Opioid Co-Prescribing with Sedatives After Implant-Based Breast Reconstruction

Abstract

Background:

Skeletal muscle relaxants (SMR) and benzodiazepines are thought to mitigate against postoperative muscle contraction. The Centers for Disease Control and the Food and Drug Administration warn against co-prescribing opioids with SMR/benzodiazepines due to increased risks of overdose and death. We evaluated the frequency of co-prescribing of opioids with SMRs/benzodiazepines after implant-based reconstruction.

Methods:

We examined healthcare claims to identify women (18–64 years old) who underwent implant-based breast reconstruction (IBBR) between January 2008 and June 2019 to determine the frequency of co-prescribing and associated factors. We determined factors associated with co-prescribing of opioids and SMRs/benzodiazepines, and the impact on opioid refills within 90 days of reconstruction.

Results:

86.7% (7,574) of women who had IBBR filled an opioid prescription peri-operatively. Of these, 27.7% of women filled opioids and benzodiazepines, 14.4% filled opioids and SMRs, and 2.4% filled opioids, benzodiazepines, and SMRs. Risk factors for co-prescribing opioids and benzodiazepines include use of acellular dermal matrix, immediate reconstruction, and history of anxiety. Women who filled opioids and SMRs, opioids and benzodiazepines, and opioids with SMRs and benzodiazepines were significantly more likely to refill opioid prescriptions, even when controlling for preoperative opioid exposure.

Conclusions:

Nearly half of women filled an opioid prescription with a benzodiazepine, SMR, or both after IBBR. Co-prescribing of opioids with SMRs may potentiate opioid use after surgery and should be avoided given the risks of sedation. Identifying strategies that avoid sedatives to manage pain following breast reconstruction is critical to mitigate high-risk prescribing practices.

INTRODUCTION

Implant-based breast reconstruction (IBBR) is commonly performed, with about 70,000 women undergoing these procedures in the United States each year.^1,2 Postoperatively, most women who undergo IBBR are prescribed opioid analgesics to manage their acute postoperative pain.³ In addition to opioid medications, surgeons and surgical providers may also prescribe skeletal muscle relaxants (SMRs) and/or benzodiazepines^4,5 as these classes of medications are thought to improve pain and mitigate postoperative muscle contraction, particularly after subpectoral implant placement for breast reconstruction. However, co-prescribing of opioids with SMRs and/or benzodiazepines may lead to significant adverse effects. The Food and Drug Administration (FDA) in 2016 mandated a black box warning emphasizing the risk of profound sedation, respiratory depression, coma, and death with concomitant use of opioids and other CNS depressants including benzodiazepines and SMRs.^6–10 The Centers for Disease Control (CDC) also recommend clinicians avoid prescribing opioids concurrently with benzodiazepines whenever possible given higher risk of overdose.^11–13

Opioid use after breast reconstruction has been extensively studied, demonstrating that about 90% of opioid naïve women who undergo breast reconstruction fill an opioid prescription after surgery.³ Moreover, one in 10 of these previously opioid naïve women undergoing breast reconstruction will meet criteria for prolonged opioid use,³ emphasizing an important risk of perioperative opioid use after breast reconstruction. In order to reduce the consumption of opioids and to achieve early and safe recovery after breast reconstruction, several groups have developed Enhanced Recovery after Surgery (ERAS) protocols that advocate for use of multimodal analgesics.^4,5,14,15 Although there is evidence that these ERAS and multimodal analgesia protocols reduce opioid consumption after breast reconstruction,^5,14 some of these pathways advocate for the use of opioids with SMRs and/or benzodiazepines,^4,5 which can lead to adverse outcomes. Despite the risks associated with concurrent use of opioids with benzodiazepines and/or SMRs, little is known about the frequency or risk factors of co-prescribing of these medications after IBBR.

Given the high volume of IBBR, we sought to evaluate the frequency of co-prescribing of opioids with benzodiazepines and/or SMRs after IBBR. We hypothesized that some women undergoing IBBR would be co-prescribed opioids with benzodiazepines and/or SMRs, and hypothesized that co-prescribing with SMRs would be more common than benzodiazepines given the known added risks of overdose when opioids are taken with benzodiazepines. Secondarily, we sought to identify risk factors associated with co-prescribing and opioid refills after IBBR. Identifying risk factors associated with co-prescribing among breast reconstruction patients is critical to preventing adverse effects and to improving the care of this patient population.

