Version July 2025
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).
Assessment and treatment of pain in critically ill adults are discussed in this topic.
General concepts regarding pain management in hospitalized patients and the use of sedative medications to alleviate distress in critically ill adults are described in separate topic reviews.
●(See "Approach to the management of acute pain in adults".)
●(See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects".)
●(See "Delirium and acute confusional states: Prevention, treatment, and prognosis".)
OVERVIEW OF PAIN PATHWAYS —
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]. Patients with pre-existing chronic pain syndrome, neuropathy, or myopathy may develop exacerbation of baseline pain due to hyperalgesia or allodynia [6].
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].
Analgesic agents and techniques are used to reduce pain by:
●Altering perception of pain in the central nervous system (eg, opioid analgesics, acetaminophen [7])
●Inhibiting local production of pain mediators (eg, blockade of prostaglandin synthesis by nonsteroidal anti-inflammatory drugs [NSAIDs])
●Interrupting neural impulses in the spinal cord (eg, postoperative regional analgesia produced by administering a local anesthetic agent via a previously placed epidural or peripheral nerve block catheter)
Opioids are the most common agents used to control pain in the intensive care unit (ICU). 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 [8]. However, effects on at least two other opiate receptors in the central nervous system (CNS) may account for multiple potential side effects (table 1). (See 'Adverse effects of opioid analgesics' below.)
PAIN ASSESSMENT —
We perform a general and formal pain assessment, and document pain severity, response to medication, and development of any side effects [9]. (See 'General assessment' below and 'Formal validated assessment tools' below.)
Pain is common and likely underreported among intensive care unit (ICU) patients [10-17]. Thus, incorporating a routine assessment for pain is paramount in this population. While it cannot be assumed that all ventilated patients are in pain, many patients experience pain at rest (eg, due to immobility, trauma, surgery), with routine patient care (eg, suctioning, repositioning, physical therapy), and with endotracheal tubes, procedures (eg, arterial line insertion, chest tube, wound dressing changes), and other monitoring devices.
All patients on neuromuscular blockers should be treated empirically for pain.
General assessment — We ask patients if they are in pain (self-report) and examine for evidence of pain including grimacing, writhing, withdrawal, combativeness, diaphoresis, piloerection, hyperventilation, and/or tachycardia and hypertension. However, 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 with a formal tool. (See 'Formal validated assessment tools' below.)
When appropriate, caregivers and surrogates can be involved in their loved one's pain assessment process, although it should not substitute for an ICU team's role.
Formal validated assessment tools — Formal assessments are performed by the bedside nurse every four hours, as well as preceding and following an invasive procedure.
Formal validated assessment tools are supplements to general assessment. Such tools help quantify pain and assess the response to therapy. The use of specific assessment tools depends upon whether patients are able to communicate. While self-report tools are the reference standard, communication in the ICU is often impaired and not always feasible such that an alternate tool is applied. (See 'Patients who can communicate' below and 'Patients who cannot communicate' below.)
When one tool is selected it cannot be interchangeably used with another tool since the correlation between tools is poor [18].
Patients who can communicate — For patients who can communicate, we use a validated pain assessment tool that includes any of the following [9,19,20]:
●Numeric rating scale (NRS), where the patient rates their pain verbally on a scale from 0-10, and NRS Visual (NRS-V) where the patient selects a discrete number on the line between 0 and 10 (figure 5). Our preference is the NRS-V since it has the best sensitivity, and is accurate and easy to use [9].
●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.
●Verbal rating scale (VRS) where the patient can choose a word or phrase describing increasing pain intensity (figure 6).
Patients who cannot communicate — For semiconscious or noncommunicative patients who cannot self-report reliably, we use a validated behavioral observation tool to assess pain [14,21,22]. The two that are considered most reliable in critically ill patients are the Behavioral Pain Scale (BPS) (table 2) and the Critical-Care Pain Observation Tool (CPOT) (table 3).
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 [9,23-28].
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) [29,30]. Nociception monitors that utilize galvanic skin responses and vital sign algorithms may also provide additional information regarding the severity of pain in the unconscious patient [31].
TREATMENT OF PAIN
Goals of pain control — The primary goal of analgesia is to provide optimal patient comfort and allow frequent interactions with the care team and family as possible, while minimizing adverse effects of pharmacologic agents. This goal is patient-specific and depends upon the clinical situation, individual patient tolerance of pain, and side effects of analgesic therapy. For example, some patients prefer to tolerate a certain pain level 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 [6,32,33]. Avoidance of painful stimuli may not be possible for patients in an intensive care unit (ICU), but adequate pain control may decrease potential for long-term pain, which occurs in many survivors of critical illness [34-37].
●Control of anxiety and agitation, particularly in intubated patients (analgosedation) [38].
General approach of analgosedation — We agree with the approach of analgosedation, recommended by the Society of Critical Care Medicine (SCCM), which promotes the use of analgesia for critically ill patients who have pain. For these patients, an opioid is the primary sedation strategy [9]:
●In the "analgesia-first" approach, pain is assessed and treated before administering a sedative.
●In the "analgesia-based" approach for patients experiencing pain, an opioid is used to reach the sedation goal instead of a sedative.
However, analgosedation using opioids may increase the risk of delirium in a dose-dependent manner, such that we avoid oversedation with opioids alone if not indicated for pain [39]. (See 'Adverse effects of opioid analgesics' below.)
