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Improved Regional Cerebral Blood Flow
in Chronic Cocaine Polydrug Users
Treated with Buprenorphine
Jonathan M. Levin, Jack H. Mendelson, B. Leonard Holman, Siew K. Teoh, Basem Garada,
Richard B. Schwartz and Nancy K. Mello
Department ofRadiology, Brigham and Women's Hospital, Boston, Massachusetts; Alcohol and Drug Abuse Research
Center, McLean Hospital, Belmont, Massachusetts and Harvard Medical School, Boston, Massachusetts
previously used SPECT with @Tc-HMPAO, lipophilica
Chroniccocaine and polydrugabuse have been assocsated with radiopharmaceuticalwith rapid and stable brain uptake in
regionalabnormalities cerebralperfusion. he authorshave proportion to cerebral perfusion (10,11), to demonstrate
in T
prevkxisly demonstrated that these abnormalities are partially focal perfusion abnormalities, especially in anterior brain
reversible after drug addiction treatment with buprenorphine. structures, in exclusively cocaine-dependent men as well
to the
Thisstudywas designed separate effecton cerebral as in cocaine-polydrug-dependent men (6). They have also
perfusionof abstinence from drug use from that of buprerior shown that these perfusion abnormalities improve with
phine directly.Methods: Fifteencocaine- and heroin-dependent treatment with the mixed opioid agonist-antagonist bu
menwerestudied with @Tc-hexamethylpropyleneamine oxime
prenorphine(12). This preliminarystudy left unclear, how
(HMPAO) brain SPECT. The men, all part of an inpatientdrug
abusetreatmentresearchprogram,were randomlyassigned ever, whether the improvement was due to buprenorphine
afterdetoxification receiveplaceboor either6 or 12 mg daily treatment itself or abstinence from drug abuse. Because
to
buprenorphine treatment. SPECT studies were performed at opioid antagonists such as naloxone have been shown to
baseline, ftermadmumdosagewasreached
a andaftertapering augment cerebral perfusion in both normal and ischemic
offthestudy S
drug. tudies erecomparedlauallywfth
w v to
regard brain (13—21), well as reverse the decrement in CBF
as
of
the numberand location perfuelon defectsby reviawers produced by opioid agonists (22,23), the authors sought to
blinded to treatment assignment. Results: Subjects receiving evaluate the effect of buprenorphine on cerebral perfusion
buprenorphinehad a significant reduction in the number of de in drug-abusing men undergoing treatment.
fectsperstudybetweenbaselineandmaximumbuprenorphine
dose as compared with those receiving placebo (decreaseof 4 METhODS
±5.4 versus increase of 4.8 ±4.7, p = 0.006). These differ
ences were dose-related.Improvementwith buprenorphinewas Pa@s
temporary, aftertapering
wfthretumtobaseline off.Conclusion: yr)
Fifteenmen (meanage 33.5yr; range 25—45 were enrolled
Buprenorphine treatment, and not abstinence from drug use in an inpatient drug abuse treatment research programafter re
alone,leadsto improvementn regionalcerebralperfusion
i ab cruitment.Each patient underwentextensive medical and neuro
normalities in chronic cocaine- and heroin-dependentmen. logicalevaluationwith routine blood work, brain MRIs and HIV
antibodytestingallnegative.Drughistorieswere obtainedvia:(a)
p c
Key Words: cerebrovascular erfusion; ocaine;heroin;tech a medical history interview with a physician; (b) written drug
netium-99m-HMPAO; s emission history questionnaires;and (c) the orally administeredStructured
buprenorphine; ingle-photon
computed tomography Clinical Interview for DSM-Ifl-R. All subjects met DSM-III-R
J Nuci Med 1995; 36:1211—1215
criteria for cocaine dependence, and all subjects used cocaine
5.2
intravenously.They reportedan averageof9.6 ± yr of cocaine
3.9
use using an average of 3.8 ± g/wk. All subjects met DSM
foropioiddependence well, reporting
HI-Rcriteria as anaverage
No
of 9.4 ±6.7 yr use of 8.2 ±5.1 “bags―/day. subject met
he medical and neurological complications associated DSM-llI-Rcriteriafor any other Axis I psychiatricdiagnosis
with cocaine and polydrug abuse are well known. Several except for nicotine dependence. All aspects of the study were
groups in the last few years have demonstrated regional by ReviewBoardsofMcLeanHospital
approved theInstitutional
abnormalities in cerebral blood flow (CBF) and metabolism and the Brigham and Women's Hospital. Written informed con
in chronic and acute cocaine use (1—9).The authors have sent was obtainedfrom each subject priorto each imagingproce
dure.