METHODS

Data Sources and Patient Cohort

We identified women aged 18–64 years old from the Optum de-identified Clinformatics Data Mart Database who underwent mastectomy between January 1, 2008 and June 30, 2018 and had breast reconstruction between January 1, 2008 and June 30, 2019. The Optum Clinformatics Data Mart Database is a nationwide administrative private insurance claims database that includes patient demographic information, medical claims data (i.e., procedure codes, diagnosis codes, admission and discharge dates, etc.), outpatient pharmaceutical claims, laboratory tests and results, utilization of inpatient and outpatient services (i.e., length of stay, admit and discharge diagnoses, facility detail, standard pricing, etc.), and provider data.¹⁶ We required continuous insurance coverage for 12 months prior to their surgery date and 3 months after their discharge date. We included women who were naive to benzodiazepines and SMRs (i.e., did not fill a benzodiazepine or SMR between 365 and 31 days prior to surgery based on pharmaceutical claims) but had differing preoperative exposures to opioids identified through opioid fills in claims data. Age 64 was used as the upper limit as we sought to exclude women 65 years and older who may have had medical and/or pharmaceutical claims through Medicare, providing our dataset with incomplete data.

Given the differences in autologous and IBBR, we chose to focus our analysis on women who had undergone IBBR and excluded patients who had autologous or hybrid procedures (i.e., latissimus dorsi flap with or without implant). Additionally, any patient who had a length of stay for more than 30 days or who was not discharged home was excluded. Recognizing that many women who undergo tissue expander placement eventually exchange the expander for a permanent implant, we did not exclude patients who had additional surgeries within the 3-month follow-up period; however, we analyzed only the first surgery encounter that met inclusion criteria to ensure patients were only included in the dataset once. This study was deemed exempt by the Human Research Protection Program at the University of Michigan.

Mastectomy and breast reconstruction codes were identified by Current Procedural Terminology Fourth Edition (CPT-4), International Classification of Diseases, 9^th edition, Clinical Modification procedure (ICD-9 CM), and/or International Classification of Diseases, 10^th edition, Procedural Classification System (ICD-10) codes (See Table, Supplemental Digital Content 1, which shows Current Procedural Terminology Fourth Edition (CPT-4), International Classification of Diseases, 9th edition, Clinical Modification procedure (ICD-9 CM), and/or International Classification of Diseases, 10th edition, Procedural Classification System (ICD-10) codes Used to Identify Mastectomy and Breast Reconstruction, INSERT HYPER LINK). Algorithms were used to classify women who underwent immediate versus delayed breast reconstruction, as previously described.^17,18

Outcomes

Our primary outcome was the frequency of co-prescribing opioids with benzodiazepines and/or SMRs, which was identified from fills from pharmaceutical claims. Included opioid, benzodiazepine, and SMR medications are shown in Table, Supplemental Digital Content 2, INSERT HYPER LINK. Prescriptions filled for opioids, SMRs, and benzodiazepines were captured as fills from 30 days before to 3 days after surgery to account for prescriptions that may have been provided prior to surgery for postoperative care. The secondary outcome was opioid refills from discharge date to 90 days after surgery. Conversion to oral morphine milligram equivalent (OME) units was performed by using a morphine equivalent conversion factor per milligram, as previously published.¹⁹

Patient Factors

Demographic variables included age and race/ethnicity (i.e., White non-Hispanic, Black non-Hispanic, Hispanic, Asian, unknown). Clinical variables included laterality of reconstruction (i.e., unilateral versus bilateral), timing of reconstruction (i.e., immediate versus delayed), type of nodal surgery (i.e., sentinel lymph node, axillary dissection, or none) (See Table, Supplemental Digital Content 3, which shows Procedure Codes for Identifying Laterality of Reconstruction, Use of Acellular Dermal Matrix (ADM) or Other Biologic, Timing of Reconstruction, Type of Nodal Surgery, INSERT HYPER LINK), comorbidities as identified by the Charlson Comorbidity Index²⁰ [few (1–2), moderate (3–4), severe (≥5)], use of acellular dermal matrix (ADM) or other biologic during breast reconstruction, presence of mental health disorders, and preoperative opioid exposure. Mental health diagnoses were identified using the Clinical Classification System (Agency of Healthcare Research and Quality) and grouped into anxiety, depression, substance use disorders (i.e., alcohol and other substance-related disorders) and other mental health disorders (i.e., adjustment disorder, suicidality or self-harm, disruptive behavior disorders, personality disorders, schizophrenia, and other psychotic disorders) (See Table, Supplemental Digital Content 4, which shows Clinical Classification System (CCS) Codes for Mental Health and Substance Use Disorders, INSERT HYPER LINK).²¹ Comorbidites, mental health diagnoses, and preoperative opioid exposure were defined in the 12 months before the surgery date for mastectomy. Groupings of preoperative opioid use are described in the Table, Supplemental Digital Content 5, INSERT HYPER LINK.

Statistical Analysis

Demographic and clinical characteristics by fill patterns of opioids, benzodiazepines and/or SMRs were compared using chi-square tests for categorical variables, the Fisher’s exact test for cells with <5 values, and t-tests for continuous variables. We used the SAS QUANTREG procedure to test differences in median amount of opioid prescriptions between different co-prescribing patterns. A multinomial logistic regression analysis was performed to identify risk factors for co-prescribing of opioids with SMRs and/or benzodiazepines. Additionally, we performed logistic regression analyses to determine the relationship between co-prescribing patterns and opioid refills within 90 days of surgery while accounting for patient demographic and clinical variables. Model fit was evaluated using the Hosmer-Lemeshow test. Statistical analyses were performed using Stata version 15.1 (Stata-Corp) and statistical significance was set at p< 0.05.

