Clinical trial NCT02901275
Conditions: Pain Cannabis Opioid Use, Unspecified
Keywords: Clinical Trial, Phase II Analgesia Abuse Potential
Sponsor: Johns Hopkins University
Start date: 2016-12-01; Completion date: 2020-03-23
Enrollment: 29 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single-group, within-subject, double-blind, double-dummy, placebo and active-controlled study evaluated whether the FDA-approved cannabinoid dronabinol (Marinol) would enhance analgesia, subjective reports, and cognitive performance when compared to the FDA-approved opioid hydromorphone (Dilaudid).

Detailed description:
This was a human laboratory systematic examination of whether adding the FDA-approved cannabinoid dronabinol (Marinol; oral) to the FDA-approved opioid hydromorphone (Dilaudid; oral) would change the experience of hydromorphone as rated by laboratory measures of pain, subjective reports of drug effects, and cognitive performance. Subjects are healthy individuals with no history of drug use disorder. Study subjects and staff were completed blinded to the study drugs and the class of drugs under investigation and were informed that subjects may receive opioids, stimulants, cannabinoids, benzodiazepines, over the counter medications, and/or placebo. All participants completed all sessions. Sessions lasted up to 8-hours and were conducted at least 7 days apart on an outpatient basis. Primary outcomes were collected from participants prior to dosing and at several hour periods post-dosing.

Arms: arm 1: Within-subject double-blind, double-dummy administration of placebo + placebo. Order of dose randomized session days 2-5. arm 2: Within-subject double-blind, double-dummy administration of hydromorphone (oral) 4mg + placebo. Always administered during session 1. arm 3: Within-subject double-blind, double-dummy administration of hydromorphone (oral) 4mg + dronabinol (oral) 2.5mg. Order of dose randomized session days 2-5. arm 4: Within-subject double-blind, double-dummy administration of hydromorphone (oral) 4mg + dronabinol (oral) 5.0mg. Order of dose randomized session days 2-5. arm 5: Within-subject double-blind, double-dummy administration of hydromorphone (oral) 4mg + dronabinol (oral) 10mg. Order of dose randomized session days 2-5 but was never the first hydromorphone 4mg + dronabinol combination dose.
Interventions: intervention 1: Within-subject test of blinded study medications
Intervention descriptions: intervention 1: Within-subject double-blind, double-dummy, study design wherein all participants received all doses in 8-hour outpatient sessions. Primary outcomes assessed during 8-hour outpatient sessions and included laboratory pain testing, subjective reports of drug effects, and cognitive performance, evaluated as a function of study medication condition.

Protocol documents:
ICF_001.pdf: 
Official Title: Usi n g Ca n na bi n oi ds t o E n ha nce 
O pi oi d A nal gesic Effects i n H u ma ns 
 
N C T: 0 2 9 0 1 2 7 5 
 
I nf or me d C o nse nt Date: N o ve m ber 1 3, 2 0 1 7 
 


 
A p p r o v e d N o v e m b e r  1 3, 2 0 1 7  
D ate: N o ve m ber 1 3 , 2 0 1 7 
Pri nci pal I n vesti gat or: Kell y D u n n, P h. D.  
A p plicati o n N o.: I R B 0 0 0 9 7 9 3 7  
 
Pa ge 1  of 1 2  
C o m bi n e d I nf or me d C o nse nt/ A ut h orizati o n J u ne 2 0 1 5 Versi o n 1 5 
 
 
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
R E S E A R C H P A R TI CI P A N T I N F O R M E D C O N S E N T A N D P RI V A C Y 
A U T H O RI Z A TI O N F O R M  
 
Pr ot oc ol Title :     
E n h a nci n g Me dic ati o n -b ase d  A n al gesi a  i n H u m a ns  
 
 
A p plic ati o n N o . :   
I R B 0 0 0 9 7 9 3 7 
 
S p o ns or:   
N ati o n al I nstit ute o n Dr u g A b use ( NI D A)   
 
Pri nci p al I n vesti g at or:  Kell y D u n n, P h. D.  
5 5 1 0 N at h a n S h oc k Dri ve  
B alti m ore M D 2 1 2 2 4  
P h o ne: 4 1 0 -5 5 0 -2 2 5 4; F a x: 4 1 0 -5 5 0 -0 0 3 0   
  
1.  
W h at y o u s h o ul d k n o w a b o ut t his st u d y
:  
•  Y o u are b ei n g as ke d t o j oi n a researc h st u d y. T his c o nse nt f or m e x plai ns t he researc h st u d y a n d y o ur 
part i n it. Please rea d it caref ull y a n d t a ke as m uc h ti me as y o u nee d. As k y o ur st u d y d oct or or t he 
st u d y tea m t o e x plai n a n y w or ds or i nf or mati o n t hat y o u d o n ot u n dersta n d. 
•  Y o u are a v ol u nteer.  If y o u j oi n t he st u d y, y o u ca n c ha n ge y o ur mi n d later.  T here will be n o p e nalt y 
or l oss of be nefits if y o u deci de t o q uit t he st u d y.    
•  D uri n g t h e st u d y, w e will tell y o u if we l ear n a n y ne w i nf or mati o n t hat mi g ht affect w het her y o u 
wis h t o c o nti n ue t o partici pate.  
•  If we t hi n k y o ur p artici pati o n i n t his st ud y ma y affect y o ur cli nical care, i nf or mati o n a b o ut y o ur 
st u d y partici p ati o n will be i ncl u de d i n y o ur me dical rec or d, w hic h is use d t hr o u g h o ut J o h ns H o p ki ns.   
D oct ors o utsi de of J o h ns H o p ki ns ma y n ot ha v e access t o t his i nf or mati o n.  Y o u ca n as k t h e res earc h 
tea m t o se n d t his i nf or mati o n t o a n y of y o ur d o ct ors. 
•  W he n J o h ns H o p ki ns is use d i n t his c o nse nt f or m, it i ncl u des T he J o h ns H o p ki ns U ni versit y, T he 
J o h ns H o p ki ns H os pital, J o h ns H o p ki ns Ba y vie w Me dical Ce nter, H o war d C o u nt y Ge n eral H os pital, 
J o h ns H o p ki ns C o m m u nit y P h ysi cia ns, S u b ur ba n H os pital, Si ble y M e m ori al H os pital a n d All 
C hil dre n’s H os pital.  
•  Bi os peci me ns will be c ollecte d i n t his st u d y.  Bi os peci me ns ma y i ncl u de a n y of t he f oll o wi n g: 
bl o o d, tiss ue, sali va, uri ne, b o ne marr o w, cells, etc.  M ost bi os peci me ns c o ntai n D N A, w hic h is t he 
ge n etic c o d e f or eac h p ers o n.  
•  A descri pti o n of t his cli nical trial will be a vaila bl e o n htt p:// w w w. Cli nical Trials. g o v, as re q uire d b y 
U. S. La w.  T his We b site will n ot i ncl u de i nf or mati o n t hat ca n i de ntif y y o u. At m os t, t he We b site 
will i ncl u de a s u m mar y of t he res ults. Y o u ca n searc h t his We b site at a n y ti me.  
•  If y o u w o ul d li ke t o re vie w t he i nf or mati o n f or t his st u d y, or a s u m mar y of t he res ults, as k t he st u d y 
tea m d oct or f or t h e Cli nical Trials. g o v st u d y re gistratio n n u m ber. 
 
 
If y o u are usi n g E pic f or t his st u d y, fa x a c o p y 
of t he si g ne d c o nse nt f or m t o 4 1 0 -3 6 7 -7 3 8 2.  
 
 
 
 
 
Patie nt I. D. plate  
 
 
 
 
                                
          
 
 
  
 
 


 
A p p r o v e d N o v e m b e r  1 3, 2 0 1 7  
D ate: N o ve m ber 1 3 , 2 0 1 7 
Pri nci pal I n vesti gat or: Kell y D u n n, P h. D.  
A p plicati o n N o.: I R B 0 0 0 9 7 9 3 7  
 
Pa ge 2  of 1 2  
C o m bi n e d I nf or me d C o nse nt/ A ut h orizati o n J u ne 2 0 1 5 Versi o n 1 5 
•  D uri n g t his st u d y, y o u will n ot ha ve access t o cert ai n me dical i nf or mati o n a n d test res ults c ollecte d 
f or st u d y p ur p oses.  If a n e mer ge n c y occ urs w hile y o u are i n t he st u d y, me dical i nf or mati o n nee d e d 
f or y o ur treat me nt ca n b e ma de a vaila ble to y o ur st u d y p h ysicia n a n d ot h er p h ysicia ns w h o treat y o u.  
W he n t he st u d y is c o m plete d, all t he i nf or mati o n i n y o ur m e dical rec or d will be a vaila ble t o y o u. 
 
2.  
W h y is t his rese arc h bei n g d o ne ?  
T h is resear c h is bei n g d o ne t o e val uate w het her c o m bi ni n g t w o me dicati o ns ca n ma ke t h e me dicati o ns 
m ore eff ecti ve at re d uci n g pai n.   
 
T h o u g h all t he me di cati o ns  bei n g use d i n t his st u d y are a p pr o ve d b y t he U. S. F o o d a n d Dr u g 
A d mi nistrati o n ( F D A) , t heir use in t his st u d y is i n vesti gati o nal  beca us e we are usi n g t he m i n a w a y t hat 
t he F D A h as n ot yet a p pr o ve d. T he F D A is all o wi n g t he us e of t hese st u d y me dicati o ns f or t his st u d y. 
 
Pe o ple wit h w h o are o v er 1 8 years ol d a n d h ealt h y ma y j oi n t his st u d y.  
 
H o w m a ny pe o ple will be i n t his st u dy ?  
T his st u d y is ai mi n g t o h a ve 6 0 pe o ple ( 3 0 me n a n d 3 0 w o me n) c o m plete t he st u d y. 
 
3.  
W h at will h a p pe n if y o u j oi n t his st u d y ?
 
If y o u a gr ee t o be i n t his st u d y, we will as k y o u t o d o t he f oll o wi n g t hi n gs: 
 
Scree ni n g Visit  1:  
Y o u will be c o m pleti n g t he first Scree n i n g visit t o da y.  
 
T he g o al of t his Scree ni n g visit is t o ma ke s ure t hat y o u are eli gi ble f or t h e st u d y a n d h ealt h y, s o t h at 
partici pati n g i n t his st u d y will n ot p ut y o u at ris k.  
 
D uri n g t his visit, we will as k y o u a seri es of q uesti o ns a n d will c ollect a bl o o d sa m ple ( n o m ore t ha n 2 
ta bles p o o ns) a n d uri ne s a m ple fr o m y o u t o e ns ure it is safe f or y o u t o be e nr olle d i nt o t he st u d y.  Y o u 
will als o c o m plete a n electr ocar di o gra m ( E C G ) t o ma ke s ure y o ur heart is healt h y.  
 
At s o me p oi nt eit her t o da y or b ef or e t he be gi n ni n g of y o ur 1 st st u d y sessi o n (see bel o w) y o u will als o 
meet wit h a me dical staff me m ber t o c o m plete a brief hist or y a n d p h ysical.   
 
St u d y Sessi o ns :   
If y o u ar e deter mi ne d t o be eli gi ble a fter c o m pleti n g t he Scree ni n g Visit  t he n y o u will be as ke d t o 
c o m plete 5 st u d y s essi o ns. Eac h sessi o n will last all da y (ar o u n d 8 h o urs). Y o u are welc o me t o s pe n d t he 
ni g ht bef ore eac h sessi o n i n o ur cli nical researc h u nit, w hic h is l ocate d o n o ur sa me h os pital ca m p us. If 
y o u pr efer n ot t o s pe n d t he ni g ht, y o u ma y arri ve t he m or ni n g of t h e sessi o n. H o we ver, si nce w e ca n n ot 
be s ure h o w y o u will f eel after ta ki n g t he st u d y me dicati o ns, we will as k y o u t o n ot dri ve t o t he sessi o ns 
a n d will pa y f or a t a xi t o bri n g y o u t o a n d fr o m t he sessi o ns if nee d e d.  
 
Bef ore w e be gi n eac h sessi o n, we will c ollect a uri ne sa m ple  t hat will be teste d f or rece nt dr u g us e. If 
y o u are f e male, w e will als o test y o u f or pre g na n c y a n d will c ollect a bl o o d sa m ple fr o m y o u t hat we 
will test t o deter mi ne y o ur h o r m o ne stat us. It is p ossi ble t hat t he staff me m ber ma y ca ncel y o ur st u d y 
sessi o n if y o ur uri ne r es ults i n dicate rece nt dr u g use or pre g n a nc y.  If y o ur st u d y sessi o n is ca n cele d, y o u 
will n ot recei ve pa y m e nt f or t hat visit a n d will ha ve t o resc h e d ule y o ur visit.  If y o u are eli gi ble f or t he 
st u d y sessi o n, t he n a staff me m ber will esc ort y o u t o t he cli nical researc h u nit t o sta y t h e ni g ht. 
De pe n di n g o n w hat ti me y o u arri ve, y o u ma y b e pr o vi de d wit h di n ner w hil e o n t he res earc h u nit.  
 
 


 
A p p r o v e d N o v e m b e r  1 3, 2 0 1 7  
D ate: N o ve m ber 1 3 , 2 0 1 7 
Pri nci pal I n vesti gat or: Kell y D u n n, P h. D.  
A p plicati o n N o.: I R B 0 0 0 9 7 9 3 7  
 
Pa ge 3  of 1 2  
C o m bi n e d I nf or me d C o nse nt/ A ut h orizati o n J u ne 2 0 1 5 Versi o n 1 5 
Eac h m or ni n g y o u will be pr o vi de d wit h a cal orie-c o ntr olle d brea kfast bef ore t he sessi o n be gi ns. St u d y 
sessi o ns are e x pecte d t o l ast all da y. D uri n g t he sessi o n y o u will first be as ke d t o c o m plete s o me 
q uesti o n naires t hat as k y o u a b o ut h o w y o u feel a n d t o c o m plete s o me pai n testi n g pr oce d ures ( t hese are 
descri be d i n m ore d e tail bel o w). Y o u will t he n recei ve ca ps ules t hat c o ntai ns t he st u d y me dicati o n s f or 
y o u  t o s wall o w. T h e  me dicati o ns y o u r ecei ve  ma y c o ntai n a pres cri pti o n sti m ula nt, a prescri pti o n 
ca n na bi n oi d (r elate d t o t he acti ve i n gr e die nt i n ca n na bis or marij ua na), a b e nz o diaze pi ne (e. g., a nti-
a n xiet y m e dicati o n), a n o pi oi d (e. g., a pai n me dicati o n), a n o ver-t he-c o u nter me dicati o n, or a pl ace b o 
(c o ntai ns n o me dicati o n, li ke a s u gar pill). Neit her y o u n or t h e staff me m b er will k n o w w hat 
c o m bi nati o n of me dicati o ns y o u ha v e recei ve d.  
 
After y o u r ecei v e t he st u d y me dicati o ns, we will as k y o u t o c o nti n ue c o m pleti n g q uesti o n naires, 
c o m p uterize d tas ks, a n d pai n testi n g pr o ce d ures at re g ul ar i nter v als t hr o u g h o ut t he sessi o n da y. We will 
als o c ollect i nf or mati o n a b o ut h o w y o ur b o d y is res p o n di n g t o t he st u d y m e dicati o ns, b y c ollecti n g y o ur 
bl o o d press ure, heart r ate, p u pil dia meter, a n d ot her meas ures of bi ol o gical res p o nse. At t he e n d of t he 
sessi o n, we will pr o vi de y o u wit h a ta xi ri de h o me.  
 
Y o u will be as ke d t o c o m plet e 5 of t hese st u d y sessi o ns. E ac h sessi o n will be i de ntic al a n d w e as k 
y o u t o c o m plete t he m a b o ut  1 w ee k a p art.  
 
P ai n Testi n g Pr oce d ures:  
We will as k y o u t o c o m plete s o me pai n testi n g pr oce d ures as part of t his st u d y. T hes e tests hel p us t o 
u n dersta n d w het h er c o m bi ni n g me dicati o ns ca n re d uce p ai n, a n d t hese d ata will hel p us lear n w h et her 
t here are ne w a n d better wa ys f or t he m e dical c o m m u nit y t o be treati n g p ai n i n t heir patie nts.  
 
We will be usi n g well - vali date d pai n-testi n g pr oce d ures t hat are use d b y se veral ot her l a b orat ories 
t hr o u g h o ut t he w orl d. S o me of t he pai n testi n g will i ncl u de t he a p plicati o n of a t o pical crea m.  
 
It is i m p orta nt t hat y o u k n o w t hat e ve n t h o u g h eac h pr oce d ure ma y pr o d u ce s o me le vel of pai n, w e 
e x pect t he pai n t o be relati vel y mil d , a n d y o u will be a ble t o e n d t he pr oce d ure at a n y ti me  wit h n o 
c o nse q ue nces. We ar e c o n d ucti n g se v eral differe nt pai n pr o ce d ures beca us e t he y all acti vate differe nt 
pai n pat h wa ys, h o w e ver t he pai n t he y pr o d uce is brief a n d n o n e of t hese pr oce d ures are e x pecte d t o 
pr o d uce a n y l asti n g p ai n or da ma ge t o y o u. S pecificall y, y o u will be as ke d t o place y o ur ar m a n d/ or 
ha n d i nt o c ol d water. T his ma y be mil dl y pai nf ul, h o we ver y o u will be a ble t o re m o ve y o ur ar m/ ha n d 
w he ne ver y o u wa nt. A st aff me m ber will als o place a s mall de vice o n s o m e of y o ur m uscles, w hic h will 
ma ke y o u feel s o me press ure  o n t h ose m uscles. T his pr oce d ure m a y als o b e mil dl y pai nf ul, a n d y o u will 
be a ble t o e n d t he pr oce d ure w he n e ver y o u wis h. We will als o ta p a place o n y o ur h a n d or els e w here 
wit h s o me pe ncil-li ke o bjects. T hese ma y als o be mil dl y p ai nf ul, b ut a gai n y o u will be a bl e t o st o p t he 
tas k w he ne ver y o u wa nt. Fi nall y, we  r u b a crea m o n y o ur h a n d t hat c o ntai ns ca psaici n, w hic h is t he 
c he mical t hat ma kes s o m e pe p pers h ot. We will t he n use a mac hi ne t hat ge nerates h eat t o e val uat e y o ur 
res p o nse t o te m per at ure-i n d uce d pai n.  A staff me m ber will i ntr o d uce y o u t o  t hese pr oce d ures d uri n g t he 
Scree ni n g visits, s o y o u will be a ble t o ma ke a n i nf or me d decisi o n a b o ut w het her y o u’ d li ke t o 
partici pate i n t his st u d y.  
 
Re q uest t o re-c o nt a ct y o u f or f ut ure rese arc h :   
We w o ul d als o li ke t o st ore t he i nf or mati o n t hat y o u pr o vi de t o us s o t hat we ma y re-c o ntact y o u i n t he 
f ut ure t o as k if y o u’ d li ke t o lear n a b o ut a d diti o nal researc h o p p ort u nities. T his d oes n ot mea n y o u 
w o ul d ha ve t o partici pat e i n a n y a d diti o nal researc h, t hat is a se parat e decisi o n t hat y o u w o ul d ma k e at 
a n ot her ti me. Rat her, it will gi ve us per missi o n t o c o ntact y o u a b o ut researc h f or w hic h w e belie ve y o u 
ma y b e i ntereste d a n d/ or eli gi ble, bas e d o n t he res p o nses t hat y o u pr o vi de t o us d uri n g t his st u d y. Y o u 
are free t o c h ose w h et her we ca n c o ntact y o u or n ot, a n d y o ur c h oice will n ot i m pact y o ur a bilit y t o be 
e nr olle d i nt o t his st u d y.  


 
A p p r o v e d N o v e m b e r  1 3, 2 0 1 7  
D ate: N o ve m ber 1 3 , 2 0 1 7 
Pri nci pal I n vesti gat or: Kell y D u n n, P h. D.  
A p plicati o n N o.: I R B 0 0 0 9 7 9 3 7  
 
Pa ge 4  of 1 2  
C o m bi n e d I nf or me d C o nse nt/ A ut h orizati o n J u ne 2 0 1 5 Versi o n 1 5 
 
W o ul d y o u li ke us t o c o ntact y o u i n t he f ut ure re gar di n g n e w researc h o p p ort u nities?  
 
Y E S      _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _      
  
NO   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
  
 
Si g nat ure of Partici pa nt   
  
  
  
    Si g nat ure of Partici pa nt   
 
 
O pti o n al g e netic testi n g :  
Y o u will be as ke d gi ve a b o ut 1- 2 ta bles p o o ns of bl o o d f or ge netic testi n g. Y o ur sa m ple ma y be st ore d 
f or f ut ure ge netic testi n g t hat st u d y h o w ge n es ma y i m pact res p o nse t o me dicati o ns or res p o n d t o pai nf ul 
sti m uli or p ossi bl y ot her diseases ma y be st u die d. T he sa m ples will n ot be use d f or p ur p os es ot her t ha n 
researc h. T h e res ults will n ot be gi ve n t o y o u. T o pr otect y o ur c o nfi de ntialit y, all e x pl orat or y sa m ples 
will be dis g uise d usi n g la bels wit h a u ni q ue c o de n u m ber. O nl y t he i n vesti gat or a n d desi g nat e d st u d y 
staff ha ve t h e ke y t o li n k t he c o de t o y o u. T he a nal ysis res ults will n ot be li n ke d t o y o u. All ge n etic 
researc h i nf or m ati o n o btai ne d fr o m y o ur s a m ples will be ke pt strictl y c o nfi de ntial.  
 
T he Ge netic I nf or m ati o n N o n discri mi nati o n Act ( GI N A) ma y h el p pr otect y o u fr o m healt h i ns ura n ce or 
healt h -rel ate d e m pl o y m e nt discri mi nati o n base d o n ge n etic i nf or mati o n.   
 
T he la w pr o vi des t hat h ealt h i ns ura nce c o m pa nies a n d gr o u p healt h pla ns  
•  ma y n ot as k f or ge n etic i nf or mati o n fr o m t his researc h a n d  
•  ma y n ot use ge netic i nf or mati o n w he n ma ki n g d ecisi o n a b o ut eli gi bilit y or pre mi u ms 
 
T he la w will n ot st o p healt h i ns ura nce c o m pa ni es fr o m usi n g ge netic i nf or mati o n t o deci de w het her t o 
pa y clai ms. T he la w d o es n ot a p pl y t o ot her t y pes of i ns ura nce (s uc h as life, disa bilit y or l o n g- ter m 
care).  
 
Des pite t he GI N A pr otecti o ns a n d t he best eff orts of t he researc h tea m t o pr otect y o ur i nf or mati o n, y o u 
ma y  still be at ris k if i nf or mati o n a b o ut y o u w ere t o bec o me k n o w n t o pe o ple o utsi de of t his st u d y. 
 
Ge netic i nf or m ati o n is u ni q ue t o y o u a n d y o ur fa mil y, e ve n wit h o ut y o ur na me or ot her i d e ntifiers.   
J o h ns H o p ki ns f oll o ws pr oce d ur es t o pre v e nt pe o ple w h o w or k wit h y o ur D N A i nf or mati o n fr o m b ei n g 
a ble t o disc o ver it bel o n gs t o y o u. H o w e ver, n e w t ec h ni q ues are c o nsta ntl y bei n g d e vel o pe d t hat ma y i n 
t he f ut ure ma k e it easier t o re-i de ntif y ge n etic data, s o we ca n n ot pr o mise t h at y o ur ge netic i nf or mati o n 
will ne ver be li n ke d t o y o u. 
 
N o i nf or mati o n will be pr o vi de d t o fa mil y m e m bers, t hir d pers o ns or or ga nizati o ns. T his s a m ple is 
c o m pletel y v ol u nt ar y a n d will n ot i m p act w het her y o u are eli gi ble f or t he pri m a r y st u d y.   
 
Will y o u all o w us t o  c oll ect a bl o o d sa m ple t o be st ore d f or f ut ure ge n etic testi n g?  
 
Y E S      _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _      
  
NO   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g nat ure of Partici pa nt   
  
  
  
    Si g nat ure of Partici pa nt   
 
 
Re q uest t o c ollect a n d st ore bi os peci me ns f or f ut ure rese a rc h:   
As part of t his resear c h st u d y, w e w o ul d li ke t o as k y o u t o let us st ore y o ur bi os peci me ns a n d healt h 
i nf or mati o n f or f ut ur e res earc h.  T his researc h c o ul d i ncl u de ot her diseases. T he st u d y d o ct or ca n 
pr o vi de y o u wit h a d diti o nal i nf or mati o n if y o u h a ve q uesti o ns. Als o, f urt h er i nf or mati o n a b o ut o ur use 


 
A p p r o v e d N o v e m b e r  1 3, 2 0 1 7  
D ate: N o ve m ber 1 3 , 2 0 1 7 
Pri nci pal I n vesti gat or: Kell y D u n n, P h. D.  
A p plicati o n N o.: I R B 0 0 0 9 7 9 3 7  
 
Pa ge 5  of 1 2  
C o m bi n e d I nf or me d C o nse nt/ A ut h orizati o n J u ne 2 0 1 5 Versi o n 1 5 
of y o ur bi os peci me ns ca n be f o u n d i n t his c o nse nt d oc u me nt u n der t he hea di n g W h at h a p pe ns t o D at a 
a n d Bi os peci me ns t h at are c ollecte d i n t he st u dy ?  
 
Will y o u all o w us t o st or e t he bi os peci me ns w e c ollect f or t his st u d y f or use i n f ut ure researc h ? 
 
Y E S      _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _      
  
NO   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g nat ure of Partici pa nt   
  
  
  
    Si g nat ure of Partici pa nt   
 
 
H o w l o n g will y o u be i n t he st u d y ?  
Y o u will be i n t his st u d y f or 6 visits ( 1 scree ni n g visit a n d 5 sessi o n visits). We e x pect t his t o ta ke a b o ut 
8- 1 0 wee ks t o c o m plet e all t he st u d y visits.  
 
4.  
W h at are t he ris ks or disc o mf orts of t he st u d y ?  
 
St u d y Dr u g s:  
T he lar gest ris k of t his st u d y is ass oci ate d wit h t he me dicati o ns  y o u will recei ve. Si de effects of t he 
me dicati o ns  y o u will be r ecei vi n g ar e e x pecte d t o be mil d a n d s h ort-li ve d. Y o u will be scree ne d bef ore 
e nr olli n g i n t he st u d y t o e ns ure y o u are at a l o w ris k of e x perie nci n g a n y st u d y me dicati o n -rel ate d si de 
effects.  
 
