Epidemiology of Pain in the ICU
Pain is common in the ICU, but is more difficult to assess than in acute care patients because of a common inability for critically ill patients to subjectively express pain. The inherent subjective nature of pain is well described by the International Association for the Study of Pain, which defines pain as an “unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”1 However, the inability to communicate pain does not mean it is not being experienced by the patient. In fact, it has been reported that the majority of critically ill patients (both medical and surgical) do experience pain1,2—which patients describe as a significant source of stress, if not the most significant source of stress during their ICU stay, even when asked 6 months later.3
In addition to an unpleasant experience, undertreated pain may have negative somatic and long-term consequences. The pain response increases plasma catecholamine levels, causing vasoconstriction, impaired tissue oxygenation, and increased myocardial oxygen demand. Pain can cause neuroendocrine activation resulting in a catabolism state, breakdown of muscle tissue, and impaired immune function, which can increase susceptibility to infection. In addition to acute anxiety and fear, acute pain is associated with chronic pain, posttraumatic stress disorder, and lower health-adjusted quality of life after ICU discharge.
Physiology and Anatomy of Pain
The pleiotropic effects of pain are due to the complicated processing of pain from stimulus to cerebral cortex. There are four described elements of pain processing:
1) Transduction. Noxious stimuli are converted to an action potential.
2) Transmission. Action potentials are conducted via afferent neurons.
3) Modulation. Afferent pain signals are altered by efferent neural inhibition via neurotransmitters, especially in the dorsal horn of the spinal cord or by augmentation via neuronal plasticity (eg, central sensitization).
4) Perception. Integration of afferent pain signals in the cerebral cortex.
Specific analgesic drugs and drug classes, which act at each of these four pathways, are presented in Table 16–1. Multimodal analgesic strategies are those considered to target more than one pathway simultaneously. Pain chronicization—a transition from acute pain to chronic pain—is a feared consequence of painful critical illness, and much research has addressed neuronal plasticity in this pathophysiology. Fortunately, therapeutic options have been developed to decrease the risk of this transition, and will be discussed further as follows (see Nonopioid Analgesics).
Table 16–1Specific analgesic drug classes and how pain signals are modulated. |Favorite Table|Download (.pdf) Table 16–1 Specific analgesic drug classes and how pain signals are modulated.
|Transduction ||Transmission ||Modulation ||Perception |
|NSAIDs ||Local anesthetics: ||Spinal opioids ||Parenteral opioids |
|Antihistamines ||Peripheral nerve blocks ||α2-Agonists ||α2-Agonists |
|Membrane stabilizing agents ||Epidural analgesia ||NMDA receptor antagonists (ketamine) ||Inhaled anesthetics |
|Opioids || ||NSAIDs || |
|Bradykinin and serotonin antagonists || ||CCK antagonists || |
|Topical anesthetics || ||K+ channel openers || |
| || ||NO inhibitors || |
Strategies for Pain Management
Techniques for appropriate pain management must be individualized to each patient, starting with an appropriate assessment of its severity. This assessment should be more detailed than a simple visual analog scale (VAS). If the patient is able to adequately communicate pain, the following should be assessed: site, onset and timing, quality, severity, exacerbating and relieving factors, response to analgesics, and assessment of pain with movement, breathing, and cough.
As mentioned earlier, critically ill patients may not be able to self-report, so behavioral assessments should be used. Based upon their psychometric properties (ie, reliability and validity), the Critical Care Pain Observation Tool and Behavioral Pain Scale are currently recommended for use in adults over other reported scales. It should also be noted that the use of vital signs as the sole surrogate for pain is strongly discouraged. Although more validation testing in certain patient populations who may fail to exhibit typical pain behaviors (eg, neurologically injured) is warranted, implementation of behavioral scales is associated with lower resource consumption—such as days of mechanical ventilation—and ICU length of stay (LOS).3
Opioids—Systemic opioids are traditionally the cornerstone of postoperative and critical care pain management. As shown in Table 16–1, opioids' sites of action affect 3 of 4 pain-processing pathways. Opioids act as ligands at G protein-coupled opioid receptors, namely, the μ (mu), δ (delta), and κ (kappa) receptors. These receptors are located peripherally, in the spinal cord dorsal horn as well as at various locations in the brain. Opioid receptors are located on primary afferent neurons and inhibit release of nociceptive substances, decrease neurotransmitter release in the spinal cord, and activate descending inhibitory neurons. The μ-receptor is thought to be responsible for much of the peripheral analgesia caused by opioid agonists. There are a number of opioid receptor subtypes that have been discovered and are expressed on a variety of different cells, some unrelated to the central nervous system (CNS) and peripheral nervous system (such as on leukocytes and vascular tissue). This broad expression of opioid receptors is likely because there are number of endogenous opioids. The complicated interaction and broad expression of opioid receptors has led to opioids being implicated in such diverse pathophysiology as increased rates of cancer recurrence and modulation of inflammation. Intensivists should, therefore, have an appreciation not only for the acute adverse effects of opioids (respiratory depression and sedation), but also more subtle, long-term effects of opioid therapy. For more information regarding specific opioids, see Table 16–2a and 16–2b.
