Different places of action of analgesics used in the perioperative period
30.2.4 Autonomic Contributions to Pain; Visceral Pain Perception and Transmis sion
A significant interaction exists between the autonomic nervous system and pain responses. An increase in the sympathetic system proportional to noxious stimulation and a decrease of parasympathetic activity occurs in response to acute pain. The magnitude of autonomic response not only correlates with the degree of activity of cortical areas such as the medial prefrontal frontal cortex but also with surgical pain responses. Clinical investigations have found that there is a negative correlation between preoperative baroreflex sensitivity and early and postoperative persistent pain. In fact, it has been suggested that activation of baroreceptors would induce antinociception. Moreover, recent evidence indicates that the contribution of the sympathetic system on acute postoperative pain is significant. The use of a preoperative stellate ganglion blockade resulted in a significant reduction in pain scores and analgesic requirements after upper extremity surgery.
Inflammation, ischemia, and distention (tension receptors) of the gut activate afferent sensory fibers located in the mucosa, muscle, and serosa . The same chemical mediators that activate somatic nociceptors including TRP receptors stimulate visceral nociceptors. For instance, ATP, bradykinins, and prostaglandins are able to induce depolarization of visceral sensory afferents. Vagal afferents have their cell bodies in the nodose and jugular ganglia, and innervate all thoracic and abdominal viscera including part of the colon; on the other hand, spinal afferents have their cell bodies in the dorsal root ganglia and uniformly innervate all the viscera. Both vagal and spinal nerves afferents are responsible for conveying information from the gastrointestinal tract to the central nervous system. It has been postulated that vagal fibers transmit physiological information while spinal nerves are responsible for conveying noxious stimulation. Once the afferent neurons reach the spinal cord, they make synaptic connections with second-order neurons that will project to the thalamus and nucleus tractus solitarious via the spinothalamic, spinoreticular, and dorsal column pathways. Significant interactions between somatic and visceral afferents are responsible for the so-called referred pain . Descending inhibition also plays a role in visceral pain. It has been demonstrated that low doses of opioids can activate descending pathways and cause antinociception.
30.2.5 Social, Vocational, and Psychological Influences on Pain Perception
Preoperative social experiences, psychological factors (i.e., anxiety and depression) and patients’ expectations have significant impact on postoperative pain perception and development of postoperative persistent pain. For instance, alexithymia, the inability to identify and express emotions, predicts the development of postoperative persistent pain after mastectomy. Along this evidence, a preoperative diagnosis of severe/definite depression or preoperative self-perceived risk of addiction is also associated with a significant increase in the risk of postoperative persistent pain. Coping strategies also can be useful to predict postoperative pain outcomes. Thus, catastrophizing patients may misinterpret and exaggerate situations since they are perceived as threatening and report worse quality of life and activity levels after surgery.
Lastly, inadequate postoperative pain management can also be associated with the development of psychiatric disorders after surgery. For instance, patients with high postoperative pain scores appear to be at risk for depression and post-traumatic stress disorder 1 year after surgery. On the other hand, perioperative cognitive interventions targeted to improve depression postoperatively have shown to decrease pain scores and improve quality of life after cardiac surgery.
30.2.6 Sex and Age Differences in Pain Perception
Overall, women are more likely to report a variety of recurrent pain, more severe and frequent compared to men. In the context of surgery, women reported higher pain scores than men after a variety of surgeries . Furthermore, women show slower recovery and have a higher risk of developing postoperative persistent pain than men. This can be explained by (1) biological factors: signs of central sensitization are less pronounced in men than women, while descending inhibition control is less efficient in women than men; (2) psychological factors: differences in coping strategies; (3) social factors (expectations); and (4) past medical history .
30.2.7 Persistent Postoperative Pain
Persistent postoperative pain (PPP) is defined as pain that persists after surgery longer than 3 months’ duration, after exclusion of other causes. Direct nerve injury (transection, stretching, or crushing) has been indicated as the cause (“primary injury”). This primary injury to the nerve is the initial step in a series of events that involves the interaction of injured and non-injured axons, resident non-neuronal cells, and immune cells. The incidence of PPP ranges from 5% to 50%. PPP can occur after major and minor surgery, and open and laparoscopic procedures; however, its incidence appears to be lower after video-assisted surgery. Risk factors include female gender, preoperative pain, diabetes mellitus, poorly managed acute postoperative pain, operative time, tissue ischemia, anxiety, and depression (◘ Table 30.1) .
Predictor factors and causes of persistent postoperative pain
Prolonged tissue ischemia
Anxiety – Depression – Catastrophizing
Diabetes mellitus (TKA)
Open > minimally invasive procedures
Type of surgery (thoracotomy, mastectomy, TKA and limb amputations)
Exaggerated acute postoperative pain
PPP is common after thoracic surgery (post-thoracotomy pain syndrome), breast surgery (postmastectomy pain syndrome), limb amputations (phantom limb syndrome), and total knee replacements . PPP has features of neuropathic pain, thus patients usually report pain as burning, tingling, numbing, or electric-like shocks 1 or 2 dermatomes around the surgical incision.