It is i m p orta nt t hat y o u u n dersta n d t he p ote ntial si de effects t hat y o u c o ul d e x perie nce fr o m t he st u d y 
me dicati o ns. T hese me di cati o ns ha ve bee n a d mi nistere d t o pe o ple pre vi o usl y eit her as treat me nts f or 
differe nt me di cal ill nesses or i n ot her e x peri me ntal st u dies. Bel o w is a list of si de effects t hat h a v e bee n 
re p orte d b y s o me p e o ple w h o ha ve ta k e n t hese me dicati o ns, h o we ver it is i m p orta nt t o re me m ber t h at 
s o me of t hese si de effects ma y be relat e d t o t he me dical ill nesses bei n g treate d a n d n ot a res ult of t he 
me dicati o n itself.  Si de effects are als o m ore li kel y t o ha p p e n w he n t he m e dicati o ns are ta k e n f or s e veral 
da ys i n a r o w, w hic h is differe nt fr o m h o w y o u will be ta ki n g t he me dicati o ns i n t his st u d y. 
 
•  Der mat ol o gic: Re d de ni n g of t he face ( 2 % of pe o ple), Itc h y s ki n ( 1-8 %  of p e o ple)  
•  Gastr oi ntesti nal : C o nsti pati o n ( 7- 3 1 % of p e o ple), Na usea (3- 2 8 % of pe o ple ), V o miti n g (3- 1 4 % of 
pe o ple), A b d o mi nal P ai n ( 3 %- 1 0 % of pe o ple), Dr y M o ut h  ( 3 8 %- 5 0 % of p e o ple) 
•  Car di o vasc ular : L o w bl o o d press ure (less t ha n 2 % of pe o ple), F ai nti n g (less t ha n 2 % of pe o ple), a n d 
H i g h bl o o d pr ess ure, H eart Pal pitati o ns, F ast heart beat , or Wi de ni n g of bl o o d vessels ( m ore t ha n 
1 % of pe o ple). 
•  Ne ur ol o gic : W ea k ness or Dizzi ness ( 1 - 1 1 % of pe o ple); Hea d ac he ( 1 - 1 2 % of pe o ple); Slee pi ness ( 3-
1 0 % of pe o ple); C o ma, J er ki n g of M uscles , a n d I ncreas e d Intracra nial Press ure (less t ha n 2 % of 
pe o ple); A m nesia or M e m or y L os, L oss of C o ntr ol of B o d y M o ve me nts, C o nf usi o n, C o or di nati o n 
Pr o ble ms, a n d Verti g o ( m ore t ha n 1 % of p e o ple i n all cases ) 
•  Ps yc hiatric: Feeli n g Hi g h E u p h oria ( 3- 1 0 % of pe o ple) ; S uici dal t h o u g hts (l ess t ha n 2 % of pe o pl e); 
A n xiet y , Feeli n gs of Pers ec uti o n, L oss of Se nse of Self , De pressi o n, or Hall uci nati o ns ( m ore t ha n 
1 % i n all cases)  
•  Res pirat or y : B ri ef St o p i n Breat hi n g, St o p pi n g B reat hi n g (less t ha n 2 % of pe o ple)  
•  Ot her : Dr u g dep e n de n ce/ A d dicti o n or Dr u g Wit h dra wal (l ess t ha n 1 % of p e o ple )  
 
It is i m p orta nt f or y o u t o k n o w t hat, i n e xtre me cases, t hese me dicati o ns m a y ca use y o ur breat hi n g t o 
sl o w d o w n or st o p. T he y c o ul d als o ca use a se vere aller gic reacti o n or e ve n deat h. Y o u will u n der g o 
e xte nsi ve me dical testi n g d uri n g t he Scree ni n g visit s t o deter mi ne  w het her y o u ha v e a n y of t he ris k 
fact ors t hat w o ul d i ncrease t he li keli h o o d t hat y o u w o ul d ha ve a n e xtre me reacti o n t o t he st u d y 
me dicati o n a n d will n ot be e nr olle d i nt o t he st u d y if we ha v e a n y reas o n t o b elie ve t hat t he st u d y 
me dicati o n w o ul d p ut y o u at u n d ue ris k. 


 
A p p r o v e d N o v e m b e r  1 3, 2 0 1 7  
D ate: N o ve m ber 1 3 , 2 0 1 7 
Pri nci pal I n vesti gat or: Kell y D u n n, P h. D.  
A p plicati o n N o.: I R B 0 0 0 9 7 9 3 7  
 
Pa ge 6  of 1 2  
C o m bi n e d I nf or me d C o nse nt/ A ut h orizati o n J u ne 2 0 1 5 Versi o n 1 5 
 
Ris ks f r o m C o m bi ni n g t he St u d y M e dic ati o ns :  
Alt h o u g h t her e is n o e vi d e nce t hat c o m bi ni n g t he st u d y me dicati o ns res ults i n ne gati ve si de effects, it is 
al wa ys p ossi ble t here m a y be s o m e i nteracti o ns bet wee n t hese me di cati o ns t hat are n ot yet k n o w n.  We 
will caref ull y m o nit or e mer gi n g me di cal i nf or mati o n a b o ut t hese dr u gs a n d will disc o nti n ue  t he st u d y 
me dicati o n s if ne w i nf or mati o n i n dicates t hese me dicati o ns s h o ul d n ot be c o m bi ne d.  
 
P ai n Testi n g:   
Y o u  will li kel y e x perie nce s o me disc o mf ort f r o m t he pai n testi n g pr oce d ures t hat are c o n d u cte d d uri n g 
t he st u d y. T he p ai n is e x pecte d t o be mil d a n d s h ort-li ve d, a n d y o u will be a ble t o e n d y o ur partici p ati o n 
i n t he pai n sessi o ns at a n y ti me. 
 
C a ps aici n : 
Ca psaici n is t he mai n i n gre die nt i n h ot pe p pers, a n d is use d as a n o ver-t he-c o u nter dr u g f or t h e treat me nt 
of pai n i n pr o d ucts li ke Ic y H ot . T he d ose of ca ps aici n we are usi n g is hi g h er t ha n w hat is a v aila ble o ver 
t he c o u nter, alt h o u g h it is less t ha n half of t he d ose i n a si n gle ha b a nera pe p per. Ca psaici n d oes ca us e 
s o me pai n t hat is si milar t o h o w a h ot pe p per ma y feel w he n it is eate n. Ca psaici n ma y pr o d uce s o me 
l ocal re d ness a n d s welli n g t hat ge n erall y disa p p ear s wit hi n a da y. T he area of s ki n w here t h e ca ps aici n is 
a p plie d c o ul d be se nsiti v e f or u p t o 4 8 h o urs. Ca psaici n ma y ca us e a b ur ni n g feeli n g i n t he e yes or ot her 
areas of t he b o d y if acci d e ntall y r u b b e d o nt o ot her s ki n areas.  We will ta ke preca uti o ns t o ma ke s ure 
t his d oes n ot ha p pe n. We will li mit t he e x p os ure area t o a s mall s q uare o n t he bac k of t h e ha n d a n d will 
was h t he ca ps aici n off wit h alc o h ol after eac h s essi o n. If n ee d e d, we ca n  us e s o me ice t o re d uce a n y 
c o nti n ue d disc o mf ort y o u ma y e x perie nce.  
 
Bl o o d Dr a w:  
We will use a nee dle t o dra w bl o o d fr o m y o u. T a ki n g bl o o d ma y ca use disc o mf ort, blee di n g, or br uisi n g 
w here t he n ee dle e nters  t he b o d y. I n rare cases, it ma y res ult i n fai nti n g. T h ere is a s mall ris k of 
i nfecti o n. 
 
Le g al Ris ks:   
It is p ossi ble t hat y o ur uri ne sa m ples will test p ositi ve f or me dicati o ns t hat c o ul d be c o nsi dere d a b us a ble 
b y y o ur e m pl o yers or la w e nf or ce me nt pr ofessi o nals (e. g., sti m ula nts, ca n na bi n oi ds, o pi oi ds). If t his is a 
c o ncer n t o y o u t he n, wit h y o ur p er missi o n, we ca n pr o vi de y o u wit h a letter t hat c o nfir ms y o ur 
partici pati o n i n t he st u d y a n d t he p ote ntial f or y o u t o test p ositi ve f or dr u gs t hat c o ul d be c o nsi dere d 
a b usa ble f or u p t o 7 da ys f oll o wi n g a st u d y sessi o n.  
 
E C G :  
A n E C G will be c o n d uct e d t o deter mi ne t hat y o u heart is healt h y e n o u g h f or st u d y partici pati o n. T o 
c o n d uct t he E C G y o u will ha ve electr o des place d o n y o ur c hest, a n d y o u m a y fi n d t hese c ol d or 
u nc o mf orta ble, t h o u g h t h e y are n ot e x pecte d t o pr o d uce a n y p ai n. It is p ossi ble t hat t he E C G ma y re veal 
a b n or malities i n y o ur h eart f u ncti o ni n g t hat c o ul d be cli nicall y si g nifica nt. I n t hese cas es, t he st u d y 
me dical tea m will i nf or m y o u of t h e a b n or malities a n d will pr o vi de y o u wit h rele va nt i nf or m ati o n  y o u 
nee d  t o f oll o w- u p wit h y o ur o w n d oct or. 
 
St u d y Q uesti o n n aires :  
Y o u ma y get tire d or b or e d w he n w e ar e as ki n g y o u q uesti o ns or y o u are c o m pleti n g q uesti o n naires. 
Y o u d o n ot ha ve t o a ns w er a n y q uesti o n y o u d o n ot wa nt t o a ns wer. 
 
C o nfi de nti alit y:   
T here is t he ris k t hat i nf or mati o n a b o ut y o u ma y b ec o me k n o w n t o pe o pl e o utsi de t his st u d y. 
 
Fi nall y, t h ere ma y b e a d diti o nal si de effects a n d disc o mf orts t hat are n ot yet k n o w n. 


 
A p p r o v e d N o v e m b e r  1 3, 2 0 1 7  
D ate: N o ve m ber 1 3 , 2 0 1 7 
Pri nci pal I n vesti gat or: Kell y D u n n, P h. D.  
A p plicati o n N o.: I R B 0 0 0 9 7 9 3 7  
 
Pa ge 7  of 1 2  
C o m bi n e d I nf or me d C o nse nt/ A ut h orizati o n J u ne 2 0 1 5 Versi o n 1 5 
5.  
Are t here ris ks rel ate d t o pre g n a nc y ?  
T his resear c h ma y h urt a n e m br y o or f et us i n wa ys we d o n ot c urre ntl y k n o w. T o pr otect a gai nst t his 
ris k, we will test all w o me n f or pr e g na nc y bef ore j oi ni n g t he st u d y a n d pri or t o e ver y st u d y sessi o n. We 
als o as k all w o me n t o practice birt h c o ntr ol met h o ds d uri n g t heir 8- 1 0 wee k partici pati o n i n t he st u d y.  
 
6.  
Are t here be nefits t o bei n g i n t he st u d y ?  
T here is n o direct be nefit t o y o u fr o m b ei n g i n t his st u d y. H o w e ver, y o ur partici pati o n i n t he st u d y will 
hel p us t o lear n m ore a b o ut h o w t o better treat p ai n, a n d w het her certai n c o m bi nati o ns of me dicati o ns 
s h o ul d be use d f or t hat p ur p ose.  
 
7.  
W h at are y o ur o pti o ns if y o u d o n ot w a nt t o be i n t he st u d y ?  
Y o u d o n ot ha ve t o j oi n t his st u d y.  If y o u d o n ot j oi n, y o ur care at J o h ns H o p ki ns will n ot be affecte d.  
 
8.  
Will it c ost y o u a n yt hi n g t o be i n t his st u d y ?
   
N o.  
 
9.  
Will y o u be p ai d if y o u j oi n t his st u d y ?  
Y o u will be c o m pe nsate d u p t o $ 1 2 8 0 f or y o ur ti me i n t he st u d y, a n d y o ur ear ni n gs are ill ustrate d i n t his 
ta ble. Y o u will recei ve eac h sessi o n pa y me nt at t h e e n d of t he s essi o n.  
 
 
 
 
 
 
 
 
 
 
 
 
Y o u ma y b e r e q uire d t o pr o vi de y o ur s ocial sec urit y n u m ber t o be p ai d f or ta ki n g part i n t his st u d y. 
Fe deral ta x la w re q uir es t hat y o u r e p ort y o ur researc h pa y me nts w h e n y o u file y o ur ta x es. If y o ur t otal 
pa y m e nts fr o m J o h ns H o p ki ns e x cee d $ 6 0 0 per year, J o h ns H o p ki ns will re p ort t hese pa y me nts t o t he 
I nter nal Re ve n u e Ser vice a n d y o u will recei v e a 1 0 9 9-MI S C f or m fr o m us.   
 
1 0.  
C a n y o u le a ve t he st u d y e arl y ?  
•  Y o u ca n a gree t o b e i n t he st u d y n o w a n d c h a n ge y o ur mi n d later. 
•  If y o u wis h t o st o p, pleas e tell us ri g ht a wa y. 
•  Lea vi n g t his st u d y earl y will n ot st o p y o u fr o m getti n g re g ular me dical care .  
 
If y o u lea v e t he st u d y earl y, J o h ns H o p ki ns ma y use or gi ve o ut y o ur healt h i nf or mati o n t hat it has 
alrea d y c ollecte d  if t he i nf or mati o n is nee de d f or t his st u d y or a n y f oll o w-u p acti vities .  
 
1 1.  
W h y mi g ht we t a ke y o u o ut of t he st u d y e arl y ?  
Y o u ma y b e ta ke n o ut of t he st u d y if: 
•  Sta yi n g i n t he st u d y w o ul d be har mf ul. 
•  Y o u nee d treat me nt n ot all o we d i n t he st u d y. 


 
A p p r o v e d N o v e m b e r  1 3, 2 0 1 7  
D ate: N o ve m ber 1 3 , 2 0 1 7 
Pri nci pal I n vesti gat or: Kell y D u n n, P h. D.  
A p plicati o n N o.: I R B 0 0 0 9 7 9 3 7  
 
Pa ge 8  of 1 2  
C o m bi n e d I nf or me d C o nse nt/ A ut h orizati o n J u ne 2 0 1 5 Versi o n 1 5 
•  Y o u fail t o f oll o w i nstr ucti o ns or fail t o a d here t o t he sessi o n visit sc he d ule. 
•  Y o u bec o me pre g na nt. 
•  T he st u d y is ca ncelle d.  
•  T here ma y b e ot her reas o ns t o ta ke y o u o ut of t h e st u d y t hat we d o n ot k n o w at t his ti me.  
 
If y o u ar e ta ke n o ut of t h e st u d y earl y, J o h ns H o p ki ns ma y use or gi ve o ut y o ur h ealt h i nf or mati o n t hat it 
has  alrea d y c ollecte d  if t he i nf or mati o n is nee de d f or t his st u d y or a n y f oll o w-u p acti vities .  
 
1 2.  
H o w will y o ur pri v ac y be pr otecte d ?   
We ha ve r ules t o pr otect i nf or mati o n a b o ut y o u.  Fe deral a n d stat e la ws an d t he fe deral me dical Pri vac y 
R ule als o pr otect y o ur pri vac y.  B y si g ni n g t his f or m y o u pr o vi de y o ur per missi o n, calle d y o ur 
“a ut h orizati o n,” f or t he use a n d discl os ure of i nf or mati o n pr otecte d b y t h e Pri vac y R ule. 
 
T he resear c h tea m w or ki n g o n t he st u d y will c ollect i nf or mati o n a b o ut y o u.  T his i ncl u des t hi n gs lear ne d 
fr o m t he pr oce d ures d escri be d i n t his c o nse nt f or m.  T he y ma y als o c ollect ot her i nf or mati o n i ncl u di n g 
y o ur n a me, a d dress, date of birt h, a n d i nf or mati o n fr o m y o ur me dical rec or ds ( w hic h ma y i ncl u de 
i nf or mati o n a b o ut HI V st at us, dr u g, alc o h ol or S T D treat me nt, ge n etic test res ults, or me ntal healt h 
treat me nt). 
 
T he resear c h tea m will k n o w y o ur i de ntit y a n d t h at y o u are i n t he researc h stu d y.  Ot her p e o ple at J o h ns 
H o p ki ns, partic ularl y y o ur d oct ors, ma y als o see or gi ve o ut y o ur i nf or mati o n. We ma ke t his i nf or mati o n 
a vaila ble t o y o ur d oct ors f or y o ur sa fet y.    
 
Pe o ple o utsi de of J o h ns H o p ki ns ma y n ee d t o see or recei ve y o ur i nf or mati o n f or t his st u d y.  E x a m ples 
i ncl u de g o v er n me nt a ge n cies  (s uc h as t h e F o o d a n d Dr u g A d mi nistrati o n), safet y m o nit ors, ot her sites i n 
t he st u d y a n d c o m pa nies t hat s p o ns or t he st u d y.  
 
We ca n n ot d o t his st u d y wit h o ut y o ur a ut h orizati o n  t o use a n d gi ve o ut y o ur i nf or mati o n.  Y o u d o n ot 
ha ve t o gi ve us t his a ut h orizati o n.  If y o u d o n ot, t he n y o u m a y n ot j oi n t his st u d y. 
 
We will use a n d discl ose y o ur i nf or mati o n o nl y as descri be d i n t his f or m a n d i n o ur N otice of Pri vac y 
Practices; h o we v er, pe o pl e o utsi de J o h ns H o p ki ns w h o recei ve y o ur i nf or mati o n ma y n ot be c o vere d b y 
t his pr o mise or b y t he f e deral Pri vac y R ule.  We tr y t o ma k e s ure t hat e ver y o ne w h o nee ds t o see y o ur 
i nf or mati o n kee ps it c o nfi de ntial – b ut we ca n n ot g uara ntee t hat y o ur i nf or mati o n will n ot be re-
discl ose d . 
 
T he use a n d discl os ur e of y o ur i nf or mati o n has n o ti me li mit. Y o u ma y re v o ke (ca n cel) y o ur per missi o n 
t o use a n d discl ose y o ur i nf or mati o n at a n y ti me b y n otif yi n g t he Pri nci pal I n v esti gat or of t his st u d y b y 
p h o ne or i n writi n g.  If y o u c o ntact t he Pri nci pal I n vesti gat or b y p h o n e, y o u m ust f oll o w- u p wit h a 
writte n re q uest t hat i ncl u des t he st u d y n u m ber a n d y o ur c o ntact i nf or m ati o n.  T he Pri nci pal 
I n v esti gat or’s na me, a d dr ess, p h o ne a n d fa x i nf or mati o n are o n pa ge o ne of t his c o nse nt f or m.  
 
If y o u d o ca n cel y o ur a ut h orizati o n t o use a n d discl ose y o ur i nf or mati o n, y o ur part i n t his st u d y will e n d 
a n d n o f urt her i nf or mati o n a b o ut y o u will be c ollecte d. Y o ur re v ocati o n ( ca ncellati o n ) w o ul d n ot affect 
i nf or mati o n alrea d y c ollecte d in t he st u d y, or i nf or mati o n we discl ose d bef ore y o u wr ote t o t he P ri nci pal 
I n v esti gat or t o ca n cel y o ur a ut h orizati o n. 
 
1 3.  
W h at if t here is a Certific ate of C o nfi de nti alit y f or t his st u d y ?  
T he Nati o nal I nstit ute o n Dr u g A b use has gi v e n us a Certificate of C o nfi de ntialit y f or t his st u d y.  T his 
Certificate pr o vi d es s o me a d diti o nal pr otecti o n f or researc h i nf or mati o n t hat i de ntifies y o u. T h e 
Certificate  all o ws us, i n s o me circ u msta nces, t o ref use t o gi v e o ut i nf or mati o n t hat c o ul d i de ntif y y o u as 


 
A p p r o v e d N o v e m b e r  1 3, 2 0 1 7  
D ate: N o ve m ber 1 3 , 2 0 1 7 
Pri nci pal I n vesti gat or: Kell y D u n n, P h. D.  
A p plicati o n N o.: I R B 0 0 0 9 7 9 3 7  
 
Pa ge 9  of 1 2  
C o m bi n e d I nf or me d C o nse nt/ A ut h orizati o n J u ne 2 0 1 5 Versi o n 1 5 
a researc h s u bj ect wit h o ut y o ur c o nse nt, w he n s u c h i nf or mati o n is s o u g ht i n a fe deral, state, or l ocal 
c o urt or p u blic a ge nc y acti o n. Still, we ma y discl ose i de ntif yi n g i nf or mati o n a b o ut y o u if, f or e x a m ple, 
y o u nee d me dical hel p. 
 
We ma y als o discl ose i de ntifia ble i nf or mati o n a b o ut y o u as d escri be d i n Secti o n 1 2 of t his f or m or i n 
ot her cas es. F or e x a m ple, t he g o v er n me nt ma y see y o ur  i nf or mati o n if it a u dits us, a n d t he researc h t ea m 
will v ol u ntaril y c o m pl y wit h re p orti n g r e q uire me nts t o t he a p pr o priate l ocal or state a ut h orities: 
 
•  if t he y s us p ect a b use, n e glect or a ba n d o n m e nt of a c hil d or v ul nera ble or d e pe n de nt a d ult; 
•  if certai n diseases are pr ese nt; a n d 
•  if t he tea m lear ns t h at y o u pla n t o har m s o me o ne. I n t his case, t he tea m als o ma y w ar n t he p ers o n 
w h o is at ris k. 
 
E ve n wit h t his Certificate i n place, y o u a n d y o ur fa mil y me m bers m ust c o nti n ue t o pr otect y o ur o w n 
pri vac y.  If y o u v ol u ntaril y gi ve y o ur writte n c o ns e nt f or a n i ns urer, e m pl o yer, or la w yer t o recei v e 
i nf or mati o n a b o ut y o ur p artici pati o n i n t he researc h, t he n we ma y n ot use t he Certificate t o wit h h ol d t his 
i nf or mati o n. 
 
T his Certific ate d oes n ot me a n t he g o ver n me nt a p pr o ves or dis a p pr o ves of t his rese arc h pr oject  
 
1 4.  
W h at tre at me nt c osts will be p ai d if y o u are i nj ure d i n t his st u d y ?  
J o h ns H o p ki ns a n d t he fe deral g o ver n me nt d o n ot ha ve pr o gra ms t o pa y y o u if y o u are h urt or ha ve 
ot her ba d r es ults fr o m bei n g i n t he st u d y.  H o we v er, me dical care at J o h ns H o p ki ns is o pe n t o y o u as it 
is t o all sic k or i nj ure d pe o ple.   
 
T he c osts f or a n y treat me nt or h os pital care y o u recei ve as t he res ult of a st u d y -relate d i nj ur y t hat are n ot 
c o vere d b y a healt h i ns urer will be bille d t o y o u. 
 
B y si g ni n g t his f or m y o u will n ot gi ve u p a n y ri g hts y o u ha v e t o see k c o m p e nsati o n f or i nj ur y.  
 
1 5.  
W h at ot her t hi n gs s h o ul d y o u k n o w a b o ut t his rese arc h st u d y ?  
a.  W h at is t he I nstit uti o n al Re vie w B o ar d (I R B) a n d h o w d oes it pr otect y o u ?  
T he J o h ns H o p ki ns Me dici ne I R B is ma d e u p of: 
•  D oct ors  
•  N urses  
•  Et hicists  
•  N o n -scie ntists 
•  a n d pe o ple fr o m t he l ocal c o m m u nit y.  
 
T he I R B re vie ws h u ma n researc h st u dies. It pr otects t he ri g hts a n d w elfare of  t he pe o ple ta ki n g part 
i n t h ose st u dies.  Y o u ma y c o nt act t he I R B if y o u ha ve q uesti o ns a b o ut y o ur ri g hts as a partici pa nt or 
if y o u t hi n k y o u ha ve n ot bee n treate d fairl y.  T he I R B office n u m ber is 4 1 0- 9 5 5- 3 0 0 8. Y o u ma y 
als o call t his n u m ber f or ot her q uesti o ns, c o ncer ns or c o m plai nts a b o ut t he researc h. 
 
W he n t he J o h ns H o p ki ns Sc h o ol of Me dici ne I nstit uti o nal Re vie w B oar d (I R B) re vi e ws a st u d y at 
a n ot her site, t hat site (i nstit uti o n) is s olel y res p o nsi ble f or t he safe c o n d u ct of t he st u d y a n d f or 
f oll o wi n g t he pr ot o c ol a p pr o ve d b y t he J o h ns H o p ki ns I R B.   
 
 
 


 
A p p r o v e d N o v e m b e r  1 3, 2 0 1 7  
D ate: N o ve m ber 1 3 , 2 0 1 7 
Pri nci pal I n vesti gat or: Kell y D u n n, P h. D.  
A p plicati o n N o.: I R B 0 0 0 9 7 9 3 7  
 
Pa ge 1 0  of 1 2  
C o m bi n e d I nf or me d C o nse nt/ A ut h orizati o n J u ne 2 0 1 5 Versi o n 1 5 
b.  W h at d o y o u d o if y o u h a ve q uesti o ns a b o ut t he st u d y ?    
Call  t he pri nci pal i n vesti gat or, Dr. K ell y D u n n P h. D. at 4 1 0- 5 5 0- 2 2 5 4. If y o u wis h, y o u ma y c o ntact 
t he pri nci pal i n vesti gat or b y letter or b y fa x.  T he a d dress a n d fa x n u m ber are o n pa ge o n e of t his 
c o nse nt f or m. If y o u ca n n ot reac h t he pri nci pal i n vesti gat or or wis h t o tal k t o s o me o ne else, call t he 
I R B office at 4 1 0- 9 5 5- 3 0 0 8.   
 
c. W h at s h o ul d y o u d o if y o u are i nj ure d or ill as a res ult of bei n g i n t his st u d y ?  
If y o u t hi n k y o u are i nj ur e d or ill beca us e of t his st u d y, y o u ma y call Dr. Traci S pee d , M. D., or Dr. 
Eric Strai n, M. D. at 4 1 0- 5 5 0- 0 0 5 2 d uri n g re g ul ar office h o urs.   
 
If y o u h a ve a n ur ge nt me dic al pr o ble m relate d t o y o ur ta ki n g part i n t his st u d y, call Dr. Traci 
S pee d , M. D., or Dr. Eric Strai n, M. D. at 4 1 0- 5 5 0- 0 0 5 2 d uri n g re g ular office h o urs a n d o n w ee ke n ds.  
 
d.  W h at h a p pe ns t o D at a  a n d Bi os peci me ns  t h at are c ollecte d i n t he st u d y ?  
J o h ns H o p ki ns a n d o ur researc h p art ners w or k t o u n dersta n d a n d c ure diseases. T he bi os peci me ns 
a n d/ or data y o u pr o vi d e are i m p orta nt t o t his eff ort. 
 
If y o u j oi n t his st u d y, y o u s h o ul d u n dersta n d t hat y o u will n ot o w n y o ur bi os peci me ns or data, a n d 
s h o ul d resear c hers us e t h e m t o creat e a ne w pr o d u ct or i dea, y o u will n ot be nefit fi na n ciall y.  
 
Wit h a p pr o priate pr otecti o ns f or pri vac y, J o h ns H o p ki ns ma y s hare y o ur bi os peci me ns a n d 
i nf or mati o n wit h o ur researc h s p o ns ors a n d part ners.    
 
