Keywords
sedation - opioids - benzodiazepines
Introduction
Opioids are often used perioperatively–short term in acute postprocedure period or
long term in patients with cancer related pain or palliative care.[1] In the past several decades, there has been an increase in opioid use for chronic
noncancer-related pain; this trend has only recently started to decrease with improved
utilization of nonopioid, nonpharmacologic interventions, and implementation of clinical
guidelines in using opioids.[1]
[2]
[3]
[4] Overall opioid prescriptions have increased from 2006 and peaked in 2012 at more
than 255 million dispensed prescriptions. It downtrended from 2012 with 168 million
prescriptions dispensed in 2018.[5] With use of opioids, there is concern for tachyphylaxis, dependence, opioid-induced
hyperalgesia, and even opioid-related respiratory depression and death.[6]
[7] Opioid tolerance, as defined by FDA, occurs when an individual takes ≥1 week of
the following agents and doses: 30 mg oral oxycodone/day, 25 mcg transdermal fentanyl/hour,
60 mg oral morphine/day, or an equivalent dose of a different opioid.[8] Therefore, even short courses of opioids can result in tolerance with patients requiring
higher doses to achieve similar analgesic effect.[7] This pattern has been seen in patients taking opioids for both cancer and noncancer-related
pain.[9]
Pain management during perioperative period can be challenging in patients who have
history of prescription opioid use, opioid misuse, or even those on opioid agonist/antagonist
regimens for withdrawal and cessation.[6] Different levels of sedation ranging from minimal sedation to general anesthesia
need to be performed, based on procedure type to provide adequate sedation and analgesia
during procedures.[6]
[10] Moderate sedation is used frequently for minimally invasive procedures including
endoscopies, bronchoscopies, port placements, central line placements, percutaneous
biopsies (i.e., liver, kidney, lung), and drain placements, etc.[10]
[11]w[12] Benzodiazepines and opioids are used during moderate sedation, wherein patients
are easily arousable to verbal and tactile stimuli and are able to protect their airway
and maintain spontaneous ventilation.[10] Benzodiazepines and opioids have several therapeutic effects, and the anxiolytic
effects of benzodiazepines allows for decreased perception of pain by working synergistically
with opioid and nonopioid analgesic medications.[10]
[13]
[14] Adequate sedation allows for timely and ease in procedure completion while minimizing
patient discomfort.[10]
Higher sedation requirements in patients with history of opioid and alcohol use disorders
has been documented during colonoscopies and mechanical ventilation.[11]
[15] Other factors contributing to higher sedation requirements include anxiety, agitation,
and pre-existing high pain sensitivity; some of these patients even have a history
of concomitant use of benzodiazepines and antidepressants.[11]
[16]
The purpose of this study is to evaluate whether use of opioids would increase sedation
medication requirements in patients undergoing minimally invasive procedures under
moderate sedation at a single tertiary care center. We elected central venous port
placement as an index minimally invasive procedure to decrease procedural heterogeneity.
Materials and Methods
Patient Selection and Data Collection
Following approval from local Institutional Review Board, a retrospective study was
performed on all the patients who had port placement between June 1, 2017, and June
30, 2019 at a single tertiary care center. Informed consent was obtained from all
patients included in the study prior to performing procedure and data collection.
A total of 430 different instances of port placement occurred during this time period.
Patients with known history of illicit opioid use and patients who had no sedation
or required general anesthesia were excluded from the current study. In addition,
cases with errors in data entry at time of procedure were also excluded. Based on
these criteria, a total of 27 cases were excluded.
For the remaining 403 patients, electronic medical records were reviewed for following
data collection: patient demographics, use of tobacco, alcohol use, and sedation data
(amounts of midazolam, fentanyl, and diphenhydramine). A procedural nurse administered
moderate sedation medications during port placement and a pain scale (1–10) goal of
< 4 was used as the target for adequate sedation. All the providers had at least 3
years of postinterventional radiology fellowship experience. The following definitions
were used for opioids and other psychotropic substances. Use of opioids was defined
as prescribed opioids for ≥ 1 week within the last 3 years prior to port placement.
Additional data collected included use of benzodiazepines (defined as current or history
of use of benzodiazepine products for at least 7 days within 5 years prior to date
of port placement), use of typical antidepressants (defined as current or history
of use of selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine
reuptake inhibitors [SNRIs] for at least 7 days within 5 years prior to date of port
placement), and any documented history of use of pregabalin/gabapentin.
Statistical Analysis
Statistical analysis was performed using SAS software version 9.4 (SAS Institute Inc.,
Cary, NC, USA). t-tests were used to identify average doses of midazolam and fentanyl used in patients
with use of opioids and other psychotropic substances including benzodiazepines, gabapentin/pregabalin,
and antidepressants. Overall mean, standard deviations, and p values were calculated using SAS software. Significance was indicated by a p value of ≤ 0.05.
