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Pain control in the critically ill adult patient

Pain control in the critically ill adult patient
Authors:
Pratik Pandharipande, MD, MSCI
Christina J Hayhurst, MD
Section Editors:
Polly E Parsons, MD
Michael F O'Connor, MD, FCCM
Deputy Editors:
Geraldine Finlay, MD
Nancy A Nussmeier, MD, FAHA
Literature review current through: Nov 2022. | This topic last updated: Aug 30, 2022.

INTRODUCTION — Many critically ill patients experience pain due to underlying illness or injury, a recent surgical or other invasive procedure, or noxious stimuli caused by interventions in the intensive care unit (ICU; eg, tracheal intubation, nasogastric tubes, mechanical ventilation, routine nursing care such as repositioning). In this topic, we review the physiology, assessment, and treatment of pain in the critical care setting. Other topics present a broader discussion of the use of sedative-analgesic medications to alleviate distress due to multiple causes (eg, anxiety, dyspnea, pain) or manage delirium with agitation in critically ill patients.

(See "Sedative-analgesic medications in critically ill adults: Selection, initiation, maintenance, and withdrawal".)

(See "Sedative-analgesic medications in critically ill adults: Properties, dose regimens, and adverse effects".)

(See "Delirium and acute confusional states: Prevention, treatment, and prognosis".)

GENERAL PRINCIPLES

Physiology of pain and pain control — Pain is sensed through the afferent pain pathway (figure 1) [1,2]. Multiple cortical and subcortical structures are involved in the experience of pain (figure 2) [3]. Recent tissue damage due to illness, injury, or surgery initiates the release of local inflammatory mediators (eg, bradykinin, substance P, prostaglandins, potassium, histamine, and serotonin) (figure 3). These mediators may cause primary hyperalgesia (augmented sensitivity to painful stimuli) or allodynia (misperception of pain with stimuli that are not noxious) (figure 4) [4,5]. Increased excitability of neurons in the central nervous system due to glutamate activation of the spinal N-methyl-D-aspartate (NMDA) receptors may exacerbate pain perception (secondary hyperalgesia) [5]. Patients with a preexisting chronic pain syndrome, neuropathy, or myopathy may develop exacerbation of baseline pain due to hyperalgesia or allodynia [6].

Analgesic agents and techniques are used to reduce pain by:

Altering perception of pain in the central nervous system (eg, opioid analgesics, acetaminophen)

Inhibiting local production of pain mediators (eg, blockade of prostaglandin synthesis by nonsteroidal antiinflammatory drugs [NSAIDs])

Interrupting neural impulses in the spinal cord (eg, local anesthetic agents used for a neuraxial block)

Assessment for pain — Routine frequent pain assessment that documents pain severity, response to medication, and development of any side effects is necessary to maintain an acceptable individualized level of comfort [7]. Such systematic pain assessment improves outcomes [8,9].

Underestimation and undertreatment of pain are common in the critical care setting, although not all critically ill patients have pain [10-16]. Intubated semi-conscious patients may be unable to communicate that they have pain. Even patients who are conscious and interactive have variable abilities to express their need for pain control.

Patients who can communicate — For patients who can communicate, pain assessment tools include the continuous visual analog scale (VAS) (form 1) where the patient makes a mark anywhere along a line from no pain to a maximum that represents the worst possible pain, the numeric rating scale (NRS) where the patient selects a discrete number on the line between 0 and 10 (figure 5), and the verbal rating scale (VRS) where the patient can choose a word or phrase describing increasing pain intensity (figure 6). Each of these scales is valid and generally reliable [7,17,18].

Patients who cannot communicate — For semiconscious or noncommunicative patients who cannot participate in the assessment, we cannot assume the patient does not have pain. Therefore, we need to use a validated tool to assess for pain [14,19,20]. There are several validated tools for nonverbal critically ill patients. The two with the strongest psychometric properties include the Behavioral Pain Scale (table 1) and the Critical Care Pain Observation Tool (table 2). These tools use both pain-related behaviors and physiologic indicators, have excellent validity and reliability, and are recommended in the Society of Critical Care Medicine (SCCM) Pain Agitation and Delirium (PAD) guidelines [7,21-26]. Limited data suggest possible efficacy of newer pain assessment methods such as the pupillary pain index, which is based on portable infrared measurements of pupil size and pupillary reflex responses to light (indicating integrity of midbrain function) or noxious stimuli (with measurements of the amplitude of reflex pupillary dilation) [27,28].

When appropriate, caregiver and family can be involved in their loved one's pain assessment process, though it should not substitute for an intensive care unit (ICU) team’s role and commitment to systematic pain assessment and optimal analgesia. Pain is suspected if grimacing, writhing, and signs of sympathetic activation are noted (eg, tachycardia, hypertension, tachypnea, diaphoresis, piloerection). Vital sign perturbations alone are not valid indicators for pain in critically ill adults and should only be used as cues to initiate further assessment using appropriate and validated methods. Although pain level may be overestimated when assessment is based solely upon such behaviors and physiologic indicators, these signs supplement information from objective pain-rating tools.

Goals of pain control — The primary goal of analgesia is to provide optimal patient comfort. This goal is patient-specific and depends upon the clinical situation, individual patient tolerance of pain, and side effects of analgesic therapy. Some patients prefer to tolerate a certain pain level in order to maintain alertness, whereas others do not.

Secondary goals include:

Attenuation of adverse physiologic responses to pain (eg, hypermetabolism, increased oxygen consumption, hypercoagulability, and alterations in immune function) [2].

Prevention of development of chronic pain syndromes. Inadequate control of acute pain can lead to changes in the central and peripheral nervous systems that result in subsequent development of chronic pain [6,29,30]. Avoidance of painful stimuli may not be possible for patients in an ICU, but adequate pain control may decrease potential for long-term pain, which occurs in many survivors of critical illness [31-34]. (See 'Physiology of pain and pain control' above.)