RESULTS

We identified 17,102 women who underwent mastectomy between 1/1/08–6/30/18 and underwent breast reconstruction between 1/1/08–6/30/19 and had continuous insurance coverage 12 months prior to and 3 months after surgery. Of these, 7,536 women (44.1%) filled a benzodiazepine prescription between 365 days and 31 days prior to their surgery date and were excluded. We also excluded an additional 828 patients (4.8%) who filled a SMR prescription between 365 days and 31 days prior to their surgery date, leaving a final cohort of 8,738 (Figure 1).

Figure 1.

Flow diagram

Most patients (86.7%) filled an opioid prescription after surgery while 13.3% of women did not. Overall, 42.1% of patients filled opioid prescriptions only, 27.7% filled an opioid and a benzodiazepine prescription, 14.4% filled an opioid and a SMR prescription, and 2.4% filled an opioid, benzodiazepine, and a SMR prescription in the perioperative period. Demographic and clinical variables between different prescribing patterns after first-stage IBBR are presented in Table 1. Age, race/ethnicity, timing of reconstruction, use of ADM, Charlson Comorbidity Index, presence of mental health disorders, and preoperative opioid exposure were significantly different between the different patient groups based on prescribing patterns. However, there were no differences in laterality or nodal surgery between groups.

Table 1.

Patient characteristics based on prescribing patterns after implant-based breast reconstruction

Characteristic	Overall (8,738, 100%)		No opioids (1,164, 13.3%)		Filled opioids only (3,680, 42.1%)		Filled opioids and muscle relaxant (1,257, 14.4%)		Filled opioids and benzodiazepine (2,424, 27.7%)		Filled opioids, muscle relaxant, and benzodiazepine (213, 2.4%)		P-value
	Number	%	Number	%	Number	%	Number	%	Number	%	Number	%
Preoperative opioid exposure													<0.001
Opioid naïve	5661	64.8%	809	69.5%	2236	60.8%	794	63.2%	1675	69.1%	147	69.0%
Low, remote opioid user	886	10.1%	102	8.8%	413	11.2%	136	10.8%	215	8.9%	20	9.4%
Low, recent opioid user	1084	12.4%	132	11.3%	481	13.1%	154	12.3%	287	11.8%	30	14.1%
Medium opioid user	849	9.7%	102	8.8%	414	11.3%	142	11.3%	181	7.5%	10	4.7%
High and recent opioid user	258	3.0%	19	1.6%	136	3.7%	31	2.5%	66	2.7%	6	2.8%
Age: Mean (SD)	49.0 (8.5)		50.1 (8.3)		49.2 (8.4)		48.8 (8.6)		48.3 (8.7)		49.2 (8.0)		<0.001
Laterality													0.134
Unilateral	6404	73.3%	859	73.8%	2739	74.4%	907	72.2%	1753	72.3%	146	68.5%
Bilateral	2334	26.7%	305	26.2%	941	25.6%	350	27.8%	671	27.7%	67	31.5%
Timing of reconstruction													<0.001
Immediate	8172	93.5%	1053	90.5%	3364	91.4%	1195	95.1%	2355	97.2%	205	96.2%
Delayed	566	6.5%	111	9.5%	316	8.6%	62	4.9%	69	2.8%	8	3.8%
Use of ADM	5231	59.9%	649	55.8%	1982	53.9%	853	67.9%	1611	66.5%	136	63.9%	<0.001
Nodal surgery
Sentinel lymph node	1088	12.5%	138	11.9%	463	12.6%	173	13.8%	283	11.7%	31	14.6%	0.328
Axillary dissection	64	0.7%	14	1.2%	19	0.5%	8	0.6%	22	0.9%	1	0.5%	0.122
Comorbidities													0.004
None (CCI=0)	570	6.5%	87	7.5%	224	6.1%	91	7.2%	160	6.6%	8	3.8%
Few (CCI=1,2)	5425	62.1%	683	58.7%	2260	61.4%	783	62.3%	1565	64.6%	134	62.9%
Moderate (CCI= 3,4)	1543	17.7%	222	19.1%	672	18.3%	201	16.0%	398	16.4%	50	23.5%
High (CCI≥5)	1200	13.7%	172	14.8%	524	14.2%	182	14.5%	301	12.4%	21	9.9%
Mental health disorders
Anxiety Disorder	967	11.1%	132	11.3%	346	9.4%	145	11.5%	297	12.3%	47	22.1%	<0.001
Depression	976	11.2%	138	11.9%	386	10.5%	145	11.5%	271	11.2%	36	16.9%	0.050
Alcohol Substance Disorder	174	2.0%	20	1.7%	62	1.7%	42	3.3%	49	2.0%	1	0.5%	0.005
Others‡	306	3.5%	30	2.6%	135	3.7%	47	3.7%	86	3.5%	8	3.8%	0.476
Race													0.012
White	6437	73.7%	841	72.3%	2668	72.5%	929	73.9%	1835	75.7%	164	77.0%
Black	659	7.5%	93	8.0%	273	7.4%	118	9.4%	165	6.8%	10	4.7%
Hispanic	754	8.6%	99	8.5%	348	9.5%	112	8.9%	177	7.3%	18	8.5%
Asian	329	3.8%	54	4.6%	140	3.8%	34	2.7%	93	3.8%	8	3.8%
Unknown	559	6.4%	77	6.6%	251	6.8%	64	5.1%	154	6.4%	13	6.1%
Higher amount of opioids filled (>75th percentile OME*)	1690	19.3%	29	2.5%	704	19.1%	284	22.6%	598	24.7%	75	35.2%	<0.001
Year when the surgery occurred													<0.001
2008	721	8.3%	109	9.4%	373	10.1%	59	4.7%	169	7.0%	11	5.2%
2009	837	9.6%	99	8.5%	438	11.9%	89	7.1%	193	8.0%	18	8.5%
2010	860	9.8%	105	9.0%	420	11.4%	95	7.6%	225	9.3%	15	7.0%
2011	835	9.6%	97	8.3%	397	10.8%	111	8.8%	208	8.6%	22	10.3%
2012	844	9.7%	106	9.1%	382	10.4%	117	9.3%	219	9.0%	20	9.4%
2013	877	10.0%	94	8.1%	334	9.1%	139	11.1%	291	12.0%	19	8.9%
2014	771	8.8%	97	8.3%	278	7.6%	113	9.0%	264	10.9%	19	8.9%
2015	821	9.4%	117	10.1%	307	8.3%	120	9.5%	251	10.4%	26	12.2%
2016	775	8.9%	116	10.0%	260	7.1%	144	11.5%	232	9.6%	23	10.8%
2017	841	9.6%	118	10.1%	297	8.1%	163	13.0%	238	9.8%	25	11.7%
2018	556	6.4%	106	9.1%	194	5.3%	107	8.5%	134	5.5%	15	7.0%