 


 
A p p r o v e d N o v e m b e r  1 3, 2 0 1 7  
D ate: N o ve m ber 1 3 , 2 0 1 7 
Pri nci pal I n vesti gat or: Kell y D u n n, P h. D.  
A p plicati o n N o.: I R B 0 0 0 9 7 9 3 7  
 
Pa ge 1 1  of 1 2  
C o m bi n e d I nf or me d C o nse nt/ A ut h orizati o n J u ne 2 0 1 5 Versi o n 1 5 
 
1 6.  
W h at d oes y o ur si g n at ure o n t his c o nse nt f or m me a n ?   
Y o ur si g nat ure o n t his f or m mea ns t hat: Y o u u n dersta n d t he i nf or mati o n gi ve n t o y o u i n t his f or m, y o u acce pt t he 
pr o visi o ns i n t he f or m a n d y o u a gree t o j oi n t he st u d y. Y o u will n ot gi ve u p a n y le gal ri g hts b y si g ni n g t his 
c o nse nt f or m.  
 
 
W E WI L L GI V E Y O U A C O P Y O F T HI S SI G N E D A N D D A T E D C O N S E N T F O R M  
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g nat ure of P artici pa nt                                                                           ( Pri nt Na me)                                                  
 
Date/ Ti me  
 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g nat ure of P ers o n O btai ni n g C o nse nt                                                  ( Pri nt Na me)                                                
 
Date/ Ti me  
 
 
 
 
N O T E : A C O P Y O F T H E SI G N E D, D A T E D C O N S E N T F O R M M U S T B E K E P T B Y T H E P RI N CI P A L I N V E S TI G A T O R; A C O P Y M U S T B E GI V E N 
T O T H E P A R TI CI P A N T; I F Y O U A R E U SI N G E PI C F O R T HI S S T U D Y A C O P Y M U S T B E F A X E D T O 4 1 0 -3 6 7 -7 3 8 2; I F Y O U A R E N O T U SI N G E PI C 
A C O P Y M U S T B E P L A C E D I N T H E P A R TI CI P A N T’ S M E DI C A L R E C O R D ( U N L E S S N O M E DI C A L R E C O R D E XI S T S O R WI L L B E C R E A T E D).  
 
O N L Y C O N S E N T F O R M S T H A T I N C L U D E T H E J O H N S H O P KI N S M E DI CI N E L O G O C A N B E U S E D T O O B T AI N T H E C O N S E N T O F R E S E A R C H 
P A R TI CI P A N T S.  
 
 


 
A p p r o v e d N o v e m b e r  1 3, 2 0 1 7  
D ate: N o ve m ber 1 3 , 2 0 1 7 
Pri nci pal I n vesti gat or: Kell y D u n n, P h. D.  
A p plicati o n N o.: I R B 0 0 0 9 7 9 3 7  
 
Pa ge 1 2  of 1 2  
C o m bi n e d I nf or me d C o nse nt/ A ut h orizati o n J u ne 2 0 1 5 Versi o n 1 5 
 
 
 
D O C U M E N T A TI O N O F P H Y SI CI A N/ MI D -L E V E L P R O VI D E R C O N S E N T  
 
M y si g n at ure bel o w i n dic ates t h at I h a ve disc usse d t he ris ks, be nefits, a n d alter n ati ves, a ns w ere d a n y 
q uesti o ns, a n d belie ve t he p artici p a nt is a ble t o m a ke a n i nf or me d c h oice t o j oi n t he st u d y.  
 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g nat ure of P h ysicia n/ Mi d -Le vel Pr o vi d er                     ( Pri nt Na me)                                                                      
 
Date/ Ti me   
 
 
 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g nat ure of P artici pa nt                                                    ( Pri nt Na me)                                                                     
 
Date/ Ti me     
 
 
 
 
N O T E : A C O P Y O F T H E SI G N E D, D A T E D C O N S E N T F O R M M U S T B E K E P T B Y T H E P RI N CI P A L I N V E S TI G A T O R; A C O P Y M U S T B E GI V E N 
T O T H E P A R TI CI P A N T; I F Y O U A R E U SI N G E PI C F O R T HI S S T U D Y A C O P Y M U S T B E F A X E D T O 4 1 0 -3 6 7 -7 3 8 2; I F Y O U A R E N O T U SI N G E PI C 
A C O P Y M U S T B E P L A C E D I N T H E P A R TI CI P A N T’ S M E DI C A L R E C O R D ( U N L E S S N O M E DI C A L R E C O R D E XI S T S O R WI L L B E C R E A T E D).  
 
 
O N L Y C O N S E N T F O R M S T H A T I N C L U D E T H E J O H N S H O P KI N S M E DI CI N E L O G O C A N B E U S E D T O O B T AI N T H E C O N S E N T O F R E S E A R C H 
P A R TI CI P A N T S.  
 
 
 

Prot_SAP_002.pdf: 
Official Title: Using Cannabinoids to Enhance Opioid 
Analgesic Effects in Humans 
NCT: 02901275 
Document Date: February 12, 2018 


Date: Februaiy 12, 2018 
P1incipal Investigator: Kelly Dunn, Ph.D. 
Application Number: IRB 00097937 
JHM IRB - eForm A - Protocol 
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Use the section headings to write the JHM IRB eFonn A, inserting the appropriate material in each. If
a section is not applicable, leave heading in and insert NIA.
•
When submitting JHM IRB eForm A (new or revised), enter the date submitted to the field at the top
of JHM IRB eForm A.
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l.
Abstract
a.
Provide no more than a one page reseai·ch abstract bdefly stating the problem, the research hypothesis,
and the impo1tance of the research.
This study will systematically evaluate whether cannabinoids can enhance the analgesic efficacy of opioids, which 
will advance the use of cannabinoids for the treatment of acute and/ or chronic pain. Chronic pain affects over 100 
million Amedcans. Opioids ai·e unanimously recognized as the most effective drugs for the relief of pain and 
suffedng, but the US is now suffe1ing from an epidemic of abuse, addiction and accidental deaths resulting from the 
increased sale and use of opioids. There is legitimate value in identifying adjuncts that 1night reduce reliance on 
opioids while maintaining adequate pain relief. Preclinical studies repo1t that co-administedng cannabinoids with 
opioid agonists significantly and reliably reduce the amount of opioids required for analgesia but this hypothesis has 
not been rigorously evaluated in humans. This proposal will evaluate the effect of dronabinol on opioid-induced 
analgesia. The study will emoll 60 healthy adults (30 men/women) to conduct a within-subject, dose-response 
evaluation of cannabinoids on the analgesic effect of hydromorphone (Dilaudid). Subjects will complete 5 
expedmental sessions that will occur at least once weekly and will enable subjects to adinit themselves into a clinical 
reseai·ch unit the night before the session to complete the study session. Subjects will receive a dose of 
hydromo1phone ( 4mg, oral) and a double-blind oral dose of study diug or placebo the morning of each expedmental 
session, and will undergo quantitative senso1y testing (QST; a comprehensive pain testing batte1y), provide self­
rep01t ratings of diug effects, and complete a neurocognitive batte1y. QST testing will comprehensively and 
systematically measure pain sensitivity, and provide info1mation on the full range of analgesic effects possible across 
a wide va1iety of pain measures, including threshold responses (the1mal, pressure), temporal summation, cold 
pressor, conditioned pain modulation, and capsaicin sensitization. Primaiy outcomes will be magnitude and duration 
of pain as a function of study drug dose. Additional p1imaiy aims include proxy measures of abuse liability and 
neurocognitive pe1fo1mance. All measures will be assessed as a function of sex, due to substantial evidence that 
men/women differ with regai·d to pain perception, endogenous cannabinoid receptor density, and opioid response. 
We hypothesize that cannabinoids will shift the analgesic curve ofhydromorphone and enhance analgesia effects. 
This will be the 1st human laborato1y study to evaluate combinations of cannabinoids and opioids using QST, and 
results will identify whether a signal for this medication combination exists that should be advanced into randomized 
controlled tdal evaluations with clinical pain populations. This study will also assess aspects that would impact di11g 
development (abuse liability, neurocognitive impainnent), as well as the effects of sex and cannabinoid type on 
outcomes. Results from this study will help advance the acceptance of cannabinoids from use with only treatment-
JHMIRB eF onnA O 1 
Version 3 Dated: 06/2007 
Page 2 of20 


 
 
J H MI R B e For m A   0 1  
Versi o n 3 Date d:   0 6/ 2 0 0 7   
 
Pa g e 3 of 2 0  
 
refra ct or y pai n c o n diti o ns t o wi des prea d s ocietal use f or cli nical pai n.   
 
2.  
O bjecti ves (i ncl u de all pri mar y a n d sec o n dar y o bjecti ves) 
 
1.  Pri m ar y Ai m 1: E v al u ate t h e m a g nit u d e a n d d u r ati o n of c o m bi n e d d r o n a bi n ol a n d h y d r o m or p h o n e t o 
re d u ce p ai n se nsiti vit y i n a v ali d ate d m o d el of p ai n . W e hy p ot hesize t hat t he a d diti o n of a dr o na bi n ol t o 
h y dr o m or p h o ne will res ult i n a d ose- de pe n de nt i ncrease i n t he ma g nit u de a n d d urati o n of a nal gesia i n 
patie nts u n der g oi n g a vali date d la b orat or y m o del of pai n. 
2.  Pri m ar y Ai m 2: E v al u ate t h e s u bjecti ve res p o nses t o c o m bi n ati o ns of d r o n a bi n ol a n d h y d r o m or p h o n e 
t o d eter mi n e t h e s u bjecti ve, e u p h oric effects of t h e c o m bi n ati o n p r o d u cts. W e h y p ot hesize t hat 
dr o na bi n ol will n ot i ncrease t he s u bjecti ve rati n gs of p ositi ve dr u g effects or ot her pr o x y meas ures of a b use 
liabilit y, relati ve t o h y dr o m or p h o ne al o ne. 
 
3.  Pri m ar y Ai m 3 : E v al u ate t h e d e gree t o w hic h c o m bi ni n g d r o n a bi n ol wit h h y d r o m or p h o n e i m p acts 
n e u r oc o g niti ve p erf or m a n ce . W e h y p ot hesize t hat dr o na bi n ol ma y re d uce ne ur oc o g niti ve perf or ma nce at 
hi g h d oses, relati ve t o h y dr o m or p h o ne al o ne, t h o u g h t he de gree t o w hic h t his ma y occ ur is u n k n o w n. T his 
ai m is critical f or t he a d va nce me nt of p ote ntial o pi oi d/ca n na bi n oi d c o m bi nati o n pr o d ucts.  
 
4.  S ec o n d ar y Ai m 1: E v al u ate w h et h er t h ere are se x differ e n ces o n st u d y o utc o m es. W e h y p ot hesize t hat 
dr o na bi n ol e n ha nce me nt of h y dr o m or p h o ne-a nal gesia will be greater a m o n g fe male vs. male s u bjects.  
 
3.  
B ac k gr o u n d ( briefl y descri be pre-cli nical a n d cli nical data, c urre nt e x perie nce wit h pr oce d ures, dr u g or 
de vice, a n d a n y ot her rele va nt i nf or mati o n t o j ustif y t he researc h). 
 
T his st u d y will s yste maticall y e val uate w het her ca n na bi n oi ds ca n e n ha nce t he a nal gesic efficac y of o pi oi ds, w hic h 
will a d va nce t he use of ca n na bi n oi ds f or t he treat me nt of ac ute a n d/ or c hr o nic pai n. 
 
S c o pe of t he pr o ble m: C hr o nic pai n affects o ver 1 0 0 milli o n A merica ns - m ore t ha n dia betes, heart disease, 
a n d ca ncer c o m bi ne d 1. It e xacts s u bsta ntial s ufferi n g, p h ysical disa bilit y, a n d is i ncre di bl y c ostl y. P ersiste nt pai n 
pr of o u n dl y i m pairs q ualit y of life 2; 3 a n d i ncreases ris k f or me dical4 a n d ps yc hiatric m or bi dit y5. Me dical pr o vi ders 
ha ve a n o bli gati o n t o treat t heir patie nt’s pai n a n d o pi oi ds are u na ni m o usl y rec o g nize d as t he m ost effecti ve dr u gs f or 
t he relief of pai n a n d s ufferi n g6. O pi oi ds are t he 3r d m ost wi del y prescri be d cate g or y of me dicati o n i n t he U S, 
h o we ver wit h i ncreases i n a vaila bilit y we ha ve see n s u bsta ntial i ncreases i n c orres p o n di n g pr o ble ms, m ost n ota bl y 
o pi oi d-relate d o ver d ose deat hs. Acci de ntal p ois o ni n gs are n o w t he lea di n g ca use of acci de ntal deat h i n a d ults a ge d 
2 5- 6 4 7, a n d 7 2 % of o ver d ose deat hs i n v ol ve o pi oi d a nal gesics,8 a hi g her pre vale nce t ha n deat hs fr o m her oi n a n d 
c ocai ne c o m bi ne d 9- 1 1. I m pr o per use of prescri pti o n pai n killers res ults i n a n esti mate d $ 7 2. 5 billi o n a n n uall y i n direct 
healt h care c osts, 1 2 w hic h d oes n ot i ncl u de s ocietal c osts li ke s ocial ser vices, la w e nf orce me nt, a n d l ost pr o d ucti vit y. 
T he p he n o me na ass ociate d wit h hi g h d osi n g, a b use, a n d a d dicti o n c o nti n ues t o c halle n ge t he cli nical c o m m u nit y a n d 
p oses a n i m p orta nt q uesti o n t o t he scie ntific c o m m u nit y – is t here a met h o d t o e n ha nce o pi oi d prescri bi n g 
re q uire me nts w hile mai ntai ni n g a de q uate pai n relief?  
  
P ote ntial t o c o m bi ne ca n na bi n oi ds wit h o pi oi ds f or pai n relief: P o p ulati o n base d st u dies i n fi br o m yal gia, 
art hritis, m usc ular scler osis a n d s pi nal c or d i nj ur y ha ve all descri be d ca n na bis use f or pai n relief 1 3. C urre ntl y, 1 2-
1 5 % of t he p o p ulati o n uses me dici nal ca n na bis a n d t he m ost c o m m o nl y cite d reas o n is f or c hr o nic pai n 1 4. A 
s yste matic re vie w re p orte d t hat > 8 0 % of trials de m o nstrate d a si g nifica nt a nal gesic effect of ca n na bi n oi d relati ve t o 
place b o 1 5 a n d t he e n d oca n na bi n oi d s yste m ( E C S) offers a str o n g mec ha nistic rati o nale f or t he pai n re d uci n g acti o ns 
of ca n na bi n oi ds 1 6. F urt her, t here is n o w s u bsta ntial precli nical e vi de nce i n r o de nts1 1 9 -1 2 2  ( Ci c he wic z, Marti n, S mit h, & 
W el c h, 1 9 9 9; Fi n n et al., 2 0 0 4; S mit h, Cic he wic z, Marti n, & W el c h, 1 9 9 8; W el c h & Ste ve ns, 1 9 9 2; Willi a ms et al., 2 0 0 6)  a n d 
pri mates 1 2 3 -1 2 5 t hat ca n na bi n oi ds a n d o pi oi ds, w he n a d mi nistere d t o get her , are e xtre mel y effecti ve i n re d uci n g pai n, 
wit h u p t o a 2 0-f ol d i ncrease i n efficac y, s u g gesti n g t hat t hese t w o me dicati o ns ma y ha ve a sy ner gistic effect o n p ai n. 
T he C B 1 rece pt or is l ocate d i n re gi o ns of t he peri p heral a n d ce ntral ner v o us s yste m w here pai n si g nali n g is me diate d, 
i ncl u di n g t he d orsal h or n of t he s pi nal c or d, P A G, t hala m us, a n d c ortical re gi o ns ass ociate d wit h ce ntral pai n 
pr ocessi n g, i ncl u di n g t he a nteri or ci n g ulate c orte x, a m y g dala a n d t he prefr o ntal c orte x 1 7. C B 2 rece pt or m o d ulati o n 
als o decreases pr o-i nfla m mat or y me diat ors i n a ma n ner t hat ma y c o ntri b ute t o a nti n ocice pti ve effects a n d i m pr o ve 
e n d o ge n o us ne ur oi nfla m mat or y pr o perties t hat pla y a n i m p orta nt r ole i n pai n perce pti o n 1 8. H o we ver, t he s y ner gistic 
c o m bi nati o n of c o-a d mi nisteri n g ca n na bi n oi ds wit h o pi oi d a g o nists has n ot e ver bee n ri g or o usl y e val uate d i n h u ma n 
s u bjects a n d t he de gree t o w hic h n o n- h u ma n a ni mal res ults will ge neralize t o h u ma n s u bjects is u n k n o w n. T he o nl y 


 
 
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P h ase I st u d y, of w hic h we are a ware, e val uati n g t his c o nce pt re p orte d t hat patie nts w h o recei ve d 1 0- 2 0 m g of 
dr o na bi n ol wit h t heir sta ble a n d n or mall y prescri be d d ose of o pi oi ds e x perie nce d decrease d pai n i nte nsit y a n d 
i ncrease d satisfacti o n relati ve t o place b o1 9. A P hase II st u d y f o u n d t hat titrate d dr o na bi n ol i n c hr o nic pai n patie nts 
recei vi n g a sta ble d ose of o pi oi ds c o nferre d si g nifica nt pai n relief, re d uce d sec o n dar y pr o ble ms ass ociate d wit h pai n, 
a n d i ncrease d rati n gs o n a self-re p ort satisfacti o n scale ( 0- 1 0) c o m pare d t o baseli ne 1 9. 
  
Q S T meas ure me nt of pai n: C hr o nic pai n is c o nce pt ualize d as a disease of t he ner v o us s yste m t hat i n v ol ves 
var yi n g de grees of peri p heral i n p ut a n d d ysre g ulati o n of ce ntral n ocice pti ve m o d ulat or y s yste ms 2 0; 2 1, w hic h are 
fre q ue ntl y assesse d wit h la b orat or y meas ures. D ue t o t he p ote ntial c o nf o u n di n g of disease-s pecific fact ors, s uc h as 
se verit y a n d d urati o n, differe nces i n pai n ma na ge me nt a n d s yste mic i ne q ualities, as well as t he p ote ntial iss ue of 
o pi oi d-i n d uce d h y peral gesia, s yste matic q ua ntitati ve se ns or y testi n g ( Q S T, i n w hic h t he n o xi o us sti m uli are 
ri g or o usl y cali brate d a n d sta n dar dize d) i n healt h y i n di vi d uals is of great val ue t o el uci date se ns or y c haracteristics 2 2 -2 5. 
H u ma n e x peri me ntal pai n m o dels li n k a ni mal a n d cli nical pai n st u dies, a n d has s pecificall y bee n rec o m me n de d f or 
testi n g a nal gesic c o m p o u n ds, a n d n ote d as “i deall y s uite d” i n pr o of- of-c o nce pt a n d d ose fi n di n g st u dies2 6. T hese 
e x peri me ntal desi g ns all o w f or precise c o ntr ol o ver t he nat ure of t he n o xi o us sti m uli a p plie d t o t he ner v o us s yste m 
a n d are cr ucial i n e xa mi ni n g a n d u n dersta n di n g t he u n derl yi n g mec ha nis ms t hat acc o u nt f or p h ysi ol o gical pai n 
se nsiti vit y a n d pai n perce pti o n i n cli nical pai n re p orts. T hat is, p h ysicall y i de ntical sti m uli ca n be a p plie d t o all 
s u bjects, per mitti n g t he st u d y of dr u g effects i n t he e x perie nce of pai n a n d mi ni mizi n g c o nf o u n di n g b y i n di vi d ual 
differe nc es i n t he n o xi o us sti m uli t hat pr o d uce t he pai n e x perie nce. S uc h varia bilit y i n ps yc h o p h ysical pai n res p o nses 
str o n gl y parallels t he varia bilit y i n cli nical pai n i n ma n y sa m ples 2 7 -3 2 (i. e., s u bjects w h o are m ost pai n-se nsiti ve i n t he 
la b orat or y als o re p ort t he m ost i nte nse or fre q ue nt cli nical pai n). T he use of Q S T t o e val uate dr u g effects o n pai n 
res p o nses is well-esta blis he d, se nsiti ve a n d fre q ue ntl y use d i n mec ha nistic st u dies3 3 -3 5. A n u m ber of st u dies ha ve 
s h o w n str o n g cr oss-secti o nal ass ociati o ns bet wee n Q S T a n d cli nical pai n res p o nses i n healt h y 2 9; 3 6 -3 8 a n d c hr o nic pai n 
patie nts 3 9 -4 3. M ore i m p orta ntl y, ma n y st u dies ha ve s h o w n t hat Q S T res p o nses pre dict p ost-s ur gical pai n4 4 -4 8 a n d 
treat me nt o utc o mes4 9; 5 0 as well as c orrelate wit h c ha n ges i n cli nical pai n5 1 -5 4. Q S T is als o pre dicti ve of o pi oi d 
a nal gesia 5 5 -6 0, a n d o pi oi d d ose c o nsiste ntl y c orrelates wit h m ulti ple Q S T meas ures i n c hr o nic pai n patie nts6 1; 6 2. I n 
a d diti o n, basal o pi oi d rece pt or bi n di n g is si g nifica ntl y ass ociate d wit h Q S T 6 3. Ele vate d pai n se nsiti vit y pr ofiles, 
esta blis he d usi n g Q S T, is als o o bser ve d i n c hr o nic pai n patie nts at ris k f or o pi oi d mis use 6 4. I m p orta ntl y, b ot h static 
( meas ures i ncl u di n g t hres h ol d a n d t olera nce) a n d d y na mic ( met h o ds t hat pr o be ce ntral pai n s yste ms) Q S T are 
res p o nsi ve t o t he i nfl ue nces of a nal gesics5 9; 6 5; 6 6 a n d are fre q ue ntl y use d t o deter mi ne a nal gesic efficac y3 5; 6 7. 
H y dr o m or p h o ne, w hic h is i de ntifie d i n t he c urre nt a p plicati o n, s pecificall y pr o d uces p ote nt a n d d ose- de pe n de nt 
a nal gesic effects o n pai n re p orte d d uri n g Q S T 6 8 a n d si g nifica ntl y s u p presses sec o n dar y h y peral gesia a n d ac ute 
t her mal n ocice pti o n6 9. As s h o w n i n o ur preli mi nar y st u dies, we are e x perie nce d i n q ua ntif yi n g o pi oi d effects o n Q S T 
usi n g t hese met h o ds (see Fi g ure 1). W e d o n ot k n o w of a n y st u dies t hat ha ve use d Q S T t o ri g or o usl y e val uate 
ca n na bi n oi d-i n d uce d a nal gesia. 
C o ncl usi o n: T his will be t he 1 st h u ma n la b orat or y st u d y t o e val uate c o m bi nati o ns of ca n na bi n oi ds a n d 
o pi oi ds o n a c o m pre he nsi ve a n d vali date d q ua ntitati ve se ns or y testi n g batter y, a n d t he res ults of t his st u d y will 
i de ntif y w het her a si g nal f or t his me dicati o n c o m bi nati o n e xists t hat s h o ul d be a d va nce d i nt o ra n d o mize d c o ntr olle d 
trial e val uati o ns wit h cli nical pai n p o p ulati o ns. T his st u d y will als o assess as pects t hat w o ul d i m pact dr u g 
de vel o p me nt (a b use lia bilit y, ne ur oc o g niti ve i m pair me nt) a n d t he effect of partici pa nt se x o n o utc o mes. T he ulti mate 
g oal of t his researc h will be t o deter mi ne w hic h me dicati o n/ d ose c o m bi nati o ns ma y e xert str o n g a nal gesic effects, 
w hile mi ni mizi n g a b use lia bilit y a n d c o g niti ve deficits, i n or der t o a d va nce t hese me dicati o ns i nt o cli nical trials f or 
t he treat me nt of c hr o nic pai n.  T his is a l o gical first ste p t o war ds e val uati n g c o m bi ne d ca n na bi n oi d/ o pi oi ds 
treat me nts f or c hr o nic pai n, a n d will pr o vi de data necessar y t o s u p p ort n u mer o us e val uati o ns of c o m bi nati o n 
treat me nts f or t his p o p ulati o n. 
 
4.  
St u d y Pr oce d u res  
a.  St u d y desi g n, i ncl u di n g t he se q ue nce a n d ti mi n g of st u d y pr oce d ures   
( disti n g uis h researc h pr oce d ures fr o m t h ose t hat are part of r o uti ne care). 
 
Pr oject O ver vie w: T his st u d y will e nr oll 1 0 0 healt h y a d ults, a n d will ai m t o c o m plete 6 0 ( 3 0 me n, 3 0 w o me n) 
partici pa nts. P artici pa nts will c o n d uct a wit hi n-s u bject e val uati o n of t he de gree t o w hic h t he F D A-a p pr o ve d 
ca n na bi n oi d dr o na bi n ol ( Mari n ol) e n ha nces t he a nal gesic effect of t he pr ot ot y pic o pi oi d h y dr o m or p h o ne ( Dila u di d). 
S u bjects will c o m plete a S cree ni n g visit t o esta blis h st u d y eli gi bilit y a n d 5 e x peri me ntal sessi o ns. E x peri me ntal 
sessi o ns will occ ur a p pr o xi matel y o nce wee kl y a n d will per mit s u bjects t o a d mit t he msel ves i nt o t he cli nical researc h 
u nit t he ni g ht bef ore t he sessi o n if i ntereste d. S u bjects will be pr o vi de d wit h ta xi ser vice t o a n d fr o m t he sessi o n. 
S u bjects will recei ve a d ose of h y dr o m or p h o ne ( 4 m g , oral ) a n d a d o u ble- bli n d oral d ose of st u d y dr u g or place b o t he 


 
 
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m or ni n g of eac h e x peri me ntal sessi o n, a n d will u n der g o Q S T  meas ures of la b orat or y e v o ke d pai n, pr o vi de self-re p ort 
rati n gs of dr u g effects, a n d c o m plete a ne ur oc o g niti ve batter y. T he or der of sessi o ns will be ra n d o mize d wit h t he 
e xce pti o n of S essi o n 1, w hic h will al wa ys be acti ve h y dr o m or p h o ne + place b o t o e ns ure t he partici pa nt has a safe 
res p o nse t o h y dr o m or p h o ne bef ore pr ocee di n g i nt o t he re mai ni n g sessi o ns.  
 
S u bject Recr uit me nt: S u bjects will be recr uite d fr o m t he greater B alti m ore area usi n g esta blis he d recr uiti n g res o urces 
a n d me dia a d vertisi n g, i ncl u di n g ne ws pa per, ra di o, a n d we bsite listi n gs. W e als o ha ve a n e xte nsi ve list of p ote ntial 
st u d y v ol u nteers w h o ha ve gi ve n per missi o n t o call t he m re gar di n g p ote ntial st u d y partici pati o n. All i ntereste d 
i n di vi d uals will first c o m plete a p h o ne scree n t o esta blis h i nitial st u d y eli gi bilit y a n d i n di vi d uals w h o pass will be 
i n vite d f or a n i n- pers o n scree ni n g d uri n g w hic h fi nal st u d y eli gi bilit y will be deter mi ne d.   
 
