Given the current opioid epidemic and its associated morbidity and mortality, it is more important than ever to control postsurgical pain while minimizing the need for powerful opioids. Often, the perioperative period is a patient’s first exposure to these medications, and indiscriminate prescription may ultimately lead to addiction, overdose, and death from the prescribed opioids. Additionally, an increasing number of surgical patients are opioid tolerant (eg, those with chronic pain conditions), and providing adequate analgesia postoperatively while minimizing the risk of overdose or relapse is challenging. For these patients, optimization of their perioperative opioid usage may make a significant impact on their recovery, and may potentially be as important as medically optimizing a patient’s cardiac or pulmonary status before surgery. Furthermore, an increasing number of surgeries are being performed on an outpatient basis; thus, the burden of pain management and weaning from opioids falls on patients and their caregivers, often without the guidance of prescribing physicians or associated health care providers.
In addition to potentially improving patient outcomes,1 use of nonopioid adjuvant medication and regional anesthesia, including peripheral and neuraxial nerve blocks, can be an integral part of a perioperative strategy to decrease opioid use and, perhaps, decrease the risk of subsequent opioid misuse and addiction. Anesthesiologists have been at the forefront of research addressing the above challenges by developing, exploring, and refining primary therapies, adjuvant medications, regional anesthesia and analgesia techniques, local anesthetic additives, acupuncture and other alternative therapies, and various combinations of the above. We examine the data describing the opioid-sparing effect of nonopioid adjuvants and regional anesthesia/analgesia and local anesthetic additives in regional anesthesia in decreasing opioid usage. We also examine the role of regional anesthesia in multimodal analgesic regimens. This review aims to broadly discuss opioid-sparing efforts in anesthesiology, providing a historical overview, a summary of current knowledge, and a perspective on future directions for research and clinical practice.
For adjuvant medications and block additives, each author performed independent literature searches using MEDLINE/Pubmed (from inception through April 2017). Search terms included the following:
- Postoperative analgesia ± dexmedetomidine, clonidine, ketamine, amantadine, dextromethorphan, gabapentin, pregabalin, duloxetine, amitriptyline, desipramine, lidocaine, esmolol, or caffeine.
- Nerve block ± opioids, morphine, tramadol, fentanyl, buprenorphine, dexmedetomidine, clonidine, dexamethasone, adjuncts, or adjuvants. For adjuvants that have benefited from recent systematic reviews, meta-analysis or Cochrane reviews, we relied on the latter to provide an overview of documented benefits. For recent randomized trials that were not covered in these reviews and for agents that have not undergone such systematic data pooling (eg, amantadine, duloxetine, tricyclic antidepressant [TCA]), trials were individually retrieved to carry out a brief narrative review.
- For regional anesthesia and analgesia: relevant studies were retrieved through a MEDLINE search from inception to April 29, 2017. MeSH terms related to anesthesia type, including “anesthesia, epidural,” “anesthesia and analgesia,” “adjuvants, anesthesia,” and “brachial plexus block,” were then combined with MeSH terms related to analgesia, such as “analgesics, opioid,” “pain, postoperative,” “pain management,” and “acute pain.” Specific block types (“quadratus lumborum block,” “serratus plane block,” “pectoral block,” “femoral nerve block,” “interscalene block,” “supraclavicular block,” “lumbar plexus block,” and “adductor canal block”) were individually searched to identify any studies that may have been missed in the core search. Additional material was retrieved by manually reviewing references of identified relevant articles. Studies were limited to those in English and conducted in human subjects.
Nonopioid Adjunct Medications
The rationale behind combining opioids and nonopioid adjuvants is based on the ability to synergistically modulate pain pathways at central and peripheral sites, thereby enhancing analgesia and decreasing opioid requirement as well as opioid-related side effects. While agents such as acetaminophen2 and nonsteroidal anti-inflammatory drugs3,4 are commonly used in clinical practice because of their well-documented opioid-sparing effects, there exists a plethora of lesser-known adjuvants. The level of evidence supporting the implementation of the different nonopioid adjuvants is notoriously variable; the use of certain adjuvants for perioperative analgesia is supported by published data, but others require either continued or confirmatory investigation.
