Abstract
Effective pain control is crucial in the management of thoracic surgical patients since it reduces postoperative morbidity and promotes recovery. These patients have co-existing respiratory diseases and impaired pulmonary function, which may be further impaired by surgery. With the adoption of minimally invasive surgical techniques and an emphasis on enhancing recovery after surgery, multimodal analgesia has gained popularity as a way to reduce perioperative opioid use and its associated adverse events such as respiratory depression. The literature related to opioid-sparing analgesia in thoracic surgery is still evolving. This review summarizes the latest research related to the use of various intravenous, oral, and perineural pharmacological agents as a part of multimodal analgesic regimen for pain relief in patients undergoing thoracic surgery and provides a summary for their application in clinical practice .
1
Introduction
Thoracic surgery increases the risk of developing significant postoperative pain. Poorly controlled postoperative pain is associated with negative outcomes such as impaired mobility and pulmonary function, delayed recovery, and development of persistent postoperative pain [ ]. With the wide adoption of minimally invasive surgical procedures, anesthesiologists are utilizing opioid-sparing multimodal analgesia to mitigate pain-related adverse effects, reduce opioid usage, and facilitate early recovery.
1.1
Various components of pain after thoracic surgery
Acute pain after thoracic surgery can be somatic in origin, resulting from surgical trauma to the skin, muscles (including the latissimus dorsi, pectoralis major, serratus anterior, and intercostal muscles), bones, and nerves, and is transmitted by the intercostal nerves [ ]. Visceral pain, however arises from the diaphragm. mediastinal and pericaridal pleura, and is carried by the phrenic and vagus nerves [ ]. The severity of acute postoperative pain has been determined to be an independent predictor of persistent postoperative pain [ ]. Persistent postoperative pain is pain that persists at the surgical site for 3 months or longer postoperatively in the absence of other causes, and is not present before the operation [ ]. It is caused by injury to the intercostal nerves during surgical incision, trocar placement, rib retraction, or suturing [ ].
In addition, thoracic surgical patients can also experience referred ipsilateral shoulder pain, which is transmitted by the phrenic nerve [ ].
1.2
Pharmacological management of pain after thoracic surgery
Different regimens can be utilized to treat pain after thoracic surgery. Opioids have traditionally been the conventional analgesics used in the perioperative period but are found to be associated with significant adverse effects. A retrospective review of patients undergoing surgery for lung adenocarcinoma suggested that higher intraoperative opioid use was associated with worse overall survival [ ].
Multimodal analgesia utilizes a combination of different pharmacological agents and regional anesthesia that target different pain receptors and provide synergistic or additive analgesia while lowering individual adverse effects [ ]. It provides postoperative pain control and reduces opioid use and related adverse effects. It also modulates nociceptive input to the central nervous system by complementary mechanisms of action [ ].
Different pharmacological agents commonly utilized as a part of multimodal treatment regimen for postoperative pain include gabapentinoids (gabapentin and pregabalin), acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), N -methyl- d -aspartate (NMDA) receptor antagonists (ketamine and magnesium), alpha receptor agonists (dexmedetomidine and clonidine), lidocaine, and opioids. Oral and intravenous routes are more commonly used. These medications are also utilized as adjunctive therapies to improve the efficacy and duration of local anesthetics (LA) during neuraxial analgesia and fascial plane blocks.
1.2.1
Gabapentinoids
Patients undergoing thoracotomy who received a thoracic epidural analgesia (TEA) and preoperative gabapentin reported no variation in acute incisional pain or shoulder pain compared to controls who received TEA alone . The use of gabapentin preoperatively with postoperative continuation for 5 days in the presence of a TEA did not inhibit the development of persistent postoperative pain after thoracotomy [ ]. However, patients who already developed persistent postoperative pain after thoracotomy reported an improvement in pain with gabapentin use [ ]. Side effects such as somnolence or drowsiness, dizziness, nausea, and diarrhea were described with gabapentin use in patients undergoing thoracic surgery .
