Two complex issues can preexist in a patient. Pain in Critically Ill Patients With Substance Use Disorder or Long-term Opioid Use for Chronic Pain

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1 AACN Advanced Critical Care Volume 22, Number 3, pp , AACN Pain in Critically Ill Patients With Substance Use Disorder or Long-term Opioid Use for Chronic Pain Debra J. Drew, RN-BC, MS, ACNS-BC Barbara J. St. Marie, RN-BC, ANP, GNP ABSTRACT Opioid tolerance resulting from long-term opioid consumption for chronic pain or from substance use disorder adds a layer of complexity to managing pain in the critical care setting. This article discusses similarities and differences of these 2 conditions. The phenomenon of tolerance and opioid-induced hyperalgesia are presented. Prevention of opioid withdrawal, when patients are on methadone or buprenorphine, is described. An overview of the neurophysiology of pain and substance use disorder is presented. Practical clinical suggestions are given to assist the critical care nurse in caring for these complex patients. Keywords: addiction, opioid-induced hyperalgesia, pain, substance use disorder, tolerance Two complex issues can preexist in a patient with pain in the critical care setting: One is an active substance use disorder and the other is the use of long-term opioid therapy for the treatment of chronic pain. These 2 issues, while similar in some ways, are also very different. Treating chronic pain with long-term opioid therapy does not constitute a substance use disorder. Yet there are some individuals who use opioids to sustain their substance use disorder. Managing pain in patients receiving long-term opioid therapy or suffering from substance abuse is a challenging and complex undertaking. Patients who are tolerant either from legitimate long-term opioid therapy or from a substance use disorder are often undertreated for pain due to clinicians lack of knowledge or unexamined biases. Every patient deserves the right to analgesia during an acute illness. There are times when opioids are the appropriate medication for moderate to severe pain. The compassionate and educated care of patients with substance use disorder or long- term opioid use for chronic pain will result in better outcomes and increased patient satisfaction. Untreated acute pain causes unnecessary suffering, prolongs hospital stays, increases medical costs, and may progress to chronic pain. 1(p5) Untreated pain can result in biologic and psychologic harm. Uncontrolled acute pain leads to tachycardia, increased myocardial oxygen consumption, hypercoagulability, and immunosuppression. 2 When we understand the risks of untreated pain, we can better advocate for more appropriate treatment of pain in the critical care setting. Debra J. Drew is Clinical Nurse Specialist, Pain Management, University of Minnesota Medical Center, Fairview, Minneapolis, MN (ddrew1@fairview.org). Barbara J. St. Marie is Supervisor, Pain and Palliative Care, Fairview Ridges Hospital, Burnsville, Minnesota. DOI: /NCI.0b013e318220c

2 VOLUME 22 NUMBER 3 JULY SEPTEMBER 2011 PAIN IN CRITICALLY ILL PATIENTS This article will provide an explanation of the neurobiology of pain and addiction that changes the brain in ways that affect arousal, emotion, motivation, perception, and learning. Assessment and treatment of pain in patients using opioids for long term either appropriately or inappropriately will be discussed. Prevention of opioid withdrawal, when patients are on methadone or buprenorphine, will be described. Finally, practical suggestions will be given for managing pain when tolerance or opioid-induced hyperalgesia is present. Interplay of Pain and Substance Use Disorder Little is understood about the augmentation of symptoms when pain and addiction coexist. The ambiguity of this phenomenon is cited as a barrier to providing quality care. 3-8 Research shows there is low provider satisfaction in providing health care in the population with coexisting addiction and pain. 4-8 Factors contributing to low satisfaction include ambiguity of care, lack of support from colleagues, lack of reimbursement for this type of work, and lack of training and mentorship. Researching pain and addiction is a mission that nurses are well positioned to advance. The prevalence data suggest that the rate of abuse of prescription pain relievers has nearly doubled between 1997 and 2002, and related overdose deaths have surpassed those of many street drugs, including heroin. 9 The National Prescription Drug Threat Assessment report 10 identified current opioid misuse and diversion as a public health threat. This is a problem that is growing and many of these patients require stays in an intensive care unit (ICU). A compassionate, confident, and caring approach to assessment and treatment of individuals with addiction or long-term opioid use will ease the pain and suffering of an acute illness. Definition of Key Terms The following terms are defined for the purposes of this article. They are commonly used in the clinical setting and in pain research. Terminology evolves over time within cultural context. New definitions are anticipated to be clearer with the publication of the future Diagnostic and Statistical Manual of Mental Disorders (DSM), Fifth Edition. The term substance use disorder is an overall category consisting of the terms substance dependence and substance abuse. The following definitions show similarities and differences with terms such as addiction, substance dependence, and substance abuse. The nuances between the terms explain why the terms are used interchangeably and therefore are misleading at times. The terms tolerance, physical dependence, addiction, pseudoaddiction, substance misuse, and aberrant drug-related behaviors are described to assist nurses in communicating consistent language as they care for individuals with the disease of addiction in the critical care setting. 11 The terms acute pain and chronic pain are used to help the nurse understand the timing of both types of pain as well as identify their characteristics when the patient presents to the critical care setting. Addiction is a primary, chronic, neurobiologic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include 1 or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. 12 The diagnosis of addiction is often made prospectively over time. 11 Substance abuse has similar characteristics as those of addiction. However, in the DSM-IV 13 there is the prerequisite of time; that is, behaviors are recurrent within a 12-month period. Substance dependence is a pattern of substance use leading to significant impairment. It is characterized by behaviors that include 1 or more of the following: tolerance, withdrawal due to physical dependence, substance use in larger amounts or longer periods of time than intended, and persistent desire for the substance. Aberrant drug-related behaviors are behaviors that suggest the presence of substance abuse or addiction, 14(p391) for example, parenteral use of an oral opioid, or repeated requests for early refill that reflect unsanctioned dose escalation. Pseudoaddiction is an iatrogenic syndrome created by the undertreatment of pain. 11 Behaviors that may appear to be suggestive of addiction resolve when pain is treated effectively. Diagnosis is made retrospectively [because with] appropriate management of pain, aberrant behavior is reduced or eliminated. 11,15(p848) Substance misuse is the use of any drug in a manner other than how it is indicated or prescribed 14(p391) ; for example, the use of opioid analgesic as a sleep aid or to treat anxiety, in the absence of pain. The term is not synonymous with addiction or abuse. Sometimes misuse is an innocent error as a result of misunderstanding the dosage, schedule, or purpose of a medication. 239

