Treatment Development: Directions and Areas in Need of Investigation

Enhanced Recovery Pathways

Enhanced recovery programs (ERPs) for surgical patients may reduce variation in care and improve perioperative outcomes through the development and implementation of standardized, evidence-based perioperative pathways. ^, Multimodal analgesia incorporating primarily non-opioid agents and techniques (e.g. regional anesthesia/analgesia, nonsteroidal anti-inflammatory agents, acetaminophen, gabapentinoids, and local anesthetics) to minimize perioperative opioid use and side effects is a central tenet of ERP programs. Although initial ERP programs focused on colorectal surgery, they have been increasingly adopted for a broad range of complex surgical procedures. The available literature indicates that implementing ERP pathways will result in decreases in hospital length of stay (LOS)/costs and perioperative morbidity, including lower risk of pulmonary, infectious, and gastrointestinal complications. ERPs have received increased interest in the United States over the past decade, in part because of the increased emphasis by payers on quality-based reimbursement and bundled payments.

As ERP programs become a more routine part of surgical care, several areas require further investigation. For example, the optimal analgesic combination for ERP programs is uncertain. There has been increased scrutiny regarding the use of analgesics commonly used in most ERP pathways. Gabapentinoids are an integral part of most multimodal analgesic regimens postoperatively, and when administered as a single dose preoperatively, they have been shown to decrease pain and nausea/vomiting. However, recent literature raises concerns about the efficacy and perioperative respiratory depressant effects of gabapentinoids. ^, The United States Food & Drug Administration (FDA) officially released new warnings for gabapentinoids regarding the risk of respiratory depression. However, the precise role of gabapentinoids in perioperative multimodal analgesia needs to be elucidated.

The use of regional anesthesia/analgesic techniques is an integral part of most ERP pathways because the benefits of its use (minimization of opioids, superior analgesia) facilitate the ERP goals of promoting earlier patient recovery. However, there is a paucity of literature examining the precise contributions of regional anesthesia/analgesia (vs. none) within the context of an ERP pathway.

Increased compliance with process measures directly influenced by the anesthesiologists, including the use of multimodal analgesia, and in conjunction with a formal anesthesia protocol, such as an ERP pathway, is associated with reduced LOS. In one study, patients who received high compliance (vs. low compliance) in ERP pathways had a significantly lower LOS, and multivariable regression indicated that utilization of multimodal analgesia and strict adherence to a postoperative opioid administration protocol for breakthrough pain were independently associated with reduced LOS.

Although the use of ERP pathways can minimize postoperative opioid use, perioperative opioid minimization does not routinely translate into decreased prescriptions for opioids upon discharge. For example, in one study, implementation of an ERP colorectal pathway did not result in significantly lower opioid prescriptions at discharge even though these patients had a combination of low discharge pain scores, no preoperative opioid use, and low morphine milligram equivalent consumption before discharge. Further studies are needed to determine how to modify opioid prescription practices on discharge after surgery in an attempt to continue opioid minimization after hospital discharge.

Chronic Post-surgical Pain

Chronic post-surgical pain (CPSP) is a potentially debilitating postoperative complication that may have a significant impact on activities of daily living and decrease the quality of life in adults and pediatric surgical patients. Large observational trials suggest that CPSP may occur in 10% of patients postoperatively and may be severe in 1 of 100 patients. ^, A neuropathic component that predicts more severe CPSP is present in a significant portion of patients with CPSP as a systematic review of CPSP noted the presence in 6% of patients after total hip/knee arthroplasty and 68% of patients after thoracic and breast surgeries.

There are many risk factors for the development of CPSP. Preoperative pain and psychological vulnerability (i.e. anxiety and catastrophizing) are two of the most important preoperative risk factors for the development of CPSP. Intraoperatively, surgical technique has also been shown to be an important risk factor for the development of CPSP, primarily because of intraoperative nerve damage. In addition, the intensity of acute pain postope­ratively has been shown to be associated with the development of CPSP. Although these risk factors are strongly associated with the development of CPSP, there is no causal relationship between any individual risk factor and the development of CPSP, such that decreasing/attenuating the severity of risk factors would automatically result in a decrease in the incidence or severity of CPSP.

Although we have improved our understanding of CPSP over the past decades, we still lack solid evidence for the prevention and treatment of CPSP in part because many studies have significant methodologic issues. Well-designed prospective trials for various modalities for the prevention and treatment of CPSP are needed as most available studies on CPSP are based on retrospective observational data. Moreover, meta-analyses of treatment modalities for either the prevention or treatment of CPSP rarely have sufficient meaningful data to perform a subgroup analysis for individual CPSP syndromes. One interesting future area of investigation is the trajectory of acute postoperative pain (i.e. the slope or resolution of pain) that may be important in predicting the development of CPSP. ^,

Treatment strategies for CPSP can be grouped into pre-, intra-, and postoperative interventions. These strategies are described below.