Dexmedetomidine is an α-2 adrenoreceptor agonist that possesses sedative and anxiolytic properties. Although dexmedetomidine is most commonly given for patient sedation in intensive care units and for procedural sedation (eg, awake fiberoptic intubation), its central antinociceptive activity (presumably mediated by the stimulation of α-2 adrenoreceptors located in the dorsal horns of the spinal cord and the locus coeruleus) makes it an attractive option for use as an analgesic adjuvant.5 A 2016 Cochrane Review6 examined 7 randomized controlled trials (RCTs) with 422 patients and concluded that dexmedetomidine (0.5–1 µg/kg bolus ± intraoperative infusion) resulted in decreased breakthrough opioid consumption in the first 24 hours; however, there was no significant reduction in pain scores. Although most studies to date have focused on abdominal surgery, recent trials seem to suggest that dexmedetomidine may also confer an opioid-sparing effect in the setting of gynecologic,7 orthopedic,8,9 and neurosurgical operations.10,11
Clonidine is an α-2 adrenoreceptor agonist 8 times less selective for α-2 adrenoreceptors than dexmedetomidine.5 Clonidine can be administered orally, transdermally, or intravenously to modulate postsurgical pain. A meta-analysis12 of 19 RCTs (1156 patients) to examine clonidine and dexmedetomidine in the postoperative setting concluded that the clonidine provides a 24-hour opioid-sparing effect but to a lesser degree than dexmedetomidine.12 Since 2012, a limited number of trials have investigated clonidine for postoperative pain and found similar results.13 In summary, clonidine provides an opioid-sparing effect that is less pronounced than the one associated with dexmedetomidine.
Tizanidine, a muscle relaxant and α-2 agonist, differs from clonidine by its shorter duration of action and its lesser effect on heart rate and blood pressure.14 In a randomized double-blind, placebo-controlled study, the use of tizanidine 1 hour before surgery and during the first operative week after inguinal hernia repair resulted in less postoperative pain.15
There are other muscle relaxants in the literature and in use, specifically, methocarbamol and cyclobenzaprine. However, the data supporting their inclusion in postoperative pain protocols for an opioid-sparing effect is sparse; what little evidence has been published is not strong enough to draw any conclusions for this outcome.
Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist that has been used in the setting of chronic, cancer, neuropathic, and postsurgical pain. NMDA receptor blockade purportedly results in decreased nociceptive and inflammatory pain transmission.16 Furthermore, preliminary evidence suggests that ketamine can also exert its analgesic effect by interacting with μ-opioid and δ-opioid receptors.17,18 A review article that analyzed the data from 39 RCTs (2482 subjects) utilizing low-dose intravenous ketamine for postoperative analgesia after a variety of surgical interventions and concluded that ketamine provides a 40% opioid-sparing effect.16 Although the degree of opioid consumption mirrors the dose of ketamine administered, a clear dose-related effect cannot be confirmed.16 Unlike its opioid-sparing benefits, the impact of ketamine on postoperative pain scores remains ambiguous.16
Amantadine is a noncompetitive NMDA receptor antagonist that is purported to decrease postoperative central sensitization, acute opioid tolerance, and opioid-induced hyperalgesia.19 Two trials comparing perioperative oral administration of amantadine (50–200 mg/d) to placebo in surgical patients have demonstrated amantadine-related decreases in perioperative opioid consumption as well as opioid-related side effects.19,20 In contrast, patients who received a single preoperative dose of intravenous amantadine (200 mg) before undergoing abdominal hysterectomy reported similar postoperative pain scores, analgesic requirements, and opioid-related side effects to those who received placebo.21 Although amantadine theoretically mitigates acute opioid tolerance and opioid-induced hyperalgesia, a recent trial comparing high-dose remifentanil infusion (≥0.2 µg/kg/min) to the same infusion combined with intravenous amantadine (200 mg) found no intergroup differences in terms of postoperative pain and opioid consumption.22 Also, a pilot study found that a 2-week course of perioperative amantadine (200 mg/d orally) did not reduce postmastectomy pain syndrome after mastectomy with axillary node dissection.23 In summary, the clinical benefits of adjuvant amantadine remain ambiguous. Possible explanations for contradictory results found in the literature include the mode of administration (oral versus intravenous), the dosing regimen (single versus repeated dosing), as well as the nature of the surgical procedure.
Traditionally used as an antitussive, dextromethorphan is an NMDA receptor antagonist that has been investigated as an analgesic adjuvant for various types of surgical procedures (eg, knee arthroscopy/replacement/reconstruction, scoliosis repair, hysterectomy, cholecystectomy).24–29 King et al30 reported in their 2016 meta-analysis of 21 trials that perioperative administration of intramuscular (40–120 mg) and oral (30–200 mg) dextromethorphan can both decrease pain from 1 to 24 hours after surgery and reduce morphine consumption 24 to 48 hours postoperatively after a variety of procedures.
Gabapentinoids (Gabapentin and Pregabalin).
