**2. Multimodal opioid sparing analgesic techniques**

Ideally multimodal analgesia for enhanced recovery should start pre-emptively which prevents central sensitization occurring from incisional and inflammatory

injury in the perioperative period. Due to the noxious input brought on by the surgical procedures, the CNS becomes hyperactive, which causes pain hypersensitivity and hyperexcitability (prolonged response of the neurons after tissue damage) which when not treated early may lead to chronic pain. When there is total multi-segmental blockage of unpleasant stimuli and its extension into the postoperative period, the greatest therapeutic improvement is seen. The intensity of immediate postoperative pain/hyperalgesia and chronic pain after surgery might theoretically be decreased or perhaps completely eliminated by preventing central sensitization with comprehensive multimodal analgesic interventions [4, 5].

Multiple strategies and drug classes can be used to control postoperative pain and to allow early mobilisation, enteral nutrition, and to decrease the perioperative stress response. Different techniques like patient education, local anaesthetic-based techniques (local infiltration, peripheral nerve blocks, and neuraxial analgesia), and a combination of analgesic drugs that act via different mechanisms on different receptors can be used [6].

These strategies collectively help in enhanced recovery of the patient and reduces hospital stay.

#### **2.1 Non opioid pharmacological techniques**

#### *2.1.1 Acetaminophen*

It acts via activating descending serotonergic pathways in the CNS and inhibiting prostaglandin synthesis [7]. When administered intravenously, onset of action is 5 minutes and peak plasma concentrations is attained within 15 minutes [8, 9]. Due to its minimal side effects and varied availability, this drug is widely used in the perioperative period. However, exceeding maximum daily dose of 4 grams in adults and 2–3 grams in frail adults can lead to dose dependant hepatotoxicity and poisoning [10]. When used with NSAIDS, opioid requirement was reduced by 20% [11]. In a study done by Moon et al. with 76 women undergoing abdominal hysterectomy, use of acetaminophen showed reduced requirement of opioid and its associated side effects [12]. Similar results were seen in the RCT study done by Unal et al., in patients undergoing open nephrectomy [13].

#### *2.1.2 Nonsteroidal anti-inflammatory drugs*

The mechanism of action is inhibition of cyclooxygenase (COX) and synthesis of prostaglandins, which are mediators of peripheral sensitization and hyperalgesia. The COX1 and COX 2 isoforms act peripherally whereas COX3 isoform acts centrally [14]. COX-1 produces prostaglandins, which are important for general functions such as gastric protection and haemostasis. Whereas COX-2, produces prostaglandins that mediate pain, inflammation, fever, and carcinogenesis.

A systematic review of randomised trials was conducted which showed very clear benefits for selective COX2 inhibitors in reducing postoperative pain and further requirement of analgesia [15]. However, they should not be used in patients with a known history of coronary artery disease or cerebrovascular disease.

NSAIDs significantly decrease opioid-related side effects such as postoperative nausea and vomiting and sedation [16].

The optimal dose of ketorolac (COX1 Inhibitor) for postoperative pain control is 15–30 mg intravenously every 6–8 hours (not to exceed 5 days). However, patients with renal dysfunction should receive a lower dose.

The recommended oral loading dose for Celecoxib (COX-2–specific inhibitor) is a 400 mg followed by 200 mg orally every 12 hours. The dose of injectable COX-2–specific inhibitor parecoxib is 40 mg intravenously or intramuscularly initially followed by 20–40 mg every 4–6 hours not to exceed 80 mg/day.

The nonselective NSAIDs may be avoided during the perioperative phase for a number of reasons, including platelet dysfunction, bronchospasm, gastrointestinal ulcers, and an increased risk of nephrotoxicity especially in patients with hypovolemia, congestive heart failure, and chronic renal insufficiency because prostaglandins dilate the renal vascular beds and mediate diuretic and natriuretic renal effects [17].

Ibuprofen IV and intranasal ketorolac are two newer NSAID formulations that have been approved for the treatment of immediate postoperative pain.

A meta-analysis done by Martinez et al. showed efficacy best with α-2 agonists, NSAIDs and COX-2 inhibitors when used alone and least with tramadol and acetaminophen [18].