In critically ill patients, treatment of pain is often done in combination with a sedative medication (eg, propofol) [28]. Further details regarding sedative selection are provided separately. (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal".)
Moderate to severe nonneuropathic pain — For most critically ill patients with moderate to severe nonneuropathic pain, we suggest an intravenous opioid rather than other agents. Importantly, the lowest effective dose should be used. This approach is supported by limited and indirect data in patients undergoing procedures [9,40-42]. A pooled analysis of three studies reported a small reduction in pain scores when high-dose opioids were compared with low-dose regimens for peri-procedural analgesia in critically ill patients (eg, turning, chest tube removal) (standard mean difference -0.26, 95% CI -0.94 to +0.42 on numeric rating scale [NRS] score) [43]. However, the population was heterogenous and response variable, limiting generalizability; in addition, improved pain control was at the expense of potential harm (eg, apnea and respiratory depression).
To achieve pain control and minimize adverse effects, we typically use a multimodal approach that combines opioids with other nonopioid agents (table 4) and/or adjunctive nonpharmacologic therapies (eg, relaxation, music, massage, good sleep hygiene). The rationale for a multimodal approach is the provision of adequate pain relief while minimizing the adverse effects of opioids. (See 'Multimodal analgesia' below and 'Choosing an opioid' below.)
Mild nonneuropathic pain — For those with mild nonneuropathic pain, we suggest a trial of nonopioid agents and nonpharmacologic approaches rather than opioids. Opioids are not typically necessary for the relief of mild pain. (See 'Choosing a nonopioid' below.)
Neuropathic pain — For those with neuropathic pain, we suggest gabapentinoids or carbamazepine rather than other agents based upon the rationale that these agents better target the primary mechanism underlying neuropathic pain. Opioids may be needed as supplemental agents, especially during titration. (See 'Choosing a nonopioid' below and "Overview of pharmacologic management of chronic pain in adults".)
Multimodal analgesia — No single agent is ideal. We agree with the recommendations set out by the 2018 guidelines of the SCCM [9], which support a multimodal approach that includes a combination of any of the following (table 4):
●Opioid analgesics (eg, morphine, fentanyl, remifentanil, hydromorphone, methadone)
●Nonopioid analgesics (eg, acetaminophen, ketamine, neuropathic pain medications [gabapentin, pregabalin, carbamazepine], nonsteroidal anti-inflammatory drugs [NSAIDs], or nefopam [available in Europe])
●Nonpharmacologic therapies (eg, massage, music, relaxation techniques)
●Regional analgesia techniques (eg, neuraxial or peripheral nerve block)
We typically individualize the strategy for analgesia based on the etiology and severity of the patient's pain [1,4,44]. When more than one pharmacologic agent is chosen, each drug should have a different mechanism of action within the central or peripheral nervous system; we do not prescribe multiple agents from the same class [9,45]. This approach minimizes the adverse effects of agents, opioids, in particular.
Multimodal approaches improve outcomes for perioperative patients [46,47], and limited data may support a similar benefit in critically ill patients (eg, duration of ventilation or length of stay in the ICU) [48,49]. (See "Approach to the management of acute pain in adults", section on 'Use multimodal analgesia'.)
Choosing an opioid — There is no ideal opioid for all critically ill patients. Selection of a specific opioid agent (typically an intravenous agent) in this population depends upon the desired onset and duration of analgesic action, as well as potential adverse effects of or contraindications to the agent [9].
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 (fentanyl, remifentanil, hydromorphone, methadone) are described in the table (table 4). Choices may also be limited by shortages that vary in timing and geographical location.
Specific considerations for selection of intravenous opioid agents include the following (table 5) [9]:
●Patients receiving mechanical ventilation – For moderate or severe nonneuropathic pain and/or distress in patients receiving mechanical ventilation, fentanyl, morphine, or hydromorphone are commonly used as a continuous infusion because they are fast-acting and titratable. In the United States, fentanyl is used most often due to its favorable pharmacokinetics and cost profile in mechanically ventilated patients, whereas hydromorphone infusions are often preferred for patients undergoing extracorporeal membrane exchange oxygenation (ECMO) [50]. (See 'Morphine' below and 'Fentanyl' below and 'Hydromorphone' below.)
If early extubation is anticipated shortly after arrival to the ICU, remifentanil may be useful because of its ultrashort duration of action. However, remifentanil use is limited in the United States due to concerns of tachyphylaxis, cost, and possible hyperalgesia after discontinuation [51-54]. (See 'Remifentanil' below.)
For select patients receiving mechanical ventilation, intermittent intravenous agents may be appropriate.
●Spontaneously breathing patients – For moderate-to-severe nonneuropathic pain in critically ill spontaneously breathing patients, we prefer intermittent bolus dosing of intravenous fentanyl, morphine, or hydromorphone. Bolus doses of these agents are short-acting, effective, and can be titrated to achieve satisfactory analgesia, while concomitantly reducing the risk of severe respiratory depression. (See 'Morphine' below and 'Fentanyl' below and 'Remifentanil' below and 'Hydromorphone' below.)
●Patients with renal and/or hepatic insufficiency – For critically ill patients with renal and/or hepatic insufficiency, we typically select intravenous fentanyl or hydromorphone, with dose adjustments as needed.
Morphine should be avoided due to its renal clearance.
