The Effect of Chronic Pain on Delay Discounting in Methadone Patients
Phase: PHASE1
Conditions: Opioid-use Disorder, Chronic Pain Syndrome
Sponsor: University of California, San Francisco

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
Versi o n #: 1. 9  
Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 1  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
D. A N D R E W  TO M P KI N S , MD M H S
Cli nic al  Rese arc h Pr ot o c ol 
T H E  EF F E C T  OF  C HR O NI C P AI N O N  D EL A Y DI S C O U N TI N G  IN 
M E T H A D O N E  P A TI E N T S 
N C T 0 4 4 7 3 9 5 0
Pr ot oc ol N u m be r: 
Z- 1 9 0 2, I R B 1 9- 2 7 8 3 8
Versi o n Date:  
1 2 -0 9 -2 0 2 0
S p o ns or: 
D.  A n dre w T o m p ki ns, M D M H S
Z uc ker b er g Sa n Fra n cisc o Ge nera l H os pital
1 0 0 1 P otrer o A ve., War d 9 5, R m 5 1 1
Sa n Fra n cisc o, C A 9 4 1 1 0
F u n di n g Or ga ni zati o n: 
NI D A  
Pri nci pal I n v esti gat or:  
Na me:   
D.  A n dre w T o m p ki ns, M D M H S
Tele p h o ne:  
6 2 8- 2 0 6- 3 6 4 5
Fa x:   
6 2 8- 2 0 6- 6 8 7 5
E- mail:
da vi d.t o m p ki ns @ ucsf.e d u
Me dical M o nit or: 
Na me:  
Sc ott Stei ger, M D  
Tele p h o ne:  
6 2 8- 2 0 6- 6 4 7 9
Fa x:   
6 2 8- 2 0 6- 4 1 5 3
E- mail:
sc ott.stei ger @ ucsf. e d u

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
Versi o n #: 1. 9  
Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 2  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
T A B L E O F C O N T E N T S  
1  
B A C K G R O U N D  ................................................................................................................. 9 
1. 2  
Bac k gr o u n d/ pre vale nce of researc h t o pic
Err or! B o o k m ar k n ot defi ne d.  
2  
S T U D Y R A TI O N A L E  ........................................................................................................ 1 0 
2. 1  
Ris k / Be nefit Assess me nt  ........................................................................................... 1 0 
3  
S T U D Y O B J E C TI V E S  ....................................................................................................... 1 1 
3. 1  
Pri mar y O bjecti ve  ....................................................................................................... 1 2 
3. 2  
Sec o n dar y O bjecti ves .................................................................................................. 1 2 
4  
S T U D Y D E SI G N  ................................................................................................................. 12  
4. 1  
St u d y O ver vie w ........................................................................................................... 1 2 
5  
C RI T E RI A F O R E V A L U A TI O N  ..................................................................................... 1 2 
5. 1  
Pri mar y Efficac y E n d p oi nt .......................................................................................... 1 2 
5. 2  
Sec o n dar y Efficac y E n d p oi nts .................................................................................... 1 3 
5. 3  
Safet y E val uati o ns ....................................................................................................... 1 3 
6  
S U B J E C T S E L E C TI O N  .................................................................................................... 1 3 
6. 1  
St u d y P o p ulati o n ......................................................................................................... 1 3  
6. 2  
I ncl usi o n Criteria ......................................................................................................... 1 3 
6. 3  
E xcl usi o n Criteria ....................................................................................................... 1 4  
7  
C O N C U R R E N T M E DI C A TI O N S  .................................................................................... 1 4 
7. 1  
All o we d  ....................................................................................................................... 1 4 
7. 2  
Pr o hi bite d .................................................................................................................... 1 4  
8  
S T U D Y M E DI C A TI O N S  .................................................................................................. 1 4 
8. 1  
Met h o d of Assi g ni n g S u bjects t o Treat me nt Gr o u ps .................................................. 1 4  
8. 2  
Bli n di n g  ....................................................................................................................... 1 4 
8. 3  
F or m ulati o n of Nal o x o ne a n d Place b o ........................................................................ 1 5  
8. 4  
S u p pl y of St u d y Me dicati o n at t he Site
Err or! B o o k m ar k n ot defi ne d.  
8. 5  
St u d y Me dicati o n Acc o u nta bilit y  ............................................................................... 1 6 
9  
S T U D Y P R O C E D U R E S A N D G U I D E LI N E S ................................................................. 1 6 
9. 1  
Cli nical Assess me nts  ................................................................................................... 1 6 
9. 2  
Cli nic al La b orat or y Meas ure me nts
Err or! B o o k m ar k n ot defi ne d.  
9. 3  P u pil o meter
Err or! B o o k m ar k n ot defi ne d.  
9. 4  
I m ps uli vit y Meas ures
Err or! B o o k m ar k n ot defi ne d.  
9. 5  
O pi oi d Wit h dra wal Meas ures
Err or! B o o k m ar k n ot defi ne d.  
9. 6  
Pai n Meas ures
Err or! B o o k m ar k n ot defi ne d.  

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
Versi o n #: 1. 9  
Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 3  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
9. 7  
Ps yc hiatric Meas ures
Err or! B o o k m ar k n ot defi ne d.  
1 0  E V A L U A TI O N S B Y VI SI T  ............................................................................................... 1 9 
1 0. 1  Visit 1 ( Scree ni n g ) ...................................................................................................... 1 9 
1 0. 2  Visit s 2-3 ( Sessi o ns 1 - 2) ............................................................................................. 2 0 
1 1  A D V E R S E E X P E RI E N C E R E P O R TI N G A N D D O C U M E N T A TI O N  ........................ 2 1 
1 1. 1  A d verse E ve nts ........................................................................................................... 2 1 
1 1. 2  Seri o us A d verse E x perie nces ( S A E) ........................................................................... 2 2  
1 1. 3  Me dical M o nit ori n g .................................................................................................... 2 3  
1 2  DI S C O N TI N U A TI O N A N D R E P L A C E M E N T O F S U B J E C T S ................................... 2 3 
1 2. 1  Wit h dra wal of S u bjects
Err or! B o o k m ar k n ot defi ne d.  
1 2. 2  Re place me nt of S u bjects ............................................................................................. 2 4  
1 3  P R O T O C O L VI O L A TI O N S  ............................................................................................. 2 4 
1 4  S T A TI S TI C A L M E T H O D S A N D C O N SI D E R A TI O N S  ............................................... 2 4 
1 4. 1  Data Sets A nal yze d  ..................................................................................................... 2 4 
1 4. 2  De m o gra p hic a n d Baseli ne C haracteristics  ................................................................. 2 4 
1 4. 3  A nal ysis of Pri mar y E n d p oi nt ..................................................................................... 2 5  
1 4. 4  A nal ysis of Sec o n dar y E n d p oi nts ............................................................................... 2 5  
1 4. 5  I nteri m A nal ysis .......................................................................................................... 2 6 
1 4. 6  Sa m ple Size a n d Ra n d o mizati o n  ................................................................................. 2 6 
1 5  D A T A C O L L E C TI O N, R E T E N TI O N A N D M O NI T O RI N G  ....................................... 2 6 
1 5. 1  Data C ollecti o n I nstr u me nt s ........................................................................................ 2 6 
1 5. 2  Data Ma na ge me nt Pr oce d ures  ..................................................................................... 2 7 
1 5. 3  Data Q ualit y C o ntr ol a n d Re p orti n g ........................................................................... 2 7  
1 5. 4  Arc hi val of Data  .......................................................................................................... 2 7 
1 5. 5  A vaila bilit y a n d Rete nti o n of I n vesti gati o nal Rec or ds ............................................... 2 7  
1 5. 6  S u bject C o nfi de nt ialit y................................................................................................ 2 7 
1 6  A D MI NI S T R A TI V E, E T HI C A L, R E G U L A T O R Y C O N SI D E R A TI O N S  .................. 2 7 
1 6. 1  Pr ot oc ol A me n d me nts ................................................................................................. 2 8  
1 6. 2  I nstit uti o nal Re vie w B oar ds a n d I n de pe n de nt Et hics C o m mittees ............................. 2 8 
1 6. 3  I nf or me d C o nse nt F or m .............................................................................................. 2 8 
1 6. 4  P u blicati o ns ................................................................................................................. 2 9  
1 6. 5  I n vesti gat or Res p o nsi bilities ....................................................................................... 2 9 
1 7  R E F E R E N C E S CI T E D  ...................................................................................................... 3 0 

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
 
Versi o n #: 1. 9  
Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 4  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
LI S T O F A B B R E VI A TI O N S  
A E  
a d verse e ve nt 
A N O V A  
A nal ysis of varia nce 
B P R U  
Be ha vi oral P har mac ol o g y Researc h U nit  
C F R  
C o de of Fe deral Re g ulati o ns 
C O W S  
Cli nical O piate Wit h dra wal Scale  
D C F  
Data c ollecti o n f or m  
E K G  
electr ocar di o gra m 
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G A D  
Ge neralize d a n xiet y dis or der  
G C P  
G o o d Cli nical Practice  
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act of 1 9 9 6 
HI V  
H u ma n i m m u n o deficie nc y vir us  
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I M 
I ntra m usc ular 
I R B 
I nstit uti o nal Re vie w B oar d 
I V 
i ntra ve n o us 
M A T  
Me dicati o n assiste d treat me nt  
M L R  
M ulti ple li near re gressi o n  
M M T  
Met ha d o ne mai nte na nce treat me nt  
NI D A  
Nati o nal I nstit ute o n Dr u g A b use 
O H R P  
Office of H u ma n Researc h Pr otecti o ns  
O T O P  
O piate treat me nt o ut pa tie nt pr o gra m 
O U D  
O pi oi d use dis or der  
P H Q  
Patie nt Healt h Q uesti o n naire  
PI  
Pri nci pal I n vesti gat or  
P C S  
Pai n catastr o p hizi n g scale 
S A E  
seri o us a d verse e x perie nce 
S C L  
S y m pt o m C hec klist  
S L R  
Si m ple li near re gressi o n  
S O W S  
S u bjecti ve O piate Wit h dra wal Sca le 
S U D  
S u bsta nce use dis or ders  
V A S  
Vis ual a nal o g scale  

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
 
Versi o n #: 1. 9  
Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 5  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
P R O T O C O L S Y N O P SI S  
TI T L E  
T he Effect of C hr o nic Pai n o n Dela y Disc o u nti n g i n Met ha d o ne 
Patie nts  
 
 
S P O N S O R  
D. A n dre w T o m p ki ns, M D M H S  
 
 
F U N DI N G 
O R G A NI Z A TI O N  
NI D A  
N U M B E R O F SI T E S  
1  
 
 
R A TI O N A L E  
T h e e pi de mic of o pi oi d o ver d ose deat hs c o nti n ues t o rise, killi n g m ore 
pers o ns i n 2 0 1 7 t ha n HI V/ AI D S at t he hei g ht of t hat e pi de mic. 
Me dicati o n assiste d treat me nt, i ncl u di n g met ha d o ne a n d 
b u pre n or p hi ne, is t he sta n dar d of care f or t he treat me nt of O U D. 
H o we v er, c hr o nic p ai n ca n re d u ce treat me nt effi cac y d uri n g 
me dicati o n assiste d treat me nt a n d is ass ociate d wit h illicit s u bsta nce 
rela pse, dr o p o ut, a n d s u bse q ue nt o ver d os e. Mec h a nis ms b y w hic h 
c hr o nic pai n ma y i nfl u e n ce t he i m p ulsi ve decisi o n ma ki n g (e. g., dr u g 
rela pse) i n p ers o ns wit h O U D ha ve n ot b ee n w ell c haracteri ze d. A 
better u n dersta n di n g is n ee de d of d ecisi o n- ma ki n g i n t his p o p ulati o n. 
T w o fact ors t h at ca n i nfl ue nce d ecisi o ns t o use dr u gs are i m p ulsi vit y 
a n d ac ute o pi oi d wit h dra wal. T his pr o p osal will test h o w c hr o nic pai n 
is ass ociate d wit h i ncreas es i n i m p ulsi ve decisi o n ma ki n g i n O U D, 
w het her i m p ulsi ve decisi o n ma ki n g is greater w h e n u n der g oi n g o pi oi d 
wit h dra wal, a n d h o w cat astr o p hizi n g ma y m o dif y t he ass ociati o n 
bet wee n wit h dra wal a n d i m p ulsi ve decisi o n ma ki n g i n patie nts wit h 
c hr o nic pai n a n d O U D. A n i deal p o p ulati o n f or t his de vel o p me ntal 
researc h pr oj ect is met ha d o ne-mai ntai ne d  patie nts, w h o s h o w hi g h 
treat me nt atte n da n ce rates a n d will t heref ore ass ure st u d y efficie n c y 
a n d relia ble c o m pleti o n.  
 
 
S T U D Y D E SI G N  
T his pr o p osa l is a ra n d o mize d d o u ble-bli n d place b o -c o ntr olle d P hase  
1 cli nical trial / h u ma n la b orat or y st u d y t o assess t he effect of ac ute 
o pi oi d wit h dra wal preci pitate d b y 0. 1 m g I M n al o x o ne o n dela y 
disc o u nti n g i n patie nts o n M M T  wit h a n d  wit h o ut c hr o nic pai n.  
 
 
P RI M A R Y 
O B J E C TI V E  
1.  Deter mi ne t he effect of a versi ve stress ors o n d ela y disc o u nti n g i n 
pers o ns i n met ha d o ne mai nte na nce. 
 
 
S E C O N D A R Y 
O B J E C TI V E S  
2.  I n v esti gate t he de gree t o w hic h trait pai n cat astr o p hizi n g m o difies 
t he ass ociati o n bet wee n o pi oi d wit h dra wal a n d dela y disc o u nti n g 
i n t he P AI N gr o u p. 
3.  E xa mi ne t he effect of bi ol o gical se x o n disc o u nti n g, o pi oi d 
wit h dra wal, pai n V A S, a n d pai n catastr o p hizi n g 
4.  E xa mi ne t he ass ociati o n bet wee n s o matizati o n, de pressi ve 
s y m pt o ms, a n xiet y a n d disco u nti n g.  
 
 
N U M B E R O F 
S U B J E C T S  
We e x p ect t o e nr oll 1 3 0 partici pa nts o n M M T, 6 5 i n t he c hr o nic pai n  
gr o u p ( P AI N) a n d 6 5 i n t he gr o u p wit h o ut c hr o nic pai n ( N O P AI N). 
Ass u mi n g a 2 5 % dr o p- o ut rate, we e x pect t o ha v e 5 0 c o m pleters of 
b ot h e x peri me ntal sessi o ns  i n eac h gr o u p. 
 
 

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
 
Versi o n #: 1. 9  
Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 6  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
S U B J E C T  
S E L E C TI O N  
C RI T E RI A  
I n cl usi o n Criteria: 
1)  M ale a n d fe male a d ults a ge d 1 8 - 6 5 
2)  St a ble met ha d o ne d ose (at least 2 1  da ys) verifie d b y 
c o ntacti n g partici pa nt’s o pi oi d treat me nt pr o gra m 
3)  U n dersta n d a n d s p ea k E n glis h 
4)  Uri ne t o xic ol o g y scree n ne gati ve f or dr u gs of a b us e a n d 
p ositi ve f or met ha d o ne 
5)  M ust be wit h o ut b y si g ns of i nt o xicati o n as e vi de n ce d b y 
a bilit y t o recei ve f ull d os e of met ha d o ne pri or t o researc h 
acti vities 
6)  Prese nce of c hr o ni c pai n ( > 3 m o nt hs) f or t he P AI N gr o u p a n d 
a bse nce of pai n f or t he N O P AI N gr o u p. 
E xcl usi o n Criteria : 
7)  U nsta ble ps yc hiatric ill ness as assesse d b y t he Mi ni 
I nter nati o nal N e ur o ps yc hiatric I nter vie w (e. g. acti ve s uici dal 
i deati o n, ps yc h osis) 
8)  U nsta ble me dical ill ness as assesse d b y t he st u d y’s 
i n de pe n de nt me dical m o nit or (e. g. u nc o ntr olle d h y perte nsi o n, 
rece nt m y ocar dial i nfarcti o n, rece nt str o ke, u nst a ble a n gi na) 
t hat ma y be affecte d b y preci pitate d wit h dra wal 
9)  Prescri pti o n o pi oi d use besi des met ha d o ne 
1 0)  Ac ute pai n pr o cess u nrelate d t o c hr o nic p ai n  
1 1)  W o me n w h o are pre g na nt or lactati n g  
1 2)  K n o w n aller g y t o nal o x o ne 
Patie nts will be all o we d t o re -scree n if it is ex p ect e d t hat a n i ncl usi o n 
criteri o n n ot met or a n e x cl usi o n criteri o n  met will c ha n ge pri or t o t he 
e n d of st u d y recr uit me nt.  
 