^†Opioid and muscle relaxant/benzodiazepine prescriptions filled during 30 days before admission date and 3 days after discharge date

^‡any of the following mental health disorders was present: adjustment disorder, disruptive disorder, personality disorder, psychosis, suicide self-harm, and other miscellaneous mental disorders

^*75th percentile OME among patients who filled opioid prescriptions 30 days before admission date and 3 days after Discharge date

The median and interquartile range of total amount of opioid prescriptions filled in the perioperative period is presented in Figure 2, which demonstrated that women who filled prescriptions for opioids, benzodiazepines, and SMRs filled the greatest amounts of opioids (median OME=375, IQR=349) compared to other groups (opioids only: median OME=300, IQR=300; opioids and SMRs: median OME=300, IQR=225; opioids and benzodiazepines: median OME=300, IQR=225).

Figure 2.

Median amount (in OMEs) and IQR of opioid prescriptions filled in perioperative period.

Risk factors for co-prescribing of opioids with benzodiazepines

After controlling for demographic and clinical covariates, use of ADM or other biologic during breast reconstruction (RR 1.46, 95%CI 1.30–1.63) and immediate reconstruction (RR 2.33, 95%CI 1.76–3.08) were significantly associated with co-prescribing of opioids and benzodiazepines after surgery. Presence of anxiety (RR 1.31, 95%CI 1.10–1.57) also predicted the likelihood of filling opioids and benzodiazepines. We did not find any effects of age, race/ethnicity except for Asian patients being less likely to be co-prescribed these two medications (RR 0.73, 95%CI 0.60–0.88), laterality of procedure, or nodal surgery on co-prescribing of opioids and benzodiazepines (Table 2).

Table 2.

Multinomial logistic regression for co-prescribing opioids, benzodiazepines, and muscle relaxants