3 DREW AND ST. MARIE AACN Tolerance is a state of adaptation in which exposure to a drug causes changes that result in a decrease of 1 or more of the drug s effects over time, for example, analgesia or respiratory depression. Tolerance alone is not a sign of addiction. Physical dependence is an adaptation that is manifested by withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, or administration of an antagonist agent, for example, naloxone. Although physical dependence is 1 feature of chronic substance use, it does not mean that the patient is addicted to the substance. Acute pain is an adaptive, beneficial response necessary for the preservation of tissue integrity and survival. Acute pain has a predictable start and end and activates the sympathetic system by release of norepinephrine. Chronic pain has no physiologic value and persists beyond the expected duration of tissue healing or has no identifiable source. Chronic pain frequently co-occurs with psychological conditions, including anxiety, depression and post-traumatic stress disorder. 16(p379) Neurophysiology of Pain Knowledge of the neurophysiology of pain has evolved in recent times. Knowing how pain is transmitted through the body helps the nurse understand the origins of a patient s pain and the treatments needed to manage the pain. Injury outside the brain and spinal cord activates primary afferent nociceptive neurons that transmit information to the dorsal horn of the spinal cord where the neurons release substance P, glutamate, and peptides to activate the connecting neurons (Figure 1). Crossing to the contralateral side of the spinal cord, these connecting neurons form an ascending spinothalamic tract, which ends in the brainstem and thalamus. Higher-order neurons then project into several cortical regions that affect the pain experience. These regions include the sensory cortex (necessary for pain perception), anterior cingulate cortex (related to affective/emotional component of pain), insular cortex (stimulated by threats to survival and contributing to autonomic response to pain), spinomesencephalic tract (integrates somatosensory information with vision and hearing), and spinoreticular tract (important in maintaining arousal). These same brain regions modulate pain with input to the periaqueductal gray region that forms a feedback regulation of pain transmission in the descending path of the spinal cord. Figure 1: Peripheral transmission of pain. This diagram shows the normal sequence of pain transmission that occurs with tissue damage, where inflammatory mediators initiate the cascade causing nociception. This is followed by ion charge changes along the afferent nerve creating action potential. The result is painful impulses that are impelled to the dorsal horn of the spinal cord. Copyright 2011 Debra Drew and Barbara St. Marie. Peripheral Nervous System Pain is transmitted from chemicals released around the peripheral nerve, resulting from an injury or illness, and in normal conditions can resolve with healing. These chemicals are called inflammatory mediators (Figure 1). Central Nervous System: Spinal Cord Following the activation of peripheral neurons, the pain impulse enters the spinal cord by way of the dorsal root ganglion that contains cell bodies of somatic and visceral sensory nerves. This is the beginning of the spinothalamic tract. The neurotransmitters, substance P, glutamate, aspartate, cholecystokinin, vasoactive intestinal polypeptide, and somatostatin 17 impel the pain impulse along the pain pathway. In addition to the neurotransmitters, opiate receptors are located in the dorsal horn of the spinal cord. This is where epidural and intrathecal opioids bind to the opiate receptor sites. When the receptors are filled with endogenous or exogenous opioids, the release of the neurotransmitters is inhibited, which can stop the nociceptive impulse before being transmitted to higher brain centers

4 NCI200157_Layout 1 7/22/11 2:18 AM Page 241 VO L U M E 2 2 N U M B E R 3 J U LY S E P T E M B E R PA I N I N C R I T I C A L LY I L L PAT I E NT S Pain in the Brain From the dorsal horn of the spinal cord, pain impulses travel to the brainstem and the thalamus through the spinothalamic tract.18 The axons in the spinothalamic tract synapse in 3 nuclei of the thalamus: the ventral posterior lateral nucleus, the ventral medial posterior nucleus, and the medial dorsal nucleus (see Figure 2). Each of these nuclei plays a role in pain perception.19 Depression or anxiety can amplify pain. This is illustrated through studies showing that a majority of patients with chronic pain and addiction report experiencing psychiatric symptoms in addition to their pain symptoms The insular and anterior cortical regions are important in the behavioral and autonomic responses to pain, and the emotions and memories these stimuli evoke.18 Nurses may find that patients in pain have difficulty articulating their pain, and their emo- tions are amplified making it difficult to relieve their sense of suffering. Neuroplasticity Neuroplasticity refers to the ability of neurons to alter their structure and function. 29(p179) Changes occur in the brain and spinal cord with prolonged pain. With repeated nociceptive stimulation, some of the cortical areas can be sensitized so that future nociception can cause pain earlier and of greater intensity. These changes related to chronic pain can affect behavior. Patients with chronic back pain or fibromyalgia demonstrate a decrease in gray matter of the prefrontal cortex that results in decreased ability to engage in behaviors that can inhibit the experience of pain.30 It appears that there are rapid changes in the gray matter of the right amygdala (responsible for emotions and reactions to stressful Figure 2: The brain in pain. Diagram of pain transmission via the spinothalamic tract to various locations in the brain. Copyright 2007 Barbara St. Marie. 241

5 DREW AND ST. MARIE AACN and threatening situations), right hippocampus (related to learning and memory), and left inferior frontal gyrus (which plays a role in cognition and executive functions) with the use of prescription opioids (Sean Mackey, MD, PhD, written personal communication, February 13, 2011). Although Dr Mackey identifies changes in the brain with opioids, Dr Apkarian reports that every year of living with chronic pain induces a decrease in grey matter volume by 1.5 cc. 31 Both these findings are preliminary and the clinical implications are yet unknown. The possible implications of this information for the nurse are that learning and behavior are impacted by chronic pain 31 and the long-term use of opioids. Our expectations of patients learning capabilities may need to be modified when patients have chronic pain and regularly use prescription opioids to treat the pain. Teaching strategies may require repetitive reinforcement and use of auditory and written instructions. Supplementing support with that of significant and trusted family or friends can reassure both the patient and the health care team that prescriptions will be taken appropriately. Neurophysiology of Addiction The enigma of chemical dependence lies in the brain where neurotransmitter activity is at the center of physiologic activity. Dopamine is a neurotransmitter produced in various locations of the brain with varying activities. The Role of Dopamine and the Dopaminergic Tract Dopamine plays a role in the activation of the reward system where pleasure or addictive response occurs. The reward system or the dopaminergic pathway begins with the production of dopamine in the ventral tegmental area. The pathway encompasses the medial forebrain bundle (specifically, the substantia nigra, nucleus accumbens, amygdala, and the limbic lobe) 32 to the prefrontal cortex 33 (see Figure 3). The limbic lobe is our emotional center. Impaired control over drug use occurs within the prefrontal cortex. Several substances act on the reward pathway. Alcohol enhances dopamine-containing neurons found in the mesolimbic system (midbrain) and reinforces changes in behavior and emotion amid alcohol intake. 34 Cocaine and amphetamine can either produce an abundance of dopamine or block dopamine from binding with its receptor, creating a pleasurable feeling and reward. Opioids also can activate dopamine and create euphoria or reward in some individuals. In addition to dopamine, there are other neurochemicals involved in the reward system; these are displayed in Table 1. In ICU practice, it is common to administer IV dopamine to activate the sympathetic system of the autonomic nervous system. While serving to increase pulse rate, blood pressure, and respiratory rate, and causing vasoconstriction, parenteral dopamine does not cross the blood-brain barrier to impact neurotransmission of endogenous dopamine. However, there are drugs such as L-dopa, cocaine, or amphetamine that cross the blood-brain barrier and alter dopamine. Opioids and the Reward System Opioids produce reward by binding to the -aminobutyric acid (GABA) receptors on the interneurons that normally inhibit dopamine in the limbic reward pathway. Opioids effect on modulating GABAnergic systems enhances the reward system. Understanding the reward system can guide rational use of opioids in the patient with moderate to severe pain and substance use disorder without holding back necessary treatment. Figure 3: The reward pathway. Originating in the ventral tegmental area of the brain, the reward pathway goes to the medial forebrain and prefrontal cortex by way of the limbic system. Reprinted from THE SCIENCE OF ADDICTION: From Neurobiology to Treatment by Carlton K. Erickson. Copyright 2007 by Carlton K. Erickson. Used with permission of the publisher, W. W. Norton & Company, Inc. 242

