Pharmacologic Treatment Of Pain In The ICUGeneral Principles for Pain ManagementPain management is a requsite part of critical care for all ICU patients based on the motivation to attempt to relieve human suffering and to mitigate systemic physiologic affects engendered by untrated pain. Opiate therapy remains the dominant treatment in the armamentarium for pain therapy in the ICU. Amongst pharmacologic anesthetics, intravenous opiates have the most appropriate potency, absence of ceiling effect, and usually desirable mild sedative and anxiolytic effect that lead to their dominance in the ICU. Opiates, however, are not without adverse drug effects, including bowel complications, delirium, respiratory suppression and others. Non pharmacologic and adjuvant therapies also have a complementary role and should be considered in ICU care.Opiate Therapy

The objective of administering opiates in the ICU is to improve patient comfort and outcomes for critically ill patients. For those with substansial injury, massive surgeries, or severe illness requiring life-support, scheduled or continous intravenous infusions ae part of ussual care. For the patient who is not responding to therapy, consistent analgesia is certainly warranted in those who eventually die of their illness. For many ICU patients, however, opiate therapy may interfere with timely achievement of anticipated outcomes, even when other therapies are resulting in restoration of health. Opiates, like other medications administered for prolonged periodes, can manifest protracted durations of effect. Analgesia and sedation can persist for days to weeks after sustained infusions are discontinued, and it is common for patients with hepatic or renal desease to experience oversedation. Evidence-based therapeutic recommendations favor bolus dosing and daily interruption of sedative and analgesic medications, except for the dying and those with uncontrolled pain. For the most part, pain management in the ICU is based on data extrapolated from other settings, and even in existing Society of Critical Care Medicine (SCCM)/American Society of Health-System Pharmacists (ASHP) clinical practice ICU guidelines, no recommendations were based on high level or grade A evidence.

No specific agent has been demonstrated to be preferable in all ICU patients or across all clinical entities. Optimized agent and dosing is a patient-specific quality that is based on the therapeutic balance that pain is relieved without intolerable adverse effects. Selection of initial analgesic therapy should be based on individual patient characteristics and knowledge of prior opiate exposure, experience, and side effects, when available. Surveys and prospective surveillance studies indicate that morphine and fentanyl are widely used around the world. For agents like morphine, the intravenous pharmacokinetics include peak effectsat 30 minutes and an approximate duration of 2 hours, thus leading to bolus therapy at a frequency of every 30 to 60 minutes. Many critically ill patients metabolism are altered, however, which can substantially lengthen the duration of effect.

Morphine and hydromorphone have an active hepatic metabolite in a glucuronide form that accumulates during renal failure. Morphine-6-glucuronide has a half life greater than 12 hours, has been demonstrated to cross the blood-brain barrier, and has been associated with prolonged sedation after discontinuation of continous infusions. Caution is warranted in using these drugs in critically ill patients with renal and/or hepatic failure. Vasodilation, cardiovascular instability and bronchospasm from histamine release are additional side effects that can complicate ICU care. The histaminic response can be diffrentiated by associated rash or pruritis, response to antihistamines, and short duration (less than a week) if therapy is continued.

Fentanyl has shorter peak and duration of action and can be bolus dosed as often as every 5 minutes, but it has been shown to accumulate when given by continues infusion based on its lipophilic properties with half times reported as lasting weeks after steady-state infusion. Fentanyl may produce less hemodynamic instability than other opiates but has a unique side effect of muscle rigidity that appears dose-related.

Remifentanil is a selective mu-opioid receptor agonist aproved for use in anesthesia induction and maintenance that may have advantageous properties for ICU care. The novelty in this agent, in contrast to fentanyl, is that remifentanil is metabolized by multiple ubiquitous esterases and its half-life is not known to be protected by critical illness nor organ dysfunction. Due to its pharmacokinetic properties, this agent has a terminal half-life of less than 30 minutes and may reduce the incidence of prolonged sedative complications seen with continuous infusions of other opiates. Preliminary work demonstrates shorter periods of mechanical ventilation when this agent is used over other opiates in short-term studies. The agent may adversely produce bradycardia and hypotension, however, which limits it widespread use in the ICU. The agent has been used in traumatic brain injury and neurosurgical settings with favorable effects on neurologic function assesment and a dose-dependent reduction in coughing associated with endotracheal suctioning. Concern remains, however, that the fast offset of this agent may lead to withdrawal and agitated behavior.