Table 16–2aOpioid analgesics (adapted from Joffe et al6). |Favorite Table|Download (.pdf) Table 16–2a Opioid analgesics (adapted from Joffe et al6).
|Opioid ||IV Dose (mg) ||PO Dose (mg) ||Time to Onset ||Time to Peak Effect ||Duration of Effect ||Infusion Rate |
|Morphine ||5 ||15 ||< 5 min (IV), 30 min (PO) ||30 min (IV) ||3-4 h ||2-30 mg/h |
|Hydromorphone ||0.7 ||4 ||< 5 min (IV), 30 min (PO) ||30 min (IV) ||4-5 h ||0.5-3 mg/h |
|Fentanyl ||0.05 ||N/A ||Immediate ||< 5 min ||30-60 min ||25-300+ mcg/h |
|Remifentanil ||N/A ||N/A ||Immediate ||< 3 min ||< 10 min ||0.05-0.3 mcg/kg/h |
|Oxycodone ||N/A ||10 ||20-30 min ||< 1h ||3-4 h ||N/A |
|Methadone || ||(variable) ||10-20 min (IV), 30 min (PO) ||10-20 min (IV), 30-60 min (PO) ||3-6 h (longer with repeat dosing) ||N/A |
Table 16–2bOpioid analgesics (adapted from Joffe et al6). |Favorite Table|Download (.pdf) Table 16–2b Opioid analgesics (adapted from Joffe et al6).
|Opioid ||Elimination Half-Life ||Metabolic Pathway ||Active Metabolites ||Notes |
|Morphine ||1.5-2 h ||Liver: glucuronidation ||Morphine 6- and 3-glucuronide ||Histamine release may be important from a cardiovascular and pulmonary perspective. Caution in renal failure. |
|Hydromorphone ||2-3 h ||Liver: glucuronidation ||None ||Accumulation with hepatic dysfunction. |
|Fentanyl ||3-4 h ||Liver: N-dealkylation CYP3A4/5 ||None ||Significant increase in context-sensitive half-time with infusions >12 h. |
|Remifentanil ||10-20 min ||Plasma esterase hydrolysis ||None ||Abrupt discontinuation of analgesia. |
|Oxycodone ||3-4 h ||Liver: CYP2D6 ||Noroxycodone and oxymorphone || |
|Methadone ||8-59 h ||Liver: N-methylation CYP3A4, 2D6 ||none ||NMDA receptor-antagonist, unpredictable pharmacokinetics (risk for accumulation). Multiple drug–drug interactions. Can prolong QTc. |
The ideal method of opioid administration will vary considerably with the clinical context and include opioids by mouth or parenteral administration either via intermittent intravenous or via patient-controlled infusion pumps (PCA, patient-controlled analgesia). For patients requiring mechanical ventilation, bolus or continuous infusion of opioids can treat both pain and ventilator-associated anxiety.
PCA—For awake, alert patients with moderate to severe pain—most commonly postoperative patients—PCA is an appropriate choice. Before initiating a PCA order, the patient must be able to understand how to appropriately use the PCA apparatus. To determine the PCA prescription, the following parameters must be specified: (1) opioid, (2) incremental (or demand) dose, (3) lockout interval, (4) background infusion rate (if any), (5) 1- and 4-hour dose limits, and (6) bolus dose administration (for breakthrough pain). A reasonable starting prescription in an opioid-naïve patient would be morphine with an incremental dose of 1 to 2 mg, a lockout of 6 to 10 min, no continuous infusion rate, a 4-hour maximum dose of 30 mg, and a bolus dose of 2 to 4 mg every 5 min for 5 doses.