In order to avoid systemic side effects transdermal patches can be used which have proven as efficacious as other routes of administration. In the study done by Bhargava et al., it is seen that diclofenac sodium patch proved to be as effective as diclofenac sodium intramuscular injection in post operative analgesia. With added advantages of longer onset of action, lesser local side effects like skin erythema, pruritis, oedema, abscess and necrosis and lesser gastrointestinal effects [19].

#### *2.1.3 N-methyl D Aspartate (NMDA) Receptor Antagonists*

The spinal cord N-methyl-D-aspartate (NMDA) receptors are activated by glutamate when C-fibre nociceptors fire repeatedly. Central sensitization results from the activation of NMDA receptors, which makes spinal cord neurons more receptive to all of their inputs thus causing prolonged postoperative pain.

Ketamine acts by non-competitively inhibiting NMDA receptors [20]. It also interacts with opioid, cholinergic, and monoaminergic receptors and blocks sodium channels [21]. Ketamine reduces postoperative pain significantly and also reduces opioid tolerance [22] and rescue analgesic requirements and pain intensity [23]. In a systematic review, it was discovered that IV ketamine for postoperative analgesia was an efficient adjunct, especially in patients undergoing major upper abdominal, thoracic, and orthopaedic surgeries [24]. Low-dose ketamine (0.25–0.5 mg intravenous bolus followed by an infusion of 2–4 μg/kg/min) can provide significant analgesia and is opioid-sparing.

Major side effect of ketamine is its impact on cognitive level (such as hallucinations, vivid dreams, diplopia, blurred vision, nystagmus, or dysphoria) of the patient which is usually not seen when administered in analgesic doses [25].

Dextromethorphan also acts by non-competitively inhibiting NMDA receptors. However, it poses a variety of side effects like nausea and vomiting (oral preparation) and hypotension and tachycardia (on large intravenous does). Hence intramuscular route od administration is preferred.

Magnesium also acts by non-competitively inhibiting NMDA receptors. A study done by Albrecht et al. showed that when magnesium was given intravenously peri-operatively, it could reduce opioid consumption, and also pain scores, in the first 24 hrs postoperatively, without any serious adverse effects [26]. Two different meta-analysis showed that magnesium showed reduction of pain both at rest and on movement with reduced postoperative requirement of opioids [27, 28].

#### *2.1.4 Gabapentinoids*

These were earlier developed as anti-epileptic drugs for the treatment of partial onset seizures which was later found to have analgesic properties and hence was used in neuropathic pain (e.g., postherpetic neuralgia), and other chronic pain states (e.g., fibromyalgia). These drugs have been recently used for acute perioperative pain relief also. These opioid sparing analgesics also have added advantage of reduced incidence of postoperative vomiting, pruritus, and urinary retention.

Tissue damage makes dorsal horn neurons hyperexcited which is decreased by gabapentinoids. They bind presynaptically with calcium receptors (both in central and peripheral nervous system) thus redistributing the calcium channels away from its functional membrane bound site to its non-functional cytosolic site [29, 30].

The dose given to manage postoperative pain in an adult is 900 mg of gabapentin orally, 1–2 hours before surgery [31]. A saturable transport system in the gastrointestinal tract allows for the absorption of gabapentin, which results in a decline in bioavailability with increasing doses. As a result, as the drug dose is raised, the plasma drug concentration grows gradually less (e.g., nonlinear pharmacokinetics [32].

Pregabalin has better potency and lesser side effects compared to gabapentin for the treating of acute perioperative pain. A RCT study showed that when pregabalin was given at a dose of 150 mg twice daily, it reduced preoperative anxiety and postoperative pain scores and analgesic requirement with better sleep quality [33]. A study done by Bekawi et al. showed that pregabalin when given perioperatively per orally with a dose of 150 mg, it proved to be very effective for postoperative pain when compared to pethidine [34].

#### *2.1.5 Intravenous lidocaine*

Lidocaine, an amide local anaesthetic and class 1b antiarrhythmic, when given intravenously inhibits voltage-gated sodium channels, voltage-gated calcium channels, various potassium channels, NMDA receptors, glycine system, and G protein pathways [35] and thus prevents hypersensitization and hyperalgesia [36].

Numerous clinical investigations indicate that perioperative systemic lidocaine administration reduces the release of pro-inflammatory cytokines caused by surgical stress [37–39].

