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Abstract
Chronic pain begins with acute pain. Physicians tend to classify pain by duration (acute vs chronic) and mechanism (nociceptive, neuropathic and nociplastic). Although this taxonomy may facilitate diagnosis and documentation, such categories are to some degree arbitrary constructs, with significant overlap in terms of mechanisms and treatments. In clinical practice, there are myriad different definitions for chronic pain and a substantial portion of chronic pain involves mixed phenotypes. Classification of pain based on acuity and mechanisms informs management at all levels and constitutes a critical part of guidelines and treatment for chronic pain care. Yet specialty care is often siloed, with advances in understanding lagging years behind in some areas in which these developments should be at the forefront of clinical practice. For example, in perioperative pain management, enhanced recovery protocols are not standardized and tend to drive treatment without consideration of mechanisms, which in many cases may be incongruent with personalized medicine and mechanism-based treatment. In this educational document, we discuss mechanisms and classification of pain as it pertains to commonly performed surgical procedures. Our goal is to provide a clinical reference for the acute pain physician to facilitate pain management decision-making (both diagnosis and therapy) in the perioperative period.
- Acute Pain
- CHRONIC PAIN
- REGIONAL ANESTHESIA
- Fibromyalgia
- Pain, Postoperative
Data availability statement
No data are available. Not applicable.
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Key messages
Categories of pain (acute vs chronic; neuropathic vs nociplastic vs nociceptive) are perhaps best viewed as points on continuums rather than distinct entities, with considerable overlap in presentation and mechanisms.
While difficult to identify and isolate, understanding the different components (eg, sensory-discriminative vs affective-motivational vs cognitive-evaluative) and mechanisms (eg, nerve injury, central sensitization, inflammation) of pain can foster personalized pain treatment and lead to better outcomes.
Acute pain care tends to be more siloed than chronic pain care, but this article provides an educational guide to steer acute pain specialists towards incorporation of concepts that can facilitate a mechanistic-based approach to pain treatment, rather than a symptom or etiologic-based approach.
Introduction
The 3-month cut-off distinction between acute and chronic pain is arbitrary, necessary for payers and regulatory bodies but devoid of any biological basis. There are no discrete mechanisms, biomarkers or pathways that distinguish the two. Whereas the chronic pain world is populated by neuroscientists, psychologists, primary care doctors and a host of specialists whose research and clinical interests overlap, the acute pain world is operationally more siloed. Thus, state of the art and emerging chronic pain paradigms that have implications for patients in the perioperative period may have limited penetration. The aim of this article is to introduce chronic pain constructs and terminology to acute pain specialists who may not be aware of them, and illustrate how these concepts can be used to improve care in a comprehensive educational guide.
Case scenario
A 39-year-old woman with chronic pain related to fibromyalgia, depression, anxiety and ulcerative colitis undergoes a colostomy takedown under general anesthesia. The patient received an enhanced recovery after surgery (ERAS) protocol with acetaminophen preoperatively, an intraoperative transversus abdominis plane block and postoperative ketorolac. The patient required intravenous hydromorphone immediately on arrival in the postanesthesia care unit due to excruciating pain, and on postoperative day (POD) 2 is on a hydromorphone patient-controlled analgesia (PCA) device. The surgical team requests an Acute Pain Medicine (APM) consult for assistance. The patient describes “total body pain” including over her back, neck and abdomen, which she rates as 10 out of 10. Her midline incision “burns” with a “numb” sensation adjacent to the incision, and she also reports diffuse abdominal cramping and tightness. She denies any flatus since surgery and is still nihil per os (NPO) but does not have a nasogastric tube (NGT). On physical examination, the patient is tearful, with a distended and tympanic abdomen. Her neck and back pain are exquisitely tender to mild pressure. She reports this is consistent with her usual symptoms of fibromyalgia, but that her current pain is “much worse.” She has not seen a psychiatrist for depression and anxiety but uses occasional marijuana for anxiolysis. She has a remote history of tramadol use for fibromyalgia but is now on a regimen of gabapentin 300 mg three times per day. Her current analgesic medications are intravenous acetaminophen, intravenous ketorolac and hydromorphone PCA (0.2 mg demand dose, 7 min lockout, 4 hour maximum of 5 mg). What are your recommendations?
Overview of pain
Common pathways
Although clinical pain is phenotypically diverse, pain pathways and processing of nociceptive information are the same for different categories. Regardless of the source of injury, after transduction (which may be absent in neuropathic pain), pain signals are transmitted via the spinothalamic (neothalamic, paleothalamic, archispinothalamic tracts) tracts to the thalamus and then onto the primary somatosensory cortex, and the spinoreticular tract to reticular formations in the brainstem, which is involved in affective aspects. All effective pain therapies in the perioperative period need to target one or more of these common pathways.
The importance of categorization
The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.”1 Pain can be distinguished on a mechanistic and even teleological basis and categorized as such. This categorization, though somewhat subjective and dynamic, is important because it affects treatment decisions. For example, medications such as non-steroidal anti-inflammatory drugs and muscle relaxants that are efficacious for nociceptive pain are not recommended as upper-tiered treatments for neuropathic or nociplastic (defined below) pain, and membrane stabilizers that are first-line treatments for neuropathic and nociplastic pain are less effective for nociceptive pain. Categorization should facilitate the anesthesiologist’s ability to diagnose different pain types and recommend therapies likely to succeed.
Challenges in mechanism-based pain treatment
Although it is widely acknowledged that mechanistic-based treatment of pain is superior to symptom-based (eg, membrane stabilizers for lancinating pain), or etiologic-based treatments, in clinical practice identifying pain mechanisms can be extremely challenging.2 Means sometimes employed in clinical practice are often considered experimental by payers and are not well validated in research studies. These include limitations in extrapolation from preclinical studies which tend to translate poorly to humans; intravenous infusions tests which can be challenging to perform and are often not reimbursed; functional imaging which is better at demonstrating associations than causality; and psychophysical tests, quantitative sensory testing (QST), pain-related evoked potentials, electrodiagnostic testing and diagnostic blocks, which can be challenging to conduct and interpret in the context of recent surgery.3–7 Despite empiric limitations in determining mechanism(s) of pain, physicians in the perioperative period can use clinical assessment to categorize pain states as described below.
Pain components of the biopsychosocial model
In addition to the sensory-discriminative component (eg, spatial and temporal) characteristics of nociception which correlate best with objective pathology that can be assessed through QST and pain descriptors, there are also affective-motivational and cognitive-evaluative components to the pain experience.8 The affective component of pain can be measured via instruments such as the Multidimensional Affect and Pain Survey and the McGill Pain Questionnaire (refer to online supplemental appendix A), is often quantified using an “unpleasantness” scale, and is influenced by fear, anxiety, mood and other emotional constituents.9 The cognitive-evaluative component takes into account catastrophizing, fear-avoidance, insight into one’s condition and past experiences, and can be quantified using questionnaires such as the Pain Catastrophizing Scale.10 Individuals with higher affective pain components (eg, pain worsened by anxiety) may respond better to antidepressants and ketamine,11 while those whose pain beliefs are grounded in misconceptions and poor insight may benefit from cognitive-behavioral therapy (CBT).