 
T E S T P R O D U C T, 
D O S E, A N D R O U T E 
O F 
A D MI NI S T R A TI O N  
Nal o x o ne 0. 1 m g I M  
Pr o d uct will be a d mi nistere d o nce at t he b e gi n ni n g of a st u d y sessi o n. 
A d mi nistrati o n will occ ur t w o h o urs after met ha d o ne d osi n g. 
 
 
C O N T R O L 
P R O D U C T, D O S E 
A N D R O U T E O F 
A D MI NI S T R A TI O N  
Place b o i njecti o n ( 0. 9 % N or mal Sali ne)  
Pr o d uct will be a d mi nistere d o nce at t he b e gi n ni n g of a st u d y sessi o n. 
A d mi nistrati o n will occ ur t w o h o urs after met ha d o ne d osi n g. 
 
 
D U R A TI O N O F 
S U B J E C T 
P A R TI CI P A TI O N 
A N D D U R A TI O N O F 
S T U D Y  
S u bjects will be o n st u d y f or a n a v era g e of t w o t o f o ur wee ks 
Scree ni n g:  3 h o urs  
Sessi o ns :  Eac h sessi o n will last a p pr o xi matel y f o ur h o urs. 
Sessi o ns m ust occ ur at least 4 8 h o urs a part. 
 
 
C O N C O M MI T A N T 
M E DI C A TI O N S  
Be y o n d t heir met ha d o ne mai nte na nce d os e, partici pa nts will  be 
all o we d t o ta ke O T C or prescri pti o n stre n gt h n o n- o pi oi d a nal gesic 
me d icati o ns s uc h as acet a mi n o p he n or i b u pr ofe n f or pai n t hr o u g h o ut 
t he st u d y, c o nsiste nt wit h sta n dar ds of care. 
Pr o hi bite d : O pi oi d a nal gesics ot her t ha n met ha d o ne  
 
 

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
 
Versi o n #: 1. 9  
Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 7  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
E V A L U A TI O N S  
 
P RI M A R Y E N D P OI N T  
•  
Dela y disc o u nti n g of m o ne y rate ( k)  
S E C O N D A R Y 
E N D P OI N T S  
•  
Pai n V A S rati n gs ( 0 -1 0 0)  
•  
Pea k C O W S  
•  
Pea k S O W S  
•  
Pea k C ha n ge fr o m Baseli ne  P u pil Dia meter  
•  
Pea k V A S of S u bjecti ve dr u g effects ( 0- 1 0 0 ) 
•  
Dr u g Effects  
•  
G o o d Effects 
•  
Ba d Effects  
•  
Li ki n g 
•  
Sic k  
O T H E R 
E V A L U A TI O N S  
•  
Pai n Catastr o p hizi n g Scale  
•  
Barratt I m p ulsi vit y Scale - 1 1 
•  
E yse nc k I m p ulsi vit y Q uesti o n naire  
•  
Se nsati o n See ki n g Scale  
•  
Zi m bar d o Ti m e Pers pecti ve I n ve nt or y  
S A F E T Y 
E V A L U A TI O N S  
•  
I n ci de nce of a d v erse e ve nts 
•  
C ha n ge i n v ital si g ns fr o m baseli ne ( H R, B P, R R, % o x y ge n 
sat urati o n) 
P L A N N E D I N T E RI M 
A N A L Y S E S  
W he n a p pr o xi mat el y 1 0  patie nts ha ve c o m plet e d t he st u d y, a n i nteri m 
a nal ysis will be c o n d ucte d b y t he st u d y statisticia n. If t here is n o tre n d 
of differe nces i n dela y disc o u nti n g bet wee n place b o a n d nal o x o ne 
a d mi nistrati o n sessi o ns, we w o ul d disc uss wit h o ur NI D A pr o gra m 
offi cial a n d i n de p e n de nt me dical m o nit or o n t he f oll o wi n g t w o 
o pti o ns: i ncreasi n g t he d ose of nal o x o ne t o 0. 1 5 m g or a d mi nisteri n g 
0. 1 m g nal o x o ne at tr o u g h i nstea d of pea k m et ha d o ne le vels. Seri o us 
a d verse e ve nts will be m o nit ore d b y t he me dical m o nit or t hr o u g h o ut 
t he d urati o n of t he st u d y. 
 
 
S T A TI S TI C S  
Pri m ar y A n al ysis Pl a n 
Usi n g met h o ds de vel o pe d b y c o -I J o h ns o n, n o nli near re gressi o n will 
be use d t o calc ul ate i n di vi d ual val ues of k, lar g er k val ues i n dicate 
greater disc o u nti n g or m ore i m p ulsi ve ness. K val u es are n or malize d 
usi n g l o g tra nsf or mati o n f or para metric a nal ysis. We will use re p eate d 
meas ures a n al yses i m ple me nte d i n S A S P R O C MI X E D. T he 
de pe n de nt varia ble is k ( disc o u nti n g). I n d e pe n de nt varia bles i ncl u de 
Gr o u p ( P AI N vs. N O P AI N), a fi xe d, bet w ee n- s ubjects effect a n d 
C o n diti o n (c o ntr ol vs. wit h dra wal), a re p eate d, w it hi n-s u bjects effect. 
T he Gr o u p x C o n diti o n i nteracti o n will be e x a mi ne d t o deter mi ne if 
gr o u p differe nces var y b y c o n diti o n. Pla n ne d c o ntrasts will e x pl ore 
a d diti ve effects of c hr o nic pai n a n d wit h dra wal b y e xa mi ni n g w het her 
disc o u nti n g b y t he P AI N gr o u p i n t he wit h dra wal c o n diti o n is greater 
t ha n 1) disc o u nti n g b y t he P AI N gr o u p i n t he c o ntr ol c o n diti o n, or 2) 
disc o u nti n g b y t he N O P AI N gr o u p i n t he wit h dra wal c o n diti o n. T o 
e xa mi ne t he effect of differi n g le vels of pea k a v ersi ve sti m uli o n 
disc o u nti n g, we will c o n d uct a nal yses usi n g o nl y data fr o m t he 
nal o x o ne -preci pitate d wit h dra wal sessi o n t hat i ncl u de pea k C O W S 

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sc ores. 
R ati o n ale f or N u m ber 
of S u bjects  
Beca use t here is n o e m pirical data  o n wit hi n -s u bject c ha n ges i n 
disc o u nti n g ass ociate d wit h nal o x o ne preci pitate d wit h dra wal, w e 
esti mate d c ha n ge usi n g d ata fr o m a st u d y b y c o ns orti u m PI J o h ns o n 
t hat use d si milar meas ures a n d f o u n d a bsti ne nce fr o m s m o ki n g i n 
nic oti ne- de pe n d e nt i n di vi d uals' decrease d  disc o u nti n g rates (f 2=. 0 2). 
F or bet w ee n gr o u p differe nces, w e relie d o n d ata fr o m o ur pil ot st u d y 
s h o wi n g a c orrelati o n bet wee n pai n a n d disc o u nti n g (r h o =. 2 5) 
c o nsiste nt wit h a s mall t o me di u m effect size ( f 2=. 0 8). T hree re p ort e d 
effect sizes f o r st u dies c o m pari n g o pi oi d a n d t o bacc o de p e n de nt 
partici pa nts a n d n o n- d e p e n de nt  partici pa nts  s h o w m uc h lar ger effects 
sizes (a p pr o xi mat el y f 2= 0. 4). T h us, basi n g t he sa m ple size o n t he 
effect size see n i n t he pil ot st u d y c o nser vati vel y yiel ds a sa m ple size 
t hat will pr o vi de m ore t ha n s ufficie nt p o w er t o det ect a gr o u p 
diff ere n ce. Usi n g t hes e wit hi n -s u bject a n d bet wee n-s u bjects effect 
sizes, a n d ass u mi n g a c orrelati o n a m o n g re p eate d meas ures of 0. 5, a 
fi nal, a nal ysis sa m ple of 1 0 0 ( 5 0 per P AI N a n d N O P AI N gr o u ps) will 
pr o vi de greater t ha n 8 0 % p o wer t o detect si g nifica nce (al p h a =. 0 5, 2-
taile d) f or bet w ee n gr o u ps mai n effects, wit hi n -s u bject effects of 
c o n diti o n, a n d t he i nteracti o n bet wee n t he t w o.  
 

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1  
B A C K G R O U N D  
1. 1  
B ac k gr o u n d/ pre v ale nce of rese a rc h t o pic  
C hr o nic pai n is pai n t hat has persiste d f or at least o ne m o nt h past t he us ual heali n g ti me of 
a s pecific i nj ur y, t y picall y lasti n g f or 6 m o nt hs or l o n ger ( 1, 2). C hr o nic p ai n is hi g hl y 
pre vale nt i n pers o ns wit h o pi oi d use dis or der ( O U D), a n d is n ot s ufficie ntl y treate d b y 
o pi oi d a g o nist treat me nt al o ne. Pers o ns i n met ha d o ne mai nte na nce treat me nt ( M M T) a n d 
office - b ase d b u pr e n or p hi ne treat me nt f or O U D h a ve hi g h rates of cli nicall y si g nifica nt 
c hr o nic pai n ( 3 7- 8 0 % de pe n di n g o n t he defi niti o n) ( 3- 6).  L o n git u di nal st u dies ha ve 
s h o w n t hat c hr o nic pai n d uri n g M A T is ass ociate d wit h greater o n g oi n g dr u g use ( 7- 1 0), 
treat me nt dr o p o ut ( 9, 1 1) a n d ris k of s uici de ( 1 2) c o m pare d t o patie nts wit h o ut c hr o nic 
pai n. T o get her, t hes e st u dies i n dicate t hat i n M A T, pai n is hi g hl y pre vale nt; M A T al o ne 
d oes n ot pr o vi de a de q u at e a nal gesic relief; a n d o n g oi n g pai n c o ntri b utes t o w orse 
treat me nt o utc o mes, i ncl u di n g illicit s u bsta nce use. Little is k n o w n a b o ut t he 
be ha vi oral/c o g niti ve pr o cesses t hat ma y be affect e d b y c hr o nic p ai n, partic ularl y 
pr ocesses ass ociate d wit h rela pse w hile o n M A T.  
 
Dela y  disc o u nti n g is t he relati ve prefere nce f or s maller s o o ner o ver larg er later re war ds, 
a n as pect of i m p ulsi vit y.  M ost i n di vi d uals w o ul d prefer a n i m me diate $ 1 0 0 o ver $ 1 0 0 
dela ye d b y 1 year.  H o we ver, w he n face d wit h t he c h oice bet w ee n recei vi n g $ 9 5 n o w 
ver s us $ 1 0 0 i n 1 year, pr efer e nces f or t he d ela ye d re war d ma y i ncrease.  B y assessi n g 
s uc h c h oices acr oss m ulti ple dela ys, dela y disc o u nti n g q ua ntifies t he de val u ati o n of 
re war ds o ver ti me, w hic h all o ws f or a n i n de x of o verall disc o u nti n g rate.  Dela y 
disc o u nti n g m o dels a f u n da me ntal decisi o n i n s u bsta nce use dis or d ers ( S U D) : t he s maller 
i m me diate re war d of dr u g e u p h oria, or t he d ela ye d b ut m ore val ua ble re war ds of 
i m pr o ve d f u ncti o ni n g a n d life satisfacti o n t hat c o me wit h pr ol o n ge d a bsti ne nce ( 1 4, 1 5). 
T he fi n di n g t hat i n di vi d uals wit h S U D disc o u nt m ore t ha n i n di vi d uals wit h o ut S U D has 
bee n s h o w n f or m ulti ple dr u gs ( 1 6- 2 1), i ncl u di n g o pi oi ds ( 2 2- 2 4). Effects are lar g e a n d 
mea ni n gf ul.  F or m atc he d c o ntr ols wit h o ut O U D, $ 1 0 0 0 l ost half its val ue i n 5 years, 
w hile it l ost 5 0 % of  its val ue i n o nl y 6 m o nt hs f or i n di vi d uals wit h O U D: a 1 0-f ol d 
differe n ce. Wit hi n patie nts wit h O U D, greater disc o u nti n g is ass ociate d wit h i ncrease d 
s hari n g of i njecti o n e q ui p me nt – a n HI V ris k fact or.  St u dies i n nic oti ne use dis or der s h o w 
t hat l o w dela y- disc o u nti n g pre dicts s uccess i n treat me nt ( 2 5- 2 7), a n d o n e st u d y s h o we d a 
si milar tre n d i n M A T ( p=. 0 8) ( 2 8). Fi nall y, rece nt researc h has s u g g este d t h at a versi ve 
states, s pecificall y o pi oi d wit h dra wal, ca n f urt her i ncreas e rat es of disc o u nti n g ( 2 9, 3 0).  
 
U n dersta n di n g t he c o g niti ve eff ect of a v ersi ve stat es (e. g. c hr o nic pai n) i n p atie nts wit h 
O U D c o ul d p r o vi de a p ot e ntial f or ti me-li mite d cli nical i nter ve nti o ns t o pre vent dr u g use. 
O ne of t he se mi nal r esear c hers i n dela y disc o u nti n g ( 3 1) has pr o p os e d t hat t he atte nti o n-
f oc usi n g pr o pert y of pai n a n d ot her a v ersi ve sti m uli is a res ult of dela y disc o u nti n g 
pr oce sses ( 3 2).  C o nsiste nt wit h t he h y per b olic b o w i n t he s ha pe of disc o u nti n g c ur ves 
( 3 1, 3 3), pai n is p ost ulate d t o create str o n g i m me di ate te m ptati o n t o f oc us atte nti o n o n t he 
pai nf ul sti m ul us, at t he e x pe nse of atte nti o n t o ot h er c o nse q u e nces, b ot h i m me diate a n d 
dela y e d.  Fr o m a c o g niti ve pers pecti ve, i m me diate f oc us o n pai n li kel y lea ds t o a re d uce d 
ca pacit y t o mai ntai n atte nti o n a n d h ol d re prese nt ati o ns of p ote ntial f ut ure o utc o mes i n 

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w or ki n g me m or y.  I n dee d, decrease d atte nti o n a n d w or ki n g me m or y l oa d ha ve bee n 
s h o w n i n c hr o nic pai n patie nts ( 3 4, 3 5).  Little e m pirical researc h t o date h as e x pl ore d t he 
ass ociati o n bet wee n pai n a n d disc o u nti n g, alt h o u g h si milar disr u pti o ns i n ce ntral re war d 
a n d e xec uti ve c o ntr ol pat h wa ys i n b ot h patie nts wit h c hr o nic pai n a n d S U D pr o vi des 
str o n g t he oretical basis f or a n ass ociati o n ( 3 6). A d diti o nall y, pre vi o us researc h has s h o w n 
a n i ncrease i n disc o u nti n g ass ociate d wit h ot her a versi ve states i ncl u di n g slee p de pri vati o n 
( 3 7), a n d i m p orta ntl y, o pi oi d wit h dra wal ( 2 9, 3 0). I n a d diti o n, o ur rece nt cr oss-secti o nal 
st u d y s h o we d a si g nifica nt ass ociati o n bet wee n d ela y disc o u nti n g of pai n-s pecific 
c o nse q ue nces a n d ris k f or o pi oi d mis use i n c hr o nic pai n patie nts ( 3 8).  
 