Results
Of the 403 remaining port placements, the following were the patient demographics:
44% were male, 92% Caucasian, 7% African-American and 1% Asian; 18% had history of
alcohol abuse and 53% had history of tobacco use. Of the 403 cases, 185/403 (46%)
had used opioids for at least 1 week in the 3 years prior to port placement, 81/403
(20%) had used benzodiazepines for at least 1 week in the 5 years prior to port placement,
81/403 (20%) of the patients had used antidepressants for at least 7 days in the 5
years prior to port placement, and 44/403 (11%) had used gabapentin/pregabalin.
Statistical analysis was performed using SAS software. Patients who were opioid users
needed 10.5% significantly higher doses of midazolam when compared with nonusers (p value = 0.04), and these patients also required 7.9% higher doses of fentanyl compared
with nonusers; however, the latter results were not statistically significant (p value = 0.09). Patients who had history of use of benzodiazepines required 11.3%
significantly higher doses of fentanyl and 16.3% significantly higher doses of midazolam
when compared with nonusers (p value = 0.05 and 0.01, respectively). Finally, patients with history of antidepressant
use required 11.9% significantly higher doses of midazolam and 7.8% higher doses of
fentanyl when compared with nonusers, however, the latter was not statistically significant
(p values 0.05 and 0.17, respectively). Patients who were users of pregabalin/gabapentin
required higher doses of fentanyl and midazolam when compared with nonusers; however,
these results were not statistically significant. [Table 1] demonstrates average dose of midazolam and fentanyl with associated standard deviations
and p values in patients with use of opioids and other psychotropic agents.
Table 1
Demonstrates the average midazolam and fentanyl doses required in patients with use
of opioids and other psychotropic agents
|
Psychotropic medication class
|
Midazolam (mg)
|
p value
|
Fentanyl (mcg)
|
p value
|
|
Opioids:
|
|
0.04
|
|
0.09
|
|
Users:
|
2.7 ± 1.3
|
123 ± 60
|
|
Nonusers:
|
2.5 ± 1.1
|
114 ± 48
|
|
Benzodiazepines:
|
|
0.01
|
|
0.05
|
|
Users:
|
2.9 ± 1.4
|
129 ± 54
|
|
Nonusers:
|
2.5 ± 1.6
|
116 ± 54
|
|
Antidepressants:
|
|
0.05
|
|
0.17
|
|
Users:
|
2.8 ± 1.2
|
126 ± 52
|
|
Nonusers:
|
2.5 ± 1.2
|
117 ± 54
|
|
Pregabalin/gabapentin:
|
|
0.81
|
|
0.62
|
|
Users:
|
2.6 ± 1.5
|
122 ± 63
|
|
Nonusers:
|
2.6 ± 1.2
|
118 ± 53
|
Discussion
After heart disease, cancer is the most common cause of death with an estimated approximately
600,000 deaths expected in 2020.[17] However, given advances in treatment, earlier detection of disease, improvement
in screening modalities, and decrease in risk factors such as smoking, cancer death
continues to decrease. This has resulted in greater number of cancer survivors, thus
resulting in a greater number of patients managing cancer-related pain on a day-to-day
basis.[9]
[17] Opioids continue to be one of the primary mainstays in treatment of severe cancer-related
pain when nonopioid interventions have failed or to augment these interventions for
breakthrough pain. In addition, there has been an overall increase in prescription
of benzodiazepines over the past several decades. One study reported a 67% increase
in number of individuals filling benzodiazepine prescriptions from 1996 to 2013.[18] During the same time period, the study noted three times increase in the quantity
of benzodiazepines filled due to increase in dosage, number of prescriptions, duration
of prescriptions, or a combination of these factors.[18]
Tachyphylaxis, physical dependence, opioid-induced hyperalgesia, addiction, and overdose
continue to be concerning factors with use of opioids. A single dose may be sufficient
to develop tolerance for some opioid effects; however, in most cases, development
of tolerance depends on duration, dose, and type of opioid utilized.[3] Tolerance to effects of analgesia and euphoria occur earlier than effects of respiratory
depression; thus, the increasing concern for overdose when dose escalation occurs.[3] It is believed that dose escalation up to 10 times initial dose may be required
for similar analgesic effects.[3] However, following cessation of opioid use, effects of tolerance and dependence
resolve within days to weeks, depending on strength, duration and type of opioid used.[3]
Various studies have looked at sedation in patients with history of substance use
disorders in various settings including endoscopies, mechanically ventilated patients,
and dental procedures.[11]
[15]
[19] Patel et al demonstrated that during sedation for colonoscopies, opioid users require
significantly higher doses of fentanyl (by 23%) and midazolam (by 24%) compared with
patients with alcohol use and control groups.[11] This is consistent with findings from this current study, and it demonstrates significantly
increased requirement of midazolam by 10.5% in patients who are opioid users in comparison
to nonusers during port placement. These patients also had required 7.9% increase
in fentanyl dosing; however, these results were not significant at the 95% confidence
interval. Another study demonstrated that during mechanical ventilation in intensive
care unit, patients with alcohol use disorder needed greater amounts of sedatives