S cree ni n g Visit: S u bjects will c o m plete a brief p h o ne scree n t o deter mi ne i nitial eli gi bilit y a n d will be i n vite d t o 
c o m plete a n i n-cli nic scree n. S u bjects will re vie w a n d si g n a n i nf or me d c o nse nt d oc u me nt wit h a st u d y staff me m ber 
t o be gi n t he S cree ni n g visit. S u bjects will pr o vi de a uri ne sa m ple t hat m ust test ne gati ve f or illicit dr u gs a n d 
pre g na nc y (f or fe males), a n d will t he n c o m plete a batter y of meas ures t o esta blis h st u d y eli gi bilit y. Me dical 
eli gi bilit y will be deter mi ne d b y me dical staff a n d will c o nsist of a n E C G, a bl o o d sa m ple t o a nal yze he patic, 
he mat ol o gic, a n d c he mistr y f u ncti o ni n g, a n d a me dical hist or y a n d p h ysical, w hic h will occ ur pri or t o a n y dr u g 
a d mi nistrati o n.  
 
E x peri me ntal S essi o ns: U p o n fi nal eli gi bilit y c o nfir mati o n, s u bjects will c o m plete 5 e x peri me ntal st u d y sessi o ns. 
T he sessi o ns will be c o n d ucte d o n a cl ose d researc h u nit a n d s u bjects will be per mitte d t o sta y t he ni g ht bef ore t he 
sessi o n o n a cli nical researc h u nit. W e ha ve c h ose n t o n ot c o n d uct t he e ntire st u d y usi n g a c o nti n u o us i n patie nt 
desi g n beca use we wa nt t o i m p ose a mi ni m u m 7- da y was h- o ut peri o d bet wee n o pi oi d e x p os ures s o t hat a n y ac ute 
t olera nce t hat ma y ha ve de vel o pe d t o t he h y dr o m or p h o ne d ose has ti me t o dissi pate a n d s o t hat dr o na bi n ol, w hic h 
has a n eli mi nati o n half life of 1 9- 3 6 h o urs , has s ufficie nt ti me t o be e xcrete d bet wee n dr u g a d mi nistrati o ns.  
  
S u bjects ma y eit her arri ve at t he B P R U i n t he earl y e ve ni n g pri or t o a n e x peri me ntal sessi o n or t he m or ni n g 
of t he sessi o n. T he y will be re q uire d t o pr o vi de a uri ne sa m ple t hat tests ne gati ve f or illicit dr u gs a n d pre g na nc y pri or 
t o a d missi o n. Fe male s u bjects will be as ke d t o pr o vi de a bl o o d sa m ple t hat will be teste d f or pr o gester o ne, w hic h will 
ser ve as a n i n de x of me nstr ual c ycle stat us. Pr o gester o ne a nal ysis is a ri g or o us met h o d f or assessi n g h or m o nal c ycle 
t hat will e na ble us t o statisticall y c o ntr ol f or t he i nfl ue nce of h or m o ne stat us o n Q S T a n d res p o nse t o me dicati o ns. 
S u bjects will t he n be a d mitte d t o t he researc h u nit. 
T he m or ni n g of eac h e x peri me ntal sessi o n, t he s u bject will recei ve a cal orie-c o ntr olle d brea kfast eac h 
m or ni n g. F oll o wi n g brea kfast, s u bjects will c o m plete a baseli ne rati n g of Q S T a n d self-re p ort meas ures (fr o m w hic h 
all s u bse q ue nt rati n gs will be c o m pare d f or data a nal ysis p ur p oses). A n oral ca ps ule c o ntai ni n g eit her st u d y dr u g or 
place b o will t he n be a d mi nistere d a n d h y dr o m or p h o ne ( 4 m g oral i n f o ur sessi o ns a n d a place b o oral d ose i n o ne 
sessi o n) will be a d mi nistere d. T he ti me of dr u g a d mi nistrati o n will be selecte d t o e na ble b ot h dr o na bi n ol a n d 
h y dr o m or p h o ne t o e xert pea k effects at t he sa me ti me. S u bjects will c o m plete Q S T (see bel o w) a n d self-re p ort 
meas ures at re g ular i nter vals f oll o wi n g st u d y dr u g a d mi nistrati o n. S elf-re p ort meas ures will i ncl u de s pecific o pi oi d 
a g o nist a n d a nta g o nist effects, t o assess w het her ca n na bi n oi ds are e xerti n g a n effect o n a partic ular cate g or y of 
o pi oi d a g o nist s y m pt o m, a n d will ca pt ure w het her a n y ne gati ve effects (e. g., na usea) occ ur as a f u ncti o n of t he 
ca n na bi n oi d d ose. Fre q ue nt c ollecti o n will e na ble e val uati o n of ti me t o pea k dr u g effects, d urati o n of effects, a n d 
ge neral ti me c o urse of effects a n d is a wi del y use d a n d acce pte d a p pr oa c h i n la b orat or y st u dies of dr u g effects. 
D uri n g t he fi nal assess me nt eac h da y, s u bjects will c o m plete a Dr u g vs. M o ne y Q uesti o n naire t o i n dicate t he d ollar 
val ue t he y w o ul d place u p o n t he dr u gs recei ve d 9 8. T his is a well-acce pte d pr o x y meas ure of a b use lia bilit y. St u d y 
staff will d oc u me nt a d verse e ve nts t hr o u g h o ut t he st u d y a n d a n y s u bject w h o e x perie nces a str o n gl y u n pleasa nt effect 
of t he me dicati o ns will be a ble t o e n d partici pati o n. A n y s u bject w h o is e x perie nci n g str o n g a g o nist effects at t he e n d 
of t he sessi o n will be pr o vi de d o ver ni g ht acc o m m o dati o n i n t he C R U; base d o n o ur e x perie nce we e x pect t his t o be 
mi ni mal a n d are b u d geti n g f or 1 0 % of sessi o ns t o ha ve a 2
n d ni g ht. 
 
Q ua ntitati ve S e ns or y Testi n g ( Q S T) Meas ures of La b orat or y E v o ke d P ai n : S u bjects will c o m plete a state- of-t he-art 
q ua ntitati ve se ns or y testi n g ( Q S T) batter y, w hic h will c o m pre he nsi vel y a n d s yste maticall y meas ure pai n se nsiti vit y. 
T his a p pr oac h will pr o vi de i nf or mati o n re gar di n g t he f ull ra n ge of a nal gesic effects p ossi ble, acr oss a wi de variet y of 
ps yc h o- p h ysi ol o gicall y- me diate d, e x peri me ntall y-i n d uce d meas ures of pai n perce pti o n. S u bjects will c o m plete a 
baseli ne Q S T sessi o n pri or t o st u d y dr u g a d mi nistrati o n o n eac h e x peri me ntal sessi o n da y, a n d will c o m plete t he pai n 
testin g batter y at re g ular i nter vals d uri n g t he e x peri me ntal sessi o n da y. Eac h a d mi nistrati o n of t he Q S T batter y will 
ta ke 2 0- 3 0 mi n utes. T he Q S T batter y will c o nsist of t hres h ol d a n d t olera nce, te m p oral s u m mati o n, a n d c o n diti o ne d 


 
 
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pai n m o d ulati o n ( C P M) tests. T he t hres h ol d res p o nses will be c o n d ucte d i n ra n d o mize d a n d c o u nter- bala nce d or der, 
a n d c o n diti o ne d pai n m o d ulati o n will al wa ys occ ur last. 
  
 T hres h ol d Res p o nses  will be assesse d usi n g t her mal a n d press ure sti m ulati o n. T her m al t hres h ol d:  All 
c o ntact heat sti m uli will be deli vere d usi n g a peltier-ele me nt- base d sti m ulat or ( Me d oc, Israel). T w o trials of heat pai n 
t hres h ol d will be a d mi nistere d usi n g a n asce n di n g met h o d of li mits para di g m. T he t her m o de will gra d uall y i ncrease 
i n te m perat ure (rate of rise = . 5oC/ sec) fr o m a pre-set baseli ne ( 3 1 oC), u ntil t he s u bject i n dicates w he n t he sti m ul us 
“first feels pai nf ul” (t hres h ol d, H P T h) a n d presses a b utt o n ( w hic h ter mi nates t he pr oce d ure) i n dicati n g t hat t he pai n 
is i nt olera ble (t olera nce, H P T o). Press ure t hres h ol d : A press ure al g o meter will be utilize d t o assess res p o nses t o 
press ure sti m ulati o n at a variet y of a nat o mical sites i n a ra n d o ml y deter mi ne d or der . T he press ure al g o meter 
( S o me dic; S we de n) uses a r u b ber pr o be c o vere d wit h 1 m m p ol y pr o p yle ne material; press ure at t he site is gra d uall y 
i ncrease d at a stea d y rate. S u bjects i n dicate w he n t he sti m ul us is first percei ve d as pai nf ul, w hic h ter mi nates t he 
a p plicati o n. T he al g o meter pr o d uces a se nsati o n of l ocalize d press ure; tec h nicia ns will place t he pr o be of t he 
alg o meter i n t he ce nter of eac h m uscle gr o u p or a nat o mic site w he n deli veri n g t he mec ha nical sti m uli. T hirt y-sec o n d 
i nter-sti m ul us i nter vals will be mai ntai ne d f or all sti m uli. Eac h trial will be a vera ge d t o get her t o res ult i n o ne H P T h, 
H P T o, a n d P P T h meas ur e. 
T e m p or al S u m m ati o n ( T S) of P ai n  will be assesse d i n 2 wa ys, usi n g re petiti ve t her mal sti m uli a n d re petiti ve 
p u nct uate sti m uli. S e q ue nces of 1 0 heat p ulses will be a p plie d usi n g t he Me d oc. ( N ote: wit hi n eac h 1 0- p ulse 
se q ue nce, t he te m perat ure of eac h p hasic sti m ul us is t he sa me). Wit hi n eac h se q ue nce, s uccessi ve t her mal p ulses at a 
gi ve n te m perat ure will be deli vere d f or a d urati o n of a p pr o xi matel y 0. 5 sec eac h, wit h a n a p pr o xi matel y 2. 5- sec 
i nter- p ulse i nter val. S u bjects will ver ball y rate t he percei ve d i nte nsit y of eac h t her mal p ulse o n a 0- 1 0 0 rati n g scale 
a n d ma y ter mi nate t he pr oce d ure at a n y ti me. Wi n d u p is meas ure d as t he differe nces bet wee n t he hi g hest rate d 
t her mal sti m ul us a n d t he 1st t her mal sti m ul us.9 9  
Mec h a nic al T e m p or al S u m m ati o n  will be st u die d usi n g p u nctate sti m ulat ors (a set of wei g hte d pi n pric k 
sti m ulat ors wit h fi xe d sti m ul us i nte nsities (flat c o ntact area of 0. 2 m m dia meter) t hat e xert f orces of 8- 5 1 2 m N). T he 
pr o bes are a p plie d per pe n dic ular t o t he s ki n. W e will a p pl y b ot h si n gle sti m uli a n d 1 0-sti m ul us trai ns at 1 H Z, a n d 
will rec or d t he s u bjects pai n rati n g ( 0- 1 0 0). Si n gle pi n pric k sti m uli are alter nate d wit h t he trai ns of 1 0 sti m uli. T he 
mea n pai n rati n g of 1 0-sti m ul us trai ns di vi de d b y t he mea n pai n rati n g t o si n gle sti m uli is t he n calc ulate d as a 
rati o.1 0 0  
C ol d Press or T esti n g a n d C P M:  A series of pr oce d ures desi g ne d t o elicit a n d meas ure e n d o ge n o us i n hi biti o n 
of pai n will be a p plie d. I n t he prese nt pr ot oc ol, s u bjects will u n der g o a series of c ol d press or tas ks (i. e., t he 
c o n diti o ni n g sti m uli) c o nsisti n g of i m mersi o n of t he ha n d f or u p t o 1 mi n ute i n a circ ulati n g c ol d water bat h. D uri n g 
ha n d i m mersi o n, press ure res p o nses or te m p oral s u m mati o n will be re-assesse d w hile s u bjects’ ha n ds re mai n i n t he 
c ol d water. S u bjects ma y re m o ve t heir ha n d at a n y ti me. T w o mi n utes after fi nis hi n g t he first i m mersi o n, s u bjects 
will re -i m merse t heir ha n d i n t he water, a n d o ne of t hese tests will be re-assesse d, eac h se parate d b y 2 mi n a n d 
i de ntical t o t he first 2 trials (t he tests will be c o n d ucte d i n ra n d o m or der). A C P M I n de x is q ua ntifie d as t he a vera ge 
perce nt c ha n ge (acr oss trials) i n P P T h or T S d uri n g t he c ol d press or tas ks relati ve t o baseli ne rati n gs [( P P T h or T S 
d uri n g c ol d press or/ P P T h or T S pri or t o c ol d press or) * 1 0 0. 1 0 1 O ne fi nal c ol d-water i m mersi o n will be perf or me d at 
t he c o ncl usi o n of t he C P M pr oce d ures. T his will i n v ol ve a t y pical c ol d press or tas k, usi n g i m mersi o n of t he ha n d 
u ntil t he s u bject’s t olera nce is reac he d, wit h a 5- mi n ute u ni nf or me d ti me li mit. 
C a ps aici n : C a psaici n se nsitizati o n pr oce d ures si milar t o well esta blis he d pr ot oc ols de vel o pe d b y P eters o n 
a n d c ollea g ues will be utilze d 7 0. Heat will be deli vere d usi n g, a c o m p uter dri ve n, peltier de vice, heati n g ele me nt 
( Me d oc T S A II). T he pr oce d ure i n v ol ves a 3 5 mi n ute se nsitizati o n peri o d (c o n d ucte d d uri n g t he baseli ne peri o d) 
wit h a 1. 2 5i nc h 2 treat me nt site o n t he n o n- d o mi na nt, ve ntral  f orear m. T he t her m o de will be heate d t o 4 5° C f or 5 
mi n utes a n d pai n rati n gs will be c ollecte d e ver y o ne mi n ute o n t he 0- 1 0 0 rati n g scale. A n o pe n s q uare raise d 
a d hesi ve fra me (i nter nal di me nsi o ns sa me as t her m o de, t o re d uce lea ka ge be y o n d t he site) will t he n be a p plie d a n d 
ca psaici n crea m ( 1 0 %) 7 1 will be s prea d o nt o t he s ki n a n d per mitte d t o a bs or b f or 3 0 mi n utes. T his i n d uces mil d-
m o derate ( 4 8. 2 5 + 2 7. 9 3), b ut well t olerate d pai n. C a psaici n is t he n re m o ve d a n d t he heat pai n t hres h ol d a n d 
mec ha nical te m p oral s u m mati o n ( descri be d a b o ve) will be c o n d ucte d a gai n i n t he area. T he treate d s ki n will be re-
ki n dle d f or eac h of t he a d diti o nal Q S T sessi o ns eac h sessi o n b y heati n g t he treat me nt site wit h t he t her m o de at 4 0° C 
f or 5 mi n. F oll o wi n g eac h re ki n dli n g e pis o de, heat pai n t hres h ol d a n d mec ha nical te m p oral s u m mati o n as well as 
meas ure me nt of sec o n dar y h y peral gesia will be c o n d ucte d. T he area of sec o n dar y h y peral gesia will be q ua ntifie d 
wit h a v o n Fre y hair b y sti m ulati n g al o n g ei g ht li near pat hs ar o u n d t he treate d site. Sti m ulati o n starts well o utsi de t he 
h y peral gesic area, a n d c o nti n ues t o war ds t he treate d s ki n area u ntil t he s u bject re p orts a c ha n ge i n se nsati o n. T he 
b or der is mar ke d o n t he s ki n wit h a pe n a n d trace d t o acetate pa per, w hic h is s u bse q ue ntl y meas ure d. St u dies ha ve 
de m o nstrate d e xcelle nt test-retest sta bilit y i n 2 o h y peral gesia meas ure me nts o ver re ki n dli n gs 7 2; 7 3; 7 3 a n d t he pr oce d ure 


 
 
J H MI R B e For m A   0 1  
Versi o n 3 Date d:   0 6/ 2 0 0 7   
 
Pa g e 7 of 2 0  
 
is i deal f or i ncl u di n g i n para di g ms wit h re peate d testi n g as t he re ki n dli n gs all o w f or ra pi d e val uati o n of ca psaici n 
se nsitizati o n ( w hic h t y picall y necessitates at least 3 0 mi n eac h).  
 
A d diti o nal St u d y Meas ures: St u d y meas ures c o m prise b ot h p har mac ol o gicall y a n d q ualitati vel y n o ns pecific 
meas ures (e. g., a n y dr u g effect) a n d q ualitati vel y s pecific meas ures (e. g., li ki n g, g o o d effects, ba d effects), t hat are 
c o nsi dere d t he g ol d sta n dar d met h o d b y c o nse ns us pa nels a n d t he F D A f or detecti n g dr u g effects  ( C o mer et al., 2 0 1 2).  
W e will als o c o n d uct c o m pre he nsi ve ne ur oc o g niti ve testi n g, usi n g a sta n dar d batter y t hat is re g ularl y use d b y o ur 
gr o u p at B P R U i n st u dies assessi n g b ot h o pi oi d a n d ca n na bi n oi d effects.  
 
St u d y Meas ures t o Esta blis h Eli gi bilit y a n d C haracteriz e S a m ple: 
•  
B P R U De m o gra p hic Q uesti o n naire: A q uesti o n naire desi g ne d b y us t o d oc u me nt sta n dar dize d de m o gra p hic 
ite ms (e. g., a ge, ge n der, marital stat us). 
•  
Alc o h ol/ Dr u g s u bscale of t he A d dicti o n S e verit y I n de x: A 3 1- q uesti o n s u bscale t o assess past 3 0 da y a n d life-
ti me use of dr u gs, hist or y of treat me nt, a n d i nterest i n treat me nt. S u bscales pr o vi de a meas ure of se verit y. 
•  
MI NI I nter nati o nal Ne ur o ps yc hiatric I nstr u me nt: A sta n dar dize d se mi-str uct ure d dia g n ostic i nter vie w assesses 
partici pa nts f or e vi de nce of ps yc hiatric dis or ders. T he MI NI will be use d t o verif y t hat partici pa nts d o n ot meet 
D S M - 5 de pe n de nce o n alc o h ol a n d/ or dr u gs. 
•  
Brief P ai n I n ve nt or y ( B PI) : A 9 -ite m wi del y- use d, sta n dar dize d, self-re p ort meas ure t o c haracterize t he prese n ce 
a n d se verit y of pai n, as well as t he i nterfere nce of pai n i n e ver y- da y acti vities. T he B PI has bee n m o difie d t o be 
a p pr o priate f or self-a d mi nistrati o n.  
•  
Fa gerstr ö m Test f or Nic oti ne De pe n de nce ( F T N D):  A 6-ite m meas ure t o deter mi ne prese nce of s m o ki n g a n d 
se verit y of nic oti ne de pe n de nce. 
•  
Bec k De pressi o n I n ve nt or y ( B DI): T he B DI- II is a 2 1-i te m self-re p ort meas ure of de pressi ve s y m pt o ms. 
•  
Bec k A n xiet y I n ve nt or y ( B AI): T he B AI is a 1 4- self-re p ort meas ure of a n xiet y s y m pt o ms. 
•  
Barratt I m p ulsi ve ness S cale: A 3 0-ite m, wi del y use d meas ure of i m p ulsi vit y t hat will pr o vi de a self-re p ort 
c o m paris o n t o t he dela y- disc o u nti n g test of i m p ulsi vit y.  
•  
T he P ositi ve a n d Ne gati ve Effect S cale ( P A N A S) : A 2 0 -ite m self-re p ort meas ure t o c haracterize p ositi ve a n d 
ne gati ve e m oti o nal res p o nses t o pai n.  
•  
P ai n Catastr o p hizi n g S cale ( P C S): A 1 4- ite m self-re p ort meas ure t o c haracteriz e t he e m oti o nal res p o nse t o pai n, 
wi t h partic ular e m p hasis o n a n xiet y a n d/ or fear of pai n. 
•  
P R O MI S Gl o bal Healt h S cale: A 1 0 ite m-self re p ort meas ure of q ualit y of life.  
•  
Distress T olera nce S cale: A 1 5- ite m self-re p ort meas ure of t olera nce t o distressi n g sit uati o ns. 
•  
Disc o mf ort I nt olera nce S ca le: A 7 -ite m self-re p ort meas ure of t olera nce t o distressi n g sit uati o ns.  
 
S essi o n Meas ures: 
•  
Cli nical O piate Wit h dra wal S cale: A wi del y use d, 1 1-ite m o bser ver-rati n g of o pi oi d wit h dra wal s y m pt o ms. 
•  
Vital Si g ns: W e will assess bl o o d press ure, p ulse, res pirati o n, a n d o x y ge n sat urati o n.  
•  
P u pillar y Dia meter: P u pil size will be assesse d usi n g a n electr o nic Ne ur o ptics P u pil o meter 
•  
Vis ual A nal o g R ati n g S cales: P artici pa nts will rate t he s u bjecti ve re p orts of dr u g effect s ite ms o n a scale of 0 
( n o ne at all) t o 1 0 0 (str o n gest p ossi ble), i ncl u di n g ite ms s uc h as g o o d effects, ba d effects, hi g h, wit h dra wal, sic k, 
li ke h o w I feel, na usea, se dati o n, feel slee p y. 
•  
O pi oi d A g o nist/ A nta g o nist R ati n g S cale: T his q uesti o n naire assesses p ositi ve a n d ne gati ve effects of o pi oi ds. 
•  
Dr u g vs. M o ne y Q uesti o n naire: T his q uesti o n naire is a fre q ue ntl y use d meas ure t o assess relati ve m o netar y val ue 
of a dr u g a n d is bei n g use d t o assess relati ve rei nf orci n g effects of t he dr u g c o m pare d t o h y p ot hetical m o netar y 
val ues. 
 
C o m p uter- base d C o g niti ve Tests: 
•  
Di vi de d Atte nti o n Tas k ( D A T): P artici pa nts si m ulta ne o usl y perf or m t w o differe nt si m ple tas ks base d o n vis ual 
sti m uli prese nte d o n a c o m p uter scree n. T his tas k is c o m p uter base d.  
•  
Di git S y m b ol S u bstit uti o n Tas k ( D S S T):  P artici pa nts m ust ha n d t y pe patter ns prese nte d t o t he m o n a c o m p uter 
scree n f or 9 0 sec o n ds 
•  
P ace d A u dit or y S erial A d diti o n Tas k ( P A S A T): P artici pa nts are pr o vi de d a stri n g of si n gle di git n u m bers o n t he 
c o m p uter a n d m ust a d d t he t otal of t he pri or t o i nte gers prese nte d a n d res p o n d b y selecti n g t he a ns wer usi n g t he 
c o m p uter m o use o n t he scree n.   
 


 
 
J H MI R B e For m A   0 1  
Versi o n 3 Date d:   0 6/ 2 0 0 7   
 
Pa g e 8 of 2 0  
 
P artici pa nts will als o be as ke d t o pr o vi de a n o pti o nal bl o o d sa m ple t hat will be ba n ke d wit h t he Ge netic R es o urces 
C ore Facilit y. S a m ples will be a nal yze d at a later date a n d g o ver ne d b y a se parate h y p ot hesis- dri ve n I R B pr ot oc ol. 
Ge netic sa m ple c ollecti o n will be o pti o nal a n d will n ot i m pact pri mar y st u d y eli gi bilit y.  
 
O pti o n al H air A n al ysis S u bst u d y:  P artici pa nts will be as ke d w het her t he y w o ul d li ke t o partici pate i n a hair 
sa m pli n g s u bst u d y. T he st u d y will be c o nsi dere d o pti o nal t o pre ve nt disi nterest i n hair sa m pli n g fr o m ne gati vel y 
i m pacti n g recr uit me nt f or t he pri mar y st u d y.  T he rati o nale f or t his s u bst u d y is t hat hair a nal yses are e mer gi n g as a n 
i m p orta nt met h o d f or detecti n g dr u gs use. T his st u d y ca n c o ntri b ute val ua ble i nf or mati o n t o eff orts t o refi ne hair 
a nal yses beca use it a d mi nisters dr u gs t hat ha ve k n o w n a b use p ote ntial i n a c o ntr olle d ma n ner a n d at k n o w n a n d 
u nif or m d ose le vels. T he st u d y PI has bee n as ke d b y a NI D A Pr o gra m Officer t o c ollect hair sa m ples fr o m willi n g 
partici pa nts t o be a nal yze d b y t he Ne ur o pr ote o mics a n d Ne ur o meta b ol o mics C e nter at N ort h wester n U ni versit y. 
S a m ples will be use d t o i m pr o ve Mal di S a m pli n g Tec h ni q ues, t o deter mi ne t he de gree t o w hic h acc urate 
i de ntificati o n a n d q ua ntificati o n of le vels of o pi oi d a n d ca n na bi n oi d e x p os ure i n hair sa m ples fr o m i n di vi d uals w h o 
are bi ol o gicall y c o nfir me d t o ha ve n o e xtra-st u d y dr u g use is p ossi ble. P artici pa nts w h o are e nr olle d i n t he pare nt 
st u d y will be as ke d a b o ut i nterest i n t his s u bst u d y a n d c o nse nte d i nt o t he s u bst u d y via a n oral c o nse nt pr oce d ure. T he 
s u bst u d y will c ollect a hair sa m ple at t he be gi n ni n g a n d e n d of t he 6-wee k  partici pati o n peri o d. S a m ples will be 
c ollecte d via t he c o m merciall y a vaila ble Hair Test C ollecti o n Kit fr o m T hera pa k a n d c o de d b y partici pa nt I D 
n u m bers s o t hat n o P HI will be s hare d wit h t he C e nter. S a m ples will be se nt a n n uall y t o t he C e nter f or a nal ys es.  
 
b.  St u d y d urati o n a n d n u m ber of st u d y visits re q uire d of researc h partici pa nt s. 
 
P artici pa nts will c o m plete a S cree ni n g visit a n d 5 e x peri me ntal sessi o n visits. T h o u g h sessi o ns are e x pecte d t o occ ur 
o nce wee kl y (f or 5 wee ks) partici pa nts will be a ble t o e xte n d sessi o ns t o greater t ha n o nce per wee k if necessar y, t o 
acc o m m o date p ote ntial sc he d uli n g barriers. 
 
c.  Bli n di n g, i ncl u di n g j ustificati o n f or bli n di n g or n ot bli n di n g t he trial, if a p plica ble. 
 
P artici pa nts a n d staff will be bli n de d t o t he d oses of st u d y me dicati o ns bei n g a d mi nistere d at eac h st u d y visit.  T his 
will all o w a ri g or o us test of t he st u d y h y p ot heses b y n ot biasi n g partici pa nts or staff t o war ds differe ntial pai n rati n gs. 
 
d.  J ustificati o n of w h y partici pa nts will n ot recei ve r o uti ne care or will ha ve c urre nt t hera p y st o p pe d. 
N/ A  
 
e.  J ustificati o n f or i ncl usi o n of a place b o or n o n-treat me nt gr o u p. 
 