Supplemental material
Pain categories
Nociceptive
Nociceptive is the most common form of pain and results from activation of neural pathways secondary to actual or potential tissue-damaging stimuli. It is typically described with terms such as “throbbing” and “aching.” Nociceptive pain can be divided into somatic pain and visceral pain. Somatic pain is typically well localized and results from injury or disease of the skin and musculoskeletal structures, while visceral pain results from internal organ pathology that can be caused by inflammation (cholecystitis), ischemia (angina) and occlusion of flow (renal stones). Because of the low density of nociceptors and spinal cord convergence, visceral pain is typically diffuse and poorly localized.12 Based on disparate responses to stimuli and differences in nociceptive signaling between visceral and somatic structures, different interventions may be needed depending on the clinical scenario. For instance, abdominal fascial plane blocks will likely be ineffective for pain related to distension of the liver capsule as the targeted nerves (anterior rami of spinal nerves) do not innervate viscera. Surgery and acute trauma always result in nociceptive pain, though other mechanisms may be involved. For chronic pain, the most common types of nociceptive pain include arthritis and most forms of spine pain.
Neuropathic
Neuropathic pain is caused by injury or disease affecting the somatosensory nervous system. In addition to prognosis which tends to be worse, the other major difference between neuropathic and nociceptive pain is the absence of transduction in the former (ie, neuropathic pain involves direct stimulation of nerves rather than transducing a mechanical or chemical signal into an electrical one). Neuropathic pain is often associated with sensory abnormalities such as numbness and allodynia, is more unpredictable and associated with more prominent pain paroxysms than nociceptive pain, and depending on the extent of injury and nerves involved, is accompanied by focal neurological findings. Descriptors of neuropathic pain typically include adjectives such as “lancinating” and “shooting.” Fifteen to 25% of chronic pain is considered neuropathic, with the most common conditions including diabetic neuropathy and radicular pain.13 Although there are several validated instruments for identifying neuropathic pain, physician designation is the gold standard.14
Compared with acute inflammatory pain and nerve injury which are harbingers of danger, chronic neuropathic pain is always maladaptive and may be associated with greater decrements in quality of life than chronic nociceptive pain.15 Neuropathic pain can be subdivided into peripheral and central neuropathic pain, which is defined as pain resulting from injury or pathology involving the central nervous system. Given its prevalence, central poststroke pain is the most common type of central pain though <10% of individuals with stroke suffer from deafferentation pain. Central pain can also occur with Parkinson’s disease, multiple sclerosis and even after neurosurgery.
In the perioperative setting, neuropathic pain may be pre-existing or develop as a consequence of nerve injury during surgery.16 Examples of the former include surgical stabilization for spinal cord injuries and decompression surgery for radiculopathy and other nerve entrapment syndromes, while common surgeries associated with the development of neuropathic pain include thoracotomy and radical mastectomy (>60% of cases of persistent postsurgical pain (PPSP)) and inguinal hernia repair (>25%).17 Although not well studied, it is possible that any pre-emptive effects of adjuvants are more likely to be realized for surgeries associated with a high incidence of neuropathic and nociplastic pain. The diagnosis of neuropathic pain in the perioperative setting is predicated on history and physical examination. Electrodiagnostic testing is unlikely to detect nerve pathology before 2 weeks have elapsed since the injury, though “baseline” testing can serve as a reference.18 If acute neuropathic pain is suspected postoperatively, the anesthesiologist might consider using systemic steroids or adjuvants that specifically address nerve dysfunction such as lidocaine infusions or membrane stabilizers. In acute nerve injury, glucocorticoids may provide benefit by reducing inflammatory mediator synthesis, thereby reducing neurogenic extravasation and edema, suppressing ectopic neural discharges, membrane stabilization, inhibiting immune reactivity at the site of injury and effecting changes in gene expression; however, the evidence for benefit is mostly limited to clinical trials evaluating high-dose methylprednisolone given within 8 hours of spinal cord injury.19
Nociplastic pain
Nociplastic pain is pain that arises from abnormal processing of nociceptive and modulatory signals without objective evidence of tissue injury or pathology involving the somatosensory system.20 Previously known as “functional pain syndromes,” these conditions include pain states such as fibromyalgia, irritable bowel syndrome and possibly non-specific spine pain. Nociplastic pain can be diffuse (fibromyalgia) or regional, in which case they usually co-occur with a primary musculoskeletal condition.21 The pathophysiological mechanisms responsible for these disorders primarily involve amplified sensory processing including but not limited to pain, along with attenuated inhibitory pathways.12 A hallmark of nociplastic conditions is the absence of identifiable biomarkers.
Appreciating this category is important for acute pain physicians because such pre-existing conditions will likely complicate the postoperative pain experience. Patients with nociplastic pain are more likely to undergo elective surgeries because they are more likely to experience symptoms disproportionate to their pathology, and they experience poor pain and non-pain outcomes at higher rates.22–25 When nociplastic pain is recognized as a contributor to the postoperative pain experience, therapies targeting enhanced central sensitization such as membrane stabilizers that reduce ectopic neuronal discharge, and antidepressants that enhance descending pain inhibition, can be strategic (see figure 1).
Proposed mechanisms for nociceptive, neuropathic and nociplastic pain. Note the significant overlap between pain categories. Drawing by Seffah Jin Cohen. CGRP, calcitonin gene-related peptide; GABA, gamma-aminobutyric acid; N-methyl-D-aspartate; TRPA, transient receptor potential cation channel, subfamily A; TRPV-1, transient receptor potential vanilloid subtype 1.
Table 1 outlines distinguishing features of the different mechanistic categories of pain, while table 2 describes the prevalence of possible nociplastic pain in certain musculoskeletal disorders.
Distinguishing features of neuropathic, nociceptive and nociplastic pain
Prevalence of possible nociplastic pain in surgically amenable regional musculoskeletal disorders
Physical trauma and surgery in particular are often cited as common causes of fibromyalgia.26 In the perioperative period, nociplastic pain may present as surgical pain that is disproportionate to the procedure performed, pain outside of the surgical field and severe pain accompanied by myriad-related non-pain measures such as anxiety, sleep dysfunction and mood disorder, and poor response (including side effects) to analgesic interventions. Nociplastic pain is associated with endogenous opioid system dysregulation (eg, less mu opioid receptor availability, lower antinociceptive activity) and a more prominent affective component, which may make symptoms less responsive to opioids.27 28 Although the studies are mixed, it appears that patients with nociplastic pain are also more likely to experience PPSP after a variety of surgeries.24 29 30 Methods that may be used to detect nociplastic mechanisms include the Central Sensitization Inventory (CSI) and measurements of conditioned pain modulation.31 32 In the postoperative period, if nociplastic pain is suspected, an acute pain physician can consider adding membrane stabilizers or antidepressants to the treatment regimen, starting a ketamine infusion in patients who are NPO or opioid tolerant, and address underlying sleep abnormalities that may worsen pain thresholds and tolerance.