All men were admitted to an inpatient drug treatment research
ReceivedJul 15, 1994;revisionaceeptedOct.24, 1994. unit where they were maintained free of illicit drugs and were
For correspondenceor reprints conta@:B. Leonard Holman, MD, Chairman,
Brighamand Women's Hospitai,75 Franos St., Boston,
Deparimentof R&@ok1gy, subjectto random a
drugscreening.All underwent 6-daydetoxi
MA02115. fication with methadone, followed by a 5-day drug-free period.
Improved AbusewithBuprenorphine€¢
rCBFin Polydrug â Levinet al. 1211
TABLE I
Comparisonof Treatment Groups
Control(n=5)6mg(n=5)l2mg(n=5)Age
3.4BMI28.4
(yr)36.2 7.632
± 5.132.2
± ±
3.2Duration 8.924.9
± ±1.923.8 ±
ofheroin
±4Amount use(yr)7.6 5.913.4
± 8.67.1
±
of heroinuse(bags/day)7.8
3.5Duration 2.81
± 6.65.2
1.7 ± ±
u
ofcocaine se(yr)132
4.7Amount ±
4.58.4 ±
5.37.3 ±
of
1Baselinecocaineuse(gi'wk)2.95 ±37.2 4.61
± .3 ±
5.8No meanlesions/study10 ±59 ±5.615 ±
difference
significant anyof thegroupa: ann-Whitney
between M U-testyieldspvalues>0.05for allcomparisons.
After detoxification,they were randomlyassigned in a double indicated by a color change from orange to blue. Defects were
blind fashion to one of three treatment groups: placebo, 6 mg considered small if they were between 0.5 and 1 cm in diameter,
or Medication admin
buprenorphine 12mgbuprenorphine. was medium ifbetween 1 and 2 cm and large ifgreater than 2 cm. Total
istered daily by the sublingualroute and subjects were observed for
numberand size of distinctdefects were determined each
for adverse reactions. Doses of medication were increased daily region (frontal, temporal, parietal, occipital, basal ganglia, thala
d
from1mgon Day 1to themaintenance osementioned aboveon mus, cerebellum) of each study and recorded on a database.
Day5. Medication at
wasthenmaintained thatsteadydose from Images were interpreted by three radiologists, each ofwhom was
to g
Day 5 until Day 16, at which point it was taperedto zero by Day blinded theidentityof thetreatment roupdesignationandthe
on
21. Fourpatients,however,weremaintained the studydrug, orderof each subject'sstudies.Discrepancies wereresolvedby
placebo or buprenorphine at their request; two received 12 mg consensus or by agreement of two of three readers.
buprenorphine,one received 6 mg buprenorphine,and one re MR studies were interpreted by a single neuroradiologist who
ceived placebo. was likewiseblindedto the treatment group designationof each
subject.
