**4. Analgesic medications used in ICU patients**

Opioids are the main medications used for analgesia in ICU patients due to potency, concomitant mild sedative and anxiolytic effects. It can be administered by multiple routes. The commonly use opioids include Fentanyl, Remifentanil, and Morphine. The choice of opioid and the dosing should be individualized based on potency, pharmacokinetics and pharmacodynamics, adverse effect, patient comorbidities and organ dysfunction [25].

#### **4.1. Morphine**

**2.5. Critical care pain observation tool (CPOT)**

**Table 1.** Behavioral pain scale and its components.

64 Pain Management in Special Circumstances

12–24 h delay in peak serum levels.

medication in patients with renal or liver failure.

**3.1. Patient-controlled analgesia (PCA)**

This pain assessment tool has four clinical components, facial expressions, body movements and muscle tension and compliance with the invasive mechanical ventilation. CPOT score

Facial expressions Relaxed 1

Upper limbs No movements 1

Compliance with mechanical ventilation Tolerating movements 1

Partially tightened 2 Fully tight 3 Grimacing 4

Partially bent 2 Fully bent with fingers flexion 3 Permanently retracted 4

Coughing but tolerating ventilation most of the time 2 Fighting with ventilator 3 Unable to control the ventilation 4

The mode of analgesic medication administration is an important factor for the pharmacologic management of pain in the ICU. Intravenous (IV) administration is more commonly the route of choice in critically ill patients because of altered GI tract function that could lead to unpredictable absorption of medication. Intravenous route is generally preferred over subcutaneous or intramuscular routes given potentially inadequate absorption due to regional hypoperfusion due to shock, subcutaneous oedema. The Fentanyl patch can be used for chronic pain relief in stable patients but not in ICUs or for acute pain relief because of the

The choice of intermittent versus continuous infusion administration depends on factors such as the frequency and severity of pain and the pharmacokinetics of the analgesic medication. The administration in bolus is associated with the variation in the peak plasma concentration, since the infusion maintains a more stable concentration but can lead to accumulation of

It is an effective method for administering analgesic medication and gives patients a sense of control over their pain. Patients have autonomy on when and how much medication

ranges from 2 to 8. A score of more than 2 requires pain management.

**3. Mode of analgesia administration in ICU patients**

It is the most frequently used medication in cancer patients. It is the standard by which other opioids are compared. Morphine is directly extracted from opium poppies; it stimulates the release of histamine which produces allergic and vasodilation-induced cardiovascular instability. Initial bolus intravenous (IV) morphine 2 mg dose administered slowly over 4–5 min then can be titrated with 1–2 mg every 10–15 min till adequate analgesia is achieved. Continuous IV morphine can be administered with an initial 2–5 mg bolus dose followed by 1 mg/h. Morphine is primarily metabolized in the liver and it is excreted through kidneys. It has active metabolites; morphine-3-glucuronide and morphine-6-gluconoride. Accumulation of these metabolites in renal insufficiency can produce opioid toxicity and adverse effects such as nausea, sedation, respiratory depression myoclonus and seizures (**Table 2**) [25].


effect includes nausea, vomiting, dizziness drowsiness, dry mouth and headache. Tramadol causes less respiratory and cardiovascular depression, euphoria and constipation. Initial bolus dosage is 100 mg. After 90 min following the initial bolus, further doses of 50 mg may be given every 30 min up to a total dose of 250 mg. Subsequent doses should be 50 or 100 mg

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Non-opioid analgesics are use in the management of mild to moderate pain and moderate to severe pain with adjunctive opioid analgesics. The potential advantages of multimodal analgesia, which involves a combination of analgesics with different mechanisms of action, include improved analgesia with a lower opioid dose required and a decreased risk of opioid-

NSAIDs have opioid-sparing effect but they are not sufficiently investigated in ICU patients. Their use in ICU patients is still controversial. The most worrying adverse effect includes

It is commonly administered for the short-term treatment of mild to moderate pain and febrile critically ill patients with infection. It differs from the available opioids and NSAIDs, since paracetamol does not increase the incidence of nausea, vomiting and respiratory depression that can occur with opioids, or the platelet dysfunction, gastritis and renal toxicity that are associated with NSAIDs. It has a relatively good safety profile but there is limited information regarding IV use in critically ill patients. The study to date has described that paracetamol can cause transient abnormalities of liver function and may cause hypotension in critically ill patients. Acute liver failure is the most serious potential complication of the use of paracetamol. The key criteria for assessing potential hepatotoxicity with conventional doses of paracetamol may include hypoxic injury, altered pharmacokinetics, relative over-dosage, muscle glutathione depletion, malnutrition, dehydration, older age and alcoholism which are often seen in critically ill patients [24].