6 VOLUME 22 NUMBER 3 JULY SEPTEMBER 2011 PAIN IN CRITICALLY ILL PATIENTS Table 1: Neurochemicals Involved in the Reward System Neurochemical Serotonin Norepinephrine -Aminobutyric acid Glutamate Acetylcholine Endorphins Dopamine Action Serotonin binds to 5-HT 3 receptors affecting mood control, behavior, sensory perception, and aggression. Serotonin levels are reduced in the cerebral spinal fluid of many alcohol abusers. Norepinephrine creates arousal to the environment, dreaming, and moods. A neurotransmitter that is an amino acid that consistently inhibits neurons. A neurotransmitter that is an amino acid that consistently excites neurons. Acetylcholine binds with the nicotinic receptor in the brain affecting muscles, tissues, and glands. Endorphins are involved in pain regulation. They also create sensations of dreaminess and calm and reduce stress and pain. Opioids such as morphine and heroin affect the endorphin receptor-binding capacity. 33 Dopamine controls movement, motivation, emotion, and the ability to experience pleasure and pain. Alcohol enhances dopamine-containing neurons. Cocaine delays reuptake of dopamine, thereby prolonging the sense of pleasure. Amphetamine increases the amount of dopamine at the synaptic cleft. Both amphetamine and cocaine are highly addictive. Coexistence of Addiction and Pain Common paths exist in the central nervous system (CNS) of the dopaminergic pathway (addiction and reward) and the spinothalamic tract (pain) that imply addiction could alter the pain pathway, which could alter the addiction or reward pathway. This area needs further research and creates a sensitive viewpoint that can enhance the care of patients with these coexisting phenomena. Pain Assessment Pain assessment is the foundation of quality pain management. In the critical care setting, patients may or may not be able to verbally communicate their pain symptoms. 35 The features of basic pain assessment in a verbal patient are described in detail in Table 2. Assessing Pain in the Nonverbal Patient Table 3 addresses pain management in the nonverbal patient, for example, intubated, sedated, or cognitively impaired. 36,37 Close monitoring of nonverbal cues and the stress response is necessary for providing safe, good-quality care of patients who cannot report their pain. For more information, a position paper titled Pain Assessment in the Nonverbal Patient is available through the American Society for Pain Management Nursing Web site: 38 Assessing Withdrawal in the Patient With History of Chronic Substance Use or Abuse Patients may present with single or multiple substances of abuse or legitimate use. Withdrawal from 1 or more substances while a patient is in the ICU may complicate assessment and treatment of pain. Substance withdrawal can mimic psychiatric and medical conditions and pain response. Withdrawal symptoms will occur with abrupt discontinuation or rapid decrease of a substance when one has become physically dependent on that substance. Table 4 will assist in assessing the patient in alcohol withdrawal. Assessing the Patient in Benzodiazepine Withdrawal Benzodiazepines can cause clinically significant dependence and withdrawal characteristics due to the binding sites at the GABA receptor in the brain. 39,40 When there is a neurophysiologic adaptation to regular or chronic benzodiazepine use, the severity of withdrawal symptoms is based on the dose, duration of use, and duration of drug action. Dependence is most likely to occur when an individual is on sedative-hypnotics for 4 to 6 months or when doses exceed 2 to 3 times the upper therapeutic limit. 39 The longer the elimination half-life of the drug, the more prolonged the withdrawal symptoms. A ranking of symptoms from very 243

7 DREW AND ST. MARIE AACN Table 2: Basic Pain Assessment of the Verbal Patient Descriptors of Types of Pain Elements of Initial Pain Assessment Intensity of pain (eg, numeric pain scale) Description (quality) Sharp, stabbing Ache, intense, deep, cramping Location (pain diagram may be used) Aggravating factors Associative factors Relieving factors Timing (onset, duration, frequency) Pain goals/functional goals Somatosensory Visceral Neuropathic Well-defined Thermal, mechanical, chemical Nonsteroidal antiinflammatory drugs, local anesthetic agents, topical analgesics, opioids Ill-defined (eg, hurts all over ) Mechanical, chemical Nausea, vomiting, constipation Opioids, epidural, and intrathecal analgesia Transient or constant Burning, prickling, tingling, lancinating Referred or localized pain Thermal, mechanical, chemical Nausea, vomiting, constipation, atrophy, progressive spreading of pain Tricyclic antidepressants, anticonvulsant agents, nerve blocks Only seconds in duration or prolonged frequent to uncommon is displayed in Table The onset of withdrawal symptoms from benzodiazepines is displayed in Table 6. Patients with psychiatric comorbidity, concurrent use of other substances, and family history of paternal alcohol dependence have greater symptomology upon discontinuing benzodiazepines. 39 Benzodiazepine withdrawal should be avoided as the physiologic stress of withdrawal can adversely affect the course of the medical or surgical condition. Continued benzodiazepine use in medical-surgical patients rarely has a negative effect on acute medical conditions. Rather than attempting complete discontinuation of benzodiazepine in the critical medical setting, a reduced dose may be all that can be achieved. Assessing the Patient in Opioid Withdrawal Symptoms of opioid withdrawal occur within 6 to 12 hours following the last dose of most µ-agonists, and 3 to 4 days following the last dose of methadone. The duration of the withdrawal symptoms is dependent on the opioid, the dose, and duration of use. To prevent complications during opioid withdrawal, the physical health and age of the patient must be considered. Manifestations of withdrawal symptoms involve vital signs, the CNS, eyes, nose, skin, and gastrointestinal signs. See Table 7 for symptoms. 41,42 When patients have used opioids for the treatment of pain, a flare of pain will occur with severe anxiety over the withdrawal from their pain reliever. Preventing Withdrawal From Opioids or Benzodiazepines A sedation vacation, 43(p1597) which is common in the ICU for assessment of a patient s readiness for ventilator extubation, puts patients who are dependent on opioids or benzodiazepines at high risk for withdrawal, pain, or anxiety. Agitation may be a sign of pain, anxiety, or withdrawal symptoms from a number of substances. Physical dependence on opioids or benzodiazepines is influenced by the dose, duration of use, and duration of drug action. 44 When opioids, benzodiazepines, or other medications with a potential for physical dependence are no longer needed, taper the drugs slowly to minimize withdrawal symptoms. Tapering opioids at a rate of 10% of the original dose per day or 244