In patients with severe multiorgan failure, remifentanil is occasionally selected because its metabolism is not dependent on renal or hepatic function. (See "Anesthesia for dialysis patients", section on 'Postoperative analgesia' and "Anesthesia for the patient with liver disease", section on 'Opioids' and 'Fentanyl' below and 'Hydromorphone' below.)
●Patients with hemodynamic instability – For patients with hemodynamic instability, we use shorter-acting agents such as fentanyl rather than morphine, which has a slightly longer duration of action. Morphine also causes more histamine release, which can exacerbate hypotension. (See 'Fentanyl' below.)
●Patients with bronchospasm – For patients with known or active bronchospasm, fentanyl or hydromorphone is preferred rather than morphine because little histamine is released by these synthetic opioids. (See 'Fentanyl' below and 'Hydromorphone' below.)
●Patients requiring frequent neurologic assessments – The ultrashort duration of action of remifentanil make it particularly suitable for patients requiring frequent neurologic assessments, as it allows prompt reversal and resumption for each assessment. Fentanyl is an alternative since it has a relatively short half-life compared with morphine or hydromorphone. (See 'Remifentanil' below and 'Fentanyl' below.)
●Patients requiring fluid restriction – Hydromorphone may be useful in fluid-restricted patients with high opioid requirements since it is available in a highly concentrated preparation (10 mg/mL).
●Patients with pain of extended duration – Methadone is often used in patients in whom prolonged pain is anticipated (eg, those with major burns injuries).
●Patients requiring intermittent bolus opioid doses – For patients with moderate pain that can be managed with intermittent bolus doses rather than an opioid infusion, we prefer a longer acting agent such as hydromorphone. For procedural pain, boluses of a quick-onset opioid can be used. (See 'Hydromorphone' below.)
Choosing a nonopioid — Selection of a specific 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 (table 6). The comparative advantages and disadvantages and typical dosage regimens of each nonopioid analgesic agent are described in the table (table 4). Nonopioids are used in combination with opioids for moderate to severe pain while nonopioids are used alone in those with mild pain.
Specific considerations for selection of intravenous nonopioid analgesics include:
●Patients with discomfort due fever or mild pain (acetaminophen) – For short-term treatment of fever in critically ill patients without hepatic insufficiency, acetaminophen (paracetamol) is effective as an antipyretic and supplemental analgesic agent [7,55-59]. Acetaminophen may also be useful in patients with mild pain (eg, drug-induced headache, rigors, body aches due to coronavirus disease 2019 [COVID-19]). There are multiple formulations, including oral, rectal and intravenous; delivery choice is individualized. NSAIDs are an alternative but infrequently administered due to relative contraindications (see bullet below on moderate acute pain).
Parenteral acetaminophen (paracetamol) is an effective analgesic and antipyretic agent, and in critically ill patients, is often used as an adjunct to opioid analgesics [7,9,45,55-62]. As a supplemental agent after surgery, intravenous acetaminophen decreases the total dose of morphine [62,63] or NSAID [64], 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 [63]. (See "Nonopioid pharmacotherapy for acute pain in adults", section on 'Acetaminophen'.)
●Patients with severe burns or postoperative pain inadequately controlled with opioids (ketamine) – In critically ill patients with burns or significant postoperative pain (eg, thoracic, upper abdominal, major orthopedic operations), ketamine administered as a low-dose infusion (ie, ≤2.5 mcg/kg/minute) typically facilitates reduction in total opioid dose for pain relief [65-67]. (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 (ketamine or dexmedetomidine) – Patients who develop tolerance, withdrawal symptoms, or opioid-induced hyperalgesia may also benefit from addition or substitution of ketamine as an analgesic agent [68-70]. Dexmedetomidine is occasionally used to help manage opioid withdrawal [71]. (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal", section on 'Discontinuation'.)
●Patients with moderate acute pain (NSAID) – A NSAID (eg, ibuprofen or ketorolac) is an option for some patients with moderate acute pain [45]. However, NSAIDs should be used cautiously in those with renal dysfunction, active 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 conditions, the use of NSAIDs in the critical care setting is uncommon. (See "Nonselective NSAIDs: Overview of adverse effects".)
●Patients with neuropathic pain (gabapentinoids or carbamazepine) – For critically ill patients with neuropathic pain (eg, Guillain-Barré syndrome [72-75], diabetic peripheral neuropathy, spinal cord injury, postherpetic neuralgia, fibromyalgia) [9,28,76], we often administer oral gabapentinoids (gabapentin or pregabalin) or carbamazepine, either as the sole analgesic agent or as a supplement to opioid analgesia (ie, as a component of multimodal analgesia) [9,45,77]. Gabapentinoids are generally first-line agents for neuropathic pain while carbamazepine is less effective and used when patients are gabapentinoid-intolerant [74].
●Patients at risk of developing chronic pain syndromes (ketamine, gabapentinoids) – Ketamine [78,79], as well as gabapentin and pregabalin [80], may help prevent chronic postsurgical pain. Risk factors for developing chronic pain are multifactorial, including the type of surgery (amputations, thoracotomies), pre-existing chronic pain conditions, younger age, female sex, and higher acute postoperative pain scores [81]. (See "Chronic postsurgical pain in adults: Incidence, risk factors, and potential risk reduction".)
Nonpharmacologic techniques — We also use nonpharmacologic techniques in most patients to maximize comfort and reduce the need for pharmacologic agents. Examples include:
●Reassurance.