To date there are no pharmacological agents that have demonstrated efficacy in the prevention of PPP. While gabapentinoids and ketamine have shown modest effect; regional anesthesia has shown promising results in the prevention of PPP .
30.3 Pain Management
Opioids provide adequate postoperative analgesia, but their routine use is often limited by adverse effects. The mechanism of action of opioids is by binding mainly to mu receptors, which results in hyperpolarization of sensory neurons, thus decreasing the release of neurotransmitters involved in nociception. In the perioperative period, opioids are typically administered intravenously, neuraxially, orally, and less often sublingually and transdermally. Intravenous patient controlled analgesia (IVPCA) is a commonly used technique in the postoperative period of any major surgery (◘ Table 30.2). Fentanyl, morphine, and hydromorphone are the most commonly used opioids for IVPCA. Intrathecal opioids provide adequate analgesia during and after surgery. Fentanyl, sufentanil, morphine, and hydromorphone are often used for neuraxial analgesia (◘ Table 30.3). Oral opioids are also available and are often used in the ambulatory setting or when systemic opioids are not required after major surgery. Oxycodone, hydrocodone, tramadol, and codeine are frequently used when patients are able to tolerate at least liquids per mouth. Opioids are associated with side effects including respiratory depression, nausea and vomiting, ileus, drowsiness, urinary retention, confusion, and hyperalgesia . Therefore, the judicious use of these drugs is recommended in the perioperative period. Tramadol is a weak μ(mu)-opioid agonist and norepinephrine and serotonin reuptake inhibitor with questionable efficacy as a single agent that has proven to be effective when given in combination with other analgesics.
Common solutions for intravenous patient (adult) controlled analgesia
Max. dose hour
Recommended solutions for epidural and peripheral nerve catheter patient controlled analgesia
Fentanyl 5–10 μ(mu)g/mL
Sufentanil 0.25–2 μ(mu)g/mL
Hydromorphone 3–10 μg ml
Clonidine 1.5 μ(mu)g/mL
10–15 min/4–6 doses/h
Peripheral nerve catheter
Fentanyl 1–2 μ(mu)g/mL
Sufentanil 0.1 μ(mu)g/mL
Hydromorphone 3–10 μg/ ml
Clonidine 1–2 μ(mu)g/mL
60 min/1 dose/h
Non-steroidal anti-inflammatory drugs (NSAIDs) are adjuvant analgesics with proven efficacy in the context of multimodal analgesia for surgery (◘ Table 30.4). Their mechanism of action is inhibition of COX-1/COX-2. The concept of COX selectivity denotes the extent to which these drugs are able to inhibit one enzyme isoform relative to the other at half maximal inhibitory concentrations. Interestingly, the same drug might show COX-1/COX-2 ratios at distinct inhibitory concentration levels, therefore each COX inhibitor has its own selectivity (◘ Table 30.2). In other words, one analgesic can be more or less selective depending on the dose used. NSAIDs have several routes of administration depending on the type of drug. Ketorolac is one of the most commonly used NSAIDs in the perioperative period because of its strong analgesic properties and the fact that it can be administered orally, sublingually, and intravenously. Other intravenous NSAIDs, although not all available in the United States, include diclofenac, ibuprofen, dexketoprofen, flurbiprofen axetil, and lornoxicam. Overall, NSAIDs can be administered safely in the perioperative period; however, their use, in particular ketorolac, should be limited to short periods of time; and avoided in patients with coagulopathy, renal failure, or history of peptic ulcer .
Recommended doses of commonly used non-opioid analgesics
1 gram every 6–8 h
15–30 mg every 6–8 h
18.75–50 mg every 6–8 h
800 mg every 6 h
Renal impairment, bleeding and gastric erosion/PUDa
Renal impairment, bleedinga
Renal impairment, bleedinga
250–500 mg every 6–12 h
200–400 mg every 6 h
15–30 mg every 8 h
200 mg every 12 h
75–150 mg every 12 h
100–300 mg every 8 h
Renal impairment, bleedinga/Delayed onset of effect
Renal impairment, bleedinga
Renal impairment, bleedinga
Sedation, confusion, dizziness
Sedation, confusion, dizziness
Among the selective COX-2 inhibitors (parecoxib, eterocoxib and lumiracoxib), celecoxib (oral) has been the most commonly used in the perioperative period after rofecoxib and valdecoxib were withdrawn from the United States market. Although, their main advantage over non-selective COX inhibitors is a lower incidence of gastrointestinal complications, recent concerns regarding an increase in major adverse cardiovascular events and anastomotic leakage after colorectal surgery has been raised with the use of non-selective and selective COX-2 inhibitors [3, 12, 13].