Initially developed as an antiepileptic drug, gabapentin also possesses analgesic properties that are purportedly mediated by its interaction with α-2-δ-subunits of voltage-gated calcium channels, decreasing the release of excitatory neurotransmitters.31 Although gabapentin is commonly used for the treatment of chronic neuropathic pain,32 contemporary evidence seems to support its use in the management of acute postsurgical pain.33–36 While previous meta-analyses33,37 indicate that the perioperative administration of gabapentin is associated with a significant decrease in postoperative opioid use, the extent of this decrease may have been overestimated as suggested by recent studies that confined their analysis to studies with low risk of bias or used meta-regression in their analysis.38,39
Pregabalin possesses a predictable pharmacokinetic profile in comparison to gabapentin because its oral absorption is both extensive and proportional to dose.40
A meta-analysis of 55 RCTs (4155 patients) concluded that all dosing regimens of pregabalin provided a significant reduction in pain scores at rest and on movement as well as opioid consumption at 2 and 24 hours compared to placebo.41 Interestingly, the authors found no significant differences in acute pain outcomes when comparing regimens of a single preoperative administration of pregabalin (100–300 mg) to repeated postoperative dosing.39 Two subsequent meta-analyses also found decreases in perioperative opioid consumption with pregabalin.40,42
Duloxetine, an oral serotonin norepinephrine reuptake inhibitor, is commonly used for the treatment of depression and anxiety. Its analgesic effect is thought to derive from a modulating effect on descending inhibitory pain pathways in the brain and spinal cord.43
To date, the limited evidence pertaining to postsurgical pain suggests that duloxetine results in an opioid-sparing effect; however, it does not consistently provide additional pain relief compared to placebo. In a study of patients undergoing total knee arthroplasty (TKA), those given duloxetine 60 mg/d had lower cumulative morphine requirements at 48 hours than those given placebo, but the former was not superior to placebo in terms of pain management.44 Similarly, when added to a multimodal analgesic regimen for TKA, a 15-day course of duloxetine 60 mg/d did not reduce subacute pain with ambulation but did decrease opioid requirements on the first postoperative day.45 Likewise, a double-blind randomized trial found that two 60-mg doses of duloxetine curtailed fentanyl consumption 48 hours after elective spine surgery, although pain scores did not differ significantly over 48 hours between the duloxetine and placebo groups.46 The opioid-sparing benefits of duloxetine were also seen at 24 hours after abdominal hysterectomy.43 In summary, the limited available evidence suggests that duloxetine provides an opioid-sparing effect even in the context of robust multimodal analgesia despite no difference in postoperative pain scores.
TCAs exert their analgesic effect by suppressing central pain sensitization through the inhibition of reuptake of norepinephrine and serotonin as well as antagonism of peripheral sodium channels and spinal NMDA receptors.47 Although TCAs play an integral part in the management of chronic pain conditions, the evidence supporting their use for postoperative pain remains scarce and ambiguous.
To date, 2 oral TCAs (amitriptyline and desipramine) have been investigated in the setting of postsurgical pain. In patients undergoing dental extraction, Levine et al48 found that combined desipramine-morphine, but not combined amitriptyline-morphine, increased and prolonged morphine analgesia; however, neither TCA decreased postoperative pain in the absence of morphine. Max et al49 randomized patients undergoing various surgical procedures to desipramine (50 mg) or placebo followed by high-dose (0.1 mg/kg) or low-dose (0.033 mg/kg) intravenous morphine. These authors observed greater pain relief and a longer time to a request for subsequent analgesic with the higher dose. However, desipramine was not found to enhance morphine analgesia.49 Similarly, a randomized double-blind placebo-controlled trial reported that patients receiving daily amitriptyline (50 mg) on 3 consecutive days starting after hip and knee arthroplasty fared no better than subjects receiving placebo.50 In contrast, in patients undergoing lumbar discectomy, Vahedi et al51 reported that a single dose of 25 mg amitriptyline administered 2 hours before surgery resulted in lower postoperative pain intensity at 24 hours but did not lead to lower morphine requirement. In summary, the limited and contradictory evidence does not currently support the use of TCAs for the management of postoperative pain.