●High-quality sleep (eg, purposefully reducing external stimuli including noise, artificial lighting, and unpleasant ambient temperature).
●Cognitive therapies such as relaxation techniques, massage therapy, and music therapy [9,28,45,82-86].
●Cold therapy (eg, cryogenically condensed, ice packs, ice water baths, and ice towels to cool the surface or deep layers of the skin) [87].
In some instances (eg, mild pain), such approaches may be adequate and may decrease the stress and anxiety that can exacerbate pain [88]. However, in many instances, supplementation with pharmacologic agents is still needed.
Data to support such therapies are provided separately. (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal", section on 'Nonpharmacologic approaches'.)
Use of regional anesthesia — Regional analgesia techniques (eg, neuraxial or peripheral nerve block) are rarely initiated in the ICU for pain management. However, if neuraxial or regional block techniques were initiated in the operating room, continuous perineural infusion of local anesthetic is typically beneficial as a component of multimodal analgesia. Management of postoperative pain with these techniques is discussed in detail elsewhere:
●(See "Approach to the management of acute pain in adults", section on 'Regional anesthesia techniques'.)
●(See "Continuous epidural analgesia for postoperative pain: Technique and management".)
Choosing route and method of administration
●Route of administration
•Intravenous – In critically ill patients, we prefer intravenous agents to ensure efficacy [9], since GI absorption of medications is unpredictable.
•Oral – In patients who tolerate oral or feeding tube intake, we administer liquid formulations of oral analgesic agents. Furthermore, oral administration may be the only choice for patients receiving neuropathic pain medications such as gabapentin or pregabalin, or patients on intravenous "holidays."
•Subcutaneous or intramuscular – We infrequently use subcutaneous or intramuscular administration of medications since their absorption is erratic and potentially inadequate [45], particularly in patients with edema, regional hypoperfusion (eg, shock), or obesity.
•Transdermal – Transdermal administration of analgesics such as fentanyl or lidocaine is inappropriate for the management of acute pain because the peak effect is delayed until 12 to 24 hours 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.
●Continuous infusions 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) [89].
For opioid analgesics, specific options include the following [28]:
•Mild or moderate acute pain (bolus intravenous injections) – We use scheduled intermittent bolus intravenous injections of opioids to control moderate nonneuropathic pain and nonopioids for mild nonneuropathic pain. Subsequent doses are titrated, and the response assessed. Scheduled oral agents may be needed for neuropathic pain.
•Procedure-related pain – Pre-emptive analgesia for a painful procedure such as dressing changes, ambulation, arterial or central line insertion, or bronchoscopy may be managed with an intravenous bolus dose (typically an opioid) administered just before the procedure, with additional doses during the procedure if needed.
•Poor control of pain with intermittent bolus doses in a sedated patient – We use continuous intravenous infusions of opioids in patients with ongoing pain that is not resolving rapidly or 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 'Adverse effects of opioid analgesics' below). If needed, supplemental bolus doses are administered.
•Patient-controlled analgesia (PCA) in an awake patient – PCA may be used in conscious patients for control of postoperative or other rapidly resolving pain [45,90]. 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. (See "Use of opioids for acute pain in hospitalized patients", section on 'Patient controlled analgesia'.)
•Patients weaning from opioid infusions – During weaning, we may use a scheduled oral opioid (eg, oxycodone or longer-acting agent such as methadone), or intermittent as needed intravenous bolus dosing with longer-acting opioids (eg, hydromorphone) for breakthrough pain or symptoms of withdrawal.
OPIOID ANALGESICS
Properties of opioid analgesics
Hydromorphone — Hydromorphone is a semisynthetic morphine derivative. Hydromorphone is 5 to 10 times more potent than morphine. 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.
●Onset – Hydromorphone has a more rapid onset of analgesia (5 to 10 minutes) than morphine.
●Dosing – Recommended doses of hydromorphone are presented in the table (table 4). Doses are titrated to the desired effect and patients are monitored closely for adverse effects.
●Pharmacokinetics – Hydromorphone has a shorter half-life than morphine (one to three hours). It 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 [91].
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. Fentanyl is about 100 times more potent than morphine as an analgesic. Its role in the palliation of dyspnea is unclear.
●Onset – Compared with morphine, fentanyl has faster onset of action (one to two minutes) 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.
●Dosing – Recommended doses of fentanyl are presented in the table (table 4). Typically, fentanyl is administered as a continuous intravenous infusion. Doses are titrated to the desired effect, with close monitoring for opioid-associated adverse effects. Alternatively, intravenous boluses may be administered every 30 to 60 minutes, although this method is less convenient and may allow breakthrough pain to occur.
●Pharmacokinetics – Fentanyl is highly lipophilic, with rapid distribution to highly perfused tissues (eg, brain, heart, kidney, and gastrointestinal [GI] tract) and a slower redistribution to muscle and fat [92]. 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'.)
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, especially during weaning from mechanical ventilation [93-95] and as an alternative to other opioids to alleviate high-dose opioid-induced hyperalgesia (OIH) [68]. Methadone is also used for acute pain management in patients previously taking methadone for opioid use disorder [96]. (See "Management of acute pain in patients with opioid use disorder", section on 'Continue methadone'.)
●Onset – Onset is in 10 to 20 minutes.