It is a prodrug form of paracetamol which is formed from the esterification of paracetamol and the carboxylic acid diethyl glycine. It has the advantage of making it more water-soluble.

The Clonidine and Dexmedetomidine are α2-adrenoceptor agonists, which provide both analgesia and sedation. Hence, they are also termed as analgosedation agents. Dexmedetomidine

Dexmedetomidine infusion has been shown to reduce the prevalence and duration of confu-

sion and delirium when compared with the use of morphine and midazolam [25].

It is used in postoperative care and is delivered by intravenous route [23].

has eight times more affinity for α2-receptors compared with clonidine.

gastrointestinal bleeding, renal dysfunction and inhibition of platelet function.

for 4–6 h up to a total daily dose of 400 mg [24].

*4.2.1. Nonsteroidal anti-inflammatory drugs (NSAIDs)*

related adverse effects [24].

*4.2.2. Paracetamol*

*4.2.3. Prop-paracetamol*

*4.2.4. α2-agonists*

**4.2. Non-opioid analgesic agent or adjuvants used in ICU patient**

**Table 2.** Various opioids and non-opioid analgesic, their dosage, half-life and side effects.

#### *4.1.1. Fentanyl*

Fetany is a synthetic opioid that is 100 times more potent than morphine. It has far more lipidsoluble property than morphine and is easily taken into the CNS. Compared to morphine, it does not cause histamine release and hence no vasodilation and hypotension, making Fentanyl the preferred choice for hemodynamically unstable patients. Its intravenous onset is immediate with a short duration of 30 min to 1 h, and it is extracted though liver. Fentanyl is given IV in 25–100 μg boluses for 1–2 min and then is repeated every 10–15 min till pain is controlled. Moderate–severe pain: a loading dose of 50–200 μg intravenously followed by 25–50 μg/hr. is typically administered. Its administration for more than 5 days causes accumulation in fatty tissue, which is mobilized after the drug is stopped and may cause prolonged sedation [25].

#### *4.1.2. Remifentanil*

It is a fast-acting and an equally fast recovery drug. It is 200 times more potent than morphine. Its metabolism does not depend on the liver. Analgesia-based sedation with remifentanil is a useful option for mechanically ventilated patients, and it can be used in patients that need frequent neurological assessment. Hence, it is a drug of choice in analgosedation in ICU. It has shown a shorter duration of mechanical ventilation and quicker ICU discharge with Remifentanil compared with other opioids. It offers precise control of analgesia for painful procedures in ICU patients and has a highly predictable onset and offset, with a stable context sensitive half-time (3–10 min). Initial dose adjustment is not required for patients with impaired renal and hepatic functions. Remifentanil can be administrated in higher doses than are normally used with other opioids without concerns about accumulation and the possibility of unpredictable and/or delayed recovery. Frequently, ICU patients are managed without bolus doses, and it is recommended that remifentanil infusions should be started at 6–9 μg/kg/h and then titrated in the range dose of 0.5–15 μg/kg/h. The major adverse effects are hypotension and bradycardia (**Table 2**) [24].

#### *4.1.3. Tramadol*

It is a centrally acting opioid-like medication, acts by binding to the μ opiate receptor; it is a pure agonist and inhibits adrenaline and serotonin reuptake. The most common adverse effect includes nausea, vomiting, dizziness drowsiness, dry mouth and headache. Tramadol causes less respiratory and cardiovascular depression, euphoria and constipation. Initial bolus dosage is 100 mg. After 90 min following the initial bolus, further doses of 50 mg may be given every 30 min up to a total dose of 250 mg. Subsequent doses should be 50 or 100 mg for 4–6 h up to a total daily dose of 400 mg [24].

#### **4.2. Non-opioid analgesic agent or adjuvants used in ICU patient**

Non-opioid analgesics are use in the management of mild to moderate pain and moderate to severe pain with adjunctive opioid analgesics. The potential advantages of multimodal analgesia, which involves a combination of analgesics with different mechanisms of action, include improved analgesia with a lower opioid dose required and a decreased risk of opioidrelated adverse effects [24].