Outcome: co-prescribing opioids and muscle relaxants/benzodiazepines Base: Opioid only	No opioids				Opioids and muscle relaxant				Opioids and benzodiazepine				Opioids, muscle relaxant and benzodiazepine
	RRR†	95% CI LL	95% CI LL	p-value	RRR	95% CI LL	95% CI LL	p-value	RRR	95% CI LL	95% CI LL	p-value	RRR	95% CI LL	95% CI LL	p-value
Preoperative opioid exposure (ref: Opioid naïve)
Low, remote opioid user	0.64	0.50	0.81	<0.001	1.02	0.83	1.27	0.825	0.79	0.66	0.95	0.012	0.82	0.50	1.33	0.420
Low, recent opioid user	0.75	0.60	0.93	0.008	0.98	0.80	1.20	0.866	0.87	0.74	1.02	0.083	1.03	0.68	1.56	0.873
Medium opioid user	0.61	0.48	0.78	<0.001	1.10	0.88	1.37	0.396	0.71	0.59	0.86	0.001	0.43	0.22	0.83	0.012
High and recent opioid user	0.33	0.20	0.55	<0.001	0.72	0.48	1.09	0.120	0.82	0.60	1.12	0.214	0.77	0.33	1.82	0.556
Age	1.01	1.01	1.02	0.001	1.00	0.99	1.00	0.325	0.99	0.98	0.99	<0.001	1.00	0.98	1.01	0.709
Bilateral (ref: Unilateral)	1.14	0.97	1.35	0.111	1.16	0.99	1.36	0.069	1.10	0.97	1.25	0.134	1.34	0.97	1.86	0.076
Use of ADM (ref: No)	0.97	0.84	1.11	0.653	1.48	1.28	1.70	<0.001	1.46	1.30	1.63	<0.001	1.22	0.90	1.64	0.199
Immediate Reconstruction (Ref: Delayed)	0.66	0.51	0.85	0.001	1.42	1.05	1.92	0.022	2.33	1.76	3.08	<0.001	1.60	0.75	3.40	0.222
Nodal surgery
Sentinel lymph node (ref: No)	1.01	0.81	1.26	0.929	1.26	1.03	1.55	0.026	0.91	0.77	1.08	0.280	1.17	0.76	1.80	0.471
Axillary dissection (ref: No)	1.93	0.95	3.90	0.068	0.94	0.40	2.18	0.881	1.52	0.81	2.84	0.193	0.75	0.10	5.69	0.779
Charlson Comorbidities Index (ref: None, CCI=0)
Few (CCI= 1,2)	0.78	0.59	1.02	0.070	1.04	0.80	1.36	0.769	1.21	0.97	1.51	0.089	2.08	0.99	4.36	0.054
Moderate (CCI=3,4)	0.84	0.62	1.15	0.276	0.89	0.65	1.21	0.445	1.09	0.85	1.40	0.495	2.58	1.18	5.67	0.018
High (CCI≥5)	0.89	0.65	1.22	0.479	1.02	0.74	1.39	0.921	1.08	0.84	1.40	0.549	1.50	0.64	3.50	0.352
Mental health disorders
Anxiety Disorder (ref: None)	1.14	0.91	1.43	0.243	1.13	0.90	1.41	0.284	1.31	1.10	1.57	0.003	2.48	1.71	3.61	<0.001
Depression (ref: None)	1.13	0.91	1.41	0.265	1.05	0.85	1.31	0.641	1.02	0.86	1.22	0.796	1.35	0.90	2.03	0.151
Alcohol Substance Disorder (ref: None)	0.88	0.52	1.48	0.622	1.53	1.02	2.31	0.042	1.06	0.72	1.56	0.777	0.18	0.02	1.32	0.092
Others‡ (ref: None)	0.72	0.48	1.08	0.117	1.00	0.71	1.42	0.981	0.97	0.73	1.28	0.824	1.22	0.58	2.54	0.604
Race/ethnicity (ref: White)
Black	1.14	0.89	1.47	0.299	0.67	0.46	0.99	0.045	0.92	0.70	1.21	0.556	0.92	0.44	1.93	0.832
Hispanic	0.92	0.72	1.16	0.479	1.28	1.01	1.62	0.037	0.91	0.74	1.12	0.386	0.62	0.32	1.20	0.154
Asian	1.20	0.86	1.66	0.280	0.91	0.72	1.14	0.402	0.73	0.60	0.88	0.001	0.86	0.52	1.42	0.549
Unknown	1.06	0.81	1.39	0.673	0.84	0.63	1.13	0.253	0.96	0.78	1.19	0.717	0.98	0.54	1.75	0.936
Year (2008 – 2018) of reconstruction	1.08	1.05	1.10	<0.001	1.12	1.10	1.15	<0.001	1.05	1.04	1.07	<0.001	1.11	1.06	1.17	<0.001

^†RRR: Relative Risk Ratio

^‡any of the following mental health disorders was present: adjustment disorder, disruptive disorder, personality disorder, psychosis, suicide self-harm, and other miscellaneous mental disorders

Associations between co-prescribing and opioid refills within 30 days of surgery

The number of patients within each group who refilled an opioid prescription within 90 days of discharge is summarized in Figure 3. The group that refilled opioids most frequently after surgery were women who filled opioids, benzodiazepines, and SMRs in the perioperative period (67.1%), followed by those who filled opioids and benzodiazepines (60.7%), opioids and SMRs (58.6%), and opioids only (54.2%). Of note, 27.6% of women who did not fill an opioid prescription in the perioperative period (defined as 30 days prior to 3 days after surgery) filled an opioid prescription within 90 days of their discharge date.

Figure 3.

