Predictors of treatment allocation guesses in a randomized controlled trial testing double-blind injectable hydromorphone and diacetylmorphine for severe opioid use disorder

Figures & data

Table 1. Reasons for perceived treatment assignment guess – summary statistics for emerging categories and association with treatment guess at six months.

	Guessed DAM	Guessed HDM	Unsure
Major categories^a	n = 64	n = 95	n = 39
Prior experience with opioids:
Yes (e.g. ‘I know how the drug feels’)^b^,^i^,^j	32 (36.0%)	53 (59.6%)	4 (4.5%)
No	32 (29.4%)	42 (38.5%)	35 (32.1%)
Presence of drug effects:
Made negative comments (e.g. ‘I get itchy’)^c^,^h^,^j	13 (16.9%)	55 (71.4%)	9 (11.7%)
Did not make negative comments	51 (42.1%)	40 (33.1%)	30 (24.8%)
Made positive or neutral comments (e.g. ‘the taste’)^d^,^h^,^i	32 (58.2%)	19 (34.5%)	4 (7.3%)
Did not make positive or neutral comments	32 (22.4%)	76 (53.1%)	35 (24.5%)
Absence of drug effects:
Made positive comments (e.g. ‘has no legs’)^e^,^h	2 (10.0%)	18 (90.0%)	0 (0.0%)
Did not make positive comments	62 (34.8%)	77 (43.3%)	39 (21.9%)
Made neutral comments (e.g. ‘I get pins and needles’)^f	9 (47.4%)	9 (47.4%)	1 (5.3%)
Did not make neutral comments	55 (30.7%)	86 (48.0%)	38 (21.2%)
Other comments:
Yes (e.g. ‘unsure’; ‘inconsistent effects’)^g^,^i^,^j	6 (12.0%)	7 (14.0%)	37 (74.0%)
No	58 (39.2%)	88 (59.5%)	2 (1.4%)

DAM: diacetylmorphine; HDM: hydromorphone.

Data shown are n (%). Significance testing from the unadjusted multinomial logistic regression p<.05.

a Categories for emerging themes from open-ended reasons for perceived treatment assignment are not mutually exclusive since participants could have referenced the presence and absence of effects within the same open comment.

b Reasons for treatment assignment guess that referenced prior experiences with illicit heroin, licit and illicit hydromorphone and morphine were coded in this theme.

c Reasons for treatment assignment guess that referenced undesirable or uncomfortable side effects (e.g. headaches, heavy feelings in chest, anxiety).

d Reasons for treatment assignment guess that referenced general side effects (e.g. the feeling) or positive effects (e.g. pain management).

e Reasons for treatment assignment guess that referenced the absence of a desired drug reaction (e.g. euphoric sensations).

f Reasons for treatment assignment guess that referenced the absence of an anticipated drug effect that was perceived to be associated with DAM or HDM.

g This theme was created to capture references by participants who were unsure, for participants with missing reasons, and references with unclear meanings (e.g. ‘inconsistent’).

h For DAM vs. HDM.

i For DAM vs. unsure.

j For HDM vs. unsure.

Table 2. Six-month primary and secondary efficacy outcomes by treatment guess.

	Guessed DAM	Guessed HDM	Unsure
Outcome variable	n = 64	n = 95	n = 39
Prior 30 days street heroin use	4.33 ± 7.94	4.58 ± 8.82	3.33 ± 6.10
Positive for street heroin markers	15 (23.8%)	24 (26.4%)	10 (25.6%)
Prior 30 days any street opioid use^a	5.47 ± 9.02	5.36 ± 9.24	4.74 ± 7.55
Prior 30 days crack cocaine use	7.03 ± 11.23	8.14 ± 11.22	8.79 ± 12.14
Prior 30 days illegal activities	5.41 ± 10.44	2.76 ± 6.59	3.53 ± 8.53
MAP Physical health score^b^,^d^,^e	9.59 ± 7.58	12.57 ± 8.39	12.61 ± 8.51
MAP Psychological health score^b^,^d^,^e	6.98 ± 7.30	9.35 ± 8.44	9.00 ± 9.40
SALOME compliance^c	54 (84.4%)	76 (80.0%)	27 (69.2%)

DAM: diacetylmorphine; HDM: hydromorphone.