Mixed pain and pain classification as a continuum
Numerous pain conditions contain a “mixed pain” phenotype (ie, do not fall neatly into one mechanistic category). This is most recognized for conditions such as back pain (>50%) and cancer (around 30%), though large studies estimate the prevalence of mixed pain phenotypes among chronic pain patients in primary care and orthopedic settings to be over 50%.33–35 Such mixed conditions are likely present in the postoperative period.
As noted above, there are no distinct pain pathways for different categories. Hence, it may be advantageous to consider pain categories to occupy different points on a continuum. This paradigm may explain why anticonvulsants can sometimes reduce osteoarthritis pain, and why non-steroidal anti-inflammatory drugs (NSAIDs), which work peripherally and are not recommended for non-nociceptive pain, may alleviate neuropathic and nociplastic pain.36 37 Mixed pain conditions may be identified clinically via diagnostic tests such as QST and by validated instruments which reveal components of nociceptive and non-nociceptive pain.14 However, in the immediate postoperative period, it is likely that diagnosing a mixed condition will be an exercise in clinical judgment.
Acute versus chronic pain
Acute pain is an unpleasant, dynamic psychophysiological response to tissue trauma and related inflammatory processes. It can arise from injury including surgery, disease or inflammation, has survival value and plays a role in healing by promoting behaviors that minimize reinjury. The WHO and IASP define chronic pain as pain that persists or recurs for more than 3 months, thus removing the subjective nature of previous definitions that tied it to usual periods of recovery.8 The time distinction is important because different disease courses influence treatment decisions in that the risk–benefit ratios and cost-effectiveness analyses for invasive procedures such as peripheral nerve stimulation are more favorable for chronic than postoperative pain.38 39 In acute pain, peripheral mechanisms predominate, though central sensitization, activation of the immune system and epigenetic modulation also contribute.40
Chronification of pain in the perioperative setting
Risk factors for the chronification of pain after surgery
PPSP, originally defined by the IASP as postsurgical discomfort in the absence of pre-existing pain or non-surgical etiologies (eg, infection) lasting at least 2 months,41 was revised in 2015 by the International Classification of Diseases (ICD) to pain lasting at least 3 months postsurgery to account for variability in healing times.42 Estimates of incidence vary widely even for identical surgical procedures (eg, 5%–35% for hernia repairs and 5%–50% for cholecystectomies),43 but the overall incidence appears to be at least 10%.44–46
Numerous risk factors and pathophysiological mechanisms have been implicated in the chronification of acute pain.45 46 Putative risk factors include demographic variables, genetics, differences in metabolism of analgesics, medical comorbidities (eg, obesity, substance misuse) and specifics regarding surgical and anesthetic care.46 Psychosocial factors such as preoperative fear, anxiety, depression, catastrophizing behavior, tobacco use and weak social support have also been associated with PPSP.46 47 Risk stratification and the identification of modifiable risk factors may optimize resource allocation. For example, individuals with multiple (>2) risk factors may be prime candidates for preventative analgesic strategies, regional anesthesia or less invasive surgical approaches, while individuals with modifiable risk factors may benefit from individualized preoperative interventions (eg, weight loss, smoking cessation, psychotherapy, pharmacotherapy, opioid weaning), even at the expense of surgical postponement. Although risk factors are divided into those that are modifiable and those that are non-modifiable, there is overlap between categories (eg, disease burden, insurance status).
Non-modifiable risk factors
Age
Age is a major contributory factor to the development of chronic pain. While most studies have reported this association in the context of PPSP, it has also been observed in trauma.48 Younger patients develop PPSP at higher rates after undergoing procedures ranging from mastectomy49 50 to herniorrhaphy51 52 to cardiac and chest surgery.53 54 Mechanisms by which age may predispose to persistent pain include greater degrees of neuroplasticity in younger people, leading to higher levels of central sensitization and medication tolerance or opioid hyperalgesia, increased fear-avoidance behaviors and less-developed coping skills.55 56
Sex and gender
Female sex confers a greater risk of chronic pain.57 However, the evidence for sex representing a distinct risk for acute-to-chronic pain is less robust. In a small cohort of living donors for liver transplant, female sex was associated with persistent pain after 112 months (71% of patients with persistent pain were women, relative risk=2.32 (0.83–6.45)).58 Mechanisms by which female sex may mediate PPSP include differences in hormone concentrations, psychosocial factors and greater degrees of central sensitization.59 In epidemiological studies evaluating nociplastic pain conditions, female sex is a strong risk factor.20
Female gender, independent of biologically determined sex, may predispose to chronification of pain. Reasons for this include gender role expectations and biases, cultural differences, and differences in the treatment of pain between women and men.57 For example, one study found that women were more likely to be treated with sedatives while men were more likely to receive analgesics for pain.60 Another study found that Israeli men and women reported more masculine views on pain sensitivity than Americans.61
Genetics
Genetic factors contribute to the risk of PPSP. Polymorphisms of COMT, a gene involved in catecholamine metabolism, have been associated with increased acute postoperative pain62 63 and PPSP.64 However, a recent meta-analysis of nine studies covering six variants of five genes found a modest increased risk only for the rs734784 variant of KCNS1 (OR 1.511 (1.000–2.285)], p=0.005).65 Genetic factors may contribute to PPSP through multiple mechanisms including a predisposition to central sensitization and psychological or personality characteristics including anxiety, depression and maladaptive coping mechanisms.