●Dosing – Dosing of methadone depends upon its indication and the amount of opioid ingested daily. In an opioid naïve patient, it can be started at 2.5 to 5 mg orally every 8 to 12 hours as intermittent doses. Individual doses up to 10 mg are rare. Methadone is not administered by continuous infusion. Dosing adjustments may be needed for those with severe renal failure.
Further dosing should be guided by clinical symptoms and the QTc interval, which is prolonged by methadone and can lead to torsades de pointes, a life-threatening cardiac arrhythmia [97]. We document the QTc on electrocardiography (ECG) before and at least every 8 to 12 hours after initiation or increasing the dose of methadone or addition of other QTc prolonging drugs [98]. If QTc prolongation is observed, we document more frequent measurements by telemetry or ECG. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)
●Pharmacokinetics – Complex, context-specific pharmacokinetics make dosing challenging. The half-life is about 30 hours, but is highly variable (range 8 to ≥59 hours), and accumulation occurs with repeated doses, particularly in patients with hepatic and/or kidney impairment and in those with concomitant CYP2B6 inhibitors [99-101].
Methadone is metabolized by the liver and can cause inhibition of serotonin and norepinephrine reuptake in the brain.
Morphine — Morphine is an effective analgesic and is also widely used in the critical care setting for the palliation of dyspnea. However, it has histamine-releasing properties and is, therefore, not generally used in patients with hemodynamic instability or bronchospasm. (See "Assessment and management of dyspnea in palliative care", section on 'Opioids'.)
●Onset of action – Onset of analgesia is 5 to 10 minutes, with the peak effect occurring in one to two hours.
●Dosing – 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.
●Pharmacokinetics – 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 the accumulation of an active metabolite (morphine-6-glucuronide), which also has mu-receptor-stimulating properties (table 1) [102]. Thus, dose adjustment is necessary in patients with impaired renal function (creatinine clearance less than 30 mL/minute) to avoid oversedation and respiratory depression [103].
Remifentanil — Remifentanil is an ultrashort-acting fentanyl derivative with similar analgesic potency 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 intensive care unit [ICU] or if frequent neurologic assessments are necessary) [104-106].
●Onset – Remifentanil has a rapid onset of action (<3 minutes) and short duration of action (5 to 10 minutes after cessation of infusion).
●Dosing – Remifentanil is administered as an infusion; recommended doses are presented in the table (table 4).
●Pharmacokinetics – Remifentanil is metabolized by nonspecific plasma esterases to inactive metabolites. Potential advantages include its lack of accumulation in patients with renal and/or hepatic dysfunction.
Despite its advantages (rapid onset and offset, potency), a 2009 meta-analysis in 1067 critically ill adult patients found that use of remifentanil did not reduce adverse outcomes compared with other analgesic agents (eg, agitation, duration of mechanical ventilation, length of ICU stay, or mortality risk) [107]. Its use is limited in the United States due to concerns of tachyphylaxis, cost, and possible hyperalgesia after discontinuation [51-54].
Adverse effects of opioid analgesics — We assess critically ill patients daily for the adverse effects of opioids (table 7). The identification and management of these complications are largely discussed in the linked topic sections. ICU-specific detail is discussed in this section.
●Depression of consciousness – Critically ill ventilated patients are often receiving more than one sedative (see "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal", section on 'Combination therapy'). Thus, in patients with depressed consciousness, it can be difficult to distinguish the contribution due to opioids. Initially, we typically attempt to reduce the dose of all sedatives first (especially benzodiazepines), before reducing doses of agents with primarily analgesic effects. Other strategies including implementation of a multimodal approach to analgesia or opioid change to a longer-acting oral opioid agent (eg, methadone, extended-release oxycodone, extended-release morphine sulfate) are discussed elsewhere. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Somnolence and mental clouding'.)
●Depression of respiratory drive – Patients receiving combinations of opioid and sedative medications are most vulnerable to adverse consequences of respiratory depression. However, depression of respiratory drive may not be clinically evident in patients who are mechanically ventilated until patients are weaned from mechanical ventilation or undergo a spontaneous breathing trial.
We minimize or avoid oversedation by using daily sedative interruption trials and/or protocols that encourage the lowest effective sedative dose. The goal should be to use the minimally effective dose to achieve pain control. Strategies are discussed separately. (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal", section on 'Avoiding oversedation'.)
Our strategy to reverse excessive opioid dosing is as follows:
•In a mechanically ventilated patient with obtundation suspected to be due to opioid toxicity, we hold or reduce the opioid dose without administering naloxone.
•For a spontaneously breathing patient, we hold or reduce the opioid dose. Naloxone is reserved for progressive obtundation or marked bradypnea <8 breaths/minute or apnea:
-For patients with bradypnea, naloxone is initially administered in small 0.04 mg intravenous bolus injections of dilute solution (prepared 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 breaths/minute. Being fully awake is not the target.
-For patients with apnea, we perform bag-mask ventilation and administer higher initial doses of intravenous naloxone (eg, 0.2 to 1 mg). We continue bag-mask ventilation until opioid-induced respiratory depression resolves or the trachea is intubated for mechanical ventilation.
Notably, after administration of naloxone at higher doses, sudden reversal of pain control may occur with associated tachycardia, hypertension, and pulmonary edema. These risks are balanced against the benefits of reversal of opioid overdose. Further details for managing opioid-related respiratory depression are provided separately. (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Prevention and management of adverse opioid effects' and "Acute opioid intoxication in adults", section on 'Management'.)