Opioid refill rates (95% CI) after implant-based breast reconstruction by co-prescribing patterns.

Results from our logistic regression for refilling an opioid prescription are presented in Table 3. Using the Hosmer-Lemeshow test (p=0.811), we determined that the model fit well. We found that all patterns of co-prescribing (Opioids and SMR: aOR 1.19, 95%CI 1.04 –1.36; Opioids and benzodiazepine: aOR 1.27, 95%CI 1.14–1.42; Opioids and benzodiazepine and SMR: aOR 1.57, 95%CI 1.16–2.12) were associated with an increased risk for refilling an opioid prescription compared to prescribing opioids only. Preoperative opioid exposure (Low, recent use: aOR 1.38, 95%CI 1.20–1.58; High, recent use: aOR 5.00, 95%CI 3.45–7.24) and higher amount of opioids filled (aOR 1.98, 95%CI 1.74–2.27) were strongly associated with an increased odds of refilling. Other factors such as bilateral reconstruction (aOR 1.27, 95%CI 1.14–1.41), immediate reconstruction (aOR 2.33, 95%CI 1.90–2.86), more comorbidities (Moderate: aOR 1.52, 95%CI 1.23–1.88), and presence of depression (aOR 1.36, 95%CI 1.17–1.59) also conferred increased risks for opioid refills after surgery. Asian race (aOR 0.68, 95%CI 0.53–0.82) and increased age (aOR 0.99, 95%CI 0.99–1.00) were associated with a decreased risk of refills.

Table 3.

Logistic regression for refilling an opioid prescription within 90 days following discharge

	aORs for Refill within 90 Days
	aOR	95% CI LL	95% CI LL	p-value
Co-prescribing Pattern (ref: Opioids only)
No opioids	0.37	0.32	0.43	<0.001
Opioids and muscle relaxants	1.19	1.04	1.36	0.011
Opioids and benzodiazepine	1.27	1.14	1.42	<0.001
Opioids, muscle relaxants and benzodiazepines	1.57	1.16	2.12	0.004
Preoperative opioid exposure (ref: Opioid naïve)
Low, remote opioid user	1.26	1.08	1.46	0.003
Low, recent opioid user	1.38	1.20	1.58	<0.001
Medium opioid user	1.16	0.99	1.36	0.067
High and recent opioid user	5.00	3.45	7.24	<0.001
Higher amount of opioids filled (>75th percentile OME*)	1.98	1.74	2.27	<0.001
Age	0.99	0.99	1.00	0.002
Bilateral (ref: Unilateral)	1.27	1.14	1.41	<0.001
Use of ADM (ref: No)	1.15	1.05	1.27	0.004
Immediate Reconstruction (Ref: Delayed)	2.33	1.90	2.86	<0.001
Nodal surgery (ref: No)
Sentinel lymph node (ref: No)	1.06	0.92	1.23	0.401
Axillary dissection (ref: No)	1.14	0.67	1.95	0.625
Comorbidities (ref: None)
Few	1.19	0.99	1.44	0.063
Moderate	1.52	1.23	1.88	<0.001
High	1.23	0.99	1.53	0.061
Mental health disorders
Anxiety Disorder (ref: None)	1.00	0.86	1.17	0.962
Depression (ref: None)	1.36	1.17	1.59	<0.001
Alcohol Substance Disorder (ref: None)	1.33	0.95	1.87	0.095
Others‡ (ref: None)	1.07	0.84	1.36	0.590
Race/ethnicity (ref: White)
Black	1.05	0.89	1.25	0.540
Hispanic	0.86	0.73	1.00	0.056
Asian	0.68	0.53	0.86	0.001
Unknown	0.86	0.71	1.03	0.093
Year (2008 – 2018) of reconstruction	0.95	0.94	0.97	<0.001

DISCUSSION

In this cohort of privately insured women aged 18–64 years old undergoing IBBR, 86.7% of women fill an opioid prescription in the perioperative period and that nearly half (44.5%) of women are co-prescribed opioids with benzodiazepines, SMRs, or both. Despite guidelines outlined by the FDA and CDC strongly discouraging co-prescribing of opioids with benzodiazepines and SMRs, about 1 in 4 women undergoing IBBR in this cohort filled opioids with benzodiazepines, and nearly 1 in 6 women filled an opioid with SMR after surgery. In addition to patient-level characteristics such as presence of anxiety, our analysis also suggests that the risk of co-prescribing of opioids with benzodiazepines is impacted by use of ADM or other biologics during breast reconstruction, and timing of reconstruction. Moreover, we found an independent association between all types of co-prescribing patterns and odds of refilling an opioid prescription after surgery.