Socioeconomic factors
Socioeconomic factors such as educational status, secondary gain and insurance have been linked to chronic pain,66 67 but evidence for their explicit contribution to PPSP is less clear. Low educational attainment (less than junior high school) was implicated as a risk factor for post-video-assisted thoracoscopic surgery PPSP in a Chinese cohort involving 2348 patients (OR 1.295 95% CI 1.090 to 1.538).68 Receiving disability benefits or being scheduled for a consultative medical examination for retirement were identified as a risk for PPSP at >6 months in a cohort of 453 patients who underwent sternotomies for cardiac surgery (HR 2.05 (1.40–3.02)).69 Non-private insurance status was found to be associated with PPSP after Caesarean pain,70–72 upper extremity surgery71 and total knee arthroplasty.72 However, other studies have failed to find insurance status, a surrogate for economic status, to be a factor.73
Trauma
The presence of trauma is independently associated with chronic pain,48 and its relationship with surgery and PPSP is extensively discussed in the surgical literature. Surgery for trauma is associated with a high rate of PPSP.74 75 In a cohort of patients who underwent surgery for orthopedic trauma, PPSP at 3 months was reported by 65% of patients (95% CI 59% to 71%).75 In some studies, patients with traumatic upper and lower limb amputations have been found to be at increased risk for phantom limb pain (PLP) compared with amputations performed for non-traumatic indications.76 77 The increased risk for PPSP conferred by trauma can be related to concomitant psychosocial trauma, suggesting that timely and targeted psychotherapy and pharmacotherapy that addresses the affective motivational component of pain (eg, ketamine and other antidepressants) may be beneficial.78 79
Modifiable risk factors
Pre-existing pain
The presence of pain at the site of surgery or other sites before surgery is a risk factor for PPSP. Multiple mechanisms and mediators for peripheral and central nervous system involvement have been identified, with considerable overlap between mechanisms and clinical symptoms.80 81 Clinically, numerous studies have found that patients with preoperative pain (at the surgical site or elsewhere) report higher rates of chronic symptoms. In a survey of patients who underwent open hernia repair, Poobalan et al reported that patients who recalled preoperative pain had a significantly higher risk of PPSP (OR 3.53 (1.40–8.32)).51 Brandsbord and colleagues found that preoperative pelvic pain (OR 3.25 (2.40–4.41)) and pain at other locations (OR 3.19 (2.29–4.44)) were significantly associated with persistent posthysterectomy pain, more so than factors such as surgical technique.82
The effect of the magnitude of preoperative or acute postoperative pain has also been investigated. Anderson et al reported that moderate-to-severe preoperative pain was associated with a greater risk of surgical site rest pain after 1 year (OR 5.776 (1.306–14.467)) than mild preoperative pain (OR 2.173 (1.211–3.899)).50 Pre-existing pain may predispose to PPSP through lowered pain thresholds and tolerance, peripheral and central sensitization, psychosocial comorbidities and learned behavior.83
Surgical approach
Different types of surgery and surgical approaches pose different risks for PPSP.
Systematic reviews and meta-analyses support the findings that minimally invasive surgery is associated with a lower incidence of PPSP. A systematic review and meta-analysis of 12 randomized controlled trials (RCTs) (n=3966) assessing laparoscopic (2040 patients) and open (1926 patients) hernia repair reported data on postoperative and chronic pain; in 3445 patients assessed for chronic pain, laparoscopic repair was associated with a lower OR at 1–5 years (OR 0.41 95% CI 0.30 to 0.56).84 For acute postoperative pain, a recent meta-analysis of 96 studies examining different approaches for cholecystectomy found that minimally invasive techniques were associated with significantly lower postoperative pain scores than open surgery.85 There appears to be a higher coprevalence of psychiatric comorbidity in patients undergoing cholecystectomy, inguinal hernia repair, hysterectomy and colectomy compared with asymptomatic controls, suggesting targeted cointerventions may be warranted.86–89
Infection
Infection may increase the risk of PPSP by compounding the tissue damage caused by surgery, amplifying systematic inflammation and sensitization.90 Multiple studies have found postsurgical infection in a variety of procedural contexts to be associated with PPSP. A large cohort study involving 11 986 adult surgical patients reported that postoperative infection was highly associated with pain 1–3 months after surgery (OR 1.53 (1.18–1.98)).91 In a multicenter trial exploring the impact of nitrous oxide anesthesia on PPSP, postoperative infection was identified as a risk factor (OR 2.34 (1.36–4.02)) for symptoms at 12 months.92
Psychiatric comorbidities
Depression, anxiety and other psychiatric conditions including post-traumatic stress disorder (PTSD) are risk factors for increased postsurgical pain and PPSP.93 94 A 2012 meta-analysis which included 15 studies reported pooled ORs of 1.55 (1.10–2.20) in a minimum effect scenario and 2.10 (1.49–2.95) in a maximum effect scenario, for the combined effect of factors such as preoperative general anxiety and catastrophizing on PPSP.95 Depression has also been identified as an independent risk factor for PPSP.96–98 Although the influence of preoperative PTSD on PPSP has not been well studied, one prospective study performed in 87 trauma patients found that PTSD symptoms were strongly associated with a worse pain trajectory.99 Factors such as pain catastrophizing, negative affect and poor coping skills are also associated with increased risk for PPSP.100
Despite the conceptual basis for targeted education and psychotherapy to reduce postoperative pain and PPSP, studies that have examined these interventions have yielded mixed results. Horn et al systematically reviewed 338 publications pertaining to preoperative educational methods and their capacity to reduce acute perioperative pain; they categorized studies into five psychological domains including preoperative pain education, procedural pain knowledge, anxiety and pain catastrophizing, information delivery strategy and psychoeducational costs.101 They reported strong evidence for pain expectations impacting postoperative recovery, and evidence for procedural pain knowledge to have a significant impact on pain control and recovery time. Nadinda et al conducted a systematic review and meta-analysis of 21 RCTs evaluating the effect of psychological interventions (CBT, acceptance and commitment therapy, mindfulness, cognitive therapy and psychoeducation) on postoperative pain.102 They found small effects for both subacute pain (d=−0.26 95% CI −0.48 to −0.04) and chronic pain (d=−0.33 95% CI −0.61 to 0.06). However, another recent systematic review of psychological interventions in orthopedic surgeries that included 19 controlled trials (n=1893) failed to detect a significant improvement in postoperative pain.103 Whereas psychologically based interventions appear to provide acute and longer term benefit, questions regarding the optimal approach remain.
Smoking
Smoking, which is more common (24.1%) in the surgical than general population,104 increases the proclivity to develop chronic pain. In an observational study of 160 patients undergoing amputations, smoking was found to be associated with an increased risk of PLP at 3 months (OR 1.403 (0.710–2.775)), with diminishing effects at 6 (OR 1.11) and 12 months (OR 0.680).105 In a non-randomized prospective study evaluating the effect of smoking cessation on acute postoperative pain in 107 individuals undergoing thoracoscopic lung cancer surgery, individuals who stopped smoking >3 weeks before surgery had lower postoperative pain scores and opioid consumption than those who quit <3 weeks before surgery, but higher pain scores and opioid consumption than non-smokers.106 Although stopping smoking even 24 hours before surgery can decrease blood levels of nicotine and carbon monoxide, most experts recommend quitting at least 4 weeks before surgery to reduce postoperative complications. Paradoxically, smokers who are deprived of nicotine immediately before surgery may actually experience increased postoperative pain and opioid requirements.107
Management of patients with chronic pain in the perioperative setting
This section focuses on the management of uncontrolled perioperative pain, which is not only one of the most consistent risk factors for PPSP44–46 but also possibly the most modifiable. Poorly controlled acute postsurgical pain is associated with harmful outcomes such as PPSP,45 46 108 increased hospital length of stay,109 110 increased risk of postsurgical end-organ injury (eg, oliguria, myocardial injury)109 111 and persistent opioid use.109 112 Because pre-existing chronic pain and preoperative opioid use increase the risk of uncontrolled postsurgical pain,45 46 it stands to reason that decreasing preoperative pain levels and opioid utilization via presurgical medication management may be beneficial. Nonetheless, evidence remains limited and mostly consists of uncontrolled studies112–114 (table 3).