Data shown are n (%) and mean ± standard deviation. Pairwise comparisons were performed using: (1) chi-square test for positive for street heroin markers and compliance; (2) regression for physical and psychological health scores; or (3) negative binomial regression for days of illicit heroin, opiates, crack cocaine, and illegal activities for continuous variables. Continuous outcomes were adjusted by their baseline values using analysis of covariance.

Data not shown: Results from the analysis of statistical interaction between treatment guess and treatment assigned on outcomes revealed a significant interaction only for physical health score (p = .03). Specifically, physical health was significantly better among those randomized to HDM and guessing DAM (mean ± SD = 9.00 ± 7.95) compared to those randomized to HDM and guessing HDM (mean ± SD = 13.14 ± 8.59; p = .017). This interaction was not observed among those randomized to diacetylmorphine and guessing diacetylmorphine (mean ± SD = 10.03 ± 7.38) compared to those randomized to diacetylmorphine and guessing hydromorphone (mean ± SD = 11.88 ± 8.19; p = 1.00).

a Includes street use of heroin, morphine, hydromorphone, and speedball (combined street opioids and stimulants).

b Maudsley Addiction Profile: Physical and psychological health scores range from 0 to 40, higher scores indicate poorer health.

c Participants receiving at least 28 out of 30 days treatment based on clinical medication dispensation records at the six-month follow-up date.

d p < .05 for DAM vs. HDM.

e p < .05 for DAM vs. unsure.

Table 3. Summary statistics and unadjusted multinomial regression analysis of predictors of treatment guess at six months.

	Guessed DAM	Guessed HDM	Unsure
Variable	n = 64	n = 95	n = 39
Age^g	42.69 ± 10.60	45.82 ± 8.61	42.44 ± 9.83
Gender
Women	22 (35.5%)	26 (41.9%)	14 (22.6%)
Men	42 (30.9%)	69 (50.7%)	25 (18.4%)
Ancestry
Aboriginal	18 (29.5%)	29 (47.5%)	14 (23.0%)
Non-Aboriginal	46 (33.6%)	66 (48.2%)	25 (18.2%)
Randomization arm
DAM	35 (35.7%)	44 (44.9%)	19 (19.4%)
HDM	29 (29.0%)	51 (51.0%)	20 (20.0%)
Week 1 Guess:^a^,^g^,^h
DAM	39 (55.7%)	23 (32.9%)	8 (11.4%)
HDM	9 (15.0%)	34 (56.7%)	17 (28.3%)
Unsure	10 (22.2%)	26 (57.8%)	9 (20.0%)
Week 1 VAS score post-drug intake^b
Drug effect	63.43 ± 27.45	55.82 ± 31.13	52.79 ± 25.68
Drug liking^g	69.30 ± 30.14	57.75 ± 32.54	61.44 ± 32.47
Good effect^g	71.79 ± 27.51	61.20 ± 33.06	61.47 ± 31.42
Bad effect	9.29 ± 19.49	10.88 ± 21.83	10.88 ± 18.81
Drug-related high^g^,^h	59.60 ± 32.15	41.54 ± 35.98	40.94 ± 32.87
Sick	6.49 ± 19.23	6.75 ± 19.74	5.53 ± 13.25
Ever used prescribed or illicit HDM
Yes	58 (33.7%)	82 (47.7%)	32 (18.6%)
No	6 (23.1%)	13 (50.0%)	7 (26.9%)
Days in SALOME treatment from 0 to 6 months^h	169.89 ± 21.03	159.69 ± 42.62	142.92 ± 57.67
Days with SALOME treatment in prior 30 days	27.00 ± 7.59	25.52 ± 9.73	23.28 ± 11.39
Average dose received in prior 30 days	517.29 ± 249.68	472.02 ± 242.47	447.27 ± 327.35
Number of related AEs	2.81 ± 4.12	2.53 ± 5.17	2.74 ± 5.23
Number of related SAEs	0.14 ± 0.47	0.09 ± 0.41	0.23 ± 0.71
Had an observed drowsiness event related to the medication^c^,^g
Yes	30 (46.2%)	23 (35.4%)	12 (18.5%)
No	34 (25.6%)	72 (54.1%)	27 (20.3%)
Had an observed allergic reaction related to the medication^d
Yes	11 (25.6%)	25 (58.1%)	7 (16.3%)
No	53 (34.2%)	70 (45.2%)	32 (20.6%)
Any negative reason for perceived treatment assignment^e^,^g^,^i
Yes	15 (16.9%)	65 (73.0%)	9 (10.1%)
No	49 (45.0%)	30 (27.5%)	30 (27.5%)
Any neutral or positive reason for perceived treatment assignment^f^,^g^,^h^,^i
Yes	40 (56.3%)	26 (36.6%)	5 (7.0%)
No	24 (18.9%)	69 (54.3%)	34 (26.8%)