Some studies showed that when lidocaine infusion with dose 2 mg/kg/hr. was given intraoperatively and postoperatively for 8 hrs in patients undergoing laparotomy or laparoscopic abdominal surgery, there was quicker return of bowel movements and reduced postoperative pain, hence reduced need of opioid consumption [40–42].

However, some studies have reported a few adverse drug reactions associated with systemic lidocaine administration like drowsiness, perioral numbness, nausea and blood pressure changes [43]. Systemic lidocaine showed be used cautiously in patients with cardiac arrhythmias.

Lidocaine is also available as transdermal patches which when applied on the laparoscopic port sites reduced postoperative pain [44].

#### *2.1.6 Alpha-2 agonists*

Analgesia is primarily mediated by presynaptic stimulation of alpha 2-receptors, which causes a reduction in the release of norepinephrine. Analgesia works at 3 sites, supraspinally (locus coeruleus), spinally (substantia gelatinosa), and peripherally.

Both clonidine and dexmedetomidine are selective partial agonists for the α2-adrenoreceptor, but the latter is 8 times more selective than the former.

Analgesia is seen supraspinally (locus coeruleus), spinally (substantia gelatinosa), and peripherally [45].

Dexmedetomidine has advantages over clonidine analgesia, titratable sedation (e.g., "cooperative sedation"), anxiolysis, cardioprotective, prevent respiratory depression associated with ketamine and opioid [46]. Loading dose of dexmedetomidine is 1 μg/kg intravenous over 10 minutes and maintenance dose is infusion of 0.2–0.7 μg/kg/hr [47].

#### *2.1.7 Glucocorticoids*

Analgesic effect mainly occurs due to by inhibiting leukotriene and prostaglandin production.

A recent study done by Koc et al. showed that when dexamethasone (8 mg intravenously) and gabapentin (800 mg orally) were administered together 1 hour prior to varicocele surgery, postoperative analgesia was much better [48].

#### *2.1.8 Surgical site infiltration*

Intraperitoneal local anaesthetics- Here the local anaesthetic is sprayed in the right subdiaphragmatic region in patients undergoing laparoscopic cholecystectomy at the beginning of the procedure. Many trials have shown significant positive results proving its efficacy extending to postoperative period. Local anaesthetics like lidocaine or bupivacaine can be used in different concentrations and volume [49, 50]. It has also been efficacious in other laparoscopic surgeries like gynaecological laparoscopy, sterilisation, fundoplication, appendectomy, etc. with postoperative analgesia upto 24 hours and reduced analgesia consumption by 50% [51].

Trocar and port site infiltration with local anaesthetics- Many studies have shown that trocar and port site infiltration of local anaesthetic in various layers of the abdominal wall is very helpful like in the preperitoneal or subfascial or subcutaneous layers [52–54]. A study done by Candiotti et al., used opioid-based intravenous patient-controlled analgesia (PCA) and liposome bupivacaine in patients undergoing laparoscopic colectomy. Here long-acting liposomal formulation of bupivacaine is infiltrated in the surgical site. This technique proved to show lower requirement of opioid and shorter duration of hospital stay [55].

#### **2.2 Preoperative patient pain education and preparedness**

Literature shows that postoperative pain remains undertreated despite decades of education and evidence-based guidelines [56]. Counselling and educating the patient and their family both preoperatively and postoperatively regarding the pain and its management plays a pivotal role in reduced pharmacological means of analgesia, especially opioids and sedatives [57].

#### **2.3 Neuraxial analgesic techniques**

Epidural analgesia is a key component of multimodal analgesia which can either be given as single shot dose or continuously with a catheter placed in situ. Successful epidural analgesia depends on a number of factors like site of catheter insertion,

choice of analgesic drugs, rates of infusion, duration of analgesia, and type of pain (rest or dynamic).

Epidural analgesia works by, spinal and supraspinal mechanism. Spinal mechanism occurs when the drug diffuses into cerebrospinal fluid.

Better analgesia is seen when a local anaesthetic is combined with an opioid for epidural analgesia because when given epidurally opioid is devoid of significant sympatholytic and motor blockade and also the combination has synergistic effect. Adjuncts like clonidine and ketamine can also be added to improve duration and efficacy.