Classification and prevalence of common pain conditions and the corresponding operations for surgical patients
Considerations for perioperative medication management
Opioids
Opioids are widely considered the reference standard for acute postoperative pain, with a recent trend in perioperative pain medicine towards opioid-free anesthesia. Yet, there is no evidence that opioid-free anesthesia is associated with reduced pain compared with opioid-based anesthesia, no evidence that it reduces postdischarge opioid use, and an absence of evidence that it changes long-term pain outcomes.115
Presurgical opioid utilization is associated with a litany of potential adverse postsurgical outcomes,112 including surgical site infection,116 117 revision surgery,118 119 prolonged inpatient admission120 121 and persistent opioid use.45 122 Despite this, as many as one out of four patients scheduled for surgery in the USA uses opioids preoperatively,123 with the prevalence rising to 50% or greater in patients undergoing orthopedic or spine surgeries.120 123 Recent retrospective analyses have utilized a dose of 50 morphine milligram equivalents per day (MME/day) as a categorical benchmark for indicating an elevated perioperative opioid requirement,124 125 but it has not been established whether there is a perioperative MME/day threshold below which a patient’s postsurgical risks are equivalent to that of an opioid-naive patient. Animal and human studies indicate that very low doses of opioids can induce hyperalgesia.126 127
Presurgical opioid exposure is associated with an increased risk of PPSP,45 108 possibly via opioid-induced hyperalgesia (OIH), increased N-methyl-D-aspartate (NMDA) receptor activation, low baseline pain thresholds or modulatory changes in medullary spinal pathways.128 129 Although there may be a dose–response relationship between preoperative120 124 125 and intraoperative130 opioid doses and adverse postsurgical outcomes, the evidence remains limited.113 A recent retrospective cohort analysis of insurance claims data comprizing over 57 000 patients did not find clinically significant differences in postsurgical opioid utilization in terms of prescriptions filled or dosages in MME/day regardless of whether patients had stable, increasing or decreasing trajectories of presurgical opioid utilization.131 However, numerous studies have found that intraoperative remifentanil use is associated with greater postsurgical opioid requirements and hyperalgesia,130 132 and a recent large prospective cohort study in over 1800 patients found that a stable or increasing trajectory of postsurgical opioid requirements within the first month after joint, spine or abdominal surgery was associated with a significantly greater likelihood of subsequent chronic opioid use (>6 months postsurgery).133 These trends suggest that the reduction of perioperative opioid exposure and opioid requirements via multimodal analgesic strategies may reduce postsurgical opioid requirements and improve safety. Opioid stewardship programs,112 perioperative surgical home care models134 or opioid task forces135 have been developed at many institutions, generally yielding decreased rates of postsurgical opioid use136 and potentially decreased postsurgical mortality rates without increased pain.135
Patients with a history of opioid use disorder may especially benefit from such perioperative opioid safety programs, particularly as they pertain to medications for opioid use disorder (MOUD). The perioperative management of MOUDs (eg, methadone, buprenorphine and naltrexone) can be challenging to coordinate, and incorrect dosages can lead to adverse events.137 Opioid stewardship programs may help streamline preoperative planning and facilitate patients’ postsurgical access to addiction medicine specialists, social workers and longitudinal care.136 Recently published guidelines from the Multisociety Working Group on Opioid Use Disorder138 emphasize the importance of precise MOUD management throughout the perioperative period and the value of appropriate discharge planning in coordination with relevant outpatient teams.
OIH and opioid tolerance
OIH is characterized by altered nociception and a decrease in pain thresholds in response to opioid exposure, while tolerance manifests as a rightward shift in the dose–response curve.139 An increase in opioid dosage will paradoxically exacerbate pain if OIH is present, but attenuate pain with tolerance. OIH manifests as diffuse hyperalgesia or allodynia extending beyond the initial locus of pain, while opioid tolerance is not associated with expansion of receptive fields or alterations in afferent processing. Nonetheless, OIH and opioid tolerance are difficult to distinguish clinically because both phenomena lead to an apparent decrease in the analgesic efficacy of opioids and an increase in self-reported pain.
OIH and opioid tolerance are the result of distinct but overlapping physiologic pathways in response to opioid exposure. OIH is primarily mediated by alterations in receptor expression (eg, increases in mu-receptor isoform variation and central NMDA and transient receptor potential ion channel expression, with a decrease in periaqueductal gray opioid receptors),140 mu-opioid signaling pathways (eg, increased G-protein-coupled receptor kinase activation of β-arrestin-2, leading to opioid receptor desensitization)141 and neuroinflammatory processes (eg, glial cell activation).140 Opioid tolerance is a consequence of opioid receptor desensitization in response to repeated agonism, though it is associated with changes in nociceptive signaling also seen in OIH (eg, NMDA-glutaminergic system activation; β-arrestin-2 recruitment leading to mu-receptor internalization).140 142
Numerous pharmacodynamic, immunologic and patient-specific factors are potentially involved with OIH and opioid tolerance, which have been reviewed elsewhere.126 139 140 142 143 Younger age (< 65 years)144 is a potential risk factor, and limited data from murine models suggest that female sex might also be a risk factor,145 though data from human studies are limited.140 A greater magnitude or duration of opioid exposure, especially to remifentanil, is a consistent risk factor. A meta-analysis of 27 RCTs demonstrated that higher intraoperative doses of remifentanil increase the risk of OIH and lead to greater pain scores and morphine utilization in the first 24 hours after surgery.146 An RCT in 91 patients undergoing thyroid surgery and receiving intraoperative remifentanil demonstrated higher rates of OIH with higher doses of remifentanil.147 In a prospective trial of 355 patients undergoing interventional pain injections, there was a linear relationship between opioid dose and pain intensity and unpleasantness (a measure of the affective pain component) in response to a standardized subcutaneous injection.127
Because decreased pain thresholds are characteristic of OIH, QST148 has been studied as a tool to identify patients experiencing OIH. However, in a recent systematic review of 14 studies, no QST modalities assessed reliably identified OIH.149 The CSI questionnaire might also be used to quantify differences in pain thresholds,150 but CSI data are self-reported and no studies to date have utilized it.
In the absence of an established method of distinguishing OIH from opioid tolerance, an empiric approach is necessary; for chronic pain, this might require an opioid holiday. It is important to recognize that OIH and opioid tolerance can coexist and develop postoperatively in previously opioid-naive patients.142 In opioid-tolerant patients, an increase in opioid dose can reduce pain in the short term and intermediate terms, while in an individual with OIH, it would likely worsen pain in the intermediate terms and long terms. However, in the acute postoperative setting, an increase in opioid dose may also reduce pain in OIH as clinically worsening central sensitization may take weeks or months to manifest.
In the postoperative setting, decreasing the opioid dose might not be feasible in OIH patients if non-opioid medication options have already been exhausted. Given the role of NMDA-glutaminergic signaling overactivation in both OIH and opioid tolerance,140 142 ketamine139 can be a valuable adjunct in either clinical scenario. For tolerance, opioid rotation can be effective due to incomplete cross-tolerance. Although theoretically attractive due to its NMDA receptor antagonist properties, rotation to methadone is generally not advisable in the postoperative period due to its very long half-life (ie, while serum levels of methadone can increase for up to 1 week, postoperative pain typically decreases over this time frame).