A n ot her critical ele me nt i n t he e x perie n ce of p ai n t hat i ncreas es atte nti o n t o pai nf ul 
sti m uli, catastr o p hizi n g ( 3 9, 4 0), pr o vi des a n a d diti o nal t he oretical basis f or t he 
ass ociati o n bet wee n pai n a n d disc o u nti n g.  Pai n catastr o p hizi n g is a set of ne gati ve 
e m oti o nal/c o g niti ve pr ocesses i n v ol vi n g r u mi nati o n a n d pessi mis m, perce pti o ns of 
hel pless ness, a n d ma g nificati o n of pai n-relate d s y m pt o ms a n d is meas ure d b y t he pai n 
catastr o p hizi n g scale ( P C S; ( 4 0)). Catastr o p hizi n g occ urs d uri n g a pai nf ul e x perie nce or i n 
a ntici pati o n of a pai nf ul e x perie n ce. Researc h s u g gests t hat catastr o p hizi n g is directl y 
ass ociate d wit h a m plificati o n of pai n pr ocessi n g a n d is a n eti ol o gic/ pr o g n ostic fact or i n 
se veral p ersiste nt pai n s y n dr o mes ( 4 1- 4 5). T h e te n de nc y t o a n d i nte nsit y of 
catastr o p hizi n g is rel ati vel y sta ble o ver ti me ( 4 0, 4 6, 4 7). Pai n catas tr o p hizi n g has bee n 
relati vel y u ne x pl or e d i n i n di vi d uals wit h O U D, b ut rece nt cli nical re p orts s u g gest 
catastr o p hizi n g ma y b e a n i m p orta nt ps yc h ol o gical ris k fact or ass o ciate d wit h o pi oi d 
o ver d ose f atalities  ( 4 8, 4 9) a n d has bee n ass oci ate d wit h cra vi n g a n d ris k of o pi oi d mis use 
i n c hr o nic pai n patie nts at ris k f or O U D ( 5 0, 5 1).  Gi ve n its i m p orta nce a n d pr o g n ostic 
val ue i n ot her c hr o nic pai n p o p ulati o ns, t his ga p s urr o u n di n g t he r ole of catastr o p hizi n g i n 
i n di vi d uals wit h O U D a n d c hr o nic pai n nee ds t o b e fille d. A n i deal p o p ulati o n t o e xa mi ne 
t hese ass ociati o ns ar e met ha d o ne- mai ntai ne d  p atie nts, w h o s h o w e xtre mel y hi g h treat me nt 
atte n da nce rates a n d will t heref or e ass ure st u d y efficie nc y a n d relia ble c o m pleti o n. 
Pr o misi n g res ults w o ul d be f oll o we d u p wit h a n R 0 1 a p plicati o n e x pa n di n g t he researc h, 
i ncl u di n g e xte nsi o n t o patie nts wit h O U D o n b u pre n or p hi ne a n d c hr o nic p ai n patie nts o n 
dail y prescri pti o n o pi oi d t hera p y wit h o ut O U D b ut at ris k f or o pi oi d mis use. B y e x pl ori n g 
mec ha nis ms lea di n g t o i m p ulsi ve rela pse d uri n g a versi ve sti m uli,  t his researc h ma y 
ulti matel y lea d t o tar gete d be ha vi oral, c o g niti v e, a n d/ or p har mac ol o gical i nter ve nti o ns 
t hat alter i m p ulsi vit y a n d pre ve nt rela pse. 
Pr o vi de a brief s u m mar y of t he n o n- cli nical d ata t hat has cli nical si g nifica n ce.  
2  
S T U D Y R A TI O N A L E  
T here is  a great n ee d t o u n dersta n d t he c o g niti ve pr ocesses u n d erl yi n g illicit o pi oi d use 
d uri n g met ha d o ne mai nte na nce tr eat me nt f or o pi oi d use dis or der, es p eciall y i n patie nts 
wit h c o - occ urri n g c hr o ni c pai n. O n g oi n g use is ass ociate d wit h i ncrease d ris k f or o pi oi d 
o ver d ose, treat me nt dr o p o ut a n d HI V ser oc o n versi o n/tra ns missi o n. 
2. 1  
Ris k / Be nefit Assess m e nt  
T he p ur p ose of t h e st u d y is t o c o n d uct a P hase 1 cli nical trial / h u ma n la b orat or y st u d y t o 
e xa mi ne t he effect of c hr o nic pai n al o ne a n d i n prese nce of ac ute o pi oi d wit h dra wal o n 

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dela y disc o u nti n g of m o ne y i n patie nts o n met ha d o n e mai nte na nce f or t h e treat me nt of 
O U D. A d diti o nall y, t his pr oject will e xa mi ne h o w pai n catastr o p hizi n g ma y m o dif y t he 
ass ociati o n of c hr o ni c pai n a n d o pi oi d wit h dra wal o n c ha n ges i n dela y dis c o u nti n g of 
m o ne y. If wit h dra wal a n d catastr o p hizi n g w ere f o u n d t o affect i m p ulsi ve decisi o n ma ki n g 
as assesse d b y d ela y disc o u nti n g, f ut ure researc h c o ul d e xte n d t he st u d y of t hese vari a bles 
t o deter mi ne if t he y pla y a n e x plicitl y ca usal r ole i n decisi o ns t o use o pi oi ds (rela pse). 
Dela y disc o u nti n g ma y t he n be s h o w n t o ser v e as a s urr o gate e n d p oi nt i n cli nical trials 
assessi n g pri mar y or sec o n dar y pre v e nti o n of o pi oi d use dis or ders. Researc hers c o ul d 
de vel o p i nter ve nti o ns t o re me diate i m p ulsi vit y as assesse d b y dela y dis c o u nti n g, t here b y 
pre ve nti n g rel a pse a n d i m pr o vi n g t he efficac y of o pi oi d use dis or der treat me nt. 
T here are n o dir ect be n efits t o t he researc h partici pa nt. T he res earc h has t h e p ote ntial t o 
i m pr o ve t he li ves of f ut ur e patie nts wit h o pi oi d use dis or der b y i m pr o vi n g treat me nt 
rete nti o n a n d r e d uci n g ris k f or o ver d os e deat hs. 
T he i m p ulsi vit y tas ks a n d assess me nts prese nt n o ris ks e xcee di n g t h ose of n or mal 
e ver y da y e x perie nces, alt h o u g h partici pa nts ma y e x perie nce b ore d o m, fati g ue, or 
fr ustrati o n d uri n g as a res ult of t hese sessi o ns a n d ot her assess me nts. 
T he  mai n p ote ntial ris k i n v ol ves preci pitate d o pi oi d wit h dra wal. O pi oi d wit h dra wal is 
distressi n g t o t he i n di vi d ual, b ut is n ot life t hreate ni n g. S y m pt o ms ma y i ncl u de na usea, 
v o miti n g, diarr hea or l o ose st o ols, b o d y ac hes, d ys p h oric m o o d, a n d g o osefles h. C ha n ges 
t o vital si g ns, i ncl u di n g ele vati o ns i n p ulse a n d bl o o d press ure, ma y als o occ ur. O T O P 
staff me m bers are well tr ai ne d t o rec o g ni ze a n d treat t hese s y m pt o ms.  
T here is a s mall ris k of w o rse ni n g ps yc hiatric s y m pt o ms or s u bsta nce rela pse w hile 
u n der g oi n g preci pitate d wit h dra wal. All atte m pts will be ma de t o scree n o ut v ul nera ble 
i n di vi d uals, a n d t o e ns ure t hat n o s y m pt o ms of pai n or wit h dra wal re mai n at t he e n d of 
sessi o ns. If rela ps e d oes occ ur, w e will c o m m u nicate t his i nf or mati o n t o t he o ut patie nt 
o pi oi d treat me nt pr o gra m. C o nse nt t o c o ntact t he pr o gra m t o verif y t h e met ha d o ne d ose is 
a pre-re q uisite f or st u d y partici pati o n. If nee d be, referrals ca n be ma d e f or ps yc hiatric or 
hi g her le vels of s u bsta nce a b use tr eat me nt, i ncl u di n g e mer ge nc y r o o m ps yc hiatr ic care at 
Z uc ker b er g Sa n Fra n cisc o Ge ner al H os pital, o n t he ca m p us w here O T O P is l ocate d. 
S us pecte d ps yc hiatric dis or ders disc o vere d d uri n g scree ni n g will be referre d f or o n g oi n g 
treat me nt. If t he p atie nt is at O T O P, Dr. T o m p ki ns will pr o vi de t his ser vice. If at a n ot her 
o pi oi d treat me nt pr o gra m, t he patie nt will be referre d t o a near- b y Sa n Fra n cisc o me ntal 
healt h treat me nt pr o vi der ( Westsi de C o m m u nit y Ser vice or D ore Ur ge nt Care Ce nter). 
T hese cli nics off er ur g e nt care, dr o p -i n a n d o n g oi n g ps yc hiatric treat me nt f or patie nts 
re gar dl ess of a bilit y t o pa y. A ncillar y, n o n- o pi oi d me dicati o ns, a n d ice p ac ks will als o be 
a vaila ble t o treat resi d ual wit h dra wal s y m pt o ms or pai n at e n d of sessi o n. 
3  
S T U D Y O B J E C TI V E S  
We h y p ot hesize t h at t he c hr o nic  pai n gr o u p ( P AI N) will s h o w great er dela y disc o u nti n g 
( great er i m p ulsi vit y) t ha n t he gr o u p wit h o ut pai n ( N O P AI N) i n b ot h t he c o ntr ol a n d 
o pi oi d wit h dra wal sessi o ns; a n d t hat disc o u nti n g will be greater i n t h e wit h dra wal sessi o n 
t ha n c o ntr ol sessi o n f or b ot h gr o u ps, wit h t he greatest disc o u nti n g o bser ve d i n t he P AI N 
gr o u p w hile i n wit h dra w al. 
 

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We als o h y p ot hesize t hat acr oss P AI N a n d N O P AI N gr o u ps, pai n catastr o p hizi n g will 
i n de pe n de ntl y m o dif y t he eff ect of preci pitate d o pi oi d wit h dra wal o n dela y disc o u nti n g, 
wit h hi g her le vels of catastr o p hizi n g ass ociate d wit h a str o n ger ass o ciati o n bet wee n 
wit h dra wal a n d d ela y dis c o u nti n g 
3. 1  
Pri m ar y O bjecti ve  
Deter mi ne t he eff ect of a versi ve stress ors o n d ela y disc o u nti n g i n pers o ns o n met ha d o ne 
mai nte na nce . 
3. 2  
Sec o n d ar y O bjecti ves  
I n v esti gate t he de gree t o w hic h trait pai n cat astr o p hizi n g m o difies t he ass ociati o n bet wee n 
o pi oi d wit h dra wal a n d dela y disc o u nti n g. 
4  
S T U D Y D E SI G N  
4. 1  
St u d y O ver vie w  
T his is a n o ut patie nt P hase 1 cli nical t rial i n vesti gati n g t he effect of nal o x o ne preci pitate d 
wit h dra wal o n dela y dis c o u nti n g. Eli gi ble partici pa nts will u n der g o t w o e x peri me ntal 
sessi o ns prese nte d i n r a n d o m or der. O ne s essi o n will i n v ol ve t he meas ure me nt of dela y 
disc o u nti n g 3 0 mi n utes after d o u ble- bli n d i ntra m usc ular (I M) a d mi nistrati o n of place b o 
( n or mal sali ne) a n d t he ot her will ha ve t he e x act s a me pr oce d ures p erf or me d after d o u ble-
bli n d I M a d mi nistrati o n of nal o x o ne ( 0. 1 m g). I njecti o ns will occ ur 2 h o urs after 
met ha d o ne d osi n g ( pea k le vels). St u d y sessi o ns will last 2 h o urs a n d i n v ol ve pai n a n d 
o pi oi d wi t h dra wal meas ures assesse d at baseli ne a n d 1 5- mi n ute  i nter vals after i njecti o ns. 
Sessi o ns will occ ur at least 4 8 h o urs a part. 
T his is a t w o-year  gra nt pr o p osal. T he first t w o m o nt hs will be use d f or st u d y start- u p, t he 
ne xt 2 0 m o nt hs f or st u d y recr uit me nt a n d c o m pleti o n of all st u d y visits, a n d t he last t w o 
m o nt hs f or data a nal ysis a n d ma n uscri pt pre p arati o n. Eac h partici pa nt is e x pecte d t o 
partici pate f or 2 - 4 w ee ks, de pe n di n g o n sc he d uli n g of t w o sessi o ns. 
T here are  t hr ee sites o n t he ca m p us of Z u c ker b er g Sa n  Fra n cisc o Ge n eral H os pital w here 
acti vities will ta ke place.  ( 1) O piate Treat me nt O ut patie nt Pr o gra m ( O T O P). Partici pa nt 
recr uit me nt, data c ollecti o n a n d st ora ge, a n d s o me st u d y visits will ta ke place at O T O P. 
( 2) U nit 5 B i n B uil di n g 5. E C Gs d uri n g scree ni n g a n d u n bli n de d st u d y me dicati o n 
pre par ati o n . ( 3) War d 8 4 i n B uil di n g 8 0. S o me st u d y sessi o ns ma y ta ke place at War d 8 4. 
J o h ns H o p ki ns U ni versit y’s Be ha vi oral P har mac ol o g y Researc h U nit ( B P R U) will be t he 
site of data a n al ysis. J o h ns H o p ki ns will o nl y ha ve access t o de-i de ntifie d h u ma n s u bject 
data, a n d s o a ce ntr al I R B is n ot nee de d f or t his st u d y.  
5  
C RI T E RI A F O R E V A L U A TI O N  
5. 1  
Pri m ar y Effic ac y E n d p oi nt 
Dela y disc o u nti n g f or m o ne y will be a ssesse d 3 0 mi n utes after st u d y me di cati o n I M 
i njecti o n i n b ot h e x peri me ntal sessi o ns. Disc o u nt rates ( k val ues) will be assesse d wit h a 
c o m p uter pr o gr a m de vel o pe d b y Dr. J o h ns o n, utilize d i n a vari et y of pre vi o us st u dies of 
dela y disc o u nti n g.  

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
 
Versi o n #: 1. 9  
Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 1 3  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
5. 2  
Sec o n d ar y Ef fic ac y E n d p oi nts 
Sec o n dar y o utc o me v aria bles will i ncl u de meas ures of pai n a n d o pi oi d wit h dra wal, i.e. 
•  
Pai n Vis ual A nal o g Scale ( V A S) 
•  
Cli nical O piate Wit h dra wal Scale ( C O W S)  
•  
S u bjecti ve O piate Wit h dra wal Scale ( S O W S)  
•  
Vital Si g ns  
•  
P u pil Dia meter  
•  
V A S Rati n gs o f S u bjecti ve Dr u g Effects 
 
I n a d diti o n, pers o nalit y q uesti o nnaires assessi n g i m p ulsi vit y will be c ollecte d at scree ni n g 
a n d c o m par e d acr oss gr o u ps, i ncl u di n g 
•  
Barratt I m p ulsi vit y Scale -1 1  
•  
E yse nc k I m p ulsi vit y Q uesti o n naire 
•  
Se nsati o n See ki n g Scale  
•  
Zi m bar d o T i me Pers pecti ve I n ve nt or y 
 
I n a d diti o n, pai n catastr o p hizi n g will be assesse d a n d will be a mai n pre dict or varia ble i n t he li near 
re gressi o n m o dels assessi n g effect m o dificati o n i n st u d y Ai m 2.  
5. 3  
S afet y E v al u ati o ns 
•  
I n ci de nce of a d v erse e ve nts 
•  
C ha n ge i n vital si g ns fr o m baseli ne 
6  
S U B J E C T S E L E C TI O N  
6. 1  
St u d y P o p ul ati o n 
T he partici pa nts will be a d ult pers o ns (a ge 1 8- 6 5) wit h o pi oi d use dis or der w h o are 
c urre ntl y mai ntai ne d o n a sta ble met ha d o ne m ai nte na nce d ose. Half ( 5 0) of t he c o m plet ers 
will ha ve c hr o nic p ai n ( P A I N gr o u p) a n d half will be pai n free ( N O P AI N gr o u p). 
Ot her wise, t he p artici pa nts will be healt h y e n o u g h (as deter mi ne d b y m e dical hist or y, 
p h ysical, a n d E K G) f or st u d y e ntr y. Partici pa nts will be re q uire d t o a bstai n fr o m illicit 
s u bsta nces a n d alc o h ol t hr o u g h o ut t he trial.   
It is esti mate d t hat ap pr o xi matel y  2 0 0 pers o ns will ha ve a n i n- pers o n scree ni n g t o e nr oll 1 3 0 
partici pa nts o n met ha d o ne mai nte na nce t hat meet all i ncl usi o n/e xcl usi o n criteria. We will nee d 
1 0 0 c o m pleters t o ha ve t he necessar y p o wer t o perf or m o ur statistical a nal ysis, 5 0 pers o n s i n t he 
P AI N gr o u p a n d 5 0 pers o ns i n t he N O P AI N gr o u p. 
6. 2  
I ncl usi o n Criteri a 
•  
M ale a n d f e male a d ults a ge d 1 8 - 6 5  
•  
St a ble met ha d o ne d ose (at least 2 1  da ys) verifie d b y c o ntacti n g 
partici pa nt’s o pi oi d treat me nt pr o gra m  
•  
U n dersta n d a n d s p ea k E n glis h 
•  
Uri ne t o xic ol o g y scree n ne gati ve f or dr u gs of a b use a n d p ositi ve f or 
met ha d o ne 
•  
M ust be wit h o ut b y si g ns of i nt o xicati o n as e vi de n ce d b y a bilit y t o recei ve 
f ull d ose of met ha d o ne pri or t o researc h acti vities 

