Clinical trial NCT04473950
Conditions: Opioid-use Disorder Chronic Pain Syndrome
Keywords: delay discounting pain catastrophizing impulsivity
Sponsor: University of California, San Francisco
Start date: 2020-01-08; Completion date: 2022-10-06
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The epidemic of opioid overdose deaths continues to rise, killing more persons in 2017 than HIV/AIDS at the height of that epidemic. Medication assisted treatment, including methadone and buprenorphine, is the standard of care for the treatment of opioid use disorder (OUD). However, chronic pain can reduce treatment efficacy during medication assisted treatment and is associated with illicit substance relapse, dropout, and subsequent overdose. Mechanisms by which chronic pain may influence the impulsive decision making (e.g., drug relapse) in persons with OUD have not been well characterized. A better understanding is needed of decision-making in this population. Two factors that can influence decisions to use drugs are impulsivity and acute opioid withdrawal. This proposal will test how chronic pain is associated with increases in impulsive decision making in OUD, whether impulsive decision making is greater when undergoing opioid withdrawal, and how catastrophizing may modify the association between withdrawal and impulsive decision making in patients with chronic pain and OUD. An ideal population for this developmental research project are methadone maintained patients, who show high treatment attendance rates and will therefore assure study efficiency and reliable completion.

Detailed description:
This is an outpatient Phase 1 clinical trial investigating the effect of naloxone precipitated withdrawal on delay discounting. Eligible participants will undergo two experimental sessions presented in random order. One session will involve the measurement of delay discounting 30 minutes after double-blind intramuscular (IM) administration of placebo (normal saline) and the other will have the exact same procedures performed after double-blind IM administration of naloxone (0.1 mg). Injections will occur 2 hours after methadone dosing (peak levels). Study sessions will last 2 hours and involve pain and opioid withdrawal measures assessed at baseline and 15 minute intervals after injections. The participant should be back to baseline and free of withdrawal by the end of the study session. Sessions will occur at least 48 hours apart.

Arms: arm 1: Patients with chronic pain who are maintained on methadone for opioid use disorder arm 2: Patients who are maintained on methadone for opioid use disorder but who do not have chronic pain.
Interventions: intervention 1: Naloxone Hydrochloride intervention 2: Placebo
Intervention descriptions: intervention 1: An intramuscular (IM) injection of naloxone will be given. intervention 2: An IM injection of 0.9% normal saline will be given.

Protocol documents:
Prot_SAP_000.pdf: 
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  
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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  
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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 
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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  
 
Versi o n #: 1. 9  
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  
 
Versi o n #: 1. 9  
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 
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 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  
 
Versi o n #: 1. 9  
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  
 
Versi o n #: 1. 9  
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 


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 5  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
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.   


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 6  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
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. 


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 7  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
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 