Other agents may have a role in the ICU, but many posses properties that limit utility in critical care settings. Meperidine is asscosiated with neuroexcitation due to a metabolite, normeperidine. Meperidine has been used in the short term for shivering associated with general anesthesia or to abate drug-induced rigors. It should never be given for more than 1 day or at a cumulative dose over 600 mg in a renal competent patient. Codein by itself needs conversion to morphine for activity but a proportion of the population lack the enzymatic mechanism. Oxycodone is pharmacologically similar to morphine but only available in oral preparations.

Methadone has many advantages in the non-ICU setting over other agents for the management of chronic pain. However, the oral requirement, slow titration to steady-state, and variable potency limits its utility in the initial unstable period that most ICU patients experience. Methadone is advantageous in those with prior pain syndromes, is inexpensive, and may be preferabe for complex pain syndromes due to its N-methyl-D-aspartate antagonism. Methadone can increase the QTc and has been associated with dysrhytmias.

Dosing and frequency are based on providing sufficient and frequent opiates to control underlying and breakthrough pain as well as anticipated prevention from interventions. Reassesment and titration are essential skills for pain management. Patients will have individualistic responses to different opiate medications that can not be predicted based on underlying characteristics and suggest a role for switching between agents to minimize adverse effects. Changing agents requires skills in equianalgesic dose. Equianalgesic dosing may be estimated by the use of tables, but in general should be decreased in the agent, espesially in the critically ill. When changing agents, the sum of administered opiates for the prior 24 hour period can be converted to 50% to 80% of the new agents equivalent dose and then dosed as a continuous infusion or at intervals. Rotation of agents during protracted courses of treatment or combination therapy with different opiates may minimize untoward effects and optimize efficacy.

Many critically ill patients suffer from chronic progressive diseases and thus do not present opiatenaive to the ICU. Particular care must be taken to avoid withdrawal syndromes and the physiologic consequences that can complicate ICU management. Recognition of withdrawal is crucial to avoid overtreatment with sedative or hypotic agents. Physical and physiologic dependence can be predicted, and ICU practicioners need to anticipate its aoccurence with regular use of opiates, either in the pre-ICU care or during prolonged ICU stays. Acute withdrawal has been shown to occur in ICU patients treated with opiates for greater than a week and may present within 6-12 hours after discontinuation of opiates. The opiate withdrawal syndrome can include sweating, discomfort, agitation, lacrimation, diarrhea, tachycardia, and rebound pain. These symptoms, however, may be blunted in the critically ill patient or in those with concomitant use of sedating medication.

In titrating opiates in those with chronic pain, a breakthrough dose should be provided with a sustained or continuous basal administration. In general, the breakthrough dose can be approximated as 10% to 20% f the 24 hour total opiate requirement. For example, an ICU patient requiring 100 mg of sustained release oral morphine every 12 hours should have 20-40 mg of oral morphine available every 1-2 hours or 7-14 mg of intravenous morphine available every 30-60 minutes. Breakthrough doses may also be titratedevery 30 minutes and by as much as 50% to 100% in subsequent doses if the initial dose did not provide sufficient relief. When increasing opiate needs are sustained, the total daily dose should be adjusted by calculating 24 hour needs and administering approximately 80% of the daily dose as a basal rate for those with stable syndromes.

For the less severly ill and especially post operative patients in the ICU, patient-controlled anesthesia (PCA) is often appropriate. In the immediate post insult period, PCA typically includes three methodes of delivering intravenuous opiates: a patient-controlled dose that is given on demand using short loskout periods for breakthrough pain, a basal or continuous infusion for patients with higher initial needs or prior tolerance from pre-existing opiate use for chronic pain, and the potential for professional care giversto administer a provider-controlled bolus as needed. Side effects and total dosage is ofen reduced with PCA and, as a result, less sedation and respiratory depression is experienced.