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
 
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Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 1 4  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
•  
Prese nce of c hr o ni c pai n ( > 3 m o nt hs) f or t he P AI N gr o u p a n d a bs e nce of 
pai n f or t he N O P AI N gr o u p 
6. 3  
E xcl usi o n Criteri a  
•  
U nsta ble ps yc hiatric ill ness  as assesse d b y t he Mi ni I nter nati o nal 
Ne ur o ps yc hiatric I nter vi e w  (e. g. acti ve s uici dal i d eati o n, ps yc h osis) 
•  
U nsta ble me dical ill ness as assesse d b y t he st u d y’s i n de pe n de nt me dical 
m o nit or (e. g. u nc o ntr olle d h y perte nsi o n, rece nt m y ocar dial i nfarcti o n, 
rece nt str o ke, u nsta ble a n gi na) t hat ma y be affecte d b y preci pitate d 
wit h dra wal  
•  
Prescri pti o n o pi oi d use besi des met ha d o ne 
•  
Ac ute pai n pr o cess u nrelate d t o c hr o nic p ai n  
•  
W o me n w h o are pr e g na nt or lactati n g 
•  
K n o w n aller g y t o nal o x o ne . 
Patie nts will be all o we d t o re -scree n if it is e x p ect e d t hat a n i ncl usi o n criteri o n n ot met or 
a n e xcl usi o n criteri o n met will c ha n ge pri or t o t he e n d of st u d y recr uit me nt. 
7  
C O N C U R R E N T M E DI C A TI O N S  
All s u bjects s h o ul d be mai ntai ne d o n t he sa me d ose of met ha d o ne t hr o u g h o ut 
partici pati o n i n t he tri al. 
7. 1  
All o we d Me dic ati o ns a n d Tre at me nts  
A ncillar y, n o n- o pi oi d me dicati o ns, a n d ice pac k will als o be a vaila ble t o treat r esi d ual 
wit h dra wal s y m pt o ms or pai n at sessi o n e n d.   
7. 2  
Pr o hi bite d Me dic ati o ns a n d Tre at me nts  
T he f oll o wi n g me dicati o ns are pr o hi bite d d uri n g t he st u d y a n d a d mi nistrati o n will be 
c o nsi dere d a pr ot oc ol vi olati o n. 
•  
Ot her o pi oi d a nal gesic a ge nts ot her t ha n met ha d o ne. 
8  
S T U D Y M E DI C A TI O N S  
8. 1  
Met h o d of Assi g ni n g S u bjects t o P AI N or N O P AI N Gr o u ps  
Patie nts wit h c hr o nic pai n will be i de ntifie d b y self -re port a n d c o nfir me d b y hist or y a n d 
p h ysical perf or me d b y Dr. T o m p ki ns or a n ot her q ualifie d st u d y cli nicia n.  P ai n will be 
assesse d usi n g t he miscella ne o us pai n q uesti o n naire fr o m t he N ati o nal Healt h a n d 
N utriti o n E xa mi nati o n S ur ve y ( N H A N E S; ( 8 3)), t he W i des prea d Pai n I n de x, a n d t he Brief 
Pai n I n ve nt or y.  Dr. Cla u dia Ca m p bell will b e c o ns ulte d o n c halle n gi n g cas es t o hel p 
clarif y t he pr ese n ce or a bse nce of c hr o nic p ai n.   
8. 2  
Bli n di n g  
D ue t o t he o bjecti ves of t he st u d y, t he i de ntit y of test a n d c o ntr ol treat me nts w ill n ot be 
k n o w n t o i n vesti gat ors, resear c h staff, or partici p a nts .  T he f oll o wi n g st u d y pr oce d ures 
will be i n place t o e ns ur e d o u ble- bli n d a d mi nistrati o n of st u d y me dicati o ns .   

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
 
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Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 1 5  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
 
•  
Access t o t he ra n d o mizati o n c o de will be strictl y c o ntr olle d.   
•  
T he v ol u me a n d c ol or of I M me di cati o n a d mi nistrati o n will be t he sa me f or 
nal o x o ne a n d place b o 
•  
Pac ka gi n g a n d la b eli n g of nal o x o ne a n d place b o will be i de ntical t o mai ntai n 
t he bli n d.  
 
T he st u d y bli n d will be br o ke n o n c o m pleti o n of t he cli nical st u d y a n d after t he stu d y 
data base h as bee n l o c ke d.  
T he or der of sessi o ns wit h e xact st u d y me dicati o ns will be gi ve n t o Dr. T o m p ki ns i n a 
seale d e n v el o pe a n d k e pt i n a l oc ke d file ca bi net. T his e n vel o pe will be rea dil y a vaila ble 
f or u n- bli n di n g i n case of me dical e mer g e nc y. T h e e n vel o pe will be destr o y e d b y Dr. 
T o m p ki ns after partici p a nt has c o m plete d st u d y partici pati o n.  
8. 3  
F or m ul ati o n of N al o x o n e a n d Pl ace b o  
I D S p har mac y st aff will be i n c har g e of p urc hasi n g st u d y me dicati o ns ( nal o x o ne a n d 
place b o ( 0. 9 % n or mal sali ne) ) fr o m c o m mercial s o urces. T he fi nal a m o u nt of eac h 
i njecti o n will be t he sa me, n ot t o e xcee d 0. 5 m L per i njecti o n. U n bli n de d n ursi n g staff o n 
U nit 5 B will dra w u p t he st u d y me dicati o n a n d pr o vi de t o st u d y staff, e ns uri n g pac ka gi n g 
a n d la beli n g ar e i de ntical.  
8. 4  
S u p pl y of St u d y Dr u g at t he Site  
I D S p har mac y will or der a n d mai ntai n t he s u p pl y of all st u d y me dicati o ns. T he y will 
f oll o w all a p plica ble r e g ulati o ns a n d p olicies f or or deri n g, pr oc ure me nt, st ora ge, 
dis pe nsi n g a n d destr o yi n g u n use d me dicati o n. St u d y me dicati o n will be pre pare d a n d 
pr o vi de d t o Dr. T o m p ki ns ’ staff pri or t o eac h s essi o n  b y u n bli n de d U nit 5 B n ursi n g staff.  
8. 4. 1  
D os a ge/ D o s a ge Re gi me n 
Nal o x o ne 0. 1 m g will be gi ve n via I M i njecti o n, prefera bl y i n t he Delt oi d re gi o n. T he 
t otal v ol u me will n ot e xcee d 0. 5 m L per i njecti o n. Nal o x o ne is a M O R a nta g o nist t hat ha d 
F D A a p pr o val t o be use d t o re verse o pi oi d t o xicit y a n d is r o uti nel y use d i n e x peri me ntal 
st u dies t o i n d uce d mil d o pi oi d wit h dra wal s y m pt o ms ( Strai n et al., 1 9 9 5, Strai n et al., 
1 9 9 2; Me n dels o n et al., 1 9 9 7; Ka n of et al., 1 9 9 1). I n a d diti o n, o ne pre- cli nical st u d y i n 
fe male st u m ptaile d maca q ues mai ntai ne d o n m or p hi ne s h o we d 0. 1 m g nal o x o ne 
a d mi nistrati o n elicite d be ha vi ors c o nsiste nt wit h mil d o pi oi d wit h dra wal ( Gra nt et al., 
1 9 8 8). N or mal sali ne will be use d as place b o a n d will als o be a d mi nistere d via I M 
i njecti o n. T he t otal v ol u me of place b o will be e q ual t o nal o x o ne i njecti o n, n ot t o e xcee d 
0. 5 m L per i njecti o n. 
8. 4. 2  
Dis pe nsi n g  
T he I D S p har m ac y staff will dis pe nse t he me dicati o ns t o U nit 5 B n ursi n g staff w h o will 
t he n dra w u p st u d y me di cati o n a n d la bel t o e ns ure bli n di n g. Dr. T o m p ki ns’ staff will 
recei v e st u d y me dicati o n fr o m U n it 5 B n ursi n g staff a n d t h e n a d mi nister it i n War d 9 5 per 
pr ot oc ol. If t he sessi o n is ca ncelle d or resc he d ule d, st u d y me dicati o n will be ret ur n e d t o 
I D S p har mac y st aff f or d estr ucti o n acc or di n g t o all a p plica ble re g ul ati o ns a n d p olicies.  

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
 
Versi o n #: 1. 9  
Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 1 6  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
8. 4. 3  
A d mi nistr ati o n I nstr ucti o ns  
Pri or t o sessi o n c o m me nci n g, partici pa nts m ust gi ve a U D S t hat is p ositi ve f or met ha d o ne 
a n d ne gati ve f or illicit s u bsta nces a n d ot her pres cri pti o n o pi oi ds. I n a d diti o n, t he 
partici pa nt m ust n ot ha ve a n y si g ns of i nt o xicati o n a n d meet pai n pa ra meters descri be d i n 
t he i ncl usi o n / e xcl usi o n criteria. D uri n g t he C O VI D- 1 9 pa n d e mic, partici p a nts m ust als o 
scree n n e gati ve p er h os pital p olic y t o be all o we d i nt o War d 9 5 t o be gi n st u d y sessi o ns. 
Lastl y, t he partici pa nt will s m o ke 1 ci garette 2 0 mi n utes pri or t o i njecti o n.  Dr. T o m p ki ns 
or a n ot her q u alifie d a n d lice nse d me dical cli nicia n will a d mi nister t he I M i njecti o n i n t he 
delt oi d m uscle of t he partici pa nt . T he i njecti o n will occ ur t w o h o urs after t h eir dail y 
met ha d o ne d ose w as gi ve n. 
8. 5  
St u d y Me dic ati o n Acc o u nt a bilit y  
A n acc urate a n d c urre nt acc o u nti n g of t he dis pe nsi n g a n d ret ur n of st u d y dr u g f or eac h 
s u bject will be mai ntai ne d o n a n o n g oi n g basis b y a me m ber of t h e I D S p har mac y ser vi ce .   
9  
S T U D Y P R O C E D U R E S A N D G UI D E LI N E S  
Pri or t o c o n d ucti n g a n y st u d y- relate d acti vities, writte n i nf or me d c o nse nt a n d t he Healt h 
I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A) a ut h orizati o n m ust be si g ne d a n d 
date d b y t he s u bject.   
9. 1  
Cli nic al Assess m e nts  
9. 1. 1  
C o nc o mit a nt Me dic ati o ns 
All c o nc o mita nt me dicati o n a n d c o nc urre nt t hera pies will be d oc u me nte d at 
Baseli ne/ Scree ni n g a n d  at eac h sessi o n.  D ose, r o ut e, u nit fre q ue n c y of a d mi nistrati o n, a n d 
i n dicati o n f or a d mi nistrati o n a n d dates of me dicati o n will be ca pt ure d. 
9. 1. 2  De m o gr a p hics  
De m o gra p hic i nf or mati o n ( date of birt h, ge n d er , race) will be rec or de d at Scree ni n g. 
9. 1. 3  Me dic al Hist or y  
Rele va nt me dical hist or y, i ncl u di n g hist or y of c urre nt disease, ot her perti n e nt res pirat or y 
hist or y, a n d i nf or mati o n re gar di n g u n d erl yi n g diseases will be rec or d e d at Scree ni n g . 
9. 1. 4  
P h ysic al E x a mi n ati o n 
A c o m plete p h ysical e x a mi nati o n will be perf or m e d b y eit her t he i n vesti gat or or a 
s u bi n vesti gat or w h o is a p h ysicia n at Scree ni n g. 
9. 1. 5  
Vit al Si g ns  
Bl o o d press ure, p ulse a n d res pirati o ns will be perf or me d aft er resti n g f or 5  mi n u tes at 
Scree ni n g a n d at be gi n ni n g of eac h s essi o n. D uri n g sessi o ns, bl o o d press ure, p ulse a n d 
res pirati o ns will be meas ure d e ver y 1 5 mi n utes u p u ntil t w o h o urs after I M i njecti o n of 
st u d y me dicati o n. 

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
 
Versi o n #: 1. 9  
Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 1 7  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
9. 1. 6  
O xi metr y  
O xi metr y will be meas ur e d o n r o o m air wit h t he s u bject at rest at Scree ni n g, at t he 
baseli ne of eac h sessi o n a n d e ver y 1 5 mi n utes d uri n g sessi o ns u p u ntil t w o h o urs after I M 
i njecti o n of st u d y me dicati o n. 
9. 1. 7  
A d verse E ve nts  
I nf or mati o n re g ar di n g occ urre n ce of a d verse e v e nts will be ca pt ure d t hr o u g h o ut t he st u d y. 
D urati o n (start a n d st o p d ates a n d ti mes), se v erit y/ gra de, o utc o me, treat me nt a n d relati o n 
t o st u d y dr u g will be rec or de d o n t he case re p ort f or m ( C R F). 
9. 2  
Cli nic al L a b or at or y Me as ure me nts  
9. 2. 1  
Pre g n a nc y Test  
A uri ne pre g n a nc y test will be o btai ne d fr o m fe m ale s u bjects w h o are of c hil d bear i n g a ge 
pri or t o t heir partici pati o n i n t he st u d y  ( Scree ni n g) a n d bef ore eac h st u d y s essi o n. 
9. 2. 2  
Uri ne dr u g scree n  
Uri ne will be c ollect e d f or uri ne dr u g scree n at scree ni n g a n d o n eac h sessi o n da y. 
Met ha d o ne m ust be p ositi ve. Alt h o u g h c urre nt illicit dr u g use is n ot e xcl usi o nar y, 
partici pa nts will be i nf or me d t he y will nee d t o ha ve ne gati ve uri n e dr u g scree n at 
be gi n ni n g of eac h s essi o n. 
9. 2. 3  
Bre at h al yzer  
Partici pa nts will pr o vi de a breat h alc o h ol test at scree ni n g a n d o n eac h s essi o n da y. 
Res ults m ust be 0. 0 0 t o c o m plete scree ni n g a n d t o be gi n sessi o ns. 
9. 3  
P u pil o m eter  
P u pil dia meter is o ne of t he m ost se nsiti ve meas ures of o pi oi d wit h dra wal acti vit y. P u pil 
dia meter will be c ollecte d wit h a p u pil o meter i n a m bie nt r o o m li g ht ( Ne ur O ptics,  Ir vi ne, 
Calif or nia) at bas eli ne a n d e ver y 1 5 mi n utes d uri n g sessi o ns u p u ntil t w o h o urs after I M 
i njecti o n of st u d y me dicati o n. 
9. 4  
I m p ulsi vit y Me as ures 
9. 4. 1  
Del a y Disc o u nti n g 
Dela y disc o u nti n g is t he relati ve pr efere nce f or s maller s o o ner o ver lar g er later re war d s, 
a n as pect of i m p ulsi vit y. M ost i n di vi d uals w o ul d prefer a n i m me diate $ 1 0 0 o ver $ 1 0 0 
dela ye d b y 1 year. H o we ver, w he n face d wit h t he c h oice bet w ee n recei vi n g $ 9 5 n o w 
vers us $ 1 0 0 i n 1 year, pr efer e nces f or t he d ela ye d re war d ma y i ncrease. B y assessi n g s uc h 
c h oices acr oss m ulti ple dela ys,  dela y disc o u nti n g q ua ntifies t he de val u ati o n of re w ar ds 
o ver ti me, w hic h all o ws f or a n i n de x of o v erall dis c o u nti n g rate ( k). Dela y disc o u nti n g 
will be meas ure d 3 0 mi n utes after I M i njecti o n d uri n g eac h s essi o n. 

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
 
Versi o n #: 1. 9  
Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 1 8  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
9. 4. 2  
V ali d ate d tr ait i m p ulsi vit y me as ures. 
Parti ci pa nts will als o be assesse d f or trait i m p ulsi vit y usi n g f o ur pers o nalit y 
q uesti o n naires assessi n g i m p ulsi vit y or cl osel y relate d c o nstr ucts d uri n g scree ni n g . Scales 
will i ncl u de t he Barratt I m p ulsi vit y Scale - 1 1 ( 8 5, 8 6); t he E yse nc k I m p ulsi vit y 
Q uesti o n n aire ( 8 7); t he Se nsati o n See ki n g Scale  ( 8 8); a n d t he Zi m bar d o Ti me Pers pecti ve 
I n v e nt or y ( 8 9). 
9. 5  
O pi oi d Wit h dr a w al Me as ures  
T hese meas ures are ver y fa miliar t o t he PI ( Dr. T o m p ki ns) a n d utilize sta n dar d t o ols t hat 
will be c ol lecte d b y trai n e d researc h st aff. I n eac h sessi o n, t he o pi oi d wit h dra wal meas ures 
will be c ollecte d at bas eli ne a n d e v er y 1 5 mi n utes f oll o wi n g I M i njecti o n. T he y i ncl u de 
t he C O W S ( 2 3, 1 0 7); S u bjecti ve O piate Wit h dra wal Scale ( S O W S) ( 2 4), a n d V A S rati n gs 
of s u bjecti ve dr u g effects ( 1 0 8, 1 0 9).  
 