Preoperative Opioid Optimization

The incidence of chronic opioid use by patients prior to surgery has been estimated to be approximately 9%. ^, The presence of opioid use prior to surgery has been associated with worse economic outcomes, including longer length of hospital stay, increased incidence of hospital readmission, increased financial costs, and lower incidence of return to work. ^, In addition, observational studies suggest that the preoperative use of opioids is correlated with an increase in postoperative patient mortality and morbidity, including higher surgical site infection rates, higher rates of reoperations, constipation, neurologic complications, acute renal failure, venous thromboembolism, and subsequent opioid abuse.

There is relatively little high quality data in preoperative opioid optimization despite the increased interest in weaning opioids prior to surgery. Future studies should attempt to confirm the correlation between preoperative opioid use and increased perioperative mortality and morbidity. In addition, substantially more data are needed to determine whether decreasing preoperative opioid use will lead to a decrease in perioperative mortality, morbidity, and other outcomes, including length of hospital stay and incidence of hospital readmission. Finally, investigators should attempt to determine the threshold at which any potential benefits may occur (i.e. what percentage decrease in preoperative opioid use is needed to affect postoperative outcomes).

Analgesia in Patients With Obstructive Sleep Apnea

Surgical patients with obstructive sleep apnea (OSA) pose significant challenges in the management of postoperative pain. This issue is complicated by the fact that a large percentage of patients with OSA (e.g. 26% of adults in the United States) are not diagnosed at the time of surgery. Unrecognized severe OSA has been associated with an increased risk of postoperative mortality and morbidity, including an increase in 30-day postoperative cardiovascular complications.

Although the standard tool to diagnose OSA is polysomnography (i.e. sleep study), it may not be completed prior to surgery or even feasible for large numbers of patients. The STOP-Bang questionnaire was specifically developed to meet the need for a reliable and easy-to-use screening tool for OSA. The STOP-Bang consists of eight dichotomous (yes/no) items related to the clinical features of sleep apnea, and patients can be classified for OSA risk based on their scores. Published guidelines recommend minimizing opioids and sedatives postoperatively for the perioperative management of patients with OSA.

Intraoperatively, the use of regional rather than general anesthesia is associated with a reduced incidence of major perioperative complications such as the need for mechanical ventilation, reintubation, and pulmonary/cardiac complications. Postoperatively, the use of regional analgesic techniques with only a local anesthetic-based regimen (when possible) and multimodal analgesia is preferred as a study in which OSA patients who received more than two additional non-opioid analgesia modes showed significantly lower odds of gastrointestinal complications, need for mechanical ventilation, and critical care admission.

Well-designed and well-executed prospective randomized controlled trials (RCTs) would help determine the optimal postoperative and post-discharge analgesic regimen for OSA patients. Although non-opioid analgesics are recommended for patients with OSA, some non-opioid analgesics are associated with sedation, which may not be ideal for OSA patients. A study on the acute effects of gabapentin on sleep breathing in older men noted that gabapentin worsened sleep breathing acutely compared with placebo. Finally, the “safety” of undertaking surgical procedures in an outpatient setting for those patients needs to be explored further. However, more recent data support the notion that moderate-risk, high-risk, or diagnosed OSA can safely undergo outpatient and advanced ambulatory surgery without extended stay or hospital admission and avoiding adverse postoperative outcomes.

Acetaminophen

Acetaminophen (paracetamol) was considered as the “analgesic of first choice” for many years, even though it is viewed as a weak analgesic. Besides its well-known hepatotoxicity with higher doses, cardiovascular (CV) and gastrointestinal (GI) effects have also been noted. Acetaminophen has not been shown to be superior to NSAIDs in the treatment of post-surgical pain or for the treatment of hip and knee osteoarthritis (OA). It was less effective than celecoxib (a selective COX-2 inhibitor) for the treatment of chronic low back pain (CLBP). In the United Kingdom, recent National Institute for Health and Care Excellence (NICE) guidelines do not recommend the use of acetaminophen for patients with LBP. Several ongoing clinical trials are testing the efficacy of acetaminophen compared to opioids for various forms of acute, chronic, and postoperative pain. There have also been investigations into different formulations combining an opioid pain reliever with acetaminophen (i.e. Percocet). One such study (NCT03088826 on clinicaltrials.gov) hypothesized that Percocet containing morphine immediate release (MSIR) would provide greater analgesic efficacy than Percocet containing oxycodone at 30 min and 1 h after administration for acute painful conditions. Research is needed to determine the optimal role of intravenous versus oral acetaminophen in perioperative analgesia and oral aceta­minophen combinations with other analgesics for long-term pain management.