Although lidocaine is commonly used for neuraxial and peripheral nerve blocks, it also possesses adjuvant analgesic properties when administered intravenously. Because plasma levels are too low to achieve direct blockade of sodium channels, postulated mechanisms of action include decreased release of proinflammatory cytokines (eg, interleukin-6, interleukin-8), nuclear factor-kB–modulated downregulation at the mRNA level, and inhibition of NMDA receptors.52
A 2015 Cochrane Review53 pooled the results of 43 RCTs (1700 patients) comparing intravenous lidocaine to placebo/treatment and concluded that a bolus of lidocaine (100 mg or 1–3 mg/kg) followed by an infusion (1–5 mg/kg/h or 2–4 mg/min) significantly lowers pain scores at 1 to 4 hours and 24 hours (but not at 48 hours) and decreases perioperative opioid requirements. Moreover, lidocaine significantly decreases postoperative nausea/vomiting (PONV) as well as ileus and, as a result, may shorten the length of hospital stay by approximately 8 hours.53 A subgroup analysis found that the analgesic relief and opioid-sparing effect of lidocaine are most pronounced in patients undergoing laparoscopic and open abdominal surgery.53
Esmolol is an intravenous, selective β-1 blocker characterized by its ultrashort onset and offset times. In fact, the ability of esmolol to rapidly achieve steady-state β-blockade makes it an ideal agent to control the hemodynamic response associated with noxious stimuli such as endotracheal intubation and pneumoperitoneum.54 In addition to its sympatholytic effects, esmolol has been used for the management of postsurgical pain. Mechanisms of action remain speculative and include blockade of the excitatory effects of pain signaling in the central and peripheral nervous systems55 as well as modulation of the central adrenergic (pronociceptive) activity.56
A meta-analysis54 (19 RCTs, 936 subjects) examining esmolol administration on early postoperative pain concluded that a perioperative infusion of esmolol (5–500 µg/kg/min) with or without a loading dose (0.5–1 mg/kg) results in lower postoperative opioid consumption (5.1 mg morphine equivalent), a 69% decrease in postoperative breakthrough opioid requirement as well as a 61% reduction in postoperative nausea and vomiting. The decrease in postoperative pain scores was statistically significant (but clinically modest), and while the opioid-sparing effect seems promising, available studies exhibit significant methodological shortcomings.54
Caffeine is a methylxanthine mainly known for its stimulant effect on the central nervous system. Although caffeine has demonstrated intrinsic analgesic properties at very high doses (ie, 50 mg/kg) in rodents,57 it is more commonly used as an analgesic adjuvant in humans, often combined with agents such as acetaminophen, ibuprofen, and aspirin. Proposed mechanisms of action include improved drug absorption due to increased gastric blood flow, reduced drug clearance due to decreased hepatic blood flow, blockade of peripheral pronociceptive adenosine signaling, and activation of the central noradenosine pathway.57–59
Multiple studies have compared oral analgesics with caffeine to the same dose of analgesics without caffeine with contradictory results. A Cochrane Review (20 RCTs, 4262 patients) concluded that the addition of caffeine (100–130 mg) to a standard dose of commonly used analgesics results in a modest but significant increase in the proportion of patients experiencing good pain relief (defined as 50% of the maximum over 4–6 hours) with a number needed to treat of 14.60
In summary, although the available evidence supports the use of dexmedetomidine, clonidine, ketamine, pregabalin, lidocaine, and esmolol as single-agent nonopioid adjuvants for the management of postoperative pain (Table 1), further trials are needed to elucidate the optimal combinations of these adjuvants. Furthermore, different surgical procedures may elicit different patterns of somatic and visceral trauma.42 Thus, the best adjuvant for each type of surgery also requires additional investigation. Future trials should also attempt to elucidate the role (if any) of adjuvants in patients receiving neuraxial and peripheral blocks as a part of a multimodal pain regimen.
Regional Anesthesia and Analgesia
There is a vast body of published data examining the use of regional anesthetic and analgesic techniques to improve perioperative or procedural pain and decrease the need for and use of opioids. Compared to general anesthesia (GA), the use of regional (both peripheral and neuraxial) blocks is associated with improved perioperative analgesia and decreased opioid usage.61,62 Several meta-analyses and systematic reviews of the available literature consistently demonstrate that the use of peripheral nerve blocks decreases opioid usage in a multitude of surgical procedures.
The use of brachial plexus blocks for upper extremity surgery has been associated with both a decrease in postoperative pain scores and perioperative opioid consumption.63 A systematic review of 36 studies examined a variety of peripheral nerve blocks (subacromial/intraarticular infiltration, suprascapular and/or axillary nerve blocks, and single-shot interscalene [SSISB] and continuous interscalene [CISB] nerve blocks) for a range of shoulder surgeries and demonstrated that use of an ISB resulted in better analgesia.64 CISBs were found to have a prolonged analgesic effect up to 24 to 48 hours postoperatively, while the SSISB groups had decreased pain only in the early postoperative period.64 Ilfeld et al65 noted lower pain, lower opioid consumption, and better patient satisfaction in patients who received a CISB at home after painful shoulder surgeries.