T he C O W S is a n 1 1 -ite m rati n g s yste m t hat is c o m plete d b y a trai ne d o bs er ver. T ot al 
sc ores r a n ge fr o m 0 t o 4 7, a n d wit h dra w al is classifie d as mil d ( 5 – 1 2), m o d erate ( 1 3 – 2 4), 
m o deratel y se v ere ( 2 5 – 3 6), or se vere ( > 3 6). 
 
T he S O W S is a self -r e p ort i nstr u me nt t hat as ks partici pa nts t o rate t heir le v el of c urre nt 
o pi oi d wit h dra wal o n 1 6 s y m pt o ms usi n g a 5- p oi nt Li kert scale ( N ot At All t o E xtre mel y). 
A ns wers t o t he 1 6 ite ms are s u m me d f or a t otal sc ore.  
 
T here are si x V A Ss o f s u bjecti ve dr u g effects: hi g h, dr u g effect, g o o d effects, ba d effects, 
li ki n g, a n d sic k. Eac h scale is a 1 0 0- p oi nt li ne a nc h ore d at o ne e n d wit h “ n ot at all,” a n d at 
t he ot her wit h “e xtr e mel y.” T he partici pa nt p ositi o ns a n arr o w al o n g t he li ne usi n g t he 
ke y pa d t o i n dicate his or her a ns w er of h o w s/ h e is feeli n g at t hat m o me nt . 
9. 6  
P ai n Me as ures  
9. 6. 1  
P ai n V A S  
Rati n gs are c o m plete d o n a c o m p uter; usi n g a m o use. T he partici p a nt p ositi o ns a n arr o w 
al o n g a 1 0 0 m m li ne mar ke d at eit her e n d wit h “ n o ne” a n d “ w orst pai n i ma gi na ble.” 
Rati n gs will be c olle cte d at Scree ni n g, sessi o n bas eli ne a n d e v er y 1 5 mi n utes d uri n g 
sessi o ns u p u ntil t w o h o urs after I M i njecti o n of st u d y me dicati o n. 
9. 6. 2  
P ai n C at astr o p hizi n g Sc ale  
T he Pai n Catastr o p hizi n g Scale ( P C S) is a 1 3 -ite m scale t hat assess es i m p orta nt affecti ve 
a n d c o g niti ve as pects of pai n. 4 3 T he P C S i nstr ucti o ns as ke d partici pa nts t o reflect o n past 
pai nf ul e x peri e nces a n d t o i n dicate t he de gree t o  w hic h t he y e x perie nce d a partic ular 
t h o u g ht or feeli n g w he n e x perie n ci n g pai n. Res p o nses  were rate d o n a 5 -p oi nt scale fr o m 
0 (“ N ot at All”) t o 4 ( “ All t he Ti me”).  Pai n Catastr o p hizi n g Scale sc ores ra n ge fr o m 0 t o 
5 2, wit h hi g her sc ores i n dicati n g hei g hte ne d distress res p o nses w h e n e x p ose d t o a versi ve 
sti m uli. T he P C S will be meas ure d i n Sess i o n 1. 

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
 
Versi o n #: 1. 9  
Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 1 9  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
9. 6. 3  
Brief P ai n I n ve nt or y – S h o rt F or m 
T he B PI ( 9 4) is a 9 ite m self -re p ort q uesti o n naire use d t o e val uate t he s e verit y of a 
patie nt's pai n a n d t he i m pact of t his pai n o n t he patie nt's dail y f u ncti o ni n g. T he patie nt is 
as ke d t o rate t h eir w orst, least, a vera ge, a n d c urre nt pai n i nte nsit y, list c urre nt treat me nts 
a n d t heir per cei ve d eff ecti ve ness, a n d rate t he de gree t hat pai n i nterferes wit h ge neral 
acti vit y, m o o d, wal ki n g a bilit y, n or mal w or k, relati o ns wit h ot her pers o ns, slee p, a n d 
e nj o y me nt of life o n a 1 0 p oi nt scale.  T he B PI  will b e use d at scree ni n g t o s cree n f or t he 
prese nce or a bs e nce of c hr o nic pai n. A d diti o nall y, B PI “ pai n ri g ht n o w” V A S will be 
as ke d at be gi n ni n g of eac h sessi o n. T his sc ore m ust be 0 f or patie nts wit h N O P AI N or t he 
sessi o n will be resc he d ul e d. P AI N gr o u p pers o ns m ust re p ort si milar le vels of pai n eac h 
sessi o n (i.e., t he B PI “ pai n ri g ht n o w” sc ore at sessi o n 2 m ust be +/ - 2 0 % of t he “ pai n ri g ht 
n o w” sc or e at sessi o n 1 ; P AI N gr o u p pers o ns ca n n ot ha ve a “ p ai n ri g ht n o w” sc ore of 0) 
or t he sessi o n will be res c he d ule d.  
9. 6. 4  
 P ai n Assess me nts  
Pai n will be assesse d usi n g t he miscella ne o us pai n q uesti o n nair e fr o m t he Nati o nal Healt h 
a n d N utriti o n E xa mi natio n S ur ve y ( N H A N E S; ( 8 3)) a n d t he Wi des prea d Pai n I n de x. 
9. 6. 5  
I ns o m ni a Assess me nt 
T he I ns o m nia Se verit y I n de x is a brief v ali da te d i nstr u me nt t hat meas ures ni g htti me a n d 
da yti me as pects of i ns o m nia ( 8 4). Sc ores 1 5 + i n dicate cli nical i ns o m nia t hat is at least 
m o derate i n se v erit y.  Pers o ns f o u n d t o ha ve cli nical i ns o m nia will be referre d f or f urt her 
e val uati o n a n d p ossi ble treat me nt b y t heir pri mar y care pr o vi der a n d/ or t h eir met ha d o ne 
mai nte na nce me di cal tea m.  
9. 7  
Ps yc hi atric Assess m e nts  
T he Mi ni I nter nati o nal N e ur o ps yc hiatric I nter vie w will be c o n d ucte d b y Dr. T o m p ki ns 
d uri n g scree ni n g t o r ul e o ut pers o ns wit h s uici dal i deati o n or ps yc h osis. I n a d diti o n, t he 
f oll o wi n g scales will als o be meas ure d at Sessi o n 1 : P H Q - 1 5 ( 3) w hic h pr o vi des a 
meas ure of s o m atizati o n), P H Q - 9 ( 4) w hic h m eas ures de pressi ve s y m pt o ms, a n d G A D- 7 
( 5) w hic h meas ures a n xiet y s y m pt o ms. 
1 0  E V A L U A TI O N S B Y VI SI T  
1 0. 1  Visit 1 ( Sc ree ni n g)  
1.  
Re vie w t he st u d y wit h t he s u bject a n d o btai n writte n i nf or me d c o ns e nt a n d HI P A A 
a ut h orizati o n 
2.  
Assi g n t he s u bject a u ni q ue scree ni n g n u m ber 
3.  
C ollect uri ne f or uri ne dr u g scree n (a n d pre g na n c y test if fe male) 
4.  
C ollect R OI f or o pi oi d treat me nt pr o gra m 
5.  
Rec or d de m o gr a p hics dat a 
6.  
Rec or d me dical hist o r y 
7.  
Rec or d dr u g use hist or y 
8.  
Rec or d c o n c o mita nt me dicati o ns  

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
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Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 2 0  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
9.  
Perf or m a c o m plet e p h ysical e xa mi nati o n  
1 0.  
Perf or m a n d r ec or d vital si g ns 
1 1.  
Perf or m a n d r ec or d o xi metr y 
1 2.  
Perf or m a n d r ec or d E K G 
1 3.  
Perf or m a n d r ec or d MI NI 
1 4.  
Perf or m  a n d r ec or d B PI 
1 5.  
Perf or m a n d r ec or d N H A N E S Mis cella ne o us Pai n Q uesti o n naire  
1 6.  
Perf or m a n d r ec or d Wi des prea d Pai n I n d e x  
1 7.  
Perf or m a n d r ec or d B PI 
1 8.  
Sc he d ule s u bject f or Visit 2 ( Sessi o n 1) as a p pr o priate. 
1 9.  
Ra n d o mize s u bject  
1 0. 2  Visit s 2- 3 (Sessi o ns 1 - 2) 
1.  
Rec or d a n y A d v e rse E x p erie nces 
2.  
C o nc o mita nt me dicati o ns re vie w 
3.  
C ollect Uri ne f or U D S (a n d pre g na nc y t est if fe male) 
4.  
Perf or m a n d r ec or d  “ pai n ri g ht n o w” V A S fr o m B PI 
5.  
Rec or d ti me of met ha d o n e d osi n g (c o nfir m b y re vie wi n g Met has oft E H R) 
6.  
Perf or m a n d r ec or d baseli ne val ues of  
a. Vi tal si g ns 
b.  O xi metr y  
c. P u pil o meter  
d.  C O W S  
e. S O W S  
f. Pai n V A S  
7.  
If s m o ker, all o w p artici p a nt t o s m o ke 2 0 mi n utes pri or t o st u d y dr u g a d mi nistrati o n 
8.  
A d mi nister I M st u d y dr u g. Rec or d o n pr o gress n ote. 
9.  
F or e v er y 1 5 mi n utes u ntil t w o h o urs after I M i njecti o n , meas ure 
a. Vit al sig ns 
b.  O xi metr y  
c. P u pil o meter  
d.  C O W S  
e. S O W S  
f. Pai n V A S  
g.  S u bjecti ve dr u g eff ect V A Ss  

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
 
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Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 2 1  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
1 0.  
3 0 mi n utes after st u d y dr u g a d mi nistrati o n, perf or m a n d rec or d dela y disc o u nti n g 
tas k 
1 1.  
Perf or m a n d r ec or d P C S 
1 2.  
Perf or m a n d r ec or d P H Q- 1 5 
1 3.  
Perf or m a n d r ec or d G A D- 7 
1 4.  
Perf or m a n d r ec or d P H Q - 9 
1 5.  
Perf or m a n d r ec or d Barr att I m p ulsi vit y Scale- 1 1 
1 6.  
Perf or m a n d r ec or d E yse nc k I m p ulsi vit y Q uesti o n naire 
1 7.  
Perf or m a n d  r ec or d Se nsati o n See ki n g Scale 
1 8.  
Perf or m a n d r ec or d Zi m bar d o Ti me Pers pecti ve I n ve nt or y 
1 9.  
Perf or m a n d r ec or d I ns o m nia Se verit y I n de x 
1 1  A D V E R S E E X P E R I E N C E R E P O R TI N G A N D D O C U M E N T A TI O N 
1 1. 1  A d verse E ve nts  
A n a d vers e e ve nt ( A E) is a n y u nt o war d me dical o cc urre nce i n a cl i nical i n vesti gati o n of a 
patie nt a d mi nistere d a p h ar mace utical pr o d uct a n d t hat d oes n ot necessaril y ha ve a ca usal 
relati o ns hi p wit h t he treatme nt.  A n A E is t heref ore a n y u nfa v ora ble a n d u ni nte n de d si g n 
(i ncl u di n g a n a b n or mal l a b orat or y fi n di n g), s y m pt o m or disease te m p orall y ass ociate d 
wit h t he a d mi nistrati o n of a n i n vesti gati o nal pr o d uct, w het her or n ot relate d t o t hat 
i n vesti gati o nal pr o d uct.  A n u ne x pect e d A E is o ne of a t y pe n ot i de ntifie d i n nat ure, 
se verit y, or fr e q ue n c y i n t he c urr e nt I n vesti gat or’s Br oc h ure or of greater s e verit y or 
fre q ue n c y t ha n e x p ecte d base d o n t he i nf or mati o n i n t he I n v esti gat or’s Br oc h ure. 
T he I n vesti gat or wi ll pro be, via disc ussi o n wit h t he s u bject, f or t he o cc urre nce of A Es 
d uri n g eac h s u bject visit a n d rec or d t he i nf or m ati o n i n t he site’s s o urce d oc u me nts.  
A d verse e ve nts will be rec or de d i n t he patie nt C R F.  A d verse e v e nts will be descri b e d b y 
d urati o n (st art an d st o p d ates a n d ti mes), se v erit y, o utc o me, treat me nt a n d relati o n t o 
st u d y dr u g, or if u nrelate d, t he ca use. 
A E  Se verit y  
T he Nati o nal Ca ncer I nstit ute’s C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts 
( C T C A E) Versi o n 3. 0 s h o ul d be use d t o assess a n d gra de A E s e verit y, i ncl u di n g 
la b orat or y a b n or malities j u d ge d t o be cli nicall y si g nifica nt. T he m o difie d criteria ca n be 
f o u n d i n t he st u d y ma n ual.  If t h e e x perie nce is n ot c o vere d i n t he m o difi e d criteria, t he 
g ui deli nes s h o w n i n Ta ble  1 bel o w s h o ul d be use d t o gra de se v erit y.  It s h o ul d be p oi nte d 
o ut t hat t he ter m “se vere” is a meas ure of i nte nsit y a n d t hat a se vere A E is n ot necessaril y 
seri o us. 

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
 
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Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 2 2  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
T a ble 1 .  A E Se verit y Gr a di n g 
Se verit y ( T o xicit y Gr a de)  
Des cri pti o n 
Mil d ( 1)  
Tra nsie nt or mil d disc o mf ort; n o li mitati o n i n acti vit y; n o me dical 
i nter ve nti o n or t hera p y re q uire d. T he s u bject ma y be a ware of t he si g n 
or s y m pt o m b ut t olerates it reas o na bl y well.  
M o derate ( 2)  
Mil d t o m o derate li mitati o n i n acti vit y , n o or mi ni mal me dical 
i nter ve nti o n/t hera p y re q uire d. 
Se vere ( 3)  
Mar ke d li mitati o n i n acti vit y, me dical i nter ve nti o n /t hera p y re q uire d, 
h os pitalizati o ns p ossi ble. 
Life -t hreate ni n g ( 4) 
T he s u bject is at ris k of deat h d ue t o t he a d verse e x perie nce as it 
oc c urred. T his d oes n ot refer t o a n e x perie nce t hat h y p ot heticall y 
mi g ht ha ve ca use d deat h if it were m ore se vere.  
 
A E Rel ati o ns hi p t o St u d y Dr u g  
T he relati o ns hi p of a n A E t o t he st u d y dr u g s h o ul d be assesse d usi n g t he f oll o wi n g t he 
g ui deli nes i n Ta ble 2 . 
T a ble 2 .  A E Rel ati o ns hi p t o St u d y Dr u g 
Rel ati o ns hi p  
t o Dr u g 
C o m me nt  
Defi nitel y  
Pre vi o usl y k n o w n t o xicit y of a ge nt; or a n e ve nt t hat f oll o ws a reas o na ble te m p oral 
se q ue nce fr o m a d mi nistrati o n of t he dr u g; that f oll o ws a k n o w n or e x pecte d res p o nse 
patter n t o t he s us pecte d dr u g; t hat is c o nfir me d b y st o p pi n g or re d uci n g t he d osa ge of 
t he dr u g; a n d t hat is n ot e x plai ne d b y a n y ot her reas o na ble h y p ot hesis. 
Pr o ba bl y 
A n e ve nt t hat f oll o ws a reas o na ble te m p oral se q ue nc e fr o m a d mi nistrati o n of t he 
dr u g; t hat f oll o ws a k n o w n or e x pecte d res p o nse patter n t o t he s us pecte d dr u g; t hat is 
c o nfir me d b y st o p pi n g or re d uci n g t he d osa ge of t he dr u g; a n d t hat is u nli kel y t o be 
e x plai ne d b y t he k n o w n c haracteristics of t he s u bj ect’s cli nical state or b y ot her 
i nter ve nti o ns. 
P ossi bl y 
A n e ve nt t hat f oll o ws a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n of t he 
dr u g; t hat f oll o ws a k n o w n or e x pecte d res p o nse patter n t o t hat s us pecte d dr u g; b ut 
t hat c o ul d rea dil y ha ve bee n pr o d uce d by a n u m ber of ot her fact ors. 
U nrelate d  
A n e ve nt t hat ca n be deter mi ne d wit h certai nt y t o ha ve n o relati o ns hi p t o  t he st u d y 
dr u g. 
1 1. 2  Seri o us A d verse E x peri e nces ( S A E)  
A n S A E is defi ne d as a n y A E occ urri n g at a n y d ose t hat res ults i n a n y of t he f oll o wi n g 
o utc o mes:  
•  
deat h  
•  
a life-t hreate ni n g a d v erse e x perie n ce 
•  
i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
•  
a persiste nt or si g nifica nt disa bilit y/i nca pacit y  

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
 
Versi o n #: 1. 9  
Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 2 3  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
•  
a c o n ge nital a n o m al y/ birt h defect  
Ot her i m p orta nt me dical e ve nts ma y als o be c o nsi der e d a n S A E w he n, bas e d o n 
a p pr o priate m e dical j u d g me nt, t he y je o par dize t he s u bject or re q uire i nter v e nti o n t o 
pre ve nt o ne of t he o utc o mes liste d.  
 
