Ketamine, described earlier as a premedicant and an i.v. anesthetic agent, also has analgesic properties in subanesthetic doses. It may prevent the development of opioid-induced hyperalgesia (OIH) and tolerance that can lead to the development of increased postoperative pain and chronic pain states [45]. OIH is a paradoxical response whereby a patient receiving opioids for the treatment of pain can become more sensitive to certain painful stimuli. The type of pain experienced might be the same as the underlying pain or might be different from the original underlying pain [46].

Ketamine for general anesthesia is usually administered intravenously at a dose of 1–2 mg/kg and for procedural sedation at a dose of 0.5 mg/kg IV. Analgesic and antihyperalgesic properties of ketamine are obtained by low-dose infusion at a dose range of 0.15–0.25 mg/kg/h [45]. Low (subanesthetic) doses of ketamine have a small incidence of side effects including dysphoria and hallucinations (1 %), nightmares (2.5 %), visual disturbances (6.2 %), and pleasant dreams (18 %). Side effects can be managed by dose reduction and the use of benzodiazepines [45, 47].

Following the Nuss procedure , a low-dose postoperative ketamine infusion (0.15 mg/kg/h), added to a pain regimen of i.v. hydromorphone PCA and ketorolac, significantly reduced opioid demand and pruritus without an increase in side effects [48]. In a similar trial, a low-dose ketamine infusion added to an i.v. fentanyl PCA resulted in reduced pain scores, consumption of fentanyl, and incidence of nausea and vomiting [49]. The addition of low-dose i.v. ketamine to a regimen of ropivacaine and morphine, by continuous thoracic epidural, has been shown to improve analgesia in postthoracotomy patients [50]. In thoracotomy patients post-lobectomy, desaturation below 90 %, decrease in forced expiratory volume in 1 s, and morphine consumption were lower when a ketamine infusion was added to PCA morphine [51]. In a Cochrane database review of 37 randomized control trials (2240 participants), perioperative subanesthetic doses of ketamine reduced rescue analgesic requirements, pain intensity, or both. Ketamine reduced 24-h PCA morphine consumption and postoperative nausea and vomiting with adverse effects being mild or absent [52, 53]. Unlike the opioids, low-dose ketamine does not depress respirations. Its benefits, as part of a multimodal pain regimen, include lower opioid demand, decreased pain scores, decreased nausea and vomiting, and decreased pruritus.

Dexmedetomidine and clonidine are useful adjuncts in perioperative pain management [54, 55]. Both have been extensively studied in both adult and pediatric populations, although studies in chest wall and intrathoracic surgeries are limited. They both provide sedation and analgesia, with dexmedetomidine having eight times more affinity for the α2-adrenoceptor.

Dexmedetomidine has multiple roles in the perioperative setting. It is used as a premedicant [8], discussed previously, and is very effective in reducing emergence delirium [16]. It has used in sedation for painless procedures, and in painful procedures when used with other medications. As an analgesic, given by i.v. infusion, it has been shown to reduce postoperative opioid requirements, but it is not as effective in reducing pain scores when used as a sole agent [56]. When used as an adjunct with epidural analgesia , it prolongs local anesthesia effect, reduces pain scores, and lowers rescue analgesic requirements [57]. It has been used for opiate withdrawal syndrome. Bradycardia and hypotension can occur, which may limit their use, and sudden cessation can cause rebound hypertension.

Gabapentin and pregabalin are considered first line therapy for neuropathic pain, but may have a role in acute perioperative pain control. They both work by binding to the α₂δ₁ subunit of presynaptic voltage-dependent calcium channels. These channels are found in the central nervous system and spinal cord dorsal horn, and their activation increases the release of excitatory neurotransmitters. Blockade of these channels therefore reduces this release. Both medications are administered orally with bioavailability inversely proportional to the oral dose. Children under 5 years of age need a 30 % increase in dose to achieve appropriate plasma concentrations [58]. Gabapentin is absorbed in the duodenum, while pregabalin in the majority of the small intestine. Both bypass the liver and are excreted mostly unchanged by the kidneys. Side effects include sedation, dizziness, confusion, and ataxia.

