[79] Saquinavir exhibited a weaker competitive inhibition (apparent Ki of 15 000 nmol/L), suggesting that it may not inhibit buprenorphine Ndealkylation in vivo.[79] It appears that concurrent administration of some protease inhibitors with buprenorphine could lead to significantly increased levels of buprenorphine exposure. This must be taken into account, since buprenorphine dosage regimens may need adjustments in these patients as protease inhibitors are added or removed from their treatment programme.
4.2 Ketoconazole and Imidazole Derivatives

caution is advised when buprenorphine and ketoconazole or other imidazole derivatives with CYP3A4 inhibition potential are used concomitantly.
4.3 Selective Serotonin Reuptake Inhibitors

The lifetime prevalence of psychiatric disorders among those with an opioid use disorder has been estimated at 65%.[80] Antidepressant medications are widely used in the treatment of mood and anxiety disorders. Nefazodone and the selective serotonin reuptake inhibitors fluoxetine and fluvoxamine are inhibitors of CYP3A4. There has been one in vitro experiment evaluating the influence of fluoxetine and fluvoxamine on buprenorphine N-dealkylation.[81] Although fluoxetine did not inhibit buprenorphine N-dealkylation, norfluoxetine did with an apparent Ki of 100 mol/L, and fluvoxamine inhibited buprenorphine metabolism with an apparent Ki of 260 mol/L. Since these Ki values are high, the investigators predict that norfluoxetine and fluvoxamine would not significantly inhibit buprenorphine metabolism in vivo.[81]
4.4 Benzodiazepines

Azole antifungals, particularly ketoconazole and itraconazole, are known inhibitors of CYP3A4. In vitro studies have shown that ketoconazole is a potent and specific inhibitor of buprenorphine Ndealkylation.[55] According to the product monograph for Suboxone 1 (a combination product of buprenorphine and naloxone), daily administration of ketoconazole 400mg to 12 subjects stabilised on 8, 12 or 16mg (buprenorphine component) led to an increase in the Cmax (from 4.3, 6.3 and 9.0 ng/mL to 9.8, 14.4 and 17.1 ng/mL, respectively) and the AUC (from 30.9, 41.9 and 52.3 ng h/mL to 46.9, 83.2 and 120 ng h/mL, respectively).[25] Therefore,
1

There have been many reports of interactions between buprenorphine and benzodiazepines, some of which have been fatal.[51,82-84] Benzodiazepines are not considered CYP3A4 inhibitors, although certain benzodiazepines are metabolised through this enzyme, including the ones most commonly abused by opioid abusers (e.g. diazepam and flunitrazepam).[85,86] As mentioned previously, it has been predicted that buprenorphine does not significantly inhibit CYP3A4, based on in vitro evidence.[73,74,87] One in vitro study has confirmed minimal inhibition of buprenorphine and flunitrazepam on each others N-dealkylation reaction at clinically relevant concentrations.[87] Therefore, it appears that the interaction between buprenorphine and benzodiazepines is more likely to be a pharmacodynamic (additive or synergistic) interaction that could result in respiratory depression.

The use of trade names is for product identification purposes only and does not imply endorsement.

2005 Adis Data Information BV. All rights reserved.

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4.5 CYP3A4 Inducers

There has been no investigation into the effect of CYP3A4 inducers on buprenorphine pharmacokinetics. Common CYP3A4 inducers include phenobarbital (phenobarbitone), carbamazepine, phenytoin and rifampicin (rifampin). It is likely that CYP3A4 inducers would increase buprenorphine metabolism, and may lead to the development of withdrawal symptoms towards the end of the dosing interval if added to a stabilised buprenorphine dose. Therefore, patients receiving buprenorphine should be monitored closely during concomitant therapy with CYP3A4 inducers. 5. Pharmacokinetic-Pharmacodynamic Link for Buprenorphine The relationship between buprenorphine plasma concentrations and response in the treatment of opioid dependence has not been well studied. Most work has focused on dosage rather than plasma concentrations. It has been shown that buprenorphine is associated with a dose-dependent increase in positive mood, sedation and respiratory depression from 1 to 16mg doses in non-physically dependent opioid abusers; after which (i.e. at 32mg) there is a plateau (ceiling effect).[3] However, a recent study indicated the ceiling effect may occur at even lower doses for some effects.[45] In a study designed to determine the optimal buprenorphine daily dose for the treatment of opioid dependence, an upward dose titration method was used to achieve stabilisation.[88] Of the 100 patients admitted to the study, 34 were stabilised at doses between 4 and 32mg (mean 14.6 6.5mg) within 16 weeks, 19 were unable to stabilise in this time period and 47 left treatment before completion of the study. In an early open-label study of 28 subjects dependent on opioids and cocaine, buprenorphine was administered at increasing dosages every 21 days, followed by a tapering regimen of decreasing dosages every 21 days.[89] When receiving 2, 4 and 8 mg/day dosages, 2732% of subjects gave entirely opioidfree urine samples, compared with 65% of subjects when receiving 16 mg/day. In addition, self-report data indicated that higher buprenorphine doses were associated with a significant reduction in opioid withdrawal symptomatology.[89]
2005 Adis Data Information BV. All rights reserved.