Epidural analgesia is contraindicated in a few conditions like severe coagulation abnormalities like disseminated intravascular coagulation. Cautious use in case of sepsis, increased intracranial pressure, thrombocytopenia, pre-existing central nervous system disorder, previous back surgery, pre-existing neurologic injury, back pain, etc.

Extended-release epidural morphine was also found effective for lower abdominal surgeries where the opioid, morphine in in a liposome delivery system. This system controls the release of morphine over a period of 48 hours postoperatively [58].

Intrathecal analgesia is a also widely accepted especially with opioids [59]. Other adjuncts can also be used like α2-agonists, NSAIDs, NMDA receptor antagonists, acetylcholinesterase inhibitors, adenosine, epinephrine, and benzodiazepines.

#### **2.4 Peripheral nerve blocks**

There are numerous peripheral nerve blocks that enhance analgesia for both intraoperative and postoperative pain due to abdominal surgeries (both laparoscopic and laparotomy). These blocks can either be performed under landmark technique or ultrasound guided. Some of the blocks that will be discussed in brief with respect to abdominal surgeries are transversus abdominis plane (TAP) block, paravertebral block, rectus sheath block, quadratus lumborum block, ilioinguinal and iliohypogastric block, erector spinae and other interfascial blocks.

#### *2.4.1 Transversus abdominis plane (TAP) block*

Four major muscles are considered with respect to transversus abdominis plane (TAP) block. The transversus abdominis plane contains T6–L1 thoracolumbar nerves which supply sensitivity to the skin and muscles of the anterior abdominal wall, upper hip, groin, and thigh.

The landmark technique block is performed at the level of the Petit triangle (formed by the iliac crest as the inferior border, the latissimus dorsi as the posterior border, and the external oblique as the anterior border) with patient in supine position. The local anaesthetic is deposited when 2 pops are felt while advancing the needle in the triangle of petit.

There are various approaches to ultrasound guided TAP block like subcostal, lateral and posterior approaches.

A meta-analysis done by Yu n et al. showed that 24 hours VAS score in patients with TAP block was much less compared to patients who were given local wound infiltration [60]. A meta-analysis done by Zhao et al. showed that TAP block used in laparoscopic surgeries reduced the analgesic requirement postoperatively [61].

#### *2.4.2 Rectus abdominus block*

Rectus sheath is formed mainly by the aponeurosis of 3 main abdominal wall muscles (external oblique, internal oblique and the transversus abdominis muscles)

#### *Pain Management in Enhanced Recovery after Emergency Surgery DOI: http://dx.doi.org/10.5772/intechopen.110180*

which thus surrounds the rectus abdominus muscle. This sheath contains nerves from ventral rami arising from T7 to T11 intercostal nerves and the subcostal nerve (T12). This block is mainly useful in umbilical surgeries. This block is best performed under ultrasound guidance. With the transducer placed in the midline at the level of the umbilicus, the needle is passed through the rectus abdomnus muscle till the tip is on the posterior rectus sheath. Where the local anaesthetic is deposited.

In the study done by Kartaloy et al., the results showed that the patients who received rectus abdominus muscle block for abdominal surgeries requiring general anaesthesia had lower pain scores and reduced need for morphine when compared to patients who were given general anaesthesia alone [62].

In a study done by Gunaney et al., ultrasound guided rectus abdominus block was better than surgical site infiltration of local anaesthetic in patients undergoing umbilical hernia surgeries [63].

#### *2.4.3 Ilioinguinal/iliohypogastric nerve block*

Both these nerves arise from L1 supplies sensory inputs to the skin of the lower abdominal wall, upper hip and upper thigh. This block has shown good analgesia in inguinal hernia surgeries especially in children.

In a study done on cadavers showed 95% successful block rates done under ultrasound guidance compared to blind technique [64].

A study done by Demirci et al. showed that this block done under ultrasound guidance for adult herniorrhaphies is better than landmark technique for providing postoperative analgesia [65].

#### *2.4.4 Thoracic paravertebral block*

This block is mainly useful for breast and thoracic surgeries but can also be used for upper abdominal surgeries when given at the level T6–T12 for providing postoperative analgesia.