W e ha ve i ncl u de d place b o c o ntr ol c o n diti o ns f or eac h st u d y dr u g, t o assist wit h i nter pretati o n of t he st u d y res ults. 
Si nce t his st u d y will recr uit healt h y i n di vi d uals a n d we will n ot be re m o vi n g access t o a k n o w n treat me nt, we belie ve 
t hat i ncl usi o n of t he place b o c o n diti o ns p oses l o w ris k t o partici pa nts.  
 
f. Defi niti o n of treat me nt fail ure or partici pa nt re m o val criteria. 
 
P artici pa nts will be re m o ve d fr o m t he st u d y if t he y re m o ve t heir c o nse nt t o partici pate, bec o me pre g na nt, ref use t o 
a d here t o t he st u d y sessi o n sc he d ule, or if it bec o mes clear t hat t heir c o nti n ue d partici pati o n c o ul d p ut t he m at 
i ncrease d ris k (e. g., de vel o p a c hr o nic pai n c o n diti o n t hat re q uires treat me nt, o nset of a me dical/ ps yc hiatric dis or der). 
T hese decisi o ns will be ma de i n c o nj u ncti o n wit h t he B P R U me dical tea m. 
 
g.  Descri pti o n of w hat ha p pe ns t o partici pa nt s recei vi n g t hera p y w he n st u d y e n ds or if a partici pa nt ’s 
partici pati o n i n t he st u d y e n ds pre mat urel y. 
N/ A  
 
5.  
I n cl usi o n/ E xcl usi o n Criteri a 
 
I ncl usi o n Criteria:  
•  
A ge d 1 8- 7 5 
•  
Uri ne sa m ple tests ne gati ve f or c o m m o n illicit s u bsta nces of a b use, i ncl u di n g ca n na bis 
•  
Me dicall y cleare d t o ta ke st u d y me dicati o ns 


 
 
J H MI R B e For m A   0 1  
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Pa g e 9 of 2 0  
 
•  
Are n ot pre g na nt or breast fee di n g 
•  
Willi n g t o c o m pl y wit h t he st u d y pr ot oc ol.  
 
E xcl usi o n Criteria :  
•  
Meet D S M - 5 criteria f or alc o h ol/s u bsta nce use dis or der 
•  
Ta ki n g o pi oi ds f or pai n 
•  
Pre vi o us a d verse reacti o n t o a ca n na bi n oi d pr o d uct 
•  
Prescri be d a n d ta ki n g sti m ula nts or be nz o diaze pi nes 
•  
A ns wer “ yes” t o ite m 1 of t he Brief P ai n I n ve nt or y i n dicati n g c hr o nic pai n 
•  
S elf -re p ort a n y illicit dr u g use i n t he past 7 da ys 
•  
Prese nce of a n y cli nicall y si g nifica nt me dical/ ps yc hiatric ill ness j u d ge d b y t he i n vesti gat ors t o p ut s u bject at 
ele vate d ris k f or e x perie nci n g a n a d verse e ve nt 
•  
Hist or y of seiz ure dis or der 
•  
Ha ve a k n o w n aller g y t o t he st u d y me dicati o ns or sesa me see d oil 
•  
Ta ki n g me dicati o ns c o ntrai n dicate d wit h h y dr o m or p h o ne or dr o na bi n ol 
•  
Ha ve a hist or y of cli nicall y si g nifica nt car diac arr h yt h mias or vas o pastic disease 
•  
Ha ve a n a b n or mal a n d cli nicall y-si g nifica nt E C G 
•  
Fail ure t o discri mi nate bet wee n h y dr o m or p h o ne a n d place b o i n t he S cree ni n g 2/ Q ualif yi n g sessi o n.  
 
6.  
Dr u gs/ S u bst a n ces/ De vices 
a.  T he rati o nale f or c h o osi n g t he dr u g a n d d ose or f or c h o osi n g t he de vice t o be use d. 
 
St u d y Dr u gs: H y dr o m or p h o ne a n d dr o na bi n ol will be o ver-e nc a ps ulate d b y o ur researc h p har mac y a n d a d mi nistere d 
orall y .  
 
Hy dr o m or p h o ne ( Di al u di d) is a p ote nt m u- o pi oi d a g o nist t hat we ha ve 
e xte nsi ve e x perie nce a d mi nisteri n g i n c o ntr olle d la b orat or y setti n gs. 
H y dr o m or p h o ne is n ot s u bject t o differe nces i n C Y P meta b olic e nz y mes (i n 
c o ntrast t o ot her o pi oi ds s uc h as o x yc o d o ne) a n d t heref ore will n ot re q uire us 
t o scree n o ut i n di vi d uals wit h rece nt e x p os ure t o C Y P i n hi bit ors/i n d ucers, or 
t o a nal yze/statisticall y c o ntr ol f or C Y P meta b olic pr ofiles. W e ha ve selecte d a 
4 m g oral h y dr o m or p h o ne d ose f or t his st u d y beca use we ha ve data fr o m 
a n ot her o n g oi n g st u d y ( I R B 0 0 0 4 7 4 2 3) i n dicati n g it pr o d uces a mil d- m o derate 
effe ct ( vers us a ceili n g or fl o or effect) a n d will t heref ore all o w us t o vis ualize 
c ha n ges as a f u ncti o n of t he dr o na bi n ol. 4 m g oral h y dr o m or p h o ne is als o a 
d ose t hat is c o m merciall y a vaila ble a n d re g ularl y prescri be d f or a nal gesia, 
w hic h i ncreases t he cli nical rele va nce of t his st u d y. B ase d o n cli nical 
e x perie nce, we e x pect it t o pr o d uce a m o derate a nal gesic effect o n pai n. T his 
is a n i m p orta nt feat ure beca use t o o str o n g a d ose c o ul d o ver w hel m t he ca n na bi n oi d effect a n d pre ve nt us fr o m 
effe cti vel y e val uati n g t he st u d y h y p ot heses. A m o derate d ose of h y dr o m or p h o ne will better e na ble us t o e val uate 
s hifts i n t he a nal gesic c ur ve as a f u ncti o n of t he st u d y dr u g, a n d pr o vi de a str o n ger assess me nt of w het her 
ca n na bi n oi ds will e n ha nce t he a nal gesic effect of h y dr o m or p h o ne.  
 
Dr o n a bi n ol ( M ari n ol) has bee n strate gicall y c h ose n f or t his st u d y beca use it is a wi del y- use d, c o m merciall y-
a vaila ble S c he d ule II ca n na bi n oi d me dicati o n t hat is c urre ntl y i n dicate d f or na usea a n d v o miti n g, a n d a n ore xia i n 
AI D S patie nts, b ut w hic h c o ul d b e p rescri b e d off-l a bel f or t h e a dj u n cti ve tre at m e nt of cli nic al p ai n.  Dr o na bi n ol 
is a s y nt hetic delta- 9-tetra h y dr oca n na bi n ol ( T H C) pr o d uct (t he pri mar y ps yc h oacti ve c o m p o u n d i n ca n na bis sati va 
( marij ua na)), a n d t h us has ge neralit y wit h ot her T H C c o m p o u n ds (s uc h as s m o ke d or e di ble marij ua na pr o d ucts). 
W he n a d mi nistere d orall y (as pr o p ose d here), dr o na bi n ol reac hes pea k c o nce ntrati o ns i n 2- 4 h o urs a n d is 9 0- 9 5 % 
a bs or be d b ut, d ue t o e xte nsi ve fir st- pass meta b olis m, is o nl y 1 0- 2 0 % bi oa vaila ble. It is e xcrete d i n fecal ( 3 5- 5 0 %) 
a n d re nal ( 1 0- 1 5 %) waste. T he eli mi nati o n half-life is bi p hasic, wit h a n i nitial half-life of 4 h o urs a n d a ter mi nal half-
life of 2 5- 3 6 h o urs, a n d a n acti ve meta b olite ( 1 1- h y dr o x y- delta- 9- T H C) is pr o d uce d. T here is n o c urre nt e vi de nce 
t hat dr o na bi n ol is differe ntiall y affecte d b y P 4 5 0 stat us. Dr o na bi n ol is s ol d c o m merciall y i n 2. 5 m g, 5 m g, a n d 1 0 m g 
d ose ra n ges. We h a ve c h ose n t o a d mi nister a 0 m g ( pl ace b o), 2. 5 m g, 5 m g, a n d 1 0 m g, d ose of d r o n a bi n ol i n t his 
st u d y, w hic h are wit hi n t he ra n ge c urre ntl y prescri be d f or c he m ot hera p y-i n d uce d na usea a n d v o miti n g a n d AI D S-
St u d y Dr u g D o si n g
C o n diti o n
H y dr o m or p h o n e
Dr o n a bi n ol
Or al
Or al
N o nr a n d o mi z e d
1
4 m g 
Pl a c e b o
R a n d o mi z e d
2
4 m g
2. 5 m g
3
4 m g
5 m g
4
4 m g
1 0 m g
5
pl a c e b o
pl a c e b o
S e s si o n 1 will b e n o nr a n d o mi z e d a n d u s e d a s a 
s af et y s cr e e ni n g d a y. S e s si o n s 2- 5 will b e 
r a n d o mi z e d a n d c o u nt er- b al a n c e d a cr o s s 
p arti ci p a nt s. 


 
 
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relate d a n ore xia, a n d t heref ore will ha ve direct cli nical a p plica bilit y. Dr o na bi n ol will be p urc hase d as a ca ps ule a n d 
will be o ver-e nca ps ulate d b y o ur researc h p har mac y t o e ns ure d o u ble- bli n d a d mi nistrati o n pr oce d ures. Place b o d oses 
will c o nsist of lact ose or a n ot her be ni g n wei g ht- matc he d filler. 
 
b.  J ustificati o n a n d safet y i nf or mati o n if F D A a p pr o ve d dr u gs will be a d mi nistere d f or n o n- F D A a p pr o ve d 
i n dicati o ns or if d oses or r o utes of a d mi nistrati o n or partici pa nt p o p ulati o ns are c ha n ge d. 
 
H y d r o m or p h o n e: H y dr o m or p h o ne h y dr oc hl ori de is a p ure m u o pi oi d a g o nist t hat ca n be a d mi nistere d i n oral, 
rectal, i ntra m usc ular (I M) or i ntra ve n o us (I V) f or m ulati o ns f or t he i n dicati o n of ac ute a n d/ or c hr o nic pai n.  
W e ha ve c h ose n t o a d mi nister 4 m g oral h y dr o m or p h o ne f or t he st u d y sessi o ns beca use we ha ve o n g oi n g 
e x perie nce wit h t his d ose i n a n ot her I R B a p pr o ve d st u d y ( PI D u n n, I R B _ 0 0 0 4 7 4 2 3) a n d we ha ve o bser ve d t hat it 
pr o d uces t he effect i nte n de d f or i n vesti gati o n i n t his st u d y; na mel y, t hat it pr o d uces a mil d- m o derate effect t hat will 
better p ositi o n t his st u d y t o e val uate w het her dr o na bi n ol ca n i ncrease or decrease dr u g effe ct s.  
H y dr o m or p h o ne was strate gicall y selecte d f or t his st u d y as t he e xe m plar o pi oi d f or t his st u d y beca use it is 
n ot s u bject t o differe nces i n C Y P meta b olic e nz y mes a n d t heref ore will n ot re q uire us t o scree n o ut i n di vi d uals wit h 
rece nt e x p os ure t o C Y P i n hi biti n g or i n d uci n g me dicati o ns, or t o a nal yze a n d statisticall y c o ntr ol f or C Y P meta b olic 
pr ofiles i n i n di vi d ual s u bjects. F urt her, i n c o ntrast t o m or p hi ne, h y dr o m or p h o ne als o d oes n ot pr o d uce a l ocalize d 
a d verse eff ect w he n a d mi nistere d I M. B ot h d oses of h y dr o m or p h o ne are wit hi n t he ra n ge t hat is c o m merciall y 
a vaila ble, w hic h i ncreases t he cli nical rele va nce a n d direct a p plicati o n of t hese st u d y res ults i nt o cli nical practice, 
a n d o ur data i n dicates 4 m g oral  h y dr o m or p h o ne will pr o d uce a m o derate a nal gesic effect f oll o wi n g pai n testi n g. 
T his is a n i m p orta nt feat ure beca use t o o str o n g a d ose of a n o pi oi d a nal gesic c o ul d o ver w hel m t he ca n na bi n oi d effect 
a n d pre ve nt us fr o m effecti vel y e val uati n g t he st u d y h y p ot heses. B y selecti n g a d ose of h y dr o m or p h o ne t hat pr o d uces 
a m o derate effect, we will be a ble t o e val uate s hifts i n t he a nal gesic c ur ve t hat occ ur as a f u ncti o n of dr o na bi n ol, 
w hic h will all o w us t o better deter mi ne t he de gree t o w hic h dr o na bi n ol ca n a u g me nt t he a nal gesic effect of 
h y dr o m or p h o ne. T here is als o n o a p pare nt effect of ge n der o n t he p har mac o ki netics of h y dr o m or p h o ne.  
W e ha ve selecte d h y dr o m or p h o ne f or t his st u d y beca use it is a pr ot ot y pical o pi oi d wit h a k n o w n safet y 
pr ofile a n d beca use we ha ve e xte nsi ve e x perie nce a d mi nisteri n g t his dr u g i n oral pre parati o ns. W e ha ve selecte d a 
mi d -le vel d ose beca use it is wit hi n t he ra n ge of d oses a p pr o ve d b y t he F D A. It is als o se nsiti ve t o t he Q S T tests we 
ha ve pr o p ose d, a n d we t heref ore belie ve it will pr o vi de a n i deal o p p ort u nit y t o e val uate w het her t he c ur ve of 
h y dr o m or p h o ne is s hifte d as a f u ncti o n of dr o na bi n ol a d mi nistrati o n.  
 
Dr o n a bi n ol: Dr o na bi n ol is a sc he d ule II dr u g t hat is bei n g a d mi nistere d at 2. 5 m g, 5 m g, a n d 1 0 m g d oses i n t his 
st u d y, w hic h is c o nsiste nt wit h t he ra n ge a p pr o ve d b y t he F D A f or t hera pe utic use i n patie nts wit h c he m ot hera p y-
i n d uce d na usea a n d v o miti n g, a n d l oss of a p petite i n patie nts wit h a d va nce d HI V ( AI D S).  Dr o na bi n ol is als o use d 
off la bel f or t he treat me nt of Gilles de la T o urett’s s y n dr o me, ge neral l oss of a p petite (relate d t o ca ncer), s pasticit y 
fr o m M ulti ple S cler osis, treat me nt refract or y a n d p ost o perati ve na usea a n d v o miti n g, a n d treat me nt refract or y 
pr urit us. W he n a d mi nistere d orall y (as pr o p ose d here), dr o na bi n ol reac hes pea k c o nce ntrati o ns i n 2- 4 h o urs a n d is 
1 0- 2 0 % bi oa vaila ble. It is s u bject t o e xte nsi ve first- pass meta b olis m a n d is e xcrete d i n fecal ( 3 5- 5 0 %) a n d re nal ( 1 0-
1 5 %) waste, wit h a n eli mi nati o n half-life of 1 9- 3 6 h o urs.  
W e ha ve selecte d oral dr o na bi n ol beca use it is F D A a p pr o ve d f or pai n c o n diti o ns, a n d we ha ve selecte d t o 
a d mi nister t he f ull ra n ge of F D A a p pr o ve d d oses t o best u n dersta n d t he d ose at w hic h a n y c ha n ge i n o pi oi d a nal gesic 
effe ct ma y e mer ge. W e belie ve t his a p pr oac h will yiel d data t hat ca n be i nsta ntl y utilize d b y pai n treat me nt 
s pecialists, w hic h i ncreases t he ge neraliza bilit y of o ur st u d y a p pr oac h.  
 
C a ps aici n:  1 0 % ca psaici n t o pic crea m will be a p plie d as part of t he sta n dar dize d q ua ntitati ve se ns or y testi n g batter y. 
T his is a c o n ve nti o nal pai n testi n g tec h ni q ue. F or a p plicati o n, a piece of t hic k, n o n- p or o us a d hesi ve dressi n g wit h a 
1. 2 5i nc h 2 o pe ni n g will be a p plie d t o t he s ki n at t he l ocati o n of i nte n de d a p plicati o n. T he area will be mar ke d wit h a 
pe n or s har pie f or later vis ualizati o n. A 0. 3 5 g a p plicati o n of 1 0 % ca psaici n crea m will be a p plie d i nsi de t his o pe ni n g 
a n d e ve nl y s prea d o n t he s ki n. T he area will t he n c o vere d b y Te ga der m tra ns pare nt dressi n g a n d t he ca psaici n crea m 
will be per mitte d t o a bs or b i nt o t he s ki n f or 3 0 mi n utes. C a psaici n will t he n be re m o ve d fr o m t he s ki n usi n g alc o h ol 
pre p pa ds.  
 
c.  J ustificati o n a n d safet y i nf or mati o n if n o n- F D A a p pr o ve d dr u gs wit h o ut a n I N D will be a d mi nistere d.  
N/ A  
 
7.  
St u d y St atistics 


 
 
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a.  Pri mar y o utc o me varia ble :  
 
•  
Pri m ar y Ai m 1: T he pri mar y o utc o me will be t he area u n der t he c ur ve of eac h Q S T pr oce d ure, w hic h will  
pr o vi de a n assess me nt of t he mea n d urati o n a n d ma g nit u de of t he dr u g effect. Pri mar y o utc o mes will be teste d wit h 
re peate d t w o-fa ct or ( Dr u g C o n diti o n x Ti me) m o dels t o e xa mi ne mai n a n d i nteracti o n effects f or all ra w data as 
desi g ne d.  If t here is lar ge variati o n acr oss s u bjects at t he baseli ne ti me p oi nt, t he ra w data will be tra nsf or me d as a 
c ha n ge fr o m baseli ne a n d a nal yze d i n dr u g c o n diti o n b y ti me m o dels. Statistical  a nal yses will be c o n d ucte d usi n g 
m ultile vel a nal yses wit h a n a ut ore gressi ve c o varia nce str uct ure usi n g S A S P R O C MI X E D S oft ware
1 3 1. T hese 
a nal yses will per mit a n e xa mi nati o n f or effects of dr u g c o n diti o n a n d ti me effects ass ociate d wit hi n t he c o urse of t he 
st u d y. I nter pretati o n of dr u g c o n diti o n mai n effects a n d i nteracti o ns will rel y o n T u ke y p ost- h oc tests. T his ai m will 
als o assess fre q ue nc y of a d verse e ve nts as a f u ncti o n of st u d y dr u g. 
 
S p ecific o utc o m e v ari a bles f or t h e Q S T p r oce d u res will b e as f oll o ws:  
a.  Heat P ai n T hres h ol d a n d T olera nce: H P T h a n d H P T o i n º C ( b ot h i n n or mal a n d ca psaici n treate d s ki n) 
b.  Press ure P ai n T hres h ol d: P P T h i n kil o pascals  
c.  T her mal a n d Mec ha nical Te m p oral S u m mati o n: Ver bal pai n rati n gs ( b ot h i n n or mal a n d ca psaici n treate d 
s ki n f or M T S) 
d.  C o n diti o ne d P ai n M o d ulati o n: T he i n de x sc ore of C P M: P P T h a n d C P M: T S (c o m pare d t o baseli ne) f or eac h 
d ose  
e.  C ol d W ater T olera nce: Ti me t o t olera nce (c o m pare d t o baseli ne) f or eac h d ose. 
 
•  Pri m ar y Ai m 2:  T he Dr u g vs. M o ne y q uesti o n naire will be c o m pare d acr oss d ose c o n diti o ns, usi n g pea k 
m o netar y rati n g f or eac h d ose as t he pri mar y o utc o me. Wit hi n-s u bject c ha n ges, as a f u ncti o n of d ose, will be 
a nal yze d usi n g a re peate d meas ures a nal ysis of varia nce ( A N O V A).  
 
•  Pri m ar y Ai m 3:  Ne ur oc o g niti ve tests will be c o m pare d as a f u ncti o n of st u d y dr u g d ose, usi n g st u d y sessi o n 
n u m ber ( 1- 6) as a c o variate t o c o ntr ol f or practice effe cts. S pecific o utc o me meas ures will i ncl u de:  
a.  Di vi de d Atte nti o n Tas k ( D A T): Acc urac y wit h w hic h t he y perf or m t he t w o tas ks 
b.  Di git S y m b ol S u bstit uti o n Tas k ( D S S T): Acc urac y, t otal n u m ber of patter ns c o m plete d i n all otte d ti me 
c.  C o m p uterize d versi o n of t he P ace d A u dit or y S erial A d diti o n Tas k ( P A S A T): S u m me d of c orrect trials 
 
b.  S ec o n dar y o utc o me varia bles. 
 
De m o gra p hic a n d dr u g use c haracteristics, i ncl u di n g a p ositi ve si g nal ( defi ne d as > 2 0 p oi nts rati n g fr o m baseli ne o n 
V A S rati n g of Dr u g Effect fr o m S essi o n 1), t hat are h y p ot hesize d a pri ori t o be ass ociate d wit h o utc o mes (e. g., B o d y 
Mass I n de x) will be c o m pare d acr oss se x gr o u ps a n d si g nifica nt differe nces will be i ncl u de d as c o variates i n t he 
s u bse q ue nt a nal yses. All a nal yses will be re peate d a n d se x ( male/fe male) will be a d de d as a fact or t o t he a nal yses. 
 
c.  Statistical pla n i ncl u di n g sa m ple size j ustificati o n a n d i nteri m data a nal ysis:  
 
Si nce t his will be t he first st u d y t o e xa mi ne t he effect of ca n na bi n oi ds o n o pi oi d-i n d uce d a nal gesia usi n g a wit hi n-
s u bject la b orat or y m o del of pai n, t here are n o data a vaila ble u p o n w hic h a p o wer a nal ysis ma y be directl y base d. 
T heref or e, we ha ve use d G- p o wer t o esti mate o ur sa m ple size. W e esti mate t hat a wit hi n-s u bject c o m paris o n usi n g 
pea k c ha n ge fr o m baseli ne as t he pri mar y o utc o me meas ure a n d c o m pari n g 6 me dicati o n c o n diti o ns will yiel d p o wer 
of 0. 9 5 t o detect a mai n effect at e ve n a l o w effect size ( 0. 2) b y e nr olli n g a sa m ple size of 4 5. F or eac h st u d y, we are 
pr o p osi n g t o e nr oll 6 0 s u bjects t o e ns ure we will ha ve 5 0 st u d y c o m pleters, a n d we will e nr oll e q ual q ua ntities of 
me n a n d w o me n t o e xa mi ne se x- base d differe nces i n res p o n di n g. T his a p pr oac h will res ult i n a n o verall c o m pleti o n 
sa m ple of 5 0 per st u d y, wit h s u bsa m ples of 2 5 per gr o u p, w hic h is c o nsiste nt wit h ot her wit hi n-s u bject e val uati o ns of 
dr u g effects. T his sa m ple size has bee n p o were d t o s u p p ort wit hi n-s u bject effects of st u d y dr u g a n d bet w ee n-s u bject 
effe cts of se x o n st u d y o utc o me meas ures. 
 
d.  Earl y st o p pi n g r ules.  
 
T he safet y of partici pa nts is a pri orit y of B P R U.  T he lar gest p ote ntial ris k of t his st u d y is car di o vasc ular i n nat ure. 
T his n oti o n is base d u p o n t he res ults of a p u blis he d st ud y t hat re p orte d a n i ncrease i n heart rate a n d bl o o d press ure 


 
 
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Pa g e 1 2  of 2 0  
 
a m o n g patie nts u n der g oi n g o pi oi d wit h dra wal ( of w hic h i ncrease d heart rate a n d bl o o d press ure is a k n o w n 
s y m pt o m) a n d w h o recei ve d a d ose of dr o na bi n ol ( 4 0 m g) t hat is d o u ble t he hi g hest p ote ntial d ose pr o p ose d here 
( 2 0 m g). T hese effects were di mi nis he d w he n t he dr o na bi n ol d ose was re d uce d t o 3 0 m g ( 1 3 2). T h o u g h we d o n ot 
belie ve t his st u d y c o m pletel y c orres p o n ds t o o ur la b orat or y desi g n, w hic h is e nr olli n g healt h y i n di vi d uals w h o are 
n ot ot her wise pre dis p ose d t o ele vate d bl o o d press ure a n d heart rate a n d w h o are recei vi n g d oses of dr o na bi n ol t hat 
are l o wer t ha n t h ose a d mi nistere d i n t he pri or st u d y, we are se nsiti ve t o t his p ote ntial o utc o me. T o a d dress t his, we 
will m o nit or vital si g ns at all st u d y data c ollecti o n ti me p oi nts a n d will f oll o w pr oce d ures t hat we ha ve de vel o pe d 
a n d s uccessf ull y use d i n pre vi o us st u dies t hat a d mi nistere d dr u gs (e. g., c ocai ne) wit h k n o w n car di o vasc ular ris ks. 
S pecificall y, if a partici pa nt’s para meters reac h t hese t hres h ol ds, t he n a st u d y p h ysicia n, w h o will al wa ys be a vaila ble 
via tele p h o ne, will be c o ntacte d a n d c o ns ulte d t o deter mi ne t he a p pr o priate c o urse of acti o n.  
o  S yst olic bl o o d press ure: > 1 8 0 m m H g 
o  Diast olic bl o o d press ure: > 1 2 0 m m H g  
o  Heart R ate: > s u b ma xi mal heart rate ( 2 2 0 – [a ge x 0. 8 5)] .  
A p pr o priate c o urses of acti o n ma y i ncl u de o bser vi n g t he partici pa nt u ntil t he para meters ret ur n t o n or mal or 
tra nsferri n g t he partici pa nt t o t he E mer ge nc y De part me nt ( E D). O ur researc h u nit, w hic h is t he l ocati o n i n w hic h all 
st u d y sessi o ns will be c o n d ucte d, is l ocate d acr oss t he street fr o m t he J o h ns H o p ki ns B a y vie w Me dical C e nter 
(J H B M C) E D. P artici pa nts w h o ca n wal k will be esc orte d t o t he E D b y a st u d y staff me m ber. If t here is a n y q uesti o n 
i n a partici pa nt’s a bilit y t o wal k safel y t he n 9 1 1 will be calle d t o ha ve a n a m b ula nce dis patc he d f or t he partici pa nt. 
 
A d diti o nal st o p pi n g r ules will i ncl u de n ot a bi di n g b y t he B P R U p olicies a n d pr oce d ures, or e n ga gi n g i n 
be ha vi ors t o war ds staff or ot her partici pa nts t hat are a b usi ve . Fi nall y, de vel o p me nt of a n i nterc urre nt ill ness or 
c o n diti o n t hat c ha n ges t he partici pa nts ris k ma y res ult i n me dical disc har ge fr o m t he st u d y. 
 
