Br. J. clin. Pharmac. (1982), 13, 665-673
`
`SUBLINGUAL BUPRENORPHINE USED POSTOPERATIVELY:
`TEN HOUR PLASMA DRUG CONCENTRATION ANALYSIS
`
`R.E.S. BULLINGHAM, H.J. McQUAY, E.J.B. PORTER, M.C. ALLEN &
`R.A. MOORE
`Nuffield Departments of Anaesthetics & Clinical Biochemistry, John Radcliffe Hospital &
`Radcliffe Infirmary, Oxford
`
`1 A 10 h study of plasma drug concentrations of the opiate buprenorphine after sublingual use was
`designed because a previous 3 h study had shown that peak plasma drug concentrations in some
`patients had not occurred by 3 h after the sublingual dose.
`Fifteen postoperative patients were studied: at 3 h after a 0.3 mg intravenous dose five patients
`2
`received a sublingual preparation of 0.4 mg of buprenorphine, five 0.8 mg of buprenorphine and five
`placebo. Plasma drug concentrations of buprenorphine were measured by specific radioimmuno-
`assay.
`Plasma drug concentrations after sublingual buprenorphine were significantly higher than those in
`3
`the placebo group by 1 h. They remained significantly higher over the succeeding nine hours. The
`mean time to peak plasma drug concentration was about 200 min in both the 0.4 mg and 0.8 mg groups
`(range 90-360 min). The plasma drug concentrations in the 0.8 mg group were approximately twice
`those in the 0.4 mg group; the ratio of the relative systemic availabilities was similarly 1.8:1. The
`absolute systemic availability was estimated at about 55% for both groups. Uptake of buprenorphine
`from the sublingual site was essentially complete by 5 h after the dose was given.
`4 The implications for the timing of sublingual doses in clinical use are discussed.
`
`Introduction
`
`Drugs which undergo extensive hepatic or gut wall
`metabolism will be subject to a large and variable
`first-pass effect (FPE) when given orally. Oral doses
`thus have to be several times larger than parenteral to
`produce the same clinical effect, and there may be
`unpredictable
`dose-effect
`Opiates
`relationships.
`generally do have a large FPE and hence their effec-
`tive oral use is precluded in the treatment of acute
`pain.
`Sublingual administration provides one strategy by
`which the portal circulation may be circumvented
`during absorption. This route is well recognised for
`trinitroglycerin, but has also been described as clini-
`cally effective for a surprising range of drugs [ergot-
`amine (Ogden, 1963; Winsor, 1960), nicotine (Russell
`1980), phenazocine (Brown, 1966) and
`al.,
`et
`etorphine (Blane & Robbie, 1972)]. Recently the
`opiate buprenorphine has shown clinical efficacy by
`the sublingual route in the treatment of acute pain
`(Edge et al., 1979; Fry, 1979; Bullingham etal., 1981).
`The route appears to have advantages not only in
`terms of efficiency, but also convenience, cost and
`safety.
`The pharmacokinetics for this route in patients has
`been studied only for trinitroglycerin. Pharma-
`ceutical investigations have centred instead on buccal
`0306-5251/82/050665-09 $01.00
`
`as a model of mucosal absorption
`absorption
`(Dearden & Tomlinson, 1971; Vora et al., 1972). A
`description of the clinical pharmacokinetics of sub-
`lingual absorption is a necessity for logical application
`of the route to other drugs.
`Preliminary investigations of the uptake of sub-
`lingual buprenorphine have been reported (Bulling-
`ham et al., 1981). Observations made for 3 h after
`administration of a single dose at one dose level (0.4
`mg) showed that half the patients failed to achieve a
`peak plasma drug concentration in that time. This
`paper describes an extended study in which plasma
`drug concentrations were measured for 10 h after a
`single sublingual dose of either 0.4 or 0.8 mg.
`
`Methods
`
`Fifteen fit patients were selected sequentially from
`those undergoing total hip replacement at the Nuffield
`Orthopaedic Centre, Oxford. Ethical consent to the
`study was obtained. Patients were excluded if they
`were over 75 years old, weighed more than 90 kg or if
`they suffered from known cardiac, respiratory, hepatic
`or renal disorders. They were also excluded if they
`took regular medication likely to affect tissue blood
`© The Macmillan Press Ltd 1982
`
`Page 1
`
`RB Ex. 2010
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
`
`