In a study by Johnson et al.,[11] 150 opioid-dependent subjects were randomised into three groups to receive, in a double-blind manner, placebo (n = 60), buprenorphine 2 mg/day (n = 60) or buprenorphine 8 mg/day (n = 30) for 6 days. They were then allowed to select a random dose change to one of the other blinded conditions for a further 8 days. A significantly higher proportion of patients in the two active buprenorphine groups remained on their initial dose longer and rated dose adequacy higher compared with placebo; however, there was no significant difference between the two active groups.[11] Likewise, in two studies by Petry et al. (n = 14[6] and n = 33[90]) examining the optimal dosing interval for buprenorphine in which subjects received either 4mg/70kg/day or 8mg/70kg/day, the only difference between the two dosage levels among the 18 outcome measures was in a subjective rating of withdrawal in one of the studies.[90] In a large study by Ling et al.,[91] 736 opioid-dependent patients were enrolled in a multicentre study of buprenorphine maintenance therapy for 16 weeks. Subjects randomised into the 8 mg/day dosage group did significantly better than those in the 1 mg/day group based on retention rates, urine opioid toxicology results and craving scores. Therefore, in general, it appears that patient outcomes are better with higher buprenorphine doses, although this has not been consistently demonstrated. Several factors may contribute to the wide variation in dosages of buprenorphine required, including the large interindividual variation in CYP3A4 activity. Therefore, plasma concentration may better reflect the dose-response relationship. In a study by Kuhlman et al.,[43] in which trough plasma concentrations were monitored during buprenorphine induction and maintenance in 11 heroin-dependent subjects, it was observed that there was an inverse relationship between buprenorphine plasma concentrations and withdrawal scores, with the suggestion that trough plasma buprenorphine and norbuprenorphine concentrations in excess of 0.7 ng/mL were associated with minimal withdrawal symptoms. In a study by Schuh and Johanson[37] in 14 opioid-dependent subjects, plasma concentrations were not significantly linked to the percentage of opioid-positive urine samples.[37]
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In a recent study,[38] 13 opioid-dependent subjects were recruited for a multiple-phase positron emission tomography (PET) scan study to determine opioid receptor availability in relation to buprenorphine dose and plasma concentrations. Subjects received buprenorphine to achieve 12 days of maintenance therapy on each of four doses of buprenorphine (0, 2, 16 and 32 mg/day). They had a PET scan (using [11C]carfentanil as a tracer) on the last day (day 12) of each maintenance phase; five subjects completed all four PET scans. Serial plasma samples were taken on the 9th day of each maintenance phase, and symptom questionnaires were administered on the 10th and 11th days of each maintenance phase. Compared with placebo, buprenorphine 2 mg/day decreased whole-brain opioid receptor availability by 41%, whereas the decreases for 16 and 32 mg/day were 8592% and 9498%, respectively. Buprenorphine plasma concentration and opioid receptor availability were inversely proportional to baseline withdrawal and heroin craving scores, as well as directly proportional to opioid receptor agonist effect scores. In a recent open-label study,[49] 24 opioid-dependent subjects received buprenorphine 16 mg/day to steady state (10 days). On day 10, plasma samples were collected and physiological, subjective and objective measures were collected at baseline and at 14 occasions over the dosing interval. The five subjects who reported high withdrawal scores towards the end of the dosing interval did not have significantly lower absolute buprenorphine concentrations than the other subjects. In the discussion, the investigators mentioned that there was a trend for more severe withdrawal scores to be associated with a faster rate of decline in plasma concentration, although the data and analysis related to this point are not provided.[49] A similar relationship has been proposed for rates of methadone concentration decline and withdrawal severity.[92] Reducing interdose withdrawal symptoms and decreasing the length of time for the induction phase with buprenorphine may be important determinants of treatment retention.[7,12,14] Patients who experience significant withdrawal during treatment (at any timepoint; induction or maintenance) are more likely to quit or relapse to opioid use. Establishing the relationships between plasma concentrations and re 2005 Adis Data Information BV. All rights reserved.

sponse to this partial opioid receptor agonist may help achieve these clinical goals. 6. Conclusion The pharmacokinetic properties of buprenorphine allow it to be a feasible option as substitution therapy in the treatment of opioid dependence. Sublingually, buprenorphine is rapidly absorbed into the oral mucosa followed by a slower absorption into the systemic circulation and a long terminal halflife. These provide the desired clinical properties for substitution therapy of a slow onset and extended duration of action. These features in combination with the pharmacodynamic properties of partial opioid receptor agonist activity and prolonged binding to opioid receptors result in a substitution therapy that can be administered less frequently than once daily, that is associated with a less severe withdrawal syndrome and that has a safer toxicity profile than other opioids. Buprenorphine is extensively metabolised by CYP3A4; therefore, it may be subject to drug interactions when used concomitantly with other drugs known to inhibit or induce CYP3A4. The relationship between buprenorphine pharmacokinetics and pharmacodynamics has not yet been fully elucidated. Acknowledgements
No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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8. 9.

10. 11. 12. 13. 14. 15. 16.

17. 18. 19.

20. 21. 22. 23. 24.

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Correspondence and offprints: Dr Beth Sproule, Clinical Research Department, Centre for Addiction and Mental Health, 33 Russell Street, Toronto, ON M5S 2S1, Canada. E-mail: beth_sproule@camh.net

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