The use of perioperative pregabalin in patients undergoing thoracotomy in the presence of a TEA resulted in a reduction in acute incisional pain [ , ] and ipsilateral shoulder pain [ ] postoperatively ; however, it had a variable effect on acute incisional pain after video assisted thoracoscopic surgery (VATS) [ , ]. Furthermore, no difference in the incidence of persistent postoperative pain [ , ] was reported after open thoracotomy [ ] and VATS [ ] with perioperative pregabalin use .
A multicenter retrospective cohort study in patients undergoing elective thoracic surgery revealed a higher risk of postoperative pulmonary complications, increased need for invasive and non-invasive mechanical ventilation, and no reduction in perioperative opioid use after a single dose of gabapentinoids on the day of surgery [ ]. These findings were reported as primary and secondary outcomes.
Another study identified 441 inpatient overdose events among more than 5.5 million eligible admissions after major surgery, reporting an absolute risk of 1.4 per 10,000 patients with gabapentinoid exposure compared to 0.7 per 10,000 patients without exposure [ ]. Thus, using a combination of gabapentinoids and opioids to treat postoperative pain was found to be associated with an increased risk of opioid overdose and other opioid-related adverse events [ ].
Perioperative use of gabapentin was also found to be associated with a higher incidence of delirium in patients with age >65 years after major surgery [ ].
A meta-analysis in cardiothoracic and non-cardiothoracic surgical patients that examined the use of gabapentinoids revealed a non-significant reduction in acute pain along with an increased rate of adverse effects such as visual disturbances and dizziness which were reported as secondary outcomes [ ].
In summary, perioperative gabapentinoids have limited efficacy in reducing acute or persistent postoperative pain and may be associated with a risk of adverse events. However, gabapentin may be useful in patients who have known persistent postoperative pain ( Table 1 ).
| Class | Drug | Analgesia | Neuraxial anesthesia | Regional anesthesia | Effect | Considerations | |
|---|---|---|---|---|---|---|---|
| Gabapentinoids | Gabapentin | Useful for treating PPP after thoracic surgery | (+) | Treating PPP | Drowsiness, dizziness, delirium, visual disturbances | ||
| Pregabalin | IP and/or ISP reduction | (+) | drowsiness and dizziness | ||||
| Acetaminophen | IP or ISP reduction | ++ | Limited to 4 g IV daily | ||||
| NSAIDs | Celecoxib, Parecoxib, Ketorolac | IP and/or ISP reduction | ++ | Perioperative myocardial infarction, atrial fibrillation, cerebrovascular accident, bleeding, nausea, vomiting, urinary retention, increased serum creatinine level, renal failure | |||
| Steroids | Dexamethasone | Not useful | Prolongation duration of the block (+) (VATS) | (+) | Regional additive | ||
| Methylprednisolone | IP reduction for a short duration (VATS) | (+) | VATS | Transient hyperglycemia | |||
| Alpha 2 agonist | Clonidine | ? | Prolongation of block (+) | Prolongation of block (+) | (+) | Regional and TEA additive | Sedation, hypotension, and shivering |
| Dexmedetomidine | IP reduction and/or reduction in the incidence of PPP | Improved analgesia (+) | Improved analgesia (+) | +++ | Regional and TEA additive | Hypotension and bradycardia | |
| Useful in PCA analgesia | Prolongation of block (+) | PCA | |||||
| NMDA antagonist | Ketamine | IP reduction (VATS) | IP reduction with epidural infusion (thoracotomy) | ++ | TEA infusion | Lightheadedness and vivid dreams | |
| Useful in PCA analgesia | PCA | ||||||
| Magnesium | IP reduction and reduction in the incidence of PPP (thoracotomy) | IP reduction with epidural infusion or in LA solution of TEA (thoracotomy) | Prolongation of block (+) | ++ | TEA infusion | ||
| Regional and TEA additive | |||||||
| Local Anesthetics | Lidocaine | IP reduction (+) for a short duration (VATS) | (+) | VATS | Drowsiness, lightheadedness, metallic taste, perioral numbness, tinnitus, visual disturbances, arrhythmias, altered mental status, or seizures | ||
1.2.2
Acetaminophen
Use of scheduled acetaminophen as an analgesic adjunct to TEA in patients undergoing thoracotomy during the perioperative period resulted in a reduction of ipsilateral shoulder pain compared to controls who received TEA alone [ ]. For patients undergoing VATS, perioperative use of acetaminophen resulted in reduced pain with coughing or movement but had a variable effect on pain scores at rest. These patients received bolus dosing during the intraoperative period, which was maintained as either bolus dosing or continuous infusion for 24–48 h postoperatively [ ].