Imaging Protocol
SPECTimaging
Brainperfusion on
wasperformed threeocca StatIstIcal Analysis
sions:Day 1 (Study1), Day S (Study2) andDay 21 (Study3). The numberof defects were treatedin a weightedfashion:
Imagingtook place several hours after the early morningadmin small defects received a weightingof 1, mediumdefects 2 and
istrationof the daily dose of the study drug. All 15subjectshad large defects 3. The number of these weighted defects was then
Studies 1 and 2. Twelve subjects had Study 3, and of these only comparedacross treatment groups (differentdoses of buprenor
two subjects were among those not tapered off the study drug. U
phineandplacebo)usingthe Mann-Whitney -test,as weredif
Imaging began10—15 rainpostintravenous of
injection 20 mCi ferences in covariates among treatmentgroups. Because each of
@‘Tc-HMPAO (Ceretec, Amersham,Ltd., Amersham,En the subjectsservedas his own controlto reducethe effect of
gland).Datawere acquiredfor 40minon an ASPECTsystem(24) intersubject variation, the change in the number of defects per
(DigitalScintigraphics,Inc., Boston, MA)in 120projectionswith study throughtime, ratherthan absolute numberof defects, was
r
a 360°otation of the collimators using a previously described used for all comparisons. All tests and reportedprobabilityvalues
method(6,12,24). Data were attenuation-corrected,reconstructed I
are two-sided. Dispersion about the mean is reported as ± s.d.
in the axial plane parallel to the orbitomeatal line and in the
coronal plane. The reconstructed slices were displayed on a 128 x
128matrix (1.67 x 1.67mm pixel size) as a set of twenty 5-mm RESULTS
thick axialslicesand as a set of twenty 5-mmthickcoronalslices. No significant differences were found among the treat
Axial magnetic resonance (MR) images were acquired using a ment groups with respect to any of the following covari
W
1.5TeslaSignaSystem(GeneralElectricCo., Milwaukee, I). ates: age, body mass index (BMI), amount of cocaine and
Spin-echo,Ti-weighted (TR = 600 msec/TE = 20 msec) and
heroin use, durationofcocaine and heroin use and alcohol
T2-weighted and proton density (TR = 3000 msec!FE = 80,30
msec/NEX = 0.5) 3-mmthick sliceswere obtainedwith a 256 x use (Table 1). All MR studies were interpretedas normal.
192matrix and a 24-cmfieldof view. Comparingthe weighted number of defects at baseline
(Study 1) and after 5 days of escalating buprenorphine
Image Analysis therapy(Study 2), subjects receiving buprenorphinehad an
Transaxial and coronal SPECT images for each study were average decrease of4 ± defects per study, while those
5.4
displayed on a computer terminal. The color display level was receiving placebo had an average increase of 4.8 ±4.7
adjustedfor each study so that the central area of the cerebellum
defects per study (p = 0.008). A comparison of buprenor
was white (greater than 90% ofthe maximum activity ofthe slice),
thus normalizingthe entire study to the @‘Tc-HMPAO in
activity phine dose revealed a dose-response relationship. Subjects
thecerebellum. achstudywasanalyzed
E fordefectsinperfusion receiving 6 mg buprenorphine had no change (±1.8) in the
visible on at least two (axial)or three (coronal)contiguous slices. number of defects per study, significantly different from
Defect determinationwas entirely visually guided, without auto placebo (p = 0.04), while subjects receiving 12 mg had an
46
marion, nda defectwas definedas an areaof at least0.5 cm in average decrease of8 ± defects per study, which is also
a
diameterin whichtotal activitywaslessthan60%ofmaximum,as significantly different from the placebo group (p = 0.009).
1212 Vol.36 • 7 • 1995
The Journal of Nudear Medicine• No. July
baseline maHimum taper
@ 12 mg . e
g
V
.1
6 mg @e 0
@ 12mg placebo
FiGURE 1. Mean difference in lesion count between Studies 1
a
and 2 by treatmentgroup. Placebotreatmentis associated @Ath FiGURE 2. Compan&onof representativebrainSPECT images
slightincrease o
inthenumber f lesions w
perstudy, hereas 12mg of COCaine-dependent In each of three treatmentgroups at
men
areassociated itha marked
buprenorphine w decrease. threeseparate
timepoints: aseline
b (Study drugtreat
1),maximum
o
ment(buprenorphine r @ecebo, Study2) andafterstudydrugtaper
(Study3).A comparab@ m@cortical sheaindudesthe basalganglia@
thaiamus,frontal,temporal,pailetal and visual cortex.The 12-mg
A direct comparison of 6 mg to 12 mg buprenorphinealso study shows marked improvementin perfuaion,while the 6-mg
achieved statistical significance (p = 0.047) (Fig. 1). Anal T
study shows mild improvement. he piacebostudy shows no im
ysis using nonweighted defect data did not alter these re provement Followingtaper,all groupsshow poorerperfusion.Ar
rowsindicaterepresentativesmallperfusiondefectsand the arrow
suits significantly. s
headindicatesa mOderately izeddefect
A comparison was also made between the number of
defects at baseline (Study 1) and after tapering off bu
prenorphine(Study 3). There was no significantdifference
phine, rather than abstinence, is responsible for the ob
between subjects who had received buprenorphine and
served improvement in cerebral perfusion.