●Hypotension – Hypotension is more common in hypovolemic patients, especially following bolus injection, and is more common with morphine than other opioids. In patients at risk for hypotension, we reduce the opioid dose and administer a bolus dose slowly (ie, over one to three minutes). If hypotension develops, temporary fluid and/or vasopressor support may be necessary.
●Nausea and vomiting – Sedated patients in the ICU may not complain of nausea, and vomiting may not be evident 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.
In awake critically ill patients, treatment of nausea and vomiting is similar to treatment in postoperative patients, initially with intravenous bolus doses of ondansetron 4 mg. Subsequent treatment details are available elsewhere. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Nausea and vomiting' and "Postoperative nausea and vomiting".)
●Ileus and constipation – Opioids contribute to ileus and constipation in critically ill adults [108]. Strategies to minimize or prevent these side effects include prophylactic laxatives and the implementation of multimodal analgesic techniques to reduce opioid dosing. If ileus is severe and opioids are used for sedation rather than analgesia, we may discontinue the continuous infusion completely and use a different sedative. Management of opioid-related ileus and constipation with laxatives is 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".)
●Hallucinations and delirium – Opioid-induced delirium in the ICU may be dose-dependent and difficult to distinguish from other etiologies of delirium, which is common in critically ill patients [39].
If opioid-induced hallucinations are suspected, management is similar to that for patients with chronic opioid use. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Opioid-induced delirium'.)
●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 morphine, while fentanyl and remifentanil release little histamine [109,110].
●Peripheral vasodilation – Due to central and peripheral vasodilatory effects, opioids may increase the volume of fluid needed during resuscitation after burn injury or major trauma (see "Anesthesia for adult trauma patients", section on 'Administration of high-dose opioids') [111]. Reduced doses or alternative analgesic medications can be used in such cases [112].
●Urinary retention – Urinary retention may be severe enough to necessitate insertion of a bladder catheter. This depends on the patient symptoms, length of time since last void, and whether bladder volume is increased, as estimated with an ultrasonic scanner (typically, >300 mL). Details regarding the management of urinary retention are provided separately. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Urinary retention' and "Acute urinary retention".)
●Pruritus – Presentation and management of opioid-induced pruritus are discussed elsewhere. (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 [113-115]. 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 [114].
●Effects on the immune system – Opioid effects on the immune system are unclear and should not influence the choice of analgesics for critically ill patients [116]. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Infection risk'.)
●Drug interactions – Numerous drugs used commonly in the ICU have the potential to interact with opioids.
•Central nervous system (CNS) and respiratory depressants (eg, benzodiazepines) enhance the CNS and respiratory depressant effect of opioids in a synergistic fashion [117]. Conversely, CNS stimulants (eg, methylphenidate) decrease the CNS depressant effect of opioids.
•Other drug interactions are related to the metabolism of opioids via CYP3A4. As examples, the azole antifungals (eg, fluconazole, itraconazole, posaconazole, ketoconazole, voriconazole) and the macrolides and related antibiotics (eg, clarithromycin, erythromycin) may prolong fentanyl activity by inhibiting CYP3A4. The rifamycins (eg, rifampin, rifabutin) may decrease the serum concentration and effects of opioids. Interactions can be identified by using UpToDate Lexidrug. The presence of an ICU-specific pharmacist during daily rounds can help increase awareness of these interactions. (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal", section on 'Role of the pharmacist'.)
●Tolerance, withdrawal – These adverse effects are more likely to develop after prolonged or high daily dose opioid administration:
•Tolerance – Patients who receive prolonged or high daily opioid doses typically develop tolerance (ie, higher doses required over time for the same effect). Treatment options include supplementation with nonopioid analgesics (eg, ketamine [69,70]) 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 [114]. (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 [71,118]. Classic symptoms may occur due to rebound increases in neurotransmitter release (eg, sweating, vomiting, lacrimation, hypertension, fever, and anxiety) (table 8), although these symptoms may be attributed to other disorders in critically ill patients [118,119].
Weaning strategies and treatment of opioid withdrawal are discussed separately. (See "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal", section on 'Discontinuation' and "Opioid withdrawal in adults in the emergency setting" and "Opioid withdrawal: Medically supervised withdrawal during treatment for opioid use disorder".)
●Opiate-induced hyperalgesia (OIH) – OIH is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain becomes more sensitive to certain painful stimuli. The diagnosis and treatment of OIH are discussed separately. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Opioid-induced hyperalgesia'.)
NONOPIOID ANALGESICS —
One or more intravenous nonopioid analgesic agents are frequently employed as primary therapy for mild pain control (nonneuropathic or neuropathic) or as part of a multimodal approach in those with moderate or severe pain (see 'Multimodal analgesia' above). Adding these agents may allow the reduction or elimination of opioids and opioid-related adverse effects.
Acetaminophen — Acetaminophen is commonly used in the intensive care unit (ICU) to treat mild pain or as an adjunct to opioids for the treatment of moderate to severe pain.
●Onset – The onset of action is 30 to 60 minutes for oral agents, 5 to 10 minutes for intravenous agents, and variable for rectal administration.
●Dosing – 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). Acetaminophen is contraindicated in patients with severe hepatic insufficiency or severe progressive liver disease. Patients with severe renal insufficiency (eg, creatinine clearance ≤30 mL/minute) may receive the standard dose, but not more often than every six hours.
