Table 2.

Adjusted Time-updated Cox Model Examining the Association between Opioid and Mortality (All-cause, Unnatural, and Overdose), among Male Veterans on Long-term Opioid Therapy (LTOT)

	All-cause		Unnatural		Overdose
	HR (95% CI)	p value	HR (95% CI)	p value	HR (95% CI)	p value
Opioid daily dose (MEDD) (ref 120 mg)	1	n/a	1	n/a	1	n/a
21–50	1.36 (1.21, 1.52)	<0.001	1.27 (0.95, 1.69)	0.11	1.38 (0.91, 2.10)	0.13
51–90	2.06 (1.82, 2.35)	<0.001	1.68 (1.19, 2.36)	0.003	2.47 (1.57, 3.87)	<0.001
≥ 91	3.03 (2.71, 3.39)	<0.001	2.01 (1.48, 2.72)	<0.001	2.65 (1.75, 4.02)	<0.001
Suspected interruption in opioid receipt	2.30 (2.09, 2.53)	<0.001	1.47 (1.13, 1.91)	0.004	1.52 (1.04, 2.23)	0.03
Age per 10 years increment	1.62 (1.57, 1.68)	<0.001	0.91 (0.82, 1.01)	0.08	0.81 (0.70, 0.94)	0.004
Black	0.88 (0.83, 0.93)	<0.001	0.68 (0.57, 0.81)	<0.001	0.66 (0.52, 0.83)	0.001
Smoking (ref never)	1	n/a	1	n/a	1	n/a
Current	1.63 (1.49, 1.78)	<0.001	1.96 (1.47, 2.62)	<0.001	1.99 (1.32, 3.01)	0.001
Former	1.10 (0.98, 1.23)	0.10	1.25 (0.86, 1.82)	0.24	1.22 (0.71, 2.09)	0.47
Hepatitis C	1.56 (1.47, 1.65)	<0.001	1.70 (1.44, 2.01)	<0.001	2.36 (1.88, 2.95)	<0.001
Substance use disorders*	1.41 (1.32, 1.50)	<0.001	1.85 (1.55, 2.20)	<0.001	2.18 (1.72, 2.76)	<0.001
Psychiatric disorders**	0.89 (0.83, 0.95)	0.0002	1.30 (1.10, 1.54)	0.002	1.30 (1.03, 1.63)	0.02
Benzodiazepine receipt	1.12 (1.04, 1.20)	0.002	1.73 (1.44, 2.07)	<0.001	2.00 (1.58, 2.54)	<0.001
VACS index score 2.0 (ref <75)	1	n/a	1	n/a	1	n/a
≥75	5.68 (4.91, 6.58)	<0.001	1.24 (0.63, 2.47)	0.53	1.27 (0.54, 2.95)	0.58
Missing	3.51 (3.21, 3.82)	<0.001	2.42 (1.95, 3.00)	<0.001	2.28 (1.73, 3.02)	<0.001

^*Substance use disorders is a composite of alcohol and drug disorder

^**Psychiatric disorders is a composite of bipolar disorder, major depression, PTSD, and schizophrenia; and MEDD – Morphine equivalent daily dose. HR (95% CI) for smoking missing vs. never was 10.69 (9.53, 12.00), 15.26 (10.56, 22.04), and 14.02 (8.25, 23.82),respectively.