Although PCA has gained significant popularity for its ease of use, when compared to intermittent bolus opioids, outcome studies show mixed results. There is some evidence that patient satisfaction is improved, possibly because of the patients' increased sense of control over pain.4 In general, there seems to be little change in analgesic efficacy, with patients reporting similar VAS pain scores with PCA and intermittent IV bolus analgesia. For patients that are taking chronic opioids when treated with a PCA, total dose of opioid was thrice higher than patients not taking opioids previously.5 Interestingly, patients with opioid tolerance had increased rates of sedation compared with opioid-naïve patients, which suggests the therapeutic index for opioid-tolerant patients may be narrower than opioid-naïve patients.
Acetaminophen and Nonsteroidal Anti-inflammatory Drugs
Acetaminophen is a ubiquitous centrally acting cyclooxygenase inhibitor with a long history of use outside the ICU, but very little research has been applied to critically ill patients. Much of the research in non-ICU patients showed modest (but statistically significant) reductions in mild and moderate pain. The notable exception regards research studying the IV formulation of acetaminophen, which became available in the United States in early 2011. Pharmacokinetic studies showed increased plasma and cerebrospinal fluid levels of acetaminophen after IV administration compared with oral or rectal administration. Although studies results are mixed, decreased VAS pain scores, opioid side effects, and early extubation following major surgery have all been demonstrated with IV acetaminophen.6 Given the common scenario of treating patients in the ICU with moderate to severe pain and concern for impaired absorption from the gastrointestinal tract or when side effects of opioids are particularly harmful, IV acetaminophen may play an important role, but attention should be paid to the increased cost of the IV formulation.
Many acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are used in acute postoperative pain and pain associated with critical illness; these drugs work primarily though cyclooxygenase and prostaglandin synthesis inhibition. All are generally effective in decreasing moderate and severe pain in equal-analgesic doses, but their utility is limited by their side effect profiles. NSAIDs can indirectly cause constriction of the afferent renal arterioles and inhibit platelet function (both in clinically significant ways), so their use is relatively contraindicated in patients at risk for renal injury and significant bleeding.
Ketamine, historically used as an IV dissociative general anesthetic with hypnotic and analgesic properties, has been the subject of much research in the treatment of acute pain. Ketamine acts primarily though N-methyl-d-aspartate (NMDA) receptor antagonism, which plays an important role in pain modulation and prevention of the transition of acute pain to chronic pain. Prevention of pain chronicization is a particularly useful characteristic of ketamine, especially in those patients that are opioid tolerant, as evidenced by a randomized controlled trial (RCT) of patients undergoing spine surgery that showed reductions in pain scores at 48 hours and 6 weeks after ketamine versus placebo infusion intraoperatively.7 Ketamine also may reduce opioid-related side effects, including nausea and vomiting. Because analgesic adjunct doses of ketamine (0.05-0.4 mg/kg/h) are significantly smaller than anesthetic doses (1-3 mg/kg/h), psychomimetic reactions from ketamine are significantly less common at these doses, and only slightly more common than placebo. Other side effects of ketamine (sympathetic stimulation and salivation) are not usually observed with analgesic doses.
Lidocaine is a well-known sodium channel antagonist local anesthetic that also has antiarrhythmic, general anesthetic, and analgesic (both antinociceptive and antineuropathic) properties. It has been studied extensively in the perioperative setting as an IV infusion, with mainly mixed results. Cytokine levels decrease after lidocaine infusion, suggesting that inflammation causing nociceptive pain may be decreased. Lidocaine has also been shown to modestly decrease VAS scores, opioid requirements, and duration of postoperative ileus postoperatively.6 A recent study enrolling patients with complex spine surgery showed a significant improvement in subjective physical health months after surgery with lidocaine infusion versus placebo (a secondary outcome measure).8 Lidocaine has significant cardiac toxicity and his cleared by the liver, and therefore, should be used with caution in critically ill patients with hepatic dysfunction.