●Pharmacokinetics – Acetaminophen is primarily metabolized in the liver and excreted by the kidneys, with less than 5 percent unchanged.
Adverse effects are few when taken in appropriate doses. However, several studies have reported hypotension (systolic blood pressure ≤90 mmHg or ≥20 percent decrease from baseline) associated with parenteral acetaminophen compared with enteral administration [120,121]. (See "Nonopioid pharmacotherapy for acute pain in adults", section on 'Acetaminophen'.)
Ketamine — Ketamine is an analgosedative that is occasionally used to help manage opioid tolerance, withdrawal, hyperalgesia, or neuropathic pain [68-70,122]. Recommended doses are presented in the table (table 4). The pharmacokinetics and adverse effects of ketamine are discussed separately. (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Ketamine'.)
Dexmedetomidine — Dexmedetomidine is also an analgosedative that is commonly used as an adjunct for postoperative analgesia and sedation in the ICU. Infusion doses for dexmedetomidine are presented in the table (table 4). Pharmacokinetics and adverse effects are discussed separately. (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Dexmedetomidine'.)
Nonsteroidal anti-inflammatory drugs (NSAIDs) — 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 [9,45]. These include (see "Nonselective NSAIDs: Overview of adverse effects"):
●Dosing onset and duration of action – Recommended doses, onset, and duration of action for oral or intravenous ibuprofen and intravenous ketorolac are presented in the table (table 4).
●Pharmacokinetics – NSAIDs are primarily metabolized through the kidney and regular use should be avoided in patients with kidney insufficiency.
●Adverse effects – Adverse effects include gastropathy and gastrointestinal (GI) bleeding, platelet dysfunction, kidney insufficiency, bronchospasm, and pulmonary edema.
Gabapentinoids — Patients who are chronically receiving gabapentin or pregabalin before ICU admission may benefit from continued administration for analgesia. These agents are gamma-aminobutyric acid (GABA) analogs that 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, anti-inflammatory actions, and influence on the affective component of pain [123]. They are primarily used to treat neuropathic pain.
●Onset – Both gabapentin and pregabalin are available only as oral medications. The onset of action is variable and may take several hours to days before the full effect is felt by the patient. Titration occurs over several weeks.
●Dosing – Recommended doses of gabapentin are presented in the table (table 4). Dose adjustment is necessary in patients with kidney insufficiency.
●Adverse effects – Although gabapentinoids are generally well-tolerated, common dose-related adverse effects include somnolence, dizziness, ataxia, peripheral edema, weight gain, and confusion. Notably, combinations of gabapentinoids with other central nervous system (CNS) 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]) [124]. Both agents have a low risk of drug interactions.
Further information regarding gabapentinoids in the treatment of chronic pain is provided separately. (See "Overview of pharmacologic management of chronic pain in adults", section on 'Gabapentin and pregabalin'.)
Carbamazepine — Carbamazepine is an oral anticonvulsant that has been used to treat neuropathic pain in trigeminal and glossopharyngeal neuralgia, and in Guillain-Barré syndrome. It is less effective than the gabapentinoids. However, we consider using carbamazepine as part of a multimodal pain regimen when there is intolerance of gabapentinoids [74].
●Onset – Peak plasma levels of the immediate release form are reached within four to five hours, compared to 12 hours with the extended-release tablets.
●Dosing – Initial doses are 200 to 400 mg/day in 2 to 4 divided doses with gradual titration over several weeks. The dose is decreased by 25 percent if creatinine clearance is <10 mL/minute.
●Adverse effects – Adverse effects include nausea, vomiting, ataxia, dizziness, and drowsiness. A rare but serious adverse effect is Stevens-Johnson syndrome (SJS). (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
Further information is provided separately. (See "Overview of pharmacologic management of chronic pain in adults", section on 'Other antiseizure medications'.)
AGENTS TO AVOID —
Agents to avoid include the following:
●Certain opioids – Several opioids are typically avoided because of specific safety concerns and/or lower potency. These include:
•Meperidine – A metabolite of meperidine, normeperidine, has neurotoxic effects (eg, delirium and seizures). Although occasionally used to treat postoperative shivering (see "Perioperative temperature management", section on 'Prevention and treatment of shivering'), meperidine is especially avoided in patients with renal insufficiency because normeperidine is renally excreted. Furthermore, large doses of meperidine cause histamine release that may result in hypotension.
•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.
•Alfentanil and sufentanil – The short-acting intravenous opioids alfentanil and sufentanil are generally not used in critically ill patients because they do not offer advantages and may be more costly.
•Tramadol – Tramadol is avoided because it is a pro-drug that must be metabolized by CYP enzymes, which can interact with other medications, especially during critical illness.
•Opiate agonist-antagonists – In chronic opioid users or in patients who have received an opioid infusion for a prolonged period, opiate agonist-antagonists are avoided as they may precipitate withdrawal symptoms (eg, buprenorphine, butorphanol, dezocine, nalbuphine). Although these agents are long-acting, they may not produce sufficient analgesia due to ceiling effects.
Whether to continue buprenorphine in patients chronically taking this agent for opioid use disorder is somewhat controversial, and dependent on dose and indication [125]. (See "Management of acute pain in patients with opioid use disorder", section on 'Patients taking buprenorphine'.)
However, in patients without chronic or long-term use, preliminary data suggest that buprenorphine may have an analgesic effect similar to enteral or oral oxycodone [126].
