Incidence of Opioid Overdose Among Patients Using ER/LA Opioid Analgesics Before and After Implementation of the Class-Wide Opioid Risk Evaluation and Mitigation Strategy

Figures & data

Figure 1 Examples of study entry and baseline covariate ascertainment windows.

Table 1 Formation of the Study Cohorts*

	Pre-Implementation Period		Active Period
	N	%	N	%
HIRD
Patients with ≥1 ER/LA opioid analgesic dispensing during the study period**	174,233
≥1 ER/LA opioid analgesic dispensing during the applicable REMS period	99,074	100.0	92,925	93.8
Enrolled in health plan 6 months prior to first ER/LA opioid analgesic dispensing during the exposure period	78,734	79.5	69,445	70.1
Retained after propensity score trimming	71,800	72.5	59,465	60.0
Medicaid
Patients with ≥1 ER/LA opioid analgesic dispensing during the study period**	23,981
≥1 ER/LA opioid analgesic dispensing during the applicable REMS period	7568	100.0	17,377	72.5
Enrolled in health plan 6 months prior to first ER/LA opioid analgesic dispensing during the exposure period	5688	75.2	10,686	61.5
Retained after propensity score trimming	4889	64.6	7921	45.6

Notes: Pre-implementation Period: 1 July 2010 to 30 June 2012. Active Period: 1 July 2012 to 30 September 2016. *For continuous variables, descriptive statistics other than N and % are shown as designated in the first column. **No patients were excluded due to missing or invalid gender or age at the ER/LA opioid dispensing.

Abbreviations: N, number; ER/LA, extended release/long-acting; HIRD, HealthCore Integrated Research DatabaseSM; REMS, Risk Evaluation and Mitigation Strategy.