Control of anxiety and agitation, particularly in intubated patients [35].

Multimodal analgesia — In critically ill patients, alleviation of pain is predominantly accomplished with analgesic drugs that alter central mechanisms. An ideal drug would have a rapid onset, rapid recovery, lack of drug accumulation, no propensity to cause allodynia, hyperalgesia, or dependence, and no side effects or toxicity. No single agent has all of these characteristics.

Opioids remain a mainstay for pain management in many critically ill patients, as noted in the 2018 Pain, Agitation/sedation, Delirium, Immobility (rehabilitation/mobilization), and Sleep (PADIS) guidelines of the Society of Critical Care Medicine [7]. However, the guidelines suggest using the lowest effective doses of opioids due to safety concerns that include depression of consciousness and respiratory drive, delirium, hypotension, ileus, nausea and vomiting, urinary retention, pruritus, immunosuppression, and development of tolerance. Thus, a multimodal approach is typically employed (ie, a combination of analgesics and techniques, each with a different mechanism of action within the central or peripheral nervous system) [7,9]. This approach may include opioid analgesics, nonopioid intravenous (IV) agents such as acetaminophen, ketamine, neuropathic pain medications (eg, gabapentin, pregabalin, carbamazepine), nonselective antiinflammatory drugs (NSAIDs), or nefopam, as well as regional anesthesia, and other adjunct therapies (eg, massage, music, relaxation techniques) [7]. The specific approach can be individualized based on the source and severity of the patient’s pain [1,4,36]. Potential advantages of a multimodal approach include improved analgesia, reduced opioid dosing to achieve effective analgesia, and decreased risk of opioid-related side effects. (See 'Type and management of side effects' below and 'Tolerance, withdrawal, and hyperalgesia' below.)

Although multimodal approaches improve outcomes for perioperative patients [37,38], limited data are available regarding outcomes in critically ill patients (eg, duration of ventilation or length of stay in the ICU [39,40]. (See "Management of acute perioperative pain in adults", section on 'General approach'.)

Analgosedation (analgesia-first or analgesia-based) — Critically ill patients often require sedatives to tolerate mechanical ventilation but have improved outcomes with light sedation compared with heavy sedation strategies [41]. In order to avoid deep or unnecessary sedation, the SCCM recommends analgosedation. Analgosedation is either an analgesia-first or analgesia-based strategy. In the analgesia-first approach, pain is assessed and treated, usually with an opioid, prior to administering a sedative. In the analgesia-based approach, an opioid is used instead of a sedative to reach the sedation goal.

Analgosedation using opioids may increase the risk of delirium. Thus, we titrate sedation to awake and calm (Richmond Agitation Sedation Scale of 0) to minimize this risk. The risk of delirium was described in a study that evaluated over 4000 ICU patients and reported that increased exposure to opioids was associated with increased delirium in a dose-dependent fashion [42]. It was also found that severe pain was inversely related to delirium. Given this data, coupled with the side effects of opioids, the risk of dependence, withdrawal, or hyperalgesia in the setting of the opioid epidemic, clinicians should carefully weigh the risks of analgesia-based sedation with opioids against the risk of delirium and other adverse outcomes.

Analgesic administration — Effectiveness of analgesic drugs, particularly opioid analgesics, may be improved by these principles:

Intravenous administration – IV administration is generally preferred in critically ill patients [7].

Gastrointestinal (GI) absorption of medications is unpredictable due to GI dysfunction in many critically ill patients. However, administration of liquid formulations of oral analgesic agents may be effective if oral or feeding tube intake has been well-tolerated.

Subcutaneous or intramuscular (IM) administration of medications often results in erratic and potentially inadequate absorption [9], particularly in critically ill patients who have edema or regional hypoperfusion (eg, shock).

Continuous or regular dosing schedule – Pain control is more consistent if analgesics are administered continuously, at regular intervals, or by patient control, rather than administered on an "as-needed" (PRN) basis or reactively (ie, by the caregiver when the patient complains of pain) [43].

For opioid analgesics, specific options include [26] (see "Sedative-analgesic medications in critically ill adults: Properties, dose regimens, and adverse effects"):

Continuous IV infusions – Continuous IV infusions of opioids are used in patients with ongoing pain that is not resolving rapidly and/or for moderate-to-severe pain that is poorly controlled with repeated bolus injections.

Typically, an initial bolus dose is given, followed by a continuous infusion at a low rate. The infusion is subsequently titrated to the desired effect, with close monitoring for opioid-associated adverse effects (see 'Type and management of side effects' below). If needed, supplemental bolus doses are administered.

Bolus IV injections – Bolus IV injections of opioids may be used for control of moderate pain, with titration of subsequent doses.

Preemptive analgesia for pain that is event-related (eg, dressing changes or ambulation) may be managed with an IV bolus dose administered just before the painful procedure, with additional doses during the procedure if needed [7].

Patient-controlled analgesia (PCA) – PCA may be used in conscious patients for control of postoperative or other rapidly resolving pain [9,44]. This technique allows self-dosing up to a predetermined limit set by the clinician. An underlying basal infusion rate can be administered if necessary to achieve adequate pain control.

Agents to avoid — Several opioids are typically avoided and are listed below (see 'Opioids to avoid' below). In addition, Cox-2 inhibitors and hypnosis are also typically avoided. Guideline groups also suggest avoiding IV lidocaine in critically ill patients, although data are lacking [7].