More recent trials have compared interscane brachial plexus block (ISB) with supraclavicular brachial plexus blockade. The advent of ultrasound (US) has renewed interest in supraclavicular blocks (SCBs) for upper extremity surgery as the potentially higher risk of pneumothorax and inconsistent coverage of the suprascapular or axillary nerves had previously led anesthesiologists to favor the ISB. However, a prospective clinical registry in 2010 showed similar success rates with US-guided ISB and SCB for ambulatory shoulder surgery with decreased hoarseness in the SCB group.66 Similarly, a study comparing ISB and SCB for 100 patients undergoing arthroscopic shoulder surgery found that the same volume of local anesthetic led to comparable anesthetic coverage, intraoperative fentanyl use, and postoperative analgesia.67 For procedures distal to the elbow, a trial assessing continuous SCB and continuous infraclavicular brachial plexus blocks (CICB) found that the CICB group reported lower average and least pain scores on the first postoperative day and less rescue oxycodone for breakthrough pain 18–24 hours after surgery.68 As evidenced in other trials comparing single-shot versus continuous blocks, patients who received an infusion of local anesthetic via an infraclavicular catheter reported reduced pain scores, opioid requirements, PONV and sedation, and higher patient satisfaction.69
A 2001 study comparing axillary nerve blocks, intravenous (IV) regional anesthesia, and GA demonstrated lower opioid requirements and PONV in the axillary and intravenous regional anesthesia groups over GA.70 After that, the same group conducted a study comparing axillary nerve blocks to GA for outpatient hand surgery and showed decreased visual analogue scale (VAS) pain scores, opioid use, longer time to first analgesic request, and a shorter hospital length of stay; however, there was no longer term difference at 24 hours, 7 days, or 14 days postoperatively.71
The use of lower extremity blocks has also been shown to significantly decrease pain scores and perioperative opioid consumption in a variety of procedures, but especially in painful surgeries like TKA. Given that TKA is such a common operation, many studies have examined the effect of various regional anesthesia modalities on pain and immediate postoperative recovery. A 2017 network meta-analysis of 170 RCTs (12,530 patients) found that combinations of blocks (femoral/sciatic/obturator, femoral/obturator, lumbar plexus/sciatic, lumbar plexus, and femoral/sciatic) decreased opioid consumption after TKA better than single nerve blocks, epidural analgesia, or periarticular injection (PAI).72 Interestingly, the authors found differences in the various block combinations with regard to pain, opioid use, and functional outcomes and concluded that a femoral/sciatic technique was overall the best modality for TKA.72 Another systematic review of 113 trials of patients undergoing TKA noted that various peripheral nerve blocks were associated with 24-hour morphine-sparing effects: 12.3 mg for continuous femoral nerve block (FNB) and 16.6 mg for single-shot FNB.73 Similarly, an earlier meta-analysis of 23 RCTs examined the addition of an FNB to a postoperative regimen that included IV patient-controlled analgesia with opioids in some patients; single-shot FNB was associated with a reduction of mean patient-controlled analgesia morphine consumption of −19.9 mg at 24 hours and −38 mg at 48 hours.74
While FNBs were frequently performed to improve postoperative pain management after TKA, more recently there has been interest in providing adequate analgesia while avoiding the quadriceps weakness from FNB. To that end, there have been a number of trials assessing the efficacy of an adductor canal block (ACB) after TKA. A meta-analysis (11 RCTs) of ACB in patients undergoing TKA showed that ACB (versus saline) resulted in decreased postoperative analgesic consumption (weighted mean difference [MD], −12.84 mg) and less pain both at rest and with activity.75
A concern with sciatic nerve blockade for TKA is the potential for masking surgical injury to the peroneal nerve; it is perhaps underutilized for this reason despite demonstrated efficacy in improving analgesia and decreasing opioid use. A trial of 80 patients who were given a selective tibial nerve block in addition to an FNB for uncomplicated TKA showed that patients had significantly less complete motor and sensory blockade of the common peroneal nerve. There was no difference in the intraoperative opioid requirement, pain scores up to 24 hours postoperatively, or opioid consumption despite the peroneal-sparing effect.76
Regarding other lower extremity procedures, a 2013 review article described improved pain control after total hip arthroplasty (THA) with both continuous lumbar plexus blockade and intraarticular local anesthetic administration; interestingly, however, there was no analgesic advantage to utilizing a lumbar plexus block over a continuous FNB.77 The same review referenced a 2006 trial that found that sciatic nerve blockade in the popliteal fossa provides superior analgesia to and decreases morphine use over patient-controlled opioid analgesia for foot and ankle surgery.78 These findings were similar to those reported in other studies that compared both single-shot and continuous popliteal fossa sciatic blocks to no blocks or oral/parenteral opioids.79,80
Transversus abdominis plane (TAP) blocks performed with and without US may also decrease postoperative opioid consumption for certain abdominal surgeries. A meta-analysis of 56 RCTs found that compared to standard care or inactive (placebo) comparators, TAP blocks reduced morphine consumption (MD, 13.05 mg) and delayed time to first analgesic request (MD, 123.49 min) with a subsequent decrease in the incidence of nausea presumably resulting from a decrease in opioid usage.81 An earlier meta-analysis also reported a decrease in opioid consumption with TAP blocks: in a meta-analysis of 51 RCTs, TAP blocks reduced morphine consumption at 24 hours after surgery (MD, −14.7 mg) compared to placebo after gynecological surgery, appendectomy, inguinal surgery, bariatric surgery, and urological surgery.82 When examining only US-guided TAP blocks, a meta-analysis of 31 RCTs demonstrated an 11-mg mean reduction in morphine consumption.83