Non-opioid medications, multimodal analgesia and ERAS
Amidst growing public awareness of opioid-related morbidity and mortality,151 152 greater emphasis has been placed on using non-opioid medications for the management of chronic pain in the outpatient setting.153 The choice of which medication classes to consider rests on an assessment of which pain mechanisms may be involved and which medications may have pertinent pharmacological mechanisms (table 4).
Evidence for analgesic categories for different classifications of pain
Acute postsurgical pain may involve a combination of nociceptive, neuropathic and nociplastic pain mechanisms,154 though the nociceptive component is predominant.155 Kehlet and Dahl may have been the first to suggest the term “multimodal analgesia,”156 which was initially one component of a wider, comprehensive model aimed at reducing the physiologic surgical stress response and improving postsurgical outcomes.157 Tenets of this holistic approach to perioperative care were eventually formalized into the ERAS movement.158 Other investigators have applied multimodal analgesic strategies to specific procedures (eg, Procedure-Specific Pain Management (PROSPECT)),159 with resources available to guiding postoperative pain management for individual surgeries such as total knee arthroplasty, abdominal hysterectomy or complex spine surgery.
Kehlet initially described the use of different classes of analgesic medications to address varying degrees of pain severity (eg, NSAIDs for mild pain and neuraxial local anesthetics for severe pain), rather than for targeting different mechanisms.157 Although achieving adequate pain relief was important, this was part of a broader effort toward reducing hospital length of stay and encouraging early ambulation and rehabilitation. In current practice, multimodal analgesia strategies aim to target as many mechanisms of nociception as feasible.155 Whereas optimization of postsurgical pain remains a key component of ERAS and similar protocols, the minimization or outright elimination of perioperative opioids has recently become a goal for some experts.112 160
In this section, we discuss non-opioid medications commonly used to treat chronic pain and how they are utilized in the perioperative period. It is important to note that there is no universal or established strategy for choosing which medication classes a multimodal analgesia strategy should comprise.155 161 Although individual studies have shown promise regarding immediate postsurgical process measures (eg, nausea, ambulation) and reductions in postsurgical opioid utilization,161–163 high-quality systematic reviews and meta-analyses yield findings that both support164 and refute165 the utility of multimodal analgesia regimens for preventing PPSP.
Acetaminophen
The mechanism of action of acetaminophen is unclear,166 but it most likely inhibits central cyclooxygenase activity and prostaglandin production.167 There is currently no evidence that acetaminophen (independent of combination therapy) reduces neuropathic pain,168 and very limited evidence via murine models that it improves nociplastic pain.169
The Centers for Disease Control and Prevention (CDC) describes acetaminophen as a first-line non-opioid medication for chronic pain.170 However, the CDC describes acetaminophen’s expected magnitude of benefit as “small”170 and there is sufficient evidence of inefficacy171 172 such that major guidelines now recommend against its use for low back pain,173 174 the most common cause of disability worldwide.175 Overall, acetaminophen appears most likely to benefit acute pain with a predominantly nociceptive component (eg, postsurgical pain).176
Acetaminophen in either an oral or intravenous formulation is often included in multimodal medication protocols owing to its generally favorable safety profile,177 but as of 2021, no RCTs have been conducted to assess its efficacy for PPSP.154
Non-steroidal antinflammatory drugs
NSAIDs inhibit the activity of peripheral cyclooxygenases (eg, COX-1 and COX-2) responsible for the production of proinflammatory prostaglandins,178 and there is limited evidence of centrally mediated activity (eg, inhibition of serotonin release and central production of prostaglandins).179 NSAIDs, along with acetaminophen, are recommended by the CDC as first-line options for chronic pain.170 NSAIDs might be expected to confer a significant magnitude of analgesia, especially for pain deriving from inflammatory, nociceptive mechanisms. However, a large Cochrane systematic review and meta-analysis found only modest benefit for reduction of pain and disability in patients with chronic low back pain, and differences in COX-selectivity did not influence efficacy.178 Another Cochrane review found modest evidence of efficacy for topical NSAIDs but only for osteoarthritis.180 NSAIDs have not been conclusively shown to alleviate neuropathic pain181 and the evidence is weak and conflicting for nociplastic pain.182
Chronic use of NSAIDs (>3 months)183 confers potentially serious gastrointestinal, renal and cardiovascular risks, though complications may occur even with short-term use. A recent large meta-analysis of over 4 40 000 patients demonstrated that the risk of myocardial infarction increases within the first week of NSAID use regardless of COXselectivity, though the risk decreases on discontinuation.184 It is therefore recommended that NSAIDs be taken at the lowest effective dose for the shortest duration of time possible.173
In the perioperative context, the routine use of NSAIDs is limited by concerns that the inhibition of COX-1, which is involved in platelet activity, might exacerbate the risk of postsurgical bleeding.185 More recent literature suggests that this risk is minimal in most routine surgeries.186 There is also conflicting evidence that NSAIDs may interfere with bone regeneration after orthopedic procedures,187 though pooled analyses suggest that low doses (eg, <120 mg/day of ketorolac) and short durations (<2 weeks) are unlikely to impair bone healing,188 189 and NSAIDs might be beneficial for managing acute fractures by decreasing inflammation and reducing opioid requirements.187 Clinicians may also be concerned for an increased risk of adverse cardiovascular events from NSAID use in coronary artery disease, but the risk conferred by a single or intermittent dose is unclear.190 Several of the largest studies examining the cardiovascular risks of NSAIDs utilized outpatient data and did not assess ketorolac,184 191 which is commonly used perioperatively. A discussion of risks and benefits should therefore guide decisions regarding NSAID use in high-risk patients, using the smallest dose and duration possible.
Regarding magnitude of analgesia, although some large meta-analyses have shown significant improvements in postsurgical pain control via the use of NSAIDs,192–194 others have shown only mild benefit.195 196 Despite the mixed evidence for clinical analgesic efficacy, NSAIDs are likely beneficial for nociceptive components of pain and should be utilized if safety considerations appear favorable.