Table 2 Patient Characteristics by Study Period and Insurance Type

	HIRD				Medicaid
	Pre-Implementation Period		Active Period		Pre-Implementation Period		Active Period
	71,800		59,465		4889		7921
	N*	%	N	%	N	%	N	%
Age category (years)
Under 18	583	0.8	454	0.8	56	1.2	106	1.3
18 to 34	6930	9.7	4953	8.3	1159	23.7	1585	20.0
35 to 49	16,604	23.1	12,435	20.9	2158	44.1	3372	42.6
50 to 64	28,746	40.0	25,328	42.6	1470	30.1	2775	35.0
65 and over	18,937	26.4	16,295	27.4	46	0.9	83	1.1
Female	39,800	55.4	32,440	54.6	3082	63.0	4920	62.1
Geographic region of patient residence (US)
Midwest	19,390	27.0	17,116	28.8	470	9.6	1149	14.5
Northeast	10,332	14.4	8091	13.6	<10		11	0.1
South	15,293	21.3	13,391	22.5	4328	88.5	6651	84.0
West	19,640	27.4	15,707	26.4	<10		<10
Missing/unknown	7145	10.0	5160	8.7	84	1.7	101	1.3
Residence type
Urban	52,358	72.9	43,039	72.4	3347	68.5	5497	69.4
Rural	12,292	17.1	11,263	18.9	1458	29.8	2323	29.3
Unknown	7150	10.0	5163	8.7	84	1.7	101	1.3
Year of cohort entry
2010	34,060	47.4	0	0.0	2317	47.4	0.00	0.00
2011	26,909	37.5	0	0.0	1332	27.2	0.00	0.00
2012	10,831	15.1	0	0.0	1240	25.4	0.00	0.00
2013	0	0.0	26,300	44.2	0	0.0	3943	49.78
2014	0	0.0	15,334	25.8	0	0.0	1530	19.32
2015	0	0.0	11,794	19.8	0	0.0	1492	18.84
2016	0	0.0	6037	10.2	0	0.0	956	12.07
Duration of baseline period (months)
Mean, SD	43.1	21.17	55.4	36.9	26.0	13.14	34.5	24.67
Median	51		48		28		27
Range (min, max)	6	78	6	129	6	54	6	105
Duration of follow-up (months)
Mean, SD	11.7	7.93	16	12.57	10.5	8.13	19.9	13.6
Median	11		13		8		18
Range (min, max)	0	24	0	39	0	24	0	39
Pain diagnosis
Abdominal pain	34,570	48.1	30,076	50.6	2629	53.8	4439	56.0
Amputation	5034	7.0	5199	8.7	222	4.5	421	5.3
Arthritis, arthropathies, osteoarthritis and musculoskeletal pain	42,609	59.3	37,899	63.7	2715	55.5	4652	58.7
Back pain	55,219	76.9	46,858	78.8	4315	88.3	6905	87.2
Chronic pain	18,519	25.8	21,701	36.5	2755	56.4	4816	60.8
Fibromyalgia	19,434	27.1	17,642	29.7	1544	31.6	2644	33.4
Headache	23,366	32.5	20,663	34.7	2285	46.7	3737	47.2
Malignancy	20,314	28.3	18,420	31.0	606	12.4	1228	15.5
Multiple sclerosis	967	1.3	811	1.4	72	1.5	122	1.5
Neuropathic pain	5472	7.6	6137	10.3	379	7.8	924	11.7
Peripheral vascular disease with claudication, ischemic extremity pain and/or skin ulcers	16,855	23.5	15,294	25.7	937	19.2	1778	22.4
Stroke	7900	11.0	7297	12.3	315	6.4	591	7.5
None of the above	3047	4.2	1743	2.9	99	2.0	170	2.1
Psychiatric comorbidities
Alcoholism	3629	5.1	3565	6.0	608	12.4	1109	14.0
Anxiety disorder	21,900	30.5	21,593	36.3	2272	46.5	4069	51.4
Bipolar disorder	3125	4.4	2791	4.7	861	17.6	1505	19.0
Depressive disorder	20,397	28.4	19,243	32.4	2147	43.9	3783	47.8
History of suicide attempt	550	0.8	552	0.9	155	3.2	248	3.1
Post-traumatic stress disorder	1226	1.7	1276	2.1	274	5.6	598	7.5
Sleep disorder	22,022	30.7	20,571	34.6	1846	37.8	3221	40.7
Somatoform disorder	125	0.2	141	0.2	10	0.2	17	0.2
Drug dependence
Opioid type dependence	4015	5.6	4372	7.4	1080	22.1	1948	24.6
Other drug dependence	4494	6.3	4852	8.2	1371	28.0	2408	30.4
ADHD	2172	3.0	2182	3.7	363	7.4	678	8.6
History of overdose/poisoning	556	0.8	686	1.2	102	2.1	220	2.8
Conditions that may affect opioid metabolism
Liver disease	11,499	16.0	10,781	18.1	351	7.2	638	8.1
Renal disease	6845	9.5	6642	11.2	363	7.4	678	8.6
Deyo-Charlson comorbidity index
Mean, SD	2.8	3.46	3.2	3.69	2.2	7.18	3	3
Median	1		2		1		1
Range (min, max)	0	20	0	23	0	18	0	20
History of healthcare utilization
All cause ED visits
Mean, SD	0.4	0.88	0.4	0.94	8.4	5.07	8.6	5.39
Median	0		0		8		8
Range (min, max)	0	40	0	44	0	40	0	56
All cause office visits
Mean, SD	7.2	5.68	7	6	1.2	2.44	1.2	2.23
Median	6		6		0		0
Range (min, max)	0	98	0	94	0	40	0	44
All cause hospitalizations
Mean, SD	0.5	0.96	1	1	0.5	1.09	0.5	1.04
Median	0		0		0		0
Range (min, max)	0	36	0	20	0	11	0	13
Distinct medication classes dispensed
Mean, SD	9.5	6.08	9.6	6.03	12.7	7.18	12.8	7.26
Median	9		9		12		12
Range (min, max)	0	52	0	59	0	50	0	57

Note: *For continuous variables, descriptive statistics other than N and % are shown as designated in the first column.

Abbreviations: HIRD, HealthCore Integrated Research Database; SD, standard deviation; min, minimum; max, maximum; US, United States; ADHD, attention-deficit/hyperactivity disorder; ED, emergency department; N, number.