1 1. 2. 1  Seri o us A d verse E x peri e nce Re p orti n g  
St u d y sites will d oc u me nt all S A Es t hat occ ur ( w h et her or n ot rela te d to st u d y dr u g) per 
U C S F  C H R G ui deli nes.  T he c ollecti o n peri o d f or all S AEs  will  be gi n after i nf or me d 
c o nse nt is o btai ne d a n d e n d after pr o ce d ures f or t he fi nal  st u d y visit ha ve bee n c o m plete d. 
In acc or da n ce wit h t he st a n dar d o perati n g  proce d ures a n d p olicies of t h e l ocal I nsti t uti o nal 
Re vie w B oar d  (I R B)/I n d e pe n de nt Et hics C o m mittee (I E C), t h e site i n vesti gat or will re p ort 
S A Es t o  t he I R B/I E C.   
1 1. 3  Me dic al M o nit ori n g 
Dr.  Sc ott Stei ger  s h o ul d be c o ntact e d directl y at t hese n u m bers t o re p ort me dical c o n cer ns 
or q uesti o ns re gar di n g sa fet y. 
P h o ne: 6 2 8- 2 0 6- 6 4 7 9 
Cell : 2 0 6- 3 7 5- 8 8 4 0  
1 2  DI S C O N TI N U A TI O N A N D R E P L A C E M E N T O F S U B J E C T S  
1 2. 1  Wit h dr a w al of S u bjects   
A s u bject ma y be disc o nti n ue d fr o m st u d y treat me nt at a n y ti me if t he s u bject or t he 
i n vesti gat or feels t hat it is n ot i n t he s u bject’s best interest t o c o nti n ue.  T he f oll o wi n g is a 
list of p ossi ble reas o ns f or st u d y treat me nt disc o nti n uati o n: 
•  
S u bject wit h dra wal of c o nse nt 
•  
S u bje ct is n ot c o m plia nt wit h st u d y pr oce d ures 
•  
A d verse e ve nt t hat i n t he o pi ni o n of t he i n vesti gat or w o ul d be i n t he best 
i nterest of t he s u bject t o disc o nti n ue st u d y treat me nt 
•  
Rec urre nt i nt o xicati o n or + U D S  
•  
L ost t o f oll o w- u p 
•  
P ositi ve pre g na nc y test (fe males)  
•  
C ha n ge i n met ha d o ne d ose bet wee n Sessi o ns 1 & 2 
•  
+ C O VI D - 1 9 t est or i na bilit y t o e nter War d 9 5 d u e t o scree ni n g p ositi ve f or 
C O VI D - 1 9 s y m pt o ms/rece nt e x pos ure 
If a s u bject is wit h dra w n fr o m treat me nt d ue t o a n a d verse e ve nt, t he s u bject will be 
f oll o we d b y t he I n vesti gat or u ntil t he a b n or mal para meter or s y m pt o m has res ol ve d or 
sta bilize d.   

P r ot oc ol Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
C o nfi de nti al  
 
Versi o n #: 1. 9  
Versi o n Date: 1 2/ 0 9 / 2 0 2 0 
Pa ge 2 4  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
All s u bjects are free t o wit h dra w fr o m partici pati o n at a n y ti me, f or a n y reas o n, s pecifie d 
or u ns pecifie d, a n d wit h o ut prej u dice. 
Reas o na ble atte m pts will be ma de b y t he  i n vesti gat or t o pr o vi de a reas o n f or s u bject 
wit h dra wals.  T he reas o n f or t he s u bject’s wit h dra wal fr o m t he st u d y will be s pecifie d i n 
t he s u bject’s s o urce d oc u me nts. 
1 2. 2  Re pl ace m e nt of S u bjects  
S u bjects w h o wit h dra w fr o m t he st u d y will n ot be re place d.    
1 3  P R O T O C O L VI O L A TI O N S  
A pr ot oc ol vi olati o n occ urs w he n t he s u bject or i n vesti gat or fails t o a d here t o si g nifica nt 
pr ot oc ol re q uire m e nts aff ecti n g t he i ncl usi o n, e xcl usi o n, s u bject safet y a n d pri mar y 
e n d p oi nt criteria.  Pr ot oc ol vi olati o ns f or t his st u d y i ncl u de, b ut are n ot li mite d t o, t he 
f oll o wi n g: 
•  
Fail ure t o meet i ncl usi o n/e xcl usi o n criteria  
•  
Use of a pr o hi bite d c o nc o mita nt me dicati o n  
Fail ure t o c o m pl y wit h G o o d Cli nical Practice ( G C P) g ui deli nes will als o res ult i n a 
pr ot oc ol vi olati o n. T h e PI  will deter mi ne if a pr ot oc ol vi olati o n will res ult i n wit h dra wal 
of a s u bject.  
W he n a pr ot o c ol vi olati o n occ urs, it will be disc usse d wit h t he i n vesti gat or a n d a Pr ot oc ol 
Vi olati o n F or m detaili n g t he vi olati o n will be ge nerate d. T his f or m will be si g ne d  b y t he 
PI . A c o p y of t he f or m will be file d i n t he site’s re g ulat or y bi n der.  
1 4  S T A TI S TI C A L M E T H O D S A N D C O N SI D E R A TI O N S  
Pri or t o t he a nal ys is of t he fi nal st u d y data, a d etaile d Statistical A nal ysis Pla n ( S A P) will 
be writte n descri bi n g all a nal yses t hat will be perf or me d.  T he S A P will c o ntai n a n y 
m o dificati o ns t o t he a nal ysis pla n descri be d bel o w.   
1 4. 1  D at a Sets A n al yze d 
All eli gi ble patie nts w h o are r a n d o mize d i nt o t he st u d y a n d recei ve at least o ne d ose of t he 
st u d y dr u g (t he Safet y P o p ulati o n) will be i ncl u de d i n t he safet y an al ysis.  
C o m pleter a nal ysis will be t he data c ollecte d f or all of t he c o m pleters ( N = 1 0 0 e x pecte d).  
1 4. 2  De m o gr a p hic a n d B as eli ne C h ar acteristics  
T he P AI N a n d N O P AI N gr o u ps will be c o m pare d o n all matc hi n g varia bles ( met ha d o ne 
d ose, ci gar ettes s m o ke d per da y, a n n u al i nc o me, years of e d ucati o n, a n d a ge) usi n g t- tests 
a n d c hi-s q uar e tests as a p pr o priate. If statisticall y si g nifica nt differe nces are detecte d 
des pite eff orts t o matc h d uri n g recr uit me nt, matc hi n g varia bles will be i ncl u de d as 
c o variates i n s u bse q u e nt a nal yses. It is rec o g nize d t hat t his met h o d is i nferi or t o f or mal 
matc hi n g; t heref or e, s u bsta ntial eff ort will be de v ote d  t o l ocati n g a p pr opriat el y matc he d 
i n di vi d uals. Meas ures o btai ne d at 1 5- mi n ute i nter vals d uri n g eac h s essi o n ( pai n, vital 
si g ns, o pi oi d wit h dra wal, etc.) will be e x a mi ne d i n ter ms of gr o u p c o m para bilit y a n d t o 

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c o nfir m t hat nal o x o ne pr eci pitate d wit h dra w al s y m pt o ms c o m pare d t o place b o. All 
ps yc h o metric, scal e d meas ures will be sc ore d acc or di n g t o sta n dar dize d al g orit h ms a n d 
i nter nal c o nsiste nc y r elia bilit y e xa mi ne d. Gi ve n t he desi g n of t he st u d y, u nit le vel missi n g 
data is n ot a ntici pate d. It e m le vel mis si n g data will be mi ni mize d t hr o u g h s u per vise d 
a d mi nistrati o n of meas ur es. Missi n g data patter ns will be e xa mi ne d a n d m ulti ple 
i m p utati o n ( S A S P R O C MI) or ot her strate gies e m pl o ye d as a p pr o priat e. Usi n g met h o ds 
de vel o pe d b y c o-I J o h ns o n, n o nli near re gressi o n w ill be use d t o calc ulate i n di vi d ual 
val ues of k, lar g er k val u es i n dicate greater disc o u nti n g or m ore i m p ulsi ve ness. K val ues 
are n or m alize d usi n g l o g tra nsf or mati o n f or p ara m etric a nal ysis ( 4 5). 
1 4. 3  A n al ysis of Pri m ar y E n d p oi nt 
T he pri mar y h y p ot hes es are t hat partici pa nts wit h c hr o nic pai n ( P AI N) are m ore i m p ulsi ve 
(lar ger k v al ues) t ha n p artici pa nts wit h o ut pai n ( N O P AI N) a n d t hat, wit hi n t he sa me 
i n di vi d ual, k val ues will be lar ger i n t he nal o x o ne- preci pitate d o pi oi d wit h dra wal sessi o n 
c o m pare d t o place b o. We will test t hese h y p ot heses usi n g re peate d meas ures a nal yses 
i m ple me nte d i n S A S P R O C MI X E D. T he d e pe n d e nt varia ble is k ( disc o u nti n g). 
I n d e pe n de nt v aria bles i n cl u de Gr o u p ( P AI N vs. N O P AI N), a fi xe d, bet w ee n-s u bjects 
effect a n d C o n diti o n (c o ntr ol vs. wit h dra wal), a re peate d, wit hi n -s u bjects effect. T he 
Gr o u p x C o n diti o n i nteracti o n will be e xa mi ne d t o deter mi ne if gr o u p differe nces var y b y 
c o n diti o n. Pla n ne d c o ntrasts will e x pl ore a d diti ve effects of c hr o ni c pai n a n d wit h dra wal 
b y e xa mi ni n g w het her disc o u nti n g b y t he P AI N gr o u p i n t he wit h dra wal c o n diti o n is 
greater t ha n 1) disc o u nti n g b y t he P AI N gr o u p i n t he c o ntr ol c o n diti o n, or 2) disc o u nti n g 
b y t he N O P AI N gr o u p i n t he wit h dra wal c o n diti o n. T o e xa mi ne t he effect of differi n g 
le vels of pea k a versi v e stim uli o n disc o u nti n g, we will c o n d uct a nal yses usi n g o nl y data 
fr o m t he nal o x o ne-preci pitate d wit h dra wal sessi o n t hat i ncl u de pea k  
C O W S  sc ores. 
1 4. 4  A n al ysis of Sec o n d ar y E n d p oi nts  
First, ge neral li near m o d el a nal yses ( S A S P R O C G L M) will be c o n d ucte d t o 
i n de pe n de ntl y e xa mi ne t he i m pact of C o n diti o n a n d Pai n Catastr o p hizi n g ( P C S) o n 
disc o u nti n g rate ( k). T h e n, a si n gle G L M a nal ysis will be c o n d ucte d t hat i n cl u des 
C o n diti o n, P C S, a n d t he C o n diti o n – b y- P C S i nteracti o n. A si g nifica nt i nteracti o n will 
i n dicate effect mo dificati o n. We will als o e xa mi ne t he effect of bi ol o gical s e x o n 
disc o u nti n g, o pi oi d wit h dra wal, pai n V A S, a n d p ai n catastr o p hizi n g. Bas e d o n pri or 
researc h, w e e x pect fe m ales t o ha ve hi g her P C S sc ores. We will als o e x pl ore h o w t he t y pe 
of c hr o nic p ai n ( m usc ul os keletal, ne ur o p at hic, mi xe d/ ot her) will effect dis c o u nti n g. We 
will als o e x pl ore ass ociati o ns bet wee n s o matizati o n ( S C L - 9 0), de pressi o n ( P H Q- 9) a n d 
a n xiet y ( G A D- 7) a n d dis c o u nti n g. n g. 
Safet y a n d t oler a bilit y data will be s u m marize d b y  st u d y me dicati o n.   
A d verse e ve nt rat es will be c o de d b y b o d y s yste m a n d Me d Dra classificati o n ter m. 
A d verse e ve nts will be ta b ulate d b y st u d y me di cati o n a n d will i ncl u de t he n u m ber of 
patie nts f or w h o m t he e v e nt occ urre d, t he rate of occ urre nce, a n d t he se v erit y a n d 
relati o ns hi p t o st u d y dr u g.   

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1 4. 5  I nteri m A n al ysis 
Researc h ers will l o o k at t he data fr o m t he first 1 0 c o m pleters. If t h ere is n o tre n d of 
differe n ces i n del a y disc o u nti n g bet wee n place b o a n d nal o x o ne a d mi nistrati o n sessi o ns, 
we w o ul d disc uss wit h o ur NI D A pr o g ra m official a n d i n de pe n de nt me dical m o nit or ( Dr. 
Sc ott Stei ger) o n t he f oll o wi n g t w o o pti o ns: i ncreasi n g t he d ose of nal o x o n e t o 0. 1 5 m g or 
a d mi nisteri n g 0. 1 m g nal o x o ne at tr o u g h i nstea d of pea k met ha d o n e le vels. 
1 4. 6  S a m ple Size a n d R a n d o miz ati o n  
Beca use  t he wit hi n s u bject eff ect size of disc o u nti n g c ha n ges ass o ciate d wit h nal o x o ne 
preci pitate d wit h dr a wal are e m piricall y u n k n o w n, a n e x pect e d effect size of f2=. 0 2 was 
ass u me d base d o n a st u d y b y Dr. J o h ns o n (c o ns orti u m PI) s h o wi n g t hat fi v e da ys of 
ci garette s m o ki n g a bsti ne nce i n nic oti ne- de p e n de nt i n di vi d uals decrease d disc o u nti n g 
rates ( 9 3). T his eff ect size was selecte d beca use it ca me fro m a st u d y c o n d u cte d b y a st u d y 
i n vesti gat or s h o wi n g a wit hi n-s u bject c ha n ge i n disc o u nti n g f or m o ne y, si milar t o t he 
dela y disc o u nti n g o utc o me i n t he pr o p ose d st u d y. T he effect size f or b et w ee n s u bject 
differe n ces i n disc o u nti n g bet wee n t he P AI N a n d N O P AI N gr o u ps is e x p ecte d t o be 
f2=. 0 8 f or t w o reas o ns. First, t he pil ot data c orrelati o n bet wee n pai n a n d disc o u nti n g 
(r ho =. 2 5) s u g g ests a n eff ect size of s mall t o me di u m ma g nit u de b y c o n ve nti o n ( 1 1 0). 
Sec o n d, t hree pre vi o usl y re p orte d effect sizes f or st u dies c o m pari n g o pi oi d a n d t o bacc o 
de pe n de nt partici pa nts t o n o n- de pe n de nt partici pa nts ( 1 0 0) s h o w lar ger effects sizes of 
a p pr o xi matel y f2=. 4. If b et wee n s u bject differe nces i n t he pr o p ose d st u d y are of t his lar ger 
ma g nit u de, t he n sa m ple size base d o n f2=. 0 8 will pr o vi de m ore t ha n s ufficie nt p o wer t o 
detect a gr o u p differe nce i n dela y disc o u nti n g rates. 
1 5  D A T A C O L L E C TI O N, R E T E N TI O N A N D M O NI T O RI N G  
1 5. 1  D at a C ollecti o n I nstr u m e nts  
T he  I n vesti gat or  will  pre par e  a n d  mai ntai n  a d e q uate  a n d  acc urate  s o urce  d o c u me nts  
desi g ne d t o rec or d all o bser vati o ns a n d ot her perti ne nt data f or eac h s u bject treate d wit h 
t he  st u d y  dr u g.   St u d y  pers o n nel  a t  eac h  site  will  e nter  data  fr o m  s o urce  d oc u m e nts  
c orres p o n di n g t o a s u bject’s visit i nt o t he pr ot oc ol -s pecific electr o nic Case Re p ort F orm 
(e C R F) O R  pa per C R F  w he n t h e i nf or mati o n c orres p o n di n g t o  t hat  visit  is a vaila ble.   
S u bjects will n ot be i de ntifie d b y na me i n t he st u d y data base or o n a n y st u d y d oc u me nts 
t o be c ollecte d b y t he S p o ns or ( or desi g nee), b ut will be i de ntifie d b y a site n u mber, 
s u bject n u m ber a n d i nitials. 
F or e C R Fs: If a c orrecti o n is re q uire d f or a n e C R F, t he  ti me a n d date sta m ps trac k t he 
pers o n e nteri n g or u p dati n g e C R F data a n d creates a n electr o ni c a u dit trail.  F or p a per 
C R Fs:   If a c orrecti o n is ma de o n a C R F, t he stu d y staff me m ber will li ne t hr o u g h t he 
i nc orrect data, write i n t h e c orr ect dat a a n d i nitial a n d date t he c ha n ge. 
T he I n vesti gat or is r es p o nsi ble f or all i nf or mati o n c ollecte d o n s u bjects e nr olle d i n t his 
st u d y.  All data c ollecte d d uri n g t he c o urse of t his st u d y m ust be re vie we d a n d verifie d f or 
c o m plete ness a n d acc urac y b y t he I n vesti gat or.  A c o p y of t he C R F will re mai n at  t he 
I n v esti gat or’s site at t he c o m pleti o n of t he st u d y. 