8 VOLUME 22 NUMBER 3 JULY SEPTEMBER 2011 PAIN IN CRITICALLY ILL PATIENTS Table 3: Pain Assessment of the Nonverbal Patient a Observing Patient s Behavior Misleading Vital signs (misleading in those with hemodynamic instability or on medications that alter vital signs) Paralysis from pharmacologic agents Suspectacute pain with the follow ing: Increase in pulse Increase in blood pressure Increase in respiratory rate Facial grimace Body splinting Vocalizations Tools to use in intensive care settings Potential Causes of Pain or Discomfort The following causes of pain can create somatosensory, visceral, or neuropathic pain in acutely ill patients 38 : Infection Injury Invasive procedures Venipunctures and arterial punctures Suctioning Turning Joint stiffness Pressure sores (open or closed) Drain and catheter removal Wound care Reports of Pain by Others Advocates for the patients can assist in reporting acute and chronic pain conditions. Advocates include Parents Family members Caregivers Surrogates Initiating an Analgesic Trial Suspect pain? Initiate trial of analgesics appropriate to the type of pain. Opioids can be given by infusion or on scheduled basis. Pain may be reduced, which diminishes the stress response. Behavioral Pain Scale 36 Critical-Care Pain Observation Tool 37 a Adapted from ASPMN Position Statement % every other day will minimize the emergence of severe withdrawal symptoms. Use of clonidine, an 2 -agonist, can attenuate the severity of opioid withdrawal. The average dose range of clonidine is 0.1 to 0.2 mg orally twice a day or via transdermal patch of 0.1 to 0.3 mg applied every 7 days. 45 Special Considerations for Patients on Methadone or Buprenorphine Maintenance Therapy for Opioid Abuse The patient s reported methadone maintenance dose should be verified with the methadone maintenance program to confirm daily dosing. Continue methadone dosing while in the critical care setting. If the maintenance program dose cannot be confirmed, it is safer to administer 1 4 of the reported daily dose every 6 hours than to administer an incorrect dose in 1 administration. Oral to intravenous dosing of methadone is a ratio of 2:1. For example, a patient receiving 100-mg oral methadone per day to maintain sobriety from heroin would require 50-mg IV methadone per day. Methadone for addiction management will not cover the pain of acute illness. Methadone should not be increased to manage acute pain because the boundaries between therapy for addiction and pain may be obscured. 46 Other short-acting opioids will be needed PRN in addition to the methadone maintenance dosing. Higher doses of methadone increase the risk of lengthening the QTc interval. In 1 study of 173 patients on methadone maintenance, a positive correlation of prolonged QTc interval of 500 or more milliseconds was found with daily doses of 245

9 DREW AND ST. MARIE AACN Table 4: Stages of Withdrawal From Alcohol Stage Time After Last Alcohol Ingestion Symptoms h Anxiety or panic attack Chills Sweating Fever Shaking Chest pain or palpitation Insomnia Headache Nausea or vomiting Abdominal pain Patient may be coherent at this time h Increased agitation Restlessness Diaphoresis Tremulousness with constant eye movement Nausea Vomiting Anorexia Diarrhea Tachycardia ( 120/min) Systolic hypertension ( 160 mm Hg) Confusion h Delirium tremens Hallucinations (auditory, visual, tactile) At hours postalcohol, withdrawal seizures may appear as (a) tonic-clonic seizures or (b) brief seizures ( 5 min). Status epilepticus is not due to alcohol withdrawal. Visual hallucinations Disorientation Delirium Severe tachycardia Hypertension Severe agitation and tremulousness Fever Severe diaphoresis 246