8.  
Ris ks  
a.  Me dical ris ks, listi n g all pr oce d ures, t heir maj or a n d mi n or ris ks a n d e x pecte d fre q ue nc y. 
 
a. H y d r o m or p h o n e: A d mi nistrati o n of a n y dr u g i n v ol ves s o me ris k beca use it is n ot al wa ys p ossi ble t o pre dict 
i n di vi d ual res p o nse t o dr u gs. T he m ost li kel y ris k i n t his st u d y is t hat s u bjects will e x perie nce si de-effe cts of t he 
dr u gs t hat ma y be u n pleasa nt. C o m m o n si de effects of h y dr o m or p h o ne are li g ht- hea de d ness, dizzi ness, se dati o n, 
na usea, v o miti n g, s weati n g, fl us hi n g, d ys p h oria, e u p h oria, dr y m o ut h, a n d pr urit us.  Less fre q ue ntl y o bser ve d si de 
effe cts are wea k ness, hea dac he, a gitati o n, tre m or, u nc o or di nate d m uscle m o ve me nts, alterati o ns of m o o d 
( ner v o us ness, a p pre he nsi o n, de pressi o n, fl oati n g feeli n gs, drea ms), m uscle ri gi dit y, parest hesia, m uscle tre m or, 
bl urre d visi o n, n ysta g m us, di pl o pia a n d mi osis, tra nsie nt hall uci nati o ns a n d dis orie ntati o n, vis ual dist ur ba nces, 
i ns o m nia, i ncrease d i ntracra nial press ure, fl us hi n g of t he face, c hills, tac h ycar dia, bra d ycar dia, pal pitati o n, fai nt ness, 
s y nc o pe, h y p ote nsi o n, h y perte nsi o n, br o nc h os pas m a n d lar y n g os pas m, c o nsti pati o n, biliar y tract s pas m, ile us, 
a n ore xia, diarr hea, cra m ps, taste alterati o n, uri nar y rete nti o n or hesita nc y, a nti di uretic effects, urticaria, ot her s ki n 
ras hes a n d dia p h oresis. Si de effects of h y dr o m or p h o ne are ge ner all y te m p orar y, dissi pate wit hi n se veral h o urs, a n d 
are d ose- de pe n de nt. T h us, partici pa nts ma y o nl y e x perie nce si de-eff ects occasi o nall y d uri n g t he researc h st u d y. 
S eri o us p ote ntial a d verse effects of h y dr o m or p h o ne a d mi nistrati o n t hat are p ossi ble b ut e xtre mel y u nli kel y t o be 
e nc o u ntere d i n t his st u d y are res pirat or y de pressi o n a n d l oss of c o nsci o us ness. T he F D A has i de ntifie d t he f oll o wi n g 
c o n diti o ns as i ncreasi n g t he ris k f or res pirat or y de pressi o n or ot her seri o us si de effects f oll o wi n g h y dr o m or p h o ne 
a d mi nistrati o n: patie nts wit h stat us ast h matic us; c hr o nic o bstr ucti ve p ul m o nar y disease; re d uce d res pirat or y f u ncti o n; 
hi g h bl o o d press ure; i m pair me nt of he patic, p ul m o nar y or re nal f u ncti o ns; m y xe de ma or h y pert h yr oi dis m; 
a dre n oc ortical i ns ufficie nc y; gall bla d der disease; ac ute alc o h olis m; hist or y of c o n v ulsi ve dis or ders; hist or y of hea d 
i nj ur y; c urre ntl y ta ki n g se dati ves, h y p n otics or p he n ot hiazi nes; a n d s ulfite aller g y. Mea n e x p os ure t o h y dr o m or p h o ne 
is als o i ncrease d 4-f ol d a m o n g patie nts wit h he patic i m pair me nt a n d 3-f ol d a m o n g patie nts wit h re nal i m pair me nt. 
T heref or e, t o f urt her re d uce t he ris k seri o us si de effects, we will e xcl u de a n y p ote ntial partici pa nt w h o e x hi bits o ne 
or m ore of t hese c o n diti o ns. 
T he m ost seri o us p ote ntial a d verse e ve nt f oll o wi n g h y dr o m or p h o ne a d mi nistrati o n is o pi oi d a g o nist 
o ver d ose, w hic h is c haracterize d b y res pirat or y de pressi o n, s o m n ole nce pr o gressi n g t o st u p or or c o ma, s keletal 
m uscle flacci dit y, c ol d a n d cla m m y s ki n, c o nstricte d p u pils, a n d s o meti mes bra d ycar dia a n d h y p ote nsi o n. I n seri o us 
o ver d osa ge, partic ularl y f oll o wi n g i ntra ve n o us i njecti o n, a p nea, circ ulat or y c olla pse, car diac arrest a n d deat h ma y 
occ ur.   W e belie ve t he ris k of o ver d ose i n t his st u d y t o be l o w f or t he f oll o wi n g reas o ns: we ha ve e xte nsi ve 
e x perie nce i n t he a d mi nistrati o n of h y dr o m or p h o ne, we ha ve c h ose n d oses t hat ha ve bee n de m o nstrate d t o be safe 
a n d t olera ble i n a n i de ntical partici pa nt p o p ulati o n, we will e xcl u de a n y i n di vi d ual w h o has a me dical c o n diti o n t hat 


 
 
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ma y i ncrease t he ris k f or res pirat or y de pressi o n a n d/ or ot her a d verse e ve nts, all me dicati o n d oses will be 
a d mi nistere d b y a trai ne d researc h n urse, a n d partici pa nts will be m o nit ore d t hr o u g h o ut t he st u d y sessi o n, u p t o 8 
h o urs, b y trai ne d staff w h o will ha ve access t o t he o pi oi d a nta g o nist nal o x o ne t o re verse t he o pi oi d a g o nist effe cts. 
H y dr o m or p h o ne has n o k n o w n i nteracti o ns wit h dr o na bi n ol. 
 
b. Dr o n a bi n ol: T he F D A i de ntifies t he f oll o wi n g a d verse effects of dr o na bi n ol: car di o vasc ular ( h y perte nsi o n, 
h y p ote nsi o n, pal pitati o ns, tac harr h yt h mia, vas o dilati o n); der mat ol o gic (fl us hi n g); gastr oi ntesti nal (a b d o mi nal pai n, 
na usea, v o miti n g, xer ost o mia); ne ur ol o gical (a m nesia, ata xia, c o nf usi o n, c o or di nati o n pr o ble m, dizzi ness, 
s o m n ole nce, verti g o), a n d ps yc hiatric (a n xiet y, del usi o n of persec uti o n, de pers o nalizati o n, de pressi o n, dist ur ba nce i n 
t hi n ki n g, e u p h oria, hall uci nati o ns), t h o u g h it s h o ul d be n ote d t hat t he a d verse effects were c ollecte d fr o m st u dies of 
patie nts u n der g oi n g c he m o t hera p y or wit h a d va nce d HI V, w hic h ma y ha ve decrease d t heir t hres h ol d f or 
e x perie nci n g ne gati ve effects. Dr o na bi n ol is liste d as pre g na nc y cate g or y C, mea ni n g t hat precli nical st u dies ha ve 
re veale d a d vers e effe cts o n t he fet us b ut t hat n o c o ntr olle d h u ma n st u dies ha ve bee n c o n d ucte d t o assess t his ris k 
( pre g na nc y or breast-fe e di n g will be a n e xcl usi o n criteri o n). T he o nl y a bs ol ute c o ntrai n dicati o n of dr o na bi n ol is 
aller g y or h y perse nsiti vit y t o ca n na bi n oi ds or sesa me oil. Dr o na bi n ol has m o derate – se vere i nteracti o ns wit h breast 
ca ncer resista nce pr otei n i n hi bit ors (t o p oteca n, atal ure n), a n d has m o derate i nteracti o ns wit h t he a ntiretr o viral 
pr otease i n hi bit or rit o na vir ( N or var), w hic h is use d t o treat HI V a n d AI D S.  
 
c. C a ps aici n : Ca psaici n is t he mai n i n gre die nt i n h ot pe p pers, a n d is use d as a n o ver t he c o u nter dr u g f or t he 
treat me nt of pai n. T he d ose of ca psaici n we are usi n g is hi g her t ha n w hat is a vaila ble o ver t he c o u nter, alt h o u g h it is 
less t ha n half of t he d ose i n a si n gle ha ba nera pe p per. Ca psaici n d oes ca use pai n, li ke a h ot pe p per ma y d o w he n it is 
eate n. Ca psaici n ma y pr o d uce s o me l ocal re d ness a n d s welli n g t hat will disa p pear wit hi n a da y. T he area of s ki n 
w here t he ca psaici n is a p plie d c o ul d be se nsiti ve f or u p t o 4 8 h o urs. C a psaici n ma y ca use a b ur ni n g feeli n g i n t he 
e yes or ot her areas of t he b o d y if acci de ntall y r u b be d o nt o ot her s ki n areas.   
  
 
d. C h a n ce T h at P artici p a nts M a y B e gi n A b usi n g O pi oi ds or C a n n a bi n oi ds F oll o wi n g E x p os u re t o St u d y 
Dr u gs : T here is a s mall b ut p ote ntial ris k t hat e x p osi n g n o n- dr u g a b usi n g i n di vi d uals t o d oses of h y dr o m or p h o ne or 
ca n na bi n oi ds ma y elicit rei nf orci n g effects t hat c o ul d preci pitate s u bse q ue nt dr u g- use be ha vi or. E nr olli n g n o n- dr u g 
users i nt o c o ntr olle d la b orat or y st u dies is a c o n ve nti o nal strate g y t hat has bee n use d e xte nsi vel y t o e val uate t he a b use 
lia bilit y p ote ntial of n u mer o us dr u gs of a b use b ot h wit hi n o ur la b orat or y a n d b y ot her la b orat ories.  
 
e. Disc o mf ort fr o m P ai n T esti n g : P artici pa nts will li kel y fi n d t he pai n testi n g pr oce d ures u nc o mf orta ble f or a brief 
peri o d of ti me. T his effect is e x pecte d t o be tra nsie nt a n d t o pr o d uce o nl y mil d le vels of disc o mf ort. 
 
f. Bre ac h of C o nfi d e nti alit y: Alt h o u g h staff me m bers are hi g hl y trai ne d t o mai ntai n partici pa nt c o nfi de ntialit y, 
t here is al wa ys a ris k t hat s o me of t he c o nfi de ntial i nf or mati o n c ollecte d c o ul d be re veale d t o pe o ple w h o are n ot 
i n v ol ve d i n t he researc h st u d y. T his c o ul d be e m barrassi n g t o t he partici pa nt if t he partici pa nt preferre d t o kee p his or 
her st u d y partici pati o n secret, or if se nsiti ve i nf or mati o n beca me k n o w n t o a n i n di vi d ual o utsi de t he st u d y. W e ha ve 
a n e xte nsi ve hist or y of c o n d ucti n g researc h a m o n g s u bsta nce a b users a n d ha ve i nstit ute d se veral practices t o pre ve nt 
a breac h fr o m c o nfi de ntialit y fr o m occ urri n g (see bel o w); t h us, we belie ve t his ris k t o be mi ni mal.  
 
b.  Ste ps ta ke n t o mi ni mize t he ris ks. 
 
a. Pr otecti o n A g ai nst H y d r o m or p h o n e Ris ks: W e ha ve e xte nsi ve e x perie nce i n t he a d mi nistrati o n of 
h y dr o m or p h o ne a n d ot her o pi oi d a g o nists i n c o ntr olle d la b orat or y setti n gs a n d t heref ore a ntici pate fe w pr o ble ms. 
A n y i n di vi d ual w h o ma y be pr o ne t o t he ris ks ass ociate d wit h h y dr o m or p h o ne will be e xcl u de d fr o m partici pati n g.  
Alt h o u g h researc h staff a n d partici pa nts will be bli n de d t o t he e xact me dicati o n pr o vi de d, b ot h gr o u ps will be 
i nf or me d of t he p ote ntial si de effects a n d ris ks ass ociate d wit h t he st u d y dr u g a d mi nistrati o n. P artici pa nts will be free 
t o disc o nti n ue st u d y partici pati o n at a n y ti me wit h o ut c o nse q ue nce. T he d ose of h y dr o m or p h o ne t hat is bei n g 
a d mi nistere d is c o nsiste nt wit h cli nical care, a n d is a me di u m le vel d ose f or t he treat me nt of pai n. F urt her, T he 
Q ualif yi n g S essi o n pr o vi des us a u ni q ue o p p ort u nit y t o assess f or se nsiti vit y t o h y dr o m or p h o ne, a n d a n y partici pa nt 
w h o s h o ws i nt olera nce t o h y dr o m or p h o ne d uri n g t he Q ualif yi n g S essi o n will be e xcl u de d fr o m t he pri mar y st u d y. 
Great car e has bee n ta ke n i n selecti n g t he a p pr o priate dr u g d oses t o e ns ure h y dr o m or p h o ne is well-t olerate d a n d safe 
f or o ur partici pa nts a n d partici pa nts will als o be a ble t o disc o nti n ue st u d y partici pati o n at a n y ti me. T he m ost seri o us 
ris k ass ociate d wit h h y dr o m or p h o ne a d mi nistrati o n is res pirat or y de pressi o n. W e belie ve t his ris k is mi ni mal i n t his 
st u d y f or se veral reas o ns. First, we are a d mi nisteri n g a mi d-le vel d ose a n d ha ve e xte nsi ve e x perie nce a d mi nisteri n g 


 
 
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t his d ose at c o ntr olle d le vels i n healt h y c o ntr ols.  S ec o n d, we ha ve de vel o pe d se veral sta n dar d criteria t hat are 
f oll o we d b y n ursi n g staff a n d researc h pers o n nel t o m o nit or partici pa nts w h o ha ve bee n pr o vi de d wit h a st u d y 
me dicati o n. All n ursi n g a n d researc h staff are i nf or me d of t hese sta n dar ds, a n d a list of t hese sta n dar ds is p oste d i n 
eac h testi n g r o o m. T he sta n dar ds are as f oll o ws: If res pirat or y rate dr o ps bel o w 1 2 breat hs/ mi n ute a n d is 
acc o m pa nie d b y se dati o n, partici pa nts are pr o m pte d ver ball y t o breat h. I n o ur e x perie nce, ver bal a n d p h ysical 
sti m ulati o n is ofte n s ufficie nt t o pr o m pt breat hi n g a n d rest ore a n or mal res pirat or y rate.  If res pirat or y rate dr o ps 
f urt her a n d/ or if o x y ge n sat urati o n rates fall bel o w 9 0 % sat urati o n, t he n patie nts are m o nit ore d caref ull y. 
S pecificall y, t he y will be acc o m pa nie d c o nti n u o usl y b y a me dical a n d/ or n ursi n g staff me m ber, e val uate d b y a staff 
p h ysicia n, a n d are gi ve n s u p ple me ntal o x y ge n at 2 L/ mi n via a nasal ca n n ula (a vaila ble o n site i n t he e xa m testi n g 
r o o m) if dee me d necessar y b y t he p h ysicia n. If cli nical e val uati o n deter mi nes t hat a partici pa nt’s se dati o n le vel is 
i ncreasi n g, t he o pi oi d a nta g o nist nal o x o ne ca n be pr o m ptl y a d mi nistere d via i ntra m usc ular r o ute t o pr o d uce a n 
i m me diate re versal of o pi oi d effects. T here ha ve bee n ver y fe w i nci de nts t hr o u g h o ut o ur > 1 5 year e x perie nce 
a d mi nisteri n g o pi oi d a g o nists t o h u ma n partici pa nts i n c o ntr olle d la b orat or y c o n diti o ns t hat ha ve necessitate d act ual 
i nter ve nti o n ( o x y ge n a n d/ or nal o x o ne), h o we ver o ur e q ui p me nt a n d me dical/ n ursi n g staff is al wa ys pre pare d f or t his 
p ossi bilit y. W e feel t hese pr oce d ures will s ufficie ntl y pr otect partici pa nts fr o m p ossi ble a d verse a n d seri o us a d verse 
e ve nts.  
 
b. Pr otecti o n A g ai nst Dr o n a bi n ol Ris ks: T he maj orit y of ris ks t hat are k n o w n t o occ ur f oll o wi n g dr o na bi n ol 
a d mi nistrati o n are ps yc hiatric i n nat ure. T hese ris ks are rec o g nize d as bei n g tra nsie nt a n d rea dil y re versi ble. T o 
miti gate t hese ris ks, we will e xcl u de partici pa nts w h o e n d orse ha vi n g pre vi o usl y e x perie nce d ne gati ve effects t o 
ca n na bi n oi d pr o d ucts. W e will als o c o n d uct ps yc hiatric scree ni n g d uri n g t he S cree ni n g sessi o n t o e ns ure t hat patie nts 
wit h c urre nt or hist or y of ps yc hiatric e ve nts are e xcl u de d fr o m st u d y partici pati o n. F urt her, all partici pa nts will be 
i nf or me d a b o ut t he p ote ntial si de effects of t he st u d y me dicati o ns a n d will be per mitte d t o e n d st u d y partici pati o n at 
a n y ti me if t he y e x perie nce ne gati ve e ve nts, wit h n o c o nse q ue nces.  Fi nall y, we are pr o vi di n g partici pa nts wit h ta xi 
ser vice t o a n d fr o m t he st u d y sessi o ns t o e ns ure n o persiste nt dr u g effects will i m pact t heir dri vi n g. W e are als o 
b u d geti n g f or t he p ote ntial f or a partici pa nt t o sta y t he ni g ht at t he C R U f oll o wi n g st u d y dr u g e x p os ure. B ase d o n o ur 
pre vi o us e x perie nce, we e x pect t his t o be a rare occ urre nce b ut are pre pare d t o ma ke t hat o pti o n a vaila ble as nee de d. 
 
c. Pr otecti o n A g ai nst Ris ks T h at P artici p a nts M a y B e gi n A b usi n g O pi oi ds or C a n n a bi n oi ds F oll o wi n g 
E x p os u re t o St u d y Dr u gs : A n ot her c o ncer n is t he p ossi bilit y t hat e x p os ure of partici pa nts wit h n o hist ories of dr u g 
a b use t o dr u gs i n o ur researc h setti n g mi g ht i n s o me wa y i ncrease t he li keli h o o d of t hese i n di vi d uals t o be gi n a b usi n g 
illicit dr u gs w he n t he y ret ur n t o t he c o m m u nit y. T he J o h ns H o p ki ns I R B cl osel y m o nit ors t his iss ue, a n d has 
re peate dl y c o ncl u de d t hat a d mi nisteri n g dr u gs t hat ha ve rei nf orci n g effects t o i n di vi d uals w h o d o n ot a b use dr u gs is 
n ot ass ociate d wit h a n i ncrease d pr o pe nsit y t o be gi n a b usi n g dr u gs. A d mi nisteri n g dr u gs t hat ma y ha ve rei nf orci n g 
effe cts t o n o n- de pe n de nt users has s u bsta ntial prece de nt i n la b orat or y e xa mi nati o ns of dr u g effects, a n d we ha ve a 
ric h a n d e xte nsi ve hist or y of utilizi n g t his practice.  S e veral researc h st u dies t hat ha ve directl y e xa mi ne d t he 
ass ociati o n bet wee n st u d y-relate d dr u g a d mi nistrati o n a n d s u bse q ue nt dr u g use be ha vi or ha ve faile d t o de m o nstrate 
t hat c o ntr olle d, la b orat or y dr u g e x p os ure i ncreases t he ris k f or de vel o pi n g f ut ure de pe n de nce. F or e xa m ple, a ut h ors 
of a rece nt st u d y t hat a d mi nistere d met ha m p heta mi ne t o a sa m ple of n o n treat me nt-see ki n g dr u g a b users re p orte d n o 
differe nc e bet wee n- gr o u p differ e nces i n dr u g use be ha vi ors, assesse d via t he A d dicti o n S e verit y I n de x, at a 6- m o nt h 
f oll o w- u p assess me nt1 2 6. S ec o n d, a s yste matic f oll o w- u p st u d y re p orte d t hat alc o h ol- de pe n de nt v ol u nteers ra n d o ml y 
assi g ne d t o la b orat or y st u dies eit her i n v ol vi n g or n ot i n v ol vi n g e x peri me ntal alc o h ol c o ns u m pti o n ha ve n ot differe d 
i n t heir f oll o w- u p o utc o mes1 2 7. T hir d, a rece nt st u d y c o ncl u de d t hat i n vesti gati o nal a d mi nistrati o n of i ntra ve n o us 
c ocai ne t o i ntra ve n o us i ne x perie nce d c ocai ne users di d n ot i ncrease t he ris k of recreati o nal i ntra ve n o us use 1 2 8. 
F o urt h, a st u d y c o n d ucte d b y o ur researc h tea m a d mi nistere d c ocai ne a n d/ or o pi oi ds t o partici pa nts wit h hist ories of 
dr u g a b use a n d o bser ve d n o si g nifica nt c ha n ges i n n u m ber of da ys of re p orte d dr u g use, d ollar a m o u nts re p orte d 
s pe nt f or vari o us dr u g classes, or a n y i ncreases i n A d dicti o n S e verit y I n de x d o mai n sc ores at a o ne m o nt h f oll o w-
u p 1 2 9. Fi nall y, t he C olle ge o n t he Pr o ble ms of Dr u g De pe n de nce, a presti gi o us i nter nati o nal ass ociati o n of dr u g 
de pe n de nce rese arc h ers, s u p p orts t he practice of e nr olli n g n o n treat me nt-see ki n g i n di vi d uals i nt o dr u g a b use lia bilit y 
e val uati o n st u dies. S pecificall y, t he C olle ge o n Pr o ble ms of Dr u g De pe n de nce re p orte d t hat e x p os ure of dr u g a b users 
t o a b use d dr u gs i n a c o ntr olle d researc h setti n g d oes n ot e n ha nce t he desire of a n i n di vi d ual t o use dr u gs, w orse n 
a d dicti o n, or ma ke a d dicti o n m ore diffic ult t o treat 1 3 0. O verall, gi ve n t he s u bsta ntial data a vaila ble i n t he literat ure 
a n d o ur o w n la b orat or y e x perie nce, we feel c o nfi de nt t hat a d mi nistrati o n of s mall q ua ntities of ps yc h oacti ve dr u gs t o 
i n di vi d uals wit h recreati o nal hist ories of dr u g a b use will n ot be ass ociate d wit h f ut ure dr u g use be ha vi or.  
  
P artici pa nts will als o n ot be i nf or me d a b o ut t he s pecific me dicati o n t he y are recei vi n g, w hic h is a c o m m o n 
pr oce d ure use d b y o ur researc h u nit t o mi ni mize bias i n res p o n di n g. T his pr oce d ure als o ma kes it diffic ult f or t he 


 
 
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partici pa nt t o see k o ut dr u gs t he y ma y ha ve f o u n d rei nf orci n g d uri n g t he st u d y sessi o n, t h us f urt her mi ni mizi n g t he 
o p p ort u nit y f or st u d y partici pati o n t o i ncrease ris k of n o n-st u d y dr u g a b use. 
  
  
d . Pr otecti o n A g ai ns t Ris ks of Disc o mf ort fr o m P ai n T esti n g: It is li kel y t hat partici pa nts will e x perie nce s o me 
ac ute a n d tra nsie nt disc o mf ort fr o m t he pai n testi n g sessi o n, h o we ver we will w or k t o miti gate t hat ris k as m uc h as 
p ossi ble. First, partici pa nts will be i nf or me d of t he pai n testi n g pr oce d ure d uri n g t he i nf or me d c o nse nt a n d will be 
a ble t o ma ke a n i nf or me d decisi o n re gar di n g t heir st u d y partici pati o n. S ec o n d, we c h ose sta n dar dize d pai n tests t hat 
are k n o w n t o pr o d uce s h ort-li ve d effects a n d t h us are u nli kel y t o pr o d uce a n y resi d ual pai n. T hir d, t he meas ures rel y 
o n t he partici pa nt e n di n g t he pai n testi n g pr oce d ure as a n o utc o me meas ure, w hic h mea ns t hat all partici pa nts are 
e nc o ura ge d t o re m o ve t he msel ves fr o m t he pai nf ul sti m ul us at a n y ti me a n d t hat t he y are i n c o ntr ol of t he ma g nit u de 
a n d d urati o n of pai n t he y e x perie nce. F o urt h, we will e nf orce a n u p per li mit o n b ot h pai n meas ures t o pre ve nt a n y 
tiss ue da ma ge fr o m occ urri n g (e. g., ha n d ca n n ot be i n c ol d presser tas k f or > 1 5 0 sec o n ds). Fift h, partici pa nts will be 
i nf or me d t hat t he y ca n re v o ke t heir c o nse nt t o partici pate i n t he pai n testi n g at a n y ti me wit h o ut pe nalt y. Fi nall y, t he 
partici pa nts will be m o nit ore d 2 4 h o urs b y st u d y staff a n d will ha ve access t o me dical care a n d c o nc o mita nt 
me dicati o ns t o treat resi d ual pai n if necessar y. W e will als o d oc u me nt a n d re vie w all a d verse e ve nts re p orte d fr o m 
t he pai n testi n g sessi o n a n d will f oll o w a n y rec o m me n dati o ns t he y ma y ha ve re gar di n g t he cessati o n of pai n testi n g. 
 
e. S p ecific Pr otecti o n A g ai nst Ris ks wit h C a ps aici n:  C a psaici n is bei n g use d t o i n d uce mil d pai n/ disc o mf ort a n d is 
a pri mar y o utc o me of t he st u d y. W e will e ns ure t hat all partici pa nts are i nf or me d a b o ut t he disc o mf ort ass ociate d 
wit h ca psaici n s o t he y ma y ma ke a n i nf or me d decisi o n re gar di n g t heir st u d y partici pati o n. O ne of t he pri mar y ris ks 
of ca psaici n is t hat it c o ul d be acci de ntall y tra nsferre d t o a n ot her part of t he b o d y. T o pre ve nt t his fr o m ha p pe ni n g, 
we will ma ke s ure t he e x p os ure site is well- mar ke d a n d t hat all resi d ual t o pical crea m is re m o ve d wit h alc o h ol pa ds 
o nce t he crea m has bee n m ostl y a bs or be d. W e will als o be a ble t o a p pl y ice t o t he e x p os ure site t o re d uce a n y 
persiste nt disc o mf ort ass ociate d wit h ca psaici n. 
 
f. Pr otecti o n A g ai nst Ris ks Ass oci ate d wit h B re ac h of C o nfi d e nti alit y : T o pr otect c o nfi de ntialit y, all researc h 
partici pa nts will be assi g ne d u ni q ue partici pa nt i de ntificati o n c o des t hat will be use d o n all st u d y –relate d f or ms a n d 
o nli ne we bsites. D oc u me nts t hat i ncl u de t he partici pa nts’ f ull na mes (e. g., si g ne d i nf or me d c o nse nt f or ms) will be 
st ore d i n a n i n de pe n de nt bi n der, c o nsiste nt wit h F D A G o o d Cli nical Practice G ui deli nes, a n d will be ke pt i n a l oc ke d 
r o o m. C o nfi de ntial i nf or mati o n will ne ver be s hare d wit h a n y o ne o utsi de of t he researc h pr o gra m wit h o ut t he e x plicit 
writte n per missi o n of t he researc h partici pa nt. O nl y selecte d desi g nate d staff me m bers will be a p pr o ve d t o s hare 
c o nfi de ntial i nf or mati o n after e x plicit writte n per missi o n is o btai ne d fr o m t he partici pa nt a n d t he partici pa nt will be 
a ble t o re v o ke writte n per missi o n at a n y ti me. I n acc or da nce wit h I R B re q uire me nts, all researc h staff will be 
f or mall y trai ne d i n t hese pr oce d ures. N o i de ntif yi n g partici pa nt i nf or mati o n will be use d i n writte n re p orts, 
ma n uscri pts a n d/ or c o nfere nce pres e ntati o ns 
 
c.  Pla n f or re p orti n g u na ntici pate d pr o ble ms or st u d y de viati o ns. 
 