Acetaminophen (intravenous, rectal, or oral) is widely used in the context of multimodal analgesia. The mechanism of analgesia of acetaminophen is still unclear; however, it can be related to a dose-dependent reduction of PgE and activation of 5HT3 receptors in the central nervous system. Intravenous acetaminophen has the advantage over the oral or rectal formulations in that it is associated with about a 2-fold the plasma and effect site concentration; which can explain the superior analgesic efficacy and improved patient satisfaction . Acetaminophen reduces morphine consumption by 20% and postoperative nausea and vomiting. This last effect can be attributed to (1) its analgesic effect, and (2) increase in anandamide levels . Acetaminophen has a duration of action of 4–6 h and can be administered every 6–8 h. A maximum dose of 3 g is recommended to avoid hepatoxicity. Its lack of interference with platelet function and safe administration in patients with a history of gastrointestinal bleeding, peptic ulcers, or asthma makes acetaminophen preferable over NSAIDs .
Gabapentinoids (pregabalin and gabapentin) are adjuvant drugs with analgesic and opioid-sparing effects. Their mechanism of action is through binding of α(alpha)2δ(delta) and thrombospondin receptors in the central nervous system. Pregabalin (75–150 mg) is commonly given orally before surgery and postoperatively every 12 h. In comparison to gabapentin, pregabalin is associated with less sedation and cognitive disturbances. Gabapentin can be administered orally three times a day (100–1200 mg); however, the side effects associated with large doses are disadvantageous when its use is considered in the perioperative period, mainly in elder patients .
Dexamethasone (intravenous) is a potent glucocorticoid that has anti-inflammatory and analgesic effects. The exact mechanism of analgesia of dexamethasone is still not clear but it appears to be related to the anti-inflammatory effects (down-regulation of cyclooxygenase-2 mRNA). Epidural dexamethasone may be acting at spinal sites by inducing the synthesis of the phospholipase-A2 inhibitory protein lipocortin, and modulating the activity of the glucocorticoid receptor at the level of the substantia gelatinosa. Dosages (4–10 mg) commonly used for postoperative nausea and vomiting prophylaxis are effective to provide analgesia and have demonstrated not to interfere with wound healing or increase the rate of complication after major surgery . Dexamethasone does not prevent the formation of persistent postoperative pain . Dexamethasone has also shown to prolong and enhance the quality of peripheral nerve blockades; although, it is unknown whether this effect is related to the systemic absorption of the drug or locally at the nerve level.
Ketamine (intravenous or epidural) is an NMDA receptor antagonist that has strong analgesic and opioid-sparing properties . Other mechanisms for ketamine-induced analgesia include direct action on monoaminergic, cholinergic, and mu receptors. Subanesthetic (or analgesic) doses of 3–5 mg/kg/min given during surgery and/or postoperatively have been shown to provide effective analgesia for a wide range of procedures . Nistagmus, diplopia, blurred vision, and hallucinations are side effects reported even with low doses of ketamine, although their incidence is low (<1%) . The preventive effects of ketamine on postoperative persistent pain formation are observed after its intravenous but not the epidural administration.
Intravenous infusions of lidocaine are commonly used in protocols of multimodal analgesia because it reduces intraoperative requirements of opioids and postoperative nausea and vomiting, improves gastrointestinal motility, and shortens length of stay; although these beneficial effects appear to be surgery specific. The mechanism of action of lidocaine is related to its properties as a local anesthetic and anti-inflammatory effect. The infusion (1.5–4 mg/kg/h) of this amide local anesthetic can be used intra- and/or postoperatively, although the maximum benefit appears related to the use of this drug during surgery compared to short-term postoperative infusions. Adverse events associated with the use of lidocaine are very low and mostly related to its actions on the central nervous system (perioral numbness, confusion, and visual disturbances). The use of perioperative intravenous lidocaine can reduce the incidence of postoperative persistent pain .
Esmolol (a selective ultra-short beta-blocker) has been used in intravenous infusions (loading dose of 0.5 mg/kg followed by 5 μ[mu]g/kg/min) to provide analgesia in major surgery. The mechanism of analgesia of esmolol is not fully understood, although it appears to be related to the activation of G proteins at a central level, which resembles the effect of clonidine. Intraoperative infusions of esmolol have not only been shown to provide adequate analgesia and hemodynamic stability but also have opioid- and anesthetic-sparing effects. Bradycardia and hypotension can be observed during infusions of larger doses than recommended.
Intravenous or intrathecal magnesium sulfate has analgesic effects. Magnesium sulfate appears to exert analgesia by at least 2 mechanisms: (1) regulation of calcium influx into neurons and (2) antagonism of the NMDA receptors at central levels. It can significantly potentiate the antinociception of drugs such as ketamine and reduce the consumption of opioids. It is commonly used intraoperatively and administered as a bolus (30–50 mg/kg) followed by a continuous infusion (8–15 mg/kg/h). Intrathecal administration of 50 mg of magnesium sulfate can delay the onset of sensory block and prolong the duration of motor block produced by local anesthetics. Hemodynamic instability (bradycardia and hypotension) and muscle weakness are commonly reported adverse events associated with the use of intravenous magnesium. Thus, caution should be advised in the dosage of muscle relaxants or in the use of other anesthetics that can trigger hemodynamic stability when magnesium sulfate is used during surgery.