`

`666
`
`R.E.S. BULLINGHAM ETAL.
`
`flows. In all cases preoperative electro-cardiogram
`(ECG), haemoglobin and plasma biochemistry were
`normal.
`All patients received the same premedication and
`anaesthetic. The premedication was 10 mg of dia-
`zepam orally 2 h preoperatively. Anaesthesia was
`induced with intravenous (i.v.) thiopentone 4 mg/kg,
`followed by pancuronium 0.1 mg/kg. After intuba-
`tion they were ventilated on a Bain circuit at a
`measured expired tidal volume of 10 ml/kg. The fresh
`gas flow of 70 ml/kg was nitrous oxide and oxygen in a
`ratio of 2:1 with 0.5% halothane. Halothane was used
`to prevent awareness and to reduce the effect of
`autonomic stimulation (Bullingham et al., 1980).
`The radial artery was cannulated after induction
`for intraoperative direct arterial pressure monitoring
`and was used for postoperative sampling. Buprenor-
`phine 0.3 mg (Temgesic, Reckitt and Colman
`Pharmaceutical), diluted to 10 ml with 0.154 M NaCl,
`was injected i.v. over 1 min. All patients received this
`initial dose. Intraoperatively all patients were supine
`on a warming blanket with temperature, ECG and
`direct arterial pressure monitoring. Fluid replace-
`ment was with Hartmann's solution at 5 ml kg-' h-1
`for 2 h and then blood was transfused according to
`a standard formula. The intraoperative loss was
`estimated by weighing of swabs and by calibrated
`suction. No further doses of pancuronium were
`given. Halothane was withdrawn about ten minutes
`before reversal which was with i.v. neostigmine 2.5
`mg and atropine 1.2 mg. After operation patients
`breathed 28% oxygen by facemask.
`At 180 min after induction the patients were
`allocated to one of three groups. The 0.4 mg group
`received 0.4 mg of buprenorphine sublingually (2 x
`0.2 mg). The 0.8 mg group received 0.8 mg of
`buprenorphine sublingually (2 x 0.4 mg). The sub-
`lingual buprenorphine was the same formulation as
`marketed by Reckitt and Colman Pharmaceuticals.
`The placebo group received placebo medication sub-
`lingually (2 x placebo). The placebo group was in-
`cluded to obtain information on the decay and effects
`of the initial i.v. buprenorphine dose. The medica-
`tions were given double-blind. Arterial samples were
`taken at 30, 60, 120 and 180 min after the i.v.
`buprenorphine dose, and then at 195, 210, 240, 270,
`300, 330, 360, 390, 420, 480, 510, 540, 570, 600, 630,
`660, 690, 720, 750 and 780 min; the sublingual medi-
`cations were given at 180 min. A basal venous blood
`sample was taken before induction of anaesthesia.
`All blood samples were taken into lithium heparin
`tubes, centrifuged and the plasma separated at room
`temperature. Plasma was stored at minus 20°C until
`required for analysis.
`
`Analytical procedures
`
`Buprenorphine was measured in whole heparinised
`plasma by a specific radioimmunoassay procedure
`(Bartlett et al., 1980).
`
`Analysis of results
`
`For measured plasma buprenorphine drug concentra-
`tions, all times were calculated from the initial 0.3 mg
`i.v. injection. For derived plasma buprenorphine,
`stripped of an initial dose contribution, times were
`calculated from when the second dose was given.
`Four samples were obtained over the first 180 min
`following the intravenous dose to allow comparison
`with data obtained previously in comparable groups
`of patients undergoing the same operation. Data
`after 180 min was analysed independently.
`In the placebo group, plasma drug concentrations
`after 180 min were analysed to define fully the
`terminal elimination phase. These values were fitted
`using NONLIN (Metzler et al., 1974) to the formula
`plasma concentration = A exp-at (Wagner, 1976).
`Weighting was not used.
`The mean monoexponential terminal decay con-
`stant derived for the placebo group (a) was calculated
`and used to compute the contribution of the i.v. dose
`to the plasma concentration for the other groups, in
`which an active sublingual dose was given at 3 h. The
`buprenorphine plasma drug concentrations at each
`sample time following the sublingual dose were
`stripped of the initial i.v. dose contribution, using the
`formula:
`Stripped plasma buprenorphine value = C1 - C180
`exp- axT where:
`= measured plasma buprenorphine concentra-
`Ct
`tion (ng/ml) for that individual at sample
`time t min
`C180 = measured plasma buprenorphine concentra-
`tion (ng/ml) for that individual at 180 min
`(i.e. just prior to sublingual administration)
`= mean terminal decay constant from placebo
`group (min-') derived as described
`= (t-180) min.
`
`T
`
`a
`
`The area under the plasma concentration against
`time curve for the sublingual component (AUCSI)
`was computed using stripped plasma drug concentra-
`tions for each patient in the 0.4 and 0.8 mg groups, by
`the formulae:
`
`AUCq}__O
`
`using a trapezoidal rule on stripped plasma
`values from 0 to 600 min
`AUCNx..,x from (C600/a)
`where:
`C6-= the stripped buprenorphine concentration
`(ng/ml) for that individual at 600 min
`= mean monoexponential terminal decay con-
`stant from placebo group
`600 = the final sample time (min); where not
`obtained, the time of the last available sample
`was substituted.
`
`a
`
`Page 2
`
`