those who had received placebo (average decrease of 2 ±
The effect ofopioids, and their agonists and antagonists,
7.9 defects per study versus average decrease of 1 ±6
on CBF and metabolism has been studied in detail in the
defect per study, p = 0.93). Comparingdoses of buprenor
normal and ischemic brain. Several groups have found that
phine did not affect these results. Those receiving 6 mg had
opioids, such as morphine or herqin, decrease global or
an average increase of 0.6 ±6.3 defects per study (p =
0.54) nd r
a thoseeceiving had 12mg anaverage of regional CBF after acute administrationin found similar
decrease tory animals (20,22,23,25,26). Others havenormal labora
9.5
6.3 ± defects per study (p = 48) as comparedto placebo
decreases in cerebral metabolism in dogs (23) and in
(Fig. 2).
chronic polydrug abusing men studied with PET (27). The
effect of the opioid antagonist naloxone, however, is less
DISCUSSION clear. Some have shown that it increases CBF in normal
Subjects treated with buprenorphine had a significant control animals (15,17,20) while causing vasodilatation of
decrease in the baseline number of SPECT perfusion de pial vessels and increases in cerebral blood volume (16,18).
fects 5 days after beginning treatment with buprenorphine It has also been shown, in similar models, that naloxone
as compared to placebo. In addition, the decrease in per reverses the decrease in CBF caused by morphine (22,23)
fusion defects was dose-related, with those receiving 12 mg and that it improves CBF in ischemic brain tissue (19,21)
having significantly more reduction in defect numberthan and neurological deficit (13,14). Others have found the
those receiving 6 mg. As the different dosage groups did opposite, however, that it causes decrement in CBF in
not differ significantly in terms of number of baseline de normal brain; (21,28) that it offers no clinical (29) or per
fects, baseline differences do not appear to underlie these fusion (30,31) benefit, or actually impairs CBF in ischemic
findings. brain; (13) or that it dangerously increases cerebral metab
By comparing the baseline study (Study 1) with the olism in injuredtissue (32). A single PET study in patients
study following discontinuation of buprenorphine(Study with complex partial epilepsy showed no change in cere
3), no difference was detected in the number ofdefects per bral metabolism but a decrease in CBF after an injection of
study between either dose of buprenorphineand placebo naloxone (33).
following drugtaper. This reversibility,along with the dose The possible effects of a potent, mixed opioid agonist
response relationship, strongly indicates that buprenor antagonist, such as buprenorphine, are thus difficult to
Levin et al.
Improved rCBF in PotydrugAbuse with Buprenorphine• 1213
predict. It is clear that buprenorphinehas little of the sys drug addiction and, potentially, the importance and nature
temic cardiovascular and respiratory effect of direct opioid of abnormalities in rCBF observed in this population. In
agonists (34), and that it is a safe and effective potential addition, such a drug could well prove useful in other
treatment for drug addiction (35). Few studies, however, settings, such as in acute cerebrovascular disease or in
have examined the effect of buprenorphineon CBF. Stein conditions in which cerebrovascular circulation is chroni
and Fuller used autoradiographyto evaluate rCBF in rats cally compromised, potentially including safer analgesia
15 ruin following buprenorphine administration (36). They without impairmentof cerebral perfusion.