Paravertebral blocks (PVBs) have engendered interest due to their potential for analgesia comparable to that provided by epidurals while minimizing epidural side effects such as hypotension, urinary retention, and pruritis. A Cochrane review comparing thoracic epidurals to PVB in thoracotomies found similar analgesic efficacy at all time points studied and moderate-quality evidence describing lower incidences of nausea and vomiting, pruritis, and urinary retention.84 A 2015 systematic review and meta-analysis of RCTs comparing PVBs to groups that received GA and systemic analgesia, spinal analgesia, or other peripheral nerve blocks for a wider variety of surgeries, however, found no significant difference in pain scores or postoperative opioid requirements in the PVB group versus the GA or spinal groups at all time points up to 72 hours postoperatively. Individual studies did show lower pain scores and/or decreased opioid consumption in patients who received PVBs over iliohypogastric or TAP blocks, and a single study in a pediatric population comparing caudal analgesia showed decreased analgesic requirements in the PVB group.85
Data for newer peripheral nerve blocks have also been shown to decrease perioperative opioid consumption. A quadratus lumborum (QL) block is performed by injecting local anesthetic into the space between the QL muscle and medial layer of the thoracolumbar fascia at the level of the umbilicus. Two recent case reports describe good analgesia, no need for intravenous opioids, and no motor weakness after continuous and single-shot QL blocks for a THA and femoral neck fracture open reduction and internal fixation, respectively.86,87 A third case report found a T6-L2/3 sensory level up to approximately 30 hours after a THA with a QL block, with pain and opioid needed for only the distal third of the incision.87
Pectoral nerve blocks (PECs I and II), designed to block the medial and lateral pectoral nerves, and T2-6 intercostal nerves (including the intercostobrachial) in addition to the long thoracic and thoracodorsal nerves were first described in 2011 and 2012, respectively.88 Two recent trials showed lower VAS scores and decreased opioid consumption after mastectomy.89,90 One group of patients also had decreased PONV and sedation scores in the postanesthesia care unit as well as a shorter length of stay when compared to mastectomy with GA and systemic opioids.90
Blanco et al91 also described a serratus plane block in 2013 as an extension of the PEC I and II blocks for improved analgesia of the lateral thorax; local anesthetic deposited superficial to the serratus anterior muscle at the T5 level in the midaxillary line demonstrated T2-9 spread in 4 volunteers. Hards et al92 found in 2016 that patients having mastectomies with a serratus plane block in addition to GA had no or mild pain, required no or only nonopioid analgesics overnight, had no nausea, and were all able to mobilize by postoperative day 1, in comparison to a GA-only group.
Neuraxial Anesthesia and Analgesia.
Similar to peripheral nerve blocks, use of neuraxial anesthesia is associated with decreased perioperative opioid usage.93 Epidural blocks with local anesthetics or intrathecal hydrophilic opioids (eg, morphine) may be associated with decreased postoperative opioid usage when compared to patients with no neuraxial blocks. In a meta-analysis of 15 RCTs in patients undergoing coronary artery bypass surgery, patients who received a thoracic epidural analgesia or intrathecal analgesia had a significant decrease in systemic morphine use by 11 mg.93 In an RCT comparing intraoperative neuraxial to GA for patients undergoing hysterectomy, postoperative opioid consumption and pain scores were higher in the GA group and there was an inverse linear relationship between opioid consumption and postoperative quality of recovery at 24 hours.94 A recently updated meta-analysis included 1498 patients from 15 trials and found that epidurals in addition to GA for open abdominal aortic aneurysm repairs demonstrated decreased VAS pain scores, although there was no data presented on opioid use.95 In THA patients, a study comparing PAIs performed by the surgeons to patient-controlled epidural analgesia showed significantly lower pain scores, opioid consumption, and scores for nausea, vomiting, and itching in the epidural group.96 Finally, use of neuraxial (intrathecal and epidural) morphine has been shown to decrease perioperative systemic opioid consumption in a variety of thoracic and abdominal procedures.97,98 In a meta-analysis of 27 RCTs where 645 patients received intrathecal morphine ranging from 100 to 4000 μg, patients who received intrathecal morphine (versus no intrathecal morphine) used significantly fewer perioperative opioids (weighted MD, −16.9 mg).98 A meta-analysis of 10 RCTs in Cesarean delivery patients noted that administration of epidural morphine (compared to systemic opioid analgesia) was associated with decreased pain scores and postoperative morphine request during the first 24 hours.99 In patients undergoing spine surgeries, a meta-analysis of 8 RCTs with 393 patients found that those who received intrathecal morphine had significantly lower pain scores and morphine use in the first 24 hours postoperatively than the controls.99 Finally, use of epidural analgesia as part of an enhanced recovery after surgery (ERAS) pathway may also decrease perioperative opioid use: 180 consecutive patients undergoing open hepatectomy were managed with traditional strategies of postoperative care and subsequently via an ERAS pathway; those who were a part of the ERAS pathway used significantly less morphine at 24 hours (median, 10.0 vs 116.0 mg), 48 hours (median, 10.1 vs 85.4 mg), and 72 hours (median, 2.5 vs 60.0 mg), and those who had an epidural as a part of their ERAS pathway used even less at 24 hours (median, 2.7 vs 65.0 mg) and 48 hours (median, 8.0 vs 50.0 mg) but not at 72 hours.100
In summary, there has been extensive investigation of a variety of regional block techniques in an effort to provide optimal analgesia and reduce the need for opioids to manage acute postoperative pain. The bulk of the available evidence suggests that peripheral and neuraxial blocks aid those goals after a range of surgical procedures; studies also point to decreased opioid-related side effects and improved patient satisfaction. The duration of analgesic and opioid-sparing effects has been found to vary but much of the literature describes outcomes up to 48 hours postoperatively unless discussing longer treatment with perineural or epidural catheters. In an effort to more effectively block target nerves with minimal to no adverse effects, more established techniques are being refined and new blocks are being described, that is, the serratus plane and QL blocks. Most recently, some regional anesthesiologists have begun performing the infiltration of the interspace between the popliteal artery and capsule of the knee block to approximate a PAI during a TKA. There are no published studies with data on the efficacy or success of the popliteal artery and capsule of the knee, but in theory, the targets are the superior medial and lateral genicular nerves with sparing of the common peroneal nerve. At least one trial is underway to our knowledge to assess postoperative pain outcomes.