#### *4.2.1. Nonsteroidal anti-inflammatory drugs (NSAIDs)*

NSAIDs have opioid-sparing effect but they are not sufficiently investigated in ICU patients. Their use in ICU patients is still controversial. The most worrying adverse effect includes gastrointestinal bleeding, renal dysfunction and inhibition of platelet function.

#### *4.2.2. Paracetamol*

*4.1.1. Fentanyl*

Morphine 2–5 mg bolus,

66 Pain Management in Special Circumstances

Fentanyl 25–100 μg bolus

Remifentanil 0.5–2 mg bolus

*4.1.2. Remifentanil*

sion and bradycardia (**Table 2**) [24].

*4.1.3. Tramadol*

Fetany is a synthetic opioid that is 100 times more potent than morphine. It has far more lipidsoluble property than morphine and is easily taken into the CNS. Compared to morphine, it does not cause histamine release and hence no vasodilation and hypotension, making Fentanyl the preferred choice for hemodynamically unstable patients. Its intravenous onset is immediate with a short duration of 30 min to 1 h, and it is extracted though liver. Fentanyl is given IV in 25–100 μg boluses for 1–2 min and then is repeated every 10–15 min till pain is controlled. Moderate–severe pain: a loading dose of 50–200 μg intravenously followed by 25–50 μg/hr. is typically administered. Its administration for more than 5 days causes accumulation in fatty tissue, which is mobilized after the drug is stopped and may cause prolonged sedation [25].

Dexmedetomidine 02–1.4 μg/kg/h 6 min to 3 h Cardiac asystole, bradycardia and hypotension

Paracetamol 1 g every 6 h 2–3 h Hypotension, liver and kidney injury

**Table 2.** Various opioids and non-opioid analgesic, their dosage, half-life and side effects.

2–4 h Purities, hypotension and metabolites accumulation

in renal in impairment

impairment

3–10 min Bradycardia and hypotension

2–5 h Muscle rigidity, accumulation in hepatic

**Analgesic medications Dosage Half-life Main adverse effects**

1–10 mg/h infusion

25–200 μg/h

0.5–15 μg/kg/h

It is a fast-acting and an equally fast recovery drug. It is 200 times more potent than morphine. Its metabolism does not depend on the liver. Analgesia-based sedation with remifentanil is a useful option for mechanically ventilated patients, and it can be used in patients that need frequent neurological assessment. Hence, it is a drug of choice in analgosedation in ICU. It has shown a shorter duration of mechanical ventilation and quicker ICU discharge with Remifentanil compared with other opioids. It offers precise control of analgesia for painful procedures in ICU patients and has a highly predictable onset and offset, with a stable context sensitive half-time (3–10 min). Initial dose adjustment is not required for patients with impaired renal and hepatic functions. Remifentanil can be administrated in higher doses than are normally used with other opioids without concerns about accumulation and the possibility of unpredictable and/or delayed recovery. Frequently, ICU patients are managed without bolus doses, and it is recommended that remifentanil infusions should be started at 6–9 μg/kg/h and then titrated in the range dose of 0.5–15 μg/kg/h. The major adverse effects are hypoten-

It is a centrally acting opioid-like medication, acts by binding to the μ opiate receptor; it is a pure agonist and inhibits adrenaline and serotonin reuptake. The most common adverse It is commonly administered for the short-term treatment of mild to moderate pain and febrile critically ill patients with infection. It differs from the available opioids and NSAIDs, since paracetamol does not increase the incidence of nausea, vomiting and respiratory depression that can occur with opioids, or the platelet dysfunction, gastritis and renal toxicity that are associated with NSAIDs. It has a relatively good safety profile but there is limited information regarding IV use in critically ill patients. The study to date has described that paracetamol can cause transient abnormalities of liver function and may cause hypotension in critically ill patients. Acute liver failure is the most serious potential complication of the use of paracetamol. The key criteria for assessing potential hepatotoxicity with conventional doses of paracetamol may include hypoxic injury, altered pharmacokinetics, relative over-dosage, muscle glutathione depletion, malnutrition, dehydration, older age and alcoholism which are often seen in critically ill patients [24].