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 8  of 3 7  
Pr ot oc ol Te m plate Effecti ve: 0 7 J A N 2 0 1 5  
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 
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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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4 9. Re y n ol ds B, Sc hiff ba uer R. Meas uri n g st ate c ha n ges i n h u ma n dela y disc o u nti n g: A n 
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C o g niti o ns, c o pi n g a n d s ocial e n vir o n me nt pre dict a dj ust me nt t o p ha nt o m li m b pai n . P ai n. 
2 0 0 2; 9 5( 1- 2): 1 3 3- 1 4 2. 
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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 
M W. T o ta ke or n ot t o ta ke: T he ass ociati o n bet w ee n percei ve d a d dicti o n ris k, e x pecte d 
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6 5. J o h ns o n M W, Bic kel W K. A n al g orit h m f or i d e ntif yi n g n o ns yste matic dela y-
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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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o pi oi d rece pt or bi n di n g p ote ntial d uri n g t o nic la b orat or y pai n i n healt h y s u bjects. P ai n 
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R R, F o ntai ne K R. C ha n ges i n pai n catastr o p hizi n g pre dict later c ha n ges i n fi br o m yal gia 
cli nical a n d e x peri me ntal pai n re p ort: Cr oss-la g ge d pa nel a nal yses of dis p ositi o nal a n d 
sit uati o nal catastr o p hizi n g. Art hritis Res T her. 2 0 1 2 Oct 2 5; 1 4( 5): R 2 3 1. P M CI D: 
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9 2. Fiel ds S, Leraas K, C olli ns C, Re y n ol ds B. Dela y disc o u nti n g as a me di at or of t he 
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1 5 9( 2): 1 6 1- 1 6 6. 
9 7. Strai n E C, Prest o n K L, Lie bs o n I A, Bi gel o w G E. B u pre n or p hi ne effects i n met ha d o ne-
mai ntai ne d v ol u nteers: Effects at t w o h o urs after met ha d o ne. J P h ar m a c ol Ex p T her. 1 9 9 5 
Fe b; 2 7 2( 2): 6 2 8- 6 3 8. 
9 8. Wals h S L, Strai n E C, Bi gel o w G E. E val uati o n of t he effects of l ofe xi di ne a n d cl o ni di ne 
o n nal o x o ne- pr eci pitate d wit h dra wal i n o pi oi d - de p e n de nt h u ma ns. A d dicti o n. 2 0 0 3 A pr; 
9 8( 4): 4 2 7- 4 3 9. 
9 9. Yi R, J o h ns o n M W, Bic kel W K. Relati o ns hi p bet wee n c o o perati o n i n a n iterate d 
pris o ner's di le m ma ga me a n d t he disc o u nti n g of h y p ot hetical o utc o mes. Le ar n Be h av. 2 0 0 5 
A u g; 3 3( 3): 3 2 4- 3 6. 
1 0 0. J o h ns o n M W. A n efficie nt o pera nt c h oice pr oce d ure f or ass essi n g del a y disc o u nti n g 
i n h u ma ns: I nitial vali dati o n i n c ocai ne- d e pe n de nt a n d c o ntr ol i n di vi d uals. Ex p Cli n 
Psyc h o p h ar m ac ol. 2 0 1 2 J u n; 2 0( 3): 1 9 1- 2 0 4. P M CI D: P M C 3 5 3 5 4 6 3. 
1 0 1. J o h ns o n M W, Br u ner N R. T he se x u al disc o u nti n g tas k: HI V ris k be ha vi or a n d t he 
disc o u nti n g of dela ye d se x ual re war ds i n c ocai ne d e pe n de n ce. Dr u g Alc o h ol De pe n d. 2 0 1 2 
J u n 0 1; 1 2 3( 1-3):  1 5- 2 1. P M CI D: P M C 3 2 9 0 6 7 6. 
1 0 2. O h m ura Y, Ta k a has hi T, Kita m ura N, We hr P. T hree- m o nt h sta bilit y of dela y a n d 
pr o ba bilit y disc o u nti n g meas ures. E x p Cli n Psyc h o p h ar m ac ol. 2 0 0 6 A u g; 1 4( 3): 3 1 8- 3 2 8. 
1 0 3. V uc hi nic h R E, Si m ps o n C A. H y per b olic te m p oral disc o u nti n g i n s ocial dri n kers a n d 
pr o ble m dri n kers. Ex p Cli n Psyc h o p h ar m ac ol. 1 9 9 8 A u g; 6( 3): 2 9 2- 3 0 5. 
1 0 4. La g ori o C H, Ma d de n GJ. Dela y disc o u nti n g of real a n d h y p ot hetical re war ds III: 
Stea d y -state assess me nts, f orce d-c h oice trials, a n d all real re war ds. B e h av P r ocesses. 2 0 0 5 
Ma y 3 1; 6 9( 2): 1 7 3- 8 7. 
1 0 5. Ma d de n GJ, Raiff B R, La g ori o C H, Be g ot ka A M, M ueller A M, He hli DJ, We ge n er 
A A. Dela y disc o u nti n g of p ote ntiall y real a n d h y p ot hetical re w ar ds: II. Bet wee n- a n d 
wit hi n -s u bject c o m paris o ns. Ex p Cli n Psyc h o p h ar m a c ol. 2 0 0 4 N o v; 1 2( 4): 2 5 1- 6 1. 
1 0 6. Ma d de n GJ, Be g ot k a A M, Raiff B R, Kaster n L L. Dela y disc o u nti n g of real a n d 
h y p ot hetical re w ar ds. Ex p Cl i n Psyc h o p h ar m ac ol. 2 0 0 3 Ma y; 1 1( 2): 1 3 9- 4 5. 
1 0 7. Wess o n, D. R., Li n g, W., Jara, G., a n d t he C o m mittee o n Treat me nt of O pi o i d 
De pe n de n ce, e dit or. B u pre n or p hi ne i n p har mac ot hera p y of o pi oi d a d di cti o n: 
I m ple me nt ati o n i n office-base d me dical practice; tra nslati n g t he e x peri e nce of cli nical trials 
i nt o cli nical practice. Sa n Fra n cisc o, C A: Calif or ni a S ociet y of A d dicti o n M e dici ne; 1 9 9 9. 