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1 5. 2  D at a M a n a ge m e nt Pr oce d ures  
T he data will be e nt ere d i nt o a vali date d data b ase .  T he Data M a na ge m e nt gr o u p will be 
res p o nsi ble f or d ata pr ocessi n g, i n acc or d a nce wit h pr oce d ural d oc u me ntati o n.  Data base 
l oc k will occ ur o nce q ualit y ass ura nce pr oce d ures ha ve bee n c o m plete d. 
All pr oce d ur es f or t he h a n dli n g a n d a nal ysis of data will be c o n d ucte d usi n g g o o d 
c o m p uti n g practices meeti n g F D A g ui deli nes f or t he ha n dli n g a n d a n al ysis of data f or 
cli nical trials . 
1 5. 3  D at a Q u alit y C o ntr ol a n d Re p orti n g 
After dat a ha ve b ee n e ntere d i nt o t he st u d y data bas e, a s yste m of c o m p uterize d data 
vali dati o n c h ec ks will be i m ple me nte d a n d a p plie d t o t he data base o n a re g ular basis. T he 
st u d y data base will be u p date d i n acc or dan ce wit h t he res ol ve d q ueries.  All c ha n ges t o 
t he st u d y data base will b e d oc u me nte d. 
1 5. 4  Arc hi v al of D at a 
T he data bas e is safe g u ar de d a gai nst  u na ut h orize d access b y esta blis he d sec urit y 
pr oce d ur es; a p pr o priate b ac k u p c o pies of t he data b ase a n d relate d s oft w ar e files will be 
mai ntai ne d.   Data b ases  are bac k e d u p b y t he dat a base a d mi nistrat or i n c o nj u ncti o n wit h 
a n y u p dates or c ha n ges t o t he data b ase.   
At critical j u nct ures of t he pr ot oc ol (e. g., pr o d ucti o n of i nteri m re p orts a n d fi nal re p orts), 
data f or a nal ysi s is l oc ke d a n d clea n e d per esta blis he d pr oce d ures. 
1 5. 5  A v ail a bilit y a n d Rete nti o n of I n vesti g ati o n al Rec or ds 
T he I n vesti gat or m ust ma ke st u d y data accessi ble t o t he m o nit or, ot her a ut h orize d 
re pres e ntati ves of t he S p o ns or ( or desi g nee), I R B/I E C, a n d R e g ulat ory A g e nc y (e. g., 
F D A) i ns pect ors u p o n r e q uest.  A file f or eac h s u bject m ust be mai ntai ne d t hat i ncl u des 
t he si g ne d I nf or me d C o nse nt, HI P A A A ut h orizati o n a n d Asse nt F or m a n d c o pies of all 
s o urce d oc u m e ntati o n rel ate d t o t hat s u bject.  T he I n v esti gat or m ust e ns ure t he relia bilit y 
a n d a vaila bilit y of s o urce d oc u me nts fr o m w hic h t he i nf or mati o n o n t he C R F was d eri ve d. 
All st u d y d oc u me nts ( patie nt files, si g ne d i nf or me d c o nse nt f or ms, c o pies of 
C R Fs, St u d y File N ote b o o k, etc.) m ust be ke pt sec ure d f or a peri o d d eter mi ne d b y U C S F 
a n d NI H g ui deli nes. 
1 5. 6  S u bject C o nfi de nti alit y  
I n or der t o mai ntai n s u bj ect c o nfi de ntialit y, o nl y a s u bject n u m ber a n d s u bject i nitials will  
i de ntif y all st u d y s u bjects o n C R Fs a n d ot her d oc u me ntati o n s u b mitte d t o t he S p o ns or. 
1 6  A D MI NI S T R A TI V E , E THI C A L, R E G U L A T O R Y C O N SI D E R A TI O N S  
T he st u d y will be c o n d ucte d acc or di n g t o t he Decl arati o n of H elsi n ki, Pr otecti o n of 
H u ma n V ol u nteers ( 2 1 C F R 5 0), I nstit uti o nal Re vie w B oar ds ( 2 1 C F R 5 6), a n d 
O bli gati o ns of Cli nical I n vesti gat ors ( 2 1 C F R 3 1 2). 
T o mai nt ai n c o nfi de ntialit y, all la b orat or y s peci me ns, e val uati o n f or ms, re p orts a n d ot her 
rec or ds will be i de ntifie d b y a c o de d n u m ber a n d i nitials o nl y.  All st u d y rec or ds will be 

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ke pt i n a l oc ke d file ca bi net a n d c o de s h eets li n ki n g a patie nt’s na me t o a patie n t 
i de ntificati o n n u m ber will be st ore d se paratel y i n a n ot her l oc ke d file ca bi net.  Cli nical 
i nf or mati o n will n ot be release d wit h o ut writte n p er missi o n of t he s u bject, e xce pt as 
necessar y f or m o nit ori n g b y t he F D A.  T h e I n vesti gat or m ust als o c o m pl y wit h a ll 
a p plica ble pri vac y re g ulati o ns (e. g., Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act 
of 1 9 9 6 ). 
1 6. 1  Pr ot oc ol A m e n d m e nts  
A n y a me n d me nt t o t he pr ot oc ol will be writte n b y t he S p o ns or.  Pr ot oc ol a me n d me nts 
ca n n ot be i m ple me nte d wit h o ut pri or writte n I R B/I E C a p pr o v al e xce pt as necessar y t o 
eli mi nate i m me diate safet y hazar ds t o patie nts.  A pr ot oc ol a me n d me nt i nte n de d t o 
eli mi nate a n a p pare nt i m me diate hazar d t o patie nts ma y be i m ple me nte d i m me diatel y, 
pr o vi de d t he I R Bs are n otifie d wit hi n fi ve w or ki n g da ys. 
1 6. 2  I nstit uti o n al Re vie w B o ar ds a n d I n de pe n de nt Et hics C o m mittees 
T he pr ot oc ol a n d c o nse nt f or m will be re vie w e d a n d a p pr o ve d b y t he I R B/I E C o f eac h 
partici pati n g ce nter pri or t o st u d y i nitiati o n.  Seri o us a d verse e x peri e nces re gar dless of 
ca usalit y will be rep ort e d t o t he I R B/I E C i n acc or da nce wit h t he sta n d ar d o perati n g 
pr oce d ur es a n d p olicies of t he I R B/I E C, a n d t h e I n vesti gat or will kee p t he I R B/I E C 
i nf or me d as t o t he pr o gr ess of t he st u d y.  T he I n vesti gat or will o btai n ass ura nce of 
I R B/I E C c o m plia nce wit h re g ulati o ns. 
A n y d oc u me nts t hat t he I R B/I E C ma y nee d t o f ulfill its res p o nsi bilities (s uc h as pr ot oc ol, 
pr ot oc ol a me n d me nts, I n vesti gat or’s Br oc h ure, c o nse nt f or ms, i nf or mati o n c o ncer ni n g 
patie nt recr uit me nt, pa y me nt or c o m pe nsati o n pr oce d ures, or ot her p e rti ne nt i nf or mati o n) 
will be s u b mitte d t o t he I R B/I E C.  T he I R B/I E Cs writte n u nc o n diti o nal a p pr o val of t he 
st u d y pr ot oc ol a n d t he i nf or me d c o nse nt f or m will be i n t he p ossessi o n of t he I n vesti gat or 
bef ore t h e st u d y is i nitiate d.  Pr ot oc ol a n d/ or i nf or me d c o nse nt m o dificati o ns or c ha n ges 
ma y n ot be i nitiate d wit h o ut pri or writte n I R B/I E C a p pr o val e xce pt w he n necessar y t o 
eli mi nate i m me diate h azar ds t o t he patie nts or w h e n t he c ha n g e(s) i n v ol ves o nl y l o gistical 
or a d mi nistrati ve as pects of t he st u d y.  S uc h m o difi cati o ns will be s u b mitte d t o t he 
I R B/I E C a n d writte n verificati o n t hat t he m o dificati o n was s u b mitte d a n d s u bse q ue ntl y 
a p pr o ve d s h o ul d be o btai ne d.   
T he I R B/I E C m ust be i nf or me d of re visi o ns t o ot her d oc u me nts ori gi nall y s u b mitte d f or 
re vie w; seri o us a n d/ or u n e x pecte d a d vers e e x p erie nces occ urri n g d uri n g t he st u d y i n 
acc or d a nce wit h t he sta n dar d o per ati n g pr oce d ures a n d p olicies of t he I R B; ne w 
i nf or mati o n t hat ma y aff ect a d versel y t he safet y of t he patie nts of t he c o n d uct of t he st u d y; 
a n a n n ual u p dat e a nd/ or r e q uest f or re-a p pr o val; a n d w he n t he st u d y has bee n c o m plete d. 
1 6. 3  I nf or m e d C o nse nt F or m  
I nf or me d c o ns e nt will be o btai ne d i n acc or da nce wit h t he Declarati o n of H elsi n ki, I C H 
G C P, U S C o de of Fe deral Re g ulati o ns f or Pr otecti o n of H u ma n S u bjects ( 2 1 C F R 
5 0. 2 5[a, b], C F R 5 0. 2 7, a n d C F R Part 5 6, S u b part A), t he Healt h I ns ura n ce P orta bilit y a n d 
Acc o u nta bilit y Act ( HI P A A, if a p plica ble), a n d l o cal re g ulati o ns. 

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T he I n vesti gat or will pre pare t he i nf or me d c o ns e nt f or m, asse nt a n d HI P A A a ut h orizati o n 
a n d pr o vi d e t he d oc u m e nts t o t he S p o ns or or desi g nee f or a p pr o val pri or t o s u b missi o n t o 
t he I R B/I E C.  T he c o nse nt f or m ge nerate d b y t he I n v esti gat or m ust be acce pta ble t o t he 
S p o ns or a n d be a p pr o v e d b y t he I R B/I E C.  T he writte n c o nse nt d oc u me nt will e m b o d y t he 
ele me nts  of i nf or me d c o nse nt as descri b e d i n t he I nter nati o nal C o nfere nce o n 
Har m o nisati o n a n d will als o c o m pl y wit h l ocal re g ulati o ns. T he I n v esti gat or will se n d a n 
I R B/I E C-a p pr o ve d c o p y of t he I nf or m e d C o nse nt F or m t o t he S p o ns or ( or desi g nee) f or 
t he st u d y file. 
A pr o perl y e x ec ute d, writte n, i nf or me d c o nse nt will be o btai ne d fr o m eac h s u bject pri or t o 
e nteri n g t he s u bject i nt o t he trial.  I nf or m ati o n s h o ul d be gi ve n i n b ot h oral a n d writte n 
f or m a n d s u bjects m ust be gi ve n a m ple o p p ort u nit y t o i n q uire a b o ut details of t he st u d y.     
A c o p y of t he si g ne d c o nse nt f or m (a n d asse nt) will be gi ve n t o t he s u bject a n d t he 
ori gi nal will be mai ntai ne d w it h t he s u bject’s rec or ds. 
1 6. 4  P u blic ati o ns  
T he p u blicati o n or pres e ntati o n of a n y st u d y res ults s hall c o m pl y wit h all a p plic a ble 
pri vac y la ws, i ncl u di n g, b ut n ot li mite d t o, t he Healt h I ns ura nce P orta bilit y a n d 
Acc o u nta bilit y Act of 1 9 9 6.  
1 6. 5  I n vesti g at or Res p onsi bilities  
B y si g ni n g t he A gree me nt of I n v esti gat or f or m, t he I n vesti gat or a grees t o: 
1.  C o n d uct t he st u d y i n acc or da nce wit h t he pr ot oc ol a n d o nl y ma ke c ha n g es after 
n otif yi n g t he S p o ns or ( or desi g nee), e xce pt w h e n t o pr otect t he safet y, ri g hts or 
welfar e o f s u bjects. 
2.  Pers o nall y  c o n d uct or s u per vise t he st u d y ( or i n vesti gati o n). 
3.  E ns ure t hat t he r e q uire m e nts relati n g t o o bt ai nin g i nf or me d c o nse nt a n d I R B re vie w 
a n d a p pr o val meet fe d eral g ui deli nes, as state d i n § 2 1 C F R, parts 5 0 a n d 5 6. 
4.  E ns ure t hat all ass oc iat es, c ollea g ues a n d e m pl o yees assisti n g i n t he c o n d uct of t he 
st u d y are i nf or me d a b o ut t heir o bli gati o ns i n meeti n g t he a b o ve c o m mit me nts.  
5.  Mai ntai n a de q uate a n d acc urat e rec or ds i n acc or d a nce wit h § 2 1 C F R 3 1 2. 6 2 a n d t o 
ma ke t h ose rec or ds a v aila ble f or i n s pecti o n wit h t he S p o ns or ( or desi g nee). 
6.  E ns ure t hat a n I R B t hat c o m plies wit h t he re q uire me nts of § 2 1 C F R part 5 6 will be 
res p o nsi ble f or i nitial a n d c o nti n ui n g re vie w a n d a p pr o val of t he cli nical st u d y. 
7.  Pr o m ptl y re p ort t o t he I R B all c ha n ges i n t he res ea rc h acti vit y a n d all u na nti ci pate d 
pr o ble ms i n v ol vi n g ris ks t o s u bjects or ot hers. 
8.  See k I R B a p pr o val bef or e a n y c h a n ge s are ma d e i n t he researc h st u d y, e x ce pt w he n 
necessar y t o eli mi nate hazar ds t o t he patie nts/s u bj ects.  
9.  C o m pl y wit h all ot her re q uire me nts re gar di n g t he o bli gati o ns of cli nical i n vesti gat ors 
a n d all ot her perti ne nt re q uire me nts liste d i n § 2 1 C F R part 3 1 2. 
 