The therapeutic plasma concentration was more reliably reached with intravenous acetaminophen compared to preoperative oral acetaminophen in the early postoperative period, but this did not influence postoperative pain scores [ , ]. A systematic review revealed no difference between oral and intravenous administration with regards to efficacy [ ].
In summary, scheduled perioperative administration of acetaminophen was useful in reducing shoulder pain or acute incisional pain after thoracic surgery. Both oral and intravenous route of administration were reasonable ( Table 1 ).
1.2.3
NSAIDs
Perioperative NSAIDs (celecoxib [ ], parecoxib [ ], or ketorolac [ ]), when used as an analgesic adjunct alone or with TEA, resulted in lower incisional pain both at rest and with coughing , reduced opioid consumption [ ], and lower the rate of moderate-to-severe shoulder pain after thoracotomy. [ ] An opioid sparing effect was seen with both preemptive and postoperative ketorolac use for pain after thoracotomy when compared to the controls [ ]. A similar reduction in acute incisional pain with coughing, but not at rest, was reported after VATS with postoperative ketorolac use [ ]. No increase in adverse effects such as nausea [ , ], vomiting [ , ], bleeding [ ], urinary retention [ ], increased serum creatinine level [ ] perioperative myocardial infarction (MI) [ ], dizziness [ ], and cerebrovascular accident [ ] was reported [ , ]. A meta-analysis in cardiothoracic surgical patients also revealed a reduction in pain and opioid consumption for 24 h postoperatively with NSAIDs use [ ]. There were no reported differences in all-cause mortality or incidence of bleeding, MI, atrial fibrillation, or other NSAID-associated side effects such as GI disturbance, GI bleeding, renal failure, increased serum creatinine levels, and pneumonia [ ].
In summary, provided there are no contraindications, scheduled perioperative administration of NSAIDs was useful in reducing acute incisional pain, rate of shoulder pain and opioid consumption after thoracic surgery ( Table 1 ).
1.2.4
Steroids
Patient undergoing thoracotomy or mini thoracotomy [ , ] who received preoperative intravenous dexamethasone along with a neuraxial or fascial plane block reported no difference in postoperative opioid consumption [ ] or epidural patient-controlled analgesia (PCA) usage [ ] compared to controls [ , ].
A limited reduction in incisional pain on the day of surgery was reported when preoperative intravenous methylprednisolone was used for VATS [ ]. Combined intravenous dexamethasone with a single shot paravertebral block (PVB) resulted in prolonged duration of analgesia after VATS [ ]. However, another study reported no difference in the postoperative analgesia when dexamethasone was combined with both a serratus anterior plane block (SAPB) and PVB in patients undergoing VATS [ ]. Transient hyperglycemia with no increase in postoperative wound infections was reported with intravenous dexamethasone use [ ]. A meta-analysis also revealed that steroids were not clinically effective in providing pain relief after thoracic surgery [ ].