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 
C o nfi de nti al  
 
Ver si o n # : 1.9  
Versi o n Date: 1 2/ 0 9/ 2 0 2 0  
Pa ge 3 7  of 3 7  
Pr ot oc ol Te m plate © C F F T T D N   Effecti ve: 1 2 S E P  2 0 0 7  
1 0 8. Prest o n K L, Bi gel o w G E, Lie bs o n I A. B ut or p ha n ol- preci pitate d wit h dra wal i n o pi oi d -
de pe n de nt h u ma n v ol u nt eers. J P h ar m ac ol Ex p T her. 1 9 8 8 A u g; 2 4 6( 2): 4 4 1- 4 4 8. 
1 0 9. Strai n E C, Prest o n K L, Lie bs o n I A, Bi gel o w G E. Ac ute effects of b u pre n or p hi n e, 
h y dr o m or p h o ne a n d n al o x o ne i n met ha d o ne- mai nt ai ne d v ol u nteers. J P h ar m ac ol Ex p T her. 
1 9 9 2 J u n; 2 6 1( 3): 9 8 5- 9 9 3. 
1 1 0. C o he n J. Statistical p o wer a n al ysis f or t he be ha vi oral scie n ces. 2 n d e d. Hills dale, NJ: 
La wre n ce Erl ba u m Ass o ciates I nc; 1 9 8 8.  
 