Gabapentinoids
Gabapentinoids (eg, gabapentin, pregabalin) decrease excitatory neurotransmission by binding to the α2δ−1 subunit of voltage-gated calcium channels and stimulate central descending inhibitory pathways.197 Because α2δ−1 receptors are found throughout the nervous system, gabapentinoids act centrally and peripherally, but central mechanisms predominate.197 198 Gabapentinoids are recommended as first-line therapy for peripheral neuropathic pain,199 200 which has been supported by several large meta-analyses, particularly for postherpetic neuralgia and painful diabetic neuropathy.201–203 Although commonly prescribed for low back pain and sciatica, gabapentinoids are not effective for these conditions,199 and evidence is insufficient regarding central neuropathic pain syndromes (eg, poststroke pain).202 203 There is limited evidence available regarding the efficacy of gabapentin for nociplastic pain syndromes,204 but there is data from murine models suggesting pregabalin may inhibit central sensitization pathways that propagate nociplastic pain.169 205 For fibromyalgia and other nociplastic conditions, there is stronger evidence for pregabalin.206 207
Although earlier meta-analyses supported using gabapentin208 and pregabalin209 for reducing acute postsurgical pain, more recent meta-analyses have demonstrated either questionably meaningful analgesia or a risk of harm that matches or outweighs potential benefits.210–212 Sedation and visual disturbances are common adverse effects, and the US Food and Drug Administration recently issued a warning regarding the risk of respiratory depression when gabapentinoids are combined with opioids or other centrally depressing medications.213 In the postsurgical period, wherein patients commonly have altered pulmonary physiology and significant serum concentrations of residual anesthetics and opioids, this safety concern is especially pertinent. However, patients using gabapentinoids chronically or at elevated doses (eg, gabapentin >3000 mg/day) might benefit from dose reduction rather than complete cessation due to the risk of withdrawal, which might begin within 12 hours of the last dose.214
Gabapentinoids have been extensively studied for the purpose of preemptive analgesia, but evidence from pooled analyses is lacking. Although individual RCTs have demonstrated promising results for pregabalin in preventing PPSP,215 216 data from large meta-analyses are mixed or negative,164 165 209 and gabapentin does not appear very effective for this indication.45 217 A recent large meta-analysis found no meaningful benefit from either gabapentin or pregabalin for postsurgical analgesia or the prevention of PPSP,211 such that there are now calls for discontinuing routine perioperative gabapentinoid administration.218
Antidepressants
Serotonin–norepinephrine reuptake inhibitors such as duloxetine and tricyclic antidepressants are first-line treatments for chronic neuropathic pain.200 201 Uniquely, duloxetine is also beneficial for chronic low back pain174 and osteoarthritis pain,219 both of which have predominantly nociceptive components. Antidepressants might reduce maladaptive neuroplasticity by stimulating dendritic arborization and neurogenesis, leading to antiallodynic and/or antihyperalgesic effects, and the modulation of serotonergic and noradrenergic systems may provide direct analgesia.198 In light of their anxiolytic and mood stabilizing properties, antidepressants may be particularly efficacious in individuals with a strong affective-motivational pain component. Because there is conflicting evidence regarding the efficacy of selective serotonin reuptake inhibitors (SSRIs) for analgesia,198 SSRIs are not included in most treatment guidelines for neuropathic pain.200 201
Given the central pathways involved in nociplastic pain and their association with mood symptoms,20 there is a mechanistic basis for antidepressants yielding potential benefit. Duloxetine and milnacipran comprise two of the three medications approved by the US Food and Drug Administration for the treatment of fibromyalgia,220 and the National Institute for Health and Care Excellence (NICE) guidelines recommend antidepressants as first-line agents for chronic primary pain (the descriptor used by NICE to denote nociplastic pain syndromes).221 However, there is a paucity of studies demonstrating the efficacy of pharmacotherapy for nociplastic pain.20
Perioperatively, antidepressants have limited practicality due to their prolonged onset of action and central nervous system effects. Several weeks might be required to titrate to a therapeutic dose,198 222 and although greater doses may confer acute analgesia, rapid up-titration increases the risk of adverse effects deleterious to postsurgical recovery.198 Despite the limitations of antidepressant utilization in the perioperative period, the ability to identify patients who would benefit from such therapy with transition of care could be strategic in the long term.
NMDA receptor antagonists
NMDA receptors are found throughout the central and peripheral nervous systems223 224 and their overactivation is implicated in central sensitization that facilitates chronic pain.224 NMDA receptor antagonism yields significant analgesia,225 and there has been growing interest in the use of NMDA receptor antagonists for the purpose of reducing opioid requirements in the perioperative and outpatient clinic settings.226 227 In the perioperative context, NMDA receptor antagonists are occasionally used to prevent central sensitization.45 In contrast, for the treatment of chronic pain, NMDA receptor antagonists are used in hopes of reversing central sensitization that has already occurred.226
NMDA receptor antagonists in clinical use include ketamine, magnesium sulfate, nitrous oxide, dextromethorphan, memantine and amantadine.45 227 Magnesium sulfate is a component of some ERAS protocols,228 and although there is limited data supporting perioperative magnesium to reduce postsurgical pain and opioid utilization,229 data are limited and mixed230 regarding its benefit for chronic pain (eg, peripheral neuropathy,231 complex regional pain syndrome (CRPS),232 with current evidence suggesting benefit for acute migraine.233 There are limited clinical data regarding the use of nitrous oxide or dextromethorphan for perioperative pain.45 Nitrous oxide is not routinely used for chronic pain, and as with other NMDA receptor antagonists, there are concerns regarding its abuse potential.234 RCTs have shown that preventive dextromethorphan may reduce immediate postsurgical opioid requirements,235 236 but evidence is mixed regarding its benefit for neuropathic pain.237 Memantine is approved for Alzheimer’s disease,238 while amantadine is used for Parkinson’s disease,239 and antipyrexia in influenza A.240 One placebo-controlled pilot trial found that a 4-week course of memantine completed before surgery significantly decreased the intensity of persistent postmastectomy pain,241 but several other small controlled trials failed to demonstrate efficacy for neuropathic pain.237 For preventive analgesia and the short-term relief of neuropathic pain, the evidence for amantadine is mixed.237 242 243
Recently published guidelines have addressed the use of ketamine for acute226 and chronic pain.244 Ketamine is a versatile perioperative analgesic drug and a useful rescue treatment for patients with postoperative pain crises and to reduce opioid requirements. In addition to NMDA receptors, ketamine acts on several targets that may pertain to peripheral and central pain transmission (eg, muscarinic, monoaminergic, dopaminergic and opioid receptors),127 226 giving it potential efficacy for nociceptive,245 neuropathic246 247 and nociplastic pain.248 249 However, data have yielded mixed results regarding long-term analgesia. In an RCT performed in 40 patients with spinal cord injury-associated neuropathic and nociplastic pain, ketamine infusions did not provide analgesia greater than placebo after 2 weeks,246 and a more recent RCT of 20 patients with either central or peripheral neuropathic pain also failed to find analgesic benefit over placebo at 5-week follow-up.231 A recent meta-analysis identified small but non-significant reductions in pain scores only for patients with CRPS type I or type II, and for only up to 2 weeks after the cessation of infusions.250 This meta-analysis failed to identify differences in outcomes between neuropathic, nociceptive and nociplastic pain. Ketamine has efficacy for psychiatric comorbidities (eg, depression, post-traumatic stress) and likely benefits the affective motivational component of pain more than the sensory discriminative.251
Ketamine has been extensively studied for preventing PPSP, with meta-analyses yielding mixed results.165 252 253 One meta-analysis found that 12 patients need to be administered intravenous ketamine to prevent one case of PPSP at 3 months (number needed-to-treat=12),252 while another found a small potential effect only up to 1 month postsurgery.253 More research is required to clarify which patients are most likely to benefit from perioperative ketamine (eg, those with psychiatric comorbidities, or scheduled for surgeries at elevated risk of nerve injury) to prevent PPSP and treat other chronic pain conditions.