`

`Then total AUCsl (ng min/ml) = AUCO1w +
`AUC600,
`Mean total AUCsI values were obtained for the 0.4
`and 0.8 mg groups. The relative systemic availability
`of the two sublingual doses was obtained by com-
`paring the mean total AUCsl values.
`To obtain an absolute bioavailability for the sub-
`lingual doses an estimate of an i.v. dose AUC
`(AUCI V ) was required. The AUOCv was derived in
`two stages, from the formulae:
`
`AUC,_180 = A/ (1-exp-al80) + B/ (1-exp-1t80) +
`C/ (1-exp-l80) [using the kinetic
`parameters from a triexponential fit for
`0.3 mg given i.v. postoperatively (Bull-
`ingham et a!., 1980)]
`
`and
`AUC180-
`where
`180
`
`aX
`
`-X = (C,80/a)
`
`= the mean stripped plasma buprenor-
`phine concentration (ng/ml) at 180 min
`= mean monoexponential terminal decay
`constant from placebo group
`
`Then
`total AUC'iV (ng min/ml) = AUCO180 + AUC,8a x
`The kinetic parameters from the previous study
`were used for the AUC' 1` 80 because they were the
`most accurate available values over this period. The
`measured drug concentrations from that study were
`stripped of the contribution of a preceding i.v. dose in
`exactly the same way as described above for the drug
`concentrations
`following
`sublingual
`the
`doses.
`Similarly, the mean monoexponential decay constant
`from the placebo drug group was the most accurate
`available decay constant for the period after 180 min,
`and hence was used for the AUO v 18-.. Combining
`results from different patient groups was justified
`by the narrow range of demographic values for the
`patient groups.
`The total AUCSI values for each individual in the
`0.4 and 0.8 mg sublingual groups were multiplied by
`3/4 and 3/8 respectively to make the dosage compar-
`
`Table 1
`
`Demographic data (mean + s.e. mean)
`
`SUBLINGUAL BUPRENORPHINE
`
`667
`
`able with the i.v. 0.3 mg dose. The percentage
`absolute availability was then obtained by comparing
`the dose corrected total AUCSI for each patient in the
`0.4 and 0.8 mg groups with the total AUO-V .
`The measured buprenorphine plasma drug concen-
`trations from the 0.4 and 0.8 mg sublingual groups
`from 2 h beyond the observed plasma drug concentra-
`tion peak were analysed by a monoexponential fit
`using NONLIN. A terminal decay constant was
`determined for each patient. A mean terminal decay
`constant was then calculated. This was compared
`with the mean terminal decay constant from the
`placebo group.
`
`Results
`
`The mean demographic data for the three groups of
`patients is shown in Table 1. There were no signifi-
`cant differences between any of the groups for any of
`these variables.
`Measured buprenorphine plasma drug concentra-
`tions for each patient at each observation time follow-
`ing the first and second dose are shown in Tables 2, 3
`and 4.
`The initial i.v. dose led to plasma buprenorphine
`drug concentrations in the present study comparable
`with those observed before (Bullingham et al., 1980).
`For the placebo group (Table 2), the mono-
`exponential fits to the data after 180 min for each
`patient provided a terminal half-life of 311 + 33 min
`(mean + s.e. mean Table 5).
`The mean buprenorphine plasma drug concentra-
`tions at each sample time following the sublingual
`dose and stripped of the initial i.v. dose contribution
`are shown in Table 6. The ratio of the plasma drug
`concentrations of the 0.8 mg group to that of the 0.4
`mg group at corresponding times was close to 2 (mean
`value + s.e. mean 1.89 + 0.08). The plasma drug
`concentrations at each time were compared using the
`Mann-Whitney U-test. Levels in the 0.4 mg group
`were significantly higher than those in the placebo
`group by 30 min (P = 0.05). By 1 h complete separa-
`tion of drug concentrations in these groups had
`occurred (P = 0.004), and this persisted throughout
`
`Group
`
`Number of patients
`Age (years)
`Sex ratio
`Weight (kg)
`Sublingual dose/kg (,ug/kg)
`Height (cm)
`Surface area (M2)
`Surgery time (min)
`Blood loss (ml)
`
`0.4mg
`
`5
`
`64.2
`2.5
`2M:3F
`66.4 + 2.9
`6.0 + 0.3
`165.3
`3.8
`1.67 + 0.1
`72.0 + 12.1
`419.6 + 60.1
`
`0.8mg
`
`5
`66.0 + 3.2
`2M:3F
`64.8+3.9
`12.5 ± 0.7
`167.0 ± 2.4
`1.68 ± 0.1
`88.4 + 9.6
`543.4 + 147.9
`
`Placebo
`
`5
`66.8 + 2.9
`2M:3F
`65.0 + 4.0
`
`162.2 + 1.2
`1.62 + 0.1
`89.4 + 9.0
`467.6 + 44.6
`
`Page 3
`
`