ICF_001.pdf: 
Versi o n 1. 2
Oct o ber 2 7, 2 0 2 1
P A G E 1 O F 9
U NI V E R SI T Y O F C A LI F O R NI A, S A N F R A N CI S C O
C O N S E N T T O P A R TI CI P A T E I N A R E S E A R C H S T U D Y
St u d y Title: 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
N C T 0 4 4 7 3 9 5 0
Researc h Pr oject 
Direct or:
D. A n dre w T o m p ki ns, M D M H S, Ass ociate Pr ofess or of
Ps yc hiatr y
Z uc ker ber g Sa n Fra ncisc o Ge neral H os pital
1 0 0 1 P otrer o A ve., War d 9 5, Sa n Fra ncisc o, C A 9 4 1 1 0
P h o ne: 6 2 8- 2 0 6- 3 6 4 5; E mail: da vi d.t o m p ki ns @ ucsf.e d u
St u d y C o or di nat or:
Ellie A h ma di
P h o ne: 6 2 8- 2 0 6- 3 3 6 5; E mail: el naz.a h ma di @ ucsf.e d u  
T his is a cli nical researc h st u d y.  Y o ur st u d y d oct or, D. D. A n dre w T o m p ki ns, M D M H S, Ellie 
A h ma di, C harl otte E va ns, or Ga brielle A gi n- Lie bes fr o m t he U C S F De part me nt of Ps yc hiatr y 
will e x plai n t he st u d y t o y o u.
S T U D Y S U M M A R Y
I ntr o d ucti o n: We are as ki n g y o u t o c o nsi der ta ki n g part i n a researc h st u d y bei n g d o ne b y Dr. 
D. A n dre w T o m p ki ns at U C S F.
T he first part of t his c o nse nt f or m gi ves y o u a s u m mar y of t his st u d y. We will gi ve y o u m ore 
details a b o ut t he st u d y later i n t his f or m. T he st u d y tea m will als o e x plai n t he st u d y t o y o u a n d 
a ns wer a n y q uesti o ns y o u ha ve.
Researc h st u dies i ncl u de o nl y pe o ple w h o c h o ose t o ta ke part. It is y o ur c h oice w het her or n ot 
y o u wa nt t o ta ke part i n t his st u d y. Please ta ke y o ur ti me t o ma ke a decisi o n a b o ut partici pati n g. 
Y o u ca n disc uss y o ur decisi o n wit h y o ur fa mil y, frie n ds a n d healt h care tea m. 
P ur p ose of t he st u d y:  T he researc hers wa nt t o lear n a b o ut t he usef ul ness of meas uri n g dela y 
disc o u nti n g, a m o del of i m p ulsi ve decisi o n- ma ki n g, i n patie nts wit h o pi oi d use dis or der ( O U D). 
Researc hers wa nt t o k n o w if dela y disc o u nti n g ma y be affecte d b y stress ors, li ke c hr o nic pai n or 
o pi oi d wit h dra wal. If s uccessf ul, dela y disc o u nti n g ma y be de vel o pe d as a cli nical t o ol t o hel p 
g ui de treat me nt of patie nts wit h O U D.
St u d y Pr oce d ures: If y o u c h o ose t o be i n t his st u d y, y o u will be as ke d t o recei ve a n i njecti o n of 
t he st u d y dr u g, nal o x o ne, or a place b o (a n i njecti o n t hat l o o ks li ke t he st u d y dr u g b ut has n o dr u g 
i n it) o nce at t he be gi n ni n g of eac h of t w o sessi o ns. Y o u will t he n be assesse d f or pai n a n d o pi oi d 
wit h dra wal e ver y 1 5 mi n utes u ntil t w o h o urs after t he i njecti o n. Lastl y, y o u will a ns wer dela y 
disc o u nti n g q uesti o ns a p pr o xi matel y 3 0 mi n utes after eac h i njecti o n. 
Y o u will be i n t his st u d y a b o ut 2- 4 wee ks. Y o u will c o me t o t he cli nic 3 ti mes, i ncl u di n g t o da y’s 
scree ni n g visit. T he scree ni n g visit s h o ul d last 3 h o urs a n d t he st u d y sessi o ns s h o ul d last a b o ut 4 
I R B N U M B E R: 1 9- 2 7 8 3 8
I R B A P P R O V A L D A T E: 1 1/ 0 2/ 2 0 2 1
I R B E X PI R A TI O N D A T E: 1 1/ 0 1/ 2 0 2 2


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hours. Study sessions will occur in Building 90, Ward 95 and Building 5, Unit 5B on the campus 
of ZSFG.
For your safety and the safety of others, you will be screened for recent positive tests, exposures, 
symptoms of COVID-19 and will be asked to wear a mask for the duration of all study visits.
Possible Risks: There are risks to taking part in a research study. Some of the most likely risks 
of participation in this study include: 

Opioid withdrawal symptoms, including nausea, vomiting, diarrhea or loose stools, body 
aches, dysphoric mood, worsening anxiety symptoms, including tunnel vision or panic 
attacks, and gooseflesh

Boredom or fatigue from answering questions
There are also rare but serious risks of participation, like: 

Relapse to opioid or other substance use

Infection at the site of injection
We’ll tell you about the other risks later in this consent form.
Possible Benefits: There will be no direct benefit to you from participating in this study.
Your Other Options: You do not have to participate in this study. Your other choices may 
include:

Not joining the study
Please talk to your doctor about your choices before agreeing to participate in this study.
Following is a more complete description of this study. Please read this description carefully. 
You can ask any questions you want to help you decide whether to join the study. If you join this 
study, we will give you a signed copy of this form to keep for future reference.
DETAILED STUDY INFORMATION
This part of the consent form gives you more detailed information about what the study involves.
Research studies include only people who choose to take part.  Please take your time to make 
your decision about participating.  You may discuss your decision with your family and friends 
and with your health care team.  If you have any questions, you may ask your study doctor.
You are being asked to take part in this study because you have opioid use disorder and are on a 
stable dose of methadone for the past 21 days.
Why is this study being done?
The purpose of this study is to learn about how stressors like chronic pain or opioid withdrawal 
may influence decision making ability in patients on methadone for OUD. We will be using a 
IRB NUMBER: 19-27838
IRB APPROVAL DATE: 11/02/2021
IRB EXPIRATION DATE: 11/01/2022