#### *4.2.3. Prop-paracetamol*

It is a prodrug form of paracetamol which is formed from the esterification of paracetamol and the carboxylic acid diethyl glycine. It has the advantage of making it more water-soluble. It is used in postoperative care and is delivered by intravenous route [23].

#### *4.2.4. α2-agonists*

The Clonidine and Dexmedetomidine are α2-adrenoceptor agonists, which provide both analgesia and sedation. Hence, they are also termed as analgosedation agents. Dexmedetomidine has eight times more affinity for α2-receptors compared with clonidine.

Dexmedetomidine infusion has been shown to reduce the prevalence and duration of confusion and delirium when compared with the use of morphine and midazolam [25].

α2-Agonists are used to improve the quality of analgesia and aid opioid rotation in opioidtolerant individuals. The side-effect profile of both α2-agonists includes bradycardia, cardiac asystole and hypotension. Although rare, it can cause rebound hypertension and can cause withdrawal syndrome.

**5.3. Reassessment**

administration [26].

**5.5. Clinical pathways**

**5.6. Checklists**

**5.7. Daily goals**

perspectives [26].

**6. Conclusions**

**5.4. Guidelines and protocols**

Patients must be evaluated hourly to ensure appropriate response to therapeutic interventions so that health-care providers can proactively act to relieve pain. If reassessment reveals inadequate pain control despite the initiation of therapeutic interventions, we should consider titration of medications, rotation of medications or changes in the route of

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These guidelines should be developed that combine a scientific basis and expert opinion. Wellness model from the World Health Organization's treatment of pain after cardiac surgery, we can see that guidelines and protocols lead to the effective management of post-cardiac surgery pain. If we look at the complexity of ICU pain, we need to have organized protocols to help us care for these patients. The examination of published literature reviews and evidence-

It provides a consistent and repeatable time line for planning individualized patient care. The pathway details the precise course of the patient, including multidisciplinary elements. It includes history, examination, diagnostics and treatment and incorporates pre-emptive treat-

It is a way to verify that clinical pathways or tasks are completed and it is a good way to

Daily goals highlighting by white board, electronic reminders to all members of the multidisciplinary team can access the plan and ensure that the patient is being treated from all

Intensive care unit (ICU) patients are at the higher risk of pain and they are having pain even while resting. If pain is not adequately treated, it leads to adverse effect and increases the chances of chronic pain and posttraumatic stress disorders in these patients. In ICU patient, anxiety, delirium and sleep deprivation increase the sensitivity to pain. The organ dysfunctions in these patients will decrease the potency of analgesic medication and increase the toxicity. Pain assessment is the basic essential factor in adequate management of pain. The different pain scales are used depending on their abilities to communicate. The commonly used analgesic medication in ICU patients is opioids but there is an increased use of multimodal

based guidelines can facilitate the development of institution-specific guidelines.

ment for procedures as well as management of chronic pain issues [26].

ensure that pathways or tasks are followed. It helps in errors prevention [26].

#### *4.2.5. Ketamine*

It is an N-methyl-aspartate antagonist, commonly used as analgosedative agent. Its use in combination with the opioid PCA reduces the opioid consumption and side effects. In combination with midazolam, ketamine provides effective analgesia in sickle cell crisis patients. Ketamine has an opioid-sparing effect and commonly used in lower dosage in burns patients. The main side effects of ketamine are tachycardia, hallucination, delirium ketotonia and increase intracranial pressure [25].

#### *4.2.6. Magnesium*

It acts through the NMDA receptors and acts as adjunct by reducing analgesic requirements without any major adverse effects, but there is no evidence that magnesium has any opioidsparing effects in the critically ill patients [25].

#### *4.2.7. Gabapentinoids*

The Gabapentin and Pregabalin work by binding to the α2δ subunits of voltage-dependent calcium ion channels. They reduce the development of hyperalgesia and central sensitization and are useful adjuncts in the treatment of neuropathic pain.

Gabapentin compared with Carbamazepine or placebo reduces pain intensity in patients with GBS (Gillian Barrie syndrome) without increasing side effects. Gabapentinoids are used mainly in neuropathic and post-burn debridement pain. The extra advantage is that these medications are available in the enteric form and get absorbed in the duodenum; hence, one has to be careful when the patient is fed through a jeujenostomy tube. The major side effects of these medications are confusion, dizziness, ataxia and convulsions [25].