All a d verse e ve nts will be re p orte d t o t he I R B a n d ot her rele va nt a ge ncies (e. g., F D A, NI D A) as re q uire d. T he 
Pri nci pal I n vesti gat or a n d C o-i n vesti gat ors are res p o nsi ble f or re p orti n g s uc h e ve nts. 
 
d.  Le gal ris ks s uc h as t he ris ks t hat w o ul d be ass ociate d wit h breac h of c o nfi de ntialit y. 
 
Alt h o u g h t here is al wa ys a s mall ris k t hat c o nfi de ntialit y will be breac he d, we belie ve t his ris k t o be ver y mi ni mal 
wit h t he c urre nt st u d y.  It is p ossi ble t hat partici pa nts’ uri ne sa m ples ma y test p ositi ve f or t he st u d y dr u gs f or u p t o 1 
wee k after ea c h sessi o n. T o miti gate a n y p ote ntial ne gati ve i m pact t his ma y ha ve o n partici pa nts, we will i nf or m 
t he m of t his p ote ntial ris k i n t he I C F s o t he y ma y ma ke a n i nf or me d decisi o n re gar di n g t heir partici pati o n des pite t his 
p ote ntial c o nse q ue nce, a n d will pr o vi de a n y i ntereste d partici pa nts ( w h o si g n a release of i nf or mati o n) wit h a letter 
si g ne d fr o m t he st u d y i n vesti gat or stati n g t hat t heir uri ne sa m ple ma y be p ositi ve f or dr u gs t hat ca n be c o nsi dere d 
a b usa ble f or u p t o 7 da ys f oll o wi n g a st u d y sessi o n .  
 
e.  Fi na ncial ris ks t o t he partici pa nt s. 
N o ne. 
 
 
9.  
Be n efits  


 
 
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a.  
Descri pti o n of t he pr o ba ble be nefits f or t he partici pa nt a n d f or s ociet y. 
 
T here is n o direct be nefit of t his st u d y t o t he partici pa nt. H o we ver, t his st u d y will pr o vi de t he first e m pirical e vi de nce 
i n h u ma ns of t he ma g nit u de a n d d urati o n b y w hic h ca n na bi n oi ds ma y e n ha nce o pi oi d a nal gesic effects, usi n g a 
sta n dar dize d q ua ntitati ve se ns or y testi n g (c o m pre he nsi ve pai n testi n g) batter y. T his i nf or mati o n will a d va nce t he use 
of ca n na bi n oi ds fr o m treat me nt-refra ct or y c o n diti o ns t o m ore wi de-s prea d use f or pai n treat me nt. A p ositi ve res ult 
will pr o vi de ne w me dicati o n tar gets a n d will hel p lea d eff orts t o re d uce s ocietal relia nce u p o n o pi oi ds f or t he 
treat me nt of pai n. R e d uce d a vaila bilit y of o pi oi ds will lea d t o re d ucti o ns i n use/a b use a n d relate d pr o ble ms (ris k y 
i njecti o n be ha vi or, o pi oi d o ver d ose).  
 
 
1 0.  
P a y m e nt a n d Re m u n er ati o n 
a.  
Detail c o m pe nsati o n f or partici pa nts i ncl u di n g p ossi ble t otal c o m pe nsati o n, pr o p ose d b o n us, a n d a n y 
pr o p ose d re d ucti o ns or pe nalties f or n ot c o m pleti n g t he pr ot oc ol. 
 
P artici pa nts will recei ve $ 3 0 f or t he S cree ni n g Visit, a n d will recei ve pa y me nts i n a n escalati n g fas hi o n t o pr o m ote 
st u d y rete nti o n. S pecificall y, partici pa nts will ear n $ 1 5 0/ S essi o n 1, $ 2 0 0/ S essi o n 2, $ 2 5 0/ S essi o n 3, $ 3 0 0/ S essi o n 4, 
a n d $ 3 5 0/ S essi o n 5. T otal p ossi bl y st u d y-relate d ear ni n gs will be $ 1, 2 8 0. 
 
P artici pa nts will be offere d $ 2 5 f or eac h hair sa m ple pr o vi de d, f or a t otal of $ 5 0 f or t he o pti o nal s u bst u d y.  
 
1 1.  
C osts 
a.  
Detail c osts of st u d y pr oce d ure(s) or dr u g (s) or s u bsta nce(s) t o partici pa nts a n d i de ntif y w h o will 
pa y f or t he m. 
 
All st u d y relate d pr oce d ures will be pai d b y a Nati o nal I nstit ute o n Dr u g A b use gra nt; partici pa nts will n ot i nc ur a n y 
direct c ost f or st u d y partici pati o n.  
 
 


 
 
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Pa g e 1 7  of 2 0  
 
R ef er e n c e s  
 
1.    
A A P M. Facts a n d Fi g ur es o n Pai n.  2 0 1 3. Last retri ve d o nli ne 1/ 2 1/ 2 0 1 5 via htt p:// w w w. pai n me d. or g/ patie ntce nt er/f acts _ o n _ pai n. as p x 
2.    
A n ne ma ns L, Le L K, Tai e b C. S oci et al a n d pati e nt b ur de n of fi br o m yal gi a s y n dr o me. P h ar m ac oec o n o mi cs  2 0 0 9; 2 7: 5 4 7- 5 5 9. 
3.    
O' C o n n or A B. Ne ur o pat hi c pai n: q ualit y-of -lif e i m pact, c osts a n d c ost effecti ve ness of t her a p y. P h ar m ac oec o n o mi cs  2 0 0 9; 2 7: 9 5- 1 1 2. 
4.    
Li n d gr e n H, Ber g ma n S. C hr o ni c m usc ul os keletal pai n pr e di ct e d h os pit alisati o n d ue t o seri o us me di cal c o n diti o ns i n a 1 0 year f oll o w 
u p st u d y. B M C M usc ul oskelet Dis or d  2 0 1 0; 1 1: 1 2 7. 
5.    
T u n ks E R, Cr o o k J, Weir R. E pi de mi ol o g y of c hr o ni c pai n wit h ps yc h ol o gi cal c o m or bi dit y: pre val e nce, ris k, c o urse, a n d pr o g n osis. 
C a n J Psyc hi atry  2 0 0 8; 5 3: 2 2 4- 2 3 4. 
6.    
P orte n o y R K. C urr e nt p har mac ot hera p y of c hr o nic pai n. J P ai n Sy m pt o m M a n a ge  2 0 0 0; 1 9: S 1 6- S 2 0. 
7.    
Ce nter f or Disease C o ntr ol. Dr u g P ois o ni n g Deat hs i n t he U nit e d Stat es, 1 9 8 0- 2 0 0 8. N C H S D at a Brief [serial o nli ne] 2 0 1 1; N o. 8 1. 
8.    
Ce nters f or Disease C o ntr ol a n d Pre ve nti o n. Pr escri pti o n Dr u g O ver d ose i n t he U nit e d St at es: Fact S heet. C D C [seri al o nli ne] 2 0 1 4. 
9.    
Pa ul ozzi L, Mac k K, R u d d R, J o nes C. Vit al si g ns: O ver d oses of prescri pti o n o pi oi d pai n reli e vers — U nite d States, 1 9 9 9 – 2 0 0 8. 
M M W R [serial o nli ne] 2 0 1 1; 6 0: 1 4 8 7- 1 4 9 2. 
1 0.    
War ner M, C he n L H, Ma k uc D M. I ncr ease i n f at al p ois o ni n gs i n v ol vi n g o pi oi d a nal gesi cs i n t he U nit e d St at es, 1 9 9 9 – 2 0 0 6. N C H S 
d at a brief, n o 2 2 Hy attsvill e, M D: N ati o n al Ce nt er f or He alt h St atisti cs [serial o nli ne] 2 0 0 9. 
1 1.    
L A Ti mes. Dr u g deat hs n o w o ut n u m ber tr affi c fataliti es i n U. S., data s h o w. htt p:// articles l ati mes c o m/ 2 0 1 1/se p/ 1 7/l oc al/l a-me - dr u gs-
e pi de mic- 2 0 1 1 0 9 1 8 [serial o nli ne] 2 0 1 1. 
1 2.    
C D C. Pr escri pti o n Pai n kill er O ver d oses i n t he U. S. htt p:// w w w c dc g ov/ Fe at ures/ Vit alsi g ns/ P ai nkiller Over d oses/ [serial o nli ne] 2 0 1 1. 
1 3.    
Ware M A, A da ms H, G u y G W. T he me di ci nal use of ca n na bis i n t he U K: r es ults of a nati o n wi de s ur ve y. I nt J Cli n Pr act 
2 0 0 5; 5 9: 2 9 1- 2 9 5. 
1 4.    
Ware M A, D o yle C R, W o o ds R, L y nc h M E, Cl ar k AJ. Ca n na bis use f or c hr o ni c n o n-ca ncer pai n: res ults of a pr os pecti ve s ur ve y. P ai n  
2 0 0 3; 1 0 2: 2 1 1- 2 1 6. 
1 5.    
L y nc h M E, Ca m p bell F. Ca n na bi n oi ds f or tr eat me nt of c hr o ni c n o n- ca ncer pai n; a s yst e matic r e vi e w of r a n d o mize d tri als. Br J Cli n 
P h ar m ac ol  2 0 1 1; 7 2: 7 3 5- 7 4 4. 
1 6.    
Ci c he wi cz D L. S y ner gisti c i nt er acti o ns bet wee n ca n na bi n oi d a n d o pi oi d a nalgesi cs. Lif e Sci  2 0 0 4; 7 4: 1 3 1 7- 1 3 2 4. 
1 7.    
Her ke n ha m M, L y n n A B, Littl e M D et al. Ca n na bi n oi d rece pt or l ocali zati o n i n br ai n. Pr oc N atl Ac a d Sci U S A  1 9 9 0; 8 7: 1 9 3 2- 1 9 3 6. 
1 8.    
R o m S, Persi ds k y Y. Ca n na bi n oi d r ece pt or 2: p ote ntial r ole i n i m m u n o m o d ul ati o n a n d ne ur oi nfl a m mati o n. J Ne ur oi m m u ne 
P h ar m ac ol  2 0 1 3; 8: 6 0 8- 6 2 0. 
1 9.    
Nar a n g S, Gi bs o n D, Wasa n A D et al. Effi cac y of dr o na bi n ol as a n a dj u va nt tr eat me nt f or c hr o ni c pai n pati e nts o n o pi oi d t hera p y. J 
P ai n  2 0 0 8; 9: 2 5 4- 2 6 4. 
2 0.    
E d war ds R R. I n di vi d ual diff er e nces i n e n d o ge n o us pai n m o d ul ati o n as a ris k f act or f or c hr o ni c pai n. Ne ur ol o gy  2 0 0 5; 6 5: 4 3 7- 4 4 3. 
2 1.    
Mel zac k R, C o derr e TJ, Katz J, V accari n o A L. Ce ntral ne ur o pl asticit y a n d pat h ol o gi cal pai n. A n n N Y Ac a d Sci  2 0 0 1; 9 3 3: 1 5 7- 1 7 4. 
2 2.    
T o d d K H. Pai n assess me nt a n d et h ni cit y. A n n als of E mer ge ncy M e di ci ne  1 9 9 6; 2 7: 4 2 1- 4 2 3. 
2 3.    
Cl eel a n d C S, G o ni n R, Baez L, L oe hrer P, Pa n d ya KJ. Pai n a n d tr eat me nt of pai n i n mi n orit y pati e nts wit h ca ncer. T he Easter n 
C o o per ati ve O nc ol o g y Gr o u p Mi n orit y O ut pati e nt Pai n St u d y. A n n als of I nt er n al M e di ci ne  1 9 9 7; 1 2 7: 8 1 3- 8 1 6. 
2 4.    
Mc Cr ac ke n L M, Matt he ws A K, Ta n g T S, C u ba S L. A c o m paris o n of blac ks a n d w hit es see ki n g tr eat me nt f or c hr o ni c pai n. Cli n J 
P ai n  2 0 0 1; 1 7: 2 4 9- 2 5 5. 
2 5.    
St e wart W F, Li pt o n R B, Li ber ma n J. Vari ati o n i n mi grai ne pre val e nce b y race. Ne ur ol o gy  1 9 9 6; 4 7: 5 2- 5 9. 
2 6.    
( Re d d y K S, Nai d u M U, Ra ni P U, Ra o T R. H u ma n e x peri me nt al pai n m o dels: A r e vi e w of sta n dar di ze d met h o ds i n dr u g de vel o p me nt. 
J Res Me d Sci  2 0 1 2; 1 7: 5 8 7- 5 9 5. 
2 7.    
Ca m p bell C M, Kr o nfli T, B ue na ver L F, Ha yt h or nt h waite J A, S mit h M T, E d war ds R R. I n vi v o vs. st a n dar d catastr o p hi zi n g i n m ulti pl e 
pai n meas ur es a m o n g healt h y, T M D a n d art hritis patie nts [ a bstr act] Ca m p bell C M, Kr o nfli T, B ue na ver L F, Ha yt h or nt h waite J A, S m it h M T, 
E d war ds R R. J o ur n al of P ai n 2 0 0 8; 9:- 5 6 
2 8.    
Ca m p bell C M, E d war ds R R. Mi n d- b o d y i nt er acti o ns i n pai n: t he ne ur o p h ysi ol o g y of a n xi o us a n d catastr o p hic pai n-r el at e d t h o u g hts. 
Tr a nsl Res  2 0 0 9; 1 5 3: 9 7- 1 0 1. 
2 9.    
Ca m p bell C M, B o u n ds S C, Si ma n g o M B et al. Self-re p ort e d slee p d ur ati o n ass oci at e d wit h distr acti o n a nal gesi a, h y per e mi a, a n d 
sec o n dar y h y peral gesi a i n t he heat-ca psaici n n oci ce pti ve m o del. E ur J P ai n  2 0 1 0. 
3 0.    
Ca m p bell C M, B o n d K, Wac ni k P et al. Alt er ati o ns i n cli ni cal pai n a n d t e m p oral s u m mati o n f oll o wi n g s pi nal c or d sti m ul ati o n 
[ a bstr act] Ca m p bell C M, B o n d K, Wac ni k P et al. J o ur n al of P ai n 2 0 1 2; 1 3: S 6 9 
3 1.    
Ca m p bell C M, E d war ds R R. Et h nic diff er e nces i n pai n a n d pai n ma na ge me nt. P ai n M a n a g  2 0 1 2; 2: 2 1 9- 2 3 0. 
3 2.    
Merr y B, Ca m p bell C M, B ue na ver L F et al. Et h nic Gr o u p Diff er e nces i n t he O ut c o mes of M ulti disci pli nar y Pai n Tr eat me nt. J 
M usc ul oskel et P ai n  2 0 1 1; 1 9: 2 4- 3 0. 
3 3.    
Gr acel y R H. E x peri me ntal pai n m o dels. I n: Ma x M B, P ort e n o y R K, Las ka E M, e ds. A dv a nces i n p ai n rese arc h a n d t he a py: T he 
desi g n of a n al gesic cli nic al tri als.  Ne w Y or k: Ra ve n Pr ess; 1 9 9 1; 3 3- 4 7. 
3 4.    
Bac k o nj a M M, Wal k D, E d war ds R R et al. Q ua ntit ati ve se ns or y t esti n g i n meas ure me nt of ne ur o pat hi c pai n p he n o me na a n d ot her 
se ns or y a b n or malities. Cli n J P ai n  2 0 0 9; 2 5: 6 4 1- 6 4 7. 
3 5.    
W o olf CJ, Ma x M B. Mec ha nis m- base d pai n di a g n osis: iss ues f or a nal gesi c dr u g de vel o p me nt. A nest hesi ol o gy  2 0 0 1; 9 5: 2 4 1- 2 4 9. 
3 6.    
E d war ds R R, Ness TJ, Wei ge nt D A, Filli n gi m R B. I n di vi d ual diff ere nces i n diff use n o xi o us i n hi bit or y c o ntr ols ( D NI C): ass oci ati o n 
wit h cli nical vari a bles. P ai n  2 0 0 3; 1 0 6: 4 2 7- 4 3 7. 
3 7.    
Filli n gi m R B, E d war ds R R, P o well T. T he r el ati o ns hi p of se x a n d cli ni cal pai n t o e x peri me nt al pai n r es p o nses. P ai n  1 9 9 9; 8 3: 4 1 9- 4 2 5. 
3 8.    
E d war ds R R, Filli n gi m R B. Et h ni c diff ere nces i n t her mal pai n r es p o nses. Psyc h os o m M e d  1 9 9 9; 6 1: 3 4 6- 3 5 4. 
3 9.    
S he ps D S, Mc Ma h o n R P, Li g ht K C et al. L o w h ot pai n t hr es h ol d pre dicts s h orter ti me t o e xer cise-i n d uce d a n gi na: r es ults fr o m t he 
ps yc h o p h ysi ol o gical i n vesti gati o ns of m y ocar di al isc he mia ( PI MI) st u d y. J o ur n al of t he A meri c a n C oll e ge of C ar di ol o gy  1 9 9 9; 3 3: 1 85 5 - 1 8 6 2. 
4 0.    
La ute n bac her S, Filli n gi m R B, ( E ds). P at h o p hysi ol o gy of P ai n Perce pti o n . Ne w Y or k: Kl u wer Aca de mic, 2 0 0 5. 
4 1.    
Cl a u w DJ, Willia ms D, La uer ma n W et al. Pai n se nsiti vit y as a c orrel at e of cli ni cal st at us i n i n di vi d uals wit h c hr o nic l o w bac k pai n. 
S pi ne  1 9 9 9; 2 4: 2 0 3 5- 2 0 4 1. 


 
 
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Pa g e 1 8  of 2 0  
 
4 2.    
E d war ds R R, Filli n gi m R B. Eff ects of a ge o n t e m p oral s u m mati o n of t her mal pai n: cli ni cal r el e va nce i n healt h y ol der a n d y o u n ger 
a d ults. J o ur n al of P ai n 2 0 0 1; 2: 3 0 7- 3 1 7. 
4 3.    
Filli n gi m R B, Mai x ner W, Ki ncai d S, Si g ur dss o n A, Harris M B. Pai n se nsiti vit y i n patie nts wit h t e m p or o ma n di b ul ar dis or ders: 
r elati o ns hi p t o cli nical a n d ps yc h os ocial fact ors. Cli n J P ai n  1 9 9 6; 1 2: 2 6 0- 2 6 9. 
4 4.    
Gr a n ot M, L o we nstei n L, Yar nits k y D, Ta mir A, Zi m mer E Z. P ostcesar ea n secti o n pai n pre di cti o n b y pre o per ati ve e x peri me nt al pai n 
assess me nt. A nest hesi ol o gy  2 0 0 3; 9 8: 1 4 2 2- 1 4 2 6. 
4 5.    
Yar nits k y D, Cris pel Y, Eise n ber g E et al. Pre dicti o n of c hr o ni c p ost- o perati ve pai n: Pr e- o per ati ve D NI C t esti n g i de ntifi es pati e nts at 
ris k. P ai n  2 0 0 8; 1 3 8: 2 2- 2 8. 
4 6.    
Ni k ol ajse n L, Il kjaer S, Je nse n T S. Rel ati o ns hi p bet wee n mec ha ni cal se nsiti vit y a n d p ost a m p utati o n pai n: a pr os pecti ve st u d y. E ur J 
P ai n  2 0 0 0; 4: 3 2 7- 3 3 4. 
4 7.    
Wer ner M U, D u u n P, K e hl et H. Pre dicti o n of p ost o perati ve pai n b y pre o per ati ve n ocice pti ve res p o nses t o heat sti m ulati o n. 
A nest hesi ol o gy  2 0 0 4; 1 0 0: 1 1 5- 1 1 9. 
4 8.    
Bis gaar d T, Klars k o v B, R ose n ber g J, K e hlet H. C har acteristics a n d pre di cti o n of earl y pai n aft er l a par osc o pi c c h ol ec yst ect o m y. P ai n  
2 0 0 1; 9 0: 2 6 1- 2 6 9. 
4 9.    
Gr a n ot M, Zi m mer E Z, Fri e d ma n M, L o we nstei n L, Yar nits k y D. Ass oci ati o n bet wee n q ua ntitati ve se ns or y t esti n g, treat me nt c h oi ce, 
a n d s u bse q ue nt pai n r e d ucti o n i n v ul var vesti b ulitis s y n dr o me. J P ai n  2 0 0 4; 5: 2 2 6- 2 3 2. 
5 0.    
E d war ds R R, D ole ys D M, L o wer y D, Filli n gi m R B. Pai n t ol er a nce as a pre dict or of o utc o me f oll o wi n g m ulti disci pli nar y tr eat me nt f or 
c hr o nic pai n: diff er e ntial effects as a f u ncti o n of se x. P ai n  2 0 0 3; 1 0 6: 4 1 9- 4 2 6. 
5 1.    
K ose k E, Or de ber g G. Lac k of press ure pai n m o d ulati o n b y heter ot o pi c n o xi o us c o n diti o ni n g sti m ulati o n i n patie nts wit h pai nf ul 
oste oart hritis bef or e, b ut n ot f oll o wi n g, s ur gical pai n r elief. P ai n  2 0 0 0; 8 8: 6 9- 7 8. 
5 2.    
K ose k E, Or de ber g G. A b n or maliti es of s o mat ose ns or y per ce pti o n i n pati e nts wit h pai nf ul ost e oart hritis n or mali ze f oll o wi n g 
s uccessf ul tr eat me nt. E ur J P ai n  2 0 0 0; 4: 2 2 9- 2 3 8. 
5 3.    
S or e nse n J, Be n gtss o n A, A hl ner J, He nri kss o n K G, E kseli us L, Be n gtss o n M. Fi br o m yal gi a--ar e t her e differe nt mec ha nis ms i n t he 
pr ocessi n g of pai n? A d o u ble bli n d cr oss o ver c o m paris o n of a nal gesi c dr u gs. J R he u m at ol 1 9 9 7; 2 4: 1 6 1 5- 1 6 2 1. 
5 4.    
P oitr as P, Ri ber d y P M, Pl o ur de V, B oi vi n M, Verrier P. E v ol uti o n of viscer al se nsiti vit y i n patie nts wit h irrit a ble b o wel s y n dr o me. 
Di g Dis Sci  2 0 0 2; 4 7: 9 1 4- 9 2 0. 
5 5.    
E d war ds R R, Ha yt h or nt h waite J, Tell a P, Ma x M B, Raj a S N. Basal heat pai n t hr es h ol ds pr e di ct o pi oi d a nal gesia i n patie nts wit h p ost-
her peti c ne ural gi a. A nest hesi ol o gy . I n pr ess. 
5 6.    
Yar nits k y D, Gra n ot M, Na h ma n- A ver b uc h H, K ha maisi M, Gr a n o vs k y Y. C o n diti o ne d pai n m o d ulati o n pr e di cts d ul o xeti ne efficac y 
i n pai nf ul di a beti c ne ur o pat h y. P ai n  2 0 1 2; 1 5 3: 1 1 9 3- 1 1 9 8. 
5 7.    
A h ma d S, De Oli veira G SJ, Bi al e k J M, Mc Cart h y RJ. T her mal q ua ntit ati ve se ns or y testi n g t o pr e di ct p ost o perati ve pai n o utc o mes 
f oll o wi n g g y nec ol o gic s ur ger y. P ai n M e d  2 0 1 4; 1 5: 8 5 7- 8 6 4. 
5 8.    
Ol ese n S S, Gra verse n C, B o u we nse S A, va n G H, Wil der- S mit h O H, Dr e wes A M. Q ua ntit ati ve se ns or y testi n g pr e dicts pr e ga bali n 
effi cac y i n pai nf ul c hr o ni c pa ncr eatitis. P L o S O ne  2 0 1 3; 8:e 5 7 9 6 3. 
5 9.    
Eise n ber g E, Mi d bari A, Ha d da d M, P u d D. Pr e dicti n g t he a nal gesic effect t o o x yc o d o ne b y 'stati c' a n d ' d y na mic' q ua ntitati ve se ns or y 
t esti n g i n healt h y s u bj ects. P ai n  2 0 1 0; 1 5 1: 1 0 4- 1 0 9. 
6 0.    
Marti nez V, Fletc her D, B o u hassira D, Sessl er DI, C ha u vi n M. T he e v ol uti o n of pri mar y h y per al gesi a i n ort h o pe dic s ur ger y: 
q ua ntit ati ve se ns or y testi n g a n d cli nical e val uati o n bef ore a n d after t otal k nee art hr o plast y. A nest h A n al g  2 0 0 7; 1 0 5: 8 1 5- 8 2 1. 
6 1.    
C he n L, Malari c k C, Seef el d L, Wa n g S, H o u g ht o n M, Ma o J. Alt ere d q ua ntit ati ve se ns or y t esti n g o ut c o me i n s u bj ects wit h o pi oi d 
t her a p y. P ai n  2 0 0 9; 1 4 3: 6 5- 7 0. 
6 2.    
H o ot e n W M, Ma ntilla C B, Sa n dr o ni P, T o w nse n d C O. Ass oci ati o ns bet wee n heat pai n per ce pti o n a n d o pi oi d d ose a m o n g pati e nts 
wit h c hr o nic pai n u n der g oi n g o pi oi d ta peri n g. P ai n M e d  2 0 1 0; 1 1: 1 5 8 7- 1 5 9 8. 
6 3.    
M ueller C, Kl e ga A, B uc h h olz H G et al. Basal o pi oi d rece pt or bi n di n g is ass oci at e d wit h diff er e nces i n se ns or y per ce pti o n i n healt h y 
h u ma n s u bj ects: a [ 1 8 F] di pre n or p hi ne P E T st u d y. Ne ur oi m a ge  2 0 1 0; 4 9: 7 3 1- 7 3 7. 
6 4.    
E d war ds R R, Wasa n A D, Mi c h na E, Gree n ba u m S, R oss E, Ja mis o n R N. El e vate d pai n se nsiti vit y i n c hr o ni c pai n pati e nts at ris k f or 
o pi oi d mis use. J P ai n 2 0 1 1; 1 2: 9 5 3- 9 6 3. 
6 5.    
Filli n gi m R B, Ness TJ, Gl o ver T L et al. M or p hi ne r es p o nses a n d e x peri me nt al pai n: se x differe nces i n si de eff ects a n d car di o vasc ular 
r es p o nses b ut n ot a nal gesia. J P ai n 2 0 0 5; 6: 1 1 6- 1 2 4. 
6 6.    
Si bill e K, Ki n dler L L, Gl o ver T L, G o nzal ez R D, Sta u d R, Rile y J L et al. I n di vi d ual Diff er e nces i n M or p hi ne a n d B ut or p ha n ol 
A nal gesi a: A La b orat or y Pai n St u d y. Pai n Me dici ne 1 2, 1 0 7 6- 1 0 8 5. 2 0 1 1.  
6 7.    
W o olf CJ. N o vel a nal gesi c de vel o p me nt: fr o m t ar get t o patie nt or pati e nt t o tar get? C urr O pi n I nvesti g Dr u gs  2 0 0 8; 9: 6 9 4- 6 9 5. 
6 8.  C o da B, Ta na ka A, Jac o bs o n R C, D o nal ds o n G, C ha p ma n C R. H y dr o m or p h o ne a nal gesi a aft er i ntra ve n o us b ol us a d mi nistr ati o n. P ai n  
1 9 9 7; 7 1: 4 1- 4 8. 
6 9.  Pet erse n K L, Mal o ne y A, H o ke F, Da hl J B, R o w b ot ha m M C. A r a n d o mi ze d st u d y of t he effect of or al l a m otri gi ne a n d h y dr o m or p h o ne o n 
pai n a n d h y peral gesi a f oll o wi n g heat/ ca psai ci n se nsiti zati o n. J P ai n 2 0 0 3; 4: 4 0 0- 4 0 6. 
7 0.    
Pet erse n K L, R o w b ot ha m M C. A ne w h u ma n e x peri me nt al pai n m o del: t he heat/ca psai ci n se nsiti zati o n m o del. Ne ur ore p ort  
1 9 9 9; 1 0: 1 5 1 1- 1 5 1 6. 
7 1.    
Ca m p bell C M, B o u n ds S C, Si ma n g o M B et al. Self-re p ort e d slee p d ur ati o n is ass oci at e d wit h distracti o n a nal gesia, h y per e mia, a n d 
sec o n dar y h y peral gesi a i n t he heat-ca psaici n pai n m o del. 2 0 1 0;I n Press. 
7 2.    
Pet erse n K L, R o w b ot ha m M C. A ne w h u ma n e x peri me nt al pai n m o del: t he heat/ca psai ci n se nsiti zati o n m o del. Ne ur ore p ort  
1 9 9 9; 1 0: 1 5 1 1- 1 5 1 6. 
7 3.    
Dir ks J, Pet erse n K L, Da hl J B. T he heat/ ca psai ci n se nsiti zati o n m o del: a met h o d ol o gi c st u d y. J P ai n 2 0 0 3; 4: 1 2 2- 1 2 8. 
7 4.    
Issa M A, Nar a n g S, Ja mis o n R N et al. T he s u bj ecti ve ps yc h oacti ve effects of or al dr o na bi n ol st u di e d i n a r a n d o mize d, c o ntr oll e d 
cr oss o ver cli nical tri al f or pai n. Cli n J P ai n  2 0 1 4; 3 0: 4 7 2- 4 7 8. 
7 5.  S t ac her G, St ei nri n ger H, Sc h mi er er G, Wi n kl e h ner S, Sc h nei der C. Cer uleti de i ncr eases t hr es h ol d a n d t olera nce t o e x peri me nt all y i n d uce d 
pai n i n healt h y ma n. Pe pti des  1 9 8 2; 3: 9 5 5- 9 6 2. 
7 6.    
St ac her G, St ei nri n ger H, Wi n kl e h ner S, Mitt el bac h G, Sc h nei der C. Effects of gr a de d oral d oses of me pt azi n ol a n d pe nt az oci ne i n 
c o m paris o n wit h pl ace b o o n e x peri me ntall y i n d uce d pai n i n healt h y h u ma ns. Britis h J o ur n al of Cli nic al P h ar m ac ol o gy  1 9 8 3; 1 6: 1 4 9- 1 5 6. 