OPIOID ANALGESICS — For most patients in the intensive care unit (ICU), including mechanically ventilated patients, intravenous (IV) opioids are a first-line treatment for nonneuropathic pain [7]. In some critically ill patients who are able to communicate and have only mild to moderate pain, nonopioid analgesics may be adequate without opioid supplementation. (See "Perioperative uses of intravenous opioids in adults: General considerations" and "Sedative-analgesic medications in critically ill adults: Properties, dose regimens, and adverse effects".)

All opioids have activity at an opiate receptor, including agonists, antagonists, and mixed agonist-antagonists. Efficacy of opioid analgesics is primarily due to binding to the mu-opioid receptor [45]. However, at least four discrete opiate receptors have been identified in the central nervous system (CNS), accounting for multiple potential side effects (table 3). (See 'Type and management of side effects' below.)

General considerations

Type and management of side effects — Risks versus benefits of opioid administration are assessed daily in critically ill patients, with vigilance for recognition of development of these opioid-associated side effects [7]:

Depressed consciousness – Opioids enhance the CNS-depressant effects of other commonly used sedative-analgesic agents (table 4). In patients who require sedation and are mechanically ventilated, this side effect is an advantage as it potentiates sedation, allowing lower doses of other sedatives. (See "Sedative-analgesic medications in critically ill adults: Properties, dose regimens, and adverse effects" and "Sedative-analgesic medications in critically ill adults: Selection, initiation, maintenance, and withdrawal".)

However, in patients who are recovering from critical illness, reduction of somnolence and mental clouding is usually desirable. Strategies to accomplish this include multimodal analgesia (eg, use of nonopioid analgesics, regional anesthesia, and/or nonpharmacologic therapy), opioid reduction, or opioid change (eg, use of longer-acting oral opioids [eg, methadone, extended-release oxycodone, extended-release morphine sulfate] rather than fentanyl injections). (See 'Multimodal analgesia' above and "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Somnolence and mental clouding'.)

Depression of respiratory drive – Depression of respiratory drive may not be clinically significant in patients who are mechanically ventilated. However, it is important to reduce total opioid dose in spontaneously breathing patients, particularly during weaning from mechanical ventilation [46,47]. The goal should be to use the minimally effective dose to achieve pain control. (See "Management and prognosis of patients requiring prolonged mechanical ventilation", section on 'Drugs'.)

Patients most vulnerable to adverse consequences of respiratory depression are those receiving combinations of opioid and sedative medications [48,49]. In one large study of over 4,500,000 medical and surgical patients, those receiving both types of medications had a greater risk of cardiopulmonary and respiratory arrest (odds ratio [OR] 3.83, 95% CI 3.74-3.92 for medical patients; and OR 2.34, 95% CI 2.25-2.42 for surgical patients), compared with those receiving neither type of medication [48]. Other risk factors in this study included comorbid conditions such as chronic obstructive pulmonary disease (COPD), hepatic insufficiency, or obesity.

Treatment with naloxone is reserved for progressive obtundation suggestive of imminent respiratory failure in nonventilated patients. If spontaneous respirations are still present, naloxone is administered in small, initial 0.04 mg bolus injections of dilute solution (eg, by diluting the 0.4 mg in a 1 mL ampule with 9 mL of normal saline, for a total volume of 10 mL). This dose is titrated upward every few minutes until the respiratory rate is 12 or greater.

If the patient is apneic, higher initial doses of naloxone are administered (eg, 0.2 to 1 mg). Patients in cardiac arrest should receive an initial naloxone dose of 2 mg. Bag-mask ventilation should be initiated prior to and during administration of naloxone in patients who are apneic or have infrequent or shallow respirations. This controlled ventilation assistance is continued until opioid-induced respiratory depression resolves with naloxone administration or the trachea is intubated for mechanical ventilation.

Administration of naloxone may cause sudden reversal of pain control, with tachycardia, hypertension, and pulmonary edema. These risks are balanced against the risks of tracheal intubation and temporary mechanical ventilation. (See "Acute opioid intoxication in adults".)

Hallucinations and delirium – Although pain itself is a significant risk factor for hallucinations and delirium, these symptoms may also be seen after administration of opioids for relief of pain. Patients should be reoriented and reassured. If possible, doses of drugs associated with delirium (eg, meperidine, benzodiazepines) are reduced or eliminated. However, agents to manage pain should not be withheld in patients with delirium since uncontrolled pain can contribute to delirium. (See 'Analgesic administration' above and 'Multimodal analgesia' above.)

In general, clinicians must balance the benefits of using opioids to treat significant pain with the potential for development of opioid-related delirium, as discussed in detail elsewhere [50]. (See "Delirium and acute confusional states: Prevention, treatment, and prognosis".)

Hypotension – Hypotension is more common in hypovolemic patients and following rapid injection. Thus, opioid doses are reduced and bolus doses are administered slowly (ie, over one to three minutes) in patients at risk for hypotension.

Histamine release – All opioids act directly on blood and tissue cells to release histamine, which may produce flushing, tachycardia, hypotension, pruritus, and bronchospasm. Histamine release is inversely correlated with analgesic potency and is greatest with large doses of meperidine or morphine, while fentanyl and remifentanil release little histamine [51,52].

Peripheral vasodilation – Due to central and peripheral vasodilatory effects, opioids may increase the volume of fluid needed during resuscitation after major trauma or burn injury [53]. Additional or alternative analgesic medications are used in such cases when possible [54].

Nausea and vomiting – Nausea and vomiting may occur due to opioid-induced direct stimulation of the chemoreceptor trigger zone. Sedated patients may not complain of nausea, and vomiting may not be evident externally in obtunded patients or those with an enteral or nasogastric tube. If the stomach appears distended on chest or abdominal radiograph, decompression by suction of these tubes may be helpful.