`

`668
`
`R.E.S. BULLINGHAM ETAL.
`
`Buprenorphine plasma levels (ng/ml) in patients receiving i.v. buprenorphine (0.3 mg) and placebo
`Table 2
`sublingual tablet
`
`2
`
`4
`
`9
`
`11
`
`15
`
`Mean (± s.e. mean)
`
`00
`
`.96 + 0.15
`0.63 + 0.07
`0.47 + 0.11
`0.32 + 0.03
`
`0.29
`0.02
`0.26±0.02
`0.22±0.02
`0.21
`0.02
`0.17
`0.03
`0.18
`0.02
`0.16±0.02
`0.15
`0.02
`0.15
`0.02
`0.15
`0.02
`0.12
`0.02
`0.12
`0.02
`0.11
`0.02
`0.12
`0.02
`0.11
`0.01
`0.10
`0.01
`0.11
`0.01
`0.10
`0.01
`0.10
`0.02
`0.10
`0.02
`0.10
`0.02
`
`00
`
`.76
`0.50
`0.33
`0.33
`
`0.29
`0.27
`0.24
`0.23
`0.22
`0.18
`0.18
`0.18
`0.18
`0.17
`0.15
`0.15
`0.12
`0.12
`0.15
`0.13
`0.13
`0.10
`0.10
`0.15
`0.14
`
`After intravenous dose (0.3 mg)
`0
`0
`1.06
`0.70
`0.55
`0.58
`0.39
`0.38
`0.32
`0.21
`Sublingualplacebo at 180 min
`0.33
`0.22
`0.23
`0.24
`0.14
`0.25
`0.14
`0.24
`0.11
`0.23
`0.11
`0.21
`0.11
`0.21
`0.08
`0.20
`0.08
`0.21
`0.08
`0.16
`0.08
`0.14
`0.08
`0.11
`0.12
`0.08
`0.06
`0.12
`0.11
`0.08
`0.06
`0.11
`0.11
`0.07
`0.11
`0.08
`0.11
`0.06
`0.04
`0.11
`0.04
`0.11
`
`01
`
`.51
`0.91
`0.91
`0.36
`
`0.34
`0.33
`0.24
`0.21
`0.18
`0.21
`0.16
`0.18
`0.16
`0.18
`NO
`0.16
`0.15
`0.18
`0.12
`0.12
`0.13
`0.14
`0.15
`0.11
`0.13
`
`00
`
`.75
`0.63
`0.36
`0.36
`
`0.26
`0.24
`0.23
`0.21
`0.12
`0.20
`0.13
`0.11
`0.14
`0.14
`0.09
`0.11
`0.07
`0.13
`0.08
`0.08
`NO
`0.08
`0.09
`0.08
`0.06
`
`Patient
`
`Time
`(min)
`
`0
`30
`60
`120
`180
`
`195
`210
`240
`270
`300
`330
`360
`390
`420
`450
`480
`510
`540
`570
`600
`630
`660
`690
`720
`750
`780
`
`NO = not obtained
`
`the remaining observations. The 0.8 mg group
`similarly had significantly higher plasma drug con-
`centrations than the placebo group at all times
`beyond 1 h.
`Comparison of the measured drug concentrations
`in the two sublingual buprenorphine groups showed
`low significance at some sample points. One of the
`patients in the 0.8 mg group (#3) had little rise in drug
`concentrations, and, as presented later, had overall
`low absorption. Exclusion of this patient produced
`significantly higher drug concentrations for the 0.8
`mg group over the 0.4 mg group at all times beyond 60
`min (P = 0.056 at 60 min and P = 0.008 beyond this
`time, Mann-Whitney U-test).
`The mean time to reach the highest stripped plasma
`drug concentration (Table 7) was 210 min for the 0.4
`mg group and 192 min for the 0.8 mg group. These
`values were not significantly different. The peak time
`obtained by combining both groups was 201 + 30 min
`(mean
`s.e. mean). The mean highest stripped
`plasma drug concentration for the 0.8 mg group (1.04
`
`ng/ml) was twice that for the 0.4 mg group (0.50
`ng/ml). These values were significantly different (P =
`0.048, Mann-Whitney U-test).
`The area under the plasma concentration against
`time curve extrapolated to infinite time, using the
`computed monoexponential terminal elimination
`constant of 0.0023 min-' from the placebo group, is
`shown for the two sublingual doses in Table 7. The
`relative systemic availability of the two sublingual
`doses was 1:1.77. This value was consistent with the
`mean plasma drug concentration ratio of 1.89 + 0.08
`(mean + s.e. mean) calculated for the two doses
`(Table 6), and with the ratio of the mean highest drug
`concentrations (2.08, Table 7).
`The mean absolute bioavailabilities for the 0.4 and
`0.8 mg sublingual doses were estimated at 57.7 and
`54.1% respectively (Table 7). The individual values
`from the two groups were not significantly different
`(Mann-Whitney U-test).
`The monoexponential decay constants were calcu-
`lated for sublingual doses using plasma drug concen-
`
`Page 4
`
`