However, perineural dexamethasone combined with PVB was more effective in increasing the duration of analgesia compared to the intravenous route [ ]. Adding dexamethasone to the LA solution for SAPB [ ] and intercostal block [ ] also prolonged the duration of analgesia [ , ] and decreased pain scores [ ] and analgesic needs [ ] after VATS [ , ]. A systematic review and meta-analysis reported extended duration of analgesia with perineural dexamethasone compared to the intravenous route; this effect was more pronounced with bupivacaine compared to ropivacaine [ ].
In summary, the available data revealed that intravenous steroids were not useful in providing pain relief after thoracic surgery. However, perineural dexamethasone prolonged the analgesic effects of LA in neuraxial and fascial plane blocks ( Table 1 ).
1.2.5
Alpha-2 agonists
1.2.5.1
Clonidine
When intravenous clonidine was utilized as part of a multimodal analgesic protocol that also included ketamine and lidocaine in patients undergoing thoracotomy, it resulted in less epidural LA usage postoperatively [ ]. However, the result could not be attributed exclusively to the use of clonidine based on the study design.
The use of clonidine in LA solutions for epidural [ ] or intercostal block [ ] improved pain scores [ , ] and prolonged the duration of analgesia after thoracotomy [ ] but was associated with greater sedation [ , ], hypotension [ ], and shivering [ ] compared to controls [ , ].
In summary, the available data could not determine the analgesic effect of intravenous clonidine in patients undergoing thoracotomy. Perineural clonidine increased the duration of epidural or intercostal block but was associated with more side effects ( Table 1 ).
1.2.5.2
Dexmedetomidine
The studies evaluated perioperative intravenous dexmedetomidine use as an analgesic adjunct during [ ] and/or after [ , , ] thoracotomy [ ] or mini thoracotomy [ ] along with TEA [ , , ] or intravenous PCA , . [ ] Most studies reported a decrease in acute pain scores for 24–48 h after surgery [ , ], opioid consumption [ ], and incidence of persistent postoperative pain [ ] in this patient population [ , , , ]. However, some studies found no difference in postoperative opioid consumption [ ] or patient-controlled epidural analgesic use [ ] when infusions were continued postoperatively [ , ].
The addition of dexmedetomidine to LA solution for continuous neuraxial block such as TEA [ ] and PVB [ ] or a continuous SAPB [ ] for thoracotomy resulted in decreased postoperative pain scores [ , ] and opioid consumption [ ] compared to controls . Similarly, when dexmedetomidine was combined with LA in a single-shot PVB [ ] or intercostal nerve blocks for treating post-thoracotomy pain, for treating post-thoracotomy pain, it provided superior analgesia compared to LA alone. Use of dexmedetomidine, however, was associated with more hypotension and bradycardia [ ].
Patients undergoing VATS [ , , ] reported reduced acute pain scores and opioid consumption [ , ] as well as improved lung function [ ] and enhanced quality of recovery [ ] with intravenous intraoperative and/or postoperative dexmedetomidine [ , , ].
The use of dexmedetomidine in LA solution for continuous PVB for VATS resulted in reduced pain scores and increased the duration of analgesia in the postoperative period [ ]. Similar analgesic benefits were reported with addition of dexmedetomidine to LA for single or multi-level injections for PVB [ ] or SAPB [ ] after VATS [ ].
When erector spinae plane block (ESPB) was performed using a combination of dexmedetomidine with different concentrations of LA, higher LA concentrations provided enhanced analgesia after VATS compared to lower concentrations [ ]. Similarly, use of dexmedetomidine at 1 mcg/kg with a single-shot ESPB [ ] or SAPB [ ] resulted in lower pain scores for 12–24 h after VATS compared to dexmedetomidine at 0.5 mcg/kg [ , ].
Adding dexmedetomidine [ ] to intravenous opioid-based PCA after thoracic surgery provided superior analgesia and enhanced patient satisfaction [ ]. While being associated with fewer side effects [ ] compared to controls [ ].