Treatment of nausea and vomiting in critically ill patients is similar to treatment in postoperative patients, initially with IV bolus doses of ondansetron 4 mg or dexamethasone 4 to 8 mg. Subsequent treatment details are available elsewhere. (See "Postoperative nausea and vomiting".)

Ileus – Gastrointestinal (GI) transit may slow with prolonged opioid administration due to binding to local opiate receptors in the gut, resulting in ileus and constipation [55]. Strategies to minimize this side effect include multimodal analgesia, opioid reduction, and opioid rotation. Further details regarding management of opioid-related ileus are presented elsewhere. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Opioid bowel dysfunction' and "Measures to prevent prolonged postoperative ileus".)

Urinary retention – Urinary retention may be severe enough to necessitate insertion of a bladder catheter. This depends on patient symptoms, length of time since last void, and whether bladder volume is elevated, as estimated with an ultrasonic scanner (typically, >300 mL). (See "Acute urinary retention".)

Pruritus – Incidence of opioid-associated pruritus varies with the specific opioid and route of administration [56]. Treatment options include administration of an antihistamine, opioid rotation, or low doses of an opioid antagonist (eg, IV naloxone 40 to 80 mcg or the mixed opioid agonist-antagonist IV nalbuphine 1 to 5 mg; these doses may be effective for treatment of pruritus without reversal of opioid analgesia) [57]. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Pruritus'.)

Increased intracranial pressure (ICP)Fentanyl and other opioids may rarely cause an increase in ICP [58-60]. The mechanism and clinical significance of this effect are unknown. Opioids are frequently administered to patients with severe head trauma, but dosing should be reduced or eliminated in patients with malignant intracranial hypertension not explained by findings on neuroimaging [59].

Effects on the immune system – The effect of opioids on the immune system is unclear and should not influence choice for patients who need it in the ICU [61].

Tolerance, withdrawal, and hyperalgesia — The following adverse effects may develop after prolonged or high-daily-dose opioid administration:

Tolerance – Patients who receive prolonged or high daily opioid doses typically develop tolerance, a phenomenon whereby administration of opioids has a diminishing effect over time. Higher doses are necessary to achieve adequate control of pain. Treatment options include supplementation with nonopioid analgesics (eg, ketamine [62,63]) and/or use of other strategies for pain control (eg, regional anesthetic techniques). Opioid rotation is rarely used in critically ill patients who develop tolerance, although this is a successful strategy in other clinical settings [59]. (See "Cancer pain management with opioids: Optimizing analgesia", section on 'How to perform opioid rotation'.)

Withdrawal – Acute opioid withdrawal may occur when opioids are rapidly tapered or abruptly discontinued, particularly if high daily doses have been administered for a prolonged period [64,65]. Classic symptoms may occur due to rebound increases in neurotransmitter release (eg, sweating, vomiting, lacrimation, hypertension, fever, and anxiety) (table 5), although these symptoms may be attributed to other disorders in critically ill patients [64,66].

To prevent acute withdrawal symptoms, opioids should be weaned slowly in critically ill patients who have received infusions for longer than one week [7]. When opioid withdrawal is suspected, opioid dosing may be temporarily increased, or a longer-acting opioid may be used. Some clinicians convert patients to bridging treatment with doses of oral methadone or buprenorphine that are tapered to minimize signs and symptoms of withdrawal [67-69]. (See "Opioid withdrawal in the emergency setting" and "Medically supervised opioid withdrawal during treatment for addiction".)

Alpha2 agonists (eg, dexmedetomidine or clonidine) may reduce the undesirable physiologic and psychologic effects of opioid withdrawal [65]. (See "Sedative-analgesic medications in critically ill adults: Selection, initiation, maintenance, and withdrawal", section on 'Withdrawal'.)

Opioid-induced hyperalgesia (OIH) – OIH is defined as a state of nociceptive sensitization caused by exposure to opioids [70]. The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain actually becomes more sensitive to certain painful stimuli. Treatment options include reducing the opioid dose, opioid rotation, supplementation with nonopioid analgesics (eg, ketamine), and use of regional anesthetic techniques [70]. (See 'Multimodal analgesia' above and "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Opioid-induced hyperalgesia'.)

Opioids to avoid — Not all parenteral opioids are appropriate for critically ill patients. Analgesics that are not recommended because of specific safety concerns and/or lower potency include:

Meperidine – A metabolite of meperidine, normeperidine, has neurotoxic effects (eg, delirium and seizures). Meperidine is rarely used in patients with renal insufficiency because normeperidine is renally excreted.

Codeine – Codeine has low analgesic potency when administered parenterally. Also, the time to onset of action is slow because most of its analgesic effect is due to hepatic metabolism to morphine.

Opiate agonist-antagonists – Opiate agonist-antagonists (eg, buprenorphine, butorphanol, dezocine, nalbuphine, pentazocine) may precipitate withdrawal in chronic opioid users or in patients who have received an opioid infusion for a prolonged period. Whether to continue buprenorphine in patients chronically taking this agent for opioid use disorder is controversial [71].

Choice of opioid analgesic — Selection of a specific IV opioid agent as the mainstay of pain control in a critically ill patient depends upon the desired onset and duration of analgesic action, as well as potential adverse effects of the agent [7]. If administered in equianalgesic doses, there are no differences among different opioid agents in analgesic efficacy. However, pharmacokinetics, metabolism, and side effects vary considerably. Comparative advantages and disadvantages and typical dosage regimens of each opioid are described in the table (table 4). The roles of nonopioid analgesics, sedatives, anxiolytics, and antipsychotics in critically ill patients are also described.