and opioids to achieve similar degree of sedation than their nonalcoholic counterparts.[15] Cook et al also demonstrated that greater amounts of diazepam are required to achieve
similar levels of sedation in patients using alcohol and benzodiazepines even at low
doses when these patients are undergoing elective dental and endoscopic procedures.[19] These results are similar to the current study. Patients who had history of benzodiazepine
use required 11.3% significantly higher doses of fentanyl and 16.3% significantly
higher doses of midazolam when compared with nonusers. Tolerance has been attributed
to increased requirements of sedatives in patients with history of benzodiazepine
use.[19]
[20] Sedative and hypnotic effects of benzodiazepines develop tolerance earlier as compared
with other therapeutic effects of benzodiazepines, and tolerance occurs much faster
with shorter half-life agents.[20]
[21] However, benzodiazepines appear to have continued efficacy against anxiolysis even
with long-term use, and some studies have attributed this as reason for lack of dose
escalation in chronic benzodiazepine users.[20]
[22] Overall, both opioids and benzodiazepines augment each other’s effects during sedation,
and the increase in dose requirements during perioperative period is likely due to
tolerance exhibited to both agents.[10]
[11]
[20]
To our knowledge, this is the first study that demonstrated not only increased midazolam
requirements in patients with history of prescription benzodiazepine use, but also
significantly increased midazolam requirements in patients with history of prescription
antidepressant use (SSRIs and SNRIs) in patients undergoing port placement. In addition,
these patients also required increased doses of fentanyl during port placement when
compared with non-users, however, these results were not significant at the 95% confidence
interval. The exact mechanism through which antidepressant users require higher benzodiazepines
is unclear. However, it is likely multifactorial, with a combination of biochemical
changes and variable neurotransmitter availability in the central nervous system (CNS)
caused by multiple psychotropic medications and presence of somatic and psychological
factors during the perioperative period.[23]
[24]
[25] In our study, anxiety and mood changes during the procedure likely potentiate pain
perception, which subsequently results in higher midazolam and fentanyl doses in patients
with history of prescription antidepressant use. Patients with preoperative depression
and anxiety reported having greater amounts of postoperative pain and resultant increase
in opioid use.[25]
[26] One study performed psychological assessment (that included patient health questionnaire
among other questionnaires) in all patients prior to oropharyngeal surgery. The study
indicated that significantly more opioids were needed for higher postoperative pain
which, in turn, was correlated to psychological anticipation of higher pain and/or
with higher degree of clinical depression.[25] Although these studies looked at postoperative pain, similar rationale can be extrapolated
to the intraoperative period.
To our knowledge, this is the first study that has looked at increased sedation requirements
during a discrete minimally invasive procedure performed under moderate sedation in
patients with known history of prescription opioid use. Central venous ports were
chosen as an ideal index procedure to limit procedural heterogeneity such as anatomical
location, procedural duration, and procedure -related pain. Port placement is a relatively
standardized procedure that is short in duration, involves minimal intraprocedural
discomfort, and has little to no postprocedural pain.
Approximately, 1.8 million new cases of cancer are expected to be diagnosed in 2020
in United States, a significant portion of whom will require central venous access
devices (i.e., port) for infusion of chemotherapy.[17] Therefore, identifying patients who have been on opioids for ≥ 1 week can allow
interventionalists to provide optimal preprocedural sedation planning.
This study does have some limitations. It is a retrospective study at a single institution,
and data was collected on a single procedure type (port placement). Additional limitations
include variable strengths and durations of use of opioids and other psychotropic
agents (ranging from 1 week to several months). Also, patient-reported pain scores
can be highly subjective and would be difficult to account for. Furthermore, nurses
and/or physicians were not blinded to patient’s medical history of opioid and/or psychotropic
use, potentially introducing an element of bias.
Conclusion
Patients with history of opioid use require significantly higher sedation drug doses
compared with nonusers, and similar trends can be seen in patients with history of
use of benzodiazepines and antidepressants. Anticipating higher requirements of these
medications in these patients can allow planning for other alternatives for analgesia/anesthesia,
increase patient satisfaction, and allow timely completion of minimally invasive procedures
performed under moderate sedation. More patient and provider awareness are needed
on this topic, as health care policy has been moving more and more toward value-based
health care, with patient satisfaction surveys being one of its indicators.