In summary, both intraoperative intravenous dexmedetomidine as well as perineural dexmedetomidine were useful in controlling pain after thoracic surgery. Addition of dexmedetomidine to opioid-based PCA provided superior analgesia after thoracic surgery when compared to opioid-based PCA alone ( Table 1 ).
1.2.6
NMDA-receptor antagonists
1.2.6.1
Ketamine
In patients undergoing thoracotomy, use of intraoperative and/or postoperative intravenous ketamine infusion along with continuous intercostal block , TEA [ , , ], PVB [ ], or intravenous PCA [ , , ] resulted in no difference in acute pain [ , ] or opioid consumption [ , ] and had a variable impact on the rate of persistent postoperative pain after thoracotomy . Similarly, the use of ketamine as an additive to LA solution in the epidural l [ did not influence the rate of persistent postoperative pain after thoracotomy . However, an intraoperative epidural infusion of S ketamine followed by postoperative LA epidural infusion resulted in a reduction in acute pain compared to controls who received only LA epidural infusion during and after thoracotomy .
Similarly, intraoperative infusion of ketamine and S ketamine combined with PVB [ , ] for patients undergoing VATS resulted in VATS resulted in improved postoperative recovery and improved postoperative recovery [ ] but offered no benefit with regards to opioid consumption [ ], incidence of persistent postoperative pain [ ], or cognitive function [ ] postoperatively [ ].
Adding ketamine to intravenous opioid-based PCA in patients undergoing thoracotomy lowered pain scores [ , ] and/or cumulative opioid usage [ , ] compared to controls receiving opioid-based PCA alone [ ]. It also resulted in greater patient satisfaction [ ] and earlier [ ] PCA discontinuation [ , ]. There were fewer episodes of nocturnal desaturation observed in the combination PCA group compared to controls . Adding ketamine to intravenous opioid-based PCA provided equivalent analgesia to TEA in patients undergoing VATS [ ]. More lightheadedness and vivid dreams were reported when ketamine was used as an intraoperative infusion or as an additive to the PCA [ , ].
In summary, most studies reported that the perioperative intravenous ketamine was not useful in reducing pain after thoracic surgery. However, adding ketamine to opioid-based PCA provided superior analgesia after thoracotomy compared to opioid-based PCA alone ( Table 1 ).
1.2.6.2
Magnesium
Studies that investigated the use of intraoperative and postoperative intravenous magnesium infusion as a part of the multimodal analgesic strategy in patients undergoing thoracotomy revealed a variable effect on postoperative analgesia in the presence of TEA [ , ]. However, when used an infusion alone or combined with postoperative PCA, it was found to decrease acute [ ] and persistent pain [ ] as well as opioid consumption [ ] after thoracotomy [ , ]. The addition of magnesium to opioid spinal analgesia resulted in reduced opioid requirements up to 36 h after thoracotomy [ ].
Furthermore, the addition of magnesium to LA solutions in TEA [ ] or PVB [ ] as well as when used as a continuous epidural infusion [ , ] resulted in decreased pain scores [ , ] and cumulative opioid consumption and prolonged the duration of analgesia [ ] after thoracotomy [ ].
In patients undergoing VATS, improved postoperative pulmonary function was reported with intraoperative magnesium infusion [ ].
In summary, a few studies found that intravenous magnesium may be useful for providing pain relief after thoracotomy. Perineural magnesium enhanced the analgesia delivered by neuraxial blocks for thoracotomy ( Table 1 ).
1.2.7
Lidocaine
In patients undergoing thoracic surgery, using perioperative intravenous lidocaine infusions (1.5 mg/kg bolus followed by an infusion of 3 mg/min for patients weighing >70 kg or 2 mg/min for patients weighing <70 kg or 33 μg/kg/min) as an analgesic adjunct resulted in similar [ ] or reduced pain scores [ ] and opioid consumption [ ] for a short duration of 6 h after surgery . However, no difference in quality of recovery [ ] was reported with the use of intraoperative lidocaine infusions compared to controls after VATS . None of the patients reported symptoms of lidocaine toxicity such as drowsiness, lightheadedness, metallic taste, perioral numbness, tinnitus, visual disturbances, arrhythmias, altered mental status, or seizures [ , ].