found that buprenorphineincreased CBF in several regions
in a dose-response fashion, with a moderate dose associ CONCLUSION
ated with the greatest effect. Two other studies in mongrelSPECT was used to serially evaluate rCBF in a placebo
dogs using the hydrogen clearance technique showed ei controlled, dose-escalating paradigm of buprenorphine
ther a slight decrease (37,38) or no change (22) in CBF with
treatment of chronic cocaine-polydrug-dependent men.
p
buprenorphine administration of 10—1000 g/kg. The au These dataindicate thatbuprenorphine,and not abstinence
thors' previous study of cocaine polydrug-dependent men alone, can lead to an improvement in abnormal cerebral
showed marked improvement in rCBF in areas identified perfusion.
as abnormalat baseline aftertreatmentwith buprenorphine
(12). There was also mild improvement in these abnormal ACKNOWLEDGMENT
areas before buprenorphine treatment was initiated, sug
This work was supportedin part by NationalInstituteon Drug
gesting an effect of abstinence as well. Since this was a 1
AbusegrantsDA00064,DAO616andDA07252.
preliminary study without a placebo control group, how
ever, direct comparison ofthe relative effects of abstinence REFERENCES
and buprenorphinewas difficult.In addition, in the absence
ND,Mullani Gould
1. Volkow N, 5, K.Cerebral
KL,Adler Krajewski blood
of a control group, serial measurement of areas of abnor flow in chronic cocaine users: a study with positron emission tomography.
mality, as previously employed, may be complicated by BrJ Psychiazrj 1988;152:641-648.
regression to the mean. The current study was prospec 2. Tumeh SS, Nagel JS, English Ri, Moore M, Holman BL. Cerebral abnor.
malitiesin cocaineabusers:demonstrationby SPECTperfusionbrain scin
tively designed specifically to avoid these potential con tigraphy. Work in progress. Radiology l990;l76:821—824.
founders and enable a direct comparison ofabstinence and 3. London ED, Cascella NG, Wong DF, Ct al. Cocaine-induced reduction of
buprenorphine on rCBF. glucoseutilization in human brain. A study using PET and ‘F
fluorodeoxyglucose.Arch Gen Psychiatry 1990;47:567—574.
There are several limitations to this study, the foremost KliegerP,
4. WeberDA, ND,SackerD,
Volkow M regional
Ivanovic .SPECF
being the extreme difficulty in controffingpotentially con cerebral blood flow studies in crack users and control subjects. I Nuc! Med
founding conditions in this patient population, as well as 1990;31:876—877.
5. Volkow ND, Fowler JS, Wolf AP, et al. Changes in brain glucose metal,
the complex interactions that may occur duringabstinence dependence
olismincocaine AmJ 1
andwithdrawal. Psychiatry99l;148:
from polydrug abuse. This difficulty is highlighted by the 621—626.
findingthat patients maintainedon placebo actually had an B PA,MendelsonH,etal.Brain
6. Holman L,Carvalbo J isabnor
perfusion
p
malin cocaine-dependent olydrugusers:a studyusing@rc-HMPAO and
increase in the number of perfusion defects over time. J
ASPECT. Nuc!Med 1991,32:1206—12l0.
These patients were polydrug-dependent,many for a num 7. Volkow ND, Hitzemann R, wang oj, et al. Long-term frontal brain mets
ber of years, and were being maintaineddrug-free after a bolicchangesin cocaineabusers. Synapse 1992;1l:184—l90.
8. weher DA, Franceschi D, Ivanovic M, et al. SPECT and planar brain
short detoxification period with methadone. Besides the imagingin crack abuse: WI.iodoamphetamineuptake and localization.J
fact that methadone is primarily useful for withdrawal from NuclMed l993;34:899—907.
opiates and not cocaine, these patients (while not exhibit GD,Jeffery J,HarrisGJ,
9. Pearlson P RossCA,Fischman MW,Camargo EE.
Correlation of acute cocaine-induced changes in local cerebral blood flow
ing the overt symptoms of acute withdrawal) were cer with subjectiveeffects.AmJ Psychiatry 1993;150:495-497.