In 2016, the CDC issued a report about the state of opioid prescribing with recommendations to curtail the national opioid crisis.¹³ Further complicating the problem, national studies found benzodiazepine use, with or without opioid use, was associated with a doubling in all-cause mortality risk in comparison with the use of low-risk antidepressants.²² Studies estimate that about one-third of opioid overdoses involve benzodiazepines, and that co-prescribing opioids with benzodiazepines is a significant risk factor for emergency visits or inpatient admission for a drug-related emergency.⁷ The risks of respiratory depression, overdose, and death due to co-prescribing of opioids and benzodiazepines resulted in the FDA to issue “black box” warnings that emphasize the dangers of using these medications together and strongly discouraged providers from prescribing these medications together whenever possible.^12,13 Despite the serious adverse effects of co-prescribing, it is troubling that nearly 30% of our cohort were prescribed opioids and benzodiazepines after breast reconstruction. Although our analysis captured prescribing patterns both before and after the CDC and FDA released guidelines in 2016, future analyses are necessary to determine if these guidelines result in future reductions in the extent and intensity of co-prescribing of opioids with benzodiazepines after IBBR.

The frequency of co-prescribing of opioids with SMRs and/or benzodiazepines we observed among women undergoing IBBR may be explained by the desire to mitigate discomfort due to postoperative muscle contraction, particularly after subpectoral implant placement. Although benzodiazepines may relieve muscle spasticity in some cases, benzodiazepines are sedatives that raise the level of GABA in the central nervous system and are primarily used for anxiety or insomnia.²³ In fact, most benzodiazepines (except diazepam) are not FDA-approved for muscle relaxation and such use of these medications would be “off-label” prescribing. Diazepam is the only benzodiazepine that is FDA approved for use in muscle spasms despite the paucity of literature supporting this indication;²⁴ for example, there is only one trial to date that has investigated the use of diazepam to reduce muscle spasms, which found no difference from placebo.²⁵ Additionally, cyclobenzaprine is a commonly prescribed SMR but despite its classification, does not act on skeletal muscle.²⁶ It acts centrally on the brainstem to decrease the activity of serotonergic descending neurons, thus decreasing muscle tone.²⁶ From 2005–2016, prescriptions for SMRs have doubled despite prominent adverse effects and limited long-term efficacy.²⁷ High-risk elderly patients received disproportionally greater SMR prescriptions, many of whom were already co-prescribed an opioid.²⁷ Co-prescribing of opioids with SMRs in any age group also carries a significant risk of opioid overdose and should also be avoided whenever possible.^27,28 The authors urge providers to educate patients of the “black box” warning and potential dangers regarding use of opioids with SMRs/benzodiazepines prior to discharge.

Another possible explanation for the high frequency of co-prescribing of opioids with benzodiazepines and/or SMRs in our cohort is the increasing popularity of ERAS protocols for many procedures that include breast reconstruction, which often include opioids, SMRs, and benzodiazepines in these protocols.^4,14,15,29 ERAS protocols focus on improving recovery after surgery, and managing pain is a central tenet of any given protocol. Unfortunately, pain is common after breast surgery as upwards of one-quarter to one-half of patients who undergo mastectomy will develop long term pain or post mastectomy pain syndrome.^30–33 To minimize the potential long term risk, ERAS protocols preemptively deploy multimodal analgesia incorporating systemic, regional, and neuraxial techniques to reduce postoperative pain and stress-inducing side effects.³⁴ In 2015, the Breast Reconstruction Advisory Group convened and developed a consensus approach to best practices for providing analgesia for common breast surgical procedures including lumpectomy, bilateral mastectomy with and without tissue expanders, and deep inferior epigastric perforator (DIEP) flap reconstruction.⁴ Interestingly, this multimodal analgesia protocol recommends either a benzodiazepine (diazepam) or a SMR (methocarbamol) postoperatively to “help with muscle spasms if elevation of the pectoralis major is performed” although it does not specify if this is intended for postoperative use while in the hospital, upon discharge, or both. In addition, a subsequent study evaluated the efficacy of the recommendations made by the Breast Reconstruction Advisory Group on the reduction of opioid use after breast reconstruction.⁵ Although the multimodal analgesic strategy was effective in reducing opioid consumption after surgery, this pathway routinely prescribed methocarbamol, a SMR, postoperatively and reserved oxycodone for “rescue,” allowing for the possibility of co-prescribing of these two medications.⁵ Most ERAS protocols, like the one outlined by the Breast Reconstruction Advisory Group pertain to inpatient pain management, possibly contributing to the postoperative co-prescribing practices described in this analysis. As ERAS protocols become more widespread, evaluating the implementation of these protocols on prescribing patterns will be important.