Considerations for selection of a specific IV opioid agent include [7]:

Patients receiving mechanical ventilation – For pain and/or distress in patients receiving mechanical ventilation, we prefer fentanyl, morphine, or hydromorphone because these agents are fast-acting and titratable. If early extubation is anticipated, remifentanil may occasionally be selected because of its ultrashort duration of action. (See "Sedative-analgesic medications in critically ill adults: Properties, dose regimens, and adverse effects", section on 'Opioid analgesics'.)

Patients who are extubated – For moderate-to-severe nonneuropathic pain in critically ill extubated patients, we prefer intermittent bolus dosing of IV fentanyl, morphine, or hydromorphone because these agents can usually be titrated to achieve satisfactory analgesia without causing severe respiratory depression. (See "Sedative-analgesic medications in critically ill adults: Properties, dose regimens, and adverse effects", section on 'Opioid analgesics'.)

Patients with renal and/or hepatic insufficiency – For critically ill patients with renal and/or hepatic insufficiency, we typically select IV fentanyl or hydromorphone, with dose adjustments as needed. Morphine should be avoided due to its renal clearance. In patients with severe multiorgan failure, remifentanil may occasionally be considered because its metabolism is not dependent on hepatic or renal function. (See "Anesthesia for dialysis patients", section on 'Postoperative analgesia' and "Anesthesia for the patient with liver disease", section on 'Opioids'.)

Patients with hemodynamic instability – For patients with hemodynamic instability, we prefer shorter-acting agents such as fentanyl, rather than a longer-acting agent such as morphine. Also, morphine causes more histamine release, which could exacerbate hypotension, compared with fentanyl.

Patients with bronchospasm – For patients with known or active bronchospasm, we prefer fentanyl or hydromorphone rather than morphine because little histamine is released by these synthetic opioids.

Patients requiring frequent neurologic assessments – For patients requiring frequent neurologic assessments, we prefer remifentanil because of its ultrashort duration of action, allowing prompt reversal for each assessment.

Patients requiring intermittent bolus opioid doses – For patients with moderate pain requiring intermittent bolus doses rather than an opioid infusion and for those requiring preemptive analgesia before a painful procedure, we prefer morphine or hydromorphone because of their longer duration of action compared with fentanyl.

Patients who may benefit from oral, enteral, or transdermal opioid administration – If oral or enteral administration is desired (eg, a recovering patient preparing for discharge from the critical care unit or a patient with symptoms of opioid withdrawal), we typically use scheduled oxycodone or occasionally a longer-acting oral opioid such as methadone.

A transdermal route is possible for fentanyl. This route is not used for management of acute pain due to the delay of 12 to 24 hours until peak effect after transdermal application. However, hemodynamically stable patients with chronic analgesic needs may benefit from the generally consistent drug delivery of a transdermal route of administration.

Specific opioid agents

Morphine — Morphine is the prototype opioid agent and remains widely used in the critical care setting. Onset of analgesia is 5 to 10 minutes, with peak effect occurring in one to two hours.

Recommended doses of morphine are presented in the table (table 4). Doses are titrated to the desired effect, with close monitoring for opioid-associated adverse effects.

Morphine has an elimination half-life of three to five hours. After hepatic conjugation to glucuronide metabolites, renal elimination usually occurs within 24 hours. Renal insufficiency permits accumulation of an active metabolite (morphine-6-glucuronide), which also has mu-receptor-stimulating properties [72]. Thus, dose adjustment is necessary to avoid oversedation and respiratory depression in patients with impaired renal function (creatinine clearance less than 30 mL/minute) [73].

Fentanyl — Fentanyl is a synthetic derivative of morphine. Compared with other opioids, fentanyl is virtually devoid of histamine-releasing properties. Thus, it is preferred in patients with hemodynamic instability or bronchospasm. Compared with morphine, it is approximately 100 times more potent and has faster onset of action due to greater lipid solubility and improved penetration of the blood-brain barrier, although maximal analgesic and respiratory depressant effects of fentanyl may not be evident for several minutes.

Recommended doses of fentanyl are presented in the table (table 4). Typically, fentanyl is administered as a continuous IV infusion. Doses are titrated to the desired effect, with close monitoring for opioid-associated adverse effects. Alternatively, IV boluses may be administered every 30 to 60 minutes, although this method is less convenient and may allow breakthrough pain to occur.

Fentanyl is highly lipophilic, with rapid distribution to highly perfused tissues (eg, brain, heart, kidney, and GI tract) and a slower redistribution to muscle and fat [74]. Compared with morphine, fentanyl has a shorter half-life (two to three hours). It is metabolized in the liver to norfentanyl, an inactive metabolite that is then excreted in the urine. Renal insufficiency does not appear to affect its pharmacokinetics. However, accumulated stores in fat and other tissue are mobilized after discontinuation of a fentanyl infusion and may result in prolonged sedation. (See "Perioperative uses of intravenous opioids: Specific agents", section on 'Fentanyl'.)

Remifentanil — Remifentanil is an ultrashort-acting fentanyl derivative with a rapid onset of action (<3 minutes), short duration of action (5 to 10 minutes after cessation of infusion), and analgesic potency approximately equal to fentanyl. Remifentanil may be considered in selected patients as the primary sedative-analgesic agent (eg, when extubation is expected shortly after arrival to the ICU or frequent neurologic assessments are necessary) [75-77].

Recommended doses of remifentanil, administered as an infusion, are presented in the table (table 4).

Remifentanil is metabolized by nonspecific plasma esterases to inactive metabolites. Potential advantages include its rapid onset and offset and its lack of accumulation in patients with renal and/or hepatic dysfunction. Despite these advantages, a 2009 meta-analysis in 1067 critically ill adult patients found that use of remifentanil did not reduce adverse outcomes (eg, agitation, duration of mechanical ventilation, length of ICU stay, or mortality risk) compared with other analgesic agents [78]. Its use is limited in the United States due to concerns of tachyphylaxis, cost, and possible hyperalgesia after discontinuation [79-81].