Published results of gabapentin use in adult thoracic surgery have shown that preoperative single-dosing regimes may not be effective in reducing overall opioid use and that continued dosing up to 6 months after surgery may not reduce pain scores and postthoracotomy pain when compared to placebo [59, 60].

In 2010, Rusy et al. studied gabapentin use in pediatric patients undergoing spinal fusion. A single preoperative dose of gabapentin 15 mg/kg was given to the study group and continued for 5 days postoperatively at 5 mg/kg every 8 h. This was compared to placebo, and they found that, on postoperative day 0 and day 1, morphine consumption was lower in the study group, although no difference thereafter. There was no difference in the opioid adverse effects [61]. The importance of postoperative dosing of gabapentin was highlighted in a study of 36 children undergoing spinal surgery in Toronto, where no statistical difference was seen in opioid use when only a single preoperative dose was given [62]. In contrast to this, Amani et al. used a single dose of gabapentin in children undergoing tonsillectomy and found that pain scores were lower in this group when compared to bupivacaine infiltration and i.v. meperidine use [63].

Magnesium is used in clinical practice to treat electrolyte imbalance, to antagonize calcium, in the treatment of pregnancy-induced hypertension, and in the treatment of refractory bronchospasm. It is also used in the treatment of Torsade de Pointes polymorphic ventricular tachycardia. In increasing dose, magnesium can cause muscle weakness and cardiovascular effects including hypotension, bradycardia, and cardiac arrest.

As an antagonist of the NMDA receptor, it may have some benefit as an opioid-sparing adjunct. In a study of 68 adult patients undergoing elective thoracotomy, an initial dose of 50 mg/kg followed by 500 mg/h intraoperative and for 24 h postoperatively reduced intraoperative analgesia requirements and the postoperative pain scores [64]. It appears not to reduce the risk of supraventricular arrhythmias associated with thoracotomy [65]. In a study of 50 adult patients undergoing gynecological surgery, the use of magnesium reduced the need for intraoperative muscle relaxation, improved postoperative pain scores, and lowered opioid consumption [66].

In pediatric patients, magnesium has been successfully used as an adjunct to epidural analgesia [67] and as an i.v. adjunct to reduce pain scores and opioid use in children with cerebral palsy undergoing orthopedic surgery [68]. However, a prospective study in 2015 found no benefit from the use of magnesium in children undergoing tonsillectomy [69], unlike in adult patients [70]. Although reducing the rate of coughing after tonsillectomy, magnesium does not decrease laryngospasm rates [71].

After a thoracic procedure, there is considerable pain and impairment in pulmonary function. Thoracic epidurals are widely regarded as the “gold standard” for analgesia following thoracic surgery. Epidural analgesia reduces pain and improves pulmonary function by restoring the vital capacity and functional residual capacity to near preoperative levels [26, 72]. Epidural local anesthetics are usually combined with epidural opioids which results in satisfactory pain control, earlier return to ambulation, lower overall opioid requirements, and reduced morbidity when compared to i.v. opioids [25, 26, 72, 73]. Epidural opioids work by binding to opiate receptors in the spinal cord. Morphine, hydromorphone, and fentanyl are the most commonly administered epidural narcotics and are usually administered via continuous infusion. Hydrophilic opioids, such as morphine and hydromorphone, diffuse widely and thus can be administered at either the thoracic or lumbar level to provide pain relief for thoracic procedures [25]. Lipophilic opioids, such as fentanyl, are more effective and smaller doses are required when administered at the thoracic region versus the lumbar region [74]. The most common local anesthetics used in epidural mixtures include bupivacaine and ropivacaine. The efficacy of ropivacaine is similar to that of bupivacaine and it has reduced potential for central nervous system and cardiac toxicity and causes less motor blockade. This may prove to be of benefit for patient mobilization and improvement of respiratory therapy [75, 76].