In summary, the available data revealed that intravenous lidocaine infusion was not effective in controlling pain after VATS ( Table 1 ).
1.2.8
Opioids
Patients undergoing thoracic surgery often have several associated respiratory co-morbidities for which opioid exposure can lead to respiratory depression [ ]. Multimodal analgesia multimodal analgesia is used in an effort to in an effort to reduce opioid needs and their associated side effects.
Enhanced recovery programs that utilized regional blocks and multimodal analgesia in the perioperative period in patients undergoing thoracotomy resulted in reduced cardiopulmonary complications compared to controls [ ]. Patients who received additional opioid-based analgesia (OBA) consisting of remifentanil intraoperatively reported higher epidural local anesthetic (LA) usage for 48 h after thoracotomy compared to controls who received additional non-opioid-based analgesia [ ].
Use of opioid free analgesia (OFA) [ ] and opioid-sparing analgesia (OSA) [ , ] with a regional block for minimally-invasive thoracic surgery resulted in similar [ , ] or decreased [ , ] cumulative opioid consumption and pain scores, lower rates of nausea and vomiting [ ], and improved recovery [ , ] after minimally-invasive thoracic surgery [ ]. These findings were disclosed as primary and secondary outcomes. Opioids utilized in various studies included fentanyl [ , ], morphine [ , ,], sufentanil [ , , , ], and remifentanil [ , , ]. OFA was found to be as effective or superior to OBA with regards to postoperative pain and analgesic use while OSA was found to be associated with reduced opioid-related side effects and postoperative complications compared to opioids alone.
In spontaneously ventilating VATS, the intraoperative use of OFA and OBA containing remifentanil and sufentanil provided similar postoperative analgesia when combined with intercostal nerve and ipsilateral vagal nerve block. However, OFA was found to be associated with a lower rate of hypotension and shorter lung functional recovery [ ]. However, the time to regain consciousness was longer in the OFA group compared to the OBA group [ ]. Furthermore, a meta-analysis reported a lower rate of postoperative complications when OFA was used for thoracic surgery compared to OBA [ ].
In summary, the use of multimodal analgesia and opioid stewardship in patients undergoing thoracic surgery was found to improve postoperative pain control, decrease opioid exposure, improve recovery, and reduce related postoperative complications. The decision to use OFA or OSA for perioperative pain management for thoracic surgery should be based on patient population, type of surgery, and targeted patient-related outcomes.
2
Summary
Postoperative pain management in thoracic surgical patients can be challenging due to pulmonary co-morbidities, which can be further impaired by surgery. Optimal multimodal analgesia is critical to their recovery and needs to be tailored to the patient population, type of surgery, and resources and expertise available at surgical institutions. Various combinations of multimodal pharmacological agents and regional techniques are useful in improving pain-related outcomes after thoracic surgery. Based on the current literature, routine perioperative use of acetaminophen and NSAIDs is effective in reducing pain in patients undergoing thoracic surgery. Intra‐operative intravenous dexmedetomidine infusion is also helpful as an analgesic adjunct for thoracic surgical patients. Furthermore, the addition of dexmedetomidine or ketamine to PCA provides superior analgesia compared to opioid-based PCA alone.
Perineural use of dexamethasone, clonidine, dexmedetomidine and magnesium with LA solutions can enhance the analgesia provided by neuraxial and fascial plane blocks. Future research to investigate which optimal analgesic combinations work the best for specific surgical procedures and patient populations can help further guide the delivery of effective perioperative pain management and improve clinically meaningful patient-related outcomes.
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