Studies were done where sole thoracic paravertebral block was compared to spinal anaesthesia for inguinal hernia surgeries which showed lower pain scores in the early postoperative period [66–69].

A study was done by Kaya et al. comparing the efficacy of thoracic paravertebral block and transversus abdominis plane block as adjunct where the former proved to be better as postoperative analgesia. This block has given good results also for cholecystectomy (both open and laparoscopic) [70–72] and ventral hernia surgeries and other urological and gynaecological procedures.

#### *2.4.5 Erector spinae plane (ESP) block*

It is an inter-fascial plane, where the local anaesthetic when deposited affects both the ventral and dorsal branches of the thoracic spinal nerves and the rami communicants that contain sympathetic nerve fibres. When given for abdominal surgeries at the level of T7, it gives both visceral and somatic analgesia. When administered the local anaesthetic spreads in both cranial and caudal directions [73, 74].

A study done by Altıparmak et al., showed erector spinae plane (US-ESP) block given under ultrasound guidance reduced the opioid requirement and pain scores postoperatively compared to TAP block for laparoscopic cholecystectomy cases [75].

#### *2.4.6 Quadratus lumborum (QL) block*

It is an interfascial block where the local anaesthetic is administered in thoracolumbar fascia which encloses quadratus lumborum, psoas major, and the erector spinae muscles which extends from T6-L1 [76].

This local anaesthetic provides blockade to referred dermatome.

Many case reports are published proving its efficacy for postoperative analgesia in major laparotomies. Two case reports done by Kadam et al. showed that QL block when given for open right hemi colectomy with a midline incision and laparotomy for duodenal tumour excision as a component of multimodal analgesia showed significant reduction of dynamic pain scores in the subsequent postoperative period [77, 78].

Another case report was done for a patient undergoing subtotal colectomy for ulcerative colitis where the patient received transmuscular QL block on the left side and TAP block on the right side (right side as control). It was found that sensation on the left side from T8-L1 was reduced and persisted for 48 hours while on the right side the sensation reduced from T10-L1 which only lasted for 48 hours.

#### **2.5 Cognitive behavioural therapies (CBT)**

Along with pharmaceutical medications, it can be employed as a component of multimodal pain control during the healing process (weak recommendation). The stress associated with anxiety for surgery aggravates pain and this will become a vicious cycle. Hence different types of cognitive behavioural therapies act like adjuncts in alleviating pain. The various types of cognitive behavioural therapies are music therapy, relaxation techniques, guided imagery, intraoperative conversation with patient, hypnosis, electro analgesia in the form of transcutaneous or peripheral electrical nerve stimulation and acupuncture [79–81].

Music therapy alleviates pain by attention shift or cognitive coping [82]. Role of music in the postoperative period was studied by Hole et al. in the form of a systematic review. It was seen that patients who used music with noise cancelling headphones during trans rectal biopsy were found to have lesser pain scores compared to use of noise-cancelling headphones alone [83]. Another analysis done with 73 randomised controlled studies and 20,458 patients showed that music reduced both post-operative pain and anxiety and hence increased patient satisfaction scores. Music therapy was also seen to be beneficial when patients were under general anaesthesia [84]. However, more research is necessary for establishing evidence on the type and duration of music therapy for adequate opioid sparing.

A randomised control trial done in patients undergoing breast cancer surgeries showed the reduced requirement of propofol and lidocaine when these patients underwent clinical hypnosis [85].

#### **3. Conclusion**

Good perioperative pain control is the key for early recovery in enhanced recovery after surgery (ERAS) especially in emergency surgeries. It is important for the clinicians to have patient-oriented strategies for the overall faster recovery of these patients. It is crucial to begin pain relief therapy before the surgery because patients scheduled for emergency surgeries already endure excruciating pain. Hence for early recovery opioid sparing multimodal analgesia management should be followed *Pain Management in Enhanced Recovery after Emergency Surgery DOI: http://dx.doi.org/10.5772/intechopen.110180*

as advocated by ERAS. Use of multiple modalities in treating perioperative pain helps reduce the dose and side effects of a single drug or modality. This strategy has been demonstrated to enhance prospects for these patients with very high risks. Use of regional anaesthetic procedures should be promoted as improved results are observed. The goal here should be to provide appropriate and safer pain management methods to reduce perioperative pain.