Local Anesthetic Additives
The opioid-sparing analgesic benefits of neuraxial and peripheral nerve blocks can be prolonged with the use of indwelling catheters and/or the addition of adjuvant medications. Inpatient use of continuous perineural local anesthetic infusions has shown opioid-sparing effects when compared to single injections of local anesthetic.101 Some centers have had success with prolonging analgesia and limiting opioid use by discharging patients home with indwelling peripheral nerve catheters.102–104 However, their use has been associated with a high burden of clinical support, catheter failure,105–107 and delayed discharge.108
Several local anesthetic adjuvants have been shown to effectively prolong analgesia from single-shot peripheral nerve blocks with associated opioid-sparing effects; however, it should be noted that while several of these agents have been studied extensively and are commonly used off-label, none has been approved for perineural use by the Food and Drug Administration. Because most adjuvants of interest are off-patent, it is unlikely that pharmaceutical companies will push for Food and Drug Administration approval given a lack of financial incentive.109
A recent meta-analysis revealed that brachial plexus blocks supplemented with 4 to 10 mg perineural dexamethasone last approximately 2-fold longer than blocks with local anesthetic alone.110 The data did not support a reduction in 72-hour opioid use, which may not be surprising given the average block duration for a long-acting local anesthetic plus dexamethasone was approximately 22 hours.110 Remarkably, Liu et al111 demonstrated that doses as low as 1, 2, and 4 mg of perineural dexamethasone also prolonged bupivacaine SCBs from 12 to 22 hours.
Several studies have concluded that high-dose IV dexamethasone (8–10 mg) can prolong peripheral nerve blocks with similar efficacy as perineural dexamethasone.112–115 However, a recent meta-analysis found that perineural dexamethasone administration increases block duration compared to intravenous administration, with a small but significant opioid-sparing effect (7.1 mg of oral morphine equivalents [95% confidence interval, 0.74–13.5 mg]) at 24 hours.115 While theoretical concerns remain regarding the potential of dexamethasone neurotoxicity, recent in vivo animal studies at clinically relevant doses do not support this concern and, in fact, demonstrate a potential neuroprotective effect.116,117 A number of studies are currently underway to further clarify the relative benefits of IV and perineural dexamethasone at different doses and with various blocks.
The α-agonist clonidine has established efficacy as an adjuvant to prolong peripheral nerve blocks; however, its use is limited by side effects including hypotension, syncope, and bradycardia.109,118 Dexmedetomidine is a more recently developed α-agonist with analgesic and opioid-sparing effects that has become an agent of interest for peripheral nerve block prolongation. Two recent meta-analyses summarize the recent literature on the effects of perineural dexmedetomidine. Vorobeichik et al119 found that dexmedetomidine increases sensory block and analgesia by >55% and has opioid-sparing effects. However, El-Boghdadly et al120 demonstrated that while dexmedetomidine enhances analgesic and sensory block duration compared to clonidine, it also has more pronounced (though transient) bradycardic and sedative effects. Of note, there is some evidence that IV dexmedetomidine may be as effective as perineural in prolonging analgesia and reducing opioid consumption in the early postoperative period.121
Perineural opiates have also been explored as potentially useful perineural nerve block adjuvants. Morphine, fentanyl, and tramadol cannot be recommended due to sedation.109 Perineural buprenorphine, in contrast, has consistently been shown to provide significant prolongation of analgesia. Several of these studies have also demonstrated an opioid-sparing effect, some exceeding 24 hours.122–125 These benefits must be considered in the context of increased rates of postoperative nausea and vomiting, and its use should only be considered in the context of maximal antiemetic prophylaxis.109,126
In summary, use of dexamethasone, dexmedetomidine, or buprenorphine as peripheral nerve block adjuvants can prolong postoperative analgesia with opioid-sparing effects in the first 24–72 hours after surgery (Table 2). However, opioid usage is not universally reported in perineural adjuvant studies and to our knowledge has not been examined as a primary outcome. The potential for the early opioid-sparing effects that have been reported to impact risk of long-term opioid use and abuse have yet to be explored and likely depend on expected duration of pain after surgery, patient education, and prescribing practices at discharge. In certain populations, opioid use may be completely avoidable with the appropriate use of long-acting nerve blocks and effective adjuvants.