●Other agents – Although intravenous lidocaine has been studied, there are scant data supporting its efficacy in controlling pain in critically ill patients [9].
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
●Pain assessment – Evaluation involves a general and formal assessment of pain with documentation of pain severity, response to medication, and development of any side effects. (See 'Pain assessment' above.)
•Patients who can communicate – Validated assessment tools include a numeric rating scale (NRS) such as the NRS Visual (NRS-V; our preference) (figure 5), a continuous visual analog scale (VAS) (form 1), or a verbal rating scale (VRS) (figure 6). (See 'Patients who can communicate' above.)
•Patients who cannot communicate – Validated pain-rating tools with pain-related behaviors and physiologic indicators include the Behavioral Pain Scale (table 2) or the Critical Care Pain Observation Tool (table 3). (See 'Patients who cannot communicate' above.)
●Goals – The primary goal of pain control is providing optimal patient comfort. Secondary goals include attenuating adverse physiologic responses to pain, preventing the development of chronic pain syndromes, and controlling anxiety and delirium. (See 'Goals of pain control' above and 'Overview of pain pathways' above.)
●Our approach – An "analgesia-first" (treat pain before administering a sedative) or "analgesia-based" (use an opioid instead of a sedative to reach the sedation goal) approach is often used. (See 'General approach of analgosedation' above.)
•Moderate to severe nonneuropathic pain – For most critically ill patients with moderate to severe nonneuropathic pain (ie, most patients in the intensive care unit [ICU]), we suggest an intravenous opioid (eg, fentanyl, hydromorphone, morphine) rather than other agents, using the lowest effective dose (Grade 2C). This approach is based upon limited and indirect data in patients in whom opioids were administered for periprocedural pain demonstrating improved pain scores but at the expense of adverse effects such as respiratory depression. (See 'Moderate to severe nonneuropathic pain' above.)
Other considerations include the following:
-Multimodal approach – To minimize the adverse effects of opioids, a multimodal approach that combines opioids with other nonopioid agents (table 4) and/or adjunctive nonpharmacologic therapies is typically used (eg, reassurance, relaxation, music, massage, good sleep hygiene). Multiple agents from the same class are not used. (See 'Multimodal analgesia' above.)
-Choosing an agent – There is no ideal opioid for all critically ill patients (eg, morphine, fentanyl, remifentanil, hydromorphone, methadone) (table 4). Selection of a specific opioid agent (typically an intravenous agent) in this population depends upon the desired onset and duration of analgesic action, as well as potential adverse effects of or contraindications to the agent (table 5). (See 'Choosing an opioid' above.)
•Mild nonneuropathic pain – For those with mild nonneuropathic pain, we suggest a trial of nonopioid agents rather than opioids (Grade 2C). In the spirit of multimodal analgesia, nonpharmacologic approaches are often combined with nonopioid agents (eg, acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs] (table 4)). Agent choice is based on the etiology of the pain (table 6). This approach should result in adequate pain relief while avoiding the effects of opioids. (See 'Mild nonneuropathic pain' above and 'Choosing a nonopioid' above.)
•Neuropathic pain – For those with neuropathic pain, we suggest gabapentinoids or carbamazepine rather than other agents (Grade 2C). These agents better target the primary mechanism underlying neuropathic pain, although supplementary opioids may be needed. (See 'Neuropathic pain' above and 'Choosing a nonopioid' above.)
•Considerations for administration – Effectiveness of analgesic drugs may be improved by (see 'Choosing route and method of administration' above):
-intravenous 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
•Adverse effects of opioids – Opioids have the potential to induce depression of consciousness and respiratory drive, development of hallucinations, delirium, nausea and vomiting, ileus and constipation, urinary retention, hypotension due to peripheral vasodilation or histamine release, pruritus, and tolerance, withdrawal, or hyperalgesia. Furthermore, numerous drugs used commonly in the ICU have the potential to interact with opioids. (See 'Adverse effects of opioid analgesics' above.)
•Individual agents – Pharmacokinetic properties and adverse effects of individual agents are discussed in the linked sections:
-Hydromorphone – (See 'Hydromorphone' above.)
-Fentanyl – (See 'Fentanyl' above.)
-Methadone – (See 'Methadone' above.)
-Morphine – (See 'Morphine' above.)
-Remifentanil – (See 'Remifentanil' above.)
●Nonopioid analgesics
•Acetaminophen – (See 'Acetaminophen' above.)
•Ketamine – (See 'Ketamine' above.)
•Dexmedetomidine – (See 'Nonsteroidal anti-inflammatory drugs (NSAIDs)' above.)
•NSAIDs – (See 'Nonsteroidal anti-inflammatory drugs (NSAIDs)' above.)
•Gabapentinoids – (See 'Gabapentinoids' above.)
•Carbamazepine – (See 'Carbamazepine' above.)
●Agents to avoid – We avoid certain opioid agents including meperidine, codeine, alfentanil, sufentanil, tramadol, and opiate agonist-antagonist agents. Although intravenous lidocaine has been studied, scant data support its efficacy in controlling pain in critically ill patients. (See 'Agents to avoid' above.)
ACKNOWLEDGMENTS —
The UpToDate editorial staff acknowledges Karen J Tietze, PharmD, and Stuart McGrane, MBChB, who contributed to earlier versions of this topic review.