10 VOLUME 22 NUMBER 3 JULY SEPTEMBER 2011 PAIN IN CRITICALLY ILL PATIENTS Table 5: Symptom Frequency of Sedative Hypnotic Withdrawal Very Frequent Less Frequent Uncommon Anxiety Insomnia Restlessness Agitation Irritability Muscle tension Nausea Diaphoresis Lethargy Aches Acute nasal inflammation Heightened hearing Blurred vision Nightmares Depression Hyperreflexia Ataxia Psychosis Seizures Confusion Paranoid delusions Hallucinations Persistent tinnitus methadone of 120 mg/d or more. 47 Another study found significantly longer QTc intervals in patients on methadone therapy compared with controls, but found that QTc interval was not associated with methadone dose, serum level, or duration of therapy. 48 The clinical concern with prolongation of QTc interval is its association with ventricular arrhythmias, torsades de pointes, and sudden cardiac death. If the patient is experiencing a prolonged QTc interval, the methadone dose must be decreased and analgesia provided by a different opioid agonist and coanalgesics. Strategies for managing patients who are in buprenorphine-maintained programs are not as well understood. Check with the buprenorphine prescriber or pain management specialist for assistance in dosing pure µ-opioids for pain Table 6: Onset of Withdrawal Symptoms From Benzodiazepines a Timing of Symptoms After Last Benzodiazepine Dose Short-Acting Benzodiazepine Long-Acting Benzodiazepine Onset 24 h 5 d Severe peak 1-5 d 1-9 d a Adapted from Myrick et al. 39 management. Buprenorphine, a partial opioid antagonist, binds tightly to opioid receptors and thus blocks the analgesic effects of other opioids given simultaneously with buprenorphine. If possible, it is best if the buprenorphine can be stopped for 24 to 48 hours before starting a pure -agonist. When this approach is not feasible because of acute pain, µ-opioids must be aggressively titrated to override the buprenorphine blockade. Buprenorphine should not be discontinued abruptly in the presence of a pure µ-opioid agonist, as this could cause excessive sedation and respiratory depression. The use of IV fentanyl, which binds tightly to the µ-opioid receptors, is often suggested. 49 Treatment of Pain in Critically Ill Patients With Opioid Tolerance Pain management in the ICU can be achieved by assuming that pain is present, especially when objective measures conflict or are limited, for example, negative laboratory values with reported pancreatitis-type pain. Untreated pain will prolong recovery. Therefore, it is necessary to identify pain early and treat it appropriately. 43 Pharmacodynamic tolerance is a result of the neuronal adaptations that reduce the sensitivity of the system to the drug. 50(p1178) When opioid tolerance occurs, there is a reduced effect of a given dose requiring a larger dose to create the original effect, that is, analgesia. Tolerance occurs in substance abuse as well as long-term opioid therapy to treat pain. Although these phenomena are very separate, the treatments are the same (ie, opioid dose adjustment and multimodal analgesia are needed to block pain transmission). Use of Opioids for Opioid-Tolerant Individuals Confirming what opioid type and dose the patient has been using can provide enough information to allow for adequate dosing to manage pain. Prescription information is not enough; it is vital to determine the details of what the patient has actually been taking. Useful and accurate medication reconciliation provides information on the frequency of dose the patient actually takes, the number of tablets/capsules per dose, the mg per tablet/capsule, and the number of doses per day. This information allows for safe calculation of an alternate route or change in medication. For example, consider the patient on oral oxycodone hydrochloride 247

11 DREW AND ST. MARIE AACN Table 7: Symptoms of Withdrawal From Opioids Vital Signs Tachycardia Central Nervous System Eyes Nose Skin Restlessness Lacrimation Rhinorrhea Piloerection Nausea Gastrointestinal Other Insomnia Hypertension Fever Irritability Insomnia Craving Yawning Pupillary dilation Vomiting Diarrhea Muscle and joint pain Marked anxiety Dysphonia controlled release tablets (OxyContin) 200 mg/d plus 20-mg oxycodone q4h as needed for breakthrough pain. If you know the patient is taking 4 doses of oxycodone per day, you then can calculate a baseline of opioid use more accurately. In this case, the patient uses 280-mg oxycodone product per day. Now the patient requires surgery. The patient is taking nothing by mouth following surgery; the dose of opioid can be changed to an equivalent dose of another opioid in IV form such as morphine (see Table 8 51 ). In this scenario, a baseline intravenous opioid is required to replace the amount used chronically. This morphine dose was calculated by using the chart s equianalgesic conversion of 20-mg oral oxycodone 10-mg IV morphine, totaling 140-mg IV morphine per day 24 h 5.8 mg/h of IV morphine. New, acute pain (eg, postoperative pain) is dosed above and beyond that baseline. The tolerant individual, with new acute pain, may require approximately 2 to 3 times the dose of an individual who is opioid naive. 52 Another citation suggests that opioidtolerant patients may require a 30% to 100% increase in postoperative opioid doses compared with the requirements of opioid-naive patients. 53(p220) In our clinical experience, a 50% to 100% increase in opioid dose is a reasonable place to begin titrating the new dose to cover the new acute pain in an opioid-tolerant patient. (For example, if the baseline of IV morphine 5.8 mg/h replaces the patient s home dose of 280 mg/d of oral oxycodone, then the patient would need mg/h of IV morphine to address the new acute pain.) If a substantial increase in opioid dose does not provide adequate analgesia, then switching to a different opioid may result in better analgesia. The reason for the change to another opioid may be due to differences in each opioid s affinity to different subtypes of the µ-opioid receptor. However, switching from methadone to another opioid generally does not improve analgesia. One hypothesis says that methadone is a more broadspectrum opioid (activates a more complete spectrum of µ-opioid subreceptors), 1 thus providing better analgesia. Although this idea suggests that methadone would be a better medication to use consistently, the complexity of using methadone requires knowledge and experience of the drug s half-life and unique cardiac adverse effects. Use the oral route and long-acting opioid analgesics when possible. The oral route is preferred for its longer duration of analgesia and ease of use. However, the onset may be slower than desired for fast pain relief compared with the intravenous route due to glucuronidation. 45 The oral route is ideal for ongoing pain when critical illness is resolving but is often inconsistent early in the ICU process when enteral absorption may be compromised. 43(p1593) Table 8: Equianalgesic Conversions of Opioids a,b Opioid Oral (mg) Parenteral (IV) (mg) Morphine Codeine Fentanyl NA 0.1 (100 mcg) Hydrocodone 20 NA Hydromorphone Oxycodone 20 NA Abbreviation: NA, not applicable. a Adapted from American Pain Society. 51 b This table is useful to calculate approximate equivalent dosing when switching routes of a particular opioid, or when switching between opioids. For example, 10 mg IV morphine 1.5 mg IV hydromorphone. 248