Different breast reconstruction options may convey differential opioid-use risk.^3,35 For example, tissue expander-based reconstruction is associated with greater analgesic use than those with direct-to-implant implant techniques.³⁵ Additionally, larger tissue expander size and higher initial fill volumes are associated with increased opioid use after surgery.³⁵ On the contrary, studies suggest that women who undergo prepectoral reconstruction may use less opioids medications and are less likely to require refills of opioids.³⁶ The development of ADM and other biologics have alleviated past concerns of prepectoral implant reconstruction and have played a key role in the resurgence of prepectoral implant-based reconstruction. Compared to total or dual-plane with ADM subpectoral expander placement, prepectoral expander placement has been found not only to be less painful in the immediate and 30-day postoperative periods, but also result in reduced opioid requirements.^37,38 In our current analysis however, we found that use of ADM or other biologics was a risk factor for co-prescribing of opioids with benzodiazepines, opioids with SMRs, and opioids with both types of medications. During this study period, the CPT code for use of ADM or other biologic changed, which making it difficult to account for in this analysis and it is possible that misclassification occurred. Additionally, the way in which ADM and other biologics are being used breast reconstruction has evolved over the study timeframe. Therefore, we advocate for more robust prospective studies that will examine details of each procedure including factors such as placement of tissue expander versus direct-to-implant, use of ADM as part of prepectoral reconstruction, use of ADM as a sling in submuscular coverage, or total submuscular placement, size of expander or implant, and initial fill volumes. Additionally, it is imperative that future studies evaluate the impact of these co-prescribing patterns on outcomes such as respiratory complications, overdose, and mortality.

Although we were able to leverage a national claims database to describe the frequency and risk factors of co-prescribing after IBBR, several limitations remain. First, this is an analysis of opioid prescriptions that were filled and thus, we cannot comment on what the patient consumed, introducing the possibility of overestimating opioid and SMR/benzodiazepine consumption; however, a refill for a medication may provide some indication of additional need of analgesia following surgery. Second, as this was a retrospective analysis of a large administrative claims database, we can only describe associations, and we lacked granular detail related to the breast reconstruction procedure such as expander/implant size, fill volume, subpectoral versus prepectoral expander placement. Additionally, we did not collect information regarding chemotherapy, radiotherapy, chronic pain diagnoses, other non-breast cancer related diagnoses, or patient’s subjective complaints which could also affect prescribing for postoperative pain and discomfort. Third, given the nature of this study design, we are unable to account for patient-reported outcomes. These data are paramount for potentially determining why patients are being co-prescribed these different medications. Fourth, we were also not able to determine if women were on an ERAS pathway using claims data. Fifth, it is likely that the opioid refills are being prescribed for the discomfort associated with tissue expansions,³⁹ which we were unable to account for. Prospective studies to evaluate the type and degree of discomfort during tissue expansions and how much opioid analgesics are being prescribed during this time would allow us to better treat the discomfort associated with expansions. Sixth, we attempted to account for the use of botulinum toxin intraoperatively but were unable to reliably capture this covariate with claims data alone. Studies to determine the efficacy of intraoperative injections of botulinum toxin into the pectoralis major muscle on postoperative pain, opioid consumption, and co-prescribing of opioids with SMRs and/or benzodiazepines are needed. Seventh, our cohort did not include women 65 years and older. Given the added risk of opioids, benzodiazepines, and SMRs with advanced age,⁴⁰ it is possible that there are greater effects of co-prescribing in older women undergoing IBBR. Finally, our analysis describes the experiences of privately insured women in the U.S. undergoing IBBR, which may not be generalizable to all cohorts of other patients. Additionally, while our analysis focused on the risk of co-prescribing, it is imperative that our goal as prescribers of these potentially harmful medications should always be to minimize on opioid analgesics whenever possible.

CONCLUSIONS

Co-prescribing of opioids with benzodiazepines and/or SMRs is common after IBBR. Prescription refill rates after breast reconstruction are higher among women co-prescribed opioids with benzodiazepines and/or SMRs and those who are preoperative opioid users. We must identify strategies to avoid sedatives to manage pain following breast reconstruction to deliver safe surgical care.

Supplementary Material

Table, SDC 1

Supplemental Digital Content 1. See Table, which shows Current Procedural Terminology Fourth Edition (CPT-4), International Classification of Diseases, 9th edition, Clinical Modification procedure (ICD-9 CM), and/or International Classification of Diseases, 10th edition, Procedural Classification System (ICD-10) codes Used to Identify Mastectomy and Breast Reconstruction, INSERT HYPER LINK.

Table, SDC 2

Supplemental Digital Content 2. See Table, which shows Opioid, Benzodiazepine, and Skeletal Muscle Relaxant (SMR) Medications, INSERT HYPER LINK

Table, SDC 3

Supplemental Digital Content 3. See Table, which shows Procedure Codes for Identifying Laterality of Reconstruction, Use of Acellular Dermal Matrix (ADM) or Other Biologic, Timing of Reconstruction, Type of Nodal Surgery, INSERT HYPER LINK

Table, SDC 4

Supplemental Digital Content 4. See Table, which shows Clinical Classification System (CCS) Codes for Mental Health and Substance Use Disorders, INSERT HYPER LINK.

Table, SDC 5

Supplemental Digital Content 5. See Table, which shows Preoperative Opioid Exposure Groups Based on Characteristics of Opioid Prescriptions, INSERT HYPER LINK.