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series of questions that ask you to choose between a reward now and a larger reward at a time in 
the future. You will not earn these rewards, but we ask that you consider each question as if you 
could receive the reward. This series of questions is known as delay discounting. This study is a 
first step. If successful, delay discounting may be developed as a clinical tool to help guide 
treatment of patients with OUD.
The National Institute on Drug Abuse, part of the National Institutes of Health is funding this 
study. 
Naloxone, an FDA approved medication for the reversal of opioid overdose, is being used in this 
study to precipitate mild symptoms of opioid withdrawal. 
How many people will take part in this study?
About 130 people will take part in this study. We will recruit roughly equal numbers of people 
with and without chronic pain to take part.
What will happen if I take part in this research study?
Before you begin the main part of the study:
You will need to have the following exams, tests or procedures to find out if you can be in the 
main part of the study. All of those exams can be completed in one day or separated out to two 
days depending on a number of factors.
Additionally, you will be screened for COVID-19 symptoms by phone (or telehealth) prior to 
and at the time of arrival for a screening visit. You will be asked about recent positive tests, 
exposures, and symptoms not explained by a pre-existing condition. If the answer to any of these 
screening questions is yes, the visit will be postponed and you will be referred to the medical 
team for further evaluation.
Study-related activities will take place via Zoom/iPads as much as possible. All study staff and 
participants will wear personal protective equipment (PPE) as necessary for the duration the 
visit.

Questions about
o
Demographics
o
Drug use history
o
Medical history
o
Psychiatric history
o
Pain

Physical exam including vital signs

Verify your methadone dose by contacting your opioid treatment program. (We must 
have your permission to do this.)

Collect urine for urine drug screen and pregnancy test (if female)

Collection of an ECG (electrocardiogram – an electronic tracing of your heart)
IRB NUMBER: 19-27838
IRB APPROVAL DATE: 11/02/2021
IRB EXPIRATION DATE: 11/01/2022


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During the main part of the study:
If the exams, tests and procedures show that you can be in the main part of the study, and you 
choose to take part, then you will need the following tests and procedures. The same tasks will 
be done in the same order in each session and the sessions will need to be at least 48 hours apart.
You will again be screened for COVID-19 symptoms by phone (or telehealth) as described 
above prior to and at the time of arrival for session visits. The same precautionary measures for 
COVID-19 as described above will be taken during session visits.

Collect urine for urine drug screen and pregnancy test (if female). The results of the urine 
drug screen must be positive for methadone and negative for illicit substances. Otherwise, 
the session will be rescheduled. A positive pregnancy test will result in withdrawal or the 
participant from the study and referral to appropriate resources.

Must be without signs of intoxication as evidenced by ability to receive full dose of 
methadone prior to research activities.

Contact your opioid treatment program to verify you have not yet taken your methadone 
dose on the day of your session. Your dose on session one must be the same dose on 
session two.

Administer your current methadone dose at OTOP / Ward 93.

If you are a smoker, you will be asked to smoke 1 cigarette 20 minutes prior to session 
and then refrain from smoking until the session is complete.

Collect baseline responses on
o
Current pain level
o
Current symptoms of withdrawal
o
Vital signs
o
Take a picture of your eye

Administer one injection in your upper arm muscles approximately 2 hours after your 
methadone dose. You and the study team will not know what you are given. One of the 
doses will be a placebo, an inactive substance, and one of the doses will contain 0.1 mg 
of naloxone. The order of the injections will be randomized, like flipping a coin.