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1 7  R E F E R E N C E S CI T E D  
1. D u n n K E, Br o o ner R K, Clar k M R. Se verit y a n d i nterfere nce of c hr o ni c p ai n i n 
met ha d o ne- mai ntai ne d o ut patie nts. P ai n M e d. 2 0 1 4; 1 5( 9): 1 5 4 0- 1 5 4 8. P MI D: 2 4 7 0 3 5 1 7 
2. Barr y D T, Pil ver C E, H off R A, P ote nza M N. P ai n i nterfere nce a n d i nci d e nt m o o d, 
a n xiet y, a n d s u bsta nce- use dis or ders: Fi n di n gs fr o m a re prese ntati ve sa m pl e of me n a n d 
w o me n i n t he ge ner al p o p ulati o n. J Psyc hi atr  Res . 2 0 1 3 N o v; 4 7( 1 1): 1 6 5 8- 1 6 6 4. P M CI D: 
P M C 3 8 3 5 1 5 4 
3. Kr oe n ke K, S pitzer R L, Willia ms J B. T he P H Q- 1 5: vali dit y of a ne w meas ure f or 
e val uati n g t he se verit y of s o matic s y m pt o ms. Psyc h os o m atic M e dici ne. 2 0 0 2 Mar 
1; 6 4( 2): 2 5 8- 6 6. 
4. Kr oe n ke K, S pitzer R L, Wi llia ms J B. T he P H Q- 9: Vali dit y of a brief d e pressi o n se verit y 
meas ure. J Ge n I nt er n M e d . 2 0 0 1 Se p; 1 6( 9): 6 0 6- 6 1 3. 
5. S pit zer R L, Kr oe n ke K, Willia ms J B, L o we B. A brief meas ure f or assessi n g ge neralize d 
a n xiet y dis or der: T he G A D- 7. Arc h I nt er n Me d . 2 0 0 6 Ma y 2 2; 1 6 6( 1 0): 1 0 9 2- 1 0 9 7. 
6. Gar net B, Beitel M, C utter CJ, Sa va nt J, Peters S, Sc h otte nfel d R S, Barr y D T. Pai n 
catastr o phizi n g a n d p ai n c o pi n g a m o n g met ha d o n e- mai ntai ne d patie nts. P ai n Me d . 2 0 1 1 
Ja n; 1 2( 1): 7 9- 8 6. P M CI D: P M C 3 0 5 9 7 7 1 
7. Rass u F S, Li nse n bar dt H R, Fiel ds S A, Mea g her M W. D oes pai n affect prefere nce? T he 
effect of t o nic la b or at or y pai n o n disc o u nti n g of dela y e d re w ar ds. J P ai n. 2 0 1 8 Se p; 1 9( 9): 
9 6 2- 9 7 2. P MI D: 2 9 6 0 1 8 9 7 
8. W orle y MJ, Hei n zerli n g K G, S h o pta w S, Li n g W. Pai n v olatilit y a n d prescri pti o n o pi oi d 
a d dicti o n treat me nt o utc o mes i n patie nts wit h c hr o nic pai n. Ex p Cli n Psyc h o p h ar m ac ol . 
2 0 1 5 Dec; 2 3( 6): 4 2 8- 4 3 5. P M CI D: P M C 4 6 5 8 2 4 0 
9. F ors yt he L P, T h or n B, Da y M, S hel b y G. Race a n d se x differe n ces i n pri mar y a p praisals, 
catastr o p hizi n g, a n d e x peri me ntal pai n o utc o mes. J P ai n. 2 0 1 1 Ma y; 1 2( 5): 5 6 3- 5 7 2. 
P MI D: 2 1 2 7 7 8 3 6 
1 0. Wij n h o ve n H A, de V et H C, Pica vet H S. E x p lai ni n g se x differe n ces i n c hr o nic 
m usc ul os keletal pai n i n a ge neral p o p ulati o n. P ai n . 2 0 0 6; 1 2 4( 1): 1 5 8- 1 6 6. 
1 1. Tresc ot A M, H el m S, Ha ns e n H, Be n y a mi n R, Glaser S E, A dla k a R, Patel S, 
Ma nc hi ka nti L. O pi oi ds i n t he ma na ge me nt of c hr o nic n o n- ca n cer p ai n: A n u p date of 
A merica n S ociet y of I nter ve nti o nal Pai n P h ysicia ns' ( A SI P P) g ui deli nes. P ai n P hysici a n . 
2 0 0 8 Mar; 1 1( 2 S u p pl): S 6 2. 
1 2. Ver haa k P F, K ersse ns JJ, De k ker J, S or bi MJ, Be nsi n g J M. Pre vale nce of c hr o nic 
be ni g n pai n dis or der a m o n g a d ults: A re vie w o f t he literat ure. P ai n . 1 9 9 8 S e p; 7 7( 3): 2 3 1-
2 3 9. 
1 3. R ose n bl u m A, J ose p h H, F o n g C, Ki p nis S, Clela n d C, P orte n o y R K. Pre vale n ce a n d 
c haracteristics of c hr o nic pai n a m o n g c he micall y de pe n de nt patie nts i n met ha d o ne 
mai nte na nce a n d resi d e ntial treat me nt fac ilities. J A M A. 2 0 0 3 Ma y 1 4; 2 8 9( 1 8): 2 3 7 0- 2 3 7 8. 
1 4. D hi n gra L, Mass o n C, Perl ma n D C, See wal d R M, Katz J, Mc K ni g ht C, H o mel P, Wal d 
E, J or da n A E, Y o u n g C, P orte n o y R K. E pi de mi ol o g y of pai n a m o n g o ut patie nts i n 
met ha d o ne mai nte na n ce treat me nt pr o gra ms. Dr u g Alc o h ol De pe n d. 2 0 1 3 Fe b 1; 1 2 8( 1- 2): 
1 6 1- 1 6 5. P M CI D: P M C 3 5 4 6 1 2 0 
1 5. Ja mis o n R N, Ka uff m a n J, Katz N P. C haracteristics of met ha d o ne mai nt e n a nce patie nts 
wit h c hr o nic pai n. J P ai n Sy m pt o m M a n a ge. 2 0 0 0 Ja n; 1 9( 1): 5 3- 6 2. 
1 6. Griffi n M L, Mc D er m ott K A, Mc H u g h R K, F it z ma urice G M, Ja mis o n R N, Weiss R D. 
L o n git u di nal ass ociati o n bet wee n p ai n se verit y a n d s u bse q ue nt o pi oi d use i n prescri pti o n 

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o pi oi d de pe n de nt patie nts wit h c hr o nic pai n. Dr u g Alc o h ol De pe n d. 2 0 1 6 J u n 1; 1 6 3: 2 1 6-
2 2 1. P M CI D: P M C 4 8 8 0 5 1 2. 
1 7. Cal deir o R M, Malte C A, Cals y n D A, Baer J S, Nic h ol P, Ki vla ha n D R, Sa x o n AJ. T he 
ass ociati o n of persiste nt pai n wit h o ut- patie nt a d dicti o n treat me nt o utc o mes a n d ser vice 
utilizati o n. A d dicti o n. 2 0 0 8 Dec; 1 0 3( 1 2): 1 9 9 6- 2 0 0 5. P MI D: 1 8 8 5 5 8 0 9. 
1 8. P otter J S, C ha kra barti A , D omier C P, Hill h o use M P, Weiss R D, Li n g W. Pai n a n d 
c o nti n ue d o pi oi d use i n i n di vi d uals recei vi n g b u pre n or p hi ne- n al o x o ne f or o pi oi d 
det o xificati o n: Sec o n dar y a nal yses fr o m t he cli nical trials net w or k. J S u bst A b use Tre at. 
2 0 1 0 J u n; 3 8 S u p pl 1: 8 0. P M CI D: P M C 3 1 5 0 5 0 7. 
1 9. T o m p ki ns D A, U m bric ht A, Wi nsta nle y E, Bi gel o w G E. I n: T he relati o ns hi p bet wee n 
pai n a n d treat me nt o utc o me d uri n g met ha d o ne mai nte na nce: A pr os p ecti ve st u d y. 2 0 1 0 
C olle ge o n Pr o ble ms of Dr u g De p e n de nce a n n u al meeti n g; J u ne 1 7, 2 0 1 0; Sc otts dale , A Z.  
2 0. Sa n dra N or d ma n n, A nt oi ne Vil otitc h, Car oli ne Li o ns, La ure nt Mic h el, Mari o n M ora, 
Br u n o S pire, G we naelle Mara da n, M arc- Kari m  Be n dia ne, Alai n M orel, Perri ne R o u x, 
Patrizia Carrieri, A N R S Met ha ville st u d y gr o u p. Pai n i n met ha d o ne patie nts: Ti me  t o 
a d dress u n dertreat me nt a n d s uici de ris k ( A N R S- met ha ville trial). P L o S O ne. 2 0 1 7 Ma y 1; 
1 2( 5): e 0 1 7 6 2 8 8. P M CI D: P M C 5 4 3 5 1 3 2. 
2 1. U m bric ht A, De F uli o A, Wi nsta nle y E L, T o m p ki ns D A, Peirce J, Mi ntzer M Z, Strai n 
E C, Bi gel o w G E. T o pira mate f or c o cai ne d e pe n d e nce d uri n g met h a d o ne mai nte na nce 
treat me nt: A ra n d o mize d c o ntr olle d trial. Dr u g Al c o h ol De pe n d. 2 0 1 4 J ul 1; 1 4 0: 9 2- 1 0 0. 
P M CI D: P M C 4 4 3 1 6 3 3. 
2 2. D yer K R, W hite J M. Patter ns of s y m pt o m c o m plai nts i n met ha d o ne mai nte na nce 
patie nts. A d dicti o n. 1 9 9 7; 9 2( 1 1): 1 4 4 5- 1 4 5 5. 
2 3. T o m p ki ns D A, Bi gel o w G E, Harris o n J A, J o h ns o n R E, F u dala PJ, Strai n E C. 
C o nc urre nt vali dati o n of t he cli nical o piate wit h dra wal scal e ( C O W S) a n d si n gle -ite m 
i n dices a gai nst t he cli nical i nstit ute narc otic assess me nt ( CI N A) o pi oi d wit h dra wal 
i nstr u me nt. Dr u g Alc o h ol De pe n d. 2 0 0 9 N o v 1; 1 0 5( 1- 2): 1 5 4- 1 5 9. P M CI D: 
P M C 2 7 7 4 2 3 6. 
2 4. Ha n dels ma n L, C oc hra ne KJ, Ar o ns o n MJ, Ness R, R u bi nstei n KJ, Ka n of P D. T w o 
ne w rati n g scales f or o pi ate wit h dra w al. A m J Dr u g Alc o h ol A b use. 1 9 8 7; 1 3( 3): 2 9 3- 3 0 8. 
2 5. T o m p ki ns D A, Ca m p bell C M. O pi oi d-i n d uce d h y peral gesia: Cli nicall y rele va nt or 
e xtra ne o us r esearc h p h e n o me n o n? C urr P ai n He a d ac he Re p. 2 0 1 1 A pr; 1 5( 2): 1 2 9- 1 3 6. 
P M CI D: P M C 3 1 6 5 0 3 2. 
2 6. Bic kel W K, J o h ns o n M W. Dela y disc o u nti n g: A f u n da me ntal be h a vi oral pr ocess of 
dr u g de pe n de nce. I n: L oe we nstei n G, Rea d D, B a u meister R, e dit ors. Ti me a n d decisi o n: 
Ec o n o mic a n d ps yc h ol o gical pers pecti ves o n i nterte m p oral c h oice. Ne w Y or k, N Y: R ussell 
Sa ge F o u n dati o n; 2 0 0 3. p. 4 1 9- 4 4 0. 
2 7. Bic kel W K, J o h ns o n M W. J u n k ti me: Pat h ol o gica l be ha vi or as t he i nteracti o n of 
e v ol uti o nar y a n d c ult ur al f orces. I n: C h oice, Be ha vi o ural Ec o n o mics a n d A d dicti o n. 
A mster da m, Net herl a n ds: Else vier Lt d; 2 0 0 3. p. 2 4 9- 2 7 8. 
2 8. C offe y S F, G u dles ki G D, Sala di n M E, Bra d y K T. I m p ulsi vit y a n d ra pi d disc o u nti n g of 
dela ye d h y p ot hetical re w ar ds i n c ocai ne- de p e n de nt i n di vi d uals. Ex p Cli n 
Psyc h o p h ar m ac ol. 2 0 0 3 Fe b; 1 1( 1): 1 8- 2 5. 
2 9. Heil S H, J o h ns o n M W, Hi g gi ns S T, Bic kel W K. Dela y dis c o u nti n g i n c urre ntl y usi n g 
a n d c urr e ntl y a bsti ne nt c ocai ne- d e pe n de nt o ut pati e n ts an d n o n- dr u g- usi n g matc he d 
c o ntr ols. A d dict Be h av. 2 0 0 6 J ul; 3 1( 7): 1 2 9 0- 4. 

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3 0. Bic kel W K, O d u m A L, Ma d de n GJ. I m p ulsi vit y a n d ci garette s m o ki n g: Dela y 
disc o u nti n g i n c urre nt, ne ver, a n d e x-s m o kers. Ps yc h o p h ar m ac ol o gy ( Berl). 1 9 9 9 Oct; 
1 4 6( 4): 4 4 7- 5 4. 
3 1. Ba ker F, J o h ns o n M W, Bic kel W K. D ela y disc o u nti n g i n c urre nt a n d ne ver- b ef ore 
ci garette s m o kers: Si milarities a n d differe nces acr oss c o m m o dit y, si g n, a n d ma g nit u de. J 
A b n or m Psyc h ol. 2 0 0 3 A u g; 1 1 2( 3): 3 8 2- 9 2. 
3 2. J o h ns o n M W, Bic kel W K, Ba ker F. M o derate dr u g use a n d del a y disc o u nti n g: A 
c o m paris o n of hea v y, li g ht, a n d ne ver s m o kers. E x p Cli n Psyc h o p h ar m ac ol. 2 0 0 7 A pr; 
1 5( 2): 1 8 7- 9 4. 
3 3. H off ma n W F, M o or e M, Te m pli n R, Mc Farla n d B, Hitze ma n n RJ, Mitc hell S H. 
Ne ur o ps yc h ol o gical f u ncti o n a n d dela y disc o u nti n g i n met ha m p heta mi ne - d e pe n de nt 
i n di vi d uals. Psyc h o p h ar m ac ol o gy ( B erl). 2 0 0 6 O ct; 1 8 8( 2): 1 6 2- 7 0.  
3 4. Kara k ula S L, Weiss R D, Griffi n M L, B or ges A M, Baile y AJ, Mc H u g h R K. Dela y 
disc o u nti n g i n o pi oi d use dis or der: Differe n ces bet wee n her oi n a n d prescri pti o n o pi oi d 
users. Dr u g Alc o h ol De p e n d. 2 0 1 6 Dec 0 1; 1 6 9: 6 8- 7 2. P M CI D: P M C 5 4 8 6 9 9 0. 
3 5. Kir b y K N, Petr y N M, Bic kel W K. Her oi n a d dicts ha ve hi g her disc o u nt rates f or 
dela ye d r e war ds t ha n n o n- dr u g- usi n g c o ntr ols. J Ex p Psyc h ol G e n. 1 9 9 9 Mar; 1 2 8( 1): 7 8-
8 7. 
3 6. K ir b y K N, Petr y N M. Her oi n a n d c ocai ne a b users ha ve hi g h er disc o u nt rates f or 
dela ye d r e war ds t ha n alc o h olics or n o n- dr u g- usi n g c o ntr ols. A d dicti o n. 2 0 0 4 A pr; 9 9( 4): 
4 6 1- 7 1. 
3 7. Daller y J, Raiff B R. Dela y disc o u nti n g pre dicts ci garette s m o ki n g i n a la b orat o r y mo del 
of a bsti ne nce rei nf or ce m e nt. Psyc h o p h ar m a c ol o gy ( Berl). 2 0 0 7 M ar; 1 9 0( 4): 4 8 5- 9 6. 
3 8. Y o o n J H, Hi g gi ns S T, Heil S H, S u gar ba ker RJ, T h o mas C S, Ba d ger GJ. Dela y 
disc o u nti n g pre dicts p ost part u m rela pse t o ci garette s m o ki n g a m o n g pre g na nt w o me n. Ex p 
C li n Psyc h o p h ar m ac ol. 2 0 0 7 A pr; 1 5( 2): 1 7 6- 8 6. 
3 9. Kris h na n- Sari n S, Re y n ol ds B, D u hi g A M, S mit h A, Liss T, Mc Fetri d ge A, Ca vall o 
D A, Carr o ll K M, P ote nza M N. Be ha vi oral i m p ulsi vit y pre dicts treat me nt o utc o me i n a 
s m o ki n g cessati o n pr o gra m f or a d olesce nt s m okers . Dr u g Alc o h ol De pe n d. 2 0 0 7 A pr 1 7; 
8 8( 1): 7 9- 8 2. 
4 0. Passetti F, Clar k L, Me hta M A, J o yce E, Ki n g M. Ne ur o ps yc h ol o gical pre dict ors of 
cli nical o utc o me i n o piate a d dicti o n. Dr u g Alc o h ol De pe n d. 2 0 0 8 A pr 1; 9 4( 1- 3): 8 2- 9 1. 
4 1. Gi or da n o L A, Bic kel W K, L o e w e nstei n G, Jac o bs E A, Marsc h L, Ba d g er GJ. Mil d 
o pi oi d de pri vati o n i ncreases t he de gree t hat o pi oi d- de pe n de nt o ut patie nts disc o u nt dela y e d 
her oi n a n d m o ne y. Psyc h o p h ar m ac ol o gy ( B erl). 2 0 0 2 Se p; 1 6 3( 2): 1 7 4- 1 8 2. 
4 2. St olt ma n JJ K, W o o dc oc k E A, Lister JJ, L u n d a hl L H, Gree n wal d M K. Her oi n dela y 
disc o u nti n g: M o d ulati o n b y p har mac ol o gical state, dr u g- use i m p ulsi vit y, a n d i ntelli ge nce. 
Ex p Cli n Psyc h o p h ar m ac ol. 2 0 1 5 Dec; 2 3( 6): 4 5 5- 4 6 3. P M CI D: P M C 4 6 6 1 7 8 2. 
4 3. Ai nslie G. S peci o us r e war d: A b e ha vi oral t he or y of i m p ulsi ve ness a n d i m p ulse c o ntr ol. 
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4 7. Berr y ma n C, Sta nt o n T R, Ja ne B o weri n g K, T a b or A, Mc Farla ne A, L ori mer M osele y 
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6 4. T o m p ki ns D A, H u h n A S, J o h ns o n P S, S mit h M T, Strai n E C, E d war ds R R, J o h ns o n 
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P M CI D: P M C 3 6 0 1 5 9 2. 

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7 7. Ca m p bell C M, B o u n ds S C, K u wa bara H, E d war ds R R, Ca m p bell J N, Ha yt h or nt h waite 
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Pr ot oc ol  Z-1 9 0 2 ; PI: D. A n dre w T o m p ki ns, M D M H S 
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