Certain medications and regional block techniques are very well studied but there is a paucity of data describing others. The literature reviewed for this article was extensive but the conclusions are limited by the outcomes in the original studies.
Not discussed in this article is the phenomenon of rebound pain after resolution of nerve blocks, as there are far fewer trials examining this outcome with a relative dearth of patients studied. However, a 2015 systematic review and meta-analysis analyzed 23 RCTs (1090 patients) studying the effect of SSISB pain outcomes up to 48 hours after shoulder surgery and found that while pain scores were better in the ISB group at 8 and 16 hours and opioid consumption was lower for the first 12 hours, there was evidence that patients in the ISB group had increased pain at the 16-hour time point as well as increased opioid use from 12 to 24 hours postoperatively.127 Goldstein et al128 reported similar findings in an earlier, small RCT of patients undergoing operative repairs of ankle fractures: those who received GA had significantly higher pain scores up to 8 hours postoperatively than those who had received a popliteal fossa sciatic block with intravenous sedation, but by 12 hours, there was no difference, and at 24 hours, patients who had popliteal blocks had significantly higher pain scores. There was no difference at 48 hours postoperatively, and the authors did not comment on opioid usage. Thus, while it is possible that there is a perceived increase in pain once a block has resolved, this phenomenon is not well studied in terms of etiology (patients’ perception of more severe pain or the lack of pain before block resolution versus a biological mechanism), risk (it is possible that certain blocks or operations are more prone to leading to rebound pain), effect of block technique (single-shot, continuous, short-, medium-, or long-acting local anesthetic) or additive used, or effect on recovery and satisfaction among other metrics.
Regarding long-term pain or opioid use and functional outcomes, the bulk of the literature describes analgesic outcomes in the first 24–48 hours after surgery. There is evidence that more severe acute pain can lead to chronic pain129 and that even relatively low-risk surgeries can lead to long-term opioid usage130 but long-term follow-up in patients receiving one or multiple opioid-sparing analgesic modalities remains understudied. Similarly, some studies do describe duration of motor and sensory blockade as well as secondary outcomes such as adverse events and functional outcomes, but these studies remain underpowered to make strong conclusions.
Good perioperative pain management is important for improved recovery, the potentially decreased risk of developing chronic pain,129 and better patient satisfaction. A 2012 retrospective study of 391,139 patients found that for low-risk procedures patients prescribed opioids within 7 days of their short-stay surgeries were 44% more likely to become long-term opioid users at 1-year postoperatively compared to those who were not given an opioid prescription.130 Certain surgeries are also known to be more likely to cause persistent pain, and there are characteristics of patients that place them at higher risk for developing chronic pain. While well-intentioned liberal usage of opioids has historically been used to control patients’ postoperative acute pain, the subsequent effects including the opioid epidemic and its morbidity have underscored the importance of alternative methods of achieving adequate analgesia.
Surgical pain is generally a good target for research and management given its often well-localized and self-limited nature. Trials in the surgical literature have found success with local anesthetic administration by surgeons during operations,131 but the bulk of research has focused on perioperative management by anesthesiologists. Discussed broadly in this article are some of the tools in an anesthesiologist’s armamentarium: nonopioid medications as adjuncts to decrease opioid use, regional anesthesia and analgesia, and regional block additives. These tools, alone and in combination, are essential in managing pain and decreasing morbidity and mortality from opioids.
While individual pieces of optimal postoperative pain management plans have been studied, long-term outcome data are lacking, as well as data regarding rebound pain. Future studies will need to focus not only on the optimal combinations of medications, techniques, and mode of administration but also on the specific procedure types maximally benefited by those modalities. The ultimate goal might be to tailor individual analgesic plans based on particular patients’ risk for given surgeries in a way that optimizes pain relief, recovery, and function while reducing or averting side effects altogether, but there is much work to be done.
Name: Kanupriya Kumar, MD.
Contribution: This author helped in the conception and design of the article, analysis and interpretation of data, drafting of content, and the revising and editing of other contributions.
Name: Meghan A. Kirksey, MD, PhD.
Contribution: This author helped in the analysis and interpretation of data, and the drafting of content.
Name: Silvia Duong, BScPharm, PharmD.
Contribution: This author helped in the analysis and interpretation of data, and the drafting of content.
Name: Christopher L. Wu, MD.
Contribution: This author helped in the conception and design of the article, analysis and interpretation of data, drafting of content, significantly revising and editing of other contributions, and guiding authors.
This manuscript was handled by: Honorio T. Benzon, MD.
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