Nonintravenuous administration of opiates is appropriate for some patients in the ICU. A subcutaneous infusion may be beneficial for rare patients, ussually those at the end of life following the withdrawal of invasive measures and is dosed similarly to intravenuous opiates. In general, the sublingual, buccal, or rectal routes are less desired as palliation can be inconsistent and side effects are increased. The transdermal route is an option for continuous basal opiate therapy, but is lessdesirable in the ICU, especially early in illness where decreased or variable perfusion may convolute stable absorption. The oral route is ideal for ongoing pain when critical illness is resolving but is often inconsistent early in the ICU process with enteral absorption often compromised.

Epidural routes are advantageous in the postoperative patient and have advantages in reducing systemic side effects. For many ICU patients, however, the safe placement and maintenance of epidural anesthesia is limited. When considering analgesia, as in most therapies administered in the ICU, dosing should be responsive to moment-to-moment experiences of pain and proactive in prevention or preemptive treatment of anticipated pain. For example, dosing an opiate at a time interval just shorter than the peak onset is appropriate before painful dressing changes or other planned procedures. The ICU patient often manifests clinical variability and instability that requires frequent intervention, including responsiveness to pain therapy and dosing adjustments based on hemodynamic and metabolic derangements.

In general, there is no upper limit in opiate dosage, and titration si based on pain levels, the patients tolerance and adverse effects. Note that for many nonopiate analgesics, toxic metabolites limit this dosing strategy and thus are not the the preferred agent to begin treating pain in the ICU. All patients should be anticipated to have predictable and manageable adverse effects with opiate use.

All opiates stimulate intestinal mu receptors and result in dysmotility and constipation. This activity and resultant constipation do not seem to be lessened over time with continued treatment. Thus, prophylaxis with stimulant medications combined with stool softener is appropriate. In the ICU, where enteral routes are not completly compromised, these agents should be administered with the first dose of opiates and titrated to loose stools. Obstipation is not infrequent and requires a digital rectal exam prior and disimpaction before beginning more aggresive bowel routines.

Other common adverse effects of opiate administration include sedation, myoclonus, nausea, and physiologic dependence. Additionally, opiates may have immunomodulating properties that could be worrisome in the ICU where infectious complications are common. Nausea and emesis are ussually due to stimulation at the chemoreceptor trigger zone, vestibular apparatus, or direct gastrointestinal effects. Antiemetics may be indicated, but the magnitude of this effect often diminishes with continued use. Myoclonus is occasionally seen when high doses of opiates are required and may be tempered by benzodiazepines, neuroleptics, or coadministration of multiple lower dosages of single agents.

Various opiates may produce reactions of varying intensity and types. If adverse effects are intractable and limit appropriate pain management, changing agents or using adjuvant therapies may be advantageous. Sedative side effects of opiates may be desirable when caring for mechanically ventilated patients. Sedation can be minimize, however, by aggresive use of nonopiates and nonpharmacologic agents as well as concurrent administration of central stimulants, such as dextroamphetamine and methylphenidate. Care must be taken to avoid withdrawal reactions once physiologic dependence has developed. Naloxone may be required in some situations where respiratory insufficiency in the spontaneuosly breathing patient is suspected to be caused by opiates. When used, naloxone should be dosed judiciously and slowly to avoid precipitating withdrawal.

Drug therapy in the ICU is subject to alterations in volume status, plasma protein binding, end-organ dysfunction, and seultant disturbances in bioavailability, clereance, volume of distribution and pharmacokinetics that, especially for opiate medication, can manifest in protracted durations of effect and other adverse effects. In the ICU, therapeutic drug monitoring does not generally apply to the predominant agents used for analgesia and, for the most part, dosing should be reduced and closely monitored for desired and adverse effects. Specific caution should occur with continuous intravenous dosing of morphine and hydromorphone in the presence of renal insufficiency, as active glucuronide metabolites can accumulate and increase the duration of undesired sedative complications. For the most part, altered pharmacokinetics in the ICU for analgesia and sedative medications are dealt with through proactive assessment and monitoring of clinical end-points