Every 15 minutes after the injection up to 2 hours the study team will collect responses 
on 
o Current pain level
o Current symptoms of withdrawal (if any)
o Vital signs
o Take a picture of your eye

Collect responses on the delay discounting task approximately 30 minutes after study 
medication is administered.
In addition, you will be asked to answer questions about the following:
o
Impulsivity
o
Sleep problems (insomnia)
o
Anxiety, somatization and depressive symptoms 
o
Pain catastrophizing
How long will I be in the study?
IRB NUMBER: 19-27838
IRB APPROVAL DATE: 11/02/2021
IRB EXPIRATION DATE: 11/01/2022


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You will be asked to complete two sessions that will last about 4 hours each in addition to a 
screening visit. The sessions must be at least 48 hours apart. On average, you will be spend 11 
hours in study related activities spread out over 2-4 weeks.
Can I stop being in the study?
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping 
or decide to stop. He will tell you how to stop your participation safely. 
It is important to tell the study doctor if you are thinking about stopping so any risks from 
naloxone or placebo can be evaluated by your doctor. Another reason to tell your doctor that you 
are thinking about stopping is to discuss what follow-up care and testing could be most helpful 
for you.
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules, or if the study is stopped.
What side effects or risks can I expect from being in the study?
You may have side effects while on the study. Everyone taking part in the study will be watched 
carefully for any side effects. However, doctors don't know all the side effects that may happen.  
Side effects may be mild or very serious. Your health care team may give you medicines to help 
lessen side effects. 
You should talk to your study doctor about any side effects you experience while taking part in 
the study.
Risks and side effects related to the study medications include those which are:
Likely 

Opioid withdrawal, including body aches, headache, nausea, vomiting, sweating, diarrhea 
or loose stools, tearing, depressed mood, worsening anxiety, including tunnel vision or 
panic attacks, and gooseflesh

Changes in vital signs, including elevations in heart rate and blood pressure

Injection site reaction, including pain and redness

Dizziness
Less Likely 

Bruising at the site of injection

Boredom or fatigue at answering questions

Sleepiness after receiving study medication
IRB NUMBER: 19-27838
IRB APPROVAL DATE: 11/02/2021
IRB EXPIRATION DATE: 11/01/2022


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Rare but serious

Relapse to substance use. If this does occur, we would communicate this to your opioid 
treatment program.

Infection at site of injection
Reproductive risks:  You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby.  Women should not breastfeed a baby 
while on this study.  It is important to understand that you need to use birth control while on this 
study.  Check with your study doctor about what kind of birth control methods to use and how 
long to use them. 
Unknown Risks: The experimental treatments may have side effects that no one knows about 
yet.  The researchers will let you know if they learn anything that might make you change your 
mind about participating in the study.
For more information about risks and side effects, ask your study doctor.
Are there benefits to taking part in the study?
There will be no direct benefit to you from participating in this study.  However, this study will 
help doctors learn more about how stressors may affect delay discounting, and it is hoped that 
this information will help in the treatment of future patients with OUD.
What other choices do I have if I do not take part in this study?
You do not have to join this study. Your care at OTOP and ZSFG will not be affected if you 
choose not to enter this study. Please talk to your doctor about your choices before deciding if 
you will take part in this study.
How will my information be used? 
Researchers will use your information to conduct this study. Once the study is done using your 
information, we may share them with other researchers so they can use them for other studies in 
the future. We will not share your name or any other personal information that would let the 
researchers know who you are. We will not ask you for additional permission to share this de-
identified information.
How will information about me be kept confidential?
Participation in research involves some loss of privacy.  We will do our best to make sure that 
information about you is kept confidential, but we cannot guarantee total privacy.  Some 
information from your medical records will be collected and used for this study.  Information 
gathered directly from you by the researchers will be part of your research records but will not be 
added to your medical record.  Your personal information may be given out if required by law.  
If information from this study is published or presented at scientific meetings, your name and 
other personal information will not be used.
IRB NUMBER: 19-27838
IRB APPROVAL DATE: 11/02/2021
IRB EXPIRATION DATE: 11/01/2022


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Authorized representatives from the following organizations may review your research data for 
the purpose of monitoring or managing the conduct of this study:

Representatives of the National Institutes of Health 

Representatives of the University of California
What is a Certificate of Confidentiality?
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health. This means that the researchers cannot release or use information, documents, or 
samples that may identify you in any action or suit unless you say it is okay. They also cannot 
provide them as evidence unless you have agreed.  This protection includes federal, state, or 
local civil, criminal, administrative, legislative, or other proceedings. An example would be a 
court subpoena.
 