`

`Buprenorphine plasma levels (ng/ml) in patients receiving i.v. buprenorphine
`Table 3
`sublingual buprenorphine tablet
`
`(0.3 mg) and 0.4 mg
`
`SUBLINGUAL BUPRENORPHINE
`
`669
`
`1
`
`5
`
`8
`
`12
`
`14
`
`Mean (+ s.e. mean)
`
`01
`
`.08 + 0.16
`0.56 + 0.05
`0.37 + 0.02
`0.32 + 0.02
`
`0.27
`0.30
`0.44
`0.52
`0.61
`0.59
`0.65
`0.63
`0.55
`0.54
`0.48
`0.48
`0.46
`0.47
`0.41
`0.35
`0.39
`0.36
`0.35
`0.35
`0.31
`
`0.01
`0.02
`0.09
`0.06
`0.07
`0.06
`0.05
`0.07
`0.05
`0.10
`0.06
`0.04
`0.05
`0.04
`0.06
`0.03
`0.03
`0.04
`0.04
`0.02
`0.02
`
`00
`
`.76
`0.58
`0.36
`0.36
`
`0.30
`0.36
`0.29
`0.52
`0.66
`0.58
`0.69
`0.85
`0.61
`0.82
`0.66
`0.50
`0.58
`0.58
`0.52
`0.42
`0.48
`0.36
`0.42
`0.38
`0.33
`
`After intravenous dose (0.3 mg)
`0
`0
`1.00
`1.40
`0.42
`0.67
`0.36
`0.42
`0.30
`0.36
`Sublingual dose (0.4 mg) at 180 min
`0.28
`0.27
`0.29
`0.29
`0.30
`0.66
`0.51
`0.63
`0.45
`0.66
`0.58
`0.51
`0.66
`0.45
`0.42
`0.58
`0.51
`0.39
`0.42
`0.42
`0.45
`0.39
`0.36
`0.45
`0.33
`0.48
`0.42
`0.36
`0.33
`0.27
`0.27
`0.36
`0.36
`0.33
`0.27
`0.32
`0.33
`0.30
`0.33
`0.34
`0.25
`NO
`
`00
`
`.76
`NO
`0.36
`0.32
`
`0.26
`0.30
`0.30
`0.30
`0.45
`0.45
`0.70
`0.60
`0.54
`NO
`0.42
`0.51
`0.43
`0.42
`0.36
`0.30
`0.33
`0.36
`0.24
`0.42
`0.30
`
`01
`
`.50
`0.57
`0.33
`0.27
`
`0.24
`0.27
`0.66
`0.66
`0.84
`0.81
`0.75
`0.69
`0.69
`0.51
`NO
`0.57
`NO
`0.55
`0.55
`0.42
`0.45
`0.51
`0.48
`0.30
`0.36
`
`Patient
`
`Time
`(min)
`
`0
`30
`60
`120
`180
`
`195
`210
`240
`270
`300
`330
`360
`390
`420
`450
`480
`510
`540
`570
`600
`630
`660
`690
`720
`750
`780
`
`NO = not obtained
`
`trations obtained two hours after the highest observed
`drug concentration. Plasma drug concentrations from
`patient #3 could not be fitted to a monoexponential
`decay curve; they showed no regular decline and
`produced a biologically unlikely half life. For the
`other nine patients who received active sublingual
`buprenorphine the decay constant (0.00189 + 0.00026,
`mean + s.e. mean) was not significantly different
`(Student's t-test) from that calculated for the placebo
`group (Table 5).
`
`Discussion
`
`Buprenorphine is a very lipophilic basic opiate
`(Hambrook & Rance, 1976). The results presented
`here help to characterise the sublingual route for such
`a drug in a clinical context where efficacy has already
`been established (Bullingham et al., 1981; Edge et al.,
`1979).
`For both doses, significant increases in plasma drug
`concentration were seen at times beyond 30 min. This
`
`correlates with the time of onset of analgesia when
`sublingual buprenorphine was administered after a
`preceding intravenous dose of buprenorphine, re-
`ported as 15 to 45 min (Bullingham et al., 1981).
`Plasma drug concentrations of buprenorphine after
`sublingual administration changed relatively slowly;
`typically highest drug concentrations were not reached
`until 3 h after administration. This suggests that
`plasma drug concentrations as low as 0.4 to 0.6 ng/ml
`are associated with appreciable analgesic effect.
`The time at which highest drug concentrations
`were observed was very variable, with a range of 90 to
`360 min. In addition, a previous study (Bullingham et
`al., 1981) reported one patient with peak drug con-
`centrations at 20 min. However, such variation will
`not be reflected in clinical effect provided that the
`patient has a pre-existing plasma drug concentration
`of buprenorphine close to that which has significant
`analgesic effect. This is confirmed in clinical practice:
`the analgesia seen postoperatively when sublingual
`buprenorphine follows parenteral use is notably
`smooth and uniform (Bullingham etal., 1981). On the
`
`Page 5
`
`