tainly in a period of acute abstinence or early protracted A H KB,et al. Extractionf [@“TcJ-d,l
10.Andersen R,Friberg , Knudsen o
abstinence (39—41),both states being associated with spe HMPAO across barrier. Cereb
theblood-brain I BloodFlowMetab1988;
8:S44—S51.
cific physiological abnormalities. It is uncertain how cere RD,Burke F,Harrison
11.Neirinckx J A A
RC,Forster M,Andersen R,Lassen
bral perfusion would be affected under these complicated mechanism
NA. Theretention of @Fc-HMPAO: reaction
intracellular
conditions of abstinence. If buprenorphine treatment re withglutathione.J CerebBloodFlow Metab 1988;8:S4—S12.
J,
12. HolmanBL, Mendelson GaradaB, et al. RegiOnal cerebralbloodflow
duces abnormalitiesin cerebral perfusion, it is reasonable improveswith treatment in chronic cocaine polydnig users. J Nuc! Med
to hypothesize that lack of treatment during early pro 199334:723—727.
tracted abstinence would be associated with no change, or P J, Y. o
13.LevyR, Feustel . Severinghaus Hosobuchi Effectof naloxone n
neumlogicdeficitand corticalbloodflowduringfocal cerebral ischemiain
perhapsa worsening, as was observed. The dose-response cats. Ljfe Sci 1982;31:2205—2208.
relationship between buprenorphine and augmented CBF DS, Y. reversal ndmorphine
14.Baskin KieckCF, Hosobuchi Naloxone a
complements both rCBF findings in rats (36) as well as exacerbationof neurologicdeficitssecondaryto focal cerebral ischemiain
baboons.Brain Res 1984290:289-296.
informationas to the optimal efficacious dose of buprenor 15. Turner DM, Kassell NF, Sasaki T, Comair YG, Beck DO, Klein SL.
phine for drug addiction treatment in patients (42). Cerebraland systemicvascular effects of naloxone in pentobarbital-anes
The ramificationsof improvement of abnormalCBF by thetized normaldogs. Neurosurgery 1984;14:276—282.
Kassdll
16.TurnerDM, T,ComairYG,
NF,Sasaki Di.
BeckDO,Boarini High
mixed opioid agonist-antagonists are many. It may help to dose naloxoneproducescerebral vasodilation.Neurosurgerj 1984;15:192—
explain the usefulness of these compounds in treatment of 197.
1214 N 1
TheJoumalofNudearMedicine•VoI. 36• o. 7•JuIy 995
r
17. PhillisJW,DeLongRE,TownerJK. Naloxoneenhancescerebral eactive 30. Hubbard SundtT Jr. Failureof naloxoneto affectfocal incomplete
JL,
hyperemiain the rat. Neurosurgery 1985;17:596—599. cerebral ischemiaand collateralblood flow in cats. J Neurosurg 1983;59:
Y
18. KobariM, GotohF, Fukuuchi , et al. Effectsof(D-Met2,Pro5)-enkepha 237—244.
linamide and naloxone on pint vessels in cats. J Cereb Blood Flow Metab JD,
31. GainesC, Nehls DC, Suess DM, Waggener CrowellRM. Effectof
l985;5:34—39. naloxoneon experimentalstroke in awake monkeys. Neurosurgery 1984;
19. HaririRJ, SupraEL, RobertsJP, Lavyne MH. Effectof naloxoneon 14:308—314.
cerebral perfusion and cardiac performance during experimental cerebral
32. KobayashiH, Ide H, HayashiM. Effectof naloxoneon focal cerebral
J
ischemia. Neurosurg1986;64:780—786.
ischemia in cats. Neurochirurgia 1992;35:69—73.