There are some important things that you need to know.  The Certificate DOES NOT stop 
reporting that federal, state or local laws require. Some examples are laws that require reporting 
of child or elder abuse, some communicable diseases, and threats to harm yourself or others.
Researchers may release information about you when you say it is okay. For example, you may 
give them permission to release information to insurers, medical providers or any other persons 
not connected with the research.  The Certificate of Confidentiality does not stop you from 
willingly releasing information about your involvement in this research. It also does not prevent 
you from having access to your own information.
Are there any costs to me for taking part in this study?
No.
Will I be paid for taking part in this study?
In return for your time, effort and travel expenses, you will be paid up to $300 for participation 
in study related activities. You can earn $50 for study screening, $75 after completion of each 
study session, and an additional $100 bonus for completion of both sessions.
If you pass study screening and complete at least one study session, you will then also be eligible 
to refer participants to the study. If participants that you have referred also pass study screening 
and complete at least one study session, you will receive a referral bonus of $50. The referred 
participant must also mention your name during their study screening for you to receive this 
referral bonus.
What happens if I am injured because I took part in this study?
It is important that you tell your study doctor, Dr. D. Andrew Tompkins, if you feel that you 
have been injured because of taking part in this study. You can tell the doctor in person or call 
him at 628-206-3645.
IRB NUMBER: 19-27838
IRB APPROVAL DATE: 11/02/2021
IRB EXPIRATION DATE: 11/01/2022


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Treatment and Compensation for Injury:  If you are injured as a result of being in this 
study, the University of California will provide necessary medical treatment.  The costs 
of the treatment may be billed to you or your insurer just like any other medical costs or 
covered by the University of California depending on a number of factors.  The 
University and the study sponsor do not normally provide any other form of 
compensation for injury.  For further information about this, you may call the office of 
the Institutional Review Board at 415-476-1814.
What are my rights if I take part in this study?
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No matter 
what decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits. Leaving the study will not affect your medical care. You can still get your medical care 
from our institution. 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.
Who can answer my questions about the study?
You can talk to your study doctor about any questions, concerns, or complaints you have about 
this study.  Contact your study doctor. Dr. D. Andrew Tompkins, at 628-206-3645.
If you wish to ask questions about the study or your rights as a research participant to someone 
other than the researchers or if you wish to voice any problems or concerns you may have about 
the study, please call the office of the Institutional Review Board at 415-476-1814.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time.
Future Contact:
We want to know if we may contact you in the future to see if you are interested in participating 
in other research studies. If you agree and we contact you to tell you about a study, you have no 
obligation to actually participate in any study. You can decide when you are told about the study 
if you want to receive more information about the study. There would be a new consent process 
for that study. If at any time you decide you no longer want to be contacted about future studies, 
please let us know by calling 628-206-3365.
IRB NUMBER: 19-27838
IRB APPROVAL DATE: 11/02/2021
IRB EXPIRATION DATE: 11/01/2022


Version 1.2
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Making Your Choices: Please read the sentence below and mark your choice by checking either 
the "Yes" or "No" box. If you have any questions, please talk to your doctor or nurse, or call our 
research review board at 415-476-1814. No matter what you decide to do, it will not affect your 
care or your participation in the main study.
I agree to allow someone to contact me in the future about taking part in more research:
YES ☐
NO ☐
CONSENT
You have been given copies of this consent form and the Experimental Subject's Bill of Rights to 
keep.
You will be asked to sign a separate form authorizing access, use, creation, or disclosure of 
health information about you.
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to 
participate or to withdraw at any point in this study without penalty or loss of benefits to which 
you are otherwise entitled.
If you wish to participate in this study, you should sign below.
Date
Participant's Signature for Consent
Date
Person Obtaining Consent
IRB NUMBER: 19-27838
IRB APPROVAL DATE: 11/02/2021
IRB EXPIRATION DATE: 11/01/2022