Hydromorphone — Hydromorphone is a semisynthetic morphine derivative. Compared with morphine, hydromorphone is 5 to 10 times more potent and has a more rapid onset of analgesia (within 30 minutes) and shorter half-life. Due to its availability in a highly concentrated preparation (10 mg/mL), this agent may be beneficial in fluid-restricted patients with high opioid requirements.

Recommended doses of hydromorphone are presented in the table (table 4). Doses are titrated to the desired effect and patients are monitored closely for drug-associated adverse effects.

Hydromorphone is primarily metabolized in the liver. A metabolite of hydromorphone, hydromorphone-3-glucuronide (H3G) causes neuroexcitatory symptoms and is renally excreted. Although H3G is effectively removed during hemodialysis, this metabolite may accumulate between treatments [82].

Methadone — Methadone is a long-acting synthetic opioid with antagonist properties at the N-methyl-D-aspartate (NMDA) receptor. It has been used successfully to avoid withdrawal syndromes in critically ill patients [83,84] and as an alternative to other opioids to alleviate high-dose OIH [70]. In adults supported with mechanical ventilation, enterally administered methadone may allow discontinuation of opioid infusion with improved spontaneous ventilation and eventual weaning from support [83,85]. Side effects of methadone include oversedation due to its long duration of action. (See 'Tolerance, withdrawal, and hyperalgesia' above.)

Methadone prolongs the QTc interval, which can rarely lead to torsades de pointes, a life-threatening cardiac arrhythmia. Electrocardiographic (ECG) documentation of the QTc interval is recommended before and at least every 8 to 12 hours after initiation or increasing the dose of QTc-prolonging drugs [86]. If QTc prolongation is observed, documentation of more frequent measurements is recommended by telemetry or EKG. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)

NONOPIOID ANALGESICS — Since opioids are not well tolerated or necessary in all critically ill patients, one or more intravenous (IV) nonopioid analgesic agents are frequently employed as primary therapy for pain control or as part of a multimodal approach (see 'Multimodal analgesia' above). Adding these agents may allow reduction or elimination of opioids and opioid-related adverse effects.

Choice of nonopioid analgesic — Selection of a specific IV nonopioid analgesic agent depends upon the type of pain (nonneuropathic versus neuropathic), severity of pain, desired degree of sedation versus wakefulness, and potential adverse effects of the agent. The comparative advantages and disadvantages and typical dosage regimens of each nonopioid analgesic agent are described in the table (table 4). Other classes of agents (sedatives, anxiolytics, and antipsychotics) are also included in the table, with a description of their roles in the management of critically ill patients. (See "Sedative-analgesic medications in critically ill adults: Properties, dose regimens, and adverse effects" and "Sedative-analgesic medications in critically ill adults: Selection, initiation, maintenance, and withdrawal".)

Considerations for selection of an IV nonopioid analgesic include:

Patients with fever – For short-term treatment of fever in critically ill patients without hepatic insufficiency, IV acetaminophen (paracetamol) is effective as an antipyretic and supplemental analgesic agent [87-91].

Patients with severe burn or postoperative pain inadequately controlled with opioidsKetamine administered as a low-dose infusion (ie, <2.5 mcg/kg/minute) typically facilitates reduction in total opioid dose in critically ill surgical patients with burns or other procedures associated with significant postoperative pain (eg, thoracic, upper abdominal, major orthopedic operations) [92-94]. (See "Management of burn wound pain and itching", section on 'Nonopioid analgesics' and "Nonopioid pharmacotherapy for acute pain in adults", section on 'Ketamine'.)

Patients with tolerance, withdrawal, or hyperalgesia after opioid therapy – Patients who develop tolerance, withdrawal symptoms, or opioid-induced hyperalgesia may benefit from addition or substitution of ketamine as an analgesic agent [62,63,70]. Dexmedetomidine is occasionally used to help manage opioid withdrawal [65]. (See "Sedative-analgesic medications in critically ill adults: Selection, initiation, maintenance, and withdrawal", section on 'Withdrawal'.)

Patients with moderate acute pain and fever – A nonsteroidal antiinflammatory drug (NSAID) (eg, ibuprofen or ketorolac) is an option for some patients with fever and moderate acute pain [9]. However, contraindications for the use of NSAIDs include any history of renal dysfunction, gastrointestinal (GI) bleeding, recent surgical bleeding, platelet abnormality, congestive heart failure, cirrhosis, asthma, concomitant angiotensin-converting enzyme inhibitor therapy, or recent cardiac or vascular surgery. Since many ICU patients have at least one of these contraindications, the use of NSAIDs in the critical care setting is uncommon. (See "Nonselective NSAIDs: Overview of adverse effects".)

Patients with neuropathic pain – For critically ill patients with neuropathic pain (eg, Guillain-Barré syndrome [95-98], diabetic peripheral neuropathy, spinal cord injury, postherpetic neuralgia, fibromyalgia) [7,99]), we often administer oral gabapentinoids (gabapentin or pregabalin) or carbamazepine, either as the sole analgesic agent or as a supplement to opioid analgesia.

Prevention of development of chronic pain syndromesKetamine [100,101], as well as gabapentin and pregabalin [102], may be useful for prevention of chronic postsurgical pain.

Specific nonopioid analgesic agents

Acetaminophen — Parenteral acetaminophen (paracetamol) is an effective analgesic and antipyretic agent used in critically ill patients to treat fever and/or mild pain, and is often used as an adjunct to opioid analgesics [7,9,87-91,103-105]. As a supplemental agent after surgery, IV acetaminophen decreases the total dose of morphine [105,106] or NSAID [107], although the magnitude of the effect is small. One trial in older cardiac surgical patients also noted a reduction in delirium when acetaminophen was added to an infusion of propofol or dexmedetomidine in the postoperative period [106]. Several studies have reported hypotension (systolic blood pressure ≤90 mmHg or ≥20 percent decrease from baseline) associated with parenteral acetaminophen, with one study reporting a higher prevalence when compared with enteral administration [108,109]. (See "Nonopioid pharmacotherapy for acute pain in adults", section on 'Acetaminophen'.)