m
20. SandorP, Cox-vanPutJ,de JongW,de WindD. Continuous easurement
of cerebral blood volume in rats with the photoelectric technique: effect of 33. Theodore WH, Leiderman D, Gaillard W, Khan I, Reeves P, Lloyd-Hontz
morphine and naloxone. Life Sci 1986;39:l657—1665. b
K. Theeffectofnaloxoneoncerebral loodflowandglucosemetabolism in
21. TurcaniP, GotohF, Ishihara et al. Dualeffectof naloxoneon blood
N, patientswith complexpartial seizures. EpilepsyRes 1993;l6:51—4.
platelet ggregation
a andcerebralbloodflowingerbils. hromb
T Res1986; 34. Shintani S, Umezato M, Toba Y, et al. Pharmacologicalproperties of
44:817—828. buprenorphine, a new analgesic agent. II. Nippon Yakurigaku Zasshi 1982;
22. Dohi S, MatsumiyaN, Abe T. Mechanismof morphine-induced suppres 79:173—191.
sion of centralnervoussystembloodflow. No To Shinkei1983 ;35:1083— Mello NK, Mendelson JH, Lukas SE, Gastfriend DR, Teoh SK, Holman
35.
1088. BL. Buprenorphine treatmentof opiateand cocaine abuse: clinicaland
N o m
23. Matsumiya , DohiS. Effectsofintravenous rsubarachnoid orphine n o precinical studies.Harvard Rev Psychiatry l993;1:168—183.
cerebral and spinal cord hemodynamicsand antagonismwith naloxonein 36. SteinEA, FullerSA. Effectsof buprenorphine regionalcerebralblood
on
dogs. Anesthesiology 198359:175—l8l. flowin the rat [Abstract].NIDARes Monogr 1994;140:118.
PA, R
24. HolmanBL, Carvaiho Zimmerman E, et al. Brainperfusion SPECT 37. TadaT, Ishidera SakaiM, Ichiyanagi . Cerebral irculation
T, K c andme
usingan annularsinglecrystalcamera:initialclinicalexperience.J Nuci tabolism during high-dose buprenorphine and fentanyl anesthesia. Masui
Med 1990;31:1456—l461. 198534:1450—1455.
25. Buchweitz E, Grandison L, Weiss HR. Effect of morphine on regional 38. Tada 1, Ishidera 1, Sakai M, Ichiyanagi K. The effect ofbuprenorphine on
cerebral oxygen consumption and supply. Brain Res 1984291:301—308.
cerebralmetabolismin mongreldogs. Masui l986;35:724—728.
Ri.
26. HoehnerPJ,WhitsonJT, KirschJR,Traystman Effectof intracarotid
p o
39. MartinWR, JasinskiDR. Physiological arameters f morphinedepen
and intraventricularmorphineon regionalcerebralbloodflowand metabo
dence in man—4olerance, early abstinence, protracted abstinence. J Psy
lism in pentobarbital-anesthetized dogs. Anesth Analg 1993;76:266—273.
27. London ED, BroussolieEP, Links JM, et al. Morphine-induced
metabolic chiatrRes l969;7:9—l7.
changes in human brain. Studies with PET and ‘F-fluorodeoxyglucose. re-evaluation.
40. MartinWR,JasinskiDR, HaertzenCA, et al. Methadone—a
Arch Gen Psychiatry 1990;47:73—81. Arch Gen Psychiatry1973;28:286—295.
28. Trusk TC, Stein EA. Effect ofintravenous heroin and naloxone on regional 41. Martin WR. Phenomenology and theoretical basis of tolerance and depen
cerebral blood flowin the consciousrat. BrainRes 1987;406:238—245. dence. NIDA Res Monogr l984;54:l2—26.
29. KastinAl, Nissen C, OlsonRD. Failureof MIF-lor naloxoneto reverse RS,
42. Schottenfeld PakesJ, ZiedonisD, KostenTR. Buprenorphine: dose
ischemic-induced neurologic deficits in gerbils. Pharmacol Biochem Be/wv relatedeffectson cocaineand opioiduse in cocaine-abusingopioid-depen
1982;17:1083—1085. dent humans. BiolPsychia:ry 1993;34:66—74.
ImprovedrCBFin Polydrug â Levinet al.
AbusewithBuprenorphine€¢ 1215