12 VOLUME 22 NUMBER 3 JULY SEPTEMBER 2011 PAIN IN CRITICALLY ILL PATIENTS Avoid the use of opioid agonist-antagonists to treat pain, as they will precipitate acute withdrawal in patients physically dependent on opioids. Agonist-antagonists to be avoided include nalbuphine, butorphanol, pentazocine, and buprenorphine. Fighting Stigma When Opioids Are Used to Treat Chronic Pain Patients with chronic pain treated with longterm opioid therapy presenting to the ICU or the critical care setting are not necessarily addicted; however, they are physically dependent and tolerant to opioids. Studies showed that patients with chronic pain are often successfully treated with long-term opioid therapy and demonstrated improvement in daily function and quality of life. 54,55 Studies found that patients with a history of substance use disorder and long-term opioid therapy for chronic pain did not meet the diagnostic criteria for substance use disorder. 56,57 Yet people on longterm opioid therapy for the treatment of pain can be stigmatized by family, friends, and health care professionals. 54,55,58,59 These patients are not to be classified as having substance use disorder. Establishing partnerships between patient and health care provider can alleviate patients fears and allow for participation in setting goals for safe and effective pain management. Considerations When Treating Pain in Patients With Substance Use Disorder Patients who have a disease of addiction and pain should be given appropriate analgesic regimens that include opioids as well as other multimodal analgesia. Opioids should be given in a scheduled fashion when individuals are recovering from injuries or surgeries. In addiction medicine, the adage of the term prn is that it stands for plan relapse now. Untreated pain and prn opioids can increase stress and lead to relapse. Both animal and human studies have shown that reward increases with the rate of rise in drug blood levels: the faster the influx of drug into the blood, the better the rush or high. 1(p14) In the ICU/critical care setting, intermittent intravenous doses of opioids cause a rapid rise in blood levels of opioids, resulting in rapid but shorter duration of analgesia and higher rates of CNS adverse effects. PRN dosing of opioids may reinforce associations of administration of a drug due to the close timing of drug administration and the effect on the reward system. 46(p1606) Avoid PRN dosing if pain is present most of the time. Analgesics should be scheduled according to their expected duration of action. A continuous intravenous administration of an opioid will be less likely to trigger the reward system than the PRN dosing of IV opioids. The exception to this rule would be the use of patient-controlled analgesia (PCA) when a smaller, frequent dose of opioid is allowed in addition to an infusion that covers baseline use of opioids. The smaller PCA doses do not provide the quick, higher rise in plasma levels of the drug. Persons with active addiction/substance use disorder must be closely supervised to ensure that there is no tampering with pumps or IV catheters containing opioids. Case Study: Patient With Acute Pain and Substance Abuse Disorder A 30-year-old woman with a history of multiple myeloma, borderline personality disorder, panic disorder, and substance abuse disorder presented to the emergency department, with syncopal episodes and chest pain over the previous 3 days. She described her chest pain as sharp and 9/10 in intensity. She was on long-term warfarin therapy status following aortic valve replacement and aortic dissection. She had a history of aberrant drug-related behaviors including preoccupation with opiate medication; bouncing between health systems, multiple providers, and pharmacies; loss of control represented by frequent admissions to cover early refill; and noncompliance with warfarin therapy and health care. Six months earlier she had been crushing oral oxycodone and injecting it into her peripherally inserted central catheter while being treated for bacteremia. Her home medications included oxycodone hydrochloride controlled release tablets 60 mg orally q6h oxycodone 20 mg orally q4h PRN pain, alprazolam 1 mg orally 3 times a day PRN panic attacks, and paroxetine 20 mg orally daily. Shortly after admission, the patient had a syncopal episode and was found lying in the bathroom with an apparent hematoma on her left forehead and a left hip fracture. She was transferred to the ICU for observation and treatment of her fracture, evaluation of head trauma, and evaluation of chest pain. Chest pain evaluation was unremarkable and resolved without treatment. Findings from imaging studies of 249

13 DREW AND ST. MARIE AACN her head were negative. The pain team assessment included new acute pain related to hip fracture on top of chronic pain related to multiple myeloma, in the setting of substance abuse. The patient is a poor candidate for long-term opioid therapy due to her history (described earlier). The recommended plan included the following: Appropriate continuation of baseline oxycodone hydrochloride controlled release tablets (Oxycontin) 60 mg orally q6h. Discontinuation of oral immediate release oxycodone and addition of hydromorphone PCA (no basal) 0.6 to 1 mg q10 min PRN pain post open reduction internal fixation of her fracture to achieve rapid comfort level. Psychiatry to evaluate medications for panic disorder. Addition of gabapentin 300 mg orally 3 times a day for chronic low back pain. When the patient is discharged, set boundaries by limiting opioid prescriptions to a 2-week supply. More frequent dispensing requires the patient to interact with more health care team members who can help monitor the patient s status. Social services to coach the patient s husband to take control of opioids in the home. Multimodal Analgesia Rarely is severe pain completely controlled with opioid analgesics alone. Multimodal analgesia is the rational use of pharmacologic intervention that acts on various pain pathways in the peripheral and CNS and is believed to have an opioid sparing effect. 45 Components of multimodal analgesic pharmacology take into account the neurophysiology of pain and how pharmacotherapeutics can work to block the mechanisms of pain. These medications include, in addition to opioids, (a) acetaminophen, (b) nonsteroidal anti-inflammatory drugs (NSAIDs), (c) local anesthetic agents, (d) ketamine, (e) antiepileptics, and (f ) dexmedetomidine. 60 Clinically, these agents have been shown to be opioid sparing due to the analgesic properties of each agent and the fact that some pain responds better to nonopioid analgesics (eg, neuropathic pain responds better to antiepileptics than to opioids). Acetaminophen Recent studies indicate that acetaminophen in high doses blocks the pain pathway at the descending tract: the serotonergic tract. 45 Suggested dosing recommendations range from 3000 mg/d 61 to 4000 mg/d. 51 These doses are recommended for short-term use. Nonsteroidal Anti-inflammatory Drugs Nonsteroidal anti-inflammatory drugs decrease the nociceptive inflammatory response in the peripheral nervous system. The American Society of Anesthesiologists recommends, unless contraindicated, all patients should receive an around-the-clock regimen of NSAIDs, COX-2, or acetaminophen for the treatment of acute pain. 62(p1577) When considering these medications, be attentive to renal function, gastrointestinal status, and hemodynamic stability. For the patient at risk for ischemic heart disease, the American Heart Association recommends starting with acetaminophen and proceeding to NSAIDs only if necessary (also known as a stepped care approach). Use the lowest dose and shortest duration of NSAIDs to achieve comfort. 63 Local Anesthetic Agents These agents block the transmission of nociception by preventing the rapid influx of sodium ions into nerve axons, thus preventing the production of an action potential. 60(p344) The American Society of Anesthesiologists recommends, Whenever possible, anesthesiologists should employ multimodal pain management therapy... In addition, regional blockade with local anesthetics should be considered... 62(p1577) Direct administration of local anesthetics into surgical wounds, as well as infusions of local anesthetics to provide peripheral nerve blockades, has been shown to have opioid sparing effects. 52 Epidural analgesia may be more successful when local anesthetics are combined with opioids. When using regional analgesia, it is important to remember that the patient who is physically dependent on an opioid must receive a portion of his baseline dose systemically (IV or oral) to prevent withdrawal symptoms. 53 Ketamine Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist. The NMDA receptor has been linked to opioid tolerance and nociceptive signal transmission. 45 When low-dose ketamine binds with the NMDA receptor, pain intensity is reduced. When low doses ( mg/kg/h or 5-10 mg IV over 2-3 minutes) are used, the adverse effects of ketamine (dissociation or bradycardia) are not as common