`

`670
`
`R.E.S. BULLINGHAM ETAL.
`
`Table 4
`Buprenorphine plasma levels (ng/ml) in patients receiving i.v.
`sublingual buprenorphine tablet
`
`buprenorphine (0.3 mg) and 0.8 mg
`
`3
`
`6
`
`7
`
`10
`
`13
`
`Mean (± s. e. mean)
`
`00
`
`.95 + 0.27
`0.98 + 0.31
`0.45 +- 0.08
`0.34 + 0.08
`
`0.31
`0.05
`0.06
`0.30
`0.62
`0.13
`0.86 + 0.16
`1.11 + 0.35
`0.97
`0.20
`0.94 + 0.21
`0.84
`0.20
`0.94
`0.22
`0.99
`0.21
`0.91
`0.25
`0.84 + 0.21
`0.76
`0.16
`0.66
`0.16
`0.67
`0.13
`0.67
`0.16
`0.56 + 0.10
`0.48
`0.08
`0.49
`0.05
`0.46
`0.07
`0.47
`0.06
`
`01
`
`.50
`0.88
`0.64
`0.58
`
`0.40
`0.48
`1.10
`1.36
`2.40
`1.60
`1.60
`1.50
`1.50
`1.66
`1.80
`1.63
`1.36
`1.27
`1.06
`1.21
`0.90
`0.61
`0.61
`0.61
`0.61
`
`After intravenous dose (0.3 mg)
`0
`0
`0.70
`0.66
`0.42
`0.42
`0.42
`0.24
`0.24
`0.16
`Sublingual dose (0.8 mg) at 180 min
`0.24
`0.17
`0.24
`0.15
`0.66
`0.54
`1.00
`0.85
`1.10
`0.82
`1.12
`0.75
`1.00
`0.70
`0.75
`0.70
`0.84
`0.67
`0.90
`0.67
`0.84
`0.58
`0.84
`0.58
`0.60
`0.45
`0.58
`0.44
`0.60
`0.48
`0.58
`0.48
`0.42
`0.48
`0.48
`0.48
`0.51
`0.48
`0.45
`NO
`0.44
`NO
`
`0
`NO
`2.12
`0.33
`0.21
`
`0.30
`0.23
`0.42
`0.70
`0.91
`0.96
`1.06
`0.96
`1.36
`1.26
`0.96
`0.63
`0.84
`0.54
`0.90
`0.78
`0.66
`0.66
`0.54
`0.48
`0.51
`
`0N
`
`O
`1.06
`0.64
`0.50
`
`0.45
`0.42
`0.40
`0.40
`0.33
`0.42
`0.33
`0.29
`0.33
`0.48
`0.36
`0.51
`0.57
`0.45
`0.33
`0.28
`0.33
`0.18
`0.29
`0.29
`0.33
`
`Patient
`
`Time
`(min)
`
`0
`30
`60
`120
`180
`
`195
`210
`240
`270
`300
`330
`360
`390
`420
`450
`480
`510
`540
`570
`600
`630
`660
`690
`720
`750
`780
`
`NO = not obtained
`
`other hand, use of the sublingual route for first ex-
`posure of the patient to buprenorphine can be ex-
`pected to result in appreciable delay in the onset of
`analgesia which is important for postoperative use.
`Assuming that a plasma drug concentration of at
`least 0.4 ng/ml must be reached, the time to reach this
`drug concentration can be estimated for an initial
`sublingual administration (Table 6). At a dose of
`0.4 mg two of the five patients never achieved this
`drug concentration; with 0.8 mg, one patient never
`reached this drug concentration but in this case the
`percentage absorbed was also uncharacteristically
`low. Even when 0.4 ng/ml was reached it took at least
`60 min from sublingual administration.
`The absolute systemic availability for either dose
`was about 50%. In view of the potential vagaries of
`this route in clinical applications, and the limited
`surface area available for absorption, this seems a
`creditable value. It may be compared with figures
`reported for the buccal absorption of solutions of
`pethidine (20%) and phenoperidine (73.6%) under
`
`experimental conditions (Chan et al., 1980). The
`extraction ratio of buprenorphine is estimated to be
`85% from intravenous studies (Bullingham et al.,
`1980). Oral systemic availability is consequently ex-
`pected to be 15% or less. Thus the degree of uptake
`achieved here with sublingual use is substantially
`more than anticipated for oral use. One patient (#3)
`had an absolute systemic availability of only 15%,
`considerably lower than any of the others. The figure
`would be compatible with inadvertent swallowing of
`the sublingual tablets.
`Sublingual doses are
`similar
`to those given
`parenterally, so that their oral use is likely to result in
`therapeutic failures. Such method failure seems in-
`frequent in practice. However, intramuscular admin-
`istration may inadvertently place the drug in adipose
`or connective tissue. Examples of low systemic avail-
`ability of buprenorphine after intramuscular use,
`presumably attributable to such mechanisms, have
`been reported (Bullingham et al., 1980).
`Two hours beyond the peak recorded plasma drug
`
`Page 6
`
`