Gabapentin and Pregabalin
As with lidocaine and ketamine, the calcium channel blockers gabapentin and pregabalin have been useful in treating neuropathic pain. There is considerable research demonstrating increased analgesic efficacy of gabapentin as part of a regimen that also includes opioids in patients with chronic pain. There is also evidence for effectiveness in reducing opioid requirements and opioid-related side effects in patients with acute postoperative pain. Data supporting use of gabapentin and pregabalin in the ICU is limited, but a study evaluating patients with pain related to Guillain-Barre demonstrated decreased pain scores and opioid consumption in the ICU compared with placebo. In a meta-analysis of postoperative patients (not necessarily in the ICU) the number-needed-to-treat-to-benefit (NNT) to achieve 50% reduction in pain for gabapentin (NNT 11) is higher than that of naproxen (2.7), ibuprofen (2.5-2.7), or oral oxycodone 15 mg (4.6).1,9,10,11,12 The most common side effect of gabapentin is sedation, but this effect is relatively rare—number needed to harm was 35.7,13 Taken together, these data suggest gabapentin and pregabalin are safe and effective adjuncts in the treatment of pain in the ICU.
A summary of nonopioid analgesics is provided in Table 16–3.
Table 16–3Nonopioid analgesics. |Favorite Table|Download (.pdf) Table 16–3 Nonopioid analgesics.
|Drug ||IV or PO Dose ||Half-Life ||Metabolism ||Notes |
|Ketamine ||IV: 0.1-0.5 mg/kg bolus, then 0.05-0.4 mg/kg/h ||2-3 h ||CYP450: 2B6, 2C9, 3A4, urinary excretion ||Attenuates opioid-induced hyperalgesia, may decrease persistent postoperative pain |
|Acetaminophen ||IV/PO: 650-1000 mg q4-6 h (<4000 mg per day) ||2-4 h ||CYP450: 1A2, 2E1, urinary excretion ||Use caution in hepatic impairment |
|Ketorolac ||IV: 15-30 mg q6 h up to 5 days ||2.4-8.6 h ||CYP450. Less than 50% metabolized. 90% excreted in the urine, 6% in bile/feces ||Avoid use in patients with aspirin allergy. Caution with renal dysfunction, patients at high risk for bleeding, and in elderly patients. |
|Ibuprofen ||PO: 400 mg q 4 h ||1.8-2.5 h ||CYP450: 2C9, urinary excretion ||Same caution as with ketorolac, IV formulation also available. |
|Gabapentin ||PO: 100 mg TID, can titrate up to maximum dose 1800 mg/day ||5-7 h ||Minimal. Excreted intact in urine. ||May cause sedation. Abrupt discontinuation may cause seizures. |
|Pregabalin ||PO: 50 mg TID, may increase to 100 mg TID ||5.5-6.7 h ||Minimal metabolism (2%). Renally excreted. || |
|Lidocaine ||IV: 1.5 mg/kg loading dose, 1-2 mg/kg/h ||1.5-2 h ||Hepatic CYP450 (1A2 and 3A4), 10% unchanged in the urine ||Active metabolites may accumulate in hepatic or renal failure |
Regional Analgesia and Nonpharmacologic Techniques
Regional analgesia—targeted administration of local anesthetics and analgesics to certain anatomic locations—may have considerable advantage in the management in acute postsurgical and traumatic pain. Lower doses of medication can be delivered in a targeted fashion to decrease the risk of side effects of systemic delivery of medication, and analgesia is often significantly improved compared to IV opioids. In certain ICU scenarios regional analgesia should be considered: (1) thoracic epidural analgesia in open abdominal aortic aneurysm surgery and (2) thoracic epidural analgesia in traumatic rib fractures, especially in the elderly. Using thoracic epidural analgesia in both these scenarios is supported by clinical practice guidelines from the Society of Critical Care Medicine,3 and have improved clinical outcomes—mainly by decreasing respiratory complications.
Although data supporting regional analgesia as a means to reduce morbidity is limited, in a broader array of scenarios regional analgesia decreases VAS pain scores, decreases systemic opioid requirements, decreases opioid side effects (postoperative ileus and urinary retention), and it may improve patient satisfaction.6 In a recent meta-analysis, regional anesthesia decreased the incidence of persistent postoperative pain 6 months postsurgery after thoracotomy and breast surgery by two-thirds (odds ratio = 0.33, 95% confidence interval [CI]: 0.2-0.66).14
In addition to pharmacologic analgesic therapy, there are a variety of nonpharmacological analgesic techniques that may be helpful to patients. These techniques include music therapy, relaxation, therapy, family presence, distraction, massage, and deep breathing. Although empiric evidence of their efficacy is mixed and precludes high-level recommendations, their low cost and safety make them a valuable consideration within the context of a multimodal analgesia strategy in the ICU.