14 VOLUME 22 NUMBER 3 JULY SEPTEMBER 2011 PAIN IN CRITICALLY ILL PATIENTS Antiepileptic Medications Gabapentin and pregabalin are common antiepileptics for the treatment of neuropathic pain. These medications treat pain by stabilizing the neuronal membrane, thereby reducing action potential and transmission of pain (Figure 1). Some increase in sedation can occur with these medications. Using these medications for neuropathic pain can reduce the need for opioid analgesics. Dexmedetomidine Dexmedetomidine, an 2 -adrenergic agonist, has been used for a rapid decrease in opioid doses. 65 At lower doses, it is an anxiolytic and has the advantage of not causing respiratory depression. It typically does not impair conscious awareness. As a class, 2 -adrenergic agonists, when combined with opioids, produce synergy for analgesia, which allows for significant decreases in the µ-opioid without causing opioid withdrawal. Benzodiazepines and Antidepressants Drugs that do not relieve pain should not be used as substitutes for analgesics. Whereas some antidepressants such as tricyclic antidepressants and serotonin and norepinephrine reuptake inhibitors have shown efficacy in treating pain, selective serotonin reuptake inhibitor antidepressants, such as paroxetine or fluoxetine, do not appear to help relieve pain. Benzodiazepines and antidepressants can be helpful adjuvant medications and should be used to treat the symptom for which they are intended (ie, anxiety and depression). Nonpharmacologic Interventions Decreasing noise and reducing lighting can help the patient relax. Coaching the patient on deep breathing, distraction, and relaxation techniques can help the patient feel more in control in the critical care setting. Humor, acupressure, and massage are examples of nonpharmacologic interventions that are valuable in augmenting analgesia and can be easily used in the critical care environment. 66 Music is another nonpharmacologic intervention that can be provided by nurses, as well as by licensed music therapists, for distraction or relaxation. Opioid-Induced Hyperalgesia A more recently studied phenomenon is that of opioid-induced hyperalgesia (OIH). It is characterized by a paradoxical increase in pain intensity, distribution, or sensitivity caused by prolonged or escalating doses of opioids. 65(p1819) The precise mechanism is not well understood. Although not all researchers are convinced that OIH is a distinct phenomenon, there are several animal and human studies suggesting that OIH results from neuroplastic changes in the peripheral and CNS that lead to a sensitization of nociceptive pathways. 67 Opioid-induced hyperalgesia differs in some distinct ways from the phenomenon of opioid tolerance (Table 9). 68 With opioid tolerance, analgesia improves when an opioid dose is increased. In contrast, increasing an opioid in OIH does not improve pain and may even make it worse. A trial of an appropriately dosed opioid should be instituted if there is doubt whether the phenomenon is tolerance or OIH. In suspected OIH, the distribution of pain broadens beyond the initial pain site. Treatment of OIH requires a multimodal approach. Early studies have shown a role for biochemical modulation with NMDA receptor antagonists, 2 -agonists, propofol due to its gabaminergic activity, and COX-2 inhibitors. Two NMDA receptor antagonists have shown clinical efficacy in treating OIH: ketamine and dextromethorphan. Low-dose ketamine has shown some modulation of OIH in the reduction of postoperative-wound hyperalgesia. In another study, a retrospective review of 11 ICU patients who received the 2 -agonist dexmedetomidine showed improved pain control in most of the patients despite substantial decreases in opioid doses. Dexmedetomidine appears to have a rebooting effect on opioid sensitivity in that lower doses of opioid provide better pain control even after dexmedetomidine is discontinued. 65 In 6 studies, opioid rotation to methadone significantly improved or resolved suspected OIH. 67 Treatment of OIH requires a significant decrease in the opioid dose, which is a frightening proposal to a patient in severe, escalating pain. The nurse is well-positioned to reassure patient, family, and colleagues that pain will decrease with the use of other medications that allow a decrease in opioids. Case Study: Managing Acute Pain in a Patient With Longterm Opioid Use A 29-year-old man with a history of pancreatitis and chronic abdominal pain since age 19 years underwent endoscopic retrograde cholangiopancreatography. He now presents with significant 251

15 DREW AND ST. MARIE AACN Table 9: Differential Assessment of Opioid-Induced Hyperalgesia Versus Other Conditions a,b Condition Opioid-induced hyperalgesia Nature of Pain Increased sensitivity to pain; diffuse pain, extending beyond the distribution of preexisting pain; allodynia may be present. Localized to site of preexisting pain or new site of pathology. Presentation or Onset of Pain Abrupt onset with rapid opioid escalation or high-dose opioid administration. Response to Opioid Administration Pain worsens. Worsening pain pathology Variable, depending on source of pain. Pain improves. Opioid tolerance Localized to site of preexisting pain. Increased sensitivity to pain; diffuse, extending beyond the distribution of preexisting pain. Gradual onset. Pain improves. Opioid withdrawal Abrupt with short-acting opioids or antagonist administration; gradual with long-acting opioids. Pain improves. Opioid addictive disease Increased sensitivity to pain; diffuse, may extend beyond the distribution of preexisting pain. Gradual onset Pain may improve but functionality may worsen. Pseudoaddiction Localized to site of preexisting pain. Variable, depending on source of pain. Pain improves. a From Compton. 68(p5) Reprinted with permission. b Characteristics of the nature of pain, the presentation or onset of pain, and the response to opioid administration are compared and contrasted between opioid-induced hyperalgesia, worsening pain pathology, opioid tolerance, opioid withdrawal, opioid addictive disease, and pseudoaddiction. postprocedural pain due to leakage of pancreatic enzymes into the abdomen. His pain is described as burning in the upper abdomen radiating to the left flank with sharp pain (10/10) radiating from the upper abdomen through to his back. Preprocedure medications included hydrocodone acetaminophen and hydromorphone tablets. Before admission, the patient had been titrated up to buccal fentanyl 800 mcg q3-4h (averaging 11 tablets per day for the last 3 weeks). The patient was also taking bupropion 150 mg orally daily, paroxetine 40 mg orally daily, alprazolam 2 mg orally q6h PRN, and diazepam. In the ICU, the patient required PCA hydromorphone 10 mg/h 4 mg q 10 minutes (averaging mg/h), ketamine 14 mg/h, and dexmedetomidine 0.4 mcg/kg/h. The pain team s assessment included (1) acute on chronic abdominal pain in an opioidtolerant patient, (2) recent perforation of pancreatic duct with enzyme leak into peritoneal cavity with uncontrolled pain despite significantly high doses of opioids, and (3) OIH as a likely compounding factor. Recommendations included the following: Increase ketamine infusion to 20 mg/h adding boluses of 10 to 20 mg q3h PRN to decrease the tolerance to opioids; decrease hydromorphone hourly infusion and PCA boluses by 50% to address opioidinduced hyperalgesia; restart diazepam 5 mg IV q3-4h PRN to address anxiety and prevent benzodiazepine withdrawal; continue to increase dexmedetomidine to a maximum of 0.7 mcg/kg/h to address OIH; start ketorolac 30 mg IV q6h for 3 to 5 days to address the inflammatory response of enzyme spillage and postsurgical pain; and start gabapentin liquid 200 mg orally 3 times a day via nasogastric tube to address any neuropathic component of pain experience. Following the recommended interventions, the patient was able to sleep through the night and appeared more comfortable. Eventually, 252