`

`SUBLINGUAL BUPRENORPHINE
`
`671
`
`Table 5
`Kinetic parameters derived for each patient given 0.3 mg intravenous buprenorphine and placebo
`sublingual tablet
`
`Patient
`
`2
`
`4
`
`9
`
`11
`
`15
`
`Mean (± s.e. mean)
`
`Dose/kg (,ug/kg)
`Number of points
`A (ng/ml)
`a (min-')
`TI,2 a (min)
`SS dev
`
`4.62
`21
`0.478
`0.0030
`232.7
`0.0216
`
`4.29
`21
`0.409
`0.0018
`379.0
`0.0212
`
`5.26
`22
`0.340
`0.0029
`237.22
`0.0094
`
`5.35
`22
`0.441
`0.0022
`322.4
`0.0090
`
`3.90
`22
`0.389
`0.0018
`383.4
`0.1126
`
`4.68 + 0.28
`
`0.411 + 0.023
`0.0023 + 0.0003
`310.9 + 32.8
`0.035 + 0.020
`
`concentration after a sublingual dose, the rate of
`decay of plasma buprenorphine was not significantly
`different from the terminal rate of decay of an intra-
`venous dose. This indicates that the major part of
`sublingual uptake had occurred by then, typically
`some 5 h after administration. This is supported by
`results reported previously (Bullingham et al., 1981),
`where systemic availabilities of about 30% were
`obtained in a 3 h study. Extending the study period by
`7 h has only increased this figure to 50%.
`Comparison of the results from the two doses pro-
`vides some preliminary data about the type of model
`
`involved in sublingual absorption for this class of
`drug. The time to the highest plasma drug concentra-
`tion was the same for both doses. A ratio of two was
`found for the 0.8 mg dose to the 0.4 mg dose for
`plasma drug concentrations at corresponding times,
`for the peak plasma drug concentrations, and for the
`total area under the plasma drug concentration-time
`curve. The simplest description of these results is that
`provided by a model with a linear basis.
`Although oversimplified, insight into the nature of
`sublingual absorption can be obtained by considering
`a particular linear model, the one compartment open
`
`Table 6 Mean buprenorphine plasma levels (ng/ml + s.e. mean) in patients following the second dose of
`buprenorphine (individual data stripped of first dose contribution)
`
`Dose
`
`Time (min after
`sublingual dose)
`0
`15
`30
`60
`90
`120
`150
`180
`210
`240
`270
`300
`330
`360
`390
`420
`450
`480
`510
`540
`570
`600
`
`*n = 4
`
`0.4 mg sublingually
`(n = 5)
`
`0.8 mg sublingually
`(n = 5)
`
`Ratio
`
`0
`-0.03 ± 0.01
`0.00 ± 0.01
`0.16 ± 0.10
`0.26 ± 0.07
`0.36 ± 0.08
`0.35 ± 0.07
`0.43 ± 0.06
`0.42 ± 0.07
`0.36 ± 0.06
`0.37 _ 0.09*
`0.31 ± 0.06*
`0.33 ± 0.04
`0.31 ± 0.05*
`0.33 ± 0.05
`0.28
`0.06
`0.24
`0.03
`0.28
`0.03
`0.26
`0.04
`0.26 ± 0.05
`0.26 ± 0.02
`0.23 ± 0.03*
`
`0
`-0.02 ± 0.04
`-0.01 ± 0.02
`0.33 ± 0.11
`0.59
`0.16
`0.85 ± 0.32
`0.73 ± 0.19
`0.71 ± 0.20
`0.63 ±0.19
`0.74 ± 0.22
`0.81 + 0.20
`0.74 ± 0.23
`0.68 ± 0.19
`0.61 ± 0.14
`0.51 ± 0.14
`0.55 + 0.13
`0.54
`0.15
`0.10
`0.44
`0.10
`0.37
`0.06
`0.39
`0.35 ± 0.07*
`0.06*
`0.37
`
`2.06
`2.27
`2.36
`2.09
`1.65
`1.50
`2.05
`2.19
`2.39
`2.06
`1.97
`1.55
`1.96
`2.25
`1.57
`1.42
`1.50
`1.35
`1.61
`Mean 1.89 + 0.08
`(n = 19)
`
`Page 7
`
`