Considerations for regional anesthesia
Regional anesthesia techniques have been studied for preventing acute postoperative pain and PPSP. Cost-effectiveness and cost-utility warrant future research, particularly for procedural interventions used to treat chronic pain such as peripheral nerve stimulation and radiofrequency ablation. Table 5 summarizes the evidence pertaining to neuraxial blocks, peripheral nerve injections and other interventions. Neuraxial analgesia has been reported to provide improved pain control in the acute postoperative setting in recent RCTs for thoracotomy254 and colorectal surgery,255 but no statistically significant improvement was found in pancreas surgery.256 As noted, there is some evidence for reduction of PPSP at 3–18 months in patients undergoing thoracic surgery. Peripheral nerve blocks and catheters have generally been found to be beneficial for acute postoperative pain; there is less available evidence for PPSP. In a Cochrane systematic review, the authors found limited evidence for reduced risk of PPSP at 3–12 months in patients receiving paravertebral blocks for breast surgery.257 Peripheral nerve stimulation has been recently investigated for acute postsurgical pain; most studies are industry funded and involve limited numbers of patients. Finally, in studies involving knee surgery, radiofrequency denervation has not been found to improve acute or PPSP.39 258
Evidence supporting regional anesthesia techniques for prevention acute and persistent postsurgical pain
Multimodal analgesia
Numerous modalities have been shown to prevent and reduce severe perioperative pain, with few studies evaluating the effect of multiple therapies. Well-designed studies are difficult to perform and have reported mixed results or limited utility when multiple medications and/or blocks are used concomitantly, which may reflect diminishing returns or overlapping mechanisms.259–261 For chronic pain, there appears to be a small added analgesic benefit for “rational polypharmacy” at the risk of increased side effects, with the therapeutic gain being greater when therapies have complementary mechanisms of action.262
Case resolution
A mechanism-based evaluation for this patient reveals signs and symptoms concerning for potential nociceptive (eg, cramping), neuropathic (eg, burning and numbing sensations adjacent to the incision which may be due to injury to small sensory nerves) and nociplastic (eg, diffuse pain extending to anatomical areas distinct from the surgical site) pain components. The patient’s distress in context of her previous medical history of undermanaged anxiety and depression suggests a strong affective component.
The APM team recommends dose optimizations for intravenous acetaminophen, ketorolac, and the hydromorphone PCA. The team also recognizes that the patient expresses symptoms of somatic (eg, incisional pain) and visceral (eg, diffuse abdominal pain) nociceptive pain. In context of the patient’s absence of flatus and the presence of a distended abdomen without an NGT for gastric decompression, the APM team communicates to the surgeons that postoperative ileus is on the differential diagnosis. After re-examining the patient, they decide to place a NGT and decompress the stomach. The teams agree that a thoracic epidural catheter with a continuous low-dose local anesthetic infusion might be needed if the PCA dose appears insufficient, due to the risk of worsening the ileus if the dose is escalated. A ketamine infusion is discussed due to its opioid-sparing properties and ability to address the affective component to her symptoms, but because the patient’s pain symptoms significantly improved after NGT placement, this is deferred.
The surgical team recommends strict NPO status for at least the next 24 hours. This precludes re-initiation of the patient’s baseline gabapentin regimen although an oral solution is available in some pharmacies (or can be compounded) and could be administered via NGT. The patient’s sensations of “burning” and “numbness” are limited to the borders of the incision and do not correspond to the distributions of distinct peripheral nerves. However, the symptomatic disruption of subcutaneous and dermal free nerve endings cannot be ruled out, and concomitant peripheral sensitization might be occurring. Lidocaine patches are placed adjacent to the incision, and the patient reports improvement.
Concurrently, the APM team consults the psychiatry service for the patient’s previously under-managed mood disorders and fibromyalgia, now exacerbated by acute pain. There is concern that the cessation of gabapentin might be contributing to withdrawal, worsening her nociplastic pain, anxiety, and sleep disturbance, and causing agitation. The surgical team and nursing staff were instructed to observe for these signs and restart gabapentin should they emerge. The psychiatry team confirms that the patient is experiencing severe levels of anxiety and depression, which is corroborated by the Hospital Anxiety and Depression Scale. The patient admits to using marijuana on occasion, but does not express any cravings or exhibit withdrawal symptoms, and declines consultation by the Addiction Medicine service. Although the NPO status precludes initiation of pharmacologic therapies (eg, duloxetine), the psychiatry team successfully builds strong rapport with the patient. They employ CBT and provide recommendations to the patient and nursing team regarding sleep hygiene. The patient’s symptoms of anxiety, depression and pain severity gradually decrease over the next few days. The psychiatry team and the patient, in conjunction with the case management service, jointly schedule a clinic appointment for the patient within a week of her anticipated discharge date.
The patient’s ileus resolves by POD 4 and her NGT is removed. The patient resumes oral intake, including re-titration of her home regimen of gabapentin, and reports that her pain is well-controlled with oral acetaminophen and one tablet of oxycodone 5 mg every 8 hours as needed. On POD 6, the patient reports adequate pain control without opioids and is successfully discharged home with instructions for follow-up with the surgery and psychiatry services.
Summary and recommendations
The classification of pain is neither categorical nor clear-cut; however, categorization is an important tool to facilitate both diagnosis and therapy planning. There are no separate pathways for acute versus chronic pain or different mechanistic categories (nociceptive vs. neuropathic vs. nociplastic pain), with frequent overlap and concurrence between different types. Based on the literature, the identification of specific pain states may allow for targeted therapies aligned with mechanisms. Figure 2 demonstrates a treatment algorithm for a theoretical acute pain consult in a patient at risk for developing, or with poorly controlled postoperative pain. Providers in a community-based setting lacking tertiary resources may still adopt multimodal pharmacological recommendations and refer patients to specialists as outpatients. Ultimately, the ability to diagnose pain states beyond standard nociception can lead to alternative therapies that improve outcomes.
Schematic diagram for the management of perioperative pain. EMG, electromyography; NCS, nerve conduction studies.
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References
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Footnotes
YC and EW are joint first authors.
X @sites_brian
Contributors SPC and BDS: conceived of study. EW, YC, BDS and SPC: wrote and edited manuscript. SPC: guarantor.
Funding Funded in part by a grant from MIRROR, Uniformed Services University of the Health Sciences, U.S. Dept. of Defense, grant # HU00011920011. The sponsor did not play a role in study design or performance, or analysis or interpretation of data.
Competing interests SPC: serves as a consultant for Avanos and SPR, which make radiofrequency equipment and peripheral nerve stimulators, that have been studied for perioperative pain.
Provenance and peer review Not commissioned; externally peer reviewed.
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