16 VOLUME 22 NUMBER 3 JULY SEPTEMBER 2011 PAIN IN CRITICALLY ILL PATIENTS the patient was able to further decrease opioids and stop coanalgesics to transition out of the ICU. Summary Pain in critically ill patients with substance use disorder or long-term opioid use for chronic pain presents unique challenges. These patients in pain are often undermedicated or untreated because of lack of knowledge about long-term opioid therapy or the disease of addiction, and unexamined biases. The stress of unrelieved pain may contribute to relapse in the recovering patient or increased drug use in the patient who is actively using. 12(p1) Patients have the right to competent, safe, compassionate care despite their past or current histories of substance use. Knowledgeable care and advocacy for patients with substance use disorder or long-term opioid use for chronic pain will result in better outcomes and increased patient satisfaction. REFERENCES 1. Savage SR, Kirsh KL, Passik SD. 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18 Test writer: Marylee Bressie, MSN, RN, CCRN, CCNS, CEN Contact hour: 1.0 Synergy CERP: Category A Passing score: 12 correct (75%) DOI: /NCI.0b013e31822bf132 CE Test Instructions AACN Advanced Critical Care To receive CE credit for this test (ID# ACC2232), mark your answers on the form below, complete the enrollment information and submit it with the $10 processing fee (nonmembers only; payable in US funds) to the American Association of Critical-Care Nurses (AACN). Answer forms must be postmarked by July 1, Within 6 weeks of AACN s receiving your test form, you will receive an AACN CE certificate. The American Association of Critical-Care Nurses (AACN) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center s Commission on Accreditation. AACN has been approved as a provider of continuing education in nursing by the State Boards of Nursing of Alabama (#ABNP0062), California (#01036), and Louisiana (#ABN12). AACN programming meets the standards for most other states requiring mandatory continuing education credit for relicensure. A B C D CE Test Form Pain in Critically Ill Patients With Substance Use Disorder or Long-term Opioid Use for Chronic Pain Mark your answers clearly in the appropriate box. There is only one correct answer per question. You may photocopy this form. A B C D A B C D A B C D Test ID#: ACC2232 FORM EXPIRES July 1, 2013 Fee: $10 (no fee for members of AACN) A B C D Last Name First Name AACN Member # Address City State ZIP Telephone State of Licensure License No(s). Payment by Visa MasterCard American Express Discover Check Card # Exp. Date Signature Program Evaluation Yes No Objective 1 was met Objective 2 was met Objective 3 was met The content was appropriate My expectations were met This method of CE is effective for this content Mail to: AACN 101 Columbia Aliso Viejo, CA The level of difficulty of this test was: easy medium difficult To complete this program, it took me hours/minutes. Or fax to Or take test online at 255

19 CE Test Questions Pain in Critically Ill Patients With Substance Use Disorder or Long-term Opioid Use for Chronic Pain Objectives: 1. Define the terms addiction, physical dependence, substance abuse, and tolerance related to opioid use. 2. Describe the neurophysiology of pain and addiction. 3. Identify features of opioid-induced hyperalgesia. 1. Uncontrolled acute pain can lead to a. bradycardia. b. decreased myocardial oxygen demand. c. hypocoagulability. d. chronic pain. 2. Which of the following terms is defined as a primary chronic, neurobiological disorder with genetic, psychosocial, and environmental factors influencing its development and manifestation? a. Addiction b. Substance abuse c. Physical dependence d. Tolerance 3. The higher-order neurons involved in the affective/emotional aspect of pain are the a. sensory cortex. b. anterior cingulate cortex. c. spinomesencephalic tract. d. spinorecticular tract. 4. Which of the following does not cross the blood brain barrier? a. Cocaine b. Amphetamine c. L-Dopa d. Dopamine 5. When a patient has been on a higher dose of opioid for 1-2 weeks, in order to decrease the potential for withdrawal, opioids should be decreased by % per day, once they are no longer needed. a. 50 b. 10 c. 25 d. No need to withdraw slowly 6. Symptoms of opioid withdrawal include a. bradycardia. b. pupillary constriction. c. somnolence. d. irritability, restlessness. 7. Ms Gray receives 100 mg/day oral methadone in her methadone maintenance program. Now, she is unable to take oral medications. How much intravenous methadone is equivalent to her oral dose? a mg per day b. 25 mg per day c. 50 mg per day d. 100 mg per day 8. At higher doses, which medication is associated with QTc prolongation? a. Methadone b. Buprenorphine c. Fentanyl d. Clonidine 9. Which of the following drug classes will block the transmission of nociception by preventing rapid influx of sodium ions into the nerve axons? a. Nonsteroidal anti-inflammatory agents b. Local anesthetic agents c. Opioids d. -2 adrenergic agonists 10. Patients with opioid-induced hyperalgesia will display a. paradoxical increase in analgesia with increased opioid doses. b. paradoxical increase in pain intensity with increased opioid doses. c. less allodynia to painful area. d. more localized distribution of their original pain. 11. The neurotransmitter that is an amino acid that consistently excites neurons is a. acetylcholine. b. endorphine. c. dopamine. d. glutamate. 12. Which of the following is considered a very frequent symptom of sedative hypnotic withdrawal? a. Seizures b. Lethargy c. Muscle tension d. Nausea 13. In peripheral transmission of pain, what initiates the cascade called nociception? a. Potassium efflux from the afferent neuron b. Sensitization of the neuron from inflammatory mediators c. Calcium influx to the afferent neuron d. Nociceptive input to the dorsal horn of the spinal cord 14. Which class of medications has shown efficacy in treating pain? a. SSRI (selective serotonin reuptake inhibitor) antidepressants b. Benzodiazepines c. Alpha adrenergic antagonists d. Tricyclic antidepressants 15. Which areas of the brain are changed by the chronic use of prescription opioids? a. Right amygdala (responsible for emotions) b. Right hippocampus (related to learning and memory) c. Left inferior frontal gyrus (plays role in cognition and executive functions) d. All of the above 16. Impaired control over drug use occurs within what area of the brain? a. Prefrontal cortex b. Limbic lobe c. Amygdala d. Nucleus accumbens 256