 
 
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Pa g e 1 9  of 2 0  
 
7 7.   
Price D D. Ps y c h o p h ysi cal meas ur e me nt of n or mal a n d a b n or mal pai n pr ocessi n g. I n: B oi vi e J, Ha nss o n P, Li n d bl o m U, e ds. T o uc h, 
Te m per at ure, a n d P ai n i n He alt h a n d Dise ase: Mec h a nis ms a n d Assess me nts.  Seattl e: I A S P Pr ess; 1 9 9 4; 3- 2 5. 
7 8.     Pri ce D D, Ma o J, Ma yer DJ. Ce ntral ne ur al mec ha nis ms of n or mal a n d a b n or mal pai n st at es. I n: Fiel ds H L, Li e bes ki n d J C, e ds. Pr o gress 
i n P ai n Rese arc h a n d M a n a ge me nt. Seattl e: I A S P Press; 1 9 9 4; 6 1- 8 4. 
7 9.    
Price D D, Ma o J, Fr e n k H, Ma yer DJ. T he N- met h yl- D- as part at e rece pt or a nt a g o nist de xtr o met h or p ha n sel ecti vel y r e d uces te m p oral 
s u m mati o n of sec o n d pai n i n ma n. P ai n  1 9 9 4; 5 9: 1 6 5- 1 7 4. 
8 0.    
W o olf CJ. Ce ntral se nsiti zati o n: i m plicati o ns f or t he dia g n osis a n d tr eat me nt of pai n. P ai n  2 0 1 1; 1 5 2: S 2- 1 5. 
8 1.    
Price D D, V o n der G A, Mill er J, Rafii A, Price C. A ps yc h o p h ysi cal a nal ysis of m or p hi ne a nal gesi a. P ai n  1 9 8 5; 2 2: 2 6 1- 2 6 9. 
8 2.    
Ye o ma ns D C, C o o per B Y, Vi er c k CJ, Jr. Effects of s yst e mic m or p hi ne o n res p o nses of pri mates t o first or sec o n d pai n se nsati o ns. 
P ai n  1 9 9 6; 6 6: 2 5 3- 2 6 3. 
8 3.   
Weiss ma n - F o gel I, Gr a n o vs k y Y, Cris pel Y et al. E n ha nce d pr es ur gi cal pai n te m p oral s u m mati o n res p o nse pr e dicts p ost-t h or ac ot o m y 
pai n i nte nsit y d uri n g t he ac ut e p ost o per ati ve p hase. J P ai n 2 0 0 9; 1 0: 6 2 8- 6 3 6. 
8 4.    
Yar nits k y D, Gra n ot M, Gr a n o vs k y Y. Pai n m o d ul ati o n pr ofil e a n d pai n t her a p y: bet wee n pr o- a n d a nti n ocice pti o n. P ai n  
2 0 1 4; 1 5 5: 6 6 3- 6 6 5. 
8 5.    
Wall ace M S, Bar ger D, Sc h ult eis G. T he eff ect of c hr o nic or al desi pr a mi ne o n ca psaici n-i n d uce d all o d y ni a a n d h y per al gesi a: a 
d o u bl e- bli n de d, pl ace b o-c o ntr oll e d, cr oss o ver st u d y. A nest h A n al g  2 0 0 2; 9 5: 9 7 3-8, t a ble. 
8 6.    
M orris V, Cr u w ys S, Ki d d B. I ncr ease d ca psaici n-i n d uce d sec o n dar y h y per al gesi a as a mar ker of a b n or mal se ns or y acti vit y i n pati e nts 
wit h fi br o m yal gi a. Ne ur oscie nce Lett ers  1 9 9 8; 2 5 0: 2 0 5- 2 0 7. 
8 7.    
Ca m p bell C M, B o u n ds S C, Si ma n g o M B et al. Self-re p ort e d slee p d ur ati o n ass oci at e d wit h distr acti o n a nal gesi a, h y per e mi a, a n d 
sec o n dar y h y peral gesi a i n t he heat-ca psaici n n oci ce pti ve m o del. E ur J P ai n  2 0 1 1; 1 5: 5 6 1- 5 6 7. 
8 8.  B u d ne y, A.J., Va n dr e y, R. G., H u g hes, J. R., M o ore, B. A., & Ba hr e n b ur g, B. ( 2 0 0 7). Or al delt a- 9- t etra h y dr oca n na bi n ol s u p presses ca n na bis 
wit h dr a wal s y m pt o ms. Dr u g a n d Al c o h ol De pe n de nce, V ol. 8 6  ( 1), p p 2 2- 2 9. 
8 9.  V a n dre y, R., Stit zer, M. L., Mi nt zer, M. Z., H uestis, M. A., M urra y, J. A., & Lee, D. ( 2 0 1 3). T he d ose eff ects of s h ort-t er m dr o na bi n ol ( oral 
T H C) mai nt e na nce i n dail y ca n na bis users. Dr u g a n d Al c o h ol De pe n de nce, V ol. 1 2 8 ( 1- 2), p p 6 4- 7 0. 
9 0.  Lile, J. A., K ell y, T. H., & Ha ys, L. R. ( 2 0 1 0). S u bstit uti o n pr ofile of t he ca n na bi n oi d a g o nist na bil o ne i n h u ma n s u bj ects discri mi nati n g 
delt a- 9-t etra h y dr oca n na bi n ol. Cli ni c al Ne ur o p h ar m ac ol o gy, V ol. 3 3 ( 5), p p 2 3 5- 2 4 2. 
9 1.  Lile, J. A., K ell y, T. H., & Ha ys, L. R. ( 2 0 1 1). Se par at e a n d c o m bi ne d effects of ca n na bi n oi d a g o nists na bil o ne a n d delat- 9- T H C i n h u ma ns 
discri mi nati n g delt a- 9- T H C. Dr u g a n d Alc o h ol De pe n de nce, V ol. 1 1 6  ( 1- 3), p p 8 6- 9 2. 
9 2.  Be di, G., C o o per, Z. D., & Ha ne y, M. ( 2 0 1 3). S u bj ecti ve, c o g niti ve, a n d car di o vasc ul ar d ose-eff ect pr ofile of na bil o ne a n d dr o na bi n ol i n 
marij ua na s m o kers. A d dicti o n Bi ol o gy, V ol. 1 8  ( 5), p p 8 7 2- 8 8 1. 
9 3.  Ha ne y, M., C o o per, Z. D., Be di, G., V os b ur g, S. K., C o mer, S. D., & F olti n, R. W. ( 2 0 1 3). Na bil o ne decr eases marij ua na wit h dra wal a n d a 
l a b or at or y meas ure of marij ua na use. Ne ur o psyc h o p h ar m ac ol o gy, V ol. 3 8 ( 8), p p 1 5 5 7- 1 5 6 5. 
9 4.  Mc C oll, S., & Sell ers, E. M. ( 2 0 0 6). Resear c h desi g n strate gi es t o e val uate t he i m pact of f or m ul ati o ns o n a b use li a bilit y.  Dr u g a n d Al c o h ol 
De pe n de nce, 8 3 S u p pl 1 , S 5 2-6 2  
9 5.  Sc h oe del, K. A., & Sell ers, E. M. ( 2 0 0 8). Assessi n g a b use li a bilit y d uri n g dr u g de vel o p me nt: C ha n gi n g st a n dar ds a n d e x pect ati o ns.  
Cli ni c al P h ar m ac ol o gy a n d T her a pe uti cs, 8 3 ( 4), 6 2 2- 6 2 6.  
9 6.  A nt oi ne, D. G., Str ai n, E. C., T o m p ki ns, D. A., & Bi gel o w, G. E. ( 2 0 1 3). O pi oi d a b users' a bilit y t o diff ere ntiate a n o pi oi d fr o m pl ace b o i n 
l a b or at or y c hall e n ge t esti n g. Dr u g a n d Alc o h ol De pe n de nce, 1 3 2( 1- 2), 3 6 9- 3 7 2. 
9 7.  T o m p ki ns, D. A., La nier, R. K., Harris o n, J. A., Strai n, E. C., & Bi gel o w, G. E. ( 2 0 1 0). H u ma n a b use li a bilit y assess me nt of o x yc o d o ne 
c o m bi ne d wit h ultr a-l o w- d ose naltr e x o ne.  Psyc h o p h ar m ac ol o gy, 2 1 0( 4), 4 7 1- 4 8 0.  
9 8.  Giriffit hs, R. R., Bi gel o w, G. E., & At or, N. A. ( 2 0 0 3). Pri nci ples of e x peri me nt al dr uf a b use lia bilit y assess me nt i n h u ma ns. Dr u g a n d 
Al c o h ol De pe n de nce, V ol. 7 0 ( 3, S u p pl); S 4 1- S 5 4 
9 9.  E d war ds, R. R., Ness, T. J., Wei ge nt, D. A., & Filli n gi m, R. B. ( 2 0 0 3). I n di vi d ual differe nces i n diff use n o xi o us i n hi bit or y c o nt r ols 
( D NI C): Ass oci ati o n wit h cli ni cal varia bles. P ai n, 1 0 6( 3), 4 2 7- 4 3 7.  
1 0 0.  
R ol ke, R., Bar o n, R., Mai er, C., T olle, T. R., Tr ee de, R. D., Be yer, A., et al. ( 2 0 0 6). Q ua ntitati ve se ns or y t esti n g i n t he ger ma n 
r esear c h net w or k o n ne ur o pat hic pai n ( D F N S): Sta n dar di ze d pr ot oc ol a n d refere nce val ues. P ai n, 1 2 3( 3), 2 3 1- 2 4 3.  
1 0 1.  
S mit h, M. T., E d war ds, R. R., Mc Ca n n, U. D., & Ha yt h or nt h wait e, J. A. ( 2 0 0 7). T he eff ects of sl ee p de pri vati o n o n pai n i n hi biti o n 
a n d s p o nta ne o us pai n i n w o me n.  Sl ee p, 3 0 ( 4), 4 9 4- 5 0 5. 
1 0 2.  
C o mer, S. D., Zac n y, J. P., D w or ki n, R. H., T ur k, D. C., Bi gel o w, G. E., F olti n, R. W., et al. ( 2 0 1 2). C ore o utc o me meas ur es f or 
o pi oi d a b use lia bilit y l a b or at or y assess me nt st u di es i n h u ma ns: I M M P A C T r ec o m me n dati o ns.  P ai n, 1 5 3( 1 2), 2 3 1 5- 2 3 2 4. 
1 0 3.  
T ot h, C., Ma wa ni, S., Bra d y, S., C ha n, C., Li u, C., Me hi na, E., Gar ve n, A., Bestar d, J., & K or n g ut, L. ( 2 0 1 2). A n e nri c he d- e nr ol me nt, 
r a n d o mi ze d wit h dr a wal, fle xi ble- d ose, d o u ble- bli n d, place b o-c o ntr olle d, parall el assi g n me nt effi cac y st u d y of na bil o ne as a n a dj u va nt i n t he 
tr eat me nt of dia betic peri p heral ne ur o pat htic pai n.   P ai n, V ol., 1 5 3  ( 1 0), p p 2 0 7 3- 2 0 8 2. 
1 0 4.  
Fa bre L F, Mc Cle n d o n D M, & Star k P D: Na bil o ne, a n d ca n na bi n oi d, i n t he tr eat me nt of a n xiet y: a n o pe n-la bel a n d d o u bl e- bli n d st u d y. 
C urr T her Res 1 9 7 8; 2 4: 1 6 1- 1 6 9. 
1 0 5.  
Price D D, H u J W, D u b ner R, a n d Gr acel y R H. Peri p her al s u p pr essi o n of first pai n a n d ce ntral s u m mati o n of sec o n d pai n e v o ke d b y 
n o xi o us heat p ulses. P ai n 3: 5 7 – 6 8, 1 9 7 7. 
1 0 6.  
E d w ar ds, R. R., S mit h, M. T., St o ner oc k, G., & Ha yt h or nt h wait e, J. A. ( 2 0 0 6). Pai n- relate d catastr o p hi zi n g i n healt h y w o me n is 
ass ociate d wit h great er t e m p or al s u m mati o n of a n d r e d uce d ha bit uati o n t o t her mal pai n.  T he Cli ni c al J o ur n al of P ai n, 2 2( 8), 7 3 0- 7 3 7.  
1 0 7.  
Yar nits k y, D. ( 2 0 1 0). C o n diti o ne d pai n m o d ulati o n (t he diff use n o xi o us i n hi bit or y c o ntr ol-li ke eff ect): Its r el e va nce f or ac ut e a n d 
c hr o nic pai n states.  C urre nt O pi ni o n i n A n aest hesi ol o gy, 2 3( 5), 6 1 1- 6 1 5. 
1 0 8.  
Yar nits k y, D., Gr a n ot, M., Na h ma n- A ver b uc h, H., K ha maisi, M., & Gr a n o vs k y, Y. ( 2 0 1 2). C o n diti o ne d pai n m o d ulati o n pr e di cts 
d ul o xeti ne efficac y i n pai nf ul di a beti c ne ur o pat h y.  P ai n, 1 5 3( 6), 1 1 9 3- 1 1 9 8.  
1 0 9.  
Strai n E C, Pr est o n K L, Li e bs o n I A, Bi gel o w G E. Ac ute eff ects of b u pr e n or p hi ne, h y dr o m or p h o ne a n d nal 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.  
Wals h S L, S ulli va n J T, Prest o n K L, Gar ner J E, Bi gel o w G E. Effects of naltr e x o ne o n res p o nse t o i ntr a ve n o us c ocai ne, 
h y dr o m or p h o ne a n d t heir c o m bi nati o n i n h u ma ns. J P h ar m ac ol Ex p T her. 1 9 9 6 N o v; 2 7 9( 2): 5 2 4- 5 3 8. 
1 1 1.  
D u ke, A. N., Bi gel o w, G. E., La ni er, R. K., & Str ai n, E. C. ( 2 0 1 1). Discri mi nati ve sti m ul us eff ects of tr a ma d ol i n h u ma ns.  T he J o ur n al 
of P h ar m ac ol o gy a n d Ex peri me nt al T her a pe uti cs, 3 3 8 ( 1), 2 5 5- 2 6 2.  


 
 
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Pa g e 2 0  of 2 0  
 
1 1 2.  
D u ke, A. N., C orreia, C. J., Wals h, S. L., Bi gel o w, G. E., & Strai n, E. C. ( 2 0 1 0). Ac ut e effects of i ntr a m usc ul ar a n d s u bli n g ual 
b u pre n or p hi ne a n d b u pr e n or p hi ne/ nal o x o ne i n n o n- de pe n de nt o pi oi d a b users.  Psyc h o p h ar m ac ol o gy, 2 1 1( 3), 3 0 3- 3 1 2.  
1 1 3.  
La nier, R. K., L of wall, M. R., Mi nt zer, M. Z., Bi gel o w, G. E., & Str ai n, E. C. ( 2 0 1 0). P h ysical de pe n de nce p ote nti al of dail y tr a ma d ol 
d osi n g i n h u ma ns.  Psyc h o p h ar m ac ol o gy, 2 1 1( 4), 4 5 7- 4 6 6.  
1 1 4.  
Strai n, E. C., Pr est o n, K. L., Li e bs o n, I. A., & Bi gel o w, G. E. ( 1 9 9 2). Ac ut e effects of b u pre n or p hi ne, h y dr o m or p h o ne a n d nal o x o ne i n 
met ha d o ne- mai nt ai ne d v ol u nteers.  T he J o ur n al of P h ar m ac ol o gy a n d Ex peri me nt al T her a pe utics, 2 6 1( 3), 9 8 5- 9 9 3.  
1 1 5.  
Strai n, E. C., Wals h, S. L., & Bi gel o w, G. E., ( 2 0 0 2). Bl oc ka de of h y dr o m or p h o ne eff ects b y b u pr e n or p hi ne/ nal o x o ne a n d 
b u pre n or p hi ne . Psyc h o p h ar m ac ol o gy, V ol. 1 5 9 ( 2), p p 1 6 1- 1 6 6.  
1 1 6.  
St olle r, K. B., Bi gel o w, G. E., Wals h, S. L., & Strai n, E. C. ( 2 0 0 1). Eff ects of b u pr e n or p hi ne/ nal o x o ne i n o pi oi d- de pe n de nt h u ma ns. 
Psyc h o p h ar m ac ol o gy, V ol. 1 5 4  ( 3), p p 2 3 0- 2 4 2. 
1 1 7.  
Strai n, E. C., St oller, K., Wals h, S. L., & Bi gel o w, G. E. ( 2 0 0 0). Eff ects of b u pr e n or p hi ne vers us b u pre n or p hi ne/ nal o x o ne t a bl ets i n n o n-
de pe n de nt o pi oi d users. Psyc h o p h ar m ac ol o gy, V ol. 1 4 8  ( 4), p p 3 7 4- 3 8 3. 
1 1 8.  
Ci c he wi cz, D. L., Marti n, Z. L., S mit h, F. L., & Wel c h, S. P. ( 1 9 9 9). E n ha nce me nt m u o pi oi d a nti n oci ce pti o n b y or al delt a 9-
t etr a h y dr oca n na bi n ol: D ose-r es p o nse a nal ysis a n d rece pt or i de ntificati o n. T he J o ur n al of P h ar m ac ol o gy a n d Ex peri me nt al T her a pe utics, 
2 8 9 ( 2), 8 5 9- 8 6 7 
1 1 9.  
Fi n n, D. P., Bec kett, S. R., R oe, C. H., Ma dj d, A., F o ne, K. C., K e n dall, D. A., et al. ( 2 0 0 4). Effects of c oa d mi nistr ati o n of 
ca n na bi n oi ds a n d m or p hi ne o n n oci ce pti ve be ha vi o ur, brai n m o n oa mi nes a n d H P A a xis acti vit y i n a r at m o del of persist e nt pai n.  T he 
E ur o pe a n J o ur n al of Ne ur osci e nce, 1 9 ( 3), 6 7 8- 6 8 6.  
1 2 0.  
S mit h, F. L., Ci c he wi cz, D., Marti n, Z. L., & Welc h, S. P. ( 1 9 9 8). T he e n ha nce me nt of m or p hi ne a nti n oci ce pti o n i n mi ce b y delt a 9-
t etr a h y dr oca n na bi n ol. P h ar m ac ol o gy, Bi oc he mistry, a n d Be h avi or, 6 0( 2), 5 5 9- 5 6 6.  
1 2 1.  
Wel c h, S. P., & St e ve ns, D. L. ( 1 9 9 2). A nti n oci ce pti ve acti vit y of i ntrat hecall y a d mi nist ere d ca n na bi n oi ds al o ne, a n d i n c o m bi nati o n 
wit h m or p hi ne, i n mice.  T he J o ur n al of P h ar m ac ol o gy a n d Ex peri me nt al T her a pe uti cs, 2 6 2( 1), 1 0- 1 8.  
1 2 2.  
Willi a ms, I. J., E d war ds, S., R u b o, A., Haller, V. L., Ste ve ns, D. L., & Wel c h, S. P. ( 2 0 0 6). Ti me c o urse of t he e n ha nce me nt a n d 
r est or ati o n of t he a nal gesi c effi cac y of c o dei ne a n d m or p hi ne b y delt a 9-tetr a h y dr oca n na bi n ol. E ur o pe a n J o ur n al of P h ar m ac ol o gy, 5 3 9( 1- 2), 
5 7- 6 3.  
1 2 3.  
Li, J. X., K oe k, W., & Fr a nce, C. P. ( 2 0 1 2). I nt er acti o ns bet wee n delta( 9)-t etra h y dr oca n na bi n ol a n d her oi n: Self-a d mi nistr ati o n i n 
r hes us m o n ke ys. Be h avi o ur al P h ar m ac ol o gy, 2 3( 8), 7 5 4- 7 6 1.  
1 2 4.  
Ma g uir e, D., & Fra nce, C. P. (i n pr ess). < br / >I m pact of effi cac y at t he m u o pi oi d r ece pt or o n a nti n oci ce pti ve effects of c o m bi nati o ns 
of m u o pi oi d rece pt or a g o nists a n d ca n na bi n oi d r ece pt or a g o nists.  J o ur n al of P h ar m ac ol o gy a n d Ex peri me nt al T her a pe utics,  
1 2 5.  
Ma g uir e, D. R., Ya n g, W., & Fr a nce, C. P. ( 2 0 1 3). I nt er acti o ns bet wee n m u- o pi oi d rece pt or a g o nists a n d ca n na bi n oi d r ece pt or 
a g o nists i n r hes us m o n ke ys: A nti n oci ce pti o n, dr u g discri mi nati o n, a n d dr u g self-a d mi nistr ati o n.  T he J o ur n al of P h ar m ac ol o gy a n d 
Ex peri me nt al T her a pe uti cs, 3 4 5 ( 3), 3 5 4- 3 6 2.  
1 2 6.  
V a d ha n N P, Hart C L, R oe B, C oll e y J, Ha ne y M, F olti n R W. S u bsta nce use a n d ps yc h os ocial o ut c o mes f oll o wi n g parti ci pati o n i n 
r esi de nti al l a b orat or y st u di es of marij ua na, met ha m p het a mi ne a n d z ol pi de m. T he A meri c a n j o ur n al of dr u g a n d alc o h ol a b use. 2 0 0 6; 3 2( 4): 
5 8 9- 9 7.  
1 2 7.  
Faillace L A, Fl a mer R N, I m ber S D, War d R F. Gi vi n g alc o h ol t o alc o h oli cs. A n e val uati o n. Q u arterl y j o ur n al of st u dies o n al c o h ol. 
1 9 7 2 Mar; 3 3( 1): 8 5- 9 0.  
1 2 8.  
K a uf ma n MJ, Le vi n J M, K u kes TJ, Villaf uert e R A, He n ne n J, L u kas S E, Me n dels o n J H, Re ns ha w P F. Illi cit c ocai ne use patt er ns i n 
i ntr a ve n o us- nai ve c ocai ne users f oll o wi n g i n vesti gati o nal i ntra ve n o us c ocai ne a d mi nistr ati o n. Dr u g a n d al c o h ol de pe n de nce. 2 0 0 0 Fe b 1; 
5 8( 1- 2): 3 5- 4 2. 
1 2 9.  
Bi gel o w G E, Br o o ner R K, Wals h S L, Pr est o n K L, Lie bs o n I A. C o m m u nit y o utc o mes f oll o wi n g researc h e x p os ur e t o c ocai ne or 
o pi oi ds. I n: Harris L S, e dit or. Pr o bl e ms of Dr u g De pe n de nce 1 9 9 4 NI D A Resear c h M o n o gra p h Series. Was hi n gt o n, D. C.: U. S. G o ver n me nt 
Pri nti n g Office; 1 9 9 5. p. 3 5 4.  
1 3 0.  
C olle ge o n Pr o bl e ms of Dr u g De pe n de nce. H u ma n s u bj ect iss ues i n dr u g a b use researc h. Dr u g a n d Al c o h ol De pe n de nce. 1 9 9 5; 3 7( 2): 
1 6 7- 1 7 5. 
1 3 1. Si n ger J D. Usi n g S A S P R O C MI X E D t o fit m ultil e vel m o dels, hierarc hical m o dels, a n d i n di vi d ual gr o wt h m o dels. J E d uc Be h av St at. 
1 9 9 8; 2 4: 3 2 3- 3 5 5. 
1 3 2. Ji c ha, C.J., L of wall, M. R., N uzz o, P. A., Ba bal o nis, S., El a yi, S. C., & Wals h, S. L. ( 2 0 1 5). Saf et y of or al dr o na bi n ol d uri n g o pi oi d 
wit h dr a wal i n h u ma ns. Dr u g a n d Al c o h ol De pe n de nce, V ol. 1 5 7, p p 1 7 9- 1 8 3.