`

`672
`
`R.E.S. BULLINGHAM ETAL.
`
`3
`
`ID
`
`.os
`
`o
`
`+
`
`+1
`
`c:~~~~~~ICo C! EC"It
`Q O
`c
`m d- Om W) w C-
`
`_
`
`!
`
`r- a,
`
`tl
`-4
`
`0
`
`CX~~
`X S X b <0 " oS-t
`
`oocC
`
`C1 i
`
`E30
`
`model with first order absorption (Gibaldi & Perrier,
`1975). This model gives an expression for the time to
`reach maximum plasma drug concentrations:
`Tmax = (loge (kel/kab))/(kel-kab)
`where: Tmax = time to maximum plasma drug con-
`centration
`kei = elimination rate constant
`kab = absorption rate constant
`Taking Tmax as the mean value of 201 min, and kel as
`the mean terminal decay rate constant of 0.00234
`min-1, a calculation by iteration gave a value for kab of
`0.00909 min-'. The half-life for the transfer of
`buprenorphine from the buccal depot of 76.3 min is
`consistent with systemic absorption of buprenorphine
`being essentially completed by 5 h. The ratio Of k/kab
`is 0.26. This has interesting pharmacodynamic im-
`plications (Wagner, 1968). A low ratio may be
`associated with greater pharmacodynamic effect than
`anticipated from the pharmacokinetics because of the
`non-linear dose response curve.
`In conclusion, sublingual administration for this
`type of drug seems to be worthwhile. Its undoubted
`practical advantages are supported by the pharma-
`cokinetic data presented here, in that the kinetic pro-
`file is distinct from that of the commonly considered
`routes. While there are limitations imposed by this
`profile on the use of the route for first dose admin-
`istration, these are only of therapeutic consequence
`in the acute context. For subsequent therapy or
`chronic administration with drugs which have a high
`first pass effect, and where there are no local
`problems such as taste, the sublingual route could
`become the route of choice.
`
`We would like to thank the surgeons and anaesthetists of the
`Nuffield Orthopaedic Centre, Oxford for allowing us to
`study their patients, and the patients for taking part in the
`study. We also thank the anaesthetic and recovery ward
`staff for their help. Reckitt and Colman Pharmaceutical
`Division kindly donated the drugs and assay materials and
`supported M.C.A. during this study. H.J.M. was supported
`by the Medical Research Council.
`
`References
`
`BARTLETT, A.J., LLOYD-JONES, J.G., RANCE, M.J.,
`FLOCKHART, I.R., DOCKRAY, G., BENNElT, M.R.D. &
`(1980). The radioimmunoassay of
`MOORE, R.A.
`buprenorphine. Eur. J. clin. Pharmac., 18, 339-345.
`BLANE, G.F. & ROBBIE, D.S. (1972). In Agonist and
`Antagonist actions ofnarcotic analgesic drugs. (Proceed-
`ings of the Symposium of the British Pharmaceutical
`Society, Aberdeen, 1971.) ed. Kosterlitz, H.W., Collier,
`A.O.J. & Villareal, J.E., pp. 120-127. London: Mac-
`millan.
`
`BROWN, A.S. (1966). Absorption of analgesics from the
`buccal mucous membrane. Practitioner, 1%, 125-126.
`BULLINGHAM, R.E.S., McQUAY, H.J., MOORE, R.A. &
`BENNETT, M.R.D. (1980). Buprenorphine kinetics.
`Clin. Pharmac. Ther., 28, 667-672.
`BULLINGHAM, R.E.S., McQUAY, H.J., DWYER, D.,
`ALLEN, M.C. & MOORE, R.A. (1981).
`Sublingual
`buprenorphine used postoperatively: clinical observa-
`tions and preliminary pharmacokinetic analysis. Br. J.
`clin. Pharmac., 12, 117-122.
`
`Page 8
`
`

`

`CHAN, K., MURRAY, G.R. & ONG, G.C. (1980). A compari-
`son of the physico-chemical properties and potency of
`pethidine and phenoperidine. Br. J. clin. Pharmac., 9,
`122P.
`DEARDEN, J.C. & TOMLINSON, E. (1971). A new buccal
`absorption model. J. Pharm. Pharmac., 23, 68S-72S.
`EDGE, W.G., COOPER, G.M. & MORGAN, M. (1979).
`Analgesic effects of sublingual buprenorphine. An-
`aesthesia, 34, 463-467.
`FRY, E.N.S. (1979). Relief of pain after surgery. Anaesthesia,
`34,549-551.
`GIBALDI, M. & PERRIER, D. (1975). Pharmacokinetics.
`New York: Marcel Dekker.
`HAMBROOK, J.M. & RANCE, M.J. (1976). The interaction
`of buprenorphine with the opiate receptor. In Opiates
`and endogenous opioid peptides, ed. Kosterlitz, H.W.,
`pp. 295-301. Amsterdam: Elsevier/North Holland Bio-
`medical Press.
`METZLER, C.M., ELFRING, G.L. & McEWEN, A.J. (1974).
`A package of computer programs for pharmacokinetic
`modelling. Biometrics, 5, 562.
`
`SUBLINGUAL BUPRENORPHINE
`
`673
`
`OGDEN, H.D. (1963).
`Sublingual ergotamine tablets.
`J. Louisiana State Med. Soc., 115, 23-24.
`RUSSELL, M.A.H., RAW, M. & JARVIS, M.J. (1980). Clinical
`use of nicotine chewing-gum.
`Br. med. J.,
`280,
`1599-1602.
`VORA, K.R.M., HIGUCHI, W.I. & HO, N.F.H. (1972).
`Analysis of human buccal absorption of drugs by
`physical model approach. J. Pharm. Sci., 61, 1785-1791.
`WAGNER, J.G. (1968). Kinetics of pharmacologic response.
`I. Proposed relationships between response and drug
`concentration in the intact animal and man. J. theoret.
`Biol., 20, 173-201.
`WAGNER, J.G. (1976). Linear pharmacokinetic equations
`allowing direct calculation of many needed pharmaco-
`kinetic parameters from the coefficients and exponents
`of polyexponential equations which have been fitted to
`the data. J. Pharmocokin. Biopharm., 4, 443-467.
`WINSOR, T. (1981). Plethysmographic comparison of sub-
`lingual and intramuscular ergotamine. Clin. Pharmac.
`Ther., 29, 94-99.
`
`(Received September 29, 1981)
`
`Page 9
`
`