Recommended doses of acetaminophen are presented in the table (table 4). Doses are reduced in adult patients with mild or moderate hepatic insufficiency, chronic alcoholism, malnutrition, dehydration, or low body weight (≤50 kg). Patients with severe renal insufficiency (creatinine clearance ≤30 mL/minute) may receive the standard dose, but not more often than every six hours. Acetaminophen is contraindicated in patients with severe hepatic insufficiency or severe progressive liver disease.

Ketamine — Ketamine provides intense analgesia by blocking N-methyl-D-aspartate (NMDA) receptors to reduce glutamate release and by binding to sigma-opioid receptors [110,111]. It is employed as a substitute or adjunct to reduce opioid consumption in selected post-surgical patients [7,9]. Ketamine is occasionally used to help manage opioid tolerance, withdrawal, hyperalgesia, or neuropathic pain [62,63,70,112]. (See 'Tolerance, withdrawal, and hyperalgesia' above.)

Recommended doses are presented in the table (table 4). Ketamine plasma concentrations producing analgesia are typically lower than concentrations producing psychomimetic effects (eg, hallucinations, confusion, nightmares) [113,114].

Dexmedetomidine — Dexmedetomidine is a highly selective alpha2 agonist with analgesic and sedative properties. It is often selected for initial sedation of mechanically ventilated patients (ie, 24 hours). Some evidence suggests that use of dexmedetomidine may reduce the duration of mechanical ventilation and risk of delirium in critically ill patients, although data are not consistent. The use of dexmedetomidine as the sole or primary sedative-analgesic agent does not confer a mortality benefit. The use of dexmedetomidine is associated with a higher incidence of bradycardia and hypotension compared with some other sedative agents (eg, midazolam) [115]. These effects of dexmedetomidine are discussed in detail in separate topics. (See "Sedative-analgesic medications in critically ill adults: Properties, dose regimens, and adverse effects", section on 'Dexmedetomidine' and "Perioperative neurocognitive disorders in adults: Risk factors and mitigation strategies", section on 'Intravenous agents associated with higher risk'.)

Dexmedetomidine is commonly used as an adjunct for postoperative analgesia. Dexmedetomidine is a weak analgesic by itself, but is a potent potentiator of the analgesic effects of opiates and endogenous enkephalins [116,117]. Dexmedetomidine is sometimes used to help manage opioid and alcohol withdrawal [65]. (See 'Tolerance, withdrawal, and hyperalgesia' above.)

Infusion doses for dexmedetomidine are presented in the table (table 4). (See "Sedative-analgesic medications in critically ill adults: Properties, dose regimens, and adverse effects", section on 'Dexmedetomidine'.)

Nonsteroidal anti-inflammatory drugs — NSAIDs (eg, ibuprofen and ketorolac) nonselectively inhibit cyclooxygenase, a potent inflammatory mediator. NSAIDs may be used as adjuncts in multimodal therapeutic regimens, but adverse effects typically limit their use in critically ill patients [7,9]. (See "Nonselective NSAIDs: Overview of adverse effects".)

Recommended doses for oral or IV ibuprofen and IV ketorolac are presented in the table (table 4).

Gabapentinoids — The gamma-aminobutyric acid (GABA) analogues gabapentin and pregabalin are anticonvulsant agents indicated in critically ill patients for management of neuropathic pain (eg, pain from Guillain-Barré syndrome [95-97], diabetic peripheral neuropathy, spinal cord injury, postherpetic neuralgia, or fibromyalgia) [26,99], and have been used as a component of multimodal analgesia [7,9,118]. Though structurally related to GABA, the gabapentinoids do not bind to GABA receptors or influence GABA synthesis or uptake. Analgesia is attributed to several mechanisms including inhibition of excitatory calcium-mediated neurotransmitter release, as well as inhibition of descending serotonergic facilitation, antiinflammatory actions, and influence on the affective component of pain [119].

Recommended doses of gabapentin are presented in the table (table 4). Dose adjustment is necessary in patients with renal insufficiency. Both gabapentin and pregabalin are available only as oral medications. Although both are well tolerated, common dose-related adverse effects include somnolence, dizziness, and confusion. Notably, combinations of gabapentinoids with other central nervous system depressants (eg, opioids, anti-anxiety agents) increase risk of respiratory depression, particularly in older patients or those with pulmonary comorbidity (eg, chronic obstructive pulmonary disease [COPD]) [120].

Carbamazepine — Carbamazepine is an anticonvulsant that has been used for pain management for neuropathic pain in trigeminal and glossopharyngeal neuralgia, and in Guillain-Barré syndrome. It is less effective than the gabapentinoids, so should be considered as part of a multimodal pain regimen when there is intolerance of gabapentinoids [97].

REGIONAL ANESTHESIA AND NONPHARMACOLOGIC INTERVENTIONS — Regional anesthetic techniques and nonpharmacologic therapy can reduce the requirement for intravenous (IV) analgesics in selected patients [9].

Neuraxial analgesia and peripheral nerve blocks — Although not commonly used as a modality for analgesia in critically ill medical patients, critically ill surgical patients may benefit from postoperative analgesia provided by a regional anesthetic technique. Typically, a neuraxial or peripheral nerve block is initiated in the operating room to control incisional pain. Management of postoperative pain with these techniques is discussed in detail elsewhere:

(See "Management of acute perioperative pain in adults", section on 'Neuraxial opioid'.)