Nonsteroidal Anti-inflammatory Drugs

NSAIDs represent a large and invaluable group of therapeutic agents used in pain management and are the first choice medications for inflammatory pain, as well as postoperative pain, traumatic pain, osteoarthritis, and rheumatic disorders. A cross-sectional study assessing the prevalence of NSAIDs reported a growing prescription trend, particularly in patients older than 60 years, female sex, and those with underlying heart conditions. However, long-term use of NSAIDs is not recommended because of serious adverse effects (AEs).

Opioids

A recent systematic review and meta-analysis showed a statistically significant, but small, improvement in physical functioning and pain but with a much greater risk of side effects when opioids were compared to placebo and similar benefits of non-opioid alternatives used in different types of chronic pain (neuropathic, nociceptive, central sensitization, or mixed types of pain).

Opioids cause many AEs such as vomiting, constipation, drowsiness, nausea, and dry mouth in addition to misuse. The FDA has been mandating and encouraging the development of new “druggable” molecules to decrease the current opioid crisis. A potential pharmacologic approach could be evaluated in the future using tissue-targeted selective opioids. It was found that µ opioid receptors displayed pH-sensitive binding. Therefore the activity of its agonist NFEPP ([{±}-N-{3-fluoro-1-phenethylpiperidin-4-y1}-N-phenylpropionamide]) is achieved in an acidic environment, which is expressed in inflamed tissue and can be limited to peripheral action only.

Tramadol and Tapentadol

Besides their µ opioid receptor agonist activity, these drugs are also norepinephrine (tramadol and tapentadol) and serotonin (tramadol) reuptake inhibitors. Tapentadol has minimal effects on serotonin. With this dual pain management approach, practitioners can go “half” up the “ladder” and still achieve substantial pain control very early in the pain development process. Tramadol provides relief of moderate to severe pain, such as LBP, OA, soft tissue surgeries, and total hip arthroplasty surgery. Physical function and social wellbeing were sufficiently improved when tramadol was used to control pain in patients with postherpetic neuralgia (PHN) and painful diabetic neuropathy (PDN). ^, Several studies evaluating tramadol, tramadol/acetaminophen, and tapentadol deemed them superior to placebo or an active compound, such as oxycodone, pregabalin, codeine/acetaminophen, or NSAIDs, in people with CLBP. ^, They expressed low to moderate AEs such as dizziness, nausea and vomiting, a low incidence of GI bleeding, and lower AEs such as dizziness, nausea, vomiting, low incidence of GI bleeding, and lower withdrawal rate compared with morphine or fentanyl. Multimodal analgesic combinations provide complementary and synergistic mechanisms of action and are promising avenues for pain relief. For instance, there is ongoing research into the use of fixed-dose combinations of weak opioids such as tramadol with NSAIDs such as diclofenac. This particular combination has shown a safe, effective, and to be well tolerated.

Anti-depressants (Tricyclic Anti-depressant, Selective Serotonin Reuptake Inhibitor, and Serotonin and Norepinephrine Reuptake Inhibitor)

Tricyclic anti-depressants (TCA) have been used for a long time in the treatment of neuropathic pain conditions (PDN, PHN, painful polyneuropathy, post-mastectomy pain, post-stroke central neuropathic pain). TCAs express analgesic effects in much lower doses than the ones used for depression management. ^, Besides inhibiting the reuptake of norepinephrine and serotonin, TCAs can have significant AEs when they interact with histamine, cholinergic receptors, and cause blockade of ion channels. Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor (SNRI), is approved by the FDA for the treatment of PDN, fibromyalgia (FM), and chronic musculoskeletal pain. Patients with CLBP and neuropathic components had better outcomes when receiving duloxetine than placebo and with a similar AE rate. Milnacipran (SNRI) was approved by the FDA for FM associated pain. The two selective serotonin reuptake inhibitors, fluoxetine and paroxetine, have been shown to alleviate pain and improve the quality of life better than placebo in patients with FM. ^, Both duloxetine and paroxetine improved quality of life and reduced pain intensity in patients with PDN. ^, TCAs, such as amitriptyline, are routinely administered as co-analgesics in pain management. However, they only provide relief for approximately one in three patients. Clinical trials of genetic determinants of anti-depressant efficacy for pain treatment (such as NCT02256943 on clinicaltrial.gov) hypothesize that more knowledge on how cytochrome variants influence experimental pain and side effects will help better predict the response of patients.

Anti-convulsants

Carbamazepine acts by decreasing the excitability of A-d and C neuronal fibers through the stabilization of voltage-gated sodium channels. The FDA approved it for neuropathy treatment in patients with trigeminal neuralgia but not in other neuropathic disorders. Dizziness, somnolence, and altered gait are the most commonly reported AEs with Stevens-Johnson syndrome, blood dyscrasias, and toxic epidermal necrolysis noted as serious AEs. A decrease in neurotransmitter release by calcium influx modification can be achieved by gabapentin, thus regulating neuropathic pain safely. A crossover study found that gabapentin was associated with mild effects on pain but with significant reversal of sensory loss in patients with complex regional pain syndrome (CRPS).