Table 3 Baseline Medication Use by Study Period and Insurance Type

	HIRD				Medicaid
	Pre-Implementation Period		Active Period		Pre-Implementation Period		Active Period
	71,800		59,465		4889		7921
	N	%	N	%	N	%	N	%
New ER/LA opioid analgesic user	45,896	63.9	37,905	63.7	2952	60.4	4473	56.5
Prior use of opioid analgesics
ER/LA opioid analgesic only	1329	1.9	1164	2.0	74	1.5	101	1.3
IR opioid analgesic only	39,195	54.6	32,617	54.9	2858	58.5	4264	53.8
Both ER/LA and IR opioid analgesics	24,575	34.2	20,396	34.3	1863	38.1	3347	42.3
Number of different ER/LA opioid analgesic dispensings
Mean, SD	1.5	0.79	1.5	0.80	1.4	0.66	1.5	0.81
Median	1		1		1		1
Range (min, max)	1	7	1	7	1	6	1	6
Duration of ER/LA opioid analgesic use (months)
Mean, SD	20.7	18.01	26.8	26.83	13.0	9.34	15.5	15.68
Median	15		17		10		10
Range (min, max)	0	57	0	92	0	32	0	67
Time since last ER/LA opioid analgesic use (months)
Mean, SD	5.2	11.87	7.4	17.67	3.1	7.64	3.3	9.53
Median	0		0		0		0
Range (min, max)	0	73	0	122	0	49	0	84
Number of ER/LA opioid analgesics dispensed
Mean, SD	21.0	20.26	26.9	29.12	14.4	12.56	0.0	18.26
Median	14		16		11		10
Range (min, max)	1	7	1	383	1	131	1	192
Prescribing physician specialty (on index date)
Pain specialist	27,644	38.5	22,711	38.2	1642	33.6	2553	32.2
General, internal medicine or family practice physician	20,944	29.2	16,367	27.5	960	19.6	1731	21.9
Other specialist	6807	9.5	5365	9.0	725	14.8	1207	15.2
Unknown	3583	5.0	3164	5.3	338	6.9	655	8.3
Non-physician	12,822	17.9	11,858	19.9	1224	25.0	1775	22.4
Number of prescribers of opioid analgesics
Mean, SD	2.8	2.24	3.3	2.90	2.5	7.64	2.7	2.38
Median	2		2		2		2
Range (min, max)	1	73	1	39	1	49	1	31
Number of pharmacies where patient obtained opioid analgesics
Mean, SD	20.7	18.01	26.8	26.83	13.0	9.34	15.5	15.68
Median	15		17		10		10
Range (min, max)	0	7	0	92	0	131	0	67
Number IR opioid analgesics dispensed
Mean, SD	18.5	24.42	21.9	31.58	24.2	20.27	27.0	27.22
Median	8		9		20		17
Range (min, max)	0	371	0	458	0	191	0	388
Non-opioid medications of abuse potential
Depressants
Benzodiazepines	32,807	45.7	27,495	46.2	2689	55.0	4250	53.7
Barbiturates	247	0.3	178	0.3	21	0.4	36	0.5
Other sleep medications	22,702	31.6	17,881	30.1	1736	35.5	2629	33.2
Stimulants
Amphetamines	2887	4.0	2648	4.5	271	5.5	462	5.8
Methylphenidate	1908	2.7	1565	2.6	72	1.5	117	1.5

Abbreviations: ER/LA, extended release/long-acting; HIRD, HealthCore Integrated Research Database; IR, immediate-release; SD, standard deviation; min, minimum; max, maximum; N, number.

Table 4 Opioid Overdose or Poisoning Events

	Pre-Implementation Period					Active Period					Unadjusted			Adjusted for Propensity Score Decile
	Cases	Person-Years	Incidence Rate	95% CI		Cases	Person-Years	Incidence Rate	95% CI		Incidence Rate Ratio	95% CI		Incidence Rate Ratio	95% CI
HIRD
Overdose emergency department visits or hospitalizations
All ER/LA opioid analgesic users	353	39,689	88.94	79.90	98.72	418	40,740	102.60	93.00	112.93	1.14	0.94	1.38	1.01	0.87	1.17
New ER/LA opioid analgesic users	116	12,458	93.11	76.94	111.68	179	12,783	140.03	120.26	162.11	1.31	0.96	1.78	1.29	1.02	1.65
Non-new ER/LA opioid analgesic users	237	27,231	87.03	76.31	98.85	239	27,956	85.49	74.99	97.04	1.03	0.80	1.31	0.87	0.72	1.05
Overdose deaths
All ER/LA opioid analgesic users	37	39,748	9.31	6.55	12.83	29	40,972	7.08	4.74	10.17	0.66	0.34	1.28	0.60	0.30	1.21
Medicaid
Overdose emergency department visits or hospitalizations
All ER/LA opioid analgesic users	69	2905	237.49	184.79	300.56	151	7865	192.00	162.60	225.18	0.89	0.63	1.27	0.70	0.52	0.93

Abbreviations: HIRD, HealthCore Integrated Research Database; ER/LA, extended release/long-acting; CI, confidence interval.

Figure 2 Incidence rate ratio of opioid overdose and opioid overdose death.

Abbreviation: HIRD, HealthCore Integrated Research Database.