(See "Management of acute perioperative pain in adults", section on 'Epidural analgesia with local anesthetics and opioids'.)

(See "Management of acute perioperative pain in adults", section on 'Peripheral nerve blocks'.)

Alleviation of sleep deprivation and anxiety — Sleep deprivation, which is common in critically ill patients, decreases pain threshold and increases distress and the stress response [7]. Stimuli that might disturb normal diurnal sleep patterns should be minimized when possible (eg, noise, artificial lighting, unpleasant ambient temperature, hands-on measurement of vital signs) [121,122].

Pain and distress due to irritating stimuli (eg, traction on the endotracheal tube), uncomfortable positioning, dyspnea, neuromuscular paralysis, or inability to communicate should also be alleviated, if possible [122-124]. Identification of the cause of distress is important. Initiation of an analgesic or sedative medication is indicated when treatment with nonpharmacological interventions does not sufficiently control pain and/or agitation [26]. (See "Sedative-analgesic medications in critically ill adults: Selection, initiation, maintenance, and withdrawal" and "Delirium and acute confusional states: Prevention, treatment, and prognosis".)

Complementary and alternative therapies — Complementary therapies such as transcutaneous electrical nerve stimulation, relaxation techniques, massage therapy, and music therapy may be helpful in selected patients [7,9,26,125-129].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute pain management".)

SUMMARY AND RECOMMENDATIONS

Rationale – Critically ill patients may experience pain due to underlying illness or injury, recent surgery, or noxious stimuli. Underestimation and undertreatment of pain are common in this setting (figure 1). (See 'Introduction' above.)

Pain assessment – Maintenance of acceptable individualized level of comfort requires routine frequent pain assessments that document severity, response to medication, and development of side effects. (See 'Assessment for pain' above.)

Patients who can communicate – For patients who can communicate, we use a visual analog (form 1) or numerical rating pain scale (figure 5). (See 'Patients who can communicate' above.)

Patients who cannot communicate – For patients who cannot communicate, we use a validated pain-rating tool with both pain-related behaviors and physiologic indicators (eg, Behavioral Pain Scale (table 1) or Critical Care Pain Observation Tool (table 2)). (See 'Patients who cannot communicate' above.)

Goals – Goals of pain control include (see 'Goals of pain control' above and 'Physiology of pain and pain control' above):

Primary goal:

-Provide optimal patient comfort

Secondary goals:

-Attenuate adverse physiologic responses to pain

-Prevent development of chronic pain syndromes

-Control anxiety and delirium

Administration – Effectiveness of analgesic drugs in critically ill patients may be improved by (see 'Analgesic administration' above):

Intravenous (IV) administration, rather than oral, subcutaneous, or intramuscular routes

Continuous or regular administration schedule rather than "as-needed" (PRN) intermittent dosing

Patient-controlled analgesia (PCA)

Opioid analgesics – IV opioids are used as first-line treatment of nonneuropathic pain for most critically ill patients, including those who are mechanically ventilated. (See 'Opioid analgesics' above.)

Considerations for selection of a specific IV opioid include (see 'Choice of opioid analgesic' above):

-Mechanical ventilation – For pain and/or distress in patients receiving mechanical ventilation, we prefer fentanyl, morphine, or hydromorphone because these agents are fast-acting and titratable. If early extubation is anticipated, remifentanil may be selected because of its ultrashort duration of action.

-Moderate-to-severe nonneuropathic pain – For moderate-to-severe nonneuropathic pain in extubated patients, we prefer IV fentanyl, morphine, or hydromorphone because these agents can usually be titrated to achieve satisfactory analgesia without causing severe respiratory depression.

-Renal and/or hepatic insufficiency – For patients with renal and/or hepatic insufficiency, we typically select IV fentanyl or hydromorphone, with dose adjustments as needed. In patients with severe multiorgan failure, remifentanil may be selected because its metabolism is not dependent on hepatic or renal function.

-Hemodynamic instability – For patients with hemodynamic instability, we prefer fentanyl or remifentanil because these agents are short-acting and release little histamine.

-Acute bronchospasm – For patients with acute bronchospasm, we prefer agents that release little histamine (eg, fentanyl, remifentanil, or hydromorphone) rather than morphine.

-Need for frequent neurologic assessments – For patients requiring frequent neurologic assessments, we prefer remifentanil because of its ultrashort duration of action, allowing prompt reversal for each assessment.

-Need for intermittent boluses – For patients who require only intermittent bolus opioid doses, we prefer morphine or hydromorphone because of their longer durations of action compared with fentanyl.

If oral or enteral administration is desired, we typically select longer-acting oral opioids (eg, methadone, extended-release oxycodone, extended-release morphine sulfate). Transdermal fentanyl may benefit hemodynamically stable patients with chronic analgesic needs, although there is a delay of 12 to 24 hours until peak effect.

Agent choice – Opioid dosing may be reduced or eliminated by use of one or more IV nonopioid analgesic agents. Selection depends upon type of pain (nonneuropathic versus neuropathic), severity of pain, desired degree of sedation versus wakefulness, and potential adverse effects of the agents. (See 'Choice of nonopioid analgesic' above.)

Multimodal approach – A multimodal approach to pain control includes a combination of opioid and nonopioid analgesics, neuraxial or peripheral nerve blocks, nonpharmacologic treatments, and/or sedative agents. Advantages of this approach include improved analgesia, lower opioid doses, and decreased risk of opioid-related side effects or development of tolerance, withdrawal, or opioid-induced hyperalgesia. (See 'Multimodal analgesia' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Karen J Tiezte, PharmD, and Stuart McGrane, MBChB, who contributed to earlier versions of this topic review.

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