DAM: diacetylmorphine; HDM: hydromorphone; VAS: Visual Analog Score; AEs: adverse events; SAEs: serious adverse events.

Data shown are n (%) and mean ± standard deviation. Significance testing from the unadjusted multinomial logistic regression p<.05.

a Treatment assignment guesses from post-titration/early in the study.

b Visual analog scale (VAS) for participant’s subjective evaluation of drug-related high score post-drug intake collected post-titration/early in the study by a trained peer-interviewer at the clinic. Completed by 175 participants.

c Related drowsiness events defined and assessed objectively by clinic nurses during the post-drug intake assessments. A related drowsiness event includes mild (easy to arouse, does NOT require intervention, able to pass post-assessment), moderate (failure of first post-assessment) and severe (requiring any treatment or intervention, such as oxygen, naloxone).

d Related allergic reactions were defined and assessed objectively by clinic nurses during the post-drug intake assessments. A related allergic reaction includes any histamine reaction localized to the application site or reactions occurring immediately post-injection.

e Participants providing an open-ended reason for perceived treatment assignment in which the discourse referenced negative or undesirable aspects of the medication. Specific themes collapsed into this category included the presence of negative drug effect or absence of a positive drug effect. Note that one participant’s reason for treatment assignment guess may have been coded at both negative and neutral. For example, seven participants’ reasons were coded at both the presence of negative and neutral drug effects.

f Participants providing an open-ended reason for perceived treatment assignment in which the discourse was neutral or positive in nature. Specific themes collapsed into this category included the presence of positive or neutral drug effects, or absence of negative or neutral drug effects.

g Significance testing from the unadjusted multinomial logistic regression p < 0.05 for DAM vs. HDM.

h Significance testing from the unadjusted multinomial logistic regression p < 0.05 for DAM vs. unsure.

i Significance testing from the unadjusted multinomial logistic regression p < 0.05 for HDM vs. unsure.

Table 4. Multivariable multinomial logistic regression models for predictors of treatment guess at six months.

	DAM vs. HDM	DAM vs. unsure	HDM vs. unsure
Predictor	OR (95% CI)	OR (95% CI)	OR (95% CI)
Week 1 VAS drug-related high score	1.02 (1.00, 1.03)^a	1.01 (1.00, 1.03)	1.00 (0.98, 1.01)
Had an observed drowsiness event related to the medication:
Yes vs. no	3.32 (1.44, 7.97)^a	1.81 (0.60, 5.68)	0.54 (0.18, 1.65)
Any negative reason for perceived treatment assignment:
Yes vs. no	0.14 (0.06, 0.31)^a	2.52 (0.75, 9.29)	18.30 (6.12, 64.33)^a
Any neutral or positive reason for perceived treatment assignment:
Yes vs. no	1.91 (0.68, 5.84)	34.77 (10.8 132.54)^a	18.22 (6.02, 65.39)^a

DAM: diacetylmorphine; HDM: hydromorphone; OR: odds ratio; 95% CI: 95% confidence interval; VAS: Visual Analog Score.

All models were fit using Firth’s Penalized Likelihood. Data shown are OR (95% confidence intervals) for the odds of guessing DAM vs. HDM, DAM vs. Unsure or HDM vs. Unsure.

a Indicates a significant association (p<.05) based on the multivariable multinomial logistic regression model, which was built on 175 observations (since the